Super fast-acting insulin compositions

• US 8,318,154 B2
• Filed: 04/28/2009
• Issued: 11/27/2012
• Est. Priority Date: 04/28/2008
• Status: Expired due to Fees

• Current Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Original Assignee: Halozyme, Inc. (Halozyme Therapeutics, Inc.)
• Inventors: Frost, Gregory I., Bilinsky, Igor, Vaughn, Daniel, Sugarman, Barry
• Primary Examiner(s): Cordero Garcia, Marcela M
• Application Number:
  US12/387,225
• Publication Number:
  US 20090304665A1
• Time in Patent Office: 1,309 Days
• Field of Search: None
• US Class Current: 424/94.5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

Provided are combinations, compositions and kits containing an fast-acting insulin composition and a hyaluronan degrading enzyme composition formulated for parenteral administration. Such products can be used in methods of treating insulin-treatable diseases or conditions. Also provided are methods for administration of a fast-acting insulin and a hyaluronan degrading enzyme.

Claims

1. A super fast-acting insulin composition, comprising:

a therapeutically effective amount of a fast-acting insulin analog for controlling blood glucose levels, wherein the fast-acting analog is insulin aspart or insulin glulisine; and

an amount of a hyaluronan degrading enzyme sufficient to render the composition a super fast-acting insulin composition, wherein;

the sufficient amount of a hyaluronan degrading enzyme to render the composition a super fast-acting insulin composition is 1 Unit or more hyaluronidase activity/mL;

the super fast-acting insulin composition has an onset of action that is shorter than the analog alone, and a duration of action that is shorter than the analog alone, whereby, upon administration, the composition closely mimics the physiologic post-prandial insulin response of a non-diabetic subject to achieve glycemic control; and

the super fast-acting insulin composition is formulated for a route of administration selected from among subcutaneous, intradermal and intraperitoneal administration.

2. The composition of claim 1, wherein

the amount of fast-acting insulin analog is from or from about 10 U/mL to at or about 500 U/ml insulin analog;

and

the sufficient amount of a hyaluronan degrading enzyme to render the composition a super fast-acting insulin composition is functionally equivalent to at least or about 1 U hyaluronidase activity/mL, 2 U/mL, 3 U/mL, 4 U/mL, 5 U/mL, 6 U/mL, 7 U/mL, 8 U/mL, 9 U/mL, 10 U/mL, 15 U/mL, 20 U/mL, 25 U /mL, 30 U/mL, 35 U/mL, 37.5 U/mL, 40 U/mL, 50 U/mL, 60 U/mL, 70 U/mL, 80 U/mL, 90 U/mL, 100 U/mL, 200 U/mL, 300 U/mL, 400 U/mL, 500 U/mL, 600 U/mL, 700 U/mL, 800 U/mL, 900 U/mL, 1000 U/mL, 2000 U/mL, 3000 U/mL or 5000 U/mL.

3. The composition of claim 1, wherein the sufficient amount of a hyaluronan degrading enzyme to render the composition a super fast-acting insulin composition is functionally equivalent to at least or about 30 to 35 Units hyaluronidase activity/mL.

4. The composition of claim 1, wherein the volume of the composition is at least or is about 1 mL, 3 mL, 5 mL, 10 mL, 20 mL or 50 mL;

and/or

the amount of fast-acting insulin analog is or is about 10 U/mL, 20 U/mL, 30 U/mL, 40 U/mL, 50 U/mL, 60 U/mL, 70 U/mL, 80 U/mL, 90 U/mL, 100 U/mL, 150 U/mL, 200 U/mL, 250 U/mL, 300 U/mL, 350 U/mL, 400 U/mL, 450 U/ml or 500 U/mL; and

/or

the amount of hyaluronan degrading enzyme is functionally equivalent to or to about at least 1 U/mL, 2 U/mL, 3 U/mL, 4 U/mL, 5 U/mL, 6 U/mL, 7 U/mL, 8 U/mL, 9 U/mL, 10 U/mL, 15 U/mL, 20 U/mL, 25 U/mL, 30 U/mL, 35 U/mL, 37.5 U/mL, 40 U/mL, 50 U/mL, 60 U/mL, 70 U/mL, 80 U/mL, 90 U/mL, 100 U/mL, 200 U/mL, 300 U/mL, 400 U/mL, 500 U/mL, 600 U/mL, 700 U/mL, 800 UlmL, 900 U/mL, 1000 U/ml, 2000 U/mL, 3000 U/mL or 5000 U/mL.

