Patent Description:
The present invention generally relates to a pharmaceutical dosage form and controlled release of biologically active agents, diagnostic agents, reagents, cosmetic agents, and agricultural/insecticide agents.

Pharmaceutical drug products must be manufactured into dosage forms in order to be marketed for use. Conventional dosage forms typically involve a mixture of active pharmaceutical ingredients and inactive components (excipients), along with other non-reusable materials such as a capsule shell. Categories of dosage forms include liquid dosage forms (e.g., solutions, syrups, elixirs, suspensions and emulsions), solid dosage forms (e.g., tablets, capsules, caplets and gel-caps), and semi-solid dosage form (e.g., ointments and suppositories), among which solid dosage forms are more advantages to administer drugs in systemic effect through oral route.

Tablets are most commonly used solid dosage forms, which shows more benefits in terms of manufacturing, packaging and shipping, and easy to identify and swallow. After being administered into a living organism, a tablet undergoes interplay with the body in exerting pharmaceutical effects. The active pharmaceutical ingredient must be released from the tablet before being absorbed into the blood circulation. The pharmaceutical ingredient then disperses, disintegrates or dissolves throughout the fluids and tissues of the body. During drug absorption, disposition, metabolism, and elimination process, dosage forms play a critical role in determining the release profile and bioavailability of the drugs. Therefore, there is a continuing needs for developing dosage forms that provides controlled drug delivery systems, which may offer desired drug plasma levels, reduced side effects as well as improved patient compliance. <CIT> discloses a pharmaceutical gastroretentive drug delivery system for controlled release of an active agent comprising a single- or multilayered matrix having a two- or three-dimensional geometric configuration comprising a polymer that does not retain in the stomach more than a conventional dosage form. <CIT> discloses a gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract, comprising an internal layer or compartment with an active agent and one or more pharmaceutical excipients, of which at least one is a polymer and two membranes forming together an envelope around the inner membrane. <CIT> provides a gastroretentive dosage form for once a day administration. <CIT> is directed to a fluid-imbibing drug delivery device having a first, low density for prolonged release in the stomach, and having a second, higher density such that the device exits the stomach for subsequent further release. <CIT> A2discloses a multipart capsule, including a plurality of capsule portions. The capsule portions are connected together in an assembled dosage form. The link component includes at least one aperture in flow communication with interiors of two adjacent capsule portions to control the release of the substance. <CIT> discloses a core-and-shell dosage form in which the core contains a drug and in which the shell substantially governs the release such as by controlling diffusion of the drug through the shell. <CIT> discloses controlled release dosage forms and methods of designing and manufacturing dosage forms to obtain specific release profiles including dosage forms having spatial variation of drug concentration or nested regions. <CIT> discloses a multiphasic dosage form comprising a three-dimensional matrix including pharmaceutically acceptable particulates adhered together and an active drug and a complexing agent incorporated therein. <CIT> discloses manufacturing method of a dosage form by three-dimensional printing that preserves the predetermined internal architecture while producing an improved surface finish. Rowe et al (<NPL>) show successful three-dimensional printing of drug delivery systems for pulsed release having at least two sections.

In one aspect, the present disclosure provides a dosage form including a substrate forming at least one compartment and a second compartment. The first compartment has a first aperture and the second compartment has a second aperture. A first drug content is loaded into the first compartment. A second drug content is loaded into the second compartment. A first plug seals the first aperture. A second plug seals the second aperture. The first plug and the second plug are water soluble or erodible. In certain embodiments, the drug content is operably linked to the substrate. In certain embodiments, the drug content is detached from the substrate and freely movable in the compartment.

In certain embodiments, the substrate is made from a thermoplastic material selected from the group consisting of a hydrophilic polymer, a hydrophobic polymer, a swellable polymer, a non-swellable polymer, a porous polymer, a non-porous polymer, an erodible polymer, a non-erodible polymer. In certain embodiments, the thermoplastic material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer <NUM>/<NUM>/<NUM>, polyvinylpyrrolidone- co-vinyl-acetate (PVP-VA), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) <NUM>/<NUM>, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) <NUM>/<NUM>, polyethylene glycol-polyvinyl alcohol graft copolymer <NUM>/<NUM>, kollicoat IR-polyvinyl alcohol <NUM>/<NUM>, polyvinyl alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl methacrylate-co-(<NUM>-dimethylaminoethyl) methacrylate-co-methyl methacrylate) <NUM>:<NUM>:<NUM>, poly(dimethylaminoethylmethacrylate-co-methacrylic esters), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)<NUM>:<NUM>: <NUM>, poly(methacrylic acid-co-methylmethacrylate) <NUM>:<NUM>, poly(methacylic acid-co-ethyl acrylate) <NUM>: <NUM>, poly(methacylic acid-co-methyl methacrylate) <NUM>: <NUM>, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulose phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or hypromellose (HMPC), hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxyl propyl cellulose (HPC), Polyoxyl <NUM> Hydrogenerated Castor Oil, Methyl cellulose (MC), Ethyl cellulose (EC), Poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP), Poloxamer, Hydrogenated Castor & Soybean Oil, Glyceryl Palmitostearate, Carnauba Wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose acetate butyrate (CAB), Colloidal Silicon, Dioxide, Sucrose, Glucose, Polyvinyl Acetate Phthalate (PVAP) and a combination thereof.

