Implantable polymer depot for controlled release of therapeutic agents

Abstract

To provide an implantable polymer depot for controlled release of therapeutic agents. [Solution] This technology relates to the assembly of a depot for controlled sustained release of a therapeutic agent. The assembly may include a depot having a therapeutic region containing the therapeutic agent, and a control region containing a bioabsorbable polymer and a release agent mixed with the polymer. The release agent may be configured to form a diffusion opening in the control region when the depot is placed in vivo. The depot may be implanted in vivo at the treatment site and may be configured to release the therapeutic agent to the treatment site for three days or more while implanted.

Description

Technical Field

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

[0002] This application incorporates by reference in their entireties the following applications: U.S. Patent Application No. �2 / 569,349, filed on October 6, 2017, U.S. Patent Application No. 62 / 614,884, filed on January 8, 2018, and U.S. Patent Application No. 62 / 640,571, filed on March 8, 2018.

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

Background Art

[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 local delivery of the selected drug. This local delivery can deliver a significant percentage of the drug to the intended target and avoid undesirable systemic side effects. However, these systems are often plagued by a lack of a true controlled - release mechanism in that they typically result in a burst release of the drug upon contact with the surrounding physiological fluids, followed by a residual release of the drug.

[0005] To improve drug release on certain polymer 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 result in the immediate release of hydrophobic drugs into a hydrophilic environment (in vivo physiological fluid), with a significant portion of the entire drug payload being released immediately or aggressively, rather than in a variable or sustained controlled release.

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

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

[0008] This technology relates to implants, as well as related systems and methods, for the controlled release of therapeutic agents to treat medical conditions. In particular, this technology relates to implants, as well as related systems and methods, for the localized, sustained release of therapeutic agents at surgical or intervention sites.

