DEVICE FOR INHALING POWDERED MEDICAMENTS

INTRODUCTION
The present invention relates to devices for inhaling powdered medicaments and methods of using such devices for pulmonary administration of drugs. More particularly, the present invention relates to devices for dispersing dry powder medicaments and administering them by inhalation to a person in need of pulmonary drug delivery.
In recent times pulmonary drug delivery is attracting increasing attention of the formulation scientists. Pulmonary drug delivery relies on inhalation of a drug dispersion or aerosol by the patient so that an active drug within the dispersion can reach the distal (alveolar) regions of the lungs. It has been found that certain drugs are readily absorbed through the alveolar region directly into blood circulation. Pulmonary delivery is particularly promising for the delivery of proteins and polypeptides, which are difficult to deliver by other routes of administration. Drug delivery by the pulmonary route is effective both for systemic delivery and for localized delivery to treat diseases of the lungs.
Inhaled drug delivery systems can be divided into three categories, namely, nebulizers, metered dose inhalers (“MDIs”) and dry powder inhalation devices (“DPIs”), each class having its own advantages and disadvantages. Whereas MDIs use propellants as pressurized delivery aids (and hence are less eco-friendly), DPIs are propellant-free and rely on the ability of the patient to inhale the dispersed dry powder. To deliver pharmaceuticals locally to the lungs, or systemically through the lungs, drugs must be transformed into an aerosol that can be inhaled by the patient. If an aerosol is to be delivered to the deep lung, the individual particles must be small and their velocity must be low as they pass through the upper airways and into the deep lung. With a DPI, the particle velocity is controlled by the patient’s breathing, unlike the situation for metered dose inhalers that emit medication under pressure and at high speed. It is desirable to efficiently deliver the dry powders to the target region of the lungs with a minimal loss of drug. It is further desirable that any powder agglomerates present in the dry powder be sufficiently broken up prior to inhalation by the patient to assure effective systemic absorption or other pulmonary delivery. DPIs are capable of delivering formulations of both large and small molecules, either in the form of a pure drug particle or in combination with an excipient. DPIs are particularly promising for delivering protein and polypeptide drugs, which may be readily formulated as dry powders.
DPIs can be classified into two types based on their delivery mechanism, namely, passive DPIs and active DPIs. Passive DPIs have been known in the art for a few decades, and have successfully reached the marketplace as well. They are available under different brand names such as ROTAHALER® (GlaxoSmithKline), AEROLIZER® (Novartis), SPINHALER® (Aventis), DISKHALER® (GlaxoSmithKline), TURBUHALER® (AstraZeneca), TWISTHALER® (Schering-Plough Corp.), EASYHALER® (Orien), and the like. Passive DPIs do not employ any external energy to disperse the powdered medicament. Instead their functioning solely relies on the ability of the patient to fluidize or disperse the powdered medicament and inhale this dispersion by the oral or nasal route. Since the patient’s aspiratory efforts to aerosolize the powdered medicament varies greatly between various patients and age groups as well as their diseased conditions, dose variability problem is frequently encountered in using passive DPIs. Some researchers have proposed modifications for these devices to minimize the dose variability, but the success is so far limited.
In an attempt to overcome dose variability limitation of passive DPIs, active DPIs (also called “energy enhanced DPIs”) were proposed. They have an external energy source to aerosolize the powdered medicament, thereby forming a cloud comprising fine particles (generally less than about 5 µm in size, and sometimes described as “respirable particles”) in a closed chamber, which the patient inhales in single or multiple breaths. So far, only one active DPI (EXUBERA® marketed by Pfizer for pulmonary delivery of insulin) based on the use of pressurized gas to form a cloud of dispersed powdered medicament in a chamber has been approved for commercial use in the United States.
U.S. Patent Nos. 3,991,761, 4,889,114, 5,070,870, 5,787,881, 6,240,918, 6,606,992, 7,143,764, 7,151,456, 7,219,665, 7,228,860, 7,234,464, 7,252,087 and 7,284,553 describe various drug inhalation devices.
U.S. Patent Application Publication Nos. 2005/0150492, 2005/0022812, 2007/0209661, 2007/0295332, 2008/0251072, 2008/0105256, and 2008/0196717, and International Application Publication Nos. WO 94/006498, WO 98/58695, WO 2005/113043, WO 2006/051300, WO 2007/007110, and WO 2007/132217, disclose inhalation devices with different designs.
U.S. Patent Nos. 6,543,448 and 6,546,929 describe dry powder dispensing apparatus wherein pressurized gas is used to aerosolize the powdered medicament.
WO2009091780 describes a dry powder inhalation device comprising a body defining a chamber for receiving a dose of powdered medicament, in communication with a mouthpiece through which the powdered medicament can be inhaled.
The present invention provides an alternative device for inhaling powdered medicaments. The device will provide higher delivery efficiency through a unique flow pattern with enhanced turbulence and with reduced resistance. The invention also provides methods of using such device for pulmonary administration of drugs.

SUMMARY
According to the present invention there is provided a dry powder inhalation device comprising a body defining a chamber for receiving a dose of powdered medicament, in communication with a mouthpiece through which the powdered medicament can be inhaled.
In one embodiment, the invention includes a dry powder inhalation device for inhalation of a medicament from a rupturable capsule, the device comprising: (a) a body comprising a top housing unit and a bottom housing unit and having a dispersing chamber for receiving a dose of powdered medicament; (b) a port in the top housing unit for inserting a medicament capsule; (c) air inlets present as a diagonally opposite holes around the neck of the dispersing chamber through which air may be admitted into the chamber during inhalation; (d) a mouthpiece which is removably attached to the top housing unit; (e) a mesh that is present in between top housing unit and mouthpiece; and (f) an impinger, which can be moved to open the capsule, located at the end opposite the mouthpiece.
