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 composition, comprising: an amide local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle, wherein the enolic-acid non-steroidal NSAID is the sole NSAID comprised in the composition.
2. The composition of claim 1 , wherein the amide local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
3. The composition of claim 1 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
4. The composition of claim 1 , wherein the amide local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
5. The composition of claim 4 , wherein the amide local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition.
6. The composition of claim 1 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
7. The composition of claim 1 , wherein the delivery vehicle is a sustained-release delivery vehicle.
8. The composition of claim 7 , wherein the sustained-release delivery vehicle is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation.
9. The composition of claim 7 , wherein the sustained-release delivery vehicle 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).
10. The composition of claim 9 , wherein the amide-typelocal anesthetic and the enolic-acid NSAID are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome.
11. The composition of claim 7 , wherein the sustained-release delivery vehicle is a microsphere comprised of a bioerodible or biodegradable polymer.
12. The composition of claim 11 , wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in the microsphere.
13. The composition of claim 8 , wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the enolic-acid NSAID.
14. The composition of claim 7 , wherein the sustained-release delivery vehicle is a non-polymeric formulation comprising sucrose acetate isobutyrate.
15. The composition of claim 7 , wherein the sustained-release delivery vehicle is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide local anesthetic and the enolic-acid NSAID.
16. The composition of claim 15 , wherein the polymer is a bioerodible or biodegradable polymer.
17. The composition of claim 15 , wherein the polymer formulation forms an implant or depot in situ.
18. The composition of claim 15 , wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters.
19. The composition of claim 15 , wherein the polymer is a polyorthoester.
20. The composition of claim 1 , wherein the delivery vehicle is an aqueous solution.
21. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition according to claim 1 .
22. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition according to claim 1 .
23. The method of claim 21 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
24. The method of claim 23 , wherein the pain is acute pain or chronic pain.
25. A semi-solid composition, comprising: a biodegradable polyorthoester, an amide local anesthetic, and an enolic-acid non-steroidal anti-inflammatory drug (NSAID), wherein the enolic-acid non-steroidal NSAID is the sole NSAID comprised in the composition.
26. The composition of claim 25 , wherein the amide local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
27. The composition of claim 25 , wherein amide local anesthetic is ropivacaine or bupivacaine.
28. The composition of claim 25 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
29. The composition of claim 25 , wherein the enolic-acid NSAID is meloxicam.
30. The composition of claim 25 , wherein the amide local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition.
31. The composition of claim 25 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
32. The composition of claim 25 , wherein the polyorthoester comprised 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.
33. The composition of claim 25 , wherein the polyorthoester is represented by Formula I:
wherein
R* is a C 1-4 alkyl, n is an integer ranging from 5 to 400, and A in each subunit is R 1 or R 3 ,
wherein R 1 is
where p and q are each independently integers that range from between about 1 to 20, each R 5 is independently hydrogen or C 1-4 alkyl; and R 6 is:
where s is an integer from 0 to 10; t is an integer from 2 to 30; and R 7 is hydrogen or C 1-4 alkyl (e.g., is H or C1, C2, C3, or C4 alkyl),
wherein R 3 is:
and x is an integer ranging from 1 to 100; y is an integer in a range from 2 to 30; and R 8 is hydrogen or C 1-4 alkyl.
34. The composition of claim 25 , further comprising a protic or an aprotic solvent.
35. The composition of claim 25 , further comprising a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms.
36. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition of claim 25 .
37. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition of claim 25 .
38. The method of claim 36 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
39. The method of claim 38 , wherein the pain is acute pain or chronic pain.
40. A composition, comprising: an amide local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID), a delivery vehicle comprised of 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, wherein the enolic-acid non-steroidal NSAID is the sole NSAID comprised in the composition.
41. The composition of claim 40 , wherein the composition has a viscosity ranging from about 2500 mPa-s to 10000 mPa-s when measured at 25° C. using a viscometer.
42. The composition of claim 40 , wherein the viscosity of the composition is 10 to 40-fold lower than the viscosity of an otherwise identical composition but for having no triglyceride viscosity reducing agent when measured at 25° C. using a viscometer.