In certain embodiments, the compartment has a shape selected from the group consisting of a pie shape, a cone shape, a pyramid shape, a cylindrical shape, a cubic or cuboidal shape, a triangular or polygonal prism shape, a tetrahedron and a combination thereof.

In certain embodiments, the first drug content is in a form of nanoparticles, microneedles or forms a net.

In certain embodiments, the drug content comprises an active pharmaceutical ingredient (API). In certain embodiments, the API is selected from the groups consisting of local anesthetics, antiepileptic drugs and anticonvulsants, anti-Alzheimer's disease drugs, analgesics, antipodagric, anti-hypertensive drugs, antiarrhythmic drugs, diuretic drugs, drugs for treating liver diseases, drugs for treating pancreatic diseases, antihistamine drugs, anti-allergic drugs, glucocorticoid drugs, hormone drugs and contraceptive drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial drugs, anti-tuberculosis drugs, antiviral drugs, anti-neoplasm drugs, immune-modulators, cosmetically active agents and traditional Chinese medicine. In certain embodiments, the API is a biologically active agent, a diagnostic agent, a reagent for scientific research, a cosmetic agent, or an agricultural/insecticide agent.

In certain embodiments, the drug content further comprises an excipient. In certain embodiments, the excipient is made from materials selected from the group consisting of cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xyloselactose, maltose, trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose, fructo-oligosaccharides, water-soluble oligomers and polymers and a combination thereof.

In certain embodiments, the first and/or second plug are made from a porous polymer, an erodible polymer, a pH sensitive polymer or natural occurring material such as shellac. In certain embodiments, the plug is made from a material selected from the group consisting of water- soluble polymers, erodible or dissolvable polymers, wax like materials or saccharides or any materials mentioned above.

In certain embodiments, the first compartment and the second compartment are connected. In certain embodiments, the first compartment and the second compartment are disconnected.

In certain embodiments, the first drug content is the same as the second drug content. In certain embodiments, the first drug content is different from the second drug content.

In certain embodiments, the first plug is more permeable than the second plug. In certain embodiments, the first plug erodes faster than the second plug.

The scope of the invention shall be defined by the appended claims.

The figures display the general principles of conventional and controlled release dosage forms, to separately illustrate technical features used for the present invention.

In the Summary of the Invention above and in the Detailed Description of the Invention, and the claims below, and in the accompanying drawings, reference is made to particular features (including method steps) of the invention. It is to be understood that the disclosure of the invention in this specification includes all possible combinations of such particular features. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, or particular claim, that feature can also be used, to the extent possible, in combination with and/or in the context of other particular aspects and embodiments of the invention, and in the invention generally.

The term "comprises" and grammatical equivalents thereof are used herein to mean that other components, ingredients, steps, etc. are optionally present. For example, an article "comprising" (or "which comprises") components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components.

Where reference is made herein to a method comprising two or more defined steps, the defined steps can be carried out in any order or simultaneously (except where the context excludes that possibility), and the method can include one or more other steps which are carried out before any of the defined steps, between two of the defined steps, or after all the defined steps (except where the context excludes that possibility).

Where a range of value is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictate otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

The term "at least" followed by a number is used herein to denote the start of a range beginning with that number (which may be a range having an upper limit or no upper limit, depending on the variable being defined). For example, "at least <NUM>" means <NUM> or more than <NUM>. The term "at most" followed by a number is used herein to denote the end of a range ending with that number (which may be a range having <NUM> or <NUM> as its lower limit, or a range having no lower limit, depending upon the variable being defined). For example, "at most <NUM>" means <NUM> or less than <NUM>, and "at most <NUM>%" means <NUM>% or less than <NUM>%. In this disclosure, when a range is given as "(a first number) to (a second number)" or "(a first number)-(a second number)," this means a range whose lower limit is the first number and whose upper limit is the second number. For example, <NUM> to <NUM> millimeters means a range whose lower limit is <NUM> millimeters, and whose upper limit is <NUM> millimeters.

It will be appreciated that for simplicity and clarity of illustration, where appropriate, reference numerals have been repeated among the different figures to indicate corresponding or analogous elements. In addition, numerous specific details are set forth in order to provide a thorough understanding of the embodiments described herein. However, the embodiments described herein can be practiced without these specific details. In other instances, methods, procedures and components have not been described in detail so as not to obscure the related relevant function being described. Also, the description is not to be considered as limiting the scope of the implementations described herein. It will be understood that descriptions and characterizations of the embodiments set forth in this disclosure are not to be considered as mutually exclusive, unless otherwise noted.

