MIXTURES OF DRUG-OLIGOMER CONJUGATES COMPRISING POLYETHYLENE GLYCOL, USES THEREOF, AND METHODS OF MAKING SAME

• US 20080312135A1
• Filed: 06/18/2008
• Published: 12/18/2008
• Est. Priority Date: 06/04/2001
• Status: Abandoned Application

• Current Assignee: Nnochiri N. Ekwuribe
• Original Assignee: Nnochiri N. Ekwuribe
• Inventors: Ekwuribe, Nnochiri N.
• Application Number:
  US12/141,466
• Publication Number:
  US 20080312135A1
• Time in Patent Office: Days
• US Class Current: 514/3
• CPC Class Codes: A61K 2039/6093 Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 1/1077 by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids

Abstract

A non-polydispersed mixture of conjugates in which each conjugate in the mixture comprises a 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 be more effective at surviving an in vitro model of intestinal digestion than polydispersed mixtures of similar conjugates. The mixture may result in less inter-subject variability than polydispersed mixtures of similar conjugates.

Claims

1. A substantially purely monodispersed mixture of conjugates, each conjugate comprising an insulin drug coupled to at least one oligomer, wherein the oligomer comprises a polyethylene glycol moiety having at least 2 polyethylene glycol subunits, wherein at least 95% of the conjugates have the same molecule weight and same molecular structure.

2. The substantially purely monodispersed mixture according to claim 1, wherein the polyethylene glycol moiety has at least 5 polyethylene glycol subunits.

3. The substantially purely monodispersed mixture according to claim 1, wherein the polyethylene glycol moiety has at least 7 polyethylene glycol subunits.

4. The substantially purely monodispersed mixture according to claim 1, wherein the oligomer is covalently coupled to the drug.

5. The substantially purely monodispersed mixture according to claim 1, wherein the oligomer further comprises a lipophilic moiety.

6. The substantially purely monodispersed mixture according to claim 1, wherein at least 96 percent of the conjugates in the mixture have the same molecular weight and the same molecular structure.

7. The substantially purely monodispersed mixture according to claim 1, wherein the mixture has an in vivo activity that is greater than the in vivo activity of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture.

8. The substantially purely monodispersed mixture according to claim 1, wherein the mixture has an in vitro activity that is greater than the in vitro activity of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture.

9. The substantially purely monodispersed mixture according to claim 1, wherein the mixture has an increased resistance to degradation by chymotrypsin when compared to the resistance to degradation by chymotrypsin of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture.

10. The substantially purely monodispersed mixture according to claim 1, wherein each conjugate comprises a plurality of oligomers.

11. The substantially purely monodispersed mixture according to claim 1, wherein the oligomer comprises a first polyethylene glycol moiety covalently coupled to the insulin drug by a non-hydrolyzable bond and a second polyethylene glycol moiety covalently coupled to the first polyethylene glycol moiety by a hydrolyzable bond.

12. A pharmaceutical composition comprising:

the mixture according to claim 1; and

a pharmaceutically acceptable carrier.

13. A substantially monodispersed mixture of conjugates, each conjugate comprising an insulin drug coupled to an oligomer that comprises a polypropylene glycol moiety wherein at least 95% of the conjugates have the same molecule weight and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes, and wherein the polypropylene glycol moiety has a uniform structure as follows:

14. The substantially monodispersed mixture according to claim 13, wherein the oligomer is covalently coupled to the drug.

15. The substantially monodispersed mixture according to claim 13, wherein said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons.

16. A pharmaceutical composition comprising:

the substantially monodispersed mixture according to claim 13; and

pharmaceutically acceptable carrier.