Patent Description:
In various embodiments, the present invention relates to devices and methods for puncturing a capsule to release a powdered medicament therefrom.

In the medical field, it is often desirable to administer various forms of medication to patients. Well known methods of introducing medication into the human body include, for example, the oral ingestion of capsules and tablets, and intravenous injection through hypodermic needles. In accordance with another exemplary method, medications are inhaled into a patient's respiratory tract and lungs through the nose or mouth. Certain ones of these medications, such as those for the treatment of asthma and/or other respiratory anomalies (e.g., bronchodilators, corticosteroids, etc.), may be aimed at the respiratory tract directly. Others may be inhaled for purposes of systemic treatment, i.e., for treatment of any area of the body through absorption from the respiratory tract through the lung tissue, into the deep lungs, and into the bloodstream. Each of these medications comes in a variety of forms, including fluids, which are commonly administered as an aerosol vapor or mist, as well as solids. Inhalable solids typically take the form of fine, dry powders. Specialized devices, such as inhalers, may be provided to assist the patient in directing these fine powder medications into the respiratory tract. <CIT> describes a method of aerosolizing a pharmaceutical formulation, which comprises providing an aerosolization device comprising an aerosolization chamber and providing a receptacle containing a pharmaceutical formulation. The receptacle comprises a wall having a weakened portion that opens when a force is applied. By applying a force to the receptacle to create an opening at the weakened portion, the pharmaceutical formulation in the receptacle is exposed so that it may be aerosolized for delivery to a patient's respiratory tract. <CIT> describes a puncturing device for puncturing of a wall, in particular the wall of a capsule containing medication for inhalation. The puncturing device or assembly comprises one or more substantially longitudinal prongs, each having a puncturing surface at its distal end as well as a primary cutting edge disposed on the periphery of the prong and terminating at the puncturing surface. A substantially planar face is disposed on the periphery of each prong opposite of the primary cutting edge.

Various types of inhalers are known for the administration of dry powder medicaments. Typically, the dry powder medicament is initially contained in a capsule. In order for the powder to be emitted from the capsule, the inhaler must first create a passage through the capsule film. This is generally done through the use of sharpened pins or staples that pierce the capsule. In particular, the capsule film is typically thin and made of a material that has relatively low strength properties, thereby facilitating the piercing of the capsule.

Generally, <NUM> to <NUM> of a traditional inhalation powder made through dry blending of an active drug substance with lactose carrier particles are included in a capsule. The volume of this powder is typically low, however, due to the density of the powder generally being on the order of <NUM>/cm<NUM>. Because the volume is low, the required capsule size is also small. For example, a lactose blend product can be easily accommodated in a size <NUM> (i.e., <NUM><NUM>) or lower (i.e., smaller) capsule. In practice, however, the final decision on capsule size is more often than not related to patient convenience than to the volumetric requirements, as capsules that are too small can be difficult for patients to handle.

In cases where a low volume of powder is to be delivered, the required volumetric flow rate of the powder (i.e., the required volume of powder delivered per unit time) through one or more openings created in the capsule is also very modest. For example, with a powder density of approximately <NUM>/cm<NUM>, a <NUM> fill of a lactose blend with a total active drug load of <NUM> has a volume of approximately <NUM><NUM>. In this example, for a <NUM> second inhalation, the required volumetric flow rate is just <NUM><NUM>/s.

However, high performance inhalation powders have recently been introduced as an alternative to traditional lactose blends. These new powders are characterized by highly efficient delivery of drug to the lungs, which is generally achieved by producing powders with low densities (i.e., typically below <NUM>/cm<NUM>). These lower density, high performance powders create new demands on the delivery devices used by patients.

One consideration is that larger capsules are required. For example, <NUM> of powder with a density of <NUM>/cm<NUM> has a volume of <NUM><NUM>. This volume of powder requires at least a size <NUM> (i.e., <NUM><NUM>) capsule, and possibly even a size <NUM> (i.e., <NUM><NUM>) capsule to allow for a reasonable commercial filling process.

Another consideration is that a full dose emission should be achievable in a single breath of a typical adult patient. As described above, the volumetric flow rate required for traditional dry powder blends is very modest. In comparison, a size <NUM> (i.e., <NUM><NUM>) capsule with a <NUM> fill of a <NUM>/cm<NUM> powder (i.e., <NUM><NUM> of powder) requires a volumetric flow rate of <NUM><NUM>/s in order to be fully emitted during a <NUM> second inhalation, which is <NUM> times greater than that required in the example provided above for lactose blends.

