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 method of treating constipation resulting from the administration of an opioid agonist to a patient in need thereof, said method comprising administering to the patient in need thereof a therapeutically effective amount of a polymer conjugate of the formula:
or pharmaceutically acceptable salt thereof, wherein:
Y is allyl;
Z is OH;
X is —NHC(O)—, —NH—, —OC(O)NH—, —O—, —S— or —NHC(O)NH—; and
POLY is methoxy poly(ethylene glycol), wherein POLY has a molecular weight of from about 100 Da to about 2,000 Da.
2. A method of treating nausea resulting from the administration of an opioid agonist to a patient in need thereof, said method comprising administer to the patient in need thereof a therapeutically effective amount of a polymer conjugate of the formula:
or pharmaceutically acceptable salt thereof, wherein:
Y is allyl;
Z is OH:
X is —NHC(O)—, —NH—, —OC(O)NH—, —O—, —S— or —NHC(O)NH—; and
POLY is methoxy poly(ethylene glycol), wherein POLY has a molecular weight of from about 100 Da to about 2.000 Da.
3. A method of treating pruritus resulting from the administration of an opioid agonist to a patient in need thereof, said method comprising administering to the patient in need thereof a therapeutically effective amount of a polymer conjugate of the formula:
or pharmaceutically acceptable salt thereof, wherein:
Y is allyl;
Z is OH;
X is —NHC(O)—, —NH—, —OC(O)NH—, —O—, —S— or —NHC(O)NH—; and
POLY is methoxy poly(ethylene glycol), wherein POLY has a molecular weight of from about 100 Da to about 2,000 Da.
4. The method 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.
5. The method of claim 4 , wherein n is from 2 to 20.
6. The method of claim 1 , wherein POLY has a molecular weight of from about 100 Da to about 500 Da.
7. The method of claim 1 , wherein X is —NHC(O)—.
8. The method of claim 1 , wherein X is —NH—.
9. The method of claim 1 , wherein X is —OC(O)NH—.
10. The method of claim 1 , wherein X is —O—.
11. The method of claim 1 , wherein X is —S—.
12. The method of claim 1 , wherein X is —NHC(O)NH—.