Pharmacy assembly machine and packaging for customised polypills, and customised antipsychotic combinations for improved compliance

Customised polypills may be produced in the pharmacy from two or more drug packages using an assembly machine. Each drug package may comprise an array of cells containing individual doses of a single drug. The individual doses may be combined within the cells of the packages to produce an end user package with an array of cells containing the combined drugs in the form of individual polypills, which may be formed as capsules or pastilles. Label indicia of the drug packages may be combined together to form a composite label of the end user package. Serialization data may be read from the packages during assembly and sent to a remote server for authentication and supply chain management. In another aspect, patients who have a history of poor compliance with a prescribed oral antipsychotic while periodically seeking symptomatic relief from another prescribed psychoactive, are provided with both medicaments in the form of polypills to be taken in place of the solo antipsychotic when the patient is in crisis. Providing the preferred psychoactive as a combination motivates the patient to resume their antipsychotic therapy when symptoms return, which may result in better compliance and more effective management of psychosis in the community.

FIELD OF THE INVENTION

In one broad aspect, this invention relates to systems for assembling together fixed dosage units of two or more different drugs to form customised polypills. In another broad aspect, the invention relates to antipsychotic drug combinations, and more particularly to the problem of non-compliance with a regimen of self-administered oral antipsychotics, in the treatment of chronic mental illness such as schizophrenia.

BACKGROUND OF THE INVENTION

Polypills which are mass produced are referred to as fixed dose combinations. Fixed dose combinations may be made available for a drug combination that is commonly prescribed for a specific therapeutic indication.

For example, in the treatment of schizophrenia it is known to combine antipsychotics with antidepressants or with benzodiazepines (effective both as anxiolytics and as sedatives).

See also: Encephale. 2006 November-December; 32(6 Pt 1):1003-10; Benzodiazepines and schizophrenia, a review of the literature.

Known combinations of antipsychotics and antidepressants include: perphenazine with fluoxetine; perphenazine with amitryptaline; olanzapine with fluoxetine; and lurasidone with D-cycloserine.

Polypills can also be customised for individuals who are prescribed multiple drugs, in order to reduce the pill burden and promote adherence to the therapeutic regimen, or to adapt the dosage or mode of delivery of the drug to the particular requirements of the patient.

For example, US2006078897 (A1) discloses capsules containing a combination of active pharmaceutical ingredients in the form of beads, pellets or minitablets having coatings selected, for example, to modify the release rate or for bioadhesion, and customized to the metabolic profile of the individual patient.

Customised polypills can be prepared by a specialised compounding pharmacy. However, this is expensive and time consuming, not only because the pharmacist must be skilled in the art of compounding but also due to the practicalities of storing and handling drugs in bulk form, including the need to carefully clean the tools that are used to combine them into individual dosage units after fulfilling each individual prescription.

Various approaches have been proposed to make customised polypills more easily available.

Customised polypills may also be produced using inkjet printing techniques, as disclosed in U.S. Pat. No. 7,707,964 B2.

See also: Inkjet printing of drug substances and use of porous substrates-towards individualized dosing, Journal of Pharmaceutical Sciences, 100: 3386-95, August 2011. Doi:10.1002/jps.22526. PMID 21360709.

See also: Electrodeless electrohydrodynamic drop-on-demand encapsulation of drugs into porous polymer films for fabrication of personalized dosage units, Journal of Pharmaceutical Sciences, 101: 2523-2533, July 2012. Doi:10.1002/jps.23165. PMID 22527973.

The storage and dispensing techniques of 3D printing and inkjet printing may not be equally suitable to all drugs, and may require additional cleaning, finishing or packaging steps, for example, where a substrate film must be inserted into a capsule to form the final dosage unit.

In an alternative approach, US2009149507 A1 teaches a polypill assembled from multiple fixed dosage units which may be connected by ultrasonic welding, snap-fit, adhesive or other techniques.

Following this approach, US2007193225 A1 and US2008306622 A1 disclose machines for receiving multiple tablet magazines, each containing a plurality of tablet components retained by releasable locks. The tablet components may have different active agents and different release rates. The tablet components may be loaded into the magazine by the user, or may be pre-loaded by the component vendor. The magazines are inserted into a mounting block of the machine, and then the releasable locks are actuated to release a first set of tablet components from each of the magazines. The tablet components released from the middle magazine are coated, e.g. sprayed with a bonding liquid. The tablet components are then pressed together by compression pins to form composite tablets which are discharged into a container. Another set of tablet components are then released from the magazines and assembled in the same way. RFID readers are arranged to read RFID tags on the magazines. A processor compares the sensed data with prescription information downloaded from a central database and prevents operation of the machine if the incorrect magazines are inserted.

Although such solid assembly techniques may be applicable to a wider range of drugs than printing techniques, the step of loading the tablet components into the magazines may introduce the potential for human error, while the use of a bonding agent within the assembly machine may give rise to special internal cleaning requirements. Further, packaging the polypills in bottles or other bulk containers may be less satisfactory than conventional blister packs or similar packaging that separates the individual single dosage units, in terms of consumer acceptability as well as stability in storage.

OBJECTS OF THE INVENTION

In its first broad aspect, the present invention sets out to provide a simple and convenient way for the small, non-specialised pharmacy, or larger “hub” pharmacy or other centralised facility, to prepare customised polypills on demand. Preferably the polypills should be produced with minimal special cleaning and handling requirements and minimal opportunity for human error. Preferably the polypills should be individually packaged for the end user. Preferably the polypills should be produced subject to a robust authentication procedure to suppress counterfeit drugs.

In its second broad aspect, the invention is directed to improving compliance with a regimen of self-administered oral antipsychotics.

SUMMARY OF THE INVENTION IN ITS FIRST BROAD ASPECT

IN ONE ASPECT, the invention provides an assembly system comprising an assembly apparatus, and a plurality of packages. The plurality of packages include at least first and second drug packages. Each package of the plurality of packages includes a plurality of cells. Each cell of the first drug package includes a single dose of a first drug, while each cell of the second drug package including a single dose of a second drug.

The assembly apparatus is configured to receive the plurality of packages including at least the first and second drug packages, and to combine together the first and second drugs of the first and second drug packages to form a plurality of single, orally ingestible bodies, wherein each single, orally ingestible body of the plurality of single, orally ingestible bodies includes the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package.

Each cell of each drug package includes only one single dose of the respective drug, and the assembly apparatus is configured to combine together the first and second drugs within the cells of the packages received in the assembly apparatus.

IN ANOTHER ASPECT, the invention provides a method for forming drugs into orally ingestible bodies. The method includes providing first and second drugs, and providing a plurality of packages, the plurality of packages including at least first and second drug packages, each package of the plurality of packages including a plurality of cells.

The method further includes packaging the first drug in the first drug package so that each cell of the first drug package includes a single dose of the first drug, and packaging the second drug in the second drug package so that each cell of the second drug package includes a single dose of the second drug.

The invention further includes, after performing the abovementioned steps, combining together the first and second drugs to form a plurality of single, orally ingestible bodies, wherein each single, orally ingestible body of the plurality of single, orally ingestible bodies includes the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package.

Only one said single dose is packaged in each respective cell of each respective drug package, and the first and second drugs are combined together within the cells of the plurality of packages.

IN ANOTHER ASPECT, the invention provides an assembly system comprising an assembly apparatus, and a plurality of packages. The plurality of packages include at least first and second drug packages, each package of the plurality of packages including a plurality of cells. Each cell of the first drug package includes a single dose of a first drug, while each cell of the second drug package includes a single dose of a second drug. Each single dose comprises one or more particles, the particles of all said single doses being of equal size and shape.

In this aspect of the invention, each particle has a dimension of at least 1.5 mm. Each cell of each drug package includes only one single dose of the respective drug. Each of the cells of the first drug package includes an equal number of particles, and each of the cells of the second drug package includes an equal number of particles.

The assembly apparatus is configured to receive the plurality of packages including at least the first and second drug packages, to receive a plurality of capsule caps and capsule bodies, and to combine together the first and second drugs of the first and second drug packages to form a plurality of capsules. For each capsule of the plurality of capsules, the single dose of the first drug of a respective one of the cells of the first drug package is encapsulated, together with the single dose of the second drug of a respective one of the cells of the second drug package, between a respective said capsule cap and capsule body.

IN ANOTHER ASPECT, the invention provides a method for filling drugs into capsules. The method includes providing first and second drugs, and providing a plurality of packages, the plurality of packages including at least first and second drug packages, each package of the plurality of packages including a plurality of cells. The method further includes packaging the first drug in the first drug package so that each cell of the first drug package includes a single dose of the first drug, and packaging the second drug in the second drug package so that each cell of the second drug package includes a single dose of the second drug. Each single dose comprises one or more particles, the particles of all said single doses being of equal size and shape.

In this aspect of the invention, each particle has a dimension of at least 1.5 mm. Only one said single dose is packaged in each respective cell of each respective drug package, so that each of the cells of the first drug package includes an equal number of particles, and each of the cells of the second drug package includes an equal number of particles.

The method further includes receiving in an assembly apparatus the plurality of packages including at least the first and second drug packages together with a plurality of capsule caps and capsule bodies, and operating the assembly apparatus to combine together the first and second drugs of the first and second drug packages to form a plurality of capsules. For each capsule of the plurality of capsules, the single dose of the first drug of a respective one of the cells of the first drug package is encapsulated, together with the single dose of the second drug of a respective one of the cells of the second drug package, between a respective said capsule cap and capsule body.

IN ANOTHER ASPECT, the invention provides a package for use in an assembly system, the package including a frame, the frame defining a plurality of cells separated by the frame to form a spaced array; wherein either:

(a) each cell includes at least one edible wall fixedly mounted in the frame, the at least one edible wall being configured to be detached from the frame and consumed in normal use by an end user; or

(b) each cell includes a cell wall, the cell wall extending along a cell axis between opposite, first and second ends of the cell at opposite, first and second sides of the frame; and each of the first and second ends of the cell is closed by a frangible foil or a movable closure element; and each cell contains a single dose of a drug; or

(c) each cell includes a cell wall, the cell wall extending along a cell axis between opposite, first and second ends of the cell at opposite, first and second sides of the frame; and each cell contains a part of an empty capsule, but without a complementary part required to complete the capsule.

IN ANOTHER ASPECT, the invention provides an assembly apparatus for filling capsules with drugs.

The apparatus includes a plurality of pushrods spaced apart in parallel relation, each pushrod having an end surface; and a pressure plate having a pressure surface arranged in opposed, spaced relation to the end surfaces of the pushrods to define a receiving space between the pressure plate and the end surfaces of the pushrods.

The apparatus further includes an actuation mechanism configured to cause relative movement between the pressure plate and the pushrods, in a compression stroke, along a displacement axis parallel with the pushrods; and an alignment structure configured to maintain a stack of packages in alignment with the pushrods when, in use, during the compression stroke, the pushrods are urged through the stack of packages positioned in the receiving space.

IN ANOTHER ASPECT, the invention provides an assembly apparatus for use in assembling together a plurality of packages. Each of the packages includes a frame which defines a plurality of cells separated by the frame to form a spaced array.

The apparatus includes an alignment structure for guiding the plurality of packages in a stacked configuration with the cells of each package in axial alignment with the cells of each other package of the plurality of packages, and a compression mechanism for compressing together the frames of the plurality of packages in the stacked configuration to form an assembly defining an end user package.

IN ANOTHER ASPECT, the invention provides an end user package including a plurality of cells and a plurality of single, orally ingestible bodies.

Each of the single, orally ingestible bodies is sealingly enclosed within a respective cell of the plurality of cells, each cell defining an enclosure which is openable by an end user to remove the respective single, orally ingestible body for use. Each single, orally ingestible body includes a single dose of a first drug, and a single dose of a different, second drug.

In this aspect, the invention further includes either feature (a) or feature (b).

According to feature (a), each single, orally ingestible body includes a capsule containing a plurality of spheroids, a first one or first ones of the spheroids containing the first drug but not the second drug, a second one or second ones of the spheroids containing the second drug but not the first drug.

According to feature (b), the end user package includes at least first and second drug packages. Each of the drug packages includes a respective frame, the frame defining a plurality of drug package cells separated by the respective frame to form a spaced array. Each of the drug package cells includes at least one edible wall fixedly mounted in the respective frame. The at least one edible wall of each of the drug package cells of the first drug package includes or encloses the single dose of the first drug but not the second drug, while the at least one edible wall of each of the drug package cells of the second drug package includes or encloses the single dose of the second drug but not the first drug. The frames are connected together, so that each of the drug package cells of the first drug package is in axial alignment with a respective one of the drug package cells of the second drug package to form together a respective one of the cells of the end user package. The edible walls of the respective drug package cells forming each cell of the end user package are connected together to form together the respective single, orally ingestible body contained within the respective cell of the end user package.

IN ANOTHER ASPECT, the invention provides an end user package including a plurality of capsules, each capsule including a single dose of a first drug, and a single dose of a different, second drug. Each capsule contains a plurality of particles, a first one or first ones of the particles containing the first drug but not the second drug, a second one or second ones of the particles containing the second drug but not the first drug.

The first and second ones of the particles are spheroids having a mean diameter of at least 1.5 mm, and all of the capsules contain an equal number of said first one or first ones of the particles, and all of the capsules contain an equal number of said second one or second ones of the particles.

SUMMARY OF THE INVENTION IN ITS SECOND BROAD ASPECT

IN ANOTHER ASPECT, the invention provides a kit of medicaments for use in the treatment of psychosis in an individual with a history of non-compliance with oral medication. The kit includes a plurality of crisis oral dosage units, and a plurality of maintenance oral dosage units.

Each of the crisis oral dosage units includes a single dose of a first drug and a single dose of a different, second drug, said single doses being combined together as a single, orally ingestible body. Each of the maintenance oral dosage units includes a single dose of the first drug without the second drug.

The first drug is an antipsychotic, while the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis.

IN ANOTHER ASPECT, the invention provides the use of a kit of medicaments as defined in the last mentioned aspect for the treatment of psychosis in an individual with a history of non-compliance with oral medication.

IN ANOTHER ASPECT, the invention provides a method for treating psychosis in an individual with a history of non-compliance with oral medication.

The method comprises providing different, first and second drugs, wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis; and combining together the first and second drugs to form a plurality of crisis oral dosage units, each of the crisis oral dosage units including a single dose of the first drug and a single dose of the second drug, said single doses being combined together as a single, orally ingestible body.

The method further comprises forming a plurality of maintenance oral dosage units, each of the maintenance oral dosage units including a single dose of the first drug without the second drug; and providing both the crisis oral dosage units and the maintenance oral dosage units to the individual for alternative self-administration at the discretion of the individual, wherein the maintenance oral dosage units are provided for self-administration when the individual feels well, and the crisis oral dosage units are provided for self-administration when the individual feels unwell.

IN ANOTHER ASPECT, the invention provides a method for manufacturing medicaments for treating psychosis in an individual with a history of non-compliance with oral medication.

The method comprises identifying the individual, and identifying different, first and second drugs prescribed for the identified individual, wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis in the identified individual.

The method further comprises combining together the first and second drugs to form a plurality of crisis oral dosage units customised for the identified individual, each of the crisis oral dosage units including a single dose of the first drug and a single dose of the second drug, said single doses being combined together as a single, orally ingestible body.

The method further comprises forming a plurality of maintenance oral dosage units, each of the maintenance oral dosage units including a single dose of the first drug without the second drug; and packaging the plurality of crisis oral dosage units and the plurality of maintenance oral dosage units, respectively as two separate components in a kit of medicaments.

Definitions

In this specification, a combination or combination drug means a single oral dosage unit which includes two or more drugs (also referred to as active pharmaceutical ingredients or APIs) combined together.

A polypill means a combination drug which is configured as a discrete solid body.

A polypill may be configured as a capsule (i.e. a shell enclosing two or more APIs) or a tablet (i.e. a solid mass incorporating two or more APIs).

A single oral dosage unit means a body of medicament that is configured to be consumed orally as a single, discrete body. The medicament body may be a discrete solid body, for example a polypill, or alternatively could be a liquid body (in which two or more drugs may be combined together in a fixed ratio) defined by a liquid measure at the point of consumption.

Psychoactive drugs of course include antipsychotics, but for convenience, unless the context indicates otherwise, the term “psychoactive” is generally used herein to refer to a psychoactive drug prescribed to alleviate an affective symptom associated with psychosis in an individual, as distinguished from an antipsychotic prescribed to alleviate hallucinations or delusions as principal symptoms of the psychosis.

It should be noted that the package transfer assembly is shown inFIGS.92,94,95,96and97as if engaged with the packages, the packages being omitted from these figures purely for better illustration of the mechanism.

Where necessary, different views in the same figure are identified by the suffix to the respective reference numeral, wherein:F indicates a front viewR indicates a rear view (opposite the front view)T indicates a top or plan viewB indicates a bottom view (opposite the plan view)E indicates an end viewS indicates a side viewIS indicates an inner side viewOS indicates an outer side viewLS indicates a left side (left end) view;RS indicates a right side (right end) view.

In some figures a positional term such as “front view” identifies a functional use position relative to the user, e.g. the front of the machine. In other figures the term “front view” is used just as a convenient way of identifying one reference view in that particular figure, to help understand the orientation of the other views in the same figure, in which case “rear view”, “end view”, “side view”, and “top view” or “plan view” should be construed accordingly as relative terms.

“Trailing end view” refers to the direction of insertion of the package into the respective slot of the second machine or its variant.

“Inner side view” and “outer side view” identify whether the illustrated side of the respective element faces inwardly or outwardly in use, for example, relative to a package to which the respective element is attached.

Reference numerals and characters appearing in more than one of the figures indicate the same or corresponding features in each of them.

In the following description, section headings are provided for ease of reference and should not be construed as limiting the scope of the respective disclosure.

Reference numerals are also provided for ease of reference, but should not be construed as limiting the scope of the respective disclosure, but rather to indicate a particular example of the element being discussed, by reference to an illustrated embodiment. In this regard it should be recognised that the embodiments illustrate examples of various features of more general application. Thus, when features are referred to in conjunction with reference numerals, but are under discussion in a way that implies a degree of generalisation, or are susceptible of application in embodiments other than the specific one containing the reference numeral, the presence of the reference numeral does not mean that the feature under discussion is of less general application than would be implied by the description without the reference numeral, or is only susceptible of application in combination with the other features of that specific embodiment.

DETAILED DESCRIPTION

Overview of the First and Second Embodiments

The first and second embodiments and their variants illustrate alternative implementations of various features that are common to both embodiments, as will now be described. It will be understood of course that features essential to each aspect of the invention are those defined in combination in the respective independent claim. Other features, whether common to both embodiments or not, are optional.

Both embodiments provide an assembly system comprising an assembly apparatus and a plurality of packages for use with the assembly apparatus. In each embodiment the assembly apparatus is configured as a small machine100,500,5000that can be mounted, e.g. on a countertop in a small pharmacy or a larger, central or “hub” pharmacy, to receive the packages which are produced in a factory and supplied in bulk to the pharmacy. The packages can be provided in different sizes, e.g. 12, 24, 36 or 48 units per package, and include different drug packages301,302,701,702,703,7001,7002,7003containing individual, fixed dosage units of different drugs, and other packages304,305,704,705,7004,7005for use in the machine in combination with the drug packages to produce an end user package300,700,7000, as further explained below. The fixed dosage units may be, for example, in the form of spheroids3, or in a flattened form, e.g. as a soft body or film, referred to hereafter as an API film31.

Advantageously, the pharmacist does not need to handle directly any of the individual, fixed dosage units, which are pre-packaged, serialized and labelled at the factory. As illustrated inFIG.60, each package may be wrapped in a protective outer wrapper709which is removed before the package is inserted into the machine. The pharmacy may be supplied with multiple units of each type of package (i.e. multiple units of each type of drug package, along with multiple units of each type of package for use therewith).FIG.60shows four stacks containing multiple units of different types of packages for use with the second machine, each package contained in a wrapper709. The wrapped packages can be boxed for delivery to the pharmacy and can be labelled externally, or the wrappers709could be transparent to allow the package labels313,713to be read through the wrappers.

Respective ones of the drug packages are selected in the pharmacy in accordance with an individual prescription or prescriptions, and then introduced into the machine100,500,5000in combination with the other packages as required. The machine is operated to combine together the first and second drugs to form a plurality of single, orally ingestible bodies or polypills20,30, which may be individually packaged in the same operation to form the end user package300,700,7000. The prescription could specify that the drugs are to be provided to the end user in the form of a polypill, or the end user could request that their prescription drugs be supplied as polypills, or the pharmacist could decide to combine together drugs that have been prescribed for the same individual, for example, to reduce the pill burden.

The end user package may be assembled from respective ones of the packages inserted into the machine, with the remaining, empty packages being discarded after the assembly operation. Alternatively, the frames or blocks of the empty packages of the first embodiment or its variant may be returned to the factory to be cleaned, re-filled, re-labelled and sealed again with new foil to form new packages. Each machine100,500,5000is configured to provide a quick and simple assembly procedure, allowing repeated operation to fulfill multiple different prescriptions.

In the first embodiment, the first machine100(FIG.1) is arranged to produce an end user package300(FIG.58) containing the polypills in the form of filled capsules20, each capsule20being sealed in an individual cell311of the end user package300and containing the first and second drugs1,2, preferably in granular, e.g. spheroidal form, so that each fixed dosage unit comprises the respective drug in the form of one or more granules, which preferably are spheroids3. The capsules20may be arranged as shown with their length axis extending in the thickness dimension of the package300which is shaped as a small block. The capsule20is removed by tearing back a strip315using a tab316to reveal the cell311, and then tapping the block so that the capsule20drops out of the cell311into the palm of the hand.

In the second embodiment, the second machine500,5000(FIG.60,FIG.88) is arranged to produce an end user package700,7000(FIG.80,FIGS.89-90) which in comparison with the first embodiment may have a relatively flat, thin form factor, and which contains the polypills in the form of compressed, relatively soft bodies that will be referred to herein as pastilles30. The pastilles30are arranged in individual cells711of the package700,7000between opposed foil walls714so that they can be pressed out of the cell into the palm of the hand.

Each of the machines100,500,5000is configured to combine together the first and second drugs1,2inside the cells311,711of the packages inserted into the machine, so that the individual fixed dosage units do not come into contact with any internal part of the machine during assembly.

Each end user package300,700,7000may include a composite label or label assembly312,712, which combines indicia, which may be in the form of physical label portions313,713that carry the indicia, from each of the drug packages inserted into the machine to ensure that the end user package is correctly labelled.

Each machine may be arranged to read and authenticate serialization data, e.g. in the form of a barcode317,717, on the drug packages during the assembly operation and upload the data to a central database, as further described below. Since each drug package is used only once, and the serialization data is read during the assembly procedure, the system provides a robust, non-repeatable, one-time authentication step that positively identifies each drug package at the point of use.

Packages

As exemplified by each of the first and second systems, each drug package, and also each package for use therewith, may include a frame310,710which defines a plurality of cells311,711, so that the cells311,711are separated by the frame310,710to form a spaced array.

The plurality of packages include at least first and second drug packages301,302,701,702,7002,7003. Each cell311,711of the first drug package301,701,7001includes a single dose of a first drug1, while each cell311,711of the second drug package302,702,7002includes a single dose (i.e. a single dosage unit) of a second, different drug2. The single doses of the first and second drugs1,2may be configured (e.g. as granules, e.g. spheroids3of the same colour) so that when combined together, they are substantially identical in appearance.

In the illustrated examples, the first drug package301,701,7001includes 12 cells containing a first drug1(olanzapine, 20 mg), while the second drug package302,702,7002includes 12 cells containing a second drug2(citalopram, 20 mg). (This particular combination of drugs is shown, purely as an example of two different drugs.)

Alternatively, the first and second drug packages could contain different doses of the same drug. For example, if a drug is provided in a binary series of multiples of a basic dosage unit (e.g. 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, etc.) then any desired multiple of the basic dosage unit (5 mg) could be produced in this way by combining together an economical number of the packages. For example, a prescription could be fulfilled by combining together one drug package7001containing a first drug1, and two drug packages7002,7003containing similar or different doses of a second drug2, as exemplified by the variant second end user package ofFIGS.89-90.

Each package may be a single use package—which is to say, it is configured to be used only once during the assembly process, after which it may be disposed of, or returned to the factory for recycling, or given to the end user as part of an end user package which, in turn, will be disposed of after the polypills are all consumed.

For example, each drug package, or each package for use therewith, may include at least one part which is configured, in use, by operation of the assembly apparatus to combine together the first and second drugs, either (a) to be irreversibly removed, destroyed or ruptured, or (b) to be irreversibly united with the corresponding at least one part of another respective one of the first and second drug packages.

In the first system, the frangible foil314of the drug package301,302is ruptured and destroyed during the assembly process, as is the frangible foil314on each of the cap and capsule body packages304,305, as the carrier320is removed from each cell311of the capsule body package305and introduced into, and irreversibly united with, the corresponding cell311of the capsule cap package304which forms the end user package300. Additionally (or alternatively, e.g. when the cells are closed by movable closure elements rather than foil), the package may include a label which is ruptured or destroyed during assembly. This process is irreversible in the sense that it is not reversed in normal use of the system—rather, the empty drug and cap packages are discarded after removal from the machine, or are returned to the factory so the frame or block can be cleaned and re-used, while the finished end user package300is given to the end user who will then discard it in due course.

Thus, it should be understood that a single use drug or capsule body package may include a re-usable frame or block which can be returned to the factory to be cleaned, re-filled, and re-labelled and/or sealed with new foil, to form a component part of another single use package.

In the second system, the frame710of each package, and the API film31of each cell311, is irreversibly united with the corresponding component of the adjacent package or packages during the assembly process to form an end user package700,7000, as further explained below.

Each cell311,711of each drug package may define an enclosure within which the respective single dose (e.g. granules or spheroids3, or API film31) is enclosed, optionally sealingly enclosed. Each dose may be separately sealingly (e.g. hermetically sealingly) enclosed within its respective cell, or the cells may retain the doses without hermetically sealingly separating them, so that the outer wrapper provides a seal to preserve the drugs in storage. For example, each package may be arranged as a foraminous block with sliding cover plates, as illustrated by the alternative drug package of the variant first embodiment, and the entire package sealingly enclosed within an outer wrapper.

As exemplified by the drug packages301,302of the first embodiment, each cell311may be closed by a frangible foil or film314which sealingly encloses the single dosage unit (spheroids3) within the cell311. The film314may form a hermetic seal for the individual cell311, and may be broken when combining together the first and second drugs1,2.

In this specification, the terms “frangible foil” or “foil” and “frangible film” or “film” are used synonymously to mean a thin sheet material that is arranged to tear or break or separate responsive to an applied force in normal use. It could be for example a sheet of thin aluminium or plastics or composite, plastic coated aluminium or aluminium coated plastics material, for example of less than 100 microns, or less than 50 microns thickness. Preferably the film or foil is selected to provide a seal sufficient to preserve the respective drug in storage, as known in the art. The film or foil could also be an animal or vegetable based material, e.g. alginate, cellulose, calcium caseinate, carragheenan, chitosan, corn starch, paper or tissue with an impermeable wax or equivalent coating, etc.

If the drug package is contained in an outer protective package, e.g. an impermeable film, then the film or foil that closes the cells could alternatively be an uncoated paper or other permeable material, or even an edible material that can be separated from the package and incorporated into the capsule together with the granules or spheroids3.

The cell wall318of each cell311of the drug or other package301,302,304,305may be configured to withstand a compressive force applied in a direction of the cell axis Xc to the frangible foil314and sufficient to break the foil.

In particular, the cell wall318may withstand the compressive force when the drug package301,302is arranged in a stacked configuration with other, like drug packages, the respective cells311of the drug packages being axially aligned, and the compressive force is applied to the foil314of each cell311of the plurality of cells by a respective one of a corresponding plurality of sliding bodies. Each sliding body may be configured to enter slidingly into the respective cell311after breaking the foil314, the sliding body having a diameter normal to the cell axis Xc and selected to be a sliding fit in the cell311, such that the sliding body is constrained to move slidingly in translation in a direction of the cell axis Xc.

The sliding body may be a carrier320for a capsule part21,22. Alternatively, if the capsule part is not arranged in a carrier but is configured to contact and break the foil314as it moves through the axially aligned cells311of the stacked packages, the sliding body may be a capsule part21,22.

If the sliding body does not form part of the assembly machine—e.g. if it is a carrier320or a capsule part21,22—then it may be slidingly guided and constrained by the cell wall318as it moves.

Alternatively, if the end surface111of the pushrod110(as further discussed below) is configured to break the foil314in advance of the respective capsule part (instead of being flat, as shown), the sliding body may be the distal end region of the pushrod, in which case the sliding body is guided by the cell wall318in the sense that the pushrod is positioned in axial alignment with the cell wall318so that there is a sliding interface between the cell wall318and the distal end region of the pushrod.

The frangible foil314may be relatively more frangible than the cell wall318.

Alternatively, as exemplified by the second embodiment, each cell711may be closed at either end by a cover706,707,7006,7007that is removed before or during the assembly procedure. The cover or covers may provide a seal (e.g. a hermetic seal) for all of the cells711together, or for each individual cell711(i.e. the cells are sealingly separated) as does the frangible film314of the first embodiment.

In the second embodiment, the temporary, front and rear covers706,707,7006,7007of each drug package701,702,703,7001,7002,7003are secured at spaced attachment points719and are removed before the package frame710(containing the API film31in each cell711) is assembled with the other package frames710. The other packages include front and rear cover packages704,705,7004,7005which seal (e.g. hermetically seal) the cells711of the end user package700,7000, thus replacing the front and rear covers706,707,7006,7007of each drug package, as further explained below.

In the second embodiment as illustrated, the temporary, front and rear covers706,707,7006,7007are principally intended to protect the adhesive surfaces of the frames710and need not hermetically seal the package. In this case the entire drug package701,702,703,7001,7002,7003containing the drugs1,2in their individual cells711, together with its temporary covers706,707,7006,7007, can be sealingly enclosed within an outer wrapper709which maintains the drugs1,2in good condition (e.g. by a hermetic seal) until the package is inserted into the machine500,5000as further explained below.

Packages Configured to Produce Capsules

Each cell311,711of each drug package301,302,701,702,703,7001,7002,7003may include a cell wall318,718which extends along a cell axis Xc between opposite, first and second ends of the cell at opposite, first and second sides of the frame310,710. In the drawings, the first and second sides are identified in different views by the suffix to the reference numeral for the respective package or package component, viz: F (front) or R (rear).

In such arrangements, each of the first and second ends of the cell may be closed by a frangible foil314to sealingly enclose the respective, single dose of the drug within the cell311.

In this configuration the drug packages301,302can be used to produce polypills in the form of capsules20. To assist assembly of the capsule20, each single dose may be in the form of one or more granules, preferably one or more spheroids3(which is to say, granules having a shape that approximates a sphere), which may have a diameter of at least 1.5 mm, preferably at least 2 mm.

Most preferably, the diameter of each spheroid is less than one half, and greater than one third, of the internal diameter of the capsule body. This ensures that the spheroids can pass one another to achieve an optimal packing density without jamming inside the capsule body.

The capsule parts21,22may be contained in further packages304,305, each package defining an array of cells311separated by a frame310, to be inserted into the machine100together with the selected drug packages301,302.

As exemplified by the capsule cap and body packages304,305of the first embodiment, each cell311may include a cell wall318which extends along a cell axis Xc between opposite, first and second ends of the cell at opposite, first and second sides of the frame, to contain a part21,22of an empty capsule, but without a complementary part21,22required to complete the capsule20. At least a first end of the cell may be closed by a frangible foil314or, as exemplified by the variants of the first embodiment, by a movable closure element.

The other end of the cell may be closed by a carrier320, as in the capsule body package305of the first embodiment, and optionally also a frangible foil (or another frangible foil) that covers the end surfaces of the carriers. Alternatively, the other end of the cell may be closed by a plug which is sealingly engaged in a respective aperture of the end user package or sub-package during the assembly operation.

Where a respective capsule part22is arranged in a carrier320or accompanied by a plug, the carrier320or plug may be received in the cell311and slidable out of the cell311along the cell axis Xc, as further described below. The carrier320may be configured to rupture the foil314by sliding movement of the carrier320out of the cell311along the cell axis Xc during the assembly procedure.

The cell311may include a locating structure supporting the respective part in spaced relation to the cell wall318. For example, a series of radially inwardly projecting annular fins325may support the capsule cap21radially centrally in the cell311, as illustrated by the cap package304of the first embodiment. Alternatively, the locating structure may be a lining of flock within the cell, as further described below with reference to the variant first embodiment, or a collapsible insert. This helps to align the two capsule parts21,22during assembly.

Where a first end of the cell311is closed by a frangible outer wall, e.g. of frangible foil314, or by a movable closure element or other package component, the second end of the cell311may be closed by a removable outer wall, e.g. a strip315, which is configured to be lifted and torn outwardly away from the frame310, e.g. by means of a tab316, by a user to open the second end of the cell311to permit the capsule20to be removed from the cell, when the package (e.g. cap package304) is formed into an end user package300containing the filled capsules20.

Packages Configured to Produce Pastilles

Each cell711of each drug package701,702,703,7001,7002,7003(and/or of another package704,705,7004,7005for use therewith) may include at least one edible wall32,33fixedly mounted to the frame711. The at least one edible wall32may be configured to be detached from the frame711in which it is mounted and consumed in normal use by an end user.

If the package is a drug package701,702,703,7001,7002,7003, then the at least one edible wall32will include or enclose the respective single dose of the respective, first or second drug1,2, e.g. in the form of an API film31.

Alternatively, if the package704,705,7004,7005is not a drug package, then the edible wall33could be configured, e.g. as a disc or wafer of rice paper or other edible sheet material, to form an outer surface or covering of the polypill30after assembly, in which case it need not include a drug.

Each cell711may be closed on one side of the frame710by an outer wall714which is sealingly attached to the frame710and configured to be ruptured or torn away from the frame710in normal use by an end user to expose the at least one edible wall33. This arrangement is exemplified by the front and rear cover packages704,705,7004,7005of the second embodiment and its variant, which serve both to seal each pastille30in its respective cell711of the end user package700,7000, and to provide the outer surface of the pastille30that can be gripped by the user without sticking to the fingers when the pastille30is removed for use.

The end user package700,7000may include the frame710, and the at least one edible wall32of each of the cells711, of each of the first and second drug packages701,702,7001,7002.

The second and variant second end user packages700,7000exemplify one such arrangement, wherein each edible wall32is formed as a film31that incorporates the respective drug1,2; alternatively, each cell711of the drug package could include two edible walls, sealed to form a compartment between them which encloses the drug1,2. The sealed compartment could form a cachet or envelope, for example, similar to the well-known “flying saucer” confectionery that has a sherbert filling between two discs of rice paper.

The frames710of such packages may be configured to be stacked and bonded together in an assembled configuration with each of the plurality of cells711of each package in axial alignment with a corresponding one of the plurality of cells711of an adjacent one of the packages, so that the cell axes X2of corresponding ones of the cells are collinear. In this arrangement, a respective edible wall32of each cell711is configured to adhere to a respective edible wall32of a corresponding one of the cells711of an adjacent one of the packages when the frames710are stacked and bonded together in the assembled configuration.

In such arrangements, the at least one edible wall32of each drug package701,702,703,7001,7002,7003may be exposed at each of two oppositely facing sides of the frame710. The frame710of the drug package701,702,703,7001,7002,7003may be coated with a tacky adhesive4on one or both of the two oppositely facing sides of the frame710. In order to protect the adhesive surfaces and API films31until the moment of assembly, the frame710may be enclosed between two temporary, removable covers706,707,7006,7007, each of which is arranged to protect a respective one of the two oppositely facing sides of the frame710, as further explained below.

Operation of the Assembly Apparatus

As explained above, the first and second drugs1,2are packaged in separate, first and second drug packages301,302,701,702,7001,7002, so that each cell311,711of each drug package includes only one, single dose of the respective, first or second drug1,2.

The first and second drug packages301,302,701,702,7001,7002(and any additional packages703,704,705,7003,7004,7005as required) are then introduced into the machine100,500,5000. After receiving the packages, the machine100,500,5000is operated to combine together the respective, single doses of the first and second drugs1,2contained in each pair of corresponding cells311,711of the first and second drug packages301,302,701,702,7001,7002, within the respective cells311,711of the plurality of packages, to form a plurality of single, orally ingestible bodies or polypills20,30. Each polypill20,30includes the respective single doses of the corresponding pair of cells311,711of the first and second drug packages301,302,701,702,7001,7002(together with any further single doses if more than two drug packages (e.g. third drug packages703,7003) were inserted into the machine100,500,5000.)

The machine100,500,5000may be configured to sealingly enclose the first and second drug packages301,302,701,702,7001,7002in a vacuum (which is to say, a full or partial vacuum) or a modified protective atmosphere, and to combine together the first and second drugs1,2of the first and second drug packages301,302,701,702,7001,7002in that vacuum or modified protective atmosphere. For example, the machine100,500,5000could include a dehumidifier so that the packages are processed, and the polypills20,30packaged, in dry, filtered ambient air. The machine100,500,5000could be partially evacuated before replacing the evacuated air with dry, filtered air. The evacuated air could be replaced by bottled nitrogen or other inert gas. In the illustrated embodiments, the second machine500is shown with a vacuum generating apparatus590, which (although not shown) is also present in the variant second machine5000, and which could also be provided for the first machine100and/or the variant first machine, to evacuate the machine before packaging the polypills, either in the vacuum or in the protective gas that replaces it.

Advantageously, in each of its first and second embodiments, the machine may combine together the first and second drugs while each drug and capsule part or other polypill component remains in contact only with the internal surfaces of the packages, hence without contact with any part of the machine. Thus, cleaning and maintenance is simplified and the possibility of contamination of the finished polypills, either from machine surfaces or from packages previously introduced into the machine, is minimised, even when the machine is not cleaned between uses.

End User Package

Preferably, as exemplified by each of the first and second embodiments, the assembly apparatus100,500,5000is configured to sealingly enclose each of the polypills20,30in a respective one of a plurality of cells311,711of an end user package300,700,7000, each cell311,711defining an enclosure which is openable by an end user to remove the polypill20,30for use.

The end user package300,700,7000may incorporate the frame310,710of at least one, or of each of two or more, of the plurality of packages received in the assembly apparatus100,500,5000.

In this case, each cell311,711of the end user package300,700,7000may include a cell311,711of the respective package or packages whose frame310,710is incorporated in the end user package300,700,7000. The end user package300,700,7000may further include at least a part (e.g. a carrier320, a plug, a plug and a collar, a foil wall714, etc.) of another one or ones of the plurality of packages (e.g. capsule body package305or front or rear cover package704,705,7004,7005), which part is applied by the assembly apparatus100,700,7000to close each cell311,711of the end user package300,700,7000.

For example, in the first embodiment, the end user package300includes the frame310and cells311of the cap package304, each cell311being closed by a carrier320from the capsule body package305. In variants, each cell1311of the end user package may be closed by a plug from the capsule body package, optionally in combination with a collar from the end user package assembly, as further described below.

In the second embodiment, the end user package700,7000includes the frames710and cells711of all of the packages received in the second machine500,5000, with the cells711being closed at each end, respectively by the frangible foils714of the front and rear cover packages704,705,7004,7005. Alternatively, one of the front and rear cover packages704,705,7004,7005could have, for each cell711, a flexible but not frangible cover that closes the respective end of the cell, and can be pressingly deformed by the user to urge the pastille30out through the frangible film714of the other cover package at the opposite end of the cell711.

Where each cell311,711of the package whose frame310,710is incorporated in the end user package300,700,7000includes a respective, orally ingestible component when received in the assembly apparatus, that orally ingestible component may be incorporated in a respective polypill20,30of the end user package.

In such arrangements, the respective orally ingestible component may not include a drug. Alternatively, it may include a drug—which is to say, the end user package may incorporate the frame of one (or each) of the drug packages, as in the second system. The orally ingestible component may form an outer surface of the respective polypill, such as a cap part21of the capsule20of the first embodiment, or a wafer33that forms the outer covering of the pastille30in the second embodiment.

Where the first and second drugs1,2are packaged in granular, e.g. spheroidal form and combined together in capsules, each polypill20contained in the end user package will include a capsule containing a plurality of the granules or spheroids3, wherein a first one or first ones of the granules or spheroids3contain the first drug1but not the second drug2, and a second one or second ones of the granules or spheroids3contain the second drug2but not the first drug1.

