Subcutaneous delivery of poly(oxazoline) polymer conjugates
The present disclosure provides polymer conjugates comprising a polymer and an agent, the agent linked to the polymer via a linking group containing a hydrolyzable moiety.
1. A method for treating a disease or condition related to dopamine insufficiency in the peripheral or central nervous system by administration of rotigotine, the method comprising the steps of selecting a polyoxazoline polymer conjugate for administration and administering to the subject the poly(oxazoline) polymer conjugate, wherein a release profile of the rotigotine 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 chain;
R 4 is —CH 2 —C(O)—O—, —CH 2 (CH 3 )—C(O)—O—, —CH 2 —CH 2 —C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—;
R is an initiating group;
R 1 is a non-reactive group;
A is rotigotine;
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;
T is a terminating group; and
wherein the release profile is dependent on the selection of R 4 .
2. The method of claim 1 , wherein the poly(oxazoline) polymer has a molecular weight range of 300 Da to 200,000 Da.
3. 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
4. The method of claim 1 , wherein L has the structure
5. 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.
6. The method of claim 1 , wherein R is hydrogen, alkyl or substituted alkyl.
7. The method of claim 1 , wherein R 1 is an alkyl or substituted alkyl.
8. The method of claim 1 , wherein the disease or condition is Parkinson's disease or restless leg syndrome.
9. The method of claim 1 , wherein the rotigotine is (−)rotigotine.
10. The method of claim 1 , wherein the polymer conjugate is administered alone or as a part of a pharmaceutical composition.
11. The method of claim 1 , wherein the polymer conjugate is administered in a therapeutically effective amount.
12. The method of claim 1 , wherein the polymer conjugate is administered by subcutaneous administration.
13. The method of claim 4 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
14. The method of claim 5 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
15. The method of claim 6 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
16. The method of claim 7 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
17. The method of claim 8 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
18. The method of claim 9 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
19. The method of claim 11 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.
20. The method of claim 12 , 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 2 (CH 3 )—C(O)—O— or —CH 2 —CH 2 —CH 2 —C(O)—O—.