5. The composition of claim 1 that is formulated for multiple dose administration or single dose administration.

6. The composition of claim 1 that is formulated for delivery in a closed loop system, an insulin pen or an insulin pump.

7. The composition of claim 1, wherein the blood glucose levels are prandial blood glucose levels.

8. The composition of claim 1, wherein the therapeutically effective amount of insulin analog for a single dosage is or is about 0.05 Units, 0.06 Units, 0.07 Units, 0.08 Units, 0.09 Units, 0.1 Units, 0.2 Units, 0.3 Units, 0.4 Units, 0.5 Units, 0.6 Units, 0.7 Units, 0.8 Units, 0.9 Units, 1 Unit, 2 Units, 5 Units, 10 Units, 15 Units, 20 Units, 25 Units, 30 Units, 35 Units, 40 Units, 50 Units or 100 units;

and/or

the amount of hyaluronan degrading enzyme for a single dosage is functionally equivalent to or to about 0.3 Units, 0.5 Units, 1 Unit, 2 Units, 5 Units, 10 Units, 20 Units, 30 Units, 40 Units, 50 Units, 100 Units, 150 Units, 200 Units, 250 Units, 300 Units, 350 Units, 400 Units, 450 Units, 500 Units, 600 Units, 700 Units, 800 Units, 900 Units, 1000 Units, 2,000 Units, 3,000 Units, 4,000 Units or more of hyaluronidase activity.

9. The composition of claim 1, further comprising a chelating agent.

10. The super fast-acting insulin composition of claim 9, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA) or ethylenediaminetetraacetate.

11. The composition of claim 9, wherein the chelating agent is provided as a complex with a metal at or about equimolar concentrations of the metal and chelating agent.

12. The composition of claim 11, wherein the chelating agent complex is calcium EDTA.

13. The composition of claim 1, further comprising an amount of zinc.

14. The composition of claim 13, containing from or from about 0.01 mg to or to about 0.02 mg zinc and from or from about 0.1 mM to or to about 50 mM calcium EDTA per 100 U fast-acting insulin analog.

15. The composition of claim 13 , comprising zinc in a molar ratio of or of about 1:

3 to the fast-acting insulin analog and calcium EDTA at a molar ratio of or of about 1;

3 to 10;

1 to the fast-acting insulin analog.

16. The composition of claim 1, wherein the pH of the composition is from or from about 6.5 to about 7.5.

17. The composition of claim 1, further comprising a stabilizer for the fast-acting insulin analog, a stabilizer for the hyaluronan degrading enzyme or both.

18. The composition of claim 17, wherein the stabilizer is a detergent, a polyalcohol, a metal, a salt, a cosolvent and/or a protein.

19. The composition of claim 1, further comprising an oxygen scavenger.

20. The composition of claim 19, wherein the oxygen scavenger is selected from among ascorbic acid, ascorbate, citric acid, citrate, methionine and albumin.

21. The composition of claim 1, wherein the insulin analog is selected from among an insulin having an A chain with a sequence of amino acids set forth in SEQ NOS:

103 and a B chain having a sequence of amino acids set forth in SEQ ID NO;

147 or 149.

22. The composition of claim 1, further comprising a basal-acting insulin.

23. The composition of claim 1, wherein the hyaluronan degrading enzyme is a hyaluronidase.

24. The composition of claim 1, wherein the precursor hyaluronidase or hyaluronidase has a sequence of amino acids set forth in any of SEQ ID NOS:

1-39 or 67-96, truncated forms thereof and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the polypeptide set forth in SEQ ID NO;

1 and that exhibit hyaluronidase activity.