Conventional solid dosage forms, e.g., compressed tablets, are composed of a substrate where active drug ingredient is dissolved or embedded (<FIG>). Currently conventional solid dosage forms exhibit first-order drug release profile (<FIG>) where the plasma level of the drug increases rapidly to an extremely high level after administration and then decreases exponentially (see <FIG>). This poses disadvantages such as minimal therapeutic efficacy due to reduced drug levels or drug toxicity which can occur at high concentrations. This type of drug release does not allow for appropriate plasma drug level balance. The instant invention relates to modified or controlled release oral drug delivery system, which offers advantages over conventional systems, including increased patient compliance, selective pharmacological action, reduced side effects and reduced dosing frequency. Controlled release offers prolonged delivery of drugs and maintenance of plasma levels within a therapeutic range. For example, a drug delivery system exhibiting zero-order drug release profile (<FIG>) allows for a constant quantity of drug to be release over an extended period of time, resulting in uniform and sustained drug delivery. As a result, zero-order release profile may be desired in antibiotic delivery, the treatment of hypertension, pain management, antidepressant delivery and numerous other conditions that require constant plasma drug levels.

Therefore, one aspect of the present disclosure provides a stable solid pharmaceutical dosage form for oral administration, which has a controlled release profile. In certain embodiments, the dosage form includes a substrate forming at least one compartment and and a drug content loaded into the compartment. The dosage form is so designed that the release of the active pharmaceutical ingredient of the drug content can be controlled, e.g., by opening the compartment in a predetermined manner.

As used herein, "substrate" refers to a structure in which a drug is enclosed or embedded. The substrate of a dosage form of the instant invention can be of any size and shape that are suitable for oral administration. In certain embodiments, the substrate is a flat round tablet having a diameter of around <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> <NUM>. In certain embodiments, the substrate is an oval tablet having a dimension of aournd a mm × b mm, wherein a is <NUM> to <NUM> and b is <NUM> to <NUM>. In certain embodiments, the substrate has a capsule shape.

In certain embodiments, the substrate is made of a hydrophilic polymer (e.g., hydroxypropylmethylcellulose (HPMC) and poly(ethylene oxide) (PEO)), a hydrophobic polymer (e.g., ethylcelluose (EC)), a swellable polymer, a non-swellable polymer, a porous polymer, a non-porous polymer, an erodible polymer, or a non-erodible polymer.

In certain embodiments, the dosage form has a monolithic substrate. In certain embodiments, the substrate consists of several pieces, each piece made of the same or different material.

In certain embodiments, the substrate is made of a thermoplastic material. As used herein, a "thermoplastic material" refers to a material having the ability to be shaped using heat and pressure. In certain embodiments, the thermoplastic materials may, for example, be hydrophilic, gel-forming materials, from which drug content release proceeds mainly by diffusion, or hydrophobic materials, from which drug content release proceeds mainly by diffusion from the pores in the substrate. Polymers, particularly cellulose ethers, cellulose esters and/or acrylic resins can be used as hydrophilic thermoplastic materials. Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the salts, amides or esters thereof are suitable for use as thermoplastic materials. Physiologically acceptable, hydrophobic materials that are known to the person skilled in the art, such as mono- or diglycerides of C12-C30 fatty acids and/or C12-C30 fatty alcohols and/or waxes or mixtures thereof may be used as thermoplastic material. Substrate prepared from hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof are also envisioned.

In certain embodiments, the thermoplastic material is selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer <NUM>/<NUM>/<NUM>, polyvinylpyrrolidone- co-vinyl-acetate (PVP-VA), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) <NUM>/<NUM>, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP) <NUM>/<NUM>, polyethylene glycol-polyvinyl alcohol graft copolymer <NUM>/<NUM>, kollicoat IR-polyvinyl alcohol <NUM>/<NUM>, polyvinyl alcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butyl methacrylate-co-(<NUM>-dimethylaminoethyl) methacrylate-co-methyl methacrylate) <NUM>:<NUM>:<NUM>, poly(dimethylaminoethylmethacrylate-co-methacrylic esters), poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)<NUM>:<NUM>: <NUM>, poly(methacrylic acid-co-methylmethacrylate) <NUM>:<NUM>, poly(methacylic acid-co-ethyl acrylate) <NUM>: <NUM>, poly(methacylic acid-co-methyl methacrylate) <NUM>: <NUM>, poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulose phthalate, hypromellose phthalate, hydroxypropyl methylcellulose or hypromellose (HMPC), hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide) (PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinyl acetate copolymer, polyethylene (PE), and polycaprolactone (PCL), hydroxyl propyl cellulose (HPC), Polyoxyl <NUM> Hydrogenerated Castor Oil, Methyl cellulose (MC), Ethyl cellulose (EC), Poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP), Poloxamer, Hydrogenated Castor & Soybean Oil, Glyceryl Palmitostearate, Carnauba Wax, polylactic acid (PLA), polyglycolic acid (PGA), Cellulose acetate butyrate (CAB), Colloidal Silicon, Dioxide, Sucrose, Glucose, Polyvinyl Acetate Phthalate (PVAP) and a combination thereof.

Properties and sources of various thermoplastic materials are listed in Table <NUM>.