Small diameter pins or staples can readily pierce a capsule without causing undue material deformation, such as collapse of the capsule's walls or domes. For higher density lactose blends, use of small diameter pins or staples does not present an issue. In particular, the low volumetric flow rates required for these products allows for the total hole area to be small. The hole made by, for example, a <NUM> diameter round pin will have an area of about <NUM><NUM>. In the first (i.e., high density powder) example above, <NUM> of the <NUM>/cm<NUM> lactose blend powder emitted from a hole of this size in <NUM> seconds will have a volumetric flux of about <NUM><NUM>/[cm<NUM>s]. This level of flux is readily obtainable in capsule-based inhalers. In the second (i.e., low density powder) example above, though, <NUM> of the <NUM>/cm<NUM> powder emitted from a <NUM> diameter hole in <NUM> seconds would require a volumetric flux of about <NUM><NUM>/[cm<NUM>s]. In practice, a volumetric flux of this magnitude is not achievable. This can be remedied by increasing the hole area, but piercing a large hole through the capsule requires high force loading which will, without more, collapse the capsule before the puncture is created. Improving the sharpness of the piercing mechanism can also provide some relief, but this is limited by the nature of the metals and forming processes used.

Accordingly, a need exists for improved devices and methods for puncturing a capsule to release a powdered medicament therefrom. In particular, an improved approach is required in order to produce enough hole area in a capsule to allow for a full dose emission of a low density powder without the capsule being collapsed.

Various embodiments of the inhalation device described herein allow for high doses of low-density inhalation powders to be delivered. In one embodiment, the inhalation device accomplishes this by strategically piercing the highest strength region of the capsule (i.e., the domes) and by positioning the piercing elements towards the perimeter of the domed regions. In other words, the piercing elements (e.g., the individual prongs or tines) are placed far apart and at the point where most of their force is transmitted to the cylindrical wall of the capsule, thus placing as little force as possible on the dome. Such a design allows for relatively large pins or staple tines to produce large openings in the capsule's dome without collapsing the capsule. In particular, the inhalation device can incorporate pins or staples with large cross-sectional areas, which results in a substantial increase in the total hole area available for dose emission from the capsule.

According to the invention the location for the center of each puncture hole is in an annular region on the dome's surface that is positioned at no less than <NUM>% (e.g., between about <NUM>% and about <NUM>%, or between about <NUM>% and about <NUM>%) of the dome's radius away from a central axis of the dome. In addition, in one such embodiment, the preferred total surface area of all puncture holes is between about <NUM>% and about <NUM>% of the total surface area of the capsule. It has been determined that these particular combinations of puncture hole location and puncture hole surface area advantageously avoid the capsule collapsing upon itself when punctured. Moreover, it has been determined that such a puncture hole surface area allows for a full dose of a low-density (i.e., below <NUM>/cm<NUM>) powder to be emitted from a capsule at a sufficient volumetric flow rate and an achievable magnitude of volumetric flux so as to be consumed in a single breath by a typical adult patient.

In general, in one aspect, embodiments of the invention feature a device for puncturing a capsule to release a powdered medicament therefrom. The device includes a chamber for receiving the capsule. The capsule includes opposing domes and a cylindrical wall portion defined by a capsule wall radius r. The device further includes a mechanism for puncturing at least one hole in at least one dome. A center of each hole is located within an annular puncture region situated at no less than <NUM>. 4r, and a total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of the capsule. The annular puncture region is situated between <NUM>. 4r and <NUM>. 8r, or between <NUM>. 4r and <NUM>.

In general, in another aspect, embodiments of the invention feature a method for puncturing a capsule to release a powdered medicament therefrom. The method includes receiving, within a chamber, a capsule that itself includes opposing domes and a cylindrical wall portion defined by a capsule wall radius r. The method also includes puncturing at least one hole in at least one dome. A center of each hole is located within an annular puncture region situated at no less than <NUM>. 4r, and a total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of the capsule. The annular puncture region is situated between <NUM>. 4r and <NUM>. 8r, or between <NUM>. 4r and <NUM>.