Where an end user package300is provided containing polypills in the form of capsules20, each capsule20may be arranged in a carrier320(which is to say, at least a part, preferably most or all of the length of a respective part of the capsule is received in the carrier), the carrier forming a plug which is fittingly received within the respective cell311of the end user package300. The carrier320can have an open end through which the capsule20may be removed from the cell311, and a closed end opposite the open end. The carrier320can help guide one part22of the capsule and break the frangible foils314(if present) as it travels through the aligned cells311of the packages, and then can seal the cell311containing the filled capsule20to become part of the end user package300, as illustrated by the first embodiment. The carrier320may isolate the drugs and capsule components from contact with the pushrods.

Alternatively, the capsule body can be arranged together with a plug, not in the form of a carrier, which is slidingly displaced by the pushrod through the aligned cells311,1311of the stacked packages, and then fittingly engaged in the open end of the respective cell of the end user package to close the cell, optionally in combination with a collar which guides the capsule body as it engages telescopically in the cap. In such arrangements, the plug may isolate the drugs and capsule components from contact with the pushrods.

Granules comprising the first and second drugs1,2may be particles which are sufficiently large (e.g. at least 1 mm in mean diameter, preferably at least 1.5 mm, more preferably at least 2 mm in mean diameter) that each granule may be coated with a coating thick enough to be effective, e.g. to delay release of the drug after ingestion, or to mask taste during ingestion, or simply to provide a desired appearance, e.g. colour, wherein the volume of the coating is less than that of the granule on which the coating is applied. It will be understood that the term “granules” may refer also to coated granules, i.e. to include the coating. The drug packages may be labelled to indicate whether or not the granules have an enteric or extended release or other coating.

Preferably the granules are formed as spheroids, which helps them to enter into the capsule body during assembly. Preferably the first and second ones of the spheroids3have a mean diameter of at least 1.5 mm, more preferably at least 2 mm, e.g. about 2.8 mm, which further helps the spheroids3to enter into the capsule during assembly.

The mean (i.e. average) diameter of the spheroids may be greater than the wall thickness of the carrier320, wherein the wall thickness is 0.5·(OD−ID), wherein OD is the carrier external diameter proximate its open end, and ID is the carrier internal diameter proximate its open end. When considered in longitudinal section, the open end of the carrier320may be bevelled or rounded, both externally and internally, to help the carrier move through the stacked packages and to help the granules or spheroids to enter into the carrier. A spheroid mean diameter greater than the carrier wall thickness means that where the carrier wall is hemispherical in longitudinal section at its open end, the equatorial plane of the spheroid will contact the inwardly sloping face of the carrier so that the spheroid is urged into the capsule body inside the carrier and will not become trapped between the carrier and the cell wall. If the cell is internally flocked then the flock may prevent the spheroids from leaving the capsule body while it enters into the cap.

The mean diameter of the spheroids may be less than half the internal diameter of the capsule body22, to ensure that the spheroids3are able to mix inside the capsule rather than being stratified inside the capsule. Using a vibration source during assembly may help to mix the spheroids or other drug particles together. Alternatively or additionally, the first and second ones of the granules or spheroids3may be substantially identical in appearance, for example, having coatings of an identical colour. Making the spheroids3identical in appearance, and preferably also mixing them together, helps ensure that the end user cannot readily separate the two drugs1,2by opening the capsule20, which may be desirable in certain applications such as the treatment of psychosis as further discussed below.

Most preferably, the diameter of each spheroid is less than one half, and greater than one third, of the internal diameter of the capsule body. This ensures that the spheroids can pass one another to achieve an optimal packing density without jamming inside the capsule body.

Operation of the Assembly Apparatus to Form an End User Package Containing Pastilles

The second embodiment exemplifies how an end user package700,7000can be formed as an assembly including two or more drug packages701,702,703, each comprising a frame710defining an array of cells711, wherein each cell711includes at least one edible wall32fixedly mounted in the frame710. As explained above, each drug package700,7000includes only one, first or second drug1,2, of which one single dose is included in, or enclosed by, the edible wall32of each respective cell. As exemplified by the illustrated embodiment, the drug may be incorporated into a body (exemplified by the API film31) which is attached to a carrier body (exemplified by the carrier film34) by which the API film body is attached to the frame710, so that these two bodies31,34together form the edible wall32.

The frames710are connected together so that each of the drug package cells711of the first drug package701is in axial alignment with a respective one of the drug package cells711of the second drug package702, the conjoined cells711thus forming together a respective one of the cells711of the end user package700,7000.

The edible walls32of the respective drug package cells711forming each cell711of the end user package700,7000are connected together to form together the respective single, orally ingestible body or polypill30contained within the respective cell711of the end user package700,7000, which in the illustrated embodiment is configured as a pastille30.

The edible walls32can be arranged to adhere together when pressed together. This can be achieved, for example, by coating the edible walls32with an edible, tacky adhesive, or forming them as a film of a material that adheres to itself, as well known in the art.

Adhesion may depend on pressure and time, so a bond may be created in a short time at higher pressure or a longer time at lower pressure.

In order to provide a quick and simple assembly procedure, a good bond, and a good shelf life for the pastille30, the end user package700,7000may be configured to compress the edible walls32together by atmospheric pressure. This means that pressure can be applied over an extended time period of much longer duration than the assembly procedure, terminating only when the pastille30is removed from the end user package700,7000for consumption. At the same time, evacuation of the enclosure711helps preserve the drugs1,2in storage.

In this arrangement, each enclosure711of the end user package700,7000includes a pair of outer walls714, which in the illustrated embodiment are formed as frangible foil walls714, spaced apart in opposed relation. The edible walls32of each single, orally ingestible body or polypill30are bonded together by adhesion, and are compressed together between the outer walls714of the respective enclosure711by external ambient atmospheric pressure acting on the outer walls714as indicated by the arrows inFIG.86.

The assembly apparatus700,7000is configured to create a vacuum (which is to say, a full or partial vacuum), and to sealingly enclose the edible walls32of each single, orally ingestible body30, in said vacuum, between the outer walls714of the respective enclosure711. The outer walls714of each enclosure711are configured to be moveable together by external ambient atmospheric pressure to compress the edible walls32of the respective single, orally ingestible body30between the respective pair of outer walls714.

Operation of the Assembly Apparatus to Form an End User Package Containing Capsules

As exemplified by the first embodiment, each polypill20may include a capsule formed from at least first and second capsule parts21,22, e.g. a conventional capsule body22and capsule cap21. The capsule parts21,22may be arranged in the cells311of an additional package or packages304,305to be received in the machine100together with the drug packages301,302; alternatively, a quantity of the capsule parts21,22could be introduced into the machine100, e.g. in loose, bulk format or in a cassette, for use with the packages301,302.

As used herein, the term “capsule” may indicate a capsule shell or a filled capsule20, i.e. a capsule shell together with the drugs1,2contained therein, according to the context. In the second sense of the term, the polypill may consist of the capsule20.

After receiving the capsule parts21,22, the machine100is arranged to collect together, between the capsule parts21,22of each capsule, one single dose of each drug1,2from one corresponding cell311of each of the drug packages301,302, and to close together the capsule parts21,22to enclose the single doses together within the capsule to form the polypill20.

The capsules20can be provided in alternative sizes, e.g. size #1, #2, and #0E. In order to ensure that the total volume of the combined drugs1,2does not exceed the capacity of the selected capsule size, each of the drug packages301,302may have a different thickness in a thickness dimension, the thickness of each package301,302being proportionate to a volume of the respective single dose of the drug1,2of each of the cells311of that package.

The machine100may be configured to receive the drug packages301,302in a stacked configuration in which corresponding cells311of the drug packages301,302are axially aligned in the thickness dimension, and to receive an indication corresponding to a maximum volume capacity of each of the capsules20. The assembly apparatus100may then prevent operation to combine together the drugs1,2if a combined thickness of the drug packages301,302is greater than a maximum combined thickness corresponding to the maximum volume capacity of each of the capsules20.

The indication may be received in the form of a user input via a user interface (e.g. a control panel displayed on a touchscreen267) of the machine, e.g. by selecting the desired capsule size on the control panel before inserting the packages, or by turning a knob (not shown) to move a profile rod152to a desired position in a manual embodiment. The profile rod152or other shape profile feature of the machine100may then be set to selectively permit or obstruct a corresponding shape profile, e.g. a profile aperture352of the packages, to prevent insertion of packages304,305containing capsule parts21,22other than the selected size, before the packages are introduced into the machine100.

Alternatively, the indication could be detected by a scanner (e.g. scanner261) of the machine100, directly from package indicia (eg. label or serialization indicia313,317or other indicia) on the inserted packages. Operation of the machine100can be prevented by selectively varying the distance between the pressure surface122and the upper end surfaces111,171of the pushrods110and pedestal block170, further described below, to prevent the pressure plate121from being closed to the operational position if the stack is too high. In the first machine100, this is accomplished by adjusting the starting position of the moving frame assembly120. In an alternative, manual embodiment, it could be achieved by rotating a profile rod (e.g. profile rod152) to define the thickness of the pressure pad250that can be fitted into the machine, as mentioned under “Alternative embodiments”, below.

Alternatively, the machine may determine the required capsule size based on the indicia on the packages which indicates the total volume of the drugs or the number of spheroids contained in each cell, or from a lookup table based on the dose and identity of the drug. The required capsule size may be displayed on a user display screen. The machine may then prevent the assembly operation if the selected drug packages are introduced into the machine together with capsule packages of an incorrect size.

The first part (e.g. the cap21) of each capsule may be contained in a first capsule package304, comprising (like the other packages) a frame310defining an array of cells311, each cell311defining an enclosure containing the respective capsule part21.

The first capsule package304may be introduced into the machine100together with the drug packages301,302before operating the machine100to sealingly enclose each capsule20containing the respective, single doses from the drug packages301,302in a respective one of the cells311of the first capsule package304to form an end user package300. Each cell311of the first capsule package304forms a cell311of the end user package300which is openable by an end user to remove the capsule20containing the respective, single doses for use.

The second capsule part22may be contained in a second capsule package305, also comprising a frame310defining an array of cells311, each cell311forming an enclosure containing the second capsule part22. The machine100may be configured to receive the first and second capsule packages304,305and the drug packages301,302in a stacked configuration in which the drug packages301,302are arranged between the first and second capsule packages304,305, and corresponding cells311of the first and second capsule packages304,305and each of the drug packages301,302are axially aligned. The machine100is then operated to urge the second capsule part22of each cell311of the second capsule package305, through the respective, axially aligned cells311of the first and second drug packages301,302into the respective, axially aligned cell311of the first capsule package304.

In this arrangement, each cell311of the second capsule package305may contain a carrier320, wherein each second capsule part22is arranged in the respective carrier320. The assembly apparatus100is arranged to urge the carrier320containing the second capsule part22through the respective, axially aligned cells311of the first and second drug packages301,302into the respective, axially aligned cell311of the first capsule package304, such that the carrier320forms a part of the end user package300. The carrier may thus act as a plug which closes the open end of the cell of the end user package containing the polypill.

Where each cell311of each drug package is dosed by a frangible foil314, the carrier320may be arranged to penetrate the foil314during the assembly process.

Alternatively, as described in the multipack variant, below, the cap21of each capsule may be contained in a cap package, optionally in a collar, wherein both the cap and the collar (if present) are slidingly displaced from the cap package during assembly. The cap package is introduced into the machine together with an end user package, optionally in the form of a multipack defining an assembly of multiple end user sub-packages. The cap package and end user package may be assembled together as an end user package assembly and introduced into the machine in that form. The end user package defines a plurality of cells which receive the polypills, and which may be closed during the assembly operation by a plug from another one of the stacked packages, which may be the capsule body package. The plug may fittingly (e.g. sealingly, or hermetically sealing) close the open end of the respective cell of the end user package after the capsule enters the cell, optionally in combination with the collar (if present).

Composite Label

Where the first drug package includes first label indicia identifying the first drug, and the second drug package includes second label indicia identifying the second drug, the assembly apparatus may be arranged to combine together the first and second label indicia from the first and second drug packages as received in the assembly apparatus, to form a composite label of the end user package identifying each of the first and second drugs. The label indicia may be printed on a label element of the package, e.g. an adhesive label, or may be printed or otherwise formed directly on the frame or block of the package.

The first and second label indicia may be transferred from the first and second drug packages to the end user package (e.g. by transferring them to the capsule cap or body package which forms the end user package), or may remain a part of the first and second drug packages when they are combined together to form component parts of the end user package, as exemplified by the second embodiment.

Providing a composite label than combines together the first and second label indicia from the first and second drug packages as received in the assembly apparatus—which is to say, the composite label includes each of the first and second label indicia that were present on the first and second drug packages as introduced into the assembly apparatus—ensures that the end user package is always correctly labelled, because whatever appears on the drug package will form part of the composite label.

As exemplified by the first and variant first embodiments, the first capsule package may include a flap with an adhesive surface (which may be protected, for example, by a release paper), which is movable to position its adhesive surface to cover a side of the first capsule package (e.g. the cap package) through which the carriers are admitted during assembly. The composite label formed during assembly of the end user package may be arranged to form a front surface of the flap facing away from the adhesive surface. This makes it possible to use the large, flat side of the end user package for the label, while also covering the exposed ends of the carriers and sealing them in their cells.

The first machine illustrates one way to provide the composite label as a mechanical assembly in which the first and second label indicia are transferred to the end user package. In this approach, the composite label is a label assembly including first and second label elements, the first label element bearing the first label indicia, the second label element bearing the second label indicia, wherein the first label element forms part of the first drug package as received in the assembly apparatus, and the second label element forms part of the second drug package as received in the assembly apparatus.

Following this approach, the end user package300,700,7000may include a label assembly312,712including first and second label elements313,713, wherein the first label element313,713bears label indicia identifying the first drug1, and the second label element313,713bears label indicia identifying the second drug2. The label elements313,713are provided as part of the first and second drug packages301,302,701,702,7001,7002, respectively, as received in the assembly apparatus100,500,5000, and are combined together to form the label assembly312,712of the end user package300,700,7000. Further label elements313,713can be included if more than two drug packages are used.

For this purpose, each drug package301,302,701,702,703,7001,7002,7003may include a label portion313,713bearing label indicia identifying the respective drug1,2contained therein. The label portions313,713of the first and second (and further) drug packages may be juxtaposed to form a composite label312,712of the end user package300,700,7000, as exemplified by each of the first and second embodiments.

The label portion313may have an adhesive surface4that is separate or separable from the frame310of the respective package301,302. This enables the label portion313to adhere to a surface of the end user package300and to be detached from the frame310of the package301,302of which it formed a part.

This is achieved in the first embodiment by means of a release surface (e.g. a release coating)5on the frame310that faces the adhesive side4of the label portion313.

Where the drug1,2is included in, or enclosed between, an edible wall or walls32of each cell711, as exemplified by the second embodiment, the frames710of the drug packages701,702,703may be configured to be stacked and bonded together in an assembled configuration with each respective one of the plurality of cells711of each package701,702,703,704,705in axial alignment with a corresponding, respective one of the plurality of cells711of an adjacent one of the packages701,702,703,704,705. In this arrangement, the frame710of each drug package may include at least one label portion713, each of the label portions713bearing label indicia identifying the respective drug1,2contained in the respective drug package701,702,703. The label portions713are configured to form a composite label712displaying a respective label portion713of each of the drug packages701,702,703when the frames710are stacked and bonded together in the assembled configuration.

One way to do this, for example, not shown in the drawings, would be to configure each drug package with an array of cells having rotational symmetry about a point, and one label portion that extends radially outwardly relative to the point, next to an opening or recess in the frame at the same radial distance from the point. By arranging each package at a different, incrementally rotated position about the point, so that the cells of the packages are all axially aligned, the labels could be juxtaposed with the label of each package exposed at the opening or recess of the other package or packages. The labels could adhere to a part of a rear cover of the end user package. In such an arrangement, the drug packages could be arranged as discs that are rotated about their central axis to arrange their respective label portions, positioned at the circumference of the discs, to extend as a juxtaposed array around a part of the circumference of the end user package.

Another way to do it, as further exemplified by the second embodiment, is by including a plurality of label portions713in the frame710of each drug package701,702,703, all of which may bear the same indicia, e.g. “olanzapine 20 mg” as shown in the first drug package701, or “citalopram 20 mg” as shown in the second drug package702. The assembly apparatus500,5000includes a cutting mechanism, exemplified in the illustrated embodiment by first and second cutters510,511, which are arranged to cut away different respective ones of the label portions713of the plurality of drug packages701,702,703, to leave each of the plurality of drug packages701,702,703, after said cutting away, with a different one or different ones of its respective label portions713when compared with each other one of the plurality of drug packages701,702,703.

This approach is exemplified by the second embodiment, wherein the frame710of each drug package701,702,703has three label portions713, comprising a left-hand label portion713′, a centre label portion713″, and a right-hand label portion713′″. The three drug packages701,702,703are received respectively in first, second and third slots501,502,503of the second or variant second machine500,5000, these slots being indicated respectively by indicia [1], [2], and [3] as shown. The first cutter510is positioned at the first slot501to cut away the centre713″ and right-hand713′″ label portions of the first drug package701. The second cutter511is positioned at the second slot502to cut away the right-hand label portion713′″ only of the second package702. There is no cutter at the third slot503and so none of the label portions713are cut away from the third drug package703. The cutters may cut away part of the temporary covers together with the label portions.

In such an arrangement, the assembly apparatus500,5000is further configured to assemble together the packages701,702,703,704,705in the stacked configuration to display a remaining one of the label portions713of each drug package of the plurality of drug packages701,702,703, said remaining ones of the label portions713being displayed in juxtaposed relation to form together a composite label712of the end user package700,7000. For example, in the second embodiment and its variant, the stacked packages display the left-hand label portion713′ of the first drug package701which is positioned on the top of the stack of drug packages (ie. at the right-hand end of the stacked drug packages as viewed from the front of the machine with the stack arranged on a horizontal axis as shown), next to the centre label portion713″ of the second drug package702beneath it, and, if a third drug package703is present (which is not shown in the front and rear views ofFIG.80, but can be seen inFIG.89), the right-hand label portion713′″ of the third drug package703.

The number of label portions713on each drug package701,702,703(and the number of slots501,502,503with cutting stations510,511for receiving the drug packages) can be increased to allow for more than three drug packages to be included in the end user package700,7000. For example, if the maximum number of packages is five, then the number of label portions713to be cut away would be, from the first (top or front-most) package to the last (bottom or rear-most) package: four, then three, then two, then one, then none.

Package Authentication

Each of the first and second drug packages301,302,701,702,7001,7002preferably includes indicia that identifies the drug1,2and dose contained therein, optionally also any excipients, modified release coatings or other therapeutic properties. This information is preferably printed so as to be legible by the user, and may form part of a composite label assembly312,712of an end user package as described above. The same information may also be provided in the form of machine readable indicia such as a barcode, as shown in the label portions313,713. Each package301,302,304,305,701,702,703,704,705,7001,7002,7003,7004,7005may further be provided with machine readable indicia317,717comprising further information, e.g. serialization data to uniquely identify each package, as well known in the art. The data may include a code that uniquely identifies the package, and/or other data such as batch number, time and/or date of manufacture, location where manufactured, and other supply chain information such as the route by which the package was distributed or the territory into which it was supplied.

One problem in authenticating drugs or other products using serialization data is that, when each package is provided with a unique serial number, that number can be copied to produce counterfeit packages. One way to address that problem is to read the serial number at the time of authentication of the package, and upload the serial number to a central database which checks to see whether the number (i) is contained in the database record of genuine serial numbers, and (ii) has ever previously been read and uploaded. If it is a genuine serial number and was not previously uploaded, then the database controller can indicate that no copies have been detected and so the package can be accepted as authentic. If it is a genuine serial number but has previously been read and uploaded, then the database controller can indicate that it may be (but is not necessarily) a counterfeit.

One problem with this methodology is that if the same package serial number is authenticated more than once, the database controller may indicate on the second occasion that the package is a counterfeit. In a busy pharmacy, it may not be practical to scan each package on arrival and then keep a detailed log of the authentication information; thus, the authentication procedure is subject to a degree of uncertainty, depending on the probability that different members of staff may have attempted authentication on more than one occasion. To address this problem, multiple codes and peel-off labels can be provided, but this adds cost and complexity.

Since the packages of the present system are used only once during the assembly process, this problem can be solved by capturing the authentication data317,717from the package during the assembly process.

Accordingly, the machine100,500,5000(specifically, one or more readers or scanners261,561and a local controller262with local memory263and external data link264) may be arranged, after introducing the packages into the machine and either before, during or after combining the drugs1,2to form the polypills20,30, to read the machine readable indicia317,717from the drug packages and optionally also the other packages used therewith.

The machine100,500,5000may also receive information from a database90(e.g. via a remote computer91controlling the database90), and, based on the indicia317,717and the received information, may identify and authenticate the respective drug packages301,302,701,702,703,7001,7002,7003including in particular the drugs1,2contained therein, and optionally also may identify and authenticate the other packages304,305,704,705,7004,7005used therewith.

Preferably, the machine100,500,5000is further arranged to upload information based on the machine readable indicia317,717to the database90.

The machine100,500,5000could download data relating to the packages from the remote database90to a local memory263of the machine before reading the package indicia317,717, and then compare the package indicia317,717with the data stored in the local memory263and perform the authentication based on that comparison. In this case the machine100,500,5000could also upload the package indicia317,717(i.e. the data represented thereby), optionally also the authentication result, to the remote computer91and database90.

Alternatively, the machine100,500,5000could upload the information from the indicia317,717to a remote computer91controlling the remote database90, and then receive an authentication message from the remote computer91after the uploaded information has been compared with the corresponding package data stored at the remote database90.

Alternatively, a combination of both methods could be employed, so the machine100,500,5000receives regular downloads and makes regular uploads, whereby its local memory263is constantly updated with the current information in the remote database90, perhaps just that information that pertains to the packages that have been logged, at the remote database90, for use (or potential use) with that individual machine100,500,5000. This enables fast operation without waiting for a real-time response from the remote computer91, while maintaining data integrity.

For example, the machine100,500,5000could receive data for all packages destined for the territory in which the machine is operated, or all packages included in a bulk container whose ID was previously logged and uploaded to the database90on despatch from the local supplier or on arrival at the pharmacy.

The information based on the package indicia317,717may be transmitted to the remote computer91that controls the database90together with a unique machine identifier which is used by the remote computer91to identify details associated with the machine100,500,5000as stored in the database90, e.g. its location and its owner or operator. Thus, the remote computer91may receive a packet of data identifying one operation of the machine100,500,5000, including the package serialisation data317,717and the identity of the machine100,500,5000.

The remote computer91may then check whether the package serialization data317,717has previously been uploaded by another machine or the same machine. If yes, the remote computer91may log the details of which packages and which machines are involved, for further investigation. Since the package manufacture and dispatch details will be stored in the database90from the time of manufacture, and the point of eventual use is identified by the machine ID, the affected supply chain can be identified.

Data sent between the machine100,500,5000and the central database90may be encrypted.

The machine100,500,5000may also include a removable data storage device92, e.g. a USB flash drive, for transferring data between the machine and the remote computer91and database90.

The machine100,500,5000may be further arranged to output information from the database90to a printer265to print an information leaflet266identifying the drugs1,2contained in the drug packages301,302,701,702,703,7001,7002,7003. The information could be retrieved from local memory263or directly from the remote database90responsive to a real-time authentication request.

The information may include information on any interaction between the identified drugs1,2. Thus, the remote database90may include special cautionary notices or other information for any relevant drug combinations, which can be displayed on the same patient information leaflet266along with (or instead of) the information relating separately to each of the drugs1,2.

If a particular combination is contra-indicated then, instead of combining the drugs1,2and providing the information leaflet266with a warning, the machine100,500,5000could be configured to reject the combination so that, instead of operating normally, it displays a warning message (e.g. via touchscreen267). This could be triggered by information in the local memory263or a command from the remote computer91, responsive to reading the package indicia317,717before commencing the operation to combine the drugs1,2or, if already commenced, before finishing it.

In the illustrated embodiments, the scanners561of the second machine500,5000are arranged to read the package indicia717before combining the drugs1,2(optionally, before removing the temporary covers706,707from the packages701,702,703,704,705). The scanner261of the first machine100is configured to read the package indicia317during the assembly operation, as the stacked packages301,302,304,305are moved down onto the pushrod assembly, as further explained below. However, the scanner261of the first machine100could alternatively be configured (e.g. with a longer scanning window268) to scan the entire stack of packages before assembly commences, in which case, e.g. if the requested operation is not permissible, the operation could be terminated before the pushrods110enter the stack.

The machine100,500,5000may be configured (or commanded by the remote computer91) to terminate or disallow an assembly operation, for example, if some or all of the packages301,302,304,305,701,702,703,704,705,7001,7002,7003,7004,7005, and particularly the drug packages are identified as counterfeit, and/or the drug combination1,2is contra-indicated.

The printer265could alternatively or additionally print an adhesive label (not shown) for attachment to the end user package300,700,7000, e.g. including patient information such as name and address and registration number. The adhesive label could be a peel-off part of the patient information leaflet266, or could be printed by a second printer265. The machine100,500,5000could be arranged to interface with a local or remote, external system (e.g. remote computer91and database90, or a further system and database, e.g. of the pharmacy or local health authority, not shown) to receive patient data and to output the patient data on the patient information leaflet266and/or the sticky label and/or to upload it to the remote computer91along with the information based on the package indicia317,717—for example, for regulatory compliance where the drugs1,2are controlled substances. This enables a drug1,2to be tracked from manufacture to the point of delivery to an identified end user.

The machine could include an external scanner (e.g. as shown in the variant first machine) which is used to identify the packages before introducing them into the machine, where they are scanned again to confirm their identity, and may communicate with the central database on either or both occasions. The moving assembly of the machine could be set to the required start position responsive to the input at the first scanner which is confirmed by the internal scanner before the assembly operation commences. Counterfeit packages could be identified and indicated to the user responsive to scanning them at the external scanner before introducing them into the machine, whereas the exhaustion event of the unique package ID is only recorded in the central database responsive to scanning the package again during the irreversible, one-time assembly operation.

Each package301,302,304,305,701,702,703,704,705,7001,7002,7003,7004,7005may include one or more shape profiles. Each shape profile could be, for example: an external contour of the package701,702,703,704,705,7001,7002,7003,7004,7005as shown in the second embodiment, or as illustrated in the variant first embodiment; or a pattern of apertures such as locator rod apertures751for use with the variant second machine5000; or a non-circular aperture defined by its angular orientation about an axis of rotation relative to the frame310of the package, such as a profile aperture352as shown in the first embodiment; or an alignment structure including alignment apertures351, or alignment and profile apertures351,352, as shown in the first embodiment.

The assembly machine100,1000,500,5000may include a corresponding shape profile configured to selectively fit or obstruct the shape profile of the or each package. The machine100,1000,500,5000may include more than one shape profile to engage with more than one shape profile on each package, and/or to engage with corresponding shape profiles on different ones of the packages. Depending on the function of each shape profile, different package types may be configured to be profile-selective or profile-agnostic—which is to say, a package may be configured to accept a particular shape profile of the machine in any position of adjustment of that shape profile. This principle is illustrated by the first embodiment, in which different ones of the packages have one or more profile apertures352in different angular positions, or one or more circular profile apertures352which do not select for different angular positions of the corresponding profile rod152of the first machine100.

Different shape profiles of the machine can select for different ones of the packages to ensure that an incompatible package cannot be received in the machine, and/or to ensure that each package type is inserted in the correct position. For example, in the second and variant second machines500,5000, each slot501,502,503,504,505is provided with a shape profile that selects for package type (so, distinguishing between drug packages, front cover packages, and rear cover packages), and further selects for the orientation of the package, to prevent the insertion into the slot of the wrong type of package, and/or of the right type of package in the wrong orientation, as further explained below.

The shape profile of the machine may be adjustable by a profile adjustment mechanism, e.g. the index mechanism153that rotates the profile rod152of the first machine100, to selectively fit or obstruct the shape profile of the respective package or packages, e.g. profile aperture352, so as to selectively permit or prevent reception of each drug or other package in the machine.

This can be useful, for example, to prevent incompatible packages (e.g. with different numbers of cells) from being used together. It can also be used to select for capsule capacity to prevent packages304,305with capsule parts21,22in a certain capsule size from being combined with drug packages301,302,303containing a volume of drugs1,2too great for the capsules, as discussed above under the heading “Operation of the assembly apparatus to form an end user package containing capsules”.

The shape profile may be configured as an axially continuous, non-circular cross section of a profile rod, e.g. profile rod152, and may be rotationally asymmetric so that it fits the corresponding shape profile352of the package in only one index position. The shape profile of the packages is similar, but its index position corresponds to the selected criterion. A profile adjustment mechanism, e.g. index mechanism153, may be arranged to rotate the profile rod152about its length axis to selectively fit or obstruct the corresponding shape profile of each of the packages301,302,304,305.

The first machine100includes by way of example three such profile rods152, indicated (from left to right) as a first profile rod152′, a second profile rod152″, and a third profile rod152′″. The second profile rod152″ selects for capsule capacity, while the third profile rod152′″ selects for package size (number of cells311). The first profile rod152′ is redundant, and could be used, for example, to control for package origin in a future segmented market (so unauthorised imports from a market region identified by one profile cannot be combined with authorised imports identified by a different profile), or for different package standards if the system parameters should change.

The scanner (i.e. sensor or reader)261,561of the machine100,1000,500,5000can also be used, additionally or alternatively to shape profile features, to detect the inserted packages301,302,304,305,701,702,703,704,705,7001,7002,7003,7004,7005and, via the controller262, to selectively permit or prevent operation of the machine100,1000,500,5000responsive to the detected characteristics of the packages or combination of packages.

Machine for Producing Polypills in the Form of Capsules—Overview

Byway of example, the first embodiment shows an assembly apparatus for filling capsules with drugs, configured as a small machine100for use in a pharmacy.

The first machine100includes a plurality of pushrods110spaced apart in parallel relation, each pushrod having an end surface111. A pressure plate121defines a pressure surface122arranged in opposed, spaced relation to the end surfaces111of the pushrods to define a receiving space101between the pressure plate121and the end surfaces111of the pushrods.

The first machine further includes an actuation mechanism. The actuation mechanism may be a powered mechanism (i.e. a mechanism driven by power from a non-human power source). In the illustrated embodiment, the actuation mechanism includes a hydraulic piston141received in a cylinder142and driven by fluid pressure from a motor driven hydraulic pump143powered by an external electric power supply10. Other types of actuation mechanism are possible; for example, the actuation mechanism could be a mechanical linkage, e.g. a geared linkage, driven by an electric motor. Alternatively, the actuation mechanism could be manually operated, i.e. driven by human effort, for example, via a lever.

It should be understood therefore that the term “machine” is used herein as a convenient shorthand for the assembly apparatus, both in its illustrated embodiments and more generally to refer to both automatic and manual variants.

The actuation mechanism141,142is configured to cause relative movement between the pressure plate121and the pushrods110, in a compression stroke, along a displacement axis Xd parallel with the pushrods110. In the first machine and variant first machine this is accomplished by moving the pressure plate121relative to the pushrods110which are fixed in the body of the machine, although it could alternatively be arranged for the pushrods to move relative to a fixed pressure plate.

The machine is configured to receive the packages in a stacked configuration in which corresponding cells of the stacked packages are axially aligned, as shown inFIG.45, and further includes an alignment structure150. The alignment structure150is configured to maintain the stack of packages in alignment with the pushrods110when, in use, during the compression stroke, the pushrods110are urged through the stack of packages positioned in the receiving space101, as shown in section in the sequence ofFIGS.52-54.

The machine100may further include a controller262for controlling the actuation mechanism, and a scanner or reader261for reading machine readable indicia371in use from the stacked packages. The controller262may be arranged to retrieve information from a remote database90to identify and authenticate the stacked packages, based on the indicia371captured by the scanner261, as discussed above.

As illustrated, the alignment structure may include a plurality of alignment rods151which extend in parallel with the pushrods110, beyond the end surfaces111of the pushrods and into the receiving space101.

The alignment structure150, and/or (if present) any shape profile (go/no-go) features, may be configured to prevent the packages from being received in the stacked configuration in more than one possible orientation. That is to say, with respect to the corresponding features of the packages which fittingly engage the alignment structure150and (if present) the shape profile features of the machine, the packages may be rotationally asymmetric about one axis or about all three orthogonal axes (or all possible axes).

In the illustrated example, the alignment rods151are slidingly received in alignment apertures351of the packages, and shape profile features are also provided in the form of profile rods152which are fittingly received in profile apertures352of the packages, as further described below. Together (and individually) these features define only one possible orientation of the packages in the stacked configuration.

The machine may further include an assembly surface171which extends between the pushrods110. The assembly surface171is positionable in a start position (FIGS.41,42) proximate the end surfaces111of the pushrods, and movable along the displacement axis Xd during the compression stroke. As illustrated, the assembly surface171may lie in a common plane with the end surfaces111of the pushrods in the start position, so as to receive the packages which are stacked onto the assembly surface before operating the machine. The flush assembly surface and pushrod ends together present a continuous surface which can easily be wiped clean.

The assembly surface171may be biased towards the pressure surface122of the pressure plate121to compress the frames of the stack of packages between the assembly surface171and the pressure surface122, in use, during the compression stroke. This maintains the stack of packages in tightly abutting relation during operation of the machine.

The machine may further include a flat, front surface172which extends in a plane parallel with the displacement axis Xd and normal to the assembly surface171. The front surface172and the assembly surface171are fixed together to move together during the compression stroke.

In the illustrated example, the assembly surface171is formed as an upper surface of a pedestal block170(FIG.31) which is resiliently biased, e.g. by compression springs173(FIGS.19,26,28), towards the pressure surface122. The flat, front surface172is a front surface of the same pedestal block170.

The machine may further include at least one cutter, the at least one cutter being arranged to cut through a portion of the stacked packages, in use, during the compression stroke. In particular, the cutter may detach a label element from each of the drug packages301,302.

In the illustrated embodiment there are two cutters190, configured as miniature circular saw blades mounted on rotating shafts191driven by electric motors192which also drive impellers193of a vacuum extraction and separation system for removing the fragments cut from the packages, as further explained below. The cutters190detach the label element313from each of the drug packages301,302, which adheres to the flap330of the cap package304to form part of the composite label assembly312of the end user package300, as shown inFIGS.50,57, and58.

Referring toFIG.1, the first machine100may include a casing201, e.g. of sheet metal, with a door130and two debris collection trays202that are slidably received in apertures in the casing201and accessible from the front of the machine. The casing201may be mounted on a base (not shown) that is attachable to a support surface, e.g. a worktop in the pharmacy, the base having two upwardly projecting lugs that extend through holes in the bottom of the casing201. After fixing the base to the support surface, the casing201is placed over the base and then the trays202are removed by sliding them out of their apertures in the casing201to expose the lugs which project into the space behind the trays202. Screws are inserted via the apertures to secure the casing201to the lugs so that the machine100is firmly secured to the support surface.

FIG.1shows various features, all of which may be present in the variant first machine and the second and variant second machines500,5000. These include the local controller262and memory263with a user interface and a data transmitter/receiver269for sending and receiving data via data link264, e.g. via the internet, and/or via a removable data storage device92, to and from the remote database90and computer91.

The user interface could be a touchscreen267as shown and/or lights, buttons or other indicators and controls. The user interface may be integrated into the casing201or may be external to the casing and adjustable to a comfortable position for each user. It could be integrated into the door130, e.g. to form part of a window131through which the user can observe the operation of the machine. An additional, external scanner1280(not shown inFIG.1) may also be included, e.g. as shown in the variant second machine.

Local controller262receives sensor signals270from all of the various sensors of the machine. In the illustrated embodiment of the first machine100these include a moving frame position sensor102, a door position sensor132, optical sensors175of the pedestal block sensor assembly174, a pressure plate sensor123for sensing the presence of the pressure pad250, the scanner261for reading package indicia317, and sensors154,165of each index mechanism153.

Local controller262sends control signals271via a control interface272which may control any or all of the various functional elements of the machine.

In the first machine100these include a door lock (not shown) for locking the door130, pedestal block latches103, the LED182of the pedestal block sensor assembly174, profile rod index mechanisms153, motors192for the cutters and debris extraction system, printer265, and the modified atmosphere system or vacuum generating apparatus590(FIG.60), if provided.

In the second and variant second machines500,5000the controller262may similarly control the vacuum generating apparatus590, cutters510,511, punches519, door lock (not shown), locator rods, grippers and other alignment and transfer assembly elements551,552,553,554, and all other functional elements of the machine.

The controller262also controls the actuation mechanism, which in the first machine100includes a hydraulic valve control assembly144for controlling the supply of hydraulic pressure from tank145via pump143to operate the actuators or pistons141. In the second and variant second machines the actuation mechanism includes actuators523which may be e.g. hydraulic, pneumatic, or electrically powered, e.g. comprising solenoids or motors, and could be integrated with the package transfer and alignment mechanism.

Further Features of the Capsule Cap Package

Byway of example,FIGS.10,11and12illustrate capsule cap packages similar to the capsule cap package304which has 12 cells, but configured respectively with 24 cells (package304′), 36 cells (package304″), and 48 cells (package304′″). In the first machine100there are 48 pushrods110with additional alignment rods151so that each size of package can be accommodated; each package is rotationally asymmetric so that it can only be positioned at the front of the machine in the position of the packages as shown. Drug packages and capsule body packages may similarly be provided with corresponding numbers of cells.

For particularly voluminous drugs, the user may need to take more than one polypill at the same time; thus, the dose of each drug may be divided between different polypills. Multiples of 12 cells may be selected so that the user can take 1, 2, 3 or 4 polypills at the same time and finish the package with none left over.

In the illustrated embodiment, to ensure that only compatible packages are used together, the right-hand profile rod152′″ is configured to select for package size, so that the corresponding, right-hand profile aperture352of each of the cap packages304,304′,304″,304′″ is in a different angular position.

Referring toFIGS.2-9, the frame310of the capsule cap package304may comprise a block360enclosed within a casing340.

The casing340may be formed from one sheet of cardboard with fold lines dividing it into integral parts that can be folded around the block360, these integral parts including the flap330which may be about the same width as the rest of the package, as shown. The sheet may be define apertures for the cells311and alignment and profile apertures351,352. The sheet340may further define a window331in the flap330so that the remaining part of the flap330defines a frame surrounding the window331, and perforations that delineate the tear-off strips315and tabs316. All of the apertures may be formed e.g. by punching.

The front surface of the sheet340may be printed with indicia317and, on one part that will form a narrow side of the end user package300, a legend indicating the number and size of the capsules: “12 capsules size #2”, and below that, the words: “EACH CAPSULE CONTAINS:—”

This phrase will appear at the top of the composite label assembly312, on the narrow side of the end user package300, followed on its adjacent broad, rear surface by a list of APIs as printed on the label portions313of the drug packages301,302.

The tabs316forming the ends of the strips315may be defined within small apertures341in the sheet so that, when the sheet340is folded over the edge of the block360, the tabs316are exposed within the apertures341to be easily engaged by the user's finger at the edge of the end user package300.

A sheet or sheets of frangible, i.e. tearable foil314(e.g. plastics film or metal, e.g. aluminium foil, or a laminate or metallised composite) may be applied to the surface of the cardboard sheet340, which is further coated with an adhesive4on the surfaces that are to be stuck to the block360and on the rear surface of the flap330. One one side of the block, the foil314forms the frangible wall of each cell. On the other side of the block, the foil314may extend over the perforations defining the strips315so that each cell311containing the capsule cap21is sealed by the foil also at that end, the foil314being broken only when the strip315is removed from the end user pack300by the user. Adhesion between the foil314and the cardboard of the strip315may cause the foil314to tear away from the block360together with the strip315to open the cell311to remove the finished capsule20from the end user package300.

The adhesive4that is to stick the cardboard sheet340(and foil314) to the block360need not be permanently tacky, and may be different from the tacky adhesive4that is applied to the rear surface of the flap330and covered by a release paper332. The function of the adhesive coating4on the flap330is to stick the flap330to the label portions313of the drug packages301,302and to the flap370of the capsule body package305when the packages are stacked in the machine100to be formed into the end user package300, as further explained below.

Illustrated inFIGS.2-9is the 12-capsule size of capsule cap package304. Comparing this package304with the 24-, 36- and 48-capsule variants304′,304″,304′″ shown inFIGS.10-12, it will be noted that the flap330of the 12-capsule size package304has a perforated tear line333defining a waste portion334, and a window331which extends through the tear line333into the waste portion, being of a different shape compared with the window of the 24-, 36- and 48-cell variants. The window331of this (smallest) pack size304is shaped to co-operate with the pedestal block sensor assembly174while the tear line333is positioned so that after assembly, the remaining part of the frame defined by the flap330will fit the broad, bottom side of the package304. In the larger package sizes the rear surface of the package will accommodate a window large enough to co-operate with the pedestal block sensor assembly174, and so there is no need for a tear line333.

