Dry Powder Inhaler and System for Drug Delivery

• US 20090308391A1
• Filed: 06/12/2009
• Published: 12/17/2009
• Est. Priority Date: 06/13/2008
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: He, Tom, Smutney, Chad C., Adamo, Benoit, McLean, Scott, Kinsey, P. Spencer, Polidoro, John M., Sahi, Carl R., Bryant, Anthony, Overfield, Dennis, Mann, Alfred
• Granted Patent: US 8,636,001 B2
• Time in Patent Office: Days
• US Class Current: 128/203.150
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61M 15/0021 Mouthpieces therefor
• CPC Class Codes: A61M 15/0023 retractable
• CPC Class Codes: A61M 15/0028 using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
• CPC Class Codes: A61M 15/0043 Non-destructive separation of the package, e.g. peeling
• CPC Class Codes: A61M 15/0045 using multiple prepacked dosages on a same carrier, e.g. blisters
• CPC Class Codes: A61M 15/0048 the dosages being arranged in a plane, e.g. on diskettes
• CPC Class Codes: A61M 15/0086 Inhalation chambers
• CPC Class Codes: A61M 15/0091 mechanically breath-triggered
• CPC Class Codes: A61M 2202/064 Powder
• CPC Class Codes: A61M 2205/6081 Colour codes
• CPC Class Codes: A61M 2206/20 having means for promoting or enhancing the flow, actively or passively

Abstract

A breath-powered, dry powder inhaler, a cartridge, and a pulmonary drug delivery system are provided. The dry powder inhaler can be provided with or without a unit dose cartridge for using with the inhaler. The inhaler and/or cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, including, peptides and proteins such as insulin and glucagon-like peptide 1 for the treatment of diabetes and/or obesity. The dry powder inhaler is compact; can be provided in various shapes and sizes, colors, and comprises a housing, a mouthpiece, a cartridge placement area, and a mechanism for opening and closing the medicament cartridge. The device is easy to manufacture, provides a pre-metered single unit dose, it is relatively easy to use, and can be reusable or disposable.

Claims

1. An inhalation system for delivering a dry powder medicament to a pulmonary tract, comprising a dry powder inhaler configured to have at least two inlet apertures having a total resistance to flow in a dosing configuration ranging in value from 0.065 to about 0.200 (√

kPa)/liter per minute.

2. The inhalation system of claim 1, further comprising an enclosure for containing the dry powder medicament for inhalation.

3. The inhalation system of claim 2, wherein the enclosure comprises a cartridge.

4. The inhalation system of claim 3, wherein the cartridge comprises a cartridge top and a cartridge bottom, wherein the cartridge top and the container are configurable to attain a containment position and a dosing or dispensing position.

5. The inhalation system of claim 1, wherein the dry powder inhaler comprises a mouthpiece and moveable member.

6. The inhalation system of claim 5, further comprising a housing.

7. The inhalation system of claim 5, wherein the moveable member comprises a sled, a slide tray, or a carriage.

8. The inhalation system of claim 6, wherein the mouthpiece comprises a flow conduit having a first inlet port in fluid communication with ambient air, a second inlet port in fluid communication with the cartridge;

and an outlet port.

9. The inhalation system of claim 2, wherein the enclosure has an internal volume configured to contain the dry powder medicament and having at least one inlet port to allow flow into the enclosure, and at least one dispensing port to allow flow out of the enclosure;

said at least one inlet port is configured to direct at least a portion of the flow entering the at least one inlet port at the at least one dispensing port within the enclosure in response to a pressure differential.

10. The inhalation system of claim 1, wherein the total resistance to flow is relatively constant across a pressure differential range between 0.5 kPa and 7 kPa.

11. An inhalation system for delivering a dry powder medicament to a patient, comprising an inhaler comprising a container mounting area configured to receive a container, and a mouthpiece having at least two inlet apertures and at least one exit aperture;

wherein one inlet aperture of the at least two inlet apertures is in fluid communication with the container area, and one of the at least two inlet apertures is in fluid communication with the at least one exit aperture via a flow path configured to bypass the container area;

wherein the flow conduit is configured to bypass the container area delivers 30% to 90% of the total flow going through the inhaler during an inhalation.

12. The inhalation system of claim 11, further comprising a container comprising a dry powder medicament mounted to the container area.

13. The inhalation system of claim 12, wherein 10% to 70% of the flow entering the inhaler transits through the container prior to merging with the flow path.

14. An inhalation system for delivering a dry powder medicament to a patient, comprising a dry powder inhaler comprising a container region and a container;

said dry powder inhaler and container combined are configured to have rigid flow conduits in a dosing configuration and a plurality of structural regions that provide a mechanisms for powder de-agglomeration of the inhalation system in use;

wherein at least one of the plurality of mechanisms for de-agglomeration is an agglomerate size exclusion aperture in the container region having a smallest dimension less than 3 mm.

16. The inhalation system of claim 14 or 15, wherein the container further comprises one of the mechanisms for de-agglomeration which is a cup-like structure configured to guide a flow entering the container to lift and circulate a powder medicament prior to exiting the container.

17. The inhalation system of claim 16, wherein the cup-like structure has one or more radii configured to prevent flow stagnation.

15. An inhalation system for delivering a dry powder medicament to a patient, comprising a dry powder inhaler comprising a mouthpiece and a container;

said dry powder inhaler and container combined are configured to have rigid flow conduits in a dosing configuration and a plurality of structural regions that provide a mechanisms for powder de-agglomeration of the inhalation system in use;

wherein at least one of the plurality of mechanisms for de-agglomeration is an air conduit configured in the mouthpiece which directs flow at an exit aperture in fluid communication with the container.