In various embodiments, the puncturing mechanism (which may include a plurality of prongs and which may be moveable between a non-puncturing position and a puncturing position) is configured to puncture only a single dome. In such instances, the total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of the single dome. In one embodiment, the capsule has a volume of at least <NUM><NUM>. The capsule may house a powdered medicament, which may have a density below <NUM>/cm<NUM> and/or contain levodopa as an active drug. Puncturing the capsule's dome causes the powdered medicament to be released from the capsule.

In certain embodiments, an outer surface of the capsule is between about <NUM> and about <NUM> thick. The capsule (i.e., the opposing domes and the cylindrical wall portion thereof) may be made from a material such as, for example, hydroxy propyl methyl cellulose or gelatin.

In one embodiment, the device further includes an inhalation portion that is coupled to the chamber. The inhalation portion may define, for example, at least one aperture for emitting the powdered medicament therethrough. For its part, the chamber may include a wall defining a plurality of vents for introducing air into the chamber to disperse the powdered medicament released from the capsule.

In general, in yet another aspect, embodiments, which are not explicitly recited by the wording of the claims, feature a punctured capsule. The punctured capsule includes opposing domes (at least one of which is punctured with at least one hole) and a cylindrical wall portion defined by a radius r. A center of each hole is located within an annular region situated at no less than <NUM>. 4r, and a total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of the capsule. The annular region is situated between <NUM>. 4r and <NUM>. 8r, or between <NUM>. 4r and <NUM>.

In various embodiments, only a single dome of the capsule is punctured. In such instances, the total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of the single dome. In one embodiment, the punctured capsule has a volume of at least <NUM><NUM>. The punctured capsule may include therein a powdered medicament, which may have a density below <NUM>/cm<NUM> and/or contain levodopa as an active drug. In addition, an outer surface of the punctured capsule may be between about <NUM> and about <NUM> thick. The opposing domes and the cylindrical wall portion of the punctured capsule may each be made from a material such as, for example, hydroxy propyl methyl cellulose or gelatin.

These and other objects, along with advantages and features of the embodiments of the present invention herein disclosed, will become more apparent through reference to the following description, the accompanying drawings, and the claims. Furthermore, it is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations.

In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:.

In various embodiments, the present invention features devices and methods for puncturing a capsule to release a powdered medicament therefrom. In particular, the capsule is punctured in a specific region with sufficiently-sized puncture holes so as to allow a full dose of a low-density (i.e., below <NUM>/cm<NUM>) powder to be emitted from the capsule and be consumed by a typical adult patient in a single breath (i.e., emitted at a sufficient volumetric flow rate and an achievable magnitude of volumetric flux), while, at the same time, not causing the capsule to collapse upon itself.

<FIG> depicts a front view of an inhalation device <NUM> in accordance with one embodiment of the invention. A rear view of the device <NUM> is substantially identical to the front view. As shown, the device <NUM> includes a first or lower casing portion <NUM> and a second or upper casing portion <NUM> removably coupled to the first casing portion <NUM>. The upper casing portion <NUM> and lower casing portion <NUM> each include a flattened region <NUM> and <NUM>, respectively, to facilitate gripping of the casing by a patient. In one embodiment, the lower casing portion <NUM> includes an outer casing <NUM> and an inner casing <NUM> movably received within the outer casing <NUM>. A removable cap <NUM> is provided at the user or inhalation end of the device <NUM>.

Preferred materials for the device <NUM> include Food and Drug Administration ("FDA") approved, and United States Pharmacopeia ("USP") tested, plastics. In one embodiment, the device <NUM> is manufactured using an injection molding process, the details of which would be readily apparent to one of ordinary skill in the art.

<FIG> is a cross-sectional view of the device <NUM> depicted in <FIG> along the line <NUM>-<NUM>. As shown in <FIG>, the device <NUM> includes an inhalation or emitter portion <NUM>. The inhalation portion <NUM> includes a hemispheric region <NUM> that defines a plurality of apertures <NUM>. It should be understood, however, that the present invention is not limited to a particular number of apertures <NUM>, and can be configured such that at least one aperture <NUM> is provided. An inhalation piece <NUM> is provided to allow for inhalation of the medicament by a user. The inhalation piece <NUM> can be configured as a mouth piece for inhalation through a user's mouth. Alternatively, the inhalation piece <NUM> can be configured as a nose piece for inhalation through a user's nose.

