Patent Description:
Aerosol delivery systems that use vibration to generate liquid droplets are well known in the art and have found use in a wide range of fields including medical drug delivery, the treatment of air (for example fragrance delivery and humidification), and used for oral delivery of compounds such as vaccines, for nicotine delivery such as devices similar to e-cigarettes and other active compounds. Some known examples of aerosol delivery systems comprise an aerosol generating device having control electronics and a power supply, such as a battery, coupled to a removable cartridge with a fluid reservoir which is receivable in the aerosol generating device and may be replaced when the fluid in the reservoir has been consumed. In other examples, the aerosol generating system may comprise an aerosol generating device and an integral fluid reservoir, which may be refillable.

International Patent Application Publication No. <CIT> provides a liquid droplet generation apparatus having a perforate membrane, a liquid supply, and an actuator which is connected to the membrane by a magnetic force so that the membrane can be vibrated by the actuator to generate and eject liquid droplets. In another example, International Patent Application Publication No. <CIT> provides an electronic nebulizer having a perforate membrane, a liquid supply, and an actuator which is clamped to the membrane by a releasable mechanical coupling means so that liquid is nebulized through the membrane when the actuator vibrates the membrane. In each case, a perforate membrane with a plurality of apertures is used to generate substantially monodispersed droplets from a liquid supply containing a liquid to be aerosolised.

European Patent Application Publication No. <CIT> describes a medicament delivery device with one or more medicament reservoirs and an ejection mechanism to eject the medicament through orifices. The ejection mechanism may be configured to dispense medicaments held by different medicament reservoirs wherein any suitable number of medicament reservoirs may be included. Orifices of one set of orifice plates may be in fluid communication with a first reservoir, and orifices of another set of orifice plates may be in fluid communication with a second reservoir. In an example, each medicament reservoir feeds a plurality of orifice plates. In alternative examples, each medicament reservoir may feed only one orifice plate. In addition, different medicament reservoirs may feed the same or different orifice plates. Furthermore, each medicament reservoir may feed a different size of orifice. Medicament reservoirs may hold the same medicament or different medicaments.

<CIT> describes a nebulizer with a removable cartridge which may have two compartments for two different fluids. The compartments each have a discrete opening with a corresponding nebulizing element provided for each opening.

<CIT> provides a disposable package for delivery aerosolised formulations. The disposable package has individual dosage containers connected by a tape and sealed by a cover. The dosage containers may be dual containers having a powdered drug in a first compartment and a liquid in a second compartment. A first piston collapses the second compartment to force out the liquid and cause it to mix with the dry drug. A second piston then collapses the first compartment to force the mixture from through a membrane.

<CIT> discloses a spray head of the type comprising: a surface for actuating the spray; a transducer adapted to be excited by vibration by electrical excitation means and adapted to transmit its vibrations to the actuating surface. The actuating surface has a plurality of distinct vibration resonance foci.

It would be desirable to provide an improved cartridge for an aerosol delivery system.

According to a first aspect of the present invention, there is provided a cartridge for an aerosol delivery system as defined in the independent claim <NUM>. The cartridge comprises a fluid reservoir including a first reservoir portion for containing a first liquid, a second reservoir portion for containing a second liquid, and at least one liquid barrier configured to separate the first and second reservoir portions, wherein the first and second reservoir portions have respective first and second openings at a first end of the cartridge, the first and second openings being configured to supply first and second liquids to a perforate membrane located over the first end of the cartridge during use. With this arrangement, different liquids can be stored in the cartridge and ejected by a single membrane.

The cartridge is intended for removable coupling to an aerosol delivery device to form an aerosol delivery system comprising a perforate membrane and an actuation means configured to vibrate the perforate membrane to cause a liquid in the cartridge to pass through the perforate membrane and to be ejected from the perforate membrane as liquid droplets. The provision of such a cartridge allows for easy removal and replacement when one or more liquids in the cartridge have been consumed.

The cartridge further includes a perforate membrane located at the first end of the cartridge and over both of the first and second openings such that a first side of the perforate membrane is in fluid communication with the first and second openings, the perforate membrane comprising a plurality of apertures configured to eject one or both of the first and second liquids from a second side of the perforate membrane in the form of liquid droplets when the perforate membrane is vibrated during use. The perforate membrane is a single membrane which extends over both of the first and second openings.

With this arrangement, the perforate membrane may be easily and regularly replaced in an aerosol delivery system simply by replacement of the cartridge. This can have benefits in terms of maintaining performance of the aerosol delivery system in which the cartridge is used. Keeping the cartridge and the perforate membrane together in this manner can also ensure that the perforate membrane is used with a liquid formulation for which the configuration of its apertures has been specifically designed. This also allows different delivery and fluid characteristics to be selected by the user to suit treatment or preference.

Some of the plurality of apertures have substantially the same configuration as each other. That is, substantially uniform size, shape, cross-sectional profile and spacing.

The plurality of apertures comprises a first array of apertures of a first configuration and a second array of apertures of a second configuration which is different to the first configuration. With this arrangement, the droplets generated by the perforate membrane can have two different size distributions which are generated simultaneously and tuned according to a specific application. For example, the apertures of the first and second arrays can be configured to generate an aerosol having a concentration of droplets of one size, for example small, and a concentration of droplets of a second size, for example large, allowing the aerosol to provide simultaneously the benefits of both droplet sizes. In the case of nicotine delivery to the lungs this can allow the mouth feel and flavour delivery to be tuned independently of uptake in the lung and the level of catch in the throat. For example, by providing a greater number of large droplets, the targeting of taste receptors in the mouth can be increased and by providing a greater number of small droplets, the uptake of medicament in the lungs can be increased.

Furthermore, providing a first array of apertures of a first configuration and a second array of apertures of a second configuration which is different to the first configuration can allow the perforate membrane to be tuned according to the characteristics of different liquid formulations stored in the first and second reservoir portions. This can be particularly beneficial when the first and second liquid formulations have different characteristics, such as viscosity, which lead to the liquid formulations having a different ejection threshold. For example, a more viscous liquid formulation may be used with larger apertures to ensure that a sufficient proportion of the apertures are vibrated above the ejection threshold.

