Formulated composition

• US 6,559,122 B1
• Filed: 03/30/2000
• Issued: 05/06/2003
• Est. Priority Date: 04/08/1999
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Oeswein, James Q., Wang, Sharon X., Yeung, Douglas A., Smikahl, John R.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Mohamed, Abdel A.
• Application Number:
  US09/539,310
• Time in Patent Office: 1,132 Days
• Field of Search: 514/3, 514/4, 514/866, 530/303, 530/399, 435/808
• US Class Current: 514/6.6
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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
• CPC Class Codes: Y10S 435/808 Optical sensing apparatus
• CPC Class Codes: Y10S 530/808 Materials and products related to genetic engineering or hybrid or fused cell technology, e.g. hybridoma, monoclonal products

Abstract

A composition is disclosed that comprises a mixture of polypeptides of opposite charge and an excipient selected from the group consisting of arginine, lysine, glutamic acid, sodium dodecyl sulfate, beta-hydroxy cyclodextrin, and beta-cyclodextrin sulfobutyl ether.

Claims

1. A composition comprising a mixture of insulin-like growth factor-I (IGF-I) and hexameric insulin without zinc and protamine (hexameric insulin) and an excipient selected from the group consisting of arginine, lysine, glutamate, sodium dodecyl sulfate, and a combination of beta-hydroxy cyclodextrin and arginine, wherein the IGF-I and hexameric insulin remain completely solvated in the composition, and wherein the hexameric insulin and IGF-I are present in a volume:

volume ratio of from about 1;

6 to 6;

1.

2. The composition of claim 1 wherein the volume:

volume ratio of hexatmeric insulin;

IGF-I is from about 0.2;

1 to 1;

1.

3. The composition of claim 1 further comprising phosphate-buffered saline.

4. The composition of claim 1 further comprising a stabilizer.

5. The composition of claim 1 wherein the excipient is arginine and additionaallyl comprising histidine and a phenol.

6. The composition of claim 1 wherein the excipient is sodium dodecyl sulfate in a concentration of about 1-10% and the hexameric insulin and IGF-I are present in a volume:

volume ratio of from about 1;

1 to 6;

1.

7. The composition of claim 1 comprising about 5-20 mg/ml IGF-I, about 2-10 mg/ml hexameric insulin, about 100-200 mM arginine, about 5-20 mM histidiine at pH about 7-7.5, and about 1-5 mg/ml phenol.

8. The composition of claim 1 comprising about 10 mg/ml IGF-I, about 3-4 mg/ml hexameric insulin, about 160 mM arginine, about 10 mM hiscidine at pH 7.2, and about 3 mg/ml phenol.

9. The composition of claim 1 wherein the IGF-I and hexameric insulin are not complexed.

10. The composition of claim 1 wherein the excipient is arginine.

11. The composition of claim 10 wherein two or more of said excipients are used.

12. The composition of claim 1 wherein two or more of said excipients are used.

13. The composition of claim 12 wherein the excipients are arginine, sodium dodecyl sulfate, and beta-cyclodextrin sulfobutyl ether.

14. The composition of claim 1 wherein the excipient is arginine in a concentration of about 100 to 300 mM.

15. The composition of claim 14 further comprising beta-cyclodextrin sulfobutyl ether as excipient in a concentration of about 1-10%.

16. The composition of claim 1 further comprising a buffer.

17. The composition of claim 16 wherein the buffer is at a pH of about 7 to 7.5.

18. The composition of claim 17 wherein the buffer is histidine.

19. A method for preparing the position of claim 1 comprising mixing together as component (a) the IGF-I in an excipient selected from the group consisting of arginine, lysine, glutamic acid, sodium dodecyl sulfate, beta-hydroxy cyclodextrin, and beta-cyclodextrin sulfobutyl ether;

and as component (b) the hexaneric insulin.

20. The method of claim 19 further comprising incubating the mixture for a period of time at about 30-40°

C., wherein the composition further comprises phosphate-buffered saline.

21. The method of claim 20 wherein the mixture is incubated for about 15 minutes at 37°

C.

22. A kit comprising:

(a) a container comprising the composition of claim 1 comprising effective amounts of the hexameric insulin and IGF-I; and

(b) instructions for using the above composition to treat a disorder against which the composition is effective.

23. The kit of claim 22 wherein the disorder is a hyperglycemic disorder.

24. A kit for preparing the composition of claim 1 comprising:

(a) a container comprising the IGF-I in an excipient selected from the group consisting of arginine, lysine, glutamic acid, sodium dodecyl sulfate, and a combination of beta-hydroxy cyclodextrin and arginine;

(b) a container comprising the hexameric insulin; and

(c) instructions for combining the contents of containers (a) and (b).

25. The kit of claim 24 wherein when the IGF-I and hexameric insulin are combined, the composition is a pharmaceutically acceptable formulation.

26. The kit of claim 25 wherein the pharmaceutically acceptable formulation is for treating a hyperglycemic disorder.

27. The kit of claim 24 wherein the excipient is arginine.

28. The kit of claim 27 wherein container (a) comprises about 5-20 mg/ml IGF-I, about 100-200 mM arginine, about 5-20 mM histidine at about pH 7-7.5, and about 1-5 mg/ml phenol.

29. The kit of claim 28 wherein container (a) comprises about 10 mg/ml IGF-I, about 160 mM arginine, about 10 mM histidine at about pH 7.2, and about 3 mg/ml phenol.

30. A composition comprising a mixture of insulin-like growth factor-I (IGF-I) and a mixture of 70% crystal suspension of insulin-protamine complex wherein the crystals contain approximately 0.9 molecules of protamine and two zinc atoms per insulin hexamer and 30% hexameric insulin without zinc and protamine (70%/30% mixture), arginine, histidine, and phenol, wherein the IGF-I and 70%/30% mixture remain completely solvated in the composition, and wherein the 70%/30% mixture and IGF-I are present in a volume:

volume ratio of from about 1;

1 to 6;

1.

31. The composition of claim 30 comprising about 5-20 mg/ml IGF-I, about 100-200 mM arginine, about 5-20 mM histidine at pH about 7-7.5 and about 1-5 mg/ml phenol.

32. The composition of claim 30 comprising about 10 mg/ml IGF-I, about 160 mM arginine, about 10 mM histidine at pH 7.2 and about 3 mg/ml phenol.