The device <NUM> also includes a cylindrical chamber <NUM> that is defined by a straight wall <NUM> of circular cross-section. The chamber <NUM> has a proximal end <NUM> that is coupled to the inhalation portion <NUM>, and an opposite, distal end <NUM>. In particular, the proximal end <NUM> of the chamber <NUM> is in fluid communication with the inhalation portion <NUM>. As shown in <FIG>, the chamber <NUM> may receive therein a capsule <NUM>. A plurality of vents <NUM> are defined by the wall <NUM>, and are configured for introducing air into the chamber <NUM> to disperse powdered medicament released from the capsule <NUM>. It should be understood that the present invention is not limited to a particular number of vents <NUM>, and can be configured such that at least one vent <NUM> is provided. Powder released from the capsule <NUM> is dispersed in the chamber <NUM> and inhaled through the apertures <NUM> and inhalation piece <NUM> by the user.

<FIG> depicts a table <NUM> of standard capsule sizes. In one embodiment of the invention, the capsule <NUM> employed in connection with the inhalation device <NUM> has a volume of at least <NUM><NUM>. In other words, with reference to the table <NUM> of <FIG>, a size <NUM> capsule is the minimum capsule size employed. Alternatively, the capsule <NUM> may be at least of size <NUM> (i.e., <NUM><NUM>), size 0E (i.e., <NUM><NUM>), size <NUM> (i.e., <NUM><NUM>), or size <NUM> (i.e., <NUM><NUM>). Suitable capsules <NUM> can be obtained, for example, from Shionogi, Inc. of Florham Park, New Jersey.

In one embodiment, the capsule <NUM> stores or encloses particles, also referred to herein as powders. The capsule <NUM> may be filled with powder in any manner known to one skilled in the art. For example, vacuum filling or tamping technologies may be used. In one embodiment, the capsule <NUM> is filled with a powdered medicament having a density below <NUM>/cm<NUM>. The powdered medicament housed by the capsule <NUM> may also include any of a variety of active drugs, including, for example, levodopa. In one embodiment, the powder housed within the capsule <NUM> has a mass of at least <NUM>. In another embodiment, the mass of the powder is at least <NUM>, and up to approximately <NUM>.

With reference again to <FIG>, the inhalation device <NUM> also includes a puncturing mechanism <NUM> that is used to puncture at least one hole in at least one dome of the capsule <NUM> to release the powdered medicament contained therein into the chamber <NUM>. In the embodiment shown in <FIG>, the puncturing mechanism <NUM> is configured as a substantially U-shaped staple having two prongs <NUM>. In one such embodiment, each of prongs <NUM> is configured with a square cross-section <NUM>, thereby providing a sharp point and two cutting edges. Alternatively, one, or a plurality of, straight needle-like implements may be used as the puncturing mechanism <NUM>. Further exemplary puncturing mechanisms suitable for use in connection with the inhalation device <NUM> are described in detail in, for example, <CIT> and <CIT>, the disclosures of which are hereby incorporated herein by reference in their entireties. The puncturing mechanism <NUM> can be configured to puncture one or, alternatively, multiple hole(s) (through a single or, alternatively, multiple piercing point(s)) in the capsule <NUM>. As described below, however, the total surface area of all puncture holes is of greater importance than the actual number of puncture holes.

The puncturing mechanism <NUM> is preferably configured to be movable between a non-puncturing position (as depicted in <FIG>) and a puncturing position. In the puncturing position, the prongs <NUM> pierce or puncture the capsule <NUM> to make holes therein. In one embodiment, a biasing mechanism is provided that biases the puncturing mechanism <NUM> in the non-puncturing position. In the embodiment shown in <FIG>, the biasing mechanism is configured as a first spring <NUM> that biases the substantially U-shaped staple <NUM> in the non-puncturing position.

As noted above with reference to <FIG>, the lower casing portion <NUM> of the device <NUM> includes the inner casing <NUM> and the outer casing <NUM>. As shown in <FIG>, a second spring <NUM> is disposed in the lower casing portion <NUM>. The second spring <NUM> biases the inner casing <NUM> in an outward position. Upon compression of the second spring <NUM>, the inner casing <NUM> moves from the outward position to an inward position, thereby drawing the lower casing portion <NUM> toward the upper casing portion <NUM>. Compression of the second spring <NUM> also causes compression of the first spring <NUM>, thereby causing the puncturing mechanism <NUM> to move upward to the puncturing position and to pierce or puncture the capsule <NUM> to make holes therein. Upon release of compression, the first and second springs <NUM>, <NUM> return to their biased state, thereby returning the puncturing mechanism <NUM> to its non-puncturing position, and the inner casing <NUM> to its outward position. In particular, upon the release of compression, the capsule <NUM> is stripped from the prongs <NUM> of the puncturing mechanism <NUM> as the first spring <NUM> returns to its biased state. The second spring <NUM> may act as a backup to strip the capsule <NUM> from the prongs <NUM> of the puncturing mechanism <NUM> in the event that the first spring <NUM> fails to do so.

