Implantable polymer reservoirs for controlled sustained release of therapeutic agents

Abstract

The invention relates to an implantable polymer repository for controlled sustained release of therapeutic agents. The present technology relates to a repository for treatment selection of symptoms by sustained controlled release of therapeutic agents. In some embodiments, the repository may include a treatment region comprising a therapeutic agent, and a control region comprising a bioresorbable polymer and a release agent mixed with the polymer. The release agent may be configured to dissolve to form diffusion openings in the control region when the reservoir is placed in the body. The repository may be configured to be implanted at a treatment site within the body and to release the therapeutic agent at the treatment site for an extended period of time when implanted.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080040292.5, application date April 11, 2020, and invention name “Implantable polymer reservoir for controlled sustained release of therapeutic agents”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. patent application No. 62 / 832,482, filed on April 11, 2019, U.S. patent application No. 62 / 832,510, filed on April 11, 2019, U.S. patent application No. 62 / 832,552, filed on April 11, 2019, U.S. patent application No. 62 / 832,742, filed on April 11, 2019, U.S. patent application No. 62 / 832,570, filed on April 11, 2019, U.S. patent application No. 62 / 832,730, filed on April 11, 2019, U.S. patent application No. 62 / 832,650, filed on April 11, 2019, and U.S. patent application No. 62 / 832,841, filed on April 11, 2019, each of which is incorporated herein by reference in its entirety.

[0004] This application also incorporates by reference in its entirety each of the following applications: International Application Nos. PCT / US2019 / 048437, filed August 27, 2019, PCT / US2019 / 048386, filed August 27, 2019, PCT / US2019 / 012795, filed January 8, 2019, PCT / US2018 / 054777, filed October 6, 2018, No. 62 / 723,478 filed on December 28, 2018, U.S. application No. 62 / 670,721 filed on May 12, 2018, U.S. application No. 62 / 640,571 filed on March 8, 2018, U.S. application No. 62 / 614,884 filed on January 8, 2018, U.S. patent application No. 62 / 742,357 filed on October 6, 2018, and U.S. application No. 62 / 569,349 filed on October 6, 2017. Technical Field

[0005] The present technology relates to implants for the controlled sustained release of therapeutic agents in vivo. Background Art

[0006] The implantable system of the controlled release of therapeutic agent provides advantage with respect to other drug administration methods such as oral or parenteral methods.The device that comprises biocompatible and / or biodegradable polymer and therapeutic agent can be implanted in the anatomical position of clinical expectation, thereby the topical administration of selected reagent is provided.This topical administration can make most reagent arrive predetermined target and can avoid undesirable systemic side effect.Yet these systems often lack real controlled release mechanism, because they provide the sudden release of medicine usually when contacting with surrounding physiological fluid, be the residual release of medicine afterwards.

[0007] To improve drug release in certain polymer carriers, hydrophilic polymers such as polysorbates have been added to these carriers as wetting agents to accelerate or enhance drug release from biocompatible polymers such as polyethylene glycol (PEG) in oral formulations (Akbari, J. et al., Adv. Pharm. Bull., 2015, 5(3):435–441). However, these formulations are intended to provide immediate release of hydrophobic drugs into a hydrophilic environment (physiological fluids in the body), with most of the entire drug payload being released immediately or suddenly, rather than variable or sustained controlled release.

[0008] While these drug release kinetics may be desirable in some clinical applications, controlled, sustained release of therapeutic agents may have clinical benefits in certain circumstances. Specifically, it may be desirable to implant a biodegradable carrier that maintains a large dose of the therapeutic agent for controlled, sustained release over time.

[0009] Therefore, there is a need for biodegradable implantable systems that can provide highly controlled release of drugs. Summary of the Invention

[0010] The present technology relates to implants and related systems and methods for the controlled release of therapeutic agents for treating medical conditions. In particular, the present technology relates to implants and related systems and methods for the sustained and / or localized release of therapeutic agents at surgical or interventional sites.

[0011] For example, the subject technology is illustrated according to various aspects described below, including reference to Figures 1-59. For convenience, various examples of various aspects of the subject technology are described as numbered clauses (1, 2, 3, etc.). These are provided as examples and do not limit the subject technology.

[0012] 1. A depot for the controlled sustained release of a therapeutic agent, comprising:

[0013] a treatment region comprising a therapeutic agent, the treatment region being elongated along a first axis; and

[0014] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is positioned within the body to form a diffusion opening in the control region;

[0015] Therein, the depot is configured to be implanted at a treatment site within the body and, when implanted, releases the therapeutic agent at the treatment site for a period of time.

[0016] 2. The depot of any of the clauses herein, wherein the maximum transverse dimension of the depot along a first axis is at least 5 times the maximum transverse dimension of the depot along a second axis orthogonal to the first axis.

[0017] 3. The depot of any of the clauses herein, wherein the maximum transverse dimension of the depot along a first axis is at least 10 times the maximum transverse dimension of the depot along a second axis orthogonal to the first axis.

[0018] 4. The depot of any one of the clauses herein, wherein the depot is substantially cylindrical.

[0019] 5. The depot of any one of the clauses herein, wherein the depot is substantially cylindrical.

[0020] 6. The depot of any one of the clauses herein, wherein the depot is configured for injection or insertion through a needle having a size no greater than 14, 16, 18, 20 or 22 gauge.

[0021] 7. The depot of any of the clauses herein, wherein the treatment area is substantially cylindrical.

[0022] 8. The depot of any of the clauses herein, further comprising at least one opening extending through the treatment area.

[0023] 9. The depot of any one of the clauses herein, wherein the opening forms a cylindrical lumen extending parallel to the first axis.

[0024] 10. The depot of any one of the clauses herein, wherein the opening comprises a lumen extending along a second axis substantially perpendicular to the first axis.

[0025] 11. The storage reservoir of any one of the clauses herein, further comprising a plurality of elongated openings extending parallel to the second axis.

[0026] 12. The depot of any one of the clauses herein, wherein the treatment region comprises a plurality of separate elongate sub-regions extending substantially parallel to the first axis.

[0027] 13. The depot of any one of the clauses herein, wherein each of the elongate sub-regions is substantially cylindrical.

[0028] 14. The depot of any one of the clauses herein, wherein each of the elongate sub-regions is radially separated from each other by a control region.

[0029] 15. The depot of any of the clauses herein, wherein the radially outermost dimension of the depot varies along the first axis.

[0030] 16. The depot of any of the clauses herein, wherein the radially outermost dimension of the treatment area varies along the first axis.

[0031] 17. The depot of any one of the clauses herein, wherein the treatment area is a series of separate areas covered and connected by a continuous control area.

[0032] 18. The depot of any one of the clauses herein, wherein the control region is narrower in the region without the inner treatment region.

[0033] 19. The depot of any one of the clauses herein, wherein the control region is designed to bend or break during or after administration.

[0034] 20. The depot of any of the clauses herein, wherein the control region has a thickness that is variable along the first axis along the length of the depot.

[0035] 21. The depot of any of the clauses herein, wherein the control region has a thickness that varies radially about the first axis.

[0036] 22. The depot of any one of the clauses herein, wherein the variable thickness of the control region causes the depot to bend or flex when deployed in vivo.

[0037] 23. The depot of any one of the clauses herein, wherein the depot is configured to preferentially bend or flex when placed in contact with a physiological fluid in vivo.

[0038] 24. A reservoir as claimed in any one of the clauses herein, wherein the reservoir comprises an elongated polymeric strip having a length between its longitudinal ends and a width between its transverse edges, the length being greater than the width, and wherein the reservoir has a pre-set shape in an expanded configuration in which the strip is curled around an axis with the width of the strip facing the axis, thereby forming an annular shape.

[0039] 25. The depot of any one of the clauses herein, wherein the depot forms an annular or semi-annular shape.

[0040] 26. The depot of any of the clauses herein, wherein the depot has a first region and a second region, each extending longitudinally and coextensive with each other over all or a portion of their respective lengths, the first region having a first elasticity and the second region having a second elasticity less than the first elasticity.

[0041] 27. The depot of any one of the clauses herein, wherein the depot is stretched beyond the elastic hysteresis point of the second region such that when released from the drug delivery device the depot transitions from a straightened state to a curved state in which the second region pulls the depot into a curved shape.

[0042] 28. The depot of any one of the clauses herein, wherein the depot has a first region and a second region, each extending longitudinally and coextensive with each other over all or a portion of their respective lengths, the first region being more hydrophilic than the second region.

[0043] 29. The depot of any of the clauses herein, wherein when the depot is released from the drug delivery device, the depot transitions from a straightened state to a curved state wherein the second region pulls the depot into a curved shape.

[0044] 30. The depot of any of the clauses herein, wherein the control region has first and second portions, the first and second portions having a first thickness, the first and second portions being separated along the first axis by a third portion having a second thickness different from the first thickness.

[0045] 31. The depot of any one of the clauses herein, wherein the depot extends along a first axis from a first end to a second end, and wherein the control region has a thickness that increases from the first end to the second end.

[0046] 32. The depot of any of the clauses herein, wherein the depot extends along a first axis from a first end to a second end, and wherein the control region does not overlap the treatment region at the first end of the depot.

[0047] 33. The depot of any of the clauses herein, wherein the depot extends along a first axis from a first end to a second end, and wherein the control region does not overlap the treatment region at either the first end or the second end.

[0048] 34. The depot of any one of the clauses herein, wherein the control region has a plurality of discrete openings formed therein.

[0049] 35. The depot of any of the clauses herein, wherein the control region has an opening that is elongated along the first axis.

[0050] 36. The depot of any one of the clauses herein, wherein the elongated opening in the control area extends along the entire length of the depot.

[0051] 37. The depot of any one of the clauses herein, wherein the control region comprises a plurality of annular holes formed therein.

[0052] 38. The depot of any of the clauses herein, wherein the therapeutic region is a first therapeutic region, the depot further comprising a second therapeutic region, each of the first and second therapeutic regions being elongated along a first axis, wherein the first and second therapeutic regions are configured to release the therapeutic agent at different rates.

[0053] 39. The depot of any of the clauses herein, wherein the therapeutic region is a first therapeutic region, the depot further comprising a second therapeutic region, each of the first and second therapeutic regions being elongated along a first axis, wherein the first and second therapeutic regions comprise different therapeutic agents.

[0054] 40. The depot of any of the clauses herein, wherein the first and second treatment zones are coaxially aligned.

[0055] 41. The depot of any one of the clauses herein, wherein the first and second treatment zones extend parallel to each other along the length of the depot.

[0056] 42. The depot of any of the clauses herein, further comprising a barrier region configured to dissolve more slowly in vivo than the control region or the treatment region.

[0057] 43. The depot of any one of the clauses herein, further comprising a barrier region configured to slow the passage of physiological fluids in the body therethrough to the control region or the treatment region.

[0058] 44. The depot of any of the clauses herein, wherein the barrier region is arranged coaxially with the treatment region such that the control region at least partially surrounds both the treatment region and the barrier region.

[0059] 45. The depot of any one of the clauses herein, wherein the barrier region is a first barrier region, the depot further comprising a second barrier region, the first and second barrier regions being axially separated from each other by the treatment region.

[0060] 46. ​​The depot of any one of the clauses herein, wherein the first and second barrier regions have different sizes.

[0061] 47. The depot of any of the clauses herein, wherein the barrier region is coaxially arranged with the control region such that the control region and the barrier region together at least partially surround the treatment region.

[0062] 48. The depot of any one of the clauses herein, wherein the first and second barrier regions are axially separated from each other by a control region.

[0063] 49. The depot of any one of the clauses herein, wherein the depot extends along a first axis from a first end to a second end, and wherein the barrier region is provided above the first end of the depot

[0064] 50. The depot of any of the clauses herein, wherein the depot extends along a first axis from a first end to a second end, and wherein the barrier region comprises a first end cap disposed over the first end of the depot and a second end cap disposed over the second end of the depot.

[0065] 51. The reservoir of any of the clauses herein, wherein the treatment area comprises a covered portion and an exposed portion, wherein the covered portion is covered by a control region such that when the reservoir is initially positioned at a treatment site in the body, the control region is between the covered portion of the treatment area and a physiological fluid at the treatment site, and the exposed portion of the treatment area is exposed to the physiological fluid.

[0066] 52. The depot of any one of the clauses herein, wherein the therapeutic agent in the treatment area comprises at least 50% of the total weight of the depot.

[0067] 53. The storage facility of any of the clauses herein, wherein the period of time is not less than 7 days, not less than 15 days, not less than 30 days, not less than 45 days, not less than 60 days, or not less than 90 days.

[0068] 54. The depot of any one of the clauses herein, wherein about 40% to about 60% of the therapeutic agent in the treatment area is released in the first half of the time period.

[0069] 55. The depot of any one of the clauses herein, wherein at least 90% of the therapeutic agent in the treatment area is released within the time period.

[0070] 56. The depot of any one of the clauses herein, wherein the depot is configured to release from about 2 μg to about 5 mg of the therapeutic agent per day to the treatment site.

[0071] 57. The depot of any of the clauses herein, wherein the depot is configured to release the therapeutic agent at the treatment site 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 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0072] 58. The depot of any one of the clauses herein, wherein the therapeutic agent is released at a substantially steady-state rate over the entire period of time.

[0073] 59. A repository as defined in any of the clauses herein, wherein:

[0074] The reservoir has a total surface area comprising the exposed surface area of ​​the control region plus the exposed surface area of ​​the treatment region, and

[0075] wherein, when the depot is initially positioned at a treatment site in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the control region is about 5% to about 20%, or about 5% to about 15%, or about 5% to about 10%.

[0076] 60. The depot of any one of the clauses herein, wherein the exposed surface area of ​​the control zone is less than the exposed surface area of ​​the treatment zone.

[0077] 61. The depot of any one of the clauses herein, wherein the exposed surface area of ​​the control zone is greater than the exposed surface area of ​​the treatment zone.

[0078] 62. The depot of any one of the clauses herein, wherein the control region is a first control region, and wherein the depot comprises a second control region.

[0079] 63. The depot of any of the clauses herein, 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.

[0080] 64. The depot of any of the clauses herein, wherein the depot comprises a plurality of control regions and a plurality of treatment regions, and wherein each of the treatment regions is separated from an adjacent one of the treatment regions by one or more control regions.

[0081] 65. The depot of any one of the clauses herein, wherein the depot comprises from about 2 to about 10 treatment areas.

[0082] 66. The storage reservoir of any one of the clauses herein, wherein the control region comprises a first control layer and a second control layer.

[0083] 67. The depot of any of the clauses herein, wherein the second control layer is adjacent to the treatment area and the first control layer encloses / surrounds the treatment area and the second control layer.

[0084] 68. The depot of any of the clauses herein, wherein the first control layer and the second control layer together enclose the treatment area.

[0085] 69. The depot of any of the clauses herein, wherein the first controlling layer comprises a first plurality of sublayers and the second controlling layer comprises a second plurality of sublayers.

[0086] 70. The depot of any of the clauses herein, wherein the first controlling layer comprises a first amount of the releasing agent and the second controlling layer comprises a second amount of the releasing agent different from the first amount.

[0087] 71. The depot of any of the clauses herein, wherein the second controlling layer is positioned between the first controlling layer and the treatment area, and wherein the first controlling layer comprises a first concentration of the releasing agent and the second controlling layer comprises a second concentration of the releasing agent greater than the first concentration.

[0088] 72. The depot of any of the clauses herein, wherein the second controlling layer is positioned between the first controlling layer and the treatment area, and wherein the first controlling layer comprises a first concentration of the releasing agent and the second controlling layer comprises a second concentration of the releasing agent that is less than the first concentration.

[0089] 73. The depot of any one of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein

[0090] The first controlling layer comprises at most 5 wt % releasing agent, at most 10 wt % releasing agent, at most 15 wt % releasing agent, at most 20 wt % releasing agent, at most 25 wt % releasing agent, at most 30 wt % releasing agent, at most 35 wt % releasing agent, at most 40 wt % releasing agent, at most 45 wt % releasing agent, or 50 wt % releasing agent; and

[0091] The second controlling layer comprises at most 5 wt % releasing agent, at most 10 wt % releasing agent, at most 15 wt % releasing agent, at most 20 wt % releasing agent, at most 25 wt % releasing agent, at most 30 wt % releasing agent, at most 35 wt % releasing agent, at most 40 wt % releasing agent, at most 45 wt % releasing agent, or at most 50 wt % releasing agent.

[0092] 74. The depot of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein the first control layer comprises a first amount of releasing agent and the second control layer comprises a second amount of releasing agent, the second amount being at least 2X, at least 3X, at least 4X, or at least 5X the first amount.

[0093] 75. The depot of any of the clauses herein, wherein the thickness of the control area is less than or equal to 1 / 10, 1 / 15, 1 / 20, 1 / 25, 1 / 30, 1 / 35, 1 / 40, 1 / 45, 1 / 50, 1 / 75 or 1 / 100 the thickness of the treatment area.

[0094] 76. The depot of any of the clauses herein, wherein the depot comprises an elongated cylindrical structure configured to be implanted in a patient.

[0095] 77. The depot of any one of the clauses herein, wherein the depot comprises one of a plurality of beads or microspheres.

[0096] 78. The depot of any one of the clauses herein, wherein the beads or microspheres have different release profiles.

[0097] 79. The depot of any one of the clauses herein, wherein the beads or microspheres comprise different amounts of the therapeutic agent.

[0098] 80. The depot of any one of the clauses herein, wherein the beads or microspheres comprise their respective control regions of varying thickness.

[0099] 81. The depot of any one of the clauses herein, wherein the beads or microspheres are of different sizes.

[0100] 82. The depot of any one of the clauses herein, wherein the depot comprises one of a plurality of pellets.

[0101] 83. The depot of any one of the clauses herein, wherein the pellets have different release profiles.

[0102] 84. The depot of any one of the clauses herein, wherein the pellets comprise different amounts of the therapeutic agent.

[0103] 85. The depot of any one of the clauses herein, wherein the pellets comprise their respective control regions of varying thickness.

[0104] 86. The depot of any one of the clauses herein, wherein the pellets are of different sizes.

[0105] 87. The depot of any one of the clauses herein, wherein the pellets are substantially cylindrical.

[0106] 88. The depot of any of the clauses herein, wherein the depot comprises a plurality of substantially cylindrical beads, each comprising a treatment region and a control region and wherein the plurality of beads are substantially aligned along a common longitudinal axis.

[0107] 89. The depot of any one of the clauses herein, wherein the depot is biodegradable and / or bioerodible.

[0108] 90. The depot of any one of the clauses herein, wherein the depot is a flexible solid that is structurally capable of being handled by a clinician in the normal course of surgery without breaking into multiple pieces and / or losing its overall shape.

[0109] 91. The depot of any one of the clauses herein, wherein the depot is configured to be placed subcutaneously in a patient and to release the therapeutic agent in vivo for up to 7 days without breaking into multiple pieces.

[0110] 92. The reservoir of any one of the clauses herein, wherein the reservoir has a surface area and a volume, and wherein the ratio of the surface area to the volume is at least 1.

[0111] 93. The depot of any one of the clauses herein, wherein the diffusion opening comprises at least one or more holes and / or one or more channels.

[0112] 94. The depot of any one of the clauses herein, wherein dissolution of the release agent after placement in vivo at the treatment site causes the control region and the treatment region to transition from a state of less porosity to a state of greater porosity to facilitate release of the therapeutic agent from the depot.

[0113] 95. The depot of any of the clauses herein, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with the therapeutic agent.

[0114] 96. The depot of any of the clauses herein, wherein the releasing agent is a first releasing agent and the polymer is a first polymer, and the treatment area comprises a second polymer mixed with the therapeutic agent and a second releasing agent.

[0115] 97. The depot of any one of the clauses herein, wherein the first releasing agent is the same as the second releasing agent.

[0116] 98. The depot of any one of the clauses herein, wherein the first releasing agent is different from the second releasing agent.

[0117] 99. The depot of any one of the clauses herein, wherein the concentration of the first releasing agent in the control zone is greater than the concentration of the second releasing agent in the treatment zone.

[0118] 100. The depot of any one of the clauses herein, wherein the concentration of the first releasing agent in the control zone is less than the concentration of the second releasing agent in the treatment zone.

[0119] 101. The depot of any one of the clauses herein, wherein the concentration of the first releasing agent in the control zone is the same as the concentration of the second releasing agent in the treatment zone.

[0120] 102. The depot of any one of the clauses herein, wherein the concentration of the first releasing agent in the control zone is different from the concentration of the second releasing agent in the treatment zone.

[0121] 103. The depot of any of the clauses herein, wherein the treatment area comprises a plurality of microlayers.

[0122] 104. The depot of any one of the clauses herein, wherein the mass of the therapeutic agent constitutes at least 50% of the mass of the depot.

[0123] 105. The depot of any of the clauses herein, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 1:1, at least 2:1, 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 16:1.

[0124] 106. The depot of any of the clauses herein, wherein the treatment area comprises a bioabsorbable polymer and a therapeutic agent.

[0125] 107. The depot of any of the clauses herein, wherein the therapeutic area comprises at least 40% by weight of the therapeutic agent, at least 50% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, at least 90% by weight of the therapeutic agent, or 100% by weight of the therapeutic agent.

[0126] 108. The depot of any of the clauses herein, wherein the depot comprises at least 15% by weight of the therapeutic agent, at least 20% by weight of the therapeutic agent, at least 30% by weight of the therapeutic agent, at least 40% by weight of the therapeutic agent, at least 50% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, at least 90% by weight of the therapeutic agent, 99% by weight of the therapeutic agent, or 99.99% by weight of the therapeutic agent.

[0127] 109. The depot of any one of the clauses herein, wherein the release agent is a nonionic surfactant.

[0128] 110. The depot of any one of the clauses herein, wherein the release agent has hydrophilic properties.

[0129] 111. The depot of any one of the clauses herein, wherein the release agent is a polysorbate.

[0130] 112. The depot of any one of the clauses herein, wherein the release agent is Tween 20.

[0131] 113. The depot of any one of the clauses herein, wherein the release agent is Tween 80.

[0132] 114. The depot of any one of the clauses herein, wherein the release agent is non-polymeric.

[0133] 115. The depot of any one of the clauses herein, wherein the release agent is not a plasticizer.

[0134] 116. The depot of any one of the clauses herein, wherein the polymer is configured to degrade only after substantially all of the therapeutic agent has been released from the depot.

[0135] 117. The depot of any one of the clauses herein, wherein the polymer is a copolymer.

[0136] 118. The depot of any one of the clauses herein, wherein the polymer is a terpolymer.

[0137] 119. The depot of any of the clauses herein, wherein the polymer comprises at least one of: polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(α-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate , polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxy-methyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycine polyphosphazene, polycaprolactone-co-butyl acrylate, polyhydroxybutyl esters, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphagene, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as α-tocopheryl acetate, d-α-tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D , L-lactide-glycolide-caprolactone (DL-G-CL), dextran, vinyl pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylate, poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronic), 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, carboxymethyl cellulose or its salt, Poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone).

[0138] 120. The depot of any one of the clauses herein, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA).

[0139] 121. The depot of any one of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of about 60:30:10.

[0140] 122. The depot of any one of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) at a molar ratio of between about 10:90 and about 90:10.

[0141] 123. The depot of any one of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) at a molar ratio of about 50:50.

[0142] 124. The depot of any one of the clauses herein, wherein the polymer is ester terminated.

[0143] 125. The depot of any of the clauses herein, wherein the polymer is a terpolymer comprising three polymers selected from the group consisting of 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.

[0144] 126. The depot of any of the clauses herein, wherein the polymer is a first polymer and the treatment area comprises a second polymer mixed with a therapeutic agent.

[0145] 127. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer comprises at least one of the following: polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(α-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS) , polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxy-methyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycine 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 (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphogen, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as α-tocopheryl acetate, d-α-tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide Ester-glycolide-caprolactone (DL-G-CL), dextran, vinyl pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylate, poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronic), 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, carboxymethyl cellulose or its salt, Poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone).

[0146] 128. The depot of any one of the clauses herein, wherein the first polymer and / or the second polymer is selected from the group consisting of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA).

[0147] 129. The depot of any one of the clauses herein, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of about 60:30:10.

[0148] 130. The depot of any one of the clauses herein, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a molar ratio of about 50:50.

[0149] 131. The depot of any one of the clauses herein, wherein the first polymer and / or the second polymer is ester terminated.

[0150] 132. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer is a terpolymer comprising three polymers selected from the group consisting of 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.

[0151] 133. The depot of any of the clauses herein, wherein the ratio of polymer to release agent in the control region is at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 15:1.

[0152] 134. The depot of any one of the clauses herein, wherein the release agent is configured to dissolve to form a diffusion opening when the depot is placed in contact with phosphate buffered saline.

[0153] 135. The depot of any of the clauses herein, wherein the exposed surface area of ​​the control zone is less than the exposed surface area of ​​the treatment zone.

[0154] 136. The depot of any of the clauses herein, wherein the exposed surface area of ​​the control zone is greater than the exposed surface area of ​​the treatment zone.

[0155] 137. The depot of any of the clauses herein, wherein the control region is a first control region, and wherein the depot comprises a second control region.

[0156] 138. The depot of any of the clauses herein, 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.

[0157] 139. The depot of any of the clauses herein, wherein the depot comprises a plurality of control regions and a plurality of treatment regions, and wherein each of the treatment regions is separated from an adjacent one of the treatment regions by one or more control regions.

[0158] 140. The depot of any one of the clauses herein, wherein each of the treatment areas and each of the control areas is a micro-thin layer.

