Flexible implantable depot for controlled drug release

Abstract

Implantable depots for delivering therapeutic agents, as well as related systems and methods, are provided. In some embodiments, an implantable depot for treating pain includes a therapeutic area comprising a polymer, an analgesic, and a plasticizer. The therapeutic area may be configured to release the analgesic over a treatment period of at least three days when implanted in vivo. The implantable depot may have a flexural modulus in the range of 1 MPa to 400 MPa.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 492,980, filed on 29 March 2023, which is incorporated herein by reference in its entirety.

[0002] Technical field The technology of the present invention generally relates to implantable depots, and more particularly to implantable depots and related systems and methods for delivering therapeutic agents. [Background technology]

[0003] background Implantable systems for controlled release of therapeutic agents offer advantages over other drug delivery methods, such as oral or parenteral administration. Devices fabricated from biocompatible and / or biodegradable polymers and therapeutic agents can be implanted in clinically desirable anatomical locations, thereby resulting in localized delivery of the selected drug. This localized delivery allows a significant proportion of the drug to reach the intended target, while avoiding undesirable systemic side effects. However, these systems often suffer from a lack of a true controlled release mechanism, typically resulting in a burst release of the therapeutic agent upon contact with surrounding physiological fluids, followed by the release of the remaining drug.

[0004] The controlled, sustained release of therapeutic agents can be clinically beneficial in certain environments. In particular, it may be desirable to implant biodegradable carriers that hold large doses of therapeutic agents for controlled, sustained release over time. This can be especially valuable when the therapeutic agent-loaded carrier is implanted in conjunction with an intervention or surgical procedure, and, if necessary, together with or as part of an implantable medical device. Therefore, there is a need for biocompatible implantable systems that can provide highly controlled release of therapeutic agents. [Overview of the project] [Means for solving the problem]

[0005] Many aspects of this disclosure can be better understood by referring to the following figures. The components in the figures are not necessarily to scale. Instead, the emphasis is on clearly illustrating the principles of this disclosure. [Brief explanation of the drawing]

[0006] [Figure 1A] Figure 1A is a partial schematic diagram of an implantable depot configured according to an embodiment of the present invention.

[0007] [Figure 1B] Figure 1B is a partial schematic diagram of another implantable depot configured according to an embodiment of the present invention.

[0008] [Figure 1C] Figure 1C is a partial schematic diagram of yet another implantable depot configured according to an articulation of the present invention.

[0009] [Figure 2A] Figure 2A is a top view of a rectangular depot configured according to an articulation of the present invention.

[0010] [Figure 2B] Figure 2B is a side view of the rectangular depot shown in Figure 2A.

[0011] [Figure 3A] Figure 3A is a top view of a triangular depot having holes configured according to an articulation of the present invention.

[0012] [Figure 3B] Figure 3B is a side view of the triangular depot shown in Figure 3A.

[0013] [Figure 4A] Figure 4A is a top view of a triangular depot having holes configured according to an articulation of the present invention.

[0014] [Figure 4B] Figure 4B is a side view of the triangular depot shown in Figure 4A.

[0015] [Figure 4C] Figure 4C is a top view of another triangular depot having holes configured according to an articulation of the present invention.

[0016] [Figure 4D] Figure 4D is a top view of yet another triangular depot having holes configured according to an articulation of the present invention.

[0017] [Figure 4E] Figure 4E is a top view of a triangular depot having holes configured according to an articulation of the present invention.

[0018] [Figure 4F] Figure 4F is a top view of another triangular depot having holes configured according to an articulation of the present invention.

[0019] [Figure 4G] Figure 4G is a top view of a triangular depot having holes configured according to an articulation of the present invention.

[0020] [Figure 4H] Figure 4H is a top view of yet another triangular depot having holes configured according to an articulation of the present invention.

[0021] [Figure 5A] Figure 5A is a top view of an arrowhead-shaped depot configured according to an articulation of the present invention.

[0022] [Figure 5B] Figure 5B is a top view of a rhomboid-shaped depot configured according to an articulation of the present invention.

[0023] [Figure 5C] Figure 5C is a top view of a rectangular depot configured according to an articulation of the present invention.

[0024] [Figure 5D] Figure 5D is a top view of a cross-shaped depot configured according to an embodiment of the present invention.

[0025] [Figure 5E] Figure 5E is a top view of an L-shaped depot configured according to an articulation of the present invention.

[0026] [Figure 5F] Figure 5F is a top view of a circular depot configured according to an embodiment of the present invention.

[0027] [Figure 5G] Figure 5G is a perspective view of a spherical depot configured according to an articulation of the present invention.

[0028] [Figure 5H] Figure 5H is a top view of a rhomboid-shaped depot configured according to an articulation of the present invention.

[0029] [Figure 6] Figure 6 is a scanning electron microscope image of a portion of an implantable depot.

[0030] [Figure 7A] Figure 7A is a graph showing in vitro elution data for implantable depots.

[0031] [Figure 7B] Figure 7B is another graph showing in vitro elution data for implantable depots.

[0032] [Figure 8A]Figure 8A is a scanning electron microscope image of an implanted depot in which approximately 25% of the material has been eluted.

[0033] [Figure 8B] Figure 8B is a scanning electron microscope image of an implanted depot in which approximately 75% of the material has been eluted.

[0034] [Figure 9A] Figure 9A is a graph showing the mean bupivacaine plasma concentration in subjects treated with implantable depot therapy after total knee arthroplasty, compared to other formulations.

[0035] [Figure 9B] Figure 9B is a graph showing the mean bupivacaine plasma concentration overlaid with postoperative pain data in patients treated with implantable depot implants after total knee arthroplasty.

[0036] [Figure 9C] Figure 9C is a graph showing the area under the curve (AUC) of bupivacaine plasma concentration in subjects treated with an implantable depot after total knee arthroplasty, compared to other formulations.

[0037] [Figure 9D] Figure 9D is a graph showing the mean bupivacaine plasma concentrations in subjects receiving various doses of bupivacaine from an implantable depot.

[0038] [Figure 9E] Figure 9E is a graph showing the relationship between Cmax and bupivacaine dose for implantable depots.

[0039] [Figure 9F] Figure 9F is a graph showing the relationship between AUC0-14d and bupivacaine dose for implantable depot therapy.

[0040] [Figure 9G]Figure 9G is a graph showing the in vivo bupivacaine release profile in subjects receiving implanted depot therapy.

[0041] [Figure 10] Figure 10 is a graph showing the mean pain intensity scores for subjects treated with implantable depots (opioid consumption has not been adjusted).

[0042] [Figure 11A] Figure 11A is a graph showing simulated bupivacaine plasma concentrations in subjects treated with an implantable depot after shoulder surgery, compared to actual bupivacaine plasma concentrations in subjects treated with other bupivacaine preparations.

[0043] [Figure 11B] Figure 11B is a graph showing simulated bupivacaine plasma concentrations in subjects treated with an implantable depot after bunion resection, compared to actual bupivacaine plasma concentrations in subjects treated with a different bupivacaine preparation.

[0044] [Figure 11C] Figure 11C is a graph showing simulated bupivacaine plasma concentrations in subjects treated with an implantable depot after open inguinal hernia repair, compared to actual bupivacaine plasma concentrations in subjects treated with other bupivacaine preparations.

[0045] [Figure 12] Figure 12 is a graph showing the cumulative in vitro release of bupivacaine from an implantable depot formulated with bupivacaine free base without a control region.

[0046] [Figure 13] Figure 13 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots with various control regions.

[0047] [Figure 14A] Figure 14A is a graph showing the cumulative in vitro release of bupivacaine from an implantable depot formulated with bupivacaine in free base and salt forms.

[0048] [Figure 14B] Figure 14B is a graph showing the cumulative in vitro release of bupivacaine from an implanted depot containing bupivacaine in free base and salt forms.

[0049] [Figure 15] Figure 15 is a semi-logarithmic graph showing the in vivo release of bupivacaine from an implantable depot formulated with free base and salt forms of bupivacaine in a rabbit subcutaneous model.

[0050] [Figure 16] Figure 16 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots with various therapeutic drug loadings.

[0051] [Figure 17] Figure 17 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots formulated with various free base:salt ratios.

[0052] [Figure 18A-B] Figures 18A and 18B illustrate Monte Carlo methods for modeling the displacement of various depot geometries.

[0053] [Figure 18C-D] Figures 18C and 18D show geometric / calculusal techniques for modeling the displacement of various depot geometric shapes.

[0054] [Figure 19] Figure 19 is a graph showing the cumulative in vitro release of bupivacaine from implanted depots with different geometric shapes at pH 5.8.

[0055] [Figure 20] Figure 20 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots formulated with different bupivacaine particle sizes at pH 5.8.

[0056] [Figure 21A] Figure 21A is a graph showing the cumulative in vitro release of bupivacaine from an implantable depot with a control region at pH 5.8, compared to a depot without a control region.

[0057] [Figure 21B] Figure 21B is a graph showing the cumulative in vitro release of bupivacaine from implantable depots with different geometric shapes and thicknesses that do not have a control region at pH 5.8.

[0058] [Figure 21C] Figure 21C is a graph showing the cumulative in vitro release of bupivacaine from implantable depots of varying thicknesses that lack a control region at pH 7.4.

[0059] [Figure 21D] Figure 21D is a graph showing the cumulative in vitro release from implantable depots without a control region, formulated with bupivacaine of different particle sizes at pH 5.8.

[0060] [Figure 22A] Figure 22A is a graph showing the in vivo release of bupivacaine from various combinations of implantable depot configurations in a rabbit subcutaneous model.

[0061] [Figure 22B] Figure 22B is a graph showing the in vivo release of bupivacaine from implantable depots of various configurations in a miniature pig abdominal hernia repair model.

[0062] [Figure 22C] Figure 22C is a graph showing the in vivo release of bupivacaine from implantable depots of various configurations in a canine subcutaneous model.

[0063] [Figure 22D] Figure 22D is a graph showing cumulative AUClast profiles for various configurations of implantable depots in different animal models.

[0064] [Figure 23] Figure 23 is a graph showing the in vivo release of bupivacaine from implantable depots of various configurations in a miniature pig abdominal hernia repair model.

[0065] [Figure 24] Figure 24 is a graph showing the in vivo release of bupivacaine from implantable depots at various doses in a rat subcutaneous model.

[0066] [Figure 25] Figure 25 shows the chemical structure of the plasticizer.

[0067] [Figure 26A] Figures 26A-26C are graphs showing the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 26A), diethyl phthalate (Figure 26B), and benzyl benzoate (Figure 26C) with a 14 wt% loading. [Figure 26B] Figures 26A-26C are graphs showing the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 26A), diethyl phthalate (Figure 26B), and benzyl benzoate (Figure 26C) with a 14 wt% loading. [Figure 26C]Figures 26A-26C are graphs showing the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 26A), diethyl phthalate (Figure 26B), and benzyl benzoate (Figure 26C) with a 14 wt% loading.

[0068] [Figure 27A] Figures 27A-27C are graphs showing the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 27A), diethyl phthalate (Figure 27B), and benzyl benzoate (Figure 27C) with a 3.2 wt% loading. [Figure 27B] Figures 27A-27C are graphs showing the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 27A), diethyl phthalate (Figure 27B), and benzyl benzoate (Figure 27C) with a 3.2 wt% loading. [Figure 27C] Figures 27A-27C are graphs showing the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 27A), diethyl phthalate (Figure 27B), and benzyl benzoate (Figure 27C) with a 3.2 wt% loading.

[0069] [Figure 28A] Figures 28A-28C are graphs showing in vitro release at pH 5.8 for depots with various plasticizer loadings and thicknesses. [Figure 28B] Figures 28A-28C are graphs showing in vitro release at pH 5.8 for depots with various plasticizer loadings and thicknesses. [Figure 28C] Figures 28A-28C are graphs showing in vitro release at pH 5.8 for depots with various plasticizer loadings and thicknesses.

[0070] [Figure 29]Figure 29 is a graph showing in vitro release at pH 5.8 for depots without plasticizers, depots containing a single plasticizer, and depots containing two plasticizers (dual plasticizers).

[0071] [Figure 30] Figure 30 is a graph showing the in vitro release at pH 5.8 for depots without plasticizers, depots containing a single plasticizer, depots containing two plasticizers, and depots containing three plasticizers.

[0072] [Figure 31] Figure 31 is a graph showing in vitro release at pH 5.8 for depots without plasticizers or depots containing two types of plasticizers.

[0073] [Figure 32A] Figure 32A shows the setup for the depot's mechanical testing.

[0074] [Figure 32B] Figure 32B is an image of a depot loaded with plasticizer during mechanical testing.

[0075] [Figure 33A] Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33B]Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33C] Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33D] Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33E] Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33F]Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33G] Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H). [Figure 33H] Figures 33A-33H are graphs showing force-displacement curves for depots formulated with 14 wt% loading using benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl o-acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H).

[0076] [Figure 34] Figure 34 is a graph showing the force-displacement curves for depots formulated with various plasticizers at a 3.2 wt% loading.

[0077] [Figure 35] Figure 35 is a graph showing force-displacement curves for depots containing one or two plasticizers at various points in time after manufacturing.

[0078] [Figure 36] Figure 36 is a graph showing the force-displacement curves for a depot containing three types of plasticizers at various points in time after manufacturing. [Modes for carrying out the invention]

[0079] Detailed explanation The present invention relates to implantable depots for sustained controlled release of therapeutic agents, as well as related systems and methods. For example, in some embodiments, an implantable depot for treating a target comprises a therapeutic area comprising a polymer (e.g., poly(lactide-co-glycolide)), an analgesic (e.g., bupivacaine), and at least one plasticizer (e.g., triacetin, diethyl phthalate, benzyl benzoate, and / or glycerol). The presence of the plasticizer can enhance the flexibility of the depot. For example, the depot may have a flexural modulus in the range of 1 MPa to 400 MPa. When implanted in vivo, the therapeutic area can release the analgesic over a desired treatment period, such as a treatment period of at least 3 days. The depot may be configured, as desired, to provide short-term release of the analgesic (e.g., treatment period of 7 days or less) or long-term release of the analgesic (e.g., treatment period of at least 14 days).

[0080] As another example, in some embodiments, an implantable depot for treating a target includes a therapeutic area having a first surface, a second surface opposite the first surface, and a lateral surface between the first and second surfaces. The therapeutic area may contain a polymer and a therapeutic agent (e.g., bupivacaine). When implanted in a target, the depot can release the therapeutic agent from the first surface, the second surface, and the lateral surface of the therapeutic area. The therapeutic agent release profile can be adjusted by changing various parameters of the depot, such as its composition (e.g., therapeutic agent, polymer, and / or other components, e.g., the amount and / or type of the releasing agent) and / or its geometry (e.g., the thickness of the therapeutic area). Thus, the depots described herein can be adapted to provide sustained, controlled release of a therapeutic agent for many different types of applications, for example, suitable for treating postoperative pain after surgical procedures.

[0081] Embodiments of this disclosure are described in full below by reference to the accompanying figures, in which similar figures represent similar elements and embodiments are shown as examples. However, embodiments of the claims can be embodied in many different forms and should not be construed as being limited to embodiments described herein. The examples described herein are non-limiting examples and are merely some of many other possible examples.

[0082] As used herein, terms such as “vertical,” “lateral,” “up,” “down,” “left,” and “right” may refer to the relative orientation or position of features of embodiments disclosed herein, taking into account the orientation shown in the figures. For example, “up” or “top” may refer to a feature that is located closer to the top than another feature on a page. However, these terms should be interpreted broadly to include embodiments having other orientations, such as inverted or inclined orientations, and top / bottom, above / below, above / below, up / down, and left / right may be interchangeable depending on the orientation.

[0083] The headings provided herein are provided solely for convenience and do not constitute an interpretation of the scope or meaning of the claimed technology of the present invention. Embodiments under any one heading may be used in conjunction with embodiments under any other heading.

[0084] I. Implantable depot for delivering therapeutic agents A. Overview Figure 1A is a partial schematic diagram of an implantable depot 100a configured according to an articulation of the present invention. The depot 100a is implanted at a treatment site on the patient's body and, once implanted, is configured to release at least one therapeutic agent at the treatment site in a controlled manner, for example, according to a desired release profile. The therapeutic agent may be any substance suitable for treating the patient's disease or condition. For example, the therapeutic agent may be or may contain an analgesic (e.g., bupivacaine) to address postoperative pain or other types of pain (e.g., chronic pain). Further examples and features of therapeutic agents that may be contained in the depot 100a are provided in Section IC1 below.

[0085] Depot 100a may be any suitable structure or device suitable for carrying and controllably releasing a therapeutic agent, such as a film, sheet, strip, ribbon, capsule, coating, matrix, wafer, sphere, pellet, bead, scaffold, or a combination thereof. In a descriptive embodiment, depot 100a is a monolithic structure including a therapeutic area 102 positioned between a first control area 104a and a second control area 104b. The therapeutic area 102 (also known as the “core area,” “drug core,” or “drug layer”) contains the therapeutic agent, while the control areas 104a, 104b (also known as the “control layers”) can modulate the release of the therapeutic agent from the therapeutic area 102. As will be discussed in detail below, the geometry and composition of the therapeutic area 102 and the control areas 104a, 104b may be configured to produce a desired release profile of the therapeutic agent.

[0086] In some embodiments, the therapeutic region 102 comprises a therapeutic agent and at least one polymer (e.g., poly(lactide-co-glycolide) (PLGA)). The polymer can be combined with the therapeutic agent to form a solid central core of the depot 100a. In some embodiments, the therapeutic agent and the polymer are separate phases within the therapeutic region 102, and the polymer acts as a “glue” to hold the therapeutic agent together. In such embodiments, the therapeutic agent can form individual crystals, particles, etc., which are bonded together by the polymer to form an integrated material. However, in other embodiments, the therapeutic agent can be dissolved in the polymer to form a single-phase drug-polymer matrix. In some embodiments, the polymer is a bioreabsorbable polymer configured to degrade when exposed to physiological fluids. The degradation characteristics of the bioreabsorbable polymer can be selected to modulate the release rate of the therapeutic agent from the therapeutic region 102. Further examples and features of polymers that may be included in the therapeutic region 102 are provided in Section IC2 below.

[0087] If necessary, the therapeutic area 102 may contain further components, such as a release agent (e.g., polysorbate). The release agent may also affect the rate of release of the therapeutic agent. In some embodiments, the release agent may have a dissolution rate faster than the rate of degradation of the polymer in the therapeutic area 102 when exposed to a fluid (e.g., a physiological fluid). Thus, when the fluid comes into contact with the therapeutic area 102 (e.g., after implantation of the depot 100a at the treatment site), the release agent dissolves in the polymer surrounding the therapeutic area 102, and thus forms openings (e.g., channels, voids, pores, etc.) in the surrounding polymer region, which facilitate the infiltration of the fluid into the therapeutic area 102 and / or the diffusion of the therapeutic agent from the therapeutic area 102. Therefore, increasing the amount of release agent in the therapeutic area 102 can increase the rate of release of the therapeutic agent after implantation, as will be discussed in more detail elsewhere herein. Alternatively or in combination, the release agent may function as a surfactant that increases the uptake of water into the depot 100a or otherwise alters the interface between the therapeutic agent, polymer, and water to enhance the release rate. If necessary, the release agent may modulate the mechanical properties of the therapeutic region 102 (e.g., increase flexibility and / or reduce brittleness), thereby facilitating the preparation, storage, and / or handling of the depot 100a. Further examples and features of release agents that may be included in the therapeutic region 102 are provided in Section IC3 below. However, in other embodiments, the therapeutic region 102 may be provided without any release agent.

[0088] As shown in Figure 1A, the therapeutic area 102 is positioned between the control areas 104a and 104b. The first control area 104a may partially or completely cover the first surface 106a (e.g., the upper surface) of the therapeutic area 102. The second control area 104b may partially or completely cover the second surface 106b (e.g., the lower surface) of the therapeutic area 102 opposite to the first surface 106a. The therapeutic area 102 may include one or more outer surfaces 108 that are not covered by the control areas 104a, 104b. In a descriptive embodiment, for example, all four outer surfaces 108 of the therapeutic area 102 are exposed. Alternatively, in other embodiments, the therapeutic area 102 may include three, two, or a single exposed outer surface 108. Alternatively, the therapeutic area 102 may be entirely enclosed by one or more control areas so that no exposed outer surfaces 108 are present.

[0089] Each of the control regions 104a and 104b may contain at least one polymer (e.g., PLGA). The first control region 104a may be made from the same polymer as the second control region 104b, or from a different polymer. Additionally, the polymers used in the first and / or second control regions 104a and 104b may be the same polymer as the polymer used in the therapeutic region 102, or from a different polymer. In some embodiments, the polymers in the first and / or second control regions 104a and 104b are bioreabsorbable polymers. Further examples and features of polymers that may be included in the first and second control regions 104a and 104b are provided in Section IC2 below.

[0090] If necessary, the control regions 104a, 104b may include further components, such as release agents (e.g., polysorbates). The first control region 104a may contain the same release agent as the second control region 104b, or it may contain a different release agent. Additionally, the release agent used in the first and / or second control regions 104a, 104b may be the same as the release agent used in the therapeutic region 102, or it may be a different release agent. Further examples and features of release agents that may be included in the first and second control regions 104a, 104b are provided in the following section IC3. However, in other embodiments, the first and / or second control regions 104a, 104b may be provided without any release agent.

[0091] The configuration (e.g., position and / or geometry) and composition of the control regions 104a and 104b can modulate the release profile of the therapeutic agent from the therapeutic region 102. For example, when a depot 100a is implanted in the treatment site, the control regions 104a and 104b can be positioned between the first and second surfaces 106a and 106b of the therapeutic region 102 and the physiological fluid of the treatment site. Thus, the control regions 104a and 104b can reduce or prevent the diffusion of fluid toward the first and second surfaces 106a and 106b. In some embodiments, the polymer within the control regions 104a and 104b creates a partially or completely impermeable barrier to fluid infiltration, such that any further components (e.g., release agents) within the control regions 104a and 104b are isolated within the polymer and not exposed to the fluid.

[0092] Control regions 104a, 104b can reduce or prevent the diffusion of the therapeutic agent from the first and second surfaces 106a, 106b. In some embodiments, the therapeutic agent is released from the surface of the therapeutic region 102 only when the surface of the therapeutic region 102 is exposed to the fluid, and thus a pathway is provided for the therapeutic agent to diffuse from the therapeutic region 102 into the surrounding environment. Control regions 104a, 104b may be configured to block the release of all or substantially all of the therapeutic agent from the first and second surfaces 106a, 106b so that all or substantially all of the therapeutic agent delivered from the depot 100a is released through the exposed outer surface 108 of the therapeutic region 102. For example, at least 80%, 85%, 90%, 95%, 99%, or 100% of the therapeutic agent delivered from depot 100a may be released through the outer surface 108, while 20%, 15%, 10%, 5%, or less than 1% of the therapeutic agent delivered from depot 100a may be released through the first and second surfaces 106a, 106b. In some embodiments, the overall release rate of the therapeutic agent is determined at least in part by the distance (e.g., maximum, minimum, and / or average distance) between individual molecules of the therapeutic agent and the exposed surface of the therapeutic area 102 closest to them, which is also referred to herein as the “travel distance” of the therapeutic agent. For example, a therapeutic agent placed around the depot 100a near the outer surface 108 may be released more rapidly than a therapeutic agent placed inside the depot 100a away from the outer surface 108, thus creating a sustained release profile, as will be described in more detail below.

[0093] In some embodiments, the control regions 104a and 104b also perform other functions, such as increasing the mechanical integrity of the depot 100a. For example, the control regions 104a and 104b may have higher tensile strength and / or fracture resistance than the therapeutic region 102. Therefore, the presence of the control regions 104a and 104b can improve the handling and storage characteristics of the depot 100a.

[0094] Depot 100a is configured to release the therapeutic agent in a highly controlled, predetermined manner, particularly tailored to the medical condition being treated and / or the therapeutic agent being used. As described in more detail below, the release kinetics of Depot 100 can be customized for a specific application by changing one or more aspects of the composition and / or structure of the depot, for example: the geometry (e.g., size and / or shape) of Depot 100a, therapeutic area 102, and / or control areas 104a, 104b; the type of therapeutic agent, polymer, and / or release agent used; and the amounts of therapeutic agent, polymer, and / or release agent contained in Depot 100a (e.g., in therapeutic area 102 and / or control areas 104a, 104b).