25. The composition of claim 23, wherein the hyaluronidase is a soluble hyaluronidase.

26. The composition of claim 25, wherein the soluble hyaluronidase is a PH20, or a truncated form thereof that lacks all or a portion of a glycosylphosphatidylinositol (GPI) anchor.

27. The composition of claim 26, wherein the PH20 is selected from an ovine, bovine or truncated human PH20.

28. The composition of claim 27, wherein the truncated human PH20 is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the polypeptides set forth in any of SEQ ID NOS;

4-9, and that exhibit hyaluronidase activity.

29. The composition of claim 23, wherein the hyaluronidase is a soluble hyaluronidase provided as a composition designated rHuPH20.

30. The composition of claim 1, wherein the hyaluronan degrading enzyme is a chondroitinase.

31. The composition of claim 30, wherein the chondroitinase is selected from among the group consisting of chondroitin ABC lyase, chondroitin AC lyase and chondroitin C lyase.

32. The composition of claim 31, wherein the precursor chondroitinase or chondroitinase has a sequence of amino acids set forth in any of SEQ ID NOS:

98-100, truncated forms thereof and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the polypeptides set forth in any of SEQ ID NOS;

98-100, and that have the ability to degrade hyaluronan.

33. A syringe or vial, comprising the composition of claim 1.

34. A closed loop system, comprising the composition of claim 1.

35. An insulin pump, comprising the composition of claim 1.

36. An insulin pen, comprising the composition of claim 1.

68. The composition of claim 1, wherein the amount of hyaluronan degrading enzyme to insulin analog in the composition is 1 hyaluronidase U/insulin analog U (1:

1) to 50;

1, or is 1;

1, 2;

1, 3;

1, 4;

1, 5;

1, 6;

1, 7;

1, 8;

1, 9;

1, 10;

1, 11;

1, 12;

1, 13;

1, 14;

1, 15;

1, 20;

1, 25;

1, 30;

1, 35;

1, 40;

1, 45;

1 or 50;

1.

69. The composition of claim 1, wherein:

the composition has a pH between or about between 6.5 to 7.5; and

the composition comprises;

a stabilizer for the fast-acting insulin analog or hyaluronan degrading enzyme or both; and

a preservative.

70. The composition of claim 69, wherein the stabilizer is selected from among a detergent, a polyalcohol, a metal, a salt a cosolvent and/or a protein.

71. The composition of claim 70, wherein:

the composition comprises a salt that is NaCl in an amount between or about between 50 mM to 200 mM; and

the composition comprises a detergent that is a surfactant in an amount between or about between 0.001% to 0.1%.

72. The composition of claim 71, wherein the surfactant is a polysorbate or is poloxamer 188.

73. The composition of claim 69, wherein the preservative contains an aromatic ring.

74. The composition of claim 73, wherein the preservative is m-cresol or phenol.

75. The composition of claim 74, wherein the amount of m-cresol is 0.05% to 0.2% and the amount of phenol is 0.05% to 0.25%.

76. The composition of claim 69, further comprising an oxygen scavenger.

77. The composition of claim 76, wherein the oxygen scavenger is selected from among ascorbic acid, ascorbate, citric acid, citrate, methionine and albumin.

78. The composition of claim 77, comprising methionine at a concentration of or about 1 mM, 2 mM, 3 mM, 5 mM, 10 mM, or 20 mM.

79. The composition of claim 69, wherein the composition comprises a pH buffer to maintain the pH, wherein the buffer is selected from among histidine, phosphate and Tris.

80. The composition of claim 1, wherein the kinetics of the onset of action of a super fast-acting insulin composition, upon administration, mimics the physiologic post-prandial insulin response in non-diabetic individuals.

81. The composition of claim 1, wherein the onset of action and duration of action mimics physiologic insulin release in a subject to maintain glucose concentrations between 70-130 mg/dL.

