Implantable polymer depots for controlled release of therapeutic agents

Abstract

To provide implantable polymer depots for controlled release of therapeutic agents.SOLUTION: The present technology relates to a depot assembly for the controlled, sustained release of a therapeutic agent. The assembly can include a depot having: a therapeutic region comprising a therapeutic agent; and a control region comprising a bioresorbable polymer and a releasing agent mixed with the polymer. The releasing agent may be configured to form diffusion openings in the control region when the depot is placed in vivo. The depot may be configured to be implanted at a treatment site in vivo and, while implanted, release the therapeutic agent at the treatment site for 3 days or more.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to PCT Application No. PCT / US19 / 12795, filed January 8, 2019, PCT Application No. PCT / US18 / 54777, filed October 6, 2018, U.S. Patent Application No. 62 / 742,357, filed October 6, 2018, U.S. Patent Application No. 62 / 723,478, filed August 28, 2018, and U.S. Patent Application No. 62 / 670,721, filed May 12, 2018, each of which is incorporated by reference in its entirety.

[0002] This application incorporates by reference in its entirety each of the following applications: U.S. Patent Application No. 62 / 569,349, filed October 6, 2017; U.S. Patent Application No. 62 / 614,884, filed January 8, 2018; and U.S. Patent Application No. 62 / 640,571, filed March 8, 2018.

[0003] The present technology relates to implants for the controlled, sustained release of therapeutic agents in vivo. [Background technology]

[0004] Implantable systems for the controlled release of therapeutic agents offer advantages over other drug delivery methods, such as oral or parenteral methods. Devices composed of biocompatible and / or biodegradable polymers and therapeutic agents can be implanted at clinically desirable anatomical sites, thereby providing localized delivery of select agents. This localized delivery can allow a significant proportion of the agent to reach its intended target and avoid unwanted systemic side effects. However, these systems often suffer from the lack of a true controlled-release mechanism, in that they typically result in a burst release of the drug upon contact with surrounding physiological fluids, followed by a residual release of the drug.

[0005] To improve drug release in certain polymeric carriers, hydrophilic polymers such as polysorbates have been added to these carriers as wetting agents to accelerate or enhance drug release from biocompatible polymers such as polyethylene glycol (PEG) in oral formulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3): 435-441). However, these formulations are intended to provide immediate release of the hydrophobic drug into a hydrophilic environment (in vivo physiological fluids), with a significant portion of the total drug payload being released immediately or actively, rather than variable or sustained controlled release.

[0006] While these drug release kinetics may be desirable in some clinical applications, controlled, sustained release of a therapeutic agent may be clinically beneficial in certain situations. In particular, it may be desirable to implant a biodegradable carrier that holds a large dose of a therapeutic agent for controlled, sustained release over time. This may be of particular value when the therapeutic-agent-loaded carrier is implanted in conjunction with an interventional or surgical procedure and, optionally, with or as part of an implantable medical device. Thus, there is a need for biocompatible implantable systems that can provide highly controlled release of drugs. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3): 435-441 Summary of the Invention [Means for solving the problem]

[0008] FIELD OF THE INVENTION The present technology relates to implants for the controlled release of therapeutic agents to treat medical conditions, and related systems and methods. In particular, the present technology relates to implants for the localized, sustained release of therapeutic agents at a surgical or intervention site, and related systems and methods.