Various other indicia may be printed on the casing340, including instructions for removing the waste portion334and indicia identifying the tabs316and cells311, which optionally may be numbered as shown, or could just have markings so that the position of each cell is evident to the end user.

The block360may be assembled from a stack of sub-blocks361separated by sheets362of paper or foil. Each sheet362may define (e.g. by punching) small holes363which are of smaller diameter than the apertures364formed in the sub-blocks361, which extend through the thickness of each sub-block361to define the cell walls318. After assembly, the portion of the sheet362surrounding these small holes363projects inwardly into the cell311to form the annular fins325that hold the capsule cap21co-axially on the axis Xc of the cell311. The holes363can be made with a larger diameter to accommodate a cap for a larger capsule size, or a smaller diameter for a smaller capsule size, without changing the diameter of the cells311.

The alignment and profile apertures351,352are also formed in the sub-blocks361and sheets362. The sheets362and sub-blocks361are coated with adhesive on their facing surfaces, and the sheets362are interleaved between the sub-blocks361before all these components are pressed together with all the apertures in axial alignment to form the block360.

Alternatively, the whole block360could be made as a monolithic unit.

Instead of the annular fins325, a body of starch foam or other compressible material (not shown) could be arranged in the cell311as a locating structure to locate the cap21on the cell axis Xc; the body is compressed by the carrier320as the cap21enters the carrier320in use, and may remain captive between the upper (open) end of the carrier320and portions of the casing340when the capsule20is removed from the cell311of the end user package300.

Alternatively, an insert (not shown) could be assembled into each cell of a monolithic block to act as a locating structure which holds the capsule component in spaced relation from the cell wall. The insert could be a tube, e.g. of paper or polymer material, with small tabs cut from its wall to extend radially inwardly. The wall of the tube could be received between the carrier and the cell wall, so that as the carrier slides into the tube, it presses the tabs radially outwardly back into the apertures in the tube wall from which they were cut.

The sub-blocks361or monolithic block360may be moulded. A simple, monolithic structure makes it possible to make the block360or sub-blocks361from a material such as a carbohydrate glass, e.g. made from sugar, isomalt, or boiled sugar and glucose syrup; perhaps with a filler such as corn starch, kraft-lignin or lignosulphonate, chalk, microcrystalline cellulose, calcium carbonate, kaolin, talc, wood flour, or other powdered material to add volume, toughness, and/or temperature stability. The cell walls318and/or other exposed surfaces of the block360can be coated with a non-sticky or lubricating coating, e.g. an oil, a water based lacquer, a resin or varnish, e.g. rosin, copal, shellac, collodion, or a wax or synthesized wax ester, e.g. paraffin wax, beeswax, lanolin, or carnauba wax. When the casing340is made from cardboard, this provides a compostable assembly made from sustainable materials. The cardboard casing could be for example a hard cardboard with a thickness of about 1 mm or less, perhaps about 0.5 mm; for example, a hard kraft paper or paperboard. The cardboard could be faced with a white sheet.

Alternatively, the block could be moulded from another material, e.g. glass such as recycled cullet. Alternatively it could be injection moulded from plastics materials. In this case, the annular fins325or other locating structure for locating the cap21in the cell311could be formed integrally with the block, e.g. as fingers arrayed both angularly around the cell axis Xc and along its length so that the block can be formed in a two-part mould. In this and other alternative embodiments, the block could be used with or without a casing340.

Referring again to the illustrated embodiment, after forming the block360, the capsule caps21(optionally also the locating structures such as starch foam bodies or paper tubes) are introduced into the cells311before the casing340is folded around the outer surface of the block360to seal the caps21in the cells311. The flap330remains hinged to the rest of the assembly via one of the fold lines of the cardboard sheet, with its adhesive surface4covered by the release paper332.

The release paper332may be a sheet of any material that is readily removable to expose the adhesive side4of the flap, e.g. a paper coated with wax, oil or silicone or a textured polymer, and may be printed with a legend visible through the window: “PUSH DOWN PRESSURE PLATE BEFORE REMOVING PAPER”. This reminds the user to make sure that the packages are all pressed together before the adhesive is exposed and the flap adheres to the front of the stack, as further explained below.

Further Features of the Capsule Body Package

Referring toFIG.13, capsule body package305may include a flap370hinged to the rest of the package305.

When stacked with the other packages in the machine100, the flap370fills that portion (if any) of the window331of the flap330of the cap package304that is not filled by the label portions313of the drug packages301,302. This ensures that the composite label assembly312of the end user package300is correctly formed, irrespective of the stack height, which varies with the aggregate volume of the drugs1,2in the packages. The variable stack height is reflected by multiple perforation lines371at which a surplus portion372of the flap370, adhered to the waste portion334of the flap330, may be detached from the end user package300after assembly.

The flap370is coated on its reverse side with a tacky adhesive surface4, to stick to the bottom surface of the cap package304which forms the body of the end user package300, when the composite label assembly312including the flap300and the flap370is folded and stuck in its final position, as shown inFIG.57, after removing the stack from the machine100. The flap370may have a fold line373at which it is folded so that it wraps around the body of the package305until ready for use. The outer surface of the body of the package305may have a release coating5so that the adhesive, rear surface4of the flap370can be separated from the rest of the package305when positioning the package305in the machine100.

The flap370may form part of a cardboard sheet, which may form an outer casing374of the package305. The flap370may be connected to a body portion375of the outer casing sheet374by a pair of wings376, defining portions of the flap370which extend outwardly beyond the ends of the block380that forms the cells311as further described below. Between the wings376the flap370may be separated from the body portion375of the outer casing374by a slit377, which may be positioned as shown collinear with a fold line378between the wings376and the body portion375. When the body portion375is positioned to form the upper surface of the package305, the wings376extend out within the thickness dimension of the package to form its front surface when the package is arranged in the stack in the machine100, and the rest of the flap is unfolded to extend downwardly in the same plane below the wings against the front surface172of the pedestal block170, as shown inFIGS.42-43. In use, the portion of the flap370between the wings376will be detached by the rotary cutters190to become part of the composite label assembly312.

The detachable part of the flap370may bear a legend: “NO OTHER ACTIVE INGREDIENTS”. This legend appears at the end of the list of APIs forming the composite label assembly312of the end user package300.

The wings (or another part of the package305) may be printed to indicate the number of capsules and the size of each capsule, e.g. twelve capsules of size #2 as shown in the illustrated embodiment. The system may be configured to work with only one capsule size, but as shown, can accommodate different capsule sizes from a #2 up to a maximum #0E. It could be designed for larger capsules, but they are harder to swallow. Different capsule sizes can be useful to allow for swallowing difficulties in different patients. For example, a patient might prefer to receive a dose divided between several, smaller capsules, each containing a single dose of each of the combined drugs1,2but in a fractional quantity of the total required dose which is obtained by taking two or more capsules together.

By way of example,FIG.13Ashows a conventional, empty capsule20assembled from a body22and a cap21, the cap21being arranged to fit telescopically over the body22. The cap21may be retained to the body22after assembly by friction, or by complementary snap-fit features (not shown) such as an annular recess and protuberance, and/or by a tacky, edible adhesive region arranged, e.g. inside the cap21, such as inside an inwardly open, radially outwardly extending, annular recess (not shown) of the cap21, to adhere to the open end or co-operating, radially outwardly extending, annular protuberance (not shown) of the body22. In such arrangements the adhesive contained in a recess of the cap only comes into contact with the body when the outer annular protuberance of the body (near its open end) enters into the inwardly open, annular recess formed in the cylindrical wall of the cap, so that the snap-fit action of the cap on the body also engages the adhesive bond between the two parts. The capsule parts21,22can be made from any conventional material, e.g. gelatin or vegetable materials such as hydroxypropyl methylcellulose (HPMC) or pullulan.

The size of the frame310of each package301,302,304,305, and of the pushrod assembly of the machine, may be selected to accommodate capsules up to a maximum capsule size, which in the illustrated embodiment is a size #E capsule. To accommodate smaller capsules such as a size #1 or size #2, the wall thickness of the carrier320may be increased to reduce its inner diameter without changing its outer diameter.

Two small sensor apertures379are formed in the flap370to co-operate with the pedestal block sensor assembly174in use, as further explained below.

A sheet of foil314may be attached to cover the inwardly facing surface of the body portion375of the outer casing374to form the frangible walls which seal the upper ends of the cells311containing the capsule bodies22in the carriers320, and which are penetrated by the carriers320as they exit the cells311during assembly.

The body of the package305may be formed from a monolithic block380, which defines the cells311and cell walls318as cylindrical apertures extending through the block380between its opposite broad, flat sides. The block380may be made the same way as the sub-blocks361of the cap package304as described above, e.g. by moulding from a glass, e.g. a carbohydrate glass, or alternatively from plastics material.

The block380may be encased in an inner casing381, which may be another sheet of cardboard formed with fold lines at which it is folded around the block380. In the illustrated embodiment, the inner casing381has a sheet of foil314on its inwardly facing surface which adheres to the block380to form a foil wall that seals the lower end of each of the cells311proximate the bottom surface of the respective carrier320. This foil wall314is penetrated by the upper end111of the respective pushrod110as it enters the stack during assembly. The inwardly facing surface of the inner casing381(except for the parts defining the foil walls that face the carriers320) is coated with adhesive4to stick to the block380.

Alternatively, the adhesive could cover also the parts of the foil walls that face the ends of the carriers, in which case the foil that overlies the end of each carrier will be detached from the capsule body package together with the carrier to become a part of the end user package, eventually being covered by the adhesive flap.

Alternatively, the end surface of each pushrod, and/or the closed (bottom) end surface of each carrier320, could be slightly convexly domed rather than flat, so as not to trap the fragments of foil covering the end of the carrier, which remain attached to the capsule body package.

Alternatively, the lower side of the capsule body package could be formed without foil and closed by the end surfaces of the carriers320. The carriers may be assembled into the frame of the capsule body package, or alternatively could be formed integrally with the cells of the capsule body package with break lines at which each carrier will separate from the frame.

The outwardly facing surface of the inner casing sheet381may be printed with indicia317, e.g. including a barcode as shown which appears on the end of the package305and is read by the scanner261during assembly.

The outwardly facing surface of the inner casing381may be provided with a release coating5to prevent adhesion of the sticky side of the flap370when it is folded around the package305in transit and storage. Alternatively the flap370could be provided with another release paper that can be removed by the user.

In order to guide the capsule body22through the aligned cells311of the stack and to help penetrate the foil walls314of the cells311during assembly of the end user package300, the capsule body22may be received in a carrier320as also shown inFIG.13A. The carrier320may be moulded, e.g. from a glass or plastics material, and may define a generally cylindrical wall extending from a closed end321to an open end322. The open end322may define one or more salient portions323which extend axially forwardly to penetrate the foil walls314of the cells as the carrier320is urged by the pushrod110through the stack of packages.

The capsule body22is received in the internal cavity defined by the cylindrical wall of the carrier320with the open end of the capsule body22at the open end of the carrier320, as shown. The internal diameter of the carrier320is selected so that the capsule body22is a sliding fit in the carrier320, and its cavity may also have a rounded lower, inner end to fit the curvature of the closed end of the capsule body22, as shown.

The outer diameter of the carrier320is selected to be a sliding fit in the aligned cells311of the stacked packages, making allowance for the thickness of the ruptured foil walls314which may extend between the carrier320and the cell wall318. The cells311of the capsule cap package304may be of slightly smaller diameter so that the carrier320is a tighter or interference fit in the respective cell311of the cap package304to close the cell containing the finished capsule20. The carrier320may be coated externally with a lubricant such as a wax or silicone to assist it to slide through the stack during assembly.

The carrier320may have a slightly enlarged internal diameter portion324proximate its open end322relative to its slightly smaller internal diameter proximate its closed end321, as shown, to accommodate the capsule cap21as it slides into the enlarged portion324between the capsule body22and the cylindrical wall of the carrier320during assembly.

The radially outer surface of the carrier may be textured or barbed for part or all of its length, e.g. as shown in the variant carrier1320, to help retain the carrier in the cell of the end user package when the end user package is removed from the machine after assembly. The surface texture or barbs may engage an internal spacing or support structure within the cell311, e.g. a flocked coating, as illustrated in the variant first embodiment.

After inserting the carriers320containing the capsule bodies22into the cells311of the block380, the inner casing381may be folded around the block, and then the outer casing374folded around the inner casing381, or alternatively the inner and outer casings381,374may be assembled together before folding them around the block380, to seal the carriers320containing the capsule bodies22in the cells311.

Further Features of the Label Portions of the Drug Packages of the First Embodiment

Referring now toFIGS.14-17, the first and second drug packages301,302of the first embodiment may be formed in a similar way to the capsule cap and body packages described above, comprising a monolithic block400encased in a casing. The casing may comprise an inner casing410and an outer casing420, each of which may comprise a flat sheet of cardboard as shown inFIG.15, with fold lines at which the sheet is wrapped around the block.

The casing, e.g. the outer casing420as illustrated, or any other part of the drug package301,302may define the label portion313, which may have indicia on its outwardly facing surface. Its opposite, inwardly facing surface may have a tacky adhesive coating4, which after assembly may face a release coating5on the narrow side of the block or, as illustrated, of the inner casing410.

The label portion13may be separated from the rest of the cardboard sheet forming the outer casing420by slits421, so that it is attached to the rest of the sheet only by outer wing portions422which extend outwardly beyond the ends of the block400. The release coating5allows the label portion313to be removed from the rest of the drug package301,302together with the flap330of the cap package304after the label portion313is separated from the wing portions422by the cutters190during assembly. In this position during assembly, the indicia on the front surface of the label portion313are exposed in the window331of the flap330.

In the illustrated embodiment these indicia read “OLANZAPINE 20 mg” on the first drug package301, and “CITALOPRAM 20 mg” on the second drug package302. There is also a “+” symbol which, when the label portion313is displayed as part of the composite label assembly312on the end user package300, indicates that the stated drug is present in combination with the next drug in the list.

In the illustrated embodiment, the number of capsules (“12 CAPSULES”) is indicated to the left of the label portion313, and to the right appears the indication “3 UNITS”. This latter indication corresponds to the thickness dimension of the package. In the illustrated embodiment, the first drug package301has a thickness dimension T1of three thickness units, while the second drug package302has a thickness dimension T2of only two thickness units—so, (T1=1·5 T2). In the illustrated embodiment, each thickness unit is about 4 mm and corresponds to about 0.07 ml of internal volume within the capsule. Each thickness unit corresponds to the same volume of drug, which in the illustrated embodiment is about three spheroids3of about 2.8 mm diameter. Thus, it can be seen that each cell311of the first drug package301contains 1-5 times as many spheroids3as the corresponding cell311of the second drug package302. The thickness T1or T2of each package in the stack height dimension (e.g. the vertical dimension of the machine100, as shown) is preferably a multiple of (i.e. perfectly divisible by) the thickness increment, i.e. the thickness unit (e.g. 4 mm).

In use, the pharmacist selects the required drug packages to be formed into the end user package300(which could be one, two, three, four or more drug packages) and then notes the total number of units. For example, if the prescription requires one first drug package301and one second drug package302as shown, then the total number of units is 3+2=5 units. Referring momentarily toFIG.13, it can be seen that the size #2 cap package indicates “SIZE #2/MAXIMUM 5 UNITS”. So, the pharmacist can see that a #2 capsule size is suitable for the required drugs. If more drugs were needed then a larger capsule size package would be selected, for example, a size #1 or a size #0E. (Capsule sizes are standardised as well known in the art.)

Further Features of the Drug Packages of the First Embodiment

Referring again toFIGS.14-17, the remainder of the outer casing420of each drug package301,302may be cut, e.g. punched to define apertures for the cells311and alignment and profile apertures351,352, which after assembly align with the corresponding apertures of the inner casing410and the block400, as shown.

The block400may be formed similarly to the block380and sub-blocks361as described above, e.g. by moulding from a glass, e.g. a carbohydrate glass, or alternatively from plastics material. The block400defines the cell walls318of the cells311, each cell containing the respective single dose of the first or second drug1,2, preferably in granular, more preferably spheroidal form, as shown. Similarly to the blocks380and361described above, each cell311may define a cylindrical hole which extends along a cell axis Xc and opens at the opposite, broad sides of the block400. The alignment apertures351and profile apertures352similarly extend along their respective axes through the thickness of the block400to open at its opposite, broad sides. If the second or central profile rod152″ is assigned to select for capsule size then the corresponding, central profile aperture352may be circular, as shown, so that the drug package is capsule size agnostic—i.e. it can be used with capsules of any size.

The inner casing410may be printed with indicia317on its outwardly facing surface, which in the regions that will be superposed on the broad sides of the block400is also covered by sheets of foil314to form the frangible walls at both opposite ends of each cell311. The portion of the outwardly facing surface of the inner casing410that will face the adhesive side of the label portion313of the outer casing420is coated with the release coating5. The inwardly facing surface (except for the frangible cell end walls314) may be coated with adhesive4to stick to the block400.

During manufacture, the single dose of the respective drug1or2is introduced into each of the cells311of the block400before the inner casing410is applied to sealingly enclose the drug, e.g. granules or spheroids3within the cells311. The inner and outer casings410,420can be assembled together before applying them to the block400, or the inner casing410can be applied first before applying the outer casing420.

Further Features of the First Machine and its Method of Operation

Cyclonic Separator, Cutters and Profile Rod Assembly

Referring toFIGS.18and19andFIG.26, the first machine100includes a fixed assembly comprising forty-eight pushrods110(one for each cell311of the largest pack size304′″,FIG.12which the machine is designed to accommodate), and six alignment rods151. The pushrods and alignment rods are spaced apart in fixed, parallel relation with the upper ends111of the pushrods lying in a common horizontal plane (when the machine100is in an upright use position as shown), and the upper end surfaces of the alignment rods151all lying in another horizontal plane, above that of the end surfaces111of the pushrods.

The pushrods110and alignment rods151may be fixed in a base plate203, made for example of cast iron or cast aluminium, to provide rigidity. The base plate203may also support fixed guide rods204which guide the moving frame assembly120, and spring guide rods205for the compression springs173.

Instead of rigidly fixing the pushrods110and alignment rods151in the base plate203, e.g. by brazing, welding, an interference fit, or a rigid adhesive bond, the pushrods and optionally also the alignment rods may be resiliently mounted, e.g. by fixing a lower end of the rod in the base plate203or other support by means of an elastomeric insert or bonding material. The variant first machine illustrates one possible arrangement. The pedestal block then slidingly supports the rods110or151in parallel relation, while the resilient mounting allows each rod to move slightly to compensate for lack of parallelism due to manufacturing tolerances. A resilient mounting may also help to decouple the pushrods110from the base plate203so that the pushrods can better conduct vibrational energy to the carriers, drug granules and capsule components during assembly, as further discussed below.

The casing201may be made from stainless steel sheet and/or cast aluminium. The casing201may define shrouds206which enclose the cutters190, which may be formed as miniature circular saw blades mounted to rotate on shafts191so that the blade is enclosed from the front and sides but projects by a few millimetres from the open, rear or inwardly facing side of the shroud206, as best seen inFIG.19A. The shafts191are driven by electric motors192which also drive impellers193to evacuate debris from the cutters190in an airflow which is drawn in through the rear openings of the shrouds206and flows as indicated by the direction of the arrows, through a cyclonic separator194which separates the debris from the airflow. The particles fall into the collection trays202while the airflow is drawn through the impellers193and then flows back through perforated wall207into the receiving space101and back into the shrouds206.

The profile rods152are arranged to rotate about axes Xp that are fixed in parallel with the pushrods110and alignment rods151, and may be arranged to pass through holes in the base plate203so that the mechanism153that rotates them can be arranged conveniently beneath the base plate203, as shown.

Byway of example, the first machine provides three profile rods152, although it could have one or two or more than three. From left to right as shown inFIG.28, the first (left-hand and rear-most) profile rod152′ is reserved for future selection criteria; the second profile rod152″ selects for capsule capacity (e.g. between a size #2, #1, or #E capsule); and the third (right-hand) profile rod152′″ selects for package size (12, 24, 36 or 48 capsules).

Each profile rod has an axially continuous, non-circular cross-section which defines its shape profile, and extends along a profile rod axis Xp in parallel with the pushrods110beyond the end surfaces111of the pushrods and into the package receiving space101to selectively permit or obstruct each package that selects for that shape profile from being received in the receiving space101. Packages that do not select for that particular shape profile have a circular hole352in that position, i.e. they are profile-agnostic.

Referring now toFIGS.36-38, each profile rod152may be mounted on a profile adjustment or index mechanism153, which may form an actuator operable by the controller262and which rotates the profile rod152about its length axis Xp. The mechanism or actuator153may be driven for example by a solenoid162as shown, or could be an electric motor or any other powered actuation device; alternatively the profile adjustment mechanism153could be manually operable by the user.

In the illustrated example there are sixteen angular index positions, defined by the position of two spring biased index plungers156,157on an index wheel158. (One index plunger could combine both functions if preferred.) A sensor154detects by the position of the index plunger156when the index wheel158is in the index position. The opposite index plunger157is locked in position by an abutment161formed on a reciprocating arm160driven by the solenoid162, so that when the arm160is in a rest position (FIG.38, suffix -a) the index wheel158is locked by the index plunger157to prevent the profile rod152from rotating.

A pawl163is mounted on a pivot block166which in turn is slidably mounted on the arm160. When the controller262commands the mechanism153to rotate the profile rod152, the solenoid162retracts the arm160from the rest position (FIG.38, suffix -a) to an unblocked position (FIG.38, suffix -b), taking up lost motion between the arm160and the pivot block166while the abutment161moves to unblock the index plunger157.

Further retraction of the arm160now engages and moves the pivot block166so that the pawl163urges the ratchet plate164in rotation to the new index position (FIG.38, suffix -d). As the index wheel158moves past an intermediate position (FIG.38, suffix -c) the index plungers156,157are urged inwardly by their springs, urging the index wheel158into its new rest position in the next index position (suffix -d). The arm160then extends through an intermediate position (FIG.38, suffix -e) back to its rest position (FIG.38, suffix -a) while the springs of the index plungers156,157prevent movement of the index wheel158, leaving the profile rod152, ratchet plate164and index wheel158in their new index position (FIG.38, suffix -d).

Sensors165identify the unique pattern of indicators155that represents each of the sixteen index positions, shown inFIG.37as a four-bit string.

Moving Frame Assembly

Referring now toFIGS.20-29, the pressure plate121may be pivotably mounted on a moving frame assembly120, which may further include a front plate220which is pivotable from a lowered position (FIG.24) to a raised position (FIG.25). The pressure plate121may be arranged as an upper plate of the assembly which is pivotable from a raised position to a lowered position, shown respectively in broken lines and in solid lines inFIG.24. A mechanism, e.g. an over-centre mechanism, may be provided to retain the pressure plate121in the raised position. When the front plate220is pivoted to the lowered position and the upper, pressure plate121is pivoted to the raised position, the packages may be inserted into and removed from the receiving space101. When the upper, pressure plate121is pivoted to the lowered position, the front plate220may be pivoted to the raised position and locked to the upper plate121. In this position the moving frame assembly may be moved by the hydraulic pistons141or other actuation mechanism so that the pressure plate121urges the stacked packages down over the fixed pushrods110. The moving frame assembly120including the upper plate121and front plate220moves as a single unit, with the pressure surface122of the upper plate121supported at the rear by its pivot axis and at the front of the machine by its connection to the front plate220.

The inwardly facing surface228of the front plate220may be arranged in parallel, opposed relation to the front surface172of the pedestal block170when the front plate220is locked to the pressure plate121. When the front plate is locked to the pressure plate121the composite label assembly312may be compressed between the inwardly facing surface228of the front plate and the front surface172of the pedestal block, as best seen inFIGS.47-48and further described below. To ensure that the applied pressure is always in a desired range, the surface228may be resiliently compressible towards the body of the front plate220. For example, the surface228can be formed as a sheet, e.g. of stainless or chrome plated steel, separated from the body of the front plate220(which may be formed as a thicker metal plate) by a resilient interlayer229of resiliently compressible material, e.g. a layer of sponge foam a few millimetres thick. The surface228may be reflective, e.g. by polishing the sheet, so as to provide a target for the optical sensors of the pedestal block170as further described below.

The moving frame assembly120may further define an inner casing230which has a lower cavity231in which the pedestal block170is slidingly received, and an upper cavity that defines the receiving space101. The lower cavity may have clearance slots236to accommodate the pedestal block latches103as further described below.

The moving frame assembly120may be guided to reciprocate along a vertical axis relative to the fixed body of the machine100. By way of example, in the illustrated embodiment, this is achieved by means of guide sleeves232slidably mounted on the guide rods204and fixed to the inner casing230. The guide sleeves232may be connected to the inner casing230as shown via an outer frame with brackets233at which the moving frame assembly120is connected to the hydraulic pistons141.

A scanning window268may be arranged in the inner casing230so that the scanner261can read the indicia317on the stacked packages as the moving frame assembly120moves relative to the scanner261; the scanner could alternatively be arranged to read the indicia317while the moving frame assembly120remains static.

The upper (pressure) plate121may include a handle124, which may be configured as a knob as shown, to be pushed or grasped by the user when pivoting the pressure plate121up and down.

As a safety feature, the machine100may be arranged such that the pressure plate121cannot be operated to form the end user package unless the door130is closed. This can be accomplished, for example, by arranging the controller262to prevent operation unless a door position sensor132indicates that the door is closed.

Where, as in the illustrated embodiment, a front plate220is arranged to provide a mechanical support for the front end of the pressure plate121, the machine100may be arranged such that the pressure plate121cannot be operated to form the end user package unless the pressure plate121is locked to the front plate220.

This can be accomplished, for example, by means of three complementary functional features (a), (b) and (c) as follows.

In accordance with feature (a), a part of the pressure plate121(e.g. the handle124, as illustrated) may project forwardly through the doorframe to prevent the user from closing the door130when the pressure plate121is pivoted away from its lowered position. In accordance with feature (b), a part of the front plate220may be arranged to project forwardly through the doorframe to prevent the user from closing the door130unless the front plate220is pivoted to a fully raised position. (In the illustrated embodiment, most of the front plate220extends through the doorframe when lowered.) In accordance with feature (c), the pressure plate121may be arranged, when pivoted to a lowered position, to prevent the front plate220from pivoting to a fully raised position unless the front plate220is locked to the pressure plate121. In the illustrated embodiment, this is accomplished by arranging for the front plate220to lock to the pressure plate121simply by pivoting the front plate220to the fully raised position when the pressure plate121is pivoted to the lowered position.

Accordingly, features (a), (b) and (c) in combination define a simple and intuitive method of operation which requires that the user first pivots the pressure plate121to its lowered position, then pivots the front plate220to its raised position to lock it in one movement to the pressure plate121, before the door130can be closed and the machine100operated.

When the pressure plate121is pivoted to a lowered position, the handle124may be received in an inwardly opening cavity133defined by the handle of the door130, within which cavity it can reciprocate up and down with the rest of the moving frame assembly120while the door is closed.

The pressure plate121may have abutments125to rest on corresponding abutments234of the inner casing230, as shown inFIG.21, when the user pivots the pressure plate121to its lowered position and then pushes down on the handle124to move the moving plate assembly vertically downwardly through a very short distance (e.g. one or two millimetres) so as to apply pressure via the pressure surface122to compact the stacked packages against the assembly surface171of the pedestal block170, before removing the release paper332.

The hydraulic valve control assembly144may be arranged to allow this movement; for example, the controller262may control the valve assembly144to permit fluid to flow through a non-return valve or valves of the assembly144as the moving frame assembly120is pressed down by the user.

The pressure plate121may have a slot126to accommodate the central group of alignment rods151and the second profile rod152″ which project into the receiving space101, as shown.

FIG.34illustrates one possible mechanism221by which the front plate220can be locked to the pressure plate121simply by pushing forward on a handle222, and then unlocked again simply by pulling back on the handle222.

As best seen inFIGS.28and29, pressure plate121includes a forwardly projecting tongue121′ with an upper surface in which are formed a shallow recess127that opens at the forward end of the tongue, and shallow recesses128and129proximate its rear end.

Front plate220includes a recess225into which the tongue121′ slidingly extends when the front plate220is pivoted upwards towards the lowered pressure plate121, and a rotatable handle or knob222which operates via a lever226its internal mechanism221as shown inFIG.34.

The mechanism221includes an assembly of steel balls including a locking ball223and a control ball224. The control ball224is outwardly spring biased by a control lever227which in turn acts on the rest of the balls.

Suffix a—indicates a rest position of the locking mechanism221wherein the two plates121,220are locked together around the stacked packages, ready for the machine100to press the stack to form the end user package. In this position the control ball224is received in recess129so that the control lever227is maintained in its rest position by its bias springs. In this position the control lever227maintains the rest of the balls in compression. The handle222is forwardly spring biased to a rest position in which the lever226also maintains the balls in compression. In this state the locking ball223is received in recess128and cannot retract, retaining the tongue121′ in the recess225so that the two plates121,220remain locked together.

Suffix b- indicates an initial, unlocked position of the mechanism221as the handle222of the front plate220is pulled backwardly to begin to move the front plate220away from the top or pressure plate121. In this state, the lever226releases the balls so that the locking ball223can retract as it is urged by the tongue121′ out of the recess128and back into its hole in the bulbous housing formed at the end of the front plate220as the tongue121′ starts to move out of the recess225.

Suffix c- illustrates an unlocked position of the mechanism221as the tongue121′ is nearly withdrawn from the recess225. The same, unlocked position is obtained when the tongue121′ initially enters the recess225as the user pushes forward on the handle222to close the front plate220onto the top, pressure plate121. Pushing forward on the handle222moves the lever226to its blocking position. However, as the tongue121′ enters the recess225, the locking ball223is able to move into recess127while the tongue121′ forces the control ball224to retract, urging the control lever227to a release position in which the rest of the balls are able to move, which allows the locking ball223also to retract as it moves out of the recess127.

Suffix d- illustrates an almost-locked position of the mechanism221as the handle222is pushed further forward to urge the front plate220through the final, short distance of travel into the locked, rest position as illustrated by suffix a- to lock the plates121,220together. The control ball224has entered the recess129, allowing the control lever227to move to its rest position; however, the control lever227is maintained in its retracted position by the pressure of the balls responsive to the locking ball223, which is maintained in its retracted position because it is engaged with the upper surface of the tongue121′, in-between recesses127and128. Further movement allows the bias spring pressure of the control lever227to urge the locking ball223to enter recess128, allowing the control lever227to move to its blocking, rest position to leave the mechanism in the locked, rest position of suffix a-.

The controller262may monitor the position of the moving frame assembly120by means of a moving frame position sensor102which senses the position of the moving frame assembly120and sends position data to the controller262. In the illustrated embodiment, the sensor102senses the vertical position of the inner casing230relative to the fixed casing201and base plate203.

The pressure plate121may include a pressure plate sensor123(FIG.42) for sensing the presence of the pressure pad250. Referring now toFIG.30, a pressure pad250may be provided to help distribute the pressure from the pressure plate121over the whole plan area of the stacked packages. The pressure pad may be a solid block, e.g. of plastics material, with holes to accommodate the alignment rods151and profile rods152when it is placed on top of the stack, as shown inFIG.45. The pressure pad may include an identifier251arranged to be sensed by the pressure plate sensor123which sends a signal to the controller262indicating that the identifier251has been sensed, which confirms that the correct pressure pad has been fitted in the correct position. The holes or other features of the pressure pad may be asymmetric so that the pressure pad can only be fitted in one position.

In the illustrated embodiment, the holes formed in the pressure pad250to accommodate the profile rods152are all round, so that the pressure pad does not select for any particular profile rod index position. As further discussed below under “Alternative embodiments”, in alternative, manual embodiments, multiple pressure pads with different thicknesses and profile rod apertures that select for different profile rod index positions could be provided as a simple, mechanical way to correlate stack height with capsule capacity without an electronic control system.

Vibration Source and Graduated Pressure

The assembly apparatus of the first or variant first embodiment may include at least one vibration source, which is configured to transfer vibrational energy to the capsule parts or the single doses during assembly.

For example, the pressure plate and/or pedestal block of the first machine could be adapted to include the vibration source, or multiple vibration sources to make the granules or spheroids3more mobile and so assist them to enter the capsule body. The vibrational energy may also introduce mechanical dither between the capsule components, assisting the cap to locate in the correct position on the capsule body.

One or more vibration sources could be arranged to induce vibrations in the pressure plate and/or the pushrods and/or the pedestal block or other machine components; the variant first machine, further discussed below, illustrates one possible arrangement in which a vibration source is located at the lower end of each pushrod which transfers vibrational energy through the stacked packages to the carrier. The frequency and/or amplitude (power) of the vibration may be constant or may vary between different stages of the operation.

The actuation mechanism may be operable to control the speed and pressure at which the pushrods110move through the stacked packages, and to reduce the speed and/or pressure at the moment that the capsule caps begin to move into the carriers320to engage the capsule bodies. One way to achieve this would be to provide a resilient buffer or lost motion mechanism in the power transmission, such as a gas spring, e.g. an accumulator in which an enclosed volume of air or other gas is separated from hydraulic fluid by a diaphragm or piston, which communicates via a valve with the hydraulic circuit to the actuator pistons141that drive the moving frame assembly120or other moving parts of the machine. The carriers320are advanced through the packages in a first, fast phase of movement, and then, with the accumulator in a de-energised condition, the valve is opened so that the hydraulic pressure is substantially decoupled from the moving parts and, instead, gradually energises the gas spring. The pressure applied at the point of contact between the capsule cap and body components now increases only very gradually in a slow phase of movement until the capsules are closed. The gradually increasing pressure provides enough time for the capsule components to become properly aligned—particularly where a vibration source is also used to provide dither—before the pressure increases to close them fully together and urge the carriers320into their final position. The gas spring or lost motion arrangement may be decoupled from the actuation mechanism (e.g. by closing the valve to the accumulator) in this final, third phase of movement. The accumulator is then de-pressurised before the next operation.

Pedestal Block

Referring toFIG.31, the pedestal block170may be moulded from plastics material. The front surface172of the block (including the front surface of the sensor assembly174) may have a low surface energy to prevent adhesion of the tacky adhesive coating of the flap370of the capsule body package305which is pressed against it in use. This can be achieved for example by making the pedestal block170from a low surface energy plastic, for example, a thermoplastic polyolefin, polytetrafluoroethylene, polyvinyl fluoride or polyvinylidene fluoride, or by providing the front surface172with a low surface energy treatment, for example, a texture or a low surface energy coating. A nanoglass coating could be used.

The pedestal block170defines through-holes to accommodate the pushrods110, alignment rods151and profile rods152, and may include further holes, opening downwardly but closed at their upper ends, to accommodate the compression springs173that apply an upwardly directed bias force to the pedestal block170.

Referring toFIGS.33and35, each profile rod152may extend within the block170through a respective profile rod sleeve176, which is rotatably received in a respective one of the circular through-holes of the block170but retained in its axial direction in a fixed position relative to the block170.

At its upper end the profile rod sleeve is configured to occupy the space between the profile rod152and the wall of the through-hole in which it is housed, so that the upper end surface of the profile rod sleeve176remains flush with the assembly surface171.

The profile rod sleeve176may be retained in the axial direction between an abutment formed by a step in the diameter of the through-hole to abut against an upper shoulder177of the sleeve176, and a lower retainer178which is screwed or otherwise engaged into the block170.

The pedestal block170may be urged downwardly against the upward, restoring force of the compression springs173by the actuation assembly, e.g. hydraulic pistons141, which act on the block170via the pressure plate121and stacked packages during the assembly procedure, or, when the packages are not present, via abutments235formed on the inner casing230of the moving frame assembly120to engage an abutment surface, which may be formed by the lower end of a slot179, of the pedestal block170.

The pedestal block is slidably received in the lower cavity231of the inner casing230with the rod assembly extending upwardly through it, and is vertically movable in this position through a range of movement between a maximally depressed position (not shown), which is obtained when the pressure plate is fully lowered with the highest possible stack of packages, through an initial, rest position (FIG.41) in which its upper, assembly surface171is flush with the upper end surfaces111of the pushrods110, to a maximally raised position (FIG.51) in which its upper, assembly surface171is flush with the upper end surfaces of the alignment rods151and profile rods152.

The compression springs173may provide a substantial spring force to urge the pedestal block towards the maximally raised position, which also provides a firm assembly surface against which the user can compact the stacked packages by gently pushing down on the pressure plate handle124when the pedestal block is in its initial, rest position (FIGS.41and42).

Each abutment235of the moving frame assembly120may be arranged also to engage the upper end of the respective slot179as the moving frame assembly120is raised to its uppermost position, for removal of the end user package300at the end of the assembly operation, so as to assist in raising and retaining the pedestal block170in its maximally raised position while the packages are removed from the machine.

In alternative arrangements, instead of using return springs173, the pedestal block170could be moved upwards by the actuation mechanism, perhaps using separate actuators, or movable abutments to selectively engage and disengage the pedestal block with the moving frame assembly.

In the initial, rest position (FIGS.41and42) the alignment rods151and profile rods152project upwardly through the assembly surface so that the packages can be stacked onto those rods, before the door130is closed by the user and the pedestal block170is urged downwardly together with the stack of packages by the descending pressure plate121(FIG.48).

Referring also toFIGS.18,19and28, the maximally raised position of the pedestal block170(FIGS.50and51) may be defined by abutment of a fixed abutment surface or surfaces104of the machine body (which may be fixed to the base plate203) against an abutment surface or surfaces of the pedestal block170, which may be defined by the lower end of another slot180in the pedestal block170into which the abutment surfaces104project.

The initial, rest position (FIGS.41and42) may be defined by abutment of the pedestal block latches103against an abutment surface of the block170, which may be the same lower end of the slot180as shown.

After the pressure plate121has reached its downward limit, defined by the thickness of the capsule cap package304above the upper end surfaces111of the pushrods110, the pistons141are actuated in the reverse direction (FIG.49) to raise the moving frame assembly120to its maximally raised position. The controller262is arranged to retract the latches103, which normally project into the slot180, to allow the pedestal block170to move upwards past its initial, rest position to its maximally raised position at the end of the assembly operation. In the maximally raised position of the pedestal block (FIGS.50and51) all of the rods110,151,152are withdrawn from the stacked packages, and the upper ends of the rods151and152may be flush with the assembly surface171, so that the end user package300along with the other, empty packages below it can all be removed from the machine100simply by sliding them forward off the assembly surface171.

When assembled in the body of the machine100, the front surface172of the pedestal block170extends on either side for a short distance behind the shrouds206. The portions of the cutters190that extend a few millimetres from the rear openings of the shrouds206are received in slots181formed in the front surface172of the pedestal block170, very close to the ends of the shrouds206.

Referring now toFIGS.31,32and33, the pedestal block170may include a sensor assembly174by means of which the controller262can sense and confirm the presence and correct configuration of the stacked packages before commencing the assembly operation.

Byway of example, the illustrated embodiment provides three optical sensors175, each of which detects light emitted by a light source, which may be the same light source for all three sensors, e.g. an LED182. Light from the LED may be transmitted via first beam splitters183and mirror184to second beam splitters185, which direct the three beams of light through windows186in a direction normal to the front surface172of the pedestal block170. If the beam is reflected from the reflective surface228of the front plate220, then it is received via the respective, second beam splitter185by the sensor175which sends a signal to the controller262.

The controller may turn on the LED182when the door position sensor132indicates that the door130is closed—which in turn means that the pressure plate121and front plate220must be locked together. The controller262then determines by the combination of signals from the three sensors175whether or not the packages are correctly stacked in the machine100. The first beam splitter183closest to the LED182may be configured to transmit two thirds of the light and reflect one third; the remaining beam splitters may transmit half and reflect half.

As shown inFIG.43, when the packages are correctly positioned in the machine100, as seen from the front of the machine, the left-hand one of the windows186and sensors175is covered by the flap370of the capsule body package305while the two windows and sensors186,175to the right are aligned with the sensor apertures379in the flap370of the capsule body package305.

When the cap package304is correctly positioned as shown inFIG.45, the window and sensor186,175furthest to the right are now covered by the flap330of the cap package while the window and sensor186,175in the middle of the array are still exposed through the window331in the flap330but are covered by the release paper332.

After the user removes the release paper332, the middle window and sensor186,175are visible through the window331while the left-hand and right-hand windows and sensors186,175are concealed.

The controller262may interpret a signal indicating “0-1- 0”, which is to say, the central sensor175detects a reflected beam while the other two do not, to indicate a correct package configuration. Other signals may be interpreted to generate an appropriate error message. If for example the signal is “0-0-0” then the controller may infer that the release paper332has not been removed, in which case an error message may be displayed on the screen267for the user to open the door and remove the release paper. If the same fault code occurs again then the controller262may prompt the user to check that the surface228is not obscured and then remove the packages and close the door, so that the controller262can illuminate the LED182to check that it is functional. Alternatively, an LED function check can be carried out automatically every time the machine is used, immediately before opening the door130to receive the packages.