In an embodiment, the dispersing chamber has a parabolic shape, and consists of vertical tubing at the centre across the mouthpiece length.Further; the angle between air inlet and longitudinal axis of the dispersing chamber is about 180°.
A mesh consist of a small central circular area of diameter of 10 mm with 3 vertical and three horizontal lines making approximately 12 apertures having sides of 1.4mm. The rest of the area of the mesh is flat and completely covered. .
In another embodiment, the port in the top housing unit has a square-shaped hole to insert the capsule during administration.
In an embodiment, the impinger has a stem with a “C” shaped groove to open an inserted capsule.
In addition, the device optionally has inlets for retrofitting an attachment for converting into an active inhaler.
In one embodiment, the dry powder inhalation device delivers a single dose, and in another embodiment, the dry powder inhalation device can deliver multiple doses. The invention includes a method of using the device of the present invention for pulmonary administration of drugs.
An embodiment of the invention includes an inhalation device for inhalation of a medicament from an openable capsule, the device comprising:
a housing unit including a dispersing chamber therein;
at least air inlets present as a diagonally opposite holes around the neck through which air may be admitted into the dispersing chamber during inhalation by a person;
a mouthpiece removably attached to the housing unit and in communication with the dispersing chamber;
a mesh provided between the dispersing chamber and the mouthpiece to prevent entry of the capsule into the mouthpiece while permitting medicament from the capsule to travel to the mouthpiece;
characterized by:
a port in the housing unit for inserting a medicament capsule there through such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and
an impinger located in the housing unit and adapted to engage the second portion of the capsule to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.
An embodiment of the invention includes a method for administering a powdered inhalation medicament, comprising:
providing a medicament capsule in a dispensing chamber in a housing having air inlets positioned transversely to a first direction;
opening the medicament capsule in the dispensing chamber; and
inhaling through a mouthpiece connected with the dispersing chamber such that air drawn into the dispersing chamber along with medicament is inhaled through the mouthpiece in the first direction;
characterized by the steps of:
inserting the medicament capsule through a port in the housing unit such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and
pressing a breaking stem of an impinger located in the housing unit against the second portion of the capsule extending into the dispersing chamber to separate the second portion of the capsule from the first portion of the capsule so as to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1(A) is a schematic top plan view of a dry powder inhalation device of the present invention.
FIG. 1(B) is a side elevational view of the device of FIG 1(A).
FIG. 1(C) is a bottom plan view of the device of FIG .1(A).
FIG. 2(A) is a perspective view of the top housing unit with a capsule.
FIG. 2(B) is an exploded perspective view of the bottom housing unit, impinger and mesh.
FIG. 2(C) is a perspective view of the mouthpiece.
FIG. 3(A) is a front elevational view of the mouthpiece.
FIG. 3(B) is a cross-sectional view of the mouthpiece of Fig. 3(C), taken
along line 3(B)-3(B) thereof.
FIG. 3(C) is a cross-sectional view of the mouthpiece of Fig. 3(B), taken
along line 3(C)-3(C) thereof.
FIG. 4(A) is a front plan view of the mesh.
FIG. 4(B) is a cross-sectional view of the mesh of Fig. 4(A), taken along line 4(B)-4(B) thereof.
FIG. 4(C) is a cross-sectional view of the mesh of Fig. 4(A), taken along line 4(C)-4(C) thereof.
FIG. 5(A) is a top plan view of the bottom housing unit.
FIG. 5(B) is a cross-sectional view of the bottom housing unit of Fig. 5(A), taken along line 5(B)-5(B) thereof.
FIG. 5(C) is a cross-sectional view of the bottom housing unit of Fig. 5(A), taken along line 5(C)-5(C) thereof.
FIG. 6(A) is a top plan view of the top housing unit.
FIG. 6(B) is a cross-sectional view of the top housing unit of Fig. 6(A), taken along line 6(B)-6(B) thereof.
FIG. 6(C) is a cross-sectional view of the bottom housing unit of Fig. 6(A), taken along line 6(C)-6(C) thereof.
FIG. 7(A) is a rear elevational view of the impinger.
FIG. 7(B) is a cross-sectional view of the impinger of Fig. 7(A), taken along line 7(B)-7(B) thereof.
FIG. 7(C) is a cross-sectional view of the impinger of Fig. 7(A), taken along line 7(C)-7(C) thereof.
FIG. 8 describes example 2 with plots show the relative distribution of the drugs in Reference and the test device in the present invention in different stages of the ACI.
FIG. 9 describes example 3 plots that show the distribution of the two drugs when analysis done with the reference and the test device.

DETAILED DESCRIPTION
The present invention relates to devices for inhaling powdered medicaments and methods of using such devices for pulmonary administration of drugs. More particularly, the present invention relates to devices for dispersing dry powder medicaments and administering them by inhalation to a person in need of pulmonary delivery.
In accordance with one aspect, the present invention is an efficient device for administering orally a powdered composition by inhalation comprising a body defining a dispersing chamber for receiving a dose of powdered medicament and having a port for inserting a medicament capsule. During administration, the patient inserts a capsule containing medicament into a port on the top housing unit and gently presses on the impinger which is located at the rear end opposite to the mouthpiece, in order to open the capsule and empty the contents (i.e., powder comprising medicament) into a dispersing chamber, followed by inhalation of the powdered medicament through a mouthpiece. Capsule fragments will be retained by a mesh that is present between the chamber and mouthpiece and the patient will receive only the powdered medicament in a single inhalation.