[0009] This technology is illustrated by various embodiments described below, including, for example, references to Figures 1 to 65. For convenience, various examples of embodiments of this technology are described in numbered bullet points (1, 2, 3, etc.). These are provided as examples and do not limit the scope of this technology. 1. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, A depot is a device implanted in vivo at the treatment site and configured to release analgesics at the treatment site for at least seven days while it is implanted. 2. A depot according to Clause 1, wherein an analgesic in the therapeutic area constitutes at least 50% of the total weight of the depot. 3. A depot according to Clause 1 or Clause 2, configured to release analgesic at the treatment site for 14 days or more. 4. A depot under Clause 3, in which approximately 20% to 50% of the analgesic is released during the first approximately 3 to 5 days of the 14-day period, and at least 80% of the remaining analgesic is released during the last 11 days of the 14-day period. 5. A depot according to clause 3, in which approximately 20% to 40% of the analgesic is released during the first three days of the 14-day period, and at least 80% of the remaining analgesic is released during the last 11 days of the 14-day period. 6. Any one of the depots according to clauses 3 through 5, in which at least 90% of the remaining analgesic is released during the last 11 days of the 14-day period. 7. One depot under any of the provisions 3 to 6, in which 15% or less of the analgesic dose is released during the first two days of the 14-day period. 8. One depot under any of the provisions 3 to 7, in which 20% or less of the analgesic dose is released during the first two days of the 14-day period. 9. Any one of the depots described in clauses 3 through 8, in which 25% or less of the analgesic dose is released during the first three days of the 14-day period. 10. One depot under any of clauses 3 through 9, in which 30% or less of the analgesic dose is released during the first three days of the 14-day period. 11. Any one of the preceding depots, configured to release analgesic at a first rate for the first period and at a second rate for the second period. 12. A depot under clause 11 where the first speed is greater than the second speed. 13. A depot under Clause 11 where the first period is longer than the second period. 14. A depot under Clause 11 where the first period is shorter than the second period. 15. Any one of the preceding provisions' depots configured to release at least 90% of the analgesic in the therapeutic area within 14 days. 16. Any one of the preceding depots, configured to release approximately 100 mg to 500 mg of analgesic to the treatment site per day. 17. Any one of the preceding depots, configured to release approximately 100 mg to 400 mg of analgesic to the treatment site per day. 18. Any one of the preceding depots, configured to release approximately 100 mg to 300 mg of analgesic to the treatment site per day. 19. Any one of the preceding depots configured to release no more than 300 mg of analgesic per day within the first three days, and no more than 200 mg per day for the remaining days. 20. Any one of the preceding depots configured to release no more than 150 mg of analgesic per day for the first three days and no more than 100 mg per day for the remaining days. 21. Any one of the preceding provisions, in which analgesic of 400 mg or less is released by any one day of the 14th. 22. One of the preceding depots containing analgesics of 300 mg or less, released by any one of the 14 days. 23. Any one of the preceding provisions' depots, in which analgesic of 250 mg or less is released by any one day of the 14th. 24. Any one of the preceding provisions' depots, in which analgesic of 200 mg or less is released by any one of the 14 days. 25. Any one of the preceding provisions' depots, in which analgesic of 150 mg or less is released by any one of the 14 days. 26. One of the preceding depots containing 100 mg or less of analgesic, released by any one of the 14 days. 27. Any one of the preceding provisions, depot configured to release an analgesic in vivo at the treatment site for a period of 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. Any one of the preceding depots, wherein the concentration of the analgesic in the plasma of a mammalian patient on day 10 is 70% or greater than the concentration of the analgesic in the plasma of the patient on day 5. 29. Any one of the preceding clauses, the depot having a treatment area including a covered portion and an exposed portion, wherein when the depot is first placed at the treatment site in vivo, the control region is located between the covered portion of the treatment area and the physiological fluid of the treatment site, and the covered portion is covered by the control region so that the exposed portion of the treatment area is exposed to the physiological fluid. 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 first 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%. The depot of any one of the preceding clauses. 31. The depot of clause 30, where the exposed surface area of the control region is smaller than the exposed surface area of the treatment region. 32. The depot of clause 30, where the exposed surface area of the control region is larger than the exposed surface area of the treatment region. 33. The depot of any one of the preceding clauses, where the control region is the first control region and the depot includes a second control region. 34. The depot of clause 33, where the first control region is disposed on the first surface of the treatment region and the second control region is disposed on the second surface of the treatment region on the side opposite to the first surface. 35. The depot of any one of the preceding clauses, where the depot includes a plurality of control regions and a plurality of treatment regions, and each of the treatment regions is separated from one of the adjacent control regions by one or more control regions. 36. The depot of clause 35, where each of the treatment regions and each of the control regions is a micro-thin layer. 37. The depot of clause 35 or clause 36, including from about 2 to about 100 treatment regions. 38. The depot of clause 35 or clause 36, including from about 2 to about 50 treatment regions. 39. The depot of clause 35 or clause 36, including from about 2 to about 10 treatment regions. 40. The depot of any one of clauses 1 to 34, where when the depot is placed at the treatment site in vivo, the treatment region is surrounded by the control region such that the control region is between the treatment region and the physiological fluid of the treatment site. 41. The depot of any one of the preceding clauses, where the control region includes a first control layer and a second control layer. 42. The depot of clause 41, where the second control layer is adjacent to the treatment region and the first control layer encapsulates / surrounds the treatment region and the second control layer. 43. A depot according to clause 41 or clause 42, in which the first and second control layers together surround the treatment area. 44. Any one of the depots described in clauses 41 to 43, wherein the first control layer is located on the first surface of the treatment area, and the second control layer is located on the second surface of the treatment area opposite to the first surface. 45. Any one of the depots described in clauses 41 to 44, wherein the first control layer includes a first number of sub-layers, and the second control layer includes a second number of sub-layers. 46. ​​Any one of the depots from clauses 41 to 45, wherein the first control layer contains a first amount of release agent, and the second control layer contains a second amount of release agent different from the first amount. 47. Any one of the depots from clauses 41 to 46, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first concentration of the release agent, and the second control layer contains a second concentration of the release agent greater than the first concentration. 48. Any one of the depots from clauses 41 to 46, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first concentration of the release agent, and the second control layer contains a second concentration of the release agent that is lower than the first concentration. 49. A second control layer is placed between the first control layer and the therapeutic area. The first control layer contains up to 5% by weight of the release agent, up to 10% by weight of the release agent, up to 15% by weight of the release agent, up to 20% by weight of the release agent, up to 25% by weight of the release agent, up to 30% by weight of the release agent, up to 35% by weight of the release agent, up to 40% by weight of the release agent, up to 45% by weight of the release agent, or up to 50% by weight of the release agent. The second control layer contains up to 5% by weight of the release agent, up to 10% by weight of the release agent, up to 15% by weight of the release agent, up to 20% by weight of the release agent, up to 25% by weight of the release agent, up to 30% by weight of the release agent, up to 35% by weight of the release agent, up to 40% by weight of the release agent, up to 45% by weight of the release agent, or up to 50% by weight of the release agent. Any one of the depots under clauses 41 to 48. 50. Any one of the depots from clauses 41 to 49, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first amount of the release agent, and the second control layer contains a second amount of the release agent, the second amount being at least twice, at least three times, at least four times, or at least five times the first amount. 51. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 10 of the thickness of the treatment region. 52. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 12.5 of the thickness of the treatment region. 53. 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. Any one of the preceding clauses in which the thickness of the control region is less than or equal to 1 / 17.5 of the thickness of the treatment region. 55. 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. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 22.5 of the thickness of the treatment region. 57. 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. 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. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 40 of the thickness of the treatment region. 60. 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. Any one of the preceding clauses in which the thickness of the control region is less than or equal to 1 / 75 of the thickness of the treatment region. 62. Any one of the preceding provisions in which the thickness of the control area is less than or equal to 1 / 100 of the thickness of the treatment area. 63. A depot of any one of the preceding clauses, which is a flexible solid that is structurally capable of being handled by a clinician during a normal surgical procedure without being broken into numerous small pieces and / or losing its overall shape. 64. Any one of the preceding provisions, a depot placed inside the patient's knee and configured to release analgesics in vivo for up to 7 days without being broken down into numerous small pieces. 65. Any one of the preceding depots having width and thickness, where the ratio of width to thickness is 21 or greater. 66. A depot of clause 65 with a ratio of 30 or greater. 67. A depot of clause 65 with a ratio of 40 or greater. 68. Any one of the preceding depots having surface area and volume, wherein the ratio of surface area to volume is at least 1. 69. A depot of any one of the preceding clauses, wherein the diffusion opening includes at least one or more pores and / or one or more channels. 70. A depot of any one of the preceding clauses, in which two or more microthin layers of bioabsorbable polymer are bonded together via thermal compression to form a therapeutic area. 71. A depot in any one of the preceding clauses, in which the control region and the therapeutic region are coupled via thermal compression. 72. A depot in any one of the preceding clauses, in which the control region and the therapeutic region are thermally bonded. 73. Any one of the preceding depots, upon dissolution of the releasing agent after in vivo placement at the treatment site, transitions the control and therapeutic regions from a state of lower porosity to a state of higher porosity, thereby facilitating the release of the analgesic from the depot. 74. The control area does not contain analgesics, and no depot is used in any of the preceding provisions prior to the implantation of the depot at least at the treatment site. 75. Any one of the depots in clauses 1 to 73, wherein the control area contains an analgesic different from the analgesic in the therapeutic area. 76. Any one of the preceding depots in the treatment area that does not contain any releasing agent before implantation of the depot at the treatment site. 77. A depot of any one of the preceding clauses, wherein the releasing agent is the first releasing agent, and the therapeutic area includes a second releasing agent mixed with an analgesic. 78. The releasing agent is the first releasing agent, the polymer is the first polymer, and the therapeutic area is A depot comprising any one of the provisions of 1 to 77, comprising a second release agent and a second polymer mixed with an analgesic. 79. Any one of the depots specified in clauses 1 through 77, wherein the first release agent is the same as the second release agent. 80. Any one of the depots specified in clauses 1 to 77, wherein the first release agent is different from the second release agent. 81. Any one of the depots described in clauses 1 to 79, wherein the concentration of the first releasing agent in the control region is greater than the concentration of the second releasing agent in the therapeutic region. 82. Any one of the depots described in clauses 1 to 81, wherein the concentration of the first releasing agent in the control region is less than the concentration of the second releasing agent in the therapeutic region. 83. Any one of the depots from clauses 1 to 81, wherein the concentration of the first releasing agent in the control area is the same as the concentration of the second releasing agent in the therapeutic area. 84. Any one of the depots described in clauses 1 to 81, wherein the concentration of the first releasing agent in the control region is different from the concentration of the second releasing agent in the therapeutic region. 85. Any one of the preceding depots in which the treatment area includes multiple microlayers. 86. Any one of the preceding clauses' depots, wherein the mass of the analgesic constitutes at least 50% of the depot's mass. 87. Any one of the preceding clauses, wherein the ratio of the mass of the analgesic in the depot to the mass of the depot polymer is at least 3:1. 88. Any one of the preceding clauses, wherein the ratio of the mass of the analgesic in the depot to the mass of the depot polymer is at least 4:1. 89. 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 5:1. 90. 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. Any one of the preceding clauses, wherein the ratio of the mass of the analgesic in the depot to the mass of the depot polymer is at least 7:1. 92. Any one of the preceding clauses, wherein the ratio of the mass of the analgesic in the depot to the mass of the depot polymer is at least 8:1. 93. 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 10:1. 94. 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 16:1. 95. A depot of any one of the preceding clauses, wherein the therapeutic area contains 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 containing 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. Any one of the preceding provisions' depots, in which the analgesic includes at least one of the following: a simple analgesic, a local anesthetic, an NSAID, and an opioid. 98. Any one of the preceding depots comprising an analgesic, local anesthetic selected from at least one of bupivacaine, ropivacaine, mepivacaine, and lidocaine. 99. Further comprising an antibiotic, antifungal, and / or antimicrobial agent, wherein the antibiotic, antifungal, and / or antimicrobial agent is amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline(or more), minocycline, tigecycline, doxycycline, rifampine, trimethoprim Losan, chlorhexidine, penicillin(s), aminoglycosides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporins(s), carbapenems, imipenems, ertapenems, antimicrobial peptides, cecropine-melittin, magainin, dermaceptin, cathelicidin, alpha-defensins, and alpha-protegrin, ketoconazole, chlortrimazole, miconazole, econazole, intraconazole, fluconazole A depot of any one of the preceding clauses, selected from at least one of the following: bifoconazole, terconazole, butaconazole, thioconazole, oxyconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naphthifine, griseofulvin, haloprogin, butenafine, tolnaftate, nistatin, cyclohexamide, cyclopirox, flucytosine, terbinafine, and amphotericin B. 100. Any one of the preceding clauses, further comprising an anti-inflammatory agent selected from at least one of the following: steroids, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, sarsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofename, mefenamic acid, and COX-2 inhibitors. 101. Any one of the preceding depots in which the analgesic is dexamethasone. 102. Any one of the preceding clauses' depots in which the analgesic is tetrodotoxin. 103. Any one of the preceding clauses' depots where the analgesic is saxitoxin. 104. Low levels of epinephrine, clonidine, and transexamic acid Any one of the preceding clauses, further including one type. 105. Any one of the preceding clauses, wherein the release agent is a nonionic surfactant. 106. A depot of any one of the preceding clauses in which the release agent is hydrophilic. 107. Any one of the preceding clauses' depots whose release agent is polysorbate. 108. Any one of the preceding provisions' depots, in which the release agent is Tween® 20. 109. One depot from any of clauses 1 through 107, where the release agent is Tween 80. 110. Depot of any one of the preceding clauses, in which the release agent is nonpolymeric. 111. Depot of any one of the preceding clauses in which the release agent is not a plasticizer. 112. Any one of the depots specified in the preceding clause, wherein the polymer is configured to degrade only after substantially all of the analgesic has been released from the depot. 113. Any one of the preceding provisions where the polymer is a copolymer. 114. The polymer is a terpolymer, according to any one of the depots in clauses 1 to 112. 115. The polymer is 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), Polydeptipeptide, 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-butyloxycarbonylmethylglutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethylglycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymer of polyhydroxybutyrate, copolymer of maleic anhydride, copolymer 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 analogs, e.g., 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 A depot comprising at least one of the following: polypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or its salts, 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), as specified in any one of the preceding clauses. 116. A depot of any one of the preceding clauses, wherein the polymer is one of the following: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 117. A 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. One depot from any of clauses 1 to 112, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a 50:50 molar ratio. 119. Any one of the preceding clauses depot, wherein the polymer is ester-terminated. 120. Any one of the preceding clauses depot, 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. A depot of any one of the preceding clauses, wherein the polymer is a first polymer and the therapeutic area contains a second polymer mixed with an analgesic. 122. Depot of clause 121, wherein the first polymer and the second polymer are the same. 123. Depot of Clause 121, wherein the first polymer and the second polymer are different. 124. The first polymer and / or the second polymer is 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), polydeptipeptide, 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), polyglyc 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(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxymethyl phosphate) Noxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymer of polyhydroxybutyrate, copolymer of maleic anhydride, copolymer 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 analogs, e.g., 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) hydroxypropylcellulose A depot comprising at least one of the following: 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, and poly(DL-lactide-co-glycolide-co-caprolactone), any one of the depots of clauses 121 to 123. 125. Any one of the depots in 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. Any one of the depots from clauses 121 to 123, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) having a molar ratio of 60:30:10. 127. 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 molar ratio of 50:50. 128. Any one of the depots from clauses 121 to 127, wherein the first polymer and / or the second polymer are terminated with an ester. 129. A terpolymer in which the first polymer and / or second polymer comprises 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. The depot is one of the depots specified in clauses 121 to 123. 130. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:2 or less. 131. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:3 or less. 132. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:4 or less. 133. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:5 or less. 134. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:6 or less. 135. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:7 or less. 136. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:8 or less. 137. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:9 or less. 138. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:10 or less. 139. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is 1:11 or less. 140. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer in the control region is at least 1:1. 141. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 2:1. 142. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 3:1. 143. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 4:1. 144. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 5:1. 145. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 6:1. 146. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 7:1. 147. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 8:1. 148. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 9:1. 149. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 10:1. 150. Any one of the depots from clauses 1 to 129, wherein the ratio of the release agent to the polymer within the controlled region is at least 15:1. 151. The polymer is the first polymer, and the therapeutic area further contains the second polymer. The depot has a depot polymer mass equal to the sum of the mass of the first polymer and the mass of the second polymer. The ratio of the mass of the analgesic in the depot to the mass of the depot polymer is approximately 1:1. Depot of any one of the preceding clauses. 152. Depot of Clause 151, wherein the first polymer is the same as the second polymer. 153. The depot of Clause 151, wherein the first polymer is different from the second polymer. 154. Any one of the depots from 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 2:1. 155. Any one of the depots from 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 3:1. 156. Any one of the depots from 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. Any one of the depots from clauses 151 to 153, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is approximately 5:1. 158. Any one of the depots from 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 6:1. 159. Any one of the depots from 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 7:1. 160. Any one of the depots from 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. Any one of the depots from 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 10:1. 162. Any one of the depots from 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 16:1. 163. Any one of the preceding clauses, where the analgesic is a local anesthetic and the release of the analgesic to the treatment site over a period of 5 days inhibits the growth of bacteria and fungi. 164. The depot of Clause 163, configured to inhibit bacterial and fungal growth such that the number of bacteria on the depot is one-tenth, one-twentieth, one-thirtieth, one-fortieth, or one-fiftieth of the number of bacteria present on an equivalent depot that does not contain analgesics. 165. Any one of the preceding depots where the release of an analgesic is high enough to create a sensory block, thereby treating postoperative pain, but low enough to avoid a motor block. 166. One of the preceding depots in which the release of an analgesic provides motor-sparing relief from postoperative pain. 167. A depot for sustained controlled release of therapeutic agents, Therapeutic areas including therapeutic agents; A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve and form a diffusion opening in the control region when the depot is placed in contact with a fluid. Includes; When the depot is placed in contact with the fluid, it is configured to release the therapeutic agent into the surrounding fluid for more than 14 days. Depot therapy releases approximately 20% to 50% of the treatment drug during the first 3 to 5 days of the 14-day period, and at least 80% of the remaining treatment drug during the last 11 days of the 14-day period. 168. Depot under Clause 167, in which at least 85% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 169. Depot under Clause 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 Clause 167, in which at least 95% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 171. Any one depot under any of clauses 167 to 170, in which 15% or less of the therapeutic agent is released during the first two days of the 14-day period. 172. Any one depot under any of clauses 167 to 170, in which 20% or less of the therapeutic agent is released during the first two days of the 14-day period. 173. Any one depot under any of clauses 167 to 170, in which 25% or less of the therapeutic agent is released during the first three days of the 14-day period. 174. Any one depot under any of clauses 167 to 170, in which 30% or less of the therapeutic agent is released during the first three days of the 14-day period. 175. Any one of the depots from Clauses 167 to 170, wherein the releasing 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, Placing a depot in an in vivo treatment site having physiological fluids, comprising (a) a control region containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic region containing at least 50% by weight of an analgesic; and The depot releases analgesics to the treatment site for more than 7 days. A method that includes this. 177. The method of Clause 176, further comprising dissolving a release agent at a first rate and decomposing a polymer at a second rate, wherein the first rate is greater than the second rate. 178. The method of Clause 176 or Clause 177, further comprising dissolving a release agent in response to contact between a control area and a physiological fluid at the treatment site. 179. Any one of the methods of the provisions of 176 to 178, further comprising creating a diffusion opening in a control area by dissolving a release agent in response to a physiological fluid at the treatment site. 180. Any one of the methods of Clauses 176 to 179, wherein the releasing agent is a first releasing agent, the therapeutic area comprises a second releasing agent, and the method further comprises creating microchannels in the therapeutic and control areas via the dissolution of the first and / or second releasing agents. 181. Any one of the methods described in clauses 176 to 180, wherein at least some of the microchannels penetrate both the therapeutic and control regions. 182. Any method of the provisions of 176 to 181, wherein the therapeutic region comprises multiple microlayers, and at least some of the microchannels extend through consecutive microlayers. 183. Any method of the provisions of 176 to 159, wherein the control region comprises first multiple microlayers, and the therapeutic region comprises second multiple microlayers, and at least some of the microchannels extend through the first and second multiple microlayers. 184. Any one of the methods of the provisions of 176 to 183, further comprising increasing the porosity of the depot by dissolving the release agent. 185. An analgesic is released one or more times in substantially separate doses after implantation, in any one of the methods of clauses 176 to 184. 186. Any one of the methods of the provisions 176 to 185, wherein an analgesic is released continuously for at least 7 days after implantation. 187. An analgesic is released over a period of 10 days or more, in any one of the manner described in clauses 176 to 186. 188. Analgesics are released over a period of 14 days or longer, in any one of the manner described in clauses 176 to 186. 189. Any one of the methods described in clauses 176 to 188, wherein 20% or less of the amount of analgesic is released on the first day of the 7-day period. 190. Any one of the methods of the provisions of 176 to 189, further comprising securing the depot to the treatment site via an attachment means. 191. The attachment means is connected to the depot before embedding, in any one of the methods of Clauses 176 to 190. 192. Any one of the methods in 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 to the treatment site over a period of seven days or more. 194. Methods for treating postoperative pain associated with orthopedic surgery, by any of the depots in Clauses 1 to 175, 225 to 227, and 273 to 429 and / or the systems in Clauses 211 to 224. 195. A method for treating postoperative pain in patients after orthopedic surgery, Implanting multiple depots at the surgical site, each depot comprising (a) a control region containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic region containing at least 50% by weight of an analgesic; and Discharging analgesics from a depot to the site for more than 7 days. A method that includes this. 196. A method for treating postoperative pain in patients after orthopedic surgery, Implanting a depot in the surgical site, wherein the depot comprises (a) a control region containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic region containing at least 50% by weight of an analgesic; and Discharging analgesics from a depot to the site for more than 7 days. A method that includes this. 197. A method for treating postoperative pain in patients after total knee arthroplasty, Placing a depot on the patient's knee, wherein the depot comprises (a) a control area containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic area containing at least 50% by weight of an analgesic; and Discharging analgesics from a depot into the patient's knee for more than 7 days. A method that includes this. 198. The method of Clause 197, wherein the depot is one of the depots of Clauses 1 to 175, 225 to 227, and 273 to 429. 199. The method of placing a depot, comprising placing at least one depot in at least one of the suprapatellar bursa, lateral groove, medial groove, posterior bursa, quadriceps tendon, skin incision, arthrotomy, adductor canal, saphenous nerve, or geniculate nerve. 200. Any one method of the provisions of 197 to 199, wherein the placement of the depot includes placing at least one depot adjacent to at least one of the saphenous nerve, adductor canal, and femoral nerve. 201. Any one of the methods of clauses 197 to 200, wherein the depot placement includes placing at least one depot near one or more nerves that innervate all or part of the anterior joint capsule of the knee. 202. Any one method of Clauses 197 to 201, which involves placing at least one depot in or near the superior lateral geniculate nerve branch from the vastus lateralis muscle, the superior medial geniculate nerve branch from the vastus medialis muscle, the medial geniculate nerve branch from the vastus intermedius muscle, the inferior lateral geniculate nerve branch from the common peroneal nerve, the inferior medial geniculate nerve branch from the saphenous nerve, and / or the lateral geniculate nerve branch from the common peroneal nerve. 203. Placing a depot involves any one method of the provisions of Clauses 197 to 200, wherein the placement of at least one depot is placed inside the bag. 204. Placing a depot involves any one method of the provisions 197 to 203, including the extra-bag placement of at least one depot. 205. The placement of the depot is any one method of the provisions of 197 to 204, including intracapsular placement without obstructing the knee joint. 206. The method of Clause 205, wherein at least one depot is placed in at least one of the suprapatellar bursa, lateral groove, medial groove, posterior bursa, quadriceps tendon, skin incision, arthrotomy, or adductor canal. 207. A system for managing postoperative pain associated with orthopedic surgery, It includes multiple depots, each of which is one of the depots described in the preceding clause. A system in which multiple depots are implanted in the patient's treatment site and configured to release analgesics to the treatment site. 208. The depot is configured to release an analgesic 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, according to Clause 207. system. 209. The system of Clause 208, wherein the depot is configured to release a total dose of no more than 250 mg of analgesic per day within the first three days, and no more than 150 mg of analgesic per day for the remaining days. 210. Delivery systems; and A depot configured to be implanted in vivo at the treatment site together with a delivery system, Depots including any of the depots in clauses 1 to 175, 225 to 227, and 273 to 429 A system for managing postoperative pain, including [mention specific features / features]. 211. Attachment means; and A depot configured to be fixed to a treatment site via an attachment means so as to be implanted in vivo at the treatment site, comprising any of the depots of Clauses 1 to 175, 225 to 227, and 273 to 429. A system for managing postoperative pain, including [mention specific features / features]. 212. The system of Clause 187, wherein the attachment means is connected to the depot before embedding. 213. A system of Clause 187 or Clause 212 in which the attachment means is at least one of sutures, tines, barbs, hooks, and screws. 214. Pain related to any one of the systems in clauses 211 to 213, as described in the Orthopedic surgery section. 215. Pain related to any one system of clauses 211 to 214, as described in the articles. 216. Pain associated with any one system of knee replacement surgery as described in clauses 211 to 215. 217. Pain associated with any one system of partial knee replacement surgery as described in clauses 211 to 215. 218. Pain associated with any one system of clauses 211 to 215 related to total knee replacement surgery. 219. Pain related to any one of the systems of clauses 211 to 215, relating to corrective surgery for knee joint replacement. 220. Any one of the systems 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. Any one of the systems of clauses 211 to 220, wherein the depot is configured to be placed adjacent to at least one of the posterior supraclavicular region of the knee, the superior region of the patella, or an incision into the knee joint capsule. 222. Any one of the systems of Clauses 211 to 191, wherein the depot is configured to be placed within the knee joint capsule in the medial and / or lateral grooves. 223. A delivery system, and a system for managing postoperative pain, including any of the depots specified in Clauses 1 to 175, 225 to 227, and 273 to 429. 224. A system for managing postoperative pain, comprising multiple depots, each containing one of the depots specified in clauses 1 to 175, 225 to 227, and 273 to 429. 225. A depot for releasing a therapeutic agent to treat or manage a specific condition or disease, Therapeutic areas including therapeutic agents and bioabsorbable polymer carriers; A control region comprising a bioabsorbable polymer layer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve over a first period after in vivo placement to form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site, and while implanted, it remains in place at the treatment site. It is configured to release the therapeutic agent over a second period; The second period is longer than the first period; After the second period, the polymer carrier in the therapeutic region and the polymer layer in the control region are depotted, containing a highly porous polymer structure configured to degrade in vivo without core acidification. 226. The depot of clause 225, wherein the highly porous polymer structure at the end of the second period has a mass that is 50% or less of the mass of the depot before in vivo placement. 227. A depot according to clause 225 or clause 226, wherein a 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, A depot is placed in an in vivo treatment site containing physiological fluids, comprising (a) a control region containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic region containing 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 analgesics from the treatment area to the treatment site through a diffusion opening for more than 5 days. A method that includes this. 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 parathoracic space. 231. The method of Clause 229 or Clause 230, wherein the analgesic released from the depot blocks at least partially the intercostal nerves. 232. The method of Clause 228, wherein 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 blocks at least one of the intercostal nerves, the medial pectoral nerve, or the lateral pectoral nerve. 235. The method of Clause 228, wherein 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 the following: colectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplantation, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid colectomy, hepatectomy, enterostomy, rectal resection, kidney stone removal, or cystectomy. 237. The method of Clause 236, wherein the analgesic released from the depot at least partially blocks a nerve located on or adjacent to the transverse abdominal 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 alveolar surgery, dental implantation, surgical orthodontics, temporomandibular joint (TMJ) surgery, or oral reconstruction. 240. The method of the surgical procedure described in Clause 228, including tumor resection. 241. The method of the surgical procedure described in Clause 228, including liposuction. 242. Any one of the methods of the provisions of 228 to 241, further comprising dissolving the release agent at a first rate and decomposing the polymer at a second rate, wherein the first rate is greater than the second rate. 243. Analgesics are released over a period of 10 days or longer, in any one of the manner described in clauses 228 to 242. 244. Analgesics are released over a period of 14 days or longer, in any one of the manner described in clauses 228 to 243. 245. No more than 20% of the amount of pain medication is released on the first day of the five-day period, clauses 228 to 24. One of the following four methods. 246. Any one of the methods of the provisions of 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 connected to the depot before embedding. 248. Any one of the methods described in 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 to the treatment site over a period of seven days or more. 250. One of the methods described in clauses 228 to 254, in which a therapeutic agent of 400 mg or less is released by any one day of the five-day period. 251. A method for treating postoperative pain following a non-orthopedic surgical procedure, Placing a depot in an in vivo treatment site containing physiological fluids, comprising (a) a control region containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic region containing at least 50% by weight of an analgesic; and The analgesic is released from the depot to the treatment site for more than 5 days. A method that includes this. 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 parathoracic space. 254. The method of clause 252 or 253, wherein the analgesic released from the depot blocks at least partially the intercostal nerves. 255. The method of Clause 251, wherein 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 blocks at least one of the intercostal nerves, the medial pectoral nerve, or the lateral pectoral nerve. 258. The method of Clause 251, wherein 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 the following: colectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplantation, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid colectomy, 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 a nerve located on or adjacent to the transversus abdominis fascia. 261. The method of Clause 251, wherein 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 alveolar surgery, dental implantation, surgical orthodontics, temporomandibular joint (TMJ) surgery, or oral reconstruction. 263. The method of the surgical procedure described in Clause 251, including tumor resection. 264. The method of the surgical procedure described in Clause 251, including liposuction. 265. A method for treating postoperative pain following a surgical procedure involving the patient's chest, Placing a depot in a treatment site with physiological fluids, near the intercostal nerves, comprising (a) a control area containing a bioabsorbable polymer and a release agent mixed with this polymer, and (b) a therapeutic area containing at least 50% by weight of an analgesic; and The depot releases analgesics into the intercostal nerves for more than 5 days. A method that includes this. 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 parathoracic space. 268. A method for treating postoperative pain following a surgical procedure involving a patient's breast, Placing a depot in a treatment site with physiological fluids, near the intercostal and / or pectoralis nerves, comprising (a) a control area containing a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a therapeutic area containing at least 50% by weight of an analgesic; and A method comprising releasing an analgesic from a depot into the intercostal and / or pectoralis nerves for a period of five days or more. 269. The method of Clause 268, wherein 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 following a surgical procedure of the whole body, abdomen, or urinary tract, Placing a depot in the vicinity of the transverse abdominis fascia surface at a treatment site with physiological fluids, comprising (a) a control area containing a bioabsorbable polymer and a release agent mixed with this polymer, and (b) a therapeutic area containing at least 50% by weight of an analgesic; and A method comprising releasing an analgesic from a depot into the intercostal and / or pectoralis nerves for a period of five days or more. 272. The method of Clause 271, wherein the surgical procedure includes at least one of the following: colectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplantation, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid colectomy, hepatectomy, enterostomy, rectal resection, kidney stone removal, or cystectomy. 273. A depot for sustained controlled release of a therapeutic agent, Therapeutic areas including therapeutic agents; A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. The depot is configured such that its flexural strength decreases by up to 75% after immersion in a buffer solution for 7 days. 274. A depot according to Clause 273, configured such that the flexural strength of the depot decreases by up to 70% after immersion in a buffer solution for 7 days. 275. A depot according to Clause 273, configured such that the flexural strength of the depot decreases by up to 65% after immersion in a buffer solution for 7 days. 276. A depot according to Clause 273, configured such that the flexural strength of the depot decreases by up to 60% after immersion in a buffer solution for 7 days. 277. A depot according to Clause 273, configured such that the flexural strength of the depot decreases by up to 55% after immersion in a buffer solution for 7 days. 278. A depot according to Clause 273, configured such that the flexural strength of the depot decreases by up to 50% after immersion in a buffer solution for 7 days. 279. A depot according to 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 therapeutic agents, Therapeutic areas including therapeutic agents; A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. A depot containing a therapeutic agent, configured to reduce the flexural strength of the depot by up to 75% after being immersed in a buffer solution until approximately 75% by weight of the therapeutic agent is released. 281. A depot according to Clause 280, configured such that after immersion in a buffer solution until approximately 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 70%. 282. A depot according to Clause 280, configured such that after immersion in a buffer solution until approximately 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 65%. 283. A depot according to Clause 280, configured such that after immersion in a buffer solution until approximately 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 60%. 284. A depot according to Clause 280, configured such that after immersion in a buffer solution until approximately 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 55%. 285. A depot according to Clause 280, configured such that after immersion in a buffer solution until approximately 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 50%. 286. A depot according to Clause 280, configured such that after immersion in a buffer solution until approximately 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 45%. 287. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for more than 14 days while implanted. Approximately 20% to 40% of the pain medication is released during the first three days of the 14-day depot, and at least 80% of the remaining pain medication is released during the last 11 days of the 14-day depot. 288. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. The control area is a depot that does not contain analgesics, at least before implantation of the depot at the treatment site. 289. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. The control area includes depots containing analgesics different from those in the therapeutic area. 290. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and remains implanted for more than 3 days. It is configured to release analgesics at the treatment site over time. The release agent is the first release agent, and the therapeutic area is a depot containing the second release agent mixed with an analgesic. 291. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. The release agent is the first release agent, the polymer is the first polymer, and the therapeutic area is a depot containing the second polymer mixed with the second release agent and an analgesic. 292. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including analgesics; A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. 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 / 30, 1 / 40, 1 / 50, 1 / 60, 1 / 70, 1 / 80, 1 / 90, or 1 / 100 of the thickness of the treatment area, depot. 293. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. The thickness of the control region is less than or equal to 1 / 75 of the thickness of the treatment region in the depot. 294. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. The thickness of the control region is less than or equal to 1 / 100th the thickness of the treatment region in a depot. 295. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release The agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. A depot comprising a first control layer containing a first amount of release agent, and a second control layer containing a second amount of release agent different from the first amount. 296. A depot for treating postoperative pain through sustained controlled release of an analgesic, Therapeutic areas including painkillers, A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed and form a diffusion opening in the control region. Includes, The depot is implanted in vivo at the treatment site and is configured to release analgesics at the treatment site for at least 3 days while implanted. 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 in which, when initially placed at the 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 approximately 5% to approximately 20%, or approximately 5% to approximately 15%, or approximately 5% to approximately 10%. 297. Depot for controlled sustained release of therapeutic agents, A therapeutic area containing a therapeutic agent and extending along the first axis; and A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when a depot is placed to form a diffusion opening in the control region. Includes, A depot implanted in vivo at the treatment site, configured to release therapeutic agents at the treatment site for at least three days while implanted. 298. Any one of the preceding clauses, whose maximum transverse dimension along the first axis is at least five times longer along the first axis than the maximum transverse dimension along the second axis perpendicular to the first axis. 299. Any one of the preceding clauses, whose maximum transverse dimension along the first axis is at least 10 times longer along the first axis than the maximum transverse dimension along the second axis perpendicular to the first axis. 300. A depot of any one of the preceding clauses that is substantially columnar. 301. A depot of any one of the preceding clauses that is substantially cylindrical. 302. A depot according to any one of the preceding clauses, wherein the treatment area is substantially cylindrical. 