Polyoxazoline-drug conjugates with novel pharmacokinetic properties
Polyoxazoline (POZ) conjugates wherein the conformation of the POZ conjugate and the release rate of an agent from the POZ conjugate can be controlled by selecting one or more characteristics of the POZ polymer and methods of controlling the conformation of a POZ conjugate and the release rate of an agent prior are provided as well as methods of treatment using such POZ conjugates and methods. Pharmaceutical compositions including a POZ conjugate are also provided.
1. A polyoxazoline (POZ) conjugate comprising a water-soluble POZ polymer and an agent linked to the water-soluble POZ polymer and having the structure:
R—{[N(CO-L 1 -R 1 )CH 2 CH 2 ] m —[N(COR 2 -A)CH 2 CH 2 ] o —[N(COX)CH 2 CH 2 ] n } a -T
wherein:
A is the agent;
R is hydrogen, unsubstituted alkyl or substituted alkyl:
R 1 is an inert pendent group, wherein the inert pendant group comprises one or more hydrophilic pendent moieties;
L 1 is a linking group;
R 2 is a pendant moiety comprising a physiologically degradable linkage;
X is a pendent group;
T is a terminating group;
a is ran, which indicates a random copolymer or block which indicates a block copolymer;
m is an integer from 1 to 50;
n is an integer from 0 to 1000; and
o is an integer from 1 to 50,
wherein a conformation of the POZ conjugate is modulated based on R 1 , and wherein a release rate of A from the POZ conjugate is modulated based on the conformation of the POZ conjugate.
2. The POZ conjugate of claim 1 , wherein the agent is a phytocannabinoid, a dopamine agonist, an anticholinergic, a monoamine oxidase-B inhibitor, a catechol-O-methyl transferase (COMT) inhibitor, an adenosine A 2A receptor antagonist, or a GABA-uptake inhibitor.
3. The POZ conjugate of claim 2 , wherein the phytocannabinoid is selected from the group consisting of: cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiolmonomethylether, cannabidiol-C4, cannabidarinic acid, cannabidivarin, cannabigerol propyl variant, tetrahydrocannabivarin, Δ 9 -THC, ajulemic acid, and dexanabinol.
4. The POZ conjugate of claim 2 , wherein the dopamine agonist is selected from the group consisting of: apomorphine, arbutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopa, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, (r)-(+)-fenoldopam, rotigotine, pramipexole, quinagolide, 5-OH-DPAT, ropinirole, pergolide, cabergoline, and bromocriptine.
5. The POZ conjugate of claim 2 , wherein the anticholinergic is selected from the group consisting of: trihexyphenidyl, biperidin and hyoscyamine.
6. The POZ conjugate of claim 2 , wherein the monoamine oxidase-B inhibitor is selected from the group consisting of: seligiline and rasagiline.
7. The POZ conjugate of claim 2 , wherein the COMT inhibitor is selected from the group consisting of: tolcapone and entacapone.
8. The POZ conjugate of claim 2 , wherein the adenosine A 2A receptor antagonist is selected from the group consisting of: preladenant, theophylline and istradefylline.
9. The POZ conjugate of claim 2 , wherein the GABA-uptake inhibitor is selected from the group consisting of: tiagabine and nipecotic acid.
10. The POZ conjugate of claim 1 , wherein the release rate of the agent is further modulated based on a loading percentage of the agent.