Sequence of Operation

The operation of the machine will now be described with reference toFIGS.41-51.

FIG.41shows the machine100with the door open and the pedestal block latches103engaged to retain the pedestal block170in its initial, rest position. The profile rods152are set to an index position that selects for a particular package size (number of cells per package) and capsule size (e.g. a #0E, #1, or #2 capsule). The position of the moving frame assembly120determines the height of the pressure plate121above the assembly surface171and so, the maximum height of the stack of packages that can be received in the machine before closing the pressure plate121and locking it to the front plate220.

Referring momentarily toFIG.24, it may be noted that the position of the pivot axis of the pressure plate121may be arranged, not only to provide easy access to the receiving space101and to ensure that the handle124extends through the doorframe when not pivoted to the lowered position, but also to provide a substantial, horizontal vector component of the direction of movement of the pressure surface122as the pressure plate is pivoted through the final few degrees into its lowered position. If the user tries to pivot the pressure plate121onto a stack that is too high, it causes a very obvious problem as the pressure plate121will not move back into position; instead, it sticks in a forward position on the stack, without generating a large mechanical advantage that could crush the stacked packages. This prompts the user to check whether the selected capsule size is large enough for the total number of units in the stack (indicated by the indicia on the forwardly facing sides of the drug packages).

If the capsule size is not large enough, then the user must remove the stacked packages, re-lock the plates121,220together and close the door130before the controller262will allow the machine to be reconfigured to accept a larger package size. Similarly, if the user changes his mind and wishes to use a smaller capsule size, he may select a smaller capsule size after closing the door130. The controller262rotates the respective profile rod152to select for a smaller capsule size before releasing the door.

FIG.42shows a new position of the moving frame assembly120. Note that the pedestal block170remains in the same, initial position, but the pressure plate121and inner casing230are lower relative to the fixed machine body and shrouds206. (Although not shown in the drawing, it should be understood that the respective profile rod152would also be rotated to the corresponding index position to select for the smaller capsule size before the controller262unlocks the door130.)

The user selects the correct package size and capsule size to fit the new position of the profile rods152, and starts by placing the capsule body package305onto the assembly surface, with its flap370unfolded against the front surface172of the pedestal block (FIG.42). The rear surface of the flap370is adhesive but does not stick to the pedestal block170because of the anti-adhesion properties of its front surface172.

Of course, if the package has a profile rod aperture that is indexed to select for a different profile rod index position from that set by the controller262, then the package will not fit. This prevents the user from inadvertently selecting the wrong number of cells or the wrong size of capsule, or from using a package that is disallowed, e.g. for commercial or regulatory reasons related to the market area in which the machine is being operated.

If (as shown) the apertures formed in this and the other packages to receive the profile rods152and alignment rods151are covered by a foil314, then the foil314is ruptured when the package is placed over the rods. In alternative arrangements, the foil314need not cover these apertures in any of the packages.

The user then stacks the required drug packages301,302in any order onto the capsule body package305(FIG.43). More than two drug packages can be used if desired. Similarly, if for any reason the user wants to make an end user package with only a single drug, then only a single drug package could be used. If the user requires a dose of any given drug that is not available in a single package, then two packages containing the same drug could be used.

Next, the user unfolds the flap330of the capsule cap package304, and stacks the cap package304on top of the drug packages with the flap330hanging down in front of the rest of the packages in the stack (FIG.44).

The legend: “PUSH DOWN PRESSURE PLATE BEFORE REMOVING PAPER” printed on the release paper332reminds the user to do exactly that. The user places the pressure pad250on top of the stacked packages (FIG.45). The controller262verifies the presence of the pressure pad250by means of the pressure plate sensor123which senses the presence of the identifier251; this can be done at this time and/or after the door is closed. The user then pivots the pressure plate121to the lowered position (FIG.46). If the pressure plate fits then the user knows that the stack height is OK. The user then presses gently down on the handle124of the pressure plate121to urge the pressure plate down, ensuring that the packages are snugly stacked against the assembly surface171. The controller262may command the valve assembly144to permit flow through a non-return valve so that pressure applied by the user is maintained by the pistons141. Permitting flow through the non-return valve may be subject to verifying the presence of identifier251.

Then, the user lifts the flap330, peels away the release paper332to expose its adhesive, rear surface (FIG.46), and then replaces the flap330against the forwardly facing surface of the stacked packages below it (FIG.47). The flap330sticks to the forwardly facing surfaces of the label portions313of the drug packages301,301and the flap370of the capsule body package305. The indicia printed on the label portions313and the legend: “NO OTHER ACTIVE INGREDIENTS” printed on the flap370are visible in the window331of the flap330, which also exposes the sensor aperture379for the middle window186of the pedestal block sensor assembly174. Thus, the flap330forms a frame around the indicia that will become the composite label assembly312of the end user package300.

Next, the user must pivot the front plate220to the raised position (FIGS.47-48) and lock it to the pressure plate121. When the front plate220is locked in its raised position (FIG.48) the composite label assembly312is compressed between the surface228of the front plate220and the front face172of the pedestal block170, which ensures a good adhesive bond between the flap330and the other components313,370of the composite label assembly312.

The user then closes the door130and the controller262(responsive to the door closing, or to a further user instruction via the user interface, e.g. touchscreen267) operates the pistons141to cause the moving frame assembly120to descend until the pressure surface122is separated from the upper surfaces111of the pushrods110by a distance equal to the thickness of the capsule cap package304. The front plate220acts in tension to maintain the pressure surface122in alignment with the horizontal surface of the stacked packages. The pedestal block170is urged downwards together with the moving frame assembly against the restoring force of the springs173by the pressure surface122acting on the frames310of the stacked packages which bear against the assembly surface171.

As the moving frame assembly120descends past the scanner261(which is fixed to the body of the machine and base plate203), the controller262commands the scanner261to read the package indicia317from the exposed ends of the packages through the scanning window268, and, using this data, contacts the remote computer and database91,90to authenticate the packages and download the data for the patient information leaflet266. The controller262may command the printer265to print the patient information leaflet266while the machine100is operating. If patient identity information is required then that may be downloaded from a local database at the pharmacy or health authority and combined with the data transmitted to the remote database90, and/or printed on the leaflet266and/or an adhesive label (not shown) to be applied to the end user package300, e.g. stating the patient's name and the dosage regimen.

Although not shown, the machine100could further include a printer for printing patient information and/or contents information (drug name and dose) directly onto a surface of the end user package300, either instead of or in addition to the composite label assembly312.

If there is an authentication issue, or if the identified combination of drugs is contra-indicated, then the controller262may terminate the operation and/or issue a warning via the screen267and/or on the patient information leaflet266, while the remote computer91updates the database90with the received information. As mentioned above, the packages may also be scanned via an additional, external scanner1280(FIG.102) before introducing them into the machine, in which case any necessary warning may be issued without unlocking the door to receive the packages in the machine.

A unique identifier of the machine100may be stored in local memory263or in separate hardware, e.g. of the controller262so that it is difficult to remove, and transmitted along with the rest of the data by the controller262. From this information and the corresponding record for the machine100in the database90the remote computer91can recognise where and by whom the machine100is being operated, and can update the database90to link this information to the package data while logging any authentication issue for investigation. Since the package indicia are read (for the first time, or again for a second time) during the assembly process which is a one-time event, there is a high degree of confidence in the received data. Alternatively or additionally, the scanner261could be configured to read the package indicia before commencing the assembly operation so as to identify counterfeits or contra-indicated drug combinations before the door130is closed.

Then, the movement is reversed (FIG.49) to raise the moving frame assembly120to its maximally raised position. The latches103are also retracted so that the pedestal block170moves upwards together with the moving frame assembly to the maximally raised position of the pedestal block170.

In this position the door130is released and opened (FIG.50) so that the capsule cap package304which now forms the end user package300can be removed together with the now empty frames310of the drug packages301and302and the capsule body package305, and the pressure pad250, leaving the machine empty at the end of the assembly operation (FIG.51).

Referring again toFIG.50, after opening the door130it can be seen that the cutters190have cut a slit190′ (best seen inFIG.57) through the casings of the stacked packages, which in combination with the slits377and421separates the label portions313and the flap370from their respective packages, leaving them adhesively attached to the flap330to become part of the composite label assembly312. The adhesive, rear surfaces of the label portions313separate from the release coating5on the facing surface of their respective packages301,302while the adhesive, rear surface of the flap370separates from the anti-adhesion front face172of the pedestal block170, so that the entire composite label assembly312presents a tacky, adhesive rear surface.

After the user removes the end user package300together with the remaining, empty packages from the machine100(FIG.51), he locks the pressure plate121and front plate220together and closes the door130. An appropriate instruction could be displayed on the screen267. The controller262senses that the door has been closed and operates the pistons141to urge the moving frame assembly120to move downwards until the abutments235contact the lower end surfaces of slots179, and then continues the movement so that the pedestal block170is urged downwards by the abutments235, together with the moving frame assembly120, from the maximally raised position of the pedestal block170(FIGS.50and51) to its initial, rest position (FIG.41) in which it is retained by the latches103which re-engage in the slots180. The machine100is now ready to receive another stack of packages.

Referring now toFIGS.52-54, the stacked packages are shown in section during the assembly operation just described.

FIG.52shows the pushrods110resting against the carriers320of the capsule body package305, immediately before the pressure plate121starts to move.

As the pressure plate descends, the frames310of the packages depress the pedestal block170, revealing the pushrods110which rupture the foil end walls314of the cells311containing the carriers320and urge the carriers through the aligned cells311of the packages. As they move through the packages, the salient portions323at the open ends of the carriers320rupture the foil end walls314of the cells311containing the first and second drugs1,2, which are collected inside the capsule body22, and then pass into the cells311of the capsule cap package304which contain the caps21of the capsules. (FIG.53.)

Further movement urges the carriers320containing the capsule bodies22, now filled with the granules or spheroids3comprising the drugs1,2, up into the cells311containing the caps21which are held axially centrally by the annular fins325. The fins325are crushed by the carrier320as each cap21passes into the enlarged inner diameter region of the upper part of the carrier320, between the wall of the carrier and the outer surface of the open end of the capsule body21. The force applied to the cap21is reacted against the strip315that closes the cell311, which in turn is supported by the pressure pad250, so that the capsule cap and body are closed together to form the filled capsule or polypill20, as best seen inFIG.54A. The filled capsule20is contained inside the carrier320, so that the closed end321of the carrier closes the lower end of the cell311; the open end322of the carrier faces the strip315.

As shown, the packages may be stacked and the machine configured so that the capsule bodies approach vertically upwardly to the capsule caps; other orientations are possible.

Referring now toFIG.57, after removing the stack from the machine the user discards the empty frames of the packages301,302,305. The cells311of the cap package304containing the polypills20are closed by the carriers320whose closed ends321form part of the rear surface of the package. The rear surface of the composite label assembly312is entirely covered by the tacky adhesive coating4, comprising the rear surfaces of label portions313and flap370which are connected together in juxtaposed relation by the flap330so that the indicia on their front surfaces are visible through the window331to form the front surface of the flap. The user now folds the flap330against the rear surface of the package304so that it adheres to the rear surface, covering the closed ends321of the carriers.

Referring toFIG.58, after sticking the flap in its final position, the legend: “TEAR HERE AND DISCARD THIS PART AFTER REMOVING FROM MACHINE” reminds the user to tear off the waste portion334of the flap330together with the surplus portion372of the flap370, leaving the composite label assembly312that now forms the rear surface of the end user package330. It will be noted that this is only necessary in the smallest package size; larger sizes do not have any waste portion.

Starting from the narrow side of the package and then turning it to continue on the adjacent, broad side, the composite label assembly reads: “12 CAPSULES SIZE #2 EACH CAPSULE CONTAINS:—OLANZAPINE 20 mg+CITALOPRAM 20 mg+NO OTHER ACTIVE INGREDIENTS”. Since the composite label assembly comprises the label portions313of each of the packages of the stack, the user has a high degree of confidence that the package is correctly labelled.

The user (e.g. the pharmacist operating the machine) can then retrieve the accompanying information leaflet266and any adhesive label (not shown) from the printer265. The leaflet266may include data on any specific interaction between the combination of drugs selected. If an adhesive label has been printed then it is applied to the end user package300, conveniently to one narrow side opposite the printed indicia.

The end user package300and the accompanying patient information leaflet266are then handed to the end user, who can lift the tabs316to tear back the strips315to open each cell311, and then remove the capsule20by turning the package over and tapping it against the palm of the hand. The carrier320remains in the cell311and will be discarded along with the frame310once all the capsules20are finished.

Patterned Foil

Referring toFIGS.55and56, the foil end wall314of each cell311may have a weakened region319(FIG.55) that causes it to tear in a predefined pattern as the carrier320presses against it. The weakened region319may be a pattern of relatively thinner parts that cause the foil to break in a star shaped pattern as shown inFIG.56, so that the fragments adhere to the frame310and are captured between the carrier320and the cell wall318as the carrier320passes through the cell. The weakened region319could be formed for example by pressing the foil with a patterned tool.

Alternatively, referring toFIG.113, the foil1314may be patterned to define regions1430, each region1430of the foil closing a respective one of the cells311and including a first layer1431and a second layer1432. Within each region1430, the first layer1431is undivided, i.e. continuous, while the second layer1432is divided into sub-regions1433which extend radially inwardly away from the cell wall318and towards the central axis Xc of the cell.

InFIGS.113and124, the second layer1432is indicated by the small horizontal dash fill, while the first layer1431is visible through the lacunae1435.

The second layer1432is selected to have sufficient toughness and tensile strength to resist rupture when force is applied to the foil1314, e.g. by the carrier320,1320, so that break lines are defined between the sub-regions1433. The foil1314ruptures at the break lines in-between the sub-regions1433, which remain as fragments attached to the block or frame. The carrier320,1320folds the fragments back against the cell wall318, as shown inFIG.142, and slides past them as it passes axially through the cell311.

The first layer1431may be a metal, and the second layer1432may be a polymer.

The polymer could be dissolved in a solvent and applied to the first layer as a solution. Alternatively, the second layer could be produced as a cut or stamped sheet, e.g. of a solid polymer or nonwoven fabric, and laminated to the first layer.

The polymer could be, for example: ethylene-vinyl acetate, polyvinylpyrrolidone, cellulose acetate, collodion, polyester, polyethylene, or a thermoseal lacquer. It could be filled with fibres or particles.

The first layer1431may be a thin aluminium foil of a similar thickness to that used for wrapping chocolate confectionary, e.g. around 6-20 microns, e.g. about 8-16 microns, so that it breaks easily.

The metal first layer1431may be entirely coated on one or both sides with a thin coating material, e.g. a lacquer or thermoseal lacquer, to prevent oxidation and ensure a good bond to the frame, and to seal pinholes to improve its barrier properties.

The second layer may be thicker than the thin coating material, and may be the same material as the thin coating material, or a different material. The second layer may face away from the cell or towards the cell, and may include a bond region1434which surrounds the cell311. The second layer may be bonded directly to the first layer, or to the thin coating material which may be interposed between the first and second layers.

The thin coating material or second layer may be bonded sealingly to the block or frame (or to a compatible coating thereon) in the bond region surrounding the open end of the cell311, e.g. by welding or adhesive, to hermetically seal the cell. The bond may be formed by applying heat, pressure, and/or high frequency electromagnetic or ultrasonic energy, e.g. via a sonotrode or other tool.

The thin coating material may be a polymer such as a vinyl or polyester lacquer or thermoseal lacquer as known in the art. The first and second layers and/or any coating of the block may be selected to be removable from the re-usable block or frame by thermolysis or hydrolysis or chemical, e.g. acid washing.

The second layer may be applied to the first layer, e.g. by printing, before the foil is sealingly bonded to the block or frame.

The patterned foil may be applied by a tool that locates the regions1430of the pattern, either relative to the tool or axially centrally over the cells311of the block. This could be accomplished by a controller using a camera and pattern recognition software to detect the pattern or registration marks on the foil. A dye visible to the camera could be incorporated into the coating material for this purpose. The tool could have a plate that is the same shape as the block, with cutting edges to stamp out the patterned foil from a printed roll, and holes corresponding to the cells which apply a partial vacuum to grip the stamped portion of foil. The plate may then position and press the foil on the block and apply the welding energy in the bonding regions, or over the whole surface of the block surrounding the cells311.

Alternatively the second layer could be applied after the foil is bonded to the block, e.g. by spraying through a mask.

As illustrated by the variant first embodiment, the patterned foil1314may be applied, for example, to both sides of the drug packages (as shown inFIG.113), to the top side of the capsule body package through which the carriers will leave the cells, and/or to the bottom side of the cap package (as shown inFIG.124) through which the carriers will enter the cells.

The patterned foil may be applied to one side of the drug package before filling the cells, optionally in a protective atmosphere (e.g. dry air or nitrogen), and then applying the foil to the other side.

As shown inFIG.113andFIG.124, the second layer1432may be divided into sub-regions1433by lacunae1435in the form of elongate gaps, as shown, or alternatively in the form of lines of smaller perforations (not shown). In the illustrated example, the elongate lacunae1435are united at the cell axis Xc and extend continuously and radially outwardly from the cell axis Xc to the cell wall318to define the break lines between the sub-regions1433.

The pattern is selected so that the first layer1431will rupture at the break lines when the desired amount of pressure is applied, e.g. by the carriers1320. For example, the foil1314may be made stronger by increasing the separation distance between adjacent perforations, or by dividing longer lacunae1435into shorter portions separated by narrow bridges (not shown) which connect the sub-regions1433together.

Spacer Block

As the carrier320enters the cap package, fragments of foil adhering to the uppermost drug package may be drawn, together with fragments of foil from the lower surface of the cap package, into the interstice between the carrier and the cell wall of the cap package.

In order to make it easier for the trapped fragments, still connected to the uppermost drug package, to slide out of the interstice when the user separates the finished end user package from the uppermost drug package, the radially outer surface of the carrier320in its lower end region may be smooth, so that any barbed or textured surface region (if present, and as illustrated in the variant first embodiment) is confined to the upper end region. The lower end region of the carrier may also have a slightly smaller diameter than its upper end region. Alternatively or additionally, each cell of the cap package may continuously taper, or reduce in diameter step-wise, from the lower end region to the upper end region of the cell, so that the upper end region of the carrier fits more tightly into the cell than its lower end region. This helps to retain the carrier in the cell while allowing the fragments of foil to slip out of the interstice when the packages are separated.

Alternatively or additionally, a spacer block (not shown), comprising a block with an array of empty cells, similar to the blocks of the drug packages of the variant first embodiment but without foil, may be inserted between the cap package and the uppermost drug package. The spacer block is of a thickness sufficient to accommodate in its empty cells the fragments of foil, so that when the finished end user package is withdrawn from the machine there are no fragments of foil connecting the end user package with the rest of the stack. The spacer block may be disposable or re-usable, like the blocks of the drug packages and the capsule body package, and one spacer block may be supplied together with each cap package to avoid cross-contamination. Of course, the same spacer block could be used for multiple operations if desired.

Granules may be formed as spheroids3in various ways as known in the art, for example, by spheronization or by pressing to form micro-tablets or pellets, e.g. rounded tablets with belly bands.

The granules, spheroids or other particles containing a drug may include excipients as known in the art, including for example microcrystalline cellulose as a spheronization enhancer. The particles or spheroids may be coated as known in the art to control (e.g. delay or prolong) the release of the drug into the body. Different drug packages could contain similar or different drugs with different coatings, so that the system can be used to prepare combinations that separately control the release of the similar or different drugs following their simultaneous consumption in the same capsule.

The capsule components could also have an enteric or other coating which is indicated on the package indicia.

Spheronization may be performed by forming an appropriate composition including the respective drug and extruding the composition to form rods which are cut to length and then introduced into a spheronizer (typically a machine having a rotating bowl with a textured surface) as well known in the art.

The diameter of the spheroids may be controlled by selecting an appropriate diameter for the extruded rods and by cutting the extruded rods to an appropriate length. The ratio of length to diameter may determine whether each cut length forms a single spheroid or breaks into multiple spheroids. For example, if the length is approximately the same as the diameter then the rod may form a single spheroid, whereas if the length is twice that required to form a rod of given diameter into a single spheroid, then the rod may form into a characteristic waisted, “dumb-bell” shape as known in the art before separating into two portions which form two respective spheroids of equal diameter.

For drugs that are provided in liquid form, the liquid may be encapsulated in a spheroidal shell. One way to do this is to form the liquid into a solid or partially solidified composition at low temperature, and then spheronize the composition at low temperature, and then coat the resulting spheroids with a coating, still at low temperature. Once the coating has solidified, the temperature may be returned to ambient so that the coating forms a shell to contain the liquefied contents. The coating material can be selected for example from suitable film forming materials as well known in the art, some of which are discussed further herein. It could be applied hot to the spheroids, which could be further sub-cooled after spheronization to a temperature selected so that the coating solidifies on the frozen composition before the composition liquefies. Alternatively the coating could be applied as a powder, e.g. in a fluidized bed, before very briefly heating the outer surface of the coated spheroids (e.g. radiatively, or with a hot gas, or by conduction) to melt and fuse the powder into a solid coating which solidifies before the frozen composition liquefies. Heating by conduction could be accomplished by maintaining the coated spheroids in motion on a hot surface, e.g. the surface of the bowl of the spheronizer, or a rapidly vibrating plate.

Variant First Embodiment

Referring toFIGS.102-145, the variant first embodiment corresponds generally to the first embodiment already described, but illustrates various optional and alternative features which may also be applied to the first embodiment, including: a profiled recess1150for aligning the stacked packages; a printed composite label1312; a resilient pushrod mounting and transducer assembly; re-usable blocks1360,1360′,1400,1400′; an alternative drug package with a re-usable block and movable closure elements, and a filling apparatus for use therewith; a cap package featuring flocked cells1311; and patterned foil1314.

Parts of the variant first machine1000are illustrated inFIGS.102-108; the remaining parts are generally the same as those of the first machine100, including its internal and external system elements as illustrated inFIG.1, except as described below.

Instead of the profile rods and alignment rods of the first machine, the variant first machine1000illustrates how the shape profile or alignment structure150of the first machine may instead be provided as a profiled recess1150, which as shown may extend to form the lower cavity1231of the moving frame assembly1120in which a pedestal block1170is slidingly received to slide over the pushrods1110. The moving frame assembly1120includes a pivotable pressure plate1121and front plate1220. The above mentioned parts of the variant first machine are similar in structure and function to the corresponding parts of the first machine, except as further explained below. However, since the variant first machine1000does not produce a mechanical composite label assembly, it does not include the cutters, cyclonic separators, and resiliently compressible surface228of the first machine100.

Since there are no rods projecting above the upper ends of the pushrods1110, the pressure plate1121need not be apertured, and so can bear directly on the whole surface area of the stacked packages; thus, the pressure pad250need not be used.

The variant first embodiment illustrates how each single use package may incorporate a re-usable block, which may be a monolithic, foraminous block, and which may be closed by foil or alternatively by movable closure elements such a sliding, foraminous plates, which may also be re-usable.

Referring toFIG.109andFIGS.113-117, each of the first and second drug packages1301,1302and the capsule body package1305may be formed from a block1400which defines the frame of the package. After the empty package is removed from the machine1000, the block can be returned to the factory where it was filled, where it is cleaned to remove the foil1314and the package label1317and any traces of the drugs1,2, and then re-used to form a fresh package with new foils and label. The cleaning process could include mechanical brushing and washing, e.g. in a solvent which is selected to dissolve the adhesive or other coating materials and possibly also the metal or polymer components of the foil1314.

The re-usable, foraminous block1400may be monolithic with a simple shape selected to minimise its surface area, so that it is easy to clean. It may be made from a smooth, impermeable, durable plastics material or alternatively from a ceramic or glass (i.e. silica glass as opposed to carbohydrate glass). For example, it could be made as a monolithic block of thermoplastic or engineering thermoplastic so that it can be recycled as a raw material at the end of its life—for example, acrylonitrile butadiene styrene, polyoxymethylene, or rigid polyvinyl chloride. It could be moulded or cut from an extrusion. The cells311could be moulded or machined. The outer surfaces of the block1400may be etched or otherwise textured to improve adhesion. Before filling the cells and applying the foil, the block could be coated (partially or entirely) with a material that can facilitate bonding and can be removed in the cleaning process. Example coating materials may include those mentioned under Patterned Foil. above, for the second layer1432or the thin coating material of the metal first layer1431.

The profiled recess1150of the machine forms an alignment structure which maintains the packages with their respective cells in axial alignment when stacked in the machine. The alignment structure may comprise any surfaces of the profiled recess, optionally but not necessarily including profile features such as asymmetric profile protuberances1159, which may be provided to prevent incorrect orientation of the package. Alternatively, this could be detected by the machine when scanning the package indicia.

Corresponding profile features, such as profile recesses1353, may be formed at the periphery, e.g. the right and left sides of the block1400, to engage profile features, e.g. profile protuberances1159, of the profiled recess1150of the machine1000. The profile features1353,1159may be asymmetric and arranged (e.g. as shown) so that the stacked packages will only fit in the profiled recess1150in the correct position (FIG.106,FIG.108).

FIG.110shows a similar block1400′ with twenty-four cells, for use in the same machine1000. The asymmetric profile features1353,1159ensure that this smaller block also will fit into the profiled recess1150only in a single, correct position.

The block1400of the drug package1301,1302may be sealed on one side with a sheet of patterned foil1314as described above under the heading Patterned foil, and then filled with the drug1or2, e.g. granules or spheroids3, before closing the other side with a second sheet of patterned foil1314as shown inFIG.113. The block1400of the capsule body package1305may be sealed on its upper (exit) side with a patterned foil1314, but on its lower side with a sheet of plain foil314which adheres to the block1400and also to the closed ends of the carriers1320containing the capsule body component22. A disc of the plain foil314remains attached to each carrier1320to form part of the end user package1300as shown inFIG.136.

An adhesive package label1317may be applied to the front side of the block1400to carry the package indicia317, which may include both human readable and machine readable indicia, as shown inFIGS.115and117. Alternatively, the package indicia317could be printed directly on the block or on a coating material of the block.

Thus, each drug package1301,1302may consist substantially of the block, the foil, the package indicia or package label, and the drugs, while the capsule body package1305may consist substantially of the block, the foil, the package indicia or package label, the capsule body and the carrier.

The drug packages1301,1302and capsule body package1305may be supplied in stacks with sheets of card in-between them to protect the foil1314from damage. The foil1314of the cap package1304may be protected in storage by folding the flap1330over the block1360as shown inFIG.125.

FIG.114A shows an alternative arrangement wherein a block1400containing drug particles3is sealed on each face with a foil, e.g. a patterned foil1314, in the same way as the drug package1301. Two additional, empty blocks1400″, which may be identical in form to the block1400or may be smaller in the thickness dimension as shown, are connected to the block1400so that the cells311are aligned. Each foil1314is sandwiched between the block1400and the respective empty block1400″, whose cells311are open at their outer ends. The blocks1400,1400″ may be bonded together, e.g. by adhesive, or connected by mechanical interlocking features. Two blocks1400,1400″ may be assembled together with one of the panels of foil1314before filling the drug particles3into the cells311of the block1400. Then the filled cells311may be sealed by applying the second panel of foil1314which may already be connected to the second empty block1400″.

Together, the blocks1400,1400″ form a composite package1303in which each portion of foil1314that seals the drug particles3in a respective cell311of the central block1400is recessed within the respective open cell311of the outer, empty block1400″, which protects it against accidental damage. The outer block1400″ also accommodates the fragments of foil formed during assembly so that they are not trapped in the cells of the end user package1300. The composite package1303could be labelled after assembly, or the label could be applied to one of the component blocks1400,1400″ before assembly. A composite capsule body package could be formed in a similar way. Like the packages previously described, each composite package1303may be supplied in a sealed outer bag or wrapping, which prevents contamination of the open cells in storage. The blocks1400,1400″ may be disassembled at the factory for cleaning and re-use, e.g. by soaking to dissolve the adhesive.

Alternative Package with Movable Closure Elements

Referring now toFIGS.146-159, an alternative package is illustrated as a drug package2301, although alternatively it could contain a capsule component (optionally, with a carrier).

As with the packages of the first embodiment, the alternative package2301includes a block2400which forms a frame defining a plurality of cells. The cells311are separated by the frame to form a spaced array, wherein each cell includes a cell wall318, the cell wall extending along a cell axis Xc between opposite, first and second ends of the cell at opposite, first and second sides of the frame or block2400. Each cell311of the package2301defines an enclosure, and the respective single dose of the drug, (or if a capsule part package (not shown), then the respective capsule part, optionally in a carrier) is enclosed within the enclosure, e.g. in the form of spheroids3, as shown.

Instead of a frangible foil, as shown in the previously described packages, the package2301includes at least one movable closure element2401which closes at least one respective end of each cell and is movable by the machine1000, relative to the frame or block2400, to open the at least one respective end of each cell311while the packages are stacked in the machine. As illustrated, the at least one movable closure element2401may close and open both respective ends of each cell311. By displacing the at least one movable closure element, relative to the block, is meant that the machine causes relative movement between those parts; this can be accomplished, for example, by moving the at least one movable closure element while the block remains static, or by moving the block while the at least one movable closure element remains static.

For example, also as illustrated, the package2301may include two separate movable closure elements2401arranged on opposite sides of the block2400to close, respectively, the first and second ends of the cells311. Alternatively, one movable closure element could be arranged to close both ends of each cell; for example, it could include two parallel plates joined together in fixed relation, wherein the block2400is received between the plates. For example, the movable closure element could be configured as a casing, with the block slidingly received inside the casing. The block could be made from metal or plastics material or glass; the movable closure element could be made from metal or plastics material. For example, a plastics block could be received inside a metal casing forming the movable closure element.

Alternatively, the cells311could be closed on one or each side of the package by a frangible foil and a movable closure element—which is to say, both the frangible foil and the movable closure element are arranged on the same side of the package, and that arrangement could be provided on one or both sides. For example, the movable closure element could protect the frangible foil against accidental damage. Alternatively, the cells could be closed at one end by a frangible foil, and at the other end by a movable closure element.

As with the other described embodiments, each drug or capsule part package2301may be a single use package, which is to say, the package is only used one time. However, as shown, the block2400, which forms a component part of the package2301, may be a re-usable, monolithic, foraminous block. After using the package2301to form the plurality of single, orally ingestible bodies or capsules20, the block2400is cleaned (e.g. to remove any traces of the drugs, and perhaps also the package label1317and/or any sealant) and re-used (e.g. with new drugs or a new capsule component, optionally with a new carrier, and perhaps also a new package label1317and/or sealant) to form part of another single use drug or capsule part package2301.

The variant first machine1000is arranged to displace each movable closure element2401, optionally slidingly, relative to the block2400, from a closed position (FIGS.153,154,155,158) to an open position (FIGS.157,159), to open the cells311while the packages are stacked in the machine1000, as one step in the process of combining together the first and second drugs to form the polypills20. This places each cell311in coaxial communication with the corresponding cells311of the other packages stacked in the machine1000, as previously described.

As illustrated, the machine1000may displace the movable closure elements2401simultaneously by means of an actuator (not shown) which moves a displacement surface or surfaces1195that engage the movable closure elements2401. The or each displacement surface1195may be formed, for example, as a bar that extends along the height of the stack of packages, and which as shown may form a movable assembly of the front plate1220of the machine1000, or alternatively could form a moving part of the moving frame assembly or other machine part. The pedestal block1170, if present, may have corresponding recesses1187to accommodate the bars. The or each displacement surface1195may move into a respective recess2402in the block2400. The block2400may be supported at abutment surfaces2403by shoulders1196at the rear of the adapted profiled recess1150, which may include a recess1197(FIG.156) to accommodate the closure elements2401as they move to the open position, which is shown (but for clarity, without the profiled recess1150) inFIG.157.

As illustrated, the or each movable closure element2401may define an array of through-holes2404which are juxtaposed in conterminous, coaxial relation with the cells311of the block2400in the open position (FIGS.157,159), while in the closed position (FIGS.153,158), the through-holes2404are misaligned with the cells311of the block2400so that the closure element2401closes the ends of the cells311on the respective side of the package2301. By “conterminous relation” is meant that the walls of the through-holes are aligned with the walls318of the cells311, so that in the open position, the through-holes2404and cells311have a cross-section that is substantially continuous (i.e. substantially unvarying) along the common axis Xc of the cells311and through-holes2404. This enables the capsule part22to capture the drug particles3as the capsule part22or carrier320,1320slides through the package2301.

As is the case also in the first embodiment and the other packages of the variant first embodiment, each cell of the package (and, in this embodiment, also each through-hole of the package) is arranged to form a respective portion (i.e. a portion of the axial length) of a respective, continuous passageway, which is formed (wholly or mostly) by the corresponding cells of all of the packages when stacked together in the machine. For example, a stack of packages with 48 cells will form48continuous passageways when stacked together in the machine. The passageway preferably has a substantially constant cross-section along the axis of the passageway, which is defined by the collinear axes Xc of its respective cells311; which is to say, its cross-section does not vary substantially along its length. The cross-section is defined by the axially aligned walls of the cells (and, in this embodiment, also of the through-holes).

The or each closure element2401may be slidingly retained by the block2400for movement between the closed and open position, for example, in slideways2405formed in the block2400. Each movable closure element2401may be separable from the block2400. Each movable closure element2401may be formed as a foraminous plate, which may be monolithic and re-usable, so that after use, the block2400and plates2401can be separated, cleaned, and re-assembled to form component parts of a new single use package2301. Thus, illustrated, a foraminous block2400may be arranged between a pair of slidable, foraminous plates2401.

The closure element2401and block2400may include co-operating retaining features (not shown), such as small protrusions that engage co-operating abutment surfaces or recesses. Such features may retain the closure elements2401in either or both of the closed and open positions relative to the block2400. The retaining features may be overcome (e.g. by resilient deformation) by application of a threshold force to move the closure elements2401from the closed to the open position, and then again by application of a further threshold force to separate the parts2400,2401of the assembly for cleaning after the opened package2301is returned to the factory.

In alternative arrangements, the outer plates of the package, described herein as movable closure elements, could remain static, and could be arranged to engage with alignment or profile features of the machine, while the inner plate, described herein as the block, is displaced by the actuator of the machine.

After filling and closing the package2301(FIGS.153,154), the adhesive package label1317, where present, may be applied (FIG.155) over the joint or sliding interface between the closure element(s)2401and the block2400to retain the parts2401,2400in the closed position, and then irreversibly ruptured when the closure elements2401are moved by the actuator of the machine1000to the open position. The label1317may be provided with a tamper evident pattern or indicium (illustrated in the multipack embodiment, below) that covers the region to be ruptured, perhaps in combination with a mechanical tamper evident feature (e.g. a pattern of cuts, as used in a tamper evident price labels on retail items). The machine1000may be configured to scan the tamper evident feature so as to recognise, by the broken pattern or indicium, a package2301that has been opened prematurely.

The label1317could be arranged to be ruptured in a direction out of its plane (as illustrated), or alternatively, as illustrated inFIG.185, could be arranged on a different surface to be ruptured in shear in its plane by sliding movement between the respective parts2401,2400, with the package2301being arranged to expose the sliding interface on that surface. For example, the package could comprise a pair of sliding plates slidably arranged on opposite sides of the block, wherein the plates define surfaces that lie in a common plane with a respective surface of the block, and the plates are slidable relative to the block in a direction parallel with the common plane. For example, the parts2400,2401could be adapted to extend the foraminous plates2401to the edges of the foraminous block2400to define a surface for the package label1317, and the image capture device1281(further explained below) arranged to read the package labels on one side of the stack rather than the front of the stack as illustrated. Or, the image capture device1281could be arranged to read the package labels on the front surface of the stack, whether as part of a front plate1220or otherwise, and the stack arranged in that orientation with the or each displacement surface1195arranged to push the moving parts of the packages (e.g. block2400or plates2401) from right to left or left to right to open the package cells.

Each cell311may contain a single dose of a drug to form a drug package2301, as illustrated. Alternatively, although not illustrated, each cell311may contain a part of an empty capsule, which may be arranged in a carrier320,1320, but without a complementary part required to complete the capsule20. The carrier320,1320may be received in the cell311and slidable out of the cell311along the cell axis Xc, as in the other embodiments. The capsule part may be a capsule body22, forming a capsule body package, similar to the capsule body package of the other embodiments.

As with the other described embodiments, although not illustrated, each package may be enclosed in a protective outer wrapper.

Each dose may be separately enclosed in its respective cell311, while the outer wrapper (e.g. a sealed film or foil bag) provides a seal (e.g. a hermetic seal) to preserve the drug in storage. For example, the outer wrapper could be sealed to retain the package in a vacuum or partial vacuum. The wrapper may be disposable and may be removed before placing the package1301in the machine1000.

Alternatively, rather than a disposable wrapper, the whole package1301could be arranged in a re-usable outer casing, e.g. a box with a lid, that is sealingly closed for storage, and openable to remove the package for use.

Alternatively, the package components may be sealingly engaged together to provide a seal that preserves the drug; for example, a mechanical seal could be arranged between the components2400,2401of the package, or the whole assembly (FIGS.153,154) could be coated with a sealant. As with the other embodiments, the drug or capsule component may be assembled into the package in a protective atmosphere.

Where the package contains the capsule cap, the capsule cap21may be supported in spaced relation to the cell wall318by flock1699or other locating structure as previously described. The machine1000may displace the foraminous plate or other movable closure element relative to the block or frame, e.g. slidingly, in a similar way to the closure elements of the drug and capsule body packages. The closure element may form a part of the end user package or may be discarded or returned to the factory for re-use.

Filling Apparatus for Use with the Alternative Drug Package

Referring now toFIGS.160-163, an example filling apparatus2430is shown, which may be used to fill the spheroids3into the cells311of the alternative drug package2301. The apparatus has a main body2431with an array of discharge nozzles2432, only one of which is shown in the drawings. Each discharge nozzle2432has a discharge chute2433, a filling chute2434which is filled with a column of equally sized spheroids3, e.g. by gravity from a vibrating hopper (not shown), and a dosing body2435that moves (e.g. rotates, as shown) relative to the main body2431between a receiving position (FIGS.160,162) and a discharge position (FIG.163). The dosing body has a dosing chute2436and optionally also a sensor or an array of sensors, e.g. an array of through-beam photoelectric sensors2437, that detect the presence of spheroids3in the dosing chute2436.

In use, the block2400of the partially assembled drug package2301may be arranged as shown inFIG.151, with the lower movable closure element2401in the closed position and the upper movable closure element2401in the open position. The main body2431is engaged with the upper movable closure element2401so that each discharge nozzle2432completely fills one of the through-holes2404, with the lower end2438of the discharge nozzle lying in the plane of the sliding interface between the movable closure element2401and the block2400. The dosing body2435is moved to the receiving position (FIGS.160,162) in which the column of spheroids3can fall from the filling chute2434into the dosing chute2436. The sensors2437may indicate whether or not the dosing chute2436is completely filled. Sensor2437output may be evaluated after moving the dosing body to an intermediate position (not shown) in which the dosing chute2436is isolated from both the filling chute2434and the discharge chute2433. If sensor2437output indicates that the dosing chute2436is completely filled, the dosing body2435is moved to the discharge position (FIG.163) in which the dosing chute2436no longer communicates with the filling chute2434but instead is axially aligned in communication with the discharge chute2433and with a plunger2439, which is extended from the main body2431through the dosing chute2436and discharge chute2433until its lower end face is flush with the lower end2438of the discharge nozzle. This ensures that all of the spheroids3are ejected from the dosing chute2436into the cell311of the block2400. The plunger2439remains in this extended position while the main body2431then translates from the open position to the closed position of the upper movable closure element2401, closing the cells311of the package, which ensures that none of the spheroids3can escape from the cell311as the package is closed. The main body2431is then withdrawn and the plunger is retracted to the start position. The filled package (FIGS.153,154) may then be labelled (FIG.155).

The length of the dosing chute2436is selected (or may be adjustable, not shown) to accommodate the desired number of spheroids to be filled into each cell311, for example, seven spheroids3as illustrated. Alternatively, the operation could be repeated before closing the package, with only one or more than one spheroid3being ejected per operation.

