Composition and lipid formulation of a hyaluronan-degrading enzyme and the use thereof for treatment of benign prostatic hyperplasia

• US 9,333,244 B2
• Filed: 02/19/2013
• Issued: 05/10/2016
• Est. Priority Date: 02/08/2011
• Status: Active Grant

• Current Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Original Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Inventors: Li, Xiaoming, Ramprasad, Mysore, Thompson, Curtis, Shepard, Harold Michael, Bookbinder, Louis Howard, Frost, Gregory Ian
• Primary Examiner(s): DESAI, ANAND U
• Application Number:
  US13/815,311
• Publication Number:
  US 20130251786A1
• Time in Patent Office: 1,176 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Provided are compositions and formulations or co-formulations containing a hyaluronan degrading enzyme. The compositions, formulations or co-formulations can also contain another therapeutic agent, such as one that is suitable for treatment of Benign Prostatic Hyperplasia, for example, a 5-alpha reductase inhibitor. The compositions and formulations can be used for the treatment of Benign Prostatic Hyperplasia. The compositions and formulations can be provided in combinations with one or more other agents for the treatment of Benign Prostatic Hyperplasia.

Claims

1. A multivesicular liposome, comprising:

a) a neutral lipid;

an amphipathic lipid; and

a hyaluronan-degrading enzyme, wherein the concentration of the hyaluronan-degrading enzyme is between or about between 0.1 mg/mL to 1 mg/mL;

or

b) a neutral lipid;

an amphipathic lipid;

a hyaluronan-degrading enzyme; and

hyaluronic acid in an amount sufficient to increase the enzymatic activity of the hyaluronan-degrading enzyme.

2. The multivesicular liposome of claim 1, wherein the multivesicular liposome is of a) and further comprises hyaluronic acid in an amount sufficient to increase the enzymatic activity of the hyaluronan-degrading enzyme.

3. The multivesicular liposome of claim 1, wherein the hyaluronic acid maintains the total activity of the enzyme of at least 40,000 U/mg.

4. The multivesicular liposome of claim 2, wherein the hyaluronic acid maintains the total activity of the enzyme of at least 40,000 U/mg.

5. The multivesicular liposome of claim 1, wherein the hyaluronan-degrading enzyme is a hyaluronidase, a chondroitinase or a lyase.

6. The multivesicular liposome of claim 5, wherein the hyaluronan-degrading enzyme is a hyaluronidase that is a PH20 hyaluronidase.

7. The multivesicular liposome of claim 6, wherein the PH20 is soluble or is a form that is secreted when expressed.

8. The multivesicular liposome of claim 7, wherein the soluble PH20 is selected from among polypeptides containing the sequence of amino acids set forth in any of SEQ ID NOS:

4-9, 47 and 48, or a sequence of amino acids that exhibits at least 91% sequence identity to any of SEQ ID NOS;

4-9, 47 and 48 and is soluble and exhibits hyaluronidase activity.

11. The multivesicular liposome of claim 1, wherein the concentration of hyaluronic acid is or is about between 0.05 mg/mL to 50 mg/mL.

12. The multivesicular liposome of claim 2, wherein the concentration of hyaluronic acid is or is about between 0.05 mg/mL to 50 mg/mL.

13. The multivesicular liposome of claim 1, wherein the neutral lipid is a diglyceride or a triglyceride.

14. The multivesicular liposome of claim 13, wherein the neutral lipid is a triglyceride that is triolein or tricaprylin, or a mixture of triolein and tricaprylin.

15. The multivesicular liposome of claim 14, wherein triolein and tricaprylin are in a 50:

50 (1;

1) molar ratio.

16. The multivesicular liposome of claim 1, wherein the amphipathic lipid is a phosphatidylglycerol (PG), cardiolipin (CL), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylinositol, phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin, or diacyl trimethylammonium propane (DITAP).

17. The multivesicular liposome of claim 16, wherein the amphipathic lipid is a phosphatidylcholine that is DEPC or DOPC, or a mixture of DEPC and DOPC.