303. A depot according to any one of the preceding clauses, further comprising at least one opening extending through the treatment area. 304. A depot of any one of the preceding clauses, the opening of which forms a cylindrical lumen extending parallel to the first axis. 305. A depot of any of the preceding clauses, wherein the opening includes a lumen extending along a second axis substantially perpendicular to a first axis. 306. A depot of any of the preceding clauses, further including a plurality of elongated openings extending parallel to a second axis. 307. A depot of any one of the preceding clauses, wherein the treatment area includes multiple separate, elongated sub-regions extending substantially parallel to the first axis. 308. Depot of any one of the preceding clauses, each of which is substantially cylindrical in shape. 309. Each of the elongated sub-regions is radially separated from each other by the control region. Depot of any one of the clauses to be executed. 310. Any one of the preceding clauses, where the outermost radial dimension of the depot varies along the first axis. 311. A depot of any one of the preceding clauses, wherein the radial outermost dimension of the treatment area varies along the first axis. 312. A depot of any one of the preceding clauses, where the treatment area is a series of separate areas covered and connected by a continuous control area. 313. A preceding depot in which the control area is narrowed in areas without an internal treatment area. 314. A preceding clause depot in which the control area is designed to bend or break during or after delivery. 315. 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. A depot according to any one of the preceding clauses, wherein the control region has a thickness that varies radially around a first axis. 317. A depot whose variable thickness in the control region curves or bends when deployed in vivo, in any one of the preceding clauses. 318. Any one of the preceding clauses, which is configured to preferentially curve or bend when placed in contact with physiological fluids in vivo. 319. A depot comprising an elongated polymer strip having a length between its longitudinal ends and a width between its transverse edges, wherein the length is greater than the width, and the depot has a predetermined shape in an extended configuration, wherein the strip is wound around an axis with the width of the strip facing the axis, thereby forming an annular shape, one of the depots of the preceding clauses. 320. Any one of the preceding clauses having an annular or semi-annular shape. 321. Any one of the preceding clauses having a first region and a second region, each extending longitudinally with the same extent to each other over all or part of its respective length, the first region having a first elasticity and the second region having a second elasticity less than the first elasticity. 322. A depot of a preceding clause, which transitions from a straight state to a curved state when emitted from a delivery device, and is stretched beyond the elastic hysteresis point of the second region so that the second region pulls the depot into a curved shape. 323. A depot having a first region and a second region, each extending longitudinally with the same extent to each other over all or part of its respective length, wherein the first region is more hydrophilic than the second region, according to any one of the preceding provisions. 324. A preceding depot that, upon being discharged from a delivery device, transitions from a straight state to a curved state, with a second region pulling the depot into a curved shape. 325. Any one of the preceding clauses, the depot having a control region having first and second parts having a first thickness, the first and second parts being separated along a first axis by a third part having a second thickness different from the first thickness. 326. A depot according to 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. Any one of the preceding clauses, the depot extends along a first axis from a first end to a second end, and the control region does not overlap the treatment region at the first end of the depot. 328. A 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 does not overlap the treatment region at either the first or second end. 329. A depot of any of the preceding clauses, in which the control region has multiple individual openings within it. 330. Any of the preceding clauses wherein the control region has an elongated opening along the first axis. One depot. 331. A depot in any of the preceding clauses, wherein an elongated opening in the control region extends along the entire length of the depot. 332. A depot of any one of the preceding clauses, in which the control region includes a plurality of circular apertures formed therein. 333. Any one of the preceding clauses, the depot having a first therapeutic area, the depot further comprising a second therapeutic area, each of the first and second therapeutic areas elongating along a first axis, and the first and second therapeutic areas being configured to release the therapeutic agent at different rates. 334. Any one of the preceding clauses, the depot having a first therapeutic area, the depot further comprising a second therapeutic area, each of the first and second therapeutic areas elongating along the first axis, and the first and second therapeutic areas containing different therapeutic agents. 335. A depot in any one of the preceding clauses, in which the first and second treatment areas are aligned coaxially. 336. A depot in which the first and second treatment areas extend parallel to each other along the length of the depot, in any one of the preceding clauses. 337. A depot comprising any one of the preceding clauses, further comprising a barrier region configured to dissolve more slowly in vivo than a control region or a therapeutic region. 338. Any one of the preceding clauses, further comprising a barrier region configured to slow the in vivo passage of physiological fluids through the interior to a control or therapeutic region. 339. A depot of any one of the preceding clauses, wherein the barrier region is positioned coaxially with the therapeutic region, such that the control region at least partially encloses both the therapeutic region and the barrier region. 340. Any one of the preceding clauses, wherein the barrier region is a first barrier region, the depot further includes a second barrier region, and the first and second barrier regions are axially separated from each other by a treatment region. 341. The first and second barrier areas are depots of any one of the preceding clauses having different dimensions. 342. A depot of any one of the preceding clauses, wherein the control region and the barrier region together enclose the treatment region at least partially, with the barrier region positioned coaxially with the control region. 343. A depot of any one of the preceding clauses, in which the first and second barrier regions are axially separated from each other by a control region. 344. A depot in any one of the preceding clauses, the depot extending along a first axis from a first end to a second end, with a barrier region located on the first end of the depot. 345. Any one of the preceding clauses, the depot extends along a first axis from a first end to a second end, and the barrier region includes a first end cap positioned on the first end of the depot and a second end cap positioned on the second end of the depot. 346. Any one of the preceding clauses, the depot having a treatment area comprising a covered portion and an exposed portion, wherein when the depot is first placed at the treatment site in vivo, the control region is located between the covered portion of the treatment area and the physiological fluid of the treatment site, and the covered portion is covered by the control region so that the exposed portion of the treatment area is exposed to the physiological fluid. 347. Any one of the preceding clauses, the depot having a therapeutic agent within the treatment area constituting at least 50% of the total weight of the depot. 348. Any one of the preceding clauses, with a duration of 7 days or more, 15 days or more, 30 days or more, 45 days or more, 60 days or more, or 90 days or more. 349. Approximately 40% to 60% of the therapeutic agent within the therapeutic area is released in one of the preceding depots, during the first half of the period. 350. At least 90% of the therapeutic agent within the therapeutic area is released within the period, preceding the condition One of the depots listed. 351. One of the depots specified in the preceding clauses, configured to release approximately 2 μg to 5 mg of the therapeutic agent to the treatment site per day. 352. Any one of the preceding provisions, a depot configured to release the therapeutic agent to the treatment site in vivo for a period of 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. 353. Any one of the preceding depots in which the therapeutic agent is released at a substantially steady-state rate throughout the entire 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 area to the exposed surface area of ​​the control area is approximately 5% to 20%, or approximately 5% to 15%, or approximately 5% to 10%. Depot of any one of the preceding clauses. 355. Any one of the preceding depots in which the exposed surface area of ​​the control region is less than the exposed surface area of ​​the treatment region. 356. Any one of the preceding depots in which the exposed surface area of ​​the control region is greater than the exposed surface area of ​​the treatment region. 357. Any one of the preceding clauses, where the control region is the first control region and the depot includes the second control region. 358. Any one of the preceding clauses, wherein the first control region is located on the first face of the treatment region, and the second control region is located on the second face of the treatment region opposite to the first face. 359. Any one of the preceding clauses, the depot comprising multiple control regions and multiple therapeutic regions, wherein each therapeutic region is separated from one or more adjacent therapeutic regions by one or more control regions. 360. One depot of any of the preceding clauses, containing approximately 2 to 10 therapeutic areas. 361. A depot of any one of the preceding clauses, wherein the control domain includes a first control layer and a second control layer. 362. A depot of any one of the preceding clauses, wherein the second control layer is adjacent to the therapeutic region, and the first control layer encapsulates / surrounds the therapeutic region and the second control layer. 363. A depot of either of the preceding clauses, in which the first and second control layers together surround the treatment area. 364. Any one of the preceding clauses, wherein the first control layer includes a first number of sublayers and the second control layer includes a second number of sublayers. 365. 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 different from the first amount. 366. A depot of any one of the preceding clauses, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first concentration of the release agent, and the second control layer contains a second concentration of the release agent greater than the first concentration. 367. A depot of any one of the preceding clauses, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first concentration of the release agent, and the second control layer contains a second concentration of the release agent that is lower than the first concentration. 368. A second control layer is placed between the first control layer and the treatment area. The first control layer contains up to 5% by weight of the release agent, up to 10% by weight of the release agent, and 15% by weight of the release agent. Including up to % of a release agent, up to 20% by weight of a release agent, up to 25% by weight of a release agent, up to 30% by weight of a release agent, up to 35% by weight of a release agent, up to 40% by weight of a release agent, up to 45% by weight of a release agent, or up to 50% by weight of a release agent; The second control layer contains up to 5% by weight of the release agent, up to 10% by weight of the release agent, up to 15% by weight of the release agent, up to 20% by weight of the release agent, up to 25% by weight of the release agent, up to 30% by weight of the release agent, up to 35% by weight of the release agent, up to 40% by weight of the release agent, up to 45% by weight of the release agent, or up to 50% by weight of the release agent. Depot of any one of the preceding clauses. 369. A depot of any one of the preceding clauses, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first amount of the release agent, and the second control layer contains a second amount of the release agent, the second amount being at least twice, at least three times, at least four times, or at least five times the first amount. 370. Any one of the preceding clauses, where 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 containing any one of the preceding clauses, including an elongated columnar structure configured to be implanted in a patient. 372. A depot of any one of the preceding clauses, containing one of several beads or microspheres. 373. Beads or microspheres having various release profiles, one of the preceding clauses in a depot. 374. Beads or microspheres containing varying amounts of the therapeutic agent in one of the preceding depots. 375. A depot of any one of the preceding clauses, each containing a control region of varying thicknesses, of which beads or microspheres. 376. A depot of micro-spherical beads having various dimensions, one of the preceding clauses. 377. A depot containing one of several pellets, which is one of the preceding clauses. 378. A depot in any of the preceding clauses in which the pellets have various release profiles. 379. A pellet containing various amounts of therapeutic agent in any one of the preceding depots. 380. A pellet in any one of the preceding clauses, each containing a control region of varying thickness. 381. Depot of any one of the preceding clauses, where the pellets have various dimensions. 382. Any one of the preceding clauses' depots in which the pellets are substantially cylindrical. 383. Any one of the preceding depots, wherein the depot comprises a plurality of substantially cylindrical beads, each comprising a therapeutic area and a control area, and the plurality of beads are substantially aligned along a common longitudinal axis. 384. A depot that is biodegradable and / or bio-erosive, according to any one of the preceding clauses. 385. A depot of any one of the preceding clauses, which is a flexible solid that is structurally capable of being handled by a clinician during a normal surgical procedure without being broken into numerous small pieces and / or losing its overall shape. 386. Any one of the preceding depots, configured to release the therapeutic agent in vivo for up to 7 days without being broken down into numerous fragments, so as to be placed subcutaneously in the patient. 387. Any one of the preceding depots having surface area and volume, wherein the ratio of surface area to volume is at least 1. 388. A depot of any one of the preceding clauses, wherein the diffusion opening includes at least one or more pores and / or one or more channels. 389. Any one of the preceding depots, in which the release agent is dissolved after being placed in vivo at the treatment site, causing the control region and the therapeutic region to transition from a state of lower porosity to a state of higher porosity, thereby facilitating the release of the therapeutic agent from the depot. 390. A depot of any one of the preceding clauses, wherein the releasing agent is the first releasing agent, and the therapeutic area includes the second releasing agent mixed with the therapeutic agent. 391. A depot of any one of the preceding clauses, wherein the release agent is the first release agent, the polymer is the first polymer, and the therapeutic area comprises the second release agent and the second polymer mixed with the therapeutic agent. 392. Any one of the preceding provisions' depots in which the first release agent is the same as the second release agent. 393. A depot in any of the preceding provisions in which the first release agent is different from the second release agent. 394. Any one of the preceding depots in which the concentration of the first releasing agent in the control region is greater than the concentration of the second releasing agent in the therapeutic region. 395. Any one of the preceding depots, wherein the concentration of the first releasing agent in the control region is less than the concentration of the second releasing agent in the therapeutic region. 396. Any one of the preceding depots, wherein the concentration of the first releasing agent in the control region is the same as the concentration of the second releasing agent in the therapeutic region. 397. Any one of the preceding depots, wherein the concentration of the first releasing agent in the control region is different from the concentration of the second releasing agent in the therapeutic region. 398. A depot of any one of the preceding clauses, in which the treatment area includes multiple microlayers. 399. Any one of the preceding depots, wherein the mass of the therapeutic agent constitutes at least 50% of the mass of the depot. 400. Any one of the preceding clauses, in which the ratio of the mass of the therapeutic agent in the depot to the mass of the 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. A depot of any one of the preceding clauses, the therapeutic area including bioabsorbable polymers and therapeutic agents. 402. A depot of any one of the preceding clauses, wherein the therapeutic area contains 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, 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 containing any one of the preceding provisions, 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. Depot of any one of the preceding clauses in which the release agent is a nonionic surfactant. 405. A depot in any of the preceding clauses in which the release agent is hydrophilic. 406. Any one of the preceding clauses' depots whose release agent is polysorbate. 407. Depot of any one of the preceding clauses, where the release agent is Tween 20. 408. Depot of any one of the preceding clauses, where the release agent is Tween 80. 409. The release agent is nonpolymeric, in any one of the preceding clauses of the depot. 410. Depot of any one of the preceding clauses in which the release agent is not a plasticizer. 411. Any one of the depots in any 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. Any one of the preceding provisions where the polymer is a copolymer. 413. A polymer is a terpolymer in any one of the preceding provisions. 414. Polymers include 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) Poly(1,3--co-glutamic acid), poly(tert-butyloxycarbonylmethylglutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethylglycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymer of polyhydroxybutyrate, copolymer of maleic anhydride, copolymer 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, alginates, albumin, fibrin, vitamin E analogs, e.g., 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) hydro A depot comprising at least one of the following: hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or salts thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone). 415. A 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. Any one of the preceding clauses depots, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of approximately 60:30:10. 417. Any one of the preceding clauses depots, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a molar ratio between approximately 10:90 and approximately 90:10. 418. Depot of any one of the preceding clauses, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a molar ratio of approximately 50:50. 419. A polymer terminated with an ester in any one of the preceding clauses. 420. 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, as per any one of the preceding clauses. 421. A depot of any one of the preceding clauses, wherein the polymer is a first polymer and the therapeutic area contains a second polymer mixed with a therapeutic agent. 422. The first polymer and / or the second polymer is 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 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-butyloxycarbonylmethylglutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethylglycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymer of polyhydroxybutyrate, copolymer of maleic anhydride, copolymer of poly(trimethylene carbonate), polyethylene glycol (PEG), hyaluronic acid Droxypropyl methylcellulose 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, alginates, albumin, fibrin, vitamin E analogs, e.g., 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) A depot comprising at least one of the following: 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, or poly(DL-lactide-co-glycolide-co-caprolactone). 423. 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) in any one of the preceding clauses of the depot. 424. 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) having a molar ratio of approximately 60:30:10. 425. The first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a molar ratio of approximately 50:50, in any one of the preceding clauses. 426. A depot of either of the preceding clauses in which the first polymer and / or the second polymer are terminated with an ester. 427. Any one of the preceding clauses, 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. Any one of the preceding clauses, where 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. Any one of the preceding clauses, 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 therapeutic agents to a treatment site, A shaft having a lumen; A pusher movably connected to the lumen; A depot positioned within the lumen and configured to be displaced from the shaft via the activation of a pusher The depot includes, A therapeutic agent is included, and firstly, a therapeutic area extending along the axis; A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when the depot is placed to form a diffusion opening in the control region, and The system includes a depot that is implanted in vivo at the treatment site and is configured to release the therapeutic agent at the treatment site for at least three days while implanted. 431. A system of clause 430 in which a depot includes one of the depots of any 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 therapeutic agents to a treatment site, 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, A therapeutic area containing a therapeutic agent and extending along the first axis; A depot comprising a control region which at least partially surrounds the therapeutic area, extends along a first axis, and includes a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve in vivo when the depot is placed to form a diffusion opening into the control region. The depot is implanted in vivo at the treatment site and remains implanted for 3 days. A system configured to release a therapeutic agent at the treatment site for a period of time or longer. 434. A system of clause 433 in which a depot includes one of the preceding clauses. 435. Any one of the preceding clauses, in which the expandable member includes a stent. 436. Any one of the preceding clauses, in which the expandable member includes a spherical, hemispherical, elliptical, or semi-elliptical structure. 437. A system according to any one of the preceding clauses, wherein an expandable member includes a curved outer surface, and a depot is located on the curved outer surface. 438. A system of any one of the preceding clauses in which the depot substantially covers at least one surface of an expandable member. 439. A system in which an expandable member includes a shape memory material, according to any one of the preceding clauses. 440. A system of any one of the preceding clauses, wherein the depot is placed within a lubricating coating, and the lubricating coating contains a hydrogel. 441. A method for delivering a therapeutic agent to a treatment site in the body, The depot is placed in an in vivo treatment site containing physiological fluids, and the depot is A therapeutic agent is included, and firstly, a therapeutic area extending along the axis; A control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, at least partially surrounding the therapeutic area and extending along a first axis. It must include; and The release agent is dissolved at the treatment site to form a diffusion opening in the control region, thereby releasing the therapeutic agent from the depot to the treatment site for more than three days. A method that includes this. 442. The method of the preceding clause, wherein the depot includes one of the depots of the preceding clause. 443. The method of the preceding clause, wherein the placement of the depot includes inserting the depot subcutaneously at the treatment site via a needle. 444. Placing a depot includes any one of the preceding methods, which involves placing the depot proximal to the nerve bundle at the treatment site. 445. Any one of the preceding methods, further comprising dissolving the release agent at a first rate and decomposing the polymer at a second rate, wherein the first rate is greater than the second rate. 446. Any one of the preceding clauses, further comprising dissolving a release agent in response to contact between a control area and a physiological fluid at the treatment site. 447. Any one of the preceding clauses, further comprising creating a diffusion opening in a control region by dissolving a release agent in response to a physiological fluid at the treatment site. 448. Any one of the methods of the preceding clauses, wherein the releasing agent is a first releasing agent, the therapeutic area comprises a second releasing agent, and the method further comprises creating microchannels in the therapeutic and control areas via the dissolution of the first and / or second releasing agents. 449. One of the preceding methods, wherein at least some of the microchannels penetrate both the therapeutic and control regions. 450. Any one of the preceding clauses, further comprising increasing the porosity of the depot by dissolving the release agent. 451. Any one of the preceding provisions, wherein the therapeutic agent is released one or more times in substantially separate doses after implantation. 452. Any one of the preceding provisions, wherein the therapeutic agent is released at a substantially steady-state rate over the duration thereof. 453. If 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 Any one of the preceding clauses, which is 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. 454. Any one of the preceding provisions, wherein the depot is a first depot, and the method further includes placing a second depot at the treatment site. 455. A depot for implantation in mammalian patients for sustained controlled release of therapeutic agents, Therapeutic areas including therapeutic agents; The invention comprises a bioabsorbable polymer and a release agent mixed with this polymer, wherein the release agent is configured to dissolve in vivo when the depot is placed in the control region and form a diffusion opening in the control region. A depot containing a drug, which is implanted in vivo at the treatment site and configured to release the therapeutic agent at the treatment site for at least three days while implanted. 456. A depot according to clause 455, wherein the therapeutic agent within the therapeutic area constitutes at least 50% of the total weight of the depot. 457. Any one of the preceding depots, configured to release the therapeutic agent at a first rate for the first period and at a second rate for the second period. 458. A depot under clause 457 where the first speed is greater than the second speed. 459. A depot under Article 457, where the first period is longer than the second period. 460. A depot under Article 457 where the first period is shorter than the second period. 461. Any one of the preceding depots, wherein the depot is configured to release the therapeutic agent in vivo to the treatment site over a period of 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. 462. A depot according to any one of the preceding clauses, wherein the treatment area includes a covered portion and an exposed portion, and when the depot is first placed at the treatment site in vivo, the control region is between the covered portion of the treatment area and the physiological fluid of the treatment site, and the covered portion is covered by the control region so that the exposed portion of the treatment area is exposed to the physiological fluid. 463. A depot having a total surface area including the exposed surface area of ​​the treatment area plus the exposed surface area of ​​the control region, When the depot is initially placed at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment area to the exposed surface area of ​​the control area is approximately 5% to 20%, or approximately 5% to 15%, or approximately 5% to 10%. Depot of any one of the preceding clauses. 464. A depot according to clause 463, where the exposed surface area of ​​the control area is less than the exposed surface area of ​​the treatment area. 465. A depot according to clause 463, wherein the exposed surface area of ​​the control area is greater than the exposed surface area of ​​the treatment area. 466. Any one of the preceding clauses, where the control region is the first control region and the depot includes the second control region. 467. The depot of Clause 466, wherein a first control region is located on a first surface of the treatment region, and a second control region is located on a second surface of the treatment region opposite to the first side. 468. Any one of the preceding clauses, the depot comprising multiple control regions and multiple therapeutic regions, wherein each therapeutic region is separated from one or more adjacent therapeutic regions by one or more control regions. 469. Each of the treatment areas and each of the control areas has a thickness of less than 1 mm. , depot under clause 468. 470. A depot according to Clause 468 or Clause 469, wherein the depot contains approximately two to approximately four therapeutic areas. 471. A depot according to clause 468 or clause 469, wherein the depot includes approximately 2 to approximately 10 control regions. 472. Any one of the depots from Clauses 1 to 461, wherein, when the depot is placed at the treatment site in vivo, the therapeutic region is surrounded by the control region such that the control region is located between the therapeutic region and the physiological fluids of the treatment site. 473. A depot of any one of the preceding clauses, wherein the control domain includes a first control layer and a second control layer. 474. The 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 and second control layers together surround the treatment area. 476. Any one of the depots specified in clauses 473 to 475, wherein the first control layer is located on the first surface of the treatment area, and the second control layer is located on the second surface of the treatment area opposite to the first surface. 477. Any one of the depots from clauses 473 to 476, wherein the first control layer includes a first number of sublayers and the second control layer includes a second number of sublayers. 478. Any one of the depots from 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 different from the first amount. 479. Any one of the depots described in clauses 473 to 478, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first concentration of the release agent, and the second control layer contains a second concentration of the release agent greater than the first concentration. 480. Any one of the depots from clauses 473 to 479, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first concentration of the release agent, and the second control layer contains a second concentration of the release agent that is lower than the first concentration. 481. A second control layer is placed between the first control layer and the therapeutic area. The first control layer contains up to 5% by weight of the release agent, up to 10% by weight of the release agent, up to 15% by weight of the release agent, up to 20% by weight of the release agent, up to 25% by weight of the release agent, up to 30% by weight of the release agent, up to 35% by weight of the release agent, up to 40% by weight of the release agent, up to 45% by weight of the release agent, or up to 50% by weight of the release agent. The second control layer contains up to 5% by weight of the release agent, up to 10% by weight of the release agent, up to 15% by weight of the release agent, up to 20% by weight of the release agent, up to 25% by weight of the release agent, up to 30% by weight of the release agent, up to 35% by weight of the release agent, up to 40% by weight of the release agent, up to 45% by weight of the release agent, or up to 50% by weight of the release agent. Any one of the depots under clauses 473 to 480. 482. Any one of the depots from clauses 473 to 481, wherein a second control layer is placed between the first control layer and the therapeutic area, the first control layer contains a first amount of the release agent, and the second control layer contains a second amount of the release agent, the second amount being at least twice, at least three times, at least four times, or at least five times the first amount. 483. 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. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 12.5 of the thickness of the treatment region. 485. 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. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 17.5 of the thickness of the treatment region. 487. The thickness of the control region is less than or equal to 1 / 20 of the thickness of the treatment region. Depot of any one of the clauses. 488. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 22.5 of the thickness of the treatment region. 489. Any one of the preceding clauses in which the thickness of the control region is less than or equal to 1 / 25 of the thickness of the treatment region. 490. 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. Any one of the preceding depots in which the thickness of the control region is less than or equal to 1 / 40 of the thickness of the treatment region. 492. 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. Any one of the preceding clauses in which the thickness of the control region is less than or equal to 1 / 75 of the thickness of the treatment region. 494. 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, which is a flexible solid that is structurally capable of being handled by a clinician during a normal surgical procedure without being broken into numerous small pieces and / or losing its overall shape. 496. One of the depots described in the preceding clauses, which is placed inside the patient's knee and configured to release the therapeutic agent in vivo for up to 7 days without being broken down into numerous small pieces. 497. Any one of the preceding depots having width and thickness, where the ratio of width to thickness is 21 or greater. 498. A depot of clause 65 with a ratio of 30 or greater. 499. A depot of clause 65 with a ratio of 40 or greater. 500. Any one of the preceding depots having a surface area and volume, wherein the ratio of surface area to volume is at least 1. 501. A depot of any one of the preceding clauses, wherein the diffusion opening includes 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 together via thermal compression to form a therapeutic area. 503. A depot in any one of the preceding clauses, in which the control region and the therapeutic region are coupled via thermal compression. 504. A depot in any one of the preceding clauses, in which the control region and the therapeutic region are thermally bonded. 505. Any one of the preceding depots, upon dissolution of the releasing agent after in vivo placement at the treatment site, transitions the control region and therapeutic region from a less porous state to a more porous state, facilitating the release of the therapeutic agent from the depot. 506. The control area is not a therapeutic agent, and does not contain any of the preceding depots, prior to the implantation of the depot at least at the treatment site. 507. Any one of the depots from clauses 1 to 505, wherein the control region contains a therapeutic agent different from the therapeutic agent in the therapeutic region. 508. Any one of the preceding depots in the treatment area that does not contain any releasing agent before implantation of the depot at the treatment site. 509. A depot of any one of the preceding clauses, wherein the releasing agent is the first releasing agent, and the therapeutic area includes the second releasing agent mixed with the therapeutic agent. 510. Any one of the depots from Clauses 1 to 509, wherein the release agent is the first release agent, the polymer is the first polymer, and the therapeutic area comprises the second release agent and the second polymer mixed with the therapeutic agent. 511. The first release agent is the same as the second release agent, any one of the provisions 1 to 509. Two depots. 512. A depot in any of the clauses 1 to 509, wherein the first discharging agent is different from the second discharging agent. 513. Any one of the depots described in clauses 1 to 512, wherein the concentration of the first releasing agent in the control region is greater than the concentration of the second releasing agent in the therapeutic region. 514. Any one of the depots described in clauses 1 to 512, wherein the concentration of the first releasing agent in the control region is less than the concentration of the second releasing agent in the therapeutic region. 515. Any one of the depots from clauses 1 to 512, wherein the concentration of the first releasing agent in the control area is the same as the concentration of the second releasing agent in the therapeutic area. 516. Any one of the depots described in clauses 1 to 512, wherein the concentration of the first releasing agent in the control region is different from the concentration of the second releasing agent in the therapeutic region. 517. A depot in any of the clauses 1 to 516, wherein the first discharging agent is different from the second discharging agent. 518. A depot of any one of the preceding clauses in which the treatment area includes multiple microlayers. 519. Any one of the preceding depots, wherein the mass of the therapeutic agent constitutes at least 50% of the mass of the depot. 520. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 3:1. 521. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 4:1. 522. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 5:1. 523. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 6:1. 524. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 7:1. 525. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 8:1. 526. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 10:1. 527. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 16:1. 528. A depot of any one of the preceding clauses, wherein the therapeutic area contains 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. A depot 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, any one of the preceding clauses. 530. Any one of the preceding provisions' depots, in which the therapeutic agent includes at least one of the following: a simple analgesic, a local anesthetic, an NSAID, and an opioid. 531. Any one of the preceding clauses' depots, wherein the therapeutic agent comprises a local anesthetic selected from at least one of bupivacaine, ropivacaine, mepivacaine, and lidocaine. 532. Further comprising antibiotics, antifungal agents, and / or antimicrobial agents, the antibiotics, antifungal agents, and / or antimicrobial agents include amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline ( (Multiple), minocycline, tigecycline, doxycycline, rifampine, triclosan, chlorexidine, penicillin (multiple), aminoglycis, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporins (multiple), carbapenems, imipenems, ertapenems, antimicrobial peptides, cecropine-melittin, magainin, dermaceptin, cathelicidin, alpha-defensins, and alpha-protegrin, ketoconazole, chlortrimazole, miconazole, econazole A depot of any one of the preceding clauses, selected from at least one of the following: intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, thioconazole, oxyconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naphthifine, griseofulvin, haloprogin, butenafine, tolnaftate, nistatin, cyclohexamide, cyclopirox, flucytosine, terbinafine, and amphotericin B. 533. Any one of the preceding clauses, further comprising an anti-inflammatory agent selected from at least one of the following: steroids, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, sarsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofename, mefenamic acid, and COX-2 inhibitors. 534. Any one of the preceding depots in which the therapeutic agent is dexamethasone. 535. Any one of the preceding depots comprising at least one of epinephrine, clonidine, or tranexamic acid. 536. Depot of any one of the preceding clauses, wherein the release agent is a nonionic surfactant. 537. A depot of any one of the preceding clauses in which the release agent is hydrophilic. 538. Any one of the preceding clauses' depots whose release agent is polysorbate. 539. Depot of any one of the preceding clauses, where the release agent is Tween 20. 540. One depot from any of clauses 1 through 107, where the release agent is Tween 80. 541. The release agent is nonpolymeric, according to any one of the preceding clauses of the depot. 542. Depot of any one of the preceding clauses in which the release agent is not a plasticizer. 543. Any one of the depots in any 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. Any one of the preceding provisions where the polymer is a copolymer. 545. The polymer is a terpolymer, according to any one of the depots from clauses 1 to 545. 546. The polymer is 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), polydeptipeptide, 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(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, Poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymer of polyhydroxybutyrate, copolymer of maleic anhydride, copolymer 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 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), 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), hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethyl A depot of any one of the preceding terms, comprising at least one of the following: 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, and poly(DL-lactide-co-glycolide-co-caprolactone). 547. A depot of any one of the preceding clauses, wherein the polymer is one of the following: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 548. A depot of any one of the clauses 1 to 545, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10. 549. A depot of any one of the clauses 1 to 545, in which the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a 50:50 molar ratio. 550. A polymer terminated with an ester in any one of the preceding clauses. 551. 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, as per any one of the preceding clauses. 552. A depot of any one of the preceding clauses, wherein the polymer is a first polymer and the therapeutic area contains a second polymer mixed with a therapeutic agent. 553. Depot of Clause 552, wherein the first polymer and the second polymer are the same. 554. Depot of Clause 552, wherein the first polymer and the second polymer are different. 555. The first polymer and / or the second polymer is 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), polyPoly(lyric acid 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(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, poly Phosphazenes, ethyl glycinate polyphosphazenes, polycaprolactone co-butyl acrylate, polyhydroxybutyrate copolymers, maleic anhydride copolymers, poly(trimethylene carbonate) copolymers, 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, alginates, albumin, fibrin, vitamin E analogs, e.g., 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) hydroxypropylcellulose A depot comprising at least one of the following: 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, and poly(DL-lactide-co-glycolide-co-caprolactone), any one of the depots of clauses 552 to 554. 556. Any one of the depots from clauses 552 to 554, wherein the first polymer and / or the second polymer is selected from: poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 557. Any one of the depots from clauses 552 to 554, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) having a molar ratio of 60:30:10. 558. Any one of the depots from clauses 552 to 554, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) having a molar ratio of 50:50. 559. Depot of either of the preceding clauses, wherein the first polymer and / or the second polymer is terminated with an ester. 560. Any one of the preceding clauses, 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. Any one of the preceding clauses, wherein the ratio of the release agent to the polymer in the control region is 1:2 or less. 562. Any one of the depots from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:3 or less. 563. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:4 or less. 564. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:5 or less. 565. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:6 or less. 566. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:7 or less. 567. Any one of the depots from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:8 or less. 568. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:9 or less. 569. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:10 or less. 570. Any one depot from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is 1:11 or less. 571. Any one of the depots from clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is at least 1:1. 572. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 2:1. 573. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 3:1. 574. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is at least 4:1. 575. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 5:1. 576. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 6:1. 577. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 7:1. 578. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the control region is at least 8:1. 579. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 9:1. 580. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 10:1. 581. Any one depot of clauses 455 to 560, wherein the ratio of the release agent to the polymer in the controlled region is at least 15:1. 582. The polymer is the first polymer, and the therapeutic area further contains the second polymer. The depot has a depot polymer mass equal to the sum of the mass of the first polymer and the mass of the second polymer. Any one of the preceding clauses, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is approximately 1:1. 583. Depot of Clause 582, wherein the first polymer is the same as the second polymer. 584. Depot of Clause 582, wherein 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, one of the depots in any of clauses 582 to 584. 586. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 3:1. 587. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 4:1. 588. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is approximately 5:1. 589. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 6:1. 590. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 7:1. 591. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 8:1. 592. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the therapeutic agent in the depot to the mass of the depot polymer is at least 10:1. 593. Any one of the depots from clauses 582 to 584, wherein the ratio of the mass of the 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 in an anatomical region of the patient's body related to surgery in or near this anatomical region, comprising improving the patient's total score on the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index by implanting one or more depots of the preceding clauses at the surgical site in the anatomical region. 595. A method for treating a patient suffering from pain in an anatomical region of the patient's body related to surgery in or near this anatomical region, comprising improving the patient's WOMAC pain subscore by implanting one or more depots of the preceding clauses at the surgical site in the anatomical region. 596. A method for treating a patient suffering from pain in an anatomical region of the patient's body related to surgery in or near this anatomical region, comprising improving the patient's WOMAC index rigidity subscore by implanting one or more depots of the preceding clauses at the surgical site in the anatomical region. 597. A method for treating a patient suffering from pain in an anatomical region of the patient's body related to surgery in or near this anatomical region, comprising improving the patient's WOMAC index physical function subscore by implanting one or more depots of the preceding clauses at the surgical site in the anatomical region. 598. A method for treating a patient suffering from pain in an anatomical region of the patient's body related to surgery in or near this anatomical region, comprising improving the patient's KOOS score by implanting one or more depots of the preceding clauses at the surgical site in the anatomical region. 599. A method for treating a patient suffering from pain in an anatomical region of the patient's body related to surgery in or near the anatomical region, comprising improving the range of motion in the anatomical region by relieving pain in the anatomical region through the implantation of one of the depots of the preceding clauses. 600. A method for treating a patient suffering from pain in an anatomical region of the patient's body related to surgery in or near this anatomical region, comprising reducing the amount of opioid consumed by the patient. 601. A method for improving the total WOMAC score of a patient suffering from pain associated with surgery in or near an anatomical region of the patient's body, comprising implanting a depot in or near the surgical site of the anatomical region, wherein the depot is one of the depots of the preceding clauses. 602. The WOMAC index total score is used for pain subscores, rigidity subscores, and / or This is the method of the preceding clause, including the physical function subscore. 603. Pain in any way related to orthopedic surgery, in any way of the preceding clause. 604. Pain is associated with any one of the preceding clauses related to joint surgery. 605. Pain is associated with any one of the preceding clauses related to total knee arthroplasty.