[0009] The present technology is illustrated by various embodiments described below, including, for example, with reference to Figures 1-65. Various examples of embodiments of the present technology are described as numbered bullet points (1, 2, 3, etc.) for convenience. These are provided as examples and are not intended to limit the present technology. 1. A depot for treating post-operative pain via sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, The depot is configured to be implanted at a treatment site in vivo and, while implanted, to release the analgesic agent at the treatment site for a period of seven days or more. 2. A depot according to clause 1, wherein the analgesic agent in the therapeutic area constitutes at least 50% of the total weight of the depot. 3. The depot of clause 1 or clause 2, wherein the depot is configured to release the analgesic agent at the treatment site for a period of 14 days or more. 4. A depot according to clause 3, wherein about 20% to about 50% of the analgesic is released in about the first 3 to about 5 days of a 14-day period, and at least 80% of the remaining analgesic is released in the last 11 days of the 14-day period. 5. The depot of clause 3, wherein about 20% to about 40% of the analgesic is released in the first 3 days of the 14-day period and at least 80% of the remaining analgesic is released in the last 11 days of the 14-day period. 6. The depot of any one of clauses 3 to 5, wherein at least 90% of the remaining analgesic is released in the last 11 days of the 14-day period. 7. A depot according to any one of clauses 3 to 6, in which not more than 15% of the amount of analgesic is released during the first 2 days of a 14-day period. 8. A depot according to any one of clauses 3 to 7, in which not more than 20% of the amount of analgesic is released during the first 2 days of a 14-day period. 9. A depot according to any one of clauses 3 to 8, in which not more than 25% of the amount of analgesic is released during the first 3 days of a 14-day period. 10. A depot according to any one of clauses 3 to 9, in which not more than 30% of the amount of analgesic is released during the first 3 days of a 14-day period. 11. The depot of any one of the preceding clauses, wherein the depot is configured to release the analgesic agent at a first rate for a first period of time and at a second rate for a second period of time. 12. Depot in clause 11, where the first rate is greater than the second rate. 13. Depot in clause 11, where the first period is longer than the second period. 14. Depot under Article 11, where the first period is shorter than the second period. 15. A depot of any one of the preceding clauses configured to release at least 90% of the analgesic in the treatment area within 14 days. 16. The depot of any one of the preceding clauses, configured to release from about 100 mg to about 500 mg of analgesic to the treatment site per day. 17. The depot of any one of the preceding clauses, configured to release from about 100 mg to about 400 mg of analgesic to the treatment site per day. 18. The depot of any one of the preceding clauses, configured to release from about 100 mg to about 300 mg of analgesic to the treatment site per day. 19. A depot of any one of the preceding clauses configured to release not more than 300 mg of analgesic per day within the first 3 days and not more than 200 mg per day for the remaining days. 20. A depot of any one of the preceding clauses configured to release not more than 150 mg of analgesic per day within the first 3 days and not more than 100 mg per day for the remaining days. 21. A depot of any one of the preceding clauses in which 400 mg or less of an analgesic is released by any of the 14 days. 22. A depot of any one of the preceding clauses in which 300 mg or less of an analgesic is released by any of the 14 days. 23. A depot of any one of the preceding clauses in which 250 mg or less of analgesic is released by any of the 14 days. 24. A depot of any one of the preceding clauses in which 200 mg or less of an analgesic is released by any of the 14 days. 25. A depot of any one of the preceding clauses in which 150 mg or less of analgesic is released by any of the 14 days. 26. A depot of any one of the preceding clauses in which 100 mg or less of an analgesic is released by any of the 14 days. 27. The depot of any one of the preceding clauses, configured to release an analgesic agent at a treatment site in vivo for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 7 days or more, 8 days or more, 9 days or more, 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 21 days or more, 22 days or more, 23 days or more, 24 days or more, 25 days or more, 26 days or more, 27 days or more, 28 days or more, 29 days or more, 30 days or more, 40 days or more, 50 days or more, 60 days or more, 70 days or more, 90 days or more, 100 days or more, 200 days or more, 300 days or more, or 365 days or more. 28. The depot of any one of the preceding clauses, wherein the concentration of the analgesic agent in the plasma of the mammalian patient on the 10th day is at least 70% of the concentration of the analgesic agent in the patient's plasma on the 5th day. 29. The depot of any one of the preceding clauses, wherein the treatment area includes a covered portion and an exposed portion, and the covered portion is covered by the control area such that when the depot is initially placed at the treatment site in vivo, the control area is between the covered portion of the treatment area and physiological fluids at the treatment site, and the exposed portion of the treatment area is exposed to physiological fluids. 30. The depot has a total surface area that includes the exposed surface area of ​​the control region plus the exposed surface area of ​​the treatment region; When the depot is initially placed at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the control region is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%. Depot of any one of the preceding clauses. 31. A depot according to clause 30, wherein the exposed surface area of ​​the control region is less than the exposed surface area of ​​the treatment region. 32. A depot according to clause 30, wherein the exposed surface area of ​​the control region is greater than the exposed surface area of ​​the treatment region. 33. The depot of any one of the preceding clauses, wherein the control area is a first control area and the depot includes a second control area. 34. The depot of clause 33, wherein the first control region is disposed on a first side of the treatment region and the second control region is disposed on a second side of the treatment region opposite the first side. 35. The depot of any one of the preceding clauses, wherein the depot comprises a plurality of control regions and a plurality of treatment regions, each of the treatment regions being spaced from an adjacent one of the treatment regions by one or more control regions. 36. The depot of clause 35, wherein each of the treatment areas and each of the control areas is a microthin layer. 37. A depot according to clause 35 or clause 36, comprising from about 2 to about 100 treatment areas. 38. A depot according to clause 35 or clause 36, comprising from about 2 to about 50 treatment areas. 39. A depot according to clause 35 or clause 36, comprising from about 2 to about 10 treatment areas. 40. The depot of any one of clauses 1 to 34, wherein the treatment region is surrounded by the control region such that when the depot is placed at the treatment site in vivo, the control region is between the treatment region and the physiological fluids at the treatment site. 41. The depot of any one of the preceding clauses, wherein the control region includes a first control layer and a second control layer. 42. The depot of clause 41, wherein the second control layer is adjacent to the treatment area and the first control layer encapsulates / surrounds the treatment area and the second control layer. 43. The depot of clause 41 or clause 42, wherein the first control layer and the second control layer together enclose the treatment area. 44. The depot of any one of clauses 41 to 43, wherein a first control layer is disposed on a first side of the treatment area and a second control layer is disposed on a second side of the treatment area opposite the first side. 45. The depot of any one of clauses 41 to 44, wherein the first control layer comprises a first plurality of sub-layers and the second control layer comprises a second plurality of sub-layers. 46. ​​The depot of any one of clauses 41 to 45, wherein the first control layer comprises a first amount of release agent and the second control layer comprises a second amount of release agent different from the first amount. 47. The depot of any one of clauses 41 to 46, wherein a second control layer is positioned between the first control layer and the treatment area, the first control layer comprising a first concentration of release agent and the second control layer comprising a second concentration of release agent that is greater than the first concentration. 48. The depot of any one of clauses 41 to 46, wherein a second control layer is positioned between the first control layer and the treatment area, the first control layer comprising a first concentration of release agent and the second control layer comprising a second concentration of release agent that is less than the first concentration. 49. A second control layer is disposed between the first control layer and the treatment area; the first control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; the second control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; Any one of the depots in clauses 41 to 48. 50. The depot of any one of clauses 41 to 49, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer comprising a first amount of release agent, and the second control layer comprising a second amount of release agent, the second amount being at least two times, at least three times, at least four times, or at least five times the first amount. 51. A depot according to any one of the preceding clauses, in which the thickness of the control area is less than or equal to 1 / 10 of the thickness of the treatment area. 52. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 12.5 of the thickness of the treatment area. 53. A depot according to any one of the preceding clauses, in which the thickness of the control area is less than or equal to 1 / 15 of the thickness of the treatment area. 54. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 17.5 of the thickness of the treatment area. 55. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 20 of the thickness of the treatment area. 56. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 22.5 of the thickness of the treatment area. 57. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 25 of the thickness of the treatment area. 58. A depot according to any one of the preceding clauses, in which the thickness of the control area is less than or equal to 1 / 30 of the thickness of the treatment area. 59. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 40 of the thickness of the treatment area. 60. A depot according to any one of the preceding clauses, in which the thickness of the control area is less than or equal to 1 / 50 of the thickness of the treatment area. 61. A depot according to any one of the preceding clauses, in which the thickness of the control area is less than or equal to 1 / 75 of the thickness of the treatment area. 62. The depot of any one of the preceding clauses, wherein the thickness of the control region is less than or equal to 1 / 100 of the thickness of the treatment region. 63. A depot according to any one of the preceding clauses that is a flexible solid that is structurally capable of being handled by a clinician during the course of a normal surgical procedure without breaking into multiple small pieces and / or losing its overall shape. 64. A depot according to any one of the preceding clauses, configured to be placed inside a patient's knee and to release an analgesic agent in vivo for up to seven days without breaking into multiple small pieces. 65. A depot of any one of the preceding clauses, wherein the depot has a width and a thickness, and the ratio of width to thickness is 21 or greater. 66. Depots under Article 65 where the ratio is 30 or greater. 67. Depots under Article 65 where the ratio is 40 or greater. 68. The depot of any one of the preceding clauses, wherein the depot has a surface area and a volume, and the ratio of surface area to volume is at least 1. 69. The depot of any one of the preceding clauses, wherein the diffusion opening comprises at least one or more pores and / or one or more channels. 70. The depot of any one of the preceding clauses, wherein two or more micro-thin layers of bioabsorbable polymer are bonded via thermocompression to form the treatment area. 71. The depot of any one of the preceding clauses, wherein the control area and the treatment area are joined via thermal compression. 72. The depot of any one of the preceding clauses, wherein the control area and the treatment area are thermally bonded. 73. The depot of any one of the preceding clauses, wherein upon dissolution of the release agent after placement in vivo at the treatment site, the control region and the treatment region transition from a less porous state to a more porous state to facilitate release of the analgesic agent from the depot. 74. The depot of any one of the preceding clauses, wherein the control region does not contain an analgesic, at least prior to implantation of the depot at the treatment site. 75. A depot according to any one of clauses 1 to 73, wherein the control area contains an analgesic different from the analgesic in the treatment area. 76. The depot of any one of the preceding clauses, wherein the treatment area does not contain any release agent prior to implantation of the depot at the treatment site. 77. The depot of any one of the preceding clauses, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with the analgesic. 78. The release agent is a first release agent, the polymer is a first polymer, and the therapeutic area is: 78. The depot of any one of clauses 1 to 77, comprising a second release agent and a second polymer mixed with the analgesic. 79. The depot of any one of clauses 1 to 77, wherein the first releasing agent is the same as the second releasing agent. 80. A depot according to any one of clauses 1 to 77, wherein the first releasing agent is different from the second releasing agent. 81. The depot of any one of clauses 1 to 79, wherein the concentration of the first release agent in the control region is greater than the concentration of the second release agent in the treatment region. 82. The depot of any one of clauses 1 to 81, wherein the concentration of the first release agent in the control region is less than the concentration of the second release agent in the treatment region. 83. The depot of any one of clauses 1 to 81, wherein the concentration of the first release agent in the control region is the same as the concentration of the second release agent in the treatment region. 84. The depot of any one of clauses 1 to 81, wherein the concentration of the first release agent in the control region is different from the concentration of the second release agent in the treatment region. 85. A depot according to any one of the preceding clauses, wherein the treatment area comprises multiple microlayers. 86. A depot of any one of the preceding clauses in which the mass of the analgesic constitutes at least 50% of the mass of the depot. 87. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 3:1. 88. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 4:1. 89. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 5:1. 90. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 6:1. 91. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 7:1. 92. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 8:1. 93. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 10:1. 94. The depot of any one of the preceding clauses, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 16:1. 95. The depot of any one of the preceding clauses, wherein the therapeutic area comprises at least 60% by weight of an analgesic, 60% by weight of an analgesic, at least 70% by weight of an analgesic, at least 80% by weight of an analgesic, at least 90% by weight of an analgesic, or 100% by weight of an analgesic. 96. A depot of any one of the preceding clauses comprising at least 15% by weight of an analgesic, at least 20% by weight of an analgesic, at least 30% by weight of an analgesic, at least 40% by weight of an analgesic, at least 50% by weight of an analgesic, at least 60% by weight of an analgesic, at least 70% by weight of an analgesic, at least 80% by weight of an analgesic, at least 90% by weight of an analgesic, or 100% by weight of an analgesic. 97. The depot of any one of the preceding clauses, wherein the analgesic comprises at least one of a simple analgesic, a local anesthetic, an NSAID, and an opioid. 98. The depot of any one of the preceding clauses, wherein the analgesic comprises a local anesthetic selected from at least one of bupivacaine, ropivacaine, mepivacaine, and lidocaine. 99. The depot of any one of the preceding clauses, further comprising an antibiotic, antifungal, and / or antibacterial agent, wherein the antibiotic, antifungal, and / or antibacterial agent is selected from amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampin, trimethoprim, riboflavin, thiazol-1, thiazol-2, thiazol-3, thiazol-4, thiazol-5, thiazol-6, thiazol-7, thiazol-8, thiazol-9, thiazol-10, thiazol-11, thiazol-12, thiazol-13, thiazol-14, thiazol-15, thiazol-16, thiazol-17, thiazol-18, thiazol-19, thiazol-20, thiazol-19 ... losan, chlorhexidine, penicillin(s), aminoglycosides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporin(s), carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropin-melittin, magainin, dermaseptin, cathelicidin, α-defensins, and α-protegrin, ketoconazole, chlortrimazole, miconazole, econazole, intraconazole, fluconazole , bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B. 100. The depot of any one of the preceding clauses, further comprising an anti-inflammatory agent selected from at least one of steroids, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and a COX-2 inhibitor. 101. A depot of any one of the preceding clauses in which the analgesic is dexamethasone. 102. The depot of any one of the preceding clauses, wherein the analgesic is tetrodotoxin. 103. The depot of any one of the preceding clauses, wherein the analgesic is saxitoxin. 104. Epinephrine, clonidine, and tranexamic acid Any one of the preceding clauses further includes one of the following: 105. The depot of any one of the preceding clauses, wherein the release agent is a non-ionic surfactant. 106. The depot of any one of the preceding clauses, wherein the release agent has hydrophilic properties. 107. The depot of any one of the preceding clauses, wherein the release agent is a polysorbate. 108. The depot of any one of the preceding clauses, wherein the release agent is Tween® 20. 109. The depot of any one of clauses 1 to 107, wherein the release agent is Tween 80. 110. The depot of any one of the preceding clauses, wherein the release agent is non-polymeric. 111. A depot of any one of the preceding clauses in which the releasing agent is not a plasticizer. 112. The depot of any one of the preceding clauses, wherein the polymer is configured to degrade only after substantially all of the analgesic agent has been released from the depot. 113. The depot of any one of the preceding clauses, wherein the polymer is a copolymer. 114. The depot of any one of clauses 1 to 112, wherein the polymer is a terpolymer. 115. The depot of any one of clauses 1 to 112, wherein the polymer is selected from the group consisting of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazenes), polyphosphates, poly(amino acids), Polydepsipeptide, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl methacrylate ... glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl Methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (Polyactive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydroxypropyl acrylate 3. The depot of any one of the preceding clauses, comprising at least one of: propylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or a salt thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone). 116. The depot of any one of the preceding clauses, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 117. The depot of any one of clauses 1 to 112, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10. 118. The depot of any one of clauses 1 to 112, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a 50:50 molar ratio. 119. The depot of any one of the preceding clauses, wherein the polymer is ester terminated. 120. The depot of any one of the preceding clauses, wherein the polymer is a terpolymer comprising three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. 121. The depot of any one of the preceding clauses, wherein the polymer is a first polymer and the treatment area comprises a second polymer mixed with an analgesic. 122. The depot of clause 121, wherein the first polymer and the second polymer are the same. 123. A depot according to clause 121, wherein the first polymer and the second polymer are different. 124. The first polymer and / or the second polymer are selected from the group consisting of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate), ) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazenes), polyphosphates), poly(amino acids), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycol Cholic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenyl)-2-methylpropional (noxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate), hydroxypropyl cellulose 124. The depot of any one of clauses 121 to 123, comprising at least one of: cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or a salt thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone). 125. The depot of any one of clauses 121 to 123, wherein the first polymer and / or the second polymer is selected from the following: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 126. The depot of any one of clauses 121 to 123, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of 60:30:10. 127. The depot of any one of clauses 121 to 123, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a 50:50 molar ratio. 128. The depot of any one of clauses 121 to 127, wherein the first polymer and / or the second polymer are ester terminated. 129. The first polymer and / or the second polymer is a terpolymer including three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. Any one of the depots in clauses 121 to 123. 130. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:2 or less. 131. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:3 or less. 132. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:4 or less. 133. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:5 or less. 134. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:6 or less. 135. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:7 or less. 136. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:8 or less. 137. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:9 or less. 138. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:10 or less. 139. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is 1:11 or less. 140. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 1:1. 141. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 2:1. 142. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 3:1. 143. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 4:1. 144. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 5:1. 145. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 6:1. 146. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 7:1. 147. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 8:1. 148. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 9:1. 149. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 10:1. 150. The depot of any one of clauses 1 to 129, wherein the ratio of release agent to polymer in the controlled region is at least 15:1. 151. The polymer is a first polymer and the therapeutic area further comprises a second polymer; the depot has a depot polymer mass equal to the mass of the first polymer plus the mass of the second polymer; the ratio of the mass of the analgesic drug in the depot to the mass of the depot polymer is about 1:1; Depot of any one of the preceding clauses. 152. The depot of clause 151, wherein the first polymer is the same as the second polymer. 153. A depot of clause 151, in which the first polymer is different from the second polymer. 154. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of the analgesic in the depot to the mass of the depot polymer is at least 2:1. 155. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 3:1. 156. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 4:1. 157. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is about 5:1. 158. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 6:1. 159. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 7:1. 160. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 8:1. 161. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 10:1. 162. The depot of any one of clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 16:1. 163. A depot of any one of the preceding clauses, wherein the analgesic is a local anesthetic and the release of the analgesic to the treatment site over a period of 5 days inhibits bacterial and fungal growth. 164. A depot of clause 163 configured to inhibit bacterial and fungal growth so that the number of bacteria on the depot is 10, 20, 30, 40, or 50 times less than the number of bacteria present on a comparable depot not containing the analgesic. 165. A depot of any one of the preceding clauses, wherein the release of analgesic agent is high enough to create a sensory block, thereby treating postoperative pain, but at a low enough level to avoid motor block. 166. A depot according to any one of the preceding clauses, wherein release of an analgesic agent provides motor-sparing relief from postoperative pain. 167. A depot for sustained controlled release of a therapeutic agent, comprising: Therapeutic areas, including therapeutic agents; a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve when the depot is placed in contact with a fluid to form diffusion openings in the control region; Includes; when the depot is placed in contact with a fluid, the depot is configured to release the therapeutic agent into the surrounding fluid for 14 days or more; A depot wherein about 20% to about 50% of the therapeutic agent is released in about the first 3 to about 5 days of a 14-day period, and at least 80% of the remaining therapeutic agent is released in the last 11 days of the 14-day period. 168. A depot under article 167 in which at least 85% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 169. A depot under article 167 in which at least 90% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 170. A depot under article 167 in which at least 95% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 171. A depot of any one of clauses 167 to 170 in which not more than 15% of the amount of therapeutic agent is released during the first two days of a 14-day period. 172. A depot of any one of clauses 167 to 170, in which not more than 20% of the amount of therapeutic agent is released during the first two days of a 14-day period. 173. A depot of any one of clauses 167 to 170 in which not more than 25% of the amount of therapeutic agent is released during the first 3 days of a 14-day period. 174. A depot according to any one of clauses 167 to 170, in which not more than 30% of the amount of therapeutic agent is released during the first three days of a 14-day period. 175. The depot of any one of clauses 167 to 170, wherein the release agent is configured to dissolve and form a diffusion opening when the depot is placed in contact with phosphate buffered saline. 176. A method for treating postoperative pain, comprising: placing at a treatment site in vivo having physiological fluid a depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases pain medication to the treatment site for at least 7 days. A method comprising: 177. The method of clause 176, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, the first rate being greater than the second rate. 178. The method of clause 176 or clause 177, further comprising dissolving the release agent in response to contact between the control region and physiological fluid at the treatment site. 179. The method of any one of clauses 176 to 178, further comprising creating a diffusion opening in the control region via dissolution of a release agent in response to physiological fluid at the treatment site. 180. The method of any one of clauses 176 to 179, wherein the release agent is a first release agent and the treatment region comprises a second release agent, and the method further comprises creating microchannels in the treatment region and the control region via dissolution of the first and / or second release agents. 181. The method of any one of clauses 176 to 180, wherein at least some of the microchannels penetrate both the treatment region and the control region. 182. The method of any one of clauses 176 to 181, wherein the treatment region comprises a plurality of microlayers and at least some of the microchannels extend through successive microlayers. 183. The method of any one of clauses 176 to 159, wherein the control region comprises a first plurality of microlayers and the treatment region comprises a second plurality of microlayers and at least some of the microchannels extend through the first and second plurality of microlayers. 184. The method of any one of clauses 176 to 183, further comprising increasing the porosity of the depot through dissolution of the release agent. 185. The method of any one of clauses 176 to 184, wherein the analgesic is released in one or more substantially discrete doses after implantation. 186. The method of any one of clauses 176 to 185, wherein the analgesic is released continuously for at least 7 days after implantation. 187. The method of any one of clauses 176 to 186, in which the analgesic is released over a period of 10 days or more. 188. The method of any one of clauses 176 to 186, in which the analgesic is released over a period of 14 days or more. 189. The method of any one of clauses 176 to 188, in which not more than 20% of the amount of analgesic is released on the first day of the seven-day period. 190. The method of any one of clauses 176 to 189, further comprising securing the depot to the treatment site via an attachment means. 191. The method of any one of clauses 176 to 190, wherein the attachment means is coupled to the depot prior to implantation. 192. The method of any one of clauses 176 to 191, wherein the depot is a first depot and the method further comprises placing a second depot at the treatment site. 193. The method of clause 192, wherein the first and second depots together release at least 1400 mg of analgesic agent to the treatment site over a period of 7 days or more. 194. A method for treating postoperative pain associated with orthopedic surgery with any of the depots of clauses 1 to 175, 225 to 227, and 273 to 429 and / or the systems of clauses 211 to 224. 195. A method for treating postoperative pain in a patient following orthopedic surgery, comprising: Implanting a plurality of depots at a surgical site, each of the depots including (a) a control region including a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region including at least 50% by weight of an analgesic; and The depot releases pain medication to the area for at least 7 days. A method comprising: 196. A method for treating postoperative pain in a patient following orthopedic surgery, comprising: Implanting a depot at a surgical site, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases pain medication to the area for at least 7 days. A method comprising: 197. A method for treating postoperative pain in a patient following total knee arthroplasty, comprising: placing a depot in the patient's knee, the depot including (a) a control region including a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region including at least 50% by weight of an analgesic; and The depot releases pain medication into the patient's knee for at least seven days. A method comprising: 198. The method of clause 197, in which the depot is one of the depots of clauses 1 to 175, 225 to 227, and 273 to 429. 199. The method of clause 197 or clause 198, wherein placing the depot includes placing at least one depot in at least one of the suprapatellar capsule, lateral sulcus, medial sulcus, posterior capsule, quadriceps tendon, skin incision, arthrotomy, adductor canal, saphenous nerve, and geniculate nerve. 200. The method of any one of clauses 197 to 199, wherein placing a depot includes placing at least one depot adjacent to at least one of the saphenous nerve, the adductor canal, and the femoral nerve. 201. The method of any one of clauses 197 to 200, wherein placing the depot includes placing at least one depot on or near one or more nerves that innervate all or part of the anterior knee joint capsule. 202. The method of any one of clauses 197 to 201, wherein placing the depot includes placing at least one depot on or near a superior lateral geniculate nerve branch from the vastus lateralis, a superior medial geniculate nerve branch from the vastus medialis, a medial geniculate nerve branch from the vastus intermedius, an inferior lateral geniculate nerve branch from the common peroneal nerve, an inferior medial geniculate nerve branch from the saphenous nerve, and / or a lateral geniculate nerve branch from the common peroneal nerve. 203. The method of any one of clauses 197 to 200, wherein placing a depot includes intracapsular placement of at least one depot. 204. The method of any one of clauses 197 to 203, wherein placing a depot includes extracapsular placement of at least one depot. 205. The method of any one of clauses 197 to 204, wherein placing the depot includes intracapsular placement without disturbing the knee joint. 206. The method of clause 205, wherein at least one depot is placed in at least one of the suprapatellar capsule, lateral sulcus, medial sulcus, posterior capsule, quadriceps tendon, skin incision, arthrotomy, and adductor canal. 207. A system for treating postoperative pain associated with orthopedic surgery, comprising: a plurality of depots, each of which is one of the depots described in the preceding clause; A system in which a plurality of depots are configured to be implanted at a treatment site on a patient and to release an analgesic agent at the treatment site. 208. The depot is configured to release the analgesic agent to the treatment site for at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days, under clause 207. system. 209. A system of clause 208 in which the depot is configured to release, in batches, not more than 250 mg of analgesic per day within the first three days and not more than 150 mg of analgesic per day for the remaining days. 210. Delivery systems; and A depot configured to be implanted at a treatment site in vivo together with a delivery system, Depots including any of the depots in clauses 1 to 175, 225 to 227, and 273 to 429 1. A system for treating post-operative pain, comprising: 211. Means of attachment; and A depot configured to be implanted at a treatment site in vivo and secured to the treatment site via an attachment means, the depot comprising any of the depots of clauses 1 to 175, 225 to 227, and 273 to 429. 1. A system for treating post-operative pain, comprising: 212. The system of clause 187, wherein the attachment means is connected to the depot prior to implantation. 213. The system of clause 187 or clause 212, wherein the attachment means is at least one of a suture, a tine, a barb, a hook, and a screw. 214. The system of any one of clauses 211 to 213, in which the pain is related to orthopedic surgery. 215. The system of any one of clauses 211 to 214, in which the pain is related to joint replacement surgery. 216. The system of any one of clauses 211 to 215, in which the pain is related to knee replacement surgery. 217. The system of any one of clauses 211 to 215, in which the pain is related to partial knee replacement surgery. 218. The system of any one of clauses 211 to 215, in which the pain is associated with total knee replacement surgery. 219. The system of any one of clauses 211 to 215, in which the pain is related to revision knee replacement surgery. 220. The system of any one of clauses 211 to 219, wherein the depot is configured to be placed adjacent to at least one of the saphenous nerve, the adductor canal, and the femoral nerve. 221. The system of any one of clauses 211 to 220, wherein the depot is configured to be placed adjacent to at least one of the posterior capsule of the knee, the region above the patella, or an incision into the knee joint capsule. 222. The system of any one of clauses 211 to 191, wherein the depot is configured for placement within the knee joint capsule in the medial and / or lateral groove. 223. A system for treating postoperative pain, comprising a delivery system and any of the depots of clauses 1 to 175, 225 to 227, and 273 to 429. 224. A system for treating postoperative pain comprising a plurality of depots, each of which comprises any of the depots of clauses 1-175, 225-227, and 273-429. 225. A depot for releasing a therapeutic agent to treat or manage a particular condition or disease, comprising: a treatment area comprising a therapeutic agent and a bioabsorbable polymer carrier; a control region comprising a bioabsorbable polymer layer and a release agent mixed with the polymer, the release agent configured to dissolve over a first period of time after in vivo placement to form diffusion openings in the control region; Including, The depot is implanted in vivo at the treatment site and, while implanted, configured to release the therapeutic agent over a second period of time; The second period is longer than the first period; After the second period of time, the polymeric carrier of the treatment region and the polymeric layer of the control region comprise a highly porous polymeric structure configured to degrade in vivo without acidification of the core, the depot. 226. The depot of clause 225, wherein the highly porous polymeric structure at the end of the second period has a mass that is no more than 50% of the mass of the depot before in vivo placement. 227. A depot according to Clause 225 or 226, wherein the highly porous polymer structure is configured to degrade in vivo via surface erosion. 228. A method for treating postoperative pain following a non-orthopedic surgical procedure, comprising: placing at a treatment site in vivo having physiological fluids a depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; dissolving the release agent in response to contact between the release agent and the physiological fluid, thereby forming a diffusion opening in the control region; and Release of pain medication from the treatment area through the diffusion opening to the treatment site for at least 5 days A method comprising: 229. The method of clause 228, wherein the surgical procedure includes at least one of thoracotomy, esophageal surgery, cardiac surgery, lung resection, or thoracic surgery. 230. The method of clause 229, wherein the treatment site includes the thoracic paravertebral space. 231. The method of clause 229 or clause 230, wherein the analgesic released from the depot at least partially blocks the intercostal nerves. 232. The method of clause 228, in which the surgical procedure includes at least one of mastectomy, breast augmentation, breast reduction, or breast reconstruction. 233. The method of clause 232, wherein the treatment site includes the subclavian space. 234. The method of clause 232 or clause 233, wherein the analgesic released from the depot at least partially blocks at least one of the intercostal nerves, the medial pectoral nerve, or the lateral pectoral nerve. 235. The method of clause 228, in which the surgical procedure includes at least one of myomectomy, cesarean section, hysterectomy, oophorectomy, or pelvic floor reconstruction. 236. The method of clause 228, wherein the surgical procedure includes at least one of proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, proctectomy, kidney stone removal, or cystectomy. 237. The method of clause 236, wherein the analgesic released from the depot at least partially blocks nerves at or adjacent to the plane of the transversus abdominis fascia. 238. The method of clause 228, wherein the surgical procedure includes at least one of tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, or submandibular gland surgery. 239. The method of clause 228, wherein the surgical procedure includes at least one of dentoalveolar surgery, dental implants, surgical orthodontics, temporomandibular joint (TMJ) surgery, or oral reconstruction. 240. The method of clause 228, in which the surgical procedure includes tumor resection. 241. The method of clause 228, in which the surgical procedure includes liposuction. 242. The method of any one of clauses 228 to 241, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, the first rate being greater than the second rate. 243. The method of any one of clauses 228 to 242, in which the analgesic is released over a period of 10 days or more. 244. The method of any one of clauses 228 to 243, in which the analgesic is released over a period of 14 days or more. 245. Not more than 20% of the analgesic dose is released on the first day of the five-day period, Articles 228-24 One of the four methods. 246. The method of any one of clauses 228 to 245, further comprising securing the depot to the treatment site via an attachment means. 247. The method of clause 246, wherein the attachment means is coupled to the depot prior to implantation. 248. The method of any one of clauses 228 to 248, wherein the depot is a first depot and the method further comprises placing a second depot at the treatment site. 249. The method of clause 248, wherein the first and second depots together release at least 1400 mg of analgesic agent to the treatment site over a period of 7 days or more. 250. The method of any one of clauses 228 to 254, in which 400 mg or less of the therapeutic agent is released on any day during a five-day period. 251. A method for treating postoperative pain after a non-orthopedic surgical procedure, comprising: placing at a treatment site in vivo having physiological fluid a depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases pain medication to the treatment site for at least 5 days. A method comprising: 252. The method of clause 251, wherein the surgical procedure includes at least one of thoracotomy, esophageal surgery, cardiac surgery, lung resection, or thoracic surgery. 253. The method of clause 252, wherein the treatment site includes the thoracic paravertebral space. 254. The method of clause 252 or 253, wherein the analgesic released from the depot at least partially blocks the intercostal nerves. 255. The method of clause 251, in which the surgical procedure includes at least one of mastectomy, breast augmentation, breast reduction, or breast reconstruction. 256. The method of clause 255, wherein the treatment site includes the subclavian space. 257. The method of clause 255 or 256, wherein the analgesic released from the depot at least partially blocks at least one of the intercostal nerves, the medial pectoral nerve, or the lateral pectoral nerve. 258. The method of clause 251, in which the surgical procedure includes at least one of myomectomy, cesarean section, hysterectomy, oophorectomy, or pelvic floor reconstruction. 259. The method of clause 251, wherein the surgical procedure includes at least one of proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, rectal resection, kidney stone removal, or cystectomy. 260. The method of clause 259, wherein the analgesic released from the depot at least partially blocks nerves at or adjacent to the plane of the transversus abdominis fascia. 261. The method of clause 251, in which the surgical procedure includes at least one of tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, or submandibular gland surgery. 262. The method of clause 251, wherein the surgical procedure includes at least one of dentoalveolar surgery, dental implants, surgical orthodontics, temporomandibular joint (TMJ) surgery, or oral reconstruction. 263. The method of clause 251, in which the surgical procedure includes tumor resection. 264. The method of clause 251, in which the surgical procedure includes liposuction. 265. A method for treating postoperative pain following a surgical procedure involving a patient's chest, comprising: placing a depot near an intercostal nerve at a treatment site having physiological fluid, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases analgesic into the intercostal nerves for at least 5 days. A method comprising: 266. The method of clause 265, wherein the surgical procedure includes at least one of thoracotomy, esophageal surgery, cardiac surgery, lung resection, or thoracic surgery. 267. The method of clause 265 or 266, wherein the treatment site includes the thoracic paravertebral space. 268. A method for treating postoperative pain following a surgical procedure involving a patient's breast, comprising: placing a depot in the vicinity of the intercostal and / or pectoral nerves at a treatment site having physiological fluid, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The method comprises releasing an analgesic agent from the depot into the intercostal and / or pectoral nerves for a period of 5 days or more. 269. The method of clause 268, in which the surgical procedure includes at least one of mastectomy, breast augmentation, breast reduction, or breast reconstruction. 270. The method of clause 268 or 269, wherein the treatment site includes the intraclavicular space. 271. A method for treating postoperative pain after a general, abdominal, or urinary surgical procedure, comprising: placing a depot near the transversus abdominis plane at a treatment site having physiological fluid, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The method comprises releasing an analgesic agent from the depot into the intercostal and / or pectoral nerves for a period of 5 days or more. 272. The method of clause 271, wherein the surgical procedure includes at least one of proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, proctectomy, kidney stone removal, or cystectomy. 273. A depot for sustained, controlled release of a therapeutic agent, comprising: a therapeutic area containing a therapeutic agent; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; wherein the depot is configured such that after immersion of the depot in a buffer solution for 7 days, the flexural strength of the depot is reduced by up to 75%. 274. A depot according to clause 273, configured such that the flexural strength of the depot is reduced by up to 70% after immersion of the depot in a buffer solution for 7 days. 275. A depot according to clause 273, configured such that the flexural strength of the depot is reduced by up to 65% after immersion of the depot in a buffer solution for 7 days. 276. A depot according to clause 273, configured such that the flexural strength of the depot is reduced by up to 60% after immersion of the depot in a buffer solution for 7 days. 277. A depot according to clause 273, configured such that the flexural strength of the depot is reduced by up to 55% after immersion of the depot in a buffer solution for 7 days. 278. A depot according to clause 273, configured such that the flexural strength of the depot is reduced by up to 50% after immersion of the depot in a buffer solution for 7 days. 279. The depot of clause 273, wherein the depot is configured such that the flexural strength of the depot decreases by up to 45% after immersion of the depot in a buffer solution for 7 days. 280. A depot for sustained controlled release of a therapeutic agent, comprising: a therapeutic area containing a therapeutic agent; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; wherein the depot is configured such that after immersion in a buffer solution until about 75% by weight of the therapeutic agent has been released, the flexural strength of the depot is reduced by up to 75%. 281. The depot of clause 280, configured such that the flexural strength of the depot is reduced by up to 70% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 282. The depot of clause 280, configured such that the flexural strength of the depot is reduced by up to 65% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 283. The depot of clause 280, configured such that the flexural strength of the depot is reduced by up to 60% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 284. The depot of clause 280, configured such that the flexural strength of the depot is reduced by up to 55% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 285. The depot of clause 280, configured such that the flexural strength of the depot is reduced by up to 50% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 286. The depot of clause 280, configured such that the flexural strength of the depot is reduced by up to 45% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 287. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for 14 days or more; The depot releases about 20% to about 40% of the analgesic over the first 3 days of the 14-day period, with at least 80% of the remaining analgesic being released over the last 11 days of the 14-day period. 288. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The control region is a depot that does not contain analgesic, at least prior to implantation of the depot at the treatment site. 289. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The control region contains a different analgesic than the analgesic in the treatment region, the depot. 290. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, The depot is implanted at the treatment site in vivo and remains implanted for at least 3 days. configured to release an analgesic agent at the treatment site over a period of time; The depot, wherein the release agent is a first release agent and the treatment area contains a second release agent mixed with an analgesic. 291. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The depot, wherein the release agent is a first release agent, the polymer is a first polymer, and the treatment area comprises a second polymer mixed with a second release agent and an analgesic agent. 292. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: therapeutic areas including pain medications; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The thickness of the control region is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 30, 1 / 40, 1 / 50, 1 / 60, 1 / 70, 1 / 80, 1 / 90, or 1 / 100 of the thickness of the treatment region, depot. 293. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The thickness of the control region is less than or equal to 1 / 75 of the thickness of the treatment region, depot. 294. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The thickness of the control region is less than or equal to 1 / 100 of the thickness of the treatment region, depot. 295. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; A controlled release region comprising a bioabsorbable polymer and a release agent mixed with the polymer. the agent is configured to dissolve upon placement of the depot in vivo to form a diffusion opening in the control region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; A depot, wherein the first controlling layer comprises a first amount of a release agent and the second controlling layer comprises a second amount of a release agent that is different from the first amount. 296. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; the depot has a total surface area that includes the exposed surface area of ​​the coverage area plus the exposed surface area of ​​the treatment area; A depot, wherein when the depot is initially placed at a treatment site in vivo, the ratio of the exposed surface area of ​​the treatment area to the exposed surface area of ​​the covered area is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%. 297. A depot for the controlled, sustained release of a therapeutic agent, comprising: a treatment region including a therapeutic agent and extending along a first axis; and a control region at least partially surrounding the treatment region and extending along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon deployment of the depot in vivo to form diffusion openings in the control region; Including, The depot is configured to be implanted in vivo at a treatment site and, while implanted, to release a therapeutic agent at the treatment site for a period of three days or more. 298. A depot of any one of the preceding clauses that is at least five times longer along a first axis than its greatest transverse dimension along a second axis perpendicular to the first axis. 299. A depot of any one of the preceding clauses that is at least 10 times longer along a first axis than its greatest transverse dimension along a second axis perpendicular to the first axis. 300. Depot of any one of the preceding clauses, which is substantially pillared. 301. A depot of any one of the preceding clauses that is substantially cylindrical. 302. The depot of any one of the preceding clauses, wherein the treatment area is substantially cylindrical. 