Compositions of hyaluronan with high elasticity and uses thereof

• US 9,492,474 B2
• Filed: 07/09/2014
• Issued: 11/15/2016
• Est. Priority Date: 07/10/2013
• Status: Active Grant

• Current Assignee: Matrix Biology Institute
• Original Assignee: Matrix Biology Institute
• Inventors: Balazs, Endre A., Belmonte, Carlos
• Primary Examiner(s): Maier, Leigh C
• Application Number:
  US14/327,321
• Publication Number:
  US 20150018303A1
• Time in Patent Office: 860 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Abstract

The present invention provides compositions comprising hyaluronan with high elasticity, as well as methods for improving joint function, reducing pain associated with joint function and treating osteoarthritis by introducing into a joint a therapeutically effective amount of a composition comprising hyaluronan with high elasticity.

Claims

1. A high elasticity composition suitable for intra-articular injection comprising hyaluronan, wherein:

the hyaluronan is present in said composition at a concentration of greater than 30 mg/mL;

the hyaluronan has an average molecular weight of between 1.3 and 2 million;

the hyaluronan is not cross-linked and/or is substantially free of chemical modifications;

wherein the composition is substantially free of a pharmaceutically active substance selected from the group consisting of a protein, a glycosaminoglycan that is different from hyaluronan, hydroxypropyl methyl cellulose and a local anesthetic;

wherein the composition is sterile; and

wherein the composition has an elasticity (G′

) of at least 900 Pascal when measured at a frequency of 5.0 Hz.

2. The composition of claim 1, wherein hyaluronan is present at a concentration of 40 mg/mL to 60 mg/mL.

3. The composition of claim 1, wherein the composition further comprises a buffer.

4. The composition of claim 3, wherein the buffer is phosphate buffered saline (PBS).

5. The composition of claim 1, wherein the composition has an elasticity of between 900 and 7,000 Pascal when measured at a frequency of 5 Hz.

6. The composition of claim 1, wherein the composition has an elasticity of at least about 1,000 Pascal when measured at a frequency of 0.5 Hz.

7. The composition of claim 1, wherein the composition has an elasticity of at least about 2,000 Pascal when measured at a frequency of 0.5 Hz.

8. The composition of claim 1, wherein the composition has an elasticity of at least about 4,000 Pascal when measured at a frequency of 0.5 Hz.

16. A method of reducing at least one symptom associated with joint dysfunction, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 1 or 9, thereby reducing at least one symptom associated with joint dysfunction.

17. The method of claim 16, wherein the joint dysfunction is joint pain or joint dysfunction associated with osteoarthritis, post-arthroscopy, post-orthoplasty, post-injury or prolonged immobilization.

18. The method of claim 17, wherein the joint dysfunction is joint pain.

19. The method of claim 16, wherein administering of the composition causes a reduction in the number of nerve impulses induced by normal and abnormal movements in an experimental rat model of osteoarthritis.

20. The method of claim 19, wherein the reduction is at least two-fold, at least three-fold, at least four-fold or at least five-fold.

21. The method of claim 16, wherein administering of the composition causes a reduction in the number of nerve impulses induced by normal movements in an experimental rat model of osteoarthritis.

22. The method of claim 21, wherein the reduction is at least two-fold, at least three-fold, at least four-fold, at least five-fold, at least six-fold, at least seven-fold or at least eight-fold.

23. The method of claim 16, wherein administering of the composition causes a reduction in the number of nerve impulses induced by abnormal movements in an experimental rat model of osteoarthritis.

24. The method of claim 23, wherein the reduction is at least two-fold, at least three-fold or at least four-fold.

25. The method of claim 19, 21 or 23, wherein the reduction is greater than the reduction caused by administering a comparable amount of hylan GF-20.

26. The method of claim 16, wherein the composition is administered by intra-articular injection.

27. A device comprising the composition of claim 1 or 9.

28. The device of claim 27, wherein the device is a pre-filled syringe.

29. The device of claim 27, wherein the pre-filled syringe is a 5-mL pre-filled syringe.

30. The device of claim 28, wherein the pre-filled syringe is sterilized.

31. A kit comprising the pre-filled syringe of claim 28.

32. The composition of claim 1, wherein the hyaluronan is present in said composition at a concentration of 45 mg/mL or greater.

34. The composition of claim 1, wherein the hyaluronan is present in said composition at a concentration of 50 mg/mL or greater.

36. The composition of claim 1, wherein the hyaluronan has an average molecular weight of between 1.3 million and 1.6 million.

39. The composition of claim 1, wherein the composition has an elasticity of at least about 6,000 Pascal when measured at a frequency of 0.5 Hz.

41. The composition of claim 1, wherein the hyaluronan is present in said composition at a concentration of 30 mg/mL to 90 mg/mL.

43. The composition of claim 1, wherein the hyaluronan is present in said composition at a concentration selected from the group consisting of at least 40 mg/mL, at least 50 mg/mL, at least 60 mg/mL, at least 70 mg/mL, at least 80 mg/mL, and at least 90 mg/mL.

45. A method of treating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1 or 14, thereby treating pain in said subject.

9. A high elasticity composition suitable for intra-articular injection comprising hyaluronan, wherein:

the hyaluronan is present in said composition at a concentration of 40 mg/mL or greater;

the hyaluronan has an average molecular weight of between 1 and 2 million;

the hyaluronan is not cross-linked and/or is substantially free of chemical modifications;

wherein the composition is substantially free of a pharmaceutically active substance selected from the group consisting of a protein, a glycosaminoglycan that is different from hyaluronan, hydroxypropyl methyl cellulose and a local anesthetic;

wherein the composition is sterile; and

wherein the composition has an elasticity (G′

) of at least 900 Pascal when measured at a frequency of 5.0 Hz.

10. The composition of claim 9, wherein the composition further comprises a buffer.

11. The composition of claim 10, wherein the buffer is phosphate buffered saline (PBS).

12. The composition of claim 9, wherein the composition has an elasticity of between 900 and 7,000 Pascal when measured at a frequency of 5 Hz.

13. The composition of claim 9, wherein the composition has an elasticity of at least about 1,000 Pascal when measured at a frequency of 0.5 Hz.

14. The composition of claim 9, wherein the composition has an elasticity of at least about 2,000 Pascal when measured at a frequency of 0.5 Hz.

15. The composition of claim 9, wherein the composition has an elasticity of at least about 4,000 Pascal when measured at a frequency of 0.5 Hz.

33. The composition of claim 9, wherein the hyaluronan is present in said composition at a concentration of 45 mg/mL or greater.

35. The composition of claim 9, wherein the hyaluronan is present in said composition at a concentration of 50 mg/mL or greater.

37. The composition of claim 9, wherein the hyaluronan has an average molecular weight of between 1.3 million and 2 million.

38. The composition of claim 37, wherein the hyaluronan has an average molecular weight of between 1.3 million and 1.6 million.

40. The composition of claim 9, wherein the composition has an elasticity of at least about 6,000 Pascal when measured at a frequency of 0.5 Hz.

42. The composition of claim 9, wherein the hyaluronan is present in said composition at a concentration of 40 mg/mL to 90 mg/mL.

44. The composition of claim 9, wherein the hyaluronan is present in said composition at a concentration selected from the group consisting of at least 50 mg/mL, at least 60 mg/mL, at least 70 mg/mL, at least 80 mg/mL, and at least 90 mg/mL.