[0095] Figure 1B is a partial schematic diagram of another implantable depot 100b configured according to an articulation of the present invention. Depot 100b is generally similar to depot 100a in Figure 1A, except that depot 100b includes a single control region instead of two control regions. In a descriptive embodiment, depot 100b includes a first control region 104a covering the first surface 106a of depot 100b such that a second surface 106b and an outer surface 108 are exposed. Thus, the control region 104a can block the release of all or substantially all of the therapeutic agent from the first surface 106a so that all or substantially all of the therapeutic agent delivered from depot 100b is released from the exposed second surface 106b and outer surface 108 of the therapeutic area 102. Alternatively, depot 100b may include a second control region 104b covering the second surface 106b of depot 100b such that the first surface 106a and an outer surface 108 are exposed. Depot 100b can be used in embodiments where a faster release rate is desired (relative to the release rate of Depot 100a), and / or in embodiments where the therapeutic agent is relatively hydrophobic, as further described below.

[0096] Figure 1C is a partial schematic diagram of yet another implantable depot 100c configured according to an articulation of the present invention. Depot 100c is generally similar to depot 100a in Figure 1A, except that depot 100c does not contain any control region so that the first surface 106a, the second surface 106b, and the outer surface 108 are exposed. Thus, the therapeutic agent can be released from the first surface 106a, the second surface 106b, and the outer surface 108 of depot 100c. Depot 100c can be used in embodiments where a faster release rate is desired (relative to the release rate of depot 100a or depot 100b), and / or in embodiments where the therapeutic agent is relatively hydrophobic, as further described below.

[0097] B. Geometric shape Figures 2A–5H show representative examples of depots 200–570 having various geometric shapes configured according to the technical embodiments of the present invention. The features of depots 200–570 may generally be similar to those of depots 100a–100c in Figures 1A–1C. Therefore, similar numbers (e.g., therapeutic area 102 vs. therapeutic area 202) are used to identify similar or identical components in Figures 1A–5H, and the discussion of depots 200–570 in Figures 2A–5H is limited to features that differ from depots 100a–100c in Figures 1A–1C. In addition, any of the features of depots 200–570 in Figures 2A–5H can be combined with each other and / or with the features of depots 100a–100c in Figures 1A–1C. Some embodiments of depots 200 to 570 in Figures 2A to 5H are shown having two control regions (similar to depot 100a in Figure 1A), but in other embodiments, any of depots 200 to 570 may have a single control region (similar to depot 100b in Figure 1B), or may not have a control region at all (similar to depot 100c in Figure 1C).

[0098] Figure 2A is a top view of the rectangular depot 200, and Figure 2B is a side view of the rectangular depot 200. As is most commonly seen in Figure 2A, the depot 200 has a generally rectangular shape with rounded corners. The depot 200 can have a length L1 in the range of 10mm to 50mm, 15mm to 45mm, 20mm to 30mm, or 25mm to 35mm. In some embodiments, the length L1 is at least 10mm, 12.5mm, 15mm, 17.5mm, 20mm, 22.5mm, 25mm, 27.5mm, 30mm, 32.5mm, 35mm, 37.5mm, 40mm, 42.5mm, 45mm, 47.5mm, or 50mm. Depot 200 can have a width W1 in the range of 5mm to 30mm, 10mm to 25mm, 10mm to 20mm, or 15mm to 25mm. In some embodiments, the width W1 is equal to or greater than 5mm, 7.5mm, 10mm, 11mm, 12mm, 12.5mm, 13mm, 14mm, 15mm, 16mm, 17mm, 17.5mm, 18mm, 19mm, 20mm, 22.5mm, 25mm, 27.5mm, or 30mm.

[0099] Next, referring to Figure 2B, the depot 200 can have a total thickness T1 in the range of 100 μm to 5 mm, 500 μm to 2.5 mm, 1 mm to 2 mm, 750 μm to 1.25 mm, 1 mm to 1.5 mm, 1.25 mm to 1.75 mm, 1.75 mm to 2.25 mm, or 2 mm to 2.5 mm. For example, the total thickness T1 is 100μm, 200μm, 300μm, 400μm, 500μm, 600μm, 700μm, 800μm, 900μm, 1mm, 1.1mm, 1.2mm, 1.25mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.7mm, 1.75mm, 1.8mm, 1.9mm, 2mm, 2.1mm, 2.2mm, 2.25mm, 2.3mm, 2.4mm, 2.5mm. m, 2.6mm, 2.7mm, 2.75mm, 2.8mm, 2.9mm, 3mm, 3.1mm, 3.2mm, 3.3mm, 3.4mm, 3.5mm, 3.6mm, 3.7mm, 3.8mm, 3.9mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, or equal to or greater than 5mm.

[0100] The therapeutic area 202 may have a thickness greater than or equal to 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 98.8%, 99%, or 99.5% of the total thickness T1 of the depot 200. In some embodiments, the thickness of the therapeutic area 202 may be in the range of 100 μm to 5 mm, 500 μm to 2.5 mm, 1 mm to 2 mm, 750 μm to 1.25 mm, 1 mm to 1.5 mm, 1.25 mm to 1.75 mm, 1.75 mm to 2.25 mm, 1.8 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.5 mm to 2.5 mm, or 2 mm to 2.5 mm. For example, the thickness of the therapeutic agent area 202 is 100μm, 200μm, 300μm, 400μm, 500μm, 600μm, 700μm, 800μm, 900μm, 910μm, 920μm, 930μm, 940μm, 950μm, 960μm, 970μm, 980μm, 990μm, 1mm, 1.1mm, 1.2mm, 1.25mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.61mm, 1.62mm, 1.63mm, 1.64mm, 1.65mm, 1.66mm, 1.67mm, 1.68mm, 1.69mm, 1.7mm, 1.75mm, 1.8mm, 1.9mm, 1.91mm. Equal to or greater than 1.92mm, 1.93mm, 1.94mm, 1.95mm, 1.96mm, 1.97mm, 1.98mm, 1.99mm, 2mm, 2.1mm, 2.2mm, 2.25mm, 2.3mm, 2.4mm, 2.5mm, 2.6mm, 2.7mm, 2.75mm, 2.8mm, 2.9mm, 3mm, 3.1mm, 3.2mm, 3.3mm, 3.4mm, 3.5mm, 3.6mm, 3.7mm, 3.8mm, 3.9mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, or 5mm.

[0101] In the descriptive embodiment, control regions 204a and 204b have the same thickness. However, in other embodiments, control regions 204a and 204b may have different thicknesses (for example, the first control region 204a may have a greater thickness than the second control region 204b, and vice versa). Each of the control regions 204a and 204b may have a thickness equal to or less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1.2%, 1%, or 0.5% of the total thickness T1 of the depot 200. In some embodiments, the respective control regions 204a and 204b have thicknesses within the ranges of 1 μm to 100 μm, 5 μm to 50 μm, 10 μm to 20 μm, 5 μm to 15 μm, or 15 μm to 25 μm. For example, each control region 204a, 204b may have a thickness equal to or less than 100 μm, 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm, 60 μm, 55 μm, 50 μm, 40 μm, 35 μm, 30 μm, 29 μm, 28 μm, 27 μm, 26 μm, 25 μm, 24 μm, 23 μm, 22 μm, 21 μm, 20 μm, 19 μm, 18 μm, 17 μm, 16 μm, 15 μm, 14 μm, 13 μm, 12 μm, 11 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm. In some embodiments, thicker control regions provide greater resistance to breakage, cracking, or other damage during manufacturing, handling, and / or storage, thus resulting in a more consistent therapeutic agent release profile across different lots or batches. However, the control regions 204a, 204b may remain thin enough so that the depot 200 still has a small size suitable for placement at the treatment site.

[0102] The combined thickness of control regions 204a and 204b may be equal to or less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1.2%, 1%, or 0.5% of the total thickness T1 of depot 200 and / or the thickness of the therapeutic region 202. In some embodiments, the ratio of the combined thickness of control regions 204a and 204b to the thickness of the therapeutic agent region 202 is 1 / 10, 1 / 20, 1 / 25, 1 / 30, 1 / 35, 1 / 39, 1 / 40, 1 / 45, 1 / 49, 1 / 50, 1 / 55, 1 / 60, 1 / 65, 1 / 70, 1 / 75, 1 / 80, 1 / 84, 1 / 85, 1 / 90, 1 / 95, or 1 / 100 or less. The combined thickness of control regions 204a and 204b may be in the range of 1 μm to 100 μm, 5 μm to 50 μm, 10 μm to 20 μm, 5 μm to 15 μm, 15 μm to 25 μm, 40 μm to 60 μm, or 45 μm to 55 μm. For example, the combined thickness of control regions 204a and 204b may be equal to or less than 100 μm, 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm, 60 μm, 55 μm, 50 μm, 40 μm, 35 μm, 30 μm, 29 μm, 28 μm, 27 μm, 26 μm, 25 μm, 24 μm, 23 μm, 22 μm, 21 μm, 20 μm, 19 μm, 18 μm, 17 μm, 16 μm, 15 μm, 14 μm, 13 μm, 12 μm, 11 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.

[0103] In some embodiments, the volume of the therapeutic agent region 202 is equal to or greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 98.8%, 99%, or 99.5% of the total volume of the depot 200. The combined volume of the control regions 204a, 204b may be equal to or less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1.2%, 1%, or 0.5% of the total volume of the depot 200. In some embodiments, the depot 200 has a volume of at least 100 mm 3 , 150 mm 3 , 200 mm 3 , 250 mm 3 , 300 mm 3 , 350 mm 3 , 400 mm 3 , 450 mm 3 , or 500 mm 3 . The therapeutic agent region 202 can have a volume of at least 100 mm 3 , 150 mm 3 , 200 mm 3 , 250 mm 3 , 300 mm 3 , 350 mm 3 , 400 mm 3 , 450 mm 3 , or 500 mm 3 . The control regions 204a, 204b, when combined, can have a volume of 1 mm 3 , 75 mm 3 , 50 mm 3 , 25 mm 3 , 10 mm 3 , 9 mm 3 , mm ' 3 , 7 mm 3 ' ' , 6 mm 3 , 5 mm 3 , 4 mm 3 , 3 mm 3 , 2 mm 3 , or 1 mm 3 or less.'

[0104] Referring together to Figures 2A and 2B, in some embodiments, the depot 200 includes one or more notches 210 (e.g., cutouts, indentations, recesses, etc.) formed on one or more outer surfaces 212 of the depot 200. The notches 210 may be configured to modulate the discharge characteristics of the depot 200 by changing the amount of surface area exposed to the fluid. Alternatively or in combination, the notches 210 may be configured to accommodate sutures or other fasteners for securing the depot 200 in place at the treatment site. However, in other embodiments, the depot 200 may be provided without any notches 210.

[0105] In a descriptive embodiment, the depot 200 includes four notches 210, i.e., one on each of the four outer surfaces 212 of the depot 200. Alternatively, the depot 200 may include a different number of notches 210 (e.g., one, two, three, five, or more notches 210). Some outer surfaces 212 of the depot 200 may include two or more notches 210 (e.g., two, three, four, or more notches 210), and / or some outer surfaces 212 may not include any notches 210 (e.g., notches 210 may be located on three, two, or a single outer surface 212 of the depot 200). Additionally, while Figures 2A and 2B show each notch 210 located at or near the center of the corresponding outer surface 212, in other embodiments, some or all of the notches 210 may be located in different places (for example, at or near the corners of the depot 200).

[0106] In a descriptive embodiment, each notch 210 extends along the entire thickness T1 of the depot 200, for example, from a first surface 214a (e.g., the top surface) of the depot 200, through a first control region 204a, a therapeutic region 202, and a second control region 204b, to a second surface 214b (e.g., the bottom surface) of the depot 200. Alternatively, part or all of the notch 210 may extend only partially along the thickness T1 of the depot 200 (for example, the notch 210 may be localized to the first control region 204a, the second control region 204b, the therapeutic region 202, the first control region 204a and the therapeutic region 202, the therapeutic region 202 and the second control region 204b, etc.).

[0107] The geometry (e.g., size, shape) of the notches 210 can be modified as desired. For example, in the embodiment of Figure 2A, each of the notches 210 has a semicircular shape. In other embodiments, some or all of the notches 210 may have different shapes, such as triangles, squares, rectangles, semi-ellipses, or combinations thereof. All or a portion of some or all of the notches 210 may form a curved portion of the corresponding outer surface, and / or all or a portion of some or all of the notches 210 may form a straight portion of the corresponding outer surface. Each notch 210 may have a diameter or width (e.g., maximum width) in the range of 0.5 mm to 10 mm, 1 mm to 5 mm, or 2.5 mm to 3.5 mm. For example, each notch 210 may have a diameter or width equal to or smaller than 10 mm, 9.5 mm, 9 mm, 8.5 mm, 8 mm, 7.5 mm, 7 mm, 6.5 mm, 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm, 2 mm, 1.5 mm, 1 mm, or 0.5 mm. In some embodiments, all of the notches 210 may have the same size and / or shape. In other embodiments, some or all of the notches 210 may have different sizes and / or shapes.

[0108] Depot 200 can be manufactured in many different ways. In some embodiments, for example, the therapeutic area 202 is first formed using a thermal compression process. The thermal compression process can be carried out at a temperature higher than room temperature (e.g., at least 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, or 120°C) and at a pressure in the range of about 0.01 MPa to about 1 MPa, or about 0.1 MPa to about 0.8 MPa, or about 0.3 MPa to about 0.6 MPa. Subsequently, the control areas 204a, 204b can be applied to the therapeutic area 202 using spray coating, dip coating, solvent casting, laser melting, or other suitable processes known to those skilled in the art. Next, the notches 210 can be cut out into the depot 200 using a blade, laser cutting, ultrasonic cutting, air knife, or other suitable technique. In some embodiments, each depot 200 is formed individually. In other embodiments, the therapeutic area 202 and the control areas 204a, 204b can be formed as a larger material sheet, which can then be cut into the individual depots 200.

[0109] Figure 3A is a top view of the triangular depot 300, and Figure 3B is a side view of the triangular depot 300. As is most commonly seen in Figure 3A, the depot 300 has a generally triangular shape with rounded corners. The triangular shape may be advantageous for conforming to the shape of certain surgical sites, such as the thigh gutter and / or the suprapatellar bursa of the knee. In a descriptive embodiment, the depot 300 is shaped as an equilateral triangle such that all three sides of the depot 300 have the same length L2. The length L2 may be in the range of 10mm to 50mm, 15mm to 45mm, 20mm to 30mm, or 25mm to 35mm. In some embodiments, the length L2 is at least 10 mm, 12.5 mm, 15 mm, 17.5 mm, 20 mm, 22.5 mm, 25 mm, 27.5 mm, 30 mm, 30.5 mm, 32.5 mm, 35 mm, 37.5 mm, 40 mm, 42.5 mm, 45 mm, 47.5 mm, or 50 mm. However, in other embodiments, some or all of the sides of the depot 300 may have different respective lengths. The depot 300 may have a height H2 in the range of 10 mm to 40 mm, 15 mm to 35 mm, 20 mm to 30 mm, or 25 mm to 35 mm. In some embodiments, the height H2 is equal to or greater than 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm, 20mm, 25mm, 25.5mm, 26mm, 2.65mm, 27mm, 27.5mm, 28mm, 28.5mm, 29mm, 29.5mm, 30mm, 30.5mm, 31mm, 31.5mm, 32mm, 32.5mm, 33mm, 33.5mm, 34mm, 34.5mm, or 35mm.

[0110] Referring next to Figure 3B, the depot 300 may have a total thickness T2. The thickness T2 of the depot 300, as well as the values ​​and ranges (and ratios between the various thicknesses) of the therapeutic region 302 and the control regions 304a, 304b, may be the same as or similar to the corresponding values ​​and ranges of the depot 200 in Figures 2A and 2B.

[0111] In some embodiments, the volume of the therapeutic area 302 of the depot 300 is equal to or greater than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 98.8%, 99%, or 99.5% of the total volume of the depot 300. The combined volume of the control areas 304a and 304b may be equal to or less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1.2%, 1%, or 0.5% of the total volume of the depot 300. In some embodiments, the depot 300 is at least 100 mm 3 , 200mm 3 , 300mm 3 , 400mm 3 , 500mm 3 , 550mm 3 , 600mm 3 , 650mm 3 , 700mm 3 , 750mm 3 , 800mm 3 , 850mm 3 , 900mm 3 , 950mm 3 , or 1000mm 3 It has a volume of . The therapeutic area 302 is at least 100 mm 3 , 200mm 3 , 300mm 3 , 400mm 3 , 500mm 3 , 550mm 3 , 600mm 3 , 650mm 3 , 700mm 3 , 750mm 3 , 800mm 3 , 850mm 3 , 900mm 3 , 950mm 3 , or 1000mm 3 It can have a volume of . The combined volume of the control regions 304a and 304b is 100 mm 3 , 75mm 3 , 50mm 3 , 45mm3 , 40mm 3 , 35mm 3 , 30mm 3 , 25mm 3 , 20mm 3 , 25mm 3 , 15mm 3 , 10mm 3 9mm 3 , 8mm 3 , 7mm 3 , 6mm 3 , 5mm 3 , 4mm 3 , 3mm 3 , 2mm 3 , or 1mm 3 It can have the following volumes.

[0112] As is most commonly seen in Figure 3A, the depot 300 may include pores 316 (e.g., openings, bores, channels) formed therein. The pores 316 may be configured to modulate the release characteristics of the depot 300, for example, by changing the amount of surface area of ​​the therapeutic area 302 exposed to the fluid. For example, the pores 316 can expose a portion of the therapeutic area 302 located away from the periphery of the depot 300, and thus facilitate the infiltration of fluid into the surface of the therapeutic area 302 exposed at the sidewalls of the pores 316 and / or the release of the therapeutic agent from that surface. When the depot 300 is implanted, the pores 316 can also facilitate the diffusion of the therapeutic agent to target tissue located immediately above and / or immediately below the depot 300. However, in other embodiments, the depot 300 may be provided without any pores 316.

[0113] In a descriptive embodiment, the depot 300 includes a single pore 316 at or near the center of the depot 300 (e.g., the center of gravity). In other embodiments, the pore 316 may be located at different locations in the depot 300. The location of the pore 316 may be chosen to reduce (e.g., minimize) the average and / or maximum migration distance between individual molecules of the therapeutic agent and the exposed surface of the therapeutic area 302 closest to them. For example, the average and / or maximum migration distance of the therapeutic agent in the depot 300 may be equal to or less than 10 mm, 9.5 mm, 9 mm, 8.5 mm, 8 mm, 7.5 mm, 7 mm, 6.5 mm, 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm, 2 mm, 1.5 mm, 1 mm, 0.5 mm, 0.25 mm, or 0.1 mm.

[0114] The pore 316 can extend across the entire thickness T2 of the depot 300, for example, from the first surface 314a (e.g., the top surface) of the depot 300, through the first control region 304a, the therapeutic region 302, and the second control region 304b, to the second surface 314b (e.g., the bottom surface) of the depot 300. Alternatively, the pore 316 can extend only partially across the thickness T2 of the depot 300 (for example, the pore 316 can extend only over the first control region 304a, only over the second control region 304b, only over the first control region 304a and the therapeutic region 302, only over the therapeutic region 302 and the second control region 304b, etc.).

[0115] The geometry (e.g., size, shape) of the hole 316 can be modified as desired. For example, as shown in Figure 3A, the hole 316 may have a circular shape. In other embodiments, the hole 316 may have different shapes, such as elliptical, triangular, square, or rectangular shapes, or combinations thereof. The hole 316 may have a diameter or width (e.g., maximum width) in the range of 0.5 mm to 10 mm, 1 mm to 5 mm, or 2.5 mm to 3.5 mm. For example, the hole 316 may have a diameter or width equal to or smaller than 10 mm, 9.5 mm, 9 mm, 8.5 mm, 8 mm, 7.5 mm, 7 mm, 6.5 mm, 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm, 2 mm, 1.5 mm, 1 mm, or 0.5 mm.

[0116] Alternatively or in combination, the holes 316 can perform other functions, for example, by accommodating fasteners (e.g., sutures) for securing the depot 300 in place at the treatment site. If necessary, the presence of the holes 316 can increase the overall flexibility of the depot 300, thereby reducing the possibility of accidental breakage during the manufacture, storage, and / or handling of the depot 300.

[0117] Depot 300 can be manufactured using techniques similar to those described above with respect to Depot 200 in Figures 2A and 2B. For example, the therapeutic area 302 can be formed using a thermal compression process, and the control areas 304a and 304b can be applied to the therapeutic area 302 using methods such as spray coating, dip coating, solvent casting, or laser melting. The holes 316 can then be cut out in Depot 300 using a blade, laser cutting, ultrasonic cutting, air knife, or other preferred techniques known to those skilled in the art.

[0118] Figure 4A is a top view of another triangular depot 400, and Figure 4B is a side view of the triangular depot 400. Depot 400 can generally be similar to depot 300 in Figures 3A and 3B. For example, the dimensional values ​​and ranges of depot 400 (e.g., length L3, height H3, and thickness T3) may be the same as or similar to the corresponding values ​​and ranges described above in relation to depot 300. Thus, the consideration of depot 400 is limited to its features that differ from depot 300.

[0119] As is most commonly seen in Figure 4A, the depot 400 includes a number of holes 416a–416d (e.g., openings, bores, channels) formed therein. The holes 416a–416d can perform the same or similar functions as the holes 316 of the depot 300 in Figures 3A and 3B (e.g., modulating the emission features of the depot 400, accommodating fasteners for securing the depot 400, and / or increasing the flexibility of the depot 400). In a descriptive embodiment, the depot 400 includes four holes 416a–416d, namely one hole 416a at the center or centroid of the depot 400, and three holes 416b–416d spaced apart from the central hole 416a and located near the three corners of the depot 400. Alternatively, the depot 400 may include a different number of holes (e.g., two, three, five, or more). For example, any of the holes 416a to 416d can be omitted. For instance, the depot 400 may include only the central hole 416a, only the surrounding holes 416b to 416d, only the central hole 416a and one surrounding hole (e.g., the upper hole 416d), or include one or more holes in addition to or as substitutes for holes 416a to 416d. Furthermore, any of the holes 416a to 416d can be randomly distributed in various parts of the depot 400, for example, at or near the edges of the depot 400.

[0120] The use of multiple holes 416a-416d can reduce the average and / or maximum travel distance of the therapeutic agent compared to, for example, depots with fewer or no holes (e.g., depot 300 in Figures 3A and 3B). In some embodiments, the average and / or maximum travel distance of the therapeutic agent in depot 400 is equal to or less than 10 mm, 9.5 mm, 9 mm, 8.5 mm, 8 mm, 7.5 mm, 7 mm, 6.5 mm, 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm, 2 mm, 1.5 mm, 1 mm, or 0.5 mm.

[0121] Each of the pores 416a to 416d can extend across the entire thickness T3 of the depot 400, for example, from the first surface 414a (e.g., the top surface) of the depot 400, through the first control region 404a, the therapeutic region 402, and the second control region 404b, to the second surface 414b (e.g., the bottom surface) of the depot 400. Alternatively, some or all of the pores 416a to 416d can extend only partially across the thickness T3 of the depot 400 (e.g., across only the first control region 404a, only the second control region 404b, only the first control region 404a and the therapeutic region 402, only the therapeutic region 402 and the second control region 404b, etc.).

[0122] In a descriptive embodiment, each of the pores 416a–416d extends across the therapeutic region 402, exposing its surface, so that the therapeutic agent can elute from the depot through the pores 416a–416d. In other embodiments, a barrier material can be placed on the surface of some or all of the therapeutic region 402 of the pores 416a–416d to reduce or prevent the release of the therapeutic agent from a particular one or more pores. The barrier material may be or include any material that inhibits the diffusion of the therapeutic agent, such as a layer or coating of a polymer. For example, the barrier material may be made from the same or similar material as the material of the control regions 404a, 404b. The barrier material may be placed only in the central pore 416a, only in the surrounding pores 416b–416d, or in any other selected subset of the pores 416a–416d. For example, the barrier material may be placed in a pore intended for use for suturing, while pores intended to modulate the therapeutic agent release profile may not contain any barrier agent.

[0123] The geometry (e.g., size, shape) of holes 416a to 416d can be changed as desired. For example, as shown in Figure 4A, holes 416a to 416d can each have a circular shape. In other embodiments, some or all of holes 416a to 416d can have different shapes, such as elliptical, triangular, square, or rectangular shapes, or combinations thereof. Holes 416a to 416d can each have a diameter or width (e.g., maximum width) in the range of 0.5 mm to 10 mm, 1 mm to 5 mm, or 2.5 mm to 3.5 mm. For example, holes 416a to 416d may have diameters or widths equal to or smaller than 10 mm, 9.5 mm, 9 mm, 8.5 mm, 8 mm, 7.5 mm, 7 mm, 6.5 mm, 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm, 2.25 mm, 2 mm, 1.75 mm, 1.5 mm, 1.25 mm, 1 mm, 0.75 mm, 0.5 mm, or 0.25 mm, respectively. In some embodiments, all of holes 416a to 416d may have the same size and / or shape. In other embodiments, some or all of holes 416a to 416d may have different sizes and / or shapes. For example, the central hole 416a may have a different size and / or shape from the surrounding holes 416b to 416d.