[0010] Many aspects of this disclosure can be better understood by referring to the following drawings. The components in the drawings are not necessarily scaled to match. Instead, they are emphasized to clearly illustrate the principles of this disclosure. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows the release of therapeutic agents over time from a conventional device.

[0012] [Figure 2] Figure 2 is an isometric view of the depot constructed using this technology.

[0013] [Figure 3] Figure 3 shows the emission profiles of one or more depots of this technology over time.

[0014] [Figure 4]Figure 4 is an isometric view of a depot according to one embodiment of this technology.

[0015] [Figure 5] Figure 5 is an isometric view of a depot according to one embodiment of this technology.

[0016] [Figure 6] Figure 6 is a cross-sectional view of a depot according to one embodiment of this technology.

[0017] [Figure 7] Figure 7 is a cross-sectional view of a depot according to one embodiment of this technology.

[0018] [Figure 8] Figure 8 is a cross-sectional view of a depot according to one embodiment of this technology.

[0019] [Figure 9A] Figure 9A is an isometric view of a depot according to one embodiment of this technology.

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

[0021] [Figure 10] Figure 10 is a cross-sectional view of a depot according to one embodiment of this technology.

[0022] [Figure 11] Figure 11 is a cross-sectional view of a depot according to one embodiment of this technology.

[0023] [Figure 12] Figure 12 is a cross-sectional view of a depot according to one embodiment of this technology.

[0024] [Figure 13] Figure 13 is an isometric view of a depot according to one embodiment of this technology.

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

[0026] [Figure 15] Figure 15 shows the maximum bending load of an implant over time from a test performed on an implant sample immersed in a buffer solution.

[0027] [Figure 16A-C] Figures 16A - 16E show various embodiments of depots including a barrier region according to the technology. [Figure 16D-E] Figures 16A - 16E show various embodiments of depots including a barrier region according to the technology.

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

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

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

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

[0032] [Figure 20] Figure 20 is a perspective view of a depot according to some embodiments of the present technology.

[0033] [Figure 21] Figure 21 is a cross - sectional view of a depot according to some embodiments of the present technology.

[0034] [Figure 22] Figure 22 is a cross-sectional view of a depot according to some embodiments of the present technology.

[0035] [Figure 23] Figure 23 is a cross-sectional view of a depot according to some embodiments of the present technology.

