Implantable depot for controlled release of therapeutic agents

Abstract

To provide a depot for treating post-operative pain via sustained controlled release of a therapeutic agent.SOLUTION: In some embodiments, the depot may comprise a therapeutic region comprising an analgesic agent and a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer. The release agent may be configured to dissolve when the depot is placed invivo to form a diffusion aperture in the control region. The depot may be configured to be implanted at a treatment site invivo and release the therapeutic agent at the treatment site for 3 days or more while implanted.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Application No. 62 / 569,349, filed October 6, 2017, U.S. Application No. 62 / 670,721, filed May 12, 2018, U.S. Application No. 62 / 640,571, filed March 8, 2018, and U.S. Application No. 62 / 723,478, filed August 28, 2018, each of which is incorporated by reference in its entirety.

[0002] The present technology relates to implants for the controlled, sustained release of therapeutic agents in vivo. [Background technology]

[0003] 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 resulting in localized delivery of the selected agent. This localized delivery can allow a significant proportion of the agent to reach its intended target and avoid unwanted systemic side effects. However, these systems often suffer from the lack of a true controlled-release mechanism, in that they typically result in a burst of drug upon contact with surrounding physiological fluids, followed by a residual release of drug.

[0004] To improve drug release in certain polymeric carriers, hydrophilic polymers such as polysorbates have been added to these carriers as wetting agents to accelerate or enhance drug release from biocompatible polymers such as polyethylene glycol (PEG) in oral formulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3): 435-441). However, these formulations are intended to provide immediate release of the hydrophobic drug into a hydrophilic environment (in vivo physiological fluids), with a significant portion of the total drug payload being released immediately or actively, rather than variable or sustained controlled release.

[0005] While these drug release kinetics may be desirable in some clinical applications, controlled, sustained release of a therapeutic agent may be clinically beneficial in certain situations. In particular, it may be desirable to implant a biodegradable carrier that holds a large dose of a therapeutic agent for controlled, sustained release over time. This may be of particular value when the therapeutic-agent-loaded carrier is implanted in conjunction with an interventional or surgical procedure and, optionally, with or as part of an implantable medical device.

[0006] Xaracoll® (Innocoll Technologies, Athlone, Ireland) is an example of a sustained-release system for postoperative pain treatment. Xaracoll® is an implantable collagen sponge loaded with bupivacaine for extended release so that local pain block in the surgical field is achieved. As shown in Figure 1, plasma bupivacaine HCl concentrations peak within 15 hours of implantation, thereby indicating poor duration of action. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Akbari, J. et al., ADV.PHARM.BULL.(2015)5(3):435~441 Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, there is a need for biocompatible implantable systems that can provide highly controlled release of drugs. [Means for solving the problem]

[0009] FIELD OF THE INVENTION The present technology relates to implants for the controlled release of therapeutic agents to treat medical conditions, and related systems and methods. In particular, the present technology relates to implants for the localized, sustained release of therapeutic agents at a surgical or intervention site, and related systems and methods. The present invention provides, for example, the following items. (Item 1) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, The depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic drug at the treatment site for a period of at least seven days. (Item 2) 10. The depot of claim 1, wherein the analgesic agent in the treatment area comprises at least 50% of the total weight of the depot. (Item 3) 10. The depot of item 1, configured to release the analgesic at the treatment site for 14 days or more. (Item 4) 4. The depot of item 3, wherein about 20% to about 50% of the analgesic agent is released in about the first 3 to about 5 days of said 14 day period, and at least 80% of the remaining analgesic agent is released in the last 11 days of said 14 day period. (Item 5) 4. The depot of item 3, wherein about 20% to about 40% of the analgesic agent is released in the first 3 days of said 14 day period, and at least 80% of the remaining analgesic agent is released in the last 11 days of said 14 day period. (Item 6) 4. The depot according to item 3, wherein at least 90% of the remaining analgesic is released in the last 11 days of said 14 day period. (Item 7) 4. The depot according to item 3, wherein no more than 15% of the amount of analgesic agent is released in the first 2 days of said 14 day period. (Item 8) 10. The depot of item 1, configured to release the analgesic drug at a first rate for a first period of time and at a second rate for a second period of time. (Item 9) 9. The depot of item 8, wherein the first rate is greater than the second rate. (Item 10) 10. The depot according to item 9, configured to release at least 90% of the analgesic in the treatment area within 14 days. (Item 11) 10. The depot of claim 1, configured to release from about 100 mg to about 500 mg of analgesic to the treatment site per day. (Item 12) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for 14 days or more; Item 13. A depot wherein about 20% to about 40% of the analgesic is released during the first 3 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. 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; A depot wherein said control region does not contain said analgesic drug, at least prior to implantation of said depot at said treatment site. (Item 14) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; A depot wherein the control region comprises an analgesic agent that is different from the analgesic agent of the treatment region. (Item 15) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; The depot, wherein the release agent is a first release agent and the treatment area comprises a second release agent mixed with the analgesic drug. (Item 16) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; The depot, wherein the release agent is a first release agent, the polymer is a first polymer, and the treatment area comprises a second release agent and a second polymer mixed with the analgesic drug. (Item 17) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; The thickness of the control region is less than or equal to 1 / 50 of the thickness of the treatment region. (Item 18) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; The thickness of said control region is less than or equal to 1 / 75 of the thickness of said treatment region. (Item 19) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; The thickness of the control region is less than or equal to 1 / 100 of the thickness of the treatment region. (Item 20) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; A depot, wherein a first controlling layer comprises a first amount of said release agent and a second controlling layer comprises a second amount of said release agent that is different from said first amount. (Item 21) 1. A depot for treating post-operative pain through sustained controlled release of an analgesic, comprising: a treatment area comprising said analgesic; a controlled region comprising a bioabsorbable polymer and a release agent mixed with said polymer, said release agent configured to dissolve upon placement of said depot in vivo to form diffusion openings in said controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for a period of three days or more; the depot has a total surface area that includes the exposed surface area of ​​the covering region plus the exposed surface area of ​​the treatment region; A depot, wherein when the depot is initially placed at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the cover region is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%.

[0010] The present technology is illustrated by various embodiments described below, including, for example, with reference to Figures 1-32. Various examples of embodiments of the present technology are described as numbered bullet points (1, 2, 3, etc.) for convenience. These are provided as examples and are not intended to limit the present technology. 1. A depot for treating post-operative pain via sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, The depot is configured to be implanted at a treatment site in vivo and, while implanted, to release the analgesic agent at the treatment site for a period of seven days or more. 2. A depot according to clause 1, wherein the analgesic agent in the therapeutic area constitutes at least 50% of the total weight of the depot. 3. The depot of clause 1 or clause 2, wherein the depot is configured to release the analgesic agent at the treatment site for a period of 14 days or more. 4. A depot according to clause 3, wherein about 20% to about 50% of the analgesic is released in about the first 3 to about 5 days of a 14-day period, and at least 80% of the remaining analgesic is released in the last 11 days of the 14-day period. 5. The depot of clause 3, wherein about 20% to about 40% of the analgesic is released in the first 3 days of the 14-day period and at least 80% of the remaining analgesic is released in the last 11 days of the 14-day period. 6. The depot of any one of clauses 3 to 5, wherein at least 90% of the remaining analgesic is released in the last 11 days of the 14-day period. 7. A depot according to any one of clauses 3 to 6, in which not more than 15% of the amount of analgesic is released during the first 2 days of a 14-day period. 8. A depot according to any one of clauses 3 to 7, in which not more than 20% of the amount of analgesic is released during the first 2 days of a 14-day period. 9. A depot according to any one of clauses 3 to 8, in which not more than 25% of the amount of analgesic is released during the first 3 days of a 14-day period. 10. A depot according to any one of clauses 3 to 9, in which not more than 30% of the amount of analgesic is released during the first 3 days of a 14-day period. 11. The depot of any one of clauses 1 to 11, wherein the depot is configured to release the analgesic agent at a first rate for a first period of time and at a second rate for a second period of time. 12. The first rate is greater than the second rate, Article 12 Depot. 13. Depot under Article 12, where the first period is longer than the second period. 14. Depot under Article 12, where the first period is shorter than the second period. 15. A depot according to any one of clauses 1 to 14, configured to release at least 90% of the analgesic in the treatment area within 14 days. 16. The depot of any one of clauses 1 to 15, configured to release from about 100 mg to about 500 mg of analgesic to the treatment site per day. 17. The depot of any one of clauses 1 to 16, configured to release from about 100 mg to about 400 mg of analgesic to the treatment site per day. 18. The depot of any one of clauses 1 to 17, configured to release from about 100 mg to about 300 mg of analgesic to the treatment site per day. 19. A depot according to any one of clauses 1 to 18, configured to release not more than 300 mg of analgesic per day within the first 3 days and not more than 200 mg per day for the remaining days. 20. A depot according to any one of clauses 1 to 19, configured to release not more than 150 mg of analgesic per day within the first 3 days and not more than 100 mg per day for the remaining days. 21. A depot according to any one of clauses 1 to 20, in which not more than 400 mg of analgesic is released on any of the 14 days. 22. A depot according to any one of clauses 1 to 21, in which not more than 300 mg of analgesic is released on any of the 14 days. 23. A depot according to any one of clauses 1 to 22, in which not more than 250 mg of analgesic is released on any of the 14 days. 24. A depot according to any one of clauses 1 to 23, in which not more than 200 mg of analgesic is released on any of the 14 days. 25. A depot according to any one of clauses 1 to 24, in which not more than 150 mg of analgesic is released on any of 14 days. 26. A depot according to any one of clauses 1 to 25, in which not more than 100 mg of analgesic is released on any of the 14 days. 27. The depot of any one of clauses 1 to 26, configured to release the analgesic agent at a treatment site in vivo for 1 day or more, 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, 7 days or more, 8 days or more, 9 days or more, 10 days or more, 11 days or more, 12 days or more, 13 days or more, 14 days or more, 15 days or more, 16 days or more, 17 days or more, 18 days or more, 19 days or more, 20 days or more, 21 days or more, 22 days or more, 23 days or more, 24 days or more, 25 days or more, 26 days or more, 27 days or more, 28 days or more, 29 days or more, 30 days or more, 40 days or more, 50 days or more, 60 days or more, 70 days or more, 90 days or more, 100 days or more, 200 days or more, 300 days or more, or 365 days or more. 28. The depot of any one of clauses 1 to 27, wherein the concentration of the analgesic agent in the plasma of the mammalian patient on the 10th day is at least 70% of the concentration of the analgesic agent in the patient's plasma on the 5th day. 29. The depot of any one of clauses 1 to 28, wherein the treatment area includes a covered portion and an exposed portion, and the covered portion is covered by the control region such that when the depot is initially placed at the treatment site in vivo, the control region is between the covered portion of the treatment area and the physiological fluids at the treatment site, and the exposed portion of the treatment area is exposed to the physiological fluids. 30. The depot has a total surface area that includes the exposed surface area of ​​the covered region plus the exposed surface area of ​​the treatment area, When the depot is initially placed at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the covered region is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%. Any one of the depots in clauses 1 to 29. 31. A depot according to clause 30, wherein the exposed surface area of ​​the control region is less than the exposed surface area of ​​the treatment region. 32. A depot according to clause 30, wherein the exposed surface area of ​​the control region is greater than the exposed surface area of ​​the treatment region. 33. The depot of any one of clauses 1 to 32, wherein the control region is a first control region and the depot comprises a second control region. 34. The depot of clause 33, wherein the first control region is disposed on a first side of the treatment region and the second control region is disposed on a second side of the treatment region opposite the first side. 35. The depot of any one of clauses 1 to 34, wherein the depot comprises a plurality of control regions and a plurality of treatment regions, each of the treatment regions being spaced from an adjacent one of the treatment regions by one or more control regions. 36. The depot of clause 35, wherein each of the treatment areas and each of the control areas is a microthin layer. 37. A depot according to clause 35 or clause 36, comprising from about 2 to about 100 treatment areas. 38. A depot according to clause 35 or clause 36, comprising from about 2 to about 50 treatment areas. 39. A depot according to clause 35 or clause 36, comprising from about 2 to about 10 treatment areas. 40. The depot of any one of clauses 1 to 34, wherein the treatment region is surrounded by the control region such that when the depot is placed at the treatment site in vivo, the control region is between the treatment region and the physiological fluids at the treatment site. 41. The depot of any one of clauses 1 to 40, wherein the control region comprises a first control layer and a second control layer. 42. The depot of clause 41, wherein the second control layer is adjacent to the treatment area and the first control layer encapsulates / surrounds the treatment area and the second control layer. 43. The depot of clause 41 or clause 42, wherein the first control layer and the second control layer together enclose the treatment area. 44. The depot of any one of clauses 41 to 43, wherein a first control layer is disposed on a first side of the treatment area and a second control layer is disposed on a second side of the treatment area opposite the first side. 45. The depot of any one of clauses 41 to 44, wherein the first control layer comprises a first plurality of sub-layers and the second control layer comprises a second plurality of sub-layers. 46. ​​The depot of any one of clauses 41 to 45, wherein the first control layer comprises a first amount of release agent and the second control layer comprises a second amount of release agent different from the first amount. 47. The depot of any one of clauses 41 to 46, wherein a second control layer is positioned between the first control layer and the treatment area, the first control layer comprising a first concentration of release agent and the second control layer comprising a second concentration of release agent that is greater than the first concentration. 48. The depot of any one of clauses 41 to 46, wherein a second control layer is positioned between the first control layer and the treatment area, the first control layer comprising a first concentration of release agent and the second control layer comprising a second concentration of release agent that is less than the first concentration. 49. A second control layer is disposed between the first control layer and the treatment area; the first control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; the second control layer comprises up to 5% by weight of a releasing agent, up to 10% by weight of a releasing agent, up to 15% by weight of a releasing agent, up to 20% by weight of a releasing agent, up to 25% by weight of a releasing agent, up to 30% by weight of a releasing agent, up to 35% by weight of a releasing agent, up to 40% by weight of a releasing agent, up to 45% by weight of a releasing agent, or up to 50% by weight of a releasing agent; Any one of the depots in clauses 41 to 48. 50. The depot of any one of clauses 41 to 49, wherein a second control layer is disposed between the first control layer and the treatment area, the first control layer comprising a first amount of release agent, and the second control layer comprising a second amount of release agent, the second amount being at least two times, at least three times, at least four times, or at least five times the first amount. 51. The depot of any one of clauses 1 to 50, wherein the thickness of the control region is less than or equal to 1 / 50 of the thickness of the treatment region. 52. The depot of any one of clauses 1 to 50, wherein the thickness of the control region is less than or equal to 1 / 75 of the thickness of the treatment region. 53. The depot of any one of clauses 1 to 50, wherein the thickness of the control region is less than or equal to 1 / 100 of the thickness of the treatment region. 54. A depot according to any one of clauses 1 to 53, which is a flexible solid that is structurally capable of being handled by a clinician during the course of a normal surgical procedure without breaking into multiple small pieces and / or losing its overall shape. 55. A depot according to any one of clauses 1 to 54, configured to be placed inside a patient's knee and to release the analgesic agent in vivo for up to 7 days without breaking into multiple small pieces. 56. A depot according to any one of clauses 1 to 55, wherein the depot has a width and a thickness, the ratio of width to thickness being 21 or greater. 57. Depots under Article 56 where the ratio is 30 or greater. 58. Depots under Article 56 where the ratio is 40 or greater. 59. The depot of any one of clauses 1 to 58, wherein the depot has a surface area and a volume, and the ratio of surface area to volume is at least 1. 60. The depot of any one of clauses 1 to 59, wherein the diffusion opening comprises at least one or more pores and / or one or more channels. 61. The depot of any one of clauses 1 to 60, wherein two or more micro-thin layers of bioabsorbable polymer are bonded via thermocompression to form the treatment area. 62. The depot of any one of clauses 1 to 61, wherein the control region and the treatment region are joined via thermal compression. 63. The depot of any one of clauses 1 to 62, wherein the control area and the treatment area are thermally bonded. 64. The depot of any one of clauses 1 to 63, wherein upon dissolution of the release agent after placement in vivo at the treatment site, the control region and the treatment region transition from a less porous state to a more porous state to facilitate release of the analgesic agent from the depot. 65. The depot of any one of clauses 1 to 64, wherein the control region does not contain an analgesic, at least prior to implantation of the depot at the treatment site. 66. A depot according to any one of clauses 1 to 64, wherein the control area contains an analgesic different from the analgesic in the treatment area. 66a. The depot of any one of clauses 1 to 66, wherein the treatment area does not contain any release agent prior to implantation of the depot at the treatment site. 67. The depot of any one of clauses 1 to 66a, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with an analgesic. 68. The depot of any one of clauses 1 to 67, wherein the release agent is a first release agent, the polymer is a first polymer, and the treatment area comprises a second release agent and a second polymer mixed with an analgesic. 69. The depot of any one of clauses 1 to 68, wherein the first release agent is the same as the second release agent. 70. A depot according to any one of clauses 1 to 68, wherein the first release agent is different from the second release agent. 71. The depot of any one of clauses 1 to 70, wherein the concentration of the first release agent in the control region is greater than the concentration of the second release agent in the treatment region. 72. The depot of any one of clauses 1 to 70, wherein the concentration of the first release agent in the control region is less than the concentration of the second release agent in the treatment region. 73. The depot of any one of clauses 1 to 70, wherein the concentration of the first release agent in the control region is the same as the concentration of the second release agent in the treatment region. 74. The depot of any one of clauses 1 to 72, wherein the concentration of the first release agent in the control region is different from the concentration of the second release agent in the treatment region. 75. The depot of any one of clauses 1 to 74, wherein the treatment area comprises multiple microlayers. 76. The depot of any one of clauses 1 to 75, wherein the mass of the analgesic agent constitutes at least 50% of the mass of the depot. 77. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 3:1. 78. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 4:1. 79. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 5:1. 80. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 6:1. 81. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 7:1. 82. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 8:1. 83. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 10:1. 84. The depot of any one of clauses 1 to 76, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 16:1. 85. The depot of any one of clauses 1 to 84, wherein the treatment area comprises at least 60% by weight of analgesic, 60% by weight of analgesic, at least 70% by weight of analgesic, at least 80% by weight of analgesic, at least 90% by weight of analgesic, or 100% by weight of analgesic. 86. A depot of any one of clauses 1 to 84 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. 87. A depot according to any one of clauses 1 to 86, wherein the analgesic comprises at least one of a simple analgesic, a local anesthetic, an NSAID, and an opioid. 88. The depot of any one of clauses 1 to 87, wherein the analgesic comprises a local anesthetic selected from at least one of bupivacaine, ropivacaine, mepivacaine, and lidocaine. 89. The method further comprising administering to a patient an antibiotic, antifungal, and / or antibacterial agent, wherein the antibiotic, antifungal, and / or antibacterial agent is selected from the group consisting of amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin(s), aminoglycosides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporin(s), carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropium, cephalosporin(s), cecropium, ... 89. The depot of any one of clauses 1 to 88, wherein the depot is selected from at least one of: alpha-melittin, magainin, dermaseptin, cathelicidin, alpha-defensin, and alpha-protegrin, ketoconazole, chlortrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B. 90. The depot of any one of clauses 1 to 89, further comprising an anti-inflammatory agent selected from at least one of steroids, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and COX-2 inhibitors. 91. The depot of any one of clauses 1 to 90, further comprising at least one of epinephrine, clonidine, and tranexamic acid. 92. The depot of any one of clauses 1 to 91, wherein the release agent is a non-ionic surfactant. 93. The depot of any one of clauses 1 to 92, wherein the release agent has hydrophilic properties. 94. The depot of any one of clauses 1 to 93, wherein the release agent is a polysorbate. 95. The depot of any one of clauses 1 to 94, wherein the release agent is Tween 20. 96. The depot of any one of clauses 1 to 94, wherein the release agent is Tween 80. 97. The depot of any one of clauses 1 to 96, wherein the release agent is non-polymeric. 98. A depot according to any one of clauses 1 to 97, in which the releasing agent is not a plasticizer. 99. The depot of any one of clauses 1 to 98, wherein the polymer is configured to degrade only after substantially all of the analgesic has been released from the depot. 100. The depot of any one of clauses 1 to 99, wherein the polymer is a copolymer. 101. The depot of any one of clauses 1 to 99, wherein the polymer is a terpolymer. 102. The polymer may be polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoates (PHAs), poly(phosphazenes), polyphosphates, poly(amino acids), polydepsin Peptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co- glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose cellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (Polyactive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydroxypropyl acrylate 102. The depot of any one of clauses 1 to 101, comprising at least one of: pyrocellulose, 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). 103. The depot of any one of clauses 1 to 102, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA). 104. The depot of any one of clauses 1 to 102, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10. 105. The depot of any one of clauses 1 to 102, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) in a 50:50 molar ratio. 106. The depot of any one of clauses 1 to 105, wherein the polymer is terminated with an ester. 107. The depot of any one of clauses 1 to 102, 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. 108. The depot of any one of clauses 1 to 107, wherein the polymer is a first polymer and the treatment area comprises a second polymer mixed with an analgesic. 109. The depot of clause 108, wherein the first polymer and the second polymer are the same. 110. The depot of clause 108, wherein the first polymer and the second polymer are different. 111. The first polymer and / or the second polymer are selected from the group consisting of polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(alpha-hydroxy acid ... (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 ... Poly(tert-butyloxy-carbonylmethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly(1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid), polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl Methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogues such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate), hydroxypropyl cellulose 111. The depot of any one of clauses 108 to 110, comprising at least one of: cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or a salt thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone). 112. The depot of any one of clauses 108 to 111, 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). 113. The depot of any one of clauses 108 to 111, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of 60:30:10. 114. The depot of any one of clauses 108 to 111, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a 50:50 molar ratio. 115. The depot of any one of clauses 108 to 114, wherein the first polymer and / or the second polymer are ester terminated. 116. The depot of any one of clauses 108 to 111, wherein the first polymer and / or the second polymer is a terpolymer comprising three polymers selected from the following: polyglycolide (PGA), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), and polyethylene glycol. 117. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 1:1. 118. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 2:1. 119. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 3:1. 120. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 4:1. 121. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 5:1. 122. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 6:1. 123. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 7:1. 124. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 8:1. 125. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 9:1. 126. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 10:1. 127. The depot of any one of clauses 1 to 116, wherein the ratio of release agent to polymer in the controlled region is at least 15:1. 128. The polymer is a first polymer and the therapeutic area further comprises a second polymer; the depot has a depot polymer mass equal to the mass of the first polymer plus the mass of the second polymer; the ratio of the mass of the analgesic drug in the depot to the mass of the depot polymer is about 1:1; Any one of the depots in clauses 1 to 127. 129. The depot of clause 128, wherein the first polymer is the same as the second polymer. 130. A depot of clause 128, wherein the first polymer is different from the second polymer. 131. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of the analgesic drug in the depot to the mass of the depot polymer is at least 2:1. 132. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 3:1. 133. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 4:1. 134. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is about 5:1. 135. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 6:1. 136. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 7:1. 137. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 8:1. 138. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of depot polymer is at least 10:1. 139. The depot of any one of clauses 128 to 130, wherein the ratio of the mass of analgesic in the depot to the mass of the depot polymer is at least 16:1. 140. A depot according to any one of clauses 1 to 139, wherein the analgesic is a local anesthetic and the release of the analgesic to the treatment site over a period of 5 days inhibits bacterial and fungal growth. 141. A depot of clause 140 configured to inhibit bacterial and fungal growth such that the number of bacteria on the depot is 10, 20, 30, 40, or 50 times less than the number of bacteria present on a comparable depot not containing the analgesic. 142. The depot of any one of clauses 1 to 141, wherein the release of analgesic agent is high enough to create a sensory block, thereby treating postoperative pain, but at a level low enough to avoid motor block. 143. The depot of any one of clauses 1 to 142, wherein the release of analgesic agent provides motor-sparing relief from postoperative pain. 144. A depot for sustained controlled release of a therapeutic agent, comprising: Therapeutic areas, including therapeutic agents; a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve when the depot is placed in contact with a fluid to form diffusion openings in the control region; Includes; when the depot is placed in contact with a fluid, the depot is configured to release the therapeutic agent into the surrounding fluid for 14 days or more; A depot wherein about 20% to about 50% of the therapeutic agent is released in about the first 3 to about 5 days of a 14-day period, and at least 80% of the remaining therapeutic agent is released in the last 11 days of the 14-day period. 145. A depot according to clause 144, in which at least 85% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 146. A depot according to clause 144, in which at least 90% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 147. A depot under article 144 in which at least 95% of the remaining therapeutic agent is released during the last 11 days of the 14-day period. 148. A depot according to any one of clauses 144 to 147, in which not more than 15% of the amount of therapeutic agent is released during the first two days of a 14-day period. 149. A depot according to any one of clauses 144 to 147, in which not more than 20% of the amount of therapeutic agent is released during the first two days of a 14-day period. 150. A depot of any one of clauses 144 to 147, in which not more than 25% of the amount of therapeutic agent is released during the first 3 days of a 14-day period. 151. A depot according to any one of clauses 144 to 147, in which not more than 30% of the amount of therapeutic agent is released during the first three days of a 14-day period. 152. The depot of any one of clauses 144 to 147, wherein the release agent is configured to dissolve and form a diffusion opening when the depot is placed in contact with phosphate buffered saline. 153. A method for treating postoperative pain, comprising: placing at a treatment site in vivo having physiological fluid a depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases pain medication to the treatment site for at least 7 days. A method comprising: 154. The method of clause 153, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, the first rate being greater than the second rate. 155. The method of clause 153 or clause 154, further comprising dissolving the release agent in response to contact between the control region and physiological fluid at the treatment site. 156. The method of any one of clauses 153 to 155, further comprising creating a diffusion opening in the control region via dissolution of a release agent in response to physiological fluids at the treatment site. 157. The method of any one of clauses 153 to 156, wherein the release agent is a first release agent and the treatment region comprises a second release agent, and the method further comprises creating microchannels in the treatment region and the control region via dissolution of the first and / or second release agents. 158. The method of any one of clauses 153 to 157, wherein at least some of the microchannels penetrate both the treatment region and the control region. 159. The method of any one of clauses 153 to 158, wherein the treatment region comprises a plurality of microlayers and at least some of the microchannels extend through successive microlayers. 160. The method of any one of clauses 153 to 159, wherein the control region comprises a first plurality of microlayers and the treatment region comprises a second plurality of microlayers and at least some of the microchannels extend through the first and second plurality of microlayers. 161. The method of any one of clauses 153 to 160, further comprising increasing the porosity of the depot through dissolution of the release agent. 162. The method of any one of clauses 153 to 161, wherein the analgesic is released in one or more substantially discrete doses after implantation. 163. The method of any one of clauses 153 to 162, wherein the analgesic is released continuously for at least 7 days after implantation. 164. The method of any one of clauses 153 to 163, in which the analgesic is released over a period of 10 days or more. 165. The method of any one of clauses 153 to 163, in which the analgesic is released over a period of 14 days or more. 166. Any one of the methods in clauses 153 to 165, in which not more than 20% of the amount of analgesic is released on the first day of the seven-day period. 167. The method of any one of clauses 153 to 166, further comprising securing the depot to the treatment site via an attachment means. 168. The method of any one of clauses 153 to 167, wherein the attachment means is coupled to the depot prior to implantation. 169. The method of any one of clauses 153 to 168, wherein the depot is a first depot and the method further comprises placing a second depot at the treatment site. 170. The method of clause 169, wherein the first and second depots together release at least 1400 mg of analgesic agent to the treatment site over a period of 7 days or more. 171. A method for treating postoperative pain associated with orthopedic surgery with any of the depots of clauses 1 to 152 and 196 to 198 and / or the systems of clauses 179 to 195. 172a. A method for treating postoperative pain in a patient following orthopedic surgery, comprising: Implanting a plurality of depots at a surgical site, each of the depots including (a) a control region including a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region including at least 50% by weight of an analgesic; and The depot releases pain medication to the area for at least 7 days. A method comprising: 172b. A method for treating postoperative pain in a patient following orthopedic surgery, comprising: Implanting a depot at a surgical site, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases pain medication to the area for at least 7 days. A method comprising: 172c. A method for treating postoperative pain in a patient following total knee arthroplasty, comprising: placing a depot in the patient's knee, the depot including (a) a control region including a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region including at least 50% by weight of an analgesic; and The depot releases pain medication into the patient's knee for at least seven days. A method including 172a. The method of clause 172, wherein the depot is any of the depots of clauses 1 through 152 and 196 through 198. 173. The method of clause 172 or clause 172a, wherein placing the depot includes placing at least one depot in at least one of the suprapatellar capsule, lateral sulcus, medial sulcus, posterior capsule, quadriceps tendon, skin incision, arthrotomy, adductor canal, saphenous nerve, and geniculate nerve. 174. The method of any one of clauses 172-173, wherein placing a depot includes placing at least one depot adjacent to at least one of the saphenous nerve, the adductor canal, and the femoral nerve. 175. The method of any one of clauses 172 to 174, wherein placing a depot includes intracapsular placement of at least one depot. 176. The method of any one of clauses 172 to 174, wherein placing a depot includes extracapsular placement of at least one depot. 177. The method of any one of clauses 172 to 176, wherein placing the depot includes intracapsular placement without disturbing the knee joint. 178. The method of clause 172, wherein at least one depot is placed in at least one of the suprapatellar capsule, lateral sulcus, medial sulcus, posterior capsule, quadriceps tendon, skin incision, arthrotomy, and adductor canal. 179. A system for treating postoperative pain associated with orthopedic surgery, comprising: a plurality of depots, each of which is one of the depots described in the preceding clause; A system in which a plurality of depots are configured to be implanted at a treatment site on a patient and to release an analgesic agent at the treatment site. 180. The system of clause 179, wherein the depot is configured to release the analgesic agent to the treatment site for at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days. 181. A system of clause 180 in which the depot is configured to release in batches not more than 250 mg of analgesic per day within the first three days and not more than 150 mg of analgesic per day for the remaining days. 182. Delivery systems; and A depot configured to be implanted in vivo at a treatment site together with a delivery system, the depot comprising any of the depots of clauses 1 to 152 and 196 to 198. 1. A system for treating post-operative pain, comprising: 182a. Attachment means; and A depot configured to be implanted in vivo at a treatment site and secured to the treatment site via an attachment means, the depot comprising any of the depots of clauses 1 to 152 and 196 to 198. 1. A system for treating post-operative pain, comprising: 183. The system of clause 182a, wherein the attachment means is coupled to the depot prior to implantation. 184. The system of clause 182 or clause 183, wherein the attachment means is at least one of a suture, a tine, a barb, a hook, and a screw. 185. The system of any one of clauses 182a to 184, in which the pain is related to orthopedic surgery. 186. The system of any one of clauses 182a to 185, in which the pain is related to joint replacement surgery. 187. The system of any one of clauses 182a to 186, in which the pain is related to knee replacement surgery. 188. The system in article 187 where pain is related to partial knee replacement surgery. 189. Article 187 system in which pain is associated with total knee replacement surgery. 190. The system in article 187 where pain is related to revision knee replacement surgery. 191. The system of any one of clauses 182a to 190, wherein the depot is configured to be placed adjacent to at least one of the saphenous nerve, the adductor canal, and the femoral nerve. 192. The system of any one of clauses 182a to 191, wherein the depot is configured to be placed adjacent to at least one of the posterior capsule of the knee, the region above the patella, or an incision into the knee joint capsule. 193. The system of any one of clauses 182a to 191, wherein the depot is configured for placement within the knee joint capsule in the medial and / or lateral groove. 194. A system for treating postoperative pain, comprising a delivery system and any of the depots of clauses 1 to 152 and 196 to 198. 195. A system for treating postoperative pain comprising a plurality of depots, each of which comprises any of the depots of clauses 1 to 152 and 196 to 198. 196. A depot for releasing a therapeutic agent to treat or manage a particular condition or disease, comprising: a treatment area comprising a therapeutic agent and a bioabsorbable polymer carrier; a control region comprising a bioabsorbable polymer layer and a release agent mixed with the polymer, the release agent configured to dissolve over a first period of time after in vivo placement to form diffusion openings in the control region; Including, the depot is configured to be implanted at the treatment site in vivo and, while implanted, to release the therapeutic agent at the treatment site over a second period of time; The second period is longer than the first period; After the second period of time, the polymeric carrier of the treatment region and the polymeric layer of the control region comprise a highly porous polymeric structure configured to degrade in vivo without acidification of the core, the depot. 197. The depot of clause 196, wherein the highly porous polymeric structure at the end of the second period has a mass that is no more than 50% of the mass of the depot before in vivo placement. 198. The depot of clause 197, wherein the highly porous polymer structure is configured to degrade in vivo via surface erosion. 199. A method for treating postoperative pain following a non-orthopedic surgical procedure, comprising: placing at a treatment site in vivo having physiological fluids a depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; dissolving the release agent in response to contact between the release agent and the physiological fluid, thereby forming a diffusion opening in the control region; and Release of pain medication from the treatment area through the diffusion opening to the treatment site for at least 5 days A method comprising: 200. The method of clause 199, wherein the surgical procedure includes at least one of thoracotomy, esophageal surgery, cardiac surgery, lung resection, or thoracic surgery. 201. The method of clause 200, wherein the treatment site comprises the thoracic paravertebral space. 202. The method of clause 200 or clause 201, wherein the analgesic released from the depot at least partially blocks the intercostal nerves. 203. The method of clause 199, in which the surgical procedure includes at least one of mastectomy, breast augmentation, breast reduction, or breast reconstruction. 204. The method of clause 203, wherein the treatment site includes the subclavian space. 205. The method of clause 203 or clause 204, wherein the analgesic released from the depot at least partially blocks at least one of the intercostal nerves, the medial pectoral nerve, or the lateral pectoral nerve. 206. The method of clause 199, in which the surgical procedure includes at least one of myomectomy, cesarean section, hysterectomy, oophorectomy, or pelvic floor reconstruction. 207. The method of clause 199, wherein the surgical procedure includes at least one of proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, proctectomy, kidney stone removal, or cystectomy. 208. The method of clause 207, wherein the analgesic released from the depot at least partially blocks nerves at or adjacent to the plane of the transversus abdominis fascia. 209. The method of clause 199, wherein the surgical procedure includes at least one of tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, or submandibular gland surgery. 210. The method of clause 199, wherein the surgical procedure includes at least one of dentoalveolar surgery, dental implants, surgical orthodontics, temporomandibular joint (TMJ) surgery, or oral reconstruction. 211. The method of clause 199, in which the surgical procedure includes tumor resection. 212. The method of clause 199, in which the surgical procedure includes liposuction. 213. The method of any one of clauses 199 to 212, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, the first rate being greater than the second rate. 214. The method of any one of clauses 199 to 213, in which the analgesic is released over a period of 10 days or more. 215. The method of any one of clauses 199 to 214, in which the analgesic is released over a period of 14 days or more. 216. Any one of the methods of clauses 199 to 215, in which not more than 20% of the amount of analgesic is released on the first day of the five-day period. 217. The method of any one of clauses 199 to 216, further comprising securing the depot to the treatment site via an attachment means. 218. The method of clause 217, wherein the attachment means is coupled to the depot prior to implantation. 219. The method of any one of clauses 199 to 218, wherein the depot is a first depot and the method further comprises placing a second depot at the treatment site. 220. The method of clause 219, wherein the first and second depots together release at least 1400 mg of analgesic agent to the treatment site over a period of 7 days or more. 221. The method of any one of clauses 199 to 220, in which 400 mg or less of the therapeutic agent is released on any day during a five-day period. 222. A method for treating postoperative pain following a non-orthopedic surgical procedure, comprising: placing at a treatment site in vivo having physiological fluid a depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases pain medication to the treatment site for at least 5 days. A method comprising: 223. The method of clause 222, wherein the surgical procedure includes at least one of thoracotomy, esophageal surgery, cardiac surgery, lung resection, or thoracic surgery. 224. The method of clause 223, wherein the treatment site includes the thoracic paravertebral space. 225. The method of clause 223 or 224, wherein the analgesic released from the depot at least partially blocks the intercostal nerves. 226. The method of clause 222, in which the surgical procedure includes at least one of mastectomy, breast augmentation, breast reduction, or breast reconstruction. 227. The method of clause 226, wherein the treatment site includes the subclavian space. 228. The method of clause 226 or 227, wherein the analgesic released from the depot at least partially blocks at least one of the intercostal nerves, the medial pectoral nerve, or the lateral pectoral nerve. 229. The method of clause 222, in which the surgical procedure includes at least one of myomectomy, cesarean section, hysterectomy, oophorectomy, or pelvic floor reconstruction. 230. The method of clause 222, wherein the surgical procedure includes at least one of proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, proctectomy, kidney stone removal, or cystectomy. 231. The method of clause 230, wherein the analgesic released from the depot at least partially blocks nerves at or adjacent to the plane of the transversus abdominis fascia. 232. The method of clause 222, in which the surgical procedure includes at least one of tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, or submandibular gland surgery. 233. The method of clause 222, wherein the surgical procedure includes at least one of dentoalveolar surgery, dental implants, surgical orthodontics, temporomandibular joint (TMJ) surgery, or oral reconstruction. 234. The method of clause 222, in which the surgical procedure includes tumor resection. 235. The method of clause 222, in which the surgical procedure includes liposuction. 236. A method for treating postoperative pain following a surgical procedure involving a patient's chest, comprising: placing a depot near an intercostal nerve at a treatment site having physiological fluid, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The depot releases analgesic into the intercostal nerves for at least 5 days. A method comprising: 237. The method of clause 236, wherein the surgical procedure includes at least one of thoracotomy, esophageal surgery, cardiac surgery, lung resection, or thoracic surgery. 238. The method of clause 236 or 237, wherein the treatment site includes the thoracic paravertebral space. 239. A method for treating postoperative pain following a surgical procedure involving a patient's breast, comprising: placing a depot in the vicinity of the intercostal and / or pectoral nerves at a treatment site having physiological fluid, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The method comprises releasing an analgesic agent from the depot into the intercostal and / or pectoral nerves for a period of 5 days or more. 240. The method of clause 239, in which the surgical procedure includes at least one of mastectomy, breast augmentation, breast reduction, or breast reconstruction. 241. The method of clause 239 or 240, wherein the treatment site includes the intraclavicular space. 242. A method for treating postoperative pain after a general, abdominal, or urinary surgical procedure, comprising: placing a depot near the transversus abdominis plane at a treatment site having physiological fluid, the depot comprising: (a) a control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, and (b) a treatment region comprising at least 50% by weight of an analgesic; and The method comprises releasing an analgesic agent from the depot into the intercostal and / or pectoral nerves for a period of 5 days or more. 243. The method of clause 242, wherein the surgical procedure includes at least one of proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, proctectomy, kidney stone removal, or cystectomy. 244. A depot for sustained, controlled release of a therapeutic agent, comprising: a therapeutic area containing a therapeutic agent; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; wherein the depot is configured such that after immersion of the depot in a buffer solution for 7 days, the flexural strength of the depot is reduced by up to 75%. 245. The depot of clause 244, configured such that the flexural strength of the depot is reduced by up to 70% after immersion of the depot in a buffer solution for 7 days. 246. The depot of clause 244, configured such that the flexural strength of the depot is reduced by up to 65% after immersion of the depot in a buffer solution for 7 days. 247. A depot according to clause 244, configured such that the flexural strength of the depot is reduced by up to 60% after immersion of the depot in a buffer solution for 7 days. 248. A depot according to clause 244, configured such that the flexural strength of the depot is reduced by up to 55% after immersion of the depot in a buffer solution for 7 days. 249. A depot according to clause 244, configured such that the flexural strength of the depot is reduced by up to 50% after immersion of the depot in a buffer solution for 7 days. 250. The depot of clause 244, 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. 251. A depot for sustained controlled release of a therapeutic agent, comprising: a therapeutic area containing a therapeutic agent; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; wherein the depot is configured such that after immersion in a buffer solution until about 75% by weight of the therapeutic agent has been released, the flexural strength of the depot is reduced by up to 75%. 252. The depot of clause 251, configured such that the flexural strength of the depot is reduced by up to 70% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 253. The depot of clause 251, configured such that the flexural strength of the depot is reduced by up to 65% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 254. The depot of clause 251, configured such that the flexural strength of the depot is reduced by up to 60% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 255. The depot of clause 251, configured such that the flexural strength of the depot is reduced by up to 55% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 256. The depot of clause 251, configured such that the flexural strength of the depot is reduced by up to 50% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 257. The depot of clause 251, configured such that the flexural strength of the depot is reduced by up to 45% after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released. 258. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for 14 days or more; A depot in which approximately 20% to approximately 40% of the analgesic is released in the first 3 days of the 14-day period, and at least 80% of the remaining analgesic is released in the last 11 days of the 14-day period. 259. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The control region is a depot that does not contain analgesic, at least prior to implantation of the depot at the treatment site. 260. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The control region contains a different analgesic than the analgesic in the treatment region, the depot. 261. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The depot, wherein the release agent is a first release agent and the treatment area contains a second release agent mixed with an analgesic. 262. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The depot, wherein the release agent is a first release agent, the polymer is a first polymer, and the treatment area comprises a second polymer mixed with a second release agent and an analgesic agent. 263. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The thickness of the control region is less than or equal to 1 / 50 of the thickness of the treatment region, depot. 264. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The thickness of the control region is less than or equal to 1 / 75 of the thickness of the treatment region, depot. 265. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; The thickness of the control region is less than or equal to 1 / 100 of the thickness of the treatment region, depot. 266. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; A depot, wherein the first controlling layer comprises a first amount of a release agent and the second controlling layer comprises a second amount of a release agent that is different from the first amount. 267. A depot for treating postoperative pain through sustained controlled release of an analgesic, comprising: Therapeutic areas include analgesics; a controlled region comprising a bioabsorbable polymer and a release agent mixed with the polymer, the release agent configured to dissolve upon placement of the depot in vivo to form diffusion openings in the controlled region; Including, the depot is configured to be implanted in vivo at a treatment site and, while implanted, to release the analgesic agent at the treatment site for at least three days; the depot has a total surface area that includes the exposed surface area of ​​the coverage area plus the exposed surface area of ​​the treatment area; A depot, wherein when the depot is initially placed at a treatment site in vivo, the ratio of the exposed surface area of ​​the treatment area to the exposed surface area of ​​the covered area is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%.