Although the puncturing mechanism <NUM> of the inhalation device <NUM> depicted in <FIG> is configured to puncture only a single dome of the capsule <NUM>, other designs are also within the scope of the invention. For example, as will be understood by one of ordinary skill in the art, the puncturing mechanism <NUM> may also be designed to (or a second puncturing mechanism may be employed to) puncture both domes of the capsule <NUM>.

As also depicted in <FIG>, a pair of flanges <NUM> is disposed on the lower casing portion <NUM>. A pair of grooves <NUM> is disposed on the upper casing portion <NUM>, so that the flanges <NUM> can be received within the grooves <NUM> to thereby couple the lower and upper casing portions <NUM>, <NUM>. In one embodiment, the lower and upper casing portions <NUM>, <NUM> are coupled with a friction-fit engagement. A friction-fit engagement may be achieved using the groove <NUM> and flange <NUM> arrangement depicted in <FIG>. Other alternative configurations for a friction-fit engagement will be readily apparent to one skilled in the art.

<FIG> depicts a side view of a capsule <NUM> that may be punctured using the exemplary inhalation device <NUM> described above. As illustrated, the capsule <NUM> includes a first dome <NUM>, a second, opposing dome <NUM>, and a cylindrical wall portion <NUM> that is defined by a radius r. The cylindrical wall portion <NUM> extends between first and second ends <NUM> and <NUM>, where it meets the first and second domes <NUM> and <NUM>, respectively.

<FIG> depicts a top view of the first dome <NUM> (i.e., a view of the dome <NUM> when it is observed in the direction of arrow <NUM>). As illustrated, the first dome <NUM> features two puncture holes <NUM>, <NUM> within an annular region <NUM>. As described further below, the annular puncture region <NUM> represents the preferred region on an outer surface <NUM> of the first dome <NUM> in which to puncture the holes <NUM>, <NUM>. In particular, in one embodiment, the puncturing mechanism <NUM> of the inhalation device <NUM> is configured to puncture a center of each hole <NUM>, <NUM> within the annular puncture region <NUM>.

In one embodiment, the outer surface <NUM> of the capsule <NUM> is between about <NUM> and about <NUM> thick. For example, the outer surface <NUM> of each of the first dome <NUM>, the second dome <NUM>, and the cylindrical wall portion <NUM> may be approximately <NUM> thick. Within that outer surface <NUM> the capsule <NUM> may be hollow and, as described above, may be at least partially filled with a powdered medicament. Materials such as, for example, hydroxy propyl methyl cellulose or gelatin may form the relatively thin outer surface <NUM> of the capsule <NUM> (i.e., the opposing domes <NUM> and <NUM> and the cylindrical wall portion <NUM>).

As illustrated in <FIG> and <FIG>, the annular puncture region <NUM> is situated on the outer surface <NUM> of the first dome <NUM> between about <NUM>. 4r and about <NUM>. In other words, the preferred location for the center of each puncture hole <NUM>, <NUM> is in an annular region of the dome <NUM> that is positioned between about <NUM>% and about <NUM>% of the dome's radius away from a central axis <NUM> of the dome <NUM>. As an example, for a size <NUM> (i.e., <NUM><NUM>) capsule <NUM>, the annular puncture region <NUM> is situated between about <NUM> and about <NUM> away from the central axis <NUM> of the dome <NUM>. It has been found that, in puncturing the dome <NUM> in this region <NUM>, most of the force is transmitted to the cylindrical wall <NUM> of the capsule <NUM>, thus placing as little force as possible on the dome <NUM>. Such an approach allows for the use of relatively large prongs <NUM> in the puncturing mechanism <NUM> so as to produce large holes <NUM>, <NUM> in the dome <NUM> without collapsing the capsule <NUM>.