[0036] [Figure 24A] Figure 24A is a perspective view of a depot according to some embodiments of the present technology.

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

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

[0039] [Figure 24D] Figure 24D is a perspective view of a depot according to some embodiments of the present technology.

[0040] [Figure 25] Figure 25 is a perspective view of a depot according to some embodiments of the present technology. ​​​​​​​​​​​​​​​​​​​​​Figure 29A is a side cross-sectional view of a depot according to one embodiment of this technology.

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

[0046] [Figure 30] Figure 30 is a side cross-sectional view of a depot according to one embodiment of this technology.

[0047] [Figure 31] Figure 31 is a side cross-sectional view of a depot according to one embodiment of this technology.

[0048] [Figure 32] Figure 32 is a perspective view of a depot according to one embodiment of this technology.

[0049] [Figure 33] Figure 33 is a side cross-sectional view of a depot according to one embodiment of this technology.

[0050] [Figure 34] Figure 34 is a side cross-sectional view of a depot according to one embodiment of this technology.

[0051] [Figure 35] Figure 35 is a side cross-sectional view of a depot according to one embodiment of this technology.

[0052] [Figure 36A] Figure 36A is a side cross-sectional view of a depot according to one embodiment of this technology.

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

[0054] [Figure 36C]Figure 36C is a side cross-sectional view of a depot according to one embodiment of this technology.

[0055] [Figure 36D] Figure 36D is a side cross-sectional view of a depot according to one embodiment of this technology.

[0056] [Figure 37A] Figure 37A is a side cross-sectional view of a depot according to one embodiment of this technology.

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

[0058] [Figure 38A] Figure 38A is a side cross-sectional view of a depot according to one embodiment of this technology.

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

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

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

[0062] [Figure 40A] Figure 40A is a perspective view of a depot according to one embodiment of this technology.

[0063] [Figure 40B] Figure 40B is a perspective view of a depot according to one embodiment of this technology.

[0064] [Figure 41A]Figure 41A is a side view of a depot in a straight position according to one embodiment of this technology.

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

[0066] [Figure 42A] Figure 42A is a side view of a depot in a straight position according to one embodiment of this technology.

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

[0068] [Figure 43A] Figure 43A is a perspective view of a depot in a straight position according to one embodiment of this technology.

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

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

[0071] [Figure 44] Figure 44 is a side view of a depot deployed at a target site in the body according to one embodiment of this technology.

[0072] [Figure 45] Figure 45 is a side view of a depot deployed at a target site in the body according to one embodiment of this technology.

[0073] [Figure 46] Figure 46 is a side view of a depot according to one embodiment of this technology.

[0074] [Figure 47] Figure 47 is a side view of a depot according to one embodiment of this technology.

[0075] [Figure 48] Figures 48A and 48B are perspective views of a depot according to some embodiments of this technology.

[0076] [Figure 49] Figures 49A to 49C are perspective, top, and side views of a depot according to some embodiments of this technology, respectively.

[0077] [Figure 50A] Figure 50A is an end view of a depot in a rolled state according to one embodiment of this technology.

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

[0079] [Figure 51] Figure 51 shows multiple depots according to some embodiments of this technology.

[0080] [Figure 52A] Figure 52A is an end view of multiple depots according to one embodiment of this technology.

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

[0082] [Figure 52C] Figure 52C shows the method for 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 using this technology.

[0084] [Figure 54] Figure 54 shows the in vitro release profile for the depot described in Example 2A using this technology.

[0085] [Figure 55] Figure 55 shows the in vitro release profile for the depot described in Example 2B using this technology.

[0086] [Figure 56] Figure 56 shows the in vitro release profile for the depot described in Example 3 using this technology.

[0087] [Figure 57A] Figure 57A shows the time course of in vivo plasma bupivacaine concentrations in rabbits implanted with the depot described in Example 4 using this technology.

[0088] [Figure 57B] Figure 57B shows the time-dependent in vivo release profile for the sample depot described in Example 4 using this technology.

[0089] [Figure 57C] Figure 57C shows the time-dependent in vivo plasma bupivacaine concentrations in rabbits implanted with the depot described in Example 4 using this technology.

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

[0091] [Figure 58] Figure 58 shows the in vivo plasma bupivacaine concentration over time for dogs implanted with the depot described in Example 5 using this technology.

[0092] [Figure 59A] Figure 59A shows the in vivo plasma bupivacaine concentration over time for sheep implanted with the depot described in Example 6 using this technology.

[0093] [Figure 59B] Figure 59B shows the in vivo synovial fluid bupivacaine concentration over time for sheep implanted with the depot described in Example 6 using this technology.

[0094] [Figure 59C] Figure 59C is a plot showing the difference between plasma bupivacaine concentration and synovial fluid bupivacaine concentration over time for sheep implanted with the depot described in Example 6 using this technology.

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

[0096] [Figure 60C] Figure 60C shows the time-dependent in vivo plasma bupivacaine concentrations in sheep implanted with the depot described in Example 7 using this technology.

[0097] [Figure 60D] Figure 60D shows the time-dependent in vivo synovial bupivacaine concentration in sheep implanted with the depot described in Example 7 using this technology.

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

[0099] [Figure 60F]Figure 60F is a plot showing the time course of plasma bupivacaine concentration versus synovial fluid bupivacaine concentration for sheep implanted with the depot described in Example 7 using this technology.

[0100] [Figure 61A] Figure 61A shows the time-dependent in vivo plasma bupivacaine concentrations in sheep implanted with the depot described in Example 8 using this technology.

[0101] [Figure 61B] Figure 61B shows the time course of in vivo synovial bupivacaine concentration in sheep implanted with the depot described in Example 8 using this technology.

[0102] [Figure 62] Figures 62A and 62B show common locations in patients 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 depots of this technique may be used to manage postoperative pain. Figure 63 also shows the nerve targets and anatomical access / locations associated with various surgeries. [Figure 63-2] Figure 63 is a table showing common surgical procedures in which depots of this technique may be used to manage postoperative pain. Figure 63 also shows the nerve targets and anatomical access / locations associated with various surgeries. [Figure 63-3] Figure 63 is a table showing common surgical procedures in which depots of this technique may be used to manage postoperative pain. Figure 63 also shows the nerve targets and anatomical access / locations associated with various surgeries.

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

[0105] [Figure 65A] Figure 65A is a dissected view of a human knee, exposing the joint cavity and identifying potential locations for placing one or more depots.

[0106] [Figure 65B] Figure 65B is a dissected view of a human knee, exposing the intra-articular cavity and showing several depots placed internally to manage postoperative pain.

[0107] [Figure 66] Figures 66A and 66B show the extracapsular areas of the anterior and posterior aspects of the human knee, indicating the locations of the nerves that innervate the knee in these extracapsular areas.

[0108] [Figure 67] Figure 67 is a partially enlarged anterior view of a human knee, showing the extracapsular space, and illustrates several depots of this technique placed in the extracapsular space to manage postoperative pain. [Modes for carrying out the invention]

[0109] This technology relates to an implantable depot for sustained, controlled release of a therapeutic agent, as well as related devices, systems, and methods of use. Examples of the depot and associated release kinetics of this technology are described below with reference to Figures 2–52C and Section I. Selected examples of the depot and associated release profiles of this technology are described below with reference to Figures 53–61B and Section II. Selected devices, systems, and methods for using the depot of this 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 depot of this technology to treat postoperative pain associated with other surgeries are described below in Section IV.

[0110] I. Examples of Depotting This Technology As mentioned above, conventional drug delivery systems often suffer from a lack of a true controlled release mechanism, typically resulting in a burst of drug upon contact with surrounding physiological fluids, followed by residual drug release. For example, Figure 1 shows an exemplary conventional biodegradable polymer-based delivery system, where drug concentrations in plasma peak within 15 hours of implantation, thereby demonstrating insufficient duration of action.

[0111] This specification discloses implantable depots and associated 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 in vivo at the treatment site. Many embodiments of the technology include one or more depots configured to be implanted in or near the surgical site of a patient 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 prescribed manner for at least three days after implantation.

[0112] As used herein, “depot” means a controlled dose of at least one therapeutic agent. The composition comprises a composition configured to be administered to a treatment site in the patient's body by a continuous method. The depot also includes the therapeutic agent itself. The depot may include a physical structure or carrier configured to perform or enhance one or more functions related to the treatment, such as facilitating implantation and / or retention at the treatment site (e.g., intra-articular and / or extra-articular space tissue of the knee joint), modulating the release profile of the therapeutic agent (e.g., creating a two-phase release profile), increasing release toward the treatment site, reducing release away from the treatment site, or a combination thereof. In some embodiments, “depot” includes, but is not limited to, films, sheets, fragments, ribbons, capsules, coatings, matrices, wafers, pills, pellets, or other drug delivery devices, or combinations thereof. Furthermore, as used herein, “depot” may refer to a single depot or to a number of depots. For example, the statement "The depot may be configured to release 2 g of the therapeutic agent to the treatment site" describes (a) a single depot configured to release 2 g of the therapeutic agent to the treatment site, and (b) multiple depots configured together to release 2 g of the therapeutic agent to the treatment site.

[0113] Figure 2 is an isometric view of an implantable depot 100 according to several embodiments of the present technology. The depot 100 may be a thin multilayer polymer film configured to be implanted at a treatment site, comprising a treatment area 200 containing a therapeutic agent (such as an analgesic) and a control area 300 configured to regulate the release of the therapeutic agent from the depot 100 in a controlled and sustained manner. The depot 100 may contain a therapeutic agent with a higher therapeutic payload compared to other known films of equal 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, the depot 100 contains at least 50% by weight of the therapeutic agent.

[0114] The control region 300 may contain at least one bioabsorbable polymer and at least one release agent mixed with this polymer, and the therapeutic region 200 may contain at least one bioabsorbable polymer, at least one release agent mixed with this polymer, and a therapeutic agent. The control region 300 may optionally contain a therapeutic agent, or it may not contain a therapeutic agent at all. The therapeutic region 200 may optionally not contain a release agent at all. The release agent in the control region 300 may be the same as or different from the release agent in the therapeutic region 200. The bioabsorbable polymer in the control region 300 may be the same as or different from the bioabsorbable polymer in the therapeutic region 200. In some embodiments, as detailed below, the therapeutic region 200 and / or the control region 300 may have different components and / or formulations.

[0115] When exposed to a fluid (e.g., a physiological fluid), the release agent can have a dissolution rate faster than the degradation rate of the bioabsorbable polymer. Therefore, when the fluid comes into contact with the depot 100 (e.g., after implantation of the depot 100 at the 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 emptied 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 the release of the therapeutic agent from the polymer region and into the surrounding physiological fluid. In some embodiments, the rate of therapeutic agent release is faster when there are diffusion openings in the polymer region compared to when there are no diffusion openings in the polymer region.

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

[0117] The position and / or geometry of the control region 300 can be configured to modulate the release profile of the therapeutic agent from the therapeutic region 200. As shown in Figure 2, at least a portion of the control region 300 may be positioned on or adjacent to the therapeutic region 200 such that when the depot 100 is first placed in vivo, the control region 300 is between at least a portion of the therapeutic region 200 and the physiological fluid of the treatment site. For example, the control region 300 can cover all or part of one or more surfaces of the therapeutic region 200. When the depot 100 is exposed to the physiological fluid, the therapeutic agent elutes from the exposed surface of the therapeutic region 200 through the control region 300 using the diffusion opening created by the dissolution of the releasing agent. Generally, the therapeutic agent elutes from the exposed surface of the therapeutic region 200 at a faster (e.g., greater) rate than it passes through the control region 300. As a result, the control region 300 extends the release of the therapeutic agent from the therapeutic region 200, resulting in a longer release time. This adjusts the drug administration rate, for example, to avoid complications associated with overdose, so that the desired degree of pain relief is achieved.

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

[0119] As shown in Figure 3, in many embodiments, the depot 100 (or system of depot 100) is configured to release a disproportionately large volume of the therapeutic agent per day over a first period compared to a longer second period. In some embodiments, the depot 100 (or system of depot 100) is configured to release the therapeutic agent for at least 14 days after implantation (or immersion in the fluid), with about 20% to 50% of the therapeutic agent payload being released in a controlled burst during 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 day 14.

[0120] Two-stage, secondary release profiles, such as those shown in Figure 3, can be particularly beneficial in the context of managing pain resulting from total knee arthroplasty ("TKA"). Patients undergoing TKA typically experience maximum 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 coincides with or is concurrent with the patient's hospitalization (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 is also 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 hospitalization, cause psychological distress, increase opioid consumption, and / or impair patient participation in physical therapy, all of which can delay and / or reduce the degree of recovery. Pain relief during the subacute period is important when the patient transitions from hospital to home environment. Patient compliance with prescribed pain management regimens may be reduced, making management particularly complex.

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

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

[0123] In some embodiments, the depot 100 is configured to release 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the therapeutic agent on day 1, 2, 3, 4, 5, 6, 6, 7, or 13 of the release duration, with at least 75%, 80%, 85%, 90%, 95%, or 100% of the remaining therapeutic agent being released over 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 cases, 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 Depot 100 during the duration of the intended treatment. The duration of the intended treatment is 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. It may be 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, Depot 100 is configured to release approximately 50 mg / day to approximately 600 mg / day, 100 mg / day to approximately 500 mg / day, or approximately 100 mg / day to approximately 400 mg / day, or approximately 100 mg / day to approximately 300 mg / day of the therapeutic agent to the treatment site. Generally, the release rate can be selected to deliver the desired dosage to provide the required degree of pain relief within a given time after the surgical procedure, control toxicity, and deliver the therapeutic agent for a sufficient period of time for pain relief.

[0126] In some embodiments, Depot 100 is configured to release approximately 50 mg / day to approximately 600 mg / day, approximately 100 mg / day to approximately 500 mg / day, or approximately 100 mg / day to approximately 400 mg / day, or approximately 100 mg / day to approximately 300 mg / day of the therapeutic agent to the treatment site during a first release period. Depot 100 can further be configured to release approximately 500 mg / day to approximately 600 mg / day, approximately 100 mg / day to approximately 500 mg / day, or approximately 100 mg / day to approximately 400 mg / day, or approximately 100 mg / day to approximately 300 mg / day of the therapeutic agent to the treatment site during 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, Depot 100 contains 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, and less than 50 mg, and at least 90 mg by any day of the first release period. It 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 the therapeutic agent. This may be useful in providing varying degrees of pain relief at different times after surgical procedures and may also be useful in controlling toxicity.In such an embodiment, Depot 100 is released by any day of the second release period at a dose of 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, and less Each may be configured to release 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 the therapeutic agent. The first release period and / or the second release period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 days. The period may be 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. Depot 100 may be configured to release the therapeutic agent at a first rate during the first period and at a second rate during the 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 come before or after 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 the therapeutic agent by any day of the release period.

[0129] In some embodiments, Depot 100 is configured to release a therapeutic agent to the treatment site in vivo and / or in the presence of one or more fluids 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.

[0130] The release kinetics of the depot in this technology may be tailored to specific applications by altering one or more aspects of the depot's structure and / or composition, such as the exposed surface area of ​​the therapeutic 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 therapeutic region, the post-production properties of the polymer, the structural integrity of the depot to avoid abrupt release of the therapeutic agent, the relative thickness of the therapeutic region 200 compared to the control region 300, and other properties of the depot. Several embodiments of the depot in this technology, combined with one or more of these properties, are intended to produce exceptional two-phase 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 shown a two-phase release profile that delivers an appropriate mass of therapeutic agent over 14 days to treat pain associated with joint replacement surgery or other applications, while maintaining sufficient structural integrity to withstand joint forces to avoid abrupt release of too much therapeutic agent. This unexpected result suggests that the depot application of this technology could, if not replace opioids, at least reduce opioid use and / or enhance other existing pain relief systems in orthopedic surgery applications, non-orthopedic surgery applications, and other applications (e.g., oncology).

[0131] For example, the release profile can be adjusted, at least in part, by controlling the amount of exposed surface area of ​​the treatment area 200, because a depot having a treatment area 200 that is only partially covered by a control area 300 (see, e.g., Figures 2, 4-8, and 13) will generally release a higher proportion of the total payload over a shorter period of time compared to embodiments in which the treatment area 200 is completely encapsulated by the control area 300 (see, e.g., Figures 9A-12). More specifically, a depot design having a treatment area 200 with an exposed surface will typically release the therapeutic agent over a first period at a high, substantially linear rate, and then over a second period at a lower, substantially linear rate. Alternatively, it may be substantially covered by one or more control areas 300. A depot design having a therapeutic area 200 with a surface that can be treated can achieve zero-order release such that the release of the therapeutic agent payload is substantially the same rate.

[0132] As shown in Figure 4, in some embodiments, the depot 100 may include a multilayer polymer film having a treatment area 200 and first and second control areas 300a, 300b placed on opposing surfaces 100a, 100b of the treatment area 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 is (a) approximately 5-40 mm, approximately 10-30 mm, approximately 15-20 mm, approximately 20-35 mm, approximately 20-30 mm, approximately 20-25 mm, approximately 26-30 mm, approximately 5 mm, approximately 10 mm, approximately 11 mm, approximately 12 mm, approximately 13 mm, approximately 14 mm, approximately 15 mm, approximately 16 mm, approximately 17 mm, approximately 18 mm, approximately 19 mm, approximately 20 mm, approximately 21 mm, approximately 22 mm, approximately 23 mm, approximately 24 mm, approximately 25 mm, approximately 26 mm, approximately 27 mm, approximately 28 mm, approximately 29 mm, approximately 30 mm, approximately 10 (b) Lengths L of ~15mm, approx. 12~16mm, approx. 15~20mm, approx. 21~23mm, approx. 22~24mm, approx. 23~25mm, approx. 24~26mm, approx. 25~27mm, approx. 26~28mm, approx. 27~29mm, or approx. 28~30mm, (b) approx. 5~40mm, approx. 10~30mm, approx. 15~20mm, approx. 20~35mm, approx. 20~30mm, approx. 20~25mm, approx. 26~30mm, approx. 5mm, approx. 10mm, approx. 11mm, approx. 12mm, approx. 13mm, approx. 14mm, approx. 15mm, approx. 16mm, approx. 17 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 It has a height H of approximately 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 L × W × H of approximately 26 mm × approximately 16 mm × approximately 1 mm, and in some embodiments, it may be approximately 27 mm × approximately 17 mm × approximately 1 mm.In some embodiments, the depot 100 may have other shapes and / or dimensions, such as those detailed below.

[0133] Furthermore, in some embodiments of the depot shown in Figure 4, the thickness of the control regions 300a and 300b is configured to be less than or equal to 1 / 10 of the thickness of the treatment region 200, individually or collectively. The thickness of the control regions 300a and 300b can be further reduced to 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 of the thickness of the treatment region 200, individually or collectively. In embodiments having multiple sub-control regions, one or more 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 embodiments in which the control region includes a single control region, the control region has a thickness of less than or equal to 1 / 100 of the thickness of the treatment region. In embodiments having multiple sub-control regions, one or more 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 depot thickness. In embodiments in which the control region includes a single control region, the control region may have a thickness of 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 depot thickness.

