Super fast-acting insulin compositions

• US 8,568,713 B2
• Filed: 05/18/2012
• Issued: 10/29/2013
• Est. Priority Date: 04/28/2008
• Status: Active Grant

• 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:
  US13/506,844
• Publication Number:
  US 20120251517A1
• Time in Patent Office: 529 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 methods for control of post-prandial glucose in diabetic subjects by administering a fast-acting insulin analog and a hyaluronidase degrading enzyme. The fast-acting insulin analog and a hyaluronidase are administered between 15 minutes before the meal and 30 minutes after commencing the meal.

Claims

1. A method for controlling post-prandial glucose levels in a subject, comprising administering to the subject a fast-acting insulin analog and a hyaluronan-degrading enzyme less than 15 minutes before a meal up until 30 minutes after commencing a meal, whereby glucose levels in the diabetic subject mimic the levels in a non-abetic subject, wherein:

the amount of hyaluronan degrading enzyme administered is sufficient to render the fast-acting insulin analog a super fast acting insulin;

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

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

administration of the fast-acting insulin analog and the hyaluronan degrading enzyme is effected via subcutaneous, intradermal, intramuscular or intraperitoneal administration.

2. The method of claim 1, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered at or at about the time ingestion of a meal is commenced.

3. The method of claim 1, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered within 10 minutes before a meal.

4. The method of claim 1, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered within 5 minutes before a meal.

5. The method of claim 1, wherein the fast-acting insulin and hyaluronan degrading enzyme are co-formulated to form a super fast-acting insulin composition.

6. The method of claim 1, wherein the fast-acting insulin and hyaluronan degrading enzyme are administered separately.

7. The method of claim 6, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered sequentially or simultaneously.

8. The method of claim 1, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered to the subject via syringe, insulin pen, insulin pump or a closed loop system.

9. The method of claim 8, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are co-formulated.

10. The method of claim 8,wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered separately.

11. The method of claim 10, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are in separate reservoirs in a closed loop system.

12. The method of claim 1, wherein the dosage of the fast-acting insulin analog is less than the dosage of the fast-acting insulin administered by the same route in the absence of the hyaluronan degrading enzyme.

13. The method 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;

and

the sufficient amount of a hyaluronan degrading enzyme to render the fast-acting insulin analog super fast-acting insulin 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 hyaluronidase activity/mL.

14. The method 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.

15. The method of claim 1, wherein the amount of insulin 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 at least 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.

16. The method of claim 1, wherein the fast-acting analog is insulin aspart, insulin lispro or insulin glulisine.

17. The method of claim 16, wherein the insulin analog is selected from among an insulin with an A chain with a sequence of amino acids set forth in SEQ ID NO:

103 and a B chain with a sequence of amino acids set forth in any of SEQ ID NOS;

147-149.

18. The method of claim 1, wherein the hyaluronan degrading enzyme is a hyaluronidase.

19. The method of claim 18, wherein the hyaluronidase is a soluble hyaluronidase.

20. The method of claim 19, wherein the soluble hyaluronidase is a PH20, or a truncated form thereof

21. The method of claim 20, wherein the PH20 is an ovine, bovine or truncated human PH20.

22. The method of claim 21, wherein the hyaluronidase is a truncated human PH20 that is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, or allelic variants or other variants thereof that have at least 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 retain hyaluronidase activity.

23. The method of claim 22, wherein the hyaluronidase is a soluble hyaluronidase provided as a composition designated rHuPH20.

24. The method of claim 1, wherein the fast-acting analog is insulin aspart or insulin glulisine.

25. The method of claim 1, wherein post-prandial blood glucose concentrations are maintained between 70-130 mg/dL.

26. The method of claim 1, wherein post-prandial blood glucose concentrations are maintained between 90-110 mg/dL.

27. A method for controlling post-prandial glucose levels in a subject, comprising administering to the subject a fast-acting insulin analog and a hyaluronan degrading enzyme, wherein:

the fast-acting analog is insulin aspart or insulin glulisine;

the amount hyaluronan degrading enzyme administered is sufficient to render the fast-acting insulin analog a super fast acting insulin;

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

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

administration of the fast-acting insulin analog and the hyaluronan degrading enzyme is effected via subcutaneous, intradermal, intramuscular or intraperitoneal administration.

28. The method of claim 27, wherein the hyaluronan degrading enzyme and fast-acting insulin analog are administered sequentially.

29. The method of claim 27, wherein the hyaluronan degrading enzyme and fast-acting insulin analog are administered simultaneously.

30. The method of claim 27, wherein the hyaluronan degrading enzyme and fast-acting insulin analog are co-formulated.

31. The method of claim 27, wherein the hyaluronan degrading enzyme and fast-acting insulin analog are administered separately.

32. The method of claim 31, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are in separate reservoirs in a closed loop system.

33. The method of claim 27, wherein the hyaluronan degrading enzyme is a hyaluronidase.

34. The method of claim 33, wherein the hyaluronidase is a soluble hyaluronidase.

35. The method of claim 34, wherein the soluble hyaluronidase is a PH20, or a truncated form thereof.

36. The method of claim 35, wherein the PH20 is an ovine, bovine or truncated human PH20.

37. The method of claim 36, wherein the hyaluronidase is a truncated human PH20 that is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, or allelic variants or other variants thereof that have at least 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 retain hyaluronidase activity.

38. The method of claim 37, wherein the hyaluronidase is a soluble hyaluronidase provided as a composition designated rHuPH20.

39. The method of claim 37, wherein the fast-acting insulin analog and hyaluronan degrading enzyme are administered to the subject via syringe, insulin pen, insulin pump or a closed loop system.

40. A method for controlling post-prandial glucose levels in a subject, comprising administering to the subject a hyaluronidase and a fast-acting insulin analog, wherein:

the hyaluronidase and fast-acting insulin analog are administered simultaneously or sequentially;

the fast-acting insulin analog is insulin aspart or insulin glulisine; and

administration is via subcutaneous, intradermal, intramuscular or intraperitoneal administration.

41. The method of claim 40, wherein the hyaluronidase is a soluble human PH20.

42. The method of claim 40, wherein the hyaluronidase is a truncated human PH20 that is selected from among polypeptides having a sequence of amino acids set forth in any of SEQ ID NOS:

4-9, or allelic variants or other variants thereof that have at least 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 retain hyaluronidase activity.