PEGylated insulin lispro compounds

Patent metadata

Field	Value
Publication number	US-9050371-B2
Application number	US-48111109-A
Country	US
Kind code	B2
Filing date	Jun 9, 2009
Priority date	Jun 13, 2008
Publication date	Jun 9, 2015
Grant date	Jun 9, 2015

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.

First claim

We claim:

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.

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.

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

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

Assignees

• Beals John Michael
• Cutler Jr Gordon Butler
• Hansen Ryan John
• Li Shun
• Zhang Lianshan
• Lilly Co Eli

Inventors

• Beals John Michael
• Cutler Jr Gordon Butler
• Hansen Ryan John
• Li Shun
• Zhang Lianshan

Classifications

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K47/50

  the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates · CPC title

• A61K38/28 Primary

  Insulins · CPC title

• C07K1/00

  General methods for the preparation of peptides {, i.e. processes for the organic chemical preparation of peptides or proteins of any length} · CPC title