TEMPERATURE SENSITIVE HYDROGEL AND BLOCK COPOLYMERS

• US 20120164100A1
• Filed: 11/02/2011
• Published: 06/28/2012
• Est. Priority Date: 11/02/2010
• Status: Abandoned Application

• Current Assignee: University Health Network
• Original Assignee: University Health Network
• Inventors: Li, Ren-Ke, Zeng, Faquan
• Application Number:
  US13/287,808
• Publication Number:
  US 20120164100A1
• Time in Patent Office: Days
• US Class Current: 424/85.2
• 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: C08G 63/664 derived from hydroxy carboxylic acids

Abstract

The present disclosure provides temperature sensitive hydrogels and block copolymers, processes for the production thereof, and therapeutic and research compositions employing these copolymers.

Claims

1. A block copolymer comprising at least one A block and at least one B block, wherein the block copolymer has the formula:

A-B;

A-B-A;

or

B-A-B;

wherein the A block comprises poly(δ

-valerolactone), poly(ε

-caprolactone), poly(lactide), poly(α

-hydroxy acid), poly(glycolide), polyanhydride, polyester, polyorthoester, polyetherester, polyesteramide, polycarbonate, polycyanoacrylate, polyurethane, polyacrylate, or a co-polymer thereof, all of which are optionally substituted;

wherein the B block comprises polyethylene glycol or polypropylene glycol, both of which are optionally substituted;

wherein the A block has a number average molecular weight between 500 and 30,000 and the B block has a number average molecular weight between 500 and 10,000;

wherein the optional substituents are selected from halo, OH, (C_1-6)-alkyl and fluoro-substituted (C_1-6)-alkyl; and

wherein the block copolymer forms a hydrogel at a temperature of above about 30°

C.

2. The block copolymer of claim 1, wherein the A block has a number average molecular weight between 500 and 10,000.

3. The block copolymer of claim 1, wherein the B block has a number average molecular weight of between 1,000 and 8,000.

4. The block copolymer of claim 1, wherein the block copolymer has the formula:

A-B-A.

5. The block copolymer of claim 1, wherein the A block is a poly(δ

-valerolactone), poly(ε

-caprolactone), poly(lactide), poly(α

-hydroxy acid), poly(glycolide) or a copolymer thereof.

6. The block copolymer of claim 1, wherein the A block comprises poly(δ

-valerolactone) or poly(ε

-caprolactone).

7. The block copolymer of claim 1, wherein the A block comprises poly(δ

-valerolactone).

8. The block copolymer of claim 1, wherein the B block comprises polyethylene glycol.

9. The block copolymer of claim 1, wherein the block copolymer comprises

10. The block copolymer of claim 1, wherein the molecular weight ratio of A to B is between about 1.05 and about 1.35.

11. The block copolymer of claim 1, wherein the molecular weight ratio of A to B is between about 1.15 and about 1.25.

12. The block copolymer of claim 1, wherein the molecular weight ratio of A to B is about 1.2.

13. The block copolymer of claim 1, wherein the block copolymer has the formula A-B-A, wherein the A block has a number average molecular weight of about 1200 and the B block has a number average molecular weight of about 1000.

14. The block copolymer of claim 1, wherein the block copolymer has the formula A-B-A, wherein the A block has a number average molecular weight of about 1800 and the B block has a number average molecular weight of about 1500.

15. The block copolymer of claim 1, wherein the block copolymer has the formula A-B-A, wherein the A block has a number average molecular weight of about 6000 and the B block has a number average molecular weight of about 5000.

16. The block copolymer of claim 1, wherein the block copolymer has the formula A-B-A, wherein the A block has a number average molecular weight of about 9600 and the B block has a number average molecular weight of about 8000.

23. A pharmaceutical composition comprising a block copolymer as defined in claim 1 and a therapeutic compound, wherein the therapeutic compound is conjugated to the copolymer.

24. The pharmaceutical composition of claim 23, wherein the therapeutic compound is a biologic.

25. The pharmaceutical composition of claim 23, wherein the biologic is stem cell factor (SCF) or vascular endothelial growth factor (VEGF).

26. A method for the treatment of cardiac abnormality and/or vascular abnormality in a patient in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition as defined in claim 23 to the site of the cardiovascular defect.

27. The method of claim 26 wherein the cardiac abnormality is myocardial infarction.

28. The method of claim 26 wherein the vascular abnormality is a vascular aneurysm.

29. A pharmaceutical composition comprising a block copolymer as defined in claim 1, a therapeutic compound and transplant cells.