The first and second arrays may at least partially overlap. This means that at least some of the apertures of the first array may be intermingled with at least some of the apertures of the second array. By providing first and second arrays which at least partially overlap, at least some of the smaller droplets generated by one of the arrays will be entrained with the flow of larger droplets generated by the other array. This has been found to delay the evaporation of the smaller droplets and allow them to travel further before entering the gaseous phase. This can allow smaller droplets to enter the lungs in the liquid phase before evaporating into the gaseous phase within the lungs. This can reduce the level of "catch" experienced by the user from droplets being in the gaseous phase in the throat, while still promoting rapid uptake of medicament in the lungs.

The degree of overlap can be determined by determining the area of the first array within a boundary defined by its outermost apertures, determining the area of the second array within a boundary defined by its outermost apertures, determining the area of the region over which the first and second arrays overlap, dividing the area of overlap by the area of the smallest of the first and second arrays and multiplying the product by <NUM> to obtain the degree of overlap in terms of a percentage. For example, where the smaller of the first and second arrays is entirely within the larger of the first and second arrays, the degree of overlap can be said to be <NUM> percent.

The degree of overlap may be at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, or at least <NUM> percent.

Substantially all of the apertures of at least one of the first and second arrays may be intermingled with the apertures of the other of the first and second arrays.

As used herein, the term "substantially all of the apertures" means at least <NUM> percent of the total number of apertures of a given array.

The first and second arrays may be substantially coincident. This means that substantially all of the apertures of the first array may be intermingled with substantially all of the apertures of the second array.

The first array of apertures may be located in a first discrete region of the perforate membrane and the second array of apertures is located in a second discrete region of the perforate membrane.

The term "first and second discrete regions" refers to distinct, nonoverlapping, areas of the perforate membrane. The discrete regions may be directly adjacent to each other, or separated by an intermediate region.

Typically, the mode of vibration of a perforate membrane in an aerosol delivery system is such that different regions of the membrane vibrate with different amplitudes. This means that the acceleration of the membrane and the fluid pressure generated in those regions can differ. To successfully generate a droplet, an aperture in the perforate membrane needs to be accelerated above a minimum acceleration threshold, or "ejection threshold". Generally, the smaller the aperture, the higher the ejection threshold. Typically, a perforate membrane will have a plurality of apertures having the same configuration. That is, the same size, shape, cross-sectional profile and spacing.

By providing a first array of apertures of a first configuration grouped together in a first discrete region of the membrane and a second array of apertures of a second configuration grouped together in a second discrete region of the membrane, droplet generation from the perforate membrane can be tuned according to the vibration characteristics or vibration pattern of the perforate membrane in the first and second discrete regions. For example, where the amplitude and/or acceleration of vibration in the first discrete region is different to that of the second discrete region and the apertures of the first and second arrays are configured with different sizes, it can be beneficial to place the small apertures in the discrete region with the greatest amplitude and/or acceleration of vibration and to place the large apertures in the discrete region with the lowest amplitude and/or acceleration of vibration. The increased vibrational activity can ensure that a higher percentage of the small apertures are above the ejection threshold. Similarly the larger apertures in a region of lower vibrational activity can also ensure that a higher percentage of the apertures in the less active region are above the ejection threshold. This can increase the utilisation of the membrane and thereby increase the amount of aerosol generated from a given vibrational input and improve the efficiency of the system.

At least one of the first and second arrays may be in fluid communication with both of the first and second reservoir portions. At least one of the first and second reservoir portions may be in fluid communication with both of the first and second arrays.

Preferably, the first reservoir is in fluid communication with the first array of apertures in the first discrete region via the first opening, wherein the first opening is separated from at least some of the second array of apertures in the second discrete region. This means that the first opening is not in fluid communication with at least some of the apertures of the second array. This arrangement allows the apertures of the first array to be tuned specifically according to the characteristics of the liquid formulation stored in the first reservoir portion. Preferably, this separation is performed by the at least one liquid barrier.

Preferably, the first opening is separated from substantially all of the apertures of the second array.

Preferably, the second reservoir is in fluid communication with the second array of apertures in the second discrete region via the second opening, and wherein the second opening is separated from at least some of the apertures of the first array in the first discrete region. This means that the second opening is not in fluid communication with at least some of the apertures of the first array. This arrangement allows the apertures of the second array to be tuned specifically according to the characteristics of the liquid formulation stored in the second reservoir portion. Preferably this separation is performed by the at least one liquid barrier.

Preferably, the second opening is separated from substantially all of the apertures of the first array.

Typically, the mode of vibration of a perforate membrane is such that different regions of the membrane vibrate with different amplitudes. This means that the acceleration of the membrane and the fluid pressure generated in those regions can differ. To successfully generate a droplet, an aperture in the perforate membrane needs to be accelerated above a minimum acceleration threshold, or "ejection threshold". Generally, the smaller the aperture, the higher the ejection threshold.

The first and second discrete regions may be located in regions of the perforate membrane having comparable vibration characteristics, for example similar amplitude and/or acceleration.

Preferably, the first discrete region is located in a region of the perforate membrane having a first vibration characteristic and the second discrete region is located in a region of the perforate membrane having a second vibration characteristic which is different to the first vibration characteristic, such that vibration of the perforate membrane during use causes the first discrete region to vibrate at a different amplitude to the second discrete region.

With this arrangement, droplet generation from the perforate membrane can be tuned according to the vibration characteristics or vibration pattern of the perforate membrane in the first and second discrete regions. For example, where the apertures of the first and second arrays are configured with different sizes, it can be beneficial to place the small apertures in the discrete region with the greater vibrational activity and to place the large apertures in the discrete region with the lower vibrational activity. The increased vibrational activity can ensure that a higher percentage of the small apertures are above the ejection threshold. Similarly having larger apertures in a region of lower vibrational activity can also ensure that a higher percentage of the apertures in the less vibrationally active region are above the ejection threshold. This can increase the utilisation of the membrane and thereby increase the amount of aerosol generated from a given vibrational input and improve the efficiency of the system.

The first and second vibration characteristics of the perforate membrane may be such that vibration of the perforate membrane by the actuation means causes the first discrete region to vibrate at a greater amplitude than the second discrete region.

The first and second discrete regions may be located in regions of the perforate membrane having low vibration activity.