[0124] Depot 400 can be manufactured using techniques similar to those described above with respect to Depot 300 in Figures 3A and 3B. For example, the therapeutic area 402 can be formed using a thermal compression process, and the control areas 404a and 404b can be applied to the therapeutic area 402 using methods such as spray coating, dip coating, solvent casting, or laser melting. Holes 416a to 416d can then be cut out in Depot 400 using a blade, laser cutting, ultrasonic cutting, air knife, or other preferred techniques known to those skilled in the art. In embodiments in which some or all of the holes 416a to 416d include barrier material, these holes can be formed in the therapeutic area 402 before the control areas 404a and 404b are applied, so that the material of the control areas 404a and 404b acts as a barrier material. Alternatively, the holes can be formed after the control areas 404a and 404b have been applied, and the barrier material is applied to the holes in a subsequent processing step.

[0125] As another example, a depot 400 may first be manufactured by forming a large sheet or film of therapeutic area material. The sheet can then be coated (e.g., spray-coated or dip-coated) with control area material. After the coating process, the top, bottom, and outer surfaces of the sheet may all be covered with control area material. The sheet can then be cut into individual depots. In the resulting depot 400, the therapeutic area 402 may be exposed on the outer surface of the cut depot 400, while all other outer surfaces may remain covered with control area material. Thus, depending on the location of the cut, each depot 400 may have one, two, or three outer surfaces on which the therapeutic area 402 is exposed. For example, a depot 400 produced by cutting a square sheet in half diagonally may have one outer surface on which the therapeutic area 402 is exposed, and two outer surfaces on which the therapeutic area 402 is covered.

[0126] Figures 4C–4H show further examples of triangular depots 420–470 configured according to the technical embodiments of the present invention. The features of depots 420–470 in Figures 4C–4H may generally be similar to the corresponding features of depot 400 in Figures 4A and 4B. Thus, similar numbers are used to identify similar or identical components in Figures 4A–4H, and the consideration of depots 420–470 is limited to features that differ from depot 400 in Figures 4A and 4B. In addition, any of the features of depots 420–470 can be combined with each other, and / or with the features of depot 400 in Figures 4A and 4B.

[0127] Figure 4C is a top view of another triangular depot 420 configured according to an art embodiment of the present invention. Depot 420 includes only the peripheral holes 416b-416d and does not include the central hole. In other embodiments, depot 420 may include only a subset of holes 416b-416d, for example, only hole 416b, or only holes 416b and 416c, etc.

[0128] Figure 4D is a top view of yet another triangular depot 430 configured according to an articulation of the present invention. In a descriptive embodiment, the central hole 416a of the depot 430 has a different geometry from the surrounding holes 416b-416d. For example, as shown in Figure 4D, the central hole 416a may be larger than the surrounding holes 416b-416d. Alternatively, in other embodiments, the central hole 416a may be smaller than some or all of the surrounding holes 416b-416d. In addition, although the central hole 416a is shown as having the same shape as the surrounding holes 416b-416d, alternatively, the central hole 416a may have a different shape from some or all of the surrounding holes 416b-416d.

[0129] Figure 4E is a top view of a triangular depot 440 configured according to an art embodiment of the present invention. In a descriptive embodiment, the depot 440 includes further holes 416e-416g. For example, as shown in Figure 4E, the depot 440 includes three further holes 416e-416g, each located near each side of the depot 440 (for example, near the midpoint of each side). In other embodiments, the depot 440 may include a different number of further holes, for example, some of the holes 416e-416g may be omitted, and / or the depot 440 may include further holes in other locations. As an alternative or in combination, some or all of the holes 416a-416d may be omitted.

[0130] Figure 4F is a top view of another triangular depot 450 configured according to an art embodiment of the present invention. In a descriptive embodiment, the depot 450 includes a plurality of randomly distributed holes 416h. Each hole 416h may have the same geometry (e.g., size and / or shape), or some or all of the holes 416h may have different geometry. In some embodiments, the holes 416h may be localized in specific parts of the depot 450, for example, only near the corners, only near the center, only near the sides, or in any other preferred structure.

[0131] If necessary, the control regions 404a, 404b of the depot 450 can extend over the outer surface of the depot 450 (not visible in Figure 4F) such that the therapeutic agent region 402 of the depot 450 is entirely surrounded by the control regions 404a, 404b and exposed only through the pores 416h. In such embodiments, the depot 450 may contain a relatively large number of pores 416h (e.g., tens, hundreds, or thousands of pores 416h) to allow for the release of the therapeutic agent.

[0132] Figure 4G is a top view of a triangular depot 460 configured according to an articulation of the present invention. The depot 460 is formed as an isosceles triangle such that one side of the depot 460 (e.g., the base) has a first length L4 and the other two sides each have a second length L5. In a descriptive embodiment, the second length L5 is greater than the first length L4, for example, at least 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.5 times, 3 times, 4 times, or 5 times greater. However, in other embodiments, the first length L4 may be greater than the second length L5. The first length L4 may be in the range of 10 mm to 40 mm, 15 mm to 35 mm, 20 mm to 30 mm, or 25 mm to 35 mm. In some embodiments, the first length L1 is at least 10 mm, 12.5 mm, 15 mm, 17.5 mm, 20 mm, 22.5 mm, 25 mm, 27.5 mm, 30 mm, 32.5 mm, 35 mm, 37.5 mm, or 40 mm. The second length L5 may be in the range of 20 mm to 60 mm, 30 mm to 50 mm, 35 mm to 45 mm, or 40 mm to 50 mm. In some embodiments, the second length L5 is at least 20 mm, 25 mm, 30 mm, 32.5 mm, 35 mm, 37.5 mm, 40 mm, 42.5 mm, 45 mm, 47.5 mm, 50 mm, 55 mm, or 60 mm. The depot 460 may have a height H4 in the range of 20 mm to 60 mm, 30 mm to 50 mm, or 35 mm to 45 mm. In some embodiments, the height H4 is equal to or greater than 20 mm, 25 mm, 30 mm, 32.5 mm, 35 mm, 37.5 mm, 40 mm, 41 mm, 42 mm, 43 mm, 44 mm, 45 mm, 47.5 mm, 50 mm, 55 mm, or 60 mm.

[0133] Figure 4H is a top view of a triangular depot 470 configured according to an art embodiment of the present invention. The depot 470 is formed as a right triangle, and the first side of the depot 470 has a first length L A The second side of the depot 470 has a second length L B The third side of the depot 470 has a third length L CIt has a first length L. A The second length L may be within the range of 5mm to 25mm, 7.5mm to 22.5mm, 10mm to 15mm, or 12.5mm to 17.5mm. B The third length L may be within the range of 8.5mm to 35mm, 13mm to 30mm, 17.5mm to 26mm, or 21.5mm to 30mm. C This can be within the range of 10mm-50mm, 15mm-45mm, 20mm-30mm, or 25mm-35mm.

[0134] Figures 5A–5H show further examples of depots 500–570 having various geometric shapes. The features of depots 500–570 in Figures 5A–5H may generally be similar to other depots described herein (e.g., depot 400 in Figures 4A and 4B). Therefore, the discussion of depots 500–570 is limited to features that differ from other embodiments of depots described herein. In addition, any of the features of depots 500–570 can be combined with each other and / or with features of other embodiments described herein.

[0135] Figure 5A is a top view of a depot 500 with an arrowhead shape configured according to an art embodiment of the present invention. As shown in Figure 5A, the depot 500 is generally triangular, except that one end 502 of the depot 500 curves toward the center of the depot 500 to form an arrowhead or V-shape. This geometry can facilitate the insertion of the depot 500 into the treatment site. For example, a surgeon can orient the vertex 504 of the depot 500 toward the treatment site and then apply force to the end 502 of the depot 500 to push the depot 500 into that site. Depot 500 is illustrated as including four holes 506a to 506d configured similarly to holes 416a to 416d in Figures 4A and 4B (for example, including a central hole 506a and three peripheral holes 506b to 506d near the corners of Depot 500), but instead, the holes in Depot 500 can be configured according to any of the other embodiments described herein, or can be omitted entirely.

[0136] Figure 5B is a top view of a rhomboid-shaped depot 510 configured according to an articulation of the present invention. As shown in Figure 5B, the depot 510 includes two angles 512a, 512b having smaller angles (e.g., angles equal to or less than 90°, 80°, 70°, 60°, 50°, 45°, 40°, 35°, 30°, 25°, 20°, 15°, or 10°) and two angles 512c, 512d having larger angles (e.g., angles equal to or greater than 90°, 100°, 110°, 120°, 125°, 130°, 135°, 140°, 145°, 150°, 155°, 160°, 165°, 170°, or 175°). Although the depot 510 is shown having four sides of equal length, in other embodiments, some of the sides of the depot 510 may have different lengths (for example, two upper sides may be longer or shorter than two lower sides). The depot 510 may have a height H6 in the range of 10mm to 70mm, 20mm to 60mm, 30mm to 50mm, 35mm to 45mm, or 40mm to 45mm. The depot 510 may have a width W6 in the range of 5mm to 50mm, 10mm to 30mm, 15mm to 25mm, or 20mm to 25mm.

[0137] In a descriptive embodiment, the depot 510 includes four holes 514a-514d near the four corners 512a-512d. In other embodiments, the number and location of the holes 514a-514d can be changed; for example, the depot 510 may include fewer or more holes 514a-514d, and the holes 514a-514d may be located in different places, etc. (for example, in or near the center of the depot 510). The geometry (e.g., shape, size) and function of the holes 514a-514d may be identical or similar to the holes 416a-416d in Figures 4A and 4B. If necessary, some or all of the holes 514a-514d may be omitted entirely.

[0138] Figure 5C is a top view of a rectangular depot 520 configured according to an articulation of the present invention. The depot 520 may have a length L7 in the range of 10mm to 50mm, 20mm to 40mm, 25mm to 35mm, or 30mm to 35mm. The depot 520 may have a width W7 in the range of 5mm to 25mm, 10mm to 20mm, 10mm to 15mm, or 15mm to 20mm. In a descriptive embodiment, the depot 520 includes four holes 522a to 522d uniformly spaced along the central longitudinal axis of the depot 520. However, in other embodiments, the depot 520 may include fewer or more holes 522a to 522d. Additionally, holes 522a to 522d can be arranged differently; for example, the spacing between holes 522a to 522d can be changed, holes 522a to 522d can be spaced along the central horizontal axis of the depot 520, holes 522a to 522d can be placed near the four corners of the depot 520, etc. The geometry (e.g., shape, size) and function of holes 522a to 522d may be identical or similar to holes 416a to 416d in Figures 4A and 4B. If necessary, some or all of holes 522a to 522d can be omitted entirely.

[0139] Figure 5D is a top view of a cruciform depot 530 configured according to an articulation of the present invention. As shown in Figure 5D, the depot 530 includes four arms 532a to 532d extending from a central body 534. The depot 530 can be thought of as equivalent to a square, with four cutouts 536a to 536d on the four sides of that square. In a descriptive embodiment, all four sides of the depot 530 have the same length L8, for example, in the range of 10mm to 40mm, 15mm to 35mm, 20mm to 30mm, 20mm to 25mm, or 25mm to 30mm. In other embodiments, some of the sides of the depot 530 may have different lengths, for example, the horizontal sides may be longer or shorter than the vertical sides.

[0140] The geometric shapes of cutouts 536a to 536d can be changed as desired. In a descriptive embodiment, for example, cutouts 536a to 536d each have a semicircular shape. However, in other embodiments, some or all of the cutouts 536a to 536d may have different shapes, such as squares, rectangles, triangles, semi-ellipses, or other shapes. Each of the cutouts 536a to 536d can independently have any preferred size, for example, a diameter D8 or width in the range of 1 mm to 20 mm, 5 mm to 15 mm, or 8 mm to 12 mm.

[0141] In a descriptive embodiment, the depot 530 includes four holes 538a-538d located near the ends of the four arms 532a-532d. In other embodiments, the number and location of the holes 538a-538d can be changed; for example, the depot 530 may include fewer or more holes 538a-538d, and the holes 538a-538d may be located in different places, for example (e.g., in or near the center of the depot 530). The geometry (e.g., shape, size) and function of the holes 538a-538d may be identical or similar to the holes 416a-416d in Figures 4A and 4B. If necessary, some or all of the holes 538a-538d may be omitted entirely.

[0142] Figure 5E is a top view of an L-shaped depot 540. The depot 540 includes a first elongated arm 542 connected to a second elongated arm 544. The angle between the first and second elongated arms 542 may be equal to or greater than 10°, 15°, 20°, 30°, 40°, 45°, 50°, 60°, 70°, 80°, 90°, 110°, 120°, 130°, 140°, or 150°. In a descriptive embodiment, the first and second elongated arms 542 are generally rectangular in structure and have the same length L9 and width W9. The length L9 may be in the range of 10mm to 50mm, 20mm to 40mm, 25mm to 35mm, 25mm to 30mm, or 30mm to 35mm. The width W9 may be in the range of 1mm to 20mm, 5mm to 15mm, 5mm to 10mm, or 10mm to 15mm. In other embodiments, the first elongated arm 542 may have a different length and / or width from the second elongated arm 544 (e.g., longer or shorter).

[0143] In a descriptive embodiment, the depot 540 includes three holes 546a–546c, namely one hole 546a near the end of the first elongated arm 542, one hole 546b located near the end of the second elongated arm 544, and one hole 546c located near the connection between the first and second elongated arms 542, 544. In other embodiments, the number and location of the holes 546a–546c can be changed; for example, the depot 540 may include fewer or more holes 546a–546c, and the holes 546a–546c may be in different locations (e.g., spaced along the length of the first elongated arm 542 and / or the second elongated arm 544). The geometry (e.g., shape, size) and function of the holes 546a–546c may be identical or similar to the holes 416a–416d in Figures 4A and 4B. If necessary, some or all of the holes 546a to 546c can be omitted entirely.

[0144] Figure 5F is a top view of the circular depot 550. The depot 550 can have a diameter OD within the range of 1 mm to 100 mm, 5 mm to 50 mm, 10 mm to 30 mm, or 10 mm to 15 mm. 10 In some embodiments, the diameter OD 10 is at least 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm. Optionally, the depot 550 can include a central hole 552. The hole 552 can increase the release rate of the therapeutic agent by increasing the surface area of the depot 550 exposed to the physiological fluid and / or reducing the distance the therapeutic agent travels to reach the exposed surface. In some embodiments, the hole 552 has a diameter ID within the range of 1 mm to 20 mm, 2 mm to 15 mm, 5 mm to 10 mm, or 1 mm to 5 mm. 10 For example, the diameter ID 10The thickness may be equal to or less than 20 mm, 15 mm, 10 mm, 5 mm, 2 mm, or 1 mm. In some embodiments, the depot 550 has a thickness in the range of 100 μm to 5 mm, 500 μm to 2.5 mm, 1 mm to 2 mm, 750 μm to 1.25 mm, 1 mm to 1.5 mm, 1.25 mm to 1.75 mm, 1.75 mm to 2.25 mm, 1.8 mm to 2.2 mm, 1.9 mm to 2.1 mm, 1.5 mm to 2.5 mm, or 2 mm to 2.5 mm. For example, the thickness of Depot 550 is 100μm, 200μm, 300μm, 400μm, 500μm, 600μm, 700μm, 800μm, 900μm, 910μm, 920μm, 930μm, 940μm, 950μm, 960μm, 970μm, 980μm, 990μm, 1mm, 1.1mm, 1.2mm, 1.25mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.61mm, 1.62mm, 1.63mm, 1.64mm, 1.65mm, 1.66mm, 1.67mm, 1.68mm, 1.69mm, 1.7mm, 1.75mm, 1.8mm, 1.9mm, 1.91mm, 1.9 2mm, 1.93mm, 1.94mm, 1.95mm, 1.96mm, 1.97mm, 1.98mm, 1.99mm, 2mm, 2.1mm, 2.2mm, 2.25mm, 2.3mm, 2.4mm, 2.5mm, 2.6mm, 2.7mm, 2.75mm, 2.8mm, 2.9mm, 3mm, 3.1mm, 3.2mm, 3.3mm, 3.4mm, 3.5mm, 3.6mm, 3.7mm, 3.8mm, 3.9mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, or equal to or greater than 5mm.

[0145] Figure 5G shows a depot 560 configured according to an embodiment of the technology of the present invention. The depot 560 has a body 562 having a spherical shape. The spherical shape may increase the mechanical strength of the depot 560 and be advantageous for packing into irregularly shaped spaces in the patient's body. The diameter D of the body 560 11can be in the range of 1 mm to 100 mm, 5 mm to 75 mm, 10 mm to 50 mm, 15 mm to 45 mm, 20 mm to 30 mm, 25 mm to 35 mm, 1 mm to 10 mm, or 1 mm to 5 mm. In some embodiments, the diameter D 11 is at least 1 mm, 2 mm, 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm. In an illustrative embodiment, the depot 520 includes a plurality of holes 566 (only two are labeled). The holes 566 can be evenly spaced along the perimeter of the outer surface of the depot 560. In some embodiments, the holes 566 are disposed only in certain portions of the body 562, such as only within one hemisphere, only within a certain quadrant, etc. If desired, the holes 566 can be randomly distributed over the outer surface of the body 562. In these and other embodiments, the holes 566 may not be evenly spaced. The geometry (e.g., shape, size) and function of the holes 566 can be the same as or similar to the holes 416a - 416d of FIGS. 4A and 4B. If desired, some or all of the holes 566 can be omitted entirely. One, some, or all of the holes 566 can have a depth d1 equal to or less than the diameter D 11 of the body 562 (e.g., holes 567 and 568). In such embodiments, the holes can have an opening at the surface of the body 562 and may end at another opening on the surface of the body 562 (e.g., hole 568), or may end within the body 562 (e.g., hole 567). Additionally or alternatively, one, some, or all of the holes 566 can have a depth equal to the diameter D 11 of the body 562 (e.g., hole 569), and thus the hole extends between two openings on the surfaces of the body 562 on opposite diametric sides. In some embodiments, at least one hole has a depth less than the diameter D 11 of the body 562, and at least another hole has a depth equivalent to the diameter D 11 of the body 562.

[0146] Figure 5H is a top view of a rhomboid-shaped depot 570 configured according to an art embodiment of the present invention. The depot 570 has smaller angles (for example, angles equal to or smaller than 90°, 80°, 70°, 60°, 50°, 45°, 40°, 35°, 30°, 25°, 20°, 15°, or 10°). Having one angle 572a, two angles 572b, 572c having intermediate angles (e.g., angles equal to or less than 120°, 110°, 100°, 90°, and / or angles greater than 60°, 70°, 80°, 90°, 100°, 110°), and one angle 572d having a larger angle (e.g., angles equal to or greater than 90°, 100°, 110°, 120°, 125°, 130°, 135°, 140°, 145°, 150°, 155°, 160°, 165°, 170°, or 175°). Depot 570 includes the same or similar length L 12 A pair of first sides 574 having the same or similar length L 13 It may have a pair of second sides 576 having a length L. 12 The length can be within the range of 5mm-30mm, 10mm-20mm, 10mm-15mm, 15mm-20mm, or 12mm-15mm. 13 This can be within the range of 1mm to 20mm, 5mm to 15mm, or 5mm to 10mm. In Figure 5H, length L 13 is, length L 12 Although shown as shorter than, in other embodiments, length L 13 is, length L 12 It may be the same length as, or longer than, the depot 570. Additionally, although the depot 570 is shown having a single hole 578, in other embodiments the depot 570 may have more holes 578, or the holes 578 may be omitted.

[0147] In some embodiments, the depots of the present invention are configured to be cut, broken, or otherwise divided into smaller pieces before use. For example, a depot formed as an equilateral triangle (e.g., depot 300 in Figure 3A or depot 400 in Figure 4A) may be designed to be broken into two smaller right triangles (e.g., similar to depot 470 in Figure 4H) or three smaller rhombuses (e.g., similar to depot 570 in Figure 5H). In such embodiments, the depot may include perforations, grooves, tapered sections, etc., that define separation points to facilitate controlled breaking of the depot. This technique makes the breaking of the depot easier while avoiding undesirable cracking of the control area. Alternatively or in combination, a mold may be provided for cutting the depot into smaller pieces (e.g., using a blade) while simultaneously using it as a guide.

[0148] C. Composition The depots of the present invention (e.g., depots 100a to 570 in Figures 1A to 5H) may have compositions configured to provide a desired release profile of a therapeutic agent. As discussed previously, the depots described herein may include a therapeutic agent and one or more further components, such as polymers and / or release agents. Each of these components is described in more detail below.

[0149] 1. Therapeutic agents The therapeutic agent carried by the depots of the present invention (e.g., depots 100a to 570 in Figures 1A to 5H) may be any biologically active substance (or combination of substances) that provides a therapeutic effect to a patient in need. As used herein, “therapeutic agent” or “drug” may refer to a single therapeutic agent or a combination of therapeutic agents. In some embodiments, the therapeutic agent comprises only a single therapeutic agent. In other embodiments, the therapeutic agent may contain two or more therapeutic agents for simultaneous or sequential release.

[0150] In some embodiments, the therapeutic agent is or contains an analgesic. The term “analgesic” or “analgesic” includes one or more topical or systemic agents administered to reduce, prevent, alleviate, or eliminate pain as a whole. Analgesics may include systemic and / or topical anesthetics, narcotics, and / or anti-inflammatory agents. Analgesics may contain pharmacologically active drugs or pharmaceutically acceptable salts thereof. Suitable analgesics include, but are not limited to, bupivacaine (e.g., bupivacaine hydrochloride monohydrate, bupivacaine hydrochloride, bupivacaine free base), ropivacaine, mepivacaine, etidocaine, levobupivacaine, trimecaine, calticaine, alticaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, dexamethasone, tetrodotoxin, saxitoxin, neosaxitoxin, capsaicin, and combinations thereof.

[0151] In some embodiments, the therapeutic agent includes narcotics, such as cocaine or anti-inflammatory agents. Examples of suitable anti-inflammatory agents include steroids, such as prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone. Other suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, sarsalat, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamete, mefenamic acid, and other COX-2 inhibitors, as well as combinations thereof.

[0152] In some embodiments, the therapeutic agent is an antibiotic, antibacterial agent, or antifungal agent, or a combination thereof, or includes them. For example, suitable antibiotics and antibacterial agents include, but are not limited to, amoxicillin, amoxicillin / clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole / trimethoprim, tetracycline, minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin, aminoglycides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporins, carbapenems, imipenems, ertapenems, antimicrobial peptides, cecropine-mellitin, magainin, dermaceptin, cathelicidine, alpha-defensins, and alpha-protegrin. Antifungal agents include, but are not limited to, ketoconazole, clotrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, thioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naphthifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, cyclopirox, flucytosine, terbinafine, and amphotericin B.

[0153] In some embodiments, the therapeutic agent is an adrenocorticostatic, β-antiadrenaline, androgens or antiandrogens, anti-anemia drugs, anthelmintics, anabolic agents, anesthetics or analgesics, stimulants, antiallergics, antiarrhythmics, anti-atherosclerotic agents, antibiotics, antidiabetic drugs, antifibrinolytics, anticonvulsants, angiogenesis inhibitors, anticholinergics, enzymes, coenzymes or corresponding inhibitors, antihistamines, antihypertensives, antihypertensives, anticoagulants, antifungals, antiseptics, antiinfectives, antihemorrhagic agents, β-receptor antagonists, calcium channel antagonists, antimyasthenics, anti-inflammatory drugs, antipyretics, antirheumatic drugs, or cardiac stimulants. The therapeutic agent is or comprises drugs, chemotherapy agents, coronary artery dilators, cell proliferation inhibitors, glucocorticoids, hemostatic agents, immunoglobulins or their fragments, chemokines, cytokines, mitogens, cell differentiation factors, cytotoxic agents, hormones, immunosuppressants, immunostimulants, morphine antagonists, muscle relaxants, narcotics, vectors, peptides, (para)sympathicomimetics, (para)sympatholytics, proteins, cells, selective estrogen receptor modulators (SERMs), sedatives, antispasmodics, substances that inhibit bone resorption, vasoconstrictors or vasodilators, viral inhibitors, or wound healing agents. In some embodiments, the therapeutic agent may include hemostatic agents (e.g., aluminum sulfate, fibrin, micronized gelfoam, etc.), which may be particularly beneficial when implanting a depot in areas with high blood flow and potentially above-average postoperative bleeding (e.g., chest, abdomen, anorectum, head and neck, etc.).

