Polymeric materials, their preparation and use

• US 20050142152A1
• Filed: 12/30/2004
• Published: 06/30/2005
• Est. Priority Date: 12/30/2003
• Status: Abandoned Application

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Konowicz, Paul A., Leshchiner, Adelya K.
• Application Number:
  US11/026,388
• Publication Number:
  US 20050142152A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Abstract

Disclosed are highly resilient and cohesive gels formed by the cross-linking of hyaluronan or hylan, their salts or derivatives thereof, using divinyl sulfone (DVS) as the cross-linking agent. Also disclosed are viscoelastic fluids containing alkylsulfone groups covalently attached to the backbone of the polymer, formed by the mono-functionalization of the cross-linking monomer DVS with hyaluronan and/or hylan. Mechanical properties such as values of hardness and cohesiveness are specified by the rheological properties of the gels. Also disclosed are methods for the preparation of such products. They have use in many applications as injectable and/or implantable devices and as drug delivery systems.

Claims

1. A process for preparing a cohesive gel comprising the steps of:

a. providing a solution of at least one starting polymer (Pol) comprising a hyaluronan, a hylan, or a mixture thereof at an initial polymer concentration (IPC) of 0.25 w % to 50 w %;

b. subjecting the starting polymer to a reaction with divinyl sulfone (DVS) to form a gel; and

c. washing the gel formed in step b with an aqueous solution having a pH≦

4.

2. The process of claim 1, wherein the IPC is from 0.25 w % to 8 w %.

3. The process of claim 1, wherein the IPC is from 3 w % to 10 w %.

4. The process of claim 1, wherein the IPC is from 3 w % to 15 w %.

5. The process of claim 1, wherein in step c the gel is washed to a pH about 2.0 to 3.0.

6. The process of claim 1 further comprising the step of adjusting the pH of the gel from ≦

4 to physiological pH.

7. The process of claim 1 further comprising the step of adjusting the pH of the gel from ≦

4 to about 4.5 to 6.5.

8. The process of claim 1, wherein step b is conducted at a pH≧

9.

9. The process of claim 1, wherein step b is allowed to proceed for ≦

24 hours.

10. The process of claim 1, wherein the average molecular weight (MW) of the starting polymer is selected from about 0.5 MDa to about 4 MDa.

11. The process of claim 10, wherein one of the starting polymer is a hyaluronan.

12. The process of claim 1, wherein the average molecular weight (MW) of the starting polymer is selected from about 30 KDa to about 500 KDa.

13. The process of claim 1 wherein the ratio of divinyl sulfone to polymer (DVS:

Pol) (w;

w) is selected from about 0.0025 to about 17.7.

14. The process of claim 1 wherein the ratio of divinyl sulfone to polymer (DVS:

Pol) (w;

w) is selected from about 0.01 to about 17.7.

15. The process of claim 1, wherein the average MW of the starting polymer is selected from about 0.5 MDa to about 4 MDa and the DVS:

Pol (w;

w) ratio is selected from about 0.01 to about 17.7.

36. A composition comprising a gel prepared according to the process of any one of claims 1, 16, 28, and 32.

40. A device or a pharmaceutical composition made by the process of any one of claims 1, 16, 28, and 32.

41. The device or the pharmaceutical composition of claim 40 further comprising a biologically active material selected from the group consisting of pharmacological drug, a protein, a DNA, a vitamin, or cells.

42. A method of treating a medical condition in a patient comprising administering the device or the pharmaceutical composition of claim 40 to the patient.

43. The method of claim 42, wherein the medical condition is osteoarthritis and the composition is administered in a joint space.

44. The method of claim 42, wherein the composition is used to create an embolism or to prevent postsurgical adhesion.

45. The method of claim 42, wherein the composition is used for soft tissue augmentation.

16. A process for preparing a cohesive gel comprising the steps of:

a. providing a solution of at least one starting polymer (Pol) comprising a hyaluronan, a hylan, or a mixture thereof at an initial polymer concentration (IPC) of >

8 w % to 50 w %; and

b. subjecting the starting polymer to a reaction with divinyl sulfone (DVS) to form a gel.

17. The process of claim 16 further comprising step c of washing the gel formed in step b with an aqueous solution having a pH≦

4.