[0134] The control regions 300a and 300b may only cover a portion of the treatment region 200 so that a portion of each of the sides (e.g., the 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%, and about 10% of the surface area of ​​the depot 100. In some embodiments, at least prior to implantation, the ratio of the exposed surface of the treatment area 200 to the exposed surface of the control area 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 and 300b only need to cover a portion of the treatment region 200 so that a portion of each surface (e.g., the sidewall) of the treatment region 200 is exposed to the physiological fluid immediately after the depot 100 is implanted in vivo. Once the depot 100 is exposed to the physiological fluid (or any similar fluid in the in vitro setting), the therapeutic agent begins to elute from the exposed surface 202 (in addition to passing through the control regions 300a and 300b), resulting in a faster release of the therapeutic agent than if the treatment region 200 had no exposed area. Therefore, the surface area of ​​the exposed surface 202 may be adjusted to provide an initial control burst followed by a gradually decreasing release (e.g., similar to that shown in Figure 3). The initial, more aggressive release of the therapeutic agent is slowed in part by the control regions 300a and 300b, which initially reduce the surface area of ​​the treatment region 200 exposed to the fluid. Unlike Depot 100 of this technology, many conventional drug dissolution technologies result in an initial, uncontrolled burst release of the drug upon exposure to physiological fluids. Some embodiments of Depot of this technology can not only embed enough therapeutic agent for several days or weeks' worth of dosage to achieve sustained, durable in vivo pharmacological treatment, but also release the therapeutic agent as prescribed, thereby preventing a significant portion of the total payload from being released in an uncontrolled manner that could lead to complications in the patient and / or reduce the remaining payload, resulting in insufficient 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 approximately 20% to 50% of the analgesic during the first approximately 3 to 5 days of the 14-day period, with at least 80% of the remaining analgesic released during the last approximately 9 to 11 days of the 14-day period. This release profile provides a higher dose of the therapeutic agent during the acute postoperative period compared to the subacute period. In some embodiments, the depot 100 shown in Figure 4 is configured to release approximately 100 mg to 500 mg of analgesic per day to the treatment site, and in some cases, 400 mg or less or 300 mg or less of analgesic per day during the first 3 days after implantation, and It is configured to release no more than 200 mg per day for the remaining days.

[0137] Some embodiments of Depot 100 shown in Figure 4 are also configured to maintain its structural integrity even after a substantial portion of the release agent has eluted from Depot 100. As the release agent(s) dissolve and the therapeutic agent(s) elute, the functional mechanical aspects of 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 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 Depot 100 shown in Figure 4 are loaded with enough therapeutic agent to deliver 100 mg to 500 mg of therapeutic agent per day while the Depot still maintains its structural integrity so that it remains largely intact for at least 14 days after implantation. The Depot can be considered sufficiently intact if, for example, it is not broken into numerous small components, and two or more of the resulting small components are at least 5% of the original size of the Depot. 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 times compared to the release rate of the therapeutic agent in a control depot immersed in buffer solution.

[0138] The therapeutic agent may be at least 50% to 95% by weight of the total weight of Depot 100 before implantation, or 55% to 85% by weight of the total weight of Depot 100 before implantation, or 60% to 75% by weight of the total weight of Depot 100 before implantation. Similarly, the polymer may be 5% to 50% or less by weight of the total weight of Depot 100 before implantation, or 10% to 50% by weight of the total weight of Depot 100 before implantation, or 15% to 45% by weight of the total weight of Depot 100 before implantation, or 20% to 40% or less by weight of the total weight of Depot 100 before implantation, or 25% or less, 30% or less, 35% or less, or 40% or less. The ratio of the mass of the therapeutic agent in depot 100 to the mass of the polymer in 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] Several embodiments of the depot 100 shown in Figure 4, having one or more combinations of the parameters described in the preceding paragraph, yielded 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, individually or collectively, was less than or equal to 1 / 50 of the thickness of the treatment region 200; (b) the mass of the therapeutic payload was sufficient to release about 100 mg to about 500 mg of analgesic per day to the treatment site; and (c) structural integrity was such that the majority of the depot remained intact for at least 14 days after implantation. These embodiments were able to release about 20% to about 50% of the analgesic payload in the first about 3 to about 5 days of the 14 days, and then at least 80% of the remaining analgesic payload in the last about 9 to about 11 days of the 14 days. This was at least in part because (a) by providing such a large payload of therapeutic agent in the therapeutic area, it was anticipated that mechanical failure of Depot 100 would occur on or before day 14 post-implantation, and (b) the disclosed device did not achieve a release profile in which approximately 20% to approximately 50% of the analgesic was released in the first approximately 3 to approximately 5 days of the 14 days, and then at least 80% of the remaining analgesic was released in the last approximately 9 to approximately 11 days of the 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 Figure 5, the depot 100 may have a first control region 300a and a second control region 300b, each of which includes 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 be the same or different in quantity. The release agent may have the same or different concentrations of the release agent, the same or different amounts of the release agent, the same or different amounts of the polymer, the same or different polymer, the ratio of the same or different polymer to the release agent, and / or the same or different thicknesses. In some embodiments, the concentration of the release agent in the individual outer control subregions 302a, 302d is lower than the concentration of the release agent in the individual inner control subregions 302b, 302c, so that the outer portion of the collective control region elutes the therapeutic agent more slowly than the inner portion of the collective control region. In some embodiments, the concentration of the release agent in the individual outer control subregions 302a, 302d is higher than the concentration of the release agent in the individual inner control subregions 302b, 302c. In embodiments in which the control region includes more than two subregions, the concentration of the release agent per subregion or layer may increase, decrease, or remain constant as the subcontrol regions are further away from the therapeutic region 200.

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

[0142] Figures 6-8 show embodiments of a depot according to the present technology having multiple alternating treatment regions 200 and control regions 300. A depot 100 may have two or more control regions 300 and / or sub-regions 302 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and a depot 100 may have one or more treatment regions 200 and / or sub-regions 202 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one control region 300 and / or sub-region 302. In some embodiments, each of the treatment regions 200 may contain a single layer, and / or each of the control regions 300 may contain a single layer. In some embodiments, one, some, or all of the treatment regions 200 may contain a multilayer, and / or one, some, or all of the control regions 300 may contain a multilayer. In some embodiments, as shown, for example in Figures 6 and 7, two or more subregions 302a-b (Figure 6) and 302a-b and 302c-d (Figure 7) may be adjacent to each other among the subregions 202 of the therapeutic region 200. Furthermore, one or more of the individual control regions 300 and / or one or more of the therapeutic regions 200 may have the same or different amounts and / or types of releasing agents, and one or more of the therapeutic 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 therapeutic area contains a large payload of the therapeutic agent (e.g., equivalent to a dosage for many days, weeks, or months). These embodiments may be beneficial because if the therapeutic area 200 is unexpectedly exposed in the body by such a large payload, the entire payload will be released prematurely, exposing the patient to an abnormal and undesirable high dose of the therapeutic agent. For example, if the integrity of the control area 300 is compromised, the patient may be exposed to the therapeutic agent in vivo at a faster rate than intended, possibly resulting in clinical complications. In particular, with regard to the administration of local anesthetics (e.g., bupivacaine, ropivacaine, etc.), manufacturing guidelines state that doses of 400 mg or less should be administered for 24 minutes. It is recommended that the drug be administered within a specified time period. However, numerous studies have demonstrated that doses higher than 400 mg from long-release products are safe due to their slow release over a longer period. Nevertheless, if the control region 300 is compromised, it is desirable that the patient be exposed to only a portion of the total payload, so that the portion to which the patient is exposed, if released early, is considered safe with respect to the particular therapeutic agent. The structural integrity of the control region 300, as well as the structural integrity of the therapeutic region(s) 200, are important properties for large depots of therapeutic agents that will be delivered over a longer period.

[0144] To address this concern, in some embodiments of the present technology, the depot 100 may include a number of therapeutic regions 200 separated by one or more control regions 300 (for example, as shown in Figures 6-8). Such a configuration individually isolates the therapeutic agent (loading a portion of the total payload) in each therapeutic region 200. If a particular control region is impaired, only the portion of the payload corresponding to the therapeutic region associated with the impaired control region may be released prematurely. For example, in some of the embodiments described above, the total payload of the depot 100 may be a therapeutic agent such as an analgesic (e.g., bupivacaine, ropivacaine, etc.) in amounts of 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. Similarly, in some embodiments, the portion of the payload of each therapeutic region or subregion may be up to 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the total payload contained within the depot 100. As a result, if any single subregion 202 of the therapeutic region 200 is damaged, it may release only a proportional proportion of the total payload of the depot.

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

[0146] Figures 9A–911 illustrate some embodiments of the present technology in which the depot 100 may have one or more treatment areas 200 that are completely enclosed or surrounded by one or more control areas 300. In contrast to the embodiments described above, at least one treatment area in such completely enclosed embodiments has no exposed surface area whatsoever. In some embodiments, as shown for example in Figures 9A and 9B, the depot 100 may include a treatment area 200 that is enclosed or completely surrounded by a control area 300 such that no portion of the treatment area 200 is exposed through the control area 300. As a result, the control area 300 substantially prevents contact between the therapeutic agent and the physiological fluid, thereby preventing uncontrolled burst release of the therapeutic agent when implanted. Over time, the release agent embedded in the polymer of the control area 300 comes into contact with the physiological fluid, dissolves, and thereby forms a diffusion opening in the control area. The combination of the restrictions imposed by the control area and the diffusion opening formed by the dissolution of the release agent allows for controlled release of the therapeutic agent from the depot over days, weeks, or months. Depot 100 is shown as a rectangular thin film in Figures 9A and 9B, but in other embodiments, depot 100 may have other shapes, sizes, or forms.

[0147] Figure 10 shows a depot 100 having a treatment area 200 completely surrounded by a control area 300 having a first control area 300a and a second control area 300b. As shown in Figure 10, in some embodiments, the treatment area 200 is comprised of a first control area 300a and a second control area 300b. The first and second control regions 300a-b may be sandwiched between the treatment region 300b, and the first and second control regions 300a-b may be bonded together by thermal compression around the treatment region 200 so as 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 surface to create a control region structure similar to that shown in Figure 9A. The outer portions of the first and second control regions 300a-b may be incorporated as a final wrap layer to seal the edges. Furthermore, the first and second control regions 300a-b can be integrally formed with each other using immersion coating and / or spray coating techniques, such as immersing the treatment region 200 in 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 Figure 10, the first control region 300a may have first and second sub-regions 302a-b, and the second control region 300b may have first and second sub-regions 302c-d. The first control region 300a may define a top control region member, and the first and second sub-regions 302a-b may include a first top control layer and a second top control layer, respectively. The second control region 300b may define a bottom control region member, and the first and second sub-regions 302c-d may include a first bottom control layer and a second bottom control layer, respectively. The first and second top / bottom control layers may be any modified form of the first and second control sub-regions discussed above with respect to Figure 5. Furthermore, the first top control layer of the top control region member may have the same or different properties as the first bottom control layer of the bottom control region member (e.g., thickness, polymer, release agent, release agent concentration, total amount of release agent, ratio of polymer to release agent, etc.). 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 of layer loading and structure may be designed within the depot 100 to achieve a release profile or dynamics suitable for the intended therapeutic purpose. In other embodiments, the first control region 300a and / or the second control region 300b have a single layer.

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

[0150] Figure 12 shows a cross-section of a spherical depot 100 according to several embodiments of the present technology, having multiple alternating treatment regions 200 and control regions 300. 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 has at least one control region 300. Therefore, it may have one or more surrounded therapeutic regions 200 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.). In some embodiments, each therapeutic region 200 may contain a single layer, and / or each control region 300 may contain a single layer. In some embodiments, one, some, or all of the therapeutic regions 200 may contain a multilayer, and / or one, some, or all of the control regions 300 may contain a multilayer. Furthermore, one or more of the individual control regions 200 and / or one or more of the therapeutic regions 300 may have the same or different amounts and / or types of releasing agents, and one or more of the therapeutic regions 200 may have the same or different amounts and / or types of therapeutic agents.

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

[0152] The release kinetics of the depot in this technology may be adjusted to suit specific application cases by changing the shape and size of the depot 100. Depending on the therapeutic drug delivery needs, anatomical targets, etc., the depot 100 can be made to different sizes, shapes, and forms to suit 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 in the target tissue site and to reduce or completely prevent the possibility of the depot moving after implantation or injection. This is especially true for depots placed in joints (such as the knee joint), in which case the depot is a flexible solid that is structurally possible to handle by a clinician in the normal course of surgery without breaking into numerous small pieces and / or losing its overall shape. Furthermore, the depot may be configured to be placed in the patient's knee and to release analgesic in vivo for up to 7 days without breaking into numerous small pieces.

[0153] Some of the shape factors that can be generated from or will be used attached to the Depot 100 for implantation and fixation in the body include strips, ribbons, hooks, rods, tubes, patches, corkscrew-shaped ribbons, partial or complete rings, nails, screws, rivets, threads, tapes, woven shapes, T-shaped anchors, staples, discs, pillows, balloons, braids, tapered shapes, wedge shapes, chisel shapes, castle shapes, stent structures, suture buttresses, coil springs, sponges, capsules, coatings, matrices, wafers, sheets, strips, ribbons, pills, and pellets.

[0154] Depot 100 may be processed into components of the shape factor described in the preceding paragraph. For example, the depot may be wound into a tube, incorporated into a screw, a rivet, or the like. In the case of a woven embodiment, the depot may be incorporated into a multilayer woven film / braid / mesh, in which case some of the filaments used are not the devices of the present invention. In one example, the depot is woven together with Dacron, polyethylene, or the like. For clarity, any shape factor corresponding to the depot of this technology, including those in which only a part or fragment of the shape factor incorporates the depot, may be referred to herein as a “depot.”

[0155] As shown in the cross-sectional views of Figures 14A to 14H, in various embodiments, the depot 100 can be formed into a sphere, a cylinder such as a rod or fiber, a plane such as a disc, a film, a ribbon, a strip or sheet, a paste, a slab, fine particles, nanoparticles, pellets, a mesh, or the like. Figure 14A shows a depot 100 enclosed by straight lines. Figure 14B shows a circular depot 100. Figure 14B shows a triangular depot 100. Figure 14D shows a cross Figure 14E shows a U-shaped depot 100, Figure 14F shows a star-shaped depot 100, Figure 14G shows a spheroidal depot 100, and Figure 14H shows a cylindrical depot 100. The shape of the depot 100 can be selected according to the anatomical structure to fit within a given space and can provide the desired fixation and flexibility. This is because the fit, fixation, and flexibility of the depot can increase the ease of implanting the depot, ensure delivery of the therapeutic agent to the target site, and extend the durability of the implant at the dynamic implantation site.

[0156] In various embodiments, the depots may be of various sizes, for example, they may be about 0.4 mm to 100 mm in length and may have a diameter or thickness of about 0.01 to about 5 mm. In various embodiments, the depots may have a layer thickness of about 0.005 to 5.0 mm, for example, 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 (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 embodiments having multiple sub-control regions, one or more sub-control regions may individually be equal to or less than 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 embodiments in which the control region includes a single control region, the control region may have a thickness of 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 embodiments having multiple sub-control regions, one or more sub-control regions may individually be equal to or less than 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 depot thickness.In embodiments in which the control region includes a single control region, the control region may have a thickness of 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 depot thickness.

[0158] In some embodiments, the depot 100 has a width and a thickness, and the ratio of the width to the 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 It is greater than that, 29 or greater than that, 30 or greater than that, 35 or greater than that, 40 or greater than that, 45 or greater than that, or 50 or greater than that.

[0159] In some embodiments, the depot 100 has a surface area and 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 embodiments described above with respect to Figures 2-14H, the dissolution of the release agent(s) and the elution of the therapeutic agent(s) may alter 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, undesirable degradation of Depot 100, such as premature degradation, may lead to mechanical failure of Depot 100, as well as the corresponding undesirable 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, at least for a predetermined period of time or until a predetermined percentage of the therapeutic agent has been released from Depot 100. Depot 100 can be considered to maintain its structural integrity if it remains largely intact and undergoes only partial or gradual reduction due to the elution of the therapeutic agent or the dissolution of the control layer or release agent. Depot 100 can be considered to have lost its structural integrity if it separates (e.g., is crushed) into numerous constituent fragments, and, for example, two or more of the resulting fragments are at least 5% of the original size of Depot 100. Alternatively, or additionally, Depot 100 can be considered to have lost its structural integrity if the release rate of the therapeutic agent increases by more than three times compared to the release rate of the therapeutic agent in a control depot immersed in a buffer solution.

[0161] In some cases, Depot 100 is configured to maintain its structural integrity in vivo for at least a predetermined period of time. For example, 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 is released from the depot. For example, the depot 100 is configured to maintain its structural integrity in vivo until at least 5% by weight of the initial payload is released, until at least 10% by weight of the initial payload is released, until at least 15% by weight of the initial payload is released, until at least 20% by weight of the initial payload is released, until at least 25% by weight of the initial payload is released, until at least 30% by weight of the initial payload is released, until at least 35% by weight of the initial payload is released, until at least 40% by weight of the initial payload is released, until at least 45% by weight of the initial payload is released, until at least 50% by weight of the initial payload is released, until at least 55% by weight of the initial payload is released, until at least 60% by weight of the initial payload is released. It can be configured to maintain until it 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 Depot 100 can be quantified, when it is in vivo, by using a three-point bending test that measures bending properties, including the bending strength and / or maximum bending stress sustained by a specimen before fracture. Such a bending test may represent (e.g., simulate) the forces that Depot 100 would encounter in vivo at an anatomical joint (e.g., the knee joint). In one example, Depot can be subjected to a three-point bending test based on 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. Depot 100 is in The depot may be suspended at approximately 37°C in a medium configured to simulate vivo conditions, such as phosphate-buffered saline (PBS). The bending test may be performed after various immersion periods in the medium to evaluate the change in the bending strength of depot 100 over time under simulated in vivo conditions.