37. A closed loop system for controlling blood glucose levels in a subject, comprising:

a fast-acting insulin analog selected from insulin aspart or insulin glulisine; and

a hyaluronan degrading enzyme, wherein;

the fast-acting insulin analog and the hyaluronan degrading enzyme are in the same or different reservoirs;

the amount of a hyaluronan degrading enzyme is sufficient, when combined with the insulin, to render the insulin a super fast-acting insulin;

the concentration of hyaluronan degrading enzyme in the closed loop system is 1 Unit or more hyaluronidase activity/mL; and

the fast-acting insulin analog and the hyaluronan degrading enzyme, when combined, form a super fast-acting insulin, which has an onset of action that is shorter than the analog alone, and a duration of action that is shorter than the analog alone, whereby, upon administration, the insulin closely mimics the physiologic post-prandial insulin response of a non-diabetic subject to achieve glycemic control.

38. The closed loop system of claim 37, further comprising one or more of a glucose sensor, a delivery system to deliver the hyaluronan degrading enzyme and fast-acting insulin analog, and software programmed to integrate the pumping and monitoring functions, whereby hyaluronan degrading enzyme and fast-acting insulin analog are delivered to achieve glycemic control that mimics the glycemic control in a non-diabetic subject.

39. The closed loop system of claim 37, wherein the insulin analog is selected from among an insulin having an A chain with a sequence of amino acids set forth in SEQ NOS:

103 and a B chain having a sequence of amino acids set forth in SEQ ID NO;

147 or 149.

40. The closed loop system of claim 37, further comprising a basal-acting insulin.

41. The closed loop system of claim 37, wherein the hyaluronan degrading enzyme is a hyaluronidase.

42. The closed loop system of claim 41, wherein the hyaluronidase is a soluble hyaluronidase.

43. The closed loop system of claim 42, wherein the soluble hyaluronidase is a PH20, or a truncated form thereof that lacks all or a portion of a glycosylphosphatidylinositol (GPI) anchor.

44. The closed loop system of claim 43, wherein the PH20 is selected from an ovine, bovine or truncated human PH20.

45. The closed loop system of claim 44, wherein the truncated human PH20 is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide set forth in any of SEQ ID NOS;

4-9, and that exhibit hyaluronidase activity.

46. The closed loop system of claim 41, wherein the hyaluronidase is a soluble hyaluronidase provided as a composition designated rHuPH20.

47. The closed loop system of claim 37, wherein the hyaluronan degrading enzyme is a chondroitinase.

48. The closed loop system of claim 47, wherein the chondroitinase is selected from among the group consisting of chondroitin ABC lyase, chondroitin AC lyase and chondroitin C lyase.

49. The closed loop system of claim 48, wherein the precursor chondroitinase or chondroitinase has a sequence of amino acids set forth in any of SEQ ID NOS:

98-100, truncated forms thereof and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide set forth in any of SEQ ID NOS;

98-100, and that have the ability to degrade hyaluronan.

50. The closed loop system of claim 37, wherein the system is capable of delivering the fast-acting insulin analog in individual dose increments of from at or about 0.1 Units, 0.2 Units, 03 Units, 0.4 Units, 0.5 Units, 0.6 Units, 0.7 Units, 0.8 Units, 0.9 Units, 1 Unit, 2 Units, 5 Units, 10 Units, 15 Units, 20 Units, 25 Units, 30 Units, 35 Units, 40 Units, 50 Units or more of fast-acting insulin analog.

51. The closed loop system of claim 37, wherein the reservoir containing the hyaluronan degrading enzyme contains an amount of hyaluronan degrading enzyme that is functionally equivalent to at or about 0.3 Units, 0.5 Units, 1 Unit, 2 Units, 5 Units, 10 Units, 20 Units, 30 Units, 40 Units, 50 Units, 100 Units, 150 Units, 200 Units, 250 Units, 300 Units, 350 Units, 400 Units, 450 Units, 500 Units, 600 Units, 700 Units, 800 Units, 900 Units, 1000 Units, 2,000 Units, 3,000 Units, 4,000 Units, 5000 Units, 6,000 Units, 7,000 Units, 8,000 Units, 9,000 Units, 10,000 Units, 20,000 Units or more hyaluronidase activity.

52. The closed loop system of claim 37, wherein the system is capable of delivering the hyaluronan degrading enzyme in individual dose increments of an amount of hyaluronan degrading enzyme that is functionally equivalent to at or about 0.3 Units, 0.5 Units, 1 Unit, 2 Units, 3 Units, 5 Units, 10 Units, 20 Units, 30 Units, 40 Units, 50 Units, 100 Units, 150 Units or more of hyaluronidase activity.