[0011] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the release of bupivacaine hydrochloride over time from a Xaracoll® sponge.

[0013] [Figure 2] FIG. 2 is an isometric view of a depot constructed in accordance with the present technology.

[0014] [Figure 3] FIG. 3 shows the release profile over time of one or more depots of the present technology.

[0015] [Figure 4] FIG. 4 is an isometric view of a depot in accordance with some embodiments of the present technology.

[0016] [Figure 5]FIG. 5 is an isometric view of a depot in accordance with some embodiments of the present technology.

[0017] [Figure 6] FIG. 6 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0018] [Figure 7] FIG. 7 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0019] [Figure 8] FIG. 8 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0020] [Figure 9A] FIG. 9A is an isometric view of a depot in accordance with some embodiments of the present technology.

[0021] [Figure 9B] FIG. 9B is a cross-sectional view of the depot shown in FIG. 9A.

[0022] [Figure 10] FIG. 10 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0023] [Figure 11] FIG. 11 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0024] [Figure 12] FIG. 12 is a cross-sectional view of a depot in accordance with some embodiments of the present technology.

[0025] [Figure 13] FIG. 13 is an isometric view of a depot in accordance with some embodiments of the present technology.

[0026] [Figure 14] 14A-H show depots with various cross-sectional areas and shapes according to the present technology.

[0027] [Figure 15] FIG. 15 shows the maximum bending load of the implant over time from tests performed on implant samples immersed in buffer solution.

[0028] [Figures 16A-C] 16A-16E show various depot embodiments including a base region and / or delayed release region in accordance with the present technology. [Figure 16D-E] 16A-16E show various depot embodiments including a base region and / or delayed release region in accordance with the present technology.

[0029] [Figure 17] FIG. 17 is a schematic diagram of prior art core acidification.

[0030] [Figure 18] FIG. 18 is a scanning electron microscope image of a prior art polymer tablet after 20 days of degradation.

[0031] [Figure 19A] FIG. 19A is a schematic illustration of the degradation of a depot of the present technology.

[0032] [Figure 19B-C] 19B and 19C are scanning electron microscope ("SEM") images of cross-sections of depots of the present technology at various times during degradation.

[0033] [Figure 20] FIG. 20 shows the in vitro release profile for the depot described in Example 1 according to the present technology.

[0034] [Figure 21] FIG. 21 shows the in vitro release profile for the depot described in Example 2A according to the present technology.

[0035] [Figure 22]FIG. 22 shows the in vitro release profile for the depot described in Example 2B according to the present technology.

[0036] [Figure 23] FIG. 23 shows the in vitro release profile for the depot described in Example 3 according to the present technology.

[0037] [Figure 24A] FIG. 24A shows the in vivo plasma bupivacaine concentration over time for rabbits implanted with the depot described in Example 4 according to the present technology.

[0038] [Figure 24B] FIG. 24B shows the in vitro release profile over time for the sample depot described in Example 4 according to the present technology.

[0039] [Figure 24C] FIG. 24C shows in vivo plasma bupivacaine concentrations over time for rabbits implanted with the depot described in Example 4 according to the present technology.

[0040] [Figure 24D] FIG. 24D shows the in vitro release profile over time of the sample depot described in Example 4 according to the present technology.

[0041] [Figure 25] FIG. 25 shows in vivo plasma bupivacaine concentrations over time for dogs implanted with the depot described in Example 5 according to the present technology.

[0042] [Figure 26A] FIG. 26A shows in vivo plasma bupivacaine concentrations over time for sheep implanted with the depot described in Example 6 according to the present technology.

[0043] [Figure 26B] FIG. 26B shows in vivo synovial fluid bupivacaine concentrations over time for sheep implanted with the depot described in Example 6 according to the present technology.

[0044] [Figure 26C] FIG. 26C is a plot showing plasma bupivacaine concentration versus synovial fluid bupivacaine concentration over time for sheep implanted with the depot described in Example 6 according to the present technology.

[0045] [Figure 27] Figures 27A and 27B show typical locations in a patient where surgery may be performed and where the depot may be administered.

[0046] [Figure 28-1] Figure 28 is a table showing common surgical procedures in which the depots of the present technology may be utilized to treat post-operative pain. Figure 28 also shows the neural targets and anatomical access / placement for various procedures. [Figure 28-2] Figure 28 is a table showing common surgical procedures in which the depots of the present technology may be utilized to treat post-operative pain. Figure 28 also shows the neural targets and anatomical access / placement for various procedures. [Figure 28-3] Figure 28 is a table showing common surgical procedures in which the depots of the present technology may be utilized to treat post-operative pain. Figure 28 also shows the neural targets and anatomical access / placement for various procedures.

[0047] [Figure 29] 29A-29C are anterior, lateral, and medial views of the human knee showing the location of the nerves that innervate the knee.

[0048] [Figure 30A] FIG. 30A shows a human knee cut open to expose the intra-articular cavity and identify potential locations for placement of one or more depots.

[0049] [Figure 30B] FIG. 30B is a cut-away view of a human knee exposing the intra-articular cavity and showing several depots placed therein to treat post-operative pain.

[0050] [Figure 31] 31A and 31B show the extracapsular views of the anterior and posterior aspects of the human knee, illustrating the location of the nerves that innervate the knee in extracapsular locations.

[0051] [Figure 32] FIG. 32 is an anterior view of a partially reamed human knee showing the extracapsular space and illustrating several depots of the present technology placed in the extracapsular space to treat post-operative pain. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present technology relates to implantable depots for the sustained, controlled release of therapeutic agents, as well as related devices, systems, and methods of use. An overview of the depots and related release kinetics of the present technology is described below with reference to Figures 2 and 3 and Section I. Selected embodiments of depots of the present technology are described below with reference to Figures 4-19C and Section II. Selected examples of depots of the present technology and related release profiles are described below with reference to Figures 20-26C and Section III. Selected devices, systems, and methods for using the depots of the present technology to treat postoperative pain associated with orthopedic surgery are described below with reference to Figures 27A-32 and Section IV. Selected devices, systems, and methods for using the depots of the present technology to treat postoperative pain associated with other surgeries are described below in Section V.

