Method of preventing adverse effects by GLP-1

• US 8,377,869 B2
• Filed: 10/24/2008
• Issued: 02/19/2013
• 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
• Primary Examiner(s): Desai, Anand
• Assistant Examiner(s): LIU, SAMUEL W
• Application Number:
  US12/258,340
• Publication Number:
  US 20090110647A1
• Time in Patent Office: 1,579 Days
• Field of Search: None
• US Class Current: 514/2
• 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 or diabetes in a patient, comprising the step of administering prandially to a patient in need of treatment an inhalable rapid-acting dry powder GLP-1 formulation, the dry powder formulation comprising microparticles comprising a therapeutically effective amount of a GLP-1 molecule in an amount of at least about 0.5% by weight and a diketopiperazine, wherein the weight ratio of diketopiperazine to GLP-1 is at least about 17:

3, and a dipeptidyl peptidase-IV (DPP-IV) inhibitor, and wherein the GLP-1 formulation comprises about 0.5 mg to about 3 mg of GLP-1 dose.

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 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.

4. The method of claim 1, wherein the GLP-1 molecule is selected from the group consisting of a native GLP-1, a GLP-1 analog, a GLP-1 derivative, a long acting GLP-1 analog, a GLP-1 mimetic, and combinations thereof.

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

6. The method of claim 5, wherein the inhalable dry powder formulation comprises the GLP-1 molecule co-formulated with the insulin molecule.

7. The method of claim 5, wherein the insulin molecule is administered separately as an inhalable dry powder formulation.

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

9. A method for reducing glucose levels in a Type 2 diabetic patient suffering from hyperglycemia, the method comprising the step of administering to said patient in need of treatment an inhalable rapid-acting dry powder GLP-1 formulation for pulmonary administration, said dry powder inhalable formulation comprising microparticles comprising a therapeutically effective amount of GLP-1 in an amount of at least about 0.5% by weight and a diketopiperazine or pharmaceutically acceptable salt thereof, wherein the weight ratio of diketopiperazine to GLP-1 is at least about 17:

3, and a DPP-IV inhibitor, and wherein the GLP-1 formulation comprises about 0.02 mg to about 2 mg of GLP-1 dose.

10. The method of claim 9, wherein the glucose levels are reduced by 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.

11. The method of claim 9, wherein the inhalable formulation is administered to said Type 2 diabetic patient prandially, preprandially, prandially, post-prandially or in a fasting state.

12. The method of claim 9, 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.

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

14. The method of claim 9, wherein the method further comprises administering insulin as an inhalable dry powder formulation.

15. The method of claim 14, wherein the insulin is a rapid acting or a long acting insulin.

16. The method of claim 9, further comprising administering a formulation comprising a long acting GLP-1 analog.

17. The method of claim 9, wherein the inhalable dry powder formulation lacks inhibition of gastric emptying.

18. A method for the treatment of hyperglycemia or diabetes in a patient, comprising the step of administering prandially to a patient in need thereof an inhalable rapid-acting dry powder GLP-1 formulation, the dry powder formulation comprising microparticles comprising a therapeutically effective amount of a GLP-1 molecule and a diketopiperazine, and a DPP-IV inhibitor;

wherein the weight ratio of diketopiperazine to GLP-1 is at least about 17;

3, wherein said GLP-1 reaches a peak plasma concentration greater than 100 pMol/L by 6 minutes after administration, and wherein the GLP-1 formulation comprises about 0.5 mg to about 3 mg of GLP-1 dose.

19. The method of claim 18, wherein the GLP-1 and the DPP-IV inhibitor are administered in separate compositions.

20. The method of claim 18, wherein the GLP-1 and the DPP-IV inhibitor are administered in a single composition.