An embodiment of the present invention includes a dry powder inhalation device for inhalation of a medicament from a rupturable capsule, the device comprising: (a) a body having a top housing unit and a bottom housing unit enclosing a dispersing chamber for receiving a dose of powdered medicament; (b) a port in the top housing unit for inserting a medicament capsule; (c) air inlets present as a diagonally opposite holes on the sides of the neck through which air may be admitted into the dispersing chamber during inhalation; (d) a mouthpiece which is removably attached to the top housing unit; (e) a mesh that is present between the top housing unit and the mouthpiece; and (f) an impinger, which can be moved to open the capsule, located at the rear end opposite the mouthpiece.
FIGS. 1(A)-1(C) are schematic illustrations of a dry powder inhalation device of the present invention. The device comprises a body (4) that is defined by bottom housing unit (6) and top housing unit (8) having a dispersing chamber (10) therein and adapted for removable attachment of a mouthpiece (2). The body (4) has reversible pushing means in the form of a plunger or an impinger (12) located at the rear end opposite to the mouthpiece (2). The top housing unit (8) has a port (14) for inserting an openable capsule (18) and air inlets (16) through which the air enters the dispersing chamber (10) of the body (4) when the patient inhales through mouthpiece (2). The openable capsule (18) can be inserted in the port (14) manually. When the impinger (12) is moved toward the mouthpiece (2), it results in opening (e.g., separation) of cap and body parts of the capsule (18), thus emptying the contents (i.e., powdered medicaments) of the capsule into the dispersing chamber (10). The powdered medicament can be inhaled by the patient through mouthpiece (2).
FIGS. 2(A)-2(C) show perspective views of various parts of the dry powder inhalation device. The mouthpiece (2) has a mesh or filter (20) fitted on it at the rear end thereof that detachably attaches to the top housing unit (8). The device is held horizontally and the capsule (18) can be inserted in an upright position in the port (14) at the top housing unit (8), with the capsule crown (22) of the capsule (18) being on top. The mesh (20) prevents capsule bottom (24) or its pieces from entering into the mouthpiece (2) upon its separation from capsule crown (22), when the patient gently pushes the impinger (12) and inhales the powdered medicaments dispersed inside the dispersing chamber (10).
The dispersing chamber (10) has a parabolic shape that provides air flow in a parabolic path which in turn provides enhanced internal reflections to maximize turbulence and has a small volume, which will enhance the air turbulence. The dispersing chamber (10) has a volume of such size that, in use, upon a single inhalation through the chamber by a patient, the medicament within the chamber is inhaled by the patient. The use of a mesh assists with aerosolizing and dispersing the particles during inhalation, due to vibratory forces created by a capsule portion impacting the mesh and walls of dispersing chamber. This can be evidenced by a rattling sound during the inhalation process. There are no corners in the dispersing chamber; instead the chamber has a curvature shape. These unique features of the device of the present invention will contribute to improve the performance of the device in terms of higher delivery efficiency.
In certain embodiments, the entire area of the dispersing chamber (10) is not entirely linearly exposed to the mouthpiece. An embodiment of the dispersing chamber (10) in the body (4) can have a generally parabolic shape. The volume can vary, but a general range of the volume is from about 3 to about 20 cm3 or from about 5 to about 15 cm3 or from about 7 to about 10 cm3. In a specific embodiment of the present invention, the volume of the dispersing chamber is about 4 cm3medicament capsule (18) is not in the same axis as that of powder flow during inhalation.
The location and dimension of the air inlet orifices provides a swirl to the capsule body. An embodiment of the location of the air inlet can have an angle between air inlet and longitudinal axis of the dispersing chamber is about 180°.Location of the two inlets is along the same axis of the powder flow over the locking of the mouth piece and the body. Such a location and diameter of the air inlet coupled with mouthpiece geometry provides a unique air flow pattern with high turbulence with minimal patient inspiratory effort.
FIGS. 3(A)-3(C) are schematic representations of the mouthpiece. The mouthpiece (2) has an outlet end (26) through which the subject inhales the powdered medicament, and an inlet end (28), which can be detachably attached to the top housing unit.
Specifically, mouthpiece (2) includes four walls (30), namely, a substantially planar bottom wall (30a), an inwardly curved top wall (30b), and two inwardly curved side walls (30c) and (30d) which connect together side edges of bottom wall (30a) and top wall (30b). FIG. 3(B) depicts a side cross-sectional view of the mouthpiece, wherein the mouthpiece walls (30) form a suction chamber (32) therein.
Mouthpiece (2) also includes a lower circumferential flange wall (31) which extends rearward from the rear edges of walls (30a) – (30d). The outer surface of flange wall (31) forms a smooth continuation with the outer surfaces of walls (30). However, the thickness of flange wall (31) is less than the thickness of walls (30), whereby an inner circumferential shoulder (33) is formed between the inner surface of flange wall (31) at the forward end thereof, and the rear edges of walls (30), the purpose for which will become apparent from the discussion hereafter. Two opposing lips (31a) are formed at the inner surfaces at the rearward ends of flange wall (31) in corresponding alignment with bottom wall (30a) and top wall (30b). This flange wall, along with two opposing lips, will provide leak-resistance to powdered medicament during inhalation, as well as assisting with component fit during assembly. The mouthpiece from inside is not hollow and consist of vertical tubing at the centre across the mouthpiece length. The diameter of the tube matches to that of the circular open area of the mesh inside of the mouth piece.
FIG. 3(C) is a cross-sectional view of the mouthpiece, taken through different axis.