18. The multivesicular liposome of claim 17, wherein DEPC and DOPC are in a molar ratio that is at least or about at least 50:

50 (1 DEPC;

1 DOPC), 75;

25 (3 DEPC;

1 DOPC) or 90;

10 (9 DEPC;

1 DOPC).

19. The multivesicular liposome of claim 1, further comprising dipalmitoyl-L-alpha-phosphatidylglycerol (DPPG).

20. The multivesicular liposome of claim 1, further comprising cholesterol.

21. The multivesicular liposome of claim 1, further comprising a therapeutic agent.

22. The multivesicular liposome of claim 21, wherein the therapeutic agent is hydrophobic.

23. The multivesicular liposome of claim 21, wherein the therapeutic agent is an agent to treat benign prostatic hyperplasia.

24. The multivesicular liposome of claim 21, wherein the therapeutic agent is selected from among an anti-androgen, an alpha blocker, a boutlinum toxin and a hydrolytic enzyme.

25. The multivesicular liposome of claim 24, wherein the anti-androgen is a steroid anti-androgen, a non-steroid anti-androgen or a 5α

-reductase inhibitor.

26. The multivesicular liposome of claim 25, wherein the agent is a 5α

-reductase inhibitor that is finasteride or dutasteride.

27. A composition, comprising a multivesicular liposome of claim 1 in a pharmaceutically acceptable carrier.

28. The composition of claim 27, comprising NaCl.

29. The composition of claim 28, wherein the concentration of NaCl is between or about between 100 mM to 150 mM.

30. The composition of claim 27, comprising histidine.

31. The composition of claim 30, wherein the concentration of histidine is between or about between 1 mM to 100 mM.

32. The composition of claim 27, wherein the pH of the composition is or is about between 6.0 to 8.0.

33. The composition of claim 27, comprising a therapeutic agent.

34. The composition of claim 33, wherein the therapeutic agent is an agent for treating benign prostatic hyperplasia.

35. The composition of claim 34, wherein the therapeutic agent is selected from among an anti-androgen, an alpha blocker, a boutlinum toxin, and a hydrolytic enzyme.

36. The composition of claim 35, wherein the anti-androgen is a steroid anti-androgen, a non-steroid anti-androgen or a 5α

-reductase inhibitor.

37. The composition of claim 36, wherein the therapeutic agent is a 5α

-reductase inhibitor that is finasteride or dutasteride.

38. A combination, comprising:

a first composition comprising a composition of claim 27; and

a second composition comprising a therapeutic agent.

39. The combination of claim 38, wherein the therapeutic agent is an agent for treating benign prostatic hyperplasia.

40. The combination of claim 38, wherein the therapeutic agent is selected from among an anti-androgen, an alpha blocker, a boutlinum toxin, and a hydrolytic enzyme.

41. The combination of claim 40, wherein the anti-androgen is a steroid anti-androgen, a non-steroid anti-androgen or a 5α

-reductase inhibitor.

42. The combination of claim 41, wherein the therapeutic agent is a 5α

-reductase inhibitor that is finasteride or dutasteride.

61. A method of treating a hyaluronan associated disease or condition, comprising administering to a subject a composition of claim 27.

62. The method of claim 61, wherein the hyaluronan associated disease or condition is benign prostatic hyperplasia.

63. The method of claim 61, wherein the composition is administered to the subject intraprostaticaly.

64. The method of claim 61, further comprising administering another agent to treat benign prostatic hyperplasia.

65. The method of claim 64, wherein the other agent is selected from among an anti-androgen, an alpha blocker, a boutlinum toxin and a hydrolytic enzyme.

66. The method of claim 65, wherein the anti-androgen is a steroid anti-androgen, a non-steroid anti-androgen or a 5α

-reductase inhibitor.

67. The method of claim 66, wherein the agent is a 5α

-reductase inhibitor that is finasteride or dutasteride.

68. The multivesicular liposome of claim 1, wherein the hyaluronan-degrading enzyme is encapsulated in the liposome.

70. The multivesicular liposome of claim 1, wherein the hyaluronan-degrading enzyme is linked, directly to indirectly, to a label or detectable moiety.