[0159] 141. The depot of any of the clauses herein, wherein the depot comprises from about 2 to about 100 treatment areas.

[0160] 142. The depot of any of the clauses herein, wherein the depot comprises from about 2 to about 50 treatment areas.

[0161] 143. The depot of any of the clauses herein, wherein the depot comprises from about 2 to about 10 treatment areas.

[0162] 144. The depot of any of the clauses herein, wherein the treatment region is surrounded by a control region such that when the depot is positioned within the body, the control region is between the treatment region and physiological fluids within the body.

[0163] 145. The storage reservoir of any of the clauses herein, wherein the control region comprises a first control layer and a second control layer.

[0164] 146. The depot of any of the clauses herein, wherein the second control layer is adjacent to the treatment area and the first control layer encloses / surrounds the treatment area and the second control layer.

[0165] 147. The depot of any of the clauses herein, wherein the first control layer and the second control layer together enclose the treatment area.

[0166] 148. The depot of any of the clauses herein, wherein the first control layer is disposed on a first side of the treatment area and the second control layer is disposed on a second side of the treatment area opposite the first side.

[0167] 149. The depot of any of the clauses herein, wherein the first controlling layer comprises a first plurality of sublayers and the second controlling layer comprises a second plurality of sublayers.

[0168] 150. The depot of any of the clauses herein, wherein the first controlling layer comprises a first amount of the releasing agent and the second controlling layer comprises a second amount of the releasing agent different from the first amount.

[0169] 151. The depot of any of the clauses herein, wherein the second controlling layer is positioned between the first controlling layer and the treatment area, and wherein the first controlling layer comprises a first concentration of the releasing agent and the second controlling layer comprises a second concentration of the releasing agent greater than the first concentration.

[0170] 152. The depot of any of the clauses herein, wherein the second controlling layer is positioned between the first controlling layer and the treatment area, and wherein the first controlling layer comprises a first concentration of the releasing agent and the second controlling layer comprises a second concentration of the releasing agent that is less than the first concentration.

[0171] 153. The depot of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein:

[0172] The first controlling layer comprises at most 5 wt % release agent, at most 10 wt % release agent, at most 15 wt % release agent, at most 20 wt % release agent, at most 25 wt % release agent, at most 30 wt % release agent, at most 35 wt % release agent, at most 40 wt % release agent, at most 45 wt % release agent, or 50 wt % release agent, and

[0173] The second controlling layer comprises at most 5 wt % releasing agent, at most 10 wt % releasing agent, at most 15 wt % releasing agent, at most 20 wt % releasing agent, at most 25 wt % releasing agent, at most 30 wt % releasing agent, at most 35 wt % releasing agent, at most 40 wt % releasing agent, at most 45 wt % releasing agent, or at most 50 wt % releasing agent.

[0174] 154. The depot of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein the first control layer comprises a first amount of releasing agent and the second control layer comprises a second amount of releasing agent, the second amount being at least 2X, at least 3X, at least 4X, or at least 5X the first amount.

[0175] 155. The depot of any of the clauses herein, wherein the thickness of the control area is less than or equal to 1 / 50, 1 / 75 or 1 / 100 the thickness of the treatment area.

[0176] 156. The depot of any of the clauses herein, wherein the depot is a flexible solid that is structurally capable of being handled by a clinician in the normal course of surgery without breaking into multiple pieces and / or losing its overall shape.

[0177] 157. The depot of any of the clauses herein, wherein the depot is configured to be placed subcutaneously in a patient and to release the therapeutic agent in vivo for up to 7 days without breaking into multiple pieces.

[0178] 158. The depot of any of the clauses herein, wherein the depot has a width and a thickness, and wherein the ratio of the width to the thickness is 21 or greater, at least 30 or greater, or at least 40 or greater.

[0179] 159. The reservoir of any of the clauses herein, wherein the reservoir has a surface area and a volume, and wherein the ratio of the surface area to the volume is at least 1.

[0180] 160. The depot of any of the clauses herein, wherein the diffusion opening comprises at least one or more holes and / or one or more channels.

[0181] 161. The depot of any one of the clauses herein, wherein two or more micro-thin layers of bioabsorbable polymer are bonded by heat compression to form the treatment area.

[0182] 162. A depot as claimed in any one of the clauses herein, wherein the control region and the treatment region are joined by thermal compression.

[0183] 163. A depot as claimed in any one of the clauses herein, wherein the control region and the treatment region are thermally bonded.

[0184] 164. The depot of any of the clauses herein, wherein dissolution of the release agent following placement in vivo causes the control region and the treatment region to transition from a state of less porosity to a state of greater porosity to facilitate release of the therapeutic agent from the depot.

[0185] 165. The depot of any of the clauses herein, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with the therapeutic agent.

[0186] 166. The depot of any of the clauses herein, wherein the releasing agent is a first releasing agent and the polymer is a first polymer, and the treatment area comprises a second polymer mixed with the therapeutic agent and a second releasing agent.

[0187] 167. The depot of any one of the clauses herein, wherein the first releasing agent is the same as the second releasing agent.

[0188] 168. The depot of any one of the clauses herein, wherein the first releasing agent is different from the second releasing agent.

[0189] 169. The depot of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is greater than the concentration of the second releasing agent in the treatment zone.

[0190] 170. The depot of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is less than the concentration of the second releasing agent in the treatment zone.

[0191] 171. The depot of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is the same as the concentration of the second releasing agent in the treatment zone.

[0192] 172. The depot of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is different from the concentration of the second releasing agent in the treatment zone.

[0193] 173. The depot of any of the clauses herein, wherein the treatment area comprises a plurality of microlayers.

[0194] 174. The depot of any one of the clauses herein, wherein the mass of the therapeutic agent constitutes at least 50% of the mass of the depot.

[0195] 175. The depot of any of the clauses herein, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 16:1.

[0196] 176. The depot of any of the clauses herein, wherein the treatment area comprises at least 50% by weight of the therapeutic agent, 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, or at least 90% by weight of the therapeutic agent.

[0197] 177. The depot of any of the clauses herein, wherein the depot comprises at least 15% by weight of the therapeutic agent, at least 20% by weight of the therapeutic agent, at least 30% by weight of the therapeutic agent, at least 40% by weight of the therapeutic agent, at least 50% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, or at least 90% by weight of the therapeutic agent.

[0198] 178. The depot of any of the clauses herein, wherein the release agent is a nonionic surfactant.

[0199] 179. The depot of any one of the clauses herein, wherein the release agent has hydrophilic properties.

[0200] 180. The depot of any one of the clauses herein, wherein the release agent is a polysorbate.

[0201] 181. The depot of any one of the clauses herein, wherein the release agent is Tween 20.

[0202] 182. The depot of any one of the clauses herein, wherein the release agent is Tween 80.

[0203] 183. The depot of any one of the clauses herein, wherein the release agent is non-polymeric.

[0204] 184. The depot of any one of the clauses herein, wherein the release agent is not a plasticizer.

[0205] 185. The depot of any one of the clauses herein, wherein the polymer is configured to degrade only after substantially all of the therapeutic agent has been released from the depot.

[0206] 186. The depot of any one of the clauses herein, wherein the polymer is a copolymer.

[0207] 187. The depot of any of the clauses herein, wherein the polymer is a terpolymer.

[0208] 188. The depot of any of the clauses herein, wherein the polymer comprises at least one of: polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(α-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS), polyethylene oxide, poly Propylene glycol 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-butoxy-methyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycine polyphosphazene, poly caprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphogen, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as α-tocopheryl acetate, d-α-tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide- Glycolide-caprolactone (DL-G-CL), dextran, vinyl pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylate, poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronic), 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, carboxymethyl cellulose or its salt, Poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone).

[0209] 189. The depot of any one of the clauses herein, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA).

[0210] 190. The depot of any one of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of about 60:30:10.

[0211] 191. The depot of any one of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) at a molar ratio of about 50:50.

[0212] 192. The depot of any one of the clauses herein, wherein the polymer is ester terminated.

[0213] 193. The depot of any of the clauses herein, wherein the polymer is a terpolymer comprising three polymers selected from the group consisting of 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.

[0214] 194. The depot of any of the clauses herein, wherein the polymer is a first polymer and the treatment area comprises a second polymer mixed with a therapeutic agent.

[0215] 195. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer comprises at least one of the following: polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(α-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS) , polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxy-methyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycine 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 (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphogen, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as α-tocopheryl acetate, d-α-tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide Ester-glycolide-caprolactone (DL-G-CL), dextran, vinyl pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylate, poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronic), 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, carboxymethyl cellulose or its salt, Poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone).

[0216] 196. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer is selected from the group consisting of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA).

[0217] 197. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of about 60:30:10.

[0218] 198. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a molar ratio of about 50:50.

[0219] 199. The depot of any one of the clauses herein, wherein the first polymer and / or the second polymer is ester terminated.

[0220] 200. The depot of any of the clauses herein, wherein the first polymer and / or the second polymer is a terpolymer comprising three polymers selected from the group consisting of 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.

[0221] 201. The depot of any of the clauses herein, wherein the ratio of release agent to polymer in the controlled region is at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 15:1.

[0222] 202. A repository as provided in any of the provisions of this Article, wherein:

[0223] The polymer is a first polymer and the treatment area further comprises a second polymer,

[0224] the depot has a mass of depot polymer equal to the mass of the first polymer plus the mass of the second polymer, and

[0225] The ratio of the mass of therapeutic agent in the reservoir to the mass of reservoir polymer is approximately 1:1.

[0226] 203. The depot of any one of the clauses herein, wherein the first polymer is the same as the second polymer.

[0227] 204. The depot of any of the clauses herein, wherein the first polymer is different from the second polymer.

[0228] 205. The depot of any of the clauses herein, wherein the ratio of the mass of therapeutic agent in the depot to the mass of depot polymer is at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 16:1.

[0229] 206. The depot of any one of the clauses herein, wherein the release agent is configured to dissolve to form a diffusion opening when the depot is placed in contact with phosphate buffered saline.

[0230] 207. The depot of any of the clauses herein, wherein the depot comprises a rolled membrane configured to be implanted in a patient.

[0231] 208. The depot of any of the clauses herein, wherein the depot comprises an elongated cylindrical structure configured to be implanted in a patient.

[0232] 209. The reservoir of any of the clauses herein, wherein the reservoir comprises a dumpling configuration.

[0233] 210. The reservoir of any of the clauses herein, wherein the reservoir comprises a plurality of discrete microreservoirs.

[0234] 211. The reservoir of any of the clauses herein, wherein the reservoir comprises one of a plurality of beads.

[0235] 212. The depot of any one of the clauses herein, wherein the depot comprises one of a plurality of microspheres.

[0236] 213. The reservoir of any of the clauses herein, wherein the reservoir comprises one of a plurality of microcylinders.

[0237] 214. The depot of any of the clauses herein, wherein the depot is configured for subcutaneous implantation.

[0238] 215. The depot of any of the clauses herein, wherein the depot is configured for intramuscular implantation.

[0239] 216. The depot of any of the clauses herein, wherein the depot is implanted at the treatment site.

[0240] 217. The depot of any of the clauses herein, wherein the treatment site comprises an area located at or near the abdomen, deltoid muscle, gluteal muscle, arm or thigh.

[0241] 218. The depot of any of the clauses herein, wherein the treatment site comprises a layer of fat between the patient's dermis and muscle.

[0242] 219. A system for administering a therapeutic agent to a treatment site, the system comprising:

[0243] a shaft having an inner lumen;

[0244] a pusher operatively connected to the lumen; and

[0245] a reservoir disposed within the lumen and configured to be moved away from the shaft by actuation of the pusher, the reservoir comprising:

[0246] a treatment region comprising a therapeutic agent, the treatment region being elongated along a first axis;

[0247] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0248] wherein the depot is configured to be implanted at a treatment site within the body and, when implanted, releases the therapeutic agent at the treatment site for a period of not less than 3 days.

[0249] 220. The system of any of the clauses herein, wherein the repository comprises the repository of any of the clauses herein.

[0250] 221. The system of any of the clauses herein, wherein the shaft comprises a needle and wherein the pusher comprises a plunger.

[0251] 222. The system of any of the clauses herein, wherein the needle size is no greater than 14, 16, 18, 20, or 22 gauge.

[0252] 223. A system for administering a therapeutic agent to a treatment site, the system comprising:

[0253] an expandable member configured to expand from a reduced volume configuration for drug delivery to an expanded volume configuration for deployment at a treatment site; and

[0254] A reservoir carried by the expandable member, the reservoir comprising:

[0255] a treatment region comprising a therapeutic agent, the treatment region being elongated along a first axis;

[0256] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0257] wherein the depot is configured to be implanted at a treatment site within the body and, when implanted, releases the therapeutic agent at the treatment site for a period of not less than 3 days.

[0258] 224. The system of any of the clauses herein, wherein the repository comprises the repository of any of the clauses herein.

[0259] 225. The system of any of the clauses herein, wherein the expandable component comprises a stent.

[0260] 226. The system of any of the clauses herein, wherein the expandable component comprises a spherical, hemispherical, ellipsoidal, or hemi-ellipsoidal structure.

[0261] 227. The system of any of the clauses herein, wherein the expandable member comprises a curved outer surface, and wherein the reservoir is disposed above the curved outer surface.

[0262] 228. The system of any of the clauses herein, wherein the reservoir substantially covers at least one surface of the expandable member.

[0263] 229. The system of any of the clauses herein, wherein the expandable component comprises a shape memory material.

[0264] 230. A system for administering a therapeutic agent to a treatment site, the system comprising:

[0265] drug delivery devices; and

[0266] A reservoir configured to be administered to a treatment site via a drug delivery device, the reservoir comprising:

[0267] a treatment area containing a therapeutic agent;

[0268] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0269] wherein the depot is configured to be implanted at a treatment site within the body and, when implanted, releases the therapeutic agent at the treatment site for a period of not less than 3 days.

[0270] 231. The system of any of the clauses herein, wherein the reservoir is disposed in a lubricious coating and wherein the lubricious coating comprises a hydrogel.

[0271] 232. The system of any of the clauses herein, wherein the exposed surface area of ​​the control zone is less than the exposed surface area of ​​the treatment zone.

[0272] 233. The system of any of the clauses herein, wherein the exposed surface area of ​​the control zone is greater than the exposed surface area of ​​the treatment zone.

[0273] 234. The system of any of the clauses herein, wherein the control region is a first control region, and wherein the reservoir comprises a second control region.

[0274] 235. The system of any of the clauses herein, 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.

[0275] 236. The system of any of the clauses herein, wherein the reservoir comprises a plurality of control regions and a plurality of treatment regions, and wherein each of the treatment regions is separated from an adjacent one of the treatment regions by one or more control regions.

[0276] 237. The system of any of the clauses herein, wherein each of the treatment regions and each of the control regions is a micro-thin layer.

[0277] 238. The system of any of the clauses herein, wherein the reservoir comprises about 2 to about 100 treatment areas, about 2 to about 50 treatment areas, or about 2 to about 10 treatment areas.

[0278] 239. The system of any of the clauses herein, wherein the treatment region is surrounded by a control region such that when the reservoir is positioned within the body, the control region is between the treatment region and physiological fluids within the body.

[0279] 240. The system of any of the clauses herein, wherein the control area comprises a first control layer and a second control layer.

[0280] 241. The system of any of the clauses herein, wherein the second control layer is adjacent to the treatment area and the first control layer encloses / surrounds the treatment area and the second control layer.

[0281] 242. The system of any of the clauses herein, wherein the first control layer and the second control layer together enclose a treatment area.

[0282] 243. The system of any of the clauses herein, wherein the first control layer is disposed on a first side of the treatment area and the second control layer is disposed on a second side of the treatment area opposite the first side.

[0283] 244. The system of any of the clauses herein, wherein the first control layer comprises a first plurality of sublayers and the second control layer comprises a second plurality of sublayers.

[0284] 245. The system of any of the clauses herein, wherein the first control layer comprises a first amount of a release agent and the second control layer comprises a second amount of a release agent different from the first amount.

[0285] 246. The system of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein the first control layer comprises a first concentration of the releasing agent and the second control layer comprises a second concentration of the releasing agent greater than the first concentration.

[0286] 247. The system of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein the first control layer comprises a first concentration of the releasing agent and the second control layer comprises a second concentration of the releasing agent that is less than the first concentration.

[0287] 248. The system of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein:

[0288] The first controlling layer comprises at most 5 wt % release agent, at most 10 wt % release agent, at most 15 wt % release agent, at most 20 wt % release agent, at most 25 wt % release agent, at most 30 wt % release agent, at most 35 wt % release agent, at most 40 wt % release agent, at most 45 wt % release agent, or 50 wt % release agent, and

[0289] The second controlling layer comprises at most 5 wt % releasing agent, at most 10 wt % releasing agent, at most 15 wt % releasing agent, at most 20 wt % releasing agent, at most 25 wt % releasing agent, at most 30 wt % releasing agent, at most 35 wt % releasing agent, at most 40 wt % releasing agent, at most 45 wt % releasing agent, or at most 50 wt % releasing agent.

[0290] 249. The system of any of the clauses herein, wherein the second control layer is positioned between the first control layer and the treatment area, and wherein the first control layer comprises a first amount of releasing agent and the second control layer comprises a second amount of releasing agent, the second amount being at least 2X, at least 3X, at least 4X, or at least 5X the first amount.

[0291] 250. The system of any of the clauses herein, wherein the thickness of the control area is less than or equal to 1 / 50, 1 / 75 or 1 / 100 of the thickness of the treatment area.

[0292] 251. The system of any of the clauses herein, wherein the reservoir is a flexible solid that is structurally capable of being handled by the clinician during the normal course of surgery without breaking into multiple pieces and / or losing its overall shape.

[0293] 252. The system of any of the clauses herein, wherein the reservoir is configured to be placed subcutaneously within a patient and to release the therapeutic agent in vivo for up to 7 days without breaking into multiple pieces.

[0294] 253. The system of any of the clauses herein, wherein the reservoir has a width and a thickness, and wherein the ratio of the width to the thickness is 21 or greater, 30 or greater, or 40 or greater.

[0295] 254. The system of any of the clauses herein, wherein the reservoir has a surface area and a volume, and wherein the ratio of the surface area to the volume is at least 1.

[0296] 255. The system of any of the clauses herein, wherein the diffusion opening comprises at least one or more holes and / or one or more channels.

[0297] 256. The system of any of the clauses herein, wherein two or more micro-thin layers of the bioabsorbable polymer are bonded by thermocompression to form the treatment area.

[0298] 257. The system of any of the clauses herein, wherein the control area and the treatment area are joined by thermal compression.

[0299] 258. A system as claimed in any of the clauses herein, wherein the control zone and the treatment zone are thermally coupled.

[0300] 259. The system of any of the clauses herein, wherein dissolution of the release agent following placement in vivo causes the control region and the treatment region to transition from a state of less porosity to a state of greater porosity to facilitate release of the therapeutic agent from the reservoir.

[0301] 260. The system of any of the clauses herein, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with the therapeutic agent.

[0302] 261. The system of any of the clauses herein, wherein the releasing agent is a first releasing agent and the polymer is a first polymer, and the treatment area comprises a second polymer mixed with the therapeutic agent and a second releasing agent.

[0303] 262. The system of any of the clauses herein, wherein the first releasing agent is the same as the second releasing agent.

[0304] 263. The system of any of the clauses herein, wherein the first releasing agent is different from the second releasing agent.

[0305] 264. The system of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is greater than the concentration of the second releasing agent in the treatment zone.

[0306] 265. The system of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is less than the concentration of the second releasing agent in the treatment zone.

[0307] 266. The system of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is the same as the concentration of the second releasing agent in the treatment zone.

[0308] 267. The system of any of the clauses herein, wherein the concentration of the first releasing agent in the control zone is different from the concentration of the second releasing agent in the treatment zone.

[0309] 268. The system of any of the clauses herein, wherein the treatment area comprises a plurality of microlayers.

[0310] 269. The system of any of the clauses herein, wherein the mass of the therapeutic agent comprises at least 50% of the mass of the reservoir.

[0311] 270. The system of any of the clauses herein, wherein the ratio of the mass of therapeutic agent in the reservoir to the mass of reservoir polymer is at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 16:1.

[0312] 271. The system of any of the clauses herein, wherein the treatment area comprises at least 50% by weight of the therapeutic agent, 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, or at least 90% by weight of the therapeutic agent.

[0313] 272. The system of any of the clauses herein, wherein the reservoir comprises at least 15% by weight of the therapeutic agent, at least 20% by weight of the therapeutic agent, at least 30% by weight of the therapeutic agent, at least 40% by weight of the therapeutic agent, at least 50% by weight of the therapeutic agent, at least 60% by weight of the therapeutic agent, at least 70% by weight of the therapeutic agent, at least 80% by weight of the therapeutic agent, or at least 90% by weight of the therapeutic agent.

[0314] 273. The system of any of the clauses herein, wherein the release agent is a nonionic surfactant.

[0315] 274. The system of any of the clauses herein, wherein the release agent has hydrophilic properties.

[0316] 275. The system of any of the clauses herein, wherein the release agent is polysorbate.

[0317] 276. The system of any of the clauses herein, wherein the release agent is Tween 20.

[0318] 277. The system of any of the clauses herein, wherein the release agent is Tween 80.

[0319] 278. The system of any of the clauses herein, wherein the release agent is non-polymeric.

[0320] 279. The system of any of the clauses herein, wherein the release agent is not a plasticizer.

[0321] 280. The system of any of the clauses herein, wherein the polymer is configured to degrade only after substantially all of the therapeutic agent is released from the depot.

[0322] 281. The system of any of the clauses herein, wherein the polymer is a copolymer.

[0323] 282. The system of any of the clauses herein, wherein the polymer is a terpolymer.

[0324] 283. The system of any of the clauses herein, wherein the polymer comprises at least one of: polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(α-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS), polyethylene oxide, poly(rich Propylene glycol malate, polyimino carbonate, 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-butoxy-methyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, ethyl glycine polyphosphazene, polycaprylic acid lactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphate, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as α-tocopheryl acetate, d-α-tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-caprolactone Lactide-caprolactone (DL-G-CL), dextran, vinyl pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylate, poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronic), 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, carboxymethyl cellulose or its salt, Poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, and poly(DL-lactide-co-glycolide-co-caprolactone).

[0325] 284. The system of any of the clauses herein, wherein the polymer is one of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA).

[0326] 285. The system of any of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide-co-caprolactone) in a molar ratio of about 60:30:10.

[0327] 286. The system of any of the clauses herein, wherein the polymer is poly(DL-lactide-co-glycolide) (PLGA) at a molar ratio of about 50:50.

[0328] 287. The system of any of the clauses herein, wherein the polymer is ester terminated.

[0329] 288. The system of any of the clauses herein, wherein the polymer is a terpolymer comprising three polymers selected from the group consisting of 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.

[0330] 289. The system of any of the clauses herein, wherein the polymer is a first polymer and the treatment area comprises a second polymer mixed with a therapeutic agent.

[0331] 290. The system of any of the clauses herein, wherein the first polymer and / or the second polymer comprises at least one of: polyglycolide (PGA), polycaprolactone (PCL), poly(DL-lactic acid) (PLA), poly(α-hydroxy acid), poly(lactide-co-glycolide) (PLGA or DLG), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), poly(phosphazene), polyphosphate), poly(amino acid), polydepsipeptide, poly(butylene succinate) (PBS), Polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxy-methyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly-1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, polyphosphazene, polyethyl glycine Phosphazene, 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 (e.g., hyaluronic acid, chitosan, and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, polyaspirin, polyphosphate, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, albumin, fibrin, vitamin E analogs such as α-tocopheryl acetate, d-α-tocopheryl succinate, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide Ester-glycolide-caprolactone (DL-G-CL), dextran, vinyl pyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylate, poly (N-isopropylacrylamide), PEO-PPO-PEO (Pluronic), 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, carboxymethyl cellulose or its salt, Poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), polyvinyl alcohol, propylene glycol, poly(DL-lactide-co-glycolide-co-caprolactone).

[0332] 291. The system of any of the clauses herein, wherein the first polymer and / or the second polymer is selected from the group consisting of poly(DL-lactide-co-glycolide-co-caprolactone) and poly(DL-lactide-co-glycolide) (PLGA).

[0333] 292. The system of any of the clauses herein, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide-co-caprolactone) and has a molar ratio of about 60:30:10.

[0334] 293. The system of any of the clauses herein, wherein the first polymer and / or the second polymer is poly(DL-lactide-co-glycolide) and has a molar ratio of about 50:50.

[0335] 294. The system of any of the clauses herein, wherein the first polymer and / or the second polymer is ester terminated.

[0336] 295. The system of any of the clauses herein, wherein the first polymer and / or the second polymer is a terpolymer comprising three polymers selected from the group consisting of 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.

[0337] 296. The system of any of the clauses herein, wherein the ratio of releasing agent to polymer in the control region is at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 15:1.

[0338] 297. A system according to any of the clauses herein, wherein:

[0339] The polymer is a first polymer and the treatment area further comprises a second polymer,

[0340] the depot has a mass of depot polymer equal to the mass of the first polymer plus the mass of the second polymer, and

[0341] The ratio of the mass of therapeutic agent in the reservoir to the mass of reservoir polymer is approximately 1:1.

[0342] 298. The system of any of the clauses herein, wherein the first polymer is the same as the second polymer.

[0343] 299. The system of any of the clauses herein, wherein the first polymer is different from the second polymer.

[0344] 300. The system of any of the clauses herein, wherein the ratio of the mass of therapeutic agent in the reservoir to the mass of reservoir polymer is at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, or at least 16:1.