In certain embodiments, the thermoplastic material allows the dosage form to be made using an additive method such as fused deposition modeling (FDM). In certain embodiments, the substrate can be made by using a three-dimensional printer (3D printer) configured to extruding the thermoplastic material. Typically, the thermoplastic material is melted in the 3D printer before being extruded to form the substrate. In certain embodiment, appropriate extruders include without limitation, single or twin screw extruders with the temperature within the extruder at a range from <NUM> to <NUM> and from <NUM>° to <NUM>. In general, the extrusion process can be conducted at temperatures <NUM>° to <NUM> above the glass transition (Tg) of the thermoplastic material. Once at a suitable temperature for use in the three-dimensional printer, the thermoplastic material can be deposited to the three-dimensional printing surface. The shape and size of the substrate and the compartment fabricated by the thermoplastic material can be controlled by programing the three-dimensional printing process.

The substrate forming a compartment can be made of a soluble material.

In certain embodiment, the dosage form disclosed herein contains at least a first and a second compartment within the substrate. As used herein, "compartment" refers to a space, part or room marked or partitioned off by the substrate. A compartment has an aperture or a passageway. A compartment can be of any geometry suitable for loading drug contents. In certain embodiments, the compartment has a shape selected from the group consisting of a pie shape, a cone shape, a pyramid shape, a cylindrical shape, a cubic or cuboidal shape, a triangular or polygonal prism shape, a tetrahedron and a combination thereof.

Containing a compartment in the dosage form can increase its retention in the gastro intestinal tract. <FIG> illustrates an exemplary dosage form having a substrate forming a compartment where drug content is loaded. Referring to <FIG>, a dosage form <NUM> has a compartment <NUM> formed by a substrate <NUM>. A drug content <NUM> is loaded in the compartment <NUM> by linking to the internal wall of the compartment <NUM>. The compartment <NUM> can provide a floating effect to the dosage form and thereby extend its residence time in the stomach or in an aqueous or acidic environment. The residency time can be a function of the erosion/dissolution rate of the materials of the substrate and result in a sustained release of API as shown in <FIG>.

<FIG> illustrates another exemplary dosage form with increased residence in the gastro intestinal tract. Referring to <FIG>, a dosage form <NUM> has a configuration that a compartment <NUM> contains a second dosage form <NUM> (e.g., a tablet) freely moving within the compartment <NUM>. The gastro intestinal residence time of a dosage form is limited. Using floating systems can allow the dosage form to stay in stomach and continuously release the drug at the upper part of GI tract and maximize the absorption in small intestine.

In certain embodiments, the shape of a compartment is uniquely created so that the drug content can be released at a controlled rate. In certain embodiments, a compartment has a shape selected from the group consisting of a wedge shape, a pie shape, a cone shape, a pyramid shape, a cylindrical shape, a cubic or cuboidal shape, a triangular or polygonal prism shape, a tetrahedron and a combination thereof.

In one embodiment, a compartment of the dosage form has different geometric shape. <FIG> shows an exemplary dosage form having a substrate forming a compartment of pie shape. <FIG> shows an exemplary dosage form having a substrate forming multiple compartments containing various sized openings. <FIG> shows an exemplary dosage form having a substrate forming an angled compartment. <FIG> shows an exemplary dosage form having a substrate forming multiple compartments of different sized radius.

The shape of a compartment can be used to control the release profile of the dosage form. For example, R. Lipper and W. Higuichi described a delivery system that provides zero-order release profile, which is illustrated in <FIG> shows a cross-sectional view of the delivery system having a pie-shaped compartment. The compartment communicates with the environment through a small opening. The compartment is loaded with a drug content that dissolves to release an API. The API is then released to the environment through the small opening. The dissolution rate of the drug content positively correlates to the area of the dissolution boundary of the drug content (the interface between the drug content and the space of the compartment). On the other hand, the diffusion rate of the API into the environment is negatively correlates to the diffusion path length λ. As a result, as the drug content dissolves, the area of the dissolution boundary increases, and the dissolution rate of the drug content increases. On the other hand, the diffusion path length λ increases as the drug content dissolves. So the API released in the compartment needs to be transported a longer length to diffuse out of the dosage form. It is assumed that the dosage form can be so designed to provide a zero-order release kinetics (<NPL>; <NPL>).

As used herein, the term "drug content" refers to a composition comprising one or more active ingredient, including active pharmaceutical ingredient (API), cosmetic agent, biological agent, diagnostic agent and reagent for scientific experiments.

As used herein, an API refers to an ingredient in a pharmaceutical drug that is biologically active. In certain embodiments, the API is selected from the groups consisting of local anesthetics, antiepileptic drugs and anticonvulsants, anti-Alzheimer's disease drugs, analgesics, antipodagric, anti-hypertensive drugs, antiarrhythmic drugs, diuretic drugs, drugs for treating liver diseases, drugs for treating pancreatic diseases, antihistamine drugs, anti-allergic drugs, glucocorticoid drugs, sex hormone drugs and contraceptive drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial drugs, anti-tuberculous drugs, antiviral drugs, anti-neoplasm drugs, immune-modulators, cosmetically active agents, traditional Chinese medicine (TCM) and TCM extracts.

In certain embodiments, the drug content further comprises medium. The medium can be associated with the API, i.e., the medium is in physical contact with the API. In certain embodiments, the API is embedded in the medium. In certain embodiments, the API is dispersed within the medium. In certain embodiments, the medium is made of a thermoplastic material as disclosed herein.

