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 delivery system, comprising:
a polyorthoester;
an aprotic solvent in which the polyorthoester is miscible to form a single phase; and
a local amide- or anilide-type anesthetic dispersed or solubilized in the single phase;
wherein the polyorthoester is represented by the structure shown as 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 to 10;
R 5 is H or methyl, and
the fraction of A units that are of the formula R 1 is between 0 and 25 mole percent
wherein the anesthetic is released from the system over a period of between approximately 1 day and approximately 8 weeks.
2. The delivery system of claim 1 , wherein the anesthetic is dispersed in the single phase.
3. The delivery system of claim 1 , wherein the anesthetic is solubilized in the single phase.
4. The delivery system of claim 1 , wherein the delivery system has a viscosity of less than about 10,000 cP at 37° C.
5. The delivery system of claim 1 , wherein the aprotic solvent is an amide or a sulfoxide.
6. The delivery system of claim 5 , wherein the aprotic solvent is an amide selected from the group consisting of 2-pyrrolidone, dimethyl formamide, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, dimethyl acetamide, N-cyclohexyl-2-pyrrolidone and caprolactam.
7. The delivery system of claim 5 , wherein the aprotic solvent is a sulfoxide selected from either dimethyl sulfoxide or decylmethylsulfoxide.
8. The delivery system of claim 1 , wherein the aprotic solvent is selected from dimethylsulfoxide, dimethyl acetamide, and N-methyl pyrrolidone.
9. The delivery system of claim 1 , wherein local amide- or anilide-type anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
10. The delivery system of claim 9 , wherein the local amide- or anilide type anesthetic is bupivacaine.
11. The delivery system of claim 9 , wherein the local amide- or anilide type anesthetic is ropivacaine.
12. The delivery system of claim 1 , where the polyorthoester has a molecular weight between about 1,000 and 10,000 daltons.
13. The delivery system of claim 1 , wherein the aprotic solvent is in an amount between 15-50 percent by weight of the delivery system; and the local amide- or anilide-type anesthetic is in an amount between 3 and 30 percent by weight of the delivery system.
14. A method of administering a local amide- or anilide-type anesthetic, comprising dispensing from a needle the delivery system of claim 1 .
15. The method of claim 14 , comprising dispensing from a needle a delivery system of claim 8 .
16. A method of providing local anesthesia to a patient, comprising administering to a patient the delivery system of claim 1 in an amount effective for reducing or preventing pain.
17. The method of claim 16 , wherein the administering comprises dispensing the delivery system from a needle.
18. The method of claim 16 , wherein the administering comprises injecting the delivery system in a region of tissue near a nerve, into an epidural space, as an intrathecal injection, around the periphery of a surgical site or wound or dispensing directly into a surgical site or wound.
19. The method of claim 16 , comprising administering to the patient the delivery system of claim 8 .