9. A multivesicular liposome, comprising:

a) a neutral lipid;

an amphipathic lipid; and

a hyaluronan-degrading enzyme, wherein the concentration of the hyaluronan-degrading enzyme is between or about between 0.1 mg/mL to 1 mg/mL;

or

b) a neutral lipid;

an amphipathic lipid;

a hyaluronan-degrading enzyme; and

hyaluronic acid in an amount sufficient to increase the enzymatic activity of the hyaluronan-degrading enzyme, wherein the hyaluronan-degrading enzyme is modified by conjugation to a polymer.

10. The multivesicular liposome of claim 9, wherein the polymer is PEG or dextran.

43. A composition, comprising:

a hyaluronan-degrading enzyme, wherein the concentration of the hyaluronan-degrading enzyme is at least 50 U/mL; and

hyaluronic acid, whereby the hyaluronan-degrading enzyme retains at least 50% of the hyaluronidase activity for at least six months at 28°

C. to 32°

C. or at least one year at 2°

C. to 8°

C.

44. The composition of claim 43 that is a pharmaceutical composition.

45. The composition of claim 43 that is formulated for direct administration.

46. The composition of claim 43, wherein the hyaluronan-degrading enzyme is a hyaluronidase, a chondroitinase or a lyase.

47. The composition of claim 46, wherein the hyaluronan-degrading enzyme is a hyaluronidase that is a PH20 hyaluronidase.

48. The composition of claim 47, wherein the PH20 is soluble or is a form that is secreted when expressed.

49. The composition of claim 48, wherein the PH20 is selected from among polypeptides containing the sequence of amino acids set forth in any of SEQ ID NOS:

4-9, 47 and 48, or a sequence of amino acids that has at least 91% sequence identity to any of SEQ ID NOS;

4-9, 47 and 48 and is soluble and exhibits hyaluronidase activity.

50. The composition of claim 43, wherein the hyaluronan-degrading enzyme is modified by conjugation to a polymer.

51. The composition of claim 50, wherein the polymer is PEG or dextran.

52. The composition of claim 43, wherein the concentration of the hyaluronan-degrading enzyme is or is about between or at least 100 U/mL to 1000 U/mL.

53. The composition of claim 43, wherein the concentration of hyaluronic acid is or is about between 1 mg/mL to 100 mg/mL.

54. The composition of claim 43, wherein the composition is formulated as a single or multiple dosage formulation for direct administration.

55. The composition of claim 43, wherein the composition is formulated in a volume per administration of between or about 0.5 mL to 50 mL.

56. The composition of claim 43, further comprising NaCl.

57. The composition of claim 56, wherein the concentration of NaCl is between or about between 100 mM to 150 mM.

58. The composition of claim 43, further comprising histidine.

59. The composition of claim 58, wherein the concentration of histidine is between or about between 1 mM to 100 mM.

60. The composition of claim 43, wherein the pH of the composition is or is about between 6.0 to 8.0 or 6.5 to 7.5 or is at least or about or 6.0, 6.5, 7.0 or 7.4.

69. A multivesicular liposome, comprising:

a neutral lipid;

an amphipathic lipid; and

a hyaluronan-degrading enzyme, wherein the concentration of the hyaluronan-degrading enzyme is between or about between 0.1 mg/mL to 1 mg/mL.

71. A multivesicular liposome, made by a process or obtainable by a process comprising the steps of:

a) forming a first aqueous component comprising a hyaluronan degrading enzyme in a concentration less than 2 mg/mL;

b) forming a lipid component comprising at least one organic solvent, at least one amphiphatic lipid and at least one neutral lipid;

c) forming an emulsion from the first aqueous component and the lipid component;

d) dispersing the emulsion into a second aqueous component to form solvent spherules; and

e) removing the organic solvent from the solvent spherules to form multivesicular liposomes suspended in the second aqueous component.

72. The multivesicular liposome of claim 71, wherein the hyaluronan -degrading enzyme is in a concentration of between or about between 0.1 mg/mL to 1.9.