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, which comprises a delivery system, an amide local anesthetic, and meloxicam, wherein the amide local anesthetic and meloxicam are present in the composition at a ratio ranging from about 10:1 to 50:1, and wherein the composition contains no additional active agents.
2. The composition of claim 1 , wherein the amide local anesthetic is bupivacaine.
3. The composition of claim 1 , wherein the amide local anesthetic is ropivacaine.
4. The composition of claim 1 , wherein the amide local anesthetic is present in the composition in an amount ranging from about 0.1 to 8.0 wt % and the meloxicam in present in the composition in an amount ranging from about 0.005% to 1%.
5. The composition of claim 1 , wherein the delivery system is a sustained-release delivery system.
6. The composition of claim 1 , wherein the delivery system is aqueous based.
7. The composition of claim 5 , wherein the sustained-release delivery system is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation.
8. The composition of claim 5 , wherein the sustained-release delivery system is a liposome selected from the group consisting of small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), multi-lamellar vesicles (MLV) and multivesicular liposomes (MVL).
9. The composition of claim 8 , wherein the amide local anesthetic and the meloxicam are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome.
10. The composition of claim 5 , wherein the sustained-release delivery system is a microsphere comprised of a bioerodible or biodegradable polymer.
11. The composition of claim 10 , wherein the amide local anesthetic and the meloxicam are entrapped in the microsphere.
12. The composition of claim 7 , wherein the implantable device is an osmotic pump with a reservoir comprising the amide local anesthetic and the meloxicam.
13. The composition of claim 5 , wherein the sustained-release delivery system is a non-polymeric formulation comprising sucrose acetate isobutyrate.
14. The composition of claim 5 , wherein the sustained-release delivery system is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide local anesthetic and the meloxicam.
15. The composition of claim 14 , wherein the polymer is a bioerodible or biodegradable polymer.
16. The composition of claim 14 , wherein the polymer formulation forms an implant or depot in situ.
17. The composition of claim 14 wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters.
18. The composition of claim 14 , wherein the polymer is a polyorthoester.
19. The composition of claim 17 , wherein the polyorthoester in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV:
wherein
R is a bond, —(CH 2 ) a —, or —(CH 2 ) b —O—(CH 2 ) c —; where a is an integer from 1 to 12, and b and c are independently integers from 1 to 5;
R* is a C 1-4 alkyl;
R o , R″ and R′″ are each independently H or C 1-4 alkyl;
n is an integer of at least 5; and
A is a diol that is R 1 , R 2 , R 3 , or R 4 , where
R 1 is
R 5 is hydrogen or C 1-4 alkyl; and
R 6 is selected from the group consisting of:
where:
s is an integer ranging from 0 to 10;
t is an integer ranging from 2 to 30; and
R 7 is hydrogen or C 1-4 alkyl;
R 2 is:
R 3 is:
where:
x is an integer ranging from 0 to 200;
y is an integer ranging from 2 to 30;
R 8 is hydrogen or C 1-4 alkyl;
R 9 and R 10 are independently C 1-12 alkylene;
R 11 is hydrogen or C 1-6 alkyl and R 12 is C 1-6 alkyl; or R 11 and R 12 together are C 3-10 alkylene; and
R 4 is the residue of a diol containing at least one functional group independently selected from an amide, an imide, a urea, and a carbmate group.
20. The composition of claim 17 , 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
21. The composition of claim 1 , wherein the delivery system comprises a polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms, and wherein the amide local anesthetic and meloxicam are present in the delivery system at a ratio ranging from about 10:1 to 50:1.
22. The composition of claim 21 , wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin.
23. The composition of claim 21 , wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide.
24. The composition of claim 21 , wherein the amide local anesthetic and meloxicam are soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof.
25. The composition of claim 21 , wherein the amide local anesthetic is present in the delivery system at between about 0.01 wt % and about 7.5 wt % of the delivery system.
26. The composition of claim 25 , wherein the meloxicam is present in the delivery system at between about 0.005 wt % to 0.25 wt % of the delivery system.
