Compositions of a polyorthoester and an aprotic solvent
View Patent ↗Delivery systems and compositions comprised of a biodegradable polyorthoester polymer, an aprotic solvent, and a drug are described. The solvent is selected to modulate release of drug from the composition, where, in some embodiments, the solvent is rapidly released after administration and provides a corresponding rapid rate of drug release. Alternatively, in other embodiments, the solvent is slowly released from the composition after its administration, and provides a correspondingly slow rate of drug release.
1. A delivery system, comprising:
(i) a polyorthoester represented by Formula III,
where
A is R 1 or R 3 ,
R* is C1-4 alkyl,
n ranges from 5 to 1000,
R 1 is:
p and q are integers that vary from between about 1 to 20 and the average number of p or the average of the sum of p and q is between 1 and 7;
R 3 and R 6 are each independently:
x is an integer of 0-10;
R 5 is H or methyl, and
the fraction of A units that are of formula R 1 is between 0 and 25 mole percent;
(ii) a solvent consisting essentially of one or more aprotic solvents, wherein at least one of the one or more aprotic solvents is selected from dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidone, in which the polyorthoester is miscible to form a single phase; and
(iii) a therapeutically active agent dispersed or solubilized in the single phase.
2. The delivery system of claim 1 , wherein the solvent is an organic solvent having a water solubility of greater than 25% by weight of the solvent in water at room temperature.
3. The delivery system of claim 1 , wherein the solvent is a dipolar aprotic solvent having a dipole moment greater than 2 Debye.
4. The delivery system of claim 1 , wherein the solvent is dimethyl sulfoxide.
5. The delivery system of claim 1 , wherein the solvent is N-methyl pyrrolidone.
6. The delivery system of claim 1 , wherein the therapeutically active agent is an anti-emetic, a local anesthetic or an opioid.
7. The delivery system of claim 6 , wherein the therapeutically active agent is granisetron, ropivacaine, or bupivacaine.
8. The delivery system of claim 1 , wherein A is R 1 in 0 to 10% of the monomeric units of the polyorthoester.
9. The delivery system of claim 1 , wherein the active agent is granisetron in an amount between 1-5 percent by weight of the delivery system, and the solvent is DMSO in an amount between 10-35 percent by weight of the delivery system.
10. The delivery system of claim 1 , wherein the system is flowable, and the solvent has a dipole moment greater than 2 Debye (D).
11. The delivery system of claim 10 , wherein the therapeutically active agent is an anti-emetic, a local anesthetic or an opioid.
12. The delivery system of claim 11 , wherein the therapeutically active agent is granisetron, ropivacaine, or bupivacaine.
13. The delivery system of claim 10 , wherein A is R 1 in 0 to 10% of the monomeric units of the polyorthoester.
14. The delivery system of claim 10 , wherein the active agent is granisetron in an amount between 1-5 percent by weight of the composition, and the solvent is DMSO in an amount between 10-35 percent by weight of the composition.
15. The delivery system of claim 1 , wherein R 3 and R 6 are both —(CH 2 —CH 2 —O) 2 —(CH 2 —CH 2 )—; R 5 is hydrogen; and p is 1 or 2.
16. The delivery system of claim 1 , wherein the polyorthoester comprises subunits selected from
where
x is an integer from 1-4,
the total amount of p is an integer from 1-20, and
s is an integer from 1-4.
17. The delivery system of claim 1 , wherein the polyorthoester comprises alternating residues of 3,9-diethyl-3,9-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diyl,
and a diol-ate residue of triethylene glycol or of triethylene glycol diglycolide, and comprises from about 0 to about 25 mole percent of glycolide-containing subunits.
18. The delivery system of claim 17 , wherein the polyorthoester has a molecular weight of 1,000 Da to 10,000 Da.
19. The delivery system of claim 1 , wherein the polyorthoester is prepared by reacting diketene acetal, 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane,
with triethylene glycol and triethylene glycol diglycolide.
20. The delivery system of claim 19 , wherein the polyorthoester comprises about 20 mole percent R 1 , where R 1 is triethylene glycol diglycolide, and 80 mole percent R 3 , where R 3 is triethylene glycol.
21. The delivery system of claim 1 , wherein the aprotic solvent is dimethyl acetamide.