[0053] I. Overview Disclosed herein are implantable depots and related devices, systems, and methods for treating (i.e., preventing, reducing, and / or eliminating) postoperative pain through the sustained, controlled release of a therapeutic agent while the depot is implanted at the treatment site in vivo. Many embodiments of the present technology include one or more depots configured to be implanted at or near a patient's surgical site to treat postoperative pain. While implanted in vivo, the depot(s) are configured to release a therapeutic agent (such as an analgesic) to the surgical site in a controlled and defined manner for at least three days after implantation.

[0054] As used herein, a "depot" includes a composition in which at least one therapeutic agent is administered to a patient's body. Thus, a depot may include a physical structure or carrier that facilitates implantation and retention at a desired site (e.g., the tissues of the intra-articular and / or extracapsular space of a knee joint). A depot also includes the therapeutic agent itself. A "depot" includes, but is not limited to, a film, sheet, strip, ribbon, capsule, coating, matrix, wafer, pill, pellet, or other pharmaceutical delivery device, or combinations thereof. Furthermore, as used herein, a "depot" may refer to a single depot or multiple depots. For example, the statement "the depot may be configured to release 2 g of therapeutic agent to a treatment site" describes (a) a single depot configured to release 2 g of therapeutic agent to a treatment site, and (b) multiple depots collectively configured to release 2 g of therapeutic agent to a treatment site.

[0055] 2 is an isometric view of an implantable depot 100 in accordance with some embodiments of the present technology. Depot 100 may be a thin, multi-layered polymer film configured to be implanted at a treatment site, including a treatment region 200 containing a therapeutic agent (such as an analgesic), and a control region 300 configured to regulate the release of the therapeutic agent from depot 100 in a controlled and sustained manner. Depot 100 may contain a high therapeutic payload of therapeutic agent, particularly compared to other known films of equivalent thickness or polymer weight percentage. For example, in some embodiments, depot 100 contains at least 50% therapeutic agent by weight.

[0056] The control region 300 may include a bioabsorbable polymer and a release agent mixed therewith, and the treatment region 200 may include a bioabsorbable polymer and a release agent mixed therewith, as well as a therapeutic agent. The control region 300 may optionally include a therapeutic agent, or the control region may be free of a therapeutic agent altogether. As discussed in more detail in Section II below, in some embodiments, the treatment region 200 and / or the control region 300 may have different components and / or formulations.

[0057] When fluid contacts depot 100, the release agent dissolves into the polymer surrounding control region 300 and / or treatment region 200 faster than the polymer degrades. As the release agent dissolves, the spaces vacated by the dissolved release agent form diffusion openings (e.g., channels, voids, pores, etc.) in the surrounding polymer region. The concentration and type of release agent, among other parameters, can be selected to regulate the release of the therapeutic agent from treatment region 200 and through control region 300 into the surrounding fluid at a controlled dosage rate over a desired period of time.

[0058] As shown in FIG. 2 , at least a portion of the control region 300 may be positioned above or adjacent to the treatment region 200 such that when the depot 100 is initially placed in vivo, the control region 300 is between at least a portion of the treatment region 200 and the physiological fluid at the treatment site. For example, the control region 300 may cover all or a portion of one or more sides or edges of the treatment region 200. When the depot 100 is exposed to physiological fluid, the therapeutic agent elutes from the exposed surface of the treatment region 200 through the control region 300 using diffusion openings created by the dissolution of the release agent. Generally, the therapeutic agent elutes from the exposed surface of the treatment region 200 at a faster (e.g., greater) rate than through the control region 300. As a result, the control region 300 extends the release of the therapeutic agent from the treatment region 200, providing a longer release time and regulating the dosing rate to achieve the desired degree of pain relief and avoid complications associated with overdosing.

[0059] The depots of the present technology are configured to release therapeutic agents in a highly controlled, predetermined manner that is specifically tailored to the medical condition being treated and the therapeutic agent being used. As described in more detail in Section II below, the release kinetics of the depot may be customized for a particular application by varying one or more aspects of the composition and / or structure of the depot, such as the shape and size of the depot; the exposed surface area of ​​the treatment region 200; the type of polymer (within the treatment region 200 and / or the control region 300); the weight percentage of the therapeutic agent, polymer, and / or release agent (within a specific region or generally throughout the depot 100); and the composition of the treatment region 200 and the control region 300.

[0060] As shown in Figure 3, in many embodiments, the depot 100 (or depot 100 system) is configured to release a disproportionately greater volume of therapeutic agent per day over a first period of time than over a second, longer period of time. In some embodiments, the depot 100 (or depot 100 system) is configured to release therapeutic agent for at least 14 days after implantation (or immersion in fluid), with a controlled burst of about 20% to about 50% of the therapeutic agent payload being released in the first 3-5 days, and at least 80% of the remaining therapeutic agent payload being released at a slower rate over the last 10-11 days. In some embodiments, at least 90% of the therapeutic agent payload is released by the end of the 14 days.

[0061] A two-stage, secondary release profile, such as that shown in Figure 3, can be particularly beneficial in the context of treating pain resulting from total knee arthroplasty ("TKA"). TKA patients typically experience maximal pain within the first 1-3 days after surgery (clinically referred to as "acute pain"), followed by a gradual decrease in pain over the next 7-10 days (clinically referred to as "subacute pain"). The acute period often overlaps or coincides with the patient's inpatient treatment (usually 1-3 days), while the subacute period generally begins when the patient is discharged and returns home. The two-stage, secondary release profile shown in Figure 3 may also be beneficial in other surgical applications, such as other orthopedic applications (e.g., ligament repair / replacement and other injuries to the knee, shoulder, ankle, etc.), or non-orthopedic surgical applications. Excessive pain after any surgery can prolong hospital treatment, cause psychological distress, increase opioid consumption, and / or impair patient participation in physical therapy, all of which can prolong and / or reduce the extent of a patient's recovery. Pain relief during the subacute period can be particularly complex to manage because patient compliance with prescribed pain management regimens decreases when patients transition from the hospital to the home environment.

[0062] To address the aforementioned challenges in postoperative pain management, the depot 100 (or a depot system including multiple depots 100) of the present technology may have release profiles tailored to meet specific pain management needs during the acute and subacute periods. For example, to address the greater acute pain experienced immediately following surgery, the depot 100 may be configured to release a therapeutic agent at a faster rate over the first 3-5 days after implantation compared to the subsequent 9-11 day period (as shown in FIG. 3). In some embodiments, the depot 100 may deliver a local anesthetic at a rate of about 150 mg / day to about 400 mg / day during this first acute period. To address the diminishing pain during the subacute period, the depot 100 may be configured to release a therapeutic agent at a slower rate over the remaining 9-11 days. In some embodiments, the depot 100 may deliver a local anesthetic at a rate of about 50 mg / day to about 250 mg / day during this second subacute period. In some embodiments, the rate of release decreases continuously throughout the first period and / or the second period.

[0063] The release profile of depot 100 may be tailored to release therapeutic agent for other durations and / or at other release rates by adjusting the structure, composition, and process by which the depot is manufactured. For example, in some embodiments, depot 100 may be configured to release therapeutic agent at a constant rate throughout the entire duration of release. In certain embodiments, depot 100 may be configured to release therapeutic agent at a constant rate for a first period of time and at a non-constant rate for a second period of time (which may occur before or after the first period of time).

[0064] In some embodiments, the depot 100 is configured to release 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, or 70% or less of the therapeutic agent on the 1st, 2nd, 3rd, 4th, 5th, 6th, 8th, 9th, 10th, 11th, 12th, or 13th day of the release duration, with at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the remaining therapeutic agent being released on the remaining days of the release duration. The intended duration of release may be at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, or at least 30 days.

[0065] In some embodiments, the depot 100 is configured to release at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the therapeutic agent within the depot 100 within the duration of the intended treatment. The duration of the contemplated treatment may be at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 40 days, 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.

[0066] In some embodiments, the depot 100 is configured to release from about 50 mg / day to about 600 mg / day, 100 mg / day to about 500 mg / day, or from about 100 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day of therapeutic agent to the treatment site. Generally, the release rate can be selected to deliver the desired dosage to provide the degree of pain relief needed at a given time after the surgical procedure, control toxicity, and deliver the therapeutic agent for a period of time sufficient for pain relief.

[0067] In some embodiments, the depot 100 is configured to release from about 50 mg / day to about 600 mg / day, from about 100 mg / day to about 500 mg / day, or from about 100 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day of therapeutic agent to the treatment site within a first release period. The depot 100 can be further configured to release from about 500 mg / day to about 600 mg / day, from about 100 mg / day to about 500 mg / day, or from about 100 mg / day to about 400 mg / day, or from about 100 mg / day to about 300 mg / day of therapeutic agent to the treatment site within a second release period. The release rate during the first period may be the same as, different from, less than, or greater than the release rate during the second period. Furthermore, the first period may be longer or shorter than the second period. The first period may occur before or after the second period.

[0068] 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 a therapeutic agent by any day of the first release period, which may be useful for providing varying degrees of pain relief at different times after a surgical procedure and may also be useful for controlling toxicity. In such embodiments, the depot 100 may be configured to release 50 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, 500 mg or less, 600 mg or less, 700 mg or less, 800 mg or less, 900 mg or less, or 1000 mg or less of therapeutic agent by any day of the second release period. The first release period and / or the second release period may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days. The depot 100 may be configured to release the therapeutic agent at a first rate during a first period of time and at a second rate during a second period of time. The first rate may be the same as, different from, less than, or greater than the second rate. Furthermore, the first period of time may be longer or shorter than the second period of time. The first period of time may precede or follow the second period of time.

[0069] In some embodiments, the depot 100 is configured to release 50 mg or less, 100 mg or less, 150 mg or less, 200 mg or less, 250 mg or less, 300 mg or less, 350 mg or less, 400 mg or less, 450 mg or less, 500 mg or less, 600 mg or less, 700 mg or less, 800 mg or less, 900 mg or less, or 1000 mg or less of therapeutic agent by any day during the duration of the release.

[0070] In some embodiments, the depot 100 is configured to release a therapeutic agent to a treatment site in vivo and / or in the presence of one or more fluids for 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 90 or more, 100 or more, 200 or more, 300 or more, or 365 or more days.

[0071] II. Selected Depot Embodiments The release kinetics of the depots of the present technology can be tailored to a particular application by varying one or more aspects of the depot's structure, such as the exposed surface area of ​​the treatment region 200, the porosity of the control region 300 during and after dissolution of the release agent, the concentration of therapeutic agent in the treatment region, the post-fabrication properties of the polymer, the structural integrity of the depot to avoid sudden release of the therapeutic agent, the relative thickness of the treatment region 200 compared to the control region 300, and other properties of the depot. Some embodiments of the depots of the present technology combine one or more of these properties to produce exceptional biphasic release profiles in animal studies that are significantly superior to existing injectable or implantable systems while also overcoming the shortcomings of the disclosed predictive devices. For example, some embodiments have demonstrated biphasic release profiles that deliver an appropriate mass of therapeutic agent to treat pain associated with joint replacement surgery or other applications over a 14-day period, while maintaining sufficient structural integrity to withstand joint forces to avoid sudden release of too much therapeutic agent. This unexpected result allows the depot of the present technology to at least reduce, if not replace, opioids and / or augment other existing pain relief systems for orthopedic, non-orthopedic, and other applications (e.g., oncology).

[0072] For example, the release profile can be tailored, at least in part, by controlling the amount of exposed surface area of ​​the therapeutic region 200, because depots having therapeutic regions 200 that are only partially covered by a control region 300 (see, e.g., Figures 2, 4-8, and 13) will generally release a higher percentage of their total payload over a shorter period of time than embodiments in which the therapeutic region 200 is fully encapsulated by a control region 300 (see, e.g., Figures 9A-12). More specifically, depot designs having a therapeutic region 200 with exposed edges will typically release therapeutic agent at a high, substantially linear rate over a first period of time, followed by a lower, substantially linear rate over a second period of time. Alternatively, depot designs having a therapeutic region 200 with edges that are substantially covered by one or more control regions 300 may achieve zero-order release, such that the release of the therapeutic agent payload is at substantially the same rate.

[0073] 4, in some embodiments, the depot 100 may include a multilayer polymer film having a treatment region 200 and first and second control regions 300a, 300b disposed on opposing sides 100a, 100b of the treatment region 200. The depot 100 may be in the form of a flexible rectangular strip having a length L, a width W, and a height H (or thickness). In some embodiments, depot 100 has a length L of about 20 mm to about 30 mm (e.g., about 25 mm, etc.), a width W of about 10 mm to about 20 mm (e.g., about 15 mm, etc.), and a height H of about 0.4 mm to about 4 mm (e.g., about 1 mm to about 3 mm, about 1 mm to about 2 mm, at least 0.4 mm, at least 0.5 mm, at least 0.6 mm, at least 0.7 mm, at least 0.8 mm, at least 0.9 mm, at least 1 mm, at least 1.2 mm, at least 1.4 mm, at least 1.5 mm, at least 1.6 mm, at least 1.7 mm, at least 1.8 mm, at least 2 mm, at least about 3 mm, etc.). In some embodiments, depot 100 may have other shapes and / or dimensions, such as those detailed below.

[0074] The control regions 300a, 300b need only cover a portion of the treatment region 200 so that a portion of each of the faces (e.g., sidewalls) of the treatment region 200 is exposed to physiological fluid immediately after implantation of the depot 100 in vivo. When the depot 100 is exposed to physiological fluid (or any similar fluid in an in vitro setting), the therapeutic agent will begin to elute from the exposed surface 202 (in addition to via the control regions 300a, 300b), resulting in a faster release of the therapeutic agent than if the treatment region 200 did not have an exposed region. Thus, the surface area of ​​the exposed surface 202 may be tailored to provide an initial, controlled burst followed by a tapering release (e.g., similar to that shown in FIG. 3). The initial, more aggressive release of the therapeutic agent is slowed, in part, by the control regions 300a, 300b, which initially reduce the surface area of ​​the treatment region 200 exposed to fluid. Unlike the depot 100 of the present technology, many conventional drug eluting technologies result in an initial, uncontrolled burst release of drug upon exposure to physiological fluids. Some embodiments of the depot of the present technology are not only capable of implanting sufficient therapeutic agent for days or weeks of dosage to achieve sustained, durable in vivo pharmacological treatment, but also release the therapeutic agent in a defined manner, thereby preventing release of a significant portion of the total payload in an uncontrolled manner that could result in complications for the patient and / or reduce the remaining payload so that there is not enough therapeutic agent remaining in the depot to deliver a therapeutic dose over the remaining release duration.

[0075] In some embodiments, the depot 100 shown in FIG. 4 is configured to release about 20% to about 50% of the analgesic agent in the first about 3 to about 5 days of a 14-day period, with at least 80% of the remaining analgesic agent being released in the last about 9 to about 11 days of the 14-day period. This release profile provides a higher dosage of therapeutic agent during the acute period after surgery compared to the subacute period. In some embodiments, the depot 100 shown in FIG. 4 is configured to release about 100 mg to about 500 mg of analgesic agent per day to the treatment site, and in some cases, no more than 400 mg or no more than 300 mg of analgesic agent per day within the first three days of implantation, and no more than 200 mg per day for the remaining days. Additionally, some embodiments of the depot shown in FIG. 4 are configured so that the thickness of the control regions 300a and 300b, individually or collectively, is less than or equal to 1 / 50 of the thickness of the treatment region 200. The thickness of the control regions 300a and 300b, individually or collectively, can further be 1 / 75 or 1 / 100 or less of the thickness of the treatment region 200. Additionally, the depot 100 shown in Figure 4 can have a ratio of analgesic drug mass in the depot to depot polymer mass that is at least 16:1, 10:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1.

[0076] Some embodiments of the depot 100 shown in FIG. 4 are also configured to maintain their structural integrity even after a significant portion of the release agent has eluted from the depot 100. As the release agent(s) dissolve and the therapeutic agent(s) elute, the functional mechanical aspects of the depot 100 may change over time. Such mechanical aspects include the structural integrity, flexural strength, tensile strength, or other mechanical properties of the depot. If the depot 100 experiences excessive degradation too quickly, it may mechanically fail and release an undesirable burst of therapeutic agent into the body. Some embodiments of the depot 100 shown in FIG. 4 are loaded with sufficient therapeutic agent to deliver 100 mg to 500 mg of therapeutic agent per day while still being able to maintain its structural integrity so that the depot remains largely intact for at least 14 days after implantation. For example, the therapeutic agent can be at least 50% to 95% by weight of the total weight of the depot 100 before implantation, or 55% to 85% by weight of the total weight of the depot 100 before implantation, or 60% to 75% by weight of the total weight of the depot 100 before implantation. A depot can be sufficiently intact, for example, if it has not broken into multiple component pieces, and two or more of the resulting pieces are at least 5% of the depot's previous size. Alternatively, or additionally, a depot can be considered sufficiently intact if the release rate of the therapeutic agent does not increase by more than three-fold compared to the release rate of the therapeutic agent from a control depot immersed in a buffer solution.

[0077] Some embodiments of the depot 100 shown in FIG. 4 having one or more combinations of the parameters described in the preceding paragraphs resulted in exceptional results in animal studies as described herein. For example, the depot 100 is configured such that (a) the thickness of the control regions 300a - b is less than or equal to 1 / 50 of the thickness of the treatment region 200, either individually or collectively, (b) the mass of the therapeutic agent payload is sufficient to release from about 100 mg to about 500 mg of analgesic per day at the treatment site, and (c) the structural integrity is such that most of the depot remains intact for at least 14 days after implantation. These embodiments were able to release from about 20% to about 50% of the analgesic payload in the first about 3 to about 5 days of the 14-day period, and then at least 80% of the remaining analgesic payload in the last about 9 to about 11 days of the 14-day period. This was at least partially unexpected because (a) providing such a large payload of the therapeutic agent in the treatment region would predict a mechanical failure of the depot 100 on or before the 14th day after implantation, and (b) the disclosed device did not achieve a release profile in which from about 20% to about 50% of the analgesic was released in the first about 3 to about 5 days of the 14-day period and then at least 80% of the remaining analgesic was released in the last about 9 to about 11 days of the 14-day period.

[0078] In some embodiments, one or more control regions 300 of depot 100 may include two or more sub-control regions. For example, as shown in Figure 5, 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. The first and second control regions 300a, 300b, and / or one, some, or all of the sub-control regions 302a-302d 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 ratios of polymer to release agent, and / or the same or different thicknesses. In some embodiments, the concentration of release agent in each outer control sub-region 302a, 302d is less than the concentration of release agent in each inner control sub-region 302b, 302c, such that the outer portions of the collective control region elute therapeutic agent more slowly than the inner portions of the collective control region. In some embodiments, the concentration of release agent in each outer control sub-region 302a, 302d is greater than the concentration of release agent in each inner control sub-region 302b, 302c. In embodiments where the control region includes more than two sub-regions, the concentration of release agent per sub-region or layer may increase, decrease, or remain constant as the sub-control regions become further apart than the treatment region 200.

[0079] In certain embodiments, the outer control sub-region comprises at least 5% by weight of a release agent, at least 10% by weight of a release agent, at least 15% by weight of a release agent, at least 20% by weight of a release agent, at least 25% by weight of a release agent, at least 30% by weight of a release agent, at least 35% by weight of a release agent, at least 40% by weight of a release agent, at least 45% by weight of a release agent, or at least 50% by weight of a release agent. In some embodiments, the inner control sub-region comprises at least 5% by weight of a release agent, at least 10% by weight of a release agent, at least 15% by weight of a release agent, at least 20% by weight of a release agent, at least 25% by weight of a release agent, at least 30% by weight of a release agent, at least 35% by weight of a release agent, at least 40% by weight of a release agent, at least 45% by weight of a release agent, or at least 50% by weight of a release agent. In some embodiments, the outer control sub-region may include a first amount of release agent and the inner control sub-region may include a second amount of release agent, the second amount being at least 200%, at least 300%, at least 400%, or at least 500% greater than the first amount.

[0080] 6-8 show embodiments of a depot having multiple alternating treatment regions 200 and control regions 300 in accordance with the present technology. The depot 100 may have two or more control regions 300 and / or subregions 302 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and the depot 100 may have one or more treatment regions 200 and / or subregions 202 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one control region 300 and / or subregion 302. In some embodiments, each of the treatment regions 200 may comprise a single layer, and / or each of the control regions 300 may comprise a single layer. In some embodiments, one, some, or all of the treatment regions 200 may comprise multiple layers, and / or one, some, or all of the control regions 300 may comprise multiple layers. In some embodiments, for example, as shown in Figures 6 and 7, two or more sub-regions 302a-b (Figure 6) and 302a-b and 302c-d (Figure 7) may be adjacent to each other between sub-regions 202 of a treatment region 200. Additionally, one or more of the individual control regions 300 and / or one or more of the treatment regions 200 may have the same or different amounts and / or types of release agents, and one or more of the treatment regions may have the same or different amounts and / or types of therapeutic agents.

[0081] The embodiments shown in Figures 6-8 may be beneficial when the treatment region contains a large payload of therapeutic agent (e.g., equivalent to many days, weeks, or months of medication). These embodiments may be beneficial because if the treatment region 200 were inadvertently exposed to such a large payload in vivo, the entire payload would be released prematurely, subjecting the patient to an abnormally and undesirably high dose of the therapeutic agent. For example, if the integrity of the control region 300 were compromised, the patient could be exposed to the therapeutic agent in vivo at a faster rate than intended, potentially resulting in clinical complications. In particular, with regard to the administration of local anesthetics (e.g., bupivacaine, ropivacaine, etc.), manufacturing guidelines recommend that no more than 400 mg should be administered within a 24-hour period. However, numerous studies have demonstrated that doses higher than 400 mg from extended-release products are safe due to their slow release over an extended period of time. Nevertheless, if the control region 300 is compromised, it is desirable that the patient be exposed to only a portion of the total payload, whereby that portion to which the patient is exposed is believed to be within a safe margin for the particular therapeutic agent if released prematurely. The structural integrity of the control region 300, as well as the structural integrity of the therapeutic region(s) 200, are important properties for depots with large masses of therapeutic agent to be delivered over long periods of time.

[0082] To address this concern, in some embodiments of the present technology, the depot 100 may include multiple treatment regions 200 spaced apart by one or more control regions 300 (e.g., as shown in Figures 6-8). Such a configuration individually isolates the therapeutic agent (loaded with a portion of the total payload) in each treatment region 200. If a particular control region is compromised, only the portion of the payload corresponding to the treatment region associated with the compromised control region may be prematurely released. For example, in some of the aforementioned embodiments, the total payload of the depot 100 may be at least 100 mg, at least 150 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or at least 1000 mg of a therapeutic agent such as an analgesic (e.g., bupivacaine, ropivacaine, etc.). Similarly, in some embodiments, that portion of the payload in each treatment region or sub-region may be up to 1%, up to 5%, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to 100% of the total payload contained within the depot 100. As a result, if any single sub-region 202 of a treatment region 200 is compromised, it may only release a proportionate fraction of the depot's total payload.

[0083] In some embodiments, each of the treatment regions and each of the control regions is a microthin layer, hi some embodiments, the depot comprises about 2 to about 100 treatment regions, or about 2 to about 50 treatment regions, or about 2 to about 10 treatment regions.

[0084] 9A-11 illustrate some aspects of the present technology in which a depot 100 may have one or more treatment regions 200 that are completely surrounded or enclosed by one or more control regions 300. In contrast to the previously described embodiments, at least one treatment region in such completely enclosed embodiments has no exposed surface area. For example, as shown in FIGS. 9A and 9B, in some embodiments, a depot 100 may include a treatment region 200 that is surrounded or completely enclosed by a control region 300, such that no portion of the treatment region 200 is exposed through the control region 300. As a result, the control region 300 substantially prevents contact between the therapeutic agent and physiological fluids, thereby preventing uncontrolled burst release of the therapeutic agent when implanted. Over time, the release agent embedded in the polymer of the control region contacts and dissolves with physiological fluids, thereby forming micro-diffusion openings in the control region. The combination of the restriction imposed by the control region and the micro-diffusion openings formed by dissolution of the release agent allows for a controlled, linear release of the therapeutic agent from the depot over the course of days, weeks, or months. Although depot 100 is shown as a rectangular thin film in Figures 9A and 9B, in other embodiments, depot 100 may have other shapes, sizes, or forms.