303. The depot of any one of the preceding clauses, further comprising at least one opening extending through the treatment area. 304. The depot of any one of the preceding clauses, wherein the opening forms a cylindrical lumen extending parallel to the first axis. 305. The depot of any of the preceding clauses, wherein the opening includes a lumen extending along a second axis substantially perpendicular to the first axis. 306. The depot of any of the preceding clauses, further comprising a plurality of elongated openings extending parallel to the second axis. 307. The depot of any one of the preceding clauses, wherein the treatment region includes a plurality of separate elongated subregions extending substantially parallel to the first axis. 308. A depot of any one of the preceding clauses, wherein each of the elongated subregions is substantially cylindrical. 309. A tip in which each of the elongated sub-regions is radially separated from each other by a control region. Provisions for carrying out any one depot. 310. The depot of any one of the preceding clauses, wherein the outermost radial dimension of the depot varies along the first axis. 311. The depot of any one of the preceding clauses, wherein the outermost radial dimension of the treatment area varies along the first axis. 312. A depot of any one of the preceding clauses in which the treatment area is a series of separate areas covered and connected by a continuous control area. 313. Depot of the preceding clause, where the control area is narrowed in the area without internal treatment area. 314. Depots of the preceding clause in which the control area is designed to bend or break during or after delivery. 315. The depot of any one of the preceding clauses, wherein the control region has a variable thickness along the length of the depot along the first axis. 316. The depot of any one of the preceding clauses, wherein the control region has a thickness that varies radially about the first axis. 317. A depot of any one of the preceding clauses, wherein the variable thickness of the control region causes the depot to curve or bend when deployed in vivo. 318. A depot of any one of the preceding clauses, configured to preferentially curve or bend when placed in contact with physiological fluids in vivo. 319. The depot of any one of the preceding clauses, wherein the depot comprises an elongated polymeric strip having a length between its longitudinal ends and a width between its transverse edges, the length being greater than the width, the depot having a predetermined shape in the expanded configuration, the strip being rolled about an axis with the width of the strip facing the axis, thereby forming an annular shape. 320. A depot of any one of the preceding clauses forming an annular or semi-annular shape. 321. A depot of any one of the preceding clauses having a first region and a second region, each longitudinally coextensive with one another and extending over all or a portion of their respective lengths, the first region having a first elasticity and the second region having a second elasticity less than the first elasticity. 322. The depot of the preceding clause, which transitions from a straight state to a curved state upon release from the delivery device and is stretched beyond the elastic hysteresis point of the second region such that the second region pulls the depot into the curved shape. 323. The depot of any one of the preceding clauses, wherein the depot has a first region and a second region, each longitudinally coextensive with one another and extending over all or a portion of their respective lengths, and wherein the first region is more hydrophilic than the second region. 324. The depot of the preceding clause, which transitions from a straight state to a curved state when released from the delivery device, the second region pulling the depot into the curved shape. 325. The depot of any one of the preceding clauses, wherein the control region has first and second portions having a first thickness, the first and second portions being separated along the first axis by a third portion having a second thickness different from the first thickness. 326. The depot of any one of the preceding clauses, wherein the depot extends along a first axis from a first end to a second end, and the control region has a thickness that increases from the first end to the second end. 327. The depot of any one of the preceding clauses, wherein the depot extends from the first end to the second end along the first axis, and the control region does not cover the treatment region at the first end of the depot. 328. The depot of any one of the preceding clauses, wherein the depot extends from the first end to the second end along the first axis, and the control region does not cover the treatment region at the first end or the second end. 329. A depot of any one of the preceding clauses in which the control area has more than one separate opening therein. 330. Any of the preceding clauses in which the control region has an elongated opening along the first axis. One depot. 331. A depot of any one of the preceding clauses, in which the elongated opening in the control area extends along the entire length of the depot. 332. A depot of any one of the preceding clauses in which the control area includes a plurality of circular apertures formed therein. 333. The depot of any one of the preceding clauses, wherein the treatment area is a first treatment area and the depot further includes a second treatment area, each of the first and second treatment areas elongating along a first axis, and the first and second treatment areas configured to release therapeutic agents at different rates. 334. The depot of any one of the preceding clauses, wherein the treatment area is a first treatment area and the depot further comprises a second treatment area, each of the first and second treatment areas elongating along a first axis, and the first and second treatment areas comprising different therapeutic agents. 335. A depot of any one of the preceding clauses in which the first and second treatment areas are coaxially aligned. 336. The depot of any one of the preceding clauses, wherein the first and second treatment regions extend parallel to each other along the length of the depot. 337. The depot of any one of the preceding clauses, further comprising a barrier region configured to dissolve in vivo more slowly than the control region or the treatment region. 338. The depot of any one of the preceding clauses, further comprising a barrier region configured to slow the passage of physiological fluids in vivo through the interior to the control region or the treatment region. 339. The depot of any one of the preceding clauses, wherein the barrier region is positioned coaxially with the treatment region such that the control region at least partially surrounds both the treatment region and the barrier region. 340. The depot of any one of the preceding clauses, wherein the barrier region is a first barrier region and the depot further comprises a second barrier region, the first and second barrier regions being axially separated from one another by a treatment region. 341. The depot of any one of the preceding clauses, wherein the first and second barrier regions have different dimensions. 342. The depot of any one of the preceding clauses, wherein the barrier region is disposed coaxially with the control region such that the control region and the barrier region together at least partially surround the treatment region. 343. The depot of any one of the preceding clauses, wherein the first and second barrier regions are axially separated from each other by a control region. 344. The depot of any one of the preceding clauses, wherein the depot extends from a first end to a second end along a first axis, and the barrier region is disposed on the first end of the depot. 345. The depot of any one of the preceding clauses, wherein the depot extends from a first end to a second end along a first axis, and the barrier region includes a first end cap disposed on the first end of the depot and a second end cap disposed on the second end of the depot. 346. The depot of any one of the preceding clauses, wherein the treatment area includes a covered portion and an exposed portion, and the covered portion is covered by the control area such that when the depot is initially placed at the treatment site in vivo, the control area is between the covered portion of the treatment area and the physiological fluids at the treatment site, and the exposed portion of the treatment area is exposed to the physiological fluids. 347. The depot of any one of the preceding clauses, wherein the therapeutic agent in the treatment area comprises at least 50% of the total weight of the depot. 348. Depot of any one of the preceding clauses, the duration of which is more than 7 days, more than 15 days, more than 30 days, more than 45 days, more than 60 days, or more than 90 days. 349. A depot of any one of the preceding clauses in which approximately 40% to 60% of the therapeutic agent in the treatment area is released in the first half of the period. 350. At least 90% of the therapeutic agent in the therapeutic area is released within a period of time, as determined by the preceding conditions. Any one of the depots in section. 351. The depot of any one of the preceding clauses, configured to release from about 2 μg to about 5 mg of therapeutic agent per day to the treatment site. 352. The depot of any one of the preceding clauses, configured to release a therapeutic agent to a treatment site in vivo for 8 or more days, 9 or more days, 10 or more days, 11 or more days, 12 or more days, 13 or more days, 14 or more days, 15 or more days, 16 or more days, 17 or more days, 18 or more days, 19 or more days, 20 or more days, 21 or more days, 22 or more days, 23 or more days, 24 or more days, 25 or more days, 26 or more days, 27 or more days, 28 or more days, 29 or more days, 30 or more days, 40 or more days, 50 or more days, 60 or more days, 70 or more days, 90 or more days, 100 or more days, 200 or more days, 300 or more days, or 365 or more days. 353. A depot according to any one of the preceding clauses, in which the therapeutic agent is released at a substantially steady-state rate throughout the period. 354. The depot has a total surface area that includes the exposed surface area of ​​the control region plus the exposed surface area of ​​the treatment region; When the depot is initially placed at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the control region is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%. Depot of any one of the preceding clauses. 355. A depot of any one of the preceding clauses in which the exposed surface area of ​​the control area is less than the exposed surface area of ​​the treatment area. 356. A depot of any one of the preceding clauses in which the exposed surface area of ​​the control area is greater than the exposed surface area of ​​the treatment area. 357. A depot of any one of the preceding clauses in which the control area is a first control area and the depot includes a second control area. 358. The depot of any one of the preceding clauses, wherein the first control region is disposed on a first side of the treatment region and the second control region is disposed on a second side of the treatment region opposite the first side. 359. The depot of any one of the preceding clauses, wherein the depot includes a plurality of control regions and a plurality of treatment regions, each of the treatment regions being spaced from an adjacent one of the treatment regions by one or more control regions. 360. A depot of any one of the preceding clauses containing from about two to about ten therapeutic areas. 361. A depot of any one of the preceding clauses, wherein the control area includes a first control layer and a second control layer. 362. The depot of any one of the preceding clauses, wherein the second control layer is adjacent to the treatment area and the first control layer encapsulates / surrounds the treatment area and the second control layer. 363. A depot according to any one of the preceding clauses, wherein the first control layer and the second control layer together enclose a treatment area. 364. The depot of any one of the preceding clauses, wherein the first control layer includes a first plurality of sublayers and the second control layer includes a second plurality of sublayers. 365. The depot of any one of the preceding clauses, wherein the first control layer contains a first amount of release agent and the second control layer contains a second amount of release agent that is different from the first amount. 366. The depot of any one of the preceding clauses, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer containing a first concentration of release agent, and the second control layer containing a second concentration of release agent that is greater than the first concentration. 367. The depot of any one of the preceding clauses, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer containing a first concentration of release agent, and the second control layer containing a second concentration of release agent that is less than the first concentration. 368. A second control layer is disposed between the first control layer and the treatment area; The first control layer may contain up to 5% by weight of the releasing agent, up to 10% by weight of the releasing agent, up to 15% by weight of the releasing agent, %, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; the second control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; Depot of any one of the preceding clauses. 369. The depot of any one of the preceding clauses, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer comprising a first amount of release agent, and the second control layer comprising a second amount of release agent, the second amount being at least two times, at least three times, at least four times, or at least five times the first amount. 370. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment area. 371. A depot of any one of the preceding clauses, comprising an elongated columnar structure configured to be implanted in a patient. 372. A depot of any one of the preceding clauses containing one of a plurality of beads or microspheres. 373. The depot of any one of the preceding clauses, wherein the beads or microspheres have a variety of release profiles. 374. A depot of any one of the preceding clauses, in which the beads or microspheres contain varying amounts of therapeutic agent. 375. The depot of any one of the preceding clauses, wherein the beads or microspheres each include a control region of varying thickness. 376. A depot of any one of the preceding clauses, in which the microspherical beads have various dimensions. 377. A depot of any one of the preceding clauses containing one of several pellets. 378. A depot of any one of the preceding clauses, in which the pellets have a varied release profile. 379. A depot according to any one of the preceding clauses, in which the pellets contain varying amounts of a therapeutic agent. 380. A depot of any one of the preceding clauses, each of which pellets includes a control region of varying thickness. 381. A depot of any one of the preceding clauses in which the pellets have various dimensions. 382. A depot of any one of the preceding clauses in which the pellets are substantially cylindrical. 383. The depot of any one of the preceding clauses, wherein the depot comprises a plurality of substantially cylindrical beads, each comprising a treatment region and a control region, the plurality of beads being substantially aligned along a common longitudinal axis. 384. A depot of any one of the preceding clauses that is biodegradable and / or bioerodible. 385. A depot according to any one of the preceding clauses, which is a flexible solid structurally capable of being handled by a clinician during the normal course of surgery without breaking into multiple small pieces and / or losing its overall shape. 386. A depot according to any one of the preceding clauses, configured to be placed subcutaneously in a patient and to release the therapeutic agent in vivo for up to seven days without breaking down into multiple small pieces. 387. A depot according to any one of the preceding clauses, wherein the depot has a surface area and a volume, the ratio of the surface area to the volume being at least 1. 388. The depot of any one of the preceding clauses, wherein the diffusion opening comprises at least one or more pores and / or one or more channels. 389. The depot of any one of the preceding clauses, wherein upon dissolution of the release agent after placement in vivo at the treatment site, the control region and the treatment region transition from a less porous state to a more porous state to facilitate release of the therapeutic agent from the depot. 390. The depot of any one of the preceding clauses, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with the therapeutic agent. 391. The depot of any one of the preceding clauses, wherein the release agent is a first release agent, the polymer is a first polymer, and the therapeutic region comprises a second release agent and a second polymer mixed with the therapeutic agent. 392. A depot of any one of the preceding clauses in which the first releasing agent is the same as the second releasing agent. 393. A depot of any one of the preceding clauses in which the first releasing agent is different from the second releasing agent. 394. The depot of any one of the preceding clauses, wherein the concentration of the first release agent in the control region is greater than the concentration of the second release agent in the treatment region. 395. The depot of any one of the preceding clauses, wherein the concentration of the first release agent in the control region is less than the concentration of the second release agent in the treatment region. 396. The depot of any one of the preceding clauses, wherein the concentration of the first release agent in the control region is the same as the concentration of the second release agent in the treatment region. 397. The depot of any one of the preceding clauses, wherein the concentration of the first release agent in the control region is different from the concentration of the second release agent in the treatment region. 398. A depot according to any one of the preceding clauses, in which the treatment area comprises multiple microlayers. 399. A depot of any one of the preceding clauses in which the mass of the therapeutic agent constitutes at least 50% of the mass of the depot. 400. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 1:1, at least 2:1, 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 16:1. 401. The depot of any one of the preceding clauses, wherein the treatment region comprises a bioabsorbable polymer and a therapeutic agent. 402. The depot of any one of the preceding clauses, wherein the therapeutic region comprises at least 40% by weight of the therapeutic agent, at least 50% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, at least 90% by weight of the therapeutic agent, or 100% by weight of the therapeutic agent. 403. A depot of any one of the preceding clauses comprising at least 15% by weight of a therapeutic agent, at least 20% by weight of a therapeutic agent, at least 30% by weight of a therapeutic agent, at least 40% by weight of a therapeutic agent, at least 50% by weight of a therapeutic agent, at least 60% by weight of a therapeutic agent, at least 70% by weight of a therapeutic agent, at least 80% by weight of a therapeutic agent, at least 90% by weight of a therapeutic agent, 99% by weight of a therapeutic agent, or 99.99% by weight of a therapeutic agent. 404. The depot of any one of the preceding clauses, wherein the release agent is a non-ionic surfactant. 405. A depot according to any one of the preceding clauses, wherein the release agent has hydrophilic properties. 406. A depot of any one of the preceding clauses in which the release agent is a polysorbate. 407. A depot of any one of the preceding clauses in which the release agent is Tween 20. 408. A depot of any one of the preceding clauses in which the release agent is Tween 80. 409. The depot of any one of the preceding clauses, wherein the release agent is non-polymeric. 410. A depot according to any one of the preceding clauses in which the release agent is not a plasticizer. 411. The depot of any one of the preceding clauses, wherein the polymer is configured to degrade only after substantially all of the therapeutic agent has been released from the depot. 412. A depot of any one of the preceding clauses in which the polymer is a copolymer. 413. The depot of any one of the preceding clauses, wherein the polymer is a terpolymer. 414. The polymer may be polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate ester, poly(amino acid), poly Depsipeptide, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate). ester-co-glutamic acid), poly(tert-butyloxycarbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxy Propylmethylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydrochloride The depot of any one of the preceding clauses, comprising at least one of: hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or salts thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone). 415. The depot of any one of the preceding clauses, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 416. The depot of any one of the preceding clauses, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of about 60:30:10. 417. The depot of any one of the preceding clauses, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a molar ratio of between about 10:90 and about 90:10. 418. The depot of any one of the preceding clauses, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a molar ratio of about 50:50. 419. A depot according to any one of the preceding clauses, wherein the polymer is terminated with an ester. 420. The depot of any one of the preceding clauses, wherein the polymer is a terpolymer comprising three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. 421. The depot of any one of the preceding clauses, wherein the polymer is a first polymer and the therapeutic region comprises a second polymer mixed with a therapeutic agent. 422. The first polymer and / or the second polymer are selected from the group consisting of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyphosphate. , poly(amino acids), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly (ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), Hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) The depot of any one of the preceding clauses, comprising at least one of: hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or salts thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone). 423. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer are selected from the following: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 424. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of about 60:30:10. 425. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a molar ratio of about 50:50. 426. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer are ester terminated. 427. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer is a terpolymer comprising three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. 428. The depot of any one of the preceding clauses, wherein the ratio of polymer to release agent in the control region is at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 15:1. 429. The depot of any one of the preceding clauses, wherein the release agent is configured to dissolve and form a diffusion opening when the depot is placed in contact with phosphate buffered saline. 430. A system for delivering a therapeutic agent to a treatment site, comprising: a shaft having a lumen; a pusher operably connected to the lumen; a depot disposed within the lumen and configured to be displaced from the shaft via activation of a pusher; wherein the depot comprises: a treatment region including a therapeutic agent and extending along a first axis; a control region at least partially surrounding the treatment region and extending along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon deployment of the depot in vivo to form diffusion openings in the control region; wherein the depot is configured to be implanted at a treatment site in vivo and, while implanted, release the therapeutic agent at the treatment site for three days or more. 431. A system of clause 430 in which the depot includes a depot of any one of the preceding clauses. 432. The system of clause 430, wherein the shaft includes a needle and the pusher includes a plunger. 433. A system for delivering a therapeutic agent to a treatment site, comprising: an expandable member configured to expand from a reduced volume configuration for delivery to an expanded volume configuration for deployment at the treatment site; A depot held by an expandable member, comprising: a treatment region including a therapeutic agent and extending along a first axis; a depot at least partially surrounding the treatment region, extending along a first axis, the depot including a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the control region; The depot is implanted at the treatment site in vivo and maintained for 3 days while implanted. The system is configured to release a therapeutic agent at a treatment site over a period of time. 434. A system of clause 433 in which the depot includes a depot of any one of the preceding clauses. 435. The system of any one of the preceding clauses, wherein the expandable member comprises a stent. 436. The system of any one of the preceding clauses, wherein the expandable member comprises a spherical, hemispherical, elliptical, or semi-elliptical structure. 437. The system of any one of the preceding clauses, wherein the expandable member includes a curved outer surface and the depot is disposed on the curved outer surface. 438. The system of any one of the preceding clauses, wherein the depot substantially covers at least one surface of the expandable member. 439. The system of any one of the preceding clauses, wherein the expandable member comprises a shape memory material. 440. The system of any one of the preceding clauses, wherein the depot is disposed within a lubricious coating, and the lubricious coating comprises a hydrogel. 441. A method for delivering a therapeutic agent to a treatment site in the body, comprising: placing the depot at a treatment site in vivo having physiological fluid, the depot comprising: a treatment region including a therapeutic agent and extending along a first axis; a control region at least partially surrounding the treatment region, extending along a first axis, and including a bioabsorbable polymer and a release agent mixed with the polymer; and and The release agent dissolves at the treatment site to form diffusion openings in the control region, thereby releasing the therapeutic agent from the depot to the treatment site over a period of 3 days or more. A method comprising: 442. The method of clause 441, wherein the depot comprises the depot of any one of the preceding clauses. 443. The method of any one of the preceding clauses, wherein placing the depot comprises inserting the depot subcutaneously at the treatment site via a needle. 444. The method of any one of the preceding clauses, wherein placing the depot includes placing the depot proximal to a nerve bundle at the treatment site. 445. The method of any one of the preceding clauses, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, the first rate being greater than the second rate. 446. The method of any one of the preceding clauses, further comprising dissolving the release agent in response to contact between the control region and physiological fluid at the treatment site. 447. The method of any one of the preceding clauses, further comprising creating a diffusion opening in the control region via dissolution of a release agent in response to physiological fluid at the treatment site. 448. The method of any one of the preceding clauses, wherein the release agent is a first release agent and the treatment region comprises a second release agent, and the method further comprises creating microchannels in the treatment region and the control region via dissolution of the first and / or second release agents. 449. The method of any one of the preceding clauses, wherein at least some of the microchannels penetrate both the treatment region and the control region. 450. The method of any one of the preceding clauses, further comprising increasing the porosity of the depot through dissolution of the release agent. 451. The method of any one of the preceding clauses, wherein the therapeutic agent is released one or more substantially discrete doses after implantation. 452. The method of any one of the preceding clauses, wherein the therapeutic agent is released at a substantially steady-state rate over the period. 453. The period is 8 days or more, 9 days or more, 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 21 days or more, 22 days or more, 23 days or more, 24 days or more, 25 days or more, 26 days or more or more, 27 days or more, 28 days or more, 29 days or more, 30 days or more, 40 days or more, 50 days or more, 60 days or more, 70 days or more, 90 days or more, 100 days or more, 200 days or more, 300 days or more, or 365 days or more in any one of the preceding clauses. 454. The method of any one of the preceding clauses, wherein the depot is a first depot and the method further comprises placing a second depot at the treatment site. 455. A depot for implantation in a mammalian patient for the sustained controlled release of a therapeutic agent, comprising: Therapeutic areas, including therapeutic agents; a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent being configured to dissolve upon placement of the depot in vivo to form a diffusion opening in the control region; and configured to be implanted in vivo at a treatment site and, while implanted, release the therapeutic agent at the treatment site for at least 3 days. 456. A depot according to clause 455, in which the therapeutic agent in the therapeutic area constitutes at least 50% of the total weight of the depot. 457. The depot of any one of the preceding clauses, configured to release the therapeutic agent at a first rate for a first period of time and at a second rate for a second period of time. 458. Depot of Article 457, where the first rate is greater than the second rate. 459. Depot of Article 457, where the first period is longer than the second period. 460. Depot of Article 457, where the first period is shorter than the second period. 461. The depot of any one of the preceding clauses, wherein the depot is configured to release the therapeutic agent to a treatment site in vivo for 4 or more days, 5 or more days, 6 or more days, 7 or more days, 8 or more days, 9 or more days, 10 or more days, 11 or more days, 12 or more days, 13 or more days, 14 or more days, 15 or more days, 16 or more days, 17 or more days, 18 or more days, 19 or more days, 20 or more days, 21 or more days, 22 or more days, 23 or more days, 24 or more days, 25 or more days, 26 or more days, 27 or more days, 28 or more days, 29 or more days, 30 or more days, 40 or more days, 50 or more days, 60 or more days, 70 or more days, 90 or more days, 100 or more days, 200 or more days, 300 or more days, or 365 or more days. 462. The depot of any one of the preceding clauses, wherein the treatment area includes a covered portion and an exposed portion, and the covered portion is covered by the control region such that when the depot is initially placed at the treatment site in vivo, the control region is between the covered portion of the treatment area and the physiological fluids at the treatment site, and the exposed portion of the treatment area is exposed to the physiological fluids. 463. The depot has a total surface area that includes the exposed surface area of ​​the control region plus the exposed surface area of ​​the treatment area, When the depot is initially placed at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the control region is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%. Depot of any one of the preceding clauses. 464. A depot of clause 463, in which the exposed surface area of ​​the control area is less than the exposed surface area of ​​the treatment area. 465. A depot under article 463 in which the exposed surface area of ​​the control area is greater than the exposed surface area of ​​the treatment area. 466. A depot of any one of the preceding clauses in which the control area is a first control area and the depot includes a second control area. 467. The depot of clause 466, wherein a first control region is disposed on a first side of the treatment region and a second control region is disposed on a second side of the treatment region opposite the first side. 468. The depot of any one of the preceding clauses, wherein the depot includes a plurality of control regions and a plurality of treatment regions, each of the treatment regions being spaced from an adjacent one of the treatment regions by one or more control regions. 469. Each of the treatment areas and each of the control areas have a thickness of less than 1 mm. , Article 468 Depot. 470. A depot according to clause 468 or clause 469, wherein the depot comprises from about two to about four therapeutic areas. 471. A depot of clause 468 or clause 469, where the depot includes from about two to about ten control areas. 472. A depot according to any one of clauses 1 to 461, wherein the treatment region is surrounded by a control region such that when the depot is placed at a treatment site in vivo, the control region is between the treatment region and the physiological fluids at the treatment site. 473. A depot of any one of the preceding clauses, wherein the control area includes a first control layer and a second control layer. 474. A depot according to clause 473, wherein the second control layer is adjacent to the treatment area and the first control layer encapsulates / surrounds the treatment area and the second control layer. 475. A depot according to clause 473 or clause 474, in which the first control layer and the second control layer together enclose the treatment area. 476. The depot of any one of clauses 473 to 475, wherein a first control layer is disposed on a first side of the treatment area and a second control layer is disposed on a second side of the treatment area opposite the first side. 477. The depot of any one of clauses 473 to 476, wherein the first control layer comprises a first plurality of sublayers and the second control layer comprises a second plurality of sublayers. 478. The depot of any one of clauses 473 to 477, wherein the first control layer contains a first amount of release agent and the second control layer contains a second amount of release agent that is different from the first amount. 479. The depot of any one of clauses 473 to 478, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer containing a first concentration of release agent, and the second control layer containing a second concentration of release agent that is greater than the first concentration. 480. The depot of any one of clauses 473 to 479, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer containing a first concentration of release agent, and the second control layer containing a second concentration of release agent that is less than the first concentration. 481. A second control layer is placed between the first control layer and the treatment area; the first control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; the second control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; Any one of the depots in Articles 473 to 480. 482. The depot of any one of clauses 473 to 481, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer comprising a first amount of release agent, and the second control layer comprising a second amount of release agent, the second amount being at least two times, at least three times, at least four times, or at least five times the first amount. 483. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 10 of the thickness of the treatment area. 484. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 12.5 of the thickness of the treatment area. 485. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 15 of the thickness of the treatment area. 486. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 17.5 of the thickness of the treatment area. 487. The thickness of the control area is less than or equal to 1 / 20 of the thickness of the treatment area. Provisions to be made to any one depot. 488. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 22.5 of the thickness of the treatment area. 489. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 25 of the thickness of the treatment area. 490. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 30 of the thickness of the treatment area. 491. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 40 of the thickness of the treatment area. 492. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 50 of the thickness of the treatment area. 493. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 75 of the thickness of the treatment area. 494. A depot of any one of the preceding clauses in which the thickness of the control area is less than or equal to 1 / 100 of the thickness of the treatment area. 495. A depot of any one of the preceding clauses, wherein the depot is a flexible solid that is structurally capable of being handled by a clinician during the normal course of surgery without breaking into multiple small pieces and / or losing its overall shape. 496. A depot according to any one of the preceding clauses, configured for placement within a patient's knee and for releasing a therapeutic agent in vivo for up to seven days without breaking down into multiple small pieces. 497. A depot of any one of the preceding clauses, in which the depot has a width and a thickness, the ratio of width to thickness being 21 or greater. 498. Depots under Article 65, where the ratio is 30 or greater. 499. Depots under Article 65, where the ratio is 40 or greater. 500. The depot of any one of the preceding clauses, wherein the depot has a surface area and a volume, and the ratio of surface area to volume is at least 1. 501. The depot of any one of the preceding clauses, wherein the diffusion opening comprises at least one or more pores and / or one or more channels. 502. A depot of any one of the preceding clauses in which two or more microthin layers of bioabsorbable polymer are bonded via thermal compression to form a treatment area. 503. A depot of any one of the preceding clauses, wherein the control area and the treatment area are joined via thermal compression. 504. A depot according to any one of the preceding clauses, in which the control area and the treatment area are joined by heat. 505. The depot of any one of the preceding clauses, wherein upon dissolution of the release agent after placement in vivo at the treatment site, the control region and the treatment region transition from a less porous state to a more porous state to facilitate release of the therapeutic agent from the depot. 506. The depot of any one of the preceding clauses, wherein the control region does not contain a therapeutic agent, at least prior to implantation of the depot at the treatment site. 507. A depot according to any one of clauses 1 to 505, wherein the control region contains a therapeutic agent different from the therapeutic agent in the treatment region. 508. The depot of any one of the preceding clauses, wherein the treatment area does not contain any release agent prior to implantation of the depot at the treatment site. 509. The depot of any one of the preceding clauses, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with the therapeutic agent. 510. The depot of any one of clauses 1 to 509, wherein the release agent is a first release agent, the polymer is a first polymer, and the therapeutic region comprises a second release agent and a second polymer mixed with the therapeutic agent. 511. Any one of clauses 1 to 509 in which the first releasing agent is the same as the second releasing agent. Two depots. 512. A depot of any one of clauses 1 to 509, in which the first release agent is different from the second release agent. 513. The depot of any one of clauses 1 to 512, wherein the concentration of the first release agent in the control region is greater than the concentration of the second release agent in the treatment region. 514. The depot of any one of clauses 1 to 512, wherein the concentration of the first release agent in the control region is less than the concentration of the second release agent in the treatment region. 515. The depot of any one of clauses 1 to 512, wherein the concentration of the first release agent in the control region is the same as the concentration of the second release agent in the treatment region. 516. The depot of any one of clauses 1 to 512, wherein the concentration of the first release agent in the control region is different from the concentration of the second release agent in the treatment region. 517. A depot of any one of clauses 1 to 516, wherein the first release agent is different from the second release agent. 518. A depot according to any one of the preceding clauses, in which the treatment area comprises multiple microlayers. 519. A depot of any one of the preceding clauses in which the mass of the therapeutic agent constitutes at least 50% of the mass of the depot. 520. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 3:1. 521. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 4:1. 522. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 5:1. 523. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 6:1. 524. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 7:1. 525. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 8:1. 526. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 10:1. 527. The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 16:1. 528. The depot of any one of the preceding clauses, wherein the therapeutic region comprises at least 60% by weight of the therapeutic agent, 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, at least 90% by weight of the therapeutic agent, or 100% by weight of the therapeutic agent. 529. The depot of any one of the preceding clauses comprising at least 15% by weight of a therapeutic agent, at least 20% by weight of a therapeutic agent, at least 30% by weight of a therapeutic agent, at least 40% by weight of a therapeutic agent, at least 50% by weight of a therapeutic agent, at least 60% by weight of a therapeutic agent, at least 70% by weight of a therapeutic agent, at least 80% by weight of a therapeutic agent, at least 90% by weight of a therapeutic agent, or 100% by weight of a therapeutic agent. 530. A depot of any one of the preceding clauses, wherein the therapeutic agent comprises at least one of a simple analgesic, a local anesthetic, an NSAID, and an opioid. 531. The depot of any one of the preceding clauses, wherein the therapeutic agent comprises a local anesthetic selected from at least one of bupivacaine, ropivacaine, mepivacaine, and lidocaine. 532. Further comprising an antibiotic, antifungal, and / or antibacterial agent, wherein the antibiotic, antifungal, and / or antibacterial agent is selected from the group consisting of amoxicillin, amoxicillin / clavulanic acid, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline ( (several), minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorexidine, penicillin(s), aminoglycosides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporin(s), carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropin-melittin, magainin, dermaseptin, cathelicidin, α-defensins, and α-protegrin, ketoconazole, chlortrimazole, miconazole, econazole The depot of any one of the preceding clauses is selected from at least one of: fluconazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B. 533. The depot of any one of the preceding clauses, further comprising an anti-inflammatory agent selected from at least one of steroids, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and a COX-2 inhibitor. 534. The depot of any one of the preceding clauses, wherein the therapeutic agent is dexamethasone. 535. A depot according to any one of the preceding clauses, further comprising at least one of epinephrine, clonidine, and tranexamic acid. 536. The depot of any one of the preceding clauses, wherein the release agent is a non-ionic surfactant. 537. A depot according to any one of the preceding clauses, wherein the release agent has hydrophilic properties. 538. A depot of any one of the preceding clauses in which the release agent is a polysorbate. 539. A depot of any one of the preceding clauses in which the release agent is Tween 20. 540. A depot according to any one of clauses 1 to 107, in which the release agent is Tween 80. 541. The depot of any one of the preceding clauses, wherein the release agent is non-polymeric. 542. A depot of any one of the preceding clauses in which the releasing agent is not a plasticizer. 543. The depot of any one of the preceding clauses, wherein the polymer is configured to degrade only after substantially all of the therapeutic agent has been released from the depot. 544. A depot of any one of the preceding clauses in which the polymer is a copolymer. 545. The depot of any one of clauses 1 to 545, wherein the polymer is a terpolymer. 546. The depot of any one of clauses 1 to 545, wherein the polymer is selected from the group consisting of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS), polyethylene oxide. , polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, Poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) ) or PEG derivatives, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol PVA, PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, Poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose The depot of any one of the preceding clauses, comprising at least one of: carboxymethylcellulose, carboxymethylcellulose or salts thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone). 547. The depot of any one of the preceding clauses, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 548. The depot of any one of clauses 1 to 545, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10. 549. The depot of any one of clauses 1 to 545, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a 50:50 molar ratio. 550. The depot of any one of the preceding clauses, wherein the polymer is terminated with an ester. 551. The depot of any one of the preceding clauses, wherein the polymer is a terpolymer comprising three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(DL-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. 552. The depot of any one of the preceding clauses, wherein the polymer is a first polymer and the therapeutic region comprises a second polymer mixed with a therapeutic agent. 553. The depot of clause 552, wherein the first polymer and the second polymer are the same. 554. A depot of clause 552, wherein the first polymer and the second polymer are different. 555. The first polymer and / or the second polymer are selected from the group consisting of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), poly(alpha-hydroxy acid ...phosphate ester), poly(amino acids), polydepsipeptide, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly (L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, poly Phosphazenes, ethyl glycinate polyphosphazenes, polycaprolactone co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate), hydroxypropyl cellulose hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or salts thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone). 556. The depot of any one of clauses 552 to 554, wherein the first polymer and / or the second polymer is selected from the following: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 557. The depot of any one of clauses 552 to 554, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of 60:30:10. 558. The depot of any one of clauses 552 to 554, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a 50:50 molar ratio. 559. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer are ester terminated. 560. The depot of any one of the preceding clauses, wherein the first polymer and / or the second polymer is a terpolymer comprising three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. 561. The depot of any one of the preceding clauses, wherein the ratio of release agent to polymer in the controlled region is 1:2 or less. 562. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:3 or less. 563. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:4 or less. 564. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:5 or less. 565. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:6 or less. 566. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:7 or less. 567. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:8 or less. 568. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:9 or less. 569. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:10 or less. 570. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is 1:11 or less. 571. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 1:1. 572. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 2:1. 573. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 3:1. 574. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 4:1. 575. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 5:1. 576. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 6:1. 577. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 7:1. 578. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 8:1. 579. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 9:1. 580. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 10:1. 581. The depot of any one of clauses 455 to 560, wherein the ratio of release agent to polymer in the controlled region is at least 15:1. 582. The polymer is a first polymer and the therapeutic area further comprises a second polymer; the depot has a depot polymer mass equal to the mass of the first polymer plus the mass of the second polymer; The depot of any one of the preceding clauses, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is about 1:1. 583. A depot of clause 582, in which the first polymer is the same as the second polymer. 584. A depot of clause 582, in which the first polymer is different from the second polymer. 585. The ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 2. :1, any one of the depots of clauses 582 to 584. 586. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 3:1. 587. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of the depot polymer is at least 4:1. 588. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is about 5:1. 589. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 6:1. 590. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 7:1. 591. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of the depot polymer is at least 8:1. 592. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 10:1. 593. The depot of any one of clauses 582 to 584, wherein the ratio of the mass of therapeutic agent in the depot to the mass of the depot polymer is at least 16:1. 594. A method for treating a patient suffering from pain associated with surgery in or near an anatomical region of the patient's body, the method comprising implanting one or more of the depots of the preceding clause at the surgical site in the anatomical region, thereby improving the patient's Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index total score. 595. A method for treating a patient suffering from pain associated with surgery in an anatomical region of the patient's body in or near said anatomical region, the method comprising implanting one or more of the depots of the preceding clause at the surgical site in the anatomical region, thereby improving the patient's WOMAC index pain subscore. 596. A method for treating a patient suffering from pain associated with surgery in an anatomical region of the patient's body in or near said anatomical region, the method comprising improving the patient's WOMAC index stiffness subscore by implanting one or more of the depots of the preceding clause at the surgical site in the anatomical region. 597. A method for treating a patient suffering from pain associated with surgery in an anatomical region of the patient's body in or near said anatomical region, the method comprising implanting one or more of the depots of the preceding clause at the surgical site in the anatomical region, thereby improving the patient's WOMAC index physical function subscore. 598. A method for treating a patient suffering from pain associated with surgery in an anatomical region of the patient's body in or near said anatomical region, the method comprising implanting one or more of the depots of the preceding clause at the surgical site in the anatomical region, thereby improving the patient's KOOS score. 599. A method for treating a patient suffering from pain associated with surgery in an anatomical region of the patient's body in or near said anatomical region, the method comprising improving range of motion in the anatomical region by alleviating pain in the anatomical region through implantation of any one of the depots of the preceding clause. 600. A method for treating a patient suffering from pain associated with surgery in an anatomical region of the patient's body at or near the anatomical region, the method comprising reducing the amount of opioid consumed by the patient. 601. A method of improving the WOMAC index total score in a patient suffering from pain associated with surgery in or near an anatomical region of the patient's body, the method comprising implanting a depot in the anatomical region or near a surgical site, the depot being any one of the depots of the preceding clause. 602. The WOMAC index total score is calculated based on the pain subscore, stiffness subscore, and / or is the method of the preceding clause, including the physical function subscore. 603. The method of any one of the preceding clauses, where the pain is related to orthopedic surgery. 604. The method of any one of the preceding clauses, in which the pain is related to surgery on a joint. 605. The method of any one of the preceding clauses in which pain is associated with total knee arthroplasty.