[0345] 301. The system of any of the clauses herein, wherein the release agent is configured to dissolve to form a diffusion opening when the reservoir is placed in contact with phosphate buffered saline.

[0346] 302. A method for administering a therapeutic agent to a treatment site in the body:

[0347] A reservoir is positioned at a treatment site in the body having a physiological fluid, the reservoir comprising:

[0348] a treatment region comprising a therapeutic agent, the treatment region being elongated along a first axis;

[0349] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer; and

[0350] The release agent is allowed to dissolve at the treatment site to form a diffusion opening in a controlled area, thereby releasing the therapeutic agent from the depot over a period of time.

[0351] 303. The method of any of the clauses herein, wherein the repository comprises the repository of any of the clauses herein.

[0352] 304. The method of any of the clauses herein, wherein positioning the depot comprises subcutaneously inserting the depot at the treatment site via a needle.

[0353] 305. The method of any of the clauses herein, wherein the needle size is no greater than 14, 16, 18, 20, or 22 gauge.

[0354] 306. The method of any of the clauses herein, wherein positioning the reservoir comprises positioning the reservoir proximate a nerve bundle at the treatment site.

[0355] 307. The method of any of the clauses herein, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, wherein the first rate is greater than the second rate.

[0356] 308. The method of any of the clauses herein, further comprising dissolving the release agent in response to contact between the control area and physiological fluids at the treatment site.

[0357] 309. The method of any of the clauses herein, further comprising generating a diffusion opening in the control area by dissolution of the release agent in response to physiological fluids at the treatment site.

[0358] 310. The method of any of the clauses herein, wherein the releasing agent is a first releasing agent and the treatment zone comprises a second releasing agent, and wherein the method further comprises generating microchannels in the treatment zone and the control zone by dissolution of the first and / or second releasing agent.

[0359] 311. The method of any of the clauses herein, wherein at least some of the microchannels penetrate both the treatment region and the control region.

[0360] 312. The method of any of the clauses herein, further comprising increasing the porosity of the reservoir by dissolution of the release agent.

[0361] 313. The method of any of the clauses herein, wherein following implantation, the therapeutic agent is released in one or more substantially discrete doses.

[0362] 314. The method of any of the clauses herein, wherein the therapeutic agent is released at a substantially steady-state rate over a period of time.

[0363] 315. The method of any of the clauses herein, wherein the time period is not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 14 days, not less than 15 days, not less than 16 days, not less than 17 days, not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0364] 316. The method of any of the clauses herein, wherein the reservoir is a first reservoir and the method further comprises positioning a second reservoir at the treatment site.

[0365] 317. A depot for treating symptoms associated with type II diabetes, comprising:

[0366] a treatment area comprising a therapeutic agent comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0367] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0368] Therein, the depot is configured to be implanted in vivo and, when implanted, releases the GLP-1 receptor agonist for a period of time.

[0369] 318. The depot of any one of the clauses herein, wherein the GLP-1 receptor agonist comprises exenatide.

[0370] 319. The depot of any of the clauses herein, wherein the GLP-1 receptor agonist comprises liraglutide.

[0371] 320. The depot of any one of the clauses herein, wherein the GLP-1 receptor agonist comprises exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, a derivative thereof, or a combination thereof.

[0372] 321. The depot of any of the clauses herein, wherein the therapeutic agent is a first therapeutic agent and the treatment area further comprises a second therapeutic agent, wherein the second therapeutic agent comprises metformin.

[0373] 322. The depot of any of the clauses herein, wherein the first therapeutic agent is released before or after the second therapeutic agent.

[0374] 323. The depot of any of the clauses herein, wherein the first and second therapeutic agents are released substantially simultaneously.

[0375] 324. The depot of any one of the clauses herein, wherein the GLP-1 receptor agonist in the treatment area comprises at least 50% of the total weight of the depot.

[0376] 325. A repository under any of the provisions of this Article, where the period of time is not less than one month.

[0377] 326. A repository as provided for in any of the provisions herein, where the period of storage is not less than 2 months.

[0378] 327. A repository under any of the provisions of this Article, where the period of storage is not less than 3 months.

[0379] 328. A repository as provided for in any of the provisions herein, where the period of storage is not less than 4 months.

[0380] 329. A repository under any of the provisions of this Article, where the period of time is not less than 5 months.

[0381] 330. A repository under any of the provisions of this Article, where the period of time is not less than 6 months.

[0382] 331. The depot of any one of the clauses herein, wherein the depot is biodegradable and / or bioerodible.

[0383] 332. The depot of any one of the clauses herein, wherein about 40% to about 60% of the GLP-1 receptor agonist in the treatment area is released in the first half of the time period.

[0384] 333. The depot of any one of the clauses herein, wherein at least 90% of the GLP-1 receptor agonist in the treatment area is released within the time period.

[0385] 334. The depot of any one of the clauses herein, wherein the depot is configured to release from about 2 μg / day to about 10 mg / day of the GLP-1 receptor agonist.

[0386] 335. The depot of any of the clauses herein, wherein the depot is configured to release less than about 10 mg / day of the GLP-1 receptor agonist.

[0387] 336. The depot of any one of the clauses herein, wherein the depot is configured to release from about 0.2 nmol / day to about 6 μmol / day of the GLP-1 receptor agonist.

[0388] 337. The depot of any of the clauses herein, wherein the depot is configured to release less than about 6 μmol / day of the GLP-1 receptor agonist.

[0389] 338. The depot of any one of the clauses herein, wherein the depot is configured to release from about 10 μg / day to about 30 μg / day of the GLP-1 receptor agonist.

[0390] 339. The depot of any one of the clauses herein, wherein the depot is configured to release less than about 30 μg / day of the GLP-1 receptor agonist.

[0391] 340. The depot of any one of the clauses herein, wherein the depot is configured to release from about 2 nmol / day to about 10 nmol / day of the GLP-1 receptor agonist.

[0392] 341. The depot of any of the clauses herein, wherein the depot is configured to release less than about 10 nmol / day of the GLP-1 receptor agonist.

[0393] 342. The depot of any one of the clauses herein, wherein the depot is configured to release from about 0.5 mg / day to about 5 mg / day of the GLP-1 receptor agonist.

[0394] 343. The depot of any of the clauses herein, wherein the depot is configured to release less than about 10 mg / day of the GLP-1 receptor agonist.

[0395] 344. The depot of any one of the clauses herein, wherein the depot is configured to release from about 0.1 μmol / day to about 0.5 μmol / day of the GLP-1 receptor agonist.

[0396] 345. The depot of any of the clauses herein, wherein the depot is configured to release less than about 0.5 μmol / day of the GLP-1 receptor agonist.

[0397] 346. The depot of any of the clauses herein, wherein the depot is configured to release from about 0.25 mg / day to about 1 mg / day of the GLP-1 receptor agonist.

[0398] 347. The depot of any of the clauses herein, wherein the depot is configured to release less than about 1 mg / day of the GLP-1 receptor agonist.

[0399] 348. The depot of any one of the clauses herein, wherein the depot is configured to release from about 0.05 μmol / day to about 0.2 μmol / day of the GLP-1 receptor agonist.

[0400] 349. The depot of any one of the clauses herein, wherein the depot is configured to release less than about 0.2 μmol / day of the GLP-1 receptor agonist.

[0401] 350. The depot of any of the clauses herein, wherein no more than 400 μg / day, no more than 300 μg / day, no more than 200 μg / day, no more than 100 μg / day, no more than 75 μg / day, no more than 50 μg / day, no more than 40 μg / day, no more than 30 μg / day, no more than 20 μg / day, no more than 10 μg / day, or no more than 5 μg / day of a GLP-1 receptor agonist is released on any day of the time period.

[0402] 351. The depot of any of the clauses herein, wherein less than about 500 nmol / day, less than about 300 nmol / day, less than about 250 nmol / day, less than about 200 nmol / day, less than about 175 nmol / day, less than about 150 nmol / day, less than about 125 nmol / day, less than about 100 nmol / day, less than about 90 nmol / day, less than about 80 nmol / day, less than about 70 nmol / day, less than about 60 nmol / day, less than about 50 nmol / day, less than about 45 nmol / day, less than about 40 nmol / day, less than about 35 nmol / day, less than about 30 nmol / day, less than about 25 nmol / day, less than about 20 nmol / day, less than about 15 nmol / day, or less than about 10 nmol / day of the GLP-1 receptor agonist is released over any day of the time period.

[0403] 352. The storage facility of any of the clauses herein, wherein the period of time is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 14 days, not less than 15 days, not less than 16 days, not less than 17 days, not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0404] 353. The depot of any one of the clauses herein, wherein the GLP-1 receptor agonist is released at a substantially steady-state rate over the entire period of time.

[0405] 354. The depot of any one of the clauses herein, wherein the GLP-1 receptor agonist is released continuously over the entire time period.

[0406] 355. The depot of any one of the clauses herein, wherein release of the GLP-1 receptor agonist reduces appetite, stimulates insulin secretion and / or slows gastric emptying.

[0407] 356. The storage reservoir of any one of the clauses herein, wherein the storage reservoir further comprises a heat stabilizer.

[0408] 357. The depot of any of the clauses herein, wherein the thermal stabilizer comprises at least one of a sugar, an antioxidant, or a buffer.

[0409] 358. The depot of any of the clauses herein, wherein the sugar comprises at least one of trehalose, raffinose, or mannitol.

[0410] 359. The depot of any of the clauses herein, wherein the antioxidant comprises at least one of methionine, ascorbic acid, sodium thiosulfate, catalase, ethylenediaminetetraacetic acid (EDTA) platinum, citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0411] 360. The depot of any of the clauses herein, wherein the buffer comprises at least one of citrate, histidine, succinate, or tris.

[0412] 361. The depot of any of the clauses herein, wherein the GLP-1 receptor agonist comprises at least one of a sugar, an antioxidant, or a buffer.

[0413] 362. The depot of any of the clauses herein, wherein at least one of a sugar, an antioxidant, or a buffer partially encapsulates the GLP-1 receptor agonist.

[0414] 363. The depot of any of the clauses herein, wherein the depot further comprises a compound configured to inhibit denaturation of the therapeutic agent in vivo.

[0415] 364. A method for treating a patient suffering from symptoms associated with diabetes mellitus, comprising:

[0416] positioning a depot at a treatment site in the body having physiological fluids, the depot comprising (a) a controlled region comprising a bioabsorbable polymer and a release agent admixed with the polymer and (b) a treatment region comprising at least 50% by weight of a therapeutic agent comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0417] The GLP-1 receptor agonist is released from the depot to the treatment site over a period of time.

[0418] 365. The method of the preceding clause, wherein the repository comprises a repository of any of the clauses herein.

[0419] 366. The method of any of the clauses herein, wherein the GLP-1 receptor agonist comprises exenatide.

[0420] 367. The method of any of the clauses herein, wherein the GLP-1 receptor agonist comprises liraglutide.

[0421] 368. The method of any of the clauses herein, wherein the GLP-1 receptor agonist comprises exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, a derivative thereof, or a combination thereof.

[0422] 369. The method of any one of the clauses herein, wherein the GLP-1 receptor agonist in the treatment area comprises at least 50% of the total weight of the depot.

[0423] 370. The method of any of the clauses herein, wherein the reservoir is biodegradable and / or bioerodible.

[0424] 371. The method of any one of the clauses herein, wherein about 40% to about 60% of the GLP-1 receptor agonist in the treatment area is released in the first half of the time period.

[0425] 372. The method of any one of the clauses herein, wherein at least 90% of the GLP-1 receptor agonist in the treatment area is released within the time period.

[0426] 373. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 2 μg / day to about 10 mg / day.

[0427] 374. The method of any of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 10 mg / day.

[0428] 375. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 0.2 nmol / day to about 6 μmol / day.

[0429] 376. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 6 μmol / day.

[0430] 377. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 10 μg / day to about 30 μg / day.

[0431] 378. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 30 μg / day.

[0432] 379. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 2 nmol / day to about 10 nmol / day of GLP-1 receptor agonist.

[0433] 380. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 10 nmol / day.

[0434] 381. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 0.5 mg / day to about 10 mg / day.

[0435] 382. The method of any of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 10 mg / day.

[0436] 383. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 0.1 μmol / day to about 0.5 μmol / day.

[0437] 384. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 0.5 μmol / day.

[0438] 385. The method of any of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 0.25 mg / day to about 1 mg / day.

[0439] 386. The method of any of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 1 mg / day.

[0440] 387. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of about 0.05 μmol / day to about 0.2 μmol / day.

[0441] 388. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of less than about 0.2 μmol / day.

[0442] 389. The method of any of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a rate of no more than about 400 μg / day, no more than 300 μg / day, no more than 200 μg / day, no more than 100 μg / day, no more than 75 μg / day, no more than 50 μg / day, no more than 40 μg / day, no more than 30 μg / day, no more than 20 μg / day, no more than 10 μg / day, or no more than 5 μg / day on any day of the time period.

[0443] 390. The method of any of the clauses herein, wherein the time period is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 14 days, not less than 15 days, not less than 16 days, not less than 17 days, not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0444] 391. The method of any one of the clauses herein, wherein releasing the GLP-1 receptor agonist comprises releasing the GLP-1 receptor agonist at a substantially steady-state rate over the entire time period.

[0445] 392. The method of any of the clauses herein, wherein the treatment site is the patient's fat layer between the dermis and muscle.

[0446] 393. The method of any of the clauses herein, wherein the reservoir further comprises a thermal stabilizer.

[0447] 394. The method of any of the clauses herein, wherein the thermal stabilizer comprises at least one of a sugar, an antioxidant, or a buffer.

[0448] 395. The method of any of the clauses herein, wherein the sugar comprises at least one of trehalose, raffinose, or mannitol.

[0449] 396. The method of any of the clauses herein, wherein the antioxidant comprises at least one of methionine, ascorbic acid, sodium thiosulfate, catalase, ethylenediaminetetraacetic acid (EDTA) platinum, citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0450] 397. The method of any of the clauses herein, wherein the buffer comprises at least one of citrate, histidine, succinate, or tris.

[0451] 398. The method of any of the clauses herein, wherein the GLP-1 receptor agonist comprises at least one of a sugar, an antioxidant, or a buffer.

[0452] 399. The method of any of the clauses herein, wherein at least one of a sugar, an antioxidant, or a buffer partially encapsulates the GLP-1 receptor agonist.

[0453] 400. The method of any of the clauses herein, wherein the treatment site comprises an area located in or adjacent to the patient's abdominal region, gluteal region, femur, or arm.

[0454] 401. The method of any of the clauses herein, wherein the treatment site is near or within the peritoneal cavity.

[0455] 402. The method of any of the clauses herein, wherein positioning the reservoir comprises subcutaneously implanting the reservoir in or near the abdominal region, gluteal region, femur, or arm of the patient.

[0456] 403. The method of any of the clauses herein, further comprising dissolving the release agent at a first rate and degrading the polymer at a second rate, wherein the first rate is greater than the second rate.

[0457] 404. The method of any of the clauses herein, further comprising dissolving the release agent in response to contact between the control area and physiological fluids at the treatment site.

[0458] 405. The method of any of the clauses herein, further comprising generating a diffusion opening in the control area by dissolution of the release agent in response to physiological fluids at the treatment site.

[0459] 406. The method of any of the clauses herein, wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent, and wherein the method further comprises generating microchannels in the treatment area and the control area by dissolution of the first and / or second releasing agent.

[0460] 407. The method of any of the clauses herein, wherein at least some of the microchannels penetrate both the treatment region and the control region.

[0461] 408. The method of any of the clauses herein, wherein the treatment area comprises a plurality of microlayers, and wherein at least some of the microchannels extend through consecutive microlayers.

[0462] 409. The method of any of the clauses herein, wherein the control area comprises a first plurality of microlayers and the treatment area comprises a second plurality of microlayers, and wherein at least some of the microchannels extend through both the first and second pluralities of microlayers.

[0463] 410. The method of any of the clauses herein, further comprising increasing the porosity of the reservoir by dissolution of the release agent.

[0464] 411. The method of any of the clauses herein, wherein following implantation, the therapeutic agent is released in one or more substantially discrete doses.

[0465] 412. The method of any of the clauses herein, wherein the reservoir is a first reservoir and the method further comprises positioning a second reservoir at the treatment site.

[0466] 413. The method of any of the clauses herein, wherein the release agent is configured to dissolve to form a diffusion opening when the depot is placed in contact with phosphate buffered saline.

[0467] 414. A system for administering a therapeutic agent to a patient, the system comprising:

[0468] a drug delivery device having a distal region configured to be positioned beneath the skin of a patient; and

[0469] a reservoir positioned within the drug delivery device and configured to discharge from the distal region to the patient, the reservoir comprising:

[0470] a treatment area comprising a therapeutic agent comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0471] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[0472] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0473] 415. A system for administering a therapeutic agent to a patient, the system comprising:

[0474] a needle having an inner lumen;

[0475] a syringe operatively connected to a needle; and

[0476] a reservoir disposed within the lumen and configured to be expelled from the needle upon actuation of the syringe, the reservoir comprising:

[0477] a treatment area comprising a therapeutic agent comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0478] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[0479] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0480] 416. The system of the preceding clause, wherein the repository comprises a repository of any of the clauses herein.

[0481] 417. The system of any of the clauses herein, wherein the needle size is no greater than 14, 16, 18, 20, or 22 gauge.

[0482] 418. A system for administering a therapeutic agent to a patient, the system comprising:

[0483] an expandable member configured to expand from a reduced volume configuration for drug delivery to an expanded volume configuration for deployment; and

[0484] A reservoir carried by the expandable member, the reservoir comprising:

[0485] a treatment area comprising a therapeutic agent comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0486] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0487] Therein, the depot is configured to be implanted in vivo and, when implanted, releases the GLP-1 receptor agonist for a period of time.

[0488] 419. The system of the preceding clause, wherein the repository comprises a repository of any of the clauses herein.

[0489] 420. The system of any of the clauses herein, wherein the GLP-1 receptor agonist comprises exenatide.

[0490] 421. The system of any of the clauses herein, wherein the GLP-1 receptor agonist comprises liraglutide.

[0491] 422. The system of any of the clauses herein, wherein the GLP-1 receptor agonist comprises exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, derivatives thereof, or combinations thereof.

[0492] 423. The system of any of the clauses herein, wherein the GLP-1 receptor agonist in the treatment area comprises at least 50% of the total weight of the depot.

[0493] 424. The system of any of the clauses herein, wherein about 40% to about 60% of the GLP-1 receptor agonist in the treatment area is released in the first half of the time period.

[0494] 425. The system of any of the clauses herein, wherein at least 90% of the GLP-1 receptor agonist in the treatment area is released within the time period.

[0495] 426. The system of any of the clauses herein, wherein the depot is configured to release about 2 μg / day to about 10 mg / day of the GLP-1 receptor agonist.

[0496] 427. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 10 mg / day of the GLP-1 receptor agonist.

[0497] 428. The system of any of the clauses herein, wherein the reservoir is configured to release from about 0.2 nmol / day to about 6 μmol / day of the GLP-1 receptor agonist.

[0498] 429. The system of any of the clauses herein, wherein the depot is configured to release less than about 6 μmol / day of the GLP-1 receptor agonist.

[0499] 430. The system of any of the clauses herein, wherein the depot is configured to release about 10 μg / day to about 30 μg / day of the GLP-1 receptor agonist.

[0500] 431. The system of any of the clauses herein, wherein the depot is configured to release less than about 30 μg / day of the GLP-1 receptor agonist.

[0501] 432. The system of any of the clauses herein, wherein the reservoir is configured to release about 2 nmol / day to about 10 nmol / day of the GLP-1 receptor agonist.

[0502] 433. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 10 nmol / day of the GLP-1 receptor agonist.

[0503] 434. The system of any of the clauses herein, wherein the reservoir is configured to release about 0.5 mg / day to about 10 mg / day of the GLP-1 receptor agonist.

[0504] 435. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 10 mg / day of the GLP-1 receptor agonist.

[0505] 436. The system of any of the clauses herein, wherein the reservoir is configured to release about 0.1 μmol / day to about 0.5 μmol / day of the GLP-1 receptor agonist.

[0506] 437. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 0.5 μmol / day of the GLP-1 receptor agonist.

[0507] 438. The system of any of the clauses herein, wherein the reservoir is configured to release from about 0.25 mg / day to about 1 mg / day of the GLP-1 receptor agonist.

[0508] 439. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 1 mg / day of the GLP-1 receptor agonist.

[0509] 440. The system of any of the clauses herein, wherein the reservoir is configured to release about 0.05 μmol / day to about 0.2 μmol / day of the GLP-1 receptor agonist.

[0510] 441. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 0.2 μmol / day of the GLP-1 receptor agonist.

[0511] 442. The system of any of the clauses herein, wherein no more than 400 μg / day, no more than 300 μg / day, no more than 200 μg / day, no more than 100 μg / day, no more than 75 μg / day, no more than 50 μg / day, no more than 40 μg / day, no more than 30 μg / day, no more than 20 μg / day, no more than 10 μg / day, or no more than 5 μg / day of a GLP-1 receptor agonist is released during any one day of the time period.

[0512] 443. A system as defined in any of the clauses herein, wherein the time period is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 14 days, not less than 15 days, not less than 16 days, not less than 17 days, not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0513] 444. The system of any of the clauses herein, wherein the GLP-1 receptor agonist is released at a substantially steady-state rate over the entire time period.

[0514] 445. The system of any of the clauses herein, wherein the GLP-1 receptor agonist is released on a continuous basis throughout the period of time.

[0515] 446. The system of any of the clauses herein, wherein the reservoir is biodegradable and / or bioerodible.

[0516] 447. The system of any of the clauses herein, wherein the reservoir further comprises a thermal stabilizer.

[0517] 448. The system of any of the clauses herein, wherein the thermal stabilizer comprises at least one of a sugar, an antioxidant, or a buffer.

[0518] 449. The system of any of the clauses herein, wherein the sugar comprises at least one of trehalose, raffinose, or mannitol.

[0519] 450. The system of any of the clauses herein, wherein the antioxidant comprises at least one of methionine, ascorbic acid, sodium thiosulfate, catalase, ethylenediaminetetraacetic acid (EDTA) platinum, citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

[0520] 451. The system of any of the clauses herein, wherein the buffer comprises at least one of citrate, histidine, succinate, or tris.

[0521] 452. The system of any of the clauses herein, wherein the GLP-1 receptor agonist comprises at least one of a sugar, an antioxidant, or a buffer.

[0522] 453. The system of any of the clauses herein, wherein at least one of a sugar, an antioxidant, or a buffer partially encapsulates the GLP-1 receptor agonist.

[0523] 454. A biodegradable depot for the sustained controlled release of a therapeutic agent, the depot comprising:

[0524] a treatment area comprising a therapeutic agent comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0525] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0526] The reservoir is configured such that after the reservoir is immersed in a buffer solution for a period of time, the flexural strength of the reservoir decreases by no more than 75%.

[0527] 455. The reservoir of any of the clauses herein, wherein the reservoir is configured such that after the reservoir is immersed in a buffer solution, the flexural strength of the reservoir decreases by no more than 70%, no more than 65%, no more than 60%, no more than 55%, no more than 50%, no more than 45%, no more than 40%, or no more than 30%.

[0528] 456. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0529] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0530] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0531] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for a period of not less than 3 days, and

[0532] wherein the control region does not include the GLP-1 receptor agonist at least prior to implantation of the depot at the treatment site.

[0533] 457. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0534] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0535] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0536] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for not less than 3 days,

[0537] wherein the control region comprises a GLP-1 receptor agonist separate from the GLP-1 receptor agonist in the treatment region.

[0538] 458. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0539] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0540] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0541] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for a period of not less than 3 days, and

[0542] wherein the releasing agent is a first releasing agent and the treatment area comprises a second releasing agent mixed with a GLP-1 receptor agonist.

[0543] 459. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0544] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0545] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0546] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for a period of not less than 3 days, and

[0547] wherein the releasing agent is a first releasing agent and the polymer is a first polymer, and the treatment area comprises a second polymer and a second releasing agent mixed with the GLP-1 receptor agonist.

[0548] 460. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0549] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0550] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0551] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for a period of not less than 3 days, and

[0552] The thickness of the control area is less than or equal to 1 / 50, 1 / 75 or 1 / 100 of the thickness of the treatment area.

[0553] 461. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0554] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0555] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0556] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for a period of not less than 3 days, and

[0557] Wherein the first control layer comprises a first amount of a release agent and the second control layer comprises a second amount of a release agent different from the first amount.

[0558] 462. A biodegradable depot for treating symptoms associated with type II diabetes, comprising:

[0559] A treatment area comprising a glucagon-like peptide-1 (GLP-1) receptor agonist; and

[0560] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[0561] wherein the depot is configured to be implanted at a treatment site in the body and, when implanted, releases the GLP-1 receptor agonist at the treatment site for not less than 3 days,

[0562] wherein the reservoir has a total surface area comprising the exposed surface area of ​​the coverage area plus the exposed surface area of ​​the treatment area, and

[0563] wherein, when the depot is initially positioned at the treatment site in vivo, the ratio of the exposed surface area of ​​the treatment area to the exposed surface area of ​​the covering area is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%.

[0564] 463. A reservoir for treating symptoms associated with a mental illness, comprising:

[0565] a treatment area containing a therapeutic agent;

[0566] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0567] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0568] 464. A repository as hereinbefore described, wherein the repository comprises a repository as hereinbefore described.

[0569] 465. The depot of any of the clauses herein, wherein the therapeutic agent comprises an antidepressant comprising at least one of the following: a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), an atypical antidepressant, or a derivative thereof.

