Novel formulations

• US 20040006000A1
• Filed: 05/05/2003
• Published: 01/08/2004
• Est. Priority Date: 05/07/2002
• Status: Abandoned Application

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Langkjaer, Liselotte
• Application Number:
  US10/429,508
• Publication Number:
  US 20040006000A1
• Time in Patent Office: Days
• US Class Current: 514/3
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

Stable insulin formulations can be prepared by mixing a monomeric insulin and a soluble acylated insulin analog.

Claims

1. A pharmaceutical soluble formulation comprising (i) a soluble acylated insulin analogue and (ii) a monomeric insulin or human insulin, wherein the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 7:

93, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 57;

43.

2. A formulation according to claim 1, wherein the lower limit is 11:

89 and the upper limit is 41;

59.

4. The formulation according to claim 1, wherein the pH of the formulation is in the range from about 7 to about 8.

5. The formulation according to claim 1, which is suitable for use in a continuous infusion system.

6. The formulation according to claim 1, further comprising one or more of:

an agent rendering the solution isotonic, an antimicrobial preservative, a pH-buffering agent, and a suitable zinc salt.

7. The formulation according to claim 1, wherein the soluble acylated insulin analogue is insulin detemir.

8. The formulation according to claim 1, comprising human insulin.

9. The formulation according to claim 1, wherein the monomeric insulin is insulin aspart.

10. The formulation according to claim 1, wherein the monomeric insulin is insulin lispro.

11. The formulation according to claim 1, wherein the monomeric insulin is insulin glulisine (Lys^B3,Glu^B29 human insulin).

12. The formulation according to claim 1, wherein the monomeric insulin is different from insulin aspart, insulin lispro, and insulin glulisine (Lys^B3,Glu^B29 human insulin).

13. The formulation according to claim 1, wherein the concentration of insulin is between about 10 U/ml and 1500 U/ml.

14. The formulation according to claim 1, wherein the preservative is phenol, m-cresol or a mixture of phenol and m-cresol.

15. The formulation according to claim 1, wherein the concentration of phenol and/or m-cresol is in the range from about 20 mM to about 50 mM.

16. The formulation according to claim 1, comprising zinc ions in an amount corresponding to from about 2.3 to about 4.5 Zn²⁺ per insulin hexamer.

17. The formulation according to claim 1, wherein the zinc salt is zinc chloride, zinc oxide, or zinc acetate.

18. The formulation according to claim 1, containing halogenide ions at a concentration from about 1 to about 100 mM.

19. The formulation according to claim 1, containing as isotonic agent glycerol, mannitol, sorbitol, or a mixture thereof in a concentration in the range from about 100 to about 250 mM.

20. The formulation according to claim 1, wherein the pH-buffer is sodium phosphate, TRIS (trometamol), N-glycylglycine, or L-arginine.

21. The formulation according to claim 1, wherein the pH-buffer is a physiologically acceptable buffer in a concentration in the range from about 3 mM to about 20 mM.

22. The formulation according to claim 1, comprising:

(i) insulin aspart (ii) insulin detemir, wherein the concentrations of (i) and (ii) are suitable for continuous infusion systems; and

(iii) a phenolic preservative at a concentration of about 30 mM to about 40 mM;

(iv) glycerol in a concentration of about 0.17 M;

(v) dibasic sodium phosphate at concentration of about 5 mM to about 7 mM;

(vi) zinc ions in an amount corresponding to about 2.5 to about 3.5 Zn²⁺/hexamer insulin or from about 0.4 to about 0.6 Zn²⁺/monomer insulin.

28. A method of treating diabetes in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical formulation according to claim 1.

29. A method, according to the previous claims, which is characterized by any of the features mentioned specifically in any of the above sub claims to pharmaceutical compositions.

31. A reservoir in a continuous infusion system comprising a pharmaceutical formulation according to claim 1.

32. The reservoir, according to claim 31, which is characterized by any of the features mentioned specifically in any of the above sub claims to pharmaceutical compositions.

3. A pharmaceutical soluble formulation comprising (i) a soluble acylated insulin analogue and (ii) a monomeric insulin or human insulin, wherein the ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is in the range from about 7:

93 to about 57;

43 on a mole to mole basis, with the proviso that if the soluble acylated insulin analogue is insulin detemir and the monomeric insulin is insulin aspart then the ratio between detemir and aspart is not more than about 41;

59 on a mole to mole basis.

23. The use of a soluble acylated insulin analogue in an amount in the range with the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin being 7%, preferably 11%, more preferred 14%, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin being 57%, preferably 41%, more preferred 31%, preferably 24% and even more preferred 20%, of the total amount of insulin to improve the physical stability in an aqueous solution containing a monomeric insulin or human insulin.

24. The use, according to any one of the previous use claims, wherein the improvement in physical stability is a reduction or avoidance of fibrillation.

25. The use, according to the previous claim, wherein the stability factor, when determined by the test described in example 1 above, of the formulation is above about 2.5, preferably above about 4.

27. The use, according to any one of the two preceding claims, which is characterized by any of the features mentioned specifically in any of the above sub claims to pharmaceutical compositions.

26. The use of a soluble acylated insulin analogue in an amount in the range with the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin being 7%, preferably 11%, more preferred 14%, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin being 57%, preferably 41%, more preferred 31%, preferably 24% and even more preferred 20%, of the total amount of insulin to reduce the risk for ketoacidosis in an aqueous solution containing a monomeric insulin or human insulin.

30. A reservoir in a continuous infusion system comprising a soluble acylated insulin analog.

33. Any novel feature or combination of features described herein.

34. A method for stabilizing a pharmaceutical formulation, said method comprising:

(i) providing as a first component of said formulation a monomeric insulin and/or human insulin, and

(ii) adding as a second component of said formulation a soluble acylated insulin analogue,

wherein the lower limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 7;

93, and the upper limit of the molar ratio between the soluble acylated insulin analogue and the monomeric insulin or human insulin is 57;

43.