[0010] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the release of therapeutic agent over time from a prior art device.

[0012] [Figure 2] FIG. 2 is an isometric view of a depot constructed in accordance with the present technology.

[0013] [Figure 3] FIG. 3 shows the release profile over time of one or more depots of the present technology.

[0014] [Figure 4]FIG. 4 is an isometric view of a depot in accordance with some embodiments of the present technology.

[0015] [Figure 5] FIG. 5 is an isometric view of a depot in accordance with some embodiments of the present technology.

[0016] [Figure 6] FIG. 6 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0017] [Figure 7] FIG. 7 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0018] [Figure 8] FIG. 8 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0019] [Figure 9A] FIG. 9A is an isometric view of a depot in accordance with some embodiments of the present technology.

[0020] [Figure 9B] FIG. 9B is a cross-sectional view of the depot shown in FIG. 9A.

[0021] [Figure 10] FIG. 10 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0022] [Figure 11] FIG. 11 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0023] [Figure 12] FIG. 12 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0024] [Figure 13] FIG. 13 is an isometric view of a depot in accordance with some embodiments of the present technology.

[0025] [Figure 14] 14A-H show depots with various cross-sectional areas and shapes according to the present technology.

[0026] [Figure 15] FIG. 15 shows the maximum bending load of the implant over time from tests performed on implant samples immersed in buffer solution.

[0027] [Figures 16A-C] 16A-16E show various depot embodiments that include barrier regions according to the technology. [Figure 16D-E] 16A-16E show various depot embodiments that include barrier regions according to the technology.

[0028] [Figure 17] FIG. 17 is a schematic diagram of prior art core acidification.

[0029] [Figure 18] FIG. 18 is a scanning electron microscope image of a prior art polymer tablet after 20 days of degradation.

[0030] [Figure 19A] FIG. 19A is a schematic illustration of the degradation of a depot of the present technology.

[0031] [Figure 19B-C] 19B and 19C are scanning electron microscope ("SEM") images of cross-sections of depots of the present technology at various times during degradation.

[0032] [Figure 20] FIG. 20 is a perspective view of a depot in accordance with some embodiments of the present technology.

[0033] [Figure 21] FIG. 21 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0034] [Figure 22] FIG. 22 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0035] [Figure 23] FIG. 23 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0036] [Figure 24A] FIG. 24A is a perspective view of a depot in accordance with some embodiments of the present technology.

[0037] [Figure 24B] FIG. 24B is a cross-sectional view of the depot shown in FIG. 24A taken along line BB.

[0038] [Figure 24C] FIG. 24C is a cross-sectional view of the depot shown in FIG. 24A taken along line CC.

[0039] [Figure 24D] FIG. 24D is a perspective view of a depot in accordance with some embodiments of the present technology.

[0040] [Figure 25] FIG. 25 is a perspective view of a depot in accordance with some embodiments of the present technology.

[0041] [Figure 26] FIG. 26 is a perspective view of a depot in accordance with some embodiments of the present technology.

[0042] [Figure 27] FIG. 27 is a perspective view of a depot in accordance with some embodiments of the present technology.

[0043] [Figure 28] FIG. 28 is a perspective view of a depot in accordance with some embodiments of the present technology.

[0044] [Figure 29A]FIG. 29A is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0045] [Figure 29B] FIG. 29B is a cross-sectional view of the depot shown in FIG. 29A taken along line BB.

[0046] [Figure 30] FIG. 30 is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0047] [Figure 31] FIG. 31 is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0048] [Figure 32] FIG. 32 is a perspective view of a depot in accordance with some embodiments of the present technology.

[0049] [Figure 33] FIG. 33 is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0050] [Figure 34] FIG. 34 is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0051] [Figure 35] FIG. 35 is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0052] [Figure 36A] FIG. 36A is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0053] [Figure 36B] FIG. 36B is a cross-sectional view of the depot shown in FIG. 36A taken along line BB.

[0054] [Figure 36C]FIG. 36C is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0055] [Figure 36D] FIG. 36D is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0056] [Figure 37A] FIG. 37A is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0057] [Figure 37B] FIG. 37B shows an exemplary release profile over time for the depot shown in FIG. 37A.

[0058] [Figure 38A] FIG. 38A is a side cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0059] [Figure 38B] FIG. 38B shows an exemplary release profile over time for the depot shown in FIG. 38A.

[0060] [Figure 39A] FIG. 39A is a side cross-sectional view of a depot according to some embodiments of the present invention.

[0061] [Figure 39B] FIG. 39B shows an exemplary release profile over time for the depot shown in FIG. 39A.

[0062] [Figure 40A] FIG. 40A is a perspective view of a depot in accordance with some embodiments of the present technology.

[0063] [Figure 40B] FIG. 40B is a perspective view of a depot in accordance with some embodiments of the present technology.

[0064] [Figure 41A]FIG. 41A is a side view of a depot in a straightened state in accordance with some embodiments of the present technology.

[0065] [Figure 41B] FIG. 41B is a side view of the depot shown in FIG. 41A in a curved state.

[0066] [Figure 42A] FIG. 42A is a side view of a depot in a straightened state in accordance with some embodiments of the present technology.

[0067] [Figure 42B] FIG. 42B is a side view of the depot shown in FIG. 42A in a curved state.

[0068] [Figure 43A] FIG. 43A is a perspective view of a depot in a straightened state in accordance with some embodiments of the present technology.

[0069] [Figure 43B] Figure 43B is a cross-sectional view of the depot shown in Figure 43A taken along line BB.

[0070] [Figure 43C] FIG. 43C is a side view of the depot shown in FIG. 43A in a curved state.

[0071] [Figure 44] FIG. 44 is a side view of a depot deployed at a target site within the body in accordance with some embodiments of the present technology.

[0072] [Figure 45] FIG. 45 is a side view of a depot deployed at a target site within the body in accordance with some embodiments of the present technology.

[0073] [Figure 46] FIG. 46 is a side view of a depot in accordance with some embodiments of the present technology.

[0074] [Figure 47] FIG. 47 is a side view of a depot in accordance with some embodiments of the present technology.

[0075] [Figure 48] 48A and 48B are perspective views of a depot in accordance with some embodiments of the present technology.

[0076] [Figure 49] 49A-C are perspective, top, and side views, respectively, of a depot in accordance with some embodiments of the present technology.

[0077] [Figure 50A] FIG. 50A is an end view of a depot in a rolled state in accordance with some embodiments of the present technology.

[0078] [Figure 50B] FIG. 50B is a side view of the depot shown in FIG. 50A in an unrolled state.

[0079] [Figure 51] FIG. 51 shows multiple depots in accordance with some embodiments of the present technology.

[0080] [Figure 52A] FIG. 52A is an end view of multiple depots in accordance with some embodiments of the present technology.

[0081] [Figure 52B] FIG. 52B is a side view of the depot shown in FIG. 52A.

[0082] [Figure 52C] Figure 52C shows a method of manufacturing the depot shown in Figures 52A and 52B.

[0083] [Figure 53] Figure 53 shows the in vitro release profile for the depot described in Example 1 according to the present technology.

[0084] [Figure 54] Figure 54 shows the in vitro release profile for the depot described in Example 2A according to the present technology.

[0085] [Figure 55] Figure 55 shows the in vitro release profile for the depot described in Example 2B according to the present technology.

[0086] [Figure 56] Figure 56 shows the in vitro release profile for the depot described in Example 3 according to the present technology.

[0087] [Figure 57A] FIG. 57A shows in vivo plasma bupivacaine concentrations over time for rabbits implanted with the depot described in Example 4 according to the present technology.

[0088] [Figure 57B] FIG. 57B shows the in vivo release profile over time for the sample depot described in Example 4 according to the present technology.

[0089] [Figure 57C] FIG. 57C shows in vivo plasma bupivacaine concentrations over time for rabbits implanted with the depot described in Example 4 according to the present technology.

[0090] [Figure 57D] Figure 57D shows the in vitro release profile over time of the sample depot described in Example 4 according to the present technology.

[0091] [Figure 58] Figure 58 shows in vivo plasma bupivacaine concentrations over time for dogs implanted with the depot described in Example 5 according to the present technology.

[0092] [Figure 59A] FIG. 59A shows in vivo plasma bupivacaine concentrations over time for sheep implanted with the depot described in Example 6 according to the present technology.

[0093] [Figure 59B] FIG. 59B shows in vivo synovial fluid bupivacaine concentrations over time for sheep implanted with the depot described in Example 6 according to the present technology.

[0094] [Figure 59C] FIG. 59C is a plot showing plasma bupivacaine concentration versus synovial fluid bupivacaine concentration over time for sheep implanted with the depot described in Example 6 according to the present technology.

[0095] [Figure 60A-B] 60A and 60B are tables showing details of the sample depot used in Example 7.

[0096] [Figure 60C] FIG. 60C shows in vivo plasma bupivacaine concentrations over time for sheep implanted with the depot described in Example 7 according to the present technology.

[0097] [Figure 60D] FIG. 60D shows in vivo synovial fluid bupivacaine concentrations over time for sheep implanted with the depot described in Example 7 according to the present technology.

[0098] [Figure 60E] FIG. 60E shows the acute and subacute mean daily AUC for the sample depot of Example 7.

[0099] [Figure 60F]FIG. 60F is a plot showing plasma bupivacaine concentration versus synovial fluid bupivacaine concentration over time for sheep implanted with a depot described in Example 7 according to the present technology.

[0100] [Figure 61A] FIG. 61A shows in vivo plasma bupivacaine concentrations over time for sheep implanted with the depot described in Example 8 according to the present technology.

[0101] [Figure 61B] FIG. 61B shows in vivo synovial fluid bupivacaine concentrations over time for sheep implanted with the depot described in Example 8 according to the present technology.

[0102] [Figure 62] Figures 62A and 62B show typical locations in a patient where surgery may be performed and where the depot may be administered.

[0103] [Figure 63-1] Figure 63 is a table showing common surgical procedures in which the depots of the present technology may be utilized to treat post-operative pain. Figure 63 also shows the neural targets and anatomical access / placement associated with various surgeries. [Figure 63-2] Figure 63 is a table showing common surgical procedures in which the depots of the present technology may be utilized to treat post-operative pain. Figure 63 also shows the neural targets and anatomical access / placement associated with various surgeries. [Figure 63-3] Figure 63 is a table showing common surgical procedures in which the depots of the present technology may be utilized to treat post-operative pain. Figure 63 also shows the neural targets and anatomical access / placement associated with various surgeries.

[0104] [Figure 64] 64A-64C are anterior, lateral, and medial views of the human knee showing the location of the nerves that innervate the knee.

[0105] [Figure 65A] FIG. 65A shows a human knee cut open to expose the intra-articular cavity and identify potential locations for placement of one or more depots.

[0106] [Figure 65B] FIG. 65B is a cut-away view of a human knee exposing the intra-articular cavity and showing several depots placed therein to treat post-operative pain.

[0107] [Figure 66] Figures 66A and 66B show the extracapsular views of the anterior and posterior aspects of the human knee, illustrating the location of the nerves that innervate the knee at extracapsular locations.

[0108] [Figure 67] FIG. 67 is an anterior view of a partially expanded human knee showing the extracapsular space and illustrating several depots of the present technology placed in the extracapsular space to treat post-operative pain. DETAILED DESCRIPTION OF THE INVENTION

[0109] The present technology relates to implantable depots for the sustained, controlled release of therapeutic agents, as well as related devices, systems, and methods of use. Examples of depots and related release kinetics of the present technology are described below with reference to Figures 2-52C and Section I. Selected examples of depots and related release profiles of the present technology are described below with reference to Figures 53-61B and Section II. Selected devices, systems, and methods for using the depots of the present technology to treat postoperative pain associated with orthopedic surgery are described below with reference to Figures 62A-67 and Section III. Selected devices, systems, and methods for using the depots of the present technology to treat postoperative pain associated with other surgeries are described in Section IV below.

[0110] I. Examples of depots using this technology As previously mentioned, prior art drug delivery systems often suffer from a lack of a true controlled release mechanism, in that they typically provide a burst of drug upon contact with surrounding physiological fluids, followed by a residual release of drug. For example, Figure 1 shows an exemplary prior art biodegradable polymer-based delivery system in which plasma drug concentrations peak within 15 hours of implantation, thereby demonstrating poor duration of action.

[0111] Disclosed herein are implantable depots and related devices, systems, and methods for treating (i.e., preventing, reducing, and / or eliminating) postoperative pain through the sustained, controlled release of a therapeutic agent while the depot is implanted at the treatment site in vivo. Many embodiments of the present technology include one or more depots configured to be implanted at or near a patient's surgical site to treat postoperative pain. While implanted in vivo, the depot(s) are configured to release a therapeutic agent (such as an analgesic) to the surgical site in a controlled and defined manner for at least three days after implantation.

[0112] As used herein, a "depot" refers to a device that contains at least one therapeutic agent in a controlled, sustained manner. Depots include compositions configured for administration to a treatment site within a patient's body in a continuous manner. Depots also include the therapeutic agent itself. Depots may include physical structures or carriers configured to perform or enhance one or more treatment-related functions, such as facilitating implantation and / or retention at the treatment site (e.g., tissues of the intra-articular and / or extracapsular space of a knee joint), modulating the release profile of the therapeutic agent (e.g., creating a biphasic release profile), increasing release toward the treatment site, decreasing release away from the treatment site, or combinations thereof. In some embodiments, a "depot" includes, but is not limited to, a film, sheet, strip, ribbon, capsule, coating, matrix, wafer, pill, pellet, or other pharmaceutical delivery device, or combinations thereof. Furthermore, as used herein, "depot" may refer to a single depot or multiple depots. By way of example, the statement "the depot may be configured to release 2 g of therapeutic agent to the treatment site" describes (a) a single depot configured to release 2 g of therapeutic agent to the treatment site, and (b) multiple depots collectively configured to release 2 g of therapeutic agent to the treatment site.

[0113] 2 is an isometric view of an implantable depot 100 in accordance with some embodiments of the present technology. Depot 100 may be a thin, multi-layered polymer film configured to be implanted at a treatment site, including a treatment region 200 containing a therapeutic agent (such as an analgesic), and a control region 300 configured to regulate the release of the therapeutic agent from depot 100 in a controlled and sustained manner. Depot 100 may contain a high therapeutic payload of therapeutic agent, particularly compared to other known films of equivalent thickness or polymer weight percentage, while exhibiting sufficient mechanical properties (e.g., flexural strength) to withstand storage, handling, implantation, and / or retention at the treatment site. For example, in some embodiments, depot 100 contains at least 50% therapeutic agent by weight.

[0114] The control region 300 may include at least one bioabsorbable polymer and at least one release agent mixed with the polymer, and the treatment region 200 may include at least one bioabsorbable polymer and at least one release agent mixed with the polymer and a therapeutic agent. The control region 300 may optionally include a therapeutic agent, or the control region 300 may be free of any therapeutic agent. The treatment region 200 may optionally include no release agent. The release agent in the control region 300 may be the same as or different from the release agent in the treatment region 200. The bioabsorbable polymer in the control region 300 may be the same as or different from the bioabsorbable polymer in the treatment region 200. As described in more detail below, in some embodiments, the treatment region 200 and / or the control region 300 may have different components and / or formulations.

[0115] Upon exposure to fluid (e.g., physiological fluid), the release agent can have a dissolution rate that is faster than the degradation rate of the bioabsorbable polymer. Thus, when fluid contacts the depot 100 (e.g., after implantation of the depot 100 at a treatment site), the release agent dissolves into the polymer surrounding the control region 300 and / or treatment region 200 faster than the polymer degrades. As the release agent dissolves, the spaces vacated by the dissolved release agent form diffusion openings (e.g., channels, voids, pores, etc.) in the surrounding polymer region. The formation of diffusion openings can enhance release of the therapeutic agent from the polymer region and into the surrounding physiological fluid. In some embodiments, the release rate of the therapeutic agent is faster when the polymer region has diffusion openings compared to when the polymer region does not have diffusion openings.