[0085] FIG. 10 illustrates a depot 100 having a treatment region completely surrounded by a control region 300 having a first control region 300a and a second control region 300b. As shown in FIG. 10, in some embodiments, the treatment region 200 may be sandwiched between the first control region 300a and the second control region 300b, and the first and second control regions 300a-b may be bonded via thermocompression around the treatment region 200 to enclose the treatment region 200 between them. In certain embodiments, a bioabsorbable polymer may be wrapped around the entire depot and sealed at the top or bottom surfaces, creating a control region structure similar to that shown in FIG. 9A. The outer portions of the first and second control regions 300a-b may be incorporated as a final wrap layer to seal the edges. Additionally, the first and second control regions 300a-b can be integrally formed with one another using dip-coating and / or spray-coating techniques, such as dipping the treatment region 200 into a solution of the control region material or spraying the solution of the control region material onto the surface of the treatment region 200.

[0086] In FIG. 10, the first control region 300a can have first and second sub-regions 302a-b, and the second control region 300b can have first and second sub-regions 302c-d. The first control region 300a can define a top control region member, and the first and second sub-regions 302a-b can include a first top control layer and a second top control layer, respectively. The second control region 300b can define a bottom control region member, and the first and second sub-regions 302c-d can include a first bottom control layer and a second bottom control layer, respectively. The first and second top / bottom control layers can be any of the variations of the first and second control sub-regions discussed above with respect to FIG. 5. Additionally, the first top control layer of the top control region member may have the same or different properties (e.g., thickness, polymer, release agent, release agent concentration, total amount of release agent, ratio of polymer to release agent, etc.) as the first bottom control layer of the bottom control region member. Similarly, the second top control layer of the top control region member may have the same or different properties as the second bottom control layer of the bottom control region member. Variations in layer loading and structure may be designed into depot 100 to achieve a release profile or kinetics suitable for the intended therapeutic goal. In other embodiments, first control region 300a and / or second control region 300b comprise a single layer.

[0087] FIG. 11 illustrates some embodiments in which a depot 100 may have a treatment region 200 completely surrounded by a control region 300 having various sub-region configurations. The depot 100 of FIG. 11 includes a first control region 300a and a second control region 300b that together completely surround the treatment region 200. In contrast to the depot 100 shown in FIG. 10, the first control region 300a has an outer apex control region 301a with first and second apex sub-control regions 302a and 302b, respectively, and an inner apex control region 301b with first and second top layers 303a and 303b. The first and second top layers 303a-b are only on the top surface of the treatment region 200, while the first and second apex sub-control regions 302a-b cover portions of the sidewalls of the treatment region 200 and the inner apex control region 301b. Second control region 300b has outer bottom control region 301c with first and second bottom sub-control regions 302c and 302d, respectively, and inner bottom control region 301d with first and second bottom layers 303d and 303e, respectively. Thus, when depot 100 is placed at a treatment site in vivo, outer apex and bottom control regions 301a and 301c are between (a) treatment region 200 and inner apex and bottom control regions 301b and 301d, respectively, and (b) physiological fluids at the treatment site. In certain embodiments, such as that shown in FIG. 11, one or more of outer apex / bottom control regions 301a / 301c may include one or more control sub-regions, and one or more inner apex / bottom control regions 301b / 301d may include one or more control sub-regions.

[0088] 12 shows a cross section of a spherical depot 100 according to some embodiments of the present technology having multiple alternating treatment regions 200 and control regions 300 according to the present technology. The depot 100 may have two or more control regions 300 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and the depot may have one or more treatment regions 200 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one control region 300. In some embodiments, each of the treatment regions 200 may comprise a single layer and / or each of the control regions 300 may comprise a single layer. In some embodiments, one, some, or all of the treatment regions 200 may comprise multiple layers and / or one, some, or all of the control regions 300 may comprise multiple layers. Additionally, one or more of the individual control regions 200 and / or one or more of the treatment regions 300 may have the same or different amounts and / or types of release agents, and one or more of the treatment regions 200 may have the same or different amounts and / or types of therapeutic agents.

[0089] 13 shows a depot 100 according to some embodiments of the present technology having a treatment region 200 surrounded on the top and bottom surfaces and on two of the four sides of the sidewall by a control region 300. This configuration is expected to release therapeutic agent more slowly, at least initially, compared to a depot with a completely exposed sidewall of the same dimensions (see, for example, the depot 100 shown in FIG. 4).

[0090] The release kinetics of the depot of the present technology may be tailored to a particular application by varying the shape and size of the depot 100. Depending on therapeutic dosing needs, anatomical target, etc., the depot 100 can be made into different sizes, shapes, and forms for implantation and / or injection into the body by a clinician. The shape, size, and form of the depot 100 should be selected to facilitate placement of the depot at the target tissue site and to reduce or completely prevent the possibility of the depot migrating after implantation or injection. This is particularly true with respect to depots placed within a joint (such as the knee), where the depot is a flexible solid that is structurally capable of being handled by a clinician during the normal course of surgery without breaking into multiple pieces and / or losing its overall shape. Furthermore, the depot may be configured to be placed in a patient's knee and release the analgesic drug in vivo for up to seven days without breaking into multiple pieces.

[0091] Some of the form factors that can be produced from or used in conjunction with the depot 100 for implantation and fixation within the body include strips, ribbons, hooks, rods, tubes, patches, corkscrew shaped ribbons, partial or full rings, nails, screws, tacks, rivets, threads, tapes, woven shapes, t-shaped anchors, staples, discs, pillows, balloons, braids, tapered shapes, wedges, chisels, castle configurations, stent structures, suture buttresses, coil springs, sponges, capsules, coatings, matrices, wafers, sheets, strips, ribbons, pills, and pellets.

[0092] The depot 100 may be fabricated into a component of the form factor described in the previous paragraph. For example, the depot may be wound into a tube, incorporated into a screw, a tack, or the like. In woven embodiments, the depot may be incorporated into a multi-layer woven film / braid / mesh, where some of the filaments used are not part of the device of the present invention. In one example, the depot is interwoven with Dacron, polyethylene, or the like. For clarity, any form factor corresponding to the depot of the present technology may be referred to herein as a "depot," including those in which only a portion or segment of the form factor incorporates the depot.

[0093] As shown in Figures 14A-14H, in various embodiments, the depot can be shaped as a cylinder such as a sphere, rod, or fiber; a flat surface such as a disk, film, ribbon, strip, or sheet; a paste, slab, microparticle, nanoparticle, pellet, mesh, or the like. Figure 14A shows a rectangular depot 100. Figure 14B shows a circular depot 100. Figure 14C shows a triangular depot 100. Figure 14D shows a cross-shaped depot 100, Figure 14E shows a star-shaped depot 100, and Figure 14F shows a toric 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 anatomy to fit within a given space and provide desired fixation and flexibility. This is because the conformability, fixation, and flexibility of the depot can enhance the ease of implantation of the depot, ensure delivery of the therapeutic agent to the target site, and extend the durability of the implant at dynamic implantation sites.

[0094] In various embodiments, the depot may be of various sizes, for example, the depot may be about 0.4 mm to 100 mm in length and have a diameter or thickness of about 0.01 to about 5 mm. In various embodiments, the depot may have a layer thickness of about 0.005 to 5.0 mm, such as 0.05 to 2.0 mm. In some embodiments, the shape may be a rectangular or square sheet having a width to thickness ratio in the range of 20 or greater, 25 or greater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

[0095] In some embodiments, the thickness of the control region (either a single sub-control region or all sub-control regions combined) is less than or equal to 1 / 50, 1 / 75, or 1 / 100 of the thickness of the treatment region.

[0096] In some embodiments, the depot 100 has a width and a thickness, and the ratio of width to thickness is 21 or greater. In some embodiments, the ratio is 22 or greater, 23 or greater, 24 or greater, 25 or greater, 26 or greater, 27 or greater, 28 or greater, 29 or greater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater.

[0097] In some embodiments, the depot 100 has a surface area and a volume, and the ratio of the surface area to the volume is at least 1, at least 1.5, at least 2, at least 2.5, or at least 3.

[0098] In any of the foregoing embodiments shown and described above with respect to Figures 2-14H, dissolution of the release agent(s) and elution of the therapeutic agent(s) may change the functional mechanical aspects of depot 100 over time. Such mechanical aspects include the structural integrity, flexural strength, tensile strength, or other mechanical properties of depot 100. In some cases, undesired degradation of depot 100, such as premature degradation, may cause mechanical failure of depot 100 and a corresponding undesired burst release of the therapeutic agent into the body. Therefore, it may be beneficial for depot 100 to maintain sufficient flexural strength and / or mechanical integrity in vivo for at least a predetermined period of time or until a predetermined percentage of the therapeutic agent has been released from depot 100. Depot 100 may be considered to maintain its structural integrity if it remains largely intact and undergoes only partial or gradual shrinkage due to elution of the therapeutic agent or dissolution of the control layer or release agent. Depot 100 may be considered to have lost its structural integrity if it separates (e.g., fractures) into multiple component pieces, for example, where two or more of the resulting pieces are at least 5% of the previous size of depot 100. Alternatively, or additionally, depot 100 may be considered to have lost its structural integrity if the release rate of the therapeutic agent increases by more than three-fold compared to the release rate of the therapeutic agent in a control depot immersed in a buffer solution.

[0099] In some embodiments, the depot 100 is configured to maintain its structural integrity in vivo for at least a predetermined period of time. For example, the depot 100 can be configured to maintain its structural integrity in vivo for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, or at least 30 days, at least 40 days, at least 50 days, at least 60 days, at least 70 days, at least 90 days, at least 100 days, at least 200 days, at least 300 days, or at least 365 days.

[0100] In some embodiments, the depot 100 is configured to maintain its structural integrity in vivo until at least a predetermined percentage of the therapeutic agent payload has been released from the depot. For example, the depot 100 maintains its structural integrity in vivo until at least 5% by weight of the original payload has been released, until at least 10% by weight of the original payload has been released, until at least 15% by weight of the original payload has been released, until at least 20% by weight of the original payload has been released, until at least 25% by weight of the original payload has been released, until at least 30% by weight of the original payload has been released, until at least 35% by weight of the original payload has been released, until at least 40% by weight of the original payload has been released, until at least 45% by weight of the original payload has been released, until at least 50% by weight of the original payload has been released. The agent can be configured to remain in the charged state until the agent is released, until at least 55% by weight of the original payload is released, until at least 60% by weight of the original payload 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.

[0101] One aspect of the structural integrity of the depot 100 can be quantified when it is in vivo using a bending test, such as a three-point bending test, which measures bending properties including bending strength and / or maximum bending stress sustained by a test specimen before failure. Such a bending test may represent (e.g., simulate) the forces that the depot 100 would encounter in vivo in an anatomical joint (e.g., a knee joint). In one example, the depot can be subjected to a three-point bending test in accordance with ASTM-D790-17, "Standard Test Methods for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials." The text of this standard is incorporated herein by reference in its entirety. The depot 100 can be subjected to a three-point bending test in accordance with ASTM-D790-17, "Standard Test Methods for Flexural Properties of Unreinforced and Reinforced Plastics and Electrical Insulating Materials." It may be suspended in a medium configured to simulate in vivo conditions, such as phosphate buffered saline (PBS), at about 37° C. Bending tests may be performed after various periods of immersion in the medium to assess changes in bending strength of the depot 100 over time under simulated in vivo conditions.

[0102] Table 1 shows the maximum bending load sustained by four different samples of depot 100 for various periods of time after immersion in a medium, measured using a three-point bending test with the maximum deflection set at 2.13 mm. The values ​​in Table 1 reflect measurements taken from two instances of each of the listed samples. Figure 15 is a graph showing these values ​​plotted on a graph and fitted with a trend line. In each of these four samples, depot 100 includes treatment region 200 surrounded by upper and lower control regions 300a-b, as shown and described above with reference to Figures 4 or 5. Treatment region 200 has exposed side edges 202 between first and second control regions 300a-b. Depot 100 each has lateral dimensions of approximately 2.5 cm x 1.5 cm and a thickness of approximately 1 mm.

[0103] Sample 1 is a depot having a therapeutic region with a weight ratio of release agent to polymer to therapeutic agent of 0.5:10:20. The polymer in this sample is P(DL)GACL with a ratio of PDLLA:PGA:PCL of 6:3:1, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. In this sample, the depot includes a first control region 300a including a single control layer on the upper surface of the treatment region 200, and a second control region 300b including a single control layer on the lower surface of the treatment region 200, as shown and described above with reference to FIG. 4. Each control region 300a-b individually has a release agent to polymer ratio of 5:10.

[0104] Sample 2 is a depot having a therapeutic region 200 with a weight ratio of release agent to polymer to therapeutic agent of 1:10:20. The polymer in this sample is PLGA with a 1:1 ratio of PLA:PGA, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. Similar to Sample 1, the depot of Sample 2 includes a control region 300 including a first control region 300a with a single control layer on the upper surface of the treatment region 200 and a second control region 300b including a single control layer on the lower surface of the treatment region 200, as shown and described above with reference to FIG. 4. Each control region 300a-b individually has a release agent to polymer ratio of 5:10.

[0105] Sample 3 is a depot having a therapeutic region 200 with a release agent to polymer to therapeutic agent weight ratio of 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 control region 300 including a first control region 300a with two sub-control regions 302a-b on the upper surface of the therapeutic region 200, and a second control region 300b with two sub-control regions 302c-d, as shown and described above with reference to FIG. 5. Each of inner sub-control regions 302b and 302c contacts the surface of the therapeutic region 200 and has a release agent to polymer ratio of 5:10, and each of outer sub-control regions 302a and 302d has a release agent to polymer ratio of 1:10. Thus, the Sample 3 depot contains a total of four minor control regions.

[0106] Sample 4 is a depot having a therapeutic region 200 with a weight ratio of release agent to polymer to therapeutic agent of 5:10:20. The polymer in this sample is PLGA with a 1:1 ratio of PLA:PGA, the release agent is Tween 20, and the therapeutic agent is bupivacaine hydrochloride. Like Sample 3, the depot of Sample 4 includes a control region 300 having first and second control regions 300a-b, each having two sub-control regions 302a-b and 302c-d, respectively, as shown and described above with reference to Figure 5. Thus, the depot of Sample 4 also has a total of four sub-control regions 302a-d, two on the upper surface of the treatment region 200 and two on the lower surface of the treatment region 200. The inside of sub-control zones 302b and 302c have a release agent to polymer ratio of 5:10, and the outside of sub-control zones 302a and 302d have a release agent to polymer ratio of 1:10. [Table 1]

[0107] As shown in Table 1, all samples were intact and maintained sufficient structural integrity to withstand bending forces before fracture after 14 days of suspension in the vehicle. Although the maximum load withstood by each sample decreased over time, the bending strength of these samples at 14 days was sufficient to maintain the structural integrity desired for implantation within an active joint such as the knee or shoulder. As noted above, in the case of two of the samples tested at 28 days, the samples had degraded and therefore could not be tested because they were no longer structurally intact. In such cases, it may be desirable to configure the depot so that all or substantially all of the therapeutic agent payload is released from the depot before it degrades and loses structural integrity.

[0108] In this series of experiments, summarized in Table 1, the sample depots were generally flexible on day 0, before immersion in PBS. After immersion, the flexural strength of the depots decreased, and the depots became more brittle over time. Yet, at days 7–14, the depots were still fully functionally intact. Without being bound by theory, it is believed that after the therapeutic agent elutes, the depots gradually become empty polymer matrices. 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 associated lower flexural strength and less resistance to bending loads.

[0109] As mentioned above, it may be advantageous for depots 100 to maintain their structural integrity and bending strength even as they gradually degrade as the therapeutic payload is released into the body. In some embodiments, depots 100 are tested in accordance with a three-point bending test. In vitro testing, the depot 100 can be configured to exhibit a flexural strength decrease of up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, or up to 5% after immersion in PBS for a predetermined period of time. In various embodiments, the predetermined period of time that the depot 100 is immersed in PBS before being subjected to the three-point bending test is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, or more. In at least some embodiments, the change in flexural strength of the depot 100 can be measured between day 0 (e.g., before immersion in PBS) and a subsequent time after immersion in PBS for a period of time. In other embodiments, the change in flexural strength of the depot 100 can be measured between day 1 (e.g., after immersion in PBS for 24 hours) and a subsequent time after longer immersion in PBS.

[0110] In some embodiments, the depot 100 can be configured such that, in an in vitro test utilizing a three-point bending test, the bending strength of the depot 100 decreases by up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, or up to 5% over a period of time during which a predetermined percentage of the initial therapeutic agent payload is released while the depot 100 is immersed in PBS. In various embodiments, the predetermined percentage of payload released when depot 100 is immersed in PBS before being subjected to a three-point bending test is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. As noted above, in at least some embodiments, the change in flexural strength of depot 100 can be measured between day 0 (before being immersed in PBS) or day 1 (after being immersed in PBS for 24 hours) and a subsequent time after longer immersion in PBS.

[0111] In some embodiments, depot 100 has (a) lateral dimensions of about 1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a therapeutic agent payload sufficient to release about 100 mg to about 500 mg of therapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, wherein depot 100 is configured to remain sufficiently mechanically intact to provide a sustained, controlled release of the therapeutic agent for at least 7 days. Such embodiments of depot 100 can include a therapeutic region 200 having a therapeutic agent and a control region 300. Control region 300 can have first and second control regions 300a-b as shown and described above with reference to Figures 4-13, wherein control region 300 includes a bioabsorbable polymer and a release agent mixed with the bioabsorbable polymer. The release agent is configured to dissolve when the depot 100 is placed in vivo to form a diffusion opening in the control region 300. The depot 100 is further configured such that after immersion of the depot 100 in a buffer solution for 7 days, the flexural strength of the depot 100 is reduced 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%.

[0112] In some embodiments, depot 100 has (a) lateral dimensions of about 1.0-3.0 cm, (b) a thickness of about 0.5-2.5 mm, and (c) a therapeutic agent payload sufficient to release about 100 mg to about 500 mg of therapeutic agent per day for up to 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days, wherein depot 100 is configured to remain sufficiently mechanically intact to provide a sustained, controlled release of the therapeutic agent for at least 7 days. Such embodiments of depot 100 can include therapeutic agent-bearing therapeutic region 200 and control region 300. Control region 300 can have first and second control regions 300a-b as shown and described above with reference to Figures 4-13, wherein control region 300 includes a bioabsorbable polymer and a release agent mixed with the bioabsorbable polymer. The release agent is configured to dissolve when the depot 100 is placed in vivo to form a diffusion opening in the control region 300. The depot is further configured such that after immersion of the depot in a buffer solution until about 75% by weight of the therapeutic agent is released, the flexural strength of the depot decreases by up to 75%, or up to 70%, or up to 65%, or up to 60%, or up to 55%, or up to 50%, or up to 45%.

[0113] A. Treatment area The total payload and release kinetics of the depot 100 of the present technology may be tailored to a particular application by varying the composition of the treatment region 200. In many embodiments, the treatment region 200 may contain a high therapeutic payload of therapeutic agent, particularly compared to other known polymeric devices of equivalent thickness or polymer weight percentage. In some embodiments, the ratio of release agent to polymer to therapeutic agent in the treatment region 200 is from about 0.1:10:20 to about 2:10:20, in some embodiments, from about 0.1:10:20 to about 1:10:20, in some embodiments, from about 0.1:10:20 to about 0.5:10:20, and in some embodiments, from about 0.5:10:20 to about 0.1:10:20.

[0114] In some embodiments, the therapeutic region 200 (or one or more therapeutic sub-regions) 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. In some embodiments, the therapeutic region 200 may comprise a single layer, and in some embodiments, the therapeutic region may comprise multiple microlayers containing the same and / or different amounts of therapeutic agent. In some embodiments, the therapeutic region 200 may comprise (a) one or more sub-regions containing the therapeutic agent and a polymer and / or release agent, and (b) one or more sub-regions containing the therapeutic agent as an essentially pure compound (i.e., without any polymer and / or release agent). In some embodiments, the therapeutic region 200 comprises a release agent, and in some embodiments, the therapeutic region 200 does not comprise any release agent prior to implantation of the depot 100 at the treatment site.

[0115] In some aspects of this technology, the treatment region 200 may comprise a microlayer structure of multiple microthin sheets of biodegradable, bioabsorbable polymer, with each microthin sheet (or layer) loaded with a therapeutic agent. In this microlayer embodiment of the treatment region 200, the microthin sheets may have a substantially uniform structure and are stacked and bonded together. These microthin polymer sheets may each 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, or 7 μm to 9 μm, with the total thickness of the treatment region being based on the total number of stacked microthin sheets. Having a treatment region 200 with multiple layers may provide a more linear, controlled release of the therapeutic agent over time (beyond the first day of implantation). Additionally, layering the treatment region may contribute to a more flexible, structurally competent depot (compared to a depot with a treatment region composed of a pure therapeutic agent). Such durability is beneficial to the clinician when handling / manipulating the depot 100 before and during placement at the treatment site.

[0116] B. Control Domain The composition of the control region 300 may vary. For example, in many embodiments, the control region 300 does not include any therapeutic agent, at least prior to implantation of the depot at the treatment site. In some embodiments, the control region 300 may include a therapeutic agent that may be the same as or different from the therapeutic agent in the treatment region 200.

[0117] Within the control region 300, the amount of release agent may be varied to achieve faster or slower release of the therapeutic agent. In embodiments in which both the treatment region 200 and the control region 300 include a release agent, the type of release agent within the treatment region 200 may be the same as or different from the release agent in the control region 300. In some embodiments, the concentration of a first release agent within the control region is greater than the concentration of a second release agent (the same or different from the first release agent) within the treatment region. In some embodiments, the concentration of a release agent within the control region is less than the concentration of a release agent within the treatment region. In some embodiments, the concentration of a release agent within the control region 300 is the same as the concentration of a release agent within the treatment region 200.

[0118] As previously mentioned, in some embodiments, the depot 100 may include a control region 300 comprised of multiple layers. In some embodiments, one, several, or all of the layers in the control region comprise microthin sheets. Without being bound by theory, it is believed that such a multilayer configuration improves the control region's ability to control the release of a therapeutic agent (compared to a single-layer control region). As shown, the channels left by the dissolution of the release agent in both microlayers of the control region create a longer and perhaps more difficult path for the released therapeutic agent to migrate compared to the more direct path created by the channels in a single-layer control region. Multiple microthin sheets of the control region in this embodiment may be heat-pressed together on the treatment region 200 to modulate the therapeutic agent release rate by forming independent, non-adjacent channels of release agent through each control region from the in vivo environment to the treatment region. Having a control region 300 with multiple layers may provide a more linear, controlled release of a therapeutic agent over time (beyond the first day of implantation). Additionally, the layering of the control region 300 may also contribute to a more flexible, structurally competent depot (compared to a depot having a treatment region composed of pure therapeutic agent). Such durability is beneficial to the clinician when handling / manipulating the depot 100 prior to and during placement of the depot 100 at the treatment site.

[0119] In various embodiments of the depot disclosed herein, the control region may take several different forms. In some embodiments (e.g., FIG. 4), the control region may include a single layer on either side of the treatment region 200 composed of a biodegradable, bioabsorbable polymer mixed with a release agent. In some embodiments, the control region itself may include a structure having multiple layers of biodegradable, bioabsorbable polymer. The layers of this multilayer structure may additionally or alternatively include multiple microthin sheets or layers (i.e., microlayers), each having a thickness of about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, or 7 μm to 9 μm. In these multilayered embodiments of the control region 300, at least one layer of the multilayer structure may include a polymer mixed with a release agent, and at least one other layer of the multilayer structure may include a polymer without a release agent mixed therein. In some embodiments, the control region 300 may include a multi-layer structure in which the multiple layers have a release agent mixed within each polymer layer, but the layers may have the release agent at different concentrations. In certain embodiments, multiple control layers may have a release agent mixed within each polymer layer, with at least one of the layers having a different release agent than at least one of the other layers.

[0120] C. Therapeutic Agents The therapeutic agent delivered by the depot 100 of the present technology may be any biologically active substance (or combination of substances) that provides a therapeutic effect in a patient in need thereof. As used herein, "therapeutic agent" or "drug" may refer to a single therapeutic agent or a combination of therapeutic agents. In some embodiments, the therapeutic agent may include only a single therapeutic agent, and in some embodiments, the therapeutic agent may include two or more therapeutic agents for simultaneous or sequential release.