[0570] 466. The depot of any one of the clauses herein, wherein the SSRI comprises at least one of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, fluvoxamine, paroxetine, or sertraline.

[0571] 467. The depot of any of the clauses herein, wherein the SNRI comprises at least one of desvenlafaxine, duloxetine, venlafaxine, milnacipran, or levorotatory milnacipran.

[0572] 468. The depot of any of the clauses herein, wherein the TCA comprises at least one of amitriptyline, desipramine, doxepin, imipramine, nortriptyline, amoxapine, clomipramine, maprotiline, trimipramine, or protriptyline.

[0573] 469. The depot of any of the clauses herein, wherein the MAOI comprises at least one of phenelzine, selegiline, or tranylcypromine.

[0574] 470. The depot of any one of the clauses herein, wherein the atypical antidepressant comprises at least one of bupropion, mirtazapine, nefazodone, trazodone, vilazodone, or vortioxetine.

[0575] 471. The depot of any of the clauses herein, wherein the therapeutic agent comprises an antipsychotic drug, the antipsychotic drug comprising at least one of the following: aripiprazole, aripiprazole lauroxil, flupentixol, palmipoxetine, haloperidol, asenapine, epiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, perphenazine, zuclopenthixol, or a derivative thereof.

[0576] 472. The depot of any of the clauses herein, wherein the therapeutic agent is formulated to treat dementia and comprises at least one of donepezil, galantamine, rivastigmine, or memantine.

[0577] 473. The depot of any of the clauses herein, wherein the therapeutic agent in the treatment area comprises at least 50% of the total weight of the depot.

[0578] 474. The depot of any of the clauses herein, wherein about 40% to about 60% of the therapeutic agent in the treatment area is released in the first half of the time period.

[0579] 475. The depot of any of the clauses herein, wherein at least 90% of the therapeutic agent in the treatment area is released within the time period.

[0580] 476. The depot of any of the clauses herein, wherein the depot is configured to release from about 0.1 mg / day to about 100 mg / day of the therapeutic agent over the time period.

[0581] 477. The depot of any of the clauses herein, wherein the depot is configured to release less than about 100 mg / day of the therapeutic agent over the time period.

[0582] 478. The depot of any of the clauses herein, wherein the depot is configured to release from about 1 mg / day to about 30 mg / day of the therapeutic agent over the time period.

[0583] 479. The depot of any of the clauses herein, wherein the depot is configured to release less than about 30 mg / day of the therapeutic agent over the time period.

[0584] 480. The depot of any of the clauses herein, wherein the depot is configured to release from about 0.5 mg / day to about 10 mg / day of the therapeutic agent over the time period.

[0585] 481. The depot of any of the clauses herein, wherein the depot is configured to release less than about 10 mg / day of the therapeutic agent over the time period.

[0586] 482. The depot of any of the clauses herein, wherein no more than 400 mg / day, no more than 300 mg / day, no more than 200 mg / day, no more than 100 mg / day, no more than 75 mg / day, no more than 50 mg / day, no more than 40 mg / day, no more than 30 mg / day, no more than 20 mg / day, no more than 10 mg / day, or no more than 5 mg / day of the therapeutic agent is released in any one day of the time period.

[0587] 483. The depot of any of the clauses herein, wherein release of the therapeutic agent selectively blocks the reuptake of serotonin and / or norepinephrine in the brain.

[0588] 484. The depot of any one of the clauses herein, wherein release of the therapeutic agent selectively blocks muscarinic M1, histamine H1 and / or alpha-adrenergic receptors.

[0589] 485. The depot of any of the clauses herein, wherein release of the therapeutic agent selectively blocks dopamine receptors, 5-HT receptors and / or dopaminergic pathways.

[0590] 486. A method for treating a patient suffering from symptoms associated with a mental illness, comprising:

[0591] Positioning a depot at a treatment site in the body having physiological fluids, the depot comprising (a) a controlled region comprising a bioabsorbable polymer and a release agent admixed with the polymer and (b) a treatment region comprising at least 50% by weight of a therapeutic agent; and

[0592] The therapeutic agent is released from the depot over a period of time.

[0593] 487. The method of the preceding clause, wherein the repository comprises a repository of any of the clauses herein.

[0594] 488. The method of any of the clauses herein, wherein the therapeutic agent comprises an antidepressant comprising at least one of a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), an atypical antidepressant, or a derivative thereof.

[0595] 489. The method of any one of the clauses herein, wherein the SSRI comprises at least one of: citalopram, escitalopram, fluoxetine, fluvoxamine, fluvoxamine, paroxetine, or sertraline.

[0596] 490. The method of any one of the clauses herein, wherein the SNRI comprises at least one of desvenlafaxine, duloxetine, venlafaxine, milnacipran, or levorotatory milnacipran.

[0597] 491. The method of any one of the clauses herein, wherein the TCA comprises at least one of amitriptyline, desipramine, doxepin, imipramine, nortriptyline, amoxapine, clomipramine, maprotiline, trimipramine, or protriptyline.

[0598] 492. The method of any of the clauses herein, wherein the MAOI comprises at least one of phenelzine, selegiline, or tranylcypromine.

[0599] 493. The method of any one of the clauses herein, wherein the atypical antidepressant comprises at least one of bupropion, mirtazapine, nefazodone, trazodone, vilazodone, or vortioxetine.

[0600] 494. The method of any of the clauses herein, wherein the therapeutic agent comprises an antipsychotic drug comprising at least one of aripiprazole, aripiprazole lauroxil, flupentixol, palmipoxetine, haloperidol, asenapine, epiriprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, perphenazine, zuclopenthixol, or a derivative thereof.

[0601] 495. The method of any of the clauses herein, wherein the therapeutic agent is configured to treat dementia and comprises at least one of donepezil, galantamine, rivastigmine, or memantine.

[0602] 496. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent such that about 40% to about 60% of the therapeutic agent in the treatment area is released in the first half of the time period.

[0603] 497. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent such that at least 90% of the therapeutic agent in the treatment area is released within the time period.

[0604] 498. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent at a rate of about 0.1 mg / day to about 100 mg / day over the time period.

[0605] 499. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent at a rate of less than about 100 mg / day over the time period.

[0606] 500. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent at a rate of about 1 mg / day to about 30 mg / day over the time period.

[0607] 501. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent at a rate of less than about 30 mg / day over the time period.

[0608] 502. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent at a rate of about 0.5 mg / day to about 10 mg / day of the therapeutic agent over the time period.

[0609] 503. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent at a rate of less than about 10 mg / day over the time period.

[0610] 504. The depot of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent so that no more than 400 mg / day, no more than 300 mg / day, no more than 200 mg / day, no more than 100 mg / day, no more than 75 mg / day, no more than 50 mg / day, no more than 40 mg / day, no more than 30 mg / day, no more than 20 mg / day, no more than 10 mg / day, or no more than 5 mg / day of the therapeutic agent is released on any day of the time period.

[0611] 505. The method of any of the clauses herein, wherein the time period is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 14 days, not less than 15 days, not less than 16 days, not less than 17 days, not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0612] 506. A system for administering a therapeutic agent to a patient for treating a mental illness, the system comprising:

[0613] a drug delivery device having a distal region configured to be positioned beneath the skin of a patient; and

[0614] a reservoir positioned within the drug delivery device and configured to discharge from the distal region to the patient, the reservoir comprising:

[0615] a treatment area comprising a therapeutic agent; and

[0616] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0617] Wherein the depot is configured to be implanted beneath the skin of a patient and, when implanted, releases the therapeutic agent for a period of no less than 7 days.

[0618] 507. A system for administering a therapeutic agent configured to treat a mental illness, the system comprising:

[0619] a needle having an inner lumen;

[0620] a syringe operatively connected to a needle; and

[0621] a reservoir disposed within the lumen and configured to be expelled from the needle upon actuation of the syringe, the reservoir comprising:

[0622] a treatment area comprising a therapeutic agent; and

[0623] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0624] Therein the depot is configured to be implanted and, when implanted, releases the therapeutic agent for a period of time.

[0625] 508. A system for administering a therapeutic agent to treat a mental illness, the system comprising:

[0626] an expandable member configured to expand from a reduced volume configuration for drug delivery to an expanded volume configuration for deployment; and

[0627] A reservoir carried by the expandable member, the reservoir comprising:

[0628] a treatment area comprising a therapeutic agent; and

[0629] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0630] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0631] 509. The system of any of the clauses herein, wherein the repository comprises the repository of any of the clauses herein.

[0632] 510. The system of any of the clauses herein, wherein the therapeutic agent comprises an antidepressant comprising at least one of the following: a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), an atypical antidepressant, or a derivative thereof.

[0633] 511. The system of any of the clauses herein, wherein the SSRI comprises at least one of the following: citalopram, escitalopram, fluoxetine, fluvoxamine, fluvoxamine, paroxetine, or sertraline.

[0634] 512. The system of any of the clauses herein, wherein the SNRI comprises at least one of desvenlafaxine, duloxetine, venlafaxine, milnacipran, or levorotatory milnacipran.

[0635] 513. The system of any of the clauses herein, wherein the TCA comprises at least one of amitriptyline, desipramine, doxepin, imipramine, nortriptyline, amoxapine, clomipramine, maprotiline, trimipramine, or protriptyline.

[0636] 514. The system of any of the clauses herein, wherein the MAOI comprises at least one of phenelzine, selegiline, or tranylcypromine.

[0637] 515. The system of any of the clauses herein, wherein the atypical antidepressant comprises at least one of bupropion, mirtazapine, nefazodone, trazodone, vilazodone, or vortioxetine.

[0638] 516. The system of any of the clauses herein, wherein the therapeutic agent comprises an antipsychotic drug comprising at least one of aripiprazole, aripiprazole lauroxil, flupentixol, palmitoylpiperazine, haloperidol, asenapine, epiriprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, perphenazine, zuclopenthixol, or derivatives thereof.

[0639] 517. The system of any of the clauses herein, wherein the therapeutic agent is configured to treat dementia and comprises at least one of donepezil, galantamine, rivastigmine, or memantine.

[0640] 518. The system of any of the clauses herein, wherein the reservoir is configured to release from about 0.1 mg / day to about 100 mg / day of the therapeutic agent over the time period.

[0641] 519. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 100 mg / day of the therapeutic agent over the time period.

[0642] 520. The system of any of the clauses herein, wherein the reservoir is configured to release from about 1 mg / day to about 30 mg / day of the therapeutic agent over the time period.

[0643] 521. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 30 mg / day of the therapeutic agent over the time period.

[0644] 522. The system of any of the clauses herein, wherein the reservoir is configured to release about 0.5 mg / day to about 10 mg / day of the therapeutic agent to the treatment site over the time period.

[0645] 523. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 10 mg / day of the therapeutic agent to the treatment site over the time period.

[0646] 524. The system of any of the clauses herein, wherein no more than 400 mg / day, no more than 300 mg / day, no more than 200 mg / day, no more than 100 mg / day, no more than 75 mg / day, no more than 50 mg / day, no more than 40 mg / day, no more than 30 mg / day, no more than 20 mg / day, no more than 10 mg / day, or no more than 5 mg / day of the therapeutic agent is released during any day of the time period.

[0647] 525. The system of any of the clauses herein, wherein release of the therapeutic agent to the treatment site selectively blocks reuptake of serotonin and / or norepinephrine in the brain.

[0648] 526. The system of any of the clauses herein, wherein release of the therapeutic agent to the treatment site selectively blocks muscarinic M1, histamine H1 and / or alpha-adrenergic receptors.

[0649] 527. The system of any of the clauses herein, wherein release of the therapeutic agent to the treatment site selectively blocks dopamine receptors, 5-HT receptors and / or dopaminergic pathways.

[0650] 528. A depot for treating symptoms or risk factors associated with cardiovascular disease, comprising:

[0651] a treatment area containing a therapeutic agent;

[0652] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0653] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0654] 529. The depot of any of the clauses herein, wherein the therapeutic agent comprises an antihypertensive drug comprising at least one of the following: a thiazide diuretic, angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), a calcium channel blocker, or a derivative thereof.

[0655] 530. The depot of any of the clauses herein, wherein the thiazide diuretic comprises at least one of chlorthalidone, hydrochlorothiazide, or indapamide.

[0656] 531. The depot of any one of the clauses herein, wherein the ACE inhibitor comprises at least one of the following: benazepril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril or trandolapril.

[0657] 532. The depot of any of the clauses herein, wherein the ARB comprises at least one of the following: azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan.

[0658] 533. The depot of any of the clauses herein, wherein the calcium channel blocker comprises at least one of a dihydropyridine blocker or a non-dihydropyridine blocker.

[0659] 534. The depot of any one of the clauses herein, wherein the dihydropyridine blocker comprises amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, bepridil, cis-diltiazem or nisoldipine.

[0660] 535. The depot of any of the clauses herein, wherein the non-dihydropyridine blocking agent comprises diltiazem or verapamil.

[0661] 536. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of a statin, a cholesterol absorption inhibitor, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, niacin, fibric acid, or an omega-3-fatty acid, or a derivative thereof.

[0662] 537. The depot of any one of the clauses herein, wherein the statin comprises at least one of the following: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0663] 538. The depot of any of the clauses herein, wherein the cholesterol absorption inhibitor comprises azeltine.

[0664] 539. The depot of any of the clauses herein, wherein PCSK9 comprises at least one of evolocumab or alirocumab.

[0665] 540. The depot of any one of the clauses herein, wherein the fibric acid comprises at least one of gemfibrozil, bezafibrate, fenofibrate, or fenofibric acid.

[0666] 541. The depot of any of the clauses herein, wherein the therapeutic agent is configured to treat hypercholesterolemia by lowering LDL levels, increasing HDL levels, and / or lowering blood triglyceride levels.

[0667] 542. The depot of any of the clauses herein, wherein the depot is configured to release from about 1 mg / day to about 600 mg / day of the therapeutic agent over the time period.

[0668] 543. The depot of any of the clauses herein, wherein the depot is configured to release less than about 600 mg / day of the therapeutic agent over the time period.

[0669] 544. The depot of any of the clauses herein, wherein the depot is configured to release from about 2 mg / day to about 40 mg / day of the therapeutic agent over the time period.

[0670] 545. The depot of any of the clauses herein, wherein the depot is configured to release less than about 40 mg / day of the therapeutic agent over the time period.

[0671] 546. The depot of any of the clauses herein, wherein the depot is configured to release from about 20 mg / day to about 80 mg / day of the therapeutic agent over the time period.

[0672] 547. The depot of any of the clauses herein, wherein the depot is configured to release less than about 80 mg / day of the therapeutic agent over the time period.

[0673] 548. The depot of any of the clauses herein, wherein the depot is configured to release from about 2 mg / day to about 60 mg / day of the therapeutic agent over the time period.

[0674] 549. The depot of any of the clauses herein, wherein the depot is configured to release less than about 60 mg / day of the therapeutic agent over the time period.

[0675] 550. The depot of any of the clauses herein, wherein the depot is configured to release from about 100 mg / day to about 480 mg / day of the therapeutic agent over the time period.

[0676] 551. The depot of any of the clauses herein, wherein the depot is configured to release less than about 480 mg / day of the therapeutic agent over the time period.

[0677] 552. The depot of any of the clauses herein, wherein the depot is configured to release from about 200 mg / day to about 600 mg / day of the therapeutic agent over the time period.

[0678] 553. The depot of any of the clauses herein, wherein the depot is configured to release from about 5 mg / day to about 80 mg / day of the therapeutic agent over the time period.

[0679] 554. The depot of any of the clauses herein, wherein the depot is configured to release less than about 80 mg / day of the therapeutic agent over the time period.

[0680] 555. The depot of any of the clauses herein, wherein the depot is configured to release from about 70 mg / day to about 150 mg / day of the therapeutic agent over the time period.

[0681] 556. The depot of any of the clauses herein, wherein the depot is configured to release less than about 150 mg / day of the therapeutic agent over the time period.

[0682] 557. The depot of any of the clauses herein, wherein the depot is configured to release from about 1 g / day to about 4 g / day of the therapeutic agent over the time period.

[0683] 558. The depot of any of the clauses herein, wherein the depot is configured to release less than about 4 g / day of the therapeutic agent over the time period.

[0684] 559. The depot of any of the clauses herein, wherein no more than about 4 g / day, no more than about 3 g / day, no more than about 2 g / day, no more than about 1 g / day, no more than about 900 mg / day, no more than about 800 mg / day, no more than about 700 mg / day, no more than about 600 mg / day, no more than about 500 mg / day, no more than about 400 mg / day, no more than about 300 mg / day, no more than about 200 mg / day, no more than about 100 mg / day, no more than about 75 mg / day, no more than about 50 mg / day, no more than about 40 mg / day, no more than about 30 mg / day, no more than about 20 mg / day, no more than about 10 mg / day, or no more than about 5 mg / day of the therapeutic agent is released over any day of the time period.

[0685] 560. The depot of any of the clauses herein, wherein release of the therapeutic agent reduces the ability of the kidney to reabsorb salt and water from the urine.

[0686] 561. The depot of any of the clauses herein, wherein release of the therapeutic agent reduces the activity of angiotensin converting enzyme.

[0687] 562. The depot of any one of the clauses herein, wherein the release of the therapeutic agent inhibits the effect of angiotensin II.

[0688] 563. A method for treating a patient suffering from symptoms or risk factors associated with cardiovascular disease, comprising:

[0689] Positioning a depot at a treatment site in the body having physiological fluids, the depot comprising (a) a controlled region comprising a bioabsorbable polymer and a release agent admixed with the polymer and (b) a treatment region comprising at least 50% by weight of a therapeutic agent; and

[0690] The therapeutic agent is released from the depot over a period of time.

[0691] 564. The method of any of the clauses herein, wherein the repository comprises the repository of any of the clauses herein.

[0692] 565. The method of any of the clauses herein, wherein the therapeutic agent comprises an antihypertensive agent comprising at least one of the following: a thiazide diuretic, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a calcium channel blocker, or derivatives thereof.

[0693] 566. The method of any of the clauses herein, wherein the thiazide diuretic comprises at least one of chlorthalidone, hydrochlorothiazide, or indapamide.

[0694] 567. The method of any one of the clauses herein, wherein the ACE inhibitor comprises at least one of: benazepril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

[0695] 568. The method of any one of the clauses herein, wherein the ARB comprises at least one of: azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan.

[0696] 569. The method of any of the clauses herein, wherein the calcium channel blocker comprises at least one of a dihydropyridine blocker or a non-dihydropyridine blocker.

[0697] 570. The method of any one of the clauses herein, wherein the dihydropyridine blocker comprises amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, bepridil, cis-diltiazem, or nisoldipine.

[0698] 571. The method of any of the clauses herein, wherein the non-dihydropyridine blocker comprises diltiazem or verapamil.

[0699] 572. The method of any of the clauses herein, wherein the therapeutic agent comprises at least one of a statin, a cholesterol absorption inhibitor, a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, niacin, fibric acid, or an omega-3-fatty acid, or a derivative thereof.

[0700] 573. The method of any one of the clauses herein, wherein the statin comprises at least one of: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0701] 574. The depot of any of the clauses herein, wherein the cholesterol absorption inhibitor comprises azeltine.

[0702] 575. The method of any of the clauses herein, wherein PCSK9 comprises at least one of evolocumab or alirocumab.

[0703] 576. The method of any one of the clauses herein, wherein the fibric acid comprises at least one of gemfibrozil, bezafibrate, fenofibrate, or fenofibric acid.

[0704] 577. The method of any of the clauses herein, wherein the therapeutic agent is configured to treat hypercholesterolemia by lowering LDL levels, increasing HDL levels, and / or lowering blood triglyceride levels.

[0705] 578. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 1 mg / day to about 600 mg / day over the time period.

[0706] 579. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at a rate of less than about 600 mg / day over the time period.

[0707] 580. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 2 mg / day to about 40 mg / day over the time period.

[0708] 581. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at a rate of less than about 40 mg / day over the time period.

[0709] 582. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 20 mg / day to about 80 mg / day over the time period.

[0710] 583. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at a rate of less than about 80 mg / day over the time period.

[0711] 584. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 2 mg / day to about 60 mg / day over the time period.

[0712] 585. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at a rate of less than about 60 mg / day over the time period.

[0713] 586. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 100 mg / day to about 480 mg / day over the time period.

[0714] 587. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at a rate of less than about 480 mg / day over the time period.

[0715] 588. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 200 mg / day to about 600 mg / day over the time period.

[0716] 589. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 5 mg / day to about 80 mg / day over the time period.

[0717] 590. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing about 80 mg / day of the therapeutic agent to the treatment site over the time period.

[0718] 591. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 70 mg / day to about 150 mg / day over the time period.

[0719] 592. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing about 150 mg / day of the therapeutic agent to the treatment site over the time period.

[0720] 593. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing the therapeutic agent to the treatment site at about 1 g / day to about 4 g / day over the time period.

[0721] 594. The method of any of the clauses herein, wherein releasing the therapeutic agent comprises releasing about 4 g / day of the therapeutic agent to the treatment site over the time period.

[0722] 595. The method of any of the clauses herein, wherein releasing the therapeutic comprises releasing no more than about 4 g / day, no more than about 3 g / day, no more than about 2 g / day, no more than about 1 g / day, no more than about 900 mg / day, no more than about 800 mg / day, no more than about 700 mg / day, no more than about 600 mg / day, no more than about 500 mg / day, no more than about 400 mg / day, no more than about 300 mg / day, no more than about 200 mg / day, no more than about 100 mg / day, no more than about 75 mg / day, no more than about 50 mg / day, no more than about 40 mg / day, no more than about 30 mg / day, no more than about 20 mg / day, no more than about 10 mg / day, or no more than about 5 mg / day of the therapeutic agent during any one day of the time period.

[0723] 596. A system for administering a therapeutic agent to a patient to treat symptoms or risk factors associated with cardiovascular disease, the system comprising:

[0724] a drug delivery device having a distal region configured to be positioned beneath the skin of a patient; and

[0725] a reservoir positioned within the drug delivery device and configured to discharge from the distal region to the patient, the reservoir comprising:

[0726] a treatment area comprising a therapeutic agent; and

[0727] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0728] Therein the depot is configured to be implanted and, when implanted, releases the therapeutic agent at the treatment site for a period of time.

[0729] 597. A system for administering a therapeutic agent configured to treat a symptom or risk factor associated with cardiovascular disease, the system comprising:

[0730] a needle having an inner lumen;

[0731] a syringe operatively connected to a needle; and

[0732] a reservoir disposed within the lumen and configured to be expelled from the needle upon actuation of the syringe, the reservoir comprising:

[0733] a treatment area comprising a therapeutic agent; and

[0734] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0735] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0736] 598. A system for administering a therapeutic agent to treat a symptom or risk factor associated with cardiovascular disease, the system comprising:

[0737] an expandable member configured to expand from a reduced volume configuration for drug delivery to an expanded volume configuration for deployment; and

[0738] A reservoir carried by the expandable member, the reservoir comprising:

[0739] a treatment area comprising a therapeutic agent; and

[0740] a control region at least partially surrounding the treatment region and elongated along a first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0741] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0742] 599. The system of any of the clauses herein, wherein the therapeutic agent comprises an antihypertensive drug comprising at least one of the following: a thiazide diuretic, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a calcium channel blocker, or derivatives thereof.

[0743] 600. The system of any of the clauses herein, wherein the thiazide diuretic comprises at least one of chlorthalidone, hydrochlorothiazide, or indapamide.

[0744] 601. The system of any one of the clauses herein, wherein the ACE inhibitor comprises at least one of: benazepril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril.

[0745] 602. The system of any of the clauses herein, wherein the ARB comprises at least one of the following: azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, or valsartan.

[0746] 603. The system of any of the clauses herein, wherein the calcium channel blocker comprises at least one of a dihydropyridine blocker or a non-dihydropyridine blocker.

[0747] 604. The system of any of the clauses herein, wherein the dihydropyridine blocker comprises amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, bepridil, cis-diltiazem, or nisoldipine.

[0748] 605. The system of any of the clauses herein, wherein the non-dihydropyridine blocker comprises diltiazem or verapamil.

[0749] 606. The system of any of the clauses herein wherein the therapeutic agent comprises at least one of a statin, a cholesterol absorption inhibitor, a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, niacin, fibric acid, or an omega-3-fatty acid, or a derivative thereof.

[0750] 607. The system of any of the clauses herein, wherein the statin comprises at least one of: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, or pitavastatin.

[0751] 608. The system of any of the clauses herein, wherein the cholesterol absorption inhibitor comprises azeltine.

[0752] 609. The system of any of the clauses herein, wherein PCSK9 comprises at least one of evolocumab or alirocumab.

[0753] 610. The system of any one of the clauses herein, wherein the fibric acid comprises at least one of gemfibrozil, bezafibrate, fenofibrate, or fenofibric acid.

[0754] 611. The system of any of the clauses herein, wherein the therapeutic agent is configured to treat hypercholesterolemia by lowering LDL levels, increasing HDL levels, and / or lowering blood triglyceride levels.

[0755] 612. The system of any of the clauses herein, wherein the reservoir is configured to release from about 1 mg / day to about 600 mg / day of the therapeutic agent over the time period.

[0756] 613. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 600 mg / day of the therapeutic agent over the time period.

[0757] 614. The system of any of the clauses herein, wherein the reservoir is configured to release about 2 mg / day to about 40 mg / day of the therapeutic agent over the time period.

[0758] 615. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 40 mg / day of the therapeutic agent over the time period.

[0759] 616. The system of any of the clauses herein, wherein the reservoir is configured to release about 20 mg / day to about 80 mg / day of the therapeutic agent over the time period.