[0116] Among other parameters, the concentration and type of release agent may regulate the release of the therapeutic agent from the treatment region 200 and / or through the control region 300 into the surrounding fluid at a controlled dosage rate. The release agent concentration can be selected to regulate over a desired period of time. For example, a higher concentration of the release agent can increase the release rate of the therapeutic agent, while a lower concentration of the release agent can decrease the release rate of the therapeutic agent. The treatment region 200 can contain a different concentration and / or type of release agent than the control region 300, or can contain the same concentration and / or type of release agent.

[0117] The location and / or geometry of the control region 300 can be configured to modulate the release profile of the therapeutic agent from the treatment region 200. As shown in FIG. 2, at least a portion of the control region 300 may be positioned on or adjacent to the treatment region 200 such that when the depot 100 is initially placed in vivo, the control region 300 is between at least a portion of the treatment region 200 and the physiological fluid at the treatment site. For example, the control region 300 can cover all or a portion of one or more surfaces of the treatment region 200. When the depot 100 is exposed to physiological fluid, the therapeutic agent elutes from the exposed surface of the treatment region 200 through the control region 300 using diffusion openings created by dissolution of the release agent. Generally, the therapeutic agent elutes from the exposed surface of the treatment region 200 at a faster (e.g., greater) rate than through the control region 300. As a result, the control region 300 extends the release of the therapeutic agent from the treatment region 200, providing a longer release time, e.g., regulating the dosing rate to achieve the desired degree of pain relief and avoid complications associated with overdosing.

[0118] The depots of the present technology are configured to release therapeutic agents in a highly controlled, predetermined manner specifically tailored to the medical condition being treated and the therapeutic agent being used. As described in more detail in Section II below, the release kinetics of the depot may be customized for a particular application by varying one or more aspects of the composition and / or structure of the depot; for example, the shape and / or size of the depot, the therapeutic region 200, and / or the control region 300; the exposed surface area of ​​the therapeutic region 200; the type of polymer (in the therapeutic region 200 and / or in the control region 300); the weight percentage of the therapeutic agent, polymer, and / or release agent (within a specific region or generally throughout the depot 100); and the composition of the therapeutic region 200 and the control region 300.

[0119] As shown in Figure 3, in many embodiments, the depot 100 (or depot 100 system) is configured to release a disproportionately greater volume of therapeutic agent per day over a first period of time than over a second, longer period of time. In some embodiments, the depot 100 (or depot 100 system) is configured to release therapeutic agent for at least 14 days after implantation (or immersion in fluid), with a controlled burst of about 20% to about 50% of the therapeutic agent payload being released in the first 3-5 days, and at least 80% of the remaining therapeutic agent payload being released at a slower rate over the last 10-11 days. In some embodiments, at least 90% of the therapeutic agent payload is released by the end of the 14 days.

[0120] A two-stage, secondary release profile, such as that shown in Figure 3, can be particularly beneficial in the context of treating pain resulting from total knee arthroplasty ("TKA"). TKA patients typically experience maximal pain within the first 1-3 days after surgery (clinically referred to as "acute pain"), followed by a gradual decrease in pain over the next 7-10 days (clinically referred to as "subacute pain"). The acute period often overlaps or coincides with the patient's inpatient treatment (usually 1-3 days), while the subacute period generally begins when the patient is discharged and returns home. The two-stage, secondary release profile shown in Figure 3 may also be beneficial in other surgical applications, such as other orthopedic applications (e.g., ligament repair / replacement and other injuries to the knee, shoulder, ankle, etc.), or non-orthopedic surgical applications. Excessive pain after any surgery can prolong hospital treatment, cause psychological distress, increase opioid consumption, and / or impair patient participation in physical therapy, all of which can prolong and / or reduce the extent of recovery. Pain relief during the subacute period can be beneficial when patients transition from hospital to a home environment. It can be particularly complex to manage as patient compliance with prescribed pain management regimens decreases.

[0121] To address the aforementioned challenges in postoperative pain management, the depot 100 (or a depot system including multiple depots 100) of the present technology may have release profiles tailored to meet specific pain management needs during the acute and subacute periods. For example, to address the greater acute pain experienced immediately following surgery, the depot 100 may be configured to release a therapeutic agent at a faster rate over the first 3-5 days after implantation compared to the subsequent 9-11 day period (as shown in FIG. 3). In some embodiments, the depot 100 may deliver a local anesthetic at a rate of about 150 mg / day to about 400 mg / day during this first acute period. To address the diminishing pain during the subacute period, the depot 100 may be configured to release a therapeutic agent at a slower rate over the remaining 9-11 days. In some embodiments, the depot 100 may deliver a local anesthetic at a rate of about 50 mg / day to about 250 mg / day during this second subacute period. In some embodiments, the rate of release decreases continuously throughout the first period and / or the second period.

[0122] The release profile of depot 100 may be tailored to release therapeutic agent for other durations and / or at other release rates by adjusting the structure, composition, and process by which the depot is manufactured. For example, in some embodiments, depot 100 may be configured to release therapeutic agent at a constant rate throughout the entire duration of release. In certain embodiments, depot 100 may be configured to release therapeutic agent at a constant rate for a first period of time and at a non-constant rate for a second period of time (which may occur before or after the first period of time).

[0123] In some embodiments, the depot 100 is configured to release 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, or 70% or less of the therapeutic agent on the 1st, 2nd, 3rd, 4th, 5th, 6th, 8th, 9th, 10th, 11th, 12th, or 13th day of the release duration, with at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the remaining therapeutic agent being released on the remaining days of the release duration. The intended duration of release may be at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, or at least 30 days.

[0124] In some embodiments, the depot 100 is configured to release at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the therapeutic agent within the depot 100 within the intended duration of treatment, which may be at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 40 days, or the like. , at least 50 days, at least 60 days, at least 70 days, at least 90 days, at least 100 days, at least 200 days, at least 300 days, or at least 365 days.

[0125] In some embodiments, the depot 100 is configured to release from about 50 mg / day to about 600 mg / day, 100 mg / day to about 500 mg / day, or from about 100 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day of therapeutic agent to the treatment site. Generally, the release rate can be selected to deliver the desired dosage to provide the degree of pain relief needed at a given time after the surgical procedure, control toxicity, and deliver the therapeutic agent for a period of time sufficient for pain relief.

[0126] In some embodiments, the depot 100 is configured to release from about 50 mg / day to about 600 mg / day, from about 100 mg / day to about 500 mg / day, or from about 100 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day of therapeutic agent to the treatment site within a first release period. The depot 100 can be further configured to release from about 500 mg / day to about 600 mg / day, from about 100 mg / day to about 500 mg / day, or from about 100 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day of therapeutic agent to the treatment site within a second release period. The release rate during the first period may be the same as, different from, less than, or greater than the release rate during the second period. Furthermore, the first period may be longer or shorter than the second period. The first period may occur before or after the second period.

[0127] In some embodiments, the depot 100 releases at least 50 mg, at most 100 mg, at most 150 mg, at most 200 mg, at most 250 mg, at most 300 mg, at most 350 mg, at most 400 mg, at most 450 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg, at most 1000 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least The endothelial cell is configured to release at least 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, at least 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at least 270 mg, at least 280 mg, at least 290 mg, or at least 300 mg of therapeutic agent, which may be useful for providing varying degrees of pain relief at different times following a surgical procedure and may also be useful for controlling toxicity.In such embodiments, the depot 100 releases 50 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, 500 mg or less, 600 mg or less, 700 mg or less, 800 mg or less, 900 mg or less, 1000 mg or less, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least The first release period and / or the second release period may be configured to release at least 100 mg, at least 110 mg, at least 120 mg, at least 130 mg, at least 140 mg, at least 150 mg, at least 160 mg, at least 170 mg, at least 180 mg, at least 190 mg, at least 200 mg, at least 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at least 270 mg, at least 280 mg, at least 290 mg, or at least 300 mg of therapeutic agent. The first release period and / or the second release period may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 11 days. The release period may be 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. The depot 100 may be configured to release the therapeutic agent at a first rate during a first period and at a second rate during a second period. The first rate may be the same as, different from, less than, or greater than the second rate. In some embodiments, the first rate is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the second rate, or vice versa. Furthermore, the first period may be longer or shorter than the second period. The first period may precede or follow the second period.

[0128] In some embodiments, the depot 100 is configured to release 50 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, 500 mg or less, 600 mg or less, 700 mg or less, 800 mg or less, 900 mg or less, or 1000 mg or less of therapeutic agent by any day during the duration of the release.

[0129] In some embodiments, the depot 100 is configured to release a therapeutic agent to a treatment site in vivo and / or in the presence of one or more fluids for 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 90 or more, 100 or more, 200 or more, 300 or more, or 365 or more days.

[0130] The release kinetics of the depots of the present technology may be tailored to a particular application by varying one or more aspects of the structure and / or composition of the depot, such as the exposed surface area of ​​the treatment region 200, the porosity of the control region 300 during and after dissolution of the release agent, the concentration of the therapeutic agent within the treatment region, the post-fabrication properties of the polymer, the structural integrity of the depot to avoid sudden release of the therapeutic agent, the relative thickness of the treatment region 200 compared to the control region 300, and other properties of the depot. Some embodiments of the depots of the present technology combine one or more of these properties to produce exceptional biphasic release profiles in animal studies that are significantly superior to existing injectable or implantable systems, while also overcoming the shortcomings of the disclosed predictive devices. For example, some embodiments have demonstrated a biphasic release profile that delivers an appropriate mass of therapeutic agent over a 14-day period to treat pain associated with joint replacement surgery or other applications, while maintaining sufficient structural integrity to withstand joint forces to avoid sudden release of too much therapeutic agent. This unexpected result allows the depot of the present technology to at least reduce, if not replace, opioids and / or augment other existing pain relief systems for orthopedic, non-orthopedic, and other applications (e.g., oncology).

[0131] For example, the release profile can be tailored, at least in part, by controlling the amount of exposed surface area of ​​the therapeutic region 200, as a depot having a therapeutic region 200 that is only partially covered by a control region 300 (see, e.g., Figures 2, 4-8, and 13) will generally release a higher percentage of the total payload over a shorter period of time compared to embodiments in which the therapeutic region 200 is fully encapsulated by the control region 300 (see, e.g., Figures 9A-12). More specifically, depot designs having a therapeutic region 200 with an exposed surface will typically release therapeutic agent at a high, substantially linear rate over a first period of time, followed by a lower, substantially linear rate over a second period of time. Alternatively, a depot having a therapeutic region 200 that is substantially covered by one or more control regions 300 will typically release a higher percentage of the total payload over a shorter period of time compared to embodiments in which the therapeutic region 200 is fully encapsulated by the control region 300 (see, e.g., Figures 9A-12). The design of the depot having a therapeutic region 200 with a surface that is curved can achieve zero order release so that the release of the therapeutic payload is at a substantially uniform rate.

[0132] 4, in some embodiments, the depot 100 may include a multilayer polymer film having a treatment region 200 and first and second control regions 300a, 300b disposed on opposing sides 100a, 100b of the treatment region 200. The depot 100 may be in the form of a flexible rectangular strip having a length L, a width W, and a height H (or thickness).In some embodiments, the depot 100 comprises (a) about 5-40 mm, about 10-30 mm, about 15-20 mm, about 20-35 mm, about 20-30 mm, about 20-25 mm, about 26-30 mm, about 5 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm, about 21 mm, about 22 mm, about 23 mm, about 24 mm, about 25 mm, about 26 mm, about 27 mm, about 28 mm, about 29 mm, about 30 mm, about 1 ... ~15mm, about 12-16mm, about 15-20mm, about 21-23mm, about 22-24mm, about 23-25mm, about 24-26mm, about 25-27mm, about 26-28mm, about 27-29mm, or about 28-30mm in length L, (b) about 5-40mm, about 10-30mm, about 15-20mm, about 20-35mm, about 20-30mm, about 20-25mm, about 26-30mm, about 5mm, about 10mm, about 11mm, about 12mm, about 13mm, about 14mm, about 15mm, about 16mm, about 17mm mm, approximately 18mm, approximately 19mm, approximately 20mm, approximately 21mm, approximately 22mm, approximately 23mm, approximately 24mm, approximately 25mm, approximately 26mm, approximately 27mm, approximately 28mm, approximately 29mm, approximately 30mm, approximately 10~15mm, approximately 12~16mm, approximately 15~20mm, Width W of approximately 21~23mm, approximately 22~24mm, approximately 23~25mm, approximately 24~26mm, approximately 25~27mm, approximately 26~28mm, approximately 27~29mm, or approximately 28~30mm, (c) approximately 0.4mm to approximately 4mm, approximately 1mm to approximately 3mm, approximately 1mm and a height H of from about 2 mm, at least 0.4 mm, at least 0.5 mm, at least 0.6 mm, at least 0.7 mm, at least 0.8 mm, at least 0.9 mm, at least 1 mm, at least 1.2 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 2 mm, at least about 3 mm, 0.5 mm or less, 0.6 mm or less, 0.7 mm or less, 0.8 mm or less, 0.9 mm or less, etc. In some embodiments, the depot 100 may have an L x W x H of about 26 mm x about 16 mm x about 1 mm, and in some embodiments, about 27 mm x about 17 mm x about 1 mm.In some embodiments, the depot 100 may have other shapes and / or dimensions, such as those detailed below.

[0133] 4 are configured such that the thickness of control regions 300a and 300b, individually or collectively, is less than or equal to 1 / 10 the thickness of treatment region 200. The thickness of control regions 300a and 300b, individually or collectively, can also be 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 30, 1 / 40, 1 / 50, 1 / 75, or 1 / 100 or less the thickness of treatment region 200. In those embodiments with multiple sub-control regions, one or more of the sub-control regions may individually be less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment region. In those embodiments in which the control region comprises a single control region, the control region has a thickness that is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment region. In those embodiments with multiple secondary control regions, one or more of the secondary control regions may individually be less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the depot. In those embodiments in which the control region comprises a single control region, the control region may have a thickness that is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the depot.

[0134] The control regions 300a, 300b may only cover a portion of the treatment region 200 such that a portion of each of the sides (e.g., sidewalls) of the treatment region 200 is exposed to physiological fluids immediately after implantation of the depot 100 in vivo. For example, at least prior to implantation, the exposed surface of the treatment region 200 may occupy about 2% to about 15%, about 3% to about 12%, about 5% to about 10%, about 6% to about 8%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% of the surface area of ​​the depot 100. In some embodiments, at least prior to implantation, the ratio of the exposed surface area of ​​the treatment region 200 to the exposed surface area of ​​the control region 300 may be about 2% to about 15%, about 3% to about 12%, about 5% to about 10%, about 6% to about 8%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% of the surface area of ​​the depot 100.

[0135] The control regions 300a, 300b need only cover a portion of the treatment region 200 so that a portion of each of the faces (e.g., sidewalls) of the treatment region 200 is exposed to physiological fluid immediately after implantation of the depot 100 in vivo. When the depot 100 is exposed to physiological fluid (or any similar fluid in an in vitro setting), the therapeutic agent will begin to elute from the exposed surface 202 (in addition to via the control regions 300a, 300b), resulting in a faster release of the therapeutic agent than if the treatment region 200 did not have an exposed region. Thus, the surface area of ​​the exposed surface 202 may be tailored to provide an initial, controlled burst followed by a tapering release (e.g., similar to that shown in FIG. 3). The initial, more aggressive release of the therapeutic agent is slowed, in part, by the control regions 300a, 300b, which initially reduce the surface area of ​​the treatment region 200 exposed to fluid. Unlike the depot 100 of the present technology, many conventional drug eluting technologies result in an initial, uncontrolled burst release of drug upon exposure to physiological fluids. Some embodiments of the depot of the present technology are not only capable of implanting sufficient therapeutic agent for days or weeks of dosage to achieve sustained, durable in vivo pharmacological treatment, but also release the therapeutic agent in a defined manner, thereby preventing release of a significant portion of the total payload in an uncontrolled manner that could result in complications for the patient and / or reduce the remaining payload so that there is not enough therapeutic agent remaining in the depot to deliver a therapeutic dose over the remaining release duration.

[0136] In some embodiments, the depot 100 shown in Figure 4 is configured to release about 20% to about 50% of the analgesic agent over about the first 3 to about 5 days of a 14-day period, with at least 80% of the remaining analgesic agent being released over about the last 9 to about 11 days of the 14-day period. This release profile provides a higher dosage of therapeutic agent during the acute period following surgery compared to the subacute period. In some embodiments, the depot 100 shown in Figure 4 is configured to release about 100 mg to about 500 mg of analgesic agent per day at the treatment site, and in some cases, no more than 400 mg or no more than 300 mg of analgesic agent per day within the first 3 days of implantation, and and is configured to release 200 mg or less per day for the remaining days.

[0137] Some embodiments of the depot 100 shown in FIG. 4 are also configured to maintain their structural integrity even after a significant portion of the release agent has eluted from the depot 100. As the release agent(s) dissolve and the therapeutic agent(s) elute, the functional mechanical aspects of the depot 100 may change over time. Such mechanical aspects include the structural integrity, flexural strength, tensile strength, or other mechanical properties of the depot. If the depot 100 experiences excessive degradation too quickly, it may mechanically fail and release an undesirable burst of therapeutic agent into the body. Some embodiments of the depot 100 shown in FIG. 4 are loaded with sufficient therapeutic agent to deliver 100 mg to 500 mg of therapeutic agent per day while still being able to maintain its structural integrity so that the depot remains largely intact for at least 14 days after implantation. A depot can be sufficiently intact, for example, if it is not broken into multiple component pieces, with two or more of the resulting pieces being at least 5% of the depot's previous size. Alternatively or additionally, a depot can be considered sufficiently intact if the release rate of the therapeutic agent does not increase by more than three-fold compared to the release rate of the therapeutic agent in a control depot immersed in a buffer solution.

[0138] The therapeutic agent can be at least 50% to 95% by weight of the total weight of the depot 100 before implantation, or 55% to 85% by weight of the total weight of the depot 100 before implantation, or 60% to 75% by weight of the total weight of the depot 100 before implantation. Similarly, the polymer may be 5% to 50% by weight or less of the total weight of the depot 100 before implantation, or 10% to 50% by weight of the total weight of the depot 100 before implantation, or 15% to 45% by weight of the total weight of the depot 100 before implantation, or 20% to 40% by weight of the total weight of the depot 100 before implantation, or 25% or less, 30% or less, 35% or less, or 40% or less. The ratio of the mass of therapeutic agent in the depot 100 to the mass of polymer in the depot 100 can be at least 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1.

[0139] Some embodiments of the depot 100 shown in FIG. 4 having one or more combinations of the parameters described in the previous paragraph produced exceptional results in animal studies as described herein. For example, the depot 100 was configured such that (a) the thickness of the control regions 300a-b was less than or equal to 1 / 50 of the thickness of the treatment region 200, either individually or combined, (b) the mass of the therapeutic agent payload was sufficient to release from about 100 mg to about 500 mg of analgesic per day at the treatment site, and (c) the structural integrity was such that most of the depot remained intact for at least 14 days after implantation. These embodiments were able to release from about 20% to about 50% of the analgesic payload from about 3 to about 5 days of the first 14 days and then at least 80% of the remaining analgesic payload from about 9 to about 11 days of the last 14 days. This was at least partially unexpected because (a) providing such a large payload of the therapeutic agent in the treatment region would have been predicted to cause mechanical failure of the depot 100 on or before the 14th day after implantation, and (b) the disclosed device did not achieve a release profile in which from about 20% to about 50% of the analgesic was released from about 3 to about 5 days of the first 14 days and then at least 80% of the remaining analgesic was released from about 9 to about 11 days of the last 14 days.

[0140] In some embodiments, one or more control regions 300 of the depot 100 may include two or more sub-control regions. For example, as shown in FIG. 5, the depot 100 may have a first control region 300a and a second control region 300b, each of which may include first and second sub-control regions 302a, 302b and 302c, 302d, respectively. One, some, or all of the first and second control regions 300a, 300b, and / or sub-control regions 302a-302d may have the same or different amounts The control region may have the same or different release agent, the same or different concentration of release agent, the same or different amount of polymer, the same or different polymer, the same or different ratio of polymer to release agent, and / or the same or different thickness. In some embodiments, the concentration of release agent in each outer control sub-region 302a, 302d is less than the concentration of release agent in each inner control sub-region 302b, 302c, such that the outer portion of the collective control region elutes therapeutic agent more slowly than the inner portion of the collective control region. In some embodiments, the concentration of release agent in each outer control sub-region 302a, 302d is greater than the concentration of release agent in each inner control sub-region 302b, 302c. In embodiments where the control region includes more than two sub-regions, the concentration of release agent per sub-region or layer may increase, decrease, or remain constant as the sub-control regions are further apart than the treatment region 200.

[0141] In certain embodiments, the outer control sub-region comprises at least 5% by weight of a release agent, at least 10% by weight of a release agent, at least 15% by weight of a release agent, at least 20% by weight of a release agent, at least 25% by weight of a release agent, at least 30% by weight of a release agent, at least 35% by weight of a release agent, at least 40% by weight of a release agent, at least 45% by weight of a release agent, or at least 50% by weight of a release agent. In some embodiments, the inner control sub-region comprises at least 5% by weight of a release agent, at least 10% by weight of a release agent, at least 15% by weight of a release agent, at least 20% by weight of a release agent, at least 25% by weight of a release agent, at least 30% by weight of a release agent, at least 35% by weight of a release agent, at least 40% by weight of a release agent, at least 45% by weight of a release agent, or at least 50% by weight of a release agent. In some embodiments, the outer control sub-region may include a first amount of release agent and the inner control sub-region may include a second amount of release agent, the second amount being at least 200%, at least 300%, at least 400%, or at least 500% greater than the first amount.

[0142] 6-8 show embodiments of a depot having multiple alternating treatment regions 200 and control regions 300 in accordance with the present technology. The depot 100 may have two or more control regions 300 and / or subregions 302 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and the depot 100 may have one or more treatment regions 200 and / or subregions 202 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one control region 300 and / or subregion 302. In some embodiments, each of the treatment regions 200 may comprise a single layer, and / or each of the control regions 300 may comprise a single layer. In some embodiments, one, some, or all of the treatment regions 200 may comprise multiple layers, and / or one, some, or all of the control regions 300 may comprise multiple layers. In some embodiments, for example, as shown in Figures 6 and 7, two or more sub-regions 302a-b (Figure 6) and 302a-b and 302c-d (Figure 7) may be adjacent to each other between sub-regions 202 of a treatment region 200. Additionally, one or more of the individual control regions 300 and / or one or more of the treatment regions 200 may have the same or different amounts and / or types of release agents, and one or more of the treatment regions may have the same or different amounts and / or types of therapeutic agents.

[0143] The embodiments shown in Figures 6-8 may be beneficial when the treatment region contains a large payload of therapeutic agent (e.g., equivalent to many days, weeks, or months of medication). These embodiments may be beneficial because if the treatment region 200 were inadvertently exposed to such a large payload in vivo, the entire payload would be prematurely released, subjecting the patient to an abnormally and undesirably high dose of the therapeutic agent. For example, if the integrity of the control region 300 were compromised, the patient could be exposed to the therapeutic agent in vivo at a faster rate than intended, potentially resulting in clinical complications. In particular, with regard to the administration of local anesthetics (e.g., bupivacaine, ropivacaine, etc.), manufacturing guidelines recommend a dose of 400 mg or less in 24 hours. It is recommended that the extended release product be administered within a period of time. However, numerous studies have demonstrated that doses higher than 400 mg from extended release products are safe due to their slow release over an extended period of time. Nevertheless, if the control region 300 is compromised, it is desirable to expose the patient to only a portion of the total payload, whereby the portion to which the patient is exposed would be within a safe range for the particular therapeutic agent if released early. The structural integrity of the control region 300, as well as that of the therapeutic region(s) 200, are important properties for depots with large masses of therapeutic agent to be delivered over an extended period of time.