At least one of the first and second discrete regions may be located in or adjacent to an excitation region of the perforate membrane in which the amplitude of vibration during use is greater than the average amplitude of vibration of the perforate membrane. Both of the first and second discrete regions may be located in or adjacent to an excitation region of the perforate membrane. At least one of the first and second discrete regions may be located in or adjacent to a maximum excitation region of the perforate membrane in which the amplitude of vibration during use is at the maximum value.

The first and second discrete regions may both be located towards the periphery of the perforate membrane. Preferably, at least one of the first and second discrete regions is located in or adjacent to a central region of the perforate membrane. For example overlapping with the central region, or entirely within the central region.

The term "central region" refers to the area of the perforate membrane which is centred on the centroid of the perforate membrane. The central region may have an area of less than <NUM> percent of the total area of the perforate membrane, preferably less than <NUM> percent, more preferably less than <NUM> percent, most preferably less than <NUM> percent of the total area of the perforate membrane.

Optionally, both of the first and second discrete regions may be located in or adjacent to the central region of the perforate membrane.

The first and second discrete regions may be approximately equidistant from the centroid of the perforate membrane.

In certain embodiments, the first discrete region is located in or adjacent to the central region and the second discrete region is located peripherally of the first discrete region. For example, the second discrete region may be disposed around the first discrete region. The second discrete region may substantially circumscribe the first discrete region. The second discrete region may form an annulus around the first discrete region.

The plurality of apertures of the first and second arrays may have substantially the same size. That is, the average size of the apertures of the first array may be within <NUM> percent, preferably <NUM> percent, of the average size of the apertures of the second array. The first and second arrays may be configured such that at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, preferably at least <NUM> percent of the apertures of the first array are within the same size range as at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, preferably at least <NUM> percent of the apertures of the second array. Where the plurality of apertures of the first and second arrays have substantially the same size, the configurations of the apertures of the first and second arrays may differ in other aspects, for example in shape, spacing, or profile in order to generate different droplet sizes.

In certain preferred embodiments, the apertures of the first array are of a first aperture size and the apertures of the second array are of a second aperture size, wherein the first and second aperture sizes are different. This has been found to provide a particularly effective means by which different droplet size distributions can be generated.

The terms "first and second aperture size" refer to the average size of the apertures of the first and second arrays, respectively. Preferably, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, more preferably at least <NUM> percent of the apertures of the first array have a size which is within <NUM> percent, preferably <NUM> percent of the first aperture size. Preferably, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, more preferably at least <NUM> percent of the apertures of the second array have a size which is within <NUM> percent, preferably <NUM> percent, of the second aperture size.

The first aperture size may be greater than the second aperture size. Preferably, the first aperture size is less than the second aperture size.

The term "aperture size" may refer to any objective size measurement. For example, maximum diameter, minimum diameter, surface area, circumference, or hydraulic diameter. Further, the term "aperture size" may refer to the dimensions of the aperture on the first side of the perforate membrane, or on the second side.

Preferably, the term "aperture size" refers to the hydraulic diameter on the second side of the perforate membrane. This has been found to be a key factor in the size of droplets generated by a given aperture.

Preferably, the apertures of the first array have a first average hydraulic diameter at the second side of the perforate membrane and the apertures of the second array have a second average hydraulic diameter at the second side of the perforate membrane, and wherein the second average hydraulic diameter is greater than the first average hydraulic diameter. The second average hydraulic diameter is preferably at least <NUM> percent greater, more preferably at least <NUM> percent greater, most preferably at least <NUM> percent greater than the first average hydraulic diameter.

Preferably, a majority of the apertures of the first array each have a hydraulic diameter at the second side of the perforate membrane of less than <NUM> microns, more preferably less than <NUM> microns, most preferably less than <NUM> microns. Preferably a majority of the apertures of the first array each have a hydraulic diameter at the second side of the perforate membrane of at least <NUM> microns, more preferably at least <NUM> micron, most preferably at least <NUM> microns. For example, at least <NUM> microns and less than <NUM> microns. The term "majority of the apertures" refers to a population of greater than <NUM> percent of all apertures of the first array. In certain embodiments, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, or at least <NUM> percent of the apertures of the first array may each have a hydraulic diameter at the second side of less than <NUM> microns, more preferably less than <NUM> microns, most preferably less than <NUM> microns. In certain embodiments, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, or at least <NUM> percent of the apertures of the first array may each have a hydraulic diameter at the second side of the perforate membrane of at least <NUM> microns, more preferably at least <NUM> micron, most preferably at least <NUM> microns. For example, at least <NUM> microns and less than <NUM> microns. This has been found to be particularly effective at generating droplet sizes of <NUM> microns and below. Such droplet sizes have been found to be beneficial in allowing the droplets to reach the lung without impact the throat. Once the droplets have passed the throat, then rapid evaporation into the gaseous phase allows a high rate of uptake of the medicament while minimising the total quantity of medicament required for that uptake.

Preferably, a majority of the apertures of the second array each have a hydraulic diameter at the second side of at least <NUM> microns, preferably from <NUM> microns to <NUM> microns, more preferably from <NUM> microns to <NUM> microns, most preferably from <NUM> microns to <NUM> microns.

The term "majority of the apertures" refers to a population of greater than <NUM> percent of all apertures of an array. The term may refer to at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, or at least <NUM> percent of the apertures of that array.

In certain embodiments, at least <NUM> percent, at least <NUM> percent, at least <NUM> percent, or at least <NUM> percent of the apertures of the second array may each have a hydraulic diameter at the second side of at least <NUM> microns, preferably from <NUM> microns to <NUM> microns, more preferably from <NUM> microns to <NUM> microns, most preferably from <NUM> microns to <NUM> microns. This has been found to be particularly effective at generating droplet sizes of <NUM> microns or larger, for example up to <NUM> microns in diameter.

The apertures of one or both of the first and second arrays may be spaced from an adjacent aperture by less than <NUM> microns, for example less than <NUM> microns. This has been found to promote coalescence and thereby promote the targeted delivery of larger droplets from the array to the user's mouth.

A majority of the apertures of the first and second arrays may be spaced, at the second side of the perforated membrane, from any adjacent aperture by at least <NUM> microns, for example at least <NUM> microns. This spacing has been found to reduce the extent to which ejected droplets tend to coalesce downstream of the perforate membrane. This can reduce the diversity in droplet size and ensure targeted delivery of droplets.