[0154] In some embodiments, the therapeutic agent is a drug used to treat cancer or a pharmaceutically acceptable salt thereof, or comprises such agents. Such chemotherapeutic agents include antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavage agents, DNA crosslinking agents, DNA insertion agents, DNA sulcus ligators, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include adalimumab, anthamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribin, cytarabin, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocalmycin, dynemycin A, epotilon, etoposide, phloxuridine, fludarabine, 5-fluorouracil, and gefitin. This list includes, but is not limited to, gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapacon, lenalidomide, irinotecan, maytansine, mechloretamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, vindesine, and tamoxifen.

[0155] In some embodiments, the therapeutic agent is or comprises botulinum toxin or other neurotoxins used to treat various neuromuscular and / or neuroglandular disorders and neuropathy associated with pain. Botulinum toxin or other neurotoxins may include pharmacologically active drugs or pharmaceutically acceptable salts thereof. Botulinum toxin can be selected from various strains of Clostridium botulinum and may include pharmacologically active drugs or pharmaceutically acceptable salts thereof. In some embodiments, botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G.

[0156] A pharmaceutically acceptable salt is a salt that retains the biological efficacy and properties of a neutral therapeutic agent, and specifically refers to a salt that is acceptable for pharmaceutical use. Pharmacochemically acceptable salts include salts of acidic or basic groups, which may be present in the therapeutic agent. The therapeutic agents that are essentially basic used in the art of this invention can form a wide variety of salts with various inorganic and organic acids. Pharmacologically acceptable acid addition salts of basic therapeutic agents used in the technology of the present invention may include salts that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (1,1'-methylene-bis-(2-hydroxy-3-naphthate)). The therapeutic agents of the present invention, which include an amino portion, can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Suitable base salts can be formed from bases that form non-toxic salts, and these salts may include aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, or diethanolamine salts.

[0157] A pharmaceutically acceptable salt may contain another molecule, such as water or another biocompatible solvent (solvate), an acetate ion, a succinate ion, or another counterion. The counterion may be any organic or inorganic part that stabilizes the charge of the parent compound. If necessary, a pharmaceutically acceptable salt may contain multiple counterions.

[0158] The therapeutic agent or a pharmaceutically acceptable salt thereof may be an essentially pure compound, or it may be formulated using a pharmaceutically acceptable carrier, such as a diluent, adjuvant, excipient, or vehicle known to those skilled in the art. The carrier(s) may be “acceptable” in the sense that they are compatible with the other components of the formulation and are not harmful to its recipient. For example, diluents may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, and the like.

[0159] The therapeutic agent or pharmaceutically acceptable salt form can be micronized, jet-milled, or sieved to form a consistent particle size, thereby further facilitating the controlled release of the therapeutic agent. This process can be useful, for example, for highly insoluble therapeutic agents. In some embodiments, the particle size of the therapeutic agent (e.g., D50 value) is equal to or less than 500 μm, 450 μm, 400 μm, 350 μm, 300 μm, 250 μm, 200 μm, 150 μm, 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, 30 μm, 20 μm, 15 μm, 14 μm, 13 μm, 12 μm, 11 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.

[0160] The preferred dosage range for using the depot technique of the present invention depends on the potency of the particular therapeutic agent, but may be in the range of about 0.001 mg to about 500 mg per kilogram of body weight, for example, in the range of about 0.1 mg to about 200 mg per kilogram of body weight, or in the range of about 1 to about 100 mg per kg of body weight. The dosage range can be easily determined by methods known to those skilled in the art. A unit dosage form may contain between about 1 mg and about 500 mg of the active ingredient.

[0161] In some embodiments, the therapeutic agent constitutes at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total mass of the depot (referred herein to as the “mass percentage” or “weight percentage” of the therapeutic agent in the depot). The mass percentage of the therapeutic agent in the depot may be in the range of 25% to 75%, 40% to 80%, 50% to 65%, or 60% to 65%. In some embodiments, the therapeutic agent constitutes at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total mass of the therapeutic area. The mass percentage of the therapeutic agent in the therapeutic area may be in the range of 25% to 75%, 40% to 80%, 50% to 65%, or 60% to 65% of the total mass of the therapeutic area.

[0162] In some embodiments, the depots described herein have a total mass (e.g., total dry mass) in the range of 100 mg to 1500 mg, 100 mg to 1000 mg, 100 mg to 500 mg, 300 mg to 500 mg, 500 mg to 1000 mg, or 800 mg to 1000 mg. For example, the total mass may be equal to or greater than 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.

[0163] The total mass of the therapeutic agent in a depot may be in the range of 100mg-1800mg, 100mg-1500mg, 100mg-1000mg, 200mg-800mg, 300mg-600mg, 500mg-700mg, 540mg-660mg, or 570mg-630mg. In some embodiments, the total mass of the therapeutic agent in individual depots may be 25mg, 50mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg g, equal to or greater than 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg.

[0164] The properties of the therapeutic agent can be selected to yield a desired release profile in vivo. For example, the therapeutic agent may be sufficiently hydrophobic to elute from the depot in a controlled and sustained manner at the in vivo treatment site when exposed to physiological fluids, even if the depot contains fewer control regions (e.g., depot 100b in Figure 1B) or does not contain any control regions (e.g., depot 100c in Figure 1C). In some embodiments, the therapeutic agent has multiple forms with varying degrees of hydrophobicity, e.g., at least one hydrophobic form and at least one hydrophilic form. For example, the therapeutic agent may be, or may contain, an amine compound having a hydrophobic free base form and a hydrophilic salt form. Amine compounds may be amine-containing analgesics, such as aminoamide local anesthetics (e.g., bupivacaine, ropivacaine, lidocaine, mepivacaine, prilocaine, etidocaine, levobupivacaine, trimecaine, alticaine) or aminoester local anesthetics (e.g., benzocaine, procaine, tetracaine, chloroprocaine). Amine-containing analgesics may have a free base form in which the amine group is deprotonated (e.g., bupivacaine free base), and a salt form in which the amine is protonated and associated with a counterion (e.g., chloride ion, bromide ion, sulfate ion, phosphate ion, nitrate ion, acetate ion, oxalate ion, citrate ion, tartrate ion) (e.g., bupivacaine hydrochloride, bupivacaine hydrochloride monohydrate). As another example, a hydrophobic form may be a salt form of a therapeutic agent that uses a relatively hydrophobic salt (e.g., palmitate rather than chloride salt). Amine-containing analgesics may contain salt forms of various counterion combinations that alter the hydrophobicity and solubility of the amine-containing analgesic.

[0165] The therapeutic agent in an implantable depot may be supplied in a partially or entirely hydrophobic (e.g., free base) form. For example, by mass, at least 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, or 100% of the therapeutic agent may be present in a hydrophobic form. Alternatively or in combination, by mass, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, or less than 20% of the therapeutic agent may be present in a hydrophobic form. If necessary, the implantable depot may include a combination of the hydrophobic and hydrophilic forms of the therapeutic agent. The relative amounts of hydrophobic and hydrophilic forms can be selected to produce a desired release profile; for example, increasing the relative amount of hydrophobic forms can produce a slower release rate, while increasing the relative amount of hydrophilic forms can produce a faster release rate. In some embodiments, the ratio of the total mass of hydrophobic forms to the total mass of hydrophilic forms is equal to or greater than 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or 20:1.

[0166] The use of hydrophobic forms of therapeutic agents can offer various advantages. For example, when a hydrophobic form is used, depots can be fabricated with fewer or even no control regions, thus simplifying the manufacturing process and / or reducing the possibility of uncontrolled accidental release due to manufacturing defects in the control region. This technique can also increase the amount of therapeutic agent that can be loaded into a single depot and / or reduce the depot size. Additionally, when a hydrophobic form of a therapeutic agent is used in combination with a control region, the duration of therapeutic agent release can also be further extended, thus enabling controlled release over longer periods that would otherwise be difficult or impossible with conventional systems. Furthermore, hydrophobic forms may exhibit different melting points (e.g., lower melting points) and / or different solubility (e.g., improved solubility in organic solvents) compared to hydrophilic forms. This can make depot fabrication easier and / or allow for further manufacturing options compared to depots formulated primarily or entirely from hydrophilic forms.

[0167] In some embodiments, the implantable depot is configured to release multiple therapeutic agents simultaneously or sequentially to provide additional clinical benefits, for example. For example, in a pain management situation, the depot may release a first analgesic that acts more rapidly (e.g., lidocaine) and a second analgesic that acts more slowly (e.g., bupivacaine). In another example, the depot may release a first therapeutic agent having a first type of therapeutic effect (e.g., analgesic effect) and a second therapeutic agent having a second type of therapeutic effect (e.g., increasing or decreasing blood flow, reducing inflammation, altering water uptake, affecting pH in the depot and / or surrounding environment). The second therapeutic agent may enhance the effectiveness of the first therapeutic agent or may independently provide therapeutic benefits to the patient. The implantable depots described herein may contain any suitable number of therapeutic agents, e.g., one, two, three, four, five, or more different therapeutic agents.

[0168] 2. Polymer The depots of the present invention (e.g., depots 100a to 570 in Figures 1A to 5H) can be made from one or more polymers. In some embodiments, the therapeutic region and the control region of the depot each contain a polymer (or combination of polymers), and these polymers may be the same or different polymers (or combination of polymers) in the same or different amounts, concentrations, and / or mass percentages. In some embodiments, the control region contains a polymer, while the therapeutic region does not. In some embodiments, the therapeutic region contains a polymer, while the control region does not.

[0169] In some embodiments, the polymer(s) used in the depot of the present invention are bioreabsorbable polymers. The bioreabsorbable polymers used in the present invention may have a predetermined degradation rate. The terms “bioreabsorbable” or “bioabsorbable” may mean that the polymer is absorbed into the patient’s body, for example, by cells or tissues. These polymers may be “biodegradable” in that all or part of the polymer is broken down over time by enzymatic action, hydrolysis, and / or other similar mechanisms in the patient’s body. In some embodiments, the therapeutic agent is released at the same time that the bioreabsorbable polymer is broken down or degraded into non-toxic components in the body. The bioreabsorbable polymer used as a basic component of the depot of the present invention may be broken down or degraded after the therapeutic agent has been completely released. The bioreabsorbable polymer may also be “bioerodible” in that it is eroded or degraded over time at least in part due to contact with surrounding tissues, substances found in fluids, or by cellular action.

[0170] Polymers suitable for use in the depot of the present invention include polyglycolides (PGA), polylactides (PLA) (e.g., poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), meso-poly(lactic acid), poly(D,L-lactic acid) (PDLLA), poly(L-lactide-co-D,L-lactide) (PLDLLA)), poly(lactide-co-glycolides) (PLGA) (e.g., poly(L-lactide-co-glycolides), poly(D,L-lactide-co-glycolide), PLA-PLGA, polycaprolactone (PCL), poly(glycolide-co-caprolactone) (PGCL), poly(lactide-co-caprolactone) (PLCL), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(α-hydroxy acid) (PAHA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), polyhydroxyalkanoate (PHA) ), polyhydroxybutyrate (PHB) (e.g., poly(4-hydroxybutyrate)), poly(phosphazene) (e.g., ethylglycinate poly(phosphazene)), poly(phosphate ester), poly(amino acid), poly(depsipeptide), poly(butylene succinate) (PBS), poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), poly(ethylene glycol) (PEG), poloxamer (e.g., PEO-PPO-PEO), PEO-PPO-poly(acrylic acid) copolymer (PEO-PPO-PAA), PLGA-PEO-PLGA, PEG-PLG, PEG-PLGA-PEG, poly(vinylpyrrolidone) (PVP), polyvinyl alcohol (PVA), PVA-grafted PLGA (PVA-g-PLGA), poly(N-isopropylacrylamide), poly(methacrylate), poly(hydroxyethyl methacrylate), poly(methoxyethyl Poly(methyl methacrylate), poly(methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), poly(propylene fumarate), poly(iminocarbonate), poly(glycolide-co-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly(1,Polymers incorporating 3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid, poly(caprolactone co-butyl acrylate), maleic anhydride copolymers, cellulose or cellulose derivatives (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose or their salts), poly(ethylene glycol terephthalate) and poly(butylene terephthalate) copolymers (PEGT-PBT) (e.g., PolyActive), polysaccharides (e.g., hyaluronic acid, chitosan, starch, pregelatinized starch, alginate, dextran), sucrose acetate isobutyrate (SAIB), poly(aspirin), vitamin E or vitamin E analogs (e.g., alpha-tocopherol acetate, D-alpha-tocopherol succinate), Carbopol®, or proteins (e.g., gelatin, collagen, albumin), or copolymer derivatives, or combinations thereof.

[0171] Where necessary, the polymers described herein may be modified to include functional side groups or side chains. For example, the polymer may be grafted with, crosslinked to, or otherwise covalently bonded to hydrophilic side chains, such as PEG. This technique may be advantageous in ensuring consistent and controlled release of therapeutic agents. In some situations, when a therapeutic agent elutes from a therapeutic region, voids or spaces in the polymer already occupied by the therapeutic agent may collapse, forming partially or completely impermeable polymer regions. If the collapse occurs near portions of the therapeutic region that come into contact with physiological fluids, this can create a barrier that partially or completely inhibits further elution of the therapeutic agent from those locations. However, polymers containing hydrophilic side chains can swell when exposed to fluids, thus reducing the likelihood of collapse and enabling continuous release of the therapeutic agent.

[0172] In some embodiments, the properties of the polymer are selected to modulate the release profile of the therapeutic agent from the depot. For example, the hydrophobicity or hydrophilicity of the polymer can affect the uptake of water into the depot, thereby altering the release rate of the therapeutic agent. More hydrophilic polymers (e.g., PLGA containing a higher glycolic acid content, polymers in which PEG is covalently incorporated into the polymer backbone) may result in a higher release rate than more hydrophobic polymers. In some embodiments, different end groups of the polymer can be selected to affect the hydrophilicity of the polymer. For example, polymers with acidic end groups may be more hydrophilic than polymers with ester end groups.

[0173] In some embodiments, the mass percentage of polymer in the depot is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or less. The mass percentage of polymer in the depot may be in the range of 10% to 60%, 20% to 50%, 25% to 40%, or 30% to 35%. In some embodiments, the mass percentage of polymer in the therapeutic area is 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or less. The mass percentage of polymer in the therapeutic region may be in the range of 10% to 60%, 20% to 50%, 25% to 40%, or 30% to 35%. In some embodiments, the mass percentage of polymer in individual control regions is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. The mass percentage of polymer in control regions may be in the range of 25% to 75%, 40% to 80%, 50% to 65%, 60% to 65%, 50% to 75%, or 75% to 100%.

[0174] The total mass of the polymer in the depot can be in the range of 100 mg to 1000 mg, 100 mg to 500 mg, 150 mg to 350 mg, 250 mg to 350 mg, or 300 mg to 350 mg. In some embodiments, the total mass of the polymer is equal to or less than 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 475 mg, 450 mg, 425 mg, 400 mg, 375 mg, 350 mg, 325 mg, 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, or 100 mg.

[0175] In some embodiments, the ratio of the mass of the therapeutic agent in the depot to the mass of the polymer in the depot is at least 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, or 16:1. In some embodiments, the ratio of the mass of the polymer in the therapeutic agent region to the mass of the therapeutic agent in the therapeutic agent region is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10 or less.

[0176] In some embodiments, the polymers disclosed herein are configured to degrade at a sufficiently slow rate so that the depot maintains sufficient flexural strength and / or mechanical integrity in vivo for at least a predetermined period of time or until a predetermined percentage of the therapeutic agent is released from the depot. A depot can be considered to maintain its structural integrity if it remains largely unchanged and is reduced only partially or progressively due to the elution of the therapeutic agent or the dissolution of the control region or the releasing agent. A depot can be considered to have lost its structural integrity if it separates into (e.g., breaks down) into multiple component fragments, for example, if two or more of the resulting fragments constitute at least 5% of the original size of the depot. Alternatively or additionally, a depot can be considered to have lost its structural integrity if the rate of therapeutic agent release increases by more than three times compared to the rate of therapeutic agent release in a control depot immersed in a buffer solution. In some embodiments, the molecular weight of the polymer can be selected to account for any molecular weight loss that occurs during the manufacturing process, such that the molecular weight after manufacturing remains greater than the minimum weight required to achieve the desired sustained release profile.

[0177] In some embodiments, the depot is configured to maintain its structural integrity in vivo over at least a predetermined length of time. For example, the depot can be configured to maintain its structural integrity in vivo for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 40 days, 50 days, 60 days, 70 days, 90 days, 100 days, 200 days, 300 days, or 365 days. In some embodiments, the depot is configured to maintain its structural integrity in vivo until at least a predetermined percentage of the therapeutic payload is released from the depot. For example, the depot can be configured to maintain its structural integrity in vivo until at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the original mass of the therapeutic agent in the depot is released.

[0178] 3. Release agent The depots of the technology of the present invention (e.g., depots 100a - 570 of FIGS. 1A - 5H) can include one or more release agents as needed. In some embodiments, the therapeutic agent region and the control region each include a release agent (or a combination of release agents), and those release agents can be the same or different release agents (or combinations of release agents) having the same or different amounts, concentrations, and / or mass percentages. In some embodiments, the control region includes a release agent and the therapeutic agent region does not include a release agent. In some embodiments, the therapeutic agent region includes a release agent and the control region does not include a release agent.

[0179] In some embodiments, the release agent is a polysorbate, such as Polysorbate 80, Polysorbate 60, Polysorbate 40, or Polysorbate 20 (Tween 20®).Other release agents suitable for use in the technology of the present invention include polyethylene glycol (e.g., PEG 3000, PEG 6000, PEG 10,000 etc.), polyvinyl alcohol, sorbitan fatty acid esters (e.g., sorbitan monostearate (Span(registered trademark) 60), sorbitan tristearate (Span(registered trademark) 65), sorbitan trioleate (Span(registered trademark) 85), sorbitan monooleate (Span(registered trademark) 80), sorbitan monopalmitate, sorbitan monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, sorbitan tribehenate), sucrose esters (e.g., sucrose monodecanoate, sucrose monolaurate, sucrose distearate, sucrose stearate), castor oil (e.g., polyethoxylated castor oil, polyoxyl hydrogenated castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 4 Castor oil, Cremophor® RH60, Cremophor® RH40, polyethylene glycol ester glycerides (e.g., Labrasol®, Labrifil® 1944), poloxamer, polyoxyethylene polyoxypropylene 1800, polyoxyethylene fatty acid esters (e.g., polyoxyl 20 stearyl ether, diethylene glycol octadecyl ether, glyceryl monostearate, triglycerol monostearate, polyoxyl 20 stearate, polyoxyl 40 stearate, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate), oleic acid, sodium deoxycholate, sodium lauryl sulfate, myristic acid, stearic acid, vitamin E This includes D-alpha-tocopherol polyethylene glycol succinate (vitamin E-TPGS), saturated polyglycolized glycerides (e.g., Gelucire® 44 / 14, Gelucire® 50 / 13), polypropoxylated stearyl alcohol (e.g., Acconon® MC-8, Acconon® CC-6), or derivatives or combinations thereof.

[0180] In some embodiments, the mass percentage of the release agent in the depot is 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less. The mass percentage of the release agent in the depot may be in the range of 0.1% to 20%, 0.5% to 10%, or 1% to 5%. In some embodiments, the mass percentage of the release agent in the therapeutic area is 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less. The mass percentage of the release agent in the therapeutic area may be in the range of 0.1% to 20%, 0.5% to 10%, or 1% to 5%. In some embodiments, the mass percentage of the release agent in individual control areas is 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less. The mass percentage of the release agent in the control area may be in the range of 0.1% to 20%, 0.5% to 10%, 1% to 5%, 10% to 50%, 20% to 40%, or 30% to 35%.

[0181] The total mass of the release agent in the depot may be in the range of 1 mg to 200 mg, 10 mg to 100 mg, 10 mg to 50 mg, 20 mg to 50 mg, 20 mg to 40 mg, or 25 mg to 35 mg. In some embodiments, the total mass of the release agent is equal to or less than 200 mg, 150 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, or 1 mg.

[0182] In some embodiments, the ratio of the mass of the release agent to the mass of the polymer in the therapeutic area is 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, or 1:16 or less. In some embodiments, the ratio of the mass of the release agent to the mass of the polymer to the mass of the therapeutic agent in the therapeutic region is within the range of 0.1:10:20 to 2:10:20, 0.1:10:20 to 1:10:20, 0.1:10:20 to 0.5:10:20, 0.5:10:20 to 0.1:10:20, 0.5:10:20 to 1:10:20, 1:10:20 to 10:10:20, 1:10:20 to 5:10:20, 2:10:20 to 5:10:20, or 5:10:20 to 10:10:20. In other embodiments, the therapeutic region may not contain any release agent.

[0183] In some embodiments, the mass-to-polymer ratio of the release agent in each control region is at least 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, or 1:25. In other embodiments, the control region may not contain any release agent.

[0184] 4. Additives The depots of the present invention (e.g., depots 100a to 570 in Figures 1A to 5H) may optionally contain one or more additives. The additives may be any components that affect the characteristics and / or performance of the depot, such as release profile, mechanical properties (e.g., flexibility, strength, surface roughness), storage stability, and degradation rate. In some embodiments, the therapeutic region and the control region each contain the same or different additives (or combinations of additives) in the same or different amounts, concentrations, and / or mass percentages. In some embodiments, the control region contains additives, while the therapeutic region does not. In some embodiments, the therapeutic region contains additives, while the control region does not.

[0185] For example, in some embodiments, the additive is or includes plasticizers or other suitable excipients that increase the flexibility of the depot, facilitate the molding of the depot into a desired shape, and / or reduce friction on one or more surfaces of the depot. Advantages of a flexible depot may include, for example, improved patient comfort (e.g., the patient feels less of the depot after implantation), reduced tissue irritation at the implantation site (e.g., application to soft tissue, or application to bone where soft tissue is present around the implantation site), enabling the depot to be molded and / or bent around rigid structures at the implantation site (e.g., bone, other implantable devices), enabling the depot to be bent to fit into confined spaces (e.g., sheath needles for minimally invasive procedures, small spaces within the patient's body), and / or reducing the possibility of damage to the depot during manufacturing and / or surgical procedures. Furthermore, in embodiments in which the implantable depot contains only a therapeutic area, the absence of any control area may make the depot more fragile. In such embodiments, the flexibility of the therapeutic region can be improved by adding a plasticizer, thereby reducing the possibility of breakage during manufacturing, handling, etc. For example, the depots of this specification can be bent at angles of at least 5°, 10°, 15°, 20°, 30°, or 45° without breakage.

[0186] In some embodiments, the depots of this specification are equal to or less than 600 MPa, 500 MPa, 400 MPa, 300 MPa, 200 MPa, 100 MPa, 75 MPa, 50 MPa, 40 MPa, 30 MPa, 20 MPa, or 10 MPa, and / or 1 MPa to 5 MPa, 1 MPa to 10 MPa, 1 MPa to 20 MPa, 1 MPa to 50 MPa, 1 MPa to 100 MPa, 1 MPa to 400 MPa, 5 MPa to The depot has a flexural modulus within the range of 10 MPa, 5 MPa to 20 MPa, 5 MPa to 50 MPa, 5 MPa to 100 MPa, 5 MPa to 400 MPa, 10 MPa to 20 MPa, 10 MPa to 50 MPa, 10 MPa to 100 MPa, 10 MPa to 400 MPa, 20 MPa to 50 MPa, 20 MPa to 100 MPa, 20 MPa to 400 MPa, 50 MPa to 100 MPa, 50 MPa to 400 MPa, or 100 MPa to 400 MPa. The flexural modulus of the depot can be measured, for example, using a three-point bending test at room temperature (e.g., 20 to 25°C) or physiological temperature (e.g., 37°C). In some embodiments, the depot maintains its flexibility over a long period after manufacturing. For example, the flexural modulus of a depot can be maintained for at least 1 day, 2 days, 5 days, 7 days, 10 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or 1 year after manufacturing (e.g., when stored at room temperature). In some embodiments, the flexural modulus is maintained for at least 1 day, 2 days, 5 days, 7 days, 10 days, 14 days, 20 days, 30 days, or 1 month after manufacturing under accelerated aging conditions (e.g., 40°C).