In particular, where the puncturing mechanism <NUM> is configured to puncture only a single dome <NUM> of the capsule <NUM> (as is the case, for example, in the exemplary inhalation device <NUM> depicted in <FIG>), the total combined surface area of all puncture holes <NUM>, <NUM> may be up to about <NUM>% of a total surface area of the dome <NUM>. As an example, each puncture hole <NUM>, <NUM> may represent about <NUM>% of the total surface area of the dome <NUM>, and, thus, in combination the puncture holes <NUM>, <NUM> may represent about <NUM>% of the total surface area of the dome <NUM>. This is a substantial total hole area that is available for dose emission from the capsule <NUM>.

In fact, in testing, it has been found that a full dose of a low-density (i.e., below <NUM>/cm<NUM>) powder may be emitted from the capsule <NUM> and consumed by a typical adult patient in a single breath (i.e., emitted at a sufficient volumetric flow rate and an achievable magnitude of volumetric flux) where the combined total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of a single dome <NUM> or, equivalently, where the combined total surface area of all puncture holes is between about <NUM>% and about <NUM>% of a total surface area of the entire capsule <NUM>. As an example, for a size <NUM> (i.e., <NUM><NUM>) capsule <NUM>, the preferred total surface area for all puncture holes <NUM>, <NUM> is between about <NUM><NUM> and <NUM><NUM>.

The effect of the total combined surface area of all puncture holes on the efficiency of dose delivery was examined using a representative low density, high performance dry powder formulation. In particular, size <NUM> (i.e., <NUM><NUM>) capsules were filled with equal quantities of powder and punctured in a manner so as to create holes with a total combined surface area ranging from <NUM><NUM> to <NUM><NUM> (i.e., <NUM> in<NUM> to <NUM> in<NUM>). Approximately <NUM> capsules were tested for each target hole area value. The percentage of the filled powder mass emitted during a simulated breath was then measured for each hole area configuration. Specifically, this dose emission study was conducted at a simulated inhalation flow rate and volume performance associated with typical pediatric patients. The study therefore represents the worst case in adult populations (i.e., the study is representative of the lower <NUM>% to <NUM>% of adults). The results of the study are shown in the table <NUM> of <FIG> and in the corresponding graph <NUM> of <FIG>.

From the results shown in <FIG> and <FIG>, it was concluded that the average fraction of powder emitted in a single breath increases asymptotically towards <NUM>% with increasing puncture hole area. In addition, the variability of dose emission follows an inverse relationship with the total combined surface area of all puncture holes, as the standard deviation (a measure of dose delivery variability) decreases with increasing puncture hole area.

In particular, as can be seen in the table <NUM> depicted in <FIG>, when a combined total surface area of all the puncture holes is about <NUM>% of the total surface area of the entire capsule, <NUM>% of the capsule's powder is emitted, on average, in a single breath of a pediatric patient. This represents the lower bound on an acceptable percentage of powder to be emitted in a single breath of a pediatric patient. In a typical adult, a much greater percentage of powder (e.g., essentially a full dose) would be emitted when the combined total surface area of all the puncture holes is about <NUM>% of the total surface area of the entire capsule. This minimum value of surface area for the puncture holes therefore also represents the lower bound on an acceptable percentage of powder to be emitted in a single breath of an adult patient.

While the percentage of powder emitted in a single patient breath increases with increasing puncture hole area, it does so generally asymptotically. It has been found that it is undesirable for the combined total surface area of all the puncture holes to be greater than about <NUM>% of the total surface area of the entire capsule, because the puncturing force that results from producing puncture holes greater than that size can approach or exceed the loading limits for typical capsule materials, such as hydroxy propyl methyl cellulose and gelatin. Moreover, it is typically unnecessary for the combined total surface area of all the puncture holes to be greater than about <NUM>% of the total surface area of the entire capsule because, as can be seen from the table <NUM> of <FIG> and the graph <NUM> of <FIG>, the percentage of powder emitted from the capsule approaches <NUM>% generally asymptotically and little to no appreciable benefit (in terms of the percentage of powder emitted from the capsule) exists for puncture hole areas beyond that size.

The use of puncture holes having a combined total surface area in narrower ranges between about <NUM>% and about <NUM>% of the total surface area of the entire capsule (e.g., with minimum values of about <NUM>%, about <NUM>%, about <NUM>%, and/or about <NUM>% of the total surface area of the entire capsule in any combination with maximum values of about <NUM>%, about <NUM>%, about <NUM>%, and/or about <NUM>% of the total surface area of the entire capsule) is also contemplated and within the scope of the present invention.