[0144] To address this concern, in some embodiments of the present technology, the depot 100 may include multiple treatment regions 200 spaced apart by one or more control regions 300 (e.g., as shown in Figures 6-8). Such a configuration individually isolates the therapeutic agent (loaded with a portion of the total payload) in each treatment region 200. If a particular control region is compromised, only the portion of the payload corresponding to the treatment region associated with the compromised control region may be prematurely released. For example, in some of the aforementioned embodiments, the total payload of the depot 100 may be at least 100 mg, at least 150 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or at least 1000 mg of a therapeutic agent such as an analgesic (e.g., bupivacaine, ropivacaine, etc.). Similarly, in some embodiments, that portion of the payload in each treatment region or sub-region may be up to 1%, up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to 100% of the total payload contained within the depot 100. As a result, if any single sub-region 202 of a treatment region 200 is compromised, it may only release a proportionate fraction of the depot's total payload.

[0145] In some embodiments, each of the treatment regions and each of the control regions is a microthin layer, i.e., has a layer thickness of less than 1 mm. In some embodiments, the depot comprises from about 2 to about 100 treatment regions, or from about 2 to about 50 treatment regions, or from about 2 to about 10 treatment regions.

[0146] 9A-11 illustrate some aspects of the present technology in which a depot 100 may have one or more treatment regions 200 completely surrounded or enclosed by one or more control regions 300. In contrast to the previously described embodiments, at least one treatment region in such completely enclosed embodiments has no exposed surface area. For example, as shown in FIGS. 9A and 9B, in some embodiments, a depot 100 may include a treatment region 200 that is surrounded or completely enclosed by a control region 300, such that no portion of the treatment region 200 is exposed through the control region 300. As a result, the control region 300 substantially prevents contact between the therapeutic agent and physiological fluids, thereby preventing uncontrolled burst release of the therapeutic agent upon implantation. Over time, the release agent embedded in the polymer of the control region 300 comes into contact with physiological fluids and dissolves, thereby forming diffusion openings in the control region. The combination of the restriction imposed by the control region and the diffusion openings formed by the dissolution of the release agent allows for controlled release of the therapeutic agent from the depot over days, weeks, or months. Although depot 100 is shown as a rectangular film in Figures 9A and 9B, in other embodiments, depot 100 may have other shapes, sizes, or forms.

[0147] 10 shows a depot 100 having a treatment region 200 completely surrounded by a control region 300 having a first control region 300a and a second control region 300b. As shown in FIG. 10, in some embodiments, the treatment region 200 is surrounded by a control region 300 having a first control region 300a and a second control region 300b. The first and second control regions 300a-b may be sandwiched between the first and second control regions 300a-b, and the first and second control regions 300a-b may be bonded via heat compression around the treatment region 200 to enclose the treatment region 200 between them. In certain embodiments, the bioabsorbable polymer may wrap around the entire depot and be sealed at the top or bottom surfaces, creating a control region structure similar to that shown in FIG. 9A. The outer portions of the first and second control regions 300a-b may be incorporated as a final wrap layer that seals the edges. Additionally, the first and second control regions 300a-b may be integrally formed with one another using dip-coating and / or spray-coating techniques, such as dipping the treatment region 200 into a solution of the control region material or spraying a solution of the control region material onto the surface of the treatment region 200.

[0148] In FIG. 10, the first control region 300a can have first and second sub-regions 302a-b, and the second control region 300b can have first and second sub-regions 302c-d. The first control region 300a can define a top control region member, and the first and second sub-regions 302a-b can include a first top control layer and a second top control layer, respectively. The second control region 300b can define a bottom control region member, and the first and second sub-regions 302c-d can include a first bottom control layer and a second bottom control layer, respectively. The first and second top / bottom control layers can be any of the variations of the first and second control sub-regions discussed above with respect to FIG. 5. Additionally, the first top control layer of the top control region member may have the same or different properties (e.g., thickness, polymer, release agent, release agent concentration, total amount of release agent, ratio of polymer to release agent, etc.) as the first bottom control layer of the bottom control region member. Similarly, the second top control layer of the top control region member may have the same or different properties as the second bottom control layer of the bottom control region member. Variations in layer loading and structure may be designed into depot 100 to achieve a release profile or kinetics suitable for the intended therapeutic goal. In other embodiments, first control region 300a and / or second control region 300b comprise a single layer.

[0149] FIG. 11 illustrates some embodiments in which a depot 100 may have a treatment region 200 completely surrounded by a control region 300 having various sub-region configurations. The depot 100 of FIG. 11 includes a first control region 300a and a second control region 300b that together completely surround the treatment region 200. In contrast to the depot 100 shown in FIG. 10, the first control region 300a has an outer apex control region 301a with first and second apex sub-control regions 302a and 302b, respectively, and an inner apex control region 301b with first and second top layers 303a and 303b. The first and second top layers 303a-b are only on the top surface of the treatment region 200, while the first and second apex sub-control regions 302a-b cover portions of the sides of the treatment region 200 and the inner apex control region 301b. Second control region 300b has outer bottom control region 301c with first and second bottom sub-control regions 302c and 302d, respectively, and inner bottom control region 301d with first and second bottom layers 303d and 303e, respectively. Thus, when depot 100 is placed at a treatment site in vivo, outer apex and bottom control regions 301a and 301c are between (a) treatment region 200 and inner apex and bottom control regions 301b and 301d, respectively, and (b) the physiological fluids at the treatment site. In certain embodiments, such as that shown in FIG. 11, one or more of outer apex / bottom control regions 301a / 301c may include one or more control sub-regions, and one or more inner apex / bottom control regions 301b / 301d may include one or more control sub-regions.

[0150] 12 shows a cross section of a spherical depot 100 according to some embodiments of the present technology having multiple alternating treatment regions 200 and control regions 300 according to the present technology. The depot 100 may have two or more control regions 300 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and the depot may have at least one control region 300. Thus, the control region 300 may have one or more treatment regions 200 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by the treatment region 200. In some embodiments, each of the treatment regions 200 may include a single layer, and / or each of the control regions 300 may include a single layer. In some embodiments, one, some, or all of the treatment regions 200 may include multiple layers, and / or one, some, or all of the control regions 300 may include multiple layers. Furthermore, one or more of the individual control regions 200 and / or one or more of the treatment regions 300 may have the same or different amounts and / or types of release agents, and one or more of the treatment regions 200 may have the same or different amounts and / or types of therapeutic agents.

[0151] 13 shows a depot 100 according to some embodiments of the present technology having a treatment region 200 surrounded on top and bottom surfaces and two of four sides by a control region 300. This configuration is expected to release therapeutic agent more slowly, at least initially, compared to a depot with fully surrounded sides of the same dimensions (see, for example, the depot 100 shown in FIG. 4).

[0152] The release kinetics of the depot of the present technology may be tailored to a particular application by varying the shape and size of the depot 100. Depending on therapeutic dosing needs, anatomical target, etc., the depot 100 can be made into different sizes, shapes, and forms for implantation and / or injection into the body by a clinician. The shape, size, and form of the depot 100 should be selected to facilitate placement of the depot at the target tissue site and to reduce or completely prevent the possibility of the depot migrating after implantation or injection. This is particularly true with respect to depots placed within a joint (such as the knee), where the depot is a flexible solid that is structurally capable of being handled by a clinician during the normal course of surgery without breaking into multiple pieces and / or losing its overall shape. Furthermore, the depot may be configured to be placed in a patient's knee and release the analgesic drug in vivo for up to seven days without breaking into multiple pieces.

[0153] Some of the form factors that can be produced from or used in conjunction with the depot 100 for implantation and fixation within the body include strips, ribbons, hooks, rods, tubes, patches, corkscrew-shaped ribbons, partial or full rings, nails, screws, tacks, rivets, threads, tapes, woven shapes, T-shaped anchors, staples, discs, pillows, balloons, braids, tapered shapes, wedges, chisels, castle configurations, stent structures, suture buttresses, coil springs, sponges, capsules, coatings, matrices, wafers, sheets, strips, ribbons, pills, and pellets.

[0154] The depot 100 may be fabricated into a component of the form factor described in the previous paragraph. For example, the depot may be wound into a tube, incorporated into a screw, a tack, or the like. In woven embodiments, the depot may be incorporated into a multi-layer woven film / braid / mesh, where some of the filaments used are not part of the device of the present invention. In one example, the depot is interwoven with Dacron, polyethylene, or the like. For clarity, any form factor corresponding to the depot of the present technology may be referred to herein as a "depot," including those in which only a portion or segment of the form factor incorporates the depot.

[0155] As shown in the cross-sectional views of Figures 14A-14H, in various embodiments, the depot 100 can be shaped as a cylinder such as a sphere, rod, or fiber; a flat surface such as a disk, film, ribbon, strip, or sheet; a paste, slab, microparticle, nanoparticle, pellet, mesh, or the like. Figure 14A shows a rectilinear depot 100. Figure 14B shows a circular depot 100. Figure 14C shows a triangular depot 100. Figure 14D shows a rectangular depot 100. FIG. 14B shows a letter-shaped depot 100, FIG. 14C shows a star-shaped depot 100, and FIG. 14D shows a toric depot 100. FIG. 14E shows a star-shaped depot 100, and FIG. 14F shows a toric depot 100. FIG. 14G shows a spheroid-shaped depot 100, and FIG. 14H shows a cylindrical depot 100. The shape of the depot 100 can be selected according to the anatomy to fit within a given space and provide desired fixation and flexibility, as the fit, fixation, and flexibility of the depot can enhance the ease of implanting the depot, ensure delivery of therapeutic agents to the target site, and potentially extend the durability of the implant at dynamic implantation sites.

[0156] In various embodiments, the depot may be of various sizes, for example, the depot may be about 0.4 mm to 100 mm in length and have a diameter or thickness of about 0.01 to about 5 mm. In various embodiments, the depot may have a layer thickness of about 0.005 to 5.0 mm, such as 0.05 to 2.0 mm. In some embodiments, the shape may be a rectangular or square sheet having a width to thickness ratio in the range of 20 or greater, 25 or greater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

[0157] In some embodiments, the thickness of the control region (either a single sub-control region or all sub-control regions combined) is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment region. In those embodiments comprising multiple sub-control regions, one or more of the sub-control regions may individually be less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment region. In those embodiments in which the control region comprises a single control region, the control region may have a thickness that is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment region. In those embodiments comprising multiple secondary control regions, one or more of the secondary control regions may individually be less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the depot.In those embodiments in which the control region comprises a single control region, the control region may have a thickness that is less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the depot.

[0158] In some embodiments, the depot 100 has a width and a thickness, and the ratio of width to thickness is 21 or greater. In some embodiments, the ratio is 22 or greater, 23 or greater, 24 or greater, 25 or greater, 26 or greater, 27 or greater, 28 or greater. or greater, 29 or greater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

[0159] In some embodiments, the depot 100 has a surface area and a volume, and the ratio of the surface area to the volume is at least 1, at least 1.5, at least 2, at least 2.5, or at least 3.

[0160] In any of the foregoing embodiments shown and described above with respect to Figures 2-14H, dissolution of the release agent(s) and elution of the therapeutic agent(s) may change the functional mechanical aspects of depot 100 over time. Such mechanical aspects include the structural integrity, flexural strength, tensile strength, or other mechanical properties of depot 100. In some cases, undesired degradation of depot 100, such as premature degradation, may cause mechanical failure of depot 100 and a corresponding undesired burst release of the therapeutic agent into the body. Therefore, it may be beneficial for depot 100 to maintain sufficient flexural strength and / or mechanical integrity in vivo for at least a predetermined period of time or until a predetermined percentage of the therapeutic agent has been released from depot 100. Depot 100 may be considered to maintain its structural integrity if it remains largely intact and undergoes only partial or gradual shrinkage due to elution of the therapeutic agent or dissolution of the control layer or release agent. Depot 100 may be considered to have lost its structural integrity if it separates (e.g., fractures) into multiple component pieces, for example, where two or more of the resulting pieces are at least 5% of the previous size of depot 100. Alternatively, or additionally, depot 100 may be considered to have lost its structural integrity if the release rate of the therapeutic agent increases by more than three-fold compared to the release rate of the therapeutic agent in a control depot immersed in a buffer solution.

[0161] In some embodiments, the depot 100 is configured to maintain its structural integrity in vivo for at least a predetermined period of time. For example, the depot 100 can be configured to maintain its structural integrity in vivo for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, or at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 70 days, at least 90 days, at least 100 days, at least 200 days, at least 300 days, or at least 365 days.

[0162] In some embodiments, the depot 100 is configured to maintain its structural integrity in vivo until at least a predetermined percentage of the therapeutic agent payload has been released from the depot. For example, the depot 100 maintains its structural integrity in vivo until at least 5% by weight of the original payload has been released, until at least 10% by weight of the original payload has been released, until at least 15% by weight of the original payload has been released, until at least 20% by weight of the original payload has been released, until at least 25% by weight of the original payload has been released, until at least 30% by weight of the original payload has been released, until at least 35% by weight of the original payload has been released, until at least 40% by weight of the original payload has been released, until at least 45% by weight of the original payload has been released, until at least 50% by weight of the original payload has been released, until at least 55% by weight of the original payload has been released, until at least 60% by weight of the original payload has been released. The agent can be configured to remain in the fluid for at least one time period until the agent is released, until at least 65% by weight of the original payload is released, until at least 70% by weight of the original payload is released, until at least 75% by weight of the original payload is released, until at least 80% by weight of the original payload is released, until at least 85% by weight of the original payload is released, until at least 90% by weight of the original payload is released, or until at least 95% by weight of the original payload is released.

[0163] One aspect of the structural integrity of the depot 100 can be quantified when it is in vivo using a bending test, such as a three-point bending test, which measures bending properties including bending strength and / or maximum bending stress sustained by a test specimen before failure. Such a bending test may represent (e.g., simulate) the forces that the depot 100 would encounter in vivo in an anatomical joint (e.g., a knee joint). In one example, the depot can be subjected to a three-point bending test in accordance with ASTM-D790-17, "Standard Test Methods for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials." The text of this standard is incorporated herein by reference in its entirety. The depot 100 can be subjected to a three-point bending test in accordance with ASTM-D790-17, "Standard Test Methods for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials." It may be suspended in a medium configured to simulate in vivo conditions, such as phosphate buffered saline (PBS), at about 37° C. Bending tests may be performed after various periods of immersion in the medium to assess changes in bending strength of the depot 100 over time under simulated in vivo conditions.

[0164] Table 1 shows the maximum bending load sustained by four different samples of depot 100 at various periods after immersion in the medium, measured using a three-point bending test with the maximum deflection set at 2.13 mm. The values ​​in Table 1 reflect measurements taken from two instances of each of the listed samples. Figure 15 is a graph showing these values ​​plotted on a graph and fitted to a trend line. In each of these four samples, depot 100 includes treatment region 200 surrounded by upper and lower control regions 300a-b, as shown and described above with reference to Figures 4 or 5. Treatment region 200 has an exposed side 202 between first and second control regions 300a-b. Depot 100 each has lateral dimensions of approximately 2.5 cm x 1.5 cm, with a thickness of approximately 1 mm.

[0165] Sample 1 is a depot having a therapeutic region with a weight ratio of release agent to polymer to therapeutic agent of 0.5:10:20. The polymer in this sample is P(DL)GACL with a ratio of PDLLA:PGA:PCL of 6:3:1, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. In this sample, the depot includes a first control region 300a including a single control layer on the upper surface of the treatment region 200, and a second control region 300b including a single control layer on the lower surface of the treatment region 200, as shown and described above with reference to FIG. 4. Each control region 300a-b individually has a release agent to polymer ratio of 5:10.

[0166] Sample 2 is a depot having a therapeutic region 200 with a weight ratio of release agent to polymer to therapeutic agent of 1:10:20. The polymer in this sample is PLGA with a 1:1 ratio of PLA:PGA, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. Similar to Sample 1, the depot of Sample 2 includes a control region 300 including a first control region 300a with a single control layer on the upper surface of the treatment region 200 and a second control region 300b including a single control layer on the lower surface of the treatment region 200, as shown and described above with reference to FIG. 4. Each control region 300a-b individually has a release agent to polymer ratio of 5:10.

[0167] Sample 3 is a depot having a therapeutic region 200 with a weight ratio of release agent to polymer to therapeutic agent of 5:10:20. The polymer in this sample was in the ratio PDLLA:PGA:PCL. The depot is P(DL)GACL with a polymer to polymer ratio of 6:3:1, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. In this sample, the depot includes a control region 300, as shown and described above with reference to FIG. 5, which includes a first control region 300a having two sub-control regions 302a-b on the upper surface of the treatment region 200, and a second control region 300b having two sub-control regions 302c-d. Each of the inner sub-control regions 302b and 302c contacts the surface of the treatment region 200 and has a release agent to polymer ratio of 5:10, and each of the outer sub-control regions 302a and 302d has a release agent to polymer ratio of 1:10. Thus, the depot of Sample 3 includes a total of four sub-control regions.

[0168] Sample 4 is a depot having a therapeutic region 200 with a weight ratio of release agent to polymer to therapeutic agent of 5:10:20. The polymer in this sample is PLGA with a 1:1 ratio of PLA:PGA, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. Like Sample 3, the depot of Sample 4 includes a control region 300 having first and second control regions 300a-b, each having two sub-control regions 302a-b and 302c-d, respectively, as shown and described above with reference to Figure 5. Thus, the depot of Sample 4 also has a total of four sub-control regions 302a-d, two on the upper surface of the treatment region 200 and two on the lower surface of the treatment region 200. The inside of sub-control zones 302b and 302c have a release agent to polymer ratio of 5:10, and the outside of sub-control zones 302a and 302d have a release agent to polymer ratio of 1:10. [Table 1]

[0169] As shown in Table 1, all samples were intact and maintained sufficient structural integrity to withstand bending forces before fracture after 14 days of suspension in the vehicle. Although the maximum load withstood by each sample decreased over time, the bending strength of these samples at 14 days was sufficient to maintain the structural integrity desired for implantation within an active joint such as the knee or shoulder. As noted above, in the case of two of the samples tested at 28 days, the samples had degraded and therefore could not be tested because they were no longer structurally intact. In such cases, it may be desirable to configure the depot so that all or substantially all of the therapeutic agent payload is released from the depot before it degrades and loses structural integrity.

[0170] In this series of experiments, summarized in Table 1, the sample depots were generally flexible on day 0, before immersion in PBS. After immersion, the flexural strength of the depots decreased and the depots became more brittle over time. Yet, at days 7-14, the depots were still fully functionally intact. Without being bound by theory, it is possible that after the therapeutic agent eluted, the depots gradually resorbed into the empty polymer matrix. For example, after 14-28 days in solution, the depots may weigh only about 30% of their starting weight before immersion in PBS. At this lower weight and in a porous state, the depots may become more brittle, with lower flexural strength and less resistance to bending loads.

[0171] As mentioned above, it may be advantageous for depots 100 to maintain their structural integrity and bending strength even as they gradually degrade as the therapeutic payload is released into the body. In some embodiments, depots 100 are tested in accordance with a three-point bending test. In vitro testing, the depot 100 can be configured to exhibit a flexural strength decrease of up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, or up to 5% after immersion in PBS for a predetermined period of time. In various embodiments, the predetermined period of time that the depot 100 is immersed in PBS before being subjected to the three-point bending test is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more. In at least some embodiments, the change in flexural strength of the depot 100 can be measured between day 0 (e.g., before immersion in PBS) and a subsequent time after immersion in PBS for a period of time. In other embodiments, the change in flexural strength of the depot 100 can be measured between day 1 (e.g., after immersion in PBS for 24 hours) and a subsequent time after longer immersion in PBS.

[0172] In some embodiments, the depot 100 can be configured such that, in an in vitro test utilizing a three-point bending test, the bending strength of the depot 100 decreases by up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, or up to 5% over a period of time during which a predetermined percentage of the initial therapeutic agent payload is released while the depot 100 is immersed in PBS. In various embodiments, the predetermined percentage of payload released when depot 100 is immersed in PBS before being subjected to a three-point bending test is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. As noted above, in at least some embodiments, the change in flexural strength of depot 100 can be measured between day 0 (before being immersed in PBS) or day 1 (after being immersed in PBS for 24 hours) and a subsequent time after longer immersion in PBS.

[0173] In some embodiments, depot 100 has (a) lateral dimensions of about 1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a therapeutic agent payload sufficient to release about 100 mg to about 500 mg of therapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, wherein depot 100 is configured to remain sufficiently mechanically intact to provide a sustained, controlled release of the therapeutic agent for at least 7 days. Such embodiments of depot 100 can include a therapeutic region 200 having a therapeutic agent and a control region 300. Control region 300 can have first and second control regions 300a-b as shown and described above with reference to Figures 4-13, wherein control region 300 includes a bioabsorbable polymer and a release agent mixed with the bioabsorbable polymer. The release agent is configured to dissolve when the depot 100 is placed in vivo to form a diffusion opening in the control region 300. The depot 100 is further configured such that after immersion of the depot 100 in a buffer solution for 7 days, the flexural strength of the depot 100 decreases by up to 75%, or up to 70%, or up to 65%, or up to The device may be configured to reduce the power consumption by up to 60%, or up to 55%, or up to 50%, or up to 45%.

[0174] In some embodiments, depot 100 has (a) lateral dimensions of about 1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a therapeutic agent payload sufficient to release about 100 mg to about 500 mg of therapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, wherein depot 100 is configured to remain sufficiently mechanically intact to provide a sustained, controlled release of the therapeutic agent for at least 7 days. Such embodiments of depot 100 can include therapeutic agent-bearing therapeutic region 200 and control region 300. Control region 300 can have first and second control regions 300a-b as shown and described above with reference to Figures 4-13, wherein control region 300 includes a bioabsorbable polymer and a release agent mixed with the bioabsorbable polymer. The release agent is configured to dissolve when the depot 100 is placed in vivo to form a diffusion opening in the control region 300. The depot is further configured such that after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 75%, or up to 70%, or up to 65%, or up to 60%, or up to 55%, or up to 50%, or up to 45%.

[0175] A. Treatment area The total payload and release kinetics of the depot 100 of the present technology can be tailored to a particular application by varying the composition of the therapeutic region 200. In many embodiments, the therapeutic region 200 may contain a high therapeutic payload of therapeutic agent, particularly compared to other known polymeric devices of equivalent thickness or polymer weight percentage. For example, the depot 100 of the present technology may contain at least 15% by weight of therapeutic agent, at least 20% by weight of therapeutic agent, at least 25% by weight of therapeutic agent, at least 30% by weight of therapeutic agent, at least 35% by weight of therapeutic agent, at least 40% by weight of therapeutic agent, at least 45% by weight of therapeutic agent, at least 50% by weight of therapeutic agent, at least 55% by weight of therapeutic agent, at least 60% by weight of therapeutic agent, at least 65% by weight of therapeutic agent, at least 70% by weight of therapeutic agent, at least 75% by weight of therapeutic agent, at least 80% by weight of therapeutic agent, at least 85% by weight of therapeutic agent, at least 90% by weight of therapeutic agent, at least 95% by weight of therapeutic agent, or 100% by weight of therapeutic agent.

[0176] The therapeutic agent may be any of the therapeutic agents disclosed herein, eg, in Section C ("Therapeutic Agents") below.

[0177] In various embodiments of the depot 100 disclosed herein, the treatment region 200 may take several different forms. In some embodiments (e.g., FIG. 4), the treatment region 200 may include a single layer composed of a therapeutic agent, a therapeutic agent mixed with a bioabsorbable polymer, or a therapeutic agent mixed with a bioabsorbable polymer and a release agent. In some embodiments, the treatment region 200 itself may include a structure having multiple layers or subregions of therapeutic agent (and / or bioabsorbable polymer and / or release agent). Some or all of the layers or subregions of such a multilayer treatment region 200 may be directly adjacent (i.e., in contact with) one another (laterally or axially), and / or some or all of the layers or subregions may be spaced apart with one or more other regions between them (such as control region(s) 300 and / or barrier region(s)). In some embodiments, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more treatment sub-regions or layers may be grouped together and spaced apart from another treatment region or group of treatment sub-regions or layers (having the same or a different number of layers than the other groups) with one or more other regions between them (control region(s)). ) 300 and / or barrier region(s), etc.) (see, e.g., Figures 5, 6, etc.).

