Compositions For the Treatment of Diabetes

• US 20090258818A1
• Filed: 04/07/2009
• Published: 10/15/2009
• Est. Priority Date: 04/07/2008
• Status: Active Grant

• Current Assignee: Extended Delivery Pharmaceuticals
• Original Assignee: National Institute Of Immunology (Government of India), Indian Institute of Science
• Inventors: Singh, Mahendra Pal, Surolia, Avadhesha, Chattopadhyay, Tandrika, Gupta, Sarika
• Granted Patent: US 8,426,362 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 of the pancreatic hormones

Abstract

A supramolecular insulin assembly and supramolecular exendin-4 assembly, which is useful as a protein therapeutic agent for the treatment of metabolic disorders particularly diabetes. The supramolecular assemblies disclosed in the present invention consists of insoluble and aggregated oligomers the protein. The invention also provides pharmaceutical compositions comprising the supramolecular assembly.

Claims

1. A supramolecular insulin assembly (SIA) useful as protein therapeutics for the treatment of metabolic disorders selected from the group consisting of type 1, type 2 diabetes mellitus and complications thereof, wherein said assembly comprises insoluble and aggregated oligomeric form of insulin.

2. The supramolecular insulin assembly (SIA) as claimed in claim 1, wherein said assembly comprises insoluble and aggregated oligomeric form of insulin as SIA I, SIA II, SIA III or combination thereof, wherein SIA I consists of elongated clusters having pearl like arrangement of insulin monomer, SIA II consists of linear association of elongated clusters having pearl like arrangement of insulin monomer and SIA III consists of about 90% SIA-Il, that is a dense, linear association of insulin oligomers.

3. The supramolecular insulin assembly (SIA) as claimed in claim 1, wherein said assembly comprises insoluble and aggregated oligomeric form of insulin as SIA I, wherein SIA I consists of elongated clusters having pearl like arrangement of insulin monomer.

4. The supramolecular insulin assembly (SIA) as claimed in claim 1, wherein said assembly comprises insoluble and aggregated oligomeric form of insulin as SIA II, wherein SIA II consists of linear association of elongated clusters having pearl like arrangement of insulin monomer.

5. The supramolecular insulin assembly (SIA) as claimed in claim 1, wherein said assembly comprises insoluble and aggregated oligomeric form of insulin as SIA III, wherein SIA III consists dense, linear association of insulin oligomers.

6. The supramolecular insulin assembly (SIA) as claimed in claim 1, wherein said insulin is recombinant human insulin, bovine or pig insulin, or mutants/analogs of insulin.

7. The supramolecular insulin assembly (SIA) as claimed in claim 1 wherein said assembly releases insulin at a rate ranging from 0.1 to 5.4 ng/ml, wherein rate of release of insulin is in the range of for about 7 to 180 days, in vivo.

8. The supramolecular insulin assembly (SIA) as claimed in claim 3, wherein said assembly releases insulin at a rate ranging from 4-5.4 ng/ml for at least 7-10 days.

9. The supramolecular insulin assembly (SIA) as claimed in claim 4, wherein said assembly releases insulin at a rate ranging from 0.5-1.8 ng/ml for at least 160 days.

10. The supramolecular insulin assembly (SIA) as claimed in claim 5, wherein said assembly releases insulin at a rate ranging from 0.1-0.7 ng/ml for at least 180 days.

11. The supramolecular insulin assembly (SIA) as claimed in claim 4, wherein said assembly upon administration to diabetic subjects maintains near-normoglycemic level (120±

30 mg/dl) for at least 160 days in a subject in need thereof.

12. The supramolecular insulin assembly (SIA) as claimed claim 1, wherein a single dose of said assembly upon administration maintains near-normoglycemic level (120±

30 mg/dl) for at least 7 to 180 days in a subject in need thereof, wherein concentration of said assembly in said dose is in the range of 0.125 to 3.75 mg/kg body weight.

13. The supramolecular insulin assembly (SIA) as claimed in claim 1, wherein a single dose of said assembly upon administration maintains near-normoglycemic level (120±

30 mg/dl) for at least 160 days in a subject in need thereof, wherein concentration of said assembly in said dose is in the range of 0.75 to 1.25 mg/kg body weight

15. The supramolecular insulin assembly as claimed in claim 1 is a non cytotoxic, non immunogenic, non-apoptotic and non-mitogenic prodrug.

17. A pharmaceutical composition for the treatment of metabolic disorders selected from the group consisting of type 1, type 2 diabetes mellitus and complications thereof, said composition comprising therapeutically effective amount of the supramolecular insulin assembly (SIA) of claim 1.