18. The process of claim 17, wherein in step c the gel is washed to a pH about 2.0 to 3.0.

19. The process of claim 17 further comprising the step of adjusting the pH of the gel from ≦

4 to physiological pH.

20. The process of claim 17 further comprising the step of adjusting the pH of the gel from ≦

4 to about 4.5 to 6.5.

21. The process of claim 16, wherein step b is conducted at a pH>

9.

22. The process of claim 16, wherein step b is allowed to proceed for ≦

24 hours.

23. The process of claim 16, wherein the average molecular weight (MW) of the starting polymer is selected from about 0.5 MDa to about 4 MDa.

24. The process of claim 23, wherein one of the starting polymer is a hyaluronan.

25. The process of claim 16, wherein the average molecular weight (MW) of the starting polymer is selected from about 30 KDa to about 500 KDa.

26. The process of claim 16, wherein the ratio of divinyl sulfone to polymer (DVS:

Pol) (w;

w) is selected from about 0.0025 to about 0.033.

27. The process of claim 16, wherein the ratio of divinyl sulfone to polymer (DVS:

Pol) (w;

w) is selected from about 0.01 to about 0.033.

28. A process for preparing a cohesive gel comprising the steps of:

a. providing a solution of at least one starting polymer (Pol) comprising a hyaluronan, a hylan, or a mixture thereof at an initial polymer concentration (IPC) of 0.25 w % to 50 w %;

b. subjecting the starting polymer to a reaction with divinyl sulfone (DVS) to form a gel at a ratio of divinyl sulfone to polymer (DVS;

Pol) (w;

w) is selected from about 0.0025 to about 0.05.

29. The process of claim 28 further comprising step c of washing the gel formed in step b with an aqueous solution having a pH≦

4.

30. The process of claim 28, wherein step b is conducted at a pH≧

9.

31. The process of claim 28, wherein the ratio of divinyl sulfone to polymer (DVS:

Pol) (w;

w) is selected from about 0.0025 to about 0.033.

32. A process for preparing a cohesive gel comprising the steps of:

a. providing a solution of at least one starting polymer (Pol) comprising a hyaluronan, a hylan, or a mixture thereof at an initial polymer concentration (IPC) of 0.025 w % to 0.9 w %; and

b. subjecting the starting polymer to a reaction with divinyl sulfone (DVS) to form a gel.

33. The process of claim 32 further comprising step c of washing the gel formed in step b with an aqueous solution having a pH≦

4.

34. The process of claim 32, wherein the average molecular weight (MW) of the starting polymer is selected from about 3 MDa to about 10 MDa.

35. The process of claim 32, wherein the ratio of divinyl sulfone to polymer (DVS:

Pol) (w;

w) is selected from about 1.4 to about 17.7.

37. A cohesive gel having hyaluronan content of 8.25±

1.75 mg/ml, shear viscosity (at 200 Hz) of 30-100 Pas, storage modulus (at 5 Hz) of 20-150 Pa, and a phase angle (at 5 Hz) of less than 35°

.

46. A device or a pharmaceutical comprising the gel of claim 37 or the composition of claim 38.

47. The device or the pharmaceutical composition of claim 46 further comprising a biologically active material selected from the group consisting of pharmacological drug, a protein, a DNA, a vitamin, or cells.

48. A method of treating a medical condition in a patient comprising administering the device or the pharmaceutical composition of claim 46 to the patient.

49. The method of claim 46, wherein the medical condition is osteoarthritis and the composition is administered in a joint space.

50. The method of claim 46, wherein the composition is used to create an embolism or to prevent postsurgical adhesion.

51. The method of claim 46, wherein the composition is used for soft tissue augmentation.

38. A composition, comprising a gel component and a fluid component, each component comprising bacterially fermented HA, wherein the components are mixed at a ratio of about 80:

20 by weight (gel;

fluid) and the total HA content is 10.5±

2.5 mg/ml.

39. The composition of claim 38, wherein the composition has shear viscosity (at 200 Hz) of 30-100 Pas, storage modulus (at 5 Hz) of 20-150 Pa, and a phase angle (at 5 Hz) of less than 35°

.