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 pharmaceutical composition, comprising: a delivery system, 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 composition forms an implant or depot in situ.
2. The composition 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 composition of claim 1 , wherein the delivery system is a sustained-release delivery system.
4. The composition of claim 1 , wherein the delivery system is aqueous based.
5. The composition of claim 3 , wherein the sustained-release delivery system is a semi-solid polymer formulation comprising a polymer.
6. The composition of claim 5 , wherein the polymer is a bioerodible or biodegradable polymer.
7. The composition of claim 5 , wherein the polymer formulation forms an implant or depot in situ.
8. The composition of claim 5 , wherein the polymer is a polyorthoester represented by the structure shown as 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 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
9. The composition of claim 8 , wherein the delivery system comprises the polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent.
10. The composition of claim 9 , wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin.
11. The composition of claim 9 , wherein the polar aprotic solvent is selected from dimethyl sulfoxide, N-methyl pyrrolidone and dimethyl acetamide.
12. The composition of claim 9 , wherein bupivacaine and meloxicam are soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof.
13. The composition of claim 9 , wherein bupivacaine is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition.
14. The composition of claim 13 , wherein the meloxicam is present in the composition at between about 0.005 wt % to 0.25 wt % of the composition.
15. The composition of claim 9 , 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 %.
16. The composition of claim 15 , wherein the delivery system further comprises 0.01 wt % to 0.3 wt % maleic acid.
17. The composition of claim 15 , wherein the polyorthoester has a weight average molecular weight between 2,500 daltons and 10,000 daltons.
18. The composition of claim 15 , wherein the delivery system has a viscosity less than 10000 mPa-s when measured at 37° C. using a viscometer.
19. The composition of claim 3 , wherein bupivacaine is released from the composition over a time period of about 1 day to about 5 days.
20. A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to claim 1 .
21. A method for managing pain in a subject in need thereof, comprising administering to the subject the composition according to claim 1 .
22. A method for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to claim 1 .
23. The method of claim 20 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
24. The method of claim 20 , wherein the pain is acute pain or chronic pain.
25. The method of claim 20 , wherein the composition is administered to a surgical wound.
26. The method according to claim 20 , wherein the pain is postsurgical pain.
27. The method of claim 20 , wherein the composition produces pain relief for a time period of about 3 days to about 5 days following administration.
28. The method of claim 20 , wherein the composition is administered as a nerve block or as a peripheral nerve block.
29. The composition of claim 1 , wherein the meloxicam is present in the composition in an amount ranging from about 0.005-0.25 wt %.
30. The composition of claim 1 , wherein the meloxicam is present in the composition in an amount ranging from about 0.005-0.125 wt %.