In certain embodiments, the volume of the suction chamber (32) of the mouthpiece is in the range from about 3 to about 12 cm3, or from about 4 to about 10 cm3, or from about 5 to about 8 cm3. Further, a thickness of the mouthpiece walls (30) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 1 to about 1.5 mm. In an embodiment, the volume of the mouthpiece (2) is about 6 cm3, a thickness of the mouthpiece walls (30) is about 1.5 mm, a length between the outlet end and the inlet end is about 30 mm, a width of the outlet end is about 19 mm and a width of the inlet end is about 30 mm.
FIG. 4(A) depicts the front plan view of the mesh (20) with a mesh rim (34) around it that fits in the mouthpiece (2) at the rear or base end, and specifically, fits within flange wall (31) and seats against circumferential shoulder (33). Apertures (36) of varying sizes can be made in the mesh (20) with complementary pitch (38) dimensions. FIG. 4(B) is a cross-sectional view of the mesh taken through different axis. The mesh (20) prevents entry of capsule fragments into the mouthpiece (2) when the patient inhales the powdered medicaments dispersed inside the body chamber.
The shape of the mesh (20) is designed to suit the device specifications, and can be any geometry such as but not limited to square, rectangle, round/circular, triangle, oval, pentagonal, octagonal, hexagonal, heptagonal, polygonal, trapezium, parabolic and rhombus. The size of the mesh is also designed to suit the device dimensions. Shapes of the apertures and the pitch can also be any geometry such as but not limited to round, square, rectangle, triangle, oval, pentagonal, octagonal, hexagonal, heptagonal, polygonal, parabolic, trapezium and rhombus.
In some embodiments, The mesh in the device has a small central circular area of diameter 10mm with 3 vertical and three horizontal lines making approximately 12 apertures (36) having sides of 1.4mm.The rest of the area/surface of the mesh is flat and completely covered. The thickness of the mesh (20) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.8 to about 1 mm. In embodiments, the horizontal pitch and vertical pitch will be the same, resulting in square apertures.
FIG. 5(A) is a schematic top plan view of the bottom housing unit (6). Specifically, bottom housing unit (6) includes a proximal end (40) that attaches to the proximal end of the top housing unit (8), and a distal end (42) where movable impinger (12) is located. Bottom housing unit (6) includes a bottom cover wall (46) and an upstanding wall (44) extending up from the edges of bottom cover wall (46) at the opposite sides and at the distal end (42) thereof. Upstanding wall (44) therefore includes opposite, spaced apart upstanding side walls (44a) and (44b), as well as an upstanding distal wall (44c). A U-shaped cut-out (44d) is formed centrally in upstanding distal wall (44c) This U shaped cut-out fits to the outer walls of the dispersing chamber. There is no upstanding wall at the proximal end (40), so that a U-shaped opening (41) is formed at proximal end (40), and defined by the proximal edges of bottom cover wall (46) and side walls (44a) and (44b). Bottom cover wall (46) is cut-out to form a parabolic shaped opening (43) at proximal end (40). In addition, two adjacent securing fingers (45), each with a hook (45a) at the upper free end thereof, extend upwardly from bottom cover wall (46) about one-third of the distance from distal end (42) to proximal end (40), although it will be appreciated that a single finger (45) can be provided. FIG. 5(B) and FIG. 5(C) are cross-sectional views of the bottom housing unit (6) taken through different axes.
The thickness of the bottom cover wall (46) of the bottom housing unit (6) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.8 to about 1.2 mm. In a specific embodiment of the present invention, a length of the bottom housing unit (6) is about 50 mm, a width at the center part is about 40 mm, and the thickness of the walls of the bottom housing unit (6) is about 1 mm.
This square-shaped hole is useful for retaining the cap during separation of cap and body parts of the capsule. If the hole is round, then the chances of slipping of the capsule from the hole during opening are increased. The width or diameter of the square shaped hole is variable to suit different size of capsules.
Specifically, top housing unit (8) includes a top cover wall (47) and a downwardly extending wall (49) extending down from the edges of top cover wall (47) at the opposite sides and at the distal end (50) thereof. Air inlets (16) through which the air enters the body (4) when the patient inhales through mouthpiece (2), are provided in top cover wall (47), in surrounding relation to port (14). Downwardly extending wall (49) includes opposite, spaced apart, downwardly extending side walls (49a) and (49b), as well as a downwardly extending distal wall (49c) connected to ends of side walls (49a) and (49b). The lower edge of downwardly extending wall (49) seats flush on the upper edge of upstanding wall (44) along all three sides, such that downwardly extending wall (49) and upstanding wall (44) together form a smooth, continuous side wall of the device according to the present invention.
The diameter of the air inlets can be optimized for suitability for the device specifications. Air inlets with larger diameters might produce a diffuse stream and not a sharp, focused one. Also the resistance might be small. Air inlets with too small diameters will have higher résistance and higher inspiratory force would be required.
In embodiments, the diameter of air inlets (16) may range from about 1 mm to about 3 mm or from about 1.25 mm to about 2.5 mm.
An L-shaped cut-out (51) is formed centrally in downwardly extending distal wall (49c) at distal end (50) and in top cover wall (47). When top housing unit (8) is assembled with bottom housing unit (6), U-shaped cut-out (44d) in upstanding distal wall (44c) forms an opening extension of L-shaped cut-out (51). There is no downwardly extending wall at the proximal end (48), so that an inverted U-shaped opening (53) is formed at proximal end (48). When top housing unit (8) is assembled with bottom housing unit (6), inverted U-shaped opening (53), together with U-shaped opening (41), form a generally rectangular opening (3) of the device.