[0187] The plasticizer may be a non-volatile or low-volatility liquid or solid substance. The plasticizer may have any suitable molecular weight, such as equal to or less than 20 kDa, 10 kDa, 5 kDa, 2 kDa, 1 kDa, 900 Daa, 800 Daa, 700 Daa, 600 Daa, 500 Daa, 400 Daa, 300 Daa, 200 Daa, or 100 Daa. Plasticizers may be or may contain hydrophobic (water-insoluble) substances such as triglycerides (e.g., Miglyol, tricaprylin), fatty acid esters (e.g., ethyl hexanoate, isopropyl palmitate, isopropyl myristate), lactic acid esters (e.g., lactic acid doecyl ester), citrates (e.g., acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate (O-acetyl citrate)), diethyl phthalate (DEP), dibutyl sebacate, acetylated monoglycerides, or benzyl benzoate. Plasticizers may be or may contain hydrophilic (water-soluble) substances such as triethyl citrate, polyethylene glycol, polysorbate, propylene glycol, glycerol triacetate (triacetin), benzyl alcohol, glycerol or glycerol derivatives (e.g., glycerol formal), or ethyl lactate.In some embodiments, the plasticizer is selected from the group consisting of triglycerides (e.g., Miglyol, tricaprylin), fatty acid esters (e.g., ethyl hexanoate, ethyl lactate, isopropyl palmitate, isopropyl myristate), lactate esters (e.g., dodecyl lactate), citrates (e.g., acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate (O-acetyl citrate)), phthalates (e.g., diethyl phthalate), glycerol esters (e.g., glycerol triacetate (triacetin)), sebacates (e.g., dibutyl sebacate), monoglyceride esters (e.g., acetylated monoglycerides), benzyl derivatives (e.g., benzyl benzoate, benzyl alcohol), polyethylene glycol (e.g., polypropylene glycol), polysorbates (e.g., polysorbate 20, polysorbate 80), diols, and triols (e.g., glycerol).

[0188] In some embodiments, the plasticizer is selected to be miscible and / or at least partially soluble with the polymer(s) of the depot. The miscibility and / or solubility between the plasticizer and the polymer can affect the degree of the plasticizing effect, for example, how much the flexibility of the depot is enhanced by the addition of the plasticizer. When the plasticizer is miscible and / or sufficiently soluble with the polymer, the plasticizer occupies the intermolecular space between polymer chains, reduces intermolecular forces along the polymer chains, increases the intermolecular spacing and free volume, and therefore increases the mobility of the polymer chains and / or the glass transition temperature (T) of the polymer. g ) can be reduced. Miscibility and / or solubility can be estimated, for example, based on the Hansen solubility parameter (HSP) of the plasticizer and polymer. HSP can be used to calculate the relative energy difference (RED) between the plasticizer and polymer according to techniques known to those skilled in the art (e.g., as described in Vebber et al., J. Appl. Polym. Sci. 2014, 131, 39696 (the whole thereof is incorporated herein by reference)). Specifically, RED is given by the formula

number

[0189] In some embodiments, the plasticizer is selected to avoid leaching from the depot during and / or after manufacturing. Leaching may correlate with the vapor pressure of the plasticizer; for example, plasticizers with higher vapor pressures may be more volatile and therefore more likely to migrate to the surface of the depot and evaporate into the surrounding environment. In some embodiments, the plasticizers used in the depots described herein have vapor pressures equal to or less than 1 Pa, 0.9 Pa, 0.8 Pa, 0.7 Pa, 0.6 Pa, 0.5 Pa, 0.4 Pa, 0.3 Pa, 0.2 Pa, or 0.1 Pa at 25°C. Miscibility and / or low solubility between the plasticizer and the polymer may also promote plasticizer leaching.

[0190] The characteristics of the plasticizer can be selected to impart flexibility to the depot while simultaneously providing a desired release profile for the therapeutic agent. For example, a more hydrophilic plasticizer can promote water uptake into the depot, thereby increasing the release rate of the therapeutic agent. Conversely, a more hydrophobic plasticizer can reduce water uptake into the depot, thereby decreasing the release rate of the therapeutic agent. The hydrophobic / hydrophilicity of the plasticizer can also affect its miscibility with polymers, in that hydrophilic plasticizers can be miscible with hydrophilic polymers, while hydrophobic plasticizers can be miscible with hydrophobic polymers. The hydrophobicity of plasticizers and polymers can be quantified based on their logP values, where higher logP values ​​correspond to higher hydrophobicity and lower logP values ​​correspond to higher hydrophilicity. In some embodiments, the plasticizers used in the depots described herein have logP values ​​in the range of -1.5 to 6, 0 to 4, or 2 to 4.

[0191] In some embodiments, the depot contains a single type of plasticizer. For example, the single plasticizer may be triacetin, diethyl phthalate, or benzyl benzoate. Alternatively, the depot may contain multiple different types of plasticizers, such as two, three, four, five, or more different types of plasticizers. For example, the depot may contain a first plasticizer, such as triacetin, and a second plasticizer, such as glycerol. The first plasticizer may be a “primary” plasticizer that is miscible with the polymer and / or very soluble in the polymer, while the second plasticizer may be a “secondary” plasticizer that is miscible with the polymer and / or not very soluble in the polymer. The secondary plasticizer can further enhance the properties of the depot, such as improving or maintaining flexibility or modulating drug release kinetics. If necessary, the depot may contain additional plasticizers, such as a third plasticizer, a fourth plasticizer, etc. For example, a depot may contain a first plasticizer such as triacetin, a second plasticizer such as benzyl benzoate, and a third plasticizer such as glycerol. One or more plasticizers may be present in any preferred portion of the depot, such as only the therapeutic region, only the control region(s), or both the therapeutic and control regions(s). The therapeutic region may have the same plasticizer(s) as the control region(s), or it may have different plasticizer(s).

[0192] In some embodiments, the mass percentage of plasticizer(s) in the depot is equal to or greater than 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 14%, 15%, or 20%, and / or 20%, 15%, 14%, 10%. , 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less, and / or within the range of 0.1% to 20%, 0.5% to 10%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 20%, or 10% to 15%. In some embodiments, the mass ratio of plasticizer(s) to polymer in the depot is equal to or greater than 0.5:10, 1:10, 1.5:10, 2:10, 2.5:10, 3:10, 3.5:10, 4:10, 4.5:10, 5:10, 6:10, 7:10, 8:10, 9:10, or 10:10, and / or equal to or less than 10:10, 9:10, 8:10, 7:10, 6:10, 5:10, 4.5:10, 4:10, 3.5:10, 3:10, 2.5:10, 2:10, 1.5:10, 1:10, or 0.5:10.

[0193] In some embodiments, the mass percentage of plasticizer(s) in the therapeutic area is equal to or greater than 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 14%, 15%, or 20%, and / or 20%, 15%, 14%, 10%. The percentages are 0%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less, and / or within the ranges of 0.1% to 20%, 0.5% to 10%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 20%, or 10% to 15%. In some embodiments, the mass ratio of plasticizer(s) to polymer in the therapeutic region is equal to or greater than 0.5:10, 1:10, 1.5:10, 2:10, 2.5:10, 3:10, 3.5:10, 4:10, 4.5:10, 5:10, 6:10, 7:10, 8:10, 9:10, or 10:10, and / or equal to or less than 10:10, 9:10, 8:10, 7:10, 6:10, 5:10, 4.5:10, 4:10, 3.5:10, 3:10, 2.5:10, 2:10, 1.5:10, 1:10, or 0.5:10. However, in other embodiments, the therapeutic region may not contain any plasticizer(s).

[0194] In embodiments in which the depot comprises one or more control regions, the mass percentage of plasticizer(s) in each control region may be equal to or greater than 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 14%, 15%, or 20%, and / or 20%, 15%. , 14%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or less than 0.1%, and / or within the range of 0.1% to 20%, 0.5% to 10%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 20%, or 10% to 15%. In some embodiments, the mass ratio of plasticizer(s) to polymer in individual control regions is equal to or greater than 0.5:10, 1:10, 1.5:10, 2:10, 2.5:10, 3:10, 3.5:10, 4:10, 4.5:10, 5:10, 6:10, 7:10, 8:10, 9:10, or 10:10, and / or equal to or less than 10:10, 9:10, 8:10, 7:10, 6:10, 5:10, 4.5:10, 4:10, 3.5:10, 3:10, 2.5:10, 2:10, 1.5:10, 1:10, or 0.5:10. However, in other embodiments, the control region(s) may not contain any plasticizer(s).

[0195] In embodiments where the depot comprises a first plasticizer (e.g., triacetin) and a second plasticizer (e.g., glycerol), the mass ratio of the first plasticizer to the second plasticizer may be equal to or greater than 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1, and / or may be 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1 or less.

[0196] In embodiments where the depot comprises a first plasticizer (e.g., triacetin), a second plasticizer (e.g., benzyl benzoate), and a third plasticizer (e.g., glycerol), the mass ratio of the first plasticizer to the second plasticizer may be equal to or greater than 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1, and / or may be 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1 or less. The mass ratio of the second plasticizer to the third plasticizer may be equal to or greater than 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1, and / or may be 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 15:1 or 20:1 or less.

[0197] As described herein, the presence of plasticizers(s) enhances the flexibility of the depot, allowing it to be bent without breakage or otherwise deformed, for example. Alternatively or in combination, the geometry of the depot can be selected to improve flexibility, such as by reducing the thickness of the depot. For example, the thickness may be equal to or less than 5 mm, 4 mm, 3 mm, 2.5 mm, 2 mm, 1.5 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm, and / or within the range of 0.1 mm to 5 mm, 0.1 mm to 1 mm, 0.5 mm to 2 mm, 1 mm to 2 mm, or 1.5 mm to 2.5 mm.

[0198] Other examples of additives that may be incorporated into the depots described herein include, but are not limited to, antioxidants and / or pH adjusters for increasing storage stability, hydrophilic additives for increasing the release rate of therapeutic agents and / or the degradation rate of polymers, and / or hydrophobic additives for decreasing the release rate of therapeutic agents and / or the degradation rate of polymers.

[0199] In some embodiments, the mass percentage of the excipient in the depot is 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less. The mass percentage of the excipient in the depot may be in the range of 0.1% to 20%, 0.5% to 10%, or 1% to 5%. In some embodiments, the mass percentage of the excipient in the therapeutic area is 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less. The mass percentage of the excipient in the therapeutic area may be in the range of 0.1% to 20%, 0.5% to 10%, or 1% to 5%. In some embodiments, the mass percentage of the excipient in the individual control area is 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% or less. The mass percentage of the excipient in the control area may be in the range of 0.1% to 20%, 0.5% to 10%, 1% to 5%, 10% to 50%, 20% to 40%, or 30% to 35%.

[0200] II. Release Profile and Pharmacokinetics Depots of the present invention (e.g., depots 100a to 570 in Figures 1A to 5H) can be configured to deliver a therapeutic agent according to a desired release profile. As described elsewhere herein, the release profile of a depot can be tuned by adjusting the geometry and / or composition of the depot. For example, a depot with two control regions (e.g., depot 100a in Figure 1A) may exhibit a slower release than a depot with a single control region (e.g., depot 100b in Figure 1B) or a depot without control regions (e.g., depot 100c in Figure 1C). The number and arrangement of control regions can affect the distance the therapeutic agent travels and, consequently, correlate with the overall release rate of the therapeutic agent. In some embodiments, a depot having both upper and lower control regions (e.g., depot 100a in Figure 1A) releases the therapeutic agent primarily or entirely from the exposed outer surface, such that the travel distance and / or overall release rate is determined primarily based on the lateral dimensions of the depot (e.g., width, length). In such embodiments, the presence of one or more pores may shorten the travel distance from the depot and / or increase the release rate by increasing the exposed surface area for release of the therapeutic agent. In some embodiments, a depot without a control region (e.g., depot 100c in Figure 1C) releases the therapeutic agent primarily from the exposed upper and lower surfaces, such that the travel distance and / or release rate is determined primarily by the vertical dimensions of the depot (e.g., thickness).

[0201] Other factors that may affect the release rate include, but are not limited to, the characteristics of the therapeutic agent (e.g., hydrophobic therapeutic agents may release more slowly than hydrophilic therapeutic agents, and larger particle sizes may reduce the release rate), the characteristics of the polymer (e.g., hydrophilic polymers may promote the infiltration of physiological fluids into the depot, thereby accelerating release), and the presence of a release agent (e.g., the release rate may increase if a release agent is present). If necessary, multiple depots with different geometries and / or compositions can be implanted to produce the desired release profile overall.

[0202] The release profile can result in a sustained release of the therapeutic agent over the desired treatment period or duration (e.g., the period after the depot is implanted in the body and / or immersed in the fluid). The treatment period may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 90, 100, 200, 300, or 365 days. Alternatively or in combination, the treatment period may be equal to or less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 90, 100, 200, 300, or 365 days. The depots herein can release at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the initial amount (e.g., by mass) of the therapeutic agent in the depot over the treatment period.

[0203] The release profile of a depot can be measured using in vitro or in vivo techniques. Any description of the depot release profile herein may refer to in vitro release, in vivo release, or both, unless otherwise specified. The release profile of a depot can be measured in vitro by immersing the depot in a suitable elution medium (e.g., phosphate-buffered saline) at a controlled temperature (e.g., 37°C) and pH (e.g., 7.4, 5.8) and measuring the amount of therapeutic agent released at various time points (e.g., using spectrophotometric techniques). When measuring in vitro release, the pH and / or other parameters of the elution may be configured to approximate in vivo physiological conditions (e.g., release is measured at pH 7.4). Alternatively, the pH and / or other parameters of the elution may be selected based on other considerations. For example, if the product proceeds to development or manufacturing, an accelerated in vitro release process may be developed, for example, to facilitate quality control testing. Accelerated in vitro release may be achieved through temperature increases, the addition of an organic cosolvent to a surfactant or aqueous buffer, and / or changes in pH. For example, accelerated in vitro release can be measured at pH 5.8.

[0204] The depot release profile can be measured in vivo by implanting the depot at the treatment site of the subject (e.g., an animal or human subject), collecting local and / or systemic samples (e.g., blood, plasma, synovial fluid samples) from the subject at various time points, and measuring the amount of therapeutic agent in the samples (e.g., using liquid chromatography-tandem mass spectrometry). If necessary, the area under the curve (e.g., AUC) of the concentration data can be measured. 0~inf or AUC last Assuming that this corresponds to 100% release of the total therapeutic agent dose in the depot, then the AUC relative to the total AUC normalized to 100% 0~t1By calculating the cumulative release percentage of the therapeutic agent at each test time point t1 from the ratio, the cumulative in vivo release profile can be estimated from the concentration data. As yet another example, the in vivo release profile can be determined by explanting the depot from the treatment site at various time points and measuring the amount of therapeutic agent remaining in the depot. For example, the depot can be dissolved by immersing it in an extraction medium (e.g., 5:3 v / v acetonitrile:methanol) to release any remaining therapeutic agent. The extraction medium can be completely evaporated, and the therapeutic agent can be recovered using a suitable solvent (e.g., methanol). The recovered sample can be analyzed via high-performance liquid chromatography (HPLC) to determine the amount of therapeutic agent in the sample.

[0205] In some embodiments, the depots of this specification are configured to release the therapeutic agent at different rates over a treatment period. For example, the depots of this specification may release the therapeutic agent at a first rate during a first treatment period and at a second rate during a subsequent second treatment period. For example, the first period may be the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of the treatment period, and the second period may be the next 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after the first period. In other words, the first period could be the first hour, 2 hours, 5 hours, 10 hours, 12 hours, 20 hours, 24 hours, 30 hours, 36 hours, 40 hours, 48 ​​hours, 50 hours, 60 hours, 70 hours, 72 hours, 80 hours, 84 hours, 90 hours, 96 hours, 100 hours, 108 hours, 120 hours, 150 hours, 200 hours, 250 hours, 300 hours, 350 hours, 400 hours, 450 hours, or 500 hours of the treatment period. The second period may be the next hour, two hours, five hours, ten hours, twelve hours, twenty hours, twenty-four hours, thirty-four hours, forty hours, forty-eight hours, fifty hours, sixty hours, seventy hours, seventy-two hours, eighty hours, ninety-five hours, or fifty-five hours following the first period and the treatment period. The first speed may be the same as the second speed, or it may be different (for example, less or greater than the second speed). In some embodiments, the first speed is at least two, three, four, five, six, seven, eight, nine or ten times the second speed, or vice versa.

[0206] In some embodiments, the depot releases a first amount of the therapeutic agent over a first period and a second amount of the therapeutic agent over a second period. The first amount may be at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the initial amount of the therapeutic agent in the depot (e.g., by mass), and / or the first amount may be 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25% or less of the initial amount of the therapeutic agent in the depot. The second amount may be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the initial amount of the agent in the depot, and / or the second amount may be 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% or less of the initial amount of the agent in the depot. If necessary, the depot may release a third amount of the agent over a third period following the second period. The third amount may be at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% of the initial amount of the agent in the depot, and / or the third amount may be 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% or less of the initial amount of the agent in the depot.

[0207] For example, when measured in vitro at pH 5.8, a depot may exhibit the following release profile: the depot can release 10% to 35% of the therapeutic agent over the first 5 to 10 hours of the treatment period, the depot can release 5% to 65% of the therapeutic agent over the next 25 to 35 hours of the treatment period, and / or the depot can release 1% to 60% of the therapeutic agent over the next 115 to 130 hours of the treatment period.

[0208] In some embodiments, the depot exhibits the following release profiles when measured in vitro at pH 5.8: the cumulative amount of therapeutic agent released over the first 6 to 8 hours of the treatment period is in the range of 5% to 40%, 10% to 35%, or 15% to 30% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 35 to 42 hours of the treatment period is in the range of 35% to 80%, 37% to 77%, 40% to 75%, or 42% to 72% of the initial amount of therapeutic agent in the depot; and / or the cumulative amount of therapeutic agent released over the first 159 to 161 hours of the treatment period is at least 60%, 70%, or 80% of the initial amount of therapeutic agent in the depot.

[0209] In some embodiments, the depot exhibits the following release profile when measured in vitro at pH 5.8: at least 10% of the therapeutic agent in the depot is released over the first 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours of the treatment period; at least 20% of the therapeutic agent in the depot is released over the first 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, or 6 hours of the treatment period; at least 30% of the therapeutic agent in the depot is released over the first 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, or 10 hours of the treatment period; and at least 40% of the therapeutic agent in the depot is released over the first 8 hours of the treatment period. The drug is released over the following intervals: 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, or 15 hours, with at least 50% of the therapeutic agent in the depot being released during the first 10, 11, 12, 13, 14, 14.5, 15, 15.5, or 16 hours of the treatment period. The drug is released over 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, or 20 hours, with at least 60% of the therapeutic agent in the depot being released during the first 15, 20, 21, 22, 22.5 hours, 23, 23.5 hours, 24, 24.5 hours, 25, 25.5 hours, 26, 26.5 hours, 27 hours, and 27 hours of the treatment period.At least 70% of the therapeutic agent is released over 5, 28, 29, or 30 hours, and at least 80% of the therapeutic agent is released over the first 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 hours of the treatment period, and at least 80% of the therapeutic agent is released over the first 50, 52, 54, 55, 56, 57, 58, 59, 60, 62, 64, or 65 hours of the treatment period, and / or at least 90% of the therapeutic agent in the depot is released over the first 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 hours of the treatment period.

[0210] In some embodiments, the depot exhibits the following release profile when measured in vitro at pH 5.8: the cumulative amount of therapeutic agent released over the first hour of the treatment period is in the range of 10% to 60%, 20% to 50%, or 25% to 45% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first two hours of the treatment period is in the range of 30% to 90%, 35% to 75%, or 40% to 50% of the initial amount of therapeutic agent in the depot; and the cumulative amount of therapeutic agent released over the first three hours of the treatment period is The cumulative amount is within the range of 40%–99%, 50%–80%, or 50%–65% of the initial amount of the agent in the depot, the cumulative amount of the agent released over the first four hours of the treatment period is within the range of 50%–99%, 55%–85%, or 60%–80%, and / or the cumulative amount of the agent released over the first five hours of the treatment period is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the initial amount of the agent in the depot.

[0211] In some embodiments, the depot exhibits the following release profile when measured in vitro at pH 5.8: up to 10% of the therapeutic agent in the depot is released over the first 5, 10, 15, 20, 30, 45 minutes, or 1 hour of the treatment period; up to 20% of the therapeutic agent in the depot is released over the first 10, 15, 20, 30, 45 minutes, 1 hour, 1.5 hours, or 2 hours of the treatment period; and up to 30% of the therapeutic agent in the depot is released over the first 15, 20, 30 minutes, or 1 hour of the treatment period. The drug is released over 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours, with up to 40% of the drug in the depot being released over the first 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours of the treatment period, with up to 50% of the drug in the depot being released over the first 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, or 6 hours of the treatment period. The treatment is released over time, with up to 60% of the treatment being released during the first 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, or 8 hours of the treatment period, and up to 70% of the treatment being released during the first 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours of the treatment period, and up to 80% of the treatment being released during the treatment period The drug is released over the first 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, or 12 hours, and / or up to 90% of the therapeutic agent in the depot is released over the first 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours of the treatment period.

[0212] In some embodiments, the depot exhibits the following release profile when measured in vitro and / or in vivo at pH 7.4: the cumulative amount of therapeutic agent released over the first 24 hours of the treatment period is in the range of 1% to 25%, 1% to 10%, or 1% to 5% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 48 hours of the treatment period is in the range of 1% to 30%, 5% to 20%, or 5% to 15% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 72 hours of the treatment period is in the range of 10% to 35%, 10% to 25%, or 15% to 25% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 96 hours of the treatment period is in the range of 15% to 50%, 10% to 40%, or 10% to 30% of the initial amount of therapeutic agent in the depot; and the cumulative amount of therapeutic agent released over the first 120 hours of the treatment period is The cumulative amount of the therapeutic agent released is within the range of 20%–60%, 25%–50%, or 30%–40% of the initial amount of the therapeutic agent in the depot; the cumulative amount of the therapeutic agent released over the first 144 hours of the treatment period is within the range of 25%–70%, 30%–50%, or 35%–45% of the initial amount of the therapeutic agent in the depot; the cumulative amount of the therapeutic agent released over the first 7–8 days of the treatment period is within the range of 30%–70% or 35%–55% of the initial amount of the therapeutic agent in the depot; the cumulative amount of the therapeutic agent released over the first 14 days of the treatment period is within the range of 50%–90% or 60%–80% of the initial amount of the therapeutic agent in the depot; and / or the cumulative amount of the therapeutic agent released over the first 21 days of the treatment period is within the range of 70%–99% or 85%–95% of the initial amount of the therapeutic agent in the depot.

[0213] In some embodiments, the depot exhibits the following release profiles when measured in vitro and / or in vivo at pH 7.4: up to 10% of the therapeutic agent in the depot is released over the first 4, 12, 24, or 48 hours of the treatment period; up to 20% of the therapeutic agent in the depot is released over the first 24, 48, 72, or 84 hours of the treatment period; up to 30% of the therapeutic agent in the depot is released over the first 48, 72, 120, or 144 hours of the treatment period; and up to 40% of the therapeutic agent in the depot is released over the first 120, 144, 168, or 192 hours of the treatment period. Up to 50% of the treatment agent is released over the first 7, 8, 9, or 10 days of the treatment period; up to 60% of the treatment agent in the depot is released over the first 10, 11, 12, or 13 days of the treatment period; up to 70% of the treatment agent in the depot is released over the first 13, 14, 15, or 16 days of the treatment period; up to 80% of the treatment agent in the depot is released over the first 16, 17, 18, or 19 days of the treatment period; and / or up to 90% of the treatment agent in the depot is released over the first 19, 20, 21, or 22 days of the treatment period.

[0214] In some embodiments, the depot exhibits the following release profile when measured in vitro and / or in vivo at pH 7.4: the cumulative amount of therapeutic agent released over the first hour of the treatment period is in the range of 5% to 40%, 10% to 30%, or 15% to 25% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first four hours of the treatment period is in the range of 40% to 80%, 50% to 75%, 60% to 80%, or 40% to 60% of the initial amount of therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 24 hours of the treatment period is at least 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the initial amount of therapeutic agent in the depot; and / or the cumulative amount of therapeutic agent released over the first 48 hours of the treatment period is at least 80%, 85%, 90%, 95%, or 99% of the initial amount of therapeutic agent in the depot.