Package Indicia and Sequence of Operation

The package indicia317may include first indicia1317′ identifying the contents, which will be transferred from each of the drug packages1301,1302and optionally also the capsule body package1305to the end user package1300, and second indicia1317″ providing data to facilitate operation of the machine1000, which need not be transferred to the end user package1300. The first indicia1317′ may include the name and dose of the drug in words and numerals, and may further include a machine readable code that embodies the same information and/or serialization data. The serialization data could alternatively form part of the second indicia1317″. The second indicia1317″ may indicate, for example, the number of spheroids3or volume of the drug1,2per cell, the vertical thickness of the package, the size of the block or total number of cells311, and/or the number and/or location of the cells311that are filled (for example, all the cells or only some of the cells, providing different end user package sizes based on the same blocks1360,1360′, as shown inFIGS.138,139and140). The local controller262(FIG.1) can use this information to set the position of the moving frame assembly1120or pressure plate1121, pedestal block1170, or other moving parts of the machine1000to match the expected stack height, and to ensure that all the packages are compatible and the capsule size is correct for the combined volume of the drugs.

To facilitate this process, and also to detect counterfeit drugs or incorrect package combinations or to check that the drugs match the prescription, the packages may be scanned at an external scanner1280before loading them into the machine1000, where they may be scanned again by an internal scanner or scanners as further explained below.

If preferred, the machine1000could operate with only external scanner1280, or only the internal scanner(s). Since the drug volume and other information may be verified by scanning the package indicia (either for the first or second time) when present inside the machine, the vertical (thickness) dimension of the drug packages need not vary with the volume of the drugs contained therein as previously described for the first embodiment.

Referring toFIG.1andFIG.102, an example sequence for manual operation of machine1000might be as follows:

i) Controller262receives prescription data, e.g. via external data link264, via user interface267, or by scanning a barcode via external scanner1280. Controller262may retrieve further information to identify or confirm the prescription, or to check for contra-indicated combinations, or to add patient-specific information, e.g. maximum capsule size.
ii) Controller262may indicate the correct capsule size and package size to match the combined drug volume and the required number of doses. The user may confirm the selection, or select a smaller capsule size (and larger package size) if it's preferred to divide the dose. The prescription information may be displayed on screen267as illustrated.
iii) The user selects the packages1301,1302,1304,1305and scans them at external scanner1280. Alternatively, the process could begin with this step.
iv) Controller262validates the scanned packages, e.g. via database90. If the packages are OK, controller262may set the machine for the expected stack height, and then opens the door.
v) The user places the packages in the machine and closes the door.
vi) The machine1000scans the packages a second time to verify their identity, to create the composite label1312, and to update the database90with the serialization data, and performs the assembly step to form the end user package1300.
vii) The user removes the end user package1300and pairs it with the patient information leaflet266. The empty packages1301,1302,1305are placed in a bin to be returned to the factory.

Printed Composite Label

As in the first embodiment, each drug package1301,1302of the variant first embodiment may include human readable and/or machine readable label indicia (indicated collectively in this embodiment as317) identifying the respective drug, and the machine1000is arranged to combine together the label indicia317from respective ones of the packages (particularly the drug packages) as received in the machine to form a composite label1312of the end user package1300which identifies each of the drugs1,2. However, instead of assembling together the mechanical parts of the drug packages that carry the indicia as described with reference to the first machine100, the variant first machine1000is arranged to accomplish this by reproducing on the end user package1300a copy1312′ of the indicia317that appear on the drug packages.

For this purpose the machine1000may include an image capture device1281for capturing an image of the label indicia1317′ from the stacked packages, and an image reproduction device1282for reproducing (e.g. printing) the captured image1312′, as a composite label1312, on the end user package1300. The image1312′ may be reproduced at the same size as the original or enlarged or reduced as shown. The machine1000may be arranged to ensure that the packages are correctly stacked (e.g. with the pressure plate and front plate closed and locked together) before the image capture device1281captures the image. Since the image reproduction device1282simply reproduces exactly what the image capture device1281sees (i.e. the image that it captures) in the target region of the stacked packages, anything visible on the target portion of the package labels will appear on the end user package, so the end user package1300cannot be mis-labelled.

Together, the image capture device and image reproduction device may be considered as a photographic reproduction or photocopying apparatus, and the reproduced image1312′ as a photocopy or photographic print of the package indicia.

Alternatively or additionally, the end user package could be labelled (or further labelled) with indicia generated from data received by the controller262, e.g. by looking up the scanned package indicia in the database90to download the associated information. For example, the image reproduction device1282may also print, as part of the composite label1312, customer information1080associated with the prescription (e.g. name, address, human or machine readable customer ID code, dosage information, etc.), which may be derived from the inputted prescription information or from a database. The same information may be reproduced on the patient information leaflet or associated adhesive label.

The image1312′ may be reproduced on a front surface of an adhesive flap1330of the capsule component package that will form the end user package1300, which in the illustrated example is the cap package1304, as in the first embodiment. The flap1330has a mostly blank front surface facing away from an opposite rear surface, which may be coated with adhesive4and protected by a release paper1332. The flap1330is hinged to the frame and movable to position its adhesive surface to cover the bottom side of the package1304through which the remaining capsule and drug components, and also the carriers if present, are admitted during assembly.

Where the machine includes a movable front plate and pressure plate, as illustrated, the drug and capsule body packages may be stacked in the machine1000before raising the front plate1220(FIG.103). The front plate1220may include a support surface1240on which the unfolded flap1330(with its release paper1332in place) can rest when the cap package1304is then added to the stack (FIG.104). The top (pressure) plate1121is then closed to position the image reproduction device1282against the front surface of the flap1330which is sandwiched between the window or print head or other active face of the image reproduction device1282and the support surface1240(FIG.105). The package indicia317are then scanned, and if validated, the controller262then actuates the moving frame assembly1120to produce the end user package1300as previously described.

The image capture device1281may be arranged in the front plate1220, which may include one or more reflectors or prisms1283to direct the scanning beam. A second internal scanner1284may be arranged to read the indicia317from the cap package1304via a reflector1285.

The image capture device1281may be a scanner or camera, and the image reproduction device1282may be a printer or writer of any suitable type. The scanner may scan line by line and send the rasterized image to the printer which prints each line as it is received. The printer could be for example an ink based printer, e.g. an inkjet printer, or a thermal printer with a moving print head, or a laser printer that works on a thermally sensitive substrate or on a plain paper or card substrate, e.g. as taught by WO2014158019 to Tocano V.O.F. The front surface of the flap1330could be configured accordingly, e.g. to include a black layer behind a white layer (the layers being e.g. paper or polymer) to provide a durable image when the front layer is locally heated by the laser, or incorporating a pigment that is actuated by heat as known in the art.

The cap and body packages1304,1305may include indicia317similar to that of the drug packages to indicate, e.g. the material or special properties (e.g. enteric coating) of the capsule components together with serialization data if required, as well as the capsule size, package size, number and position of the filled cells, and other information required by the machine1000. These indicia may remain visible on the capsule component package1304that forms the end user package1300, and may be captured and transferred from the other capsule component package1305along with the indicia from the drug packages to form the composite label1312. As in the first embodiment, the captured indicia from the capsule component package1305may include a legend: “NO FURTHER ACTIVE INGREDIENTS” which will appear at the end of the list of drugs in the composite label1312.

Cap Package: Flocked Cells

Where the cells of the block of the first capsule package include a locating structure for locating the capsule body or cap centrally within the cell in spaced relation to the cell wall, the locating structure may be a lining of flock within the cell, as will now be described with reference to the cap package1304.

Referring toFIGS.111and112, the cap package1304may be formed from a monolithic block1360which forms the frame defining a spaced array of cells. The block1360has the same overall shape as the block1400of the drug and capsule body packages, optionally including profile recesses1353or other asymmetric peripheral shape profile features that serve to prevent incorrect insertion into the profiled recess1150of the machine. A half size variant1360′ corresponds to the block1400′.

The blocks1360,1360′ may be moulded from a similar material to the block360of the first embodiment, for example, a biodegradable material, e.g. a carbohydrate glass, perhaps filled with lignin or wood flour or the like. The block may be coated, e.g. with a coating material similar to that of the block1400.

As shown inFIGS.120-121, the cell wall318of each cell311of the block1360may be lined with flock1699to form a flocked cell1311. The flock1699comprises short fibres, e.g. of rayon or nylon, which may be for example around 1 mm-3 mm in length. The outer end of each fibre is bonded by adhesive to the cell wall318, so that the fibre extends radially inwardly towards the cell axis Xc. The adhesive may be applied over only part of the cell wall318, leaving a short, unflocked region1311′ at the upper end of the cell through which the finished capsule20will be removed by the end user (FIGS.143,144).

The capsule component (in the illustrated embodiment, the cap21) is inserted into the flocked cell1311of the package1304so that the fibres of the flock hold it centrally in the cell in spaced relation to the cell wall318(FIGS.123,128).

During assembly, as the carrier1320enters the flocked cell1311(FIG.141), the carrier1320moves into the space occupied by the flock1699which is folded back against the cell wall318as the cap21enters the annular space between the capsule body22and the carrier.

As shown inFIG.145, the carrier may be similar to the carrier320of the first embodiment but with a radially outwardly facing, textured, e.g. barbed or serrated surface portion1328. The texture engages the fibres of the flock1699as the carrier enters the cell (FIG.141) so that they retain the carrier1320in the cell as the end user package1300is removed from the machine.

A smooth surface portion1329may be left at the lower end of the carrier1320to help release fragments of foil1314, forming part of the uppermost drug package, from in-between the carrier1320and the cell wall318when the end user package1300is separated from the stack. Alternatively, the carrier may be serrated or textured for its whole length, which may be preferred where the foil of the uppermost drug package is spaced apart from the cap package, or where the drug packages are closed instead by movable closure elements, e.g. sliding foraminous plates as described above.

The carrier1320could be made from a similar material to the carrier320, e.g. a carbohydrate glass with a filler material for strength, or hard gelatin, HPMC, biodegradable cellulose acetate, or other plastics material. It could be partially coated with a wax. A filler material may include fine grained particles, whiskers, or a mixture thereof.

The flocked lining of the cell may accommodate and retain carriers of different diameters for different sized capsules.

FIGS.130and131show the opposite sides of the outer casing sheet1342of the cap package1304, in the form of a flat sheet of card, before it is folded around the block1360to form part of the casing1340. The sheet is printed on its outer surface with indicia317and, on the portion that will form the flap1330, with the legend “EACH CAPSULE CONTAINS:”, which will appear above the printed copy of the indicia captured from the other packages in the stack. Strips1315terminating at tabs1316, identified by printed triangles, are defined by cut lines that separate the strips from the sheet, but leaving them in position for assembly. Printed numerals on each strip identify the position of each of three cells1311that will be covered by the strip.

FIG.132shows the inner casing sheet1343, also a flat sheet of card with discs1344defined by cut lines but left in place in the sheet. The inner casing sheet1343is coated on one side with adhesive, which is then covered by a sheet of plain foil314(FIG.133). The opposite side of the inner casing sheet1343, not shown, is not coated with adhesive.

Referring toFIG.134, the inner surface of the outer casing sheet1342is coated selectively with adhesive. The adhesive covers entirely the inner surface of the part forming the flap1330, which is subsequently covered by a release paper1332(FIG.135).

On the inner surface of each strip1315, the adhesive4is applied in a pattern which defines three circular patches1345, each of which will be conterminous with a respective one of the discs1344when the inner casing sheet1343is superposed on the outer casing sheet1342as shown inFIG.135. Additionally, a small dot1346of adhesive4extends from each circular patch1345towards the tab1316of the respective strip1315. The rest of the strip1315is free from adhesive. The remaining parts of the inner surface of that portion of the outer casing sheet1342which defines the strips1315—which is to say, the parts in-between the strips1315—are also covered with adhesive4, as shown.

FIG.135shows how the uncoated side of the inner casing sheet1343with its attached sheet of plain foil314, as shown inFIG.133, is then superposed on the patterned adhesive over the inner surface of the outer casing sheet1342defining the strips1315, so that each disc1344is superposed on a respective patch1345of adhesive. In this position, the body of the inner casing sheet1343(i.e. the solid part in-between the discs1344) adheres strongly to the body of the outer casing sheet1342, i.e. the solid part in-between the strips1315, so that both sheets1343,1342are united into a single assembly.

Each disc1344is connected to the body of the inner casing sheet1343only by the sheet of plain foil314. Each strip1315overlies three discs1344, and is connected strongly to each of those discs1344by the respective patch of adhesive1345. However, the strip1315is connected to the body of the inner casing sheet1343, i.e. the solid part in-between the discs1344, only by the three small dots of adhesive1346.

Referring now toFIG.122, the block1360with flocked cells1311is now coated with adhesive on one flat side and on its narrow sides, and then the adhesive side is placed onto the plain foil sheet314, and the flaps of the outer casing sheet1342are folded around the narrow sides of the block1360, to unite the assembly of inner and outer casing sheets1343,1342with the block1360. In the regions in-between the strips1315, the foil sheet314adheres strongly to the surface of the block1360in-between the flocked cells1311. The regions of the foil sheet which sealingly close the upper end of the cell1311are supported by the respective disc1344, backed by the strip1315, which as explained above is connected to the rest of the assembly only by the three small dots of adhesive1346. However, the discs1344and strips1315are also held in place securely by the bodies of the sheets that surround them, and so resist any accidental force applied in the plane of the sheet, until the end user pulls upwards on the tab1316to lift them out of their assembled position.

The capsule caps21are then inserted into the flocked cells1311, as described above and as shown inFIG.123, before the open end of each cell1311is sealed by a sheet of patterned foil1314as previously described, as shown inFIG.124. The flap1330with its attached release paper1332is then folded over the patterned foil1314to protect it in storage, as shown inFIGS.125and127, before placing the finished cap package1304in a protective outer wrapper (not shown).

Referring toFIG.136, in use, after removing the cap package1304containing the finished polypills20from the machine1000as previously described, each cell1311is closed by the closed end of the respective carrier1320, to which adheres a disc of foil314that was detached from the capsule body package. Then, the release paper1332is peeled away before closing the flap1330over the remains of the patterned foil1314and the carriers that fill the open ends of the cells1311to seal the end user package1300. The printed indicia1317′ captured from the stacked packages are exposed on the outer surface of the flap1330as shown inFIG.137. The strips1315are exposed on the opposite side of the end user package1300as shown inFIG.138. A similar arrangement is provided in smaller variants of the end user package1300′,1300″ which may use the same block and an adapted casing so that only some of the cells are filled, as shown inFIGS.139and140.

Referring toFIGS.143and144, when the user lifts the tab1316, the first small dot of adhesive1346tears away from the body of the inner casing sheet1343as the strip1315lifts out of the body of the outer casing sheet1342, pulling the first disc1344out of its position in the inner casing sheet1343as the foil314ruptures around the edge of the respective cell1311, so that a disc of foil314(adhering over its whole surface area to the cardboard disc1344) is removed cleanly from the cell, exposing the open end of the cell through which the finished polypill20drops out when the end user package1300is inverted and tapped against a hard surface or the palm of the hand. The carrier1320is retained in the cell1311by the body of the assembled sheets1342,1343. Once the third cell1311is opened, the strip detaches from the package.

In order to assist in removing the polypill20from the end user package, in this and other embodiments where the polypill20is located inside a carrier320,1320, the carrier may include a small resilient body (not shown) which is compressed during assembly between the closed end of the capsule body22and the closed end of the carrier. The resilient body may remain in an uncompressed state in the carrier or plug package, so that it is compressed only during assembly of the capsule. The resilient body remains under slight compression when the end user package is sealed, and resiles when the cell is opened to urge the capsule20out of the cell so that it can be grasped by the user. To maintain the resilient body in compression, the holding force of the carrier in the cell of the end user package is preferably greater than the spring force applied to the capsule20by the resilient body. The resilient body could be a moulded, integral feature of the carrier, such as an elastically deformable internal projection, e.g. in a straight or spiral shape, or a plurality of such projections, or a co-moulded elastomeric element. Alternatively, it could be, for example, a solid piece of foamed material which could be assembled into the carrier. The resilient body could react the full axial force applied to the capsule during assembly, or it could be partly received in a recess in the carrier so that it is only partially compressed as the capsule body engages a seat in the carrier during assembly with the cap.

Flocking Apparatus

Referring toFIGS.118and119, a flocking apparatus1600may be used to apply the flock1699to the cells of the block1360.

In use, the cell walls of the block1360(not shown) are coated with an adhesive, and then the block1360is clamped between plates1601,1602, each plate having an array of nozzles1603, so that the open ends of each cell311are engaged between a respective pair of nozzles1603. One of the plates1602is at ground or negative potential, and applies that potential to the adhesive, relative to a positive electrode or grid1604which charges the flock1699which is dispensed from a hopper1605. A blower1606circulates a gentle flow of gas, e.g. dry air, which carries the flock in suspension between the opposed nozzles1603, through the cells of the block where the fibres stick to the adhesive. Surplus flock1699may be removed by a filter1607and returned to the hopper1605. A valve1608may be operable to introduce clean air or gas to flow through the cells to clear loose fibres after the flocking operation. Although illustrated in spool valve notation, valve1608might be implemented e.g. as a baffle or flap.

Resilient Pushrod Mounting and Transducer Assembly

As discussed above under the heading “Vibration source and graduated pressure”, in embodiments where pushrods are urged through the aligned cells of the stacked packages, the pushrods (e.g. the pushrods110of the first machine) may be arranged to transmit vibrational energy to the drug particles3and/or capsule components21,22to assist assembly.

Referring toFIG.107, the variant first machine1000illustrates one way to achieve this, wherein each pushrod1110is connected to a rigid baseplate1203(similar to base plate203of the first machine100) via a resilient connector, e.g. an elastomeric body1208, which decouples vibration of the pushrod from the baseplate. The pushrods may be slidingly received in through-holes in the pedestal block1170, similarly to the first embodiment, which helps to maintain them in parallel relation.

Each pushrod1110is provided with a respective transducer1209, which may be mounted beneath the baseplate1203as shown. The transducer1209is driven by a signal source1210to generate vibration energy in the pushrod1110, which transmits the vibration axially along its length to its end surface which contacts the carrier1320, which transmits the energy to the capsule components and drug particles.

Further Variants of the First Embodiment, Having a Plug not Formed as a Carrier: End User Multipacks

The first embodiment and variants thereof exemplify a method of assembling a capsule by receiving in the assembly apparatus at least first and second capsule parts of a plurality of capsules, collecting together between the at least first and second capsule parts of each capsule the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package, and closing together the at least first and second capsule parts to enclose within each capsule the respective single dose of the first drug and the respective single dose of the second drug.

As illustrated by each of the above described first embodiment and variants thereof, and further illustrated by two further variant embodiments which will now be described, the packages may include an end user package and a plug package, wherein each cell of the plug package defines an enclosure containing a plug. In such arrangements, the assembly machine1000is configured to receive the end user package together with the plug package and the first and second drug packages, and to slidingly displace each plug through respective axially aligned cells of the plurality of packages, to close an open end of a respective one of the cells of the end user package. In this way each capsule containing the single doses of the first and second drugs is sealing enclosed in the respective cell of the end user package. Each cell of the end user package is openable by an end user to remove the respective capsule20containing the single doses of the first and second drugs for use.

The method of operation may include receiving an end user package together with the plug package and the first and second drug packages in the assembly machine, and slidingly displacing each plug through respective axially aligned cells of the plurality of packages, to close an open end of a respective one of the cells of the end user package, to sealingly enclose a respective capsule containing the single doses of the first and second drugs in said respective one of the cells of the end user package. Each cell of the end user package is openable by an end user to remove the respective capsule containing said single doses of the first and second drugs for use. Optionally in such arrangements, the plug may form a carrier that contains the capsule body.

Conveniently, as illustrated, each cell of the plug package may define an enclosure containing the plug together with a respective capsule body22; alternatively (not shown), the capsule body22could be contained in a different package from the plug. Each cell of the end user package, as received in the assembly machine, may contain a respective capsule cap21, and optionally also a locating structure which supports the capsule cap21in spaced relation to the cell wall318.

As illustrated by the first embodiment and above described variants thereof, the plug may be formed as a carrier320,1320, wherein the capsule body22is arranged in the carrier. The carrier may constrain the cap and body in axial alignment as the cap slides into the annular gap between the outer wall of the carrier and the capsule body.

In such arrangements, it is convenient to remove the finished polypill20from the axial end of the cell of the end user package opposite the open end through which it enters.

Alternatively, as will now be described with reference to further variants of the first embodiment, the plug need not be formed as a carrier. The end user package may have a slim form factor with length, width and thickness dimensions, wherein the thickness dimension is less than the length and width dimensions. The thickness dimension may be only slightly greater than the diameter of the capsules and less than the capsule length, so that the length axis of the capsule extends in the width or length dimension of the end user package, conveniently in the width dimension as will now be described.

The capsules may be removed from an axial end of the cell via a narrow side of the end user package extending in its thickness dimension, as in the above described embodiments. Alternatively, the capsules may be removed via a broad side of the end user package that extends in its length and width dimensions, as will now be described.

In the latter case, the broad side of the package may be defined by a foil wall which is ruptured when the capsule is removed, optionally by pressing against an opposite wall of the cell to force the capsule through the foil wall. In this case, since the foil wall may not be configured to maintain the capsule cap and body in axial alignment, the cap may be arranged in a cap package separate from the end user package, so that the capsule is closed before it enters the cell of the end user package, as illustrated by the first of these further variants, which also illustrates how the plug may be combined with a sliding collar to close the open end of the cell containing the finished capsule20.

If assembly occurs outside the end user package, then a restraining element may be arranged to restrain the cap21while it engages with the body22, and then to move to allow the finished capsule20to enter into the end user package. The restraining element could be an elastically or plastically deformable or frangible element which is moved aside or broken by the finished capsule, e.g. a membrane that tears at a force greater than the force required to close the cap and body together, or it could be a movable closure element which is displaced by an actuator of the machine100,1000after the capsule assembly step, as illustrated by the first of these further variants, described below.

Alternatively, as illustrated by the second of these further variants, also described below, a part of the cell wall at the broad side of the package may be detachable by the end user to open the cell to remove the capsule20via the broad side of the package, wherein the cell wall is configured to maintain the capsule cap and body in axial alignment as the capsule is closed. In this way, the cap may be located inside the end user package which then forms the cap package, so that the capsule is closed inside the cap package.

During manufacture of the cap package, the cap21may be introduced into the cell before closing together the two parts of a clamshell package, as shown. Alternatively (not shown), the cap21may be introduced axially through an open end of the cell, and then retained by closing the open end of the cell or by a cylindrical sleeve which is inserted after the cap and which then forms a guide for the capsule body during assembly.

As further illustrated by each of these two further variants, the end user package having a slim form factor may be a sub-package forming part of a multipack comprising a plurality of such end user sub-packages; thus, the term “end user package” may refer to the end user multipack or to the individual end user sub-package. Each sub-package includes a row of cells which can be opened by the end user through one or both of the broad sides of the sub-package. The sub-packages could be held together by frangible or releasable connections or by a film or wrapper or (as illustrated) a box, to form an assembly so that they can be separated by the end user as required. Conveniently, the box can be arranged to display the package indicia and to contain the patient information leaflet, if provided.

Thus, as illustrated by each of the further variants which will now be described, the end user package may include an assembly of sub-packages, each sub-package including a plurality of cells, wherein the sub-packages are separable for use by the end user. The first of these variants illustrates how the sub-package may be separate from the cap package, wherein the capsule is assembled inside the cap package and outside the end user sub-package. The second illustrates how the sub-package may form the cap package, so that the capsule is assembled inside the sub-package.

Capsule Assembly Outside the End User Package; Plug and Collar

Referring now toFIGS.164-206, the stacked packages may include a cap package3040which defines a spaced array of cells311, each of which includes capsule cap21and a collar3060. The collar3060defines an aperture3061and is configured to guide the respective capsule body22to enter telescopically into the respective capsule cap21via the aperture3061. The cap21may be arranged in the aperture3061, as further described below.

The assembly machine1000is arranged and operated generally as described above with reference to the variant first embodiment, but with some adaptations as will be evident from the following discussion. For example, the image reproduction device (not shown) may be arranged in a different position; there may be more than one image reproduction device; and the machine may have an additional actuator (not shown) which is configured to actuate an additional movable closure element3043of the cap package3040, as further explained below.

The assembly machine is configured to displace the collar3060slidingly into the open end3022of the respective cell3021of the end user package or sub-package3020, and to slidingly displace the plug3070, from the respective cell of the plug package3050into the aperture3061of the collar3060, so that the plug3070and the collar3060together close the open end3022of the respective cell3021of the end user package or sub-package3020containing the capsule20.

As illustrated, the cap package3040and the end user package3001may be connected together to form an end user package assembly, wherein the machine1000is configured to receive the end user package assembly together with the drug packages3051and plug package3050.

The drug packages3051and plug package3050may have re-usable monolithic foraminous blocks and movable closure elements, as illustrated, thus corresponding generally to the alternative package2301previously described. Alternatively, the drug packages and/or plug package could be closed by foil, corresponding to the drug packages1301,1302or1303previously described. Each cell of the plug package3050may contain a plug3070and a capsule body22, with the plug being arranged in use between the capsule body22and the pushrod1110, as shown inFIG.201.

Referring toFIGS.165-173, each sub-package3020may include a body3027formed as a unitary plastics moulding defining a single row of cells3021, each cell opening through the broad, front side of the body3027, which defines a flat surface3028, and via an aperture3022formed in the narrow, bottom side of the body3027. The aperture3022may have a projecting rim3023. A pair of location tabs3026may be moulded at the opposite narrow, top side of the body.

The foil wall3024is applied (e.g. ultrasonically welded) to the flat surface3028to sealingly close the front side of each cell3021as shown inFIG.164.

Referring toFIGS.174-178, a number of sub-packages (e.g. six sub-packages3020, as illustrated) are then assembled together, e.g. in a box3002as shown, to form the empty end user package3001. The box may have apertures3008formed in its base, through which the rims3023of the sub-packages project.

The top of the box may be left open to expose the narrow, top sides of the sub-packages, which may have a surface suitable (e.g. having a suitable coating) for indicia to be printed directly onto said surface, or (as illustrated) may be covered by an adhesive label or labels3009to facilitate printing the package indicia captured from the stacked drug packages on each sub-package, optionally with additional package indicia and/or customer details, as earlier described. The label may be perforated between the sub-packages so that it holds them together but makes it easy to separate them by tearing along the perforation; alternatively, each sub-package could have a separate label. The box3002may have closure elements, e.g. end flaps3003and side flaps3004,3007which are folded down against its outer surface. The distal edge region of the front side flap3004may have a band of adhesive covered by a release paper3006, and may be connected to the rest of the side flap via a tear-off strip3005with a tab3010.

Referring toFIGS.190-198, the cap package3040may be an assembly of re-usable, separable parts. For example, as illustrated, it may include upper and lower foraminous blocks3042,3041having marginal projections defining slideways3044which are aligned when the blocks are superposed. The blocks are connected together by a movable closure element3043formed as a foraminous plate which, when in the closed position (wherein its holes are misaligned with the holes in the blocks) engages in both slideways. When the plate3043is moved by the machine actuator (not shown) to the open position, its holes are axially aligned with the corresponding holes or cells in each block, and recesses in its edges align with the marginal projections in the upper block3042so that the upper block3042can be lifted away from the lower block3041after the packages are removed from the machine. The plate3043can then be removed from the lower block3041so all three components can be cleaned and re-assembled at the factory to form a new package.

As shown inFIG.201, the upper part of each cell311of the lower block3041is enlarged, relative to its lower part, to define an annular seat3048which axially retains the collar3060which is received in the enlarged upper part of the cell, with the cap21being arranged in the aperture3061of the collar. The upper end of each cell of the upper block3042may define a chamfered recess3045which receives a respective one of the rims3023of a respective sub-package3020, locating the cell3021of the sub-package in axial alignment with the corresponding cell of the cap package3040.

Referring toFIGS.183-189, the end user package3001is placed on top of the cap package3040so that the rims3023locate in the recesses3045, and may be retained by a casing3011which is locked to the cap package, e.g. by marginal portions of the plate3043which engage in hooks3012of the casing; when the plate3043is moved to its open position, the hooks3012are disengaged so that the casing3011can be lifted away from the cap package3040after the packages are removed from the machine1000.

Pressure bars3015may be provided at the upper end of the casing to engage the location tabs3026of the sub-packages3020so as to maintain the upper ends of the sub-packages3020in the correct position. During assembly, the stacked packages are maintained in compression between the pressure plate1121of the machine1000, which bears against the top surface of the casing3011, and the pedestal block1170on which the packages are stacked as previously described.

It should be understood that although the pedestal block and pressure plate have been described as features of the first machine and each of its variants, they are merely convenient ways to maintain the stacked packages in compression; alternative arrangements are possible.

Windows3013,3014may be formed in the top and side of the casing3011, through which the image reproduction devices (not shown) can write the captured package indicia onto one side of the box3002, as shown inFIG.180, and/or onto the labels3009of the sub-packages3020, as shown inFIG.179.

After the casing3011is locked to the cap package3040, a tamper evident label3046may be applied to the finished assembly as shown inFIG.185. When the plate3043is moved by the machine actuator (not shown) to its open position, a projection3047of the plate tears the label3046so that the label indicia are disrupted. The damaged indicia can then be detected by a scanner and processor262of the machine1000, optionally also by validating the label indicia via its data link with the remote computer91and database90(as shown inFIG.1andFIG.102, mutatis mutandis).

Referring toFIG.200, the collar3060may include a radially outwardly facing, annular sealing surface3062which is configured to seal against a corresponding, inwardly facing surface of the aperture3022of the sub-package, and a set of resilient, radially inwardly compressible prongs3063which define latching surfaces3064. An internal annular seat3066may be arranged to retain the cap21in the aperture3061.

Referring toFIG.199, the plug3070may include, similarly, a radially outwardly facing, annular sealing surface3072, which is configured to seal against a corresponding, inwardly facing surface of the aperture3061of the collar3060, and a set of resilient, radially inwardly compressible prongs3073which define latching surfaces3074. A central post3071may project axially between the prongs3073to bear against the closed end of the capsule body22in use.

The sealing surfaces3062,3072may be arranged not to contact the cell walls of the packages during assembly. Thus, either or both of the sealing surfaces3062,3072may include a sealing material, e.g. an adhesive or a co-moulded elastomer.

The re-usable package components may be moulded or machined from plastics material, e.g. engineering plastics. The collar and plug may be moulded in plastics material, e.g. biodegradable cellulose acetate.

Referring now toFIGS.201-206, the movable closure elements (if present) of the plug package3050and the drug packages3051are moved to the open position by the machine actuator and displacement surface (1195,FIG.156, mutatis mutandis), as previously described, and then the pushrods1110are urged to push the plug3070through the axially aligned cells of the stacked packages. The plug3070in turn pushes the capsule body22towards the cap package, collecting the drug particles (e.g. spheroids)3inside it (FIG.202). The capsule body22passes through the aperture3061of the collar into the cap21, which is restrained by the plate3043which remains in the closed position until the capsule is closed (FIG.203). The plate3043is then opened by the additional actuator and displacement surface of the machine (1195,FIG.156, mutatis mutandis), and further movement of the pushrod1110urges the filled capsule20through the aperture3022of the end user sub-package3020into the respective cell3021(FIG.204). At the same time, the plug3070enters the aperture3061of the collar, while the collar3060is also slidingly displaced to enter the aperture3022of the sub-package3020(FIG.205). Finally, the prongs3073of the plug3070move outwardly so that the latching surfaces3074engage a confronting, axial abutment surface3065of the collar, while the prongs3063of the collar move outwardly so that the latching surfaces3064engage a confronting, axial abutment surface3029of the aperture3022of the sub-package, locking the plug and collar in position to close the cell3021as permanent parts of the sub-package3020(FIG.206).

Referring toFIGS.179-182, the end user package3001containing the polypills20sealed in the individual cells3021of the sub-packages3020is then removed from the machine1000and separated from the cap package3040and casing3011which are returned to the factory to be cleaned and re-assembled to form a new package. The box3002and sub-package labels3009may display the composite label1312which may be a reproduced image comprising the package indicia, which may be captured from the stacked packages, uploaded and validated as previously described, and patient indicia downloaded from the server and database91,90(FIG.1) as previously described; as illustrated, the sub-package labels may bear a subset of the indicia to fit the available space.

The end flaps3003are then folded over to retain the patient information leaflet266, which is printed from data downloaded from the remote server91(FIG.1) as previously described, folded and placed on top of the sub-package assembly. Then, after removing the release paper3006, the front flap3004is folded over the rear flap3007so that the adhesive strip seals the flaps together. The end user package3001is now ready for delivery to the customer. In use, the customer opens the box by pulling the tab3010to remove the tear-off strip3005, and then separates the sub-packages3020as required for use. Each polypill20can be removed by pressing against the rear wall3025of the cell to push the capsule out through the opposite foil wall3024.

Capsule Assembly Inside the End User Sub-Package

Referring now toFIGS.207-217, this variant is generally the same as the last described variant, except that the end user sub-package is formed as a cap package3080having a plurality of cells3081containing the capsule caps21. Thus, the separate cap package and collar, and the additional actuator of the machine as shown in the last described variant are not required.

Each cell3081of the cap package3080has an open end forming an aperture3082, which may have a projecting rim3083similar to the rim3023of the last described embodiment. In this variant, and in the first embodiment and other variants thereof, the packages may be arranged to mutually interlock with their cells in axial alignment. For example, the drug packages3051and plug package3050may be adapted to include a recess or chamfer3100at the upper end of each cell, and a corresponding projecting collar3101to engage in the corresponding recess3100of the package immediately below. The recess3100of the uppermost drug package3051in the stack receives the rim3083of the cap package3080(which may project through the bottom of the box3002as previously described) to locate the cell3081in axial alignment with the cells311of the rest of the packages. Alternatively, the recess3100and collar3101could be arranged respectively on the lower and upper sides of each package rather than, respectively, the upper and lower sides, and the open end of the cell3081of the cap package3080could define a recess to receive the upwardly projecting collar of the uppermost drug package in the stack. Alternatively, other mutually interlocking alignment features could be provided.

In such arrangements, the recess3100and collar3101may be formed on the previously described movable closure elements2401, but the packages adapted so that the previously described block2400of the package is displaced by the machine1000while the movable closure elements2401remain static.

A plurality of sub-packages3080are assembled together, e.g. with releasable connectors, in a wrapper, or in a box as shown in the last described variant, and then stacked in the machine1000(FIG.1,FIG.102, mutatis mutandis) together with the drug packages3051and the plug package3050, which may contain the capsule body22as well as the plug3070(FIG.201).

As previously described and shown inFIGS.214-217, during operation of the machine1000, the pushrod1110urges the capsule body22followed by the plug3070axially slidingly through the aligned cells311to collect the drug particles3. The capsule body22enters the cell3081via aperture3082before sliding telescopically into the capsule cap21to close the capsule, followed by the plug3070which is received fittingly, optionally sealingly or even hermetically sealingly in the aperture3082to close the open end of the cell3081containing the finished capsule20. In the illustrated example, the prongs3073move resiliently outwardly to engage latching surfaces3074with the axial abutment surface3084of the aperture3082, retaining the plug3070in the aperture3082to form a permanent part of the end user sub-package3080.

Referring toFIGS.207-211, the cap package3080may be formed as a clamshell style assembly of front and rear mouldings3085,3086which are connected together, e.g. by an ultrasonic weld line3087that extends around each cell to join together the confronting, flat surfaces3088,3089of the two parts.

During assembly of the cap package3080, each capsule cap21may be arranged over the rounded end of a respective cylindrical rod (not shown), equal in diameter to the capsule body22. The rods are laid in the open half cells3081of the rear moulding3086with the caps positioned in the slightly larger diameter, upper end portion of the cell, in which they are retained by the axial abutment surface3093located between the upper and lower portions of the cell3081. The rods (not shown) remain in place while the two mouldings3085,3086are welded together, and are then withdrawn axially through the cell apertures3082leaving the caps in place inside the cell.

Weakened break lines3090may be defined in the package mouldings3085,3086to define a detachable portion3091of the cell wall. A tab3092may be formed as part of the detachable portion3091so that in use, the end user may press against the tab3092to break away the detachable portion3091of the cell wall to open the cell3081to remove the finished capsule20, as shown inFIGS.212and213. The detachable portion3091may detach entirely or, as shown, partially to form a hinged flap.

Automated Assembly

In each of its embodiments, instead of a human operator, the machine may be configured as an integral part of a fully automated system, so that all its functional features are machine controlled. In this case the machine need not include features configured for human use, e.g. handles, a user interface or an outer casing or door, except as required, e.g. to control and monitor the system or to retain a modified atmosphere or negative pressure. The pressure plate and/or front plate or equivalent features, where present, may be operated by actuators.

The machine may not include a front plate. The machine may not include a moving frame assembly. The machine may not include a pedestal block. The pressure plate, if present, could move in translation, rather than in rotation, to accommodate loading of the packages as well as to accomplish the assembly stroke.

The steps of reading the package labels and printing the end user package label could be accomplished during, before, and/or after the assembly stroke.

Where the cap package includes a flap that will become the end user package label, the flap could be printed before or after sticking it to cover the respective side of the finished end user package. The release paper could be a flexible sheet or a stiffer sheet of card. The machine could grip and rotate the tab of the release paper to open the flap for the assembly operation, and then rotate and lift the tab to remove the release paper before sticking down the flap. Alternatively, the adhesive could be applied to the flap during assembly.

Alternatively, the end user package label could be formed as a separate part that is applied to the end user package after the assembly stroke, rather than as a surface of the box of an end user multipack or as a flap that forms a part of the cap package. For example, it could be a self adhesive label mounted on a release paper, perhaps formed on a roll. The label could be peeled from the release paper as the release paper passes around a roller. The end user package label could be applied to the end user package either before or after it is printed.

Robotic handling machines may be arranged to select and retrieve the packages from a storage location and deliver them to the machine. Similar handling machines may remove the finished end user package from the machine and prepare it for delivery to the end user, e.g. via a local pharmacy, or by post to the user's home address. The customer name, address and other details may be printed by the apparatus on the end user package, the patient information leaflet and/or a separate adhesive label when preparing the end user package. The empty packages may be removed by the handling machine and placed in a bin to be returned to the manufacturing location for recycling as previously described.

Common Features of the First Embodiment and Variants Thereof as Described Above

It will be understood that each of the first embodiment and its variants as described above defines, by way of example, an assembly system and method for filling drugs into capsules to produce customised polypills in the form of capsules20.

The assembly system includes the following common features:—An assembly apparatus (e.g. the first or variant first machine100,1000).A plurality of packages, including at least first and second drug packages, each package of the plurality of packages including a plurality of cells.Each cell of the first drug package includes a single dose of a first drug, while each cell of the second drug package includes a single dose of a second drug.Each cell of each drug package includes only one single dose of the respective drug.The assembly apparatus is configured to receive the plurality of packages including at least the first and second drug packages, to receive a plurality of capsule caps21and capsule bodies22, and to combine together the first and second drugs of the first and second drug packages to form a plurality of capsules20.For each capsule20of the plurality of capsules, the single dose of the first drug of a respective one of the cells of the first drug package is encapsulated, together with the single dose of the second drug of a respective one of the cells of the second drug package, between a respective said capsule cap21and capsule body22.

The method includes the following features:—Providing first and second drugs, and a plurality of packages, the plurality of packages including at least first and second drug packages, each package of the plurality of packages including a plurality of cells.Packaging the first drug in the first drug package so that each cell of the first drug package includes a single dose of the first drug, and packaging the second drug in the second drug package so that each cell of the second drug package includes a single dose of the second drug, wherein only one said single dose is packaged in each respective cell of each respective drug package.Receiving in an assembly apparatus (e.g. the first or variant first machine100,1000) the plurality of packages including at least the first and second drug packages together with a plurality of capsule caps21and capsule bodies22, and operating the assembly apparatus to combine together the first and second drugs of the first and second drug packages to form a plurality of capsules20.For each capsule20of the plurality of capsules, the single dose of the first drug of a respective one of the cells of the first drug package is encapsulated, together with the single dose of the second drug of a respective one of the cells of the second drug package, between a respective said capsule cap21and capsule body22.

Preferably, in each of the first embodiment and its variants as described above, each single dose comprises one or more particles, wherein the particles of all said single doses are of equal size and shape, and each of the cells of the first drug package includes an equal number of particles, and each of the cells of the second drug package includes an equal number of particles.

By equal shape is meant, of substantially the same shape—for example, all of the particles may have a spheroidal shape. A spheroid may be, for example, a sphere, or a sphere with a raised belly band.

By equal size is meant, of substantially equal size, or within a relatively narrow target size range. For example, each particle could have a maximum dimension within +/−5%, preferably +/−3%, more preferably +/−2%, yet more preferably +/−1%, of a mean maximum dimension.

Further preferably, in each of the first embodiment and its variants as described above, each particle has a dimension of at least 1.5 mm.

Further preferably, in each of the first embodiment and its variants as described above, each particle is a spheroid3with a diameter of at least 1.5 mm.