27. The composition of claim 1 , wherein the delivery system comprises:
40 wt % to 75 wt % of a polyorthoester;
5 wt % to 12 wt % dimethyl sulfoxide;
20 wt % to 40 wt % triacetin;
1 wt % to 5 wt % bupivacaine or ropivacaine; and
0.005 wt % to 1 wt % meloxicam.
28. The composition of claim 27 , wherein the delivery system further comprises 0.01 wt % to 0.30 wt % maleic acid.
29. The composition of claim 27 , wherein the polyorthoester is represented by the structure shown as Formula I:
where
R* is C 1-4 alkyl,
n ranges from 5 to 400, and
A is a diol.
30. The composition of claim 29 , where
A is R 1 and/or R 3 , where fraction of A units that are of formula R 1 is between 0 and 25 mole percent,
R 1 is
p and q are each independently integers ranging from between about 1 and 20 and the average number of p or the average sum of p and q is between about 1 and 7, and
R 5 is H or methyl,
R 6 is
where s is an integer ranging from 0 to 10, and
R 3 is
where x is an integer ranging from 1 to 10.
31. The composition of claim 30 , wherein s is 2 and x is 2.
32. The composition of claim 30 , wherein R 3 and R 6 are both —(CH 2 —CH 2 —O) 2 —(CH 2 —CH 2 )—; R 5 is H; and p is 1 or 2.
33. The composition of claim 30 , wherein R 5 is hydrogen.
34. The composition of claim 30 , wherein
when A is R 1 , R 1 is
R 5 is H, and R 6 is
where the resulting polyorthoester comprises the subunit
where the sum of p and q is, on average, 2 and s is 2, and
when A is R 3 , x is 2.
35. The composition of claim 30 , wherein the fraction of A units that are of formula R 1 is about 20 mole percent.
36. The composition of claim 27 , wherein the polyorthoester has a weight average molecular weight between 2,500 daltons and 10,000 daltons.
37. The composition of claim 27 , wherein the delivery system has a viscosity less than 10000 mPa-s when measured at 37° C. using a viscometer.
38. The composition of claim 27 , wherein the bupivacaine or ropivacaine and the meloxicam are solubilized in a single phase.
39. The composition of claim 27 , wherein the composition is an extended-release composition.
40. The composition of claim 5 , wherein the amide local anesthetic is released from the composition over a time period of about 1 day to about 5 days.
41. 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 .
42. A method for managing pain in a subject in need thereof, comprising administering to the subject the composition according to claim 1 .
43. A method for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to claim 1 .
44. The method of claim 41 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
45. The method of claim 41 , wherein the pain is acute pain or chronic pain.
46. The method of claim 41 , wherein the composition or delivery system is administered to a surgical wound.
47. The method according to claim 46 , wherein the pain is postsurgical pain.
48. The method of claim 41 , wherein the composition produces pain relief for a time period of about 3 days to about 5 days following administration.
49. The method of claim 41 , wherein the composition or delivery system is administered as a nerve block.
50. The method of claim 41 , wherein the composition or delivery system is administered as a peripheral nerve block.
51. The method of claim 41 , further comprising administering the composition to a person in need thereof, whereby said administering provides, as measured in an in vivo model for postsurgical pain, an initial decrease in pain relief between about 1 hour and 24 hours after administering and a period of increased pain relief between about 1-3 days after administering, wherein the initial decrease in pain relief is with respect to pain relief provided immediately after administering.
52. The method of claim 51 , wherein the composition provides pain relief over days 2 to 5 following administration that is at least, on average, about 50% of the average pain relief provided by the composition 1-5 hours post-administration.
53. The method of claim 51 , whereby the administering is effective to provide a measurable plasma concentration of the amide local anesthetic and of the meloxicam for a period up to 5 days following administration.
54. The method of claim 51 , wherein about 80% by weight or more of both the amide local anesthetic and the meloxicam are released from the composition over a period of up to about 3 days when measured in an in vitro test at 37° C.