In certain embodiments, the medium comprises a water-soluble excipient selected from the group consisting of cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactose, fructose, xyloselactose, maltose, trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose, fructo-oligosaccharides and a combination thereof. In certain embodiments, the substrate further comprises a plasticizer.

The drug content can be of any suitable shape and size to be loaded into the compartment.

In certain embodiments, the drug content is operably linked to the compartment via covalent bond, non-covalent interactions or through a linker. Thus, the drug content and the substrate can be made separately and associate together through a covalent bond or non-covalent interactions. In certain embodiments, dosage form is made by producing the drug content and the substrate in a single process using 3D printing methods.

In certain embodiments, the drug content is formed in the shape of a compressed tablet, an oval tablet, a pill, or a capsulet. In certain embodiments, the shape of the drug content matches the shape of the compartment. For example, when the compartment is a pie-shape, the drug content is also of a pie-shape, e.g., to fill the compartment.

In certain embodiments, the drug content is in the form of nanoparticles as illustrated in <FIG>. The drug content can be mixed with solution in which the API is either dissolved or suspended. The solution is then atomized/sprayed atop a printing layer during the course of the three-dimensional printing of the dosage form. Once the solution containing the drug content dries, the drug content is dispersed in the dosage form. Nanoparticles have large surface area and will have high dissolution rate.

The size of the nanoparticles ranges from <NUM> to <NUM> in size (preferable <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>- <NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> in size). The size of nanoparticles can be controlled by selecting appropriate synthesis methods and/or systems. To obtain nanoparticles within a desired size range, the synthesis conditions may be properly controlled or varied to provide for, e.g., a desired solution concentration or a desired cavity range (a detailed review can be found at, e.g., Vincenzo Liveri, Controlled synthesis of nanoparticles in microheterogeneous systems, Published by Springer, <NUM>).

In certain embodiments, the drug content is in the form of microneedles as illustrated in <FIG>. The microneedle would be printed in conjunction with the dosage form or inserted into the dosage form during the three-dimensional printing of the dosage form. The microneedles can be composed of a saccharide, a PLGA polymer or an API or a combination thereof. The microneedle can assist in the penetration of an API into the circulatory system of a patient when administered either parenteral or enteric.

In certain embodiments, the drug content forms a network. As shown in <FIG>, a dosage form has a substrate forming a compartment loaded with a drug content. The drug content has a substrate forming a network. The frame structure of tablet is made of a material that dissolves between <NUM>-<NUM> minutes, and the substrate dissolves in <NUM>-<NUM> seconds, preferably in <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> seconds. As shown in <FIG>, the API can be released in seconds after the dosage form is administered.

The drug content can be made using an additive method such as fused deposition modeling (FDM). In certain embodiments, the drug content can be made by using a three-dimensional printer (3D printer) configured to extruding a mixture of API and the excipient. The API can be melted and mixed homogenously with the melted substrate before being extruded. Alternatively, the API in a solid form (e.g., powder) can be mixed with and dispersed in the melted substrate before being extruded. In general, the extrusion process can be conducted at temperatures <NUM>° to <NUM> above the glass transition (Tg) of the substrate and a temperature close to the melting point of the API. Once at a suitable temperature for use in the three-dimensional printer, the substrate can be deposited to the three-dimensional printing surface. The shape and size of the drug content can be controlled by programing the three-dimensional printing process. In certain embodiments, the drug content is fabricated in the same process of the substrate. In certain embodiments, the drug content is fabricated before the making of the substrate and loaded into the compartment during or after the substrate is fabricated.

In certain embodiments, when the drug content is loaded into the compartment, it is associated with the substrate, e.g., embedded or fixed in the substrate. In certain embodiments, the drug content is detachable from the substrate when loaded into the compartment.

The dosage form disclosed herein can offer various release profiles after oral administration. In certain embodiments, the dosage form provides a constant release profile, pulsatile or delayed delivery, or non-linear drug release. In certain embodiments, the dosage form provides a zero-order release kinetics.

A proper release profile may offer benefits to certain drug therapy regimes. For example, a pulsatile release profile offers controlled absorption with resultant reduction in peak through ratios, targeted release of the drug to specific areas within the gastro intestinal tract, and absorption independent of the feeding state, thus may be used to prevent tolerance, reduce the side-effects and improve patient compliance, which is desirable to treat diseases like ADHD. For another example, a release profile with a loading dose followed by a maintenance dose may be good for treating chronic conditions such as hypertension and diabetes.

Some of the mechanisms to control the release profile using the dosage from disclosed herein have been discussed above. For example, by manipulating the exposed surface area of the substrate that erodes constantly over time, the drug content embedded in the substrate is able to deliver a constant amount of drug over time. In addition, the release profile can be controlled by the size of compartment opening and/or by the geometric shape of the compartment.