A generally parabolic shaped separating wall (55a) extends down from the inner surface of top cover wall (47) at proximal end (48), and opens at rectangular opening (3) at proximal end (48). Parabolic shaped separating wall (55a) is closed at its upper end by top cover wall (47), and at its lower end by a planar, parabolic shaped bottom wall (55b) which fits snugly into parabolic shaped opening (43) at proximal end (40) of bottom cover wall (46). It will therefore be appreciated that parabolic shaped separating wall (55a), top cover wall (47), and planar, parabolic shaped bottom wall (55b), together separate the interior of the device into a proximal dispersing chamber (10) and distal passive chamber (52). A small opening (55c) is provided centrally in generally parabolic shaped separating wall (55a).
Top housing unit (8) further includes a generally rectangular, forward circumferential flange wall (57) which extends forwardly from the front or proximal edges of top cover wall (47), downwardly extending wall (49) at the opposite sides of top cover wall (47) and parabolic shaped bottom wall (55b). The inner surface of flange wall (57) forms a smooth continuation with the inner surfaces of top cover wall (47), downwardly extending wall (49) and parabolic shaped bottom wall (55b). However, the thickness of flange wall (57) is less than the thickness of walls (47), (49) and (55b), whereby an outer circumferential shoulder (57a) is formed between the outer surface of flange wall (57) and the forward or proximal edges of walls (44a), (44b), (47), (49a), (49b) and (55b). Two opposing depressions or channels (57b) are formed at the outer surfaces at the rearward or distal ends of flange wall (57) in corresponding alignment with top cover wall (47) and parabolic shaped bottom wall (55b). In this manner, circumferential flange wall (31) of mouthpiece (2) is positioned snugly over circumferential flange wall (57) with opposing lips (31a) resiliently snapping into depressions or channels (57b) in order to releasably retain mouthpiece (2) thereon.
Top housing unit (8) further includes two parallel, spaced apart plunger housing walls (61) which are fixed to the underside of top cover wall (47) at distal end (50), and which extend in the lengthwise direction of the device from downwardly extending distal wall (49c) at opposite sides of L-shaped cut-out (51) at distal end (50), towards proximal end (48). The length of each plunger housing wall (61) is about one-half the distance from distal end (50) to parabolic shaped wall (55a), and has a height that extends down to bottom cover wall (46) of bottom housing unit (6). The lower edges of plunger housing walls (61) are connected together by a bottom guide wall (63), which includes a cut-out notch (63a) centrally at the forward or proximal edge thereof. When bottom housing unit (6) and top housing unit (8) are assembled together, hooks (45a) of adjacent securing fingers (45) each engage within notch (63a) to secure hold bottom housing unit (6) and top housing unit (8) together in a unitary assembly.
Two guide track walls (65) extend down from the undersurface of top cover wall (47) and extend in parallel, spaced apart relation from the forward or proximal edges of plunger housing walls (61), to the rear or distal surface of generally parabolic shaped wall (55a). However, the height of guide track walls (65) is much less than that of plunger housing walls (61).
In a specific embodiment, the volume of passive chamber (52) is in the range from about 5 to about 50 cm3, or from about 10 to about 40 cm3, or from about 15 to about 30 cm3.
The thickness of the walls of top housing unit (8) is in the range from about 0.3 to about 3 mm, or from about 0.5 to about 2 mm, or from about 0.8 to about 1.2 mm.
In a specific embodiment, the length of top housing unit (8) is about 54 mm, the width at the capsule insert port (14) is about 27 mm, the thickness of the walls is about 1 mm, and the volume of the passive chamber (52) is about 24 cm3.
FIG. 7 is a schematic rear elevational view of the impinger (12), and FIGS. 7(B) and 7(C) are various cross-sections taken through different axes. The impinger (12) includes a generally rectangular parallelepiped plunger (56). Plunger (56) includes a rear wall (56a), a top wall (56b), a parallel, spaced apart bottom wall (56c) and two parallel, spaced apart side walls (56d) and (56e). There is no front wall, so that the front face of generally rectangular parallelepiped plunger (56) is open at (56f). The width dimension of generally rectangular parallelepiped plunger (56), measured between outer surfaces of spaced apart side walls (56d) and (56e), is slightly smaller than the distance between plunger housing walls (61). In like manner, the height dimension of generally rectangular parallelepiped plunger (56), measured between outer surfaces of spaced apart top and bottom walls (56b) and (56c), is slightly smaller than the distance between top cover wall (47) and bottom cover wall (46). As a result, plunger (56) is guided for linear movement in the lengthwise direction of the device.
A breaking stem (58) has a distal end (62) fixed to the inner surface of rear wall (56a), and a free proximal end (60). The proximal end (60) slightly extends through small opening (55c) in parabolic shaped wall (55a) of top housing unit (8). As shown in FIG. 7(B), a coil spring (72) extends around breaking stem (58) such that one end thereof abuts against the inner surface of rear wall (56a) and the opposite end thereof abuts against parabolic shaped wall (55a). As a result, plunger (56) is biased by spring (72) rearwardly of the device toward distal end (50) of top housing unit (8), that is, in a direction out of the device. A user can move plunger (56) in the opposite direction toward the front of the device against the force of spring (72), and in such case, forward movement of plunger (56) is limited when plunger (56) abuts against parabolic shaped wall (55a). The impinger (12) thereby reversibly moves forward and backward when pressure is applied and released, respectively.