The plurality of apertures of the first array may be evenly or unevenly spaced. The plurality of apertures of the second array may be evenly or unevenly spaced.

A majority of the apertures of the first array may be spaced, at the second side of the perforate membrane, from any adjacent aperture by a first spacing and a majority of the apertures of the second array may be spaced, at the second side of the perforate membrane, from any adjacent aperture by a second spacing. The second spacing may be different to the first spacing. This can enhance the difference between droplet sizes generated by the first and second arrays and can, therefore, enhance the degree to which droplet sizes can be tuned according to the specific application.

As used herein, the terms "spaced" and "spacing" refer to the minimum distance between the outer edges of two adjacent apertures in the plane of the perforate membrane.

Varying the spacing between apertures can allow some droplets to coalesce into larger droplets while allowing other droplets to continue as individual droplets. As with the provision of different sized apertures, this allows different size droplets to be generated by the aerosol delivery system. This can allow the mouth feel and flavour delivery to be tuned independently of uptake in the lung and the level of catch in the throat. Coalescence from closely spaced holes tends to occur within <NUM> millimetres of the ejection from the perforate membrane and so is well established before the droplets enter the user's mouth and throat.

Preferably the first spacing is at least <NUM> microns, preferably at least <NUM> microns. This has been found to reduce the occurrence of coalescence and promote the delivery of smaller droplets from the first array. Preferably, the second spacing is less than <NUM> microns, preferably less than <NUM> microns. This has been found to promote coalescence and thereby promote the delivery of larger droplets.

The at least one liquid barrier may comprise a rigid seal. Preferably, the at least one liquid barrier comprises a resilient seal. The resilient seal may be in contact with the first side of the perforate membrane. The provision of a resilient seal can improve the effectiveness of the seal formed between the first and second reservoir portions and thereby reduce the extent to which first and second liquids in the first and second liquid portions come into contact with each other prior to ejection from the perforate membrane. This can increase the shelf life of the cartridge. This can also improve the consistency of aerosol properties by ensuring that each liquid is ejected from the correct region of the perforate membrane.

Preferably, at least one of the first and second reservoir portions comprises a porous carrier material adjacent to the perforate membrane. With this arrangement, the liquid formulation can be held in close proximity to the perforate membrane independent of the orientation of the cartridge or aerosol delivery device within which the cartridge is received. The porous carrier material may be in contact with the first side of the perforate membrane. Each of the first and second reservoir portions may comprise a porous carrier material adjacent to the perforate membrane.

The second reservoir portion is annular and defines a cavity, and the first reservoir portion is disposed in the cavity defined by the second reservoir portion. The first reservoir portion may extend along the central axis of the second reservoir portion so that the first opening is adjacent to the centre of the perforate membrane.

The first reservoir portion may contain any suitable liquid formulation. The first reservoir portion may contain a first liquid formulation comprising a biologically active ingredient. The first reservoir portion may contain a first liquid formulation comprising a flavourant. Preferably, the first reservoir portion contains a liquid formulation comprising nicotine. Alternatively, or in addition, the first reservoir portion may contain a liquid formulation comprising biologically active molecules in solvents, and/or biologically active molecules held in and on carrier systems. Carriers may be particulates of inorganic and organic materials. Carriers may be viral capsids or entities designed to mimic viral capsids.

The second reservoir portion may contain any suitable liquid formulation. The second reservoir portion may contain a second liquid formulation comprising a biologically active ingredient. The second reservoir portion may contain a second liquid formulation comprising a flavourant. Preferably, the second reservoir contains a liquid formulation comprising one or more flavour compounds. For example, biologically active molecules in solvents, and/or biologically active molecules held in and on carrier systems. Carriers may be particulates of inorganic and organic materials. Carriers may be viral capsids or entities designed to mimic viral capsids.

Where the first and/or second reservoir portions contain a liquid formulation comprising biologically active molecules, the biologically active molecules may be small molecules with molecular mass of less than <NUM> daltons; may be small molecules with molecular mass of less than <NUM> daltons; molecules may be biologically derived macromolecules such as proteins and nucleic acids; molecules may be polymeric materials; molecules may be systems with long chain backbones or branched chain systems such as denrimers- for example with peptide, sugar phosphate, polyethylene oxide polysaccharide or other sugar; length of polymeric backbone may be from <NUM> units to many units. Molecules may be fusions of the above where more than one molecule may be formulated or covalently bound together.

According to a second aspect of the present invention, there is provided an aerosol delivery system comprising: a cartridge according to the first aspect; an aerosol delivery device with which the cartridge is configured to be removably coupled. The aerosol delivery device comprises actuation means configured to vibrate the perforate membrane to cause first and second liquids in the first and second reservoirs to be ejected as liquid droplets from a second side of the perforate membrane.

The perforate membrane forms part of the removable cartridge. With this arrangement, the perforate membrane may be easily and regularly replaced along with the removable cartridge. This can have benefits in terms of maintaining performance. Keeping the cartridge and the perforate membrane together in this manner can ensure that the perforate membrane is used with a liquid formulation for which the configuration of its apertures has been specifically designed.

Features described in relation to one aspect of the invention may also be applicable to another aspect of the invention. In particular, features described in relation to the removable cartridge of the first aspect may be applicable to the aerosol delivery system of the second aspect.

The invention will now be further described, by way of example only, with reference to the accompanying drawings, in which:.

<FIG> shows a schematic representation of an aerosol delivery system <NUM> comprising a handheld, portable aerosol delivery device <NUM> and a removable cartridge <NUM> according to a first embodiment of the invention. The aerosol delivery device <NUM> comprises a main housing <NUM> and a mouthpiece <NUM> which is removably coupled to the main housing <NUM> to define a chamber within which the cartridge <NUM> is removably received during use. An air inlet <NUM> is provided at a distal end of the main housing <NUM> and the mouthpiece <NUM> defines an air outlet <NUM> at the proximal end of the device <NUM>. An airflow pathway extends through the device <NUM> between the air inlet <NUM> and the air outlet <NUM>. Also included in the device <NUM> is a flow sensor <NUM>, preferably mounted on a printed circuit board (PCB) <NUM>, a controller <NUM>, a battery <NUM> and an actuation means <NUM> adjacent to the cartridge <NUM>. The PCB <NUM> and the controller <NUM> are shown schematically in <FIG> as different components. However, they could be combined into a single component. For example, one PCB including the sensor and the controller. The battery <NUM> supplies electrical power to the PCB <NUM>, the controller <NUM> and the actuation means <NUM>. The actuation means <NUM> may comprise any suitable actuator <NUM> or vibrator element but it is of particular benefit if the actuation means comprises an actuator that has an active component comprising a piezoelectric, electrostrictive or magnetostrictive material (i.e. a material that changes shape in response to an applied electric or magnetic field) in combination with a passive component by which the active component is supported. In this example, the actuation means <NUM> comprises a lead zirconate titanate (PZT) ceramic active component <NUM>, which is bonded to a passive substrate <NUM>. The actuation means may have any suitable shape. In this example, the actuation means is planar and annular.

