Diketopiperazine microparticles with defined specific surface areas

• US 8,778,403 B2
• Filed: 09/03/2013
• Issued: 07/15/2014
• Est. Priority Date: 06/12/2009
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Grant, Marshall L., Stowell, Grayson W., Menkin, Paul
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): FALKOWITZ, ANNA R
• Application Number:
  US14/017,143
• Publication Number:
  US 20140045745A1
• Time in Patent Office: 315 Days
• Field of Search: 424/489, 424/400, 514/252.16, 514/262.1, 514/6.5, 514/11.8, 514/11.9, 514/11.7, 514/9.7
• US Class Current: 424/489
• 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 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• 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 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• 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 15/0091 mechanically breath-triggered
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

Disclosed herein are diketopiperazine microparticles having a specific surface area of less than about 67 m²/g. The diketopiperazine microparticle can be fumaryl diketopiperazine and can comprise a drug such as insulin.

Claims

1. A method of delivering an active agent to a patient in need thereof comprising administering a dry powder comprising microparticles of a diketopiperazine, the microparticles having a specific surface area of about 40 m²/g to 67 m²/g, the microparticles having been loaded with a drug or active agent, by inhalation of said dry powder by said patient.

2. The method of claim 1, wherein the active agent is an endocrine hormone selected from the group consisting of insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide-1, oxyntomodulin, and an analog or active fragment of said endocrine hormone.

3. The method of claim 1, wherein the patient has been diagnosed with diabetes.

4. The method of claim 1, wherein said diketopiperazine is 2,5-diketo-3,6-bis(N-fumaryl-4-amino-butyl)piperazine.

5. An inhalation system comprising a breath powered inhaler and a dry powder comprising microparticles of a diketopiperazine, the microparticles having a specific surface area of about 40 m²/g to 67 m²/g.

6. The inhalation system of claim 5, wherein said diketopiperazine is 2,5-diketo-3,6-bis(N-fumaryl-4-amino-butyl)piperazine.

7. The inhalation system of claim 5 wherein said dry powder is provided in a unit dose cartridge.

8. The inhalation system of claim 5 wherein said dry powder is provided prefilled in the inhaler.

9. The inhalation system of claim 5 wherein said inhaler has a resistance to flow of about 0.065 (√

kPa)/liter per minute to 0.200 (√

kPa)/liter per minute.

10. The inhalation system of claim 5 wherein said inhaler has a flow path passing through an area of powder containment and a flow path bypassing said area of powder containment, wherein in use 10-70% of the total flow existing the inhaler passes through said area of powder containment and 90-30% of the total flow existing the inhaler bypasses said area of powder containment.

11. The inhalation system of claim 10, said inhaler having a mouthpiece, wherein said flow through the powder containment area and said flow bypassing the powder containment area combine prior to exiting the mouthpiece.

12. The inhalation system of claim 5 comprising 1 to 30 mg of said dry powder.

13. The inhalation system of claim 12, wherein greater than 75% of the powder is dispensed when the flow rate through the inhaler is from 7 to 70 liters per minute.

14. The inhalation system of claim 13 wherein greater than 85% of the powder is dispensed.

15. The inhalation system of claim 5 wherein respirable fraction/fill is greater than 40%.

16. The inhalation system of claim 15 wherein respirable fraction/fill is greater than 50%.

17. The inhalation system of claim 15 wherein respirable fraction/fill is greater than 60%.

18. A method of delivering an active agent to a patient in need thereof comprising administering a dry powder using the inhalation system of claim 5, the microparticles having been loaded with a drug or active agent.

19. The inhalation system of claim 5 wherein the active agent comprises an endocrine hormone selected from the group consisting of insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide-1, oxyntomodulin, an analog or active fragment of said endocrine hormone.

20. The inhalation system of claim 5 wherein the active agent comprises insulin.