[0760] 617. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 80 mg / day of the therapeutic agent over the time period.

[0761] 618. The system of any of the clauses herein, wherein the reservoir is configured to release about 2 mg / day to about 60 mg / day of the therapeutic agent over the time period.

[0762] 619. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 60 mg / day of the therapeutic agent over the time period.

[0763] 620. The system of any of the clauses herein, wherein the reservoir is configured to release about 100 mg / day to about 480 mg / day of the therapeutic agent over the time period.

[0764] 621. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 480 mg / day of the therapeutic agent over the time period.

[0765] 622. The system of any of the clauses herein, wherein the reservoir is configured to release about 200 mg / day to about 600 mg / day of the therapeutic agent over the time period.

[0766] 623. The system of any of the clauses herein, wherein the reservoir is configured to release about 5 mg / day to about 80 mg / day of the therapeutic agent over the time period.

[0767] 624. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 80 mg / day of the therapeutic agent over the time period.

[0768] 625. The system of any of the clauses herein, wherein the reservoir is configured to release about 70 mg / day to about 150 mg / day of the therapeutic agent over the time period.

[0769] 626. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 150 mg / day of the therapeutic agent over the time period.

[0770] 627. The system of any of the clauses herein, wherein the reservoir is configured to release from about 1 g / day to about 4 g / day of the therapeutic agent over the time period.

[0771] 628. The system of any of the clauses herein, wherein the reservoir is configured to release less than about 4 g / day of the therapeutic agent over the time period.

[0772] 629. The system of any of the clauses herein, wherein no more than about 4 g / day, no more than about 3 g / day, no more than about 2 g / day, no more than about 1 g / day, no more than about 900 mg / day, no more than about 800 mg / day, no more than about 700 mg / day, no more than about 600 mg / day, no more than about 500 mg / day, no more than about 400 mg / day, no more than about 300 mg / day, no more than about 200 mg / day, no more than about 100 mg / day, no more than about 75 mg / day, no more than about 50 mg / day, no more than about 40 mg / day, no more than about 30 mg / day, no more than about 20 mg / day, no more than about 10 mg / day, or no more than about 5 mg / day of the therapeutic agent is released during any day of the time period.

[0773] 630. The system of any of the clauses herein, wherein release of the therapeutic agent reduces the ability of the kidney to reabsorb salt and water from the urine.

[0774] 631. The system of any of the clauses herein, wherein release of the therapeutic agent reduces the activity of angiotensin converting enzyme.

[0775] 632. The system of any of the clauses herein, wherein the release of the therapeutic agent inhibits the effects of angiotensin II.

[0776] 633. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0777] a treatment area comprising a therapeutic agent; and

[0778] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0779] wherein the depot is configured to be implanted in vivo and, when implanted, releases the therapeutic agent for a period of not less than 3 days, and

[0780] wherein the control region does not include the therapeutic agent at least prior to implantation of the depot.

[0781] 634. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0782] a treatment area comprising a first therapeutic agent; and

[0783] a control region comprising a bioabsorbable polymer, a release agent admixed with the polymer, and a second therapeutic agent, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0784] wherein the depot is configured to be implanted in vivo and, when implanted, releases the first and second therapeutic agents for a period of no less than 30 days.

[0785] 635. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0786] a treatment area comprising a therapeutic agent and a first release agent mixed with the therapeutic agent; and

[0787] a controlled region comprising a biodegradable polymer and a second release agent mixed with the polymer,

[0788] wherein the first and second release agents are configured to dissolve when the depot is placed in the body to form a diffusion opening in the control area,

[0789] The depot is configured to be implanted in vivo and, when implanted, releases the therapeutic agent for a period of not less than 3 days.

[0790] 636. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0791] a treatment area comprising a therapeutic agent; and

[0792] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0793] wherein the depot is configured to be implanted in vivo and, when implanted, releases the therapeutic agent for a period of not less than 3 days, and

[0794] wherein the releasing agent is a first releasing agent and the polymer is a first polymer, and the treatment area comprises a second polymer mixed with the therapeutic agent and a second releasing agent.

[0795] 637. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0796] a treatment area comprising a therapeutic agent; and

[0797] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0798] wherein the depot is configured to be implanted in vivo and, when implanted, releases the therapeutic agent for a period of not less than 3 days, and

[0799] The thickness of the control area is less than or equal to 1 / 50 of the thickness of the treatment area.

[0800] 638. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0801] a treatment area comprising a therapeutic agent; and

[0802] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0803] wherein the depot is configured to be implanted in vivo and, when implanted, releases the therapeutic agent for a period of not less than 3 days, and

[0804] Wherein the first control layer comprises a first amount of a release agent and the second control layer comprises a second amount of a release agent different from the first amount.

[0805] 639. A biodegradable depot for treating symptoms associated with cardiovascular disease, comprising:

[0806] a treatment area comprising a therapeutic agent; and

[0807] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[0808] wherein the depot is configured to be implanted in vivo and, when implanted, releases the therapeutic agent at the treatment site for a period of not less than 3 days,

[0809] wherein the reservoir has a total surface area comprising the exposed surface area of ​​the coverage area plus the exposed surface area of ​​the treatment area, and

[0810] wherein, when the depot is initially positioned in vivo, the ratio of the exposed surface area of ​​the treatment region to the exposed surface area of ​​the covering region is from about 5% to about 20%, or from about 5% to about 15%, or from about 5% to about 10%.

[0811] 640. A depot for treating or preventing HIV-related symptoms, comprising:

[0812] a treatment area comprising a therapeutic agent; and

[0813] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0814] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0815] 641. The depot of any of the clauses herein, wherein the therapeutic agent comprises an antiretroviral.

[0816] 642. The depot of any one of the clauses herein, wherein the antiretroviral comprises at least one of dolutegravir, cabotegravir or riplivirine.

[0817] 643. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of: an entry inhibitor, a pharmacokinetic enhancer, an integrase inhibitor, a nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a protease inhibitor.

[0818] 644. The depot of any of the clauses herein, wherein the entry inhibitor comprises at least one of enfuvirtide or maraviroc.

[0819] 645. The depot of any of the clauses herein, wherein the pharmacokinetic enhancer comprises at least one of ritonavir or cobicistat.

[0820] 646. The depot of any of the clauses herein, wherein the integrase inhibitor comprises at least one of raltegravir, dolutegravir, or elvitegravir.

[0821] 647. The depot of any one of the clauses herein, wherein the nucleoside or nucleotide reverse transcriptase inhibitor comprises at least one of: tricitabine, lamivudine, zidovudine, didanosine, tenofovir, stavudine, or abacavir.

[0822] 648. The depot of any one of the clauses herein, wherein the non-nucleoside reverse transcriptase inhibitor comprises at least one of: rilpivirine, etravirine, delavirdine, doravirine, efavirenz, or nevirapine.

[0823] 649. The depot of any one of the clauses herein, wherein the protease inhibitor comprises at least one of the following: tipranavir, indinavir, saquinavir, lopinavir and norvir, fosamprenavir, darunavir, atazanavir or nelfinavir.

[0824] 650. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of sustiva, viread, emtricitabine, bictegravir, tenofovir alagenamide, rilpivirine, pifeltro, epivir, vitekta, tybost, tivicay, zidovudine, or ziagen.

[0825] 651. The depot of any of the clauses herein, wherein the treatment area contains at least 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1.0 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, or 1.5 g of therapeutic agent.

[0826] 652. The depot of any of the clauses herein, wherein the depot is configured to release the therapeutic agent at a rate of no more than 10 mg / day, no more than 1 mg / day, no more than 500 μg / day, no more than 100 μg / day, no more than 90 μg / day, no more than 80 μg / day, no more than 70 μg / day, no more than 60 μg / day, or no more than 50 μg / day over a period of time.

[0827] 653. The depot of any of the clauses herein, wherein the treatment area is configured to provide from about 100 μg / day to 50 mg / day, 100 μg / day to 40 mg / day, 100 μg / day to 30 mg / day, 100 μg / day to 20 mg / day, 100 μg / day to 10 mg / day, 100 μg / day to 5 mg / day, 100 μg / day to 1000 μg / day, 100 μg / day to 10000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 μg / day, 100 μg / day to 100000 mg ... The therapeutic agent is released at a rate of 100 μg / day to 100 μg / day, 100 μg / day to 800 μg / day, 100 μg / day to 700 μg / day, 100 μg / day to 600 μg / day, 100 μg / day to 600 μg / day, 200 μg / day to 600 μg / day, 300 μg / day to 600 μg / day, 400 μg / day to 600 μg / day, or 400 μg / day to 500 μg / day.

[0828] 654. A depot for treating or preventing symptoms associated with malaria, comprising:

[0829] a treatment area comprising a therapeutic agent; and

[0830] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region,

[0831] Therein, the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

[0832] 655. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of an antimalarial drug, an artemisinin-based combination therapy, or a vaccine.

[0833] 656. The depot of any of the clauses herein, wherein the antimalarial drug comprises at least one of quinine, chloroquine, amodiaquine, mefloquine, primaquine, sulfadoxine-pyrimethamine, intravenous artesunate, atovaquone-proguanil, azithromycin, ferroquine, artesunate, foxmidomycin, clindamycin, ozonide, piperaquine, spiroindolinone, artesunate-amodiaquine, artesunate, coartem, piperaquine phosphate, pyramax, imidazopiperazine, timidazole, tafenoquine, or brulamaquine.

[0834] 657. The depot of any of the clauses herein, wherein the vaccine comprises RTS,S.

[0835] 658. The depot of any of the clauses herein, wherein the therapeutic agent comprises chemoprevention.

[0836] 659. The depot of any of the clauses herein, wherein the therapeutic agent is formulated to treat or prevent infection by Plasmodium falciparum.

[0837] 660. The depot of any of the clauses herein, wherein the therapeutic agent is configured to target at least one infected red blood cell (iRBC).

[0838] 661. The depot of any of the clauses herein, wherein the treatment area contains at least 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1.0 g, 1.5 g, 2.0 g, 3.0 g, 4.0 g, 5.0 g, 6.0 g, 7.0 g, 8.0 g, 9.0 g or 10 g of therapeutic agent.

[0839] 662. The depot of any of the clauses herein, wherein the depot is configured to release the therapeutic agent at a rate of no greater than 400 mg / day, no greater than 300 mg / day, no greater than 200 mg / day, no greater than 150 mg / day, no greater than 100 mg / day, or no greater than 50 mg / day over a period of time.

[0840] 663. The depot of any of the clauses herein, wherein the treatment area is configured to release the therapeutic agent at a rate from about 10 mg / day to 400 mg / day, 10 mg / day to 350 mg / day, 10 mg / day to 300 mg / day, 10 mg / day to 250 mg / day, 50 mg / day to 250 mg / day, 100 mg / day to 250 mg / day, 150 mg / day to 250 mg / day, 200 mg / day to 250 mg / day over a period of time.

[0841] 664. A storage facility as described in any of the preceding clauses, wherein the period of time is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 1 week, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 8 weeks, not less than 2 months, not less than 3 months, not less than 4 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, or not less than 12 months.

[0842] 665. The depot of any of the clauses herein, wherein the treatment area further comprises an analgesic.

[0843] 666. The depot of any of the clauses herein, wherein the analgesic comprises at least one of bupivacaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine, trimecaine, carticaine, articaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, or chloroprocaine.

[0844] 667. The depot of any of the clauses herein, wherein the treatment area further comprises a chemotherapeutic agent.

[0845] 668. The depot of any of the clauses herein, wherein the chemotherapeutic agent comprises at least one of: an antibody, an alkylating agent, an angiogenesis inhibitor, an antimetabolite, a DNA cleaving agent, a DNA cross-linking agent, a DNA intercalator, a DNA minor groove binder, an enediyne, a heat shock protein 90 inhibitor, a histone deacetylase inhibitor, an immunomodulator, a microtubule stabilizer, a nucleoside (purine or pyrimidine) analog, a nuclear export inhibitor, a proteasome inhibitor, a topoisomerase (I or II) inhibitor, a tyrosine kinase inhibitor, and a serine / threonine kinase inhibitor. Specific therapeutic agents include, but are not limited to, adalimumab, ansamycin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribin, cytarabine, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin, and cytochrome P3. )A, epothilone, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapachone, lenalidomide, irinotecan, maytansine, nitrogen mustard, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, vorinostat (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, vindesine, or tamoxifen.

[0846] 669. A depot as claimed in any of the clauses herein, wherein the treatment area further comprises an anti-inflammatory drug.

[0847] 670. The depot of any of the clauses herein, wherein the anti-inflammatory drug comprises at least one of prednisolone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, 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, or a COX-2 inhibitor.

[0848] 671. The depot of any of the clauses herein, wherein the treatment area further comprises an antibiotic and / or antimicrobial agent.

[0849] 672. The depot of any one of the clauses herein, wherein the antibiotic and / or antimicrobial agent comprises at least one of the following: amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole, azole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampicin, triclosan, chlorhexidine, penicillin(s), aminoglycoside(s), quinolone, fluoroquinolone, vancomycin, gentamicin, cephalosporin(s), carbapenem, imipenem, ertapenem, antimicrobial peptide, cephalicidin-melittin, magainin, dermaseptin, cathelicidin, α-defensin or α-endogenous antimicrobial peptide (α-protegrin).

[0850] 673. The depot of any of the clauses herein, wherein the treatment area further comprises an antifungal agent.

[0851] 674. The depot of any of the clauses herein, wherein the antifungal agent comprises at least one of ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifonaazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogen, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, or amphotericin.

[0852] 675. The depot of any of the clauses herein, wherein the treatment area further comprises a steroid.

[0853] 676. The depot of any of the clauses herein, wherein the steroid comprises at least one of: prednisolone, betamethasone, cortisone, dexamethasone, hydrocortisone, or methylprednisolone.

[0854] 677. The depot of any of the clauses herein, wherein the treatment area further comprises an immunosuppressant.

[0855] 678. The depot of any of the clauses herein, wherein the immunosuppressant comprises at least one of cyclosporine, pimecrolimus, sirolimus, or tacrolimus.

[0856] 679. The depot of any of the clauses herein, wherein the treatment area comprises a first portion and a second portion, wherein the first portion comprises the therapeutic agent and the second portion comprises at least one immunotherapeutic agent, analgesic, anti-inflammatory, antibiotic, antifungal, steroid or immunosuppressant.

[0857] 680. The reservoir of any of the clauses herein, wherein the first portion is closer to the outer surface of the reservoir than the second portion.

[0858] 681. The reservoir of any of the clauses herein, wherein the first portion is further from the outer surface of the reservoir than the second portion.

[0859] 682. The depot of any of the clauses herein, wherein the treatment area is configured to continuously release the immunotherapeutic, analgesic, anti-inflammatory, antibiotic, antifungal, steroid and / or immunosuppressant over a period of time.

[0860] 683. The depot of any of the clauses herein, wherein the depot is configured to release the therapeutic agent at a first rate and the immunotherapeutic agent, analgesic agent, anti-inflammatory agent, antibiotic, antifungal agent, steroid and / or immunosuppressant agent at a second rate.

[0861] 684. The depot of any of the clauses herein, wherein the first rate is the same as the second rate.

[0862] 685. The depot of any of the clauses herein, wherein the first rate is different from the second rate.

[0863] 686. The depot of any of the clauses herein, wherein the first rate is greater than the second rate.

[0864] 687. The storage reservoir of any of the clauses herein, wherein the first rate is less than the second rate.

[0865] 688. A system for treating or preventing HIV by controlled sustained release of a therapeutic agent, the system comprising:

[0866] a repository for any of the terms herein; and

[0867] A drug delivery device configured to deliver a drug depot beneath the skin of a patient.

[0868] 689. A system for treating or preventing HIV-related symptoms, comprising:

[0869] a plurality of repositories, each repository comprising a repository of any one of the clauses herein; and

[0870] A drug delivery device configured to position the reservoir beneath the skin of a patient.

[0871] 690. A system for treating or preventing malaria by controlled sustained release of a therapeutic agent, the system comprising:

[0872] a repository for any of the terms herein; and

[0873] A drug delivery device configured to deliver a drug depot beneath the skin of a patient.

[0874] 691. A system for treating or preventing symptoms associated with malaria, comprising:

[0875] a plurality of repositories, each repository comprising a repository of any one of the clauses herein; and

[0876] A drug delivery device configured to position the reservoir beneath the skin of a patient.

[0877] 692. The system of any of the clauses herein, wherein the drug delivery device is a syringe.

[0878] 693. The system of any of the clauses herein, further comprising securing the reservoir to or near the abdomen, deltoid muscle, gluteal muscle, arm, and thigh / femur.

[0879] 694. The system of any of the preceding clauses, wherein the time period is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 1 week, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 8 weeks, not less than 2 months, not less than 3 months, not less than 4 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, not less than 12 months, not less than 18 months, not less than 24 months, not less than 30 months, or not less than 36 months.

[0880] 695. A method for treating or preventing symptoms associated with HIV by controlled sustained release of a therapeutic agent, the method comprising:

[0881] A repository of any of the clauses herein is provided.

[0882] 696. A method for treating or preventing symptoms associated with HIV by controlled sustained release of a therapeutic agent, the method comprising:

[0883] positioning a depot of any of the clauses herein near a treatment site of a patient's eye; and

[0884] The therapeutic agent is administered to the patient over a period of time.

[0885] 697. A method for treating or preventing symptoms associated with malaria by controlled sustained release of a therapeutic agent, the method comprising:

[0886] A repository of any of the clauses herein is provided.

[0887] 698. A method for treating or preventing symptoms associated with malaria by controlled sustained release of a therapeutic agent, the method comprising:

[0888] positioning a depot of any of the clauses herein near a treatment site of a patient's eye; and

[0889] The therapeutic agent is administered to the patient over a period of time.

[0890] 699. The method of any of the clauses herein, further comprising securing the reservoir to or near the abdomen, deltoid muscle, gluteal muscle, arm, and thigh / femur.

[0891] 700. The method of any of the preceding clauses, wherein the time period is not less than 1 day, not less than 2 days, not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 1 week, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 8 weeks, not less than 2 months, not less than 3 months, not less than 4 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, not less than 12 months, not less than 18 months, not less than 24 months, not less than 30 months, or not less than 36 months.

[0892] 701. An implantable medical device (IMD) cap comprising a reservoir configured to provide controlled sustained release of a therapeutic agent, the reservoir comprising:

[0893] a treatment area containing a therapeutic agent;

[0894] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0895] Wherein the cover is configured to at least partially cover the IMD and, when implanted, release the therapeutic agent for a period of no less than 3 days.

[0896] 702. A reservoir configured to be disposed along an exterior of an implantable medical device (IMD) component, the reservoir configured to provide controlled sustained release of a therapeutic agent, the reservoir comprising:

[0897] a treatment area containing a therapeutic agent;

[0898] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0899] Therein, the IMD is configured to be implanted in a patient's body and, while implanted, releases a therapeutic agent for a period of time.

[0900] 703. A reservoir configured to cover at least a portion of an implantable medical device (IMD) and provide controlled sustained release of a therapeutic agent, the reservoir comprising:

[0901] a treatment area comprising a therapeutic agent; and

[0902] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[0903] Therein, the reservoir is configured to cover the IMD and, when implanted, release the therapeutic agent for a period of time.

[0904] 704. A depot configured to provide controlled, sustained release of a therapeutic agent to treat or prevent infection, the depot comprising:

[0905] a treatment area containing a therapeutic agent;

[0906] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0907] The cap is configured to at least partially cover the IMD and to release the therapeutic agent for a period of time when implanted.

[0908] 705. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of an antibiotic, an anti-biofilm agent, an antiseptic, or an antifungal agent.

[0909] 706. The depot of any of the clauses herein, wherein the therapeutic agent comprises one or more of the following: amoxicillin, amoxicillin / clavulanate, ampicillin, cephalexin, cefixime, ceftriaxone, ciprofloxacin, clindamycin, cloxacillin, cotrimaxazole, metronidazole, clindamycin, azithromycin, erythromycin, and clarithromycin, levofloxacin, ofloxacin, sulfamethoxazole, azole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampicin, triclosan, chlorhexidine, penicillin(s), aminoglycosides, quinolones, fluoroquinolones, beta-lactams, rifampicin, vancomycin, daptomycin, fostomycin, gentamicin, cephalosporin(s), carbapenems, imipenem, ertapenem, antimicrobial peptides, cephalicidal peptide-melittin, magainin, dermaseptin, cathelicidin, alpha-defensin, alpha-endogenous antimicrobial peptide, lactoferrin, ethylenediaminetetraacetic acid (EDTA), xylitol, gallium, dispersin B, farsenol, RNA-III inhibitory peptide (RIP), and furanone C30, lysostaphin, DN aseI, V8 protease, apotransferrin, ethylene glycol tetraacetate (EGTA), 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG), cis-2-decenoic acid (C2DA), diarylacrylonitrile, aryl ethyl ketone, vinyl sulfone, N-acetyl-L-cysteine ​​(NAC), ethanol, chlorhexidine, ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifonaazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogen, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, or amphotericin B.

[0910] 707. The repository of any of the clauses herein, wherein the IMD comprises one or more of: an endovascular IMD, a cardiovascular IMD, a neurosurgical IMD, an orthopedic IMD, a urological IMD, a gynecological IMD, an otolaryngological IMD, an ophthalmic IMD, or a dental IMD.

[0911] 708. The repository of any of the clauses herein, wherein the IMD comprises one or more of the following: a peripheral intravenous catheter, a peripheral arterial catheter, a midline catheter, a central venous catheter, a non-tunneled catheter, a tunneled catheter, a pulmonary artery catheter, a fully implanted port, a vascular access device, a mechanical heart valve, an implantable defibrillator, a vascular graft, a ventricular assist device, a coronary artery stent, an implantable patient monitor, a ventricular shunt, an Omayor reservoir, an intracranial pressure device, an implantable neurostimulator, a joint prosthesis, a reconstructive orthopedic implant, a spinal implant, a fracture fixation device, an inflatable penile implant, an IMD, a cochlear implant, a middle ear implant, an intraocular lens, a glaucoma tube, a dental prosthesis, and a dental appliance.

[0912] 709. The reservoir of any of the clauses herein, wherein the reservoir substantially encapsulates the IMD.

[0913] 710. The reservoir of any of the clauses herein, wherein the reservoir comprises an aperture configured to receive an IMD therethrough.

[0914] 711. The reservoir of any of the clauses herein, wherein the reservoir circumferentially surrounds at least a portion of the IMD.

[0915] 712. The reservoir of any of the clauses herein, wherein the reservoir forms a sleeve, cannula, or band configured to at least partially surround the IMD.

[0916] 713. The depot of any of the clauses herein, wherein the depot is elastic and configured to stretch around at least a portion of the IMD.

[0917] 714. The depot of any of the clauses herein, wherein the therapeutic agent in the treatment area comprises at least 50% of the total weight of the depot.

[0918] 715. The depot of any of the clauses herein, wherein about 40% to about 60% of the therapeutic agent in the treatment area is released in the first half of the time period.

[0919] 716. The depot of any of the clauses herein, wherein at least 90% of the therapeutic agent in the treatment area is released within the time period.

[0920] 717. The depot of any of the clauses herein, wherein the depot is configured to release the therapeutic agent at a rate of at least 100 mg / day, at least 200 mg / day, at least 300 mg / day, at least 400 mg / day, at least 500 mg / day, at least 600 mg / day, at least 700 mg / day, at least 800 mg / day, at least 900 mg / day, at least 1 g / day, at least 1.5 g / day, at least 2 g / day, at least 2.5 g / day, at least 3 g / day, at least 4 g / day, at least 5 g / day, at least 6 g / day, at least 7 g / day, at least 8 g / day, at least 9 g / day, or at least 10 g / day.

[0921] 718. The depot of any of the clauses herein, wherein the depot is configured to release the therapeutic agent at a rate of no more than 100 mg / day, no more than 200 mg / day, no more than 300 mg / day, no more than 400 mg / day, no more than 500 mg / day, no more than 600 mg / day, no more than 700 mg / day, no more than 800 mg / day, no more than 900 mg / day, no more than 1 g / day, no more than 1.5 g / day, no more than 2 g / day, no more than 2.5 g / day, no more than 3 g / day, no more than 4 g / day, no more than 5 g / day, no more than 6 g / day, no more than 7 g / day, no more than 8 g / day, no more than 9 g / day, or no more than 10 g / day.

[0922] 719. The depot of any of the clauses herein, wherein the depot is configured to continuously release the therapeutic agent to the treatment site over the time period.

[0923] 720. The depot of any of the clauses herein, wherein the depot is configured to intermittently release the therapeutic agent to the treatment site over the time period.

[0924] 721. The depot of any of the clauses herein, wherein the therapeutic agent is released at a substantially steady-state rate over the entire time period.

[0925] 722. The storage facility of any of the clauses herein, wherein the period of time is not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 14 days, not less than 15 days, not less than 16 days, not less than 17 days, not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[0926] 723. The depot of any of the clauses herein, wherein the depot is biodegradable and / or bioerodible.

[0927] 724. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least 10 mg, at least 20 mg, at least 30 mg, at least 40, at least 50 mg, 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 1 g, at least 1.25 g, at least 1.5 g, at least 1.75 g, at least 2.0 g, at least 2.25 g, at least 2.5 g, at least 2.75 g, at least 3.0 g, at least 3.25 g, at least 3.5 g, at least 3.75 g, at least 4.0 g, at least 4.25 g, at least 4.5 g, at least 4.75 g, or at least 5.0 g.

