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Claims for Patent: 5,461,031

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Claims for Patent: 5,461,031

Title: Monomeric insulin analog formulations
Abstract:The present invention discloses various parenteral pharmaceutical formulations, which comprise: a monomeric insulin analog, zinc, protamine, and phenolic derivative. The analog formulations provide a prolonged duration of action. A process for preparing insulin analog-protamine formulations is also described.
Inventor(s): De Felippis; Michael R. (Indianapolis, IN)
Assignee: Eli Lilly and Company (Indianapolis, IN)
Application Number:08/260,633
Patent Claims: 1. A parenteral pharmaceutical insulin analog-protamine formulation, consisting essentially of: a monomeric insulin analog, protamine, zinc, and a phenolic derivative; wherein a monomeric insulin analog is human insulin wherein Pro at position B28 is substituted with Lys, Leu, Val, or Ala; Lys at position B29 is Lys or Pro; des(B28-B30)-human insulin; or des(B27)-human insulin.

2. A formulation of claim 1, wherein the concentration of protamine is about 0.2 to about 1.5 mg of protamine to 100 IU of insulin analog on a free base basis.

3. A formulation of claim 2, wherein the concentration of zinc is about 0.35 to about 0.9 percent by weight.

4. A formulation of claim 3, wherein the phenolic derivative is phenol and m-cresol.

5. A parenteral pharmaceutical formulation, which comprises: a monomeric insulin analog, about an isophane ratio of protamine, about 0.35 to about 0.9% zinc by weight, and a phenolic derivative; wherein a monomeric insulin analog is human insulin wherein Pro at position B28 is substituted with, Lys, Leu, Val, or Ala; Lys at position B29 is Lys or Pro; des(B28-B30)-human insulin or des(B27)-human insulin.

6. A parenteral pharmaceutical formulation, consisting essentially of: Lys.sup.B28 Pro.sup.B29 -human insulin, about 0.27 to about 0.32 mg protamine/100 U of insulin analog, about 0.35 to about 0.9% zinc by weight, and a phenolic derivative.

7. The parenteral pharmaceutical formulation of claim 6, wherein the Lys.sup.B28 Pro.sup.B29 -human insulin and protamine are crystalline.

8. The parenteral pharmaceutical formulation of claim 7, which further comprises an isotonicity agent.

9. The parenteral pharmaceutical formulation of claim 8, which further comprises a physiologically tolerated buffer.

10. The parenteral pharmaceutical formulation of claim 9, wherein the concentration of protamine is about 0.30 mg protamine/100 U of Lys.sup.B28 Pro.sup.B29 -human insulin.

11. The parenteral pharmaceutical formulation of claim 10, wherein the concentration of zinc is about 0.7%.

12. The parenteral pharmaceutical formulation of claim 5, wherein the insulin analog is Leu.sup.B28 PRO.sup.B29 -human insulin, des(B27)-human insulin, or des(B28-B30)-human insulin.

13. A process for preparing Lys.sup.B28 Pro.sup.B29 -human insulin-protamine crystals, which comprises:

combining an aqueous solution of Lys.sup.B28 Pro.sup.B29 -human insulin in a hexamer association state, and a protamine solution at a temperature from about 8.degree. C. to about 17.degree. C. to form crystals;

said aqueous solution comprising from about 0.35 to about 0.9% zinc by weight, Lys.sup.B28 Pro.sup.B29 -human insulin, and a phenolic derivative at a pH of about 7.1 to about 7.6;

said protamine solution comprising protamine at a pH of about 7.1 to about 7.6 such that the final concentration of protamine is about 0.27 to about 0.32 mg protamine/100 U of insulin analog provided that the process is carried out in less than 4 mg/mL sodium chloride.

14. The process of claim 13, wherein the temperature is from about 13.degree. C. to about 17.degree. C.

15. The process of claim 13, wherein the concentration of zinc is about 0.7%.

16. A parenteral pharmaceutical formulation, which comprises: a mixture of soluble monomeric insulin analog and insulin analog-NPD crystals, in an aqueous diluent wherein the ratio of the two insulin analogs is about 1:99-99:1 by volume insulin analog-NPD to soluble monomeric insulin analog, and wherein said soluble monomeric insulin analog is human insulin wherein Pro at position B28 is substituted with Lys, Leu, Val, or Ala; Lys at position B29 is Lys or Pro; des(B28-B30)-human insulin or des(B27)-human insulin.

17. A parenteral pharmaceutical formulation of claim 16, wherein the mixture is Lys.sup.B28 Pro.sup.B29 -human insulin and Lys.sup.B28 Pro.sup.B29 -human insulin-protamine crystals.

18. The parenteral pharmaceutical formulation of claim 17, wherein the ratio is 75:25 to 25:75.

19. The parenteral pharmaceutical formulation of claim 18, wherein the ratio is 50:50.

20. A method of treating a patient suffering from diabetes mellitus, which comprises administering to said patient a pharmaceutical formulation of claim 1.

21. The method of claim 20, wherein the insulin analog is Lys.sup.B28 Pro.sup.B29 -human insulin.
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