Subcutaneous delivery of polymer conjugates of therapeutics 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 related to dopamine insufficiency in the peripheral or central nervous system in a subject, 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 the agent is a dopamine agonist, an adenosine A2A receptor antagonist, an anticholinergic, a monamine oxidase-B inhibitor or a catechol—O—methyl transferase inhibitor, and 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 2 (CH 3 )—O—C(O)—, —CH 2 —CH 2 —O—C(O)—or —CH 2 —O—CH 2 —O—C(O)—;
R is an initiating group;
R 1 is a non-reactive group;
A is the agent;
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 —.
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 disease or condition is Parkinson's disease or restless leg syndrome.
7. The method of claim 1 , wherein the agent is rotigotine.
8. The method of claim 1 , wherein the polymer conjugate is administered alone or as a part of a pharmaceutical composition.
9. The method of claim 1 , wherein the polymer conjugate is administered in a therapeutically effective amount.
10. The method of claim 1 , wherein the polymer conjugate is administered by subcutaneous administration.
11. A method for treating a disease or condition related to dopamine insufficiency in the peripheral or central nervous system in a subject, the method comprising the step of administering to the subject a poly(oxazoline) polymer conjugate comprising a water soluble poly(oxazoline) polymer and a dopamine agonist, wherein a release profile of the dopamine agonist 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 2 (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 the dopamine agonist;
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 .
12. The method of claim 11 , wherein the dopamine agonist comprises rotigotine, pramipexole, quinagolide, fenoldopam, apomorphine, 5-OH-DPAT, ropinirole, pergolide, cabergoline, or bromocriptine.
13. The method of claim 11 , wherein the disease or condition is Parkinson's disease or restless leg syndrome.
14. The method of claim 11 , wherein the polymer conjugate is administered by subcutaneous administration.
15. The method of claim 11 , 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.
16. A method for treating a disease or condition related tO dopamine insufficiency in the peripheral or central nervous system in a subject, the method comprising the step of subcutaneously administering to the subject a therapeutically effective amount of a poly(oxazoline) polymer conjugate comprising a water soluble poly(oxazoline) polymer and an agent, wherein the agent is a dopamine agonist, an adenosine A2A receptor antagonist, an anticholinergic, a monamine oxidase-B inhibitor or a catechol-O-methyl transferase inhibitor, and 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 2 (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 the agent;
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 .
17. The method of claim 16 , wherein the disease or condition is Parkinson's disease or restless leg syndrome.
18. The method of claim 16 , wherein the agent is rotigotine, pramipexole, quinagolide, fenoldopam, apomorphine, 5—OH—DPAT, ropinirole, pergolide, cabergoline, or bromocriptine.
19. The method of claim 16 , wherein the agent is trihexyphenidyl, biperiden, or hyoscyamine.
20. The method of claim 16 , wherein the agent is seligiline or rasagiline.
21. The method of claim 16 , wherein the agent is tolcapone or entacapone.
22. The method of claim 16 , wherein the agent is caffeine, theophylline, istradefylline, or preladenant.