Preferably the dimension of each particle, or the diameter of each spheroid, is at least 2 mm, more preferably at least 2.5 mm, for example, about 2.8 mm.

The dimension is taken in a straight line through the geometric centre of the particle.

Most preferably, the diameter of each spheroid is less than one half, and greater than one third, of the internal diameter of the capsule body. This ensures that the spheroids can pass one another to achieve an optimal packing density without jamming inside the capsule body.

Further Variant Embodiments for Producing Polypills as Capsules, Wherein Each Single Dose is Packaged in a Respective Cell of a Respective Drug Package

Further variant embodiments which include the common features of the first embodiment and variants thereof, as listed above, will now be described, including a variant described below under the heading “Single dose drug packages and bulk capsule components”.

In each of these further variant embodiments, each single dose is packaged in a respective cell of a respective drug package, and each single dose comprises one or more particles3, wherein the particles of all said single doses are of equal size and shape, and each of the cells of the first drug package includes an equal number of particles, and each of the cells of the second drug package includes an equal number of particles. That is to say, all of the cells of the first drug package include the same number n1 of first particles, and all of the cells of the second drug package include the same number n2 of second drug particles, wherein n1 and n2 are whole numbers equal to or greater than 1. Each particle has a dimension of at least 1.5 mm.

By equal shape is meant, of substantially the same shape—for example, all of the particles may have a spheroidal shape. A spheroid may be, for example, a sphere, or a sphere with a raised belly band.

By equal size is meant, of substantially equal size, or within a relatively narrow target size range. For example, each particle could have a maximum dimension within +/−5%, preferably +/−3%, more preferably +/−2%, yet more preferably +/−1%, of a mean maximum dimension.

Preferably, each particle is a spheroid3with a diameter of at least 1.5 mm.

Preferably the dimension of each particle, or the diameter of each spheroid3, is at least 2 mm, more preferably at least 2.5 mm, for example, about 2.8 mm.

The dimension is taken in a straight line through the geometric centre of the particle.

Most preferably, the diameter of each spheroid is less than one half, and greater than one third, of the internal diameter of the capsule body. This ensures that the spheroids can pass one another to achieve an optimal packing density without jamming inside the capsule body.

As with the previously described embodiments, if the volume of the combined drugs1,2is too great to be enclosed in a single capsule20, then the dose may be divided between two of more capsules20. Thus, the single dose contained in each capsule20may represent a total therapeutic amount constituting a single dose of the respective drug1,2, or a fraction of a total therapeutic amount, wherein two or more identical polypills20are to be taken together, said fractions when combined together constituting the total therapeutic amount of the respective drug1,2in a single dose.

The term “particle” is synonymous with the term “granule” as referred to above. The first and second particles may be configured and manufactured as described for the earlier embodiments, preferably as spheroids3. Advantageously, by packaging and subsequently encapsulating each single dose in the form of one or more relatively large, discrete particles, preferably spheroids, the method avoids contaminating the assembly apparatus with a finely divided powder, as is commonly employed when encapsulating conventional, fixed dose combinations. (This is the case even where the machine is optionally arranged to come into direct contact with the particles during assembly, as further described below in another variant embodiment under the heading “Bulk drug packages and bulk capsule components”.) This makes it possible to form multiple batches of customised polypills without stripping down and radically cleaning the machine between batches. The machine may incorporate a cleaning system (e.g. cleaning rods, not shown, that reciprocate in its internal passageways, e.g. in the chutes of the filling apparatus2430when configured as a dosing apparatus4070, further discussed below under the heading “Bulk drug packages and bulk capsule components”) that can be used to remove any broken or stuck drug particles between operations.

Thus, each single dose of the first particles3may be defined by a first target number of the first particles3, and each single dose of the second particles3defined by a second target number of the second particles3. That is to say, the single dose of each drug1,2may be defined by the number of particles3, rather than in terms of mass or volume as is conventional in powder filling techniques.

This may be facilitated particularly by arranging for each particle3to contain a consistent quantity of the respective drug1,2, e.g. by forming the particles3by known tabletting techniques, or perhaps by spheronization where the diameter of each spheroid is closely controlled, e.g. including a grading step after spheronizing to remove, optionally also reprocess any spheroids outside a narrow, target diameter range. Alternatively or additionally, spheronized particles could be further processed to obtain a constant diameter (e.g. by abrading or rolling between opposed surfaces) and then perhaps also graded by mass.

Preferably, the particles3are of equal mass, which is to say, of substantially equal mass, wherein the mass of each particle lies within a relatively narrow range. For example, the mass of each particle could lie within +/−10%, preferably +/−5%, more preferably +/−3% of a mean mass. The particles could be graded by mass to remove out-of-specification particles, for example, by centrifugal separation, or by a winnowing process in which the particles fall through a moving current of dry gas, with lighter particles being deflected by the gas to a reject bin, over-weight particles being deflected relatively little and falling nearly directly into another reject bin, and particles in the target range being deflected by an intermediate degree to fall into a target bin.

As in the previous embodiments, the assembly apparatus may be further configured to package the plurality of polypills20in individual cells of an end user package, each cell sealingly enclosing a respective one of the polypills20and being openable by an end user to remove the polypill from the cell, as further discussed below. This may be preferred because it extends shelf life after delivery to the customer, and obviates the possibility of misdentification which could occur for example after a bottle containing a quantity of capsules is first opened, after which it is no longer possible to verify its contents. Alternatively however, the polypills20could be packaged together in a single container.

The capsule caps21and bodies22may be packaged singly in individual cells311of capsule cap and body packages, e.g. as illustrated in the first and variant first embodiments, or may be provided as bulk capsule components as further described below.

End User Package Containing Polypills in the Form of Capsules

It will be appreciated that each of the first embodiment and its variants as described above provides an end user package including a plurality of capsules, wherein each capsule includes a single dose of a first drug, and a single dose of a different, second drug. Each capsule contains a plurality of particles, a first one or first ones of the particles containing the first drug but not the second drug, a second one or second ones of the particles containing the second drug but not the first drug.

In accordance with another aspect of the invention, in such an end user package, the first and second ones of the particles are spheroids3having a mean diameter of at least 1.5 mm, and all of the capsules contain an equal number of said first one or first ones of the particles, and all of the capsules contain an equal number of said second one or second ones of the particles. That is to say, all of the capsules contain the same number n1 of the first particles, and the same number n2 of the second particles, wherein n1 and n2 are whole numbers equal to or greater than 1.

By mean diameter is meant the average diameter of all of the particles. By diameter is meant the maximum diameter of the particle. For example, if the particle is a spheroid in the form of a sphere with a belly band, i.e. a slightly raised equatorial region (commonly formed when tablets are formed by pressing), then the diameter is taken across the belly band (which is to say, between oppositely facing surfaces of the belly band, in a diametric plane passing through the belly band).

In this aspect of the invention, preferably the spheroids have a mean diameter of at least 2 mm, more preferably at least 2.5 mm, for example, about 2.8 mm.

In this aspect of the invention, preferably all the spheroids are of equal diameter. By equal diameter is meant, of substantially equal diameter, or within a relatively narrow target diameter range. For example, each particle could have a diameter within +/−5%, preferably +/−3%, more preferably +/−2%, yet more preferably +/−1%, of the mean diameter.

Most preferably, the diameter of each spheroid is less than one half, and greater than one third, of the internal diameter of the capsule body. This ensures that the spheroids can pass one another to achieve an optimal packing density without jamming inside the capsule body.

End user packages that may be produced in accordance with this aspect of the invention (e.g. end user packages300,1300,3001,1380) are described above, and further such packages (e.g. blister packages4062) that may be produced in accordance with this aspect of the invention are described below. In yet further variants, the end user package need not include individual cells in which the polypills are packaged individually, as exemplified by each of the illustrated embodiments; it could be a container, for example a bottle or a packet, containing a quantity of the capsules.

Further Variant Embodiments with Bulk Capsule Components

The further variants of the first embodiment discussed below with reference toFIGS.218-230illustrate how the capsule caps21and bodies22may be introduced in bulk form into the assembly machine, instead of packaging them in individual cells of cap and body packages as in the first embodiment and its variants as previously described.

Referring toFIG.218, the assembly machine4000may be adapted to receive the capsule components in bulk form, e.g. in a bulk capsule cap package4001and a bulk capsule body package4002as illustrated. The packages4002,4002contain, respectively, in a single compartment or individual compartments, multiple caps21and multiple bodies22, which are dispensed from the packages into a capsule assembly mechanism of the machine4000. Alternatively, a single bulk package could contain, in one compartment or individual compartments, multiple empty capsules which the machine is configured (in a manner known in the art) to separate into their caps21and bodies22prior to assembly of the polypill20.

The capsule assembly mechanism can take any conventional form as known in the art, but in the illustrated examples includes a capsule body handling mechanism4010, which defines one or more capsule body chambers4011for receiving the capsule bodies22, and a capsule cap handling mechanism4020which includes one or more capsule cap chambers4021for receiving the capsule caps. A closing mechanism is also provided, which as illustrated may include one or more pushrods4030which extend axially through the body chambers to urge the capsule components21,22together.

In such arrangements, as illustrated by the variant embodiment described below under the heading “Single dose drug packages and bulk capsule components”, each of the first and second drug packages may include a plurality of cells311, wherein each cell311contains only one said single dose of the respective, first or second drug. Each drug package may be as earlier described with reference to the first and embodiment and variants thereof, e.g. drug packages301or1301which are closed by foil or, as illustrated, drug packages2301which are closed by movable closure elements.

Alternatively, as illustrated by the further variant embodiment described below under the heading “Bulk drug packages and bulk capsule components”, each of the first and second drug packages may be a respective, bulk drug package4071,4072, including more than one single dose of the respective, first or second drug1,2in the form of a quantity of relatively large particles3of equal size and shape contained in a single compartment. In this case, a dosing apparatus4070may be arranged to dispense a quantity of the particles3corresponding to a single dose of the first or second drug1,2which are encapsulated between the cap and body components21,22as further discussed below.

One way to do this is by defining a first target number of the first particles3and a second target number of the second particles3required to form said respective single dose, as mentioned above; and, for each of the plurality of polypills20, removing from the respective first and second bulk drug packages4071,4072and encapsulating between the respective capsule cap21and capsule body22the first target number of the first particles3and the second target number of the second particles3to form the respective polypill20.

For example, as shown inFIG.230and further described below, the dosing apparatus4070may be arranged to transfer an exact number of particles3into a dosing chamber or capsule body in a single operation. In the illustrated example, the dosing apparatus4070comprises two filling apparatuses2430, each of which is generally as previously described and illustrated inFIGS.160-163, but adapted mutatis mutandis to fill a single capsule body22seated in the capsule body chamber4011, instead of a respective cell of the drug package as previously described.

In the first embodiment and variants thereof as discussed above, the assembly apparatus may be configured to form the polypills20without direct contact between the assembly apparatus and any of the capsule cap21, the capsule body22, and the first and second drug particles3. This may be achieved by packaging the capsule components21,22and drug1,2doses singly, combining the doses together within the cells of the packages, and arranging the carrier320,1320or plug3070in-between the pushrods110,1110and the capsule components. In this way, even if the machine100,1000should become contaminated, e.g. by making a set of polypills from contaminated packages, or by a worker with dirty hands, a subsequent set of polypills made in the same machine, even without cleaning the machine, will not be contaminated by contact with the machine components. This helps to make it possible to operate the machine with high productivity, even in an environment such as a pick-and-place warehouse or logistics centre where less stringent cleaning routines are used in place of traditional pharmacy procedures.

Alternatively however, the assembly machine may be configured to manipulate the capsule components21,22by direct contact with contact surfaces of the machine.

In such arrangements, as exemplified by the variant embodiment further discussed below under the heading “Single dose drug packages and bulk capsule components”, the machine need not come into contact with the drug particles3, which by virtue of their consistent, relatively large size and shape, tend to roll in a predictable manner in contact with the surfaces of the package cells and capsule components during assembly. A spheroidal shape is particularly preferred because it ensures a rolling motion of the particles in any orientation. This minimises the risk of contamination of the machine by drug fragments. Thus, where sterile capsule components are loaded into the assembly machine in bulk packages4001,4002, the machine may still be operated substantially without the risk of contamination or cross-contamination between successive batches of polypills containing different drugs for different customers.

In yet further such arrangements, as exemplified by the further variant embodiment discussed below under the heading “Bulk drug packages and bulk capsule components”, the machine may contact both the capsule components and the drug particles3. In such arrangements, although there is direct contact with machine components, the consistent shape and relatively large size of the preferably spheroidal particles3again minimises the risk of entrapment of particles3or damage to the particles3leading to cross-contamination.

Most preferably in each case, the particles3are spheroids with a diameter less than one half, and greater than one third, of the internal diameter of the capsule body22. This ensures that the spheroids3can pass one another to achieve an optimal packing density without jamming inside the capsule body22, which further ensures reliable and repeatable assembly without contamination of the machine.

In each of the below described variant embodiments, as in the previously described first embodiment and variants thereof, a package label may be produced by the machine4000to list the first and second drugs1,2and optionally also related information, e.g. customer information1080which may be downloaded from the server as previously described. The label could be printed or stuck directly on the blister pack4062or other end user package and/or on an outer wrapper, e.g. a box4061or a bag in which the end user package is delivered to the end user, as shown inFIGS.228and229. The label may be produced from indicia or data captured from the (bulk or cellular) drug packages2301,4071,4072, either in visible or non-visible form, e.g. as a barcode or an electronic ID tag. In each case, the label may include a composite label1312which reproduces the visible indicia captured from the drug packages as a reproduced image as earlier described.

The (bulk or cellular) first and second drug packages2301,4071,4072may be arranged with other drug packages in the apparatus, e.g. in a carousel (not illustrated) or in a defined location in a pick-and-place mechanism, and the assembly machine4000arranged to select the required drug packages for each set of polypills according to the prescription data which are received by the machine; alternatively, the drug packages2301,4071,4072could be inserted and removed manually for each operation.

As with the other variants of the first embodiment, the assembly machine4000may include data upload/download and drug (optionally also capsule component) serialization data validation and anti-counterfeiting functions similar to those of the first and variant first machines100,1000as described with reference toFIG.1.

Single Dose Drug Packages and Bulk Capsule Components

Referring first to the example ofFIGS.218-229, as in the first embodiment and variants thereof as previously described, each of the first and second drug packages2301includes a plurality of cells311, wherein each cell311contains only one said single dose of the respective, first or second drug1,2as a defined number of relatively large particles3of equal size and shape. Each cell311contains the same number of particles3. The assembly apparatus comprising assembly machine4000is configured, for each of the polypills20, to urge at least one of the respective capsule cap21and capsule body22(as illustrated, the capsule body22) through corresponding, axially aligned cells311of the first and second drug packages2301to encapsulate the respective first and second particles3between the capsule cap21and the capsule body22.

In this way the machine is isolated from the drug particles3and contacts only the cap21and body22of the capsules, reducing the possibility of cross-contamination between successive operations, particularly when the particles3are formed as spheroids to minimise damaging interactions with the cell walls of the drug packages during assembly.

The relatively large dimension of the drug particles3, which preferably is the diameter of the spheroids3, ensures that the drug particles or spheroids3do not become trapped between the pushrods4030of the machine and the other machine parts or the cell walls of the drug packages2301, and so helps avoid cross-contamination between different batches of polypills20.

As shown inFIG.218, the drug packages2301may be introduced into the machine4000via window4004and stacked with their corresponding cells311in axial alignment as in the earlier described embodiments. The cap21and body22of the capsule may be positioned in axial alignment with the cells311(hence, on the cell axis Xc.) This can be achieved as shown by dispensing the capsule components21,22from their bulk packages4001,4002into the capsule cap and body chambers4021,4011, and arranging the stacked drug packages2301in-between the capsule body handling mechanism4010and the capsule cap handling mechanism4020so that the capsule body and cap chambers4011,4021containing the respective capsule body22and cap21are aligned with the cells311of the drug packages2301, as shown inFIG.222. As indicated by the arrow inFIG.218, relative axial movement may be provided between the capsule body handling mechanism4010and the capsule cap handling mechanism4020to accommodate the stacked drug packages2301and maintain the stack in compression during the capsule assembly operation. The first and second drug particles3are then combined together within the axially aligned cells311of the drug packages2301.

The drug packages may be formed as described in the earlier, first and variant first embodiments; for example, as drug packages closed by foil, e.g. drug packages301or1301, or with movable closure elements such as drug package2301as illustrated. In the illustrated example, first and second drug packages2301are formed in the same way as drug package2301described earlier, and the machine4000is configured to move the movable closure elements or foraminous plates2401to the open position before each capsule body22is advanced by a respective pushrod4030through the aligned cells311, collecting within it the drug particles3from each of the drug packages2301(FIG.223).

As best seen inFIG.221, the capsule cap handling mechanism4020may include a cap chamber4021separated by a shutter4023from a capsule transfer chamber4022. The cap chamber4021may have a reduced diameter aperture defined by a radially inwardly extending retaining collar4026which retains the cap21in the cap chamber4021during assembly of the capsule.

Each cap21may be dispensed from the bulk cap package4001into the cap chamber4021, for example, via a filling aperture4025closed by another shutter4024. This could be achieved, for example, by opening the shutters4023,4024and passing an insertion rod (not shown) via the collar4026, through the cap and transfer chambers4021,4022, then positioning the cap21on the rounded distal end of the insertion rod (not shown) and retaining it there by another, confronting, collinear, smaller diameter retaining rod (not shown). The rods and cap are moved axially simultaneously to position the cap in the cap chamber4021. Then the retaining rod is withdrawn via the filling aperture4025and the shutter4024is closed before withdrawing the insertion rod through the collar4026. Alternatively, the insertion rod could retain the cap21by suction so that no retaining rod is needed. Those skilled in the art will appreciate that there are many alternative ways to dispense the capsule components from the bulk packages4001,4002and position them in alignment with the cells311of the drug packages2301, and the capsule assembly mechanism can be adapted accordingly. It is possible also that the capsule could be closed in a position not aligned axially with the cells311of the drug packages2301, in which case the cap21need not be aligned on the cell axis Xc as shown.

Returning to the assembly steps as illustrated,FIG.224shows how the capsule body22may enter telescopically into the cap21via the collar4026. The cap may be restrained as shown by the closed shutter4023while the capsule is closed. Then, as shown inFIG.225, the shutter4023may be opened, and the pushrod4030advanced to move the filled capsule20into the capsule transfer chamber4022. The edges of the apertures in the shutter4023may be chamfered or rounded, as may be the distal end of the pushrod4030, so that the shutter4023can then be closed between the capsule20and the pushrod4030without damaging the capsule, to urge the capsule20to enter fully into the transfer chamber4022and then retain it therein, as shown inFIG.226.

The assembly machine4000may then be operated to package the plurality of polypills20in individual cells4064of an end user package, which as illustrated may be a blister pack4062. Each cell4064sealingly encloses a respective one of the polypills20and is openable by an end user to remove the polypill20from the cell. Several such blister packs4062may be filled with the capsules produced from one set of drug packages2301, thus forming end user sub-packages which can be assembled together, e.g. in a box4061to form the end user package4060. A patient information leaflet266may be printed as previously described and included in the box4061.

As shown inFIG.227, the finished capsules20may then be moved to a packaging station4050of the machine4000. This can be achieved, for example, by detaching the capsule cap handling mechanism4020from the capsule body handling mechanism4010and then moving it, e.g. in rotation and translation as shown, to the packaging station4050. The packaging station4050may be configured to fill and seal blister packs4062, and may be supplied in bulk with pre-formed, generally conventional blister pack trays4063(FIG.219) and foil314(e.g. a plastics film, metal foil, metallised film or the like) for sealing the trays.

As shown inFIG.230, each of the capsule transfer chambers4022may be arranged to communicate with an individual cell4064of a blister pack tray4063. A capsule release shutter4027may then be opened to release each capsule from the transfer chamber4022into the respective cell4064(FIG.220), optionally by means of a capsule ejection mechanism (not shown), before closing the cells with the foil314, e.g. by heat, pressure, ultrasonic welding, adhesive or other techniques as well known in the art. Each cell4064is openable by the end user to remove the single polypill20contained therein by pressing the polypill20through the foil314, as well known in the art. The blister pack4062may present a surface on which the package label can be printed, as shown inFIG.228.

As with the previously described embodiment, the machine may include an array of pushrods4030corresponding to the array of cells in the drug package (e.g.48pushrods, or 48 pairs of pushrods, for a 48 cell package). The capsule assembly mechanism may be configured with separately movable machine parts (e.g. separately movable capsule cap handling mechanisms4020) for each row of cells, so that each row of capsules20can be formed by axial movement through the cells311of the drug packages2301, and then transferred laterally out of the respective machine part (e.g. transfer chamber4022) into the respective cell4064of the blister pack4062or other end user package. For simplicity, only one such separately movable machine part4020is illustrated.

In alternative arrangements, not shown, the machine may include a pair of opposed pushrods for each capsule20, wherein one or each pushrod defines a respective cavity to receive a part or the whole of the respective capsule body22or cap21. The cavity for the capsule body22may be shaped similarly to that of the carrier320or1320, defining an annular space which receives the cap21during assembly. The cap21and body22may thus be closed together within the aligned cells311of the drug packages. The closed capsule or polypill20containing the combined particles3forming a single dose of each of the first and second drugs1,2may then be transferred to a packaging station4050. The transferring step may include moving the capsule20out of the aligned cells311of the packages by the movement of one of the pushrods, or the simultaneous movement of both of the pushrods, in the axial direction of the cells311, optionally followed by another movement away from the cell axis, e.g. in rotation and translation as in the illustrated embodiment.

Bulk Drug Packages and Bulk Capsule Components

FIG.230illustrates a further alternative variant in which the drug particles3are loaded into the assembly machine4000(FIG.218) in first and second bulk drug packages4071,4072, each of which contains a large quantity of the relatively large, preferably spheroidal drug particles3of equal size and shape. The particles3in the first bulk drug package4071contain the first drug1but not the second drug2, whereas the particles in the second bulk drug package4072contain the second drug2but not the first drug1.

Of course, the machine4000may be arranged to receive more than two bulk drug packages, or even just one bulk drug package, for any given set of polypills20. (As previously discussed, using the system to make capsules containing just a single drug may be helpful to obtain a customised dosage of the drug, where different drug packages contain particles with different dosages, or to reduce stockholding by supplying less commonly prescribed, single drugs in the same packaging as the polypills.)

In the illustrated example, the capsule cap handling mechanism4020and packaging station4050are arranged as described in the previous example to close the capsules and package them in blister packages4062, but the machine4000does not have a window4004for receiving cellular drug packages2301. Instead, the capsule body handling mechanism4010is adapted to cooperate with a dosing apparatus4070, which may comprise two filling apparatuses2430as previously described and shown inFIGS.160-163. Other dosing or filling mechanisms could be used as known in the art.

As illustrated, the capsule body handling mechanism4010may be configured as a carousel (e.g. a rotating disc) which moves in turn through a series of stations at which consecutive operations A-H are performed. Of course, many alternative arrangements are possible as well known in the art of filling capsules.

At stage A, each capsule body22may be dispensed from the capsule body package4002into the capsule body chamber4011to receive the drug particles3, as shown. In an alternative arrangement (not shown) the drug particles3may be dispensed into the capsule body chamber11which acts as a dosing chamber, and afterwards transferred to the capsule body22, e.g. by inserting the capsule body22into the dosing chamber to collect the drug particles3present therein.

At stage B, the first filling apparatus2430fills a single dose consisting of five particles3of the first drug1from the first bulk drug container4071, then the capsule body chamber4011moves to the next filling position C in which the next filling apparatus2430fills it with another six particles of the second drug2from the second bulk drug container4072, all of said particles3being of equal size and shape. Alternatively, as also described above with reference to the filling apparatus2430, the dosing apparatus4070may be operated for a defined number of operations to introduce one or more particles3on each operation, until the defined number of particles3is received in the dosing chamber4011or capsule body22.

The capsule is then closed as previously described in stages D-G, and at stage H moves to the packaging station4050where it is packaged in the blister package4062.

Spheroidal particles3are particularly preferred since their packing density, and their mechanical interaction with the assembly apparatus, is not affected by their spatial orientation. Moreover, a rounded surface allows each particle to move rollingly through the assembly apparatus, for example, when transferring from the filling chute2434into the dosing chute2436of the above described filling apparatus2430as shown inFIGS.160-163. The rounded surface avoids damage by entrapment between machine parts. For example, it allows the solid upper face of the dosing body to lift the column of spheroids3remaining in the filling chute2434through a small distance of less than half a particle diameter, representing the tolerance in the length of the dosing chute2436for variations in particle diameter, as the dosing body2435moves towards the dosing position. This is evident from the position of the lowest particle3visible inFIG.160, which extends slightly below the upper end of the dosing body2435. A rounded lower edge (not shown) of the filing chute2434can gently engage the lowest particle to assist this slight upward movement of the column.

Machine for Producing Polypills in the Form of Pastilles—Overview

Byway of example, the second embodiment provides an assembly apparatus in the form of a second machine500,5000for use in a pharmacy to assemble together a plurality of second packages701,702,703,704,705,7001,7002,7003,7004,7005. Each of the second packages includes a frame710defining a plurality of cells711, which are separated by the frame to form a spaced array.

The second and variant second machines500,5000include an alignment structure for guiding the plurality of packages in a stacked configuration with each of the cells711of each package in axial alignment with a corresponding one of the cells711of each other package of the plurality of packages701,702,703,704,705,7001,7002,7003,7004,7005.

In this specification, a stacked configuration includes a stack in any orientation, irrespective of whether formed along a vertical or horizontal or inclined axis, and irrespective of whether the packages of the stack are spaced apart in superposed, parallel relation, or pressed together in superposed, parallel, abutting relation.

The second and variant second machines500,5000further include a compression mechanism for compressing together the frames710of the plurality of packages in the stacked configuration to form an assembly defining an end user package700,7000(FIG.80).

In the illustrated embodiments, the compression mechanism includes a pair of opposed pressure plates521which are urged together by actuators523to compress the stacked packages between their opposed compression surfaces522. Although the opposed compression surfaces522of the pressure plates521are illustrated as flat in the first machine of500, they may be contoured, e.g. as shown in the variant second machine5000, to correspond to the different thicknesses of different portions of the end user package700,7000, e.g. including protruding portions522′ to engage the respective parts of the composite label assembly712as shown, and/or to apply pressure to the frames710of the stacked packages without applying pressure (or while applying relatively less pressure) to the cells711.

The alignment structure may include alignment surfaces550that engage an outer profile of the packages in an assembly position. As exemplified by the second machine500, such alignment surfaces may include upper and lower alignment surfaces550(FIG.76) and front and rear alignment surfaces550(FIG.75) which constrain the packages in an aligned, horizontally stacked configuration in the assembly position, as shown inFIGS.75and76, before and during operation of the compression mechanism to produce the end user package700.

Alternatively or additionally, the alignment structure may include alignment elements that engage the packages to maintain the packages in parallel relation. In use, the machine may be configured to slide the packages together along the alignment elements, optionally by operation of the compression mechanism. The alignment elements may form part of a package transfer assembly that is operable to move the packages from an initial, receiving position to an assembly position in which the packages are compressed together by the compression mechanism. The package transfer may be further operable to move the end user package, formed by compressing the packages together, from the assembly position to a delivery position, e.g. a delivery window507as illustrated inFIGS.88and90.

The alignment elements could engage correspondingly profiled portions of the packages, e.g. at the edges of the packages or in apertures formed in the packages.

Such alignment elements could engage, for example, recesses or other profile features at an outer edge of the packages, so that they can engage and release the packages by moving inwardly or outwardly in a direction of the plane of the major, front and rear surfaces of the packages.

Alternatively, such alignment elements could engage the packages by gripping the packages, e.g. by means of opposed gripping portions that act on opposite parts of the major, front and rear surfaces of the packages, e.g. in a similar way to the grippers553of the alignment mechanism of the variant second machine5000as further described below.

Alternatively, such alignment elements could engage in apertures formed in the packages, so that they can engage and release the packages by moving axially through the packages in a direction normal to the plane of the major, front and rear surfaces of the packages.

This latter arrangement is exemplified by the variant second machine5000which provides a plurality of (e.g. three, as shown) alignment elements in the form of package locator rods551which are axially movable to engage in a pattern of locator rod apertures751in each of the packages7001,7002,7003,7004,7005.

The package locator rods551may be mounted as shown to a package transfer actuator body552to form a package transfer assembly, which is movable from the position ofFIG.96to the position ofFIG.97to transfer the packages7001,7002,7003,7004,7005from the receiving slots501,502,503,504,505to the assembly position in which the stacked packages are located in-between the compression surfaces522. The packages can slide along the locator rods551as they are compressed together to form the end user package7000.

In another possible arrangement (not shown), where the packages are arranged to slide along the package locator rods or other alignment elements, the package locator rods or other alignment elements could be arranged to move together with the compression mechanism when removing the packages from the receiving slots. For example, the package locator rods could be advanced through holes in the pressure plates to engage in the locator rod apertures751in the stacked packages, before moving the pressure plates and locator rods away from the receiving position, to extract the packages from their temporary covers which remain in the receiving slots of the machine, as shown. Once the packages and locator rods are in the assembly position, clear of the receiving slots, the compression mechanism may be activated to compress the stacked packages to form the end user package. Then, the locator rods and pressure plates may be moved again to locate the end user package at a delivery window507of the machine, before retracting the locator rods and separating the pressure plates to allow removal of the end user package.

The locator rods may be arranged as shown to maintain the packages in parallel relation. In the variant second machine as illustrated there are three locator rods551which are spaced apart in two orthogonal dimensions (the height and width dimensions of the packages). Since the locator rods551are a sliding fit in the locator rod apertures751, the packages are constrained by the locator rods to remain in parallel relation with their height and width dimensions normal to the locator rods.

Optionally as shown, in order to further constrain the packages in normal relation to the locator rods, an additional alignment mechanism can be employed, e.g. with grippers553mounted on an alignment body554, to move the packages closer together along the alignment elements before compression begins; alternatively, the alignment mechanism553,554need not be provided, and the packages could remain at their initial spacing as received in the machine until they are urged together by the compression plates521.

The assembly apparatus500,5000may include a plurality of elongate slots501,502,503,504,505, each slot being configured to receive a respective one of the packages701,702,704,704,705,7001,7002,7003,7004,7005. Each slot may include a shape profile, e.g. as shown inFIG.77, configured to selectively fit or obstruct a corresponding shape profile of a respective one of the packages introduced into the slot. Different ones of the slots may have different shape profiles.

The abutment surfaces defined by the slots or other package receiving portions of the machine may be configured, e.g. as shown, to engage and retain the temporary covers706,707of each package when the frame710of the package is detached from the temporary covers and moved to the assembly position. The temporary covers706,707remaining in the slots can then be removed by the user for disposal before the next assembly operation.

In the illustrated embodiment, the slots501,502,503,504,505are identified by indicia, with slots504,505marked [A] and [B] respectively being configured to receive the front and rear cover packages704,705respectively, and slots501,502,503marked [1], [2] and [3] respectively being configured to receive drug packages, wherein the first drug package701is inserted into slot [1] (501), the second drug package702(if present) is inserted into slot [2] (502), and the third drug package703(if present) is inserted into slot [3] (503).

It should be understood that any of the drug packages701,702,703can be introduced into any of the three drug package slots501,502,503; the point is that if there is only one drug package then it should be in slot501, and if there are only two drug packages then they should be in slots501and502. The order of priority of the slots ensures that the composite label assembly712is correctly configured (because different slots have differently positioned label cutters), while the different shape profiles of the slots are arranged to prevent each package type from being introduced into the wrong slot, as further explained below.

In order to ensure that the user does not introduce packages into the third, or second and third slots502,503while leaving the first, or first and second slots501,502empty, the machine500,5000may be configured to obstruct access to the second and third slots until the first slot is filled, and to obstruct access to the third slot until the second slot is filled. This could be done for example by advancing the respective punches519to an obstructing position. Alternatively or additionally, the scanners561or other sensors could be used to sense the presence of the packages and send a signal to the controller262to prevent operation of the machine if the slots are not correctly occupied. Lights could be used to indicate which slot should be filled next.

The alignment structure can be any convenient arrangement for maintaining the packages in alignment while the frames are pressed together. For example, the packages could be aligned using rods or other structures that engage corresponding shaped portions of the packages while the packages slide towards each other along the alignment structures, e.g. by operation of the compression mechanism, as exemplified by the variant second machine5000.

Instead of moving all the packages simultaneously from an initial position into the assembly position as shown, the machine could be arranged to move the packages one by one into a stacked configuration, perhaps urging them together to adhere to one another as each package is added to the stack. Alternatively, the packages could be placed in a stacked configuration by the user, instead of moving them automatically from an initial receiving position as shown. The packages could be stacked vertically (i.e. one on top of another) instead of horizontally (i.e. in a row next to one another) as shown, either by the user (one by one) or by operation of the machine (simultaneously or one by one). For example, the package receiving portion of the machine could be arranged at 90° to the illustrated configuration so that the slots extend horizontally and are spaced apart to form a vertically rather than horizontally stacked configuration, one above another. The packages could then be moved, simultaneously or one by one, by the package transfer assembly so that each package rests on top of the one below in a vertical stack, either during or before operation of the compression mechanism to press them together.

The machine100,500,5000may include a vacuum generating apparatus which is arranged to create a vacuum, (which is to say, a full or partial vacuum), wherein the machine is arranged to compress together the frames310,710of the plurality of packages within the vacuum.

In the illustrated embodiment, each of the second and variant second machines500,5000includes a vacuum generating apparatus590(shown only inFIG.60) including a vacuum pump591which evacuates a reservoir592. A valve (not shown) is operated by a controller262of the machine, after closing the door530to seal the interior space within the machine, to connect the interior space within the machine to the reservoir592. The evacuated volume of the reservoir592rapidly depressurises the machine500,5000. This speeds up the assembly procedure and may also help in detaching the temporary covers706,707as described below, while the vacuum pump591starts up again to evacuate the reservoir592ready for the next operation.

The machine500,5000may be arranged, before compressing together the frames710of the plurality of packages, to detach and separate the frame710of each of two or more of the packages from a cover or covers706,707removably connected to the frame710. For ease of reference these covers706,707are also referred to herein as temporary covers to distinguish them from the front and rear cover packages704,705, which form the front and rear covers of the end user package and which may also include temporary covers that are removed before assembly.

As exemplified by the illustrated embodiment, the frame710of each package may be coated with a tacky adhesive4. Each of the front and rear cover packages704,705may be coated only on the inwardly facing side of its frame710, while each of the drug packages701,702,703may be coated on both of the two oppositely facing sides of its frame710, as shown.

As previously mentioned, in order to protect the adhesive surfaces4and API films31until the moment of assembly, the frame710of each drug package701,702,703may be enclosed between two removable, temporary covers706,707, each of which is arranged to protect a respective one of the two oppositely facing sides of the frame710. The sticky, inwardly facing side of the frame710of the front cover package704is protected by a removable cover707(FIG.69), while the sticky, inwardly facing side of the frame710of the rear cover package705is protected by a removable cover707(FIG.68).

The removable covers706,707are separated from the frame710of the respective package after closing the door530of the machine500,5000by operation of a punch mechanism519, assisted by the rapid depressurisation of the machine500,5000, as further explained below.

Further Features of the Second Machine

Referring toFIG.60, the second machine500has a casing506with a door530to form a sealable enclosure that can be evacuated by the vacuum generating apparatus590. Within the enclosure are defined the package receiving slots and a package delivery window507from which the user can collect the finished end user package700,7000. A finger recess508may be provided to expose a part of each package to be gripped by the user's fingers while the package is inserted into, or the temporary covers are removed from, the respective slot.

The second machine may be configured to prevent each package type from being introduced into the wrong slot.

Byway of example, this may be achieved by arranging for the shape profiles of different ones of the slots to vary in two, mutually orthogonal dimensions D1, D2of the slot, which limit corresponding dimensions of the packages by abutment between internal surfaces of the slot and the external surfaces of the package. A sequence may be arbitrarily defined for the slots fitting different package types—e.g. front cover package slot504may be first in the sequence, then drug package slots501,502,503may be second in the sequence, and rear cover package slot505may be third in the sequence. Dimension D1is then arranged to increase progressively for each slot type in the sequence, while dimension D2decreases progressively for each slot type in the same sequence. This ensures that one of the two dimensions acts as a no-go feature if the wrong package type is introduced into any of the slots.

This arrangement is illustrated inFIG.77with reference to the second machine500, wherein the go/no-go abutment surfaces of each slot are arranged to engage the varying profiles of the different front and/or rear, temporary covers706,707of each package. Alternatively or additionally, the frame710of the package could define the go/no-go abutment surfaces.

Alternatively or additionally, the controller262could be arranged to read the package indicia717during assembly, via the reader561of each slot, and to interrupt the assembly procedure and/or generate an error message (e.g. via screen267) if the wrong package type is detected in any of the slots, or if less than a full complement of drug packages are present but the wrong slots are occupied.

In use, the user selects the required combination of packages and inserts each package into the correct slot. The front and rear cover packages704,705or7004,7005are inserted respectively into slot504(marked [A]) and slot505(marked [B]), while the drug packages are inserted into the drug package slots in their numerical order, i.e. slot501first, then slot502, then slot503, and then the next if further drug package slots (not shown) are provided. Then, if the screen267indicates that the machine500,5000is ready, the user closes the door530which is locked by controller262before starting the assembly operation, commencing with evacuation of the casing506. The door530could be configured to press against the exposed ends of the packages to ensure they are fully inserted into the slots.

The package authentication procedure via the remote computer and database91,90may be carried out generally as described with reference to the first machine100, except that the package data are read by controller262of the second or variant second machine500,5000individually, optionally simultaneously, from each package via the respective reader561,561′ associated with the slot in which that package is received (FIG.72). As with the first machine100and the variant first machine, the package data may be read both before and after the door is closed; reading the package data before the door is closed allows the user to identify and correct any error, while reading the package data after the door is closed allows a high level of confidence to be placed in that data when used for the authentication procedure, since the data is collected during a one-time operation after which each package is irreversibly changed and cannot be used again. Although not illustrated, each machine100,500,5000may be configured to identify and reject a previously used package, e.g. by sensing the altered feature, such as a punched-out region of the package.

The controller262may then activate punches519and label cutters510,511to separate each package from its removable covers and to remove the respective label portions so that the cut regions will reveal the corresponding label portions of the rearwardly positioned packages in the assembled stack (FIG.73).

Each machine may include a package transfer assembly, having an actuator controlled by the controller262, for moving the packages from the receiving position (e.g. slots, as shown) to the assembly position in which they will be pressed together by the pressure plates521. Removing the packages from the receiving position may also accomplish the step of removing the packages from their temporary covers, which may be left behind in the receiving position to be removed by the user after opening the door to collect the end user package700,7000at the end of the assembly process.

Where the packages are received respectively in slots501,502,503,504,505or other positioning features at which an initial operation is performed (e.g. reading indicia from the packages, cutting parts of the packages, and/or removing temporary covers from the packages), the slots or other positioning features may be spaced apart by a sufficient distance to accommodate the cutters510,511, punches519, scanners561, grippers or other functional parts of the machine associated with the slot, which conveniently may be positioned in-between the slots.

The packages may then be moved to the assembly position in which they are urged together by the compression plates521.

FIGS.74and78show the package transfer arrangement of the second machine500, comprising grippers553which are mounted on an alignment mechanism body554.

The grippers553engage the package frames710before the alignment mechanism body554is moved from the receiving position to the assembly position (FIGS.75and79). The grippers are then released and removed with the body554leaving the packages between alignment surfaces550(FIGS.75and76) before it is dropped or otherwise urged into the package delivery window507.

The variant second machine5000illustrates an alternative arrangement in which package locator rods551are used, both to move the packages to the assembly position, and also as an alignment structure to maintain the packages in parallel relation while they are pressed together from their initial, spaced-apart arrangement by the compression plates521.

As best seen inFIG.91, the package locator rods551can be arranged to engage the package frame710without engaging the temporary covers706,707during movement of the package locator rods551away from the receiving position into the assembly position.

FIG.92shows how the package locator rods551(shown in cross-section inFIG.91) are mounted on an actuator body552which is operable by the controller262to slide the rods551axially to insert them through all the packages in their initial position in the slots of the machine5000. After inserting the rods551through the apertures751of the packages, the controller262commands the actuator body552to move to the assembly position, withdrawing all the package frames710from between their temporary covers7006,7007which remain in the slots, as shown inFIG.92. For clarity, only one package is shown inFIG.92, but it will be understood that the rods551pass through all of the packages which are held in parallel relation and moved simultaneously in this way.

As shown inFIG.97(in which, for clarity, the packages are present but not shown), the actuator body552moves the packages between the compression plates521which are then actuated to compress the stacked package frames710together as shown inFIGS.98-99. The adhesive facing surfaces of the packages stick together so that the frames are combined to form the end user package7000.

