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 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 pharmaceutical composition comprising a therapeutically effective amount of 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 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, and wherein A is selected from the group consisting of a dopamine agonist, dopamine antagonist, an adenosine A2A antagonist, an anticholinergic, a monamine oxidase-B inhibitor or a catechol-O-methyl transferase inhibitor;
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 A is a dopamine agonist selected from the group consisting of rotigotine, pramipexole, quinagolide, fenoldopam, apomorphine, 5-OH-DPAT, ropinirole, pergolide, cabergoline, and bromocriptine.
8. The method of claim 1 , wherein A is an anticholinergic selected from the group consisting of trihexyphenidyl, biperidin and hyoscyamine.
9. The method of claim 1 , wherein the polymer conjugate is administered alone or as a part of a pharmaceutical composition.
10. The method of claim 1 , wherein the polymer conjugate is administered by subcutaneous administration.
11. The method of claim 1 , wherein A is a monamine oxidase-B inhibitor selected from the group consisting of seligiline and rasagiline.
12. The method of claim 1 , wherein A is an adenosine A2A antagonist selected from the group consisting of caffeine, theophylline, istradefylline, and preladenant.
13. The method of claim 1 , wherein A is a COMT inhibitor selected from the group consisting of tolcapone and entacapone.