30. The pharmaceutical composition of claim 29, wherein the therapeutic compound is an immunosuppressant.

31. The pharmaceutical composition of claim 29, wherein the therapeutic compound is selected from the group consisting of PGE2, interleukins, cyclosporin, cyclophosphamide, FK506, rapamycin, corticosteroids, mycophenolate mofetil, leflunomide, deoxyspergualin, azathioprine, and OKT-3.

32. A method for treating or preventing cell transplant rejection in a patient in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition as defined in claim 29.

33. The method of claim 32 wherein the therapeutically effective amount of the pharmaceutical composition is an amount effective to inhibit a T-cell mediated immune response in the patient to the transplanted cells.

34. The method of claim 32, wherein the cell transplant is autologous, homologus (allogenic) or xenogenic to the patient.

35. The method of claim 32, wherein the cell transplant comprises bone marrow cells.

39. A method for establishing tumor or cancer cells in a host comprising:

preparing a mixture of a block copolymer of claim 1 and the cells;

administering the mixture to the host; and

growing the cells in the host;

wherein the mixture forms a temperature sensitive hydrogel upon administration to the host.

40. The method of claim 39, wherein the mixture further comprises a therapeutic compound.

41. The method of claim 39, wherein the mixture further comprises a growth factor or an immunosuppressant.

17. A process for the preparation of a block copolymer comprising at least one A block and at least one B block having the formula A-B, A-B-A, or B-A-B, the process comprising reacting

(i) polyethylene glycol or polypropylene glycol comprising the B block, both of which are optionally substituted;

with,

(ii) monomeric units of the A block, the monomeric units comprising δ

-valerolactone, ε

-caprolactone, lactide, an α

-hydroxy acid, glycolic acid, an anhydride, an ester, an orthoester, an etherester, an esteramide, a carbonate, a cyanoacrylate, a urethane, an acrylate, or a mixture thereof, all of which are optionally substituted, wherein the optional substituents are selected from halo, OH, (C_1-6)-alkyl and fluoro-substituted (C_1-6)-alkyl;

in the presence of an acid catalyst having a pKa of less than −

12, and wherein the process is optionally performed at a temperature between −

10°

C. and 35°

C.

18. The process of claim 17, wherein the number average molecular weight of the A block is controlled by the molar ratio of the monomeric units of the A block to the B block.

19. The process of claim 17, wherein the A block has a number average molecular weight between 500 and 30,000 and the B block has a number average molecular weight between 500 and 10,000.

20. The process of claim 17, wherein the acid catalyst is a sulfonic acid.

21. The process of claim 17, wherein the acid catalyst is trifluoromethanesulfonic acid or fluorosulfonic acid.

22. A block copolymer comprising at least one A block and at least one B block, wherein the block copolymer has the formula:

A-B;

A-B-A;

or

B-A-B;

produced by the process as defined in claim 17.

36. A block copolymer comprising at least one A block and at least one B block, wherein the block copolymer has the formula:

A-B-A

wherein the A block comprises poly(δ

-valerolactone) or poly(ε

-caprolactone), or a co-polymer thereof, all of which are optionally substituted;

wherein the B block comprises polyethylene glycol, which is optionally substituted;

wherein the A block has a number average molecular weight between 500 and 10,000 and the B block has a number average molecular weight between 1,000 and 8,000;

wherein the molecular weight ratio of A to B is between about 1.15 and about 1.25;

wherein the optional substituents are selected from halo, OH, (C_1-5)-alkyl and fluoro-substituted (C_1-6)-alkyl;

wherein the polymer is further functionalized with a vascular growth agent, and

wherein the block copolymer forms a hydrogel at a temperature of above about 30°

C.

37. A temperature sensitive injectable hydrogel formulation for use in treating a vascular abnormality, the hydrogel formulation comprising:

a triblock polymer comprising blocks of biodegradable polymer having substantially equal number average molecular weights such that a honeycomb structure is formed above 30°

C. with a pore size of about 1 μ

m,

and a vascular growth agent conjugated to the polymer,

wherein the formulation is injectable at ambient temperature, gels at body temperature, and substantially or completely degrades within 2 months.

38. A method for treating a vascular abnormality comprising:

administering the temperature sensitive hydrogel formulation of claim 37 to a site of vascular abnormality, such that the vascular abnormality is treated.