18. A method of de-agglomerating a powder medicament in a dry powder inhalation system, comprising:

providing the dry powder medicament in a container having an internal volume to a dry powder inhaler;

allowing a flow to enter said container which is configured to direct a flow to lift, entrain and circulate the dry powder medicament until the powder medicament comprises individual particle and particle aggregates sufficiently small to pass through one or more dispensing apertures into a mouthpiece.

19. The method of claim 18, further comprising the step of accelerating the powder particles and/or particle aggregates entrained in the flow leaving the one or more dispensing apertures and entering the mouthpiece.

20. A method of treatment using a dry powder medicament to be delivered to the pulmonary tract with a dry powder inhalation system, comprising:

obtaining a dry powder inhaler in a closed position and having a mouthpiece;

obtaining a cartridge comprising a pre-metered dose of a dry powder medicament in a containment configuration;

opening the dry powder inhaler to load the cartridge;

closing the inhaler to effectuate movement of the cartridge to a dosing position;

placing the mouthpiece in one'"'"'s mouth, and

inhaling once through the mouthpiece to deliver the dry powder medicament.

21. The method of claim 20, wherein the system of the dry powder inhaler and the cartridge have a resistance value ranging from 0.065 to about 0.200 (√

kPa)/liter per minute.

22. An inhalation system, comprising:

a dry powder inhaler;

a cartridge comprising a top and a container;

wherein the top and the container are moveable relative to one another and configurable to a containment position and to a dosing position, and in the dosing position, the cartridge and the inhaler form a rigid flow conduit for a gas to flow through the cartridge and said rigid flow conduit is substantially perpendicular to a flow conduit in the mouthpiece.

23. An inhalation system, comprising:

a dry powder inhaler;

a cartridge comprising a top and a container;

wherein the top and the container are moveable relative to one another and configurable to a containment position to a dosing position, with an internal volume to contain a dry powder medicament and having at least one air inlet port to allow ambient air to flow into the internal volume and at least one air outlet having a flow direction which allows airflow containing medicament to exit or flow out of the internal volume, and

a housing in which to mount said cartridge and defining two flow pathways, a flow pathway allowing air to enter the at least one air inlet of the cartridge;

wherein an airflow entering the cartridge air inlet is directed across the air outlet ports within the internal volume to meter the medicament leaving the cartridge; and

wherein airflow bypassing the cartridge air inlet is directed to impinge upon the airflow exiting the cartridge substantially perpendicular to the air outlet flow direction.

24. A method for de-agglomerating and dispersing a dry powder medicament for inhalation, comprising the steps of:

generating an airflow in a dry powder inhaler comprising a mouthpiece and a container having at least one inlet port and at least one dispensing port and containing a dry powder medicament;

said container forming an air conduit between the at least one inlet port and the at least one dispensing port and said

inlet port directs a portion of the airflow entering said container at the at least one dispensing port;

allowing airflow to circulate powder within the container so as to lift and mix the dry powder medicament in the container to form an airflow medicament mixture; and

accelerating the airflow exiting the container through the at least one dispensing port.

25. A dry powder inhalation system comprising a dry powder inhaler comprising a mouthpiece and a container to enclose a dry powder medicament comprising diketopiperazine particles;

wherein in use at a pressure differential of 4 kPa, the diketopiperazine particles emitted from the mouthpiece have a volumetric median geometric diameter of less than 7 μ

m as measured by geometric size distribution analysis.

26. The dry powder inhalation system of claim 25, wherein the diketopiperizine particles have a Carr'"'"'s index of 16 to 50.

27. The dry powder inhalation system of claim 25, wherein the diketopiperizine particles are composed of FDKP crystals wherein the ratio of FDKP isomers is in the range of 50% to 65% trans:

cis.

28. The dry powder inhalation system of claim 25, wherein the diketopiperizine particles are composed of FDKP crystals having a specific surface area ranging from 45 to 65 cm²/g.

29. A system for the delivery of an inhalable dry powder comprising:

a) a cohesive powder comprising a medicament, and

b) an inhaler comprising a powder containing cartridge, the cartridge defining an internal volume and comprising at least one inlet aperture and at least one outlet aperture wherein the at least one inlet aperture and the at least one outlet aperture are positioned so that a flow into the internal volume through the at least one inlet aperture is directed at the at least one outlet aperture.

30. The system of claim 29, wherein the cohesive powder has a Carr'"'"'s index of from 16 to 50.

31. The system of claim 29, wherein the cohesive powder has an angle of repose from 30°

to 55°

.

32. The system of claim 29, wherein the cohesive powder is characterized by a critical orifice dimension of ≦

3.2 feet for funnel flow or ≦

2.4 feet for mass flow.

33. The system of claim 29, wherein the cohesive powder comprises particles composed of FDKP crystals wherein the content of FDKP isomers is in the range of 50% to 65% trans:

cis.

34. The system of claim 29, wherein the cohesive powder comprises particles comprising DKP crystals having a specific surface area ranging between 35 and 67 m²/g.

35. The system of claim 29, wherein the medicament comprises insulin.

36. The system of claim 29, wherein the inhaler comprises a mouthpiece and upon applying a pressure drop of ≧

2 kPa across the inhaler a plume of particles is emitted from the mouthpiece and wherein 50% of said emitted particles have a VMGD of ≦

10 microns.

37. The system of claim 29, wherein the cohesive powder has a rugosity >

6.