Subcutaneous delivery of polymer conjugates of therapeutic agents
The present disclosure provides polymer conjugates comprising a polymer and an agent, the agent linked to the polymer via a linking group containing a cleavable moiety.
1. A method for treating a disease or condition selected from the group consisting of restless leg syndrome and Parkinson's disease in a subject in need thereof, the method comprising the step of administering to the subject a poly(oxazoline) polymer conjugate comprising a water soluble poly(oxazoline) polymer and an agent, wherein a release profile of the agent is selectable based on the selection of the poly(oxazoline) polymer conjugate, the poly(oxazoline) polymer conjugate having the structure:
wherein
L is
R 3 forms a linkage with the poly(oxazoline) polymer;
R 4 is —CH 2 —C(O)—O—, —CH(CH 3 )—C(O)—O—, —CH 2 —CH 2 —C(O)—O—, —CH 2 —CH 2 —CH 2 —C(O)—O—, —CH 2 —O—C(O)—, —CH(CH 3 )—O—C(O)—, —CH 2 —CH 2 —O—C(O)— or —CH 2 —CH 2 —CH 2 —O—C(O)—;
R is an initiating group;
R 1 is a non-reactive group;
A is rotigotine, pramipexole, quinagolide, fenoldopam, apomorphine, 5-OH-DPAT, ropinirole, pergolide, cabergoline, bromocriptine, theophylline, istradefylline, preladenant trihexyphenidyl, biperidin, hyoscyamine, selegiline, rasagiline, tolcapone or entacapone;
a is ran which indicates a random copolymer or block which indicates a block copolymer;
o is from 1-50;
m is from 1-1000; and
T is a terminating group,
wherein the release profile is dependent on the selection of R 4 .
2. The method of claim 1 , wherein R 3 is —C(O)—(CH 2 ) 3 and R 4 is —CH 2 —C(O)—O—, —CH 2 —CH 2 —C(O)—O—, —CH(CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
3. The method of claim 1 , wherein L has the structure
4. The method of claim 1 , wherein T is —Z—B-Q
wherein
Z is S, O, or N;
B is an optional linking group; and
Q is a terminal portion of a terminating nucleophile.
5. The method of claim 1 , wherein R is hydrogen, alkyl or substituted alkyl.
6. The method of claim 1 , wherein the agent is rotigotine.
7. The method of claim 1 , wherein the polymer conjugate is administered alone or as a part of a pharmaceutical composition.
8. The method of claim 1 , wherein the polymer conjugate is administered in a therapeutically effective amount.
9. The method of claim 1 , wherein the polymer conjugate is administered by subcutaneous administration.
10. The method of claim 6 , wherein the release profile provides a controllable delivery of the rotigotine over a period of days.
11. The method of claim 6 , wherein the release profile provides a controllable delivery of the rotigotine over a period of weeks.
12. The method of claim 1 , wherein R 3 is —C(O)—(CH 2 ) 3 — and R 4 is —CH 2 —CH 2 —C(O)—O—.
13. The method of claim 1 , wherein R 3 is —C(O)—(CH 2 ) 3 — and R 4 is —CH(CH 3 )—C(O)—O—.
14. The method of claim 1 , wherein R 3 is —C(O)—(CH 2 ) 3 — and R 4 is —CH 2 —C(O)—O—.
15. The method of claim 1 , wherein R 1 is —CH 3 or —CH 2 CH 3 .
16. The method of claim 1 , wherein T is —S—CH 2 CH 2 —COOH.
17. The method of claim 1 , wherein R 3 is —C(O)—(CH 2 ) 3 —, R 4 is —CH 2 —CH 2 —C(O)—O—, CH(CH 3 )—C(O)—O—, or —CH 2 —C(O)—O—, and the disease or condition is Parkinson's disease.
18. The method of claim 17 , wherein the agent is rotigotine, pramipexole, apomorphine, ropinirole, trihexyphenidyl, seligiline, rasagiline, tolcapone or entacapone.
19. The method of claim 18 , wherein T is —S—CH 2 CH 2 —COOH.
20. The method of claim 19 , wherein R 1 is —CH 3 or —CH 2 CH 3 .