[0928] 725. A method for treating or preventing an infection associated with an implantable medical device (IMD), the method comprising:

[0929] Provide IMD; and

[0930] A repository of any of the clauses herein is provided.

[0931] 726. A method for treating or preventing an infection associated with an implantable medical device (IMD), the method comprising:

[0932] Positioning the reservoir of any of the clauses herein proximate to a treatment site of an IMD implanted in a patient;

[0933] The therapeutic agent is administered to the treatment site for a period of no less than 3 days.

[0934] 727. The method of any of the clauses herein, wherein positioning the reservoir comprises covering at least a portion of the IMD with the reservoir.

[0935] 728. The method of any of the clauses herein, wherein positioning the reservoir comprises connecting the reservoir to the IMD and then implanting the IMD in the patient.

[0936] 729. A depot for treating an ocular condition in a patient by sustained controlled release of a therapeutic agent to the patient, the depot comprising:

[0937] a treatment area containing a therapeutic agent;

[0938] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0939] The depot is configured to be implanted at or near a treatment site in a patient's eye and, when implanted, releases the therapeutic agent at the treatment site for a period of time.

[0940] 730. The depot of any of the clauses herein, wherein the treatment site comprises the conjunctiva, subconjunctival space, punctal space, cornea, sclera, pars plana, macula, vitreous cavity, choroid, suprachoroidal space, retina, posterior chamber, or anterior chamber of the eye.

[0941] 731. The depot of any of the clauses herein, wherein the depot comprises a fixing portion configured to adhere to a surface of at least one of the following: the conjunctiva, subconjunctival space, punctal space, cornea, sclera, pars plana, macula, vitreous cavity, choroid, suprachoroidal space, retina, posterior chamber, or anterior chamber of the eye.

[0942] 732. A reservoir as claimed in any of the clauses herein, wherein the reservoir comprises an anchoring member connected to the treatment region, the control region and / or the base region, and wherein the anchoring member is configured to self-expand to attach to at least a portion of a surface, thereby securing the reservoir to or within the eye.

[0943] 733. The reservoir of any of the clauses herein, wherein the reservoir comprises a reinforcement portion configured to penetrate at least a portion of the thickness of the iris, choroid, or retina of the eye, thereby securing the reservoir to the eye.

[0944] 734. The depot of any of the clauses herein, wherein the eye condition comprises at least one of glaucoma, inflammation, macular degeneration, macular edema, cataracts, intraocular hypertension, uveitis, or dry eye.

[0945] 735. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of: a cholinergic agonist, a prostaglandin analog, a carbonic anhydrase inhibitor, an alpha and / or beta adrenergic agonist, an antibody, a fusion protein, a peptide, a chemokine, an interleukin, or a neuroprotectant.

[0946] 736. The depot of any of the clauses herein, wherein the cholinergic agonist comprises at least one of pilocarpine or cevimeline.

[0947] 737. The depot of any of the clauses herein, wherein the prostaglandin analogue comprises at least one of latanoprost, travoprost, bimatoprost, or unoprostine.

[0948] 738. The depot of any of the clauses herein, wherein the carbonic anhydrase inhibitor comprises at least one of methazolamide, 5-acylimine- or related imine-substituted analogs.

[0949] 739. The depot of any of the clauses herein, wherein the alpha and / or beta adrenergic agonist comprises at least one of brimonidine, brimonidine tartrate, apraclonidine, timolol, levobunalol, carteolol, metipranolol, or betaxolol.

[0950] 740. The depot of any of the clauses herein, wherein the antibodies comprise at least one of adalimumab, afacept, basiliximab, bevacizumab, certolizumab pegol, daclizumab, efalizumab, golimumab, infliximab, natalizumab, ranibizumab, or rituximab.

[0951] 741. The depot of any of the clauses herein, wherein the fusion protein comprises at least one of abatacept, afacept, anakinra, or etanercept.

[0952] 742. The depot of any of the clauses herein, wherein the peptide comprises at least one of an antimicrobial peptide, a calcitonin gene-related peptide, a cell penetrating peptide, an adhesion protein-derived peptide, a neurotransmitter, substance P, a tachykinin, or a vasoactive intestinal peptide.

[0953] 743. The depot of any one of the clauses herein, wherein the chemokine comprises CC motif chemokine 22.

[0954] 744. The depot of any of the clauses herein, wherein the interleukin comprises at least one of IL-2, TNF, or IL-1β.

[0955] 745. The depot of any of the clauses herein, wherein the neuroprotectant comprises brain-derived neurotrophic factor, glial cell line neurotrophic factor, or nerve growth factor.

[0956] 746. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of dipivefrin, carbachol, acetazolamide, dorzolamide, ethacrynic acid, mitomycin C, diclofenac, flurbiprofen, dexamethasone, coenzyme-Q10, ganciclovir, fluocinolone acetate, triamcinolone acetate, hydroxypropylcellulose, brinzolamide, albumin, or immunoglobulin.

[0957] 747. The depot of any of the clauses herein, wherein the treatment area is configured to release pilocarpine at a rate of about 0.2 mg / day to about 0.8 mg / day.

[0958] 748. The depot of any of the clauses herein, wherein the treatment area is configured to release dexamethasone at a rate of about 1 μg / day to about 100 μg / day.

[0959] 749. The depot of any of the clauses herein, wherein the treatment area is configured to release triamcinolone acetate at a rate of about 1 μg / day to about 100 μg / day.

[0960] 750. The depot of any one of the clauses herein, wherein the treatment area is configured to release ganciclovir at a rate of about 0.1 μg / day to about 10 μg / day.

[0961] 751. The depot of any of the clauses herein, wherein the treatment area is configured to release fluocinolone acetonide at a rate of less than about 100 ng / day.

[0962] 752. The depot of any of the clauses herein, wherein the treatment area is configured to release dexamethasone at a rate of about 900 μg / day to about 1.2 mg / day.

[0963] 753. The depot of any of the clauses herein, wherein the treatment area is configured to release triamcinolone acetate at a rate of about 0.5 μg / day to about 5 μg / day.

[0964] 754. The depot of any of the clauses herein, wherein the treatment area is configured to release fluocinolone acetonide at a rate of about 0.1 μg / day to about 0.8 μg / day.

[0965] 755. The depot of any of the clauses herein, wherein the treatment area is configured to release ciliary neurotrophic factor at a rate of less than about 50 ng / day.

[0966] 756. The depot of any of the clauses herein, wherein the treatment area is configured to release hydroxypropyl cellulose at a rate of about 1 mg / day to about 10 mg / day.

[0967] 757. A repository as described in any of the provisions herein, wherein the period of time is not less than two weeks, not less than three weeks, not less than four weeks, not less than five weeks, not less than eight weeks, not less than two months, not less than three months, not less than four months, not less than six months, not less than seven months, not less than eight months, not less than nine months, not less than 10 months, not less than 12 months, not less than 18 months, not less than 24 months, not less than 30 months, or not less than 36 months.

[0968] 758. The depot of any of the clauses herein, wherein the therapeutic agent contains at least 10 μg, 50 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg or 10 mg of the therapeutic agent.

[0969] 759. The depot of any of the clauses herein, wherein the treatment area contains less than 20 mg, less than 15 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 900 μg, less than 800 μg, less than 700 μg, less than 600 μg, less than 500 μg, less than 400 μg, less than 300 μg, less than 200 μg, less than 100 μg, less than 50 μg, less than 25 μg, or less than 10 μg of therapeutic agent.

[0970] 760. The depot of any of the clauses herein, wherein the treatment area contains from 10 μg to 10 mg, 10 μg to 1000 μg, 10 μg to 900 μg, 10 μg to 800 μg, 10 μg to 700 μg, 10 μg to 600 μg, 10 μg to 500 μg, 10 μg to 400 μg, 10 μg to 300 μg, 10 μg to 200 μg, 10 μg to 100 μg, 10 μg to 75 μg, 10 μg to 50 μg, or 10 μg to 20 μg of the therapeutic agent.

[0971] 761. The depot of any of the clauses herein, wherein the treatment area is configured to provide from about 10 ng / day to 900 μg / day, 10 ng / day to 700 μg / day, 10 ng / day to 500 μg / day, 10 ng / day to 400 μg / day, 10 ng / day to 300 μg / day, 10 ng / day to 200 μg / day, 10 ng / day to 100 μg / day, 10 ng / day to 10 μg / day, 10 ng / day to 900 ng / day, The therapeutic agent is released at a rate of 10 ng / day to 800 ng / day, 10 ng / day to 700 ng / day, 10 ng / day to 600 ng / day, 10 ng / day to 500 ng / day, 10 ng / day to 400 ng / day, 10 ng / day to 300 ng / day, 10 ng / day to 200 ng / day, 10 ng / day to 100 ng / day, 10 ng / day to 75 ng / day, 10 ng / day to 50 ng / day, and 10 ng / day to 25 ng / day.

[0972] 762. The depot of any of the clauses herein, wherein the treatment area is configured to receive no more than 10 mg / day, no more than 1 mg / day, no more than 500 μg / day, no more than 100 μg / day, no more than 90 μg / day, no more than 80 μg / day, no more than 70 μg / day, no more than 60 μg / day, no more than 50 μg / day, no more than 40 μg / day, no more than 30 μg / day, no more than 20 μg / day, no more than 10 μg / day, no more than 5 μg / day, The therapeutic agent is released at a rate of no more than 1 μg / day, no more than 900 ng / day, no more than 800 ng / day, no more than 700 ng / day, no more than 600 ng / day, no more than 500 ng / day, no more than 400 ng / day, no more than 300 ng / day, no more than 200 ng / day, no more than 100 ng / day, no more than 50 ng / day, no more than 40 ng / day, no more than 30 ng / day, no more than 20 ng / day, or no more than 10 ng / day.

[0973] 763. A method for treating an ocular condition by controlled sustained release of a therapeutic agent, the method comprising:

[0974] A repository of any of the clauses herein is provided.

[0975] 764. A method for treating an ocular condition by controlled sustained release of a therapeutic agent, the method comprising:

[0976] positioning a depot of any of the clauses herein near a treatment site of a patient's eye; and

[0977] The therapeutic agent is administered to the treatment site for a period of time.

[0978] 765. The method of any of the clauses herein, further comprising securing the reservoir to the conjunctiva, subconjunctival space, punctal space, cornea, sclera, pars plana, macula, vitreous cavity, choroid, suprachoroidal space, retina, posterior chamber, or anterior chamber of the eye.

[0979] 766. The method of any of the clauses herein, further comprising securing the reservoir to a portion of the eye.

[0980] 767. The method of any of the clauses herein, wherein the target site comprises the conjunctiva, subconjunctival space, punctal space, cornea, sclera, pars plana, macula, vitreous cavity, choroid, suprachoroidal space, retina, posterior chamber, or anterior chamber of the eye.

[0981] 768. The method of any of the clauses herein, wherein the time period is not less than two weeks, not less than three weeks, not less than four weeks, not less than five weeks, not less than eight weeks, not less than two months, not less than three months, not less than four months, not less than six months, not less than seven months, not less than eight months, not less than nine months, not less than 10 months, not less than 12 months, not less than 18 months, not less than 24 months, not less than 30 months, or not less than 36 months.

[0982] 769. The method of any of the clauses herein, wherein the reservoir is a first reservoir and the method further comprises positioning a second reservoir at the treatment site.

[0983] 770. A system for treating symptoms associated with an ocular disorder by controlled, sustained release of a therapeutic agent, the system comprising:

[0984] a repository for any of the terms herein; and

[0985] A drug delivery device configured to position the depot at a target site in an eye of a patient.

[0986] 771. The system of any of the clauses herein, wherein the target site comprises the conjunctiva, subconjunctival space, punctal space, cornea, sclera, pars plana, macula, vitreous cavity, choroid, suprachoroidal space, retina, posterior chamber, or anterior chamber of the eye.

[0987] 772. The system of any of the clauses herein, wherein the drug delivery device is a syringe and the target site is the vitreous cavity of the eye.

[0988] 773. A system for treating an eye condition, comprising:

[0989] a plurality of repositories, each repository comprising a repository of any one of the clauses herein; and

[0990] A drug delivery device configured to position the depot at a target site in an eye of a patient.

[0991] 774. A depot for treating an ear, nose, and throat condition in a patient by sustained controlled release of a therapeutic agent to the patient, the depot comprising:

[0992] a treatment area containing a therapeutic agent;

[0993] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; and

[0994] The reservoir is configured to be implanted at or near a treatment site in the nasal cavity of a patient and, when implanted, releases the therapeutic agent at the treatment site for a period of time.

[0995] 775. The depot of any of the clauses herein, wherein the treatment site comprises the nasal cavity, frontal sinus, sphenoid sinus, ethmoid sinus, maxillary sinus, superior turbinate, middle turbinate, inferior turbinate, vestibule, or nasopharynx.

[0996] 776. The depot of any of the clauses herein, wherein the depot comprises a securing portion configured to adhere to a surface of at least one of the nasal cavity, frontal sinus, sphenoid sinus, ethmoid sinus, maxillary sinus, superior turbinate, middle turbinate, inferior turbinate, vestibule, or nasopharynx.

[0997] 777. A reservoir as claimed in any of the clauses herein, wherein the reservoir comprises an anchoring member connected to the treatment area, the control area and / or the base area, and wherein the anchoring member is configured to self-expand to attach to at least a portion of a surface, thereby securing the reservoir to or within the nasal cavity.

[0998] 778. The reservoir of any of the clauses herein, wherein the reservoir comprises a reinforcement portion configured to penetrate at least a portion of the thickness of the nasal wall, superior turbinate, middle turbinate, inferior turbinate, vestibule, or nasopharynx, thereby securing the reservoir in the nasal cavity.

[0999] 779. The depot of any of the clauses herein, wherein the ear, nose, and throat condition comprises at least one of sinusitis, allergic rhinitis, nasal infection, or chronic nasal congestion.

[1000] 780. The depot of any of the clauses herein, wherein the treatment area is configured to continuously release the therapeutic agent at a substantially constant rate over the time period.

[1001] 781. The depot of any of the clauses herein, wherein the treatment area is configured to continuously release the therapeutic agent at an increased rate over the time period.

[1002] 782. The depot of any of the clauses herein, wherein the time period comprises a first time period and a second time period following the first time period, and wherein the treatment area is configured to release the therapeutic agent at a first rate during the first time period and at a second rate during the second time period, the second rate being less than the first rate.

[1003] 783. The depot of any of the clauses herein, wherein the therapeutic agent is configured to treat sinusitis.

[1004] 784. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of a steroid, an anti-inflammatory drug, or an antibiotic.

[1005] 785. The depot of any of the clauses herein, wherein the steroid comprises at least one of mometasone, triamcinolone, prednisolone, prednisolone, methylprednisolone, ciclesonide, fluticasone furoate, fluticasone propionate, mometasone, beclomethasone, budesonide, flunisolide, or triamcinolone, cortisone, dexamethasone, or hydrocortisone.

[1006] 786. The depot of any of the clauses herein, wherein the antibiotics comprise at least one of the following: amoxicillin, amoxicillin / clavulanate, clindamycin, cephalexin, metronidazole / cefalexin, metronidazole / cefluroxime, metronidazole / cefuroxime, moxifloxacin, levofloxacin, clarithromycin, tobramycin, cefuroxime, ceftazidime, ofloxacin, gentamicin, mupirocin, a macrolide, doxycycline, ceftriaxone, femifloxacin, trimethoprim-sulfa-methoxazole azole, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole azole / trimethoprim, tetracycline(s), minocycline, tigecycline, doxycycline, rifampicin, triclosan, chlorhexidine, penicillin(s), aminoglycoside, quinolone, fluoroquinolone, vancomycin, gentamicin, cephalosporin(s), carbapenem, imipenem, ertapenem, antimicrobial peptide, cephalosporin, magainin, dermaseptin, cathelicidin, α-defensin or α-endogenous antimicrobial peptide.

[1007] 787. The depot of any of the clauses herein, wherein the anti-inflammatory drug comprises one or more of the following: a macrolide, erythromycin, roxithromycin, azithromycin, prednisolone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, 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, or a COX-2 inhibitor.

[1008] 788. The depot of any of the clauses herein, wherein the treatment area is configured to release mometasone furoate at a rate of about 1 μg / day to about 30 μg / day.

[1009] 789. The depot of any of the clauses herein, wherein the treatment area is configured to release mometasone furoate at a rate of about 10 μg / day to about 20 μg / day.

[1010] 790. The depot of any of the clauses herein, wherein the treatment area is configured to release triamcinolone acetate at a rate of about 1 μg / day to about 100 μg / day.

[1011] 791. The depot of any of the clauses herein, wherein the treatment area is configured to release prednisolone at a rate of about 25 mg / day to about 75 mg / day.

[1012] 792. A storage facility as described in any of the provisions herein, wherein the period of time is not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 8 weeks, not less than 2 months, not less than 3 months, not less than 4 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, not less than 12 months, not less than 18 months, not less than 24 months, not less than 30 months, or not less than 36 months.

[1013] 793. The depot of any of the clauses herein, wherein the therapeutic agent contains at least 10 μg, 50 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg or 10 mg of therapeutic agent.

[1014] 794. The depot of any of the clauses herein, wherein the treatment area contains less than 20 mg, less than 15 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 900 μg, less than 800 μg, less than 700 μg, less than 600 μg, less than 500 μg, less than 400 μg, less than 300 μg, less than 200 μg, less than 100 μg, less than 50 μg, less than 25 μg, or less than 10 μg of therapeutic agent.

[1015] 795. The depot of any of the clauses herein, wherein the treatment area contains from 10 μg to 10 mg, 10 μg to 1000 μg, 10 μg to 900 μg, 10 μg to 800 μg, 10 μg to 700 μg, 10 μg to 600 μg, 10 μg to 500 μg, 10 μg to 400 μg, 10 μg to 300 μg, 10 μg to 200 μg, 10 μg to 100 μg, 10 μg to 75 μg, 10 μg to 50 μg, or 10 μg to 20 μg of the therapeutic agent.

[1016] 796. The depot of any of the clauses herein, wherein the treatment area is configured to provide from about 10 ng / day to 900 μg / day, 10 ng / day to 700 μg / day, 10 ng / day to 500 μg / day, 10 ng / day to 400 μg / day, 10 ng / day to 300 μg / day, 10 ng / day to 200 μg / day, 10 ng / day to 100 μg / day, 10 ng / day to 10 μg / day, 10 ng / day to 900 ng / day, The therapeutic agent is released at a rate of 10 ng / day to 800 ng / day, 10 ng / day to 700 ng / day, 10 ng / day to 600 ng / day, 10 ng / day to 500 ng / day, 10 ng / day to 400 ng / day, 10 ng / day to 300 ng / day, 10 ng / day to 200 ng / day, 10 ng / day to 100 ng / day, 10 ng / day to 75 ng / day, 10 ng / day to 50 ng / day, and 10 ng / day to 25 ng / day.

[1017] 797. The depot of any of the clauses herein, wherein the treatment area is configured to receive no more than 10 mg / day, no more than 1 mg / day, no more than 500 μg / day, no more than 100 μg / day, no more than 90 μg / day, no more than 80 μg / day, no more than 70 μg / day, no more than 60 μg / day, no more than 50 μg / day, no more than 40 μg / day, no more than 30 μg / day, no more than 20 μg / day, no more than 10 μg / day, no more than 5 μg / day, The therapeutic agent is released at a rate of no more than 1 μg / day, no more than 900 ng / day, no more than 800 ng / day, no more than 700 ng / day, no more than 600 ng / day, no more than 500 ng / day, no more than 400 ng / day, no more than 300 ng / day, no more than 200 ng / day, no more than 100 ng / day, no more than 50 ng / day, no more than 40 ng / day, no more than 30 ng / day, no more than 20 ng / day, or no more than 10 ng / day.

[1018] 798. A method for treating ear, nose and throat disorders by controlled sustained release of a therapeutic agent, the method comprising:

[1019] A repository of any of the clauses herein is provided.

[1020] 799. A method for treating ear, nose and throat disorders by controlled sustained release of a therapeutic agent, the method comprising:

[1021] positioning a depot of any of the clauses herein at a treatment site proximate to the patient's nasal cavity; and

[1022] The therapeutic agent is administered to the treatment site for a period of time.

[1023] 800. The method of any of the clauses herein, further comprising securing the reservoir to the nasal cavity, frontal sinus, sphenoid sinus, ethmoid sinus, maxillary sinus, superior turbinate, middle turbinate, inferior turbinate, vestibule, or nasopharynx.

[1024] 801. The method of any of the clauses herein, further comprising securing the reservoir to a portion of the nasal cavity.

[1025] 802. The method of any of the clauses herein, wherein the treatment site comprises the nasal cavity, frontal sinus, sphenoid sinus, ethmoid sinus, maxillary sinus, superior turbinate, middle turbinate, inferior turbinate, vestibule, or nasopharynx.

[1026] 803. The method of any of the clauses herein, wherein the time period is not less than 3 days, not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 8 weeks, not less than 2 months, not less than 3 months, not less than 4 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, not less than 12 months, not less than 18 months, not less than 24 months, not less than 30 months, or not less than 36 months.

[1027] 804. A system for treating ear, nose and throat disorders by controlled sustained release of a therapeutic agent, the system comprising:

[1028] a repository for any of the terms herein; and

[1029] A drug delivery device configured to position the depot at a target location in the nasal cavity of a patient.

[1030] 805. The system of any of the clauses herein, wherein the treatment site comprises the nasal cavity, frontal sinus, sphenoid sinus, ethmoid sinus, maxillary sinus, superior turbinate, middle turbinate, inferior turbinate, vestibule, or nasopharynx.

[1031] 806. The system of any of the clauses herein, wherein the drug delivery device is a syringe.

[1032] 807. A system for treating ear, nose and throat disorders, comprising:

[1033] a plurality of repositories, each repository comprising a repository of any one of the clauses herein; and

[1034] A drug delivery device configured to position the depot at a target location in the nasal cavity of a patient.

[1035] 808. A cover comprising a reservoir configured to provide controlled sustained release of a therapeutic agent, the reservoir comprising:

[1036] a treatment area comprising a therapeutic agent; and

[1037] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[1038] Wherein the cover is configured to at least partially cover the breast implant and to release the therapeutic agent for a period of time when implanted.

[1039] 809. An assembly comprising a reservoir positioned along an exterior of a breast implant, the reservoir configured to provide controlled sustained release of a therapeutic agent, the reservoir comprising:

[1040] a treatment area comprising a therapeutic agent; and

[1041] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[1042] The breast implant is configured to be implanted in a patient's breast and to release a therapeutic agent for a period of time while implanted.

[1043] 810. A depot configured to cover at least a portion of a breast implant and to provide controlled sustained release of a therapeutic agent, the depot comprising:

[1044] a treatment area comprising a therapeutic agent; and

[1045] a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region;

[1046] The reservoir is configured to cover a breast implant and release the therapeutic agent for a period of time when implanted.

[1047] 811. The depot of any of the clauses herein, wherein the therapeutic agent comprises one or more of: an antimicrobial agent, an anti-inflammatory agent, an anti-scar agent, and a leukotriene inhibitor.

[1048] 812. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of montelukast or zafirlukast.

[1049] 813. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least one of tranilast.

[1050] 814. The depot of any of the clauses herein, wherein the therapeutic agent comprises triamcinolone.

[1051] 815. The depot of any of the clauses herein, wherein the therapeutic agent comprises pirfenidone.

[1052] 816. The depot of any of the clauses herein, wherein the therapeutic agent comprises an anti-adhesive barrier solution.

[1053] 817. The depot of any of the clauses herein, wherein the therapeutic agent comprises an antibacterial agent.

[1054] 818. The depot of any of the clauses herein, wherein the therapeutic agent comprises at least 10 mg, at least 20 mg, at least 30 mg, at least 40, 50 mg, 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 1 g, at least 1.25 g, at least 1.5 g, at least 1.75 g, at least 2.0 g, at least 2.25 g, at least 2.5 g, at least 2.75 g, at least 3.0 g, at least 3.25 g, at least 3.5 g, at least 3.75 g, at least 4.0 g, at least 4.25 g, at least 4.5 g, at least 4.75 g, or at least 5.0 g.

[1055] 819. The depot of any of the clauses herein, wherein the treatment area is configured to release the therapeutic agent continuously over the time period.

[1056] 820. The storage facility of any of the clauses herein, wherein the period of time is not less than 4 days, not less than 5 days, not less than 6 days, not less than 7 days, not less than 8 days, not less than 9 days, not less than 10 days, not less than 11 days, not less than 12 days, not less than 13 days, not less than 2 weeks, not less than 3 weeks, not less than 4 weeks, not less than 5 weeks, not less than 6 weeks, not less than 7 weeks, not less than 8 weeks, not less than 2 months, not less than 3 months, not less than 4 months, not less than 6 months, not less than 7 months, not less than 8 months, not less than 9 months, not less than 10 months, not less than 12 months, or not less than 1 year.

[1057] 821. The depot of any of the clauses herein, wherein the depot substantially encloses a breast implant.

[1058] 822. The reservoir of any of the clauses herein, wherein the reservoir comprises an aperture configured to receive a breast implant therethrough.

[1059] 823. The depot of any of the clauses herein, wherein the depot circumferentially surrounds at least a portion of the breast implant.

[1060] 824. A method for treating or preventing breast implant capsular contracture, the method comprising:

[1061] providing breast implants; and

[1062] A repository of any of the clauses herein is provided.

[1063] 825. A method for treating and / or preventing capsular contracture, the method comprising:

[1064] positioning a depot of any of the clauses herein proximate to a treatment site of a patient's breast implant; and

[1065] The therapeutic agent is administered to the treatment site for a period of no less than 3 days.