The cartridge <NUM> includes an outer casing <NUM> defining a fluid reservoir containing a liquid formulation for aerosolisation and having an opening at a first end of the cartridge, and a perforate membrane <NUM> mounted across the opening such that a first side of the perforate membrane <NUM> is in fluid contact with the liquid formulation in the fluid reservoir and such that a second, opposite side of the perforate membrane <NUM> is facing the air outlet <NUM> in the mouthpiece <NUM>. The fluid reservoir may include a porous carrier material (not shown) by which the liquid formulation is delivered to the perforate membrane <NUM> by capillary action. Alternatively, the liquid formulation may be delivered to the perforate membrane under the action of gravity or through other capillary means such as a capillary plate located close to the first face of the perforate membrane so as to hold liquid in contact with the perforate membrane. The actuation means <NUM> is removably coupled to the cartridge <NUM> such that vibration of the actuation means <NUM> is transferred to the cartridge <NUM>. The removable coupling (not shown) also allows the cartridge <NUM> to be exchanged when empty or when a different formulation is required. Any suitable coupling may be used. For example, the coupling can be mechanical, bayonet, compression fit, magnetic coupling, or any combination thereof. In this example, the actuation means is coupled to the cartridge by a magnetic coupling.

In use, when a user inhales on the mouthpiece <NUM>, air is drawn into the device <NUM> through the air inlet <NUM> and along the airflow pathway to trigger the flow sensor <NUM> which sends a signal to the controller <NUM>. The controller <NUM> then generates a drive signal to drive the actuation means <NUM> to vibrate and induce vibration in the perforate membrane <NUM>. Vibration of the perforate membrane <NUM> causes the liquid formulation to pass through apertures in the perforate membrane <NUM> and to be ejected as liquid droplets from a second side of the perforate membrane <NUM>. The droplets are fed into the air stream flowing along the airflow pathway to form an aerosol, which can be inhaled by the user via the mouthpiece <NUM>. For details of the operation of the device <NUM>, along with suitable actuator design and coupling of the actuation means to the perforate membrane, reference is made to <CIT> in which these aspects are described in detail. The configuration of the apertures in the perforate membrane is discussed below in relation to <FIG>.

<FIG> is a schematic cross-sectional view of a removable cartridge <NUM> according to a second embodiment. As with the first embodiment of cartridge <NUM>, the cartridge <NUM> includes an outer casing <NUM> defining a fluid reservoir <NUM> with an opening at the first end of the cartridge, and a perforate membrane <NUM> across the opening in the fluid reservoir <NUM>. When the perforate membrane <NUM> is vibrated, a liquid formulation in contact with the first side of the perforate membrane <NUM> can be drawn through apertures in the perforate membrane <NUM> and ejected as liquid droplets from the second side of the perforate membrane <NUM>. The fluid reservoir <NUM> includes a first reservoir portion <NUM> for containing a first liquid formulation, a second reservoir portion <NUM> for containing a second liquid formulation, and a liquid barrier <NUM> configured to separate the first and second reservoir portions <NUM>, <NUM>. The liquid barrier <NUM> extends along the length of through the fluid reservoir <NUM> from a base of the casing <NUM> at the second end of the cartridge to the perforate membrane <NUM> to separate the first and second reservoir portions. The first and second reservoir portions have respective first and second openings at the first end of the cartridge. The first and second openings are configured to allow fluid communication between the perforate membrane and the first and second reservoir portions so that first and second liquids in the first and second reservoir portions can be delivered to the membrane during use.

The second reservoir portion <NUM> comprises a porous carrier material <NUM> in which the second liquid formulation may be absorbed and retained. The porous carrier material <NUM> is in contact with the first side of the perforate membrane <NUM> so that the second liquid formulation can be delivered to the first side of the perforate membrane <NUM> by capillary action. The porous carrier material may be formed from any suitable material or materials. For example, the porous carrier material may comprise open-cell foam such as polyurethane foam, polyvinyl alcohol (PVA) foam, polyether foam or a combination of foams, a felt material such as polypropylene, polyester, or rayon, a filter material such as polypropylene or a fibrous material such as polyester material in woven or non-woven forms. The porous material could be provided by a sequence of moulded channels of such size that capillary action will retain fluid. The preferred material should have appropriate pore size or capillary channel size to retain the operating fluid and should have properties that are compatible with the fluid (chemical resistance) non contaminating (extractables and leachables) and non-binding such that the target fluid or in particular the active component does not preferentially adhere to the material and so inhibit delivery.

The second reservoir portion <NUM> is annular and defines a cavity extending along its central axis in which the first reservoir portion <NUM> and the liquid barrier <NUM> are disposed.

In this example, the liquid barrier <NUM> comprises a barrier wall <NUM> extending from the base of the fluid reservoir <NUM> at its first end, and having a flexible seal <NUM> at its second end. The flexible seal <NUM> contacts the first side of the perforate membrane <NUM> and is configured to ensure that the first and second reservoir portions <NUM>, <NUM> are separated even when the perforate membrane is vibrated. The flexible seal <NUM> is preferably a resilient seal. With this arrangement, when the flexible seal <NUM> is deflected by vibration of the perforate membrane <NUM>, the flexible seal <NUM> is pressed against the first side of the perforate membrane <NUM> to improve sealing between the liquid barrier <NUM> and the perforate membrane <NUM>. This can reduce the extent to which first and second liquid formulations might mix prior to aerosolisation by passing around the upper end of the liquid barrier <NUM>, particularly during vibration of the perforate membrane <NUM>. As shown in <FIG>, the flexible seal <NUM> preferably tapers inwardly towards the perforate membrane <NUM>. This can reduce the force required for the perforate membrane <NUM> to deflect the flexible seal <NUM> and so minimise the impact that the flexible seal has on the deflection of the perforate membrane during operation. Where the perforate membrane <NUM> includes first and second arrays of apertures arranged in first and second discrete regions of the perforate membrane <NUM>, as discussed in more detail below, the liquid barrier <NUM> is preferably configured to separate the first and second discrete regions on the first side of the perforate membrane. With this arrangement, the first liquid formulation is ejected only from the first array of apertures and the second liquid formulation is ejected only from the second array of apertures.