The release profile is controlled by the design of a compartment having an aperture that is sealed or blocked by a plug. The plug is made of a water-soluble, porous, or erodible material or pH sensitive materials or hydrophobic material that will undergo attrition when the dosage form passing the GI tract. When the dosage form is administered to a subject, the plug is dissolved, permeated or eroded, thus releasing the drug content from the compartment. The release profile of the drug content can be controlled by choosing a plug of proper erosion/dissolution rate or permeation rate. Alternatively, the release profile of the drug content can be controlled by using the shape and/or the size of the plug (e.g., a rod shape of proper length). The release profile can also be controlled by the number of the compartments. <FIG> shows an exemplary dosage form having a substrate forming a plurality of column-shaped compartments residing on both sides of the dosage form. Each compartment is loaded with a drug content. Each compartment has an aperture that is blocked by a rod-shaped plug. The plugs have different dissolution rate. Depending on the size, shape and dissolution rate of the plug, the APIs can be released in a sustained, continuous, simultaneous, consecutive or pulsatile manner.

<FIG> shows an exemplary dosage form providing a consecutive release profile. Referring <FIG>, the dosage form <NUM> has a substrate <NUM> forming three column-shaped compartments <NUM>~<NUM>. Each compartment is loaded with a drug content of the same API. Each compartment has an aperture that is blocked by a rod-shaped plug <NUM>~<NUM>. The plugs are made of the same material but have different length. Consequently, it takes different amount of time to dissolve the plugs and to open the compartments to release the drug content. As illustrated in <FIG>, the shortest plug dissolves first, releasing the API from the first compartment. When the API in the first compartment is completely released, the plug of the median length dissolves, releasing the API from the second compartment. When the API in the second compartment is completely released, the third plug dissolves to release the API from the third compartment. As a result, the plasma drug level reaches the first peak when the drug content in the first compartment is released. When the API released from the first compartment starts to be eliminated, the plasma drug level starts to decrease (see <FIG>). Before the plasma drug level falls below the critical level (the horizontal line, below which the drug would be ineffective), the API from the second compartment is released, and the plasma drug level increases again. When the API released from the second compartment reaches the second peak and starts to be eliminated, the plug of the third compartment dissolves to open the compartment. As a result, the plasma API level is maintained above the critical level for a long time, which benefits certain diseases.

Not according to the invention, but for illustration of alternatives only, reference is made to <FIG>, displaying that the consecutive release manner can also be achieved through another dosage form having several drug contents packed in the form of layers as illustrated in <FIG>. The API can be released in a sustained manner by having each layer dissolving in synchrony to provide a continuous, sustained release of API as depicted in <FIG>. The outer layers of the dosage form dissolve immediately and release the embedded drug content when the dosage form is administered. But the layers sandwiched in the middle do not dissolve or dissolve much slower because the outer layers block their interface with the environment. The dissolution of the outer layers exposes the layers sandwiched in the middle and expedites their dissolution, thus providing a consecutive release profile as illustrated in <FIG>.

The dosage form disclosed herein may comprise one or more drug content at least partially in delayed-release form, wherein the delayed release may be achieved with the assistance of conventional materials and methods known to the person skilled in the art, for example by embedding the API in a delayed-release substrate/substrate or by the application of one or more delayed-release coatings. Through delayed release, API release may be so controlled that twice or once daily administration of the dosage form is sufficient, which is advantageous in particular in the case of a need for a sustained level active compound, e.g., for combatting pain.

The dosage form may be intended to release one of the first or the second drug in oral cavity instantly. One example is to be given to oral cavity or take sublingual region.

In certain embodiments, the drug form can further comprise conventional auxiliary substances known to the person skilled in the art, preferably selected from the group consisting of glyceryl monostearate, semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, talcum, sodium benzoate, boric acid and colloidal silica, fatty acids, substituted triglycerides, glycerides, polyoxyalkylene glycols and the derivatives thereof.

The controlled release dosage forms disclosed herein can be manufactured using any appropriate process. In certain embodiments, the dosage forms are produced using three-dimensional printing (3D printing).

As used herein, 3D printing refers to a process that produce 3D objects layer-by-layer from digital designs. The basic process of 3D printing has been described in <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>. Additional U. patents and applications related to 3D printing include: <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>;<CIT>; <CIT>. Reference can be made to the patents and applications listed above for a detailed description of 3D printing.

Different 3D printing methods have been developed for dosage form manufacturing in terms of raw materials, equipment and solidification. These 3D printing methods include binder deposition (see <NPL>; <NPL>; <NPL>; <NPL>. ; <NPL>), material jetting (see <NPL>), extrusion (see <NPL>) and photopolymerization (see <NPL>).

In certain embodiments, the dosage forms disclosed herein are manufactured using extrusion methods. In an extrusion process, material is extruded from robotically-actuated nozzles. Unlike binder deposition, which requires a powder bed, extrusion methods can print on any substrate. A variety of materials can be extruded for 3D printing, including thermoplastic materials disclosed herein, pastes and colloidal suspensions, silicones and other semisolids. One common type of extrusion printing is fused deposition modeling, which uses solid polymeric filaments for printing. In fused deposition modeling, a gear system drives the filament into a heated nozzle assembly for extrusion (see <NPL>).

The manufacturing instructions for a print job may be generated a variety of ways, including direct coding, derivation from a solid CAD model, or other means specific to the 3D printing machine's computer interface and application software. These instructions may include information on the number and spatial placement of droplets, and on general print parameters such as the drop spacing in each linear dimension (X, Y, Z), and volume or mass of fluid per droplet. For a given set of materials, these parameters may be adjusted in order to refine the quality of structure created. The overall resolution of the structure created is a function of the powder particle size, the fluid droplet size, the print parameters, and the material properties.