[1066] 826. The method of any of the clauses herein, wherein positioning the reservoir comprises covering at least a portion of the breast implant with the reservoir.

[1067] 827. The method of any of the clauses herein, wherein positioning the reservoir comprises connecting the reservoir to a breast implant and then implanting the breast implant into the patient.

[1068] 828. The method of any of the clauses herein, wherein the therapeutic agent comprises at least one of montelukast or zafirlukast.

[1069] 829. The method of any of the clauses herein, wherein the therapeutic agent comprises at least one of tranilast.

[1070] 830. The method of any of the clauses herein, wherein the therapeutic agent comprises triamcinolone.

[1071] 831. The method of any of the clauses herein, wherein the therapeutic agent comprises pirfenidone.

[1072] 832. The method of any of the clauses herein, wherein the therapeutic agent comprises an anti-adhesive barrier solution.

[1073] 833. The method of any of the clauses herein, wherein the therapeutic agent comprises an antibacterial agent.

[1074] 834. The method of any of the clauses herein, wherein the therapeutic agent comprises at least 10 mg, at least 20 mg, at least 30 mg, at least 40, 50 mg, 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 1 g, at least 1.25 g, at least 1.5 g, at least 1.75 g, at least 2.0 g, at least 2.25 g, at least 2.5 g, at least 2.75 g, at least 3.0 g, at least 3.25 g, at least 3.5 g, at least 3.75 g, at least 4.0 g, at least 4.25 g, at least 4.5 g, at least 4.75 g, or at least 5.0 g.

[1075] 835. The method of any of the clauses herein, wherein the time period is not less than two weeks, not less than three weeks, not less than four weeks, not less than five weeks, not less than eight weeks, not less than two months, not less than three months, not less than four months, not less than six months, not less than seven months, not less than eight months, not less than nine months, not less than ten months, not less than 12 months, or not less than one year. BRIEF DESCRIPTION OF THE DRAWINGS

[1076] Many aspects of the present disclosure may be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed upon clearly illustrating the principles of the present disclosure.

[1077] FIG1 depicts the release of a therapeutic agent over time from a prior art drug delivery system.

[1078] Figure 2 is an isometric view of a storage facility configured in accordance with the present technology.

[1079] Figure 3A Example release profiles over time are described for one or more depots of the present technology.

[1080] Figure 3B Example release profiles over time are described for one or more depots of the present technology.

[1081] Figure 4 is an isometric view of a storage reservoir according to some embodiments of the present technology.

[1082] Figure 5 is an isometric view of a storage reservoir according to some embodiments of the present technology.

[1083] Figure 6 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1084] Figure 7 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1085] Figure 8 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1086] Figure 9A is an isometric view of a storage reservoir according to some embodiments of the present technology.

[1087] Figure 9B is Figure 9A A cross-sectional view of the reservoir is shown in .

[1088] Figure 10 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1089] Figure 11 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1090] Figure 12 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1091] Figure 13 is an isometric view of a storage reservoir according to some embodiments of the present technology.

[1092] Figure 14A –H is a reservoir with different cross-sectional areas and shapes according to the present technology.

[1093] Figure 15A -15E describes various reservoir embodiments including barrier regions according to the present technology.

[1094] Figure 16 is a perspective view of a reservoir according to some embodiments of the present technology.

[1095] Figure 17 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1096] Figure 18 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1097] Figure 19 is a cross-sectional view of a reservoir according to some embodiments of the present technology.

[1098] Figure 20A is a perspective view of a reservoir according to some embodiments of the present technology.

[1099] Figure 20B is Figure 20A A cross-sectional view of the reservoir shown in FIG is taken along line BB.

[1100] Figure 20C is Figure 20A A cross-sectional view of the reservoir shown in FIG is taken along line CC.

[1101] Figure 20D is a perspective view of a reservoir according to some embodiments of the present technology.

[1102] Figure 21 is a perspective view of a reservoir according to some embodiments of the present technology.

[1103] Figure 22 is a perspective view of a reservoir according to some embodiments of the present technology.

[1104] Figure 23 is a perspective view of a reservoir according to some embodiments of the present technology.

[1105] Figure 24 is a perspective view of a reservoir according to some embodiments of the present technology.

[1106] Figure 25A is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1107] Figure 25B is Figure 25AA cross-sectional view of the reservoir shown in FIG is taken along line BB.

[1108] Figure 26 is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1109] Figure 27 is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1110] Figure 28 is a perspective view of a reservoir according to some embodiments of the present technology.

[1111] Figure 29 is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1112] Figure 30 is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1113] Figure 31 is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1114] Figure 32A is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1115] Figure 32B is Figure 32A A cross-sectional view of the reservoir shown in FIG is taken along line BB.

[1116] Figure 32C is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1117] Figure 32D is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1118] Figure 33A is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1119] Figure 33B describe Figure 33A Example release profiles of the depot over time are shown in .

[1120] Figure 34A is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1121] Figure 34B describe Figure 34A Example release profiles of the depot over time are shown in .

[1122] Figure 35A is a side cross-sectional view of a reservoir according to some embodiments of the present technology.

[1123] Figure 35B describe Figure 35A Example release profiles of the depot over time are shown in .

[1124] Figure 36A is a perspective view of a reservoir according to some embodiments of the present technology.

[1125] Figure 36B is a perspective view of a reservoir according to some embodiments of the present technology.

[1126] Figure 37A is a side view of a storage reservoir in an extended state according to some embodiments of the present technology.

[1127] Figure 37B is Figure 37A Figure 4 shows a side view of the reservoir in a bent state.

[1128] Figure 38A is a side view of a storage reservoir in an extended state according to some embodiments of the present technology.

[1129] Figure 38B is Figure 38A Figure 4 shows a side view of the reservoir in a bent state.

[1130] Figure 39A is a perspective view of a storage reservoir in an extended state according to some embodiments of the present technology.

[1131] Figure 39B is Figure 39A A cross-sectional view of the reservoir shown in FIG is taken along line BB.

[1132] Figure 39C is Figure 39A Figure 4 shows a side view of the reservoir in a bent state.

[1133] Figure 40 is a side view of a depot deployed at a target site within the body according to some embodiments of the present technology.

[1134] Figure 41 is a side view of a depot deployed at a target site within the body according to some embodiments of the present technology.

[1135] Figure 42 is a side view of a storage reservoir according to some embodiments of the present technology.

[1136] Figure 43 is a side view of a storage reservoir according to some embodiments of the present technology.

[1137] Figure 44A and 44Bis a perspective view of a reservoir according to some embodiments of the present technology.

[1138] Figure 45A -C are perspective, top, and side views, respectively, of a reservoir according to some embodiments of the present technology.

[1139] Figure 46A is an end view of a reservoir in a bent state according to some embodiments of the present technology.

[1140] Figure 46B is Figure 46A The reservoir is shown in a side view in its extended position.

[1141] Figure 47 A plurality of reservoirs according to some embodiments of the present technology are described.

[1142] Figure 48A is an end view of multiple reservoirs according to some embodiments of the present technology.

[1143] Figure 48B is Figure 48A Side view of the storage reservoir shown in.

[1144] Figure 48C Description Figure 48A and 48B Method for manufacturing the reservoir shown in .

[1145] Figure 49 Describes the maximum flexural load of the implant over time from the start of testing of the implant sample immersed in buffer solution.

[1146] Figure 50 is a schematic representation of prior art core acidulation.

[1147] FIG. 51 is a scanning electron microscope image of a prior art polymer tablet after 20 days of degradation.

[1148] This figure is taken from Avgoustakis, K., Synthesis and Evaluation of Some Poly(Lactide-co-Glycolides) for Use in Sustained Release Tablets, PhD thesis, University College London, 1992. Figure 2 Scanning electron microscopy images of DL-PLGA (50:50) tablets after incubation in phosphate buffer, pH 7.4, at 37°C for 20 days (from reference

[17] ).

[1149] Figure 52A is a schematic representation of the degradation of a reservoir of the present technology.

[1150] Figure 52B and 52C are scanning electron microscope ("SEM") images of cross-sections of depots of the present technology at various time points during the degradation process.

[1151] Figure 53A -C is a partially schematic perspective illustration of a drug delivery system for subcutaneously delivering a depot to a target site in accordance with some embodiments of the present technology.

[1152] Figure 54 A reservoir coupled to an implantable medical device according to embodiments of the present technology is described.

[1153] Figure 55 is an anatomical cross-sectional illustration of an eye including a plurality of depots according to embodiments of the present technology.

[1154] Figure 56 Illustrate the anterior and lateral anatomy of the nasal cavity and paranasal sinuses.

[1155] Figure 57 is an anatomical cross-sectional illustration of a nasal cavity including a plurality of depots according to embodiments of the present technology.

[1156] Figure 58 To describe breast implant capsular contracture associated with breast implant surgery.

[1157] Figure 59 A reservoir coupled to a breast implant according to embodiments of the present technology is described. DETAILED DESCRIPTION

[1158] The present technology relates to implantable reservoirs for sustained controlled release of therapeutic agents, and related devices, systems, and methods of use. Figure 2 –52C and Section I describe examples of depots of the present technology and associated release kinetics. Reference is now made to Section II for describing uses of depots of the present technology for treating symptoms associated with T2D. Reference is now made to Section III for describing uses of depots of the present technology for treating symptoms associated with psychiatric disorders. Reference is now made to Section IV for describing uses of depots of the present technology for treating cardiovascular disease. Reference is now made to Section V for describing uses of depots of the present technology for treating or preventing symptoms associated with HIV or malaria. Figure 54 and Section VI describe the use of the present technology depot for treating or preventing infections associated with implantable medical devices (IMDs). Below, with reference to FIG55, Section VII describes the use of the present technology depot for treating eye conditions. Below, with reference to FIG56-57, Section VIII describes the use of the present technology depot for treating otolaryngology conditions. Finally, below, with reference to FIG56-57, Section VIII describes the use of the present technology depot for treating otolaryngology conditions. Figure 58 and 59and Section IX describes the use of the depot of the present technology for or prevention of capsular contracture or other conditions associated with breast implants.

[1159] I. Example Repository of the Present Technology

[1160] Disclosed herein are implantable depots and related devices, systems, and methods for treating certain conditions by providing sustained, controlled release of one or more therapeutic agents when the depot is implanted at a treatment site within the body. As understood in the art, "release" of a therapeutic agent includes movement of the therapeutic agent away from the depot, as well as continued presence of the therapeutic agent at the treatment site after implantation of the depot, regardless of relative movement of the therapeutic agent relative to the confines of the depot. Thus, any therapeutic agent that remains substantially fixed relative to its position when initially implanted is still considered "released" as long as it provides therapeutic efficacy at the treatment site.

[1161] As mentioned previously, prior art drug delivery systems often lack a true controlled release mechanism, as they typically provide a sudden burst of drug upon contact with surrounding physiological fluids, followed by a residual release of the drug. For example, FIG1 shows an example prior art biodegradable polymer-based drug delivery system, in which the drug concentration in plasma peaks within 15 hours of implantation, thereby demonstrating an insufficient onset of action.

[1162] Disclosed herein are implantable depots and related devices, systems, and methods, for example, for treating certain conditions by providing sustained, controlled release of a therapeutic agent when the depot is implanted at a treatment site within the body. When implanted within the body, the depot(s) are configured to release the therapeutic agent in a controlled, pre-determined manner to the treatment site for an extended period of time after implantation.

[1163] As used herein, " depot " comprises the composition that is configured to at least one therapeutic agent in a controlled and continuous manner to be applied to the treatment site in the patient's body. The depot also comprises the therapeutic agent itself. The depot can include a physical structure or a carrier, and the physical structure or the carrier are configured to carry out or enhance one or more functions relevant to treatment, such as promoting implantation and / or being retained in the treatment site (such as in the capsule of the knee joint and / or the tissue of the extracapsular space, in the patient's abdomen subcutaneous, in the bladder, etc.), regulating the release curve of the therapeutic agent (such as producing a two-stage release curve), improving the release towards the treatment site, reducing the release away from the treatment site, or a combination thereof. In some embodiments, " depot " includes but is not limited to film, sheet, strip, strip, capsule, coating, matrix, thin slice, pill, pellet or other drug delivery device or a combination thereof. In addition, as used herein, " depot " can refer to a single depot or can refer to multiple depots. As an example, the statement "the depot can be configured to release 2 g of therapeutic agent to the treatment site" describes (a) a single depot configured to release 2 g of therapeutic agent to the treatment site, and (b) multiple depots that are collectively configured to release 2 g of therapeutic agent to the treatment site.

[1164] Figure 2 is an isometric view of an implantable depot 100 according to several embodiments of the present technology. The depot 100 can be a thin, multi-layer polymeric film configured to be implanted at a treatment site, comprising a treatment region 200 containing a therapeutic agent and a control region 300 configured to regulate the release of the therapeutic agent from the depot 100 in a controlled and sustained manner. The depot 100 can include a high therapeutic payload of therapeutic agent, particularly compared to other known films of equivalent thickness or polymer weight percentage, while exhibiting mechanical properties (e.g., flexural strength) sufficient to withstand storage, handling, implantation, and / or retention at the treatment site. For example, in some embodiments, the depot 100 comprises at least 50% by weight of the therapeutic agent.

[1165] The control region 300 can comprise at least one bioabsorbable polymer and at least one releasing agent mixed with the polymer, and the treatment region 200 can comprise at least one bioabsorbable polymer and at least one releasing agent mixed with the polymer and the therapeutic agent. The control region 300 can optionally include a therapeutic agent, or the control region 300 can include no therapeutic agent at all. The treatment region 200 can optionally include no releasing agent at all. The releasing agent in the control region 300 can be the same as or different from the releasing agent in the treatment region 200. The bioabsorbable polymer in the control region 300 can be the same as or different from the bioabsorbable polymer in the treatment region 200. As described in detail below, in some embodiments, the treatment region 200 and / or the control region 300 can have different compositions and / or formulations.

[1166] When exposed to fluid (e.g., physiological fluid), the release agent may have a dissolution rate faster than the degradation rate of the bioabsorbable polymer. Therefore, when the fluid contacts the reservoir 100 (e.g., after the reservoir 100 is implanted in the treatment site), the release agent dissolves faster than the polymer degradation in the surrounding polymer of the control area 300 and / or the treatment area 200. As the release agent dissolves, the space vacated by the dissolved release agent forms diffusion openings (e.g., channels, cavities, holes, etc.) in the surrounding polymer area. The formation of diffusion openings can enhance the release of the therapeutic agent from the polymer area and into the surrounding physiological fluid. In some embodiments, the release rate of the therapeutic agent is higher when there are diffusion openings in the polymer area than when there are no diffusion openings in the polymer area.

[1167] The concentration and type of release agent, among other parameters, can be selected to regulate the release of the therapeutic agent from the treatment region 200 and / or through the control region 300 into the surrounding fluid at a controlled dosage rate over a desired period of time. For example, a higher concentration of release agent can increase the release rate of the therapeutic agent, while a lower concentration of release agent can decrease the release rate of the therapeutic agent. The treatment region 200 can contain a different concentration and / or type of release agent than the control region 300, or can contain the same concentration and / or type of release agent.

[1168] The position and / or geometry of the control region 300 can be configured to adjust the release profile of the therapeutic agent from the treatment region 200. Figure 2 As shown in FIG, at least a portion of the control region 300 can be positioned on or adjacent to the treatment area 200 such that, when the depot 100 is initially positioned within the body, the control region 300 is between at least a portion of the treatment area 200 and the physiological fluid at the treatment site. For example, the control region 300 can cover all or a portion of one or more surfaces of the treatment area 200. When the depot 100 is exposed to the physiological fluid, the therapeutic agent elutes from the exposed surface of the treatment area 200 and through the control region 300 through the diffusion openings created by the dissolution of the release agent. In general, the therapeutic agent elutes from the exposed surface of the treatment area 200 at a faster (e.g., greater) rate than through the control region 300. As a result, the control region 300 prolongs the release of the therapeutic agent from the treatment area 200 to provide a longer release time and adjust the dosage rate, for example, to provide the desired effect and avoid complications associated with overdose.

[1169] The reservoirs of the present technology are configured to release the therapeutic agent 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 below in Section II, the release kinetics of the reservoir can be tailored for a particular application by varying one or more of the following: reservoir composition and / or structure, such as the shape and / or size of the reservoir, treatment region 200, and / or control region 300; the exposed surface area of ​​the treatment region 200; the type of polymer (in the treatment region 200 and / or in the control region 300); the weight percentage of the therapeutic agent, polymer, and / or releasing agent (in a specific region or generally throughout the reservoir 100); and the composition of the treatment region 200 and the control region 300.

[1170] like Figure 3A As shown in FIG, in some embodiments, the reservoir 100 (or system of reservoirs 100) is configured to release the therapeutic agent at a substantially constant rate. Figure 3B , in some embodiments, depot 100 (or a system of depots 100 ) is configured to release a disproportionately greater volume of therapeutic agent per day during a first time period than during a second, longer time period. Figure 3A and 3B Two example release profiles are described, however, the depot 100 (or system of depots 100) can be configured to achieve a wide range of different release profiles depending on the specific clinical need and underlying condition being addressed. For example, while the release profile may be determined based on the Figure 3A The zero-order release profile shown in

[0014] is advantageous for administering certain therapeutic agents, but in other cases it may be useful to administer a zero-order release profile such as that shown in

[0014] Figure 3B In certain embodiments, the reservoir 100 can be configured to release the therapeutic agent at a constant rate for a first time period and at a non-constant rate for a second time period (which can occur before or after the first time period). In addition to different release profiles (e.g., zero order, first order, second order, etc.), the total release time can be precisely controlled by adjusting the structure, composition, and / or manufacturing method of the reservoir, as described in more detail below. For example, as in Figure 3A showed that more than 90% of the therapeutic agent could be released after 14 weeks, while Figure 3B In the ELISA, greater than 90% of the therapeutic agent was released after 14 days.

[1171] In some embodiments, the depot 100 is configured to release the drug within the first day, 2 days, 3 days, 4 days, 5 days, 6 days, 8 days, 9 days, 10 days, 11 days, 12 days, or 13 days of the release duration, or within the first week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, or 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks. No more than 20%, no more than 25%, no more than 30%, no more than 35%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, or no more than 70% of the therapeutic agent is released over 3 weeks, or 24 weeks, and wherein at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% of the remaining therapeutic agent is released over the remaining days of the release duration. The predetermined duration of release can 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 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, or at least 24 weeks.

[1172] In some embodiments, 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 in depot 100 over a predetermined duration of treatment. The predetermined duration of treatment can 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 day, 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.

[1173] In some embodiments, the reservoir 100 can be configured to release a selected amount of therapeutic agent over a defined time period (e.g., daily, weekly, etc.). The specific amount of therapeutic agent administered can be selected based on the specific therapeutic agent. In some embodiments, the reservoir 100 is configured to release a sufficient amount of therapeutic agent to provide a therapeutic effect while also not releasing an excess amount that would cause toxicity or other adverse effects. For example, in the case of bupivacaine hydrochloride as the therapeutic agent, the reservoir 100 can be configured to release approximately 50 mg / day to approximately 600 mg / day, 100 mg / day to approximately 500 mg / day, or approximately 100 mg / day to approximately 400 mg / day, or approximately 100 mg / day to approximately 300 mg / day of bupivacaine hydrochloride to the treatment site. The specific dosage range, upper and lower limits can be selected based on the specific therapeutic agent(s) to achieve the desired effect. In general, the release rate can be selected to administer the desired dose, thereby providing the desired degree of efficacy, controlling toxicity, and administering the therapeutic agent for a sufficient period of time.

[1174] In some embodiments, the depot 100 is configured to release the therapeutic agent at the treatment site in vivo and / or in the presence of one or more fluids for no less than 1 day, no less than 2 days, no less than 3 days, no less than 4 days, no less than 5 days, no less than 6 days, no less than 7 days, no less than 8 days, no less than 9 days, no less than 10 days, no less than 11 days, no less than 12 days, no less than 13 days, no less than 14 days, no less than 15 days, no less than 16 days, no less than 17 days, no less than 18 days, no less than 19 days, no less than 20 days, no less than 21 days, no less than 22 days, no less than 23 days, no less than 24 days, no less than 25 days, no less than 26 days, no less than 27 days, no less than 28 days, no less than 29 days, no less than 30 days, no less than 31 days, no less than 32 days, no less than 33 days, no less than 34 days, no less than 35 days, no less than 36 days, no less than 37 days, no less than 38 days, no less than 39 days, no less than 40 days, no less than 41 days, no less than 42 days, no less than 43 days, no less than 44 days, no less than 45 days, no less than 46 days, no less than 47 days, no less than 48 days, no less than 49 days, no less than 50 days, no less than 51 days, no less than 52 days, no less than 53 days, no less than 54 days, no less than 55 days, no less than 56 days, no less than 57 days, no less than 58 days, no less than 59 days, no less than 60 days, no less than Not less than 18 days, not less than 19 days, not less than 20 days, not less than 21 days, not less than 22 days, not less than 23 days, not less than 24 days, not less than 25 days, not less than 26 days, not less than 27 days, not less than 28 days, not less than 29 days, not less than 30 days, not less than 40 days, not less than 50 days, not less than 60 days, not less than 70 days, not less than 90 days, not less than 100 days, not less than 200 days, not less than 300 days, or not less than 365 days.

[1175] The release kinetics of the depots of the present technology can be tailored for specific applications by varying one or more of the following: the structure of the depot, such as the exposed surface area of ​​the therapeutic region 200, the porosity of the control region 300 during and after dissolution of the releasing agent, the concentration of the therapeutic agent in the therapeutic region, the post-manufacturing properties of the polymer, the structural integrity of the depot to avoid sudden release of the therapeutic agent, the relative thickness of the therapeutic region 200 compared to the control region 300, and other properties of the depot. Several embodiments of the depots of the present technology combine one or more of these properties in a manner that produces an unusual sustained controlled release profile that significantly outperforms existing injectable or implantable systems in animal studies, while also overcoming the shortcomings of the disclosed pre-set devices. This enables the depots of the present technology to at least reduce, if not replace, other existing therapeutic systems.

[1176] For example, the release profile can be adjusted by (at least partially) controlling the amount of exposed surface area of ​​the treatment region 200, as a reservoir having a treatment region 200 that is only partially covered by the control region 300 (see, e.g., Figure 2 、 4 -8, 13, 15-27 and 32-41) and embodiments where the treatment region 200 is completely enclosed by the control region 300 (see e.g. Figure 9A –12) will generally release a higher proportion of the total payload in a shorter period of time. More specifically, a depot design having a treatment region 200 with an exposed surface can be configured to release the therapeutic agent at a high, substantially linear rate for a first period of time and then release the therapeutic agent at a lower, substantially linear rate for a second period of time. Alternatively, a depot design having a treatment region 200 with a surface substantially covered by one or more control regions 300 can achieve zero-order release, such that the payload of therapeutic agent is released at substantially the same rate. Figure 4 -48B shows and describes various examples of different repository configurations. The features of any of these example repository configurations can be combined with any other repository configuration disclosed herein.

[1177] like Figure 4, in some embodiments, a reservoir 100 can comprise a multilayer polymer film having a treatment region 200 and first and second control regions 300a, 300b positioned on opposing surfaces 100a, 100b of the treatment region 200. The reservoir 100 can take the form of a flexible rectangular strip having a length L, a width W, and a height H (or thickness). In some embodiments, the depot 100 has (a) a length L of about 5-40 mm, about 10-30 mm, about 15-20 mm, about 20-35 mm, about 20-30 mm, about 20-25 mm, about 26-30 mm, about 5 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm, about 21 mm, about 22 mm, about 23 mm, about 24 mm, about 25 mm, about 26 mm, about 27 mm, about 28 mm, about 29 mm, about 30 mm, about 31 mm, about 32 mm, about 33 mm, about 34 mm, about 35 mm, about 36 mm, about 37 mm, about 38 mm, about 39 mm, about 40 mm, about 41 mm, about 42 mm, about 43 mm, about 44 mm, about 45 mm, about 46 mm, about 47 mm, about 48 mm, about 49 mm, about 50 mm, about 51 mm, about 52 mm, about 53 mm, about 54 mm, about 55 mm, about 56 mm, about 57 mm, about 58 mm, about 59 mm, about about 29 mm, about 30 mm, about 10–15 mm, about 12–16 mm, about 15–20 mm, about 21–23 mm, about 22–24 mm, about 23–25 mm, about 24–26 mm, about 25–27 mm, about 26–28 mm, about 27–29 mm, or about 28–30 mm, (b) a width W of about 5–40 mm, about 10–30 mm, about 15–20 mm, about 20–35 mm, about 20–30 mm, about 20–25 mm, about 26–30 mm, about 5 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, about 20 mm, about 21 mm, about 22 mm, about 23 mm, about 24 mm, about 25 mm, about 26 mm, about 27 mm, about 28 mm, about 29 mm, about 30 mm, about 10–15 mm, about 12–16 mm, about 15–20 mm, about 21–23 mm, about 22–24 mm, about 23–25 mm, about 24–26 mm, about 25–27 mm, about 26–28 mm, about 27–29 mm, or about 28–30 mm. In some embodiments, the depot 100 can have other shapes and / or sizes, such as those described below.

