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 postoperative pain, comprising:
administering to a subject a composition comprising an amide-type local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle.
2. The method of claim 1 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
3. The method of claim 1 , wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
4. The method of claim 1 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
5. The method of claim 1 , wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
6. The method of claim 4 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
7. The method of claim 1 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
8. The method of claim 1 , wherein the delivery vehicle is a sustained-release delivery vehicle.
9. The method of claim 8 , wherein the sustained-release delivery vehicle is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation.
10. The method of claim 8 , 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).
11. The method of claim 10 , wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome.
12. The method of claim 8 , wherein the sustained-release delivery vehicle is a microsphere comprised of a bioerodible or biodegradable polymer.
13. The method of claim 12 , wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in the microsphere.
14. The method of claim 9 , wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the enolic-acid NSAID.
15. The method of claim 8 , wherein the sustained-release delivery vehicle is a non-polymeric formulation comprising sucrose acetate isobutyrate.
16. The method of claim 8 , wherein the sustained-release delivery vehicle is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide-type local anesthetic and the enolic-acid NSAID.
17. The method of claim 16 , wherein the polymer is a bioerodible or biodegradable polymer.
18. The method of claim 16 , wherein the polymer formulation forms an implant or depot in situ.
19. The method of claim 16 , wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters.
20. The method of claim 16 , wherein the polymer is a polyorthoester.
21. The method of claim 1 , wherein the delivery vehicle is an aqueous solution.
22. The method of claim 1 , wherein said administering comprises administering to a surgical site.
23. The method of claim 1 , wherein said administering comprises administering the composition to a surgical wound.
24. The method of claim 23 , wherein said administering is via instillation.
25. A method for producing post-surgical analgesia, comprising: administering to a subject a composition comprising an amide-type local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle.
26. The method of claim 25 , wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
27. The method of claim 25 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
28. The method of claim 25 , wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
29. The method of claim 28 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
30. The method of claim 25 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
31. The method of claim 25 , wherein the delivery vehicle is a sustained-release delivery vehicle.
32. The method of claim 31 , wherein the sustained-release delivery vehicle is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation.
33. The method of claim 31 , 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).
34. The method of claim 33 , wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome.
35. The method of claim 31 , wherein the sustained-release delivery vehicle is a microsphere comprised of a bioerodible or biodegradable polymer.
36. The method of claim 35 , wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in the microsphere.
37. The method of claim 32 , wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the enolic-acid NSAID.
38. The method of claim 31 , wherein the sustained-release delivery vehicle is a non-polymeric formulation comprising sucrose acetate isobutyrate.
39. The method of claim 31 , wherein the sustained-release delivery vehicle is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide-type local anesthetic and the enolic-acid NSAID.
40. The method of claim 39 , wherein the polymer is a bioerodible or biodegradable polymer.
41. The method of claim 39 , wherein the polymer formulation forms an implant or depot in situ.
42. The method of claim 39 , wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters.
43. The method of claim 39 , wherein the polymer is a polyorthoester.
44. The method of claim 25 , wherein the delivery vehicle is an aqueous solution.
45. A method for reducing postoperative pain in a subject in need thereof, comprising:
administering to the subject a semi-solid composition comprising a biodegradable polyorthoester, an amide-type local anesthetic, and an enolic-acid non-steroidal anti-inflammatory drug (NSAID).
46. The method of claim 45 , wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
47. The method of claim 45 , wherein amide-type local anesthetic is ropivacaine or bupivacaine.
48. The method of claim 45 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
49. The method of claim 45 , wherein the enolic-acid NSAID is meloxicam.
50. The method of claim 45 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
51. The method of claim 45 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
52. The method of claim 45 , wherein the polyorthoester comprised in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV.
53. The method of claim 45 , wherein the polyorthoester is represented by Formula I.
54. The method of claim 45 , further comprising a protic or an aprotic solvent.
55. The method of claim 45 , 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.
56. The method of claim 45 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
57. A method for producing post-surgical analgesia in a subject, comprising:
administering to the subject a semi-sold composition comprising a biodegradable polyorthoester, an amide-type local anesthetic, and an enolic-acid non-steroidal anti-inflammatory drug (NSAID).
