Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin

• US 7,169,889 B1
• Filed: 06/19/2000
• Issued: 01/30/2007
• Est. Priority Date: 06/19/1999
• Status: Expired due to Term

• Current Assignee: Biocon Limited (Biocon Incorporated), Protein Delivery Inc.
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri N., Ramaswamy, Muthukumar, Rajagopalan, Jayanthi
• Primary Examiner(s): Russel; Jeffrey E.
• Application Number:
  US10/018,879
• Time in Patent Office: 2,416 Days
• Field of Search: 530/300, 530/322, 530/345, 530/409, 530/410, 530/411, 530/303, 514/2, 514/3, 514/8, 514/12, 514/21
• US Class Current: 530/303
• 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 following general formula:

D—

[(H—

H′

_q)—

L_o]_p 

 

(Formula

     10)

wherein

D is insulin or a functional equivalent thereof;

H is a PEG polymer having from 1 to 10 PEG units;

H′

is a hydrophilic moiety;

L is a lipophilic moiety;

the H—

H′

bond is hydrolyzable;

q is a number from 1 to the maximum number of covalent bonding sites at which H′

can form a bond with H;

o is a number from 1 to the maximum number of covalent bonding sites at which L can form a bond with H′

; and

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

[(H—

H′

_q)—

L_o] can form a bond with D.

2. The drug-oligomer conjugate of claim 1, wherein H, H′

and L are selected and arranged such that the drug-oligomer conjugate is amphiphilic.

3. The drug-oligomer conjugate of claim 1, wherein H is a PEG polymer having from 2 to 8 PEG units.

4. The drug-oligomer conjugate of claim 1, wherein H is a PEG polymer having from 2 to 7 PEG units.

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

6. The drug-oligomer conjugate of claim 1, wherein H is a PEG polymer having 4 PEG units.

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

8. The drug-oligomer conjugate of claim 1, wherein H is a PEG polymer having 6 PEG units.

9. The drug-oligomer conjugate of claim 1, wherein H′

is a hydrophilic moiety selected from the group consisting of straight or branched PEG polymers and sugars.

10. The drug-oligomer conjugate of claim 1, wherein H′

is a straight PEG polymer.

11. The drug-oligomer conjugate of claim 10, wherein the PEG polymer has from 1 to 130 PEG units.

12. The drug-oligomer conjugate of claim 10, wherein the PEG polymer has from 1 to 100 PEG units.

13. The drug-oligomer conjugate of claim 1, wherein L is a lipophilic moiety selected from the group consisting of alkyl moieties, cholesterol, and fatty acid moieties.

14. The drug-oligomer conjugate of claim 1, wherein L is an alkyl moiety.

15. The drug-oligomer conjugate of claim 1, wherein L is cholesterol.

16. The drug-oligomer conjugate of claim 1, wherein L is a fatty acid moiety.

17. The drug-oligomer conjugate of claim 16, wherein the fatty acid moiety has between 2 and 28 carbon atoms.

18. The drug-oligomer conjugate of claim 16, wherein the fatty acid moiety has between 12 and 22 carbon atoms.

19. The drug-oligomer conjugate of claim 1, wherein D is insulin or insulin lispro.

20. The drug-oligomer conjugate of claim 1, wherein the H′

—

L bond is non-hydrolyzable.

21. The drug-oligomer conjugate of claim 1, wherein H′

and L are present as a component H′

—

L having the formula CH₃(CH₂)_n(OC₂H₄)_mOH (Formula

     3), wherein n=3 to 25 and m=1 to 7.

22. The drug-oligomer conjugate of claim 1, wherein H′

and L are present as a component H′

—

L having the formula CH₃(CH₂)_n(OC₂H₄)_mOCH₂CO₂H (Formula

     4), wherein n=3 to 25 and m=1 to 6.

23. The drug-oligomer conjugate of claim 1, wherein H′

and L are present as a component H′

—

L having the formula R—

(OC₂H₄)_mCH₂CO₂H (Formula

     6), wherein m=0 to 5 and R=cholesterol or adamantane.

24. The drug-oligomer conjugate of claim 1, wherein H′

and L are present as a component H′

—

L having the formula CH₃(CH₂—

CH═

CH)₆(CH₂)₂CH₂(OC₂H₄)_mOH (Formula

     8), wherein m=1 to 7.

25. The drug-oligomer conjugate of claim 1, wherein H′

and L are present as a component H′

—

L having the formula CH₃(CH₂—

CH═

CH)₆(CH₂)₂CX(OC₂H₄)_mOH (Formula

     9), wherein m=1 to 7.