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Claims for Patent: 5,948,751

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Claims for Patent: 5,948,751

Title: X14-mannitol
Abstract:Insulin preparations of superior physical stability, comprising dissolved and/or precipitated human insulin or an analogue or derivative thereof, and a water-soluble reduced or non-reducing carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or a water-soluble non-reducing ester and/or ether derivative of a carbohydrate or reduced carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or mixtures thereof are disclosed.
Inventor(s): Kimer; Lone L.o slashed.gstrup (Farum, DK), Balschmidt; Per (Esperg.ae butted.rde, DK), Jensen; Steen (Drag.o slashed.r, DK)
Assignee: Novo Nordisk A/S (Bagsvaerd, DK)
Application Number:08/879,691
Patent Claims: 1. An aqueous insulin preparation comprising:

(i) dissolved and/or precipitated protein selected from the group consisting of human insulin, an analogue of human insulin, a derivative of human insulin, and mixtures of the foregoing; and

(ii) a water-soluble reduced or non-reducing carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or a water-soluble non-reducing ester and/or ether derivative of a carbohydrate or reduced carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or mixtures thereof, wherein said carbohydrate is present in an amount corresponding to 100 to 400 mM.

2. The insulin preparation of claim 1, wherein said carbohydrate or carbohydrate derivative contains from 5 to 18 carbon atoms in the main carbohydrate structure.

3. The insulin preparation of claim 2, wherein said carbohydrate is selected from the group consisting of mannitol, sorbitol, xylitol, trehalose, sucrose, and any mixture thereof.

4. The insulin preparation of claim 3, wherein said carbohydrate is mannitol.

5. The insulin preparation of claim 1, which further comprises a halogenide.

6. The insulin preparation of claim 5, wherein the halogenide is a chloride.

7. The insulin preparation of claim 6, wherein the chloride is sodium chloride.

8. An insulin preparation according to claim 7, wherein said sodium chloride is present at a concentration of 0 to 100 mM.

9. The insulin preparation of claim 1, wherein said analogue of human insulin is selected from the group consisting of: (i) human insulin in which position B28 is Asp, Lys, Leu, Val or Ala and position B29 is Lys or Pro; des (B28-B30) human insulin; des(B27) human insulin; and des(B30) human insulin.

10. The insulin preparation of claim 9, wherein said analogue of human insulin is an insulin in which position B28 is Asp or Lys, and position B29 is Lys or Pro.

11. The insulin preparation of claim 10, wherein the analogue is Asp.sup.B28 human insulin or Lys.sup.B28 Pro.sup.B29 human insulin.

12. The insulin preparation of claim 1, wherein said derivative of human insulin has one or more lipophilic subsitituents.

13. The insulin preparation of claim 12, wherein the derivative is an acylated insulin.

14. The insulin preparation of claim 1, wherein said derivative of human insulin is selected from the group consisting of:

B29-N.sup..epsilon. -myristoyl-des(B30)-humaninsulin, B29-N.sup..epsilon. -myristoylhumaninsulin, B29-N.sup..epsilon. -palmitoyl human insulin, B28-N.sup..epsilon. -myristoyl Lys.sup.B28 Pro.sup.B29 human insulin, B28-N.sup..epsilon. -palmitoyl Lys.sup.B28 Pro.sup.B29 human insulin, B30-N.sup..epsilon. -myristoyl-Thr.sup.B29 Lys.sup.B30 -human insulin, B30-N.sup..epsilon. -palmitoyl-Thr.sup.B29 Lys.sup.B30 -human insulin, B29-N.sup..epsilon. -(N-palmitoyl-.gamma.-glutamyl)-des(B30-human insulin, B29-N.sup..epsilon. -(N-lithocholyl-.gamma.-glutamyl)-des(B30)-human insulin and B29-N.sup..epsilon. -(.omega.-carboxyheptadecanoyl)-des(B30)-human insulin.

15. The insulin preparation of claim 14, wherein the derivative is B29-N.sup..epsilon. -myristoyl-des(B30)-human insulin.

16. The insulin preparation of claim 1, wherein said precipitated protein comprises crystals comprising (i) insulin, insulin analogue or insulin derivative, and (ii) protamine.

17. The insulin preparation of claim 16, in which the crystals further comprise zinc and optionally one or more phenolic compounds.

18. The insulin preparation of claim 1, wherein said dissolved and precipitated insulin or insulin analogue is present in a weight ratio of 1:99 to 99:1.

19. The insulin preparation of claim 18, wherein the precipitated insulin or insulin analogue is crystalline.

20. The insulin preparation of claim 18, wherein said weight ratio is 20:80 to 80:20.

21. The insulin preparation of claim 20, wherein said weight ratio is 30:70 to 70:30.

22. The insulin preparation of claim 1, in which the carbohydrate is mannitol.

23. The insulin preparation of claim 22, wherein the carbohydrate is present in an amount corresponding to 150 to 250 mM.

24. The insulin preparation of claim 23, wherein the carbohydrate is present in an amount corresponding to 180 to 230 mM.

