Polymer conjugates of opioid antagonists
View Patent ↗The invention provides polymer conjugates of opioid antagonists comprising a polymer, such as poly(ethylene glycol), covalently attached to an opioid antagonist. The linkage between the polymer and the opioid antagonist is preferably hydrolytically stable. The invention also includes a method of treating one or more side effects associated with the use of opioid analgesics, such as constipation, nausea, or pruritus, by administering a polymer conjugate of the invention.
1. A polymer conjugate according to the formula:
or pharmaceutically acceptable salt thereof, wherein:
Y is allyl;
Z is OH;
X is amide, amine, carbamate, sulfide, ether, thioether or urea; and
POLY is methoxy poly(ethylene glycol), wherein POLY has a molecular weight of from about 100 Da to about 2,000 Da.
2. The polymer conjugate of claim 1 , wherein POLY has the formula
CH 3 O—(CH 2 CH 2 O) n —CH 2 CH 2 —
wherein n is from 2 to 45.
3. The polymer conjugate of claim 2 , wherein n is from 2 to 20.
4. The polymer conjugate of claim 1 , wherein POLY has a molecular weight of from about 100 Da to about 500 Da.
5. The polymer conjugate of claim 1 , wherein X is amide.
6. The polymer conjugate of claim 1 , wherein X is amine.
7. The polymer conjugate of claim 1 , wherein X is carbamate.
8. The polymer conjugate of claim 1 , wherein X is sulfide.
9. The polymer conjugate of claim 1 , wherein X is ether.
10. The polymer conjugate of claim 1 , wherein X is thioether.
11. The polymer conjugate of claim 1 , wherein X is urea.
12. A pharmaceutical composition comprising
a polymer conjugate and
a pharmaceutically acceptable carrier
wherein the polymer conjugate has the formula:
or pharmaceutically acceptable salt thereof, wherein:
Y is allyl;
Z is OH;
X is amide, amine, carbamate, sulfide, ether, thioether or urea; and
POLY is methoxy poly(ethylene glycol), wherein POLY has a molecular weight of from about 100 Da to about 2,000 Da.
13. The pharmaceutical composition of claim 12 , wherein POLY has the formula
CH 3 O—(CH 2 CH 2 O) n CH 2 CH 2 —
wherein n is from 2 to 45.
14. The pharmaceutical composition of claim 12 , wherein n is from 2 to 20.
15. The pharmaceutical composition of claim 12 , wherein POLY has a molecular weight of from about 100 Da to about 500 Da.
16. The pharmaceutical composition of claim 12 , wherein X is amide.
17. The pharmaceutical composition of claim 12 , wherein X is amine.
18. The pharmaceutical composition of claim 12 , wherein X is carbamate.
19. The pharmaceutical composition of claim 12 , wherein X is sulfide.
20. The pharmaceutical composition of claim 12 , wherein X is ether.
21. The pharmaceutical composition of claim 12 , wherein X is thioether.
22. The pharmaceutical composition of claim 12 , wherein X is urea.