Claims for Patent: 11,413,350

Summary for Patent: 11,413,350

Title:	Long-acting polymeric delivery systems
Abstract:	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).
Inventor(s):	Ottoboni; Thomas B. (Belmont, CA), Girotti; Lee Ann Lynn (San Bruno, CA)
Assignee:	Heron Therapeutics, Inc. (San Diego, CA)
Application Number:	17/129,715
Patent Claims:	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.degree. 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.degree. 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.degree. 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.