Polyoxazoline-drug conjugates with novel pharmacokinetic properties
The present disclosure provides for 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. 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 comprising a POZ conjugate are also provided.
1 . A polyoxazoline (POZ) conjugate comprising a POZ polymer and an agent 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 linking R 1 to the POZ polymer or is absent;
R 2 is a pendent moiety comprising a physiologically degradable linkage linking the POZ polymer and A;
X is a pendent 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,
wherein a release rate of A from the POZ conjugate is modulated based on R 1 .
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, or 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, 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, or (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 from the POZ conjugate is further modulated based on a loading percentage of the agent.
11 . The POZ conjugate of claim 1 , wherein the release rate of the agent from the POZ conjugate is further modulated based on an agent characteristic selected from the group consisting of agent solubility in water, agent molecular volume, total polar surface area, or a combination of the foregoing.
12 . The POZ conjugate of claim 1 , wherein the agent is a phytocannabinoid and the POZ conjugate comprises a loading percentage of the phytocannabinoid from 1.6% to 10.3% (w/w phytocannabinoid to POZ polymer), and the release rate of the phytocannabinoid from the POZ conjugate is further controlled by the loading percentage.
13 . The POZ conjugate of claim 1 , wherein R 1 is linked to the POZ polymer by a non-degradable linkage.
14 . A method for modulating the release rate of an agent from a polyoxazoline (POZ) conjugate comprising:
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 release rate of the agent from the POZ conjugate by selecting the hydrophilic or hydrophobic character.
15 . The method of claim 14 , 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 A2A receptor antagonist, or a GABA-uptake inhibitor.
16 . The method of claim 15 , 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.
17 . The method of claim 15 , 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, and dexanabinol.
18 . The method of claim 15 , wherein the anticholinergic is selected from the group consisting of: trihexyphenidyl, biperidin and hyoscyamine.
19 . The method of claim 15 , wherein the monoamine oxidase-B inhibitor is selected from the group consisting of: seligiline and rasagiline.
20 . The method of claim 14 , 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 ] 0 —[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, 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 pendent 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.
21 . The POZ conjugate of claim 1 , wherein R 1 is a water soluble polymer, a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted aralkyl or a substituted heterocyclylalkyl group.
22 . The POZ conjugate of claim 21 , wherein the water soluble polymer is selected from the group consisting of polyethylene glycol, poly(propylene glycol), copolymers of ethylene glycol and propylene glycol, and POZ.
23 . The method of claim 20 , wherein R 1 is a water soluble polymer.
24 . The method of claim 23 , wherein the water soluble polymer is selected from the group consisting of polyethylene glycol, poly(propylene glycol), copolymers of ethylene glycol and propylene glycol, and POZ.