11. The POZ conjugate of claim 10 , wherein the loading percentage is from 1.6% to 10.3% (w/w agent to POZ polymer).
12. The POZ conjugate of claim 11 , wherein the loading percentage is from 1.6% to 8.9% (w/w agent to POZ polymer).
13. A polyoxazoline (POZ) conjugate comprising: having the structure:
R—{[N(CO-L 1 -R 1 )CH 2 CH 2 ] m —[N(COR 2 -A)CH 2 CH 2 ] o —[N(COX)CH 2 CH 2 ] n } a -T
wherein:
A is the agent;
R is hydrogen, unsubstituted alkyl or substituted alkyl;
R 1 is an inert pendent group, wherein the inert pendant group comprises one or more hydrophilic pendent moieties;
L 1 is a linking group;
R 2 is a pendent moiety comprising a physiologically degradable linkage;
X is a pendent group;
T is a terminating group;
a is ran, which indicates a random copolymer or block which indicates a block copolymer;
m is an integer from 1 to 50;
n is an integer from 0 to 1000; and
o is an integer from 1 to 50,
wherein a conformation of the POZ conjugate is modulated based on R 1 , and wherein a release rate of A from the POZ conjugate is modulated based on a loading percentage of A and the conformation of the POZ conjugate.
14. The POZ conjugate of claim 13 , wherein the agent is a phytocannabinoid, a dopamine agonist, an anticholinergic, a monoamine oxidase-B inhibitor, a catechol-O-methyl transferase (COMT) inhibitor, an adenosine A 2A receptor antagonist, or a GABA-uptake inhibitor.
15. The POZ conjugate of claim 14 , wherein the phytocannabinoid is selected from the group consisting of: cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiolmonomethylether, cannabidiol-C4, cannabidarinic acid, cannabidivarin, cannabigerol propyl variant, tetrahydrocannabivarin, Δ 9 -THC, ajulemic acid, and dexanabinol.
16. A method of modulating conformation of a POZ conjugate comprising the steps of:
linking an agent to a water-soluble POZ polymer by a physiologically degradable linkage to form a POZ conjugate, wherein the water-soluble POZ polymer comprises one or more inert pendent groups with hydrophilic or hydrophobic character; and
modulating the conformation of the POZ conjugate by selecting the hydrophilic or hydrophobic character.
17. The method of claim 16 , wherein the agent comprises a phytocannabinoid, a dopamine agonist, an anticholinergic, a monoamine oxidase-B inhibitor, a catechol-O-methyl transferase (COMT) inhibitor, an adenosine A2A receptor antagonist, or a GABA-uptake inhibitor.
18. The method of claim 17 , wherein the phytocannabinoid is selected from the group consisting of: cannabidiol, cannabigerol, cannabigerolic acid, cannabidiolic acid, cannabidiolmonomethylether, cannabidiol-C4, cannabidarinic acid, cannabidivarin, cannabigerol propyl variant, tetrahydrocannabivarin, Δ 9 -THC, ajulemic acid, and dexanabinol.
19. The method of claim 17 , wherein the dopamine agonist is selected from the group consisting of: apomorphine, arbutamine, carbidopa, dobutamine, dopamine, entacapone, epinephrine, fenoldopam, isoetharine, isoproterenol, levodopalevopoda, levonordefrin, masaprocol, methyldopa, methyldopate, norepinephrine, protokylol, tolcapone, or (r)-(+)-fenoldopam, rotigotine, pramipexole, quinagolide, 5-OH-DPAT, ropinirole, pergolide, cabergoline, and bromocriptine.
20. The method of claim 16 , wherein the POZ conjugate has the structure:
R—{[N(CO-L 1 -R 1 )CH 2 CH 2 ] m —[N(COR 2 -A)CH 2 CH 2 ]—[N(COX)CH 2 CH 2 ] n } a -T
wherein:
A is the agent;
R is hydrogen, unsubstituted alkyl or substituted alkyl;
R 1 is the inert pendent group, and wherein the inert pendant group has hydrophilic character;
L 1 is a linking group linking R 1 to the POZ polymer or is absent;
R 2 is a pendent moiety comprising the physiologically degradable linkage linking the POZ polymer and A;
X is a pendant group;
T is a terminating group;
a is ran that indicates a random copolymer or block that indicates a block copolymer;
m is an integer from 1 to 50;
n is an integer from 0 to 1000; and
o is an integer from 1 to 50.