[0121] In some embodiments, the therapeutic agent includes an analgesic. The term "analgesic" or "analgesic drug" includes one or more local or general anesthetic agents administered to generally reduce, prevent, alleviate, or eliminate pain. Analgesics may include systemic and / or local anesthetics, narcotics, and / or anti-inflammatory agents. Analgesics may include pharmacologically active drugs or pharmaceutically acceptable salts thereof. Suitable local anesthetics include, but are not limited to, bupivacaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine, trimecaine, carticaine, articaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, and combinations thereof. Preferred local anesthetics include bupivacaine, lidocaine, and ropivacaine. Typically, local anesthetics produce anesthesia by inhibiting excitation of nerve endings or by blocking transmission in peripheral nerves. Such inhibition is achieved by anesthetics that reversibly bind to and inactivate sodium channels. Sodium influx through these channels is necessary for depolarization of the nerve cell membrane and the subsequent propagation of impulses along nerve tracts. When a nerve loses its ability to depolarize and propagate impulses, an individual loses sensation in the area supplied by the nerve. Any compound that possesses such anesthetic properties is suitable for use in the present technology.

[0122] In some embodiments, the therapeutic agent includes a narcotic, such as cocaine, and an anti-inflammatory agent. Examples of suitable anti-inflammatory agents include steroids, such as prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone. Other suitable anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and other COX-2 inhibitors, and combinations thereof.

[0123] In some embodiments, the therapeutic agent comprises an antibiotic, antibacterial, or antifungal agent, or a combination thereof. For example, suitable antibiotics and antibacterial substances include, but are not limited to, amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin(s), aminoglycides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporin(s), carbapanem, imipenem, ertapenem, antimicrobial peptides, cecropin-melittin, magainin, dermaseptin, cathelicidin, alpha-defensin, and alpha-protegrin. Antifungal agents include, but are not limited to, ketoconazole, chlortrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

[0124] In some embodiments, the therapeutic agent is an adrenocorticostatic, a beta-antiadrenergic, an androgen or antiandrogen, an antianemic, an antiparasitic, an anabolic, an anesthetic or analgesic, a stimulant, an antiallergic, an antiarrhythmic, an antiarteriosclerotic, an antibiotic, an antidiabetic, an antifibrinolytic, an antispasmodic, an angiogenesis inhibitor, an anticholinergic, an enzyme, coenzyme or corresponding inhibitor, an antihistamine, an antihypertensive, an antihypotensive, an anticoagulant, an antifungal, an antiseptic, an anti-infective, a hemostatic, a beta-receptor antagonist, a calcium channel antagonist, an antimyasthenic, an anti-inflammatory The compound may be a drug, antipyretic, antirheumatic, cardiac inotropic, chemotherapeutic, coronary vasodilator, cytostatic, glucocorticoid, hemostatic, immunoglobulin or fragment thereof, chemokine, cytokine, mitogen, cell differentiation factor, cytotoxic agent, hormone, immunosuppressant, immunostimulant, morphine antagonist, muscle relaxant, narcotic, vector, peptide, (para)sympathomimetic, (para)sympatholytic, protein, cell, selective estrogen receptor modulator (SERM), sedative, anticonvulsant, substance that inhibits bone resorption, vasoconstrictor or vasodilator, viral growth inhibitor, or wound healing agent.

[0125] In various embodiments, the therapeutic agent comprises a drug or a pharmaceutically acceptable salt thereof used in the treatment of cancer. Such chemotherapeutic agents include antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleaving agents, DNA cross-linking agents, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include, but are not limited to, adalimumab, ansamitocin P3, auristatins, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, calystatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribine, cytarabine, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, These include gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, vindesine, and tamoxifen.

[0126] In some embodiments, the therapeutic agent comprises a botulinum toxin (or neurotoxin) agent used to treat various pain-related neuromuscular and / or neuroglandular disorders and neuropathies. The botulinum toxin (or neurotoxin) may comprise a pharmacologically active drug or a pharmaceutically acceptable salt thereof. The botulinum toxin (or neurotoxin) described and used herein may be selected from various strains of Clostridium botulinum and may comprise a pharmacologically active drug or a pharmaceutically acceptable salt thereof. In one embodiment, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G. In a preferred embodiment, the botulinum toxin is botulinum toxin type A. The commercially available botulinum toxin, BOTOX® (Allergan, Inc., Irvine, Calif.), consists of lyophilized purified botulinum toxin type A complex, albumin, and sodium chloride packaged in sterile, vacuum-dried form.

[0127] The paralytic effect of botulinum toxin is the most common benefit of commercial therapeutic agents, relaxing muscles to treat dystonia, wrinkles, and the like. However, in addition to its anticholinergic effects on muscle and smooth muscle, neurotoxins have been shown to have therapeutic effects on other non-muscle cell types and on inflammation itself. For example, it has been shown that cholinergic goblet cells, which produce mucus throughout the respiratory system, can be blocked by the introduction of botulinum toxin in response to it. Studies also show that botulinum toxin has direct anti-inflammatory capabilities. All of these therapeutic effects, muscle, smooth muscle, goblet cell, and anti-inflammatory effects, can be derived from the delivery of toxin from the device of the present invention.

[0128] Pharmaceutically acceptable salts refer to salts that retain the biological effectiveness and properties of the neutral therapeutic agent and are not otherwise unacceptable for pharmaceutical use.Pharmaceutically acceptable salts include salts of acidic or basic groups, which may be present in the therapeutic agent.The therapeutic agent used in the present technology that is basic in nature can form a wide variety of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts of basic therapeutic agents used in the present technology are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzethosulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts).Therapeutic agents of the present technology containing an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Suitable base salts are formed from bases which form non-toxic salts, examples of which are aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.

[0129] Pharmaceutically acceptable salts may contain other molecules, such as water or another biologically compatible solvent (solvate), acetate ions, succinate ions, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples in which multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0130] The therapeutic agent or its pharmaceutically acceptable salt may be an essentially pure compound or may be formulated with a pharmaceutically acceptable carrier, such as a diluent, adjuvant, excipient, or vehicle known to those skilled in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. For example, diluents include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, and the like. For examples of other pharmaceutically acceptable carriers, see Remington: THE SCIENCE AND PRACTICE OF PHARMACY (21st Edition, University of the Sciences in Philadelphia, 2005).

[0131] The therapeutic agent or pharmaceutically acceptable salt form may be jet milled or otherwise passed through a sieve to form a consistent particle size, thereby further enabling a regulated, controlled release of the therapeutic agent. This process may be particularly useful for highly insoluble therapeutic agents.

[0132] In one embodiment, the biodegradable, bioabsorbable polymers used in the various layers of the depot may appear as layers of electrospun microfibers or nanofibers. Biocompatible electrospun microfibers / nanofibers are known in the art and have been used, for example, for the formation of transplant organs in vivo (U.S. Patent Publication No. 2014 / 0272225; Johnson; Nanofiber Solutions, LLC), for musculoskeletal and skin tissue engineering (R. Vasita and D.S. Katti, Int. J. Nanomedicine, 2006, 1:1, 15-30), for skin or oral applications (PCT Publication No. 2015 / 189212; Hansen; Dermtreat APS), or for postoperative pain management (US Patent Publication No. 2013 / 0071463; Palasis et al.). As a manufacturing technique, electrospinning offers the opportunity to control the thickness and composition of nano- or microfibers along with the porosity of the fiber mesh (Vasita and Katti, 2006). These electrospun scaffolds are three-dimensional and therefore provide an ideal support for the cultivation of cells in vivo for tissue formation. Typically, these scaffolds have a porosity of 70 to 90% (US Patent No. 9,737,632; Johnson; Nanofiber Solutions, LLC). Suitable biodegradable polymers and copolymers for producing electrospun microfibers include, but are not limited to, natural materials such as collagen, gelatin, elastin, chitosan, silk fibrion, 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).

[0133] Electrospun microfibers made from bioabsorbable polymers or copolymers and used in conjunction with therapeutic agents are known in the art. For example, Johnson et al. disclosed the treatment of joint inflammation and other conditions by injecting electrospun fiber fragments of a biocompatible polymer together with a carrier medium containing chitosan (U.S. Published Application No. 2016 / 0325015; Nanofiber Solutions, LLC). Weldon et al. reported the use of electrospun bupivacaine-eluting sutures made from poly(lactic-co-glycolic acid) in a rat skin wound model, which provided local anesthesia at the incision site (J. Control Release, 2012, 161:3, 903-909). Similarly, Palasis et al. disclosed the treatment of postoperative pain by implanting electrospun fibers loaded with opioids, anesthetics, or non-opioid analgesics at the surgical site (U.S. Patent Publication No. 2013 / 0071463; Palasis et al.). Electrospun microfibers suitable for use in the present technology can be obtained by the methods disclosed in the above-cited references, which are incorporated herein in their entireties.

[0134] An important criterion for determining the amount of therapeutic agent required to treat a particular medical condition is the rate of drug release from the depot of the present technology. The release rate is controlled by various factors, including, but not limited to, the rate at which the release agent dissolves in the surrounding fluid in vivo and the in vivo degradation rate of the bioabsorbable polymer or copolymer utilized. For example, the release rate may be controlled by the use of multiple control regions between the treatment region and physiological fluids. See, for example, Figures 6-8.

[0135] Suitable dosage ranges utilizing the depot technology of the present invention depend on the potency of the particular therapeutic agent, but are generally from about 0.001 mg to about 500 mg of drug per kilogram of body weight per day, e.g., from about 0.1 mg to about 200 mg of drug per kilogram of body weight, or from about 1 to about 100 mg per kg of body weight. Dosage ranges can be readily determined by methods known to those skilled in the art. Unit dosage forms will generally contain between about 1 mg and about 500 mg of active ingredient. For example, commercially available bupivacaine hydrochloride, sold under the trade name Marcaine™ (Pfizer; New York, NY), is commonly administered as a peripheral nerve block using a dosage range of 37.5 to 75 mg at a 0.25% concentration and 25 mg to a maximum daily level (up to 400 mg) at a 0.5% concentration (Marcaine™ package insert; FDA Reference ID: 3079122). Additionally, commercially available ropivacaine hydrochloride, sold under the trade name Naropin® (Fresenius Kabi USA, LLC; Lake Zurich, IL), is administered in doses of 5 to 300 mg for minor and major nerve blocks (Naropin® package insert; Reference ID: 451112G). The appropriate dosage range for the depot of the present technology is equivalent to commercially available medications routinely administered by injection.

[0136] In some embodiments, the treatment area 200 comprises at least 15% by weight of analgesic, at least 20% by weight of analgesic, at least 30% by weight of analgesic, at least 40% by weight of analgesic, at least 50% by weight of analgesic, at least 60% by weight of analgesic, at least 70% by weight of analgesic, at least 80% by weight of analgesic, at least 90% by weight of analgesic, or 100% by weight of analgesic.

[0137] In some embodiments, the depot comprises at least 15% by weight analgesic, at least 20% by weight analgesic, at least 30% by weight analgesic, at least 40% by weight analgesic, at least 50% by weight analgesic, at least 60% by weight analgesic, at least 70% by weight analgesic, at least 80% by weight analgesic, at least 90% by weight analgesic, or 100% by weight analgesic. In many embodiments, the depot 100 comprises at least 50% by weight analgesic.

[0138] In some aspects of the technology, the treatment region 200 may include multiple layers. In such embodiments, multiple layers may improve the efficient loading of therapeutic agents. For example, multi-layering can be a straightforward and effective way to load significant amounts of therapeutic agent. Often, it can be difficult to load large amounts of therapeutic agent into a single film layer, even by increasing the drug-to-polymer ratio or by increasing the layer thickness. Even if the thickness of the treatment region could theoretically be increased to load more drug, consistently fabricating thick treatment regions via casting may prove difficult. In contrast, stacking and bonding thin films or sheets, each with a predetermined loading of therapeutic agent, may offer a more reliable alternative to casting. Data from an example loading an analgesic drug (i.e., ropivacaine) is presented in Table 2. [Table 2]

[0139] As an example only, a single layer loaded with ropivacaine and having a thickness of 0.019 mm was produced. A five-layer film sample was also produced, with each layer loaded with ropivacaine, having a thickness of 0.046 mm. Although the thickness of the five-layer film sample was only 2.42 times that of the single layer, the loading of therapeutic agent in the five-layer sample was 5.27 times that of the single layer sample. Thus, the multi-layer approach allowed for a substantially higher density of therapeutic agent.

[0140] As discussed above, thermal compression bonding of multiple layers allowed for an effective reduction in membrane thickness and increased density of therapeutic agent loading. In the example illustrated in Table 2, the multi-layer structure allowed for a 124% increase in therapeutic agent density. In other embodiments, the increase in therapeutic agent density allowed by the multi-layer structure of the treatment region can be about 50%, 75%, 100%, 125%, 150%, or 200%.

[0141] D. Biodegradable Polymers The depot 100 of the present technology is composed of a bioabsorbable polymer. In some embodiments, both the treatment region 200 and the control region 300 comprise a polymer (or a mix of polymers), which may be the same or different amounts, concentrations, and / or weight percentages of the same or different polymers (or mixes of polymers). In some embodiments, the control region 300 comprises a polymer and the treatment region 200 does not comprise a polymer. In some embodiments, the treatment region 200 comprises a polymer and the control region 300 does not comprise a polymer. As used at least in this section, "polymer" refers to a polymer that may be used in the treatment region 200 and / or the control region 300.

[0142] The bioabsorbable polymers used in the present technology preferably have a predetermined degradation rate. The terms "bioresorbable" or "bioabsorbable" mean that the polymer is absorbed into the patient's body, for example, by cells or tissues. These polymers are "biodegradable" in that all or part of the polymer film will degrade over time by enzymatic action, hydrolytic action, and / or other similar mechanisms within the patient's body. In various embodiments, the biodegradable, bioabsorbable polymer film can be broken down or degraded into non-toxic components within the body, with the therapeutic agent released. The polymers used as the base component of the depots in the present technology can be broken down or degraded after the therapeutic agent has been completely released. Bioabsorbable polymers are also "bioerodible" in that they will erode or degrade over time, at least in part, due to contact with substances found in surrounding tissues, fluids, or by cellular action.

[0143] Criteria for selecting bioabsorbable polymers suitable for use in this technology include: 1) in vivo safety and biocompatibility; 2) therapeutic agent loading capacity; 3) therapeutic agent release capability; 4) degradation profile; 5) potential for inflammatory response; and 6) mechanical properties, which may be related to form factors and manufacturability. Therefore, the choice of bioabsorbable polymer may depend on the clinical objectives of a particular treatment and may involve tradeoffs between competing objectives. For example, PGA (polyglycolide) is known to have a relatively fast degradation rate but is also very brittle. Conversely, polycaprolactone (PCL) has a relatively slow degradation rate and is very elastic. Copolymerization offers some versatility when it is clinically desirable to have a blend of properties from multiple polymers. For biomedical applications, particularly as biodegradable depots for drug release, polymers or copolymers using at least one of poly(L-lactic acid) (PLA), PCL, and PGA are generally preferred. Physical properties for some of these polymers are presented in Table 3 below. [Table 3]

[0144] In many embodiments, the polymer may comprise polyglycolide (PGA). PGA is one of the simplest linear aliphatic polyesters. It is prepared by ring-opening polymerization of the cyclic lactone, glycolide. It is highly crystalline, with a crystallinity of 45-55% and therefore insoluble in most organic solvents. It has a high melting point (220-225°C) and a glass transition temperature of 35-40°C (Vroman, L., et al., Materials, 2009, 2:307-44). Rapid in vivo degradation of PGA results in loss of mechanical strength and substantial local production of glycolic acid, which, in significant amounts, can induce an inflammatory response.

[0145] In many embodiments, the polymer may include polylactide (PLA). PLA is a hydrophobic polymer due to the presence of methyl (-CH3) side groups pendant from the polymer backbone. It is more resistant to hydrolysis than PGA due to the steric shielding effect of the methyl side groups. The typical glass transition temperature for a representative commercial PLA is 63.8°C, the elongation at break is 30.7%, and the tensile strength is 32.22 MPa (Vroman, 2009). Tuning of the physical properties and biodegradability of PLA can be achieved by using hydroxy acid comonomer components or by racemization of the D- and L-isomers (Vroman, 2009). PLA exists in four forms: poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), meso-poly(lactic acid), and poly(D,L-lactic acid) (PDLLA), a racemic mixture of PLLA and PDLA. PLLA and PDLLA have been the most studied for biomedical applications.

[0146] Copolymerization of PLA (both L- and D,L-lactide forms) and PGA results in poly(lactide-co-glycolide) (PLGA), one of the most commonly used degradable polymers in biomedical applications. In many embodiments, the polymer may comprise PLGA. Because PLA and PGA have significantly different properties, careful selection of PLGA composition can optimize performance in the intended clinical application. Modulation of physical properties is even more significant for PLGA copolymers. When the composition is comprised of 25-75% lactide, PLGA forms an amorphous polymer that is highly hydrolytically unstable compared to the more stable homopolymer. This is demonstrated by the degradation times of 50:50 PLGA, 75:25 PLGA, and 85:15 PLGA, which are 1-2 months, 4-5 months, and 5-6 months, respectively. In some embodiments, the polymer may be a 50:50 molar ratio ester-terminated poly(DL-lactide-co-glycolide) (“PLGA”) (DURECT Corporation).

[0147] In some embodiments, the polymer may include polycaprolactone (PCL). PCL is a semicrystalline polyester with high organic solvent solubility, a melting temperature of 55-60°C, and a glass transition temperature of -54°C (Vroman, 2009). PCL has a low in vivo degradation rate and high drug permeability, making it more suitable as a depot for longer-term drug delivery. For example, Capronor® is a commercial contraceptive PCL product capable of delivering levonorgestrel in vivo for over a year. PCL is often blended or copolymerized with other polymers, such as PLLA, PDLLA, or PLGA. Blending or copolymerization with polyethers accelerates overall polymer erosion. Furthermore, PCL has a relatively low tensile strength (approximately 23 MPa) but a very high elongation at break (4700%), making it a very elastic biomaterial. PCL is also highly processable, allowing for many potential shape factors and production efficiencies.

[0148] Suitable bioabsorbable polymers and copolymers for use in the present technology include, but are not limited to, poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone (DL-PLCL), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxybenzoates (PDQ), polyhydroxybenzoates (PB ... Alkanoates (PHAs), poly(phosphazenes), polyphosphates), poly(amino acids), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide). Poly(lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(glycolide-co-carolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, Included are ethyl glycinate polyphosphazene, polycaprolactone co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan, and starch), proteins (such as gelatin and collagen), or PEG derivatives and copolymers thereof.Other suitable polymers or copolymers include polyaspirin, polyphosphagen, collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as alpha tocopheryl acetate, d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (PolyActive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (Pluronics), and the like. ), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose acetate isobutyrate) hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or a salt thereof, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol, or a combination thereof.

[0149] In various embodiments, the molecular weight of the polymer can vary over a wide range: the average molecular weight of the polymer can be from about 1,000 to about 10,000,000; or from about 1,000 to about 1,000,000; or from about 5,000 to about 500,000; or from about 10,000 to about 100,000; or from about 20,000 to 50,000.

[0150] As mentioned above, in certain clinical applications using depots for controlled delivery of therapeutic agents, it may be desirable to use copolymers comprising at least two of PGA, PLA, PCL, PDO, and PVA, including, for example, poly(lactide-co-caprolactone) (PLCL) (e.g., having a PLA to PCL ratio of 90:10 to 60:40) or derivatives and copolymers thereof, poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a DL-PLA to PCL ratio of 90:10 to 50:50) or derivatives and copolymers thereof, poly(glycolide-co-caprolactone) (PGCL) (e.g., having a PGA to PCL ratio of 90:10 to 10:90) or derivatives and copolymers thereof, or blends of PCL and PLA (e.g., blends of PCL and PLA having a wt:wt ratio of 1:9 to 9:1). In one preferred embodiment, the bioabsorbable polymer comprises a copolymer of polycaprolactone (PCL), poly(L-lactic acid) (PLA), and polyglycolide (PGA). In such a preferred embodiment, the PGA to PLA to PCL ratio of the copolymer may be 5-60% PGA, 5-40% PLA, and 10-90% PCL. In additional embodiments, the PGA:PLA:PCL ratio may be 40:40:20, 30:30:50, 20:20:60, 15:15:70, 10:10:80, 50:20:30, 50:25:25, 60:20:20, or 60:10:30. In some embodiments, the polymer is ester-terminated poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of 60:30:10 (DURECT Corporation).

[0151] In some embodiments, terpolymers can be beneficial, such as to increase degradation rate and ease of manufacturing.

[0152] To minimize the size of a bioresorbable depot, it is generally preferable to maximize the loading of the therapeutic agent in the polymer so that the highest possible density of therapeutic agent is achieved. However, polymeric carriers with high densities of therapeutic agent are more susceptible to burst release kinetics, resulting in poor control of release over time. As discussed above, one significant benefit of the depot structures described herein, and particularly the control region feature of the depot, is the ability to control and attenuate therapeutic agent release kinetics, even at therapeutic agent densities that may cause instability in other carriers. In certain embodiments, the therapeutic agent loading capacity comprises a therapeutic agent to biodegradable polymer ratio (wt:wt) of about 1:3, 1:2, 1:1, 3:2, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, or 16:1. In some embodiments, it may be desirable to increase the therapeutic effect or efficacy of a therapeutic agent released from the depots described herein while still maintaining the same or similar polymer to therapeutic agent ratio. This can be achieved by using an essentially pure form of the therapeutic agent, as opposed to a salt derivative. Additionally or alternatively, the therapeutic agent can be mixed with clonidine or epinephrine, which are known to increase the therapeutic effect of certain drugs.

[0153] When implanted in a patient's joint (e.g., knee), the biodegradable depot described above may be placed intra-articularly to bridge the joint throughout the duration of release. It is desirable for the depot to have a threshold level of mechanical integrity and stability until most of the analgesic has been released, so that premature release of the analgesic is avoided. As noted above, maximizing the therapeutic agent loading in the biodegradable depot may be desirable, but such maximization may typically come at the expense of the mechanical integrity and stability of the depot. Given the high dosage of anesthetic required to provide analgesia throughout both acute and subacute postoperative pain periods and in the limited space of the knee, it is desirable for the depot described herein to have a high density loading of anesthetic while still maintaining sufficient mechanical integrity and stability in the knee. The layered structure, particularly the presence of a control region, provides some protection against premature release of the anesthetic. Furthermore, the use of thermal compression in the manufacturing process allows for substantial loading of the anesthetic into the treatment area while creating a thermal bond between the treatment and control areas, thereby preventing delamination and resulting uncontrolled drug release when the depot is subjected to mechanical stress in the knee.

[0154] In general, it is desirable for the implanted polymer to completely degrade after complete delivery of the therapeutic agent. Complete degradation is preferred because, unless the implanted polymer provides some structural function or support, the clinician would have to deal with leaving a foreign body without a functional purpose, which could become a source of inflammation or infection, or would have to perform another surgery just to remove the remaining polymer. As an alternative to complete degradation, it would be desirable for any remaining polymer to be completely encapsulated by the body.

[0155] The degradation of implanted polymers essentially consists of two sequential processes: diffusion of aqueous solutions (i.e., physiological fluids), followed by hydrolysis. Degradation typically takes one of two forms: (1) surface erosion; and (2) bulk degradation. Surface erosion of a polymer occurs when the polymer erodes inward from the surface, and hydrolytic erosion at the surface is faster than water can penetrate into the polymer. Conversely, bulk degradation occurs throughout the polymer, degrading the interior of the material faster than water can penetrate and erode the surface. Polymers such as PLA, PGA, PLGA, and PCL are all absorbed into the body via bulk degradation.

[0156] The time required for complete degradation can vary significantly based on the selected material and the clinical performance requirements of the depot. For example, when treating and managing postoperative pain, it may be desirable for the polymer depot to release a therapeutic agent (i.e., an analgesic) over anywhere from 5 to 30 days. When treating or preventing infection in a prosthetic joint (e.g., a knee or hip implant), it may be desirable for the polymer depot to release an anti-infective agent over anywhere from 2 to 4 months. Alternatively, even if the entire amount of therapeutic agent loaded within the polymer is released, it may be desirable for the polymer to degrade over a period longer than the sustained drug release period. For example, rapid degradation can often make the polymer brittle and prone to breakage, thereby compromising mechanical performance or eliciting an inflammatory response from the body. In particular, in certain clinical applications, it may be desirable to have embodiments in which polymer degradation begins only after substantially all of the therapeutic agent has been released.