Because of its ability of handling a range of pharmaceutical materials and control both composition and architecture locally, 3D printing is well suited to the fabrication of dosage forms with complex geometry and composition in accordance with the present invention.

Manufacturing the dosage forms using 3D printing methods also facilitate personalized medicine. Personalized medicine refers to stratification of patient populations based on biomarkers to aid therapeutic decisions and personalized dosage form design. Modifying digital designs is easier than modifying physical equipment. Also, automated, small-scale 3D printing may have negligible operating cost. Hence, 3D printing can make multiple small, individualized batches economically feasible and enable personalized dosage forms designed to improve adherence.

Personalized dosage form allows for tailoring the amount of drug delivered based on a patient's mass and metabolism. 3D printed dosage forms could ensure accurate dosing in growing children and permit personalized dosing of highly potent drugs. Personalized dosage forms can also combine all of patients' medications into a single daily dose, thus improve patients' adherence to medication.

<FIG> illustrates a process of using 3D printing to manufacture personalized dosage forms. For each patient, a variety of clinical testing results can be obtained, including body weight, age, metabolism indicator and genomic biomarkers, etc. The clinical testing results are input into computer software. The information is combined with the prescription of physician and pharmaco-kinetic model to design a dosage form of specific dose and drug combination. The instruction is then sent to a 3D printer to manufacture the dosage form designed, which is administered to the patient.

The dosage form and methods disclosed herein can be used to control release of two or more drugs in order to optimize the drug combinations in certain therapeutic regimes. For example, a tablet to treat hypercholesterolemia can be designed to offer immediate release of Atorvastatin calcium and extended release of nicotinic acid. In another example, a non-steroidal anti-inflammatory drug (NSAID) for pain relief may be designed to provide sustained release of NSAID and a rapid release of H2-receptor antagonist for preventing NSAID-induced mucosal damage.

The substrate forms at least a first compartment and a second compartment. In certain embodiments, the substrate may form multiple compartments, each loaded with a drug content. In certain embodiments, the multiple compartments are connected. In certain embodiments, the multiple compartments are disconnected. In certain embodiments, the drug contents loaded into different compartments are the same. In certain embodiments, the drug contents loaded into different compartments are different. The dosage form can be so designed to provide simultaneous or sequential release of multiple drug content to exert synergistic therapeutic effects.

<FIG>, for illustration only, shows an exemplary dosage form that can release APIs simultaneously. Referring to <FIG>, the dosage form <NUM> includes three stacked layers <NUM>~<NUM>, each of which is embedded with a different drug content. As illustrated in <FIG>, when the dosage form <NUM> is administered, the drug contents are released simultaneously but at different rates as the layers dissolve.

<FIG>, for illustration only, depicts another exemplary dosage form of simultaneous release profile. Referring to <FIG>, the dosage form <NUM> includes three column shaped compartments <NUM>~<NUM>, in which three drug contents are loaded. Each drug content contains an API embedded in a substrate of different dissolution rate. As illustrated in <FIG>, when the dosage form <NUM> is administered, the three APIs are released simultaneously but at different rates as the substrates of the drug contents dissolve. The release rate of the APIs can also be controlled by the shape of the compartments or the size of the opening of the compartments.

<FIG>, for illustration only, depict additional exemplary dosage forms of simultaneous release profile of three APIs. Referring to <FIG>, the dosage form <NUM> contains three pie-shaped segments <NUM>~<NUM> wherein drug contents are embedded. As illustrated in <FIG>, he drug contents release simultaneously as the segments dissolve, and the release rate of the drug contents can be controlled by the dissolution rate of the segments. Referring to <FIG>, for illustration only, the dosage form <NUM> contains three pie-shaped segments <NUM>~<NUM>, which are wrapped by a shell <NUM> that dissolves slower than the segments. The release rates of the drug contents embedded in the segments are reduced as the shell <NUM> blocks the interface of the segments <NUM>~<NUM> with the environment.

<FIG>, for illustration only, shows an exemplary dosage form of sequential release profile of two APIs. Referring to <FIG>, the dosage form <NUM> includes a substrate <NUM> forming a compartment that is filled by a drug content <NUM>. The substrate <NUM> contains a first API, and the drug content <NUM> contains a second API. As illustrated in <FIG>, the first API releases as the substrate dissolves when the dosage form is administered. The second API does not release until the substrate dissolves to expose the drug content, providing a sequential release profiles of the APIs.

<FIG> shows an exemplary dosage form of sequential release profiles according to the invention. Referring to <FIG>, the dosage form <NUM> has a substrate <NUM> forming three column-shaped compartments <NUM>~<NUM> loaded with three drug contents. The compartments <NUM>~<NUM> have an aperture that are blocked by rod-shaped plugs that have different length and/or dissolution rate. As illustrated in <FIG>, the APIs are released in a sequential manner as the plugs dissolve sequentially to open the compartments.