43. The composition of claim 40 , wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin.
44. The composition of claim 40 , wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide.
45. The composition of claim 40 , wherein the amide local anesthetic is soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof.
46. The composition of claim 40 , wherein the amide local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
47. The composition of claim 40 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
48. The composition of claim 40 , wherein the amide local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
49. The composition of claim 48 , wherein the amide local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition.
50. The composition of claim 48 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
51. The composition of claim 40 , wherein the polyorthoester 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.
52. The composition of claim 40 , wherein the polyorthoester is represented by Formula I:
wherein
R* is a C 1-4 alkyl, n is an integer ranging from 5 to 400, and A in each subunit is R 1 or R 3 ,
wherein R 1 is
where p and q are each independently integers that range from between about 1 to 20, each R 5 is independently hydrogen or C 1-4 alkyl; and R 6 is:
where s is an integer from 0 to 10; t is an integer from 2 to 30; and R 7 is hydrogen or C 1-4 alkyl (e.g., is H or C1, C2, C3, or C4 alkyl),
wherein R 3 is:
and x is an integer ranging from 1 to 100; y is an integer in a range from 2 to 30; and R 8 is hydrogen or C 1-4 alkyl.
53. The pharmaceutical composition of claim 40 , wherein the amide local anesthetic is released from the composition over a time period of about 1 day to about 8 weeks.
54. A method of treatment, comprising: administering to a patient in need thereof the pharmaceutical composition according to claim 40 .
55. The method according to claim 54 , wherein the patient is experiencing pain or is in need of prophylactic treatment for pain and the first therapeutic agent provides pain relief.
56. The method of claim 55 , wherein the pain is acute pain or chronic pain.
57. The method of claim 54 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
58. A method for prophylactic treatment of nausea, comprising: administering to a patient in need thereof the composition according to claim 54 , wherein the first therapeutic agent is granisetron.
59. A method for extending duration of pain relief of a polyorthoester composition comprising an amide-type local anesthetic, comprising: incorporating in the composition an enolic acid-NSAID in an amount effective to extend the duration of pain relief provided by the composition when compared to a similar composition lacking the effective amount of the enolic acid-NSAID.
60. The method of claim 59 , wherein the enolic acid-NSAID containing composition provides pain relief for a period of time of about 3 days to about 5 days following administration.
61. The method of claim 59 , wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
62. The method of claim 59 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
63. The method of claim 59 , wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
64. The method of claim 59 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
65. The method of claim 64 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
66. The method of claim 59 , wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV.
67. The method of claim 59 , wherein the polyorthoester is represented by Formula I.
68. The method of claim 59 , further comprising administering the composition to a person in need thereof, whereby said administering provides, as measured in an in vivo model for post-operative pain, an initial decrease in pain relief between about 1 hours 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.
69. The method of claim 68 , wherein the composition provides pain relief over days 2-5 following administration that is at least, on average, about 50% of the average pain relief provided by the composition 1-5 hours post-administration.
70. The method of claim 59 , whereby the administering is effective to provide a measurable plasma concentration of the amide-type local anesthetic and of the NSAID for a period of at least 5 days following administration.
71. The method of claim 59 , wherein about 80% by weight or more of both the local anesthetic and the enolic-acid NSAID are released from the composition over a period of 5 days when measured in an in vitro test at 37° C.
72. The method of claim 59 , wherein the administering is at a nerve, into the epidural space, intrathecal, or directly to a surgical site or wound.
73. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 1 , and
instructing that the composition be administered to the patient to provide pain relief for an extended period.
74. The method of claim 73 , wherein the extended period is for at least 5 days.
75. The method of claim 73 , wherein the extended period is for up to 5 days.
76. The method of claim 73 , wherein the extended period is from about 1 day to at least about 5 days.
77. The method of claim 73 , wherein the extended period is for about 3 days.
78. The method of claim 73 , wherein the instructing that the composition be administered comprises instructing that the composition be administered subcutaneously at or near a wound site.
79. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 40 , and
instructing that the composition be administered to the patient to provide pain relief for an extended period.