[0164] Table 1 shows the maximum bending loads sustained by four different samples of Depot 100 at various time intervals after immersion in the medium, measured using a three-point bending test with a maximum deflection set at 2.13 mm. The values ​​in Table 1 reflect the measurements obtained from two cases for 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 a treatment area 200 surrounded by upper and lower control areas 300a-b, as shown and described above with reference to Figure 4 or 5. The treatment area 200 has exposed sides 202 between the first and second control areas 300a-b. Each Depot 100 has transverse dimensions of approximately 2.5 cm × 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 PDLLA:PGA:PCL 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 first control region 300a containing a single control layer on the upper surface of the therapeutic region 200, and a second control region 300b containing a single control layer on the lower surface of the therapeutic region 200, as shown and described above with reference to Figure 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 treatment region 200 in which the weight ratio of release agent to polymer to therapeutic agent is 1:10:20. In this sample, the polymer is PLGA with a PLA:PGA ratio of 1:1, 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 which comprises a first control region 300a having a single control layer on the upper surface of the treatment region 200, and a second control region 300b having a single control layer on the lower surface of the treatment region 200, as shown and described above with reference to Figure 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 area of ​​200 with a weight ratio of release agent to polymer to therapeutic agent of 5:10:20. The polymer in this sample has a ratio of PDLLA:PGA:PCL. The polymer is P(DL)GACL in a 6:3:1 ratio, 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 Figure 5, which includes a first control region 300a having two sub-control regions 302a-b on the upper surface of the therapeutic 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 is in contact with the surface of the therapeutic region 200 and has a release agent-to-polymer ratio of 5:10, while 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 PLA:PGA ratio of 1:1, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. Similar to 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 therapeutic region 200 and two on the lower surface of the therapeutic region 200. The inner side of sub-control regions 302b and 302c has a ratio of release agent to polymer of 5:10, while the outer side of sub-control regions 302a and 302d has a ratio of release agent to polymer of 1:10. [Table 1]

[0169] As shown in Table 1, all samples remained intact and withstood the pre-fracture flexural forces while maintaining sufficient structural integrity after 14 days of suspension in the medium. Although the maximum load withstood by each sample decreased over time, the flexural strength of these samples on day 14 was sufficient to maintain the structural integrity desired for implantation in active joints such as the knee or shoulder. As indicated above, in the case of two samples tested on day 28, the samples degraded and therefore could not be tested as they were no longer structurally intact. In such cases, it is desirable to configure the depot so that all or substantially all of the therapeutic payload is released from the depot before the depot degrades and loses its 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. Nevertheless, on days 7–14, the depots were still fully functionally intact. Not bound by theory, after the therapeutic agent eluted, the depots gradually became empty polymer matrix. It is thought that, 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 reduced resistance to bending loads.

[0171] As described above, Depot 100 may be advantageous in that it maintains its structural integrity and flexural strength even if the therapeutic payload gradually degrades as it is released into the body. In some embodiments, Depot 100 utilizes a three-point bending test in In a microscopic test, after immersion in PBS for a predetermined period, the flexural strength of Depot 100 can be configured to decrease 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%. In various embodiments, the predetermined period during which Depot 100 is immersed in PBS before being subjected to a three-point bending test is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 days, or longer. In at least some embodiments, the change in the bending strength of Depot 100 can be measured between day 0 (e.g., before immersion in PBS) and subsequent time after immersion in PBS for a certain period. In other embodiments, the change in the bending strength of Depot 100 can be measured between day 1 (e.g., after immersion in PBS for 24 hours) and subsequent time after longer immersion in PBS.

[0172] In some embodiments, the depot 100 may be configured to decrease in flexural strength 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 payload is released while the depot 100 is immersed in PBS, in an in vitro test utilizing a three-point flex test. In various embodiments, a predetermined percentage of the 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 described above, in at least some embodiments, the change in the bending strength of Depot 100 can be measured between day 0 (before immersion in PBS) or day 1 (after 24 hours of immersion in PBS) and subsequent time after longer immersion in PBS.

[0173] In some embodiments, the depot 100 has (a) a transverse dimension of about 1.0 to 3.0 cm, (b) a thickness of about 0.5 to 2.5 mm, and (c) a therapeutic agent payload sufficient to release about 100 mg to about 500 mg of the therapeutic agent per day over up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, and the depot 100 is configured to remain mechanically intact enough to provide sustained controlled release of the therapeutic agent for at least 7 days. Such embodiments of the depot 100 may include a therapeutic area 200 and a control area 300 containing the therapeutic agent. The control area 300 may have first and second control areas 300a to b as shown and described above with reference to Figures 4 to 13, and the control area 300 contains a bioabsorbable polymer and a release agent mixed with this bioabsorbable polymer. The release agent is configured to dissolve when the depot 100 is placed in vivo, forming a diffusion opening within the control region 300. The depot 100 is further immersed in a buffer solution for 7 days, after which the flexural strength of the depot 100 is reduced to a maximum of 75%, or a maximum of 70%, or a maximum of 65%, or a maximum of 75%. It is configured to reduce by a maximum of 60%, or up to 55%, or up to 50%, or up to 45%.

[0174] In some embodiments, the depot 100 has (a) a transverse dimension of about 1.0 to 3.0 cm, (b) a thickness of about 0.5 to 2.5 mm, and (c) a therapeutic agent payload sufficient to release about 100 mg to about 500 mg of the therapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, and the depot 100 is configured to remain sufficiently mechanically intact to provide sustained controlled release of the therapeutic agent for at least 7 days. Such embodiments of the depot 100 may include a therapeutic agent 200 having the therapeutic agent and a control region 300. The control region 300 may have first and second control regions 300a to b as shown and described above with reference to Figures 4 to 13, and the control region 300 includes a bioabsorbable polymer and a release agent mixed with this bioabsorbable polymer. The release agent is configured to dissolve when the depot 100 is placed in vivo, forming a diffusion opening within the control region 300. The depot is further configured to reduce the flexural strength of the depot 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%, after the depot has been immersed in the buffer solution until approximately 75% by weight of the therapeutic agent has been released.

[0175] A. Treatment area The total payload and release dynamics of the depot 100 of this technology can be adjusted to suit specific applications by changing the composition of the therapeutic region 200. In many embodiments, the therapeutic region 200 may contain a therapeutic agent with a higher therapeutic payload compared to other known polymer devices of equal thickness or polymer weight percentage. For example, the depot 100 of this technology may contain at least 15% by weight of the therapeutic agent, at least 20% by weight of the therapeutic agent, at least 25% by weight of the therapeutic agent, at least 30% by weight of the therapeutic agent, at least 35% by weight of the therapeutic agent, at least 40% by weight of the therapeutic agent, at least 45% by weight of the therapeutic agent, at least 50% by weight of the therapeutic agent, at least 55% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, at least 65% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 75% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, at least 85% by weight of the therapeutic agent, at least 90% by weight of the therapeutic agent, at least 95% by weight of the therapeutic agent, or 100% by weight of the therapeutic agent.

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

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

[0178] In any of the depot embodiments disclosed herein, the ratio of the mass of the therapeutic agent in the depot to the mass of the 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 depot embodiments disclosed herein, the ratio of the mass of the polymer in the therapeutic region 200 to the mass of the 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 the release agent to the polymer in the therapeutic 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 therapeutic area 200 is approximately 0.1:10:20 to approximately 2:10:20, approximately 0.1:10:20 to approximately 1:10:20, approximately 0.1:10:20 to approximately 0.5:10:20, approximately 0.5:10:20 to approximately 0.1:10:20, or approximately 0.5:10:20 to approximately 1:10:20.

[0182] In any embodiment disclosed herein having a single therapeutic area 200, the therapeutic area 200 is approximately 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, and 15 μm to 50μm, approx. 15μm, approx. 20μm, approx. 25μm, approx. 30μm, approx. 35μm, approx. 40μm, approx. 45μm, approx. 50μm, approx. 55μm, approx. 60μm, approx. 65μm, approx. 70μm, approx. 75μm, approx. 80μm, approx. 85μm, approx. 90μm, approx. 95μm, approx. 100μm, 100μm to 2mm, 100μm to 1.5mm, 100μm to 1mm, from 100μm 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, It may have a thickness of 800 μm to 1.1 mm, approximately 200 μm, approximately 300 μm, approximately 400 μm, approximately 500 μm, approximately 600 μm, approximately 700 μm, approximately 800 μm, approximately 900 μm, approximately 1 mm, approximately 1.1 mm, approximately 1.2 mm, approximately 1.3 mm, approximately 1.4 mm, approximately 1.5 mm, approximately 1.6 mm, approximately 1.7 mm, approximately 1.8 mm, approximately 1.9 mm, or approximately 2 mm.

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

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

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

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

[0187] In embodiments disclosed herein, where the therapeutic region 200 comprises multiple therapeutic regions or sub-regions, some or all of the therapeutic regions or sub-thermal regions may have the same or different amounts of release agent, the same or different concentrations of release agent, the same or different release agent, the same or different amounts of polymer, the same or different polymer, the same or different polymer to the release agent ratio, the same or different amounts of therapeutic agent, the same or different types of therapeutic agent, and / or the same or different thicknesses. Furthermore, a single therapeutic region or sub-region may have a single type of polymer or multiple types of polymer, a single type The system may contain a release agent or multiple types of release agents, and / or a single type of therapeutic agent or multiple types of therapeutic agents. In embodiments having multiple therapeutic regions and / or subregions, one, some, or all of the individual therapeutic regions and / or subregions may not contain any polymer.

[0188] In some embodiments, the therapeutic region 200 (or one or more therapeutic subregions) 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 Domain The composition of the control region 300 may be varied. For example, in many embodiments, the control region 300 does not contain any therapeutic agent, at least before the depot is implanted at the treatment site. In some embodiments, the control region 300 may contain 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 the release agent may be varied to achieve a faster or slower release of the therapeutic agent. In embodiments where both the therapeutic region 200 and the control region 300 contain a release agent, the type of release agent in the therapeutic region 200 may be the same as or different from the release agent in the control region 300. In some embodiments, the concentration of the first release agent in the control region is greater than the concentration of the second release agent (same as or different from the first release agent) in the therapeutic region. In some embodiments, the concentration of the release agent in the control region is less than the concentration of the release agent in the therapeutic region. In some embodiments, the concentration of the release agent in the control region 300 is the same as the concentration of the release agent in the therapeutic 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., Figure 4), the control region 300 may include a monolayer on either side of the therapeutic region 200, which is composed of a bioabsorbable polymer mixed with a release agent. In some embodiments, the control region 300 itself may include a structure having multiple layers or sub-regions of the bioabsorbable polymer and the release agent. Some or all of the layers or sub-regions of such a multilayer control region 300 may be directly adjacent (i.e., in contact) with each other (laterally or axially), and / or some or all of the layers or sub-regions may be spaced apart with one or more other regions (such as therapeutic regions 200 and / or barrier regions) between them. In some embodiments, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more control subregions or layers may be grouped together and arranged at intervals from other groups of control regions or control subregions or layers (having the same or different number of layers as other groups), with one or more other regions in between them (e.g., therapeutic regions(s) 200 and / or barrier regions(s)) (see, for example, Figures 5, 6, etc.).

[0192] While not strictly theoretical, such multilayer configurations are thought to improve the ability of the control region to control the release of the therapeutic agent compared to a single-layer control region, even if the multilayer configuration has the same or smaller thickness as a single-layer control region. The channels left by the dissolution of the releasing agent in both the microlayer and / or sub-regions of the control region are pathways for the released therapeutic agent, creating longer and possibly more cumbersome pathways to traverse compared to the more direct pathways created by the channels of the single-layer control region. Thus, the control region(s) and / or sub-regions regulate the rate of therapeutic agent release by causing the releasing agent to form independent, non-adjacent channels through one or more control regions and / or sub-regions. Embodiments of such configurations having multiple control layers or sub-regions Then, some or all of the control layers or sub-regions may be thermally compressed together. One or more control regions may be thermally compressed together with the treatment region 200, whether or not they were thermally compressed first. Having a multilayered control region 300 may provide a more linear controlled release of the therapeutic agent over time (beyond the first day of implantation). Furthermore, the layering of the control region 300 may also contribute to a more flexible, structurally competent depot (compared to a depot having a therapeutic 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 embodiments having a number of control regions and / or subregions, individual subregions or combinations of some or all subregions may have a thickness of approximately 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, approximately 15 μm, approximately 20 μm, approximately 25 μm, approximately 30 μm, approximately 35 μm, approximately 40 μm, approximately 45 μm, approximately 50 μm, approximately 55 μm, approximately 60 μm, approximately 65 μm, approximately 70 μm, approximately 75 μm, approximately 80 μm, approximately 85 μm, approximately 90 μm, approximately 95 μm, or approximately 100 μm.

[0194] In any of the embodiments disclosed herein, the weight ratio of the release agent to the 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 contain at least 5% by weight of the release agent, at least 10% by weight of the release agent, at least 15% by weight of the release agent, at least 20% by weight of the release agent, at least 25% by weight of the release agent, at least 30% by weight of the release agent, at least 35% by weight of the release agent, at least 40% by weight of the release agent, at least 45% by weight of the release agent, or at least 50% by weight of the release agent. In those embodiments having a number of control regions or sub-regions, one or more control regions or sub-control regions may individually contain at least 5% by weight of the release agent, at least 10% by weight of the release agent, at least 15% by weight of the release agent, at least 20% by weight of the release agent, at least 25% by weight of the release agent, at least 30% by weight of the release agent, at least 35% by weight of the release agent, at least 40% by weight of the release agent, at least 45% by weight of the release agent, or at least 50% by weight of the release agent.

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

[0197] In embodiments disclosed herein, where the control region 300 comprises a number of 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 agent, the same or different amounts of polymer, the same or different polymer, the same or different polymer to the release agent ratio, and / or the same or different thicknesses. A single control region or sub-region may contain a single type of polymer or a number of types of polymers, and / or a single type of release agent or a number of types of release agents.

[0198] C. Therapeutic agents The therapeutic agent delivered by Depot 100 of this technology may be any biologically active substance (or combination of substances) that produces a therapeutic effect in a patient who requires it. 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 consist of only a single therapeutic agent, and in some embodiments, the therapeutic agent may consist of 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” includes one or more local or general anesthetics administered to reduce, prevent, alleviate, or eliminate pain as a whole. 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, calticaine, alticaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, and combinations thereof. Preferred local anesthetics include bupivacaine, lidocaine, and ropivacaine. Typically, local anesthetics cause loss of sensation by inhibiting the 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. The influx of sodium through these channels is necessary for the depolarization of nerve cell membranes and the subsequent propagation of impulses along the nerve pathway. When nerves lose their ability to depolarize and propagate impulses, the individual loses sensation in the area supplied by the nerve. Any compound possessing such anesthetic properties is suitable for use in this technique.

[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 analgesics is dexamethasone. Dexamethasone may also act as an anti-inflammatory agent.

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

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

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

[0204] In some embodiments, the therapeutic agent includes an antibiotic, antibacterial agent, 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, rifampine, triclosan, chlorhexidine, penicillin(s), aminoglycis, quinolone, fluoroquinolone, vancomycin, gentamicin, cephalosporin(s), carbapanem, imipenem, ertapenem, antimicrobial peptides, cecropine-melittin, magainin, dermaceptin, cathelicidine, alpha-defensin, and alpha-protegrin. Antifungal agents include, but are not limited to, ketoconazole, chlortrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, thioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naphthifine, griseofulvin, haloprogin, butenafine, tolnaftate, nistatin, cyclohexamide, cyclopirox, flucytosine, terbinafine, and amphotericin B.

[0205] The analgesic is a local anesthetic, and the release of the analgesic to the treatment site over a 5-day period inhibits the growth of bacteria and fungi, as described in one of the preceding clauses.

[0206] In some embodiments, the therapeutic agent is a local anesthetic, and the 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 1 / 10, 1 / 20, 1 / 30, 1 / 40, or 1 / 50 of the number of bacteria present on an equivalent depot that does not contain an analgesic.

[0207] In some embodiments, the therapeutic agent is an adrenocorticostatic agent, a β-antiadrenergic agent, an androgen or antiandrogen, an anti-anemia agent, an antiparasitic agent, an anabolic agent, an anesthetic or analgesic, an stimulant, an anti-allergic agent, an antiarrhythmic agent, an anti-atherosclerotic agent, an antibiotic, an antidiabetic agent, an antifibrinolytic agent, an antispasmodic agent, angiogenesis inhibitor, an anticholinergic agent, an enzyme, a coenzyme or corresponding inhibitor, an antihistamine, an antihypertensive agent, or an antihypertensive agent. The substance may be a drug, anticoagulant, antifungal agent, antiseptic, anti-infective agent, hemostatic agent, β-receptor antagonist, calcium channel antagonist, antimyasthenic agent, anti-inflammatory agent, antipyretic, antirheumatic agent, cardiac agent, chemotherapy agent, coronary artery dilator, cell proliferation inhibitor, glucocorticoid, hemostatic agent, immunoglobulin or its fragments, chemokine, cytokine, mitogen, cell differentiation factor, cytotoxic agent, hormone, immunosuppressant, immunostimulant, morphine antagonist, muscle relaxant, narcotic, vector, peptide, (adverse)sympathomimetic agent, (adverse)sympathomimetic agent, protein, cell, selective estrogen receptor modulator (SERM), sedative, anticonvulsant, substance that inhibits bone resorption, vasoconstrictor or vasodilator, viral replication inhibitor, or wound healing agent.

[0208] In various embodiments, the therapeutic agent comprises drugs used to treat cancer or pharmaceutically acceptable salts thereof. Such chemotherapeutic agents include antibodies, alkylating agents, angiogenesis inhibitors, anti-metabolites, DNA cleavage agents, DNA crosslinking agents, DNA insertion agents, DNA 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. While not limited to specific therapeutic agents, adalimumab, ansamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, calistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribine, cytarabine, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocalmycin, dinemycin A, epotilon, etoposide, phloxuridine, fludarabine, 5-fluorouracil, gefitinib, This includes gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapacon, lenalidomide, irinotecan, mytansine, mechloretamine, 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) drug used to treat various neuromuscular disorders and / or neurosecretory disorders and neuropathy associated with pain. 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. Commercially available botulinum toxin, BOTOX® (Allergan, Inc., Irvine, CA), consists of lyophilized, purified botulinum toxin type A complex, albumin, and sodium chloride, packaged in a sterile, vacuum-dried form.

[0210] The paralyzing effect of botulinum toxin is the most common benefit of commercial therapeutics, as it relaxes muscles to treat conditions such as muscular dystonia and wrinkles. However, in addition to its anticholinergic effects on muscle and smooth muscle, the neurotoxin has 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, may be blocked by the introduction of botulinum toxin in response to its effects. Research suggests that botulinum toxin may possess direct anti-inflammatory capabilities. It also shows that all of these therapeutic effects, including those on muscle, smooth muscle, goblet cells, and anti-inflammatory effects, can be derived from the delivery of toxins from the device of the present invention.

