Claims for Patent: 10,898,575

Summary for Patent: 10,898,575

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:	15/621,782
Patent Claims:	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: ##STR00032## wherein R is a bond, --(CH.sub.2).sub.a--, or --(CH.sub.2).sub.b--O--(CH.sub.2).sub.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.sub.1-4 alkyl; R.sup.o, R'' and R''' are each independently H or C.sub.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: ##STR00033## wherein R* is a C.sub.1-4 alkyl, n is an integer ranging from 5 to 400, and A in each subunit is R.sup.1 or R.sup.3, wherein R.sup.1 is ##STR00034## where p and q are each independently integers that range from between about 1 to 20, each R.sup.5 is independently hydrogen or C.sub.1-4 alkyl; and R.sup.6 is: ##STR00035## where s is an integer from 0 to 10; t is an integer from 2 to 30; and R.sup.7 is hydrogen or C.sub.1-4 alkyl (e.g., is H or C1, C2, C3, or C4 alkyl), wherein R.sup.3 is: ##STR00036## and x is an integer ranging from 1 to 100; y is an integer in a range from 2 to 30; and R.sup.8 is hydrogen or C.sub.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.degree. 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.degree. 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: ##STR00037## wherein R is a bond, --(CH.sub.2).sub.a--, or --(CH.sub.2).sub.b--O--(CH.sub.2).sub.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.sub.1-4 alkyl; R.sup.o, R'' and R''' are each independently H or C.sub.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: ##STR00038## wherein R* is a C.sub.1-4 alkyl, n is an integer ranging from 5 to 400, and A in each subunit is R.sup.1 or R.sup.3, wherein R.sup.1 is ##STR00039## where p and q are each independently integers that range from between about 1 to 20, each R.sup.5 is independently hydrogen or C.sub.1-4 alkyl; and R.sup.6 is: ##STR00040## where s is an integer from 0 to 10; t is an integer from 2 to 30; and R.sup.7 is hydrogen or C.sub.1-4 alkyl (e.g., is H or C1, C2, C3, or C4 alkyl), wherein R.sup.3 is: ##STR00041## and x is an integer ranging from 1 to 100; y is an integer in a range from 2 to 30; and R.sup.8 is hydrogen or C.sub.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.degree. 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.