18. A pharmaceutical composition for the treatment of metabolic disorders selected from the group consisting of type 1, type 2 diabetes mellitus and complications thereof, said composition comprising therapeutically effective amount of the supramolecular insulin assembly (SIA) of claim 1 and supramolecular exendin-4 assembly (SEA) as claimed in claim 14.

19. The pharmaceutical composition as claimed in claim 17 further comprising pharmaceutically acceptable carriers, additives or diluents.

20. The pharmaceutical composition as claimed in claim 18 further comprising pharmaceutically acceptable carriers, additives or diluents.

21. The pharmaceutical composition as claimed in claim 17 in a form suitable for administration intramuscularly, intradermally or subcutaneously.

22. The pharmaceutical composition as claimed in claim 18 in a form suitable for administration intramuscularly, intradermally or subcutaneously.

23. The pharmaceutical composition as claimed in claim 17, wherein said composition is administered through a device capable of releasing the said composition, wherein said device is selected from a group consisting of pumps, catheters, patches and implants.

24. The pharmaceutical composition as claimed in claim 18, wherein said composition is administered through a device capable of releasing the said composition, wherein said device is selected from a group consisting of pumps, catheters, patches and implants

25. A process of preparation of supramolecular insulin assembly (SIA) as claimed in claim 1, said process comprising;

a. dissolving insulin at a temperature of about 25 to 60°

C. in a solution having pH in the range of about 1.5 to 7.8; and

b. incubating the above for a period of about 6 to 48 hours with constant shaking to obtain Supramolecular Insulin Assembly (SIA), wherein SIA comprises insoluble and aggregated oligomeric form of insulin.

26. The process as claimed in claim 25, wherein said process further comprises

a washing said SIA with PBS;

and

b re-suspending said SIA in PBS

27. The process as claimed in claim 25, wherein said period is about 8 to 12 hours preferably 10 hours.

31. The process as claimed in claim 25, wherein the solution is selected from hydrochloric or acetic acid in water having pH in the range of about 1.5 to 2.5;

sodium acetate buffer having pH in the range of about 3.5 to 5.5;

phosphate buffer (PBS) having pH 6 to 7.8, and citrate buffer having pH in the range of about 4 to 6.

33. The process as claimed in claim 25, wherein said temperature is 37°

C.

36. The process as claimed in claim 25, wherein said period is 6-192 hours.

39. A method for treating metabolic disorders selected from the group consisting of type 1, type 2 diabetes mellitus and complications thereof, wherein said method comprising

administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition comprising the supramolecular insulin assembly as claimed in claim 17 which is effective for the alleviation of said disorder.

40. A method for treating metabolic disorders selected from the group consisting of type 1, type 2 diabetes mellitus and complications thereof, wherein said method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition comprising the supramolecular insulin assembly as claimed in claim 18, which is effective for the alleviation of said disorder.

14. A supramolecular exendin-4 assembly (SEA) useful as protein therapeutics for the treatment of diabetes, wherein said assembly comprises insoluble and aggregated oligomeric form of exendin-4.

16. The supramolecular exendin-4 assembly as claimed in claim 14 is a non cytotoxic, non immunogenic, non-apoptotic and non-mitogenic prodrug.

28. A process of preparation of supramolecular exendin-4 assembly as claimed in claim 14, said process comprising;

a. dissolving exendin-4 at a temperature of about 25 to 60°

C. in a solution having pH in the range of about 2.0 to 7.6; and

b. incubating the above for a period of 6 to 192 hours with constant shaking to obtain Supramolecular Exendin-4 Assembly (SEA), wherein SEA comprises insoluble and aggregated oligomeric form of Exendin-4.

29. The process as claimed in claim 28, wherein said process further comprises

a. washing said SEA with PBS;

and

b. re-suspending said SEA in PBS.

30. The process as claimed in claim 28, wherein said period is 148 hours.

32. The process as claimed in claim 28, wherein the solution is selected hydrochloric or acetic acid in water having pH in the range of about 1.5 to 2.5;

sodium acetate buffer having pH in the range of about 3.5 to 5.5;

phosphate buffer (PBS) having pH 6 to 7.8, and citrate buffer having pH in the range of about 4 to 6.

34. The process as claimed in claim 28, wherein said temperature is 37°

C.

35. The process as claimed in claim 28, wherein pH of said solution is 6.8 to 7.4 preferably 7.2.

37. The process as claimed in claim 28, wherein pH of said solution is 6.8 to 7.4 preferably 7.2.

38. The process as claimed in claim 28, wherein said period is 6-192 hours.