[1178] In addition, configure Figure 4 Some embodiments of the depot shown in are such that the thickness of the control zones 300a and 300b, individually or collectively, is less than or equal to 1 / 10 the thickness of the treatment zone 200. The thickness of the control zones 300a and 300b, individually or collectively, may also be no greater than 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 30, 1 / 40, 1 / 50, 1 / 75, or 1 / 100 the thickness of the treatment zone 200. In those embodiments having multiple sub-control regions, one or more of the sub-control regions can individually be less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 of the thickness of the treatment region. In those embodiments where the control region comprises a single control region, the control region can have a thickness less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 the thickness of the treatment region. In those embodiments having multiple sub-control regions, one or more of the sub-control regions can individually be less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 the thickness of the reservoir. In those embodiments where the control region comprises a single control region, the control region can have a thickness less than or equal to 1 / 10, 1 / 12.5, 1 / 15, 1 / 17.5, 1 / 20, 1 / 22.5, 1 / 25, 1 / 27.5, 1 / 30, 1 / 32.5, 1 / 35, 1 / 37.5, 1 / 40, 1 / 42.5, 1 / 45, 1 / 47.5, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 the thickness of the reservoir.

[1179] The control regions 300a, 300b may cover only a portion of the treatment area 200, such that a portion of each of the side surfaces (e.g., sidewalls) of the treatment area 200 is immediately exposed to physiological fluids when the depot 100 is implanted in vivo. When the depot 100 is exposed to physiological fluids (or any similar fluid in an in vitro environment), the therapeutic agent will elute from the exposed surfaces 202 (in addition to through the control regions 300a, 300b), such that the therapeutic agent is released more rapidly than if the treatment area 200 had no exposed areas. In this manner, the surface area of ​​the exposed surfaces 202 may be adjusted to provide an initial controlled burst of release, followed by a gradually decreasing release (e.g., with Figure 3A 200). The initial more aggressive release of therapeutic agent is slowed in part by the control regions 300a, 300b that initially reduce the surface area of ​​the treatment region 200 exposed to the fluid. Unlike the reservoir 100 of the present technology, many conventional drug eluting technologies provide an initial uncontrolled burst release of drug when exposed to physiological fluids. Several embodiments of the reservoirs of the present technology not only enable implantation of sufficient therapeutic agent to maintain a dose for days, weeks, or months to achieve sustained in vivo pharmacological therapy, but they also release the therapeutic agent as prescribed and thereby prevent a significant portion of the entire payload from being released in an uncontrolled manner, which could potentially lead to complications for the patient and / or reduce the remaining payload such that there is not enough therapeutic agent remaining in the reservoir to administer a therapeutic amount for the remaining release duration.

[1180] In some embodiments, the configuration Figure 4 The depot 100 shown in FIG. 1 is such that about 20% to about 50% of the therapeutic agent is released from about 3 days to about 5 days prior to the 14-day period, and wherein at least 80% of the remaining therapeutic agent is released from about 9 days to about 11 days after the 14-day period. In some embodiments, Figure 4 Depot 100 shown in is configured to release about 100 mg to about 500 mg of therapeutic agent per day to the treatment site, and in some cases to release no more than 400 mg or no more than 300 mg of therapeutic agent per day during the first three days of implantation and no more than 200 mg per day during the remaining days.

[1181] Will also Figure 4 Several embodiments of the depot 100 shown in FIG are configured to maintain their structural integrity even after a substantial portion of the release agent has been 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 structural integrity, flexural strength, tensile strength, or other mechanical properties of the depot. If the depot 100 undergoes excessive, rapid degradation, it may mechanically fail and release an undesirable burst of therapeutic agent into the body. Figure 4Several embodiments of the depot 100 shown in FIG are loaded with sufficient therapeutic agent to administer 100 mg to 500 mg of therapeutic agent per day, while still being able to maintain its structural integrity such that the depot remains substantially intact for at least 14 days after implantation. For example, a depot may be sufficiently intact if it does not break into multiple component pieces, wherein two or more of the resulting pieces are at least 5% of the depot's previous size. Alternatively or additionally, a depot may be considered sufficiently intact if the release rate of the therapeutic agent is not increased by more than three-fold compared to the release rate of the therapeutic agent from a control depot immersed in a buffer solution.

[1182] The therapeutic agent may comprise at least 50% to 95% by weight of the total weight of the depot 100 prior to implantation, or 55% to 85% by weight of the total weight of the depot 100 prior to implantation, or 60% to 75% by weight of the total weight of the depot 100 prior to implantation. Likewise, the polymer may comprise no more than 5% to 50% by weight of the total weight of the depot 100 prior to implantation, or 10% to 50% by weight of the total weight of the depot 100 prior to implantation, or 15% to 45% by weight of the total weight of the depot 100 prior to implantation, or 20% to 40% by weight of the total weight of the depot 100 prior to implantation, or no more than 25%, no more than 30%, no more than 35%, or no more than 40%. The ratio of the mass of therapeutic agent in depot 100 to the mass of polymer in depot 100 can be at least 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, or 2:1.

[1183] In some embodiments, one or more control regions 300 of a reservoir 100 may comprise two or more sub-control regions. Figure 5, the reservoir 100 can have a first control region 300a and a second control region 300b, each of which comprises first and second sub-control regions 302a, 302b and 302c, 302d, respectively. One, some, or all of the first and second control regions 300a, 300b, and / or sub-control regions 302a-302d can have the same or different amounts of releasing agent, the same or different concentrations of releasing agent, the same or different releasing agents, the same or different amounts of polymer, the same or different polymers, the same or different polymer to releasing agent ratios, and / or the same or different thicknesses. In some embodiments, the concentration of releasing agent in a single outer control sub-region 302a, 302d is less than the concentration of releasing agent in a single inner control sub-region 302b, 302c, such that the outer portion of the total control region will elute the therapeutic agent more slowly than the inner portion of the total control region. In some embodiments, the concentration of releasing agent in a single outer control sub-region 302a, 302d is greater than the concentration of releasing agent in a single inner control sub-region 302b, 302c. In those embodiments where the control region includes more than two subregions, the concentration of released agent per subregion or layer may increase, decrease, or remain constant as the subcontrol region moves away from the treatment region 200 .

[1184] In certain embodiments, the outer control subregion comprises at least 5% by weight of the releasing agent, at least 10% by weight of the releasing agent, at least 15% by weight of the releasing agent, at least 20% by weight of the releasing agent, at least 25% by weight of the releasing agent, at least 30% by weight of the releasing agent, at least 35% by weight of the releasing agent, at least 40% by weight of the releasing agent, at least 45% by weight of the releasing agent, or at least 50% by weight of the releasing agent. In some embodiments, the inner control subregion comprises at least 5% by weight of the releasing agent, at least 10% by weight of the releasing agent, at least 15% by weight of the releasing agent, at least 20% by weight of the releasing agent, at least 25% by weight of the releasing agent, at least 30% by weight of the releasing agent, at least 35% by weight of the releasing agent, at least 40% by weight of the releasing agent, at least 45% by weight of the releasing agent, or at least 50% by weight of the releasing agent. In some embodiments, the outer control subregion may include a first amount of releasing agent and the inner control subregion may include a second amount of releasing agent, wherein the second amount is at least 200%, at least 300%, at least 400%, or at least 500% greater than the first amount.

[1185] Figure 6-8An embodiment of a reservoir having multiple alternating treatment regions 200 and control regions 300 in accordance with the present technology is shown. A reservoir 100 can have two or more control regions 300 and / or sub-regions 302 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and a reservoir 100 can have one or more treatment regions 200 and / or sub-regions 202 (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, etc.) surrounded by at least one control region 300 and / or sub-region 302. In some embodiments, each of the treatment regions 200 can comprise a single layer and / or each of the control regions 300 can comprise a single layer. In some embodiments, one, some, or all of the treatment regions 200 can comprise multiple layers and / or one, some, or all of the control regions 300 can comprise multiple layers. In some embodiments, for example Figure 6 and 7 As shown in FIG. 1 , two or more sub-regions 302a-b ( Figure 6 ) and 302a-b and 302c-d( Figure 7 ) can be adjacent to each other between sub-regions 202 of the treatment region 200. In addition, one or more of the individual control regions 300 and / or one or more of the treatment regions 200 can have the same or different amounts and / or types of released agents, and one or more of the treatment regions can have the same or different amounts and / or types of therapeutic agents.

[1186] Figure 6-8 The embodiments shown in can be advantageous when the treatment area contains a large payload of therapeutic agent (e.g., a dose equivalent to many days, weeks, or months). These embodiments can be advantageous because with such a large payload, if the treatment area 200 is suddenly exposed to the body, the entire payload may 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 area 300 is compromised, the patient may be exposed to the therapeutic agent in the body at a higher rate than expected, potentially leading to clinical complications. In the event that the control area 300 is compromised, it is desirable for the patient to only be subjected to a portion of the total payload, so that the portion of the patient that is exposed if released prematurely will be within the safety limits of the specific therapeutic agent. The structural integrity of the control area 300, as well as the structural integrity of the treatment area(s) 200, are important properties for a reservoir having a large mass of therapeutic agent that is administered over a long period of time.

[1187] To address this issue, in some embodiments of the present technology, the reservoir 100 may comprise multiple treatment regions 200 (e.g., Figure 6-8). This configuration allows the therapeutic agent in each treatment region 200 (which carries a portion of the total payload) to be individually isolated. In the event of a compromise of a particular control region, only the portion of the payload corresponding to the treatment region associated with the compromised control region will be prematurely released. For example, in some of the aforementioned embodiments, the total payload of the reservoir 100 can 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 therapeutic agent. Likewise, in some embodiments, the portion of the payload per treatment area or sub-area may be at most 1%, at most 5%, at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100% of the total payload contained within the depot 100. As a result, if any individual sub-area 202 of the treatment area 200 is compromised, it may release only a proportional portion of the depot's total payload.

[1188] In some embodiments, each of the treatment regions and each of the control regions is a micro-thin layer, i.e., having a layer thickness of less than 1 mm. In some embodiments, the reservoir comprises about 2 to about 100 treatment regions, or about 2 to about 50 treatment regions, or about 2 to about 10 treatment regions.

[1189] Figure 9A-11 Some aspects of the present technology are shown in which a reservoir 100 can 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 of such a completely enclosed embodiment does not have any exposed surface area. For example, Figure 9A and 9B , in some embodiments, the reservoir 100 can include a treatment region 200 surrounded or completely surrounded 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 treatment region and physiological fluids, thereby preventing uncontrolled sudden release of the therapeutic agent when implanted. Over time, the release agent embedded in the polymer of the control region 300 contacts the physiological fluid and dissolves, thereby forming a diffusion opening in the control region. The combination of the restriction imposed by the control region and the diffusion opening formed by the dissolution of the release agent enables controlled release of the therapeutic agent from the reservoir over the course of days, weeks, or months. Although in Figure 9A and 9B The intermediate reservoir 100 is shown as a rectangular film, but in other embodiments the reservoir 100 may have other shapes, sizes, or forms.

[1190] Figure 10 A reservoir 100 is illustrated having a treatment area 200 completely surrounded by a control area 300 having a first control area 300a and a second control area 300b. Figure 10 As described in , in some embodiments, the treatment area 200 can be sandwiched between a first control area 300a and a second control area 300b, and the first and second control areas 300a-b can be combined by heat compression around the treatment area 200 to enclose the treatment area 200 therebetween. In certain embodiments, a bioabsorbable polymer can be wrapped around the entire reservoir and sealed on the top or bottom surface to create a Figure 9A A similar control zone structure is described in [ 15 ]. The outer portions of the first and second control zones 300a-b can be included as a final wrap to seal the edges. Alternatively, the first and second control zones 300a-b can be integrally formed with one another using dipping and / or spraying techniques, such as dipping the treatment area 200 in a solution of the control zone material or spraying a solution of the control zone material onto the surface of the treatment area 200.

[1191] exist Figure 10 , the first control region 300a may have first and second sub-regions 302a-b, and the second control region 300b may have first and second sub-regions 302c-d. The first control region 300a may define a top control region component, and the first and second sub-regions 302a-b may include a first top control layer and a second top control layer, respectively. The second control region 300b may define a bottom control region component, and the first and second sub-regions 302c-d may include a first bottom control layer and a second bottom control layer, respectively. The first and second top / bottom control layers may be the same as those described above with reference to Figure 5 Any variation of the first and second control sub-regions discussed above. In addition, the first top control layer of the top control region component can have the same or different properties (e.g., thickness, polymer, release agent, concentration of release agent, total amount of release agent, polymer to release agent ratio, etc.) as the first bottom control layer of the bottom control region component. Similarly, the second top control layer of the top control region component can have the same or different properties as the second bottom control layer of the bottom control region component. Variations in the loading and structure of the layers can be designed into the reservoir 100 to achieve a release profile or kinetics suitable for the intended therapeutic target. In other embodiments, the first control region 300a and / or the second control region 300b comprise a single layer.

[1192] Figure 11 Some embodiments are shown in which the depot 100 can have a treatment region 200 completely surrounded by a control region 300 having a different sub-region configuration. Figure 11The reservoir 100 includes a first control area 300a and a second control area 300b, which together completely surround the treatment area 200. Figure 10 In contrast to the reservoir 100 shown in FIG. 1 , a first control region 300a has an outer top control region 301a having first and second top sub-control regions 302a and 302b, respectively, and an inner top control region 301b having first and second top layers 303a and 303b. The first and second top layers 303a-b are only above the top surface of the treatment area 200, while the first and second top sub-control regions 302a-b cover a portion of the side surface of the treatment area 200 and the inner top control region 301b. The second control region 300b has an outer bottom control region 301c having first and second bottom sub-control regions 302c and 302d, respectively, and an inner bottom control region 301d having first and second bottom layers 303d and 303e, respectively. Thus, when the reservoir 100 is positioned at a treatment site within the body, the outer top and bottom control regions 301a and 301c are positioned between: (a) the treatment area 200 and the inner top and bottom control regions 301b and 301d, respectively, and (b) the physiological fluid at the treatment site. In certain embodiments, for example Figure 11 As shown in FIG, one or more of the outer top / bottom control regions 301a / 301c may contain one or more control sub-regions, and one or more of the inner top / bottom control regions 301b / 301d may include one or more control sub-regions.

[1193] Figure 12 A cross-section of a spherical reservoir 100 is shown having a plurality of alternating treatment regions 200 and control regions 300 according to the present technology, in accordance with several embodiments of the present technology. The reservoir 100 can have two or more control regions 300 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, etc.), and the reservoir can 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 can comprise a single layer and / or each of the control regions 300 can comprise a single layer. In some embodiments, one, some, or all of the treatment regions 200 can comprise multiple layers and / or one, some, or all of the control regions 300 can comprise multiple layers. Furthermore, one or more of the individual control regions 200 and / or one or more of the treatment regions 300 may have the same or different amounts and / or types of release agents, and one or more of the treatment regions 200 may have the same or different amounts and / or types of therapeutic agents.

[1194] Figure 13A depot 100 is shown having a treatment area 200 surrounded by a control area 300 on the top and bottom surfaces and two of the four side surfaces in accordance with several embodiments of the present technology. Figure 4 This configuration is expected to release the therapeutic agent more slowly (at least initially) compared to the depot 100 shown in FIG.

[1195] The release kinetics of the reservoir of the present technology can also be adjusted for a specific application by changing the shape and size of the reservoir 100. Depending on the therapeutic dose requirements, anatomical targets, etc., the reservoir 100 can be of different sizes, shapes and forms for implantation and / or injection into the body by a clinician. The shape, size and form of the reservoir 100 should be selected to facilitate positioning the reservoir at the target tissue site and to reduce the possibility of the reservoir moving after implantation or injection or to completely prevent the reservoir from moving after implantation or injection. In some embodiments, the reservoir is a flexible solid that can be handled by the clinician in the normal course of surgery in structure without breaking into multiple pieces and / or losing its overall shape. In addition, the reservoir can be configured to be placed at a mass site in the body and release the therapeutic agent in the body for up to 3 days or longer without breaking into multiple pieces.

[1196] Some of the form factors that can be produced from or used in conjunction with the depot 100 for implantation and fixation into the body include: strips, straps, hooks, rods, tubes, patches, spiral-shaped straps, partial or complete rings, nails, screws, tacks, rivets, wires, tapes, braided forms, T-shaped anchors, U-shaped staples, discs, pillows, balloons, braided wires, cone forms, wedge forms, chisel forms, tooth forms, stent structures, suture buttresses, coil springs, sponges, capsules, coatings, matrices, flakes, sheets, strips, straps, pills, and pellets.

[1197] The reservoir 100 can also be processed into an assembly having the form factor mentioned in the previous paragraph. For example, the reservoir can be rolled into and incorporated into a tube, screw, tack, etc. In the case of a braided embodiment, the reservoir can be incorporated into a multilayer braided membrane / braided wire / mesh, some of the filaments used are not devices of the present invention. In one example, the reservoir is interwoven with Dacron, polyethylene, etc. For clarity, any form factor corresponding to a reservoir of the present technology, including those in which only a portion or fragment of the form factor contains a reservoir, may be referred to herein as a "reservoir."

[1198] like Figure 14A The cross-sectional view of -14H shows that, in various embodiments, the reservoir 100 can be shaped like a sphere, a cylinder such as a rod or fiber, a flat surface such as a disk, a film, a strip, a ribbon or sheet, a paste, a slab, microparticles, nanoparticles, pellets, a mesh, etc. Figure 14AA straight line reservoir 100 is shown. Figure 14B A circular reservoir 100 is shown. FIG. (14C) shows a triangular reservoir 100. Figure 14D Showing the cross repository 100, Figure 14E Shows a star repository 100, and Figure 14F An annular reservoir 100 is shown. Figure 14G The spherical reservoir 100 is shown, and Figure 14H A cylindrical reservoir 100 is shown. The shape of the reservoir 100 can be selected based on anatomy to fit within a given space and provide desired fixation and flexibility properties. This is because the installation, fixation, and flexibility of the reservoir can enhance the ease of implanting the reservoir, ensure the delivery of the therapeutic agent to the target site, and prolong the durability of the implant in dynamic implantation sites.

[1199] In some embodiments, the reservoir 100 can be configured to release the therapeutic agent in an omnidirectional manner. In other embodiments, the reservoir can include one or more barrier regions 400 covering one or more portions of the treatment area 200 and / or the control area 300, thereby restricting the release of the therapeutic agent to certain directions. The barrier region 400 can provide structural support for the reservoir. The barrier region 400 can comprise a low-porosity, high-density bioabsorbable polymer configured to provide the reservoir with directional release capabilities. In this configuration, the substantial impermeability of the low-porosity, high-density polymer structure in the barrier region 400 blocks or hinders the passage of the agent released from the treatment area 200. As a result, the agent released from the treatment area 200 takes a path of less resistance through the control area 300 opposite the barrier region 400, particularly after a diffusion opening is created in the control area 300.

[1200] exist Figure 15A An example of a reservoir 100 of the present technology having a barrier region 400 is shown in FIG. The barrier region 400 can comprise a low porosity, high density, bioresorbable polymer configured to provide a directed release capability to a multi-region reservoir. In this configuration, the low porosity, high density polymer structure in the barrier region 400 blocks or hinders the passage of the agent released from the treatment region 200. Thus, the agent released from the treatment region 200 takes a path of less resistance through the control region opposite the barrier region 400, especially after a channel is created in the control region. In other embodiments, the porosity of other regions of the multi-region reservoir can be varied to facilitate the release of the therapeutic agent. For example, in such an embodiment, in Figure 15AThe barrier region 400, therapeutic region 200, and control region 300 of the multi-region reservoir described in

[0014] can have varying porosities ranging from a low porosity in the barrier region 400 to higher porosities in the therapeutic and control regions to facilitate release of the therapeutic agent from the multi-region reservoir. In further embodiments, the porosity within the edge of the multi-region reservoir or a portion of any individual region can be varied to appropriately tailor or control the release of the therapeutic agent.

[1201] exist Figure 15B In the embodiments described in

[0015] , a multi-region reservoir provides for bidirectional or dual-directional release of a therapeutic agent. This bidirectional release capability is achieved by symmetrical partitioning around a high-density barrier region 400, wherein, as described above, the therapeutic agent is released along a path of less resistance, thereby being released away from the high-density barrier region 400. More specifically, disposed on one side of the barrier region 400 are a control region 300a and a therapeutic region 200a, and disposed on the other side of the barrier region 400 are a pair of substantially similar control regions 300b and therapeutic regions 200b on the other side. These pairs on either side of the barrier region 400 are configured to produce substantially equivalent bidirectional release of the therapeutic agent. In alternative embodiments, unequal (i.e., release agent and / or release rate differ in each direction) bidirectional release can be achieved by asymmetric partitioning, whereby the control region and therapeutic region pairs on either side of the barrier region 400 are substantially different.

[1202] In other embodiments, it may be desirable for multiple regional reservoirs to release multiple therapeutic agents. This capability may be particularly useful when multimodal drug therapy is indicated. Figure 15C In the embodiment shown in FIG, a multi-region reservoir comprises an uppermost or outermost control region 300a, a first therapeutic region 200a adjacent to the control region, a second therapeutic region 200b adjacent to the first therapeutic region 200a, and a barrier region 400 adjacent to the second therapeutic region 200b. In this embodiment, the first therapeutic region 200a and the second therapeutic region 200b contain 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 reservoir is configured to release the first and second therapeutic agents sequentially, simultaneously, or in an overlapping manner to produce complementary or synergistic benefits. In this configuration, the presence and function of the control region 300a can also ensure consistent and, if desired, substantially smooth release of the multiple underlying therapeutic agents. Because many conventional drug delivery devices may not provide for smooth release of multiple drugs having different molecular weights, solubilities, etc., the role of the control region in achieving substantially smooth release of the different therapeutic agents can be a significant advantage.

[1203] 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 zones, respectively, representing different doses to be administered. In some embodiments, the first and second therapeutic agents in the first and second treatment zones, respectively, may not have any clinical association or relationship whatsoever. For example, in some embodiments, it may be clinically desirable to administer the first therapeutic agent near the surgical site for several days or weeks after surgery and to administer the second therapeutic agent for several weeks or months after surgery. In this embodiment, the first treatment zone 200a may include a therapeutically effective dose of the first therapeutic agent and the second treatment zone 200b may include a therapeutically effective dose of the second therapeutic agent.

[1204] In some embodiments, as Figure 15D , depot 100 comprises a first dosing area and a second dosing area, wherein the first and second dosing areas correspond to first and second dosing regimens. More specifically, each dosing area comprises a pair of control and therapeutic areas, wherein each pair is configured to controllably release a therapeutic agent from therapeutic areas 200a, 200b according to a predetermined dosing regimen. In this exem...

Claims

1. A depot for treating symptoms associated with type II diabetes, comprising: a treatment area comprising a therapeutic agent including a glucagon-like peptide-1 (GLP-1) receptor agonist; and a control region comprising a bioabsorbable polymer and a release agent admixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region, Therein the depot is configured to be implanted in vivo and, when implanted, releases the GLP-1 receptor agonist for a period of time.

2. The depot of claim 1, wherein the GLP-1 receptor agonist comprises at least one of the following: exenatide, liraglutide, albiglutide, dulaglutide, or lixisenatide, semaglutide, derivatives thereof, or combinations thereof.

3. The depot of claim 1 or claim 2, wherein the therapeutic agent is a first therapeutic agent and the treatment region further comprises a second therapeutic agent, wherein the second therapeutic agent comprises metformin.

4. The depot of claim 3, wherein the first therapeutic agent is released before or after the second therapeutic agent.

5. The depot of claim 3, wherein the first and second therapeutic agents are released substantially simultaneously.

6. The depot according to any one of claims 1 to 5, wherein the GLP-1 receptor agonist in the treatment area accounts for at least 50% of the total weight of the depot.

7. The storage depot according to any one of claims 1 to 6, wherein the time period is not less than 1 month.

8. The depot of any one of claims 1 to 7, wherein the depot is biodegradable and / or bioerodible.

9. The depot of any one of claims 1-8, wherein about 40% to about 60% of the GLP-1 receptor agonist in the treatment area is released in the first half of the time period.

10. The depot of any one of claims 1-9, wherein the depot is configured to release about 2 μg / day to about 10 mg / day of the GLP-1 receptor agonist.

11. The depot of any one of claims 1-10, wherein the GLP-1 receptor agonist is released at a substantially steady-state rate over the entire period of time.

12. The depot according to any one of claims 1 to 11, wherein the depot further comprises a heat stabilizer.

13. The depot of claim 12, wherein the thermal stabilizer comprises at least one of a sugar, an antioxidant, or a buffer.

14. The depot of claim 13, wherein the sugar comprises at least one of trehalose, raffinose or mannitol.

15. The depot of claim 13, wherein the antioxidant comprises at least one of methionine, ascorbic acid, sodium thiosulfate, catalase, ethylenediaminetetraacetic acid (EDTA) platinum, citric acid, cysteine, monothioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, or propyl gallate.

16. The depot of claim 13, wherein the buffer comprises at least one of citrate, histidine, succinate, or tris.

17. The depot of any one of claims 1-16, wherein the depot further comprises a compound configured to inhibit denaturation of the therapeutic agent in vivo.

18. A system for administering a therapeutic agent to a patient, the system comprising: a needle having an inner lumen; A syringe operatively connected to a needle; and a reservoir disposed within the lumen and configured to be expelled from the needle upon actuation of the syringe, the reservoir comprising: a treatment area comprising a therapeutic agent including a glucagon-like peptide-1 (GLP-1) receptor agonist; and a control region at least partially surrounding the treatment region and elongated along the first axis, the control region comprising a bioabsorbable polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve when the depot is placed in vivo to form a diffusion opening in the control region; Therein the depot is configured to be implanted in the body and, when implanted, releases the therapeutic agent for a period of time.

19. The system of claim 18, wherein the reservoir comprises the reservoir of any one of claims 1-17.

20. The system of claim 18 or claim 19, wherein the needle has a lumen no larger than 22 gauge.

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