[0157] In certain embodiments of the present technology, it may be desirable to completely absorb the polymer into the body after substantially all of the therapeutic agent loaded therein has been released. In certain embodiments, this degradation may be as short as one month. Alternatively, in other embodiments, complete degradation may take as long as two, three, four, six, nine, or twelve months. In some embodiments, the bioabsorbable polymer substantially degrades in vivo within about one month, about two months, about three months, about four months, about five months, or about six months. In some embodiments, it may be desirable to achieve complete degradation within six months, so that the mechanical properties of the implanted polymer are preserved over the first two months after implantation.

[0158] Core Acidification Traditional biodegradable orthopedic implants often result in tissue inflammation due to a phenomenon known as "core acidification." For example, as shown schematically in Figure 17, polymer implants with thicknesses greater than 1 mm degrade by bulk erosion (i.e., degradation occurs evenly throughout the material; both the surface and interior of the material degrade substantially simultaneously). As the polymer degrades, lactate accumulates in the interior region of the implant. Eventually, the high pH in the interior region of the implant causes lactate to become lactic acid. The accumulated lactic acid is constantly released into the body, thereby triggering an inflammatory response. For example, Figure 18 shows a scanning electron microscope ("SEM") image of a prior art polymer tablet after 20 days of degradation. Inflammation in and around artificial joints can be of particular concern because of the risk of inflammation-induced osteolysis, which can lead to loosening of newly implanted joints. Furthermore, core acidification lowers extracellular pH, which in turn reduces the amount of free base bupivacaine. Only free base bupivacaine can cross the lipid bilayer that forms the cell membrane and reach neurons.When bupivacaine enters neurons, the percentage of bupivacaine HCl increases.This is the bupivacaine HCl form that becomes active by blocking sodium from entering neurons, thus inducing analgesia.Thus, any reduction in extracellular pH (for example, through core acidification) slows down the movement of analgesics into neurons, thereby reducing or eliminating the therapeutic effect of analgesics.

[0159] The extent of core acidity is determined in large part by the geometry and dimensions of the polymer implant (e.g., Grizzi et al., Hydrolytic degradation of devices based on poly(dl-lactic 16 No. 4, pp. 305-11;Fukuzaki et al., in vivo characteristics of high molecular weight copoly(l-lactide / glycolide) with S-type degradation pattern for application in drug delivery systems, Biomaterials 1991, Vol. 12 May, pp. 433-37;Li et al., Structure-property relationships in the case of degradation of massive alipathic poly-(α-hydroxy acids) in aqueous media, JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE I (1990), pp. 123-130). For example, degradation of larger monolithic devices (on the mm-size scale and larger) proceeds much more rapidly in their interior than at their surface, resulting in a slowly degrading outer layer of polymer that traps more advanced internal degradation products from autocatalysis in the interior zone (a so-called "S-shaped" nonlinear kinetic degradation profile). In contrast to thicker films, thin films less than 1 mm thick will typically degrade via surface erosion, and lactate resulting from degradation will not accumulate in the interior of the film. Thin films are known to degrade uniformly due to their high surface area to volume ratio, without core oxidation (see Grizzi et al.).

[0160] As shown schematically in Figure 18, the depot of the present technology can lose 50%, 60%, 70%, or 80% of its individual mass (anesthetic and release agent) over the course of anesthetic release (e.g., 5, 7, 10, 14, 20, 30, etc. days), resulting in a highly porous, mesh-like system that behaves like a thin film (at least for degradation purposes) due to its high surface area-to-volume ratio. Body fluids penetrate the highly porous polymer carrier and degrade the remaining polymer via surface erosion, thereby avoiding core acidification and the resulting inflammatory response. Without being bound by theory, it is believed that the drug core matrix in the treatment region becomes highly porous as degradation continues. For example, Figures 19B and 19C are scanning electron microscope ("SEM") images showing the treatment region before and after elution, respectively. However, even after releasing the therapeutic agent, the distinct porous structure remains intact, allowing water and acid to effectively diffuse through it. Thus, depots 100 of the present technology having thicknesses greater than about 1 mm degrade like thin films and unexpectedly do not exhibit core acidification.

[0161] E. Releasing Agent In many implantable drug-eluting technologies, depots provide an initial, uncontrolled burst release of drug followed by a residual release. While these drug release kinetics may be desirable for certain clinical applications, they may be unavoidable even when undesirable. Hydrophilic drugs loaded onto polymeric carriers typically provide a burst release upon exposure to physiological fluids. This kinetics can present challenges, particularly when it is desirable to load large drug volumes for controlled, sustained in vivo administration. For example, implanting a dosage for several days or weeks may be desirable to achieve sustained, durable in vivo pharmacological treatment, but it is essential that the therapeutic agent be released as specified; otherwise, release of the entire payload could result in severe patient complications.

[0162] To achieve finer control of the release of the therapeutic agent upon exposure to fluid, the depot 100 of the present technology may include a release agent. In some embodiments, the treatment region 200 and the control region 300 both include a release agent (or a mixture of release agents), which can be the same or different release agents (or mixtures of release agents) in the same or different amounts, concentrations, and / or weight percentages. In some embodiments, the control region 300 includes a release agent and the treatment region 200 does not include a release agent. In some embodiments, the treatment region 200 includes a release agent and the control region 300 does not include a release agent. As used at least in this section, "release agent" applies to a release agent that may be used in the treatment region 200 and / or the control region 300.

[0163] The type and / or amount of release agent in the treatment region 200 and / or control region 300 may be varied depending on the desired release rate of the therapeutic agent into the surrounding biological fluid. For example, selecting release agents with different dissolution times will affect the release rate. Also, the weight percentage of the release agent in the polymeric region will affect the number and size of diffusion openings subsequently formed in the polymer, thereby affecting the release rate of the therapeutic agent from the depot 100 (e.g., the greater the weight percentage of the release agent, the faster the release). The presence of the release agent in selected regions also affects the release rate of the therapeutic agent. For example, a depot with a release agent in the control region 300 and / or treatment region 200 will generally release the therapeutic agent at a faster rate compared to a depot without the release agent. Similarly, a release agent in both the control region 300 and the treatment region 200 will generally release the therapeutic agent at a faster rate than if the release agent were only in the control region.

[0164] In certain embodiments of the present technology, the ratio of release agent to bioabsorbable polymer per layer can be adjusted to control the rate at which the therapeutic agent is released from depot 100. For example, in many embodiments of the present technology, depot 100 includes treatment region 200 having a weight percentage of release agent that differs from the weight percentage of release agent in control region 200. For example, treatment region 200 may have a greater or lesser weight percentage of release agent than control region 300. In some embodiments, control region 300 may have a weight percentage of release agent that is at least two times greater than the weight percentage of release agent in treatment region 200. In some embodiments, control region 300 may have a weight percentage of release agent that is at least three to twenty times greater than the weight percentage of release agent in treatment region 200.

[0165] In many embodiments of the present technology, the release agent is a surfactant. Unlike their use as release agents described herein, surfactants are typically used to control the dispersion, aggregation, and wettability of drugs or polymers. Essentially, surfactants operate at the interface between the polymer and drug, or the interface between the drug and biological membrane. Depending on the type of formulation, surfactants typically play a role in several aspects of drug delivery: (1) solubilization or stabilization of hydrophobic drugs by reducing the entropic cost of solvating the hydrophobic drug through complexation with drug molecules in solution (C. Bell and KA Woodrow, ANTIMICROB. AGENTS CHEMOTHER., 2014, 58:8, 4855-65); (2) improving the wetting of tablets or polymers for rapid disintegration (M. Irfan, et al., SAUDI PHARM. J., 2016, 24, 537-46); (3) forming colloidal drug delivery systems such as reverse micelles, vesicles, liquid crystal dispersions, nanoemulsions, and nanoparticles (M. Fanun, Colloids in Drug Delivery, 2010, p. 357); and (4) improving the biological performance of drugs by altering the permeability of biological membranes and, consequently, the infiltration / permeation profile of the drug (S. Jain, et al., Lipid Based Vesicular Drug Delivery Systems, 2014, Vol. 2014, Article ID 574673).

[0166] To illustrate the unique aspect of using release agents in polymer-controlled regions to form microchannels in this technology, it is helpful to describe a more general approach of using hydrophilic molecules to enhance drug release. Traditionally, drug release is enhanced by creating a larger surface area to increase contact between the drug and body fluids, thereby accelerating drug release. The most common pore-forming mechanism is the use of non-surfactant hydrophilic molecules as pore-forming agents within a polymer layer, either as a coating layer or a freestanding film (Kanagale, P., et al., AAPS PHARM. SCI.TECH., 2007; 8(3), E1-7). Typically, pores are preformed by blending hydrophilic molecules with a polymer and then removing the hydrophilic molecules by contacting with water. However, when hydrophilic molecules are blended with a hydrophobic polymer, the molecules tend to form hydrophilic and hydrophobic domains, which is energetically favorable due to increased entropy. When the film comes into contact with water, the hydrophilic domains are removed and replaced by large pores. The drug release rate in this case is controlled solely by the porosity of the film, resulting in an increased total surface area. The typical drug release curve in this case is a high, uncontrolled initial burst, followed by a much slower release of the remaining drug.

[0167] Previously, when non-surfactant hydrophilic molecules were mixed with a polymer and then removed, a film with a porous structure was created. This porous layer reduced the mechanical strength and elasticity, making it less suitable for certain applications. Furthermore, this structure could not withstand thermocompression bonding of the film because the pores could collapse. The loss of the porous structure during thermocompression negates the original intent of using hydrophilic molecules, thus resulting in a densely packed film without any high therapeutic agent release capacity.

[0168] Furthermore, if the hydrophilic molecules remain within the polymer layer during thermal compression, their dissolution in vivo leads to the formation of very large pores, approximately 3–10 μm in diameter. Such large pores provide a large surface area, thereby triggering burst release of the drug. In contrast to the use of hydrophilic molecules, the use of surfactants as release agents in this technology allows for the formation of microchannels approximately 5–20 nanometers in diameter, two orders of magnitude smaller than the pores obtained from the use of hydrophilic molecules. This allows for tight control of drug release by diffusion and, if desired, without uncontrolled burst release after implantation. Furthermore, the use of surfactants as release agents allows the drug to remain present in the polymer prior to use; preformed pores are not created. This approach is particularly advantageous because the mechanical properties of the polymer are preserved, allowing the polymer to be easily processed and engineered into different configurations.

[0169] In this technique, the release agent is premixed into the bioabsorbable polymer so that each layer of polymer is contiguous and dense. These layers are then bonded together via thermal compression without any adverse effect on the functional capabilities of the film to form the depot 100. When the densely packed film is finally implanted, the release agent dissolves, allowing for efficient, controlled release of the therapeutic agent.

[0170] In some embodiments, the release agent comprises a polysorbate. Polysorbates are commonly used in the pharmaceutical industry as excipients and solubilizers. Polysorbates are nonionic surfactants formed by the ethoxylation of sorbitan and subsequent esterification with lauric acid. Polysorbate 20 [IUPAC name: polyoxyethylene (20) sorbitan monolaurate] contains a mixture of ethoxylated sorbitan and 20 repeating units of polyethylene glycol distributed among four different sites in the sorbitan molecule. Common trade names include Tween™ and Tween 20™ (Croda International Plc, Goole, East Yorkshire, UK) and Alkest® TW 20 (Oxiteno, Houston, TX).

[0171] Polysorbates are often used to improve the oral bioavailability of poorly water-soluble / hydrophobic drugs. For example, polysorbates are used to improve the bioavailability of active molecules with low solubility and / or intestinal epithelial permeability. It has been observed that the bioavailability of these poorly water-soluble drugs is significantly enhanced in formulations with polysorbates or similar surfactants (WO2008 / 030425; Breslin; Merck). Akbari et al. observed that the use of the hydrophilic carrier polyethylene glycol (PEG) with polysorbates results in a faster oral enhanced drug release rate because the polysorbates bring the drug into intimate contact with the PEG (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3): 435-41).

[0172] Polysorbates also function as water-soluble emulsifiers to promote the formation of oil / water emulsions. For example, the drug famotidine is known to have high solubility in water but low in vivo permeability. Polysorbates were used in oral microemulsion formulations to enhance the bioavailability of famotidine (Sajal Kumar Jha, et al., IJDDR, 2011, 3(4): 336-43). Polysorbates are also used as wetting agents to achieve rapid drug delivery. For example, Ball et al. achieved rapid delivery of maraviroc via a combination of polyvinylpyrrolidone (PVP) electrospun nanofibers and 2.5 wt% Tween 20, enabling the complete release of 28 wt% of maraviroc in just 6 minutes. The use of Tween 20 as a wetting agent was thought to allow water to penetrate the PVP nanofiber matrix more quickly, thereby increasing the rate of drug release (Ball, C., et al., ANTIMICROB. AGENTS CHEMOTHERAPY, 2014, 58:8, 4855-65).

[0173] As mentioned above, to improve drug release in certain polymeric carriers, hydrophilic polymers such as polysorbates have been added to these carriers to accelerate or enhance drug release from biocompatible polymers such as polyethylene glycol (PEG) in oral formulations (Akbari, J., et al., ADV. PHARM. BULL., 2015, 5(3): 435-441). However, these formulations are intended to provide immediate release of the hydrophobic drug into a hydrophilic environment (in vivo physiological fluids) rather than variable or sustained controlled release as part of a controlled region.

[0174] In some embodiments, the release agent is polysorbate 20, commercially known as Tween 20™.Other release agents suitable for use in the present technology include polysorbates, such as Polysorbate 80, Polysorbate 60, Polysorbate 40, and Polysorbate 20; sorbitan fatty acid esters, such as sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), sorbitan trioleate (Span 85), sorbitan monooleate (Span 80), sorbitan monopalmitate, sorbitan monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, and sorbitan tribehenate; sucrose esters, such as sucrose monodecanoate, sucrose monolaurate, sucrose distearate, and sucrose stearate; castor oils, such as polyethoxylated castor oil, polyoxyl hydrogenated castor oil, polyoxyl 35 castor oil, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 40 castor oil, Cremophor® RH 60, and Cremophor® RH 40; polyethylene glycol ester glycerides, e.g., Labrasol®, Labrifil® 1944; poloxamers; polyoxyethylene polyoxypropylene 1800; polyoxyethylene fatty acid esters, e.g., Polyoxyl 20 stearyl ether, diethylene glycol octadecyl ether, glyceryl monostearate, triglycerol monostearate, Polyoxyl 20 stearate, Polyoxyl 40 stearate, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate; oleic acid; sodium desoxycholate; sodium lauryl sulfate; myristic acid; stearic acid; vitamin E-TPGS (vitamin E d-alpha-tocopherol polyethylene glycol succinate; saturated polyglycolized glycerides such as Gelucire® 44 / 14 and Gelucire® 50 / 13; and polypropoxylated stearyl alcohols such as Acconon® MC-8 and Acconon® CC-6.

[0175] Diffusion Aperture The channels or voids formed within the treatment region 200 and / or control region 300 by the dissolution of the release agent may take the form of a plurality of interconnected openings or pores and / or a plurality of interconnected pathways. In some embodiments, one or more of the channels may take the form of individual pathways, channels, or openings within the respective treatment and / or control region. Depending on the chemical and material composition of the treatment and control regions, one or more of the formed channels may extend: (a) from a first end within the treatment region to a second end also within the treatment region; (b) from a first end within the treatment region to a second end at the interface of the treatment region and the control region; (c) from a first end within the treatment region to a second end within the control region; (d) from a first end within the treatment region, through the control region, to a second end at the outer surface of the control region; (e) from a first end at the interface between the treatment region and the control region, through the control region, to a second end within the control region; (f) from a first end at the interface between the treatment region and the control region to a second end at the outer surface of the control region; (g) from a first end within the control region to a second end also within the control region; and (h) from a first end within the control region to a second end at the outer surface of the control region. Additionally, one or more of the channels may extend between two or more microlayers in the treatment region and / or the control region.

[0176] F. Component ratio In some embodiments, the ratio of polymer in the control region 300 to release agent in the control region 300 is at least 1:1. In some embodiments, the ratio may be at least 1.5:1, at least 2:1, at least 2.5:1, or at least 3:1.

[0177] In some embodiments, the ratio of the mass of therapeutic agent in the depot 100 to the mass of the polymer of the depot 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, at least 11:1, at least 12:1, at least 13:1, at least 14:1, at least 15:1, or at least 16:1.

[0178] In some embodiments, the ratio of release agent to polymer to therapeutic agent in the treatment area 200 is from about 0.1:10:20 to about 2:10:20, in some embodiments, from about 0.1:10:20 to about 1:10:20, and in some embodiments, from about 0.1:10:20 to about 0.5:10:20.

[0179] In some embodiments, the ratio of release agent to polymer in the control region 300 is from about 1:2 to about 1:10. In some embodiments, one or more of the control regions may have a release agent to polymer ratio of 1:2, while one or more of the other control regions may have a release agent to polymer ratio of 1:10.

[0180] G. Selected Depot Embodiments, Including a Base Region In some embodiments, the depot 100 may be configured to release therapeutic agent in all directions. In other embodiments, the depot may include one or more base regions that cover one or more portions of the treatment region 200 and / or control region 300 so that release of the therapeutic agent is limited to a specific direction. The base region may provide structural support for the depot. The base region may include a low-porosity, high-density bioabsorbable polymer configured to provide the depot with directional release capabilities. In this configuration, the substantial impermeability of the low-porosity, high-density polymer structure of the base region blocks or prevents the passage of agent released from the treatment region 200. Thus, agent released from the treatment region 200 takes the path of less resistance through the control region 300 opposite the base region, particularly after the creation of diffusion openings in the control region 300.

[0181] An example of a depot 100 of the present technology having a base region is shown in FIG. 16A. The base region may comprise a low-porosity, high-density bioabsorbable polymer configured to provide the multi-region depot with directional release capabilities. In this configuration, the low-porosity, high-density polymer structure in the base region blocks or prevents the passage of drug release from the treatment region 200. Thus, drug released from the treatment region 200 takes a path of less resistance through the control region opposite the base region, particularly after the creation of channels in the control region. In additional embodiments, the porosity of other regions of the multi-region depot can be varied to facilitate release of the therapeutic agent. For example, in this embodiment, the base region, treatment region 200, and control region 300 of the multi-region depot shown in FIG. 16A may have different porosities ranging from low porosity in the base region to higher porosity in the therapeutic and control regions to facilitate release of the therapeutic agent from the multi-region depot. In additional embodiments, the porosity at the edges of the multi-region depot or any portion of the individual regions can be varied to precisely regulate or manipulate the release of the therapeutic agent.

[0182] In the embodiment shown in FIG. 16B, the multi-region depot provides bilateral or bidirectional release of therapeutic agent. This bidirectional release capability is achieved through symmetrical region formation relative to the dense base region, such that, as described above, the therapeutic agent is released along a path of less resistance, thereby releasing away from the dense base region. More specifically, a control region 300a and a therapeutic region 200a are disposed on one side of the base region, and a control region 300b and a therapeutic region 200b are disposed on the other side of the base region, which are substantially similar to the pair on the other side. These pairs on either side of the base region are configured to provide substantially equal bidirectional release of therapeutic agent. In an alternative embodiment, unequal bidirectional release (i.e., the therapeutic agent and / or release rate in each direction are not the same) may be achieved through asymmetrical region formation, whereby the pairs of control and therapeutic regions on either side of the base region are substantially different.

[0183] In additional embodiments, it may be desirable for the multi-region depot to release multiple therapeutic agents. This capability may be particularly useful when multimodality pharmacological therapy is indicated. In the embodiment shown in FIG. 16C, the multi-region depot includes an uppermost or outermost control region 300a, a first treatment region 200a adjacent to the control region, a second treatment region 200b adjacent to the first treatment region 200a, and a base region adjacent to the second treatment region 200b. In this embodiment, the first treatment region 200a and the second treatment region 200b include a first therapeutic agent and a second therapeutic agent, respectively. In certain embodiments, the first and second therapeutic agents are different. In one embodiment, the multi-region depot is configured to release the first and second therapeutic agents sequentially, simultaneously, or in an overlapping manner to provide complementary or synergistic benefits. In this configuration, the presence and function of the control region 300a may ensure consistency and, if desired, substantially uniform release of multiple underlying therapeutic agents. Since many conventional drug delivery devices are unable to provide uniform release of multiple drugs with different molecular weights, solubilities, etc., the role of the controlling region in achieving substantially uniform release of different therapeutic agents can be a significant advantage.

[0184] In some embodiments, the first and second therapeutic agents are the same therapeutic agent, but are present in different relative concentrations in the first and second treatment areas, respectively, representing different dosages. In some embodiments, the first and second therapeutic agents in the first and second treatment areas, respectively, may not have any clinical relevance or relationship. For example, in embodiments used as part of a total joint replacement (e.g., total knee arthroplasty, total hip arthroplasty) or other surgical procedure, it may be clinically desirable to administer near the surgical site both an analgesic (e.g., local anesthetic) to treat and better manage postoperative pain for days or weeks after surgery, and an antibiotic to treat or prevent surgical site infections associated with the surgery or implanted prosthesis (if present) for weeks or months after surgery. In this embodiment, the first treatment area 200a may include a therapeutically effective dose of a local anesthetic to substantially provide pain relief for at least three days and up to fifteen days after surgery, and the second treatment area 200b may include a therapeutically effective dose of an antibiotic to substantially provide a minimum effective concentration of antibiotic near the surgical site for up to three months after surgery.

[0185] In some embodiments, as shown in FIG. 16D, depot 100 includes a first dosing region and a second dosing region, where the first and second dosing regions correspond to first and second dosing regimens. More specifically, each dosing region includes a pair of control and treatment regions, where each pair is configured for controlled release of a therapeutic agent from treatment regions 200a, 200b according to a predetermined dosing regimen. For example, in the treatment and / or management of postoperative pain, it may be desirable for a multi-region depot to consistently release 50-400 mg / day of a local anesthetic (e.g., bupivacaine, ropivacaine, and the like) for at least 2-3 days after surgery (i.e., first dosing regimen), and then release the local anesthetic at a slower rate (e.g., 25-200 mg / day) for the next 5-10 days (i.e., second dosing regimen). In this exemplary embodiment, the first dosing region and its pair of control and therapeutic regions are sized, dimensioned, and configured so that the multi-region depot releases a first therapeutic agent in a manner consistent with a first prescribed dosing regimen. Similarly, the second dosing region and its pair of control and therapeutic regions are sized, dimensioned, and configured so that the multi-region depot releases a second therapeutic agent in a manner consistent with a second prescribed dosing regimen. In another embodiment, the first and second dosing regions may correspond to dosing regimens utilizing different therapeutic agents. In one embodiment, the multi-region depot 100 is configured to administer the first and second dosing regimens sequentially, simultaneously, or in an overlapping manner to provide complementary or synergistic benefits. In an alternative embodiment of this scenario, the first and second dosing regimens may not have any clinical relevance or relationship to each other. For example, as described above in connection with the embodiment shown in FIG. 16C, a first dosing regimen administered via a first dosing region may treat or manage post-operative pain management, and a second dosing regimen administered via a second dosing region may treat or prevent infection of the surgical site or implanted prosthesis (if present).

[0186] Certain embodiments of the present invention utilize a delayed-release agent. As shown in FIG. 16E, the depot 100 may include a delay region as the outermost (i.e., uppermost) region relative to the multi-region depot and adjacent to the control region 300 containing the release agent. The delay region provides a barrier to physiological fluids reaching and dissolving the release agent within the control region. In one embodiment, the delay region may include a delay-release agent mixed with a bioabsorbable polymer, but no release agent. The delay-release agent is different from the release agent used in the multi-region depots of the present invention. The delay-release agent dissolves in physiological fluid more slowly than the release agent, thus providing the potential for releasing the therapeutic agent over a defined amount of time after implantation of the multi-region depot. In embodiments where the delay-release agent is not present in the delay region, it may take longer for physiological fluids to traverse the delay region and come into contact with the release agent. It is not until the physiological fluid comes into contact with the control region that the release agent begins to dissolve, thus allowing for controlled release of the therapeutic agent. Delayed-release agents may be advantageously used in the treatment methods of the present invention where the therapeutic agent is not needed immediately. For example, nerve blocking agents may be injected prior to a surgical procedure to numb the entire area around the surgical site. Controlled release of local anesthetics is not required in such procedures until the nerve block has worn off.

