Methods of treating diabetes mellitus

• US 20060100137A1
• Filed: 12/21/2005
• Published: 05/11/2006
• Est. Priority Date: 02/15/2001
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Odenbaugh, Amy L., Price, Christopher H., Still, James Gordon, Ansari, Aslam M., Filbey, Jennifer Ann
• Granted Patent: US 7,423,014 B2
• Time in Patent Office: Days
• US Class Current: 514/6.200
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Methods of treating diabetes mellitus in a patient in need of such treatment include administering an effective amount of an insulin drug to the patient in order to treat diabetes mellitus in the patient. Methods according to the present invention may “activate” the liver, potentially restoring normal glucose homeostasis to individuals suffering from diabetes mellitus.

Claims

1. An insulin polypeptide-oligomer conjugate comprising the structure of Formula V:

2. The insulin polypeptide-oligomer conjugate of claim 1 wherein upon administration to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient wherein the effective amount of the conjugate of Formula V is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.

3. The insulin polypeptide-oligomer conjugate of claim 2 wherein the oral administration of the effective amount of the conjugate of Formula V provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/mi within about 30 minutes of administration.

4. The insulin polypeptide-oligomer conjugate of claim 2 wherein the effective amount of the conjugate of Formula V is between about 0.05 and 10 mg per kilogram body weight.

5. The insulin polypeptide-oligomer conjugate of claim 2 wherein the oral administration of the effective amount of the conjugate of Formula V provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.

6. The insulin polypeptide-oligomer conjugate of claim 2 wherein the oral administration of the effective amount of the conjugate of Formula V stabilizes peripheral glucose concentration to within about +/−

50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.

7. The insulin polypeptide-oligomer conjugate of claim 2 wherein the conjugate of Formula V clears the bloodstream of the patient within about 4 hours following administration.

8. The insulin polypeptide-oligomer conjugate of claim 2 wherein the administration of the effective amount of the conjugate of Formula V reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.

9. The insulin polypeptide-oligomer conjugate of claim 2 wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.

10. The insulin polypeptide-oligomer conjugate of claim 2 wherein when the conjugate of Formula V is orally administered at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.

11. The insulin polypeptide-oligomer conjugate of claim 2 wherein the insulin drug concentration occurs when the conjugate of Formula V is orally administered less than about one hour prior to ingestion of a meal by the patient.

12. The insulin polypeptide-oligomer conjugate of claim 2 wherein the insulin drug concentration occurs when the conjugate of Formula V is orally administered substantially contemporaneously with the ingestion of a meal by the patient.

13. The insulin polypeptide-oligomer conjugate of claim 2 wherein the insulin drug concentration occurs when the conjugate of Formula V is orally administered less than one about hour after ingestion of a meal by the patient.

14. The insulin polypeptide-oligomer conjugate of claim 5 wherein the insulin polypeptide is insulin.

15. The insulin polypeptide-oligomer conjugate of claim 1 wherein the oligomer is coupled to the lysine at the B29 position of the insulin.

16. The insulin polypeptide-oligomer conjugate of claim 1 wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly^A21 insulin, human;

Gly^A21 Gln^B3 insulin, human;

Ala^A21 insulin, human;

Ala^A21 Gln^B3 insulin, human;

Gln^B3 insulin, human;

Gln^B30 insulin, human;

Gly^A21 Glu^B30 insulin, human;

Gly^A21 Gln^B3 Glu^B30 insulin, human;

Gln^B3 Glu^B30 insulin, human;

Asp^B28 insulin, human;

Lys^B28 insulin, human;

Leu^B28 insulin, human;

Val^B28 insulin, human;

Ala^B28 insulin, human;

Asp^B28 Pro^B29 insulin, human;

Lys^B28 Pro^B29 insulin, human;

Leu^B28 Pro^B29 insulin, human;

Val^B28 Pro^B29 insulin, human;

Ala^B28 Pro^B29 insulin, human.

17. A composition comprising the insulin polypeptide-oligomer conjugate of claim 1 wherein the conjugate of Formula V is present as a substantially monodispersed mixture.

18. A composition comprising the insulin polypeptide-oligomer conjugate of claim 1 wherein the conjugate of claim 1 wherein the conjugate of Formula V is present as a monodispersed mixture.

19. A composition comprising the insulin polypeptide-oligomer conjugate of claim 1 wherein the conjugate of Formula V is amphiphilically balanced.

20. A composition comprising the insulin polypeptide-oligomer conjugate of claim 1 wherein the composition is a pharmaceutical composition.