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 poly(oxazoline) polymer conjugate, the poly(oxazoline) polymer conjugate comprising an agent linked to the poly(oxazoline) polymer by a linker, wherein the linker has the structure
wherein R 3 is a forms a linkage with the poly(oxazoline) 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 a hydrolyzable moiety;
R 8 is absent or is O, S, CR c , or NR c ; and
R c is H or substituted or unsubstituted alkyl.
2 . The polymer conjugate of claim 1 , wherein, the conjugate provides a sustained, controllable delivery of the agent over a period of days to weeks.
3 . The polymer conjugate of claim 1 , wherein the agent is a dopamine agonist.
4 . The polymer conjugate of claim 1 , wherein the dopamine agonist is rotigotine, (−) rotigotine or ropinirole.
5 . The polymer conjugate of claim 1 , wherein the poly(oxazoline) polymer has a molecular weight range of 300 Da to 200,000 Da.
6 . The polymer conjugate of claim 1 , wherein the releasable, hydrolyzable linker contains at least one carboxylate ester, carbonate, ester, carbamate, disulfide, sulfide, acetal, hemiacetal, phosphate, phosphonate or amide group.
7 . The polymer conjugate of claim 1 , 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 1 , 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, wherein 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 a —S—R b —, R a and R b are each absent and R 8 is absent.
9 . The polymer conjugate 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— or —CH 2 (CH 3 )—C(O)—O—.
10 . The polymer conjugate of claim 1 , wherein L has the structure
11 . A poly(oxazoline) polymer conjugate, wherein the poly(oxazoline) polymer conjugate has the formula
wherein
R is an initiating group;
POZ is a poly(oxazoline) polymer of the formula —{[N(COX)CH 2 CH 2 ] o —[N(COR 1 )CH 2 CH 2 ] m } a —, wherein R 1 is H, alkyl or substituted alkyl, X is a pendent moiety containing a functional group capable of forming a linkage with the linker or the agent, o is an integer from 1 to 50 and m is an integer from 1 to 950;
L is
wherein R 3 is a linker linking L 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 a hydrolyzable moiety, R 8 is absent or is O, S, CR c , or NR c , and R c is H or substituted or unsubstituted alkyl;
A is an agent;
a is 1 to 50; and
Nuc is a terminating nucleophile.
12 . The polymer conjugate of claim 11 , 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.
13 . The polymer conjugate of claim 11 , wherein R is hydrogen, alkyl or substituted alkyl.
14 . The polymer conjugate of claim 11 , wherein the functional group of X 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.
15 . The polymer conjugate of claim 11 , wherein the releasable, hydrolyzable linker contains at least one carboxylate ester, carbonate ester, carbamate, disulfide, sulfide, acetal, hemiacetal, phosphate, phosphonate or amide group.
16 . The polymer conjugate of claim 11 , wherein L has the structure
17 . The polymer conjugate of claim 11 , 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.
18 . The polymer conjugate of claim 11 , 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, wherein 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 a —S—R b —, R a and R b are each absent and R 8 is absent.
19 . The polymer conjugate 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— or —CH 2 (CH 3 )—C(O)—O—.
20 . The polymer conjugate of claim 11 , wherein the polymer conjugate has structure:
wherein
p is 1 to 18 (revise to replace drug structure with A and H with R).
21 . The polymer conjugate of claim 11 , wherein the polymer conjugate has structure:
wherein
p is 1 to 18 (revise to replace H with R).
22 . The polymer conjugate of claim 11 , wherein the polymer conjugate provides a sustained, controllable delivery of the dopamine agonist over a period of days to weeks
23 . 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 a poly(oxazoline) polymer conjugate containing a dopamine agonist, the dopamine agonist linked to the polymer by a linker, wherein the linker has the structure
wherein R 3 is a forms a linkage with the poly(oxazoline) 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 a hydrolyzable moiety, R 8 is absent or is O, S, CR c , or NR c ; and
R c is H or substituted or unsubstituted alkyl.
24 . The method of claim 23 , wherein the poly(oxazoline) polymer conjugate provides a sustained, controllable delivery of the dopamine agonist over a period of days to weeks.
25 . The method of claim 23 , wherein the disease or condition is Parkinson's disease o restless leg syndrome.
26 . The method of claim 23 , wherein the dopamine agonist is rotigotine, (−)rotigotine or ropinirole.
27 . The method of claim 23 , wherein the polymer conjugate is administered alone or as a part of a pharmaceutical composition.
28 . The method of claim 23 , wherein the polymer conjugate is administered in a therapeutically effective amount.
29 . The method of claim 23 , wherein the polymer conjugate is administered by subcutaneous administration.