It will be understood that after closing the door530and evacuating the casing506, all of the foregoing steps may be performed in a partial vacuum, so that the cells711of the end user package7000may be hermetically sealed by the mutual adhesion of the frames710with their internal space at a pressure below ambient. If gas is present then it may be dried or otherwise modified, e.g. to be mostly inert to better preserve the drugs1,2.

The controller262may then command the actuator body552to move to deliver the finished end user package7000to the delivery window507(FIG.100) before withdrawing the rods551axially from the end user package (FIG.101). The controller262then opens a valve (not shown) to admit air (or dried air or inert gas) into the casing506before releasing the door lock (not shown) so that the user can remove the end user package7000from the delivery window.

If desired, a similar arrangement to the grippers553and alignment mechanism body554could be used to move the packages closer together along the package locator rods551before operation of the compression mechanism of the variant second machine5000. Although optional, this additional arrangement is illustrated inFIGS.91-97, which show how the grippers553are actuated (FIGS.94-95) by the alignment mechanism body554to grip each package before the actuator body552withdraws the package from the slot (FIG.93). Then, the grippers553are moved together to reduce the spacing between the packages (FIG.96) while maintaining the packages in parallel relation before the actuator body552moves to position the packages between the pressure plates521(FIG.97).

Although only one package size is illustrated, the second machine500,5000may be configured to receive different sized packages (e.g. 12, 24, 36 or 48 cells). For example, the slots could be adjustable (e.g. by moving a machine component forming their lower boundary) to accommodate different sized packages. The controller262could be configured to permit operation only subject to the scanners561detecting package indicia713,717indicating the correct package size for the selected slot size, and/or the different sized packages could be provided with different shape profiles that interact with a corresponding shape profile of the slot (which may be an adjustable shape profile) to prevent insertion of a package of an incorrect size.

Byway of example, the illustrated second machine500includes additional scanners and adjustable shape profile blocks561′ at the rear of the slot, operable respectively to sense, and to selectively permit or obstruct, corresponding, additional shape profile features752of the packages.

Further Features of the Second Packages

As exemplified by the second embodiment, each drug package may comprise a frame710made from a sheet or two or more sheets laminated together, wherein apertures are formed in the sheet or sheets to define the spaced array of cells711. The or each sheet may be made from cardboard, although of course plastics or other materials could alternatively be used.

As illustrated for example inFIG.61, the carrier film34or other structure of the edible wall32of each cell711is exposed at the aperture forming the cell711and connected to the frame710. The carrier film34or other structure forming the edible wall32of the cell711of the drug package may be provided with perforations35or otherwise weakened, to allow its central region to be more easily detached from the frame710to remove the finished polypill30from the end user package700,7000.

FIG.81shows one possible structure for the frame710of each drug package, which may be formed from two sheets36of cardboard laminated together by adhesive. Apertures are formed in both sheets but of slightly different diameters, so that the lower sheet forms a supporting structure upon which the carrier film34is attached, for example, by adhesive. The respective drug1or2is incorporated into the API film31which is applied to the carrier film34, either before or after attaching the carrier film34to the frame710. The API film31could be extruded and/or rolled to a predefined thickness and then punched to form discs, or extruded as a round bar and cut into slices, before the discs or slices are attached to the carrier film34. Alternatively for example, the edible wall32could comprise two sheets of rice paper or other edible material which are attached to the frame710to enclose the drug in-between them, e.g. in particulate or pulverulent form. Or, the drug1or2could be impregnated into the edible wall32formed from rice paper or other suitable carrier material. In each case the or each edible component may include an edible adhesive on both sides.

After the package comprising the frame710and the edible wall32of each cell711has been formed, the tacky adhesive surfaces4of the frame710(and the adhesive surfaces of the edible walls32) are protected by the temporary covers706,707, which may be sheets of cardboard with a release coating5on their inwardly facing surfaces, except in regions that form the attachment points719. The release coating is absent from these regions so that the tacky adhesive sticks the temporary covers706,707to the frame710, which is released during assembly by the punches519which punch out these regions of the temporary covers706,707and frame710.

Other arrangements could be used to attach the temporary covers to the frame; for example, the temporary covers could be attached in regions proximate the edges of the frame710which are cut away during assembly.

FIG.70shows another possible arrangement, in which the temporary covers706,707are separated from the frame710of the drug package by separators720, which may be formed as strips that extend around the margins of the frame710. The separators could be cut away during assembly, or removed as part of the temporary covers706,707, which are separated from the frame710by cutting away respective attachment portions connecting together the temporary covers706,707and the frame710, or just by pulling the frame710out of an enclosure formed by the covers706,707. The air- (or inert gas-) filled space surrounding the frame may assist in forcing the covers and separators (coated with release coating5) away from the frame710as the air or other gas expands responsive to depressurisation of the machine.

FIG.71illustrates an alternative arrangement whereby the frame710of each package is formed, rather than in the form of a flat sheet as in the other illustrated embodiments, to define channels721, which may be generally V-shaped or U-shaped as shown, and which may surround all of the cells and/or each of the cells711. Such frames could be moulded from plastics material (e.g. polylactic acid) or could be pressed, e.g. from cardboard. The channels nest together to facilitate alignment of the frames710of the packages as they are pressed together during assembly. An adhesive4may be arranged in each channel721so that it is protected from accidental contact until assembly, when the base of the corresponding channel721of the adjacent frame710contacts the adhesive4to bond the frames of the packages together into the end user package.

FIG.82shows one cell of a cover package in cross-section, which may be formed similarly to the drug packages from one or two flat sheets36of cardboard or other material which are punched or otherwise formed to define apertures. The apertures are aligned but may have different diameters as shown, to form an attachment surface to which the outer margin of the edible wall33is attached, e.g. by adhesive. Perforations35or other weakening features may be arranged as shown to facilitate detachment of its central region together with the rest of the polypill of which it will form a part.

The foil wall714of the cover package704,705,7004,7005may form part of a single sheet of foil714which is laminated to the cardboard or other sheets of the frame710, or could be applied as individual pieces of foil714to each cell. Each foil wall714may be shaped to facilitate its movement along the cell axis Xc while remaining intact and sealingly attached to the frame710; the shape may be accommodated in the thickness of the frame710to protect the foil wall714from damage in storage and may comprise a region in which the foil wall714extends in the direction of the cell axis Xc, for example, in the form of an annular fold715, as shown.

Each temporary cover706,707,7006,7007may extend upwardly and downwardly as shown beyond the upper and lower edges of the frame710of the respective drug or cover package, so as to engage abutment surfaces of the slot to retain the temporary cover in the slot when the frame710is withdrawn during assembly. These upwardly and downwardly extending portions may define go/no-go features to ensure that the packages cannot be inserted into the wrong slots, as further discussed herein.

The frame710of the front cover package7004could incorporate a window721(FIG.89) through which is revealed the label portion713′ of the uppermost drug package in the assembly. The window721allows a more robust construction of the frame710of the front cover package when its trailing end extends upwards to provide a suitable location for a locator rod aperture751, which is located proximate its trailing edge and above the upper edges of the drug packages. In this way the package locator rods551can be spaced apart both vertically and horizontally to better maintain the packages in parallel relation, without being obstructed by the temporary covers. At the same time, the temporary cover of the front cover package7004can extend upwardly at its trailing edge, similarly to the temporary cover7006of the drug package7002as shown inFIG.91, to engage an abutment surface of the slot above the upper edge of the frame710of the respective package, so that the frame710can be withdrawn by the rods551while the temporary cover is retained in the slot.

FIGS.83-85show an alternative arrangement in which the cardboard or other sheets36forming the frame710of each drug package are shaped to form a cell711(FIG.83) to which a carrier film34may be applied, e.g. as a liquid that fills the recesses formed by the cell wall at the margin of the cell, or by pressing it into the recesses, after which the carrier film may be punched to form perforations35(FIG.84). The API film31can then be applied in a liquid state as a drop of defined volume to the surface of the carrier film34(FIG.85).

In a further alternative arrangement (not shown), the carrier film34of each drug package could be formed as a unitary sheet which extends over a sheet of the frame710, or between two sheets of the frame (wherein the or each sheet of the frame may be for example a cardboard sheet36) to form a laminated assembly, wherein a respective portion of the unitary sheet of carrier film is exposed at each of the apertures or cells711. For example, the carrier sheet can be laminated in-between two cardboard sheets36that define apertures forming the cells711. This provides a simple assembly procedure since the apertures can be formed in the cardboard sheet or sheets of the frame before laminating it or them together with the carrier sheet, such that a portion of the carrier sheet remains a permanent part of the frame after the respective portions of the carrier sheet are removed together with the polypills of which they form a part. As in the illustrated arrangement, the carrier sheet may be perforated, thinned or otherwise locally weakened proximate a margin of each of the cells to assist in detaching the finished polypill. After forming the frame710including the carrier film34as a unitary sheet laminated to the frame, the API film31could be applied locally to each cell711, e.g. as a disc as shown inFIG.81, or as a drop of liquid as shown inFIG.85.

A similar arrangement (not shown) could be adopted for the cover packages, by forming each disc or wafer as a respective portion of a unitary sheet of edible material (e.g. rice paper) which is laminated to the frame710, e.g. between two sheets of cardboard36, so that the portion forming each edible wall33is exposed at the aperture or apertures forming the respective one of the cells711, while the remainder of the edible sheet forms a permanent layer of the frame710. Again, perforations35or other weakening features may be arranged around the portion forming each edible wall33to facilitate removal of the polypill.

As shown inFIGS.61and81, the edible wall32comprising the API film31and carrier film34may extend across the cell711of each drug package so that, after removal of the temporary covers706,707, it is exposed on either side of the frame710. As shown inFIGS.68and69andFIG.82, the edible wall33(e.g. rice paper disc or wafer) of each cell711of the front or rear cover package704,705,7004,7005may be exposed on one side of the frame710while on the other side of the frame it is covered by the foil wall714of the cell711. The surfaces of the package frames710that will be pressed together are coated with a tacky adhesive4so that they adhere together to form the composite frame710of the end user package700,7000. The edible walls32are also configured to adhere together, and to the edible walls33that will form the opposite sides of the pastille30. For this purpose the edible walls33may be adhesive on that side that faces away from the foil wall714of the cell, but not adhesive on the side that faces the foil wall714, so that the pastille30can be removed and handled easily.

The tacky adhesive coating4of the frames710can be any suitable tacky adhesive as known in the art. It could be for example a pressure sensitive adhesive with an extended open time or permanent tack, as well known in the art and as used in glue traps for vermin and various industrial and construction applications.

In order to adhere readily to the edible wall32of the drug package, the edible wall33of the cover package may be coated on one side with an adhesive layer, e.g. the same material that forms the API film31or carrier film34, or a component thereof.

The API film31could be used on its own to form the edible wall32of the drug package, but may be applied to a carrier film which incorporates a perforated, thinned or otherwise weakened region allowing the entire quantity of API film31to be detached with the polypill30to ensure an accurate dose without wastage of the drug.

The drug or API may incorporated into the API film31in solution or in particulate form. It could be in granular form, in which case the granules may be coated with a coating to modify the release rate or other bioavailability characteristic of the drug, as may the spheroids3or other granules of the first embodiment. If the drug is homogeneously distributed in the API film31then the dose can be established by controlling the volume of the API film that is applied to each cell711of the drug package. For example, the API film could be formulated with a known concentration of the drug1or2and then rolled to a predefined thickness and stamped into discs of predefined diameter, or could be deposited onto the carrier film34as a drop of predefined volume.

The carrier film34could be the same material as the API film31or could be a different material, e.g. a film forming polymer as further discussed below.

The finished end user package700,7000is shown inFIGS.80,89and90. It can be seen that the label portion713′ of the uppermost drug package is adhered to the front surface of the underlying label portion713′ of the second drug package, which (if three drug packages are provided) adheres in turn to the underlying label portion713′ of the third drug package. The second label portion713″ of the first drug package is absent, revealing the second label portion713″ of the second drug package which adheres to the front surface of the second label portion713″ of the third drug package. The third label portion713′″ of the first and second drug packages is absent, revealing the third label portion713′″ of the third drug package which, together with its concealed, first and second label portions713′,713″, adheres to the rear cover package7005(if three packages are included). If only two packages are included, as illustrated in the front view inFIG.80, then the position of the third label portion713′″ is occupied by the blank, non-adhesive, forwardly facing surface of the rear cover package705. The juxtaposed label portions thus form a stepped configuration in which the overall thickness of the end user package reduces step-wise from left to right, which is why the pressure plates521may include a similar, stepped configuration522′.

FIG.86shows a cross-section through one of the cells711, whileFIG.87shows the same section after removal of the pastille or polypill30, which in the illustrations has only two API films31including two respective drugs1,2; if more than two drug packages are used then more than two edible walls32, e.g. API films31, will be present.

In the illustrated embodiment, each pastille30comprises the API films31which are compressed together with the carrier films34between the discs or wafers33of the front and rear cover packages, which provide a convenient, non-sticky surface for the user to handle. Ambient air pressure acting on the foil walls714may apply pressure over an extended time period, as long as the respective cell711of the end user package remains unopened, sufficient to cause full adhesion between the walls32and33, e.g. film walls31and34and wafers33as shown.

In use, the end user simply presses against one of the foil walls714to push the pastille30through the opposite wall714out of its cell711; the carrier films34and walls33rupture at the perforations35to release the pastille30from the frame710.

Edible Walls

The film of the at least one edible wall32, e.g. the API film31and/or the carrier film34, may be based on a film forming polymer as well known in the art, e.g. a water soluble polymer such as hydroxypropyl methylcellulose, carboxymethyl cellulose, e.g. sodium carboxymethyl cellulose, hydroxypropyl cellulose, or hydroxyethylcellulose.

The edible wall33forming the outer surface of the polypill30could be, for example, an edible paper, e.g. edible rice paper (made from dried starch, e.g. a mixture of rice and tapioca flour); a non-tacky film based on a film former as used for the edible wall32; or an edible paper made from edible (i.e. non-toxic) fibres made from cellulose, e.g. cotton, vegetable protein, collagen or other fibre forming material and bound together, e.g. with a film former, optionally including one or more disintegrants, fillers, or other components as known in the art. The edible wall33may include a tacky layer facing away from the foil wall714of the cell to bond with the adjacent edible wall32, and a non-tacky layer facing the foil wall714of the cell which allows the polypill30to be removed from the cell711without sticking to the foil714.

Where the edible wall32of the drug package includes an API film31and/or a carrier film34, either or both of the API film31and the carrier film34may be made in one layer or as a laminate of more than one layer with different compositions. Alternatively, the at least one edible wall32may be made from a similar material to the edible wall33, but sticky on both sides so as to bond to the at least one edible wall32of the adjacent package during assembly.

For example, the at least one edible wall32could be made in two layers to enclose the drug1,2in-between the layers, or in one or more layers with the drug1,2included in the or each layer as an homogeneously distributed component of the film or wall, e.g. by mixing or impregnating it into the material of the film or wall before or after forming the film or edible wall32, or printing onto the formed film or wall, e.g. in particulate, e.g. pulverulent or granular form, or as a solution or a dried suspension. The drug1,2may be incorporated into the film or applied to the at least one edible wall32in micro- or nano-particulate form, e.g. as taught by US2016022599 A1. The at least one edible wall32could be coated on one or both sides, e.g. with a film former or edible tackifier to preserve the drug and/or to modify its release characteristics and/or to promote adhesion. Modified release may also be obtained by applying a modified release coating to the drug in granular form as contained in the film or between the layers of the at least one edible wall32, and/or by incorporating the drug into multiple layers of the film with different compositions, e.g. different solubility.

The film forming polymer may be a combination of a first carboxymethyl cellulose of relatively lower molecular weight and a second carboxymethyl cellulose of relatively higher molecular weight, as taught by US2009035426 A1.

The film may include a tackifier to improve its adhesion to the films of the other packages. Films with tackifiers are taught for example in US2009035426 A1.

The film may include further ingredients such as one or more plasticizers, surfactants, disintegrants, etc. as known in the art.

In order to promote adhesion to the edible wall32or33of the adjacent package, the edible wall32of the drug package may be an adhesive composition based on carboxypolymethylene as taught by U.S. Pat. No. 5,851,512, wherein “carboxypolymethylene” includes in particular copolymers of acrylic acid and polyallyl sucrose. Carboxypolymethylene may be mixed with glycerine to form a sticky gel. Suitable carboxypolymethylene compositions are commercially available as CARBOMER® CARBOPOL®, e.g. from The Lubrizol Corporation of Cleveland, Ohio, USA.

A particularly tacky film may be obtained by the addition of Gelucire® 44/14. Gelucire® 44/14, with HLB value of 14, is a mixture of monoesters, diesters and triesters of glycerol, and monoesters and diesters of polyethylene glycols, belonging to the lauryl polyoxylglycerides (macroglycerides) family, and available from Gattefossd SAS of Saint-Priest, France.

A film obtained by hot melt extrusion from a mixture of Eudragit RS PO powder with Gelucire® 44/14 is reported by Esra'a Albarahmieha, Sheng Qia, and Duncan Q. M. Craig—“Hot Melt Extruded Transdermal Films based on Amorphous Solid Dispersions in Eudragit® RS PO: The Inclusion of Hydrophilic Additives to Develop Moisture-Activated Release Systems”—International Journal of Pharmaceutics, 514 (1). 270-281. ISSN 0378-5173—available online at https://ueaeprints.uea.ac.uk/

Eudragit® RS powder (PO) grade is a glassy copolymer synthesized from acrylic acid and methacrylic acid esters with 5% of functional quaternary ammonium groups, and available from Evonik Nutrition & Care GmbH of Essen, Germany.

Alternative Embodiments

In alternative embodiments, the capsule part (e.g. the capsule body22) of the capsule body package could be arranged in the cell without a carrier, in which case it could be urged through the aligned cells of the packages by the respective pushrod (like the pushrods of the first machine or variant first machine) and could rupture the foil of each cell by direct contact.

In further alternative embodiments, the end surfaces of the pushrods of the first machine or variant first machine could have a recess to receive the respective capsule part (e.g. the capsule body) which is supported in the recess during assembly. In this case the leading end of the pushrod could contact and rupture the film of each cell during assembly. An inner pushrod could be arranged to expel the finished capsule as the main pushrod retracts from the cell. The cell could then be closed by the flap of the end user package forming the composite label or label assembly, without the need for an insert or carrier. The cells of the end user package could be configured to restrain the finished capsule to prevent it leaving the cell in the final stage of assembly. For example, the cell could include an element or elements located at or proximate the end through which the capsule enters, perhaps similar to the inwardly projecting tabs of the alternative locating structures as described with reference to the cap package of the first embodiment, which are deflected by the capsule or pushrod and then return to a rest position to retain it in the cell.

In alternative embodiments it is conceivable that a structural part of the end user package, and/or a part of each capsule or other polypill, could be formed from a part that is introduced into the machine without being part of a package. For example, the machine could be loaded with a cassette or a hopper containing multiple capsule parts which are introduced into the cells of the packages of the first embodiment or variant first embodiment to receive the combined drugs, or could include a roll or sheets of a frangible film that is applied within the machine to dose the cells of the end user package of the second embodiment or variant second embodiment to seal the polypills in the cells.

It is desirable to package the polypills individually in individual cells of an end user package, both because it better preserves them in storage, and because it obviates the risk of mixing them up with other medicaments. It is conceivable however, although less preferred, that the polypills could be delivered instead in a bulk end user package (such as a pill bottle).

In yet further possible arrangements, the first machine or variant first machine could be configured to urge the first and second drugs out of the aligned cells of the stacked drug packages using a first set of pushrods arranged generally as shown, and then to use another set of pushrods arranged orthogonally to the first set to encapsulate the drugs within the cells of the end user package which define cavities containing the capsule parts, which are spaced apart facing each other in the cavity with their length axis orthogonal to the length direction of the first pushrods.

In this arrangement the carriers320could be replaced by solid plugs or plungers, with each plunger being received (in the direction of movement of the first pushrods, orthogonal to the second pushrods) in a hole that intersects the capsule cavity to urge the drugs in front of the solid plunger, into the cavity between the opposed capsule parts21,22.

The second pushrod could then close the capsule at a position in the cavity beyond the plunger. The plunger could then be pushed deeper into the hole, by the first pushrod, after the second pushrod is withdrawn, to become a part of the end user package which seals both the hole that receives the plunger, and the hole that admits the second pushrod. This again provides encapsulation entirely within the cells of the introduced packages without contact between the drugs and any parts of the machine, and delivers an end user package with a somewhat slimmer form factor at the cost of a more complex machine.

In yet further embodiments, rather than having a powered actuator, the machine could be manually operated (e.g. by a lever or the like) so that the mechanism is driven only by the user.

For example, the first machine100could be adapted for the user to depress the pressure plate by means of a lever. A set of pressure pads (similar to pressure pad250) could be provided in different thicknesses with a profile aperture defining a different shape profile index position for each pressure pad, so that each pad can be received in the machine in a different index position of a respective profile rod. A manual knob could be provided for rotating that respective profile rod to the desired position, to set the capsule size, which in turn defines the thickness of the pressure pad that will fit that profile rod, which in turn defines the height of the receiving space between the pressure plate and the upper surfaces of the pedestal block and pushrod ends. Thus, the stack height is controlled for capsule capacity in a similar way to the first machine, but in a simple, manual mechanism that does not need a powered actuator or position sensor to set the position of the pressure plate. The pressure pads could be colour coded for convenience.

The second machine or variant second machine could include a heat source or ultrasonic or other welding means for welding the package frames together.

Many further adaptations are possible within the scope of the claims.

SUMMARY

In summary, in embodiments, customised polypills may be produced in the pharmacy from two or more drug packages using an assembly machine. Each drug package may comprise an array of cells containing individual doses of a single drug. The individual doses may be combined within the cells of the packages to produce an end user package with an array of cells containing the combined drugs in the form of individual polypills, which may be formed as capsules or pastilles. Label indicia of the drug packages may be combined together to form a composite label of the end user package. Serialization data may be read from the packages during assembly and sent to a remote server for authentication and supply chain management.

In another aspect, in embodiments, patients who have a history of poor compliance with a prescribed oral antipsychotic while periodically seeking symptomatic relief from another prescribed psychoactive, are provided with both medicaments in the form of polypills to be taken in place of the solo antipsychotic when the patient is in crisis. Providing the preferred psychoactive as a combination motivates the patient to resume their antipsychotic therapy when symptoms return, which may result in better compliance and more effective management of psychosis in the community.

Treating Psychosis

The discussion turns now to the second broad aspect of the invention as directed to the treatment of psychosis.

Psychosis is characterised by symptoms including hallucinations (typically, hearing voices) and/or delusions (i.e. delusional thoughts or beliefs, e.g. paranoia). Psychosis is a defining aspect of chronic mental illness such as schizophrenia and so, in this specification, the treatment of psychosis is synonymous with the treatment of the underlying mental illness.

Individuals suffering from chronic mental illness resulting in psychosis are often treated in the community with a maintenance regimen of oral antipsychotics for self-administration (i.e. relying on the individual to take the pills regularly). One common problem is poor compliance with the therapeutic regimen, resulting in periodic episodes of acute psychosis with repeat hospital admissions.

As an alternative, a depot injection can be given periodically to release the antipsychotic over a prolonged period. However, some individuals are unwilling to receive a depot injection, or may respond better to antipsychotics which are unsuitable for delivery in that form.

Psychotic symptoms may worsen responsive to stressors in the patient's home or work environment. Typically it is impractical for the clinician to monitor the individual in the community closely enough to adjust their medication to respond to such events. On the contrary, as the patient's condition worsens it may become less rather than more likely that the patient will continue to comply with a regular maintenance regimen of oral antipsychotics.

The invention identifies, and is directed particularly to, a group of individuals who:

i) are diagnosed with a chronic mental illness, e.g. schizophrenia, characterised by psychosis;
ii) are prescribed an oral antipsychotic for self-administration as an ongoing maintenance therapy to treat the underlying mental illness to prevent the re-emergence of hallucinations and/or delusions as acute psychotic symptoms;
iii) are also prescribed, in acute phases of their illness, another psychoactive drug for use over a more limited time period to alleviate one or more affective symptoms associated with the re-emergence of the psychosis;
iv) have a history of poor compliance with the oral antipsychotic regimen; and
v) in contrast, demonstrate a positive inclination to take the psychoactive.

As a sub-group within this patient group, some individuals may further be diagnosed with a personality disorder. A personality disorder will affect thinking and behaviour and may be a persistent contributory factor in non-compliance, even when antipsychotic therapy is effective in managing the underlying mental illness. Thus, the invention may be applied particularly to improve compliance in this sub-group.

In this patient group, the antipsychotic is prescribed as an ongoing maintenance therapy for self-administration by the individual living in the community. The additional, psychoactive medication is prescribed for the same individual from time to time, only for a more limited period, to alleviate affective symptoms during an acute psychotic episode. Prescribing for a limited period may avoid the development of tolerance, dependence or addiction that could result from longer term use. An acute psychotic episode may result in hospitalization or, if symptoms are less severe, could be managed in the community.

The invention recognises that the causes of noncompliance with a maintenance regimen of oral antipsychotic therapy may be partly psychological. Objectively rational fears of adverse side-effects may be exaggerated while the behavioural consequences of the illness are denied. For such individuals, denial or lack of insight could be regarded rather as a coping strategy, which may have supported the individual for many years before diagnosis and treatment. The coping strategy may lead the individual to eschew treatment for their psychosis—which is to say, for the specific symptoms (hallucinations and/or delusions) that are targeted by their oral antipsychotic therapy.

A delusional belief system may include, for example, attributing negative intentions or hallucinatory voices to real or imagined people, and so may give rise to problematic behaviour which imposes a burden on friends, neighbours, work colleagues, health and criminal justice services and others in the affected community. Problematic behaviour results in adverse social experiences which in turn may reinforce the paranoid or other delusional beliefs that drive the behaviour. Thus, adherence to a maintenance regimen of antipsychotic therapy may be key to successful management of the illness in the community.

However, an individual who denies that they are ill and rationalizes imagined voices or other hallucinations as real sensory experiences may reject compliance with a regimen of antipsychotic medication, prescribed to treat the hallucinations and delusions, as unnecessary and even as an act of self-betrayal, insofar as compliance implies acceptance of a rejected diagnosis of mental illness.

The invention recognises that although such patients may be highly resistant to taking their oral antipsychotic when they believe they are well, for the reasons discussed above, the aversion may be to the act of compliance with the therapeutic regimen as much as to any real or exaggerated fear of adverse side-effects. This is reinforced by the relatively gradual and cumulative action of antipsychotics which may make it more difficult for the individual to be convinced that their medication is effective. Thus, noncompliance may result from denial in combination with lack of perceived benefit of the medication, as much as any perceived disbenefit of the medication.

The invention further recognises that an individual who has developed a coping strategy to tolerate the hallucinations and delusions that characterise their psychosis, and who eschews compliance with the antipsychotic regimen, may nevertheless actively seek to take another psychoactive drug, prescribed during acute phases of their illness, to alleviate distressing affective symptoms that may be associated in that individual with the re-emergence of their psychosis.

In contrast with the rejection of compliance with the antipsychotic regimen as an act of self-betrayal, compliance with a regimen of psychoactive medication which is perceived to alleviate an affective symptom may be regarded as an act of self-affirmation (taking back control).

This motivation may be stronger if the psychoactive is selected to exert a relatively more rapid therapeutic effect—for example, relatively more rapid than that of the antipsychotic—and so gives rise to a relatively stronger association with the expected benefit in the mind of the individual.

The invention further recognises that by adapting the range of choices available to the individual, this motivation can be harnessed to improve compliance with a therapeutic maintenance regimen of oral antipsychotics.

This can be achieved by means of a kit of medicaments; the use of the kit of medicaments for the treatment of psychosis; a method of treating psychosis; and/or a method for manufacturing medicaments for treating psychosis, as will now be discussed.

Aspects of the Invention as Directed to the Treatment of Psychosis

In one aspect, the invention provides a kit of medicaments for use in the treatment of psychosis in an individual with a history of non-compliance with oral medication. The kit includes a plurality of crisis oral dosage units, and a plurality of maintenance oral dosage units. Each of the crisis oral dosage units includes a single dose of a first drug and a single dose of a different, second drug, said single doses being combined together as a single, orally ingestible body. Each of the maintenance oral dosage units includes a single dose of the first drug without the second drug. The first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the individual's psychosis.

In another aspect, the invention relates to the use of a kit of medicaments as defined above, for the treatment of psychosis in an individual with a history of non-compliance with oral medication.

The treatment of psychosis may comprise the treatment of schizophrenia.

Both the crisis oral dosage units and the maintenance oral dosage units may be provided to the individual for alternative self-administration at the discretion of the individual, wherein the maintenance oral dosage units are provided for self-administration when the individual feels well, and the crisis oral dosage units are provided for self-administration when the individual feels unwell.

In another aspect, the invention provides a method for treating psychosis in an individual with a history of non-compliance with oral medication. The method comprises providing different, first and second drugs, wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis. The method further comprises combining together the first and second drugs to form a plurality of crisis oral dosage units, each of the crisis oral dosage units including a single dose of the first drug and a single dose of the second drug, said single doses being combined together as a single, orally ingestible body. The method further comprises forming a plurality of maintenance oral dosage units, each of the maintenance oral dosage units including a single dose of the first drug without the second drug; and providing both the crisis oral dosage units and the maintenance oral dosage units to the individual for alternative self-administration at the discretion of the individual, wherein the maintenance oral dosage units are provided for self-administration when the individual feels well, and the crisis oral dosage units are provided for self-administration when the individual feels unwell.

The method may be applied for the treatment of schizophrenia.

In another aspect, the invention provides a method for manufacturing medicaments for treating psychosis in an individual with a history of non-compliance with oral medication. The method comprises identifying the individual, and identifying different, first and second drugs prescribed for the identified individual, wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis in the identified individual. The method further comprises combining together the first and second drugs to form a plurality of crisis oral dosage units customised for the identified individual, each of the crisis oral dosage units including a single dose of the first drug and a single dose of the second drug, said single doses being combined together as a single, orally ingestible body. The method further comprises forming a plurality of maintenance oral dosage units, each of the maintenance oral dosage units including a single dose of the first drug without the second drug; and packaging the plurality of crisis oral dosage units and the plurality of maintenance oral dosage units, respectively as two separate components in a kit of medicaments.

The elements of the kit may be supplied simultaneously or sequentially, but in either case are supplied for alternative self-administration by the individual at the discretion of the individual. The individual is instructed to take the maintenance oral dosage units but not the crisis oral dosage units when they are feeling well, and to take the crisis oral dosage units but not the maintenance oral dosage units for additional symptomatic relief when they are feeling stressed or otherwise unwell.

Byway of example,FIG.59shows a kit of medicaments, comprising first and second components300,900packaged together in a pharmacy bag901for delivery to the user. The first component is the end user package300as described above, containing a plurality of crisis oral dosage units in the form of capsules20. Each capsule contains in combination a single dose of the first drug1, which is an antipsychotic (olanzapine, 20 mg), and a single dose of the second drug2(citalopram, 20 mg), which is a psychoactive selected to alleviate an affective symptom associated with the psychosis. This particular combination is shown purely by way of example. The second component900is a conventional blister pack containing a plurality of maintenance oral dosage units in the form of tablets or capsules, each containing a single dose of the antipsychotic (olanzapine, 20 mg). In alternative embodiments, both packages may be of similar appearance—for example, the second component could be another end user package300made with only one drug instead of two. The packages could be colour coded for easy recognition by the user. Included in the pharmacy bag may be a patient leaflet266, instructing the user to take the maintenance oral dosage units when they feel well, and to take the crisis oral dosage units instead of the maintenance oral dosage units when they feel unwell.

In this context, “well” and “unwell” are defined by the presence or absence or relative severity or lack of severity of the affective symptom. For example, on a scale rating the affective symptom from not present, through mild to moderate to severe, “well” might be interpreted as not present or mild, and “unwell” might be interpreted as moderate or severe.

The psychoactive should be a drug that the individual is motivated to take in order to alleviate one or more affective symptoms associated with a recurrence of their psychosis. The psychoactive may be selected to alleviate, in particular, transient affective symptoms that increase and decrease in severity together with the psychosis.

In the context of this invention, the therapeutic action of the psychoactive is significant principally for its motivational influence on the individual. What matters is that the affective symptom makes the individual feel unwell, and the individual associates the psychoactive with its therapeutic effect in alleviating the affective symptom. The act of taking the combined medicament may be perceived on balance as an act of self-affirmation in which the presence of the antipsychotic is of relatively minor significance. Thus, the individual is motivated by the presence of the affective symptom to take the psychoactive in order to feel better.

For this reason it is important that the psychoactive is selected for the individual patient. Since there are numerous possible combinations and dosages, the crisis oral dosage units may be prepared as customised, single oral dosage units, which are preferably polypills but could alternatively be in liquid form and defined by a liquid measure at the point of consumption. Conveniently, such polypills may be prepared using the novel methods and apparatus as discussed above.

The psychoactive may be considered a reward substance, in the sense that the individual associates it with an emotional reward (e.g. elevated mood, reduced anxiety.) Importantly however, the psychoactive alleviates an affective symptom associated with the individual's psychosis, which will be different for different individuals—and so, the individual is motivated to take the second medicament, particularly by the onset of the affective symptom which occurs together with the recurrence of their psychosis.

A drug that provides more rapid relief from the affective symptom may be more strongly associated by the individual with its therapeutic effect, and so the individual may be more strongly motivated to take it at the onset of the affective symptom.

Accordingly, when taken at a prescribed frequency: the first drug (i.e. the antipsychotic) may be selected to alleviate a first symptom of the psychosis within a first time period from initial administration, the first symptom being one of hallucinations and delusions, and the second drug (i.e. the psychoactive) may be selected to alleviate the affective symptom within a second time period from initial administration; the second time period being shorter than the first time period.

That is to say, the psychoactive may be selected to relieve the target affective symptom, when taken by the individual at the prescribed frequency, in a relatively shorter time period from first administration than the simultaneously ingested antipsychotic relieves the first symptom (hallucinations or delusions) in that individual.

Alternatively or additionally, the psychoactive may be selected to relieve the target affective symptom, when taken by the individual at the prescribed frequency, in a period of less than 24 hours, preferably less than 12 hours, more preferably less than 6 hours, yet more preferably less than 3 hours from first administration.

The antipsychotic may be provided at the same dose in both the crisis and maintenance oral dosage units, or may be provided at a different dose (e.g. a higher dose) in the crisis oral dosage units relative to the maintenance oral dosage units.

The maintenance oral dosage units could be packaged as conventional fixed dosage units, e.g. capsules or tablets, or could be packaged using the novel assembly machine in packaging similar to that of the crisis oral dosage units. In either case, colour coding or other suitable indicia could be used to distinguish the maintenance oral dosage units (e.g. in a blue pack) from the crisis oral dosage units (e.g. in a red pack).

Affective symptoms associated with the psychosis may include one or more positive affective symptoms such as anxiety, agitation, and irritability. Such positive affective symptoms may particularly motivate the individual to turn to the psychoactive for relief.

Some individuals may also be motivated by depressive affective symptoms associated with the psychosis to turn to the psychoactive for relief from those depressive affective symptoms. Depressive affective symptoms may include sadness, anhedonia, feelings of guilt or low self-worth, or apathy.

Affective symptoms are symptoms expressive of mood or emotion. It will be understood of course that hallucinations and delusions are not classed as affective symptoms.

The psychoactive may alleviate the affective symptom associated with the psychosis by removing the affective symptom, or reducing the severity of the affective symptom.

Of course, the antipsychotic should be selected and prescribed in accordance with good clinical practice to minimise unwanted side-effects, in order that the presence of the antipsychotic should not deter the patient from taking the combined dosage unit. The invention is not intended to overcome noncompliance that represents a proportionate avoidance of severe side-effects.

It may also be noted that noncompliant patients may have relatively difficult or chaotic life circumstances with limited choices, and so the ease of availability of the psychoactive in the combination dosage unit on prescription from the pharmacy may be a relatively significant factor influencing the patient's behaviour. The balance of convenience may induce such patients to take the combination medicament rather that obtaining the desired psychoactive on its own via illicit sources.

The invention provides a further benefit in that the compliant behaviour encouraged by the novel combination is self-regulating. The patient is a sensitive barometer of their own mental state and will turn to the psychoactive medicament of choice for relief when their affective symptoms return. Through managing patient choice by combining the antipsychotic with the preferred, psychoactive medicament, the previously non-compliant patient may be encouraged to voluntarily resume their antipsychotic therapy with the first symptoms of their returning psychosis.

In contrast, conventional approaches rely on visiting clinicians to respond to the patient's condition, which may not happen until the patient's symptoms have worsened to such an extent that the clinician is called by concerned friends and neighbours, perhaps resulting in an emergency hospital admission.

The invention may thus provide cheaper, more effective and more responsive management of psychosis in the community.

For chronically ill and noncompliant patients who do not take the conventional antipsychotic or who only take it sporadically, the invention may be expected to result in a cycle of illness and wellness wherein the periods of illness are less severe than would be the case with the conventional approach of management in the community.

Antipsychotics and Psychoactives

The psychoactive may be an antidepressant.

The psychoactive may be an anxiolytic or a sedative or hypnotic.

An anxiolytic or sedative or hypnotic may be a benzodiazepine or a “Z” drug. A “Z” drug means one of zaleplon, zolpidem, and zopiclone.

A benzodiazepine may be selected for effect principally as an anxiolytic; for example, it could be one of alprazolam, chlordiazepoxide, diazepam, lorazepam, and oxazepam.

Alternatively, a benzodiazepine may be selected for effect both as a sedative and as an anxiolytic; for example, it could be one of flurazepam, nitrazepam, loprazolam, lormetazepam, and temazepam.

The antipsychotic may be selected to alleviate a first symptom of the psychosis, the first symptom being one of hallucinations and delusions, while the psychoactive is selected to alleviate the affective symptom without alleviating the first symptom. Thus, the psychoactive need not be an antipsychotic.

Affective symptoms may include negative affective symptoms of psychosis. The psychoactive may be selected to alleviate at least one negative affective symptom of the psychosis without alleviating hallucinations, delusions, or other positive symptoms. In this case the psychoactive may also be an antipsychotic, for example tiapride, which is effective to alleviate negative symptoms but not positive symptoms of psychosis.

Alternatively, the psychoactive may also be an antipsychotic that helps to alleviate also hallucinations or delusions as principal symptoms of the psychosis. For example, the psychoactive could be an atypical antipsychotic effective also as an anxiolytic, such as carpipramine; or an atypical antipsychotic effective also as an antidepressant, such as amoxapine.

As referred to herein, an antipsychotic or a particular class of psychoactive may be a drug listed with a corresponding therapeutic indication (whether or not also with other therapeutic indications) in the pharmacopoeia for the jurisdiction where the respective prescription is issued—for example, the European Pharmacopoeia, the Japanese Pharmacopoeia, or the United States Pharmacopeia.

An antidepressant may be an SSRI (selective serotonin reuptake inhibitor); for example, it may be one of citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline.

In this specification, drugs may be taken to include, where therapeutically equivalent, their respective prodrugs, pharmaceutically acceptable salts and structural analogues.

Of course, if a specific psychoactive is known to have an adverse interaction with a specific antipsychotic then that combination is not selected.

The crisis oral dosage units may include only one, or more than one antipsychotic in addition to the psychoactive, and/or only one, or more than one psychoactive in addition to the antipsychotic.

The antipsychotic and/or the psychoactive could be in solid or liquid form. For example, cannabidiol (CBD) may be included as an antipsychotic or as an adjunct to an antipsychotic, and may be in a liquid form, e.g. as a tincture or an oil.

Efficacy

The efficacy of the novel approach to the treatment of psychosis can readily be assessed by means of a clinical trial which may be designed as follows.

A group of individuals are identified who satisfy the five criteria (i)-(v) as set out above.

Consent is obtained from each individual to comply with a regular assessment of their mental health, conducted in the conventional way, e.g. using the PANSS scale or equivalent, for the duration of the trial. The assessment may include a questionnaire on compliance; however, this is of limited use since it relies on the truthfulness of the patient.

Consent may be obtained from each individual to deliver their existing prescribed drugs in new packaging, and in combination. Preferably however, since efficacy turns on managing choice, if it is determined that consent is not required, then consent is not obtained.

For each individual, their existing prescribed antipsychotic and psychoactive are provided in three different end user packages. All three packages are of generally identical appearance except for their labels which correctly indicate the respective drugs contained therein. Each package contains a plurality of solid, single oral dosage units, e.g. tablets or capsules, which should also be generally similar in appearance, and for the three different packages comprise respectively: Package a) the antipsychotic alone; Package b) the psychoactive alone; and Package c) the antipsychotic and psychoactive in combination.