[0178] In any of the embodiments of the depot disclosed herein, the ratio of the mass of therapeutic agent in the depot to the mass of polymer in the depot is at least 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, or 16:1.

[0179] In any of the embodiments of the depot disclosed herein, the ratio of the mass of polymer in the therapeutic region 200 to the mass of therapeutic agent in the therapeutic region 200 is at least 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10.

[0180] In any of the embodiments disclosed herein, the weight ratio of release agent to polymer in the treatment area 200 may be 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, or 1:16.

[0181] In some embodiments, the ratio of release agent to polymer to therapeutic agent in the treatment region 200 is from about 0.1:10:20 to about 2:10:20, from about 0.1:10:20 to about 1:10:20, from about 0.1:10:20 to about 0.5:10:20, from about 0.5:10:20 to about 0.1:10:20, or from about 0.5:10:20 to about 1:10:20.

[0182] In any of the embodiments disclosed herein having a single treatment region 200, the treatment region 200 may be between about 5 μm and 100 μm, 5 μm and 50 μm, 5 μm and 25 μm, 5 μm and 10 μm, 5 μm and 7 μm, 7 μm and 9 μm, 10 μm and 80 μm, 10 μm and 70 μm, 10 μm and 60 μm, 20 μm and 60 μm, 15 μm and 160 μm, 17 μm and 180 μm, 19 μm and 200 μm, 20 μm and 210 μm, 220 μm and 230 μm, 240 μm and 250 μm, 260 μm and 270 μm, 280 μm and 290 μm, 300 μm and 310 μm, 320 μm and 330 μm, 340 μm and 350 μm, 360 μm and 370 μm, 370 μm and 380 μm, 380 μm and 400 μm, 390 μm and 400 μm, 400 μm and 410 μm, 410 μm and 420 μm, 420 μm and 430 μm, 430 μm and 440 μm, 440 μm and 450 μm, 450 μm and 460 μm, 460 μm and 470 μm, 470 μm and 480 μm, 480 μm and 500 μm, 490 μm and 500 μm, 500 μm and 510 μm, 510 μm and 52 50 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, about 100 μm, 100 μm to 2 mm, 100 μm to 1.5 mm, 100 μm to 1 mm, 100 μm to 200μm, 200μm to 300μm, 300μm to 400μm, 400μm to 500μm, 500μm to 600μm, 600μm to 700μm, 700μm to 800μm, 800μm to 900μm, 900μm to 1mm, 1mm to 1.5mm, 200μm to 600μm, 400μm to 1mm, 500μm to 1.1mm, It may have a thickness of 800 μm to 1.1 mm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, or about 2 mm.

[0183] In those embodiments having multiple treatment regions and / or subregions, individual subregions or combinations of some or all of the subregions may have diameters of about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, 7 μm to 9 μm, 10 μm to 80 μm, 10 μm to 70 μm, 10 μm to 60 μm, 20 μm to 60 μm, 15 μm to 50 μm, about 1 μm to 50 μm, 5 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, about 100 μm, 100 μm to 2 mm, 100 μm to 1.5 mm, 100 μm to 1 mm, 100 μm to 200 μm, 200 μm to 300 μm, 300 μm to 400 μm , 400 μm to 500 μm, 500 μm to 600 μm, 600 μm to 700 μm, 700 μm to 800 μm, 800 μm to 900 μm, 900 μm to 1 mm, 1 mm to 1.5 mm, 200 μm to 600 μm, 400 μm to 1 mm, 500 μm to 1.1 mm, 800 μm to 1.1 mm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, or about 2 mm.

[0184] The therapeutic region 200 of the present technology may comprise at least 15% by weight of a therapeutic agent, at least 20% by weight of a therapeutic agent, at least 25% by weight of a therapeutic agent, at least 30% by weight of a therapeutic agent, at least 35% by weight of a therapeutic agent, at least 40% by weight of a therapeutic agent, at least 45% by weight of a therapeutic agent, at least 50% by weight of a therapeutic agent, at least 55% by weight of a therapeutic agent, at least 60% by weight of a therapeutic agent, at least 65% by weight of a therapeutic agent, at least 70% by weight of a therapeutic agent, at least 75% by weight of a therapeutic agent, at least 80% by weight of a therapeutic agent, at least 85% by weight of a therapeutic agent, at least 90% by weight of a therapeutic agent, at least 95% by weight of a therapeutic agent, or 100% by weight of a therapeutic agent.

[0185] In any of the embodiments disclosed herein, the treatment area 200 may include about 0.1% to 10% by weight of the releasing agent, about 0.1% to 6% by weight of the releasing agent, 0.2% to 10% by weight of the releasing agent, about 0.3% to 6% by weight of the releasing agent, about 0.1% to 1% by weight of the releasing agent, about 0.1% to 0.5% by weight of the releasing agent, 1% to 2% by weight of the releasing agent, about 1% to 3% by weight of the releasing agent, or about 2% to 6% by weight of the releasing agent. In those embodiments having multiple treatment regions or sub-regions, one or more of the treatment regions or sub-regions may individually comprise about 0.1% to 10% by weight of the release agent, about 0.1% to 6% by weight of the release agent, 0.2% to 10% by weight of the release agent, about 0.3% to 6% by weight of the release agent, about 0.1% to 1% by weight of the release agent, about 0.1% to 0.5% by weight of the release agent, about 1% to 2% by weight of the release agent, about 1% to 3% by weight of the release agent, or about 2% to 6% by weight of the release agent. Treatment region 200 may not comprise any release agent. In those embodiments having multiple treatment regions and / or sub-regions, one, some, or all of the individual treatment regions and / or sub-regions may not comprise any release agent.

[0186] In any of the embodiments disclosed herein, the treatment region 200 may comprise 5% or less by weight of polymer, 10% or less by weight of polymer, 15% or less by weight of polymer, 20% or less by weight of polymer, 25% or less by weight of polymer, 30% or less by weight of polymer, 35% or less by weight of polymer, 40% or less by weight of polymer, 45% or less by weight of polymer, or 50% or less by weight of polymer. In those embodiments having multiple treatment regions or sub-regions, one or more of the treatment regions or sub-regions may individually comprise 5% or less by weight of polymer, 10% or less by weight of polymer, 15% or less by weight of polymer, 20% or less by weight of polymer, 25% or less by weight of polymer, 30% or less by weight of polymer, 35% or less by weight of polymer, 40% or less by weight of polymer, 45% or less by weight of polymer, or 50% or less by weight of polymer. In some embodiments, the treatment region 200 may not comprise any polymer.

[0187] In those embodiments disclosed herein in which treatment region 200 includes multiple treatment regions or sub-regions, some or all of the treatment regions or sub-regions may have the same or different amounts of release agent, the same or different concentrations of release agent, the same or different release agents, the same or different amounts of polymer, the same or different polymers, the same or different ratios of polymer to release agent, the same or different amounts of therapeutic agent, the same or different types of therapeutic agent, and / or the same or different thicknesses. Additionally, a single treatment region or sub-region may contain a single type of polymer or multiple types of polymers, a single type of polymer, or multiple types of polymers. The therapeutic region and / or subregion may comprise a single or multiple types of release agents, and / or a single type of therapeutic agent or multiple types of therapeutic agents. In those embodiments having multiple therapeutic regions and / or subregions, one, some, or all of the individual therapeutic regions and / or subregions may be free of any polymer.

[0188] In some embodiments, the therapeutic area 200 (or one or more therapeutic sub-areas) comprises a therapeutic agent, either as an essentially pure compound or formulated with a pharmaceutically acceptable carrier, such as a diluent, adjuvant, excipient, or vehicle known to those skilled in the art.

[0189] B. Control Region The composition of the control region 300 may vary. For example, in many embodiments, the control region 300 does not include any therapeutic agent, at least prior to implantation of the depot at the treatment site. In some embodiments, the control region 300 may include a therapeutic agent that may be the same as or different from the therapeutic agent in the treatment region 200.

[0190] Within the control region 300, the amount of release agent may be varied to achieve faster or slower release of the therapeutic agent. In embodiments in which both the treatment region 200 and the control region 300 include a release agent, the type of release agent within the treatment region 200 may be the same as or different from the release agent in the control region 300. In some embodiments, the concentration of a first release agent within the control region is greater than the concentration of a second release agent (the same or different from the first release agent) within the treatment region. In some embodiments, the concentration of a release agent within the control region is less than the concentration of a release agent within the treatment region. In some embodiments, the concentration of a release agent within the control region 300 is the same as the concentration of a release agent within the treatment region 200.

[0191] In various embodiments of the depot disclosed herein, the control region 300 may take several different forms. In some embodiments (e.g., FIG. 4), the control region 300 may comprise a single layer on either side of the treatment region 200 comprised of a bioabsorbable polymer mixed with a release agent. In some embodiments, the control region 300 itself may comprise a structure having multiple layers or subregions of bioabsorbable polymer and release agent. Some or all of the layers or subregions of such a multi-layer control region 300 may be directly adjacent (i.e., in contact with) one another (laterally or axially), and / or some or all of the layers or subregions may be spaced apart with one or more other regions (such as the treatment region(s) 200 and / or barrier region(s)) between them. In some embodiments, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more control sub-regions or layers may be grouped together and spaced apart from another control region or group of control sub-regions or layers (having the same or a different number of layers as the other groups) with one or more other regions between them (such as treatment region(s) 200 and / or barrier region(s)) (see, e.g., Figures 5, 6, etc.).

[0192] Without being bound by theory, it is believed that such a multi-layer configuration improves the ability of the control region to control the release of the therapeutic agent compared to a single-layer control region, even when the multi-layer configuration has the same or a smaller thickness than the single-layer control region. The channels left by the dissolution of the release agent in both the microlayers and / or sub-regions of the control region create a longer and perhaps more cumbersome path for the released therapeutic agent to traverse compared to the more direct path created by the channels of the single-layer control region. The control region(s) and / or sub-regions thereby modulate the release rate of the therapeutic agent by causing the release agent to form independent, non-adjacent channels through one or more control regions and / or sub-regions. Those embodiments having multiple control layers or sub-regions In some embodiments, some or all of the control layers or sub-regions may be heat-compressed together. One or more control regions may be heat-compressed together with the treatment region 200, whether or not they are heat-compressed first. Having a control region 300 with multiple layers may provide a more linear, controlled release of the therapeutic agent over time (beyond the first day of implantation). Additionally, the layering of the control region 300 may also contribute to a more flexible, structurally competent depot (compared to a depot with a treatment region composed of pure therapeutic agent). Such durability is beneficial to the clinician when handling / manipulating the depot 100 before and during placement of the depot 100 at the treatment site.

[0193] In any of the embodiments disclosed herein having a single control region 300, the thickness of the control region 300 may be about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, 7 μm to 9 μm, 10 μm to 80 μm, 10 μm to 70 μm, 10 μm to 60 μm, 20 μm to 60 μm, 15 μm to 50 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, or about 100 μm. In those embodiments having multiple control regions and / or subregions, individual subregions or combinations of some or all of the subregions may have a thickness of about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, 7 μm to 9 μm, 10 μm to 80 μm, 10 μm to 70 μm, 10 μm to 60 μm, 20 μm to 60 μm, 15 μm to 50 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, or about 100 μm.

[0194] In any of the embodiments disclosed herein, the weight ratio of release agent to polymer in the control region 300 may be 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, or 1:25.

[0195] In any of the embodiments disclosed herein, the control region 300 may comprise at least 5% by weight of a release agent, at least 10% by weight of a release agent, at least 15% by weight of a release agent, at least 20% by weight of a release agent, at least 25% by weight of a release agent, at least 30% by weight of a release agent, at least 35% by weight of a release agent, at least 40% by weight of a release agent, at least 45% by weight of a release agent, or at least 50% by weight of a release agent. In those embodiments having multiple control regions or sub-regions, one or more of the control regions or sub-control regions may individually comprise at least 5% by weight of a release agent, at least 10% by weight of a release agent, at least 15% by weight of a release agent, at least 20% by weight of a release agent, at least 25% by weight of a release agent, at least 30% by weight of a release agent, at least 35% by weight of a release agent, at least 40% by weight of a release agent, at least 45% by weight of a release agent, or at least 50% by weight of a release agent.

[0196] In any of the embodiments disclosed herein, the control region 300 may comprise at least 5% by weight of a polymer, at least 10% by weight of a polymer, at least 15% by weight of a polymer, at least 20% by weight of a polymer, at least 25% by weight of a polymer, at least 30% by weight of a polymer, at least 35% by weight of a polymer, at least 40% by weight of a polymer, at least 45% by weight of a polymer, at least 50% by weight of a polymer, at least 55% by weight of a polymer, at least 60% by weight of a polymer, at least 65% by weight of a polymer, at least 70% by weight of a polymer, at least 75% by weight of a polymer, at least In those embodiments having multiple control regions or sub-regions, one or more of the control regions or sub-control regions may individually comprise at least 5% by weight of polymer, at least 10% by weight of polymer, at least 15% by weight of polymer, at least 20% by weight of polymer, at least 25% by weight of polymer, at least 30% by weight of polymer, at least 35% by weight of polymer, at least 40% by weight of polymer, at least 45% by weight of polymer, at least 50% by weight of polymer, at least 55% by weight of polymer, at least 60% by weight of polymer, at least 65% by weight of polymer, at least 70% by weight of polymer, at least 75% by weight of polymer, at least 80% by weight of polymer, at least 85% by weight of polymer, at least 90% by weight of polymer, at least 95% by weight of polymer, or 100% by weight of polymer.

[0197] In those embodiments disclosed herein in which the control region 300 includes multiple control regions or sub-regions, some or all of the control regions or sub-control regions may have the same or different amounts of release agent, the same or different concentrations of release agent, the same or different release agents, the same or different amounts of polymer, the same or different polymers, the same or different ratios of polymer to release agent, and / or the same or different thicknesses. A single control region or sub-region may include a single type of polymer or multiple types of polymers and / or a single type of release agent or multiple types of release agents.

[0198] C. Therapeutic Agents The therapeutic agent delivered by the depot 100 of the present technology may be any biologically active substance (or combination of substances) that provides a therapeutic effect in a patient in need thereof. As used herein, "therapeutic agent" or "drug" may refer to a single therapeutic agent or a combination of therapeutic agents. In some embodiments, the therapeutic agent may include only a single therapeutic agent, and in some embodiments, the therapeutic agent may include two or more therapeutic agents for simultaneous or sequential release.

[0199] In some embodiments, the therapeutic agent includes an analgesic. The term "analgesic" or "analgesic drug" includes one or more local or general anesthetic agents administered to generally reduce, prevent, alleviate, or eliminate pain. Analgesics may include systemic and / or local anesthetics, narcotics, and / or anti-inflammatory agents. Analgesics may include pharmacologically active drugs or pharmaceutically acceptable salts thereof. Suitable local anesthetics include, but are not limited to, bupivacaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine, trimecaine, carticaine, articaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, and combinations thereof. Preferred local anesthetics include bupivacaine, lidocaine, and ropivacaine. Typically, local anesthetics produce anesthesia by inhibiting excitation of nerve endings or by blocking transmission in peripheral nerves. Such inhibition is achieved by anesthetics that reversibly bind to and inactivate sodium channels. Sodium influx through these channels is necessary for depolarization of the nerve cell membrane and the subsequent propagation of impulses along nerve tracts. When a nerve loses its ability to depolarize and propagate impulses, an individual loses sensation in the area supplied by the nerve. Any compound that possesses such anesthetic properties is suitable for use in the present technology.

[0200] In some embodiments, the analgesic may include dexamethasone. In some embodiments, the therapeutic agent may include a first analgesic and a second analgesic. In some such embodiments, one of the first or second analgesic is dexamethasone. Dexamethasone may also act as an anti-inflammatory agent.

[0201] In some embodiments, the analgesic may include tetrodotoxin. In some embodiments, the therapeutic agent may include a first analgesic and a second analgesic. In some such embodiments, one of the first or second analgesic is tetrodotoxin.

[0202] In some embodiments, the analgesic may include saxitoxin. In some embodiments, the therapeutic agent may include a first analgesic and a second analgesic. In some such embodiments, one of the first or second analgesic is saxitoxin.

[0203] In some embodiments, the therapeutic agent includes a narcotic, such as cocaine, and an anti-inflammatory agent. Examples of suitable anti-inflammatory agents include steroids, such as prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone. Other suitable anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and other COX-2 inhibitors, and combinations thereof.

[0204] In some embodiments, the therapeutic agent comprises an antibiotic, antibacterial, or antifungal agent, or a combination thereof. For example, suitable antibiotics and antibacterial substances include, but are not limited to, amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporin(s), carbapanem, imipenem, ertapenem, antimicrobial peptides, cecropin-melittin, magainin, dermaseptin, cathelicidin, alpha-defensin, and alpha-protegrin. Antifungal agents include, but are not limited to, ketoconazole, chlortrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

[0205] The depot of any one of the preceding clauses, wherein the analgesic is a local anesthetic and wherein release of the analgesic to the treatment site over a period of 5 days inhibits bacterial and fungal growth.

[0206] In some embodiments, the therapeutic agent is a local anesthetic, and release of the anesthetic to the treatment site over the duration of delivery inhibits bacterial and fungal growth. In some embodiments, the depot is configured to inhibit bacterial and fungal growth such that the number of bacteria on the depot is 10, 20, 30, 40, or 50 times lower than the number of bacteria present on a comparable depot that does not contain the analgesic.

[0207] In some embodiments, the therapeutic agent is an adrenocorticostatic, a beta-antiadrenergic, an androgen or antiandrogen, an antianemic, an antiparasitic, an anabolic, an anesthetic or analgesic, a stimulant, an antiallergic, an antiarrhythmic, an antiarteriosclerotic, an antibiotic, an antidiabetic, an antifibrinolytic, an antispasmodic, an angiogenesis inhibitor, an anticholinergic, an enzyme, a coenzyme or corresponding inhibitor, an antihistamine, an antihypertensive, an antihypertensive The compound may be a drug, anticoagulant, antifungal agent, antiseptic, anti-infective agent, hemostatic agent, beta-receptor antagonist, calcium channel antagonist, antimyasthenic agent, anti-inflammatory agent, antipyretic agent, antirheumatic agent, cardiotonic agent, chemotherapeutic agent, coronary vasodilator, cytostatic agent, glucocorticoid, hemostatic agent, immunoglobulin or fragment thereof, chemokine, cytokine, mitogen, cell differentiation factor, cytotoxic agent, hormone, immunosuppressant, immunostimulant, morphine antagonist, muscle relaxant, narcotic, vector, peptide, (para)sympathomimetic agent, (para)sympatholytic agent, protein, cell, selective estrogen receptor modulator (SERM), sedative, anticonvulsant, substance that inhibits bone resorption, vasoconstrictor or vasodilator, viral growth inhibitor, or wound healing agent.

[0208] In various embodiments, the therapeutic agent comprises a drug or a pharmaceutically acceptable salt thereof used in the treatment of cancer. Such chemotherapeutic agents include antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleaving agents, DNA cross-linking agents, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include, but are not limited to, adalimumab, ansamitocin P3, auristatins, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, calystatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribine, cytarabine, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, These include gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, vindesine, and tamoxifen.

[0209] In some embodiments, the therapeutic agent comprises a botulinum toxin (or neurotoxin) agent used to treat various pain-related neuromuscular and / or neuroglandular disorders and neuropathies. The botulinum toxin (or neurotoxin) may comprise a pharmacologically active drug or a pharmaceutically acceptable salt thereof. The botulinum toxin (or neurotoxin) described and used herein may be selected from various strains of Clostridium botulinum and may comprise a pharmacologically active drug or a pharmaceutically acceptable salt thereof. In one embodiment, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G. In a preferred embodiment, the botulinum toxin is botulinum toxin type A. The commercially available botulinum toxin, BOTOX® (Allergan, Inc., Irvine, Calif.), consists of lyophilized purified botulinum toxin type A complex, albumin, and sodium chloride packaged in sterile, vacuum-dried form.

[0210] The paralytic effect of botulinum toxin is the most common benefit of commercial therapeutics, relaxing muscles to treat dystonia, wrinkles, etc. However, in addition to its anticholinergic effects on muscle and smooth muscle, neurotoxins have been shown to have therapeutic effects on other non-muscle cell types and on inflammation itself. For example, it has been shown that cholinergic goblet cells, which produce mucus throughout the respiratory system, can respond to and be shut down by the introduction of botulinum toxin. Studies have shown that botulinum toxin has direct anti-inflammatory capabilities. All of these therapeutic effects, muscle, smooth muscle, goblet cell, and anti-inflammatory effects, can be derived from the delivery of toxins from the devices of the present invention.

[0211] Pharmaceutically acceptable salts refer to salts that retain the biological effectiveness and properties of the neutral therapeutic agent and are not otherwise unacceptable for pharmaceutical use.Pharmaceutically acceptable salts include salts of acidic or basic groups, which may be present in the therapeutic agent.The therapeutic agent used in the present technology that is basic in nature can form a wide variety of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts of basic therapeutic agents used in the present technology are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzethosulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts).Therapeutic agents of the present technology containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Suitable base salts are formed from bases which form non-toxic salts, examples of which are aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.

[0212] Pharmaceutically acceptable salts may contain other molecules, such as water or another biologically compatible solvent (solvate), acetate ions, succinate ions, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples in which multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0213] The therapeutic agent or its pharmaceutically acceptable salt may be an essentially pure compound or may be formulated with a pharmaceutically acceptable carrier, such as a diluent, adjuvant, excipient, or vehicle known to those skilled in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. For example, diluents include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, and the like. For examples of other pharmaceutically acceptable carriers, see Remington: THE SCIENCE AND PRACTICE OF PHARMACY (21st Edition, University of the Sciences in Philadelphia, 2005).

[0214] The therapeutic agent or pharmaceutically acceptable salt form may be jet milled or otherwise passed through a sieve to form a consistent particle size, thereby further enabling a regulated, controlled release of the therapeutic agent. This process may be particularly useful for highly insoluble therapeutic agents.

[0215] An important criterion for determining the amount of therapeutic agent required to treat a particular medical condition is the rate of drug release from the depot of the present technology. The release rate is controlled by various factors, including, but not limited to, the rate at which the release agent dissolves in the surrounding fluid in vivo and the in vivo degradation rate of the bioabsorbable polymer or copolymer utilized. For example, the release rate can be controlled by the use of multiple control regions between the treatment region and the physiological fluid. See, for example, Figures 6-8.

[0216] Suitable dosage ranges utilizing the depot technology of the present invention depend on the potency of the particular therapeutic agent, but are generally from about 0.001 mg to about 500 mg of drug per kilogram of body weight per day, e.g., from about 0.1 mg to about 200 mg of drug per kilogram of body weight, and from about 1 to about 100 mg per kilogram of body weight. Dosage ranges can be readily determined by methods known to those skilled in the art. Unit dosage forms will generally contain between about 1 mg and about 500 mg of active ingredient. For example, commercially available bupivacaine hydrochloride, sold under the brand name Marcaine™ (Pfizer; New York, NY), is commonly administered for peripheral nerve blocks using dosage ranges of 37.5 to 75 mg for a 0.25% concentration and 25 mg for a 0.5% concentration, up to a maximum daily level (up to 400 mg) (Marcaine™ package insert; FDA Reference ID: 3079122). Additionally, Naropin® (Fresenius Kabi Commercially available ropivacaine hydrochloride, sold under the brand name Naropin® (Naropin®) of the University of California, San Diego, CA, USA, LLC; Lake Zurich, IL, is administered in doses of 5 to 300 mg for minor and major nerve blocks (Naropin® package insert; Reference ID: 451112G). The dosage range appropriate for the depot technology is equivalent to the commercially available medication routinely administered by injection.