25. The insulin preparation of claim 1, wherein said human insulin or insulin analogue or derivative is present in an amount of 60 to 3000 nmol/ml.

26. The insulin preparation of claim 25, wherein the amount of human insulin or insulin analogue or derivative is 240 to 1200 nmol/ml.

27. The insulin preparation of claim 8, wherein said sodium chloride is present at a concentration of 5 to 40 mM.

28. The insulin preparation of claim 27, wherein said concentration is 5 to 20 mM.

29. The insulin preparation of claim 1, further comprising a physiologically tolerated buffer.

30. The insulin preparation of claim 29, wherein the buffer is a phosphate buffer.

31. A parenteral pharmaceutical formulation comprising the insulin preparation of claim 15.

32. A method for preparing an insulin preparation containing both dissolved and precipitated insulin analogue, comprising the steps of:

a) providing an acidic solution comprising an analogue of human insulin, zinc, and a sub-isophanic amount of protamine;

b) providing an alkaline solution comprising a substance which acts as a buffer at physiological pH;

wherein the solution of step a) and/or step b) comprises a water-soluble reduced or non-reducing carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or a water-soluble non-reducing ester and/or ether derivative of a carbohydrate or reduced carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or mixtures thereof, in an amount corresponding to 100 to 400 mM and wherein at least one of the above solutions further comprises a phenolic compound;

c) mixing the acidic and alkaline solutions and, optionally, adjusting the pH to a value in the range of 6.5 to 8.0; and

d) leaving the resulting suspension for precipitation.

33. The method of claim 32, wherein the weight ratio of insulin analogue to protamine in the solution of step a) is selected so as to obtain in the final product a weight ratio of dissolved to precipitated insulin analogue in the range of 1:99 to 99:1.

34. The method of claim 33, wherein the solution of step a) comprises 120 to 6000 nmol/ml of insulin analogue and 0.01 to 5.0 mg/ml of protamine.

35. The method of claim 32, wherein said zinc is present in the solution of step a) in an amount corresponding; to 10-40 .mu.g zinc/100 IU insulin.

36. The method of claim 32, wherein solution a) and/or solution b) comprises chloride in an amount corresponding to 0 to 100 mM in the final product.

37. The method of claim 32, wherein the pH of the acidic solution of step a) is below 5.

38. The method of claim 32, wherein the insulin analogue is selected from the group consisting of: human insulin wherein position B28 is iasp, Lys, Leu, Val or Ala and position B29 is Lys or Pro; des (B28-B30) human insulin, des(B27) human insulin and des(B30) human insulin.

39. The method of claim 38, wherein the insulin analogue is selected from the group consisting of Asp.sup.B28 human insulin and Lys.sup.B28 Pro.sup.B29 human insulin.

40. The method of claim 32, wherein the phenolic compound is selected from the group consisting of phenol, m-cresol or a mixture thereof.

41. The method of claim 32, wherein said carbohydrate or carbohydrate derivative contains from 5 to 18 carbon atoms in the main carbohydrate structure.

42. The method of claim 41, wherein said carbohydrate or carbohydrate derivative is selected from the group consisting of mannitol, sorbitol, xylitol, trehalose, sucrose, and any mixture thereof.

43. The method of claim 32, wherein the buffer substance employed in the alkaline solution of step b) is a physiologically tolerated buffer.

44. The method of claim 32, wherein the precipitated insulin analogue is in the form of crystals comprising insulin analogue and protamine.

45. The method of claim 32, wherein the suspension obtained in step d) is left at a temperature in the range of 5.degree. C. to 40.degree. C. for precipitation.

46. The method of claim 32, wherein in step (c) the pH is adjusted to between 7.0 and 7.8.

47. The method of claim 33, wherein the insulin or insulin analogue is in the weight ratio of 20:80 to 80:20.

48. The method of claim 34, wherein the insulin or insulin analogue is in the weight ratio of 30:70 to 70:30.

49. The method of claim 35, wherein said zinc is zinc chloride.

50. The method of claim 35, wherein the amount of zinc corresponds to 15-35 .mu.g zinc/100 IU insulin.

51. The method of claim 36, wherein said chloride is sodium chloride.

52. The method of claim 51, wherein said chloride is present in an amount corresponding to 5 to 20 mM in the final product.

53. The method of claim 37, wherein the pH of the acidic solution of step a) is in the range of 2 to 3.5.

54. The method of claim 39, wherein the insulin analogue is Asp.sup.B28 human insulin.

55. The method of claim 42, wherein said carbohydrate or carbohydrate derivative is selected from the group consisting of mannitol, sorbitol, and mixtures thereof.

56. The method of claim 43, wherein the buffer is a phosphate buffer.

57. The method of claim 56, wherein the buffer is disodium phosphate dihydrate.

58. The method of claim 45, wherein the temperature is 20.degree. C. to 36.degree. C.

59. The method of claim 58, wherein the temperature is 30.degree. C. to 34.degree. C.
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