A limiting factor for positioning a puncture hole in a capsule's dome is the capsule material's strength and tendency to deflect under load. In order for the capsule material to be penetrated, the capsule material has to essentially maintain its position prior to the penetrating tip perforating the capsule's surface. If the capsule material deflects (e.g., bends inward) to too great a degree before perforation occurs, the capsule's dome will tend to collapse before the tip fully penetrates and creates a hole in the capsule material. Using Finite Element Analysis ("FEA") and the mechanical properties of the capsule material, the capsule material's response to a constant force loading at different positions along the radius of the capsule's dome was simulated. The results of that analysis are shown in the table <NUM> of <FIG> and in the corresponding graph <NUM> of <FIG>.

The analysis predicts, as can be observed from <FIG> and <FIG>, that a change in degree of deflection in response to a constant loading force similar to that imparted to the capsule material during puncturing will occur between <NUM>% to <NUM>% of the dome radius. The change, as one moves from a puncture hole centered at <NUM>% of the dome radius towards a puncture hole centered at <NUM>% of the dome radius, is a transition from minor bending (which is recoverable or elastic deformation) to plastic or irreversible deformation. This transition occurs when the capsule material begins to yield under load. Once this transition point is reached, the efficiency of puncture hole generation is significantly reduced as the capsule's dome will continue to deflect under increasing load rather than being penetrated.

A separate laboratory study measuring the efficiency of puncture hole generation for various geometric positions of two penetrating tips was conducted to confirm these simulation results. The study showed that once the centers of the puncture holes reached values below <NUM>. 4r the rate of dome collapse increased dramatically. The nature of the dome collapse was such that a reliable dose emission was unlikely to occur with penetration positions at less than <NUM>.

Accordingly, as mentioned above, the preferred location for the center of each puncture hole is in an annular region of the capsule's dome that is situated at no less than <NUM>. 4r (and, in some embodiments, at no less than <NUM>. For example, the annular puncture region may be situated between about <NUM>. 4r and about <NUM>. 6r, or between about <NUM>. 4r and about <NUM>. In fact, in practice, the annular puncture region may be situated in any region on the capsule's dome having a minimum value of about <NUM>. 4r, about <NUM>. 5r, and/or about <NUM>. 6r in any combination with a maximum value of about <NUM>. 6r, about <NUM>. 7r, and/or about <NUM>. Attempting to puncture the capsule's dome in a region greater than <NUM>. 8r is undesirable for several reasons. For instance, beyond <NUM>. 8r the prong of the puncturing mechanism could slip off the capsule's dome and/or tear down the cylindrical wall portion of the capsule. Tearing down the cylindrical wall portion of the capsule could leave too great a hole in the capsule and/or cause portions of the capsule to be ripped apart and (potentially) be inhaled by the patient. Attempting to puncture the capsule's dome in a region greater than <NUM>. 8r could also create a side load on the capsule, causing it to detrimentally deflect within the inhaler's chamber.

In an exemplary method of use of the inhalation device <NUM>, a user (e.g., a patient) places the capsule <NUM> containing a powdered medicament within the cylindrical chamber <NUM>. When the user compresses the inhalation device <NUM>, the puncturing mechanism <NUM> is moved toward the capsule <NUM>, thereby puncturing the capsule <NUM> and causing the release of powdered medicament into the chamber <NUM>. After release into the chamber <NUM>, the powdered medicament is then inhaled by the user through the apertures <NUM> and the inhalation piece <NUM>. As noted, the inhalation piece <NUM> can be configured as either a mouth piece or a nose piece. For subsequent uses, the user merely replaces the emptied capsule <NUM> with another capsule <NUM> that contains a new supply of the powdered medicament.

Claim 1:
A device for puncturing a capsule to release a powdered medicament therefrom, the device comprising:
a chamber adapted to receive a capsule comprising opposing domes and a cylindrical wall portion defined by a capsule wall radius r; and
a puncturing mechanism adapted to puncture a received capsule by way of puncturing at least one hole in at least one dome of the received capsule, wherein a centre of each hole being punctured by the puncturing mechanism is located within an annular puncture region of the capsule situated between <NUM>.4r and <NUM>.8r,
wherein the puncturing mechanism is adapted to puncture a total surface area of all puncture holes between <NUM>% and <NUM>% of a total surface area of the received capsule.