METHOD OF PREVENTING ADVERSE EFFECTS BY GLP-1

• US 20090110647A1
• Filed: 10/24/2008
• Published: 04/30/2009
• Est. Priority Date: 10/24/2007
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Richardson, Peter, Baughman, Robert A., Costello, Donald
• Granted Patent: US 8,377,869 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61M 15/00 Inhalators drug delivery in endotracheal tubes A61M16/04
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

A method for preventing or reducing adverse effects such as profuse sweating, nausea and vomiting, which normally are associated with subcutaneous and intravenous administration of glucagon-like peptide 1 (GLP-1) therapy is provided. In particular, the method comprises the rapid administration of a GLP-1 formulation into the pulmonary circulation such as by inhalation, directly into pulmonary alveolar capillaries using a dry powder drug delivery system.

Claims

1. A method for the treatment of hyperglycemia and/or diabetes in a patient, comprising the step of administering prandially to a patient in need of treatment an inhalable dry powder formulation, comprising a therapeutically effective amount of a GLP-1 molecule;

wherein said administration does not result in at least one side effect selected from the group consisting of nausea, vomiting and profuse sweating.

2. The method of claim 1, wherein the patient is a mammal suffering with Type 2 diabetes mellitus.

3. The method of claim 1, wherein the GLP-1 formulation comprises about 0.5 mg to about 3 mg of GLP-1 in the formulation.

4. The method of claim 1, wherein the inhalable dry powder formulation further comprises a DPP-IV inhibitor.

5. The method of claim 1, wherein the inhalable dry powder formulation comprises a diketopiperazine.

6. The method of claim 5, wherein the 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.

7. The method of claim 1, wherein the GLP-1 molecule is selected from the group consisting of a native GLP-1, a GLP-1 metabolite, a GLP-1 analog, a GLP-1 derivative, a long acting GLP-1 analog, a GLP-1 mimetic, an exendin, a GLP-1 peptide analog, or a biosynthetic GLP-1 analog, or combinations thereof.

8. The method of claim 1, further comprising administering to a patient a therapeutically amount of an insulin molecule.

9. The method of claim 8, wherein the inhalable dry powder formulation comprises the GLP-1 molecule co-formulated with the insulin molecule.

10. The method of claim 8, wherein the insulin molecule is administered separately as an inhalable dry powder formulation.

11. The method of claim 1, wherein the inhalable dry powder formulation lacks inhibition of gastric emptying.

12. A kit for the treatment of diabetes and/or hyperglycemia comprising:

a) a medicament cartridge operably configured to fit into a dry powder inhaler and containing a dry powder formulation comprises a GLP-1 molecule, and a diketopiperazine of the formula;

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 salt thereof, and

b) an inhalation device operably configured to receive/hold and securely engage said cartridge.

14. The method of claim 12, wherein the glucose levels are reduced by from about 0.1 mmol/L to about 3 mmol/L for a period of approximately four hours after administration of said inhalable formulation to said patient.

15. The method of claim 12, wherein the inhalable formulation is administered to said Type 2 diabetic patient prandially, preprandially, prandially, post-prandially or in a fasting state.

16. The method of claim 12, wherein the GLP-1 formulation comprises from about 0.02 mg to about 2 mg of GLP-1 in the formulation.

17. The method of claim 12, wherein the inhalable dry powder formulation further comprises a DPP-IV inhibitor.

18. The method of claim 12, wherein the inhalable dry powder formulation comprises a diketopiperazine.

20. The method of claim 12, wherein the inhalable dry powder formulation comprises the GLP-1 molecule co-formulated with an insulin molecule.

23. The method of claim 12, further comprising administering a formulation comprising a long acting GLP-1 analog.

24. The method of claim 12, wherein the inhalable dry powder formulation lacks inhibition of gastric emptying.

13. A method for reducing glucose levels in a Type 2 diabetic patient suffering with hyperglycemia, the method comprising the step of administering to said patient in need of treatment a dry powder inhalable formulation for pulmonary administration comprising a therapeutically effective amount of GLP-1, and a diketopiperazine or pharmaceutically acceptable salt thereof.

19. The method of claim 19, wherein the 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.

21. The method of claim 19, wherein the method further comprises administering insulin as an inhalable dry powder formulation.

22. The method of claim 21, wherein the insulin is a rapid acting or a long acting insulin.

25. A kit for the treatment of hyperglycemia in a type 2 diabetic patient, which comprises a pulmonary drug delivery system, comprising:

a) a medicament cartridge operably configured to fit into a dry powder inhaler and containing a dry powder formulation comprises a GLP-1 molecule, and a diketopiperazine of the formula;

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 salt thereof, and

b) an inhalation device operably configured to adapt and securely engage said cartridge.