Compositions of a polyorthoester and an aprotic solvent
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 method of administering a therapeutically active agent to a subject in need thereof, comprising:
dispensing and administering to the subject a delivery system, wherein the delivery system comprises:
a polyorthoester of 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 1-4;
R 5 is H or methyl, and
the fraction of A units that are of formula R 1 is between 10-25 mole percent;
an aprotic solvent in which the polyorthoester is miscible to form a single phase, wherein the aprotic solvent is selected from dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidone; and
a local amide- or anilide-type anesthetic dispersed or solubilized in the single phase,
wherein the aprotic solvent is present in amounts ranging from about 10-25% by weight of the delivery system and the polyorthoester of formula III is present in amounts ranging from about 45-80% by weight of the delivery system.
2. A method of treating pain in a subject in need thereof, comprising:
dispensing and administering to the subject a composition comprised of a therapeutically effective amount of a delivery system, wherein the delivery system comprises:
a polyorthoester of 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 1-4;
R 5 is H or methyl, and
the fraction of A units that are of formula R 1 is between 10-25 mole percent;
an aprotic solvent in which the polyorthoester is miscible to form a single phase, wherein the aprotic solvent is selected from dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidone; and
a local amide- or anilide-type anesthetic dispersed or solubilized in the single phase.
3. The method of claim 2 , wherein the method reduces or prevents pain in the subject.
4. The method of claim 2 , wherein the administering comprises administering the composition locally.
5. The method of claim 4 , wherein the administering comprises administering the composition intrathecally, at a nerve, into the epidural space, or to a surgical wound.
6. The method of claim 2 , wherein the administering comprises administering the composition regionally.
7. The method of claim 6 , wherein the administering comprises administering the composition as a nerve block or as a sensory block.
8. The method of claim 2 , wherein the active agent is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
9. The method of claim 2 , wherein the therapeutically active agent is bupivacaine.
10. The method of claim 2 , wherein the therapeutically active agent is ropivacaine.
11. The method of claim 2 , wherein the delivery system has a viscosity of less than about 10,000 cP at 37° C.
12. The method of claim 2 , wherein the aprotic solvent is dimethyl sulfoxide.
13. The method of claim 1 , wherein the method comprises dispensing the delivery system from a tube.
14. The method of claim 1 , wherein the method comprises administering to the subject the delivery system in an amount effective to prevent or reduce pain.
15. The method of 1 , wherein the aprotic solvent is dimethyl sulfoxide.