The patients are divided into two groups. For a first time period, the first group receives packages a) and b), while the second group receives packages a) and c). For a second, consecutive time period, the first group receives packages a) and c), while the second group receives packages a) and b).

Individuals receiving packages a) and c) are instructed to take the maintenance oral dosage units but not the crisis oral dosage units when they are feeling well, and to take the crisis oral dosage units but not the maintenance oral dosage units for additional symptomatic relief when they are feeling stressed or otherwise unwell. Individuals receiving packages a) and b) are instructed to take the antipsychotic when they are feeling well, and to take the psychoactive in addition to the antipsychotic for additional symptomatic relief when they are feeling stressed or otherwise unwell.

The patients are assessed regularly for the duration of the trial as mentioned above.

The visual similarity of the oral dosage units and the packaging controls for the placebo effect of new packaging and new routines, while the staged time periods control for global external factors like weather and socioeconomic environment. The objective is for the only change to be whether the psychoactive is available with or without the antipsychotic in combination.

Since cycles of illness and wellness can last a long time, the time periods should be as long as possible, e.g. one or two years or more, and the group should be as large as possible.

The groups are randomised. Of course, the trial is open label for the patients, but preferably is blinded for the psychiatrist or other clinician involved in the assessment—which is to say, they know what medications the patient is receiving but they don't know whether they are in the combined form or the separate form. This controls for bias in the assessment. This may have to change during the trial if a particular individual is hospitalised or their medication is changed.

After the trial, the assessment outcomes are collated and analysed for statistical significance.

LIST OF REFERENCE NUMERALS

Variant First Embodiment

Further Variant: End User Multipack, External Capsule Assembly

Further Variant: End User Multipack, Internal Capsule Assembly

Further Variant Embodiments Using Bulk Capsule Components

F or (F) Front viewR or (R) Rear view (opposite the front view)Tor (T) Top or plan viewB or (B) Bottom view (opposite the plan view)E or (E) End viewS or (S) Side viewIS or (IS) Inner side viewOS or (OS) Outer side viewLS indicates a left side (left end) viewRS indicates a right side (right end) view(X1), (X2), (X3) or -X1, -X2, -X3Sections identified by their respective section lines (refer to the brief description of the drawings)(FIG.34) a-, b-, c-, d-(FIG.38)-a, -b, -c, -d, -eDifferent positions (refer to the brief description of the drawings)

Generally in the drawings, a horizontal dash fill pattern indicates foil314or714, while a vertical dash fill pattern indicates a release surface or release coating5.

Non-Exhaustive List of Selected Feature Combinations

The following is a non-exhaustive, numbered list of selected feature combinations in accordance with various aspects of the invention as described above, wherein FC means “feature combination”, and FCn indicates feature combination number n as defined in this list. The feature combination numbers in this list refer only to this list.

FC1. An assembly system comprising:

an assembly apparatus, and

a plurality of packages, the plurality of packages including at least first and second drug packages; each package of the plurality of packages including a plurality of cells; each cell of the first drug package including a single dose of a first drug, each cell of the second drug package including a single dose of a second drug; the assembly apparatus being configured:

to receive the plurality of packages including at least the first and second drug packages, and

to combine together the first and second drugs of the first and second drug packages to form a plurality of single, orally ingestible bodies, wherein each single, orally ingestible body of the plurality of single, orally ingestible bodies includes the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package;

characterised in that each cell of each drug package includes only one single dose of the respective drug, and the assembly apparatus is configured to combine together the first and second drugs within the cells of the packages received in the assembly apparatus.
FC2. An assembly system according to FC1, wherein each drug package is a single use drug package which includes at least one part which is configured, in use, by operation of the assembly apparatus to combine together the first and second drugs, either

(a) to be irreversibly removed, destroyed or ruptured, or

(b) to be irreversibly united with the corresponding at least one part of another respective one of the first and second drug packages.

FC3. An assembly system according to FC1, wherein each drug package includes a frame, the respective plurality of cells being separated by the frame to form a spaced array.
FC4. An assembly system according to FC3, wherein each cell includes at least one edible wall fixedly mounted to the frame, the at least one edible wall including or enclosing the respective single dose of the respective, first or second drug.
FC5. An assembly system according to FC1, wherein, when combined together, the first and second drugs are substantially identical in appearance.
FC6. An assembly system according to FC1, wherein the assembly apparatus is configured to sealingly enclose the first and second drug packages in a vacuum or a modified protective atmosphere, and to combine together the first and second drugs of the first and second drug packages in said vacuum or modified protective atmosphere.
FC7. An assembly system according to FC1, wherein the assembly apparatus is configured to sealingly enclose each of the plurality of single, orally ingestible bodies in a respective one of a plurality of cells of an end user package, each cell of the end user package defining an enclosure which is openable by an end user to remove the respective single, orally ingestible body for use.
FC8. An assembly system according to FC7, wherein each package of the plurality of packages includes a frame, the respective plurality of cells being separated by the frame to form a spaced array; and the end user package incorporates the frame of at least one of the plurality of packages received in the assembly apparatus.
FC9. An assembly system according to FC8, wherein each cell of the end user package includes a cell of said at least one of the plurality of packages received in the assembly apparatus; and the end user package includes at least a part of another respective one of the plurality of packages received in the assembly apparatus, wherein the assembly apparatus is arranged to close each cell of the end user package with said at least a part.
FC10. An assembly system according to FC8, wherein the end user package incorporates the frame of each of two or more of the plurality of packages received in the assembly apparatus.
FC11. An assembly system according to FC8, wherein each cell of said at least one of the plurality of packages whose frame is incorporated in the end user package includes a respective, orally ingestible component when received in the assembly apparatus; and each orally ingestible component is incorporated in a respective single, orally ingestible body of the end user package.
FC12. An assembly system according to FC11, wherein said orally ingestible component does not include a drug.
FC13. An assembly system according to FC11, wherein said orally ingestible component forms an outer surface of the respective single, orally ingestible body.
FC14. An assembly system according to FC9, wherein each drug package includes a frame, the respective plurality of cells being separated by the frame to form a spaced array; and each cell of each drug package includes at least one edible wall fixedly mounted to the frame, the at least one edible wall including or enclosing the respective single dose of the respective, first or second drug; and the end user package includes the frame, and the at least one edible wall of each of the cells, of each of the first and second drug packages.
FC15. An assembly system according to FC14, wherein each enclosure of the end user package includes a pair of outer walls spaced apart in opposed relation; and

the assembly apparatus is configured to create a vacuum, and to sealingly enclose the edible walls of each single, orally ingestible body, in said vacuum, between the outer walls of the respective enclosure; and

the outer walls of each enclosure are configured to be moveable together by external ambient atmospheric pressure to compress the edible walls of the respective single, orally ingestible body between the respective pair of outer walls.

FC16. An assembly system according to FC7, wherein the first drug package includes first label indicia identifying the first drug, and the second drug package includes second label indicia identifying the second drug;

and the assembly apparatus is arranged to combine together the first and second label indicia from the first and second drug packages as received in the assembly apparatus to form a composite label of the end user package identifying each of the first and second drugs.

FC17. An assembly system according to FC16, wherein the composite label is a label assembly including first and second label elements, the first label element bearing the first label indicia, the second label element bearing the second label indicia;

the first label element forming part of the first drug package as received in the assembly apparatus,

the second label element forming part of the second drug package as received in the assembly apparatus.

FC18. An assembly system according to FC1, wherein each of the first and second drug packages includes machine readable indicia, and the assembly apparatus is arranged:to read the machine readable indicia from the first and second drug packages,to receive information from a database, and,based on the indicia and the received information, to identify and authenticate the first and second drugs in the first and second drug packages.
FC19. An assembly system according to FC18, wherein the assembly apparatus is further arranged to upload information based on the machine readable indicia to the database.
FC20. An assembly system according to FC18, wherein the assembly apparatus is further arranged to output information from the database to a printer to print an information leaflet identifying the first and second drugs.
FC21. An assembly system according to FC1, wherein the assembly apparatus is configured to receive the first and second drug packages in a stacked configuration in which corresponding cells of the first and second drug packages are axially aligned; and

each of the first and second drug packages includes at least one shape profile, and

the assembly apparatus includes at least one corresponding shape profile, the shape profile of the assembly apparatus being adjustable to selectively fit or obstruct the shape profile of each of the first and second drug packages so as to selectively permit or prevent reception of each of the first and second drug packages in the assembly apparatus.

FC22. An assembly system according to FC1, wherein each drug package includes a frame, the respective plurality of cells being separated by the frame to form a spaced array; and

each cell of each drug package defines an enclosure, and the respective single dose is enclosed within the enclosure.

FC23. An assembly system according to FC22, wherein each drug package includes at least one movable closure element which closes at least one respective end of each cell;

and the assembly apparatus is arranged to displace the at least one movable closure element, relative to the frame, to open the at least one respective end of each cell while the plurality of packages are stacked in the machine.

FC24. An assembly system according to FC22, wherein each cell is closed by a frangible foil.
FC25. An assembly system according to FC22, wherein each single dose is enclosed in spheroidal form within the respective enclosure.
FC26. An assembly system according to FC25, wherein each single dose comprises one or more spheroids having a diameter of at least 2 mm.
FC27. An assembly system according to FC22, wherein each of the plurality of single, orally ingestible bodies includes a capsule formed from at least first and second capsule parts, the assembly apparatus being configured:

to receive the at least first and second capsule parts of a plurality of said capsules,

to collect together between the at least first and second capsule parts of each capsule the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package, and

to close together the at least first and second capsule parts to enclose within each capsule the respective single dose of the first drug and the respective single dose of the second drug.

FC28. An assembly system according to FC27, wherein the first and second capsule parts comprise a cap and a body, the body being received in the cap; and each single dose comprises at least one spheroid, the spheroids of all of said single doses being of equal diameter; and a diameter of each spheroid is less than one half, and greater than one third, of an internal diameter of the body of the capsule.
FC29. An assembly system according to FC27, wherein the plurality of packages further includes an end user package and a plug package;
each cell of the plug package defining an enclosure containing a plug;
the assembly machine being configured:
to receive the end user package together with the plug package and the first and second drug packages; and
to slidingly displace each plug through respective axially aligned cells of the plurality of packages, to close an open end of a respective one of the cells of the end user package, to sealingly enclose a respective capsule containing said single doses of the first and second drugs in said respective one of the cells of the end user package;
wherein each cell of the end user package is openable by an end user to remove the respective capsule containing said single doses of the first and second drugs for use.
FC30. An assembly system according to FC29, wherein the first capsule part is a capsule cap, and the second capsule part is a capsule body; and each cell of the plug package defines an enclosure containing the plug together with a respective capsule body.
FC31. An assembly system according to FC30, wherein the plug defines a carrier, and the capsule body is arranged in the carrier.
FC32. An assembly system according to FC29, wherein the first capsule part is a capsule cap, and the second capsule part is a capsule body; and each cell of the end user package, as received in the assembly machine, contains a respective said capsule cap.
FC33. An assembly system according to FC32, wherein each cell of the end user package contains a locating structure, the locating structure supporting the capsule cap in spaced relation to a cell wall of the cell.
FC34. An assembly system according to FC29, wherein the end user package includes an assembly of sub-packages, each sub-package including a plurality of said cells, the sub-packages being separable for use by an end user.
FC35. An assembly system according to FC29, wherein the first capsule part is a capsule cap, and the second capsule part is a capsule body; and the plurality of packages further includes a cap package, each cell of the cap package including a respective capsule cap, and a collar; the collar defining an aperture and being configured to guide the respective capsule body to enter telescopically into the respective capsule cap via the aperture; the assembly machine being configured:

to displace the collar slidingly into the open end of the respective cell of the end user package; and

to slidingly displace the plug into the aperture of the collar, so that the plug and the collar together close the open end of the respective cell of the end user package containing the capsule.

FC36. An assembly system according to FC35, wherein the cap package and the end user package are connected together to form an end user package assembly, the machine being configured to receive the end user package assembly.
FC37. An assembly system according to FC27, wherein the assembly apparatus includes at least one vibration source, the at least one vibration source being configured to transfer vibrational energy to the capsule parts or the single doses during assembly.
FC38. An assembly system according to FC27, wherein each of the first and second drug packages has a different thickness in a thickness dimension, the thickness of each of the packages being proportionate to a volume of the respective single dose of the first or second drug of each of the cells of the respective package; and

the assembly apparatus is configured:to receive the first and second drug packages in a stacked configuration in which corresponding cells of the first and second drug packages are axially aligned in the thickness dimension, andto receive an indication corresponding to a maximum volume capacity of each of the capsules, andto prevent operation of the assembly apparatus to combine together the first and second drugs of the first and second drug packages where a combined thickness of the first and second drug packages is greater than a maximum combined thickness corresponding to the maximum volume capacity of each of the capsules.
FC39. An assembly system according to FC27, wherein the plurality of packages further includes a first capsule package, each cell of the first capsule package defining an enclosure containing the first capsule part of a respective one of the capsules; the assembly machine being configured:

to receive the first capsule package together with the first and second drug packages; and

to sealingly enclose each capsule containing said single doses of the first and second drugs in a respective one of the cells of the first capsule package to form an end user package;

wherein each cell of the first capsule package forms a cell of the end user package which is openable by an end user to remove the capsule containing said single doses of the first and second drugs for use.

FC40. An assembly system according to FC39, wherein the plurality of packages further includes a second capsule package, each cell of the second capsule package forming an enclosure containing the second capsule part of a respective one of the capsules; the assembly apparatus being configured:

to receive the first and second capsule packages and the first and second drug packages in a stacked configuration in which the first and second drug packages are arranged between the first and second capsule packages, and corresponding cells of the first and second capsule packages and the first and second drug packages are axially aligned; and

to urge the second capsule part of each cell of the second capsule package through the respective, axially aligned cells of the first and second drug packages into the respective, axially aligned cell of the first capsule package.

FC41. An assembly system according to FC40, wherein each cell of the second capsule package contains a carrier, each second capsule part is arranged in the respective carrier, and the assembly apparatus is arranged to urge the carrier containing the second capsule part through the respective, axially aligned cells of the first and second drug packages into the respective, axially aligned cell of the first capsule package, such that the carrier forms a part of the end user package.
FC42. An assembly system according to FC41, wherein each cell of each drug package is closed by a frangible foil, and the carrier is arranged to penetrate the foil.
FC43. An assembly system according to FC42, wherein the foil is patterned to define regions, each region of the foil closing a respective one of the cells and including a first layer and a second layer;

wherein the first layer is undivided, and the second layer is divided into sub-regions which extend radially inwardly away from a wall of the cell and towards a central axis of the cell.

FC44. An assembly system according to FC43, wherein the first layer is a metal, and the second layer is a polymer.
FC45. An assembly system according to FC41, wherein the first capsule package includes a flap, the flap having an adhesive surface and being movable to position its adhesive surface to cover a side of the first capsule package through which the carriers are admitted during assembly.
FC46. An assembly system according to FC45, wherein the first drug package includes first label indicia identifying the first drug, and the second drug package includes second label indicia identifying the second drug;

and the assembly apparatus is arranged to combine together the first and second label indicia from the first and second drug packages as received in the assembly apparatus to form a composite label of the end user package identifying each of the first and second drugs;

and the composite label is arranged to form a front surface of the flap facing away from the adhesive surface.

FC47. An assembly system according to FC41, wherein the first drug package includes first label indicia identifying the first drug, and the second drug package includes second label indicia identifying the second drug;

and the assembly apparatus is arranged to combine together the first and second label indicia from the first and second drug packages as received in the assembly apparatus to form a composite label of the end user package identifying each of the first and second drugs;

and the composite label is fixed by adhesive to cover a side of the first capsule package through which the carriers are admitted during assembly.

FC48. A method for forming drugs into orally ingestible bodies, including:

providing first and second drugs;

providing a plurality of packages, the plurality of packages including at least first and second drug packages, each package of the plurality of packages including a plurality of cells;

packaging the first drug in the first drug package so that each cell of the first drug package includes a single dose of the first drug;

packaging the second drug in the second drug package so that each cell of the second drug package includes a single dose of the second drug; and then

combining together the first and second drugs to form a plurality of single, orally ingestible bodies, wherein each single, orally ingestible body of the plurality of single, orally ingestible bodies includes the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package;

characterised in that only one said single dose is packaged in each respective cell of each respective drug package, and the first and second drugs are combined together within the cells of the plurality of packages.
FC49. A method according to FC48, wherein each drug package is a single use drug package and is disposed of after forming the plurality of single, orally ingestible bodies.
FC50. A method according to FC48, wherein each drug package is a single use drug package and includes at least one re-usable, monolithic, foraminous block; and after using the drug package to form the plurality of single, orally ingestible bodies, the block is cleaned and re-used to form part of another single use drug package.
FC51. A method according to FC48, wherein each drug package includes a frame, the respective plurality of cells being separated by the frame to form a spaced array; and

each cell of each drug package defines an enclosure, and the respective single dose is enclosed within the enclosure.

FC52. A method according to FC51, wherein each drug package includes at least one movable closure element which closes at least one respective end of each cell;

and the at least one movable closure element is displaced, relative to the frame, to open the at least one respective end of each cell when combining together the first and second drugs.

FC53. A method according to FC51, wherein each enclosure is sealed by a frangible film, and the film is broken when combining together the first and second drugs.
FC54. A method according to FC48, further including: sealingly enclosing each of the plurality of single, orally ingestible bodies in a respective one of a plurality of cells of an end user package, wherein each cell of the end user package defines an enclosure which is openable by an end user to remove the respective single, orally ingestible body for use.
FC55. A method according to FC48, wherein each of the plurality of single, orally ingestible bodies includes a capsule formed from at least first and second capsule parts; the method further including:

receiving in the assembly apparatus the at least first and second capsule parts of a plurality of said capsules,

collecting together between the at least first and second capsule parts of each capsule the single dose of the first drug of a respective one of the cells of the first drug package, and the single dose of the second drug of a respective one of the cells of the second drug package, and

closing together the at least first and second capsule parts to enclose within each capsule the respective single dose of the first drug and the respective single dose of the second drug.

FC56. A method according to FC55, wherein the plurality of packages further includes an end user package and a plug package;
each cell of the plug package defining an enclosure containing a plug;
the method further including:
receiving the end user package together with the plug package and the first and second drug packages in the assembly machine, and
slidingly displacing each plug through respective axially aligned cells of the plurality of packages, to close an open end of a respective one of the cells of the end user package, to sealingly enclose a respective capsule containing said single doses of the first and second drugs in said respective one of the cells of the end user package;
wherein each cell of the end user package is openable by an end user to remove the respective capsule containing said single doses of the first and second drugs for use.
FC57. A method according to FC54, further including:

providing the first drug package with first label indicia identifying the first drug;

providing the second drug package with second label indicia identifying the second drug; and

combining together the first and second label indicia from the first and second drug packages as received in the assembly apparatus to form a composite label of the end user package identifying each of the first and second drugs.

FC58. A method according to FC48, further including:

providing each of the first and second drug packages with machine readable indicia, and

introducing the plurality of packages including at least the first and second drug packages into an assembly apparatus, and operating the assembly apparatus:to combine together the first and second drugs to form said plurality of single, orally ingestible bodies,to read the machine readable indicia from the first and second drug packages,to receive information from a database, and,based on the indicia and the received information, to identify and authenticate the first and second drugs in the first and second drug packages.
FC59. A method according to FC58, further including: uploading information based on the machine readable indicia to the database.
FC60. A method according to FC58, further including: outputting information from the database to a printer to print an information leaflet identifying the first and second drugs.
FC61. A package for use in an assembly system, the package including a frame, the frame defining a plurality of cells separated by the frame to form a spaced array; wherein either:

(a) each cell includes at least one edible wall fixedly mounted in the frame, the at least one edible wall being configured to be detached from the frame and consumed in normal use by an end user; or

(b) each cell includes a cell wall, the cell wall extending along a cell axis between opposite, first and second ends of the cell at opposite, first and second sides of the frame; and each of the first and second ends of the cell is closed by a frangible foil or a movable closure element; and each cell contains a single dose of a drug; or

(c) each cell includes a cell wall, the cell wall extending along a cell axis between opposite, first and second ends of the cell at opposite, first and second sides of the frame; and each cell contains a part of an empty capsule, but without a complementary part required to complete the capsule.

FC62. A package according to FC61, wherein the package is a single use package.
FC63. A package according to FC61, wherein (a) each cell includes at least one edible wall fixedly mounted in the frame, the at least one edible wall being configured to be detached from the frame and consumed in normal use by an end user.
FC64. A package according to FC63, wherein each cell is closed on one side of the frame by an outer wall, the outer wall sealingly attached to the frame and configured to be ruptured or torn away from the frame in normal use by an end user to expose the at least one edible wall.
FC65. A plurality of packages according to FC63, wherein the frames of the packages are configured to be stacked and bonded together in an assembled configuration with the plurality of cells of each package in axial alignment with the plurality of cells of an adjacent one of the packages; and wherein a respective edible wall of each cell is configured to adhere to a respective edible wall of a corresponding one of the cells of an adjacent one of the packages when the frames are stacked and bonded together in the assembled configuration.
FC66. A plurality of packages according to FC65, wherein the at least one edible wall includes or encloses a single dose of a drug.
FC67. A plurality of packages according to FC66, wherein the at least one edible wall is exposed at each of two oppositely facing sides of the frame.
FC68. A plurality of packages according to FC67, wherein the frame is coated with a tacky adhesive on each of the two oppositely facing sides of the frame.
FC69. A plurality of packages according to FC68, wherein the frame is enclosed between two removable covers, each cover being arranged to protect a respective one of the two oppositely facing sides of the frame.
FC70. A plurality of packages according to FC63, wherein the frames of the packages are configured to be stacked and bonded together in an assembled configuration with the plurality of cells of each package in axial alignment with the plurality of cells of an adjacent one of the packages; and wherein each frame includes at least one label portion, each of the label portions bearing label indicia identifying the respective drug contained in the respective package; the label portions being configured to form a composite label displaying a respective label portion of each of the packages when the frames are stacked and bonded together in the assembled configuration.
FC71. A plurality of packages according to FC70, wherein each frame includes a plurality of label portions bearing identical label indicia.
FC72. A package according to FC61, wherein (b) each cell includes a cell wall, the cell wall extending along a cell axis between opposite, first and second ends of the cell at opposite, first and second sides of the frame; and each of the first and second ends of the cell is closed by a frangible foil or a movable closure element; and each cell contains a single dose of a drug.
FC73. A package according to FC72, wherein each of the first and second ends of the cell is closed by a frangible foil, and the foil is patterned to define regions, each region of the foil closing a respective one of the cells and including a first layer and a second layer; wherein the first layer is undivided, and the second layer is divided into sub-regions which extend radially inwardly away from the cell wall and towards the cell axis.
FC74. A package according to FC73, wherein the first layer is a metal, and the second layer is a polymer.
FC75. A package according to FC72, wherein each single dose comprises at least one spheroid.
FC76. A package according to FC75, wherein the at least one spheroid has a diameter of at least 2 mm.
FC77. A package according to FC72, wherein the package includes a label portion bearing label indicia identifying the drug, the label portion having an adhesive surface separate or separable from the frame.
FC78. A package according to FC61, wherein (c) each cell includes a cell wall, the cell wall extending along a cell axis between opposite, first and second ends of the cell at opposite, first and second sides of the frame; and each cell contains a part of an empty capsule, but without a complementary part required to complete the capsule.
FC79. A package according to FC78, wherein the part is arranged in a carrier, the carrier being received in the cell and slidable out of the cell along the cell axis.
FC80. A package according to FC79, wherein at least the first end of the cell is closed by a frangible foil, and the carrier is configured to rupture the foil by sliding movement of the carrier out of the cell along the cell axis.
FC81. A package according to FC78, FC79 or FC80, wherein at least the first end of the cell is closed by a frangible foil which is patterned to define regions, each region of the foil closing a respective one of the cells and including a first layer and a second layer;

wherein the first layer is undivided, and the second layer is divided into sub-regions which extend radially inwardly away from a wall of the cell and towards a central axis of the cell.

FC82. A package according to FC81, wherein the first layer is a metal, and the second layer is a polymer.
FC83. A package according to FC78, wherein the cell includes a locating structure supporting the part in spaced relation to the cell wall.
FC84. A package according to FC83, wherein the locating structure is a lining of flock within the cell.
FC85. A package according to FC83 or FC84, wherein the second end of the cell is closed by a removable outer wall, the outer wall configured to be lifted and torn outwardly away from the frame by a user to open the second end of the cell to permit the capsule to be removed from the cell.
FC86. An assembly apparatus for filling capsules with drugs, including:

a plurality of pushrods spaced apart in parallel relation, each pushrod having an end surface;

a pressure plate having a pressure surface arranged in opposed, spaced relation to the end surfaces of the pushrods to define a receiving space between the pressure plate and the end surfaces of the pushrods;

an actuation mechanism configured to cause relative movement between the pressure plate and the pushrods, in a compression stroke, along a displacement axis parallel with the pushrods; and

an alignment structure configured to maintain a stack of packages in alignment with the pushrods when, in use, during the compression stroke, the pushrods are urged through the stack of packages positioned in the receiving space.

FC87. An assembly apparatus according to FC86, including an assembly surface extending between the pushrods, the assembly surface being positionable in a start position proximate the end surfaces of the pushrods, and movable along the displacement axis during the compression stroke.
FC88. An assembly apparatus according to FC87, wherein the assembly surface is biased towards the pressure surface to compress the stack of packages between the assembly surface and the pressure surface, in use, during the compression stroke.
FC89. An assembly apparatus according to FC87, including a flat, front surface extending in a plane parallel with the displacement axis and normal to the assembly surface; the front surface and the assembly surface being fixed together to move together during the compression stroke.
FC90. An assembly apparatus according to FC86, including at least one cutter, the at least one cutter being arranged to cut through a portion of the stacked packages, in use, during the compression stroke.
FC91. An assembly apparatus according to FC86, wherein the alignment structure includes a plurality of alignment rods, the alignment rods extending in parallel with the pushrods beyond the end surfaces of the pushrods and into the receiving space.
FC92. An assembly apparatus according to FC86, including at least one shape profile, and a profile adjustment mechanism for adjusting the at least one shape profile to selectively fit or obstruct a corresponding shape profile of each of the packages so as to selectively permit or prevent each of the packages from being received in the receiving space.
FC93. An assembly apparatus according to FC92, wherein the at least one shape profile is an axially continuous, non-circular cross-section of at least one profile rod; the at least one profile rod extending along a profile rod axis in parallel with the pushrods beyond the end surfaces of the pushrods and into the receiving space; the profile adjustment mechanism being configured to rotate the at least one profile rod about the profile rod axis.
FC94. An assembly apparatus according to FC86, further including:a controller for controlling the actuation mechanism, anda reader for reading machine readable indicia in use from the stacked packages;

the controller being arranged to retrieve information from a database to identify and authenticate the stacked packages.

FC95. An assembly apparatus according to FC94, wherein the controller is arranged to upload information based on the machine readable indicia to the database.
FC96. An assembly apparatus according to FC94, wherein the controller is arranged to output information from the database to a printer to print an information leaflet identifying first and second drugs contained in the stacked packages.
FC97. An assembly apparatus according to FC86, wherein the apparatus is arranged to combine together indicia from respective ones of the packages as received in the machine to form a composite label of an end user package.
FC98. An assembly apparatus according to FC86, wherein the apparatus is arranged to displace movable closure elements of the packages while the packages are stacked in the apparatus.
FC99. An assembly apparatus according to FC86, including at least one vibration source, the at least one vibration source being configured to transfer vibrational energy to the drugs or respective parts of the capsules during assembly.
FC100. An assembly apparatus for use in assembling together a plurality of packages, each of the packages including a frame, the frame defining a plurality of cells separated by the frame to form a spaced array; the apparatus including:

an alignment structure for guiding the plurality of packages in a stacked configuration with the cells of each package in axial alignment with the cells of each other package of the plurality of packages; and

a compression mechanism for compressing together the frames of the plurality of packages in the stacked configuration to form an assembly defining an end user package.

FC101. An assembly apparatus according to FC100, wherein the assembly apparatus is arranged to create a vacuum, and to compress together the frames of the plurality of packages within the vacuum.
FC102. An assembly apparatus according to FC100, wherein the assembly apparatus is arranged, before compressing together the frames of the plurality of packages, to detach and separate the frame of each of two or more of the packages from a cover or covers removably connected to the frame.
FC103. An assembly apparatus according to FC100, wherein the assembly apparatus includes a plurality of elongate slots, each slot being configured to receive a respective one of the packages.
FC104. An assembly apparatus according to FC103, wherein each slot includes a shape profile configured to selectively fit or obstruct a corresponding shape profile of a respective one of the packages introduced into the slot.
FC105. An assembly apparatus according to FC104, wherein different ones of the slots have different shape profiles.
FC106. An assembly apparatus according to FC100, wherein the frame of each package includes a plurality of label portions; and

the assembly apparatus includes a cutting mechanism arranged to cut away different respective ones of the label portions of the plurality of packages, to leave each of the plurality of packages, after said cutting away, with a different one or different ones of its respective label portions when compared with each other one of the plurality of packages; and

the assembly apparatus is configured to assemble together the packages in the stacked configuration to display a remaining one of the label portions of each package of the plurality of packages, said remaining ones of the label portions being displayed in juxtaposed relation to form together a composite label of the end user package.

FC107. An assembly apparatus according to FC100, wherein the alignment structure includes alignment elements configured to engage the packages to maintain the packages in parallel relation, and the machine is configured to slide the packages together along the alignment elements.
FC108. An assembly apparatus according to FC107, wherein the alignment elements form part of a package transfer assembly, and the package transfer assembly is arranged to move the packages from an initial, receiving position to an assembly position in which the packages are compressed together by the compression mechanism.
FC109. An assembly apparatus according to FC100, wherein the assembly apparatus is arranged to read machine readable indicia from the packages, and to retrieve information from a database to identify and authenticate each of the packages.
FC110. An assembly apparatus according to FC109, wherein the assembly apparatus is further arranged to upload information based on the machine readable indicia to the database.
FC111. An assembly apparatus according to FC109, wherein the assembly apparatus is further arranged to output information from the database to a printer to print an information leaflet identifying drugs contained in the packages.
FC112. An end user package including a plurality of cells and a plurality of single, orally ingestible bodies;

each of the single, orally ingestible bodies being sealingly enclosed within a respective cell of the plurality of cells, each cell defining an enclosure which is openable by an end user to remove the respective single, orally ingestible body for use;

wherein each single, orally ingestible body includes a single dose of a first drug, and a single dose of a different, second drug; and either:

(a) each single, orally ingestible body includes a capsule containing a plurality of granules, a first one or first ones of the granules containing the first drug but not the second drug, a second one or second ones of the granules containing the second drug but not the first drug; or

(b) the end user package includes at least first and second drug packages, each of the drug packages including a respective frame, the frame defining a plurality of drug package cells separated by the respective frame to form a spaced array, each of the drug package cells including at least one edible wall fixedly mounted in the respective frame;

the at least one edible wall of each of the drug package cells of the first drug package including or enclosing the single dose of the first drug but not the second drug;

the at least one edible wall of each of the drug package cells of the second drug package including or enclosing the single dose of the second drug but not the first drug;

the frames being connected together, each of the drug package cells of the first drug package being in axial alignment with a respective one of the drug package cells of the second drug package, to form together a respective one of the cells of the end user package;

the edible walls of the respective drug package cells forming each cell of the end user package being connected together to form together the respective single, orally ingestible body contained within the respective cell of the end user package.

FC113. An end user package according to FC112, wherein (a) each single, orally ingestible body includes a capsule containing a plurality of granules, a first one or first ones of the granules containing the first drug but not the second drug, a second one or second ones of the granules containing the second drug but not the first drug.
FC114. An end user package according to FC113, wherein the first and second ones of the granules are spheroids having a mean diameter of at least 2 mm.
FC115. An end user package according to FC114, wherein the capsule includes a body and a cap, the body being received in the cap, and a diameter of each spheroid is less than one half, and greater than one third, of an internal diameter of the body of the capsule.
FC116. An end user package according to FC113, FC114, or FC115, wherein all of the capsules contain an equal number of said first one or first ones of the granules, and all of the capsules contain an equal number of said second one or second ones of the granules.
FC117. An end user package according to FC113, wherein each capsule is arranged in a carrier, the carrier being fittingly received within the cell and having an open end through which the capsule may be removed from the cell, and a closed end opposite the open end.
FC118. An end user package according to FC117, wherein each cell is internally flocked.
FC119. An end user package according to FC114 or FC115, wherein the first and second ones of the spheroids are substantially identical in appearance.
FC120. An end user package according to FC112, wherein (b) the end user package includes at least first and second drug packages, each of the drug packages including a respective frame, the frame defining a plurality of drug package cells separated by the respective frame to form a spaced array, each of the drug package cells including at least one edible wall fixedly mounted in the respective frame;

the at least one edible wall of each of the drug package cells of the first drug package including or enclosing the single dose of the first drug but not the second drug;

the at least one edible wall of each of the drug package cells of the second drug package including or enclosing the single dose of the second drug but not the first drug;

the frames being connected together, each of the drug package cells of the first drug package being in axial alignment with a respective one of the drug package cells of the second drug package, to form together a respective one of the cells of the end user package;

the edible walls of the respective drug package cells forming each cell of the end user package being connected together to form together the respective single, orally ingestible body contained within the respective cell of the end user package.

FC121. An end user package according to FC120, wherein each enclosure of the end user package includes a pair of outer walls spaced apart in opposed relation; and the edible walls of each single, orally ingestible body are bonded together by adhesion, and are compressed together between the outer walls of the respective enclosure by external ambient atmospheric pressure acting on the outer walls.
FC122. An end user package according to FC120, wherein each frame includes a label portion bearing label indicia identifying the respective drug contained in the respective drug package; the label portions being juxtaposed to form a composite label of the end user package.
FC123. An assembly system comprising:

an assembly apparatus, and

a plurality of packages, the plurality of packages including at least first and second drug packages; each package of the plurality of packages including a plurality of cells;

each cell of the first drug package including a single dose of a first drug, each cell of the second drug package including a single dose of a second drug;
each single dose comprising one or more particles, the particles of all said single doses being of equal size and shape, each particle having a dimension of at least 1.5 mm;
wherein each cell of each drug package includes only one single dose of the respective drug,
and each of the cells of the first drug package includes an equal number of particles,
and each of the cells of the second drug package includes an equal number of particles;
and the assembly apparatus is configured:

to receive the plurality of packages including at least the first and second drug packages,

to receive a plurality of capsule caps and capsule bodies, and

to combine together the first and second drugs of the first and second drug packages to form a plurality of capsules, wherein for each capsule of the plurality of capsules, the single dose of the first drug of a respective one of the cells of the first drug package is encapsulated, together with the single dose of the second drug of a respective one of the cells of the second drug package, between a respective said capsule cap and capsule body.

FC124. An assembly system according to FC1, wherein each of said particles is a spheroid having a diameter of at least 1.5 mm.
FC125. A method for filling drugs into capsules, including:

providing first and second drugs;

providing a plurality of packages, the plurality of packages including at least first and second drug packages, each package of the plurality of packages including a plurality of cells;

packaging the first drug in the first drug package so that each cell of the first drug package includes a single dose of the first drug; and

packaging the second drug in the second drug package so that each cell of the second drug package includes a single dose of the second drug;

wherein each single dose comprises one or more particles, the particles of all said single doses being of equal size and shape, each particle having a dimension of at least 1.5 mm;
and only one said single dose is packaged in each respective cell of each respective drug package,
and each of the cells of the first drug package includes an equal number of particles,
and each of the cells of the second drug package includes an equal number of particles;
the method further including:

receiving in an assembly apparatus the plurality of packages including at least the first and second drug packages together with a plurality of capsule caps and capsule bodies; and

operating the assembly apparatus to combine together the first and second drugs of the first and second drug packages to form a plurality of capsules, wherein for each capsule of the plurality of capsules, the single dose of the first drug of a respective one of the cells of the first drug package is encapsulated, together with the single dose of the second drug of a respective one of the cells of the second drug package, between a respective said capsule cap and capsule body.

FC126. An end user package including a plurality of capsules;
each capsule including a single dose of a first drug, and a single dose of a different, second drug;
each capsule containing a plurality of particles, a first one or first ones of the particles containing the first drug but not the second drug, a second one or second ones of the particles containing the second drug but not the first drug;
wherein the first and second ones of the particles are spheroids having a mean diameter of at least 1.5 mm, and all of the capsules contain an equal number of said first one or first ones of the particles, and all of the capsules contain an equal number of said second one or second ones of the particles.
FC127. An end user package according to FC126, wherein each capsule comprises a cap and a body, the body being received in the cap; and each single dose comprises at least one spheroid, the spheroids of all of said single doses being of equal diameter; and a diameter of each spheroid is less than one half, and greater than one third, of an internal diameter of the body of the capsule.
FC128. A kit of medicaments for use in the treatment of psychosis in an individual with a history of non-compliance with oral medication, including:
a plurality of crisis oral dosage units, and
a plurality of maintenance oral dosage units;
each of the crisis oral dosage units including a single dose of a first drug and a single dose of a different, second drug, said single doses being combined together as a single, orally ingestible body;
each of the maintenance oral dosage units including a single dose of the first drug without the second drug;
wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis.
FC129. A kit of medicaments according to FC128, wherein the first drug is selected to alleviate a first symptom of the psychosis, the first symptom being one of hallucinations and delusions; and the second drug is selected to alleviate the affective symptom without alleviating the first symptom.
FC130. A kit of medicaments according to FC128, wherein, when taken at a prescribed frequency: the first drug is selected to alleviate a first symptom of the psychosis within a first time period from initial administration, the first symptom being one of hallucinations and delusions, and the second drug is selected to alleviate the affective symptom within a second time period from initial administration; the second time period being shorter than the first time period.
FC131. The use of a kit of medicaments as defined in any of FC128, FC129 or FC130 for the treatment of psychosis in an individual with a history of non-compliance with oral medication.
FC132. The use of a kit of medicaments according to FC131, wherein the treatment of psychosis comprises the treatment of schizophrenia.
FC133. The use of a kit of medicaments according to FC131, wherein both the crisis oral dosage units and the maintenance oral dosage units are provided to the individual for alternative self-administration at the discretion of the individual, wherein the maintenance oral dosage units are provided for self-administration when the individual feels well, and the crisis oral dosage units are provided for self-administration when the individual feels unwell.
FC134. A method for treating psychosis in an individual with a history of non-compliance with oral medication, comprising:

providing different, first and second drugs, wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis;

combining together the first and second drugs to form a plurality of crisis oral dosage units, each of the crisis oral dosage units including a single dose of the first drug and a single dose of the second drug, said single doses being combined together as a single, orally ingestible body;

forming a plurality of maintenance oral dosage units, each of the maintenance oral dosage units including a single dose of the first drug without the second drug; and

providing both the crisis oral dosage units and the maintenance oral dosage units to the individual for alternative self-administration at the discretion of the individual, wherein the maintenance oral dosage units are provided for self-administration when the individual feels well, and the crisis oral dosage units are provided for self-administration when the individual feels unwell.

FC135. A method according to FC134, wherein the first drug is selected to alleviate a first symptom of the psychosis, the first symptom being one of hallucinations and delusions; and the second drug is selected to alleviate the affective symptom without alleviating the first symptom.
FC136. A method according to FC134, wherein, when taken at a prescribed frequency: the first drug is selected to alleviate a first symptom of the psychosis within a first time period from initial administration, the first symptom being one of hallucinations and delusions, and the second drug is selected to alleviate the affective symptom within a second time period from initial administration; the second time period being shorter than the first time period.
FC137. A method according to FC134, for the treatment of schizophrenia.
FC138. A method for manufacturing medicaments for treating psychosis in an individual with a history of non-compliance with oral medication, comprising:

identifying the individual;

identifying different, first and second drugs prescribed for the identified individual, wherein the first drug is an antipsychotic, and the second drug is a psychoactive selected to alleviate an affective symptom associated with the psychosis in the identified individual;

combining together the first and second drugs to form a plurality of crisis oral dosage units customised for the identified individual, each of the crisis oral dosage units including a single dose of the first drug and a single dose of the second drug, said single doses being combined together as a single, orally ingestible body;

forming a plurality of maintenance oral dosage units, each of the maintenance oral dosage units including a single dose of the first drug without the second drug; and packaging the plurality of crisis oral dosage units and the plurality of maintenance oral dosage units, respectively as two separate components in a kit of medicaments.

In the claims, reference numerals or characters may be inserted in parentheses, purely for ease of reference, and when so inserted should not be construed as limiting features.