[0187] Suitable delayed-release agents for use in the present invention are pharmaceutically acceptable hydrophobic molecules such as fatty acid esters.Such esters include, but are not limited to, esters of myristoleic acid, sapienic acid, vaccenic acid, stearic acid, arachidic acid, palmitic acid, erucic acid, oleic acid, arachidonic acid, linoleic acid, linoelaidic acid, eicosapentaenoic acid, and docosahexaenoic acid.Preferred esters include methyl stearate, ethyl oleate, and methyl oleate.Other suitable delayed-release agents include tocopherol and tocopherol esters, such as tocopheryl nicotinate and tocopheryl linoleate.

[0188] H. Exemplary Manufacturing Methods The depots of the present technology may be constructed using various combinations of biodegradable, bioabsorbable polymer layers, which may contain various combinations and concentrations of therapeutic agents, release agents, delayed-release agents, etc. to meet the requirements of the intended clinical application(s). In some embodiments, the polymer layers may be constructed using any number of known techniques to form multilayer films of specific configurations. For example, bioabsorbable polymers and therapeutic agents can be solubilized and then applied to the film via spray coating, dip coating, solvent casting, and the like. In an alternative embodiment, the polymer layers used as control layers and / or therapeutic agent layers can be constructed from electrospun nanofibers.

[0189] The depot 100 described herein may be constructed by placing the treatment regions (and / or subregions) and / or control regions (and / or subregions) on top of each other in the desired order and heat compressing the resulting multi-layer configuration to bond the layers together. Heat compression may be accomplished using any suitable device known in the art. In one embodiment, the thermal compression process utilizes a thermal compressor (Kun Shan Rebig Hydraulic Equipment Co. Ltd., China) to thermally compress the laminated assembly of the treatment region 200 and / or control region 300 at a temperature above room temperature (e.g., at least 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, or 120°C, etc.) and a pressure of about 0.01 MPa to about 1.0 MPa, or about 0.10 MPa to about 0.8 MPa, or about 0.2 MPa to about 0.6 MPa. The inventors have discovered that heating the treatment and control regions during compression (separately or after lamination) increases the density of the therapeutic agent in the depot 100. The inventors have also discovered that heat compaction at lower pressures allows for higher drug densities.

[0190] Depending on the therapeutic dosing needs, anatomical target, etc., the depot 100 can be processed, shaped, and otherwise fabricated to produce form factors that can be administered to a patient by implantation within the body by a clinician. For example, various configurations of the film may be achieved by using a jig with pre-formed notches, by manually cutting the desired shape, or both. Some of the form factors that can be produced from the multilayer film for implantation within the body include strips, ribbons, hooks, rods, tubes, patches, corkscrew-shaped ribbons, partial or full rings, nails, screws, tacks, rivets, threads, tapes, woven shapes, T-shaped anchors, staples, discs, pillows, balloons, braids, tapered shapes, wedges, chisels, castellated forms, stent structures, suture buttresses, coil springs, and sponges. The depot 100 may be fabricated into components of the above-mentioned form factors. For example, depot 100 may be wound and incorporated into a tube, a screw, a tack, or the like. In woven embodiments, depot 100 may be incorporated into a multi-layer woven film, where some of the filaments used are not devices of the present invention. In one example, depot 100 is interwoven with Dacron, polyethylene, or the like. [Example]

[0191] III. Working Example The following examples are offered by way of illustration and not by way of limitation.

[0192] Example 1 Preparation of Bioabsorbable Polymer / Drug Films. Two depots of the present technology containing high payload, local anesthetic bupivacaine were prepared according to the following procedure.

[0193] Each sample depot consisted of a heat-pressed multilayer film having the configuration shown in Figure 5. The treatment region consisted of a single layer sandwiched between two inner control layers (closest to the treatment layer, e.g., 302b and 302c in Figure 5, referred to as "Control Layer A" in Table 4 below) and two outer control layers (farthest from the treatment region, e.g., 302a and 302d in Figure 5, referred to as "Control Layer B" in Table 4). The components of the treatment and control regions are detailed in Table 4. [Table 4]

[0194] Treatment Area Components. The treatment area was prepared by combining the polymer, release agent, anesthetic, and 3.15 mg of acetone (Merck; Kenilworth, NJ) in a glass vial and mixing thoroughly. The resulting blend was poured onto a flat plate and compressed multiple times to form a thick film (approximately 1 mm thick) upon drying.

[0195] Control Region Components. The control region was prepared by combining the polymer, release agent, and 4.7 mg of acetone (Merck; Kenilworth, NJ) in a glass vial and mixing thoroughly. The resulting blend was poured onto a flat plate and drawn with a film applicator to form a thin film (<200 μm thick) upon drying.

[0196] For the sample depot, a single layer treatment region and four layers including a control region were aligned and compressed in a thermocompressor. The thin films were cut to form 25 mm x 15 mm samples with a total thickness of <1.2 mm.

[0197] In vitro drug release testing of bupivacaine depots. The purpose of this procedure was to measure the release of bupivacaine from a bioabsorbable polymer depot into a receiver fluid of 1x PBS. Each release experiment was performed in duplicate. The in vitro release procedure consisted of placing a film of known size into a device containing receiver fluid. The in vitro release device consisted of a 200 mL glass vial. A volume of 100 mL of receiver fluid was added to each sample vial. During the release study, the device was placed in a water bath maintained at 37±2°C. At predetermined intervals, samples of the receiver fluid were removed and analyzed for bupivacaine concentration by UV-visible spectrophotometry.

[0198] FIG. 20 shows the drug release profile for the depot with an effectively reduced initial burst effect, demonstrating the desired consistent and controlled release of drug.

[0199] Example 2A Preparation of Bioabsorbable Polymer / Drug Films. Two depots of the present technology containing the local anesthetic bupivacaine were prepared as described in Example 1, except that the depots of this example comprised two of the depots of Example 1 stacked on top of each other and were heat-pressed to form a new, thicker sample with a total thickness of approximately 2 mm (see, e.g., the configuration shown in Figure 6).

[0200] In vitro drug release testing of the bupivacaine depot. In vitro drug release testing of the depot was performed as described in Example 1.

[0201] Release Profile. Figure 21 shows the mean cumulative dose profile of the bupivacaine film. The graph shows controlled release over 500 hours, with approximately 20% release in the first 24 hours.

[0202] Example 2B Preparation of Bioabsorbable Polymer / Drug Films. Two depots of the present technology containing the local anesthetic bupivacaine were prepared as described in Example 1, except that the depots of this example comprised three of the depots of Example 1 stacked on top of each other and were heat-pressed to form a new, thicker sample with a total thickness of approximately 3 mm (see, e.g., the configuration shown in Figure 7).

[0203] In vitro drug release testing of the bupivacaine depot. In vitro drug release testing of the depot was performed as described in Example 1.

[0204] Release Profile. Figure 22 shows the mean cumulative dose profile of the bupivacaine film. The graph shows controlled release over 500 hours, with approximately 20% release in the first 24 hours.

[0205] Example 3 Preparation of Bioabsorbable Polymer / Drug Films: Four depots of the present technology containing the local anesthetic bupivacaine were prepared as described below.

[0206] Each of the sample depots consisted of a heat-compressed multilayer film formed with an inner depot similar to that shown in Figure 5 encapsulated by a different control region (described below). The inner depot of each sample depot consisted of a treatment region (formed of 10 heat-compressed treatment layers) sandwiched between two inner control layers (closest to the treatment region, e.g., 302b and 302c in Figure 5 , referred to as Control Layer A in Table 5 below) and two outer control layers (farthest from the treatment region, e.g., 302a and 302d in Figure 5 , referred to as Control Layer B in Table 5). The components of the treatment and control regions are detailed in Table 5. [Table 5]

[0207] Treatment Area: The treatment area components (see Table 5 above) were added to a glass vial and mixed thoroughly. The resulting blend was poured onto a flat plate and drawn with a film applicator to form a thin film (<200 μm thick) upon drying.

[0208] Control Region. The components of the control region (see Table 5 above) were added to a glass vial and mixed thoroughly. The resulting blend was poured onto a flat plate and drawn with a film applicator to form a thin film (<200 μm thick) upon drying.

[0209] For each sample film, 10 drug layers (each initially <200 μm thick) and 4 control layers were aligned (Control B-Control A-10 therapeutic layers-Control A-Control B) and compressed in a thermocompressor (Kun Shan Rebig Hydraulic Equipment Co. The resulting thin films were compressed using a thermocompressor (Kun Shan Rebig Hydraulic Equipment Co. Ltd.; People's Republic of China). The resulting thin films were cut to form 20 mm × 20 mm triangular specimens with a total thickness of <0.2 mm. The triangular specimens were further aligned and fully encapsulated with (a) control layer A on both sides (i.e., two additional control layers), (b) control layer B on both sides (i.e., two additional control layers), (c) two control layers A on both sides (i.e., four additional control layers), and (d) two control layers B on both sides (i.e., four additional control layers). The resulting assemblies were then compressed using a thermocompressor (Kun Shan Rebig Hydraulic Equipment Co. Ltd.; People's Republic of China).

[0210] In vitro drug release testing of bupivacaine depots. The purpose of this procedure was to measure the release of bupivacaine from a bioabsorbable polymer depot into a receiver fluid of 1x PBS. Each release experiment was performed in duplicate. The in vitro release procedure consisted of placing a film of known size into a device containing receiver fluid. The in vitro release device consisted of either a 20 mL or 100 mL glass vial. A volume of 12 mL or 50 mL of receiver fluid was added to each sample vial. During the release study, the device was placed in a water bath maintained at 37±2°C. At predetermined intervals, samples of the receiver fluid were removed and analyzed for bupivacaine concentration by UV-visible spectrophotometry.

[0211] Release Profiles. Figure 23 shows the mean cumulative dose profile of bupivacaine films. The graph shows controlled release over 1500 hours for several of the configurations.

[0212] Example 4 Sample depots of this technology were implanted subcutaneously into living rabbits (one depot per rabbit). The depots were placed in subcutaneous pockets.

[0213] Each of the sample depots consisted of a heat-pressed multilayer film having the configuration shown in Figure 5. The treatment area consisted of a single layer, sandwiched between two inner control layers (closest to the treatment layer, e.g., 302b and 302c in Figure 5) and two outer control layers (farthest from the treatment area, e.g., 302a and 302d in Figure 5).

[0214] This example tested two groups of depots, each utilizing a different polymer. Group A depots contained poly(DL-lactide-glycolide-ε-caprolactone) in a 60:30:10 molar ratio, and Group B depots contained poly(DL-lactide-co-glycolide) in a 50:50 molar ratio. Each group contained a depot with low, medium, or high doses of bupivacaine HCl.

[0215] For Group A depots, each inner control layer consisted of 3.9 mg, 4.0 mg, or 4.7 mg of polymer (for the low, medium, and high dose groups, respectively) and 1.9 mg, 2.0 mg, or 2.3 mg of release agent (polysorbate 20) (for the low, medium, and high dose groups, respectively). Each outer control layer consisted of 5.3 mg, 5.5 mg, or 6.3 mg of polymer (for the low, medium, and high dose groups, respectively) and 1.9 mg, 2.0 mg, or 2.3 mg of release agent (polysorbate 20) (for the low, medium, and high dose groups, respectively).

[0216] For Group A depots, the treatment area consisted of 71.5 mg, 152.6 mg, or 269 mg of polymer (for the low, medium, and high dose groups, respectively), 34.9 mg, 74.6 mg, or 131.5 mg of release agent (polysorbate 20) (for the low, medium, and high dose groups, respectively), and 142.9 mg, 305.2 mg, or 538.1 mg of local anesthetic (bupivacaine HCl).

[0217] For Group B depots, each inner control layer consisted of 4.7 mg, 5.1 mg, or 5.3 mg of polymer (for the low, medium, and high dose groups, respectively) and 2.3 mg, 2.5 mg, or 2.6 mg of release agent (polysorbate 20) (for the low, medium, and high dose groups, respectively). Each outer control layer consisted of 6.4 mg, 6.9 mg, or 7.3 mg of polymer (for the low, medium, and high dose groups, respectively) and 0.6 mg, 0.7 mg, or 0.7 mg of release agent (polysorbate 20) (for the low, medium, and high dose groups, respectively).

[0218] For Group B depots, the treatment area consisted of 87.0 mg, 171.1 mg, or 317.7 mg of polymer (for the low, medium, and high dose groups, respectively), 42.5 mg, 83.6 mg, or 155.2 mg of release agent (polysorbate 20) (for the low, medium, and high dose groups, respectively), and 173.9 mg, 342.2 mg, or 635.4 mg of local anesthetic (bupivacaine HCl).

[0219] In each of Groups A and B, the low-dose depot was approximately 20 mm x 20 mm x <1 mm (e.g., 0.89 mm and 0.9 mm), the medium-dose depot was approximately 20 mm x 20 mm x <2 mm (e.g., 1.8 mm and 1.6 mm), and the high-dose depot was approximately 20 mm x 20 mm x <3 mm (e.g., approximately 2.7 mm and approximately 2.8 mm).

[0220] Blood samples for bupivacaine concentration analysis were collected up to 28 days.

[0221] Group A The Group A depot was administered to 3 rabbits per dose group, and PK samples were collected through Day 28. A semi-log plot of the group mean data for each dose is shown in Figure 24A. Regardless of dose, the product exhibits peak exposure within the first 72 hours, followed by a dose-determined plateau of exposure (the higher the dose, the longer the plateau), followed by more rapid terminal clearance. Bupivacaine release is rapid with a consistent and similar profile for each rabbit, with moderate variability over the first 72 hours.

[0222] The in vitro pharmacokinetic ("PK") profile for Group A is shown in Figure 24B. The half-life of the early distribution phase through the first 72 to 96 hours was generally consistent across the three dose strengths (implant sizes), with T max occurs within the first 24 hours, with a median T max The peak exposure (C) for the high doses was between 4 and 8 hours. max) showed a low CV% of 17.6%. This data appears to indicate a controlled initial rapid release of bupivacaine during the period of greatest discomfort after TKA surgery. The exposure profile was stable from 72 hours to at least 436 hours. The terminal half-life was significantly longer, especially at the terminal t 1 / 2 At the higher dose, where the half-life was 17.4 hours, bupivacaine began to exhibit a more specific half-life, which would suggest that the depot had almost completely released the drug by day 21.

[0223] The high-dose, Group A depot had consistent mean exposure from days 3 through 18, while the medium- and low-dose depots were consistent from days 3 through 14. There was no significant difference in exposure between the medium- and high-dose groups on days 3 through 14, while the low dose had nearly half the exposure level during this period.

[0224] Group B The 50:50 copolymer formulation was administered to three rabbits per dose group, and PK samples were collected for up to 672 hours (day 28). A semi-logarithmic plot of the group mean data for each dose is presented in Figure 24C. The product, regardless of dose, exhibited peak exposure within the first 72 hours, followed by a gradual decline in exposure, followed by a rapid secondary release associated with a secondary peak in exposure at approximately days 19-21. After the secondary peak, bupivacaine exposure declined at different rates depending on dose (the lower the dose, the faster the clearance). Figure 24C highlights group means (SD) and shows individual rabbits at the low dose (126 mg) in panel A, the medium dose (252 mg) in panel B, and the high dose (420 mg) in panel C throughout the first 96 hours. Bupivacaine release was rapid, with moderate variability over the first 72 hours, and a consistent, similar profile for each rabbit.

[0225] The in vitro pharmacokinetic profile is shown in Figure 24D. The 50:50 copolymer did not exhibit the initial distribution half-life of the 631 terpolymer, but showed a T max occurs within the first 24 hours, with a median T maxThe peak exposure (C) occurred some time later, between 16 and 20 hours. max ) showed a very low CV% of 5.99%. This data appears to indicate a controlled, initial rapid release of bupivacaine during the acute postoperative pain period (i.e., the period of greatest discomfort following TKA surgery), followed by a more gradual decrease in release rate throughout the subacute postoperative pain period, consistent with the estimated steady decrease in pain during that same period. This release profile, with a steady decrease in release rate during the acute postoperative pain period, contrasts with the release rate of the 631 polymer formulation, where the release rate remains essentially constant throughout the entire postoperative pain period.

[0226] All three dose levels resulted in a slow decline in exposure over the period from days 3 to 18.

[0227] Example 5 Two sample depots of this technology were implanted into the intra-articular cavity of the knee joint of a living dog. The surgeon performed a medial and lateral parapatellar arthrotomy and inserted one sample depot into the medial groove and one into the lateral groove. The depots were secured in place with 4-0 PDS II sutures. Two dogs were the subjects of this study.

[0228] Each sample depot consisted of a heat-pressed multilayer film with the configuration shown in Figure 5. The treatment area consisted of a single layer sandwiched between two inner control layers (closest to the treatment layer, e.g., 302b and 302c in Figure 5) and two outer control layers (farthest from the treatment area, e.g., 302a and 302d in Figure 5). Each inner control layer consisted of 5.7 mg of bioabsorbable polymer (60:30:10 terpolymer, poly(DL-lactide-glycolide-ε-caprolactone)) and 2.8 mg of release agent (polysorbate 20). Each outer control layer consisted of 7.7 mg of bioabsorbable polymer (60:30:10 terpolymer, poly(DL-lactide-glycolide-ε-caprolactone)) and 0.8 mg of release agent (polysorbate 20).

[0229] The treatment area contained a monolayer consisting of 118 mg of bioabsorbable polymer (60:30:10 terpolymer, poly(DL-lactide-glycolide-ε-caprolactone)), 57.6 mg of release agent (polysorbate 20), and 235.9 mg of local anesthetic (bupivacaine HCl).

[0230] Each of the depots was approximately 15 mm x approximately 25 mm x approximately 1 mm.

[0231] After implantation, dogs were evaluated at scheduled intervals to determine the postoperative pharmacokinetic (PK) profiles of bupivacaine in synovial fluid and plasma. For plasma bupivacaine PK values ​​(i.e., representing systemic bupivacaine levels), blood was collected at scheduled intervals after depot implantation. PK results for plasma fluid samples are shown in Figure 25.

[0232] As shown in Figure 25, depot 100 released an initial controlled burst over the first approximately 3 days, followed by a tapering release over the remaining 11 days.

[0233] Example 6 Three sample depots of this technology were implanted into the intra-articular cavity of the knee joint of a living sheep. The surgeon performed medial and lateral parapatellar arthrotomy and inserted one sample depot into the medial groove and two sample depots into the lateral groove. The depots in the lateral groove were sutured side-by-side prior to implantation to hold them in place relative to each other within the groove. The depots were then secured in place to the joint capsule tissue with 4-0 PDS II sutures.

[0234] Each sample depot consisted of a heat-pressed multilayer film having the configuration shown in Figure 5. The treatment area consisted of a single layer sandwiched between two inner control layers (closest to the treatment layer, e.g., 302b and 302c in Figure 5) and two outer control layers (farthest from the treatment area, e.g., 302a and 302d in Figure 5). Each inner control layer consisted of 5.3 mg of bioabsorbable polymer (poly(DL-lactide-co-glycolide) in a 50:50 molar ratio) and 2.6 mg of release agent (polysorbate 20). Each outer control layer consisted of 7.2 mg of bioabsorbable polymer (poly(DL-lactide-co-glycolide) in a 50:50 molar ratio) and 0.7 mg of release agent (polysorbate 20).

[0235] The treatment area contained a monolayer consisting of 118.1 mg of bioabsorbable polymer (poly(DL-lactide-co-glycolide) in a 50:50 molar ratio), 57.7 mg of release agent (polysorbate 20), and 236.3 mg of local anesthetic (bupivacaine HCl).

[0236] Each of the depots was approximately 15 mm x approximately 25 mm x approximately 1 mm.

[0237] After implantation, sheep were evaluated on days 1, 4, 8, 15, and 30 to determine the postoperative pharmacokinetic (PK) profile of bupivacaine in synovial fluid and plasma.

[0238] For plasma bupivacaine PK values ​​(i.e., representing systemic bupivacaine levels), 1 mL of blood was collected from all animals at 1, 2, 4, 8, 12, 16, 20, 24, and 48 hours after depot implantation, and then every 48 hours (at the same times as on previous days, ±1 hour) until 28 days before sacrifice. PK results for plasma fluid samples are shown in Figure 26A. As shown, systemic plasma bupivacaine concentrations showed an initial controlled burst over the first 2-4 days, followed by a tapering release for the remainder of the period.

[0239] For PK values ​​of bupivacaine in synovial fluid (i.e., representing local bupivacaine levels), a minimum of 0.5 mL of synovial fluid was aspirated from the joint at 0 hours (i.e., immediately before surgery), 24 hours, 96 hours, and 192 hours. PK results for the synovial fluid samples are shown in Figure 26B. As shown, local synovial fluid concentrations showed an initial controlled burst over the first 2-4 days, followed by a tapered release over the remaining period.

[0240] Figure 26C is a plot showing plasma bupivacaine concentrations versus synovial fluid bupivacaine concentrations over time. As demonstrated in Figure 26C, PK values ​​describe the release profile achieved in previous in vitro and in vivo studies, with an initial controlled burst over the first 2-4 days providing a significant dose of bupivacaine during the acute postoperative pain period, followed by a tapered release providing a therapeutic dose during the subacute postoperative pain period. As shown, local bupivacaine levels were an order of magnitude greater than systemic bupivacaine levels. Achieving high local concentrations of bupivacaine without correspondingly high systemic levels allows for optimized analgesia without the risk of systemic toxicity.

[0241] IV. SELECTED SYSTEMS AND METHODS FOR TREATING POST-SURGICAL PAIN ASSOCIATED WITH ORTHOPEDIC SURGERY The depot 100 of the present technology may be used to treat various orthopedic injuries or diseases depending on the nature of the therapeutic agent delivered, as described above. The therapeutic agent may be delivered to a specific area of ​​the patient's body depending on the medical condition being treated. The depot 100 of the present technology may be placed in vivo near a target tissue (i.e., bone, soft tissue, etc.) within the patient's body to provide a controlled, sustained release of the therapeutic agent for the treatment of a specific condition. This implantation may be associated with surgery or intervention to acutely treat a specific condition, whereby the depot allows for chronic, sustained pharmacological treatment after the surgery or intervention is completed. The depot may be a free-standing element or may be connected to or integrated as part of an implantable device or prosthesis associated with the intervention or surgery.

[0242] The amount of therapeutic agent that will be effective in patients who need it will depend on the specific nature of the condition and can be determined by standard clinical techniques known in the art.In addition, in vitro or in vivo assays can be used as needed to help identify optimal dosage ranges.The specific dosage level for any specific individual will depend on various factors, including drug activity, age, weight, overall physical and mental health, genetic factors, environmental influences, sex, diet, administration time, administration site, excretion rate, and the severity of the specific problem being treated.

[0243] Some aspects of the present technology include a system comprising multiple depots (each of which can be any of the depots described herein) provided for implantation by a clinician. In this system, each depot may be configured for controlled release of a therapeutic agent to tissues near the depot's implantation site. The depots within the system may be identical or may vary in several respects (e.g., form factor, therapeutic agent, release profile, etc.). For example, a system may be comprised of depots with release profiles that provide immediate release of the therapeutic agent and other depots with release profiles that provide delayed release of the therapeutic agent.

[0244] Many depots of the present technology are configured to be implanted at or near a surgical site to treat postoperative pain. As used herein, the term "pain" includes nociception and pain sensation, both of which can be assessed objectively and subjectively using pain scores and other methods known in the art, such as the use of opioids. In various embodiments, pain may include allodynia (e.g., an increased response to normally non-noxious stimuli) or hyperalgesia (e.g., an increased response to normally noxious or unpleasant stimuli), which may be thermal or mechanical (tactile) in nature. In some embodiments, pain is characterized by thermal sensitivity, mechanical sensitivity, and / or rest pain. In other embodiments, pain includes mechanically induced pain or rest pain. In still other embodiments, pain includes rest pain. Pain can be primary or secondary pain, as known in the art. Exemplary types of pain that can be reduced, prevented, or treated by the methods and compositions disclosed herein include, but are not limited to, postoperative pain, such as pain in the back of the lower back (lumbar back pain) or neck (neck pain), leg pain, radicular pain (experienced in the lower back and legs from lumbar surgery, in the neck and arms from cervical surgery), or abdominal pain from abdominal surgery, as well as neuropathic pain in the arms, neck, back, lower back, legs, and referred pain distribution resulting from disc or spinal surgery. Neuropathic pain may include pain resulting from surgery on a nerve root, dorsal root ganglion, or peripheral nerve.