<FIG>, for illustration only, shows an exemplary dosage form having a simultaneous release profile or sequential release profile. Referring to <FIG>, the dosage form <NUM> has a substrate containing four segments <NUM>~<NUM> having different dissolution rate. In certain embodiments, as illustrated in <FIG>, the drug contents are embedded in the segments <NUM>~<NUM> and are released simultaneously when the substrate dissolves. In certain embodiments, each segment contains a compartment where a drug content is loaded. As illustrated in <FIG>, the drug contents are released in a sequential manner when the substrate dissolves.

This example illustrates a design of dosage form that has controlled release profile, to show the principle of the release kinetics of a pie shaped compartment.

As shown in <FIG>, the dosage form comprised a flat tablet substrate forming a pie shaped compartment. The substrate was made of PEG8000. Benzoic acid was used as a module drug content.

The release profile of the benzoic acid from the dosage form was measured as the following method. Na<NUM>HPO<NUM> solution of pH <NUM> was prepared as dissolvent of benzoic acid. Benzoic acid solution of 120µg/mL was serially diluted to 30µg/mL, 15µg/m, <NUM>. 5µg/m, <NUM>. 75µg/mL, and <NUM>. 875µg/mL solutions, whose absorbance at <NUM> was measured using a UV spectrophotometer. The numbers obtained were treated with linear regression to generate a standard curve of benzoic acid concentration with the formula y=<NUM>. 0599x+<NUM>. To measure the released amount of benzoic acid, the dosage form was dissolved in degassed pH <NUM> Na<NUM>HPO<NUM> solution at <NUM> ± <NUM> and centrifuged at <NUM> rpm. <NUM> solution was collected from the solution at each time point to measure the concentration of benzoic acid with <NUM> dissolvent added back to the solution. The collected solution was filtered through <NUM> membrane before transferred to an UV spectrophotometer for measuring the absorbance at <NUM>. The percentage of benzoic acid released was calculated using the following formula:
<MAT>.

The release of PEG8000 is measured using the following method. To prepare a standard curve of PEG8000, <NUM> PEG8000 standard sample was dissolved in water in a <NUM> volumetric flask. Transferring <NUM>, <NUM> <NUM> and <NUM> to <NUM> volumetric flask, respectively, and diluted in water to prepare the control solution. Injecting <NUM> ul control solutions to a liquid chromatography (three Waters Ultrahydrogel™ <NUM>/<NUM>/<NUM> connected in series, flow speed at <NUM>/min, temperature at <NUM>, measured by a differential refraction detector). The areas of the volume were measured and used as y-axis. The log numbers of the control solution concentration were used as x-axis. A standard curve of PEG8000 was generated with the formula of y=<NUM>. 024x+<NUM>. The percentage of PEG800 released was calculated using the following formula: <MAT> wherein Cn means concentration measured,.

Results: as illustrated in <FIG>, the release profile of the benzoic acid matches a model profile according to <NPL>) and was controlled by the interface. Therefore, a controlled release profile can be designed according to the dosage forms disclosed herein.

This example illustrates a design of dosage form that controls release of drug contents from different compartments to display general release kinetics, when two compartments open at different times.

Dosage design: two dosage forms were produced using fused deposition modeling methods. The substrate of the dosage forms was made of Copovidone (Kollidon® VA64) <NUM>%, PEG1500 <NUM>% and Soluplus® <NUM>%. The drug content was consisted of Moxifloxacin Hydrochloride <NUM>%, PEG1000 <NUM>%. The schematic of the dosage forms are illustrated in <FIG>. Referring to <FIG>, the dosage form <NUM> contained a substrate <NUM> that forms two compartments <NUM> and <NUM>. The compartments were enclosed by a wall <NUM> and <NUM>, respectively. For the first dosage form, the two compartments were enclosed by walls having a thickness of <NUM> and <NUM>, respectively. For the second dosage form, the two compartments were enclosed by walls having a thickness of <NUM> and <NUM>, respectively.

To detect the release of the drug content, the dosage form was added to <NUM> phosphate buffer of pH6. <NUM> at <NUM> rpm. The UV absorption of the buffer was assayed to determine the release of the drug content.

The results of the release assays were illustrated in <FIG>. As shown in <FIG>, when the first dosage form was added to the buffer for <NUM>, the first compartment was open, and the drug content in the first compartment was released. The second compartment was not open till <NUM> after the dosage form was added to the buffer. For the second dosage form, whose results were illustrated in <FIG>, the second compartment was not open till <NUM> after the dosage form was added to the buffer. Therefore, the release profile of the dosage form can be controlled through the thickness of the wall that encloses a compartment.

While the principles of this invention have been described in connection with specific embodiments, it should be understood clearly that these descriptions are made only by way of example and are not intended to limit the scope of the invention. What has been disclosed herein has been provided for the purposes of illustration and description. Many modifications and variations will be apparent to the practitioner skilled in the art. It is intended that the scope of what is disclosed be defined by the following claims and their equivalence.

Claim 1:
A dosage form comprising: a substrate that forms at least a first compartment and a second compartment, wherein the first compartment has a first aperture and the second compartment has a second aperture;
a first drug contained in the first compartment; and
a second drug contained in the second compartment;
a first plug that seals the first aperture; and
a second plug that seals the second aperture;
wherein the first plug and the second plug are water soluble or erodible.