Long-acting polymeric delivery systems
Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).
1. A method for reducing pain, comprising:
administering to a wound a composition comprised of a delivery system that is in the form of a semi-solid polymer formulation comprising a polyorthoester, bupivacaine, and meloxicam, wherein bupivacaine and meloxicam are present in the composition at a ratio ranging from about 15:1 to 50:1, wherein meloxicam is present in the composition in an amount between about 0.005-0.75 wt %, and wherein the polyorthoester is represented by Formula I:
where:
R* is a C 1-4 alkyl,
n is an integer ranging from 5 to 400, and
A is a diol, where A is R 1 and/or R 3 , where the fraction of A units that are of formula R 1 is between 0 and 25 mole percent, where
when A is R 3 , R 3 is
where x is 2; and
when A is R 1 , R 1 is
R 5 is H, and R 6 is
the sum of p and q is, on average, 2 and s is 2,
where the resulting component of the polyorthoester comprises the subunit
2. The method of claim 1 , wherein bupivacaine is present in the composition in an amount ranging from about 0.1 to 8.0 wt % and the meloxicam is present in the composition in an amount ranging from about 0.01-0.5 wt %.
3. The method of claim 1 , wherein meloxicam is present in the composition in an amount ranging from about 0.005-0.25 wt %.
4. The method of claim 1 , wherein meloxicam is present in the composition in an amount ranging from about 0.005-0.125 wt %.
5. The method of claim 1 , wherein said administering comprises administering a composition wherein the delivery system is a sustained-release delivery system.
6. The method of claim 1 , wherein the delivery system further comprises a polar aprotic solvent and a triglyceride viscosity reducing agent.
7. The method of claim 6 , wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin.
8. The method of claim 6 , wherein the polar aprotic solvent is selected from dimethyl sulfoxide, N-methyl pyrrolidone and dimethyl acetamide.
9. The method of claim 6 , wherein bupivacaine and meloxicam are soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof.
10. The method of claim 6 , wherein bupivacaine is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition.
11. The method of claim 6 , wherein the meloxicam is present in the composition at between about 0.005 wt % to 0.25 wt % of the composition.
12. The method of claim 6 , wherein the delivery system comprises:
40 wt % to 75 wt % of the polyorthoester;
5 wt % to 12 wt % dimethyl sulfoxide; and
20 wt % to 40 wt % triacetin;
and wherein bupivacaine is present in an amount of between about 1 wt % to 5 wt %.
13. The method of claim 12 , wherein the delivery system further comprises 0.01 wt % to 0.3 wt % maleic acid.
14. The method of claim 12 , wherein the polyorthoester has a weight average molecular weight between about 2,500 Daltons and about 10,000 Daltons.
15. The method of claim 12 , wherein the delivery system has a viscosity less than 10000 mPa-s when measured at 37° C. using a viscometer.
16. The method of claim 5 , wherein bupivacaine is released from the composition over a time period of about 1 day to about 5 days.
17. The method of claim 1 , wherein the administering to a wound is via instillation to the wound.
18. The method of claim 1 , wherein the administering to a wound is via instillation to an open wound as part of a surgical procedure.
19. The method of claim 1 , wherein the composition is administered to a surgical wound.
20. The method of claim 1 , wherein the pain is post-operative pain.
21. The method of claim 1 , wherein the administering produces pain relief for a time period of about 3 days to about 5 days following administration.
22. The method of claim 1 , wherein the administering to a wound is via instillation to an open wound as part of a surgical procedure and wherein the administering produces pain relief for a time period of about 3 days.
23. The method of claim 1 , wherein the administering to a wound is via instillation to an open wound as part of a surgical procedure and wherein the administering produces pain relief for a time period of at least about 3 days.
24. The method of claim 1 , wherein the composition forms an implant or depot in situ.