To prevent escape of plunger (56) from the device, side walls (56d) and (56e) are provided with openings (67), and resilient spring fingers (69) are mounted in a cantilevered manner to side walls (56d) and (56e) within openings (67). A hook end (64) is provided at the free end of each spring finger (69). When coil spring (72) moves plunger (56) rearwardly in the absence of any force applied thereto, hook ends (64) engage front edges of plunger housing walls (61) to prevent escape of plunger (56) from the device and provide a limit on rearward movement of plunger (56). The proximal end (60) of the stem (58) includes a “C”-shaped capsule opening groove (66). When plunger (56) is moved forward against the force of coil spring (72), groove (66) engages the capsule (18) which has been pushed through opening (14) into dispersing chamber (10), and separates the anchored capsule into its crown (22) and capsule bottom (24) parts, thereby spilling the contents of capsule (18) into dispersing chamber (10) where it can be inhaled through mouthpiece (2).
It will be appreciated that, among the unique features of the impinger (12) of the present invention is its stem (58) with the “C”-shaped groove (66) and the angle at which the stem (58) will break the inserted capsule (18), to make sure the capsule is broken without any failure. This “C” shaped groove acts to push the body part of the capsule uniformly during the process of separation, as the capsule is cylindrical in shape. Other shapes such as rectangles could touch only at one point and lead to formation of a dent or bend on the body part of the capsule.
The thickness or height of the stem (58) for breaking capsule (18) is in the range from about 0.2 to about 15 mm, or from about 0.5 to about 10 mm, or from about 0.8 to about 2 mm. The width of the stem (58) for breaking capsule (18) is in the range from about 3 to about 25 mm, or from about 4 to about 20 mm, or from about 5 to about 10 mm.
In a specific embodiment, the length between the proximal end and the distal end of the stem (58) is about 33 mm, the width of the stem (58) is about 6 mm and the thickness of the stem (58) is about 1.5 mm, the distance between the two hook ends (64) is about 20 mm, the width of the spring fingers (69) is about 1 mm and the thickness of the spring fingers (69) is about 2 mm.
Alternatively, in place of groove (66), impinger (12) can include a blade for cutting a bottom end portion from capsule (18) to cause emptying of the capsule, or a sharply pointed tip for piercing the capsule near its bottom end, to cause emptying of the capsule contents.
The reversible movement of the impinger (12) in an assembled condition of the device of the present invention can be brought about by various mechanisms including spring (72). Although the spring (72) is shown as a coil spring, it may be a compression spring, strip spring, tension spring, torsion spring, wire form spring, and the like or their combinations. Springs can be made of materials including but not limited to stainless steel, mild steel, aluminium, any hardened steel, plastic, any metal with powder coating or any other coating, any other elastic materials or combinations thereof. The length of the coil spring (72) varies to suit the device specifications, which can vary between about 0.5 cm to about 25 cm, or about 1 cm to about 12 cm, or about 2 cm to about 4 cm. The diameter of the spring will be determined by the device specifications and will vary between about 3 mm to about 25 mm, or about 4 mm to about 15 mm, or about 6 mm to about 7 mm. The thickness of the spring wire will also be determined by the device specifications and will vary between about 0.1 mm to about 1 mm, or about 0.2 mm to about 0.8 mm, or about 0.3 mm to about 0.5 mm.
In operation, a user inserts a capsule (18) through port (14) into dispersing chamber (10). The user then presses plunger (56) against the force of spring (72), until plunger (56) abuts against parabolic shaped wall (55a). During this operation, breaking stem (58) moves proximally with plunger (56) such that groove (66) opens capsule (18). Specifically, capsule crown (22) of the capsule (18) remains in port (14) while capsule bottom (24) is broken away and falls into dispersing chamber (10). The powder medicament from capsule (18) also falls into dispersing chamber (10) where it is inhaled through mouthpiece (2). When the user releases the force on plunger (56), after the capsule (18) has been opened, spring (72) biases plunger (56) and breaking stem (58) therewith, back to the distal position. After the medicament has been inhaled, mouthpiece (2) is removed to discard capsule bottom (24) which remained in dispersing chamber (10) because it was blocked by mesh (20). After mouthpiece (2) is reassembled, the device is ready for another dose.
It will therefore be appreciated that the present invention provides a dry powder inhalation device capable of dispensing complete doses of powdered medicament. Normally, the capsules are formed of gelatin, although any suitable material, which is both inert to the drug contained within and able to be satisfactorily ruptured or otherwise opened, may be used. The inhalation device of the present invention may be of either single dose format, requiring insertion of a new dose after each successive use, or multiple dose format in which the device contains a plurality of such doses.
Single medicament doses are generally enclosed in a separable capsule, which is normally inserted into the device just prior to use. After opening of the capsule (18), the capsule top (22) will continue to remain in the slot (14) of the top housing unit (8) to prevent moisture ingress into the device and will be pushed inwardly during the insertion of the next capsule. After every single use the mouthpiece needs to be opened to empty the separated pieces of the capsule from the dispersing chamber (10) by simple tapping, before reloading the next dose. Typically, the patient will carry a plurality of such capsules in a pop-out blister package or in some other container.
In the case of a multiple dose format, there can be a design format where a disc capable of loading multiple capsules and which can be rotated to align with the capsule inlet port, will be retrofitted to the top housing unit (8). The operation will again involve adjusting the capsule to the required height as in the case of single capsules.
Thus, in one embodiment, the invention includes dry powder inhalation devices for inhalation of a medicament from a separable capsule, wherein the devices deliver a single dose before reloading.
In another embodiment, the invention includes dry powder inhalation devices for inhalation of a medicament from a separable capsule, wherein the devices deliver multiple doses before reloading.
