Dry powder drug delivery system and methods

• US 9,358,352 B2
• Filed: 06/21/2011
• Issued: 06/07/2016
• Est. Priority Date: 06/13/2008
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Smutney, Chad C., Adamo, Benoit, Polidoro, John M., Kinsey, P. Spencer, Overfield, Dennis, Sahi, Carl, Billings, Christine, Marino, Mark T.
• Primary Examiner(s): Woodward, Valerie L
• Application Number:
  US13/702,024
• Publication Number:
  US 20130104887A1
• Time in Patent Office: 1,813 Days
• US Class Current: 1/1
• CPC Class Codes: A61M 11/06 of the injector type
• CPC Class Codes: A61M 15/0021 Mouthpieces therefor
• CPC Class Codes: A61M 15/0025 with caps
• 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 15/0091 mechanically breath-triggered
• CPC Class Codes: A61M 2202/064 Powder
• CPC Class Codes: A61M 2205/6045 having complementary physical shapes for indexing or registration purposes
• CPC Class Codes: A61M 2205/6081 Colour codes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications

Abstract

A pulmonary drug delivery system is disclosed, including a breath-powered, dry powder inhaler, and a cartridge for delivering a dry powder formulation. The inhaler and cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, including, small organic molecules, peptides and proteins, including, insulin and glucagon-like peptide 1 for the treatment of disease and disorders, for example, endocrine disease such as diabetes and/or obesity.

Claims

1. A dry powder inhaler comprising:

a) a mouthpiece;

b) a housing comprising a cartridge-mounting area and a cartridge, the cartridge comprising a movable container having a dry powder, the container configured to move with respect to the cartridge and the cartridge configured to form a flow path between one or more inlet ports and one or more dispensing ports within the housing; and

c) at least one rigid air conduit;

wherein the rigid air conduit is configured so that the dry powder inhaler emits greater than about 75% of the dry powder from the container oriented in the container housing as powder particles in a single inhalation, and the powder particles emitted have a volumetric median geometric diameter of less than about 5 microns when the single inhalation through the mouthpiece generates a peak inspiratory pressure of about 2 kPa within two seconds.

2. The dry powder inhaler of claim 1 having a resistance value to airflow ranging from about 0.065 (√

kPa)/liter per minute to about 0.200 (√

kPa)/liter per minute.

3. The dry powder inhaler of claim 1, wherein the dry powder is a formulation for pulmonary delivery and comprises an amount from about 1 mg to about 30 mg of the dry powder.

4. The dry powder inhaler of claim 1, wherein the dry powder comprises a diketopiperazine or a pharmaceutically acceptable salt thereof.

5. The dry powder inhaler of claim 4, wherein the diketopiperazine is of the formula 2,5-diketo-3,6-bis(N—

X-4-aminobutyl)piperazine,

wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, and glutaryl.

6. The dry powder inhaler of claim 5, wherein the diketopiperazine is

7. The dry powder inhaler of claim 1, wherein the dry powder comprises a drug or an active agent.

8. The dry powder inhaler of claim 7, wherein the active agent is an endocrine hormone.

9. The dry powder inhaler of claim 1, wherein the dry powder comprises a peptide, a polypeptide, or fragments thereof, a small organic molecule or a nucleic acid molecule.

10. The dry powder inhaler of claim 9, wherein said peptide is insulin, glucagon, glucagon-like peptide-1, parathyroid hormone, oxytocin, oxyntomodulin, peptide YY, an exendin, analogs thereof or fragments thereof.

11. The dry powder inhaler of claim 9, wherein the small organic molecule is a vasodialator, a vasoconstrictor, a neurotransmitter agonist or a neurotransmitter antagonist.

12. The dry powder inhaler of claim 1, wherein the single inhalation generates an area under the curve (AUC) from a pressure versus time curve within one second of at least about 1.0, 1.1 or 1.2 kPa*sec.

13. The dry powder inhaler of claim 1, wherein the container is integrated into the container housing and filled with a dry powder.

14. A method of delivering of a dry powder using a high resistance dry powder inhaler comprising:

providing a dry powder inhaler with an airflow resistance value ranging from about 0.065 (√

kPa)/liter per minute to about 0.200 (√

kPa)/liter per minute, and containing the dose of the dry powder within cartridge comprising a container configured to move with respect to the cartridge to form a flow path for the delivery of the dry powder;

applying sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and

generating an area under the curve in the first second (AUC0-1 sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec;

wherein greater than 75% of the dose of the dry powder is discharged or emitted from the inhaler as powder particles.

15. The method of claim 14, wherein the dry powder is a formulation for pulmonary delivery and comprises an amount from about 1 mg to about 30 mg of the dry powder.

16. The method of claim 15, wherein the dry powder comprises a diketopiperazine or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein the diketopiperazine is of the formula 3,6-bis(N—

X-4-aminobutyl)-2,5-diketopiperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, and glutaryl.

18. The method of claim 17, wherein the diketopiperazine is

19. The method of claim 18, wherein the dry powder formulation comprises fumaryl diketopiperazine microparticles which upon discharge from the dry powder inhaler are measured to have a volumetric median geometric diameter (VMGD) ranging from about 2 μ

m to 8 μ

m and a geometric standard deviation of less than 4 μ

m.

20. The method of claim 14, wherein the dry powder formulation comprises a drug or an active agent selected from the group consisting of a small organic molecule, peptide, polypeptide, a protein, or a nucleic acid molecule.

21. The method of claim 20, wherein the small organic molecule is a vasoactive agent, a neurotransmitter agonist, a neurotransmitter antagonist, or a steroid molecule.