[0215] In some embodiments, the depot exhibits the following release profile when measured in vitro and / or in vivo at pH 7.4: up to 10% of the therapeutic agent in the depot is released over the first 5, 10, 15, 20, 30, 45 minutes or 1 hour of the treatment period; up to 20% of the therapeutic agent in the depot is released over the first 10, 15, 20, 30, 45 minutes, 1 hour, 1.5 hours or 2 hours of the treatment period; and up to 30% of the therapeutic agent in the depot is released over the first 15, 20 minutes of the treatment period. The drug is released over 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours, with up to 40% of the drug in the depot being released over the first 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours of the treatment period, with up to 50% of the drug in the depot being released over the first 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours of the treatment period. Up to 60% of the therapeutic agent is released over 6 hours, and up to 70% of the therapeutic agent is released over the first 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, or 8 hours of the treatment period, and up to 80% of the therapeutic agent is released over the first 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20 hours of the treatment period. The agent is released over the first 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 24, or 30 hours of the treatment period, and / or up to 90% of the therapeutic agent in the depot is released over the first 5, 6, 7, 8, 9, 10, 11, 12, 15, 20, 24, 30, 36, 40, or 48 hours of the treatment period.

[0216] In some embodiments, the release profile of the therapeutic agent is the primary release profile (this is the equation

number

[0217] The depots described herein may be configured to release a larger amount of the therapeutic agent per day over a first period than over a longer second period. In some embodiments, the depot is configured to release the therapeutic agent over at least 14 days after implantation (or immersion in the fluid), where a controlled burst of about 20% to 50% of the therapeutic agent payload is released during the first 3 to 5 days, and at least 80% of the remaining therapeutic agent payload is released at a slower rate over the last 10 to 11 days. In some embodiments, at least 90% of the therapeutic agent payload is released by the end of the 14 days.

[0218] The two-stage release profile may be particularly advantageous in the context of managing pain resulting from total knee arthroplasty ("TKA"). TKA patients typically experience the greatest pain within the first 1 to 3 days after surgery (clinically referred to as "acute pain"), followed by a gradual decrease in pain over the next 7 to 10 days (clinically referred to as "subacute pain"). The acute period often overlaps with or coincides with the patient's inpatient care (usually 1 to 3 days), while the subacute period generally begins when the patient is discharged and goes home. The two-stage release profile may also be beneficial in other surgical applications, e.g., other orthopedic applications (e.g., ligament repair / replacement and other injuries to the knee, shoulder, ankle, etc.) or non-orthopedic surgical applications, as will be described in more detail below. Excessive pain after any surgical procedure can prolong hospitalization, cause psychological distress, increase opioid consumption, and / or impair patient engagement with physical therapy, all of which can prolong and / or reduce the degree of recovery. Pain management during the subacute period can be particularly complex, as patient compliance with prescribed pain management regimens tends to decrease as patients transition from hospitalization to a home environment.

[0219] To address the aforementioned difficulties in pain management after surgery, the depot of the present invention may have a release profile that is tailored to meet the specific pain management needs of the acute and subacute periods. For example, to address greater acute pain that appears immediately after surgery, the depot may be configured to release the therapeutic agent at a more rapid rate over the first 3 to 5 days after implantation compared to the following 9 to 11 days. In some embodiments, the depot delivers the local anesthetic at a rate of about 150 mg / day to about 400 mg / day during this first acute period. To address decreasing pain during the subacute period, the depot may be configured to release the therapeutic agent at a slower rate over the remaining 9 to 11 days. In some embodiments, the depot delivers the local anesthetic at a rate of about 50 mg / day to about 250 mg / day during this second subacute period. In some embodiments, the release rate decreases continuously throughout the first and / or second period. The timing of the release profile stages corresponding to the acute and subacute phases, as well as the release rate at each stage, can be adjusted according to the expected degree and duration of pain after the surgical procedure. For example, in procedures expected to cause less pain than total knee arthroplasty (TKA), such as soft tissue procedures (e.g., abdominal hernia repair), the duration of the acute and subacute phases can be shortened.

[0220] The release profile of a depot can be tuned to release the therapeutic agent over other durations and / or at other release rates by adjusting the structure, composition, and / or process by which the depot is manufactured. For example, in some embodiments, the depot is configured to release the therapeutic agent at a constant rate throughout its entire release duration. In some embodiments, the depot will release the therapeutic agent at a constant rate over a first period and at a non-constant rate over a second period (which may exist before or after the first period).

[0221] In some embodiments, the depot is configured to release 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% or less of the therapeutic agent during the first 1, 2, 3, 4, 5, 6, 6, 7, or 13 days of the release period, with at least 75%, 80%, 85%, 90%, 95%, or 100% of the remaining therapeutic agent being released during the remaining days of the release period. The intended duration of release may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. Alternatively or in combination, the intended duration of release may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days or less.

[0222] In some embodiments, the depot is configured to release 50 mg to 600 mg / day, 100 mg to 500 mg / day, 100 mg to 400 mg / day, or approximately 100 mg to 300 mg / day of the therapeutic agent to the treatment site. Generally, the release rate can be selected to deliver the desired dose to provide the degree of pain relief required in a given time after a surgical procedure, control toxicity, and deliver the therapeutic agent for a sufficient period of time for pain relief. In some embodiments, the depot is configured to release 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of the therapeutic agent within a release duration of any day.

[0223] In some embodiments, the depot is configured to release a therapeutic agent at a dose of 50 mg / day to 600 mg / day, 100 mg / day to 500 mg / day, 100 mg / day to 400 mg / day, or 100 mg / day to 300 mg / day to the treatment site within a first release period. The depot may further be configured to release a therapeutic agent at a dose of 500 mg / day to 600 mg / day, 100 mg / day to 500 mg / day, 100 mg / day to 400 mg / day, or 100 mg / day to 300 mg / day to the treatment site within a second release period. The release rate during the first period may be the same as or different from the release rate during the second period, or it may be less or greater. Furthermore, the first period may be longer or shorter than the second period. The first period may occur before or after the second period.

[0224] In some embodiments, the depot is configured to release a therapeutic agent in doses of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg or less within a first release period on any given day. Alternatively or in combination, a depot may be configured to release at least 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg of the therapeutic agent within the first release period of any day. This may be useful for providing different degrees of pain relief at different times after a surgical procedure and may also be useful for controlling toxicity. In such embodiments, the depot may be configured to release at least 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of the therapeutic agent within a second release period on any given day. The first period and / or the second period may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days.

[0225] One or more depots of the technology of the present invention can be implanted at the treatment site in a subject (e.g., a human patient or an animal model) to produce a desired level of therapeutic agent in vivo, for example, a level at or above the therapeutic threshold and / or a level below the toxicity threshold. For example, one or more depots of the technology of the present invention, when implanted, may be 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 mg / ml, 25 ng / ml, 30 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, 100 ng / ml, 110 ng / ml, 120 ng / ml, 130 ng / ml, 140 ng / ml, 150 ng / ml, 160 ng / ml, 170 ng / ml, 180 ng / ml, 190 ng / ml This can produce mean plasma concentrations of the therapeutic agent equal to or greater than the therapeutic threshold of 200 ng / ml, 210 ng / ml, 220 ng / ml, 230 ng / ml, 240 ng / ml, 250 ng / ml, 300 ng / ml, 400 ng / ml, 500 ng / ml, 600 ng / ml, 700 ng / ml, 800 ng / ml, 900 ng / ml, or 1000 ng / ml. As an alternative or in combination, depots may produce mean plasma concentrations of the therapeutic agent equal to or below the toxicity thresholds of 9000 ng / ml, 8000 ng / ml, 7000 ng / ml, 6000 ng / ml, 5000 ng / ml, 4000 ng / ml, 3000 ng / ml, 2500 ng / ml, 2400 ng / ml, 2300 ng / ml, 2200 ng / ml, 2100 ng / ml, 2000 ng / ml, 1900 ng / ml, 1800 ng / ml, 1700 ng / ml, 1600 ng / ml, 1500 ng / ml, 1400 ng / ml, 1300 ng / ml, 1200 ng / ml, 1100 ng / ml, or 1000 ng / ml.

[0226] In some embodiments, when one or more depots of the present invention are implanted, the mean plasma concentration of the therapeutic agent reaches or exceeds the therapeutic threshold within the first 12 hours, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of the treatment period. The mean plasma concentration of the therapeutic agent should be maintained for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 90, 100, 200, 300 or 365 days, and / or 1, 2 days The levels may be maintained above the therapeutic threshold and / or below the toxicity threshold for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 90, 100, 200, 300, or 365 days or less.

[0227] In some embodiments, the depot(s) implanted have an average C of the therapeutic agent equal to or less than 5000 ng / ml, 4000 ng / ml, 3000 ng / ml, 2000 ng / ml, 1000 ng / ml, 900 ng / ml, 800 ng / ml, 700 ng / ml, 600 ng / ml, 500 ng / ml, 400 ng / ml, 300 ng / ml, 200 ng / ml, 100 ng / ml, or 50 ng / ml. max This results in the average C of the therapeutic agent, either as an alternative or in combination. maxThis may be equal to or greater than 50 ng / ml, 100 ng / ml, 200 ng / ml, 300 ng / ml, 400 ng / ml, 500 ng / ml, 600 ng / ml, 700 ng / ml, 800 ng / ml, 900 ng / ml, 1000 ng / ml, 2000 ng / ml, 3000 ng / ml, 4000 ng / ml, or 5000 ng / ml. Depot(s) are equal to or greater than 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 30 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, and / or equal to or less than 7 days, 6 days, 5 hours, 4 days, 3 days, 2 days, 1 day, 30 hours, 22 hours, 20 hours, 18 hours, 16 hours, 14 hours, 12 hours, or 8 hours, with an average treatment duration of t 1 / 2 This may occur. Depot(s) are for an average time of at least 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, 48 ​​hours, 36 hours, 72 hours, 96 hours, 120 hours, 144 hours or 168 hours, and / or 144 hours, 120 hours, 96 hours, 72 hours, 36 hours, 48 ​​hours, 24 hours, 12 hours, 4 hours or 2 hours or less of the therapeutic agent. max This may occur. Depot(s) are for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 25, 30, 35, 40 or 45 days and / or 30, 25, 20, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 day or less of average t of the treatment agent. last This can occur.

[0228] In some embodiments, the depot(s) have an average AUC of at least 500-day-ng / ml, 1000-day-ng / ml, 1500-day-ng / ml, 2000-day-ng / ml, 2500-day-ng / ml, 3000-day-ng / ml, 3500-day-ng / ml, 4000-day-ng / ml, 4500-day-ng / ml, 5000-day-ng / ml, 5500-day-ng / ml, 6000-day-ng / ml, 6500-day-ng / ml, 7000-day-ng / ml, 7500-day-ng / ml, or 8000-day-ng / ml when implanted. t1~t2This occurs, and the period t1-t2 can be any of the following: 0-1 day, 0-2 days, 0-3 days, 0-4 days, 0-5 days, 0-6 days, 0-7 days, 0-14 days, 0-21 days, 0-30 days, 1-7 days, 1-6 days, 1-5 days, 1-4 days, 1-3 days, 1-2 days, 2-7 days, 2-6 days, 2 days ~5 days, 2-4 days, 2-3 days, 3-7 days, 3-6 days, 3-5 days, 3-4 days, 4-7 days, 4-6 days, 4-5 days, 5-7 days, 5-6 days, 7-14 days, 7-21 days, 7-30 days, 14-21 days, 14-30 days, 21-30 days, or 0 days until the final measurable concentration of the treatment is reached. Depots (multiple depots are possible) must be at least 500 days-ng / ml, 1000 days-ng / ml, 1500 days-ng / ml, 2000 days-ng / ml, 2500 days-ng / ml, 3000 days-ng / ml, 3500 days-ng / ml, 4000 days-ng / ml, 4500 days-ng / ml, 5000 days-ng / ml, 5500 days-ng / ml, 6000 days-ng / ml, The mean AUC of therapeutic agents with 6,500 days-ng / ml, 7,000 days-ng / ml, 7,500 days-ng / ml, 8,000 days-ng / ml, 9,000 days-ng / ml, 10,000 days-ng / ml, 11,000 days-ng / ml, 12,000 days-ng / ml, 13,000 days-ng / ml, 14,000 days-ng / ml, or 15,000 days-ng / ml. last This can occur.

[0229] In some embodiments, when one or more depots of the technology of the present invention are implanted in an animal model (e.g., mouse, rat, rabbit, dog, miniature pig, sheep), acute toxicity is not observed even if the total dose of the therapeutic agent in the depot(s) exceeds the dose that would be expected to cause acute toxicity if administered via other routes (e.g., oral, subcutaneous, intravenous, paraperiosteal). For example, when one or more depots are implanted in an animal model and the total dose of the therapeutic agent is at least 50 mg / kg, 100 mg / kg, 500 mg / kg, 1000 mg / kg, 1500 mg / kg or 2000 mg / kg, and / or 2000 mg / kg, 1500 mg / kg, 1000 mg / kg or 500 mg / kg or less, acute toxicity may not be observed.

[0230] III. System and Usage The depots of the present invention (e.g., depots 100a to 570 in Figures 1A to 5H) can be used to treat a variety of injuries, conditions, or diseases, depending on the nature of the therapeutic agent delivered as described above. The therapeutic agent can be delivered to a specific area of ​​the patient's body, depending on the medical condition being treated. The depots of the present invention can be placed in vivo in close proximity to target tissue (e.g., bone, soft tissue, etc.) within the patient's body to provide a controlled, sustained release of the therapeutic agent for the treatment of a particular condition. This implantation may be associated with a surgical procedure or intervention to acutely treat a particular condition, thereby providing a long-term, sustained pharmacological treatment after the completion of the surgical procedure or intervention. The depots may be standalone elements, or they may be connected to or integrated as part of an implantable device or prosthesis associated with an intervention or surgical procedure.

[0231] The effective amount or dose of a therapeutic agent in a patient requiring it may vary depending on the specific nature of the condition and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may be used as needed to help identify the optimal dosage range. A specific dose level for any particular individual will vary depending on a variety of factors, including drug activity, age, weight, overall physical and mental health, genetic factors, environmental influences, sex, diet, timing of administration, site of administration, excretion rate, and / or the severity of the specific problem being treated.

[0232] Some aspects of the technology of the present invention include a system comprising one or more depots provided for implantation by a clinician (each of which may be any of the depots described herein). For example, the system may include one, two, three, four, five, six, seven, eight, nine, ten, or more implanted depots. Each depot may be configured to release the therapeutic agent in a controlled manner into the tissue adjacent to the implantation site of the depot. Thus, the depots together may provide a desired dose, e.g., 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, This can result in doses of the therapeutic agent equal to or greater than 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg. The doses delivered by an individual depot or a series of depots can be expressed in terms of the mass of the therapeutic agent used in the depot(s) or in terms of the mass of the therapeutic agent in another form (e.g., in the form of the active portion or in an established salt form). For example, the dose of bupivacaine in a depot formulation using bupivacaine hydrochloride monohydrate can be expressed in terms of the equivalent mass of free bupivacaine base (e.g., 595 mg of bupivacaine hydrochloride monohydrate is equivalent to 500 mg of free bupivacaine base) or in terms of the equivalent mass of bupivacaine hydrochloride (e.g., 595 mg of bupivacaine hydrochloride monohydrate is equivalent to 563 mg of bupivacaine hydrochloride).

[0233] In embodiments where the system includes multiple depots, some or all of the depots in the system may be identical, and / or some or all of the depots may be different from one another (e.g., in terms of geometry, composition, and / or release profile). For example, the system may include at least one depot having a release profile that results in immediate release of the therapeutic agent, and at least one other depot having a release profile that results in delayed release of the therapeutic agent.

[0234] Many of the depots of the present invention are configured to be implanted at or near a surgical site to treat postoperative pain therein. As used herein, the term “pain” includes pain sensation and pain perception, which together can be assessed objectively and subjectively using pain scores and other methods well known in the art, e.g., opioid use methods, as further described below. Pain may include allodynia (e.g., increased response to stimuli that are not normally harmful) or hyperalgesia (e.g., increased response to stimuli that are normally harmful or unpleasant), and they may, by extension, be thermal or mechanical (tactile). In some embodiments, pain is characterized by thermal sensitivity, mechanical sensitivity, and / or resting pain. Pain may be primary or secondary pain, as well as well known in the art. Examples of pain that can be reduced, prevented or treated by the methods and compositions disclosed herein include, but are not limited to, postoperative pain from the posterior lumbar region (lumbar pain) or the neck (cervical pain), leg pain, radiculopathy (experienced in the lumbar region and leg resulting from lumbar spine surgery, and in the neck and arm resulting from cervical surgery), or abdominal pain resulting from abdominal surgery, as well as neuropathic pain in the arm, neck, back, lumbar region, leg and associated pain distribution resulting from intervertebral disc or spinal surgery. Neuropathic pain may include pain resulting from surgery on nerve roots, dorsal root ganglia, or peripheral nerves.

[0235] In some embodiments, pain includes “post-surgical pain,” “postoperative pain,” or “surgical-induced pain,” which are interchangeable as used herein, and refer to pain that occurs in a recovery period of seconds, minutes, hours, days, or weeks following a surgical procedure (e.g., hernia repair, orthopedic or spinal surgery). A surgical procedure may include any procedure that penetrates beneath the skin and causes pain and / or inflammation in the patient. A surgical procedure may be performed in various locations within the patient's body. For example, surgery may be performed in the patient's knee, hip, upper limb, lower limb, neck, spine, shoulder, chest, nasal / sinus region, abdomen, and / or pelvic region.

[0236] Some embodiments of the technology of the present invention include one or more depots (e.g., having the same or different configurations and / or dosages) placed at or near the surgical site of the knee joint to treat pain associated with total knee arthroplasty, also known as TKA. In some cases, it may be beneficial to place one or more depots within the joint capsule. In some embodiments, one or more depots are placed in or near the suprapatellar bursa, particularly subperiosteally, and attached to the quadriceps tendon. Further areas for placing one or more depots may generally include medial and lateral grooves (including, as needed, fixation to tissue on the medial or lateral surface of each groove), on the femur, on the tibia (e.g., posterior attachment to the tibial plateau, on or near the anterior tibia to anesthetize the infrapatellar branch of the saphenous nerve). In some embodiments, one or more depots are placed adjacent to at least one of the arthrotomy incisions into the posterior capsule of the knee, the suprapatellus, and / or the knee capsule. In some embodiments, one or more depots are placed in or near the saphenous nerve, adductor canal, and / or femoral nerve. In some embodiments, one or more depots are placed in or near the infrapatellar branch of the saphenous nerve, one or more geniculate nerves of the knee, or above the patella. It may be desirable to place the depot(s) within the knee joint capsule, but away from any articular joint portion of the knee joint itself.

[0237] In some embodiments, one or more depots are placed near or adjacent to one or more nerves that innervate the anterior knee joint capsule. For example, the depot(s) may be configured to be located near or adjacent to the superior lateral genicular branch from the vastus lateralis muscle, the superior medial genicular branch from the vastus medialis muscle, the medial (retinaculous) genicular branch from the vastus intermedius muscle, the inferior lateral genicular branch from the common peroneal nerve, the inferior medial genicular branch from the saphenous nerve, and / or the lateral (retinaculous) genicular branch from the common peroneal nerve. Instead of placing the depot within the capsule, or in addition to that, one or more depots may be placed in an extracapsular location. In some embodiments, the depot(s) are implanted adjacent to one or more extracapsular nerves. In some embodiments, one or more depots are placed along or adjacent to a subcutaneous incision in the skin.

[0238] One or more depots may include a feature to delay release 6 to 24 hours after implantation, if necessary, so as not to interfere with or overlap with peripheral nerve blocks administered to the patient during the perioperative period. In some embodiments, one or more depots placed in the adductor canal and knee joint capsule are configured to delay the release of the therapeutic agent by at least 24 hours.

[0239] In some embodiments, the depot of the technology of the present invention utilizes a local procedure to control pain after total knee arthroplasty (TKA). Such a procedure may include infiltrating a local anesthetic between the popliteal artery and the knee joint capsule (IPACK) block. The IPACK block procedure typically involves scanning the popliteal fossa using a probe proximal to the popliteal fold and injecting an analgesic (e.g., 20 ml of 0.25% ropivacaine) between the patient's popliteal artery and the femur. Unlike other known procedures for treating postoperative pain after TKA (e.g., adductor canal block (ACB) and femoral nerve catheter (FNC) block), the IPACK block targets only the terminal branches of the sciatic nerve. In doing so, it is possible to deliver analgesics and / or other therapeutic agents to the posterior knee without causing distal neurological defects. In some embodiments, the depot of the technology of the present invention is implanted using a combination of the IPACK block procedure and the ACB or FNC block procedure. For example, a patient may receive one or more depots using FNC blocks before surgery, and then one or more further depots using IPACK blocks postoperatively. Utilizing the IPACK block procedure in conjunction with depots of the present invention is advantageous in that it can provide adequate analgesia after TKA, promote improved physical therapy performance, reduce the incidence of foot drop, reduce opioid consumption, and / or better control post-TKA posterior knee pain compared to other known techniques for pain management after TKA, such as ACB, FNC blocks, and in many cases, allow for earlier discharge from the hospital.

[0240] The depots disclosed herein can be used to treat postoperative pain associated with other knee surgeries. For example, one or more depots can be used to treat postoperative pain associated with ACL repair surgery, medial collateral ligament ("MCL") surgery, and / or posterior cruciate ligament ("PCL") surgery. For ACL repair, one or more depots can be positioned to deliver analgesics to the femoral nerve and / or sciatic nerve, while for PCL repair surgery, one or more depots can be positioned parasacral to deliver analgesics to the sciatic nerve. One or more depots can be used to treat postoperative pain associated with partial knee replacement, total knee replacement, and / or corrective knee replacement surgery. In such procedures, one or more depots can be placed adjacent to the joint or repair site to produce a local block, or otherwise preferably to produce a local block by delivering analgesics to one or more of the femoral nerve or sciatic nerve, for example, via placement in the adductor canal.

[0241] In addition to the knee-related surgical procedures described above, the depot embodiments disclosed herein can be used to treat postoperative pain associated with other orthopedic surgical procedures, such as those involving the ankle, hip, shoulder, wrist, hand, spine, leg, or arm. For at least some of these surgical procedures, analgesics may be provided to deliver local or regional blocks to treat postoperative pain. For regional blocks, one or more depots may be attached under direct visualization during open surgery, such as during arthroplasty, open reduction and internal fixation (ORIF), or ligament reconstruction. In joint procedures, one or more depots may be placed in the joint capsule (e.g., within or near the joint capsule) and / or in adjacent soft tissue spaced away from the joint surface to avoid the depot being obstructed by joint movement or damaged by contact with the joint surface. In procedures involving fracture or ligament repair, one or more depots may be placed at or adjacent to the repair site to provide a local block. For local blocks, one or more depots may be placed at the treatment site adjacent to the target nerve via ultrasound guidance using a blunt trocar catheter or other suitable instrument. In some embodiments, delivery of analgesics or other therapeutic agents via depots may be beneficial in combination with NSAIDs, long-acting narcotics delivered preoperatively, and / or acetaminophen. Sustained controlled release of analgesics via one or more depots can work in conjunction with these other therapeutic agents to reduce postoperative pain associated with orthopedic and other surgical procedures.

[0242] For example, one or more depots can be used to treat postoperative pain associated with surgical procedures of the foot and / or ankle, such as ankle arthroplasty (including ankle correction, ankle replacement, and total ankle replacement), ankle fusion, hindfoot fusion, ligament reconstruction, corrective osteotomy (e.g., bunion excision, flatfoot surgery), or ORIF of ankle or foot fractures. In treating postoperative pain associated with such surgical procedures, one or more depots may be configured and placed adjacent to the joint or repair site to provide a local block. In addition or alternatively, one or more depots may be placed parasacral or in other locations suitable for targeting one or more of the subgluteal sciatic nerve, popliteal sciatic nerve, deep peroneal nerve, or superficial peroneal nerve. In some embodiments, a depot placed to treat postoperative pain associated with ankle or foot surgery has a release profile configured to deliver therapeutically beneficial analgesic levels over a period of 3 to 7 days.

[0243] In another example, one or more depots can be used to treat postoperative pain associated with hip surgery, such as hip arthroplasty (including hip correction, partial hip replacement, and total hip replacement) or ORIF of hip fracture. In treating postoperative pain associated with such surgery, one or more depots can be configured and positioned adjacent to the joint or repair site to produce a local block. In addition or alternatively, a local block can be produced by placing the depots in the lumbar compartment, lumbar paravertebral space, iliac fascia, or other locations suitable for targeting one or more of the lumbar plexus, sacral plexus, femoral nerve, sciatic nerve, superior gluteal nerve, or obturator nerve. In some embodiments, it may be beneficial to fix one or more depots (e.g., using sutures, fasteners, or other fixation mechanisms) to maintain the anterior position of the depots, thereby preventing or reducing exposure of motor nerves (e.g., the sciatic nerve or femoral nerve) to the analgesic. In some embodiments, a depot deployed to treat postoperative pain associated with hip surgery has a release profile configured to deliver therapeutically beneficial analgesic levels over a period of 5 to 7 days or 7 to 10 days, depending on the specific surgical procedure.

