Drug-oligomer conjugates with polyethylene glycol components

• US 7,030,084 B2
• Filed: 02/10/2004
• Issued: 04/18/2006
• Est. Priority Date: 06/19/1999
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Nobex Corporation (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri N., Ramaswamy, Muthukumar, Rajagopalan, Jayanthi
• Primary Examiner(s): RUSSEL, JEFFREY E
• Application Number:
  US10/774,903
• Publication Number:
  US 20040223948A1
• Time in Patent Office: 798 Days
• Field of Search: None
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

The present invention relates generally to hydrolyzable drug-oligomer conjugates, pharmaceutical compositions comprising such conjugates, and to methods for making and using such conjugates and pharmaceutical compositions. For example, a conjugate of insulin, PEG, and oleic acid can be orally administered.

Claims

1. A drug-oligomer conjugate having the formula:

D—

H_p

wherein D is a therapeutic drug moiety selected from the group consisting of insulin, insulin lispro, and a functional equivalent of insulin;

H is a PEG polymer having from 1 to 7 PEG units; and

p is a number from 1 to the maximum number of covalent bonding sites at which —

H can form a bond with D.

2. The drug-oligomer conjugate of claim 1, wherein the D—

H bonds are non-hydrolyzable.

3. The drug-oligomer conjugate of claim 1, wherein the D—

H bonds are selected from the group consisting of carbamate, amide and secondary amine.

4. The drug-oligomer conjugate of claim 1, wherein H is a PEG polymer having 2, 3, 4 or 5 PEG units.

5. The drug-oligomer conjugate of claim 1, wherein H is a PEG polymer having 3 PEG units.

7. A method of treating an insulin deficiency comprising causing the drug-oligomer conjugate of claim 1 to circulate in the bloodstream of a subject.

8. A method of treating an insulin deficiency comprising causing the drug-oligomer conjugate of claim 2 to circulate in the bloodstream of a subject.

9. A method of treating an insulin deficiency comprising causing the drug-oligomer conjugate of claim 3 to circulate in the bloodstream of a subject.

10. A method of treating an insulin deficiency comprising causing the drug-oligomer conjugate of claim 4 to circulate in the bloodstream of a subject.

11. A method of treating an insulin deficiency comprising causing the drug-oligomer conjugate of claim 5 to circulate in the bloodstream of a subject.

6. A drug-PEG conjugate having the formula:

D—

H_p

wherein D is selected from the group consisting of insulin, insulin lispro, and a functional equivalent of insulin;

H is a PEG polymer having from 1 to 7 PEG units; and

p is a number from 1 to the maximum number of covalent bonding sites at which

—

H can form a bond with D,

wherein the drug-PEG conjugate has enhanced activity in comparison with a corresponding unconjugated insulin molecule, unconjugated insulin lispro molecule or unconjugated functional equivalent thereof.

12. A method of treating an insulin deficiency comprising causing the drug-PEG conjugate of claim 6 to circulate in the bloodstream of a subject.