<FIG> is a schematic cross-sectional view of a removable cartridge <NUM> according to a third embodiment. The removable cartridge <NUM> of the third embodiment is similar in construction and operation to the cartridge <NUM> of the second embodiment and similar reference numerals are used to denote similar components. However, unlike the cartridge <NUM> of the second embodiment, neither of the first and second reservoir portions <NUM>, <NUM> of the removable cartridge <NUM> of the third embodiment contain a porous carrier material. Instead, fluid contact is maintained with the perforate membrane <NUM> through orientation of the cartridge of through geometric considerations. For example, where the volume of one or both reservoir portions is relatively small, fluid contact with the membrane can be maintained by capillary action which dominates gravitational forces for smaller volumes. Where the volume of the reservoir portions is larger and the geometry of the reservoir portions is wider, gravitational forces dominate capillary forces and fluid contact with the perforate membrane <NUM> can be maintained under gravity by inverting the cartridge.

<FIG> is a schematic cross-sectional view of a removable cartridge <NUM> according to a fourth embodiment. The removable cartridge <NUM> of the fourth embodiment is similar in construction and operation to the cartridge <NUM> of the third embodiment and similar reference numerals are used to denote similar components. However, unlike the cartridge <NUM> of the third embodiment, instead having a liquid barrier comprising a barrier wall and a resilient seal which presses against the membrane, the liquid barrier <NUM> of the removable cartridge <NUM> of the fourth embodiment comprises a flexible divider <NUM> which is fixed to the first side of the perforate membrane <NUM> to form a seal. The cartridge <NUM> also includes a magnetic element <NUM> around the casing <NUM> by which the perforate membrane <NUM> can be magnetically coupled to a magnetic ring <NUM>' bonded on the end of the actuator <NUM>' of the actuation means <NUM>'. The magnetic element <NUM> may be annular and may comprise any suitable magnetic material. For example, the magnetic element <NUM> may be a Neodymium magnet ring.

<FIG> is a perspective view illustrating a removable cartridge <NUM> according to a fifth embodiment, in which the casing and membrane are not shown. As with the cartridges <NUM>, <NUM>, <NUM> of the second, third, and fourth embodiments, the cartridge <NUM> has a fluid reservoir <NUM> including a first reservoir portion <NUM> for containing a first liquid formulation, a second reservoir portion <NUM> for containing a second liquid formulation, and a liquid barrier <NUM> configured to separate the first and second reservoir portions <NUM>, <NUM>. The first reservoir portion <NUM> includes a first porous carrier material <NUM> in which the first liquid formulation may be absorbed and retained. The second reservoir portion <NUM> includes a second porous carrier material <NUM> in which the second liquid formulation may be absorbed and retained. The porous carrier materials <NUM>, <NUM> are both in contact with the first side of the perforate membrane <NUM> so that the first and second liquid formulations can be delivered to the first side of the perforate membrane <NUM> by capillary action. The second reservoir portion <NUM> is annular and defines a cavity extending along its central axis in which the first reservoir portion <NUM> and the liquid barrier <NUM> are disposed. The liquid barrier <NUM> comprises a barrier wall <NUM> around the first carrier material <NUM> of the first reservoir portion <NUM>. The barrier wall <NUM> may be an individual component, or a coating applied to the outer surface of the first carrier material <NUM> and/or the inner surface of the second carrier material <NUM>.

<FIG> is a schematic end view of a first embodiment of perforate membrane <NUM> comprising a plurality of apertures extending through the thickness of the membrane. The plurality of apertures comprises a first array <NUM> of apertures having a first aperture size and a second array <NUM> of apertures having a second aperture size which is larger than the first aperture size. Preferably, the apertures of the first array have an average hydraulic diameter of less than <NUM> microns, for example in the range of <NUM> to <NUM> microns. This generates droplets of <NUM> microns or less in diameter. Such droplets have been found to be beneficial for uptake of medicament in the lungs of a user for a given flow rate. Preferably, the apertures of the second array have an average hydraulic diameter of at least <NUM> microns, preferably from <NUM> microns to <NUM> microns. This has been found to be particularly effective at generating droplet sizes of <NUM> microns or larger, for example up to <NUM> microns in diameter. Such droplet sizes have been found to be beneficial for flavour delivery and mouth feel.

In this example, the first and second arrays are substantially coincident in the central region of the perforate membrane. This means that the two arrays overlap to form a mixed region of apertures in which substantially all of the apertures of the first array are intermingled with substantially all of the apertures of the second array. With this arrangement, the smaller droplets generated by the first array are entrained with the flow of larger droplets generated by the second array. Small amounts of evaporation from the larger droplets will saturate and cool the surrounding air and greatly reduce evaporation of the entrained smaller droplets. The large droplets thus act as a buffer to delay evaporation of the smaller droplets, allowing the smaller droplets to travel further before entering the gaseous phase. In the case of delivery to the lung, the change in air flow direction between the mouth and the throat may allow separation of the two droplet size distributions so that the small droplets can continue into the lungs while the larger droplets will be deposited in the mouth and throat and thereby target taste receptors in the mouth. Once in the lungs, the small droplets can evaporate into the gaseous phase for rapid uptake of the medicament in the first liquid. Preferably, the majority of the apertures of both of the first and second arrays are spaced from any adjacent aperture by at least <NUM> microns, preferably at least <NUM> microns, to reduce the tendency of droplets to coalesce downstream of the perforate membrane and to maintain the droplet size distribution substantially as generated by the first and second arrays.

For a circular perforate membrane which is vibrated around its periphery, the amplitude of vibration increases towards the centre of the perforate membrane. Thus, the central region of the perforate membrane can be regarded as an "excitation region" in which the amplitude of vibration is greater than the average amplitude of vibration for that membrane. The geometric centre, or "centroid" of the perforate membrane is generally where the amplitude of vibration is at its greatest value. Thus, the centroid and its immediate surroundings can be regarded as the "maximum excitation region" of the perforate membrane. By positioning both of the first and second arrays in the central region of the perforate membrane, the number of apertures of the first and second arrays which are vibrated to above the ejection threshold can be maximised to increase the flow of droplets generated for a given mode of vibration. This can reduce the power requirements of the aerosol delivery system for a given flow rate and can be particularly beneficial when the apertures of one or both of the first and second arrays are small in size.

In this example, the first and second arrays are coincident. As such, there is <NUM> percent overlap between the two arrays. However, in other examples, the degree of overlap can be less. This will reduce the proportion of small droplets which are entrained into the flow of large droplets but can still provide substantial benefits from delayed evaporation of the small droplets which are entrained.

<FIG> is a schematic end view of a second embodiment of perforate membrane <NUM>. As with the first embodiment of membrane <NUM>, perforate membrane <NUM> includes a plurality of apertures arranged in a first array <NUM> of apertures and a second array <NUM> of apertures. However, unlike with the perforate membrane <NUM> of the first embodiment, the first and second arrays <NUM>, <NUM> do not overlap. Instead, the apertures of the first array <NUM> are grouped together in a first discrete region of the perforate membrane <NUM> and the apertures of the second array <NUM> are grouped together in a second discrete region of the perforate membrane <NUM>. The first and second discrete regions are separated from each other by an intermediate region <NUM> of the perforate membrane, which may be unperforated. Thus, the apertures of the first and second arrays <NUM>, <NUM> are not mixed or intermingled. The apertures of the first array <NUM> have a first configuration and the apertures of the second array <NUM> have a second configuration which is different from the first configuration. The different configurations allows the first array to generate droplets having a different size distribution to those generated by the second array. The "configuration" of the apertures may refer to their shape, dimensions, cross-sectional profile, or to the spacing between adjacent apertures. In this example, the spacing, shape, and cross-section profile of the apertures of the first and second arrays are generally the same. However, the apertures of the first array <NUM> are formed with a first aperture size while the apertures of the second array <NUM> are formed with a second aperture size which is greater than the first aperture size.

Preferably, the apertures of the first array have an average hydraulic diameter of less than <NUM> microns, for example in the range of <NUM> to <NUM> microns. This generates droplets of <NUM> microns or less in diameter. Such droplets have been found to be beneficial for uptake of medicament in the lungs of a user for a given flow rate. Preferably, the apertures of the second array have an average hydraulic diameter of at least <NUM> microns, preferably from <NUM> microns to <NUM> microns. This has been found to be particularly effective at generating droplet sizes of <NUM> microns or larger, for example up to <NUM> microns in diameter. Such droplet sizes have been found to be beneficial for flavour delivery and mouth feel.

This different "configuration" means that the droplets generated by the first array tend to be smaller than those generated by the second array. The range of droplet sizes generated by the first and second arrays can be further distinguished from each other by arranging the apertures of the first array with a first spacing between adjacent apertures and arranging the apertures of the second array with a second spacing between adjacent apertures, which is different to the first spacing.

By arranging the first and second arrays in discrete regions, the aperture size of each array can be tuned according to properties of the liquid formulation or formulations in fluid contact with those discrete regions and according to the desired aerosol properties. Where the perforate membrane <NUM> is used in a cartridge having first and second reservoir portions separated by a liquid barrier, as described above in relation to <FIG>, the first array is preferably in fluid contact with the opening of the first reservoir portion and the second array is preferably in fluid contact with the second reservoir portion. The position of the liquid barrier may correspond with the position of the intermediate region <NUM> between the first and second arrays <NUM>, <NUM>. Thus, separating the different regions of apertures allows fluid feed arrangements in the cartridge to deliver different liquid formulations to the different aperture types.

<FIG> is a schematic end view of a third embodiment of perforate membrane <NUM>. As with the second embodiment of membrane <NUM>, perforate membrane <NUM> includes a plurality of apertures arranged in a first array <NUM> of apertures in a first discrete region, and a second array <NUM> of apertures in a second discrete region. Again, the apertures of the first array <NUM> have a first configuration and the apertures of the second array <NUM> have a second configuration which is different from the first configuration. Perforate membrane <NUM> further includes a third array <NUM> of apertures in a third discrete region, the third array <NUM> of apertures having a third configuration which may be different to both of the first and second configurations. This arrangement allows greater variety in the droplet size distribution generated by the perforate membrane. It may also be particularly useful if used in conjunction with a cartridge having a fluid reservoir with three reservoir portions, since it allows fluid feed arrangements in the cartridge to delivery different liquid formulations to the three different aperture types, as will be readily understood by the skilled person.

<FIG> is a schematic end view of a fourth embodiment of perforate membrane <NUM>. As with the membrane <NUM> of the second embodiment, the perforate membrane <NUM> includes a plurality of apertures arranged in a first array <NUM> of apertures with a first configuration and a second array <NUM> of apertures with a second configuration. Again, the apertures of the first array <NUM> are grouped together in a first discrete region of the perforate membrane <NUM> and the apertures of the second array <NUM> are grouped together in a second discrete region of the perforate membrane <NUM>, the first and second discrete regions being separated from each other by an intermediate region <NUM> of the perforate membrane, which may be unperforated. In this example, the first array <NUM> is disposed in a central region of the perforate membrane and the second array <NUM> is disposed around the first array <NUM> towards the periphery of the perforate membrane <NUM>. This configuration is of particular benefit for cartridges in which the fluid reservoir comprises a first reservoir portion positioned along the central axis of an annular second reservoir portion, as illustrated in <FIG>.

Typically, the mode of vibration of the membrane is such that different regions of the membrane vibrate with different amplitudes such that acceleration and pressure in the fluid in those regions is different. With the configuration shown, the apertures of the first array <NUM> are located in a first discrete region which is in an excitation region of the perforate membrane and the apertures of the second array <NUM> are not. Thus, the first discrete region and therefore the apertures of the first array vibrate with a greater amplitude than the second discrete region and the apertures of the second array, such that acceleration and pressure in the fluid in contact with the first array is greater than that in the fluid in contact with the second array.