[0244] Postoperative pain associated with shoulder and humeral surgery can also be treated using one or more depots disclosed herein. Examples of such surgeries include shoulder arthroplasty (including shoulder repair, partial shoulder replacement, and total shoulder replacement), humeral fracture repair (e.g., scapula, humerus), ligament / tendon repair (e.g., rotator cuff, labrum, biceps, etc.), or ORIF for shoulder or humeral fractures. In treating postoperative pain associated with such surgeries, one or more depots may be configured and placed adjacent to the joint or repair site to provide a local block. In addition or alternatively, one or more depots may be configured and placed to target the brachial plexus by placing one or more depots in the paracervical space, interscalene space, or supraclavicular fossa. In some embodiments, placement of a depot in interscalene space can avoid exposure of the analgesic to the natural cartilage, thereby reducing the risk of chondrotoxicity. In some embodiments, a depot placed to treat postoperative pain associated with shoulder or upper arm-related surgery has a release profile configured to deliver therapeutically beneficial analgesic levels over a period of 3 to 7 days.

[0245] In another example, one or more depots described herein can be used to treat postoperative pain associated with elbow surgery, such as elbow arthroplasty (including elbow repair, partial elbow replacement, and total elbow replacement), ligament reconstruction, or ORIF of elbow fracture. In treating postoperative pain associated with such surgery, one or more depots can be placed adjacent to the joint or repair site to produce a local block. In addition or alternatively, one or more depots can be configured and placed to target the brachial plexus nerves by being placed in or near, for example, the cervical paravertebral space, subclavian, or axillary location, or other preferred location. In some embodiments, a depot placed to treat postoperative pain associated with elbow surgery has a release profile configured to deliver a therapeutically beneficial level of analgesia over a period of 3 to 7 days.

[0246] Postoperative pain associated with wrist and hand surgery can also be treated using one or more depots described herein. Examples of wrist and hand surgery include wrist arthroplasty (including wrist repair, partial wrist replacement, and total wrist replacement), wrist fusion, carpal tunnel surgery, and ORIF for wrist fractures. In treating postoperative pain associated with such surgery, one or more depots may be configured and placed adjacent to the wrist joint or repair site to provide a local block. In addition or alternatively, one or more depots may be configured and placed to target the ulna, median, radial, and cutaneous brachial nerves via placement in, for example, the cubital fossa, paracervical space, subclavian, or axillary location. In some embodiments, a depot placed to treat postoperative pain associated with wrist and hand surgery has a release profile configured to deliver a therapeutically beneficial level of analgesia over a period of 3 to 7 days.

[0247] The depots disclosed herein can also be used to treat postoperative pain from other orthopedic surgical procedures, such as spinal surgery (e.g., laminectomy, spinal fusion) and fractures (e.g., hip fracture, radial fracture, ulnar fracture, tibia fracture, fibula fracture, ankle fracture). For example, postoperative pain associated with spinal fusion can be treated by placing one or more depots subcutaneously or paravertebrally. In treating postoperative pain associated with fibula fracture repair, one or more depots can be configured and placed targeting the sciatic nerve and / or popliteosciatic nerve, for example, parasacral. Various other placements and configurations are also possible to provide therapeutic relief from postoperative pain associated with orthopedic surgical procedures.

[0248] The depots disclosed herein can be used to treat postoperative pain associated with other types of surgery, in addition to orthopedic surgery. For example, depots can be used to treat postoperative pain in thoracic surgery; breast surgery; gynecological or obstetric surgery; general surgery; abdominal surgery; urinary surgery; ear, nose, and throat (ENT) surgery; oral and maxillofacial surgery; oncological surgery; or cosmetic surgery. In certain surgical procedures or certain classes of surgery, one or more depots may be placed at the treatment site to treat postoperative pain. The treatment site may be at or near the surgical site, or it may be spaced away from the surgical site (for example, in close proximity to a target nerve or nerve bundle innervating the surgical site).

[0249] For example, one or more depots described herein can be used to treat postoperative pain associated with thoracic-related surgical procedures, such as thoracotomy, sternotomy, esophageal surgery, cardiac surgery, lung resection, thoracic surgery, or other such procedures. In treating postoperative pain associated with such surgical procedures, one or more depots can be configured and positioned to target the intercostal nerves, for example, by placing them in or near the paravertebral space of the thoracic region. The analgesic delivered to the intercostal nerves can reduce pain in the patient's thoracic region, thereby alleviating postoperative pain associated with the thoracic-related surgical procedures described above.

[0250] In another example, one or more depots disclosed herein can be used to treat postoperative pain associated with breast-related surgical procedures, such as mastectomy, breast augmentation (macroplasty), breast reduction, breast reconstruction, or other such procedures. To treat postoperative pain from such procedures, one or more depots may be positioned and configured to deliver analgesics or other therapeutic agents to the intercostal nerves, for example, by placement in or near the subclavian space of the patient or other preferred location. In addition or alternatively, one or more depots may be positioned and configured to deliver analgesics or other therapeutic agents to the lateral and / or medial pectoral nerves, for example, by placement between the serratus anterior and latissimus dorsi muscles or other preferred location. As noted above, analgesics delivered to the intercostal nerves can reduce pain in the patient's chest region, while analgesics delivered to the lateral and / or medial pectoral nerves can reduce pain in the pectoralis major and / or minor muscles, thereby reducing postoperative pain associated with the chest-related surgical procedures described above.

[0251] As another example, one or more depots can be used to treat postoperative pain associated with generalized, abdominal, pelvic, and / or urinary tract procedures. Examples of such procedures include colectomy, colectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplantation, nephrectomy, radical prostatectomy, nephrectomy, gastrectomy, gastric surgery, small bowel resection, splenectomy, open surgery, laparoscopy, hernia repair (e.g., inguinal, abdominal wall, umbilical, scar), sigmoid colectomy, corectomy, hepatectomy, enterostomy, rectal resection, nephrolithotomy, cystectomy, and sex reassignment surgery. In such surgeries, postoperative pain can be treated by placing one or more depots targeting nerves in the transversus abdominis surface (TAP). The analgesic delivered to the TAP anesthetizes the nerves supplying the anterior abdominal wall, thereby reducing postoperative pain in this area. In some embodiments, one or more depots are positioned between the internal oblique and transversus abdominis muscles. In some embodiments, one or more depots can be positioned in or near the abdominal wall and can be fixed in place, for example, via sutures, fasteners, or other fixation mechanisms.

[0252] In some embodiments, one or more depots are used to treat postoperative pain associated with gynecological and obstetric surgical procedures, such as myomectomy, cesarean section, hysterectomy (e.g., vaginal hysterectomy), oophorectomy, pelvic floor reconstruction, or other such surgical procedures. In such procedures, the depot(s) may be configured and positioned to deliver analgesics or other therapeutic agents to one or more nerves innervating the pelvic and / or genital region, such as the pudendal nerve, intercostal nerves, or other suitable nerves.

[0253] In some embodiments, one or more depots can be used to treat postoperative pain associated with ENT surgical procedures, such as tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotid gland excision, submandibular gland surgery, or other such procedures. Similarly, one or more depots can be used to treat postoperative pain associated with oral and maxillofacial surgery, such as alveolar surgery, dental implant surgery, mandibular orthodontic surgery, temporomandibular joint (TMJ) surgery, dental reconstruction surgery, or other such procedures. In ENT surgical procedures and / or oral and maxillofacial surgical procedures, the depot(s) may be configured and positioned to deliver analgesics or other therapeutic agents to one or more nerves innervating the area affected by the surgical procedure, such as the mandibular nerve, mylohyoid nerve, lingual nerve, inferior alveolar nerve, buccal nerve, auriculotemporal nerve, anterior ethmoid nerve, or other suitable nerves.

[0254] Furthermore, one or more depots can be used to treat postoperative pain resulting from other surgical procedures, such as oncological surgery (e.g., tumor resection), cosmetic surgery (e.g., liposuction, abdominal wall reconstruction), amputation, or other surgical procedures that result in postoperative pain. If necessary, one or more depots can be used to treat pain for indications not related to surgical procedures, for example, in the treatment of neuroma or phantom limb pain.

[0255] The number of depots and the characteristics of each depot (e.g., geometry, composition, release profile) can be selected to deliver the desired therapeutic benefit to the specific condition being treated. For example, a patient recovering from hard tissue surgery (e.g., knee replacement) may benefit from analgesic delivery for a relatively longer period (e.g., at least 7, 14, or 21 days post-surgery), while a patient recovering from other types of surgery may not require the same level or duration of analgesic delivery. In some embodiments, a patient recovering from soft tissue surgery (e.g., tonsillectomy, hernia repair, abdominal wall reconstruction, mastoplasty) may benefit from analgesic delivery for a shorter period, e.g., up to 4, 5, 6, or 7 days post-surgery. Therefore, depots delivered to a patient for the treatment of postoperative pain after soft tissue surgery may require fewer depots, depots with smaller payloads of therapeutic agent, or depots(s) with faster release profiles (e.g., depots with fewer or no control areas). In another example, the systemic therapeutic threshold of the therapeutic agent that correlates with the desired amount of pain relief may vary depending on the condition being treated, and the number and characteristics of the depot(s) selected for implantation may be chosen to deliver the therapeutic agent to or above the systemic therapeutic threshold over an appropriate period after surgery. Additionally, the number and characteristics of the depot(s) selected for implantation may be tailored to adapt to the target anatomical region for placement within the patient's body.

[0256] IV. Clinical Outcomes The effectiveness of the depots of the present invention that provide therapeutic benefits (e.g., depots 100a to 570 in Figures 1A to 5H) can be evaluated using a variety of metrics. For example, the effectiveness of one or more depots that provide pain relief through the delivery of analgesics can be evaluated based on pain scores, quality of recovery, opioid consumption and associated side effects, and / or functional assessments, such as range of motion tests, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) indices, and the Knee Injury and Osteoarthritis Outcome Score (KOOS).

[0257] The Numeric Rating Scale (NRS) is a pain scoring system in which patients assess their pain on a scale from 0 (no pain) to 10 (worst possible pain). Pain can be measured at rest (NRS-R) or with activity (NRS-A). Any reference to NRS scores herein may encompass NRS-R scores, NRS-A scores, or combinations thereof. The NRS scores described herein may be measured at a time of day before the patient consumes any opioid or other pain management medication, and / or at a time of day when the patient does not consume any opioid or other pain management medication. In some embodiments, the NRS scores of patients who received one or more depots of the technology of the present invention ("treated patients") at one or more time points after surgery are significantly lower than the NRS scores of patients who did not receive any depots ("control patients"). The time points could be 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after surgery. The NRS score of the treated patient may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the NRS score of the control patient at the same time point.

[0258] In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of treated patients are pain-free based on an NRS score (e.g., NRS score 0 or 1) at one or more time points after surgery, such as 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after surgery. Treated patients may achieve a pain-free state at least 1, 2, 3, 4, 5, 6, 7, 14, 28, or 30 days earlier than control patients.

[0259] In some embodiments, postoperative pain is assessed by comparing the patient's NRS-R score to the NRS-A score at one or more time points. In the context of total knee arthroplasty (TKA), activity may redistribute the anesthetic within the synovial space of the knee, thereby reducing the NRS-A score. Consequently, the difference between the NRS-A and NRS-R scores at a given time point may be smaller in the treated patient compared to the control patient (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% smaller).

[0260] If necessary, postoperative pain can be assessed by comparing the AUC of the NRS score of the treated patient ("NRS AUC") over one or more time periods after surgery with the NRS AUC of the control patient. The time periods are: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0-7 days, 0-14 days, 0-15 days, 0-30 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12-7 days, 12-10 days, 12-14 days, 12-21 days, 12-30 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 1-15 days, 1-21 days, 1-30 days, 2-3 days, 2-4 days, 2-7 days, 2-14 days, 2-15 days, 2-21 days, 2-30 days, 3-4 days, 3-7 days, 3-14 days, 3-15 days, 3-21 days, 3-30 days Between 4-5 days, 4-7 days, 4-14 days, 4-15 days, 4-21 days, 4-30 days, 5-6 days, 5-7 days, 5-14 days, 5-15 days, 5-21 days, 5-30 days, 6-7 days, 6-14 days, 6-15 days, 6-21 days, 6-30 days, 7-8 days, 7-14 days, 7 days The treatment period may be between 15 days, 7-21 days, 7-30 days, 8-9 days, 9-10 days, 10-11 days, 11-12 days, 12-13 days, 13-14 days, 14-15 days, 14-21 days, 14-30 days, 15-21 days, 15-30 days, 16-21 days, 16-30 days, or 21-30 days. The NRS AUC of the treated patient may be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower compared to the NRS AUC of the control patient over the same period.

[0261] The effectiveness of the depot of the present invention in pain management can also be assessed based on the consumption of supplemental opioid medications prescribed to patients for pain management. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of treated patients are still not using opioids for one or more periods post-surgery. As an alternative or in combination, the total amount of opioids consumed by treated patients may be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower than the total amount of opioids consumed by control patients over the same period post-surgery. The total amount of opioids consumed by the treated patient over a specified period may be 600 morphine milligram equivalents (MME), 550 MME, 500 MME, 450 MME, 400 MME, 350 MME, 300 MME, 250 MME, 200 MME, 150 MME, 100 MME, or 50 MME or less.The time periods for assessing postoperative opioid consumption are: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0-7 days, 0-14 days, 0-15 days, 0-30 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12-7 days, 12-10 days, 12-14 days, and 12-21 hours after surgery. Days, 12 hours to 30 days, 1 to 2 days, 1 to 4 days, 1 to 7 days, 1 to 14 days, 1 to 15 days, 1 to 21 days, 1 to 30 days, 2 to 3 days, 2 to 4 days, 2 to 7 days, 2 to 14 days, 2 to 15 days, 2 to 21 days, 2 to 30 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 3 to 15 days, 3 to 21 days Between 3 and 30 days, 4 and 5 days, 4 and 7 days, 4 and 14 days, 4 and 15 days, 4 and 21 days, 4 and 30 days, 5 and 6 days, 5 and 7 days, 5 and 14 days, 5 and 15 days, 5 and 21 days, 5 and 30 days, 6 and 7 days, 6 and 14 days, 6 and 15 days, 6 and 21 days, 6 and 30 days, 7 and 8 days, 7 and 14 days The interval could be 7-15 days, 7-21 days, 7-30 days, 8-9 days, 9-10 days, 10-11 days, 11-12 days, 12-13 days, 13-14 days, 14-15 days, 14-21 days, 14-30 days, 15-21 days, 15-30 days, 16-21 days, 16-30 days, or 21-30 days.

[0262] In some embodiments, the time to first opioid consumption after surgery for the treated patient (e.g., time to rescue opioid) is delayed by, for example, at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 96 hours, 5 days, 6 days, or 7 days compared to the control patient. The treated patient does not need to consume any opioid for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 20 hours, 24 hours, 30 hours, 36 hours, 40 hours, or 48 hours after surgery. Treated patients also experience fewer or no opioid-related adverse events (e.g., nausea, vomiting, constipation, ileus) compared to control patients. In some embodiments, the percentage of treated patients experiencing opioid-related adverse events is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients.

[0263] The effectiveness of the depot technique of the present invention in pain management can also be assessed based on motion parameters, e.g., range of motion of movement and / or other activities. For example, in the case of total knee arthroplasty (TKA), the range of motion can be assessed based on the degree of knee flexion and / or extension after surgery. In some embodiments, the time it takes for the treated patient to achieve the desired degree of flexion and / or extension after surgery is reduced compared to a control patient by, for example, at least 1, 2, 3, 4, 5, 6, 7, 14, 28, or 30 days. The desired degree of flexion and / or extension may vary based on the activity being assessed (e.g., walking, sitting, climbing stairs, etc.) and may be determined according to criteria known to those skilled in the art. The treated patient may achieve the desired degree of flexion and / or extension within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after surgery. As another example, the treated patient may be able to resume normal physical activity earlier than the control patient, for example, at least 1, 2, 3, 4, 5, 6, 7, 14, 28, or 30 days after surgery. Other suitable activity parameters include overall activity level (e.g., stepping, time spent walking, time spent running, 6-minute walk distance, etc.), gait (e.g., time to recovery of normal gait), and / or other metrics. Motion parameter measurements can be assessed based on the change or rate of change of the measured values ​​over time, and / or a comparison of the measured values ​​with those of a control patient, a healthy individual (e.g., an individual of similar age to the patient before surgery, an individual with a similar activity profile, etc.), and / or the preoperative level of a particular patient. In some embodiments, the patient's physical activity is tracked and assessed using wearables or sensors, such as fitness monitors.

[0264] In some embodiments, the effectiveness of depot treatment of the present invention in pain management is assessed based on compliance with the prescribed physiotherapy regimen. Patients experiencing significant postoperative pain are often unable to attend or absent from physiotherapy sessions (e.g., on-site or virtual), and / or significantly reduce their effort as quantified by time, repetition, flexion / extension, and / or other parameters. Therefore, treated patients may demonstrate higher physiotherapy compliance compared to control patients based on one or more of these metrics. Reduced physiotherapy compliance may lead to the formation of adhesions and / or scar tissue causing stiffness in the surgical area (e.g., knee joint), thereby potentially requiring a return to the hospital for knee surgery. Thus, the rate or incidence of surgical procedures may be another clinical endpoint to demonstrate the benefit; for example, the rate of surgical procedures in treated patients may be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower compared to control patients.

[0265] The effectiveness of the depot technique of the present invention in pain management can be assessed, alternatively or additionally, based on other factors. For example, treated patients may be discharged from the hospital at least 12, 24, 36, 48, 72, 60, or 96 hours earlier than control patients. The time of discharge may be related to the amount of pain the patient is experiencing, in that patients experiencing more postoperative pain may be discharged later than patients experiencing less postoperative pain. In further examples, the readmission rate of treated patients may be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% lower compared to control patients. Readmission may occur if the patient is experiencing prolonged and / or severe pain, if corrective surgery is required, and / or if other factors are present. In yet another example, the percentage of patients who contact their surgeon or doctor after discharge to seek treatment for postoperative pain may be at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90% lower compared to control patients.

[0266] As another example, treated patients may exhibit improved postoperative recovery compared to control patients, as measured by one or more Quality of Recovery (QoR) scores. QoR scores allow patients to provide self-reported assessments based on recovery-related measures, such as pain, physical comfort, physical independence, psychological support, emotional state, and mental health. QoR scores can be assessed using a longer 40-item score (QoR-40) or a shorter 15-item score (QoR-15) derived from the QoR-40. In some embodiments, the treated patient exhibits an improved QoR score compared to the control patient at one or more postoperative time points, such as 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after surgery.

[0267] In some embodiments, the effectiveness of the depot technique of the present invention is evaluated using the WOMAC index, a set of standardized questionnaires used by healthcare professionals to assess the condition of patients with joint pain of various origins. The WOMAC measures five items for pain (score range 0-20), two items for stiffness (score range 0-8), and seventeen items for functional limitation (score range 0-68). Questions about physical function cover daily activities such as climbing stairs, getting up from a seated or lying position, standing upright, flexing, walking, getting in and out of a car, shopping, putting on and taking off socks, lying in bed, getting in and out of a bathtub, sitting, and performing difficult and easy household chores. The WOMAC questions are a subset of the questions in the Hip Disability and Osteoarthritis Outcome Score (HOOS). Therefore, the WOMAC score can also be determined using the HOOS survey.

[0268] Some embodiments of the technology of the present invention include a method for treating a patient suffering from postoperative pain in an anatomical region of the patient's body. The pain may be associated with surgery in or near the anatomical region. In some embodiments, the method includes improving the patient's overall WOMAC score by implanting one or more of the depots disclosed herein into the anatomical region of the surgical site. The method may include improving the WOMAC pain subscore, stiffness subscore, and / or physical function subscore. The overall WOMAC score and / or one or more of the subscores may be evaluated at predetermined time intervals (e.g., weekly, monthly, bi-monthly) and may be compared with the patient's past scores, the patient's preoperative scores, and / or scores of patients of similar age, physical health, and health status who have undergone the same surgery but have not been treated with one of the depots of the technology of the present invention.

[0269] KOOS was developed as an extension of the WOMAC index to assess short-term and long-term symptoms and function in subjects with knee injury and osteoarthritis. KOOS includes five separately scored subscales: pain, other symptoms, function in daily living (ADL), function in sports and recreation (Sports / Recreation), and knee-related quality of life (QOL). KOOS has been validated for several orthopedic interventions, such as anterior cruciate ligament reconstruction, meniscectomy, and total knee replacement. Effect sizes are generally largest for the QOL subscale, followed by the pain subscale. In some embodiments, the method includes improving a patient's KOOS score by implanting one or more of the depots disclosed herein into an anatomical region of the surgical site. The method may include improving KOOS subscores, including at least one of pain, other symptoms, function in daily living (ADL), function in sports and recreation (Sports / Recreation), and / or knee-related quality of life (QOL). The KOOS score and / or one or more subscores may be evaluated at predetermined time intervals (e.g., weekly, monthly, bi-monthly) and may be compared with the patient's past scores, the patient's preoperative scores, and / or the scores of control patients (patients of similar age, physical health, and health status who have undergone the same surgical procedure but have not been treated with one of the depots of the present invention).

[0270] In some embodiments, a method for treating a subject suffering from pain after a surgical procedure (e.g., TKA or any other surgical procedure described herein) includes placing one or more of the depots described herein (e.g., one or more of depots 100a to 570 in Figures 1A to 5H) within the subject (e.g., at or near the surgical site or another treatment site). The depot(s) may be configured such that a group of patients treated with the depot(s) ("treatment group") exhibits improvement in at least one clinical outcome compared to a group of patients not treated with the depot(s) ("control group"). Improvement in clinical outcome may include any of the metrics described herein. For example, the treatment group may exhibit one or more improvements in the following outcomes compared to the control group: a lower mean NRS score, a lower mean difference between the NRS-A score and the NRS-R score, a lower mean NRS AUC, a higher percentage of patients who were pain-free, lower mean opioid consumption, a higher percentage of patients who did not use opioids, a longer mean time to first opioid consumption, a lower incidence of opioid-related adverse events, improved mean flexion and / or extension, a shorter mean time to achieve the desired flexion and / or extension, a shorter mean time to discharge from the hospital, a lower hospitalization rate, a higher mean QoR score, a higher mean WOMAC score, and / or a higher mean KOOS score. Improvements in clinical outcomes can be assessed at any point in time and / or over any period following the surgical procedure described herein. [Examples]

[0271] The following examples are included to further illustrate some aspects of the technology of the present invention and should not be used to limit the scope of the technology of the present invention.

[0272] (Example 1) Configuration of an implantable depot for managing postoperative pain This embodiment describes three configurations of depots designed to be implanted at the surgical site to treat postoperative pain: (1) a rectangular depot with a notch ("R300"), similar to depot 200 shown in Figures 2A and 2B; (2) a triangular depot with a single hole ("T600"), similar to depot 300 shown in Figures 3A and 3B; and (3) a triangular depot with four holes ("T500"), similar to depot 400 shown in Figures 4A and 4B. Each depot contained a single therapeutic area positioned between two control regions. The dimensions of each depot are provided in Table 1 below.

[0273] [Table 1-1] [Table 1-2]

[0274] Tables 2 and 3 below provide the dry mass compositions for the therapeutic and controllative regions of the R300, T600, and T500 depots, respectively. "BUP-HCl" refers to bupivacaine hydrochloride monohydrate (therapeutic agent), "PLGA5050" refers to PLGA 50:50 (polymer), and "PS20" refers to Polysorbate 20 (release agent).

[0275] [Table 2]

[0276] [Table 3]

[0277] Table 4 provides the theoretical composition of the components of R300, T600, and T500 depots by dry mass. The theoretical composition percentage of each component was calculated on a mass basis derived from the thickness of the therapeutic and control regions, respectively, and the composition percentage of each formulation. In the calculations, the density of all components was assumed to be equivalent (i.e., 1.0 g / cm³). 3 ) was assumed.

[0278] [Table 4]

[0279] (Example 2) Preparation and characterization of implantable depots This example describes the preparation and characterization of R300, T600, and T500 depots. The therapeutic regions of all three depots were formulated with PS20, PLGA5050, BUP-HCl, and acetone in a mass ratio of 1:10:20:30. The control regions of R300 and T600 were formulated with PS20, PLGA5050, and acetone in a mass ratio of 1:2:6. The control region of T500 was formulated with PLGA5050 and acetone in a mass ratio of 1:4.