[0245] In various embodiments, the pain results from "post-surgical pain" or "post-operative pain" or "surgery-induced pain," which are used interchangeably herein and refer to pain that occurs during the seconds, minutes, hours, days, or weeks of recovery following a surgical procedure (e.g., hernia repair, orthopedic surgery, or spinal surgery, etc.). Surgical procedures include any procedure that penetrates beneath the skin and causes pain and / or inflammation in the patient. Surgical procedures also include arthroscopic surgery, mass resection, spinal fusion, thoracic, cervical, or lumbar surgery, pelvic surgery, or a combination thereof.

[0246] Figures 27A and 27B show common locations on a patient where surgery may be performed and where the depot of the present technology may be administered. It will be understood that the locations shown in Figures 27A and 27B are merely illustrative of the many different locations on a patient where surgery may be performed. For example, surgery may be required on a patient's knee, hip, upper extremity, lower extremity, neck, spine, shoulder, abdomen, and pelvis. Figure 28 is a table showing common surgical procedures in which the depot 100 of the present technology may be utilized to treat post-operative pain.

[0247] Many embodiments of the present technology include one or more depots having the same or different configurations and / or dosages configured to be placed at or near the surgical site of a knee joint to treat pain associated with total knee replacement surgery. As previously described, the depots of the present technology may be solid, self-supporting, flexible membranes structurally capable of being handled by a clinician during the normal course of surgery without breaking into multiple small pieces and / or losing their overall shape. In this manner, a clinician may place one or more of the depots in various locations in or near the intracapsular and / or extracapsular spaces of the knee joint as needed to address specific patient needs and / or target specific nerves innervating the knee.

[0248] 29A-29C are, for example, frontal, lateral, and medial views of a human knee showing the location of nerves that innervate the extracapsular and intracapsular portions of the knee joint. In some embodiments, the depot may be implanted adjacent to one or more nerves that innervate the knee (the nerves shown in FIGS. 29A-29C).

[0249] In some cases, it may be beneficial to place one or more depots within the joint capsule. For example, FIG. 30A is a view of a human knee cut open to expose the intracapsular cavity and identify potential locations for placing one or more depots, and FIG. 30B is a view of a human knee cut open to expose the intracapsular cavity and show several depots 100 placed therein to treat postoperative pain. As shown in FIGS. 30A and 30B, in some cases, one or more depots may be placed at or near the suprapatellar capsule (SPP), particularly subperiosteally, and attached to the quadriceps tendon. Additional areas for placing one or more depots 100 may include the medial and lateral grooves (MG, LG), generally (with fixation to tissue medial or lateral to the respective grooves), on the femur (F), on the tibia (T) (e.g., posterior attachment to the tibial plateau at or near the anterior tibia to anesthetize the infrapatellar branch of the saphenous nerve). In some embodiments, one or more depots may be placed adjacent to at least one of the posterior capsule PC of the knee, the superior region of the patella P, and / or an arthrotomy into the knee joint capsule. In some embodiments, one or more depots 100 may be placed on or near the saphenous nerve, the adductor canal, and / or the femoral nerve. In some embodiments, one or more of the depots may be configured to be placed on or near the infrapatellar branch of the saphenous nerve, one or more genicular nerves in the knee, or the superior region of the patella P. It may be desirable to place the depot within the knee joint capsule, but away from any articular portion of the knee joint itself.

[0250] Instead of or in addition to placing a depot in the intra-articular space, one or more depots may be placed in an extracapsular location. Figures 31A and 31B, for example, show anterior and posterior views, respectively, of a nerve when placed in an extracapsular location. In some embodiments, a depot may be implanted adjacent to one or more extracapsular nerves (such as the nerves shown in Figures 31A and 31B). As shown in Figure 32, in some embodiments, one or more depots 100 may be placed along or adjacent to a subcutaneous skin incision.

[0251] In some embodiments, the system includes a first depot (or depots) and a second depot (or depots), all configured to be implanted at or near the knee joint. The first depot(s) may have the same or different release profile, release rate, therapeutic agent (e.g., non-narcotic analgesic, NSAID, antibiotic), release duration, size, shape, configuration, total payload, etc. as the second depot(s).

[0252] One or more of the depots may optionally include delayed release capabilities ranging from 6 to 24 hours after implantation so as not to interfere with or overlap with peripheral nerve blocks administered to the patient during surgery. In some embodiments, one or more depots placed in the adductor canal and knee capsule may be configured to have a delayed release of therapeutic agent that may exceed 24 hours.

[0253] The depot 100 disclosed herein may also be used to treat postoperative pain associated with other knee surgeries. For example, one or more depots may be used to treat postoperative pain associated with ACL repair surgery, medial collateral ligament ("MCL") surgery, and / or posterior cruciate ligament ("PCL") surgery. In ACL repair, one or more depots may be placed to deliver analgesics to the femoral and / or sciatic nerves, while in PCL repair surgery, one or more depots may be placed parasacral to deliver analgesics to the sciatic nerve. One or more depots may also be used to treat postoperative pain associated with partial knee replacement surgery, total knee replacement surgery, and / or revision knee replacement surgery. In such procedures, one or more depots may be placed adjacent to the joint or repair site to provide a regional block, or may otherwise be appropriately positioned to provide a regional block by delivering an analgesic to one or more of the femoral or sciatic nerves, for example, through placement in the adductor canal.

[0254] In addition to the knee-related procedures described above, embodiments of the depots disclosed herein can be used to treat postoperative pain associated with other orthopedic procedures, as described in more detail below and summarized in part in FIG. 28. Examples include surgical procedures involving the ankle, hip, shoulder, wrist, hand, spine, foot, or arm. In at least some of these surgical procedures, analgesics can be provided so that a regional or local block is delivered to treat postoperative pain. For regional blocks, one or more depots can be attached under direct vision during open surgery, such as during arthroplasty, open reduction and internal fixation (ORIF), ligament reconstruction, etc. In such procedures involving a joint, one or more depots can be placed in the joint capsule (e.g., in or near the intracapsular and / or extracapsular space of the joint) or in adjacent soft tissue spaced from the articular surface to avoid the depot interfering with joint motion or being damaged by contact with the articular surface. In cases involving fracture or ligament repair, one or more depots can be placed at or adjacent to the repair site to achieve a local block. For a local block, one or more depots can be placed at the treatment site adjacent to the target nerve via ultrasound guidance using a blunt trocar catheter or other suitable instrument. In at least some embodiments, it may be beneficial to combine delivery of an analgesic or other therapeutic agent via the depot with delivery of an NSAID, a long-acting narcotic delivered preoperatively, and / or acetaminophen. The sustained, controlled release of an analgesic via one or more depots can work in concert with these other therapeutic agents to provide a reduction in postoperative pain associated with orthopedic and other surgical procedures.

[0255] In one example, one or more depots described herein can be used to treat postoperative pain associated with foot and ankle surgery, such as ankle arthroplasty (including ankle revision, ankle replacement, and total ankle replacement), ankle fusion, ligament reconstruction, corrective osteotomy (e.g., bunionectomy, flatfoot surgery), or open reduction and internal fixation (ORIF) of an ankle or foot fracture. When treating postoperative pain associated with such surgery, one or more depots can be configured and placed adjacent to the joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be placed parasacral or in another suitable location to target one or more of the inferior gluteal sciatic nerve, popliteal sciatic nerve, deep peroneal nerve, or superficial peroneal nerve. In some embodiments, a depot placed to treat post-operative pain associated with ankle or foot surgery can have a release profile configured to deliver therapeutically beneficial levels of analgesic over a period of between 3 and 7 days.

[0256] In another example, one or more depots described herein can be used to treat postoperative pain associated with hip surgery, such as hip arthroplasty (including hip revision, partial hip replacement, and total hip replacement) or open reduction and internal fixation (ORIF) of a hip fracture. When treating postoperative pain associated with such surgery, one or more depots can be configured and placed adjacent to the joint or repair site to provide a regional block. Additionally or alternatively, regional block can be provided by placing the depot in the psoas compartment, lumbar paravertebral space, fascia iliaca, or other suitable location to target one or more of the lumbar plexus, sacral plexus, femoral nerve, sciatic nerve, superior gluteal nerve, or obturator nerve. In some embodiments, it may be beneficial to fixate one or more depots (e.g., using a fixation mechanism described herein) to maintain the anterior position of the depot, thereby preventing or reducing exposure of the analgesic to motor nerves (e.g., the sciatic or femoral nerve). In some embodiments, a depot placed to treat post-operative pain associated with hip surgery can have a release profile configured to deliver therapeutically beneficial levels of analgesic over a period of 5 to 7 or 7 to 10 days depending on the particular surgical procedure.

[0257] Postoperative pain associated with shoulder and upper arm surgery can also be treated using one or more depots disclosed herein. Examples of such surgeries include shoulder arthroplasty (including shoulder revision, partial shoulder replacement, and total shoulder replacement), humeral fracture repair (scapula, humerus), ligament / tendon repair (e.g., rotator cuff, labrum, biceps, etc.), or open reduction and internal fixation (ORIF) of a shoulder or upper arm fracture. In treating postoperative pain associated with such surgeries, one or more depots can be configured and placed adjacent to the joint or repair site to provide regional blockade. Additionally or alternatively, one or more depots can be configured and placed to target the brachial plexus by placing one or more depots in the cervical paraspinal space, interscalene space, or supraclavicular space. In some embodiments, interscalene placement of the depot can avoid exposing the analgesic to native cartilage, thereby reducing the risk of cartilage toxicity. In some embodiments, a depot placed to treat post-operative pain associated with surgery involving the shoulder or upper arm can have a release profile configured to deliver therapeutically beneficial levels of analgesic over a period of 3 to 7 days.

[0258] In another example, one or more depots described herein can be used to treat postoperative pain associated with elbow surgery, such as elbow arthroplasty (including elbow revision, partial elbow replacement, and total elbow replacement), ligament reconstruction, or open reduction and internal fixation (ORIF) of an elbow fracture. In treating postoperative pain associated with such surgery, one or more depots can be placed adjacent to the joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be configured and positioned to target the brachial plexus nerves, for example, by placement in or near the cervical paravertebral space, subclavian, or axillary region, or other suitable location. In some embodiments, a depot placed to treat postoperative pain associated with elbow surgery can have a release profile configured to deliver therapeutically beneficial levels of analgesic over a period of 3 to 7 days.

[0259] Postoperative pain associated with wrist and hand surgery can also be treated using one or more depots described herein. Examples of wrist and hand surgery include wrist arthroplasty (including wrist revision, partial wrist replacement, and total wrist replacement), wrist fusion, and open reduction and internal fixation (ORIF) of wrist fractures. When treating postoperative pain associated with such surgeries, one or more depots can be configured and placed adjacent to the wrist joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be configured and placed to target the ulnar, median, radial, and cutaneous antebrachial nerves, for example, via placement in the antecubital fossa, cervical paraspinal space, subclavian, or axillary region. In some embodiments, a depot placed to treat postoperative pain associated with wrist and hand surgery can have a release profile configured to deliver therapeutically beneficial levels of analgesic over a period of 3 to 7 days.

[0260] The depots disclosed herein may also be used to treat postoperative pain from other orthopedic procedures. For example, postoperative pain associated with spinal fixation can be treated by placing one or more depots subcutaneously or in the paraspinal space. In treating postoperative pain associated with fibular fracture repair, one or more depots can be configured and positioned to target the sciatic nerve and / or popliteal sciatic nerve, for example, by placing them parasacral. Various other placements and configurations are possible to provide therapeutic relief from postoperative pain associated with orthopedic procedures.

[0261] V. SELECTED SYSTEMS AND METHODS FOR TREATING POST-SURGICAL PAIN ASSOCIATED WITH NON-ORTHOPEDIC SURGERY The depot 100 of the present technology may be used to treat a variety of medical conditions depending on the nature of the therapeutic agent being delivered, as described above. The therapeutic agent may be delivered to a specific region of the patient's body depending on the medical condition being treated. The depot 100 of the present technology may be placed in vivo near a target tissue within the patient's body to provide a controlled, sustained release of the therapeutic agent for the treatment of a specific condition. This implantation may be associated with surgery or intervention to acutely treat a specific condition, whereby the depot allows for chronic, sustained pharmacological treatment after the surgery or intervention is completed. The depot 100 may be a free-standing element or may be connected to or integrated as part of an implantable device or prosthesis associated with the intervention or surgery.

[0262] The amount of therapeutic agent that will be effective in patients who need it will depend on the specific nature of the condition and can be determined by standard clinical techniques known in the art.In addition, in vitro or in vivo assays can be used as needed to help identify optimal dosage ranges.The specific dosage level for any particular individual will depend on various factors, including drug activity, age, weight, overall physical and mental health, genetic factors, environmental influences, sex, diet, administration time, administration site, excretion rate, and the severity of the specific problem being treated.

[0263] Some aspects of the present technology include a system comprising multiple depots (each of which can be any of the depots described herein) provided for implantation by a clinician. In this system, each depot may be configured for controlled release of a therapeutic agent to tissues near the depot's implantation site. The depots within the system may be identical or may vary in several respects (e.g., form factor, therapeutic agent, release profile, etc.). For example, a system may be comprised of depots with release profiles that provide immediate release of the therapeutic agent and other depots with release profiles that provide delayed release of the therapeutic agent.

[0264] Many depots of the present technology are configured to be implanted at or near a surgical site to treat postoperative pain. As used herein, the term "pain" includes nociception and pain sensation, both of which can be assessed objectively and subjectively using pain scores and other methods known in the art, such as the use of opioids. In various embodiments, pain may include allodynia (e.g., an increased response to normally non-noxious stimuli) or hyperalgesia (e.g., an increased response to normally noxious or unpleasant stimuli), which may be thermal or mechanical (tactile) in nature. In some embodiments, pain is characterized by thermal sensitivity, mechanical sensitivity, and / or rest pain. In other embodiments, pain includes mechanically induced pain or rest pain. In still other embodiments, pain includes rest pain. Pain can be primary or secondary pain, as known in the art. Exemplary types of pain that can be reduced, prevented, or treated by the methods and compositions disclosed herein include, but are not limited to, postoperative pain, and neuropathic pain in the arms, neck, back, lower back, legs, and related pain distributions. Neuropathic pain may include pain resulting from surgery on a nerve root, dorsal root ganglion, or peripheral nerve.

[0265] In various embodiments, the pain results from "post-surgical pain" or "post-operative pain" or "surgery-induced pain," which are used interchangeably herein and refer to pain that occurs during the seconds, minutes, hours, days, or weeks of recovery following a surgical procedure. Surgical procedures include any procedure that penetrates beneath the skin and causes pain and / or inflammation to the patient. Surgical procedures also include arthroscopic surgery, lumpectomy, spinal fusion, thoracic, cervical, or lumbar surgery, pelvic surgery, chest-related surgery, breast-related surgery, gynecological surgery, general, abdominal, or urological surgery, ear, nose, and throat (ENT) surgery, oral and maxillofacial surgery, oncological surgery, cosmetic surgery, or a combination thereof. FIG. 28 is a table illustrating common surgical procedures for treating post-operative pain utilizing the depot 100 of the present technology.

[0266] Many embodiments of the present technology include one or more depots having the same or different configurations and / or dosages configured to be placed at or near a surgical site to treat pain associated with recovery from a surgical procedure. As previously described, the depots of the present technology may be solid, self-supporting, flexible membranes structurally capable of being handled by a clinician during the normal course of surgery without breaking into multiple small pieces and / or losing their overall shape. In this manner, a clinician may place one or more of the depots in various locations at or near the treatment site as needed to address specific patient needs and / or target specific nerves innervating the surgical site.

[0267] In some embodiments, the system includes a first depot (or depots) and a second depot (or depots), all configured to be implanted at or near a treatment site. The first depot(s) may have the same or different release profile, release rate, contained therapeutic agent (e.g., non-narcotic analgesic, NSAID, antibiotic), release duration, size, shape, configuration, total payload, etc. as the second depot(s).

[0268] One or more of the depots may optionally include delayed release capabilities ranging from 6 to 24 hours after implantation so as not to interfere with or overlap with peripheral nerve blocks administered to the patient during surgery. In some embodiments, one or more depots placed at the treatment site may be configured to have a delayed release of therapeutic agent that may exceed 24 hours.

[0269] The depots disclosed herein may be used to treat postoperative pain associated with a wide variety of surgeries. For example, as summarized in FIG. 28, the depots may be used to treat postoperative pain associated with chest-related surgery, breast-related surgery, obstetric and gynecological surgery, general, abdominal, or urological surgery, ear, nose, and throat (ENT) surgery, oral and maxillofacial surgery, oncological surgery, or cosmetic surgery. For particular surgeries or classes of surgeries, one or more depots can be placed at the treatment site to treat postoperative pain. The treatment site may be at or near the surgical site, or in some embodiments, may be remote from the surgical site and near the target nerve or nerve bundle that innervates the surgical site.

[0270] In one example, one or more depots described herein can be used to treat postoperative pain associated with chest-related surgery, such as thoracotomy, esophageal surgery, cardiac surgery, lung resection, thoracic surgery, or other such procedures. In treating postoperative pain associated with such surgery, one or more depots can be configured and positioned to target the intercostal nerves, for example, by being placed in or near the thoracic paravertebral space or other suitable location. Analgesic drugs delivered to the intercostal nerves can reduce pain in the patient's chest region, thereby alleviating postoperative pain associated with the aforementioned chest-related surgical procedures.

[0271] In another example, one or more depots disclosed herein can be used to treat postoperative pain associated with breast-related surgery, such as mastectomy, breast augmentation, breast reduction, breast reconstruction, or other such procedures. To treat postoperative pain from such procedures, one or more depots can be configured to deliver an analgesic or other therapeutic agent to the intercostal nerves, for example, via placement in or near the patient's subclavian space or other suitable location. Additionally or alternatively, one or more depots can be configured to deliver an analgesic or other therapeutic agent to the lateral and / or medial pectoral nerves, for example, via placement between the serratus anterior and latissimus dorsi muscles or other suitable location. As described above, an analgesic delivered to the intercostal nerves can reduce pain in the patient's chest region, while an analgesic delivered to the lateral and / or medial pectoral nerves can reduce pain in the pectoralis major and minor muscles, thereby reducing postoperative pain associated with the aforementioned chest-related surgical procedures.

[0272] As another example, one or more depots can be used to treat postoperative pain associated with systemic, abdominal, and / or urological procedures. Examples of such procedures include proctocolectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, nephrectomy, gastrectomy, small bowel resection, splenectomy, incisional hernia repair, inguinal hernia repair, sigmoid resection, hepatectomy, enterostomy, rectal resection, kidney stone removal, and cystectomy. For such surgeries, postoperative pain can be treated by placing one or more depots to target nerves at the transversus abdominis plane (TAP). Analgesics delivered to the TAP can anesthetize nerves supplying the anterior abdominal wall, thereby reducing postoperative pain in this region. In some embodiments, one or more depots are placed between the internal oblique and transversus abdominis muscles. In some embodiments, one or more depots may be placed on or adjacent to the abdominal wall and secured in place, for example via a securing mechanism, described in more detail below.

[0273] In some embodiments, the one or more depots are used to treat post-operative pain associated with gynecological surgery, such as a myomectomy, cesarean section, hysterectomy, oophorectomy, pelvic floor reconstruction, or other such surgical procedures. For such procedures, the depot(s) can be configured and positioned to deliver an analgesic or other therapeutic agent to one or more of the nerves innervating the pelvic and / or genital region, such as the pudendal nerve, intercostal nerve, or other suitable nerve.

[0274] In some embodiments, one or more depots can be used to treat postoperative pain associated with ear, nose, and throat (ENT) surgical procedures, such as tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, submandibular gland surgery, or other such procedures. Similarly, one or more depots can be used to treat postoperative pain associated with oral and maxillofacial procedures, such as alveolar surgery, dental implant surgery, surgical orthodontics, temporomandibular joint (TMJ) surgery, dental reconstructive surgery, or other such procedures. For ENT and oral and maxillofacial surgical procedures, the depot(s) can be configured and positioned to deliver an analgesic or other therapeutic agent to one or more nerves innervating the area affected by the surgical procedure, such as the mandibular nerve, mylohyoid nerve, lingual nerve, inferior alveolar nerve, buccal nerve, auriculotemporal nerve, anterior ethmoidal nerve, or other suitable nerve.

[0275] One or more depots 100 can also be used to treat postoperative pain associated with other surgical procedures, such as oncological surgery (e.g., tumor resection), cosmetic surgery (e.g., liposuction), or other surgical procedures that result in postoperative pain. To treat postoperative pain associated with any particular surgery, the number of depots and the characteristics of each individual depot can be selected to deliver the desired therapeutic benefit. For example, the dimensions of the depot(s), the amount of therapeutic agent per depot, the release profile, and other characteristics can be tailored to achieve the desired treatment of postoperative pain. For example, a patient recovering from knee replacement surgery may benefit from at least 14 days of pain medication delivery, while a patient recovering from a tonsillectomy may not require the same level or duration of pain medication delivery. Thus, depots delivered to a patient for treatment of postoperative pain after a tonsillectomy may require fewer depots, or depots with a smaller payload of therapeutic agent, or depot(s) with a steeper release profile, etc. Additionally, the number and characteristics of the depot(s) selected for implantation can be tailored to accommodate the target anatomical region for placement within the patient.

[0276] VI. Conclusion While many of the embodiments are described above with respect to systems, devices, and methods for treating postoperative pain, the technology is applicable to other applications and / or other approaches. Furthermore, other embodiments in addition to those described herein are within the scope of the technology. Furthermore, some other embodiments of the technology may have different configurations, components, or procedures than those described herein. Thus, those skilled in the art will appreciate that the technology may have other embodiments with additional elements, or may have other embodiments lacking some of the features shown and described above with reference to FIGS. 2-32.

[0277] The above detailed description of embodiments of the technology is not exhaustive or intended to limit the technology to the precise form disclosed above. Where the context allows, singular or plural terms may include the plural or singular terms, respectively. Specific embodiments or examples of the technology are described above for illustrative purposes; however, those skilled in the art will recognize that various equivalent modifications are possible within the scope of the technology. For example, while steps are presented in a given order, alternative embodiments may perform the steps in a different order. Various embodiments described herein may be combined to provide further embodiments.

[0278] Furthermore, unless the word "or" is expressly limited to referring to a list of two or more items to mean only a single item exclusively from the other items, the use of "or" in such a list shall be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. Furthermore, the term "comprising" is used throughout to mean the inclusion of at least the recited feature(s), but not excluding any greater number of the same feature and / or additional features of additional types. While specific embodiments have been described herein for illustrative purposes, it will be understood that various modifications may be made without departing from the technology. Furthermore, while advantages associated with certain embodiments of the technology have been described in the context of the embodiments, other embodiments may exhibit such advantages, and it is not necessary for all embodiments to indicate that such advantages are encompassed within the scope of the technology. Thus, the present disclosure and related technology may encompass other embodiments not expressly shown or described herein.

[0279] Unless otherwise indicated, all numbers expressing quantities of ingredients, percentages or proportions of materials, reaction conditions, and other numerical values ​​used in the specification and claims are to be understood as modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present technology. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Furthermore, all ranges disclosed herein will be understood to encompass any and all subranges therein. For example, a range "1 to 10" includes any and all subranges between (and including) a minimum value of 1 and a maximum value of 10, i.e., any and all subranges having a minimum value equal to or greater than 1 and a maximum value equal to or less than 10, such as 5.5 to 10.

[0280] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless clearly and unambiguously limited to one referent. For example, reference to a "therapeutic agent" includes one, two, three, or more therapeutic agents.

[0281] The above headings are not intended to limit the disclosure in any way: embodiments under any one heading may be used in conjunction with embodiments under any other heading.

Claims

[Claim 1] The invention described in the specification.

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