PEGylated insulin lispro compounds

• US 9,050,371 B2
• Filed: 06/09/2009
• Issued: 06/09/2015
• Est. Priority Date: 06/13/2008
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Beals, John Michael, Hansen, Ryan John, Li, Shun, Zhang, Lianshan, Cutler, Gordon Butler Jr.
• Primary Examiner(s): PAK, MICHAEL D
• Application Number:
  US12/481,111
• Publication Number:
  US 20090312236A1
• Time in Patent Office: 2,191 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• 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: C07K 1/00 General methods for the preparation of peptides , i.e. processes for the organic chemical preparation of peptides or proteins of any length

Abstract

The present invention relates to the field of diabetes. More particularly, the invention relates to PEGylated insulin lispro compounds that are PEGylated with high molecular weight poly(ethylene glycol), are highly soluble at physiological pH, have an extended duration of action, and characterized by pharmacokinetic, pharmacodynamic, and/or activity peak-trough ratios of less than 2. The invention also relates to methods of providing such molecules, to pharmaceutical compositions containing them, and to their therapeutic uses.

Claims

1. A PEGylated insulin lispro compound of the formula:

P-[(A)-(B)], or a pharmaceutically acceptable salt thereof, wherein;

A is the A-chain of insulin lispro (SEQ ID NO;

     1);

B is the B-chain of insulin lispro (SEQ ID NO;

     3); and

P is a PEG having a molecular weight in the range from about 17.5 kDa to about 25 kDa, and wherein A and B contain a disulfide bond between the cysteine at position 7 of A (SEQ ID NO;

     1) and the cysteine at position 7 of B (SEQ ID NO;

     3), a disulfide bond between the cysteine at position 20 of A (SEQ ID NO;

     1) and the cysteine at position 19 of B (SEQ ID NO;

     3), and a disulfide bond between the cysteine at position 6 of A (SEQ ID NO;

     1) and the cysteine at position 11 of A (SEQ ID NO;

     1) and P is attached via a urethane covalent bond to the epsilon-amino group of the lysine at position 28 of B.

3. The PEGylated insulin lispro compound of claim 1 wherein the PEG has a molecular weight of about 20 kDa.

2. A pharmaceutical composition comprising a PEGylated insulin lispro compound of the formula:

P-[(A)-(B)], or a pharmaceutically acceptable salt thereof, wherein;

A is the A-chain of insulin lispro (SEQ ID NO;

     1);

B is the B-chain of insulin lispro (SEQ ID NO;

     3); and

P is a PEG having a molecular weight in the range from about 17.5 kDa to about 25 kDa, and wherein A and B contain a disulfide bond between the cysteine at position 7 of A (SEQ ID NO;

     1) and the cysteine at position 7 of B (SEQ ID NO;

     3), a disulfide bond between the cysteine at position 20 of A (SEQ ID NO;

     1) and the cysteine at position 19 of B (SEQ ID NO;

     3), and a disulfide bond between the cysteine at position 6 of A (SEQ ID NO;

     1) and the cysteine at position 11 of A (SEQ ID NO;

     1) and P is attached via a urethane covalent bond to the epsilon-amino group of the lysine at position 28 of B, and one or more pharmaceutically acceptable excipients, diluents, or carriers.

4. The pharmaceutical composition according to claim 2 wherein the PEG has a molecular weight of about 20 kDa.