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

[0212] A pharmaceutically acceptable salt may contain water or another biocompatible solvent (solvate), another molecule such as 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 of pharmaceutically acceptable salts where multiple charged atoms are part of the 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 a pharmaceutically acceptable salt thereof may be an essentially pure compound, or it may be formulated with a pharmaceutically acceptable carrier such as a diluent, auxiliary agent, excipient, or vehicle known to those skilled in the art. The carrier(s) must be “acceptable” in the sense that they are compatible with the other components of the formulation and are not harmful to its recipient. Examples of diluents include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine. For other examples of 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 sieved by other means to form a consistent particle size, thereby further enabling regulated and controlled release of the therapeutic agent. This process may be particularly useful for highly insoluble therapeutic agents.

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

[0216] The appropriate dosage range for using this technology's depot depends on the potency of the specific therapeutic agent, but is generally about 0.001 mg to 500 mg of the drug per kilogram of body weight per day, for example, about 0.1 mg to 200 mg of the drug per kilogram of body weight, and about 1 to 100 mg per kilogram of body weight. The dosage range can be readily determined by methods known to those skilled in the art. Unit dosage forms generally contain between about 1 mg and 500 mg of the active ingredient. For example, commercially available bupivacaine hydrochloride, marketed under the brand name Marcaine (Pfizer; New York, NY), is generally administered as a peripheral nerve block using dosage ranges of 37.5–75 mg at a 0.25% concentration, and from 25 mg to the maximum daily level (up to 400 mg) at a 0.5% concentration (Marcaine (Registered Trademark) (Trademark) Package Insert; FDA Reference ID: 3079122). Furthermore, Naropin (registered trademark) (Fresenius Kabi The commercially available ropivacaine hydrochloride, marketed under the brand name (USA, LLC; Lake Zurich, IL), is administered in doses of 5–300 mg for non-major and major nerve blocks (Naropin® package insert; Reference ID: 451112G). The appropriate dosage range for depot use of this technology is equivalent to that of commercially available medications administered habitually by injection.

[0217] In some embodiments of the technology, the therapeutic area 200 may include multiple layers. In such embodiments, multiple layers can improve the efficient loading of the therapeutic agent. For example, multilayering can be a direct and effective method for loading a considerable amount of therapeutic agent. Often, loading a large amount of therapeutic agent onto a single film layer can be difficult, even by increasing the ratio of drug to polymer or by increasing the thickness of the layers. Even if theoretically increasing the thickness of the therapeutic area allows for loading more drug, consistent fabrication of thick therapeutic areas via casting will prove difficult. In contrast, lamination and bonding of thin films or sheets, each with a predetermined loading of therapeutic agent, can be presented as a more reliable alternative to casting. Data from an example loading an analgesic (i.e., ropivacaine) are presented in Table 2. [Table 2]

[0218] As a simple example, a monolayer loaded with ropivacaine and having a thickness of 0.019 mm was produced. A five-layer film sample with a thickness of 0.046 mm, in which each layer was loaded with ropivacaine, was also produced. Although the thickness of the five-layer film sample was only 2.42 times that of the monolayer, the loading of the therapeutic agent in the five-layer sample was 5.27 times that of the monolayer sample. Therefore, the multilayering method enabled a substantially higher density of the therapeutic agent.

[0219] As described above, multilayer thermal compression bonding enabled an effective reduction in film thickness and increased the density of the therapeutic agent load. In the example illustrated in Table 2, the multilayer structure enabled a 124% increase in therapeutic agent density. In other embodiments, the increase in therapeutic agent density enabled by the multilayer structure of the therapeutic region may be approximately 50%, 75%, 100%, 125%, 150%, or 200%.

[0220] D. Polymer The depot 100 of this technology is composed of a bioabsorbable polymer. In some embodiments, both the therapeutic region 200 and the control region 300 are composed of a polymer (or a mixture of polymers). These may include the same or different polymers (or mixes of polymers) in the same or different amounts, concentrations, and / or weight percentages. In some embodiments, the control area 300 contains a polymer, while the treatment area 200 does not. In some embodiments, the treatment area 200 contains a polymer, while the control area 300 does not. Where used at least in this section, “polymer” refers to a polymer that may be used in the treatment area 200 and / or the control area 300.

[0221] The bioabsorbable polymers used in this 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 be broken down over time by the action of enzymes, by hydrolysis, and / or by other similar mechanisms in the patient’s body. In various embodiments, the bioabsorbable polymer film can be broken down or degraded in the body into non-toxic components, with the therapeutic agent being released along with them. The polymer used as the base component of the depot in this technology may be broken down or degraded after the therapeutic agent has been completely released. Bioabsorbable polymers are also “endoerosive” in that they will be eroded or degraded over time, at least in part, as a result of contact with surrounding tissues, substances found in fluids, or by cellular action.

[0222] Criteria for selecting a suitable bioabsorbable polymer for use in this technology include: 1) in The selection of bioabsorbable polymers includes: 1) in vivo safety and biocompatibility; 2) therapeutic agent carrying capacity; 3) therapeutic agent release capacity; 4) degradation profile; 5) potential for inflammatory response; and 6) mechanical properties that may relate to shape factors and manufacturability. Therefore, the selection of bioabsorbable polymers may depend on the clinical objective of the particular treatment, and there may be trade-offs 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 provides some diversity when it is clinically desirable to have a mixture of properties from multiple polymers. In the case of biomedical applications, polymers or copolymers using at least one of poly(L-lactic acid) (PLA), PCL, and PGA are generally preferred, especially as bioabsorbable depots for drug release. The physical properties of some of these polymers are presented in Table 3 below. [Table 3]

[0223] In many embodiments, the polymer may contain polyglycolide (PGA). PGA is one of the simplest linear aliphatic polyesters. It is prepared by ring-opening polymerization of cyclic lactone, glycolide. It is highly crystalline, with a degree of crystallinity of 45-55%, and is therefore insoluble in most organic solvents. It has a high melting point (220°C). It has a glass transition temperature of ~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 leads to loss of mechanical strength and substantial local production of glycolic acid, which can induce an inflammatory response in considerable amounts.

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

[0225] Copolymerization of PLA (both L- and D,L-lactide forms) and PGA yields poly(lactide-co-glycolide) (PLGA), which is one of the most commonly used biodegradable polymers in biomedical applications. In many embodiments, the polymer may contain PLGA. Since PLA and PGA have significantly different properties, careful selection of the PLGA composition can enable optimization of performance in the intended clinical application. Modification of physical properties is even more significant for PLGA copolymers. When the composition consists of 25–75% lactide, PLGA forms an amorphous polymer that is highly hydrolyzably 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 an ester-terminated poly(DL-lactide-co-glycolide) (DURECT Corporation) with a molar ratio of 50:50.

[0226] In some embodiments, the polymer may contain 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, thereby making it more suitable as a depot for longer-term drug delivery. For example, Capronor® is a commercial contraceptive PCL product that can deliver levonorgestrel in vivo for one year. PCL is often blended or copolymerized with other polymers such as PLLA, PDLLA, or PLGA. Blending or copolymerizing with polyethers accelerates overall polymer erosion. Furthermore, PCL has a relatively low tensile strength (about 23 MPa) but a very high elongation at break (4700%), making it a very good 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 this technology include, but are not limited to, poly(alpha-hydroxy acids), 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), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate esters), poly(amino acids), polydeptides, and poly(butylene) Xicinate (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-calolactone) (PGCL), poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate) This includes poly(glycerol sebacate), tyrosine-derived polycarbonates, 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), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronic Acid). This includes PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, Poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or its salts, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, or combinations thereof.

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

[0229] As described above, in certain clinical applications where depots are used for controlled delivery of therapeutic agents, it is desirable to use copolymers containing at least two of PGA, PLA, PCL, PDO, and PVA. These include, for example, poly(lactide-co-caprolactone) (PLCL) (e.g., having a ratio of PLA to PCL of 90:10 to 60:40) or its derivatives and copolymers thereof, poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a ratio of DL-PLA to PCL of 90:10 to 50:50) or its derivatives and copolymers thereof, poly(glycolide-co-caprolactone) (PGCL) (e.g., having a ratio of PGA to PCL of 90:10 to 10:90) or its derivatives and copolymers thereof, or blends of PCL and PLA (e.g., ratios of PCL and PLA blends 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 copolymer comprises polyglycolide (PLA) and polyglycolide (PGA). In such preferred embodiments, the PGA:PLA: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) with a molar ratio of 60:30:10 (DURECT Corporation).

[0230] In some embodiments, terpolymers may be beneficial for increasing the degradation rate and facilitating production, among other things.

[0231] To minimize the size of bioabsorbable depots, it is generally preferable to maximize the loading of the therapeutic agent in the polymer so that the highest possible density of the therapeutic agent is achieved. However, polymer carriers with high concentrations of therapeutic agent are susceptible to burst release kinetics, resulting in inadequate control of time release. As described above, one significant benefit of the depot structures described herein, particularly the depot control region feature, is that the release kinetics of the therapeutic agent can be controlled and attenuated, even at therapeutic agent densities that may cause instability in other carriers. In certain embodiments, the therapeutic agent loading capacity includes ratios of therapeutic agent to bioabsorbable polymer (wt:wt) of approximately 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 is desirable to increase the therapeutic effect or potency of the therapeutic agent released from the depot described herein, while still maintaining the ratio of the same or similar polymer to the therapeutic agent. This can be achieved by using the therapeutic agent in an essentially pure form, as opposed to salt derivatives. Furthermore, or alternatively, the therapeutic agent can be mixed with clonidine or epinephrine, which are known to enhance the therapeutic effect of certain drugs.

[0232] In some embodiments, the bioabsorbable polymer used within 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 manufacture implantable supports for the formation of transplanted organs in vivo (U.S. Patent Publication 2014 / 0272225; Johnson; Nanofiber Solutions, LLC), for musculoskeletal and dermal tissue engineering (R. Vasita and DS Katti, Int. J. Nanomedicine, 2006, 1:1, 15-30), for skin or oral applications (PCT Publication 2015 / 189212; Hansen; Dermtreat APS), or for the management of postoperative pain (U.S. Patent Publication 2013 / 0071463; Palasis et al.). Electrospinning offers the opportunity to control the thickness and composition of nano or microfibers, along with the 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 in vivo cell culture for tissue formation. Typically, these scaffolds have a porosity of 70–90% (U.S. Patent No. 9,737,632; Johnson; Nanofiber Solutions, LLC). Suitable bioabsorbable polymers and copolymers for the production of electrospun microfibers include, but are not limited to, natural materials such as collagen, gelatin, elastin, chitosan, silk, fibrions, 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] Made from bioabsorbable polymers or copolymers, and used in combination with therapeutic agents, Electrospun microfibers are known in the art. For example, Johnson et al. disclosed the treatment of arthritis and other conditions by injection of electrospun fiber fragments of a biocompatible polymer together with a carrier medium containing chitosan (U.S. Publication No. 2016 / 0325015; Nanofiber Solutions, LLC). Weldon et al. reported the use of electrospun bupivacaine-eluting sutures made from poly(lactic acid-coglycolic 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 a method for treating postoperative pain by implanting electrospun fibers loaded with opioids, anesthetics, or non-opioid analgesics into the surgical site (U.S. Patent Publication 2013 / 0071463; Palasis et al.). Electrospun microfibers suitable for use in this technique may be obtained by the methods disclosed in the above-mentioned cited references, which are incorporated entirely herein.

[0234] When implanted in a patient's joint (e.g., the knee joint), the bioabsorbable depot described above may be placed intraarticular to connect the joint throughout the entire duration of release. To avoid premature release of the analgesic, it is desirable that the depot has a threshold level of mechanical integrity and stability until most of the analgesic has been released. As mentioned above, it is desirable to maximize the load of the therapeutic agent in the bioabsorbable depot, but such maximization can typically come at the expense of the mechanical integrity and stability of the depot. Considering the high doses of anesthetic required to induce analgesia in the confined space of the knee throughout both acute and subacute postoperative pain periods, it is desirable that the depot described herein have a high-density load of anesthetic while still maintaining sufficient mechanical integrity and stability in the knee. The presence of a layered structure, particularly a control region, provides some precaution 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 therapeutic area, thereby creating a thermal bond between the therapeutic and control areas, which in turn prevents layer delamination and resulting uncontrolled drug release when the depot is subjected to mechanical stress in the knee.

[0235] Generally, it is desirable for implanted polymers to degrade completely after the complete delivery of the therapeutic agent. Complete degradation is preferable because, unless the implanted polymer provides some structural function or support, clinicians would have to come to terms with leaving a foreign body without a functional purpose, which could become a source of inflammation or infection, or require another surgery solely to remove the remaining polymer. As an alternative to complete degradation, it is considered desirable to completely encapsulate any remaining polymer within the body.

[0236] The degradation of embedded polymers essentially consists of two sequential processes: diffusion of an aqueous solution (e.g., a physiological fluid), followed by hydrolysis. Degradation usually 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, and hydrolytic erosion at the surface is faster than water can penetrate into the polymer. Conversely, bulk degradation occurs throughout the polymer, degrading the inside of the material faster than water can penetrate and erode the surface. Polymers such as PLA, PGA, PLGA, and PCL are all reabsorbed into the body via bulk degradation.

[0237] The time required for complete decomposition can vary significantly depending on the selected material and the clinical performance requirements of the depot. For example, when treating and managing postoperative pain, it is desirable for the polymer depot to release therapeutic agents (i.e., analgesics) over a period of 5 to 30 days. When treating or preventing infection in artificial joints (e.g., knee or hip implants), it is desirable for the polymer depot to release anti-infective agents over a period of 2 to 4 months. Alternatively, if the entire amount of therapeutic agent loaded into the polymer is released... However, it is desirable that the polymer degrades over a period longer than the duration of drug release. For example, rapid degradation can often make the polymer brittle and fragile, thereby impairing its mechanical properties or inducing an inflammatory response from the body. In particular, in certain clinical applications, it is 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 this technology, it is desirable to allow the polymer to be completely absorbed into the body after substantially all of the internally loaded therapeutic agent has been released. In certain embodiments, this degradation can be shortened to about one month. Alternatively, in other embodiments, complete degradation may take about two, three, four, six, nine, or twelve months. In some embodiments, the bioabsorbable polymer degrades substantially in vivo within about one, two, three, four, five, or six months. In some embodiments, it is desirable to allow complete degradation to take six months so that the mechanical properties of the implanted polymer are preserved for the first two months after implantation.

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

[0240] The degree of core acidity is largely determined 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. (See 123-130). For example, the decomposition of larger monolithic devices (on a mm scale and larger) proceeds much more rapidly internally than on its surface, resulting in a slowly decomposing polymer outer layer that captures more advanced internal decomposition products from the autocatalysts in the internal zones (the so-called "S-type" nonlinear dynamic decomposition profile). In contrast to thicker films, thin films less than 1 mm thick typically decompose via surface erosion, and the lactates obtained from the decomposition do not accumulate inside the film. Thin films are known to decompose uniformly due to their high surface area-to-volume ratio and do not result in core oxidation (see Grizzi et al.).

[0241] As schematically shown in Figure 19A, the depot of this technique may lose 50%, 60%, 70%, or 80% of its individual mass (anesthetic and release agent) during the process of releasing the anesthetic (e.g., over 5, 7, 10, 14, 20, or 30 days), resulting in a highly porous, mesh-like system that behaves like a thin film (at least for the purpose of degradation) due to its high surface-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. While not bound by theory, it is thought that the drug core matrix of the therapeutic region becomes highly porous as degradation continues. For example, Figures 19B and 19C are scanning electron microscope ("SEM") images showing the therapeutic region before and after elution, respectively. However, even after the release of the therapeutic agent, the distinct porous structure remains intact, through which water and acid can effectively diffuse. Thus, Depot 100 of this technology, which has a thickness greater than approximately 1 mm, decomposes like a thin film and, surprisingly, does not show core acidification.

[0242] E. Release agent In many implantable drug dissolution technologies, the depot provides an initial, uncontrolled burst release of the drug followed by a residual release. These drug release kinetics may be desirable for certain clinical applications, but may be unavoidable even if undesirable. Hydrophilic drugs loaded onto polymer carriers typically provide a burst release when exposed to physiological fluids. This kinetic can present challenges, especially when loading large volumes of drug for controlled, sustained in vivo administration is desirable. For example, to achieve sustained, durable in vivo pharmacological treatment, it may be desirable to implant a dose equivalent to several days or weeks, but it is essential that the therapeutic agent is released as prescribed; otherwise, the release of the entire payload could lead to serious complications for the patient.

[0243] To achieve finer control of the release of the therapeutic agent when exposed to a fluid, the depot 100 of this technology may contain a release agent. In some embodiments, the therapeutic region 200 and the control region 300 both contain a release agent (or mixture of release agents), which may be the same or different amounts, concentrations, and / or weight percentages of the same or different release agent (or mixture of release agents). In some embodiments, the control region 300 contains a release agent, and the therapeutic region 200 does not. In some embodiments, the therapeutic region 200 contains a release agent, and the control region 300 does not. Where used at least in this section, “release agent” refers to a release agent that may be used in the therapeutic region 200 and / or the control region 300.

[0244] The type and / or amount of the release agent in the therapeutic region 200 and / or control region 300 may be varied depending on the desired release rate of the release agent into the surrounding biological fluid. For example, the selection of release agents with different dissolution times will affect the release rate. Also, the weight percentage of the release agent in the polymer region will affect the number and size of diffusion openings later formed in the polymer, thereby affecting the release of the release agent from the depot 100. The rate is affected (for example, the higher the weight percentage of the release agent, the faster the release). The presence of the release agent in the selection region also affects the rate of therapeutic agent release. For example, a depot with a release agent in the control region 300 and / or therapeutic region 200 will generally release the therapeutic agent at a faster rate than a depot without a release agent. Similarly, a release agent in both the control region 300 and therapeutic region 200 will generally release the therapeutic agent at a faster rate than when the release agent is only in the control region.

[0245] In certain embodiments of this technology, the rate at which the therapeutic agent is released from the depot 100 can be controlled by adjusting the layer-by-layer ratio of the release agent to the bioabsorbable polymer. For example, in many embodiments of this technology, the depot 100 includes a therapeutic region 200 having a different weight percentage of the release agent than the weight percentage of the release agent in the control region 200. For example, the therapeutic region 200 may have a larger or smaller weight percentage of the release agent than the control region 300. In some embodiments, the control region 300 may have a weight percentage of the release agent that is at least twice as large as the weight percentage of the release agent in the therapeutic region 200. In some embodiments, the control region 300 may have a weight percentage of the release agent that is at least 3 to 20 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, at least 25 times, at least 30 times, about 5 to 10 times, about 10 to 15 times, about 5 to 15 times, or about 15 to 25 times larger than the weight percentage of the release agent in the therapeutic region 200.

[0246] In many embodiments of this technology, the release agent is a surfactant. Unlike its use as a release agent as described herein, surfactants are typically used to control the dispersion, aggregation, and wettability of drugs or polymers. Essentially, surfactants operate at the interface be...

Claims

[Claim 1] The invention described in the specification.

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