53. A combination, comprising:

a first composition containing from or from about 10 Units (U) to or to about 500 U of a fast-acting insulin analog selected from insulin aspart or insulin glulisine; and

a second composition containing a sufficient amount of a hyaluronan degrading enzyme that, when administered with the insulin, renders the composition containing the fast-acting insulin analog a super fast-acting insulin composition;

wherein;

the sufficient amount of hyaluronan degrading enzyme is functionally equivalent to at least or about 1 U hyaluronidase activity/mL, 2 U/mL, 3 U/mL, 4 U/mL, 5 U/mL, 6 U/mL, 7 U/mL, 8 U/mL, 9 U/mL, 10 U/mL, 15 U/mL, 20 U/mL, 25 U/mL, 30 U/mL, 35 U/mL, 37.5 U/mL, 40 U/mL, 50 U/mL, 60 U/mL, 70 U/mL, 80 U/mL, 90 U/mL, 100 U/mL, 200 U/mL, 300 U/mL, 400 U/mL, 500 U/mL, 600 U/mL, 700 U/mL, 800 U/mL, 900 U/mL, 1000 U/mL, 2000 U/mL, 3000 U/mL or 5000 U/mL; and

the fast-acting insulin analog and the hyaluronan degrading enzyme, when combined, form a super fast-acting insulin, which has an onset of action that is shorter than the analog alone, and a duration of action that is shorter than the analog alone, whereby, upon administration, the insulin closely mimics the physiologic post-prandial insulin response of a non-diabetic subject to achieve glycemic control.

54. The combination of claim 53, wherein the sufficient amount of hyaluronan degrading enzyme is functionally equivalent to at least or about 30 to 35 Units hyaluronidase activity/mL.

55. The combination of claim 53, wherein the amount of fast-acting insulin analog in the first composition is or is about 10 U/mL, 20 U/mL, 30 U/mL, 40 U/mL, 50 U/mL, 60 U/mL, 70 U/mL, 80 U/mL, 90 U/mL, 100 U/mL, 150 U/mL, 200 U/mL, 250 U/mL, 300 U/mL, 350 U/mL, 400 U/mL, 450 U/ml or 500 U/mL.

56. The combination of claim 53, wherein the compositions are formulated for subcutaneous administration.

57. The combination of claim 53, wherein the insulin analog is selected from among an insulin having an A chain with a sequence of amino acids set forth in SEQ NOS:

103 and a B chain having a sequence of amino acids set forth in SEQ ID NO;

147 or 149.

58. The combination of claim 53, wherein the hyaluronan degrading enzyme is a hyaluronidase.

59. The combination of claim 58, wherein the hyaluronidase is a soluble hyaluronidase.

60. The combination of claim 59, wherein the soluble hyaluronidase is a PH20, or a truncated form thereof that lacks all or a portion of a glycosylphosphatidylinositol (GPI) anchor.

61. The combination of claim 60, wherein the PH20 is selected from an ovine, bovine or truncated human PH20.

62. The combination of claim 61, wherein the truncated human PH20 is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide set forth in any of SEQ ID NOS;

4-9, and that exhibit hyaluronidase activity.

63. The combination of claim 53, wherein the hyaluronidase is a soluble hyaluronidase provided as a composition designated rHuPH20.

64. The combination of claim 53, wherein the hyaluronan degrading enzyme is a chondroitinase.

65. The combination of claim 64, wherein the chondroitinase is selected from among the group consisting of chondroitin ABC lyase, chondroitin AC lyase and chondroitin C lyase.

66. The combination of claim 65, wherein the precursor chondroitinase or chondroitinase has a sequence of amino acids set forth in any of SEQ ID NOS:

98-100, truncated forms thereof and variants thereof that have 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a polypeptide set forth in any of SEQ ID NOS;

98-100, and that have the ability to degrade hyaluronan.

67. A kit comprising the combination of claim 53, and optionally instructions.