Monomeric insulin analog formulations

• US 5,650,486 A
• Filed: 06/01/1995
• Issued: 07/22/1997
• Est. Priority Date: 06/16/1994
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: De Felippis, Michael R.
• Primary Examiner(s): SCHAIN, HOWARD
• Application Number:
  US08/458,150
• Time in Patent Office: 782 Days
• Field of Search: 530/303, 530/304, 530/305, 514/3, 514/4
• US Class Current: 530/305
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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
• CPC Class Codes: A61P 5/48 of the pancreatic hormones

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.

Claims

1. A process for preparing an insulin analog-protamine crystal, which comprises:

combining an aqueous solution of human insulin wherein Pro at position B28 is substituted with Asp, and Lys at position B29 is substituted with Lys or Pro in a hexamer association state, and a protamine solution at a temperature from about 5°

C. to about 22°

C.;

said aqueous solution comprising from about 0.35 to about 0.9% zinc by weight, human insulin wherein Pro at position B28 is substituted with Asp, and Lys at position B29 is substituted with Lys or Pro, 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 0.35 mg protamine to 100 IU of insulin analog.

2. The process of claim 1, wherein the process is carried out at a temperature from about 8°

C. to about 22°

C.

3. The process of claim 2, wherein the process is carried out at a temperature from about 13°

C. to about 17°

C.

4. The process of claim 3, wherein the process is carried out in less than about 4 mg/mL sodium chloride.

5. The process of claim 4, wherein the insulin is AspB28-human insulin.

6. The process of claim 5, wherein the phenotic derivative is phenol or m-cresol.

7. The process of claim 6, wherein the phenolic derivative is phenol.