According to the present invention, the device optionally has inlets for retrofitting an attachment for converting the device into an active inhaler, by way of applying positive pressure either pneumatically or by other means so as to create a standing cloud aerosol. In such case, a one-way valve can be used to accompany such retrofits to prevent back pressure or back flow.
In certain embodiments, the dimensions of different parts of the device described will vary, and can further be manipulated according to the needs of the person skilled in the art.
Other, optional embodiments of the present invention include use of an interlock cover for the mouthpiece to prevent accidental inhalation, and a dose counter that indicates the number of doses inhaled for a device in a multi-dose format.
In another embodiment of the invention, the mouthpiece can have a tortuous pathway whereby aerosol formation of the drug in the inert carrier can be enhanced.
Individual components of the inhalation device of the present invention can be made of any suitable material, including but not limited to polycarbonate (PC), polystyrene, polypropylene, polyethylene group, high density polyethylene (HDPE), low density polyethylene (LDPE), polyvinyl chloride (PVC), rubber, glass, K–resin, acrylic, Surlyn™, styrene-acrylonitrile, acrylonitrile-butadiene-styrene (“ABS”), metals such as stainless steel, and combinations thereof.
The inhalation device of the present invention can be provided as part of a kit that is provided to patients for pulmonary administration of many drugs, including but not limited to salbutamol, salmeterol, formoterol, formoterol fumarate, tiotropium, tiotropium bromide monohydrate, ipratropium bromide, fluticasone, fluticasone propionate, budesonide, ciclesonide, mometasone, mometasone furoate, apomorphine, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, trimcinoline acetonide, flunisolide, ergotamine tartrate, macromolecule and non-macromolecule based pharmaceuticals, insulin, interleukin-1 receptors, parathyroid hormone (PTH-34), alpha-1 antitrypsin, calcitonin, low molecular weight heparin, heparin, interferon, nucleic acids, and combinations thereof. Many drug substances can be used in the forms of salts, esters, solvates, hydrates, etc., and the above listing does not mention all of the forms of the drug compounds that are useful.
The invention includes use of packaging materials, including but not limited to polymeric bags, paper based cartons, plastic or metal boxes, wooden boxes, and any bag made of derivatives of plastic materials, etc. for packaging the inhalation device of the present invention, either alone or as a part of a kit.
The inhalation device of the present invention can be subjected to dose retention studies according to the “Uniformity of Delivered Dose” test in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 (“USP”). The content of active substance can be determined in dose retention studies using analytical techniques such as high performance liquid chromatography.
According to the USP test for “Uniformity of Delivered Dose,” unless otherwise specified in an individual monograph, the drug content of at least 9 of 10 doses collected from one inhaler are between 75% and 125% of the target-delivered dose, and none is outside the range of 65% to 135% of the target-delivered dose. If the content of not more than 3 doses are outside the range of 75% to 125%, but within the range of 65% to 135%, of the target-delivered dose, select 2 additional inhalers and follow the same test for analyzing 10 doses from each. The requirements are met if not more than 3 results, out of 30 values, lie outside the range of 75% to 125% of the target-delivered dose, and none is outside a range of 65 to 125% of the target-delivered dose.
According to the MDI DPI Guidance Document (“Guidance for Industry, Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products,” United States Food and Drug Administration, CDER, October 1998, Section III.F.2.h), the test for “Emitted Dose Content Uniformity” is an amount of active ingredient per determination not outside of 80-120 percent of the label claim for more than one of ten containers, none of the determinations is outside of 75-125 percent of the label claim, and the mean is not outside of 85-115 percent of the label claim. If two or three of the ten determinations are outside of 80-120 percent of the label claim, none is outside of 75-125 percent of the label claim, and the mean is not outside of 85-115 percent of the label claim, an additional 20 containers should be sampled (second tier). For the second tier of testing of a batch, the amount of active ingredient per determination is not outside of 80-120 percent of the label claim for more than 3 of all 30 determinations, none of the 30 determinations is outside of 75-125 percent of the label claim, and the mean is within 85-115 percent of the label claim.
Particle size data for aerosols exiting MDIs and DPIs are usually obtained using cascade impactors, where the aerosol cloud is drawn at a pre-determined air-flow rate through an apparatus containing a series of impaction plates or stages, arranged in such a way that particles of different sizes are collected on different stages. The individual stages can then be washed quantitatively to recover collected drug, and the mass of drug associated with each size band can be determined. Cascade impactors represent the measurement devices of choice for particle size analysis in pharmacopeias, and are recommended in guidance documents issued by regulatory authorities. The Andersen cascade impactor (ACI), multi-stage liquid impinger and Marple-Miller impactor are the three systems most often used for particle size distribution measurements. The ACI, currently a product of Thermo Fisher Scientific Inc., Waltham, Massachusetts USA, is often a preferred device, since it divides the aerosol cloud into the largest number of fractions, allowing the particle size distribution to be examined in detail.
The inhalation device of the present invention can be subjected to a flow resistance study. In general, the resistance to airflow of a device restricts the inspiratory flow through the DPI that can be generated by the patient, and is a predictor of patient comfort during use. Device resistance is calculated using the following equation:
Device resistance = (∆P) 0.5 ÷ Q
Where ∆P is pressure drop and Q is volumetric flow rate. Low resistance devices have resistance values less than 0.05 (cm H2O)0.5 (L/minute), medium resistance devices have resistance values of 0.05 to 1 (cm H2O)0.5 (l/minute) and high resistance devices have resistance values of more than 1 (cm H2O)0.5 (L/minute). (A. R. Clark and A. M. Hollingworth, “The relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers - implications for in vitro testing,” Journal of Aerosol Medicine, Vol. 6, pp. 99-110, 1993).