By configuring the apertures of the first and second arrays differently and locating the first and second arrays in first and second discrete regions having different vibration characteristics, the generation of droplets can be tuned to the preferred performance. This is illustrated in the table below in which the different permutations of aperture size and aperture spacing for first and second arrays with different configurations are compared and their relevant application and resulting performance is discussed. In the below table, the terms "small" and "big" are used to describe the relative aperture sizes and the terms "Dense" and "Well-spaced" are used to describe the spacing between adjacent apertures in each array. By way of illustration, the term "small" may refer to apertures having a diameter of less than <NUM> microns and the term "big" may refer to apertures having a diameter of <NUM> microns or more. Similarly, the term "dense" may refer to an arrangement in which a spacing of less than <NUM> microns, for example less than <NUM> microns, is provided between adjacent apertures, and the term "well-spaced" may refer to an arrangement in which a spacing of more than <NUM> microns is provided between adjacent apertures. Although this table is discussed with reference to the embodiment of perforate membrane shown in <FIG>, it is applicable to any perforate membrane having a first array of apertures with a first configuration in a first discrete region, and a second array of apertures with a second configuration in a second discrete region, where the first and second discrete regions have different vibration characteristics.

<FIG> shows the calculated droplet size distribution from the fourth embodiment of perforate membrane <NUM>, in which the apertures of the first array have a diameter of <NUM> microns, the apertures of the second array have a diameter of <NUM> microns, and the apertures of both arrays are spaced by more than <NUM> microns. As can be seen, the trace <NUM> illustrates the simultaneous generation of a dual droplet size distribution in which droplet size is concentrated around two different droplet sizes D1 and D2. The ACI stage reference on the Y axis refers to the stage of an Anderson Cascade Impactor which is used to characterise droplet streams by collecting particles on a series of stages where the flow path in the impactor is arranged such that larger particles are captured on earlier stages and smaller particles on later stages. At <NUM> litres per minute of flow through an Anderson Cascade Impactor the cut off levels (microns) for the stages are: stage <NUM>: <NUM>, stage <NUM>: <NUM>, stage <NUM>: <NUM>, stage <NUM>: <NUM>, stage <NUM>: <NUM>, stage <NUM>: <NUM>, stage <NUM>: <NUM>, stage <NUM>: <NUM>.

There are a number of different methods by which the apertures in the perforate membranes can be formed. For example, the apertures can be formed by electroforming the membrane, or by laser drilling.

Electroforming typically involves over growing nickel based alloys over a smooth substrate with a pattern of photo resist spots used to define the pattern of holes, as carried out by Veco B. Eerbeek, of The Netherlands. The size of the holes is then typically a function of the thickness of material grown over the resist spots. However, this method may make it difficult to control hole size, especially for smaller holes. The strong dependency on the thickness of deposited material means that the tolerance for small holes is relatively broad. A second issue is that forming two size holes at the same time is inconsistent as this will depend on the size of resistance spot applied and the thickness of deposited plating. This means that the process control has the challenge of controlling two variables with only one control parameter, thickness, further leading to yield issues. This process also has a limited choice of materials which can be used with some robustness and compatibility issues. As above the overgrowing method of forming small holes is problematic but there is an alternative of using a thick resist method where the hole size is defined by the photo resist, or photo-defined hole size. In its simplest form this allow formation of parallel sided holes where their diameter is defined by the photo resist pattern, which in turn allows a range of hole sizes to be formed at the same time. The combination of using two resist layers such that one defines a larger hole and the second layer defines a smaller hole. In this way a stepped hole with parallel sides can be defined. While this provides an approximation of the preferred hole geometry the parallel sides are a significant compromise for the fluid dynamic properties of the hole and the resist patterning and alignment adds complexity to the process.

Laser Drilling provides an alternative method for forming perforate membranes with well controlled distributions of hole sizes in the target size range. Control of the laser power, number of pulses, focal position, and focal length of the final objective allows independent control of the hole size and profile for two or more target hole sizes. This technique offers the choice of a much greater range of materials including many metals, ceramics and polymer materials. Different thicknesses of materials can be selected and the drill parameters adapted to suit the material thickness. This allows decoupling of the holes size, pitch and material thickness compared to the process limitations of electroforming. This can help the design of the perforate membrane as it allows tuning of the mechanical vibrational behaviour to the preferred frequency of operation and so optimising the resonant behaviour. This control is dominated by the thickness and geometry of the perforate membrane. Material selection also allows perforate membranes to be formed into a domed or other out or plane shape and the combination of formable materials, geometry and material thickness greatly enhance design freedom and optimisation for vibration across a wide area of perforate membrane and so maximising the area with sufficient vibration to generate droplets and so with a suitable hole pattern maximise delivery rate of the chosen droplet sizes.

Using a higher power and larger spot size allows larger holes to be formed and similarly using a lower power and tightly focussed small spot size allows small holes to be formed. Drilling a population of two different hole sizes requires switching between the two different drilling parameters. This can be achieved in a number of ways; simply changing the control parameters for a single laser, switching between two laser systems within the same overall drilling instrument, or by drilling the two or more distributions on separate drilling instruments.

Claim 1:
A cartridge (<NUM>) for an aerosol delivery system (<NUM>), the cartridge comprising:
a fluid reservoir (<NUM>) including a first reservoir portion (<NUM>) for containing a first liquid, a second reservoir portion (<NUM>) for containing a second liquid, and at least one liquid barrier (<NUM>) configured to separate the first and second reservoir portions, wherein the first and second reservoir portions have respective first and second openings at a first end of the cartridge; and
a perforate membrane (<NUM>) located at the first end of the cartridge and extending over both of the first and second openings such that a first side of the perforate membrane is in fluid communication with the first and second openings, the first and second openings being configured to supply first and second liquids to the perforate membrane during use, the perforate membrane comprising a plurality of apertures configured to eject one or both of the first and second liquids from a second side of the perforate membrane in the form of liquid droplets when the perforate membrane is vibrated during use, wherein the plurality of apertures of the perforate membrane comprises a first array (<NUM>) of apertures of a first configuration and a second array (<NUM>) of apertures of a second configuration which is different to the first configuration, wherein the second reservoir portion (<NUM>) is annular and defines a cavity in which the first reservoir portion (<NUM>) is disposed.