Insulin analog formulations

• US 5,547,929 A
• Filed: 09/12/1994
• Issued: 08/20/1996
• Est. Priority Date: 09/12/1994
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Anderson, James H. Jr., Havel, Henry A., De Felippis, Michael R., Frank, Bruce H.
• Primary Examiner(s): Nucker, Christine M.
• Assistant Examiner(s): Prickril, Benet
• Application Number:
  US08/304,070
• Time in Patent Office: 708 Days
• Field of Search: 530/303, 530/304, 530/305, 514/3, 514/4
• US Class Current: 514/6.1
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention discloses various parenteral pharmaceutical formulations, which comprise a mixture of a monomeric insulin analog and insulin-NPH. The analog formulations provide a rapid onset and a prolonged duration of action.

Claims

1. A parenteral pharmaceutical formulation comprising a soluble phase comprising an insulin analog and a solid phase comprising insulin-NPH crystals;

wherein;

the insulin analog is human insulin wherein Pro at position B28 is substituted with Asp, Lys, Leu, Val, or Ala, and Lys at position B29 is Lysine or Proline, des(B28-B30), or des(B27);

the insulin-NPH crystals comprise about 0.25 to about 0.30 mg of protamine per 100 U of insulin; and

the soluble phase contains less than about 20% insulin relative to the total soluble protein concentration.

2. The formulation of claim 1, wherein the soluble phase contains less than 10% insulin relative to the total soluble protein concentration.

3. The formulation of claim 2 wherein the insulin-NPH crystals comprise about 0.27 mg of protamine per 100 U of human insulin.

4. The formulation of claim 3 wherein the ratio of insulin analog to insulin-NPH crystals is about 1:

99 to 99;

1.

5. The formulation of claim 4 wherein the insulin analog is Lys^B28 Pro^B29 -human insulin.

6. The formulation of claim 5 wherein the ratio of Lys^B28 Pro^B29 -human insulin to insulin-NPH is about 75:

25 to 25;

75.

7. The formulation of claim 6 wherein the ratio of Lys^B28 Pro^B29 -human insulin to insulin-NPH is about 50:

50.

8. The formulation of claim 7 which further comprises a pharmaceutically acceptable preservative.

9. The formulation of claim 8 wherein the preservative is phenol, m-cresol, or a mixture thereof.

10. The formulation of claim 9 which further comprises an isotonicity agent.

11. A process for preparing a heterogeneous parenteral formulation, which comprises mixing a soluble phase comprising an insulin analog, and a solid phase comprising insulin-NPH wherein the insulin analog is human insulin wherein Pro at position B28 is substituted with Asp, Lys, Leu, Val, or Ala, and Lys at position B29 is Lysine or Proline, des(B28-B30), or des(B27);

and the formulation contains less than 20% insulin relative to the total soluble protein concentration in the soluble phase.

12. The process of claim 11, wherein the insulin-NPH comprises about 0.25 to about 0.30 mg of protamine per 100 U of insulin;

and the insulin-NPH is aged for at least two days.

13. The process of claim 12, wherein the soluble phase contains less than 10% insulin relative to the total soluble protein concentration.

14. The process of claim 13, wherein the insulin analog is Lys^B28 Pro^B29 -human insulin.

15. An insulin formulation produced by the process of claim 14.