The device can be used with methods for pulmonary administration of drugs.
The present invention is not limited to specific embodiments described above. Further modifications and suitable materials will be apparent to a person skilled in the art.
The following examples further describe and explain certain specific aspects and embodiments of the invention. These examples are provided solely for purposes of illustration, and the invention is not to be limited thereto. The dose retention studies and cascade impact study results illustrate the performance of an inhalation device of the present invention.

Example 1: A drug retention study was performed with a prototype formulation containing formoterol fumarate 6 µg and fluticasone propionate 500 µg, per dose. The test was performed in triplicate using a test device of the present invention and a commercial device available in the Indian market, using a glass impinger assembly, and a vacuum to obtain a of 60 L/minute air flow was applied for 5 seconds. Data averages are expressed below.

Combihale product Reference Test Device
Formoterol & Budesonide (6+200 mcg) 22 & 21 33 & 23
Formoterol & Fluticasone (6+250 mcg) 10 &10 19 & 20
Formoterol & Tiotropium (12+18 mcg) 10 &13 21 & 23
Tiotropium
(18 mcg)
13 26

Example 2: Drug retention study with Anderson Cascade Impactor (ACI) was also performed with prototype formulations containing formoterol fumarate 6 µg and fluticasone propionate 250 µg per dose. The test was performed in triplicate using a test device of the present invention and a commercial device available in the Indian market (Reference), using a Anderson cascade impactor assembly, and a vacuum to obtain a of 60 L/minute air flow was applied for 5 seconds. Data averages are expressed below:

Combihale product Reference Test Device
Formoterol & Fluticasone (6+250 mcg) 10 &11 23 & 21

Example 3: Similarly drug retention study in ACI was also performed with prototype formulations containing formoterol fumarate 12 µg and tiotropium bromide 18 µg per dose. The test was performed in triplicate using a test device of the present invention and a commercial device available in the Indian market, using an ACI assembly, and a vacuum to obtain a of 60 L/minute air flow was applied for 5 seconds.
Combihale product Reference Test Device
Formoterol & tiotropium (12+18 mcg) 10 & 12 26 & 18

Example 4: The device resistance of test device and the reference device at three different insipiratory flow rates generated is summarized in the following table:

Resistance
Flow (LPM) Test Device Reference
30 0.069 0.110
60 0.065 0.109
90 0.059 0.999

Example 5: Dose uniformity and device retention study was carried out with the prototype formulation containing Formoterol fumarate (12 mcg) and Tiotropium bromide (18 mcg), per dose. The test was performed on the test device and reference. An inhalation flow rate of 60 LPM for 4 seconds was used in this study and the results are given below:
Test Device Reference
Formoterol fumarate Tiotropium bromide Formoterol fumarate Tiotropium bromide
Delivered Dose Uniformity % 92.16 88.25 87.96 85.74
Drug Retention % 15.12 9.95 21.46 12.28

Claims:
1. An inhalation device for inhalation of a medicament from an openable capsule, the device comprising:
a housing unit including a dispersing chamber therein;
air inlets present as a diagonally opposite holes around the neck of the dispersing chamber through which air may be admitted into the dispersing chamber during inhalation by a person;
a mouthpiece removably attached to the housing unit and in
communication with the dispersing chamber;
a mesh consisting of a small central circular area provided between the dispersing chamber and the mouthpiece, while rest of the area of the mesh is flat and completely covered to prevent entry of the capsule into the mouthpiece while permitting medicament from the capsule to travel through the mouthpiece;
characterized by:
a port in the housing unit for inserting a medicament capsule there through such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and
an impinger located in the housing unit and adapted to engage the second portion of the capsule to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.
2. An inhaler according to claim 1, wherein the at least one air inlets present as a diagonally opposite holes around the neck of the dispersing chamber such that an air stream that flows into dispersing chamber from the at least one air inlet is at an angle of about 90 degrees to a direction of powder flow through the mouthpiece during inhalation, to create high turbulence.
3. An inhaler according to any of claims 1 -3, further characterized in those walls defining the dispersing chamber have a parabolic shape.
4. An inhaler according to any of claims 1 -4, wherein the impinger is movable between a first position and a second position that opens the capsule extending through the port.
5. An inhaler according to any of claims 1 -5, wherein the port has square-shaped hole to insert the capsule during administration.
6. An inhaler according to any of claims 1 -6, further characterized in that the impinger has a breaking stem with a distal end having a C-shaped capsule opening groove.
7. An inhaler according to any of claims 1-7, wherein the mouthpiece is removably attached to the top housing unit.
8. A method for administering a powdered inhalation medicament, comprising: providing a medicament capsule in a dispensing chamber in a housing air inlets present as a diagonally opposite holes around the neck of the dispersing chamber;
opening the medicament capsule in the dispensing chamber; and
inhaling through a mouthpiece connected with the dispersing chamber such that air drawn into the dispersing chamber along with medicament is inhaled through the mouthpiece in the first direction;
characterized by the steps of:
inserting the medicament capsule through a port in the housing unit such that a first portion of the capsule is captured in the port and a second portion of the capsule extends into the dispersing chamber; and pressing a breaking stem of an impinger located in the housing unit against the second portion of the capsule extending into the dispersing chamber to separate the second portion of the capsule from the first portion of the capsule so as to open the capsule and thereby permit escape of the medicament from the capsule into the dispersing chamber.
9. A method according to claim 8, wherein the plunger is pressed against a spring force.
10. A method according to either of claims 8 and 9, further characterized by the breaking stem having a distal end with a groove thereat for breaking the capsule.