[0217] In some aspects of the technology, the treatment region 200 may include multiple layers. In such embodiments, multiple layers may improve the efficient loading of therapeutic agents. For example, multi-layering can be a straightforward and effective way to load significant amounts of therapeutic agent. Often, it can be difficult to load large amounts of therapeutic agent into a single film layer, even by increasing the drug-to-polymer ratio or by increasing the layer thickness. Even if the thickness of the treatment region could theoretically be increased to load more drug, consistently fabricating thick treatment regions via casting may prove difficult. In contrast, stacking and bonding thin films or sheets, each with a predetermined loading of therapeutic agent, may offer a more reliable alternative to casting. Data from an example loading an analgesic drug (i.e., ropivacaine) is presented in Table 2. [Table 2]

[0218] As an example only, a single layer loaded with ropivacaine and having a thickness of 0.019 mm was produced. A five-layer film sample was also produced, with each layer loaded with ropivacaine, having a thickness of 0.046 mm. Although the thickness of the five-layer film sample was only 2.42 times that of the single layer, the loading of therapeutic agent in the five-layer sample was 5.27 times that of the single layer sample. Thus, the multi-layer approach allowed for a substantially higher density of therapeutic agent.

[0219] As discussed above, thermal compression bonding of multiple layers allowed for an effective reduction in membrane thickness and increased density of therapeutic agent loading. In the example illustrated in Table 2, the multi-layer structure allowed for a 124% increase in therapeutic agent density. In other embodiments, the increase in therapeutic agent density allowed by the multi-layer structure of the treatment region can be about 50%, 75%, 100%, 125%, 150%, or 200%.

[0220] D. Polymer The depot 100 of the present technology is composed of a bioabsorbable polymer. In some embodiments, both the treatment region 200 and the control region 300 comprise a polymer (or a mix of polymers). In some embodiments, the control region 300 includes a polymer and the treatment region 200 does not include a polymer, and the control region 300 does not include a polymer. At least as used in this section, "polymer" refers to a polymer that may be used in the treatment region 200 and / or the control region 300.

[0221] The bioabsorbable polymers used in the present technology preferably have a predetermined degradation rate. The terms "bioresorbable" or "bioabsorbable" mean that the polymer is absorbed into the patient's body, for example, by cells or tissues. These polymers are "biodegradable" in that all or part of the polymer film will degrade over time by the action of enzymes, hydrolysis, and / or other similar mechanisms within the patient's body. In various embodiments, the bioabsorbable polymer film can be broken down or degraded into non-toxic components within the body, with the therapeutic agent released. The polymers used as the base component of the depot of the present technology can be broken down or degraded after the therapeutic agent has been completely released. The bioabsorbable polymers are also "bioerodible" in that they will erode or degrade over time, at least in part, due to contact with substances found in surrounding tissues, fluids, or by cellular activity.

[0222] Criteria for the selection of a suitable bioabsorbable polymer for use in the present technology include: 1) in These include: 1) in vivo safety and biocompatibility; 2) therapeutic agent loading capacity; 3) therapeutic agent release capacity; 4) degradation profile; 5) potential for inflammatory response; and 6) mechanical properties, which may be related to form factors and manufacturability. Therefore, the choice of bioabsorbable polymer may depend on the clinical objectives of a particular treatment and may involve tradeoffs between competing objectives. For example, PGA (polyglycolide) is known to have a relatively fast degradation rate but is also very brittle. Conversely, polycaprolactone (PCL) has a relatively slow degradation rate and is quite elastic. Copolymerization offers some versatility when it is clinically desirable to have a blend of properties from multiple polymers. For biomedical applications, particularly as bioabsorbable depots for drug release, polymers or copolymers using at least one of poly(L-lactic acid) (PLA), PCL, and PGA are generally preferred. Physical properties for some of these polymers are presented in Table 3 below. [Table 3]

[0223] In many embodiments, the polymer may comprise polyglycolide (PGA). PGA is one of the simplest linear aliphatic polyesters. It is prepared by the ring-opening polymerization of the cyclic lactone, glycolide. It is highly crystalline, with a crystallinity of 45-55% and therefore not soluble in most organic solvents. It has a high melting point (220 ~225°C) and a glass transition temperature of 35-40°C (Vroman, L., et al., Materials, 2009, 2:307-44). Rapid in vivo degradation of PGA results in loss of mechanical strength and substantial local production of glycolic acid, which, in significant amounts, can induce an inflammatory response.

[0224] In many embodiments, the polymer may include polylactide (PLA). PLA is a hydrophobic polymer due to the presence of methyl (-CH3) side groups pendant from the polymer backbone. It is more resistant to hydrolysis than PGA due to the steric shielding effect of the methyl side groups. The typical glass transition temperature for a representative commercial PLA is 63.8°C, the elongation at break is 30.7%, and the tensile strength is 32.22 MPa (Vroman, 2009). Tuning of the physical properties and biodegradability of PLA can be achieved by using hydroxy acid comonomer components or by racemization of the D- and L-isomers (Vroman, 2009). PLA exists in four forms: poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), meso-poly(lactic acid), and poly(D,L-lactic acid) (PDLLA), a racemic mixture of PLLA and PDLA. PLLA and PDLLA have been the most studied for biomedical applications.

[0225] Copolymerization of PLA (both L- and D,L-lactide forms) and PGA results in poly(lactide-co-glycolide) (PLGA), one of the most commonly used degradable polymers for biomedical applications. In many embodiments, the polymer may comprise PLGA. Because PLA and PGA have significantly different properties, careful selection of PLGA composition can allow for optimization of performance in the intended clinical application. Modulation of physical properties is even more significant for PLGA copolymers. When the composition is comprised of 25-75% lactide, PLGA forms an amorphous polymer that is highly hydrolytically unstable compared to the more stable homopolymer. This is demonstrated by the degradation times of 50:50 PLGA, 75:25 PLGA, and 85:15 PLGA, which are 1-2 months, 4-5 months, and 5-6 months, respectively. In some embodiments, the polymer may be ester-terminated poly(DL-lactide-co-glycolide) in a 50:50 molar ratio (DURECT Corporation).

[0226] In some embodiments, the polymer may include polycaprolactone (PCL). PCL is a semicrystalline polyester with high organic solvent solubility, a melting temperature of 55-60°C, and a glass transition temperature of -54°C (Vroman, 2009). PCL has a low in vivo degradation rate and high drug permeability, making it more suitable as a depot for longer-term drug delivery. For example, Capronor® is a commercial contraceptive PCL product capable of delivering levonorgestrel in vivo for over a year. PCL is often blended or copolymerized with other polymers, such as PLLA, PDLLA, or PLGA. Blending or copolymerization with polyethers accelerates overall polymer erosion. Furthermore, PCL has a relatively low tensile strength (approximately 23 MPa) but a very high elongation at break (4700%), making it a very elastic biomaterial. PCL is also highly processable, allowing for many potential shape factors and production efficiencies.

[0227] Suitable bioabsorbable polymers and copolymers for use in the present technology include, but are not limited to, poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone (DL-PLCL), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazenes), polyphosphates), poly(amino acids), polydepsipeptides, poly(butylene glycol), ... succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(glycolide-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxycarbonylmethyl glutamate) , poly(glycerol sebacate), tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen), or PEG derivatives and copolymers thereof.Other suitable polymers or copolymers include polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), and the like. ), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or a salt thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, or a combination thereof.

[0228] In various embodiments, the molecular weight of the polymer can vary over a wide range: the average molecular weight of the polymer can be from about 1,000 to about 10,000,000; or from about 1,000 to about 1,000,000; or from about 5,000 to about 500,000; or from about 10,000 to about 100,000; or from about 20,000 to 50,000.

[0229] As mentioned above, in certain clinical applications using depots for controlled delivery of therapeutic agents, it may be desirable to use copolymers comprising at least two of PGA, PLA, PCL, PDO, and PVA, including, for example, poly(lactide-co-caprolactone) (PLCL) (e.g., having a PLA to PCL ratio of 90:10 to 60:40) or derivatives and copolymers thereof, poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a DL-PLA to PCL ratio of 90:10 to 50:50) or derivatives and copolymers thereof, poly(glycolide-co-caprolactone) (PGCL) (e.g., having a PGA to PCL ratio of 90:10 to 10:90) or derivatives and copolymers thereof, or blends of PCL and PLA (e.g., blends of PCL and PLA having a wt:wt ratio of 1:9 to 9:1). In one preferred embodiment, the bioabsorbable polymer is polycaprolactone (PCL), poly(L-lactic acid) The copolymers include copolymers of poly(DL-lactide-co-glycolide-co-caprolactone) (PLA) and polyglycolide (PGA). In such preferred embodiments, the PGA to PLA to PCL ratio of the copolymer may be 5-60% PGA, 5-40% PLA, and 10-90% PCL. In additional embodiments, the PGA:PLA:PCL ratio may be 40:40:20, 30:30:50, 20:20:60, 15:15:70, 10:10:80, 50:20:30, 50:25:25, 60:20:20, or 60:10:30. In some embodiments, the polymer is ester-terminated poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10 (DURECT Corporation).

[0230] In some embodiments, terpolymers can be beneficial, such as to increase degradation rate and ease of manufacturing.

[0231] To minimize the size of the bioabsorbable depot, it is generally preferable to maximize the loading of the therapeutic agent in the polymer so that the highest possible density of therapeutic agent is achieved. However, polymeric carriers with high densities of therapeutic agent are prone to burst release kinetics, resulting in poor control of time release. As mentioned above, one significant benefit of the depot structures described herein, and particularly the control region feature of the depot, is the ability to control and attenuate the release kinetics of the therapeutic agent, even at therapeutic agent densities that may cause instability in other carriers. In certain embodiments, the therapeutic agent loading capacity comprises a therapeutic agent to bioabsorbable polymer ratio (wt:wt) of about 1:3, 1:2, 1:1, 3:2, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, or 16:1. In some embodiments, it may be desirable to increase the therapeutic effect or efficacy of a therapeutic agent released from the depots described herein while still maintaining the same or similar polymer to therapeutic agent ratio. This can be achieved by using an essentially pure form of the therapeutic agent, as opposed to a salt derivative. Additionally or alternatively, the therapeutic agent can be mixed with clonidine or epinephrine, which are known to increase the therapeutic effect of certain drugs.

[0232] In some embodiments, the bioabsorbable polymers used within the various layers of the depot may appear as layers of electrospun microfibers or nanofibers. Biocompatible electrospun microfibers / nanofibers are known in the art and can be used, for example, to fabricate implantable supports for in vivo organ implant formation (U.S. Patent Publication No. 2014 / 0272225; Johnson; Nanofiber Solutions, LLC), for musculoskeletal and skin tissue engineering (R. Vasita and D.S. Katti, Int. J. Nanomedicine, 2006, 1:1, 15-30), for skin or oral applications (PCT Publication No. 2015 / 189212; Hansen; Dermtreat APS), or for post-operative pain management (U.S. Patent Publication No. 2013 / 0071463; Palasis et al.). Manufacturing techniques and Thus, electrospinning offers the opportunity to control the thickness and composition of nano- or micro-fibers along with control of the porosity of the fiber mesh (Vasita and Katti, 2006). These electrospun scaffolds are three-dimensional and therefore provide an ideal support for the in vivo culture of cells for tissue formation. Typically, these scaffolds have a porosity of 70-90% (U.S. Patent No. 9,737,632; Johnson; Nanofiber Solutions, LLC). Bioabsorbable polymers and copolymers suitable for the fabrication of electrospun microfibers include, but are not limited to, natural materials such as collagen, gelatin, elastin, chitosan, silk, fibrin, and hyaluronic acid, as well as synthetic materials such as poly(ε-caprolactone) (PCL), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(l-lactide-co-ε-caprolactone), and poly(lactic acid) (PLA).

[0233] have been made from bioabsorbable polymers or copolymers and used in conjunction with therapeutic agents; Electrospun microfibers are known in the art. For example, Johnson et al. disclosed the treatment of joint inflammation and other conditions by injecting electrospun fiber fragments of a biocompatible polymer together with a carrier medium containing chitosan (U.S. Published Application No. 2016 / 0325015; Nanofiber Solutions, LLC). Weldon et al. reported the use of electrospun bupivacaine-eluting sutures made from poly(lactic-co-glycolic acid) in a rat skin wound model, which provided local anesthesia at the incision site (J. Control Release, 2012, 161:3, 903-909). Similarly, Palasis et al. disclosed the treatment of postoperative pain by implanting electrospun fibers loaded with opioids, anesthetics, or non-opioid analgesics at the surgical site (U.S. Patent Publication No. 2013 / 0071463; Palasis et al.). Electrospun microfibers suitable for use in this technology can be obtained by the methods disclosed in the above-cited references, which are incorporated herein in their entireties.

[0234] When implanted in a patient's joint (e.g., knee), the bioabsorbable depot described above may be placed intra-articularly to bridge the joint throughout the duration of release. It is desirable for the depot to have a threshold level of mechanical integrity and stability until most of the analgesic has been released, so that premature release of the analgesic is avoided. As noted above, maximizing the therapeutic agent load in the bioabsorbable depot may be desirable, but such maximization may typically come at the expense of the mechanical integrity and stability of the depot. Given the high dosage of anesthetic required to provide analgesia in the limited space of the knee throughout both acute and subacute postoperative pain periods, it is desirable for the depot described herein to have a high density load of anesthetic while still maintaining sufficient mechanical integrity and stability in the knee. The layered structure, particularly the presence of a control region, provides some protection against premature release of the anesthetic. Furthermore, the use of thermal compression in the manufacturing process allows for substantial loading of the anesthetic into the treatment area while creating a thermal bond between the treatment and control areas, thereby preventing delamination and resulting uncontrolled drug release when the depot is subjected to mechanical stress in the knee.

[0235] In general, it is desirable for the implanted polymer to completely degrade after complete delivery of the therapeutic agent. Complete degradation is preferred because, unless the implanted polymer provides some structural function or support, the clinician would have to deal with leaving a foreign body without a functional purpose, which could become a source of inflammation or infection, or would have to perform another surgery just to remove the remaining polymer. As an alternative to complete degradation, it would be desirable for any remaining polymer to be completely encapsulated by the body.

[0236] Degradation of implanted polymers essentially consists of two sequential processes: diffusion of aqueous solutions (e.g., physiological fluids), followed by hydrolysis. Degradation typically takes one of two forms: (1) surface erosion; and (2) bulk degradation. Surface erosion of a polymer occurs when the polymer erodes inward from the surface, where hydrolytic erosion is faster than water can penetrate into the polymer. Conversely, bulk degradation occurs throughout the polymer, degrading the interior of the material faster than water can penetrate and erode the surface. Polymers such as PLA, PGA, PLGA, and PCL are all resorbed by the body via bulk degradation.

[0237] The time required for complete degradation can vary widely based on the material selected and the clinical performance requirements of the depot. For example, when treating and managing post-operative pain, it may be desirable for the polymer depot to release a therapeutic agent (i.e., an analgesic) over anywhere from 5 to 30 days. When treating or preventing infection in a prosthetic joint (e.g., knee or hip implant), it may be desirable for the polymer depot to release an anti-infective agent over anywhere from 2 to 4 months. Alternatively, when the entire amount of therapeutic agent loaded within the polymer has been released. Even if the polymer is highly soluble in water, it may be desirable for the polymer to degrade over a period longer than the duration of drug release. For example, rapid degradation can often make the polymer brittle and prone to breakage, thereby compromising mechanical performance or eliciting an inflammatory response from the body. In particular, in certain clinical applications, it may be desirable to have embodiments in which polymer degradation begins only after substantially all of the therapeutic agent has been released.

[0238] In certain embodiments of the present technology, it may be desirable to completely absorb the polymer into the body after substantially all of the therapeutic agent loaded therein has been released. In certain embodiments, this degradation may be as short as one month. Alternatively, in other embodiments, complete degradation may take as long as two, three, four, six, nine, or twelve months. In some embodiments, the bioabsorbable polymer substantially degrades in vivo within about one month, about two months, about three months, about four months, about five months, or about six months. In some embodiments, it may be desirable to achieve complete degradation within six months, so that the mechanical properties of the implanted polymer are preserved over the first two months after implantation.

[0239] Core Acidification Traditional bioresorbable implants often result in tissue inflammation due to a phenomenon known as "core acidification." For example, as shown schematically in Figure 17, polymer implants with thicknesses greater than 1 mm degrade by bulk erosion (i.e., degradation occurs evenly throughout the material; both the surface and interior of the material degrade substantially simultaneously). As the polymer degrades, lactate accumulates in the interior region of the implant. Eventually, the high pH in the interior region of the implant causes lactate to become lactic acid. The accumulated lactic acid is constantly released into the body, thereby triggering an inflammatory response. Figure 18, for example, shows a scanning electron microscope ("SEM") image of a prior art polymer tablet 20 days after degradation. Inflammation in and around artificial joints can be of particular concern due to the risk of inflammation-induced osteolysis, which can cause loosening of newly implanted joints. Furthermore, core acidification lowers extracellular pH, which in turn lowers the amount of free base bupivacaine. Only free base bupivacaine can cross the lipid bilayer that forms the cell membrane and reach neurons. When bupivacaine enters neurons, the percentage of bupivacaine HCl increases. This is the bupivacaine HCl form that is active by blocking sodium from entering neurons, thus inducing analgesia. Thus, any reduction in extracellular pH (e.g., through core acidification) slows the movement of analgesics into neurons, thereby reducing or eliminating the therapeutic effect of the analgesic.

[0240] The extent of core acidity is determined in large part by the geometry and dimensions of the polymer implant (e.g., Grizzi et al., Hydrolytic degradation of devices based on poly(dl-lactic 16 No. 4, pp. 305-11;Fukuzaki et al., in vivo characteristics of high molecular weight copoly(l-lactide / glycolide) with S-type degradation pattern for application in drug delivery systems, Biomaterials 1991, Vol. 12 May, pp. 433-37;Li et al., Structure-property relationships in the case of degradation of massive alipathic poly-(α-hydroxy acids) in aqueous media, JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE I (1990), pp. 123-130). For example, degradation of larger monolithic devices (on the mm-size scale and larger) proceeds much more rapidly in their interior than at their surface, resulting in a slowly degrading outer layer of polymer that traps more advanced internal degradation products from autocatalysis in the interior zone (a so-called "S-shaped" nonlinear kinetic degradation profile). In contrast to thicker films, thin films less than 1 mm thick will typically degrade via surface erosion, and lactate resulting from degradation will not accumulate in the interior of the film. Thin films are known to degrade uniformly due to their high surface area to volume ratio, without core oxidation (see Grizzi et al.).

[0241] As shown schematically in Figure 19A, the depot of the present technology can lose 50%, 60%, 70%, or 80% of its individual mass (anesthetic and release agent) over the course of releasing the anesthetic (e.g., 5, 7, 10, 14, 20, 30, etc. days), resulting in a highly porous, mesh-like system that behaves like a thin film (at least for degradation purposes) due to its high surface area-to-volume ratio. Body fluids penetrate the highly porous polymer carrier and degrade the remaining polymer via surface erosion, thereby avoiding core acidification and the resulting inflammatory response. Without being bound by theory, it is believed that the drug core matrix in the treatment region becomes highly porous as degradation continues. For example, Figures 19B and 19C are scanning electron microscope ("SEM") images showing the treatment region before and after elution, respectively. However, even after releasing the therapeutic agent, the distinct porous structure remains intact, allowing water and acid to effectively diffuse through it. Thus, depots 100 of the present technology having thicknesses greater than about 1 mm degrade like thin films and unexpectedly do not exhibit core acidification.

[0242] E. Releasing Agent In many implantable drug-eluting technologies, depots provide an initial, uncontrolled burst release of drug followed by a residual release. While these drug release kinetics may be desirable for certain clinical applications, they may be unavoidable even when undesirable. Hydrophilic drugs loaded onto polymeric carriers typically provide a burst release upon exposure to physiological fluids. This kinetics can present challenges, particularly when it is desirable to load large drug volumes for controlled, sustained in vivo administration. For example, implanting a dosage for several days or weeks may be desirable to achieve sustained, durable in vivo pharmacological treatment, but it is essential that the therapeutic agent be released as specified; otherwise, release of the entire payload could result in severe patient complications.

[0243] To achieve finer control of the release of the therapeutic agent upon exposure to fluid, the depot 100 of the present technology may include a release agent. ...

Claims

1. A depot for the treatment of post-operative pain associated with a surgical procedure, said depot comprising: a treatment area comprising poly(lactide-co-glycolide) (PLGA) and an analgesic agent, said treatment area having a first surface, a second surface opposite said first surface, and a sidewall between said first surface and second surface; a first control region overlying the first surface of the treatment area, the first control region comprising PLGA, the first control region having a thickness less than or equal to 1 / 50 of the thickness of the treatment area; a second control region overlying the second surface of the treatment area, the second control region comprising PLGA, the second control region having a thickness less than or equal to 1 / 50 of the thickness of the treatment area; at least one aperture extending from the first control region, through the treatment region, and to the second control region; Including, wherein the depot is configured to be implanted at a treatment site in vivo and to release the analgesic drug over a release duration of 14 days or more during the period during which the depot is implanted at the treatment site; and wherein the depot has a thickness of at least 0.5 mm; depot.

2. 2. The depot of claim 1, wherein the analgesic comprises bupivacaine, lidocaine, ropivacaine, or a pharma- ceutically acceptable salt thereof.

3. A depot as described in claim 1 or 2, wherein the analgesic drug in the treatment area constitutes at least 50% of the total weight of the depot.

4. A depot as described in claim 1 or 2, wherein the treatment area contains at least 500 mg of the analgesic drug.

5. 3. The depot according to claim 1 or 2, wherein said release duration is 21 days or more.

6. 3. The depot of claim 1 or 2, wherein the release duration comprises a first period and a second period following the first period, and the depot is configured to release the analgesic drug at a first rate during the first period and at a second rate during the second period, the second rate being slower than the first rate.

7. The depot described in claim 6, wherein the first period corresponds to an acute pain period following the surgical procedure, and the second period corresponds to a subacute pain period following the surgical procedure.

8. 3. The depot of claim 1 or 2, wherein the depot is configured to release up to 50% of the analgesic drug during the first 8 days of the release period.

9. 3. The depot of claim 1 or 2, wherein the thickness of the depot is at least 0.8 mm.

10. A depot as described in claim 1 or 2, wherein the thickness of the depot is within the range of 1 mm to 3 mm.

11. A depot as described in claim 1 or 2, wherein the side walls of the treatment area are exposed.

12. The depot of claim 10, wherein the exposed surface area of ​​the sidewall is less than the combined exposed surface area of ​​the first control region and the second control region.

13. The depot of claim 1 or 2, wherein the first control region and the second control region do not contain an analgesic, at least prior to implantation of the depot at the treatment site.

14. A depot as described in claim 1 or 2, wherein the at least one opening is pre-formed in the depot prior to implantation of the depot at the treatment site.

15. A depot as described in claim 1 or 2, wherein at least one of the openings is cylindrical.

16. A depot as described in claim 1 or 2, wherein at least one opening is configured to release the analgesic drug directly from the treatment area to the treatment site.

17. A depot as described in claim 1 or 2, wherein the depot has a triangular shape.

18. The depot of claim 1 or 2, wherein the treatment area further comprises a surfactant.

19. The depot described in claim 1 or 2, wherein the surgical procedure includes knee surgery.

20. The depot of claim 1 or 2, wherein the surgical procedure comprises hip surgery, shoulder surgery, hernia repair surgery, bunionectomy, breast surgery, abdominal surgery, spinal surgery, or gynecological surgery.

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