Mixtures of insulin drug-oligomer comprising polyalkylene glycol

• US 7,084,114 B2
• Filed: 04/29/2004
• Issued: 08/01/2006
• Est. Priority Date: 06/04/2001
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Odenbaugh, Amy L., Price, Christopher H., Ansari, Aslam M.
• Primary Examiner(s): Russel, Jeffrey Edwin
• Application Number:
  US10/835,018
• Publication Number:
  US 20040198949A1
• Time in Patent Office: 824 Days
• Field of Search: None
• US Class Current: 514/6.3
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

A mixture of conjugates in which each conjugate in the mixture comprises an insulin drug coupled to an oligomer that includes a polyalkylene glycol moiety is disclosed. The mixture may exhibit higher in vivo activity than a polydispersed mixture of similar conjugates. The mixture may also be more effective at surviving an in vitro model of intestinal digestion than polydispersed mixtures of similar conjugates. The mixture may also result in less inter-subject variability than polydispersed mixtures of similar conjugates.

Claims

1. A substantially monodispersed mixture of conjugates each comprising human insulin covalently coupled at Lys^B29 of the human insulin to an oligomer having a formula:

2. The substantially monodispersed mixture according to claim 1, wherein the conjugates each consist of human insulin covalently coupled at Lys^B29 of the human insulin to an oligomer having a formula:

4. The mixture according to claim 1, wherein the substantially monodispersed mixture exhibits an in vitro activity that is greater than the in vitro activity of a corresponding polydispersed mixture of the insulin drug-oligomer conjugates.

5. The mixture according to claim 1, wherein the substantially monodispersed mixture exhibits an increased resistance to degradation by chymotrypsin when compared to the resistance to degradation by chymotrypsin of a corresponding polydispersed mixture of insulin drug-oligomer conjugates.

6. The mixture according to claim 1, wherein the substantially monodispersed mixture exhibits an inter-subject variability that is less than the inter-subject variability of a corresponding polydispersed mixture of insulin drug-oligomer conjugates.

3. A substantially monodispersed mixture of conjugates each comprising an insulin drug coupled to an oligomer having a formula:

7. A mixture of conjugates each comprising an insulin drug coupled at Lys^B29 to an oligomer having a formula:

8. The mixture according to claim 7, wherein the standard deviation of the molecular weight distribution is less than about 14 Daltons.

9. The mixture according to claim 7, wherein the standard deviation of the molecular weight distribution is less than about 11 Daltons.

10. A mixture of conjugates in which each conjugate:

(a) comprises an insulin drug coupled to an oligomer having a formula;

11. A substantially monodispersed mixture of conjugates each comprising human insulin covalently coupled at Lys^B29 of the human insulin to an oligomer having a formula: