Subcutaneous delivery of poly(oxazoline) 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 polymer conjugate, wherein the polymer conjugate has the formula
wherein
R is an initiating group;
L is a releasable, hydrolyzable linker containing a hydrolyzable moiety;
A is an agent;
X is a pendent moiety containing a functional group capable of forming a linkage with the releasable linker;
R 1 is H, alkyl or substituted alkyl;
a is ran which indicates a random copolymer or block which indicates a block copolymer;
o is an integer from 1 to 50;
m is an integer from 190 to 950; and
Nuc is a terminating nucleophile.
2. The polymer conjugate of claim 1 , wherein Nuc is represented by —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.
3. The polymer conjugate of claim 1 , wherein R is hydrogen, alkyl or substituted alkyl.
4. The polymer conjugate of claim 1 , wherein the functional group of the POZ component is alkyne, amine, oxyamine, aldehyde, ketone, acetal, ketal, maleimide, ester, carboxylic acid, activated carboxylic acid, active carbonate, chloroformate, alcohol, azide, vinyl sulfone, or orthopyridyl disulfide.
5. The polymer conjugate of claim 1 , wherein the releasable, hydrolyzable linker contains at least one ester, carboxylate ester, carbonate ester, carbamate, disulfide, sulfide, acetal, hemiacetal, phosphate, phosphonate or amide group.
6. The polymer conjugate of claim 1 , wherein L has the structure
wherein
R 3 is a linker linking the triazole moiety to the polymer chain;
R 4 is —R 6 —R 7 —R 8 —;
R 6 is a substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl
R 7 is a group containing the cleavable moiety;
R 8 is absent or is O, S, CR c , or NR c ; and
R c is H or substituted or unsubstituted alkyl.
7. The polymer conjugate of claim 6 , wherein R 7 is —R a —C(O)—R b —, —R a —CH(OH)—R b —, —R a —S—S—R b —, —R a —O—P(O)(OR 11 )—R b —, or —R a —C(O)—R b —, wherein R a and R b are each independently absent or substituted or unsubstituted alkyl and R 11 is H or a substituted or unsubstituted C1-C5 alkyl.
8. The polymer conjugate of claim 6 , wherein R 7 is —R a —C(O)—R b —, —R a —O—C(O)—R b —, —R a —CH(OH)—R b — or —R a —O—P(O)(OR 11 )—R b —, R a and R b are each absent and R 8 is O, R 7 is —R a —O—C(O)—R b — or —R a —C(O)—R b , R a and R b are each absent and R 8 is NH, or R 7 is —R a —S—S—R b —, —R—S—R b —, R a and R b are each absent and R 8 is absent.
9. The polymer conjugate 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— or —CH 2 (CH 3 )—C(O)—O—.
10. The polymer conjugate of claim 1 , wherein the polymer conjugate has structure:
wherein
Z is S, O, or N;
B is an optional linking group; and
Q is a terminal portion of a terminating nucleophile.
11. The polymer conjugate of claim 10 , wherein the releasable, hydrolyzable linker contains at least one ester, carboxylate ester, carbonate ester, carbamate, disulfide, sulfide, acetal, hemiacetal, phosphate, phosphonate or amide group.
12. The polymer conjugate of claim 10 , wherein the releasable, hydrolyzable linker contains a carboxylate ester.
13. The polymer conjugate of claim 1 , wherein the polymer conjugate has structure:
wherein
p is 1 to 18.
14. A method for treating a disease or condition related to dopamine insufficiency in the peripheral or central nervous system, the method comprising the step of administering to the subject an amount of the polymer conjugate of claim 1 , the releasable, hydrolyzable linker providing a sustained, controllable delivery of the dopamine agonist over a period of days to weeks.
15. The method of claim 14 , wherein the disease or condition is Parkinson's disease or restless leg syndrome.
16. The method of claim 14 , wherein the dopamine agonist is rotigotine or (-)rotigotine.
17. The method of claim 14 , wherein the dopamine agonist is ropinirole.
18. The method of claim 14 ; wherein the polymer conjugate is administered alone or as a part of a pharmaceutical composition.
19. The method of claim 14 , wherein the polymer conjugate is administered in a therapeutically effective amount.
20. The method of claim 14 , wherein the polymer conjugate is administered by subcutaneous administration.
21. The method of claim 14 , wherein release of the dopamine agonist is controlled by the nature of the linking group, the size of the polymer, the method of delivery or a combination of the foregoing.
22. The method of claim 14 , wherein the polymer conjugate has the structure
wherein
p is 1 to 18.
23. A method for treating Parkinson's disease, the method comprising the step of administering to the subject an amount of a polymer conjugate, wherein the polymer conjugate has the structure
wherein
R is an initiating group;
p is 1 to 18;
a is ran which indicates a random copolymer or block which indicates a block copolymer;
o is an integer from 1 to 50;
and m is an integer from 190 to 950.