Delivery of active agents

• US 8,372,804 B2
• Filed: 10/24/2008
• Issued: 02/12/2013
• Est. Priority Date: 10/24/2007
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Richardson, Peter, Baughman, Robert A., Leone-Bay, Andrea, Costello, Donald
• Primary Examiner(s): Rao, Manjunath
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US12/258,341
• Publication Number:
  US 20090111749A1
• Time in Patent Office: 1,572 Days
• Field of Search: None
• US Class Current: 514/5.3
• 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 38/26 Glucagons
• 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• 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: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

Abstract

A method of introducing a physiologically-active agent into the circulatory system of a mammal is disclosed herein. The method utilizes a rapid drug delivery system which prevents deactivation or degradation of the active agent being administered to a patient in need of treatment. In particular, the drug delivery system is designed for pulmonary drug delivery such as by inhalation, for delivery of the active agents such as proteins and peptides to the pulmonary circulation in a therapeutically effective manner avoiding degradation of the active agents in peripheral and vascular tissue before reaching the target site.

Claims

1. A method of providing a labile peptide hormone to a patient in need thereof comprising:

administering a suitable pharmaceutical composition comprising microparticles produced from formulation of a diketopiperazine with the labile peptide hormone by pulmonary inhalation;

wherein said labile peptide hormone is subject to degradation in said patient as a result of exposure of said agent to peripheral tissue, vascular venous tissue, or the liver, prior to reaching the agent'"'"'s site of action, wherein the effectiveness of said labile peptide hormone is reduced by said degradation;

wherein said labile peptide hormone is not GLP-1 or insulin; and

wherein about 35% to about 75% of said microparticles have an aerodynamic diameter of less than 5.8 micrometer for said pulmonary inhalation; and

further, wherein the pulmonary inhalation results in a greater therapeutic effect from a lower exposure of said labile peptide hormone than oral, subcutaneous and intravenous administration of said labile peptide hormone.

2. The method of claim 1, wherein said diketopiperazine is 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine;

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

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the pharmaceutical composition is an inhalable dry powder formulation.

4. The method of claim 3, wherein said inhalable dry powder formulation further comprises a pharmaceutically acceptable carrier or excipient.

5. The method of claim 3, wherein the inhalable dry powder formulation is provided to said patient by pulmonary inhalation using a dry powder inhalation system.

6. The method of claim 1, wherein the peptide hormone is an endocrine hormone or an analog thereof.

7. The method of claim 6, wherein the endocrine hormone is a hormone associated with diabetes, hyperglycemia and/or obesity.

8. The method of claim 7, wherein the diabetes is type 2 diabetes mellitus.

9. The method of claim 1 wherein said exposure is a result of subcutaneous administration of said agent.

10. The method of claim 1 wherein said exposure of said agent is in the vascular venous tissue.

11. The method of claim 1 wherein said peptide hormone does not bind to specific receptors in lung tissue.

12. The method of claim 1 wherein said exposure to said labile peptide hormone administered by said pulmonary inhalation is less than about 50% of said exposure to said labile peptide hormone administered by said oral, subcutaneous and intravenous administration.

13. A method of treating a disease comprising:

administering by pulmonary inhalation to a patient with a condition treatable by a labile peptide hormone a pharmaceutical composition comprising said peptide hormone which has been formulated into microparticles comprising a diketopiperazine and said peptide hormone, wherein the pharmaceutical composition is suitable for said pulmonary inhalation, wherein said labile peptide hormone is not GLP-1 or insulin; and

wherein about 35% to about 75% of said microparticles have an aerodynamic diameter of less than 5.8 micrometer for said pulmonary inhalation, and wherein the pulmonary inhalation results in a greater therapeutic effect from a lower exposure of said labile peptide hormone than oral, subcutaneous and intravenous administration of said labile peptide hormone.

14. The method of claim 13, wherein said diketopiperazine is 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine;

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

or a pharmaceutically acceptable salt thereof.

15. The method of claim 13, wherein said composition is an inhalable dry powder formulation.

16. The method of claim 15, wherein said inhalable dry powder formulation further comprises a pharmaceutically acceptable carrier or excipient.

17. The method of claim 13, wherein the peptide hormone is an endocrine hormone or an analog thereof.

18. The method of claim 17, wherein the endocrine hormone is a hormone associated with diabetes, hyperglycemia and/or obesity.

19. The method of claim 18, wherein the diabetes is type 2 diabetes mellitus.

20. The method of claim 13, wherein the step of administering said composition to said patient comprises pulmonary administration of said composition using a dry powder inhaler comprising a cartridge.

21. The method of claim 13 wherein said exposure to said labile peptide hormone administered by said pulmonary inhalation is less than about 50% of said exposure to said labile peptide hormone administered by said oral, subcutaneous and intravenous administration.