58. The method of claim 57 , wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine.
59. The method of claim 57 , wherein amide-type local anesthetic is ropivacaine or bupivacaine.
60. The method of claim 57 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
61. The method of claim 57 , wherein the enolic-acid NSAID is meloxicam.
62. The method of claim 57 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
63. The method of claim 57 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
64. The method of claim 57 , wherein the polyorthoester comprised in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV.
65. The method of claim 57 , wherein the polyorthoester is represented by Formula I.
66. The method of claim 57 , further comprising a protic or an aprotic solvent.
67. The method of claim 57 , 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.
68. A method for reducing postoperative pain, comprising:
administering to a patient in need thereof a pharmaceutical composition comprising a first therapeutic agent and 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.
69. The method according to claim 68 , wherein the patient is experiencing pain or is in need of prophylactic treatment for pain and the first therapeutic agent provides pain relief.
70. The method of claim 69 , wherein the pain is acute pain or chronic pain.
71. The method of claim 68 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
72. The method of claim 68 , wherein the composition has a viscosity ranging from about 2500 mPa-s to 10000 mPa-s when measured at 25° C. using a viscometer.
73. The method of claim 68 , wherein the viscosity of the composition is 10 to 40-fold lower than the viscosity of a similar composition with no triglyceride viscosity reducing agent when measured at 25° C. using a viscometer.
74. The method of claim 68 , wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin.
75. The method of claim 68 , wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide.
76. The method of claim 68 , wherein the first therapeutic agent is soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof.
77. The method of claim 68 , wherein the first therapeutic agent is a local anesthetic.
78. The method of claim 68 , wherein the first therapeutic agent is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
79. The method of claim 68 , wherein the composition comprises a second therapeutic agent.
80. The method of claim 68 , wherein the first therapeutic agent is an amide-type local anesthetic and the second therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID).
81. The method of claim 68 , wherein the first therapeutic agent is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
82. The method of claim 68 , wherein the NSAID is an enolic-acid NSAID.
83. The method of claim 68 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
84. The method of claim 68 , wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
85. The method of claim 68 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
86. The method of claim 68 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
87. The method of claim 68 , wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV.
88. The method of claim 68 , wherein the polyorthoester is represented by Formula I.
89. The method of claim 68 , wherein the first therapeutic agent is released from the composition over a time period of about 1 day to about 8 weeks.
90. 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.
91. The method of claim 90 , 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.
92. The method of claim 90 , wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine.
93. The method of claim 90 , wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam.
94. The method of claim 90 , wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam.
95. The method of claim 90 , wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %.
96. The method of claim 90 , wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition.
97. The method of claim 90 , wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV.
98. The method of claim 90 , wherein the polyorthoester is represented by Formula I.
99. The method of claim 90 , further comprising administering the composition to a subject 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.
100. The method of claim 99 , 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.
101. The method of claim 90 , 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 3 days following administration.
102. The method of claim 90 , 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.
103. The method of claim 90 , wherein the administering is at a nerve, into the epidural space, intrathecal, or directly to a surgical site or wound.
104. A method for reducing post-operative pain in a patient in need thereof, comprising:
providing a composition comprising an amide-type local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle, and
instructing that the composition be administered to the patient to reduce pain after a surgical procedure for an extended period.
105. The method of claim 104 , wherein the extended period is for at least 3 days.
106. The method of claim 104 , wherein the extended period is for up to 3 days.
107. The method of claim 104 , wherein the extended period is from about 1 day to at least about 3 days.
108. The method of claim 104 , wherein the extended period is for up to 5 days.
109. The method of claim 104 , wherein the instructing that the composition be administered comprises instructing that the composition be administered subcutaneously at or near a wound site.
110. A method to produce post-surgical analgesia in a patient in need thereof, comprising:
providing a composition comprising a first therapeutic agent and 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, and
instructing that the composition be administered to the patient to provide pain relief for an extended period.