[0280] Therapeutic areas for R300, T600, and T500 were prepared by combining PS20, PLGA5050, and acetone, and mixing until PLGA5050 was completely dissolved. Next, BUP-HCl was mixed into the polymer solution to create a dough-like consistency. The dough was divided into smaller portions and stirred. Each portion was subjected to a series of heat compression steps to form discs of the desired thickness. The discs were then dried.

[0281] After drying the disks, control regions were applied to both sides of the disks. For R300 and T600 depots, the control regions were formed by dissolving PLGA5050 and PS20 in acetone, and then pouring the polymer solution into a thin film of the desired thickness. The thin film was then bonded to each side of the disk using thermal compression. For T500 depots, the control regions were formed by dissolving PLGA5050 in acetone, and then immersing the disk in the polymer solution. After applying the control regions, individual depots were cut from the disks.

[0282] Figure 6 shows a scanning electron microscope (SEM) image of a portion of the R300 depot. The depot was freeze-churned, sputter-coated, and then imaged. As seen in Figure 6, the therapeutic region is a two-phase structure with BUP-HCl crystals held together by PLGA5050. The control region is a layer approximately 10 μm thick on top of the therapeutic region.

[0283] (Example 3) In vitro release profile This example describes in vitro release data for T500 depots. In vitro elution tests were performed in phosphate-buffered saline (PBS) at pH 5.8. The depots were placed in a basket rotating at 10 RPM at 37°C in 750 mL of elution medium. The elution medium was periodically analyzed spectrophotometrically at 262 nm, and the BUP-HCl concentration was quantified using a USP reference standard in a separate, sealed cuvette.

[0284] Figure 7A is a graph showing the percentage of BUP-HCl released from the T500 depot over time. The release profile was highly consistent across the different depot samples tested (n=12), with a standard deviation of less than 10% for the release during the first 80 hours.

[0285] Figure 7B is a semi-logarithmic graph showing the percentage of BUP-HCl remaining in the T500 depot over time. As can be seen in the graph, the in vitro elution of BUP-HCl from the T500 depot is in the primary release kinetics (R 2 Strictly following the formula (=0.9979), the observed rate constant is 0.023 hours. -1 Its half-life is 30 hours.

[0286] Figure 8A is a 50x magnification SEM image of a T500 depot with approximately 25% eluted, and Figure 8B is a 50x magnification SEM image of a T500 depot with approximately 75% eluted. The depots were microtome-sectioned before imaging. In the 75% eluted sample, the depot portions around and near the pore were significantly thinner compared to the 25% eluted sample, indicating that the BUP-HCl payload had been released in those areas. In contrast, the internal portions of the depot, both around the pore and away from it, maintained their original thickness, indicating that the BUP-HCl payload was still present. These results demonstrate that the BUP-HCl release rate correlates with the distance traveled, with BUP-HCl molecules located closer to the exposed surface of the depot eluting more rapidly than those located further away from the exposed surface.

[0287] (Example 4) In vivo pharmacokinetics of implantable depots This example describes in vivo pharmacokinetic data for R300 and T600 depots implanted in human subjects for the management of postoperative pain after total knee arthroplasty (TKA). The safety and pharmacokinetics of R300 and T600 depots were investigated in an open-label study involving 22 patients. The patients were adults between 18 and 80 years of age undergoing unilateral primary TKA. One or more depots were placed in the knee joint capsule of each subject after the TKA procedure and before surgical closure of the knee joint capsule. Depending on the dose level, the depot(s) were placed in one or more of the following locations: suprapatellar bursa, medial groove adjacent to the capsular tissue, and / or lateral groove adjacent to the capsular tissue. Table 5 below provides the depot configurations and bupivacaine doses for each cohort (in Examples 4–6 and the accompanying figures, “BUP” or “bupivacaine” refers to bupivacaine free base).

[0288] [Table 5]

[0289] Venous blood samples (4 mL) for plasma pharmacokinetic analysis were collected at various time intervals: during surgery, within the first 24 hours post-surgery, then approximately every 4 hours from 24 to 96 hours post-surgery, then daily until day 15, and during follow-up visits on days 30, 45, and 60 (Cohort 3C subjects were further visited on days 18, 21, 24, and 27). Bupivacaine was extracted from human plasma by protein precipitation using acetonitrile. Bupivacaine-d9 was added as an internal standard before extraction. A portion of the organic supernatant was transferred to a new 96-well plate and diluted with water. The samples were injected into a liquid chromatography-tandem mass spectrometry (LC-MS / MS) system using an Agilent Zorbax SB-C18 column with a gradient mobile phase containing acetonitrile, water, and formic acid.

[0290] Figure 9A is a graph showing the mean bupivacaine plasma concentrations over time in subjects who received R300 or T600 depot after TKA (line 902), compared to subjects treated with other bupivacaine preparations (lines 904-910). Line 902 shows data from subjects in cohorts 3A-3C (data for days 1-14 and 30 are from all subjects in cohorts 3A-3C, while data for days 18, 21, 24, and 27 are from subjects in cohort 3C only). Line 904 shows data from subjects treated with Exparel liposomal bupivacaine injection (n=24, 266 mg bupivacaine, Bramlett et al., The Knee 19 (2012), 530-536). Line 906 shows data from subjects treated with Marcaine bupivacaine injection (n=30, 133 mg bupivacaine, Bramlett et al.). Line 908 shows data from subjects treated with Exparel and Marcaine (n=11, 400 mg bupivacaine, Marino et al., The Journal of Arthroplasty 34 (2019) 495-500). Line 910 shows data from subjects treated with Zynrelef bupivacaine and meloxicam injection (n=58, 400 mg bupivacaine, Lachiewicz et al., The Journal of Arthroplasty 35 (2020) 2843-2851).

[0291] As shown in Figure 9A, the mean bupivacaine plasma concentration (line 902) in subjects treated with R300 or T600 depot remained close to or above the therapeutic threshold of 200 ng / ml until day 21. In contrast, the mean bupivacaine plasma concentration in subjects treated with other formulations decreased to below the therapeutic threshold within the first 3–5 days. This data demonstrates that implantable depots can provide sustained release of bupivacaine at therapeutic levels for a significantly longer period than conventional formulations.

[0292] Figure 9B is a graph overlaying the mean bupivacaine plasma concentration over time in subjects receiving R300 or T600 depots, with the NRS-R postoperative pain score (line 912, right vertical axis) of primary TKA patients obtained from the Force Therapeutics database (n=103,818–296,286). As shown in Figure 9B, pain scores rise immediately after TKA and gradually decrease over the next 30 days. In some cases, local anesthetics should be present until the pain score drops below 4 (approximately 21 days post-TKA) to allow for a milder recovery and rehabilitation. The release profiles of R300 and T600 depots are consistent with the temporal development of pain scores by resulting in higher bupivacaine levels during the acute pain period (days 0–4) and sustained lower bupivacaine levels throughout the recovery period (days 4–30).

[0293] Figure 9C is a graph showing the AUC of bupivacaine plasma concentration over various periods in subjects receiving R300 or T600 depot (bars 914-918) compared to subjects treated with other bupivacaine preparations (bars 920-926). Bar 914 shows data from subjects in Cohort 1, bar 916 shows data from subjects in Cohort 2, and bar 918 shows data from subjects in Cohorts 3A-3C (the dashed lines for bars 914-918 on days 14-30 indicate that these AUC values ​​were calculated over a longer interval (2 weeks) compared to other AUC values ​​shown in Figure 9C (3-4 days)). Bar 920 shows data from subjects receiving Exparel, bar 922 shows data from subjects receiving Marcaine, bar 924 shows data from subjects receiving both Exparel and Marcaine, and bar 926 shows data from subjects receiving Zynrelef. Data for other formulations were obtained from the same source as in Figure 9A. As shown in Figure 9B, the AUC values ​​for subjects treated with R300 or T600 depots were comparable to those for other formulations during the acute period (0–4 days) and superior to those for other formulations throughout the recovery period (4–30 days).

[0294] Figure 9D is a graph showing the mean bupivacaine plasma concentrations in subjects receiving various doses of bupivacaine from an implantable depot. Specifically, line 902 shows data from subjects receiving 1512 mg of bupivacaine (cohorts 3A-3C), line 928 shows data from subjects receiving 756 mg of bupivacaine (cohort 2), and line 930 shows data from subjects receiving 252 mg of bupivacaine (cohort 1). Figure 9E shows C max This graph shows the relationship between AUC and bupivacaine dose, and Figure 9F is shown. 0~14d This graph shows the relationship between the drug and bupivacaine dose. The data in Figures 9D-9F show that the pharmacokinetic parameters of R300 and T600 depots exhibit a linear dose response.

[0295] Figure 9G is a graph showing the in vivo bupivacaine release profile in subjects receiving implantable depot therapy. The release profile shown in Figure 9G was estimated from the bupivacaine plasma concentration levels (cohorts 3A-3C) of subjects receiving 1512 mg of bupivacaine. In short, the area under the curve (AUC) of bupivacaine plasma concentration over time. 0~inf This was assumed to correspond to 100% release of the total bupivacaine dose in the depot. The cumulative percentage of bupivacaine released over time was normalized to 100% in AUC. 0~inf AUC for 0~t1 The ratio was calculated at each trial time point t1. As shown in Figure 9G, the depot exhibited sustained release of bupivacaine for more than 21 days after implantation. Approximately 50% of the total bupivacaine dose was released in the first 7-8 days, and approximately 90% of the total bupivacaine dose was released in the first 21 days. This data demonstrates that implantable depots can maintain sustained release of bupivacaine during the acute and recovery periods after surgery.

[0296] (Example 5) Clinical efficacy of implantable depot therapy This example describes postoperative pain and opioid consumption in patients treated with implantable depot implants after total knee arthroplasty (subjects of cohorts 1-3C of Example 4). The primary endpoint of the study was bupivacaine concentration, while exploratory analyses of clinical efficacy were also evaluated for pain intensity and opioid consumption in terms of NRS-R.

[0297] Intraoperative and postoperative medications for all subjects in Cohort 1 included, in addition to implantable depots, intrathecal morphine; adductor canal block; a local infiltration cocktail consisting of ropivacaine, clonidine, ketorolac, and epinephrine; a long-acting opioid (Targin); and, if necessary, a rescue opioid (mostly oxycodone). These subjects also consumed acetaminophen and celecoxib for varying durations during the study. These subjects were able to use ropivacaine at doses of 255 mg or less in the local infiltration cocktail, adductor canal block, and / or spinal anesthesia.

[0298] Intraoperative and postoperative medications for all subjects in Cohort 2 included, in addition to implantable depots, intrathecal morphine; adductor canal block; a local infiltration cocktail consisting of ropivacaine, clonidine, ketorolac, and epinephrine; a long-acting opioid (Targin); and, if necessary, a rescue opioid (mostly oxycodone). These subjects also consumed acetaminophen and celecoxib for varying durations during the study. These subjects were able to use ropivacaine at doses of 165 mg or less in the local infiltration cocktail, adductor canal block, and / or spinal anesthesia.

[0299] For subjects in cohorts 3A-3C (collectively, "subjects of cohort 3"), intraoperative and postoperative medications included, in addition to implantable depots, intrathecal morphine in 6 of the 15 subjects; a local infiltration cocktail consisting of clonidine, ketorolac, and epinephrine in 6 of the 15 subjects, and no local infiltration in the remaining 9 subjects; a long-acting opioid (Targin) in 3 of the 15 subjects; and a rescue opioid (mostly oxycodone) if necessary. These subjects also consumed acetaminophen and celecoxib for varying durations during the study. Only ropivacaine was permitted as spinal anesthesia in these subjects. Adductor canal block and local infiltration of anesthetics were not permitted.

[0300] NRS-R was performed before and after surgery, at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 28 hours, 32 hours, 36 hours, 40 hours, 44 hours, 48 ​​hours, 52 hours, 56 hours, 60 hours, 64 hours, 68 hours, 72 hours, 76 hours, 80 hours, 84 hours, 90 hours, and 96 hours, as well as on days 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30, 45, and 60. In addition, due to protocol modifications, NRS-R for pain intensity was also performed on days 18, 21, 24, and 27 for subjects in Cohort 3C. Participants were asked to complete the NRS-R (Numerical Rating Scale) for pain intensity before consuming any opioids up to 15 days after the surgical procedure.

[0301] Figure 10 is a graph showing the mean NRS-R pain scores for each cohort (not adjusted for opioid consumption). There were no significant differences in pain scores between the cohorts. However, a comparison of total opioid consumption (64% less in cohort 3 compared to cohort 1; see Table 8 below) and a limited range of pain scores suggests that patients consume opioids to maintain tolerable pain intensity levels during the first two weeks after TKA surgery. Overall, patients' pain was manageable, and pain intensity scores were generally 3 or lower.

[0302] The AUC of the NRS-R for opioid use-adjusted pain intensity was calculated daily using the trapezoidal method and cumulatively to the end of each day. Table 6 below shows the AUC for the first 72 hours. The AUC was similar between cohorts 1 and 3, except that all subjects in cohorts 1 and 2, and 6 of the 15 subjects in cohort 3, received intrathecal morphine, which resulted in a lower AUC for the first approximately 24 hours in those subjects.

[0303] [Table 6]

[0304] Table 7 below shows the AUC over the first 15 days (2 weeks post-surgery). The AUC was similar between cohorts 1 and 3, but subjects in cohort 3 consumed 64% less opioids over the 2 weeks compared to subjects in cohort 1 (see Table 8 below) and did not receive adjunctive anesthetics during surgery (adductor canal block or local anesthetic infiltration).

[0305] [Table 7]

[0306] Table 8 below shows the opioid consumption of patients during the first two weeks after surgery. All cases of opioid consumption were followed from the day of the TKA surgery (day 1) to day 15. A preliminary interim analysis showed that 80% (12 / 15) of subjects in Cohort 3 at a 1,512 mg dose discontinued all opioid use for knee pain due to TKA within the first two weeks after TKA surgery (Table 1), compared to 52.8% in the literature (Runner et al., The Journal of Arthroplasty 35 (2020), S158-S162). Subjects in Cohort 2 (756 mg) did not consume opioids beyond day 15, while half (50%) of subjects in Cohort 1 (252 mg) continued to consume opioids beyond day 15.

[0307] [Table 8]

[0308] The results showed that increasing the bupivacaine dose reduced postoperative opioid consumption (MME) during the first two weeks after surgery. The literature indicates that the mean MME consumed after total knee arthroplasty (TKA) is between 428 MME and approximately 700 MME (Runner et al.; Ruddell et al., The Journal of Bone and Joint Surgery 103 (2021), 106-114). Participants in Cohort 3 consumed less opioid than half of the total opioids reported in the literature (176.77 MME compared to 428 MME). Twenty percent (3 out of 15) of participants in Cohort 3 actually consumed additional opioids after the first two weeks as needed for knee pain, but these additional opioids (beyond two weeks) are not included in the 176.77 MME reported in Table 8.

[0309] Of the 15 subjects in Cohort 3, one subject did not consume any opioids at all (6.7%). Among the remaining subjects who did consume opioids, the time to first consumption was 6.283 hours, calculated using the Kaplan-Meyer method (95% CI; 3.117, 22.533).

[0310] (Example 6) Simulated pharmacokinetics of implantable depots This example describes simulated pharmacokinetic data for an implantable depot for treating postoperative pain following shoulder surgery, bunion resection, and inguinal hernia repair. Pharmacokinetic data for other bupivacaine formulations using the same bupivacaine dosage in the treatment of total knee arthroplasty (TKA) and other indications of interest ("new indications") are also included. max and T max We created simulated data by calculating scaling factors in pharmacokinetic data for new indications. Specifically, we calculated the C max C in TKA pharmacokinetic data max By taking the ratio of C, max The scaling factors were processed by computer. Next, C max Scaling factors were multiplied with bupivacaine plasma concentration data from cohort 3 across all time points to obtain scaled bupivacaine plasma concentration data for the new indication. Similarly, pharmacokinetic data for the new indication were obtained using T max T pharmacokinetic data for TKA max By taking the ratio of T, max The scaling factor was processed by computer. Next, T max The scaling factor was multiplied with the bupivacaine time data from Cohort 3 across all bupivacaine plasma concentration data to obtain scaled time data for the new indication. The bupivacaine plasma concentration data was multiplied with the linear C obtained in Example 4 above. maxBy further scaling based on dose relationships, we were able to simulate the pharmacokinetics resulting from various bupivacaine dosages. The obtained data provide a schematic simulation of the pharmacokinetics of implantable depots when implanted in other anatomical locations to treat other indications.

[0311] Figure 11A is a graph showing the simulated mean bupivacaine plasma concentrations over time (lines 1102 and 1104) for subjects treated with an implantable depot after shoulder surgery, compared to the actual mean bupivacaine plasma concentrations (lines 1106 and 1108) for subjects treated with other bupivacaine preparations. Specifically, line 1102 shows the simulated bupivacaine levels for subjects treated with a depot containing a 1000 mg dose of bupivacaine (e.g., two T500 depots), line 1104 shows the simulated bupivacaine levels for subjects treated with a depot containing a 750 mg dose of bupivacaine (e.g., three R300 depots), line 1106 shows the bupivacaine levels for subjects treated with Exparel (266 mg of bupivacaine, Patel et al., Pain Medicine 21 (2020), 387-400), and line 1108 shows the bupivacaine levels for subjects treated with Posimir (extended-release bupivacaine solution, 660 mg of bupivacaine, FDA Briefing Document, Meeting of Anesthetic and Analgesic Drug Products Advisory Committee (2020)). As shown in Figure 11A, implantable depots result in bupivacaine plasma levels higher than the therapeutic threshold of 200 ng / ml for more than 10 days, and are therefore expected to cover the acute and subacute pain period after shoulder surgery. In contrast, bupivacaine plasma levels in subjects treated with Exparel and Posimir formulations fall below the therapeutic threshold within the first 3–4 days after surgery.

[0312] Figure 11B is a graph showing the simulated mean bupivacaine plasma concentration over time (line 1110) for subjects treated with an implantable depot after bunion resection, compared to the actual mean bupivacaine plasma concentration (line 1112) for subjects treated with a different bupivacaine preparation. Specifically, line 1110 shows the simulated bupivacaine level for subjects treated with a depot containing 250 mg of bupivacaine (e.g., one R300 depot), while line 1112 shows the bupivacaine level for subjects treated with Zynrelef (60 mg of bupivacaine, Viscusi et al., ASRA poster (2017), Viscusi et al., ESRA poster (2017)). Zynrelef is approved for postoperative analgesia up to 72 hours after bunion resection. As shown in Figure 11B, the implantable depot maintains bupivacaine plasma levels at or above the levels achieved by Zynrelef at 72 hours for more than 12 days, maintaining bupivacaine plasma levels at or above the estimated therapeutic threshold of 5 ng / ml, and is therefore expected to cover the acute and subacute pain period after bunion resection.

[0313] Figure 11C is a graph showing the simulated mean bupivacaine plasma concentrations over time (lines 1114 and 1116) for subjects treated with an implantable depot after open inguinal hernia repair, compared to the actual mean bupivacaine plasma concentrations (lines 1118 and 1120) for subjects treated with other bupivacaine preparations. Specifically, line 1118 shows simulated bupivacaine levels for subjects treated with a depot containing a 1500 mg dose of bupivacaine (e.g., three T500 depots), line 1116 shows simulated bupivacaine levels for subjects treated with a depot containing a 1000 mg dose of bupivacaine (e.g., two T500 depots), line 1118 shows bupivacaine levels in subjects treated with Xaracoll (bupivacaine implant, 266 mg BUP, Leiman et al., Advances in Therapy 38 (2021), 691-706), and line 1120 shows bupivacaine levels in subjects treated with Zynrelef (300 mg bupivacaine, Viscusi et al., ESRA poster (2017)). As shown in Figure 11C, implantable depots result in bupivacaine plasma levels higher than the therapeutic threshold of 200 ng / ml for more than 7 days, and are therefore expected to cover the acute and subacute pain period after open inguinal hernia repair. In contrast, bupivacaine plasma levels in subjects treated with Exparel and Posimir formulations fall below the therapeutic threshold in the first 1-2 days after surgery.

[0314] (Example 7) In vitro release from bupivacaine free base depot without a regulatory region This example describes the in vitro release from a depot containing bupivacaine free base ("BUPFB"). The depot contained only the therapeutic region and no regulatory region (similar to depot 100c in Figure 1C). The composition and geometry of the depot are listed in Table 9 below.

[0315] [Table 9]

[0316] The therapeutic area was prepared by mixing PS20, PLGA5050, BUPFB, and acetone in a mass ratio of 1:10:20:30. The formulation was compressed using a hot press and dried to form a large circular disc. The larger disc was then cut into smaller circular discs (similar to Depot 550 in Figure 5F) with an outer diameter of 14 mm and a targeted drug loading of 100 mg of BUPFB.

[0317] Figure 12 is a graph showing the cumulative in vitro release of bupivacaine from the C100-FB-TR depot (n=3). Release data was obtained using an accelerated in vitro release test. Samples were immersed in phosphate buffer at pH 5.8. At predetermined time points, a fixed amount of buffer was withdrawn and analyzed using UV-Vis spectroscopy to quantify the amount of bupivacaine released. As shown in Figure 12, the C100-FB-TR depot exhibited controlled payload release over 6 days.

[0318] (Example 8) In vitro release from bupivacaine free base depot containing various regulatory regions This embodiment describes in vitro release from BUPFB depots containing two, one, and no control regions. The depot compositions and geometries are listed in Table 10 below.

[0319] [Table 10]

[0320] The therapeutic regions of R300-FB-TR, R300-FB-1CR, and R300-FB-2CR were prepared according to the process of Example 7, except that the therapeutic regions were cut into rectangles.

[0321] The R300-FB-TR depot contained no control region, the R300-FB-1CR depot contained a single control region (similar to depot 100b in Figure 1B), and the R300-FB-2CR depot contained two control regions (similar to depot 100a in Figure 1A). The control regions were prepared by mixing PS20, PLGA5050, and acetone in a mass ratio of 1:2:6. The control regions were then formed using a solvent casting process, in which the formulation was spread thinly across a polytetrafluoroethylene (PTFE) block and the acetone was flashed off. The control regions were then applied to the therapeutic region by thermal compression using a hot press.

[0322] Figure 13 is a graph showing the cumulative in vitro release of bupivacaine from depots (n=2 for each depot type). The depots were immersed in pH 7.4 phosphate buffer. At predetermined time points, the depots were removed from the pH 7.4 buffer and placed in fresh pH 7.4 buffer. The amount of bupivacaine released at each time point was quantified by analyzing the buffer using UV-Vis spectroscopy. As shown in Figure 13, all three depots exhibited controlled release over a 14-day period. The release rate slowed as the number of controlled regions increased.

[0323] (Example 9) In vitro release of bupivacaine free base, salt, and hybrid depot. This example describes in vitro release from depots formulated with BUPFB, bupivacaine hydrochloride monohydrate ("BUP-HCl"), or a mixture of BUPFB and BUP-HCl ("hybrid" depots). The composition and geometry of the depots are listed in Table 11 below.

[0324] [Table 11]

[0325] Depots were prepared according to the method described in Example 7 above, with the following modifications: (1) For the C100-hybrid-TR depot, the therapeutic region was formulated using a mixture of PS20, PLGA5050, BUP-HCl, BUPFB, and acetone in a mass ratio of 1:10:10:10:30, with targeted drug loading of 50 mg of BUPFB and 60 mg of BUP-HCl (equivalent to 100 mg of BUPFB); (2) For the T400-salt-TR depot, the therapeutic region was formulated using a mixture of PS20, PLGA5050, BUP-HCl, and acetone in a mass ratio of 1:10:20:30, with targeted drug loading of 480 mg of BUP-HCl (equivalent to 400 mg of BUPFB), and cut into a triangular shape.

[0326] Figure 14A is a graph showing the cumulative in vitro release of bupivacaine from C100-FB-TR and C100-Hybrid-TR depots (n=3 for each depot type). Release data were obtained using the accelerated in vitro release test described in Example 7 above. As shown in Figure 14A, the hybrid depot exhibited a more rapid release than the depot formulated with BUPFB.

[0327] Figure 14B is a graph showing the cumulative in vitro release of bupivacaine from all three depots. Release data were obtained using the accelerated in vitro release test described in Example 7 above. As shown in Figure 14B, the depot formulated with BUP-HCl alone (T400-salt-TR, n=5) released the most rapidly, followed by the hybrid depot (C100-hybrid-TR, n=6), and then the depot formulated with BUPFB alone (C100-FB-TR, n=3).

[0328] (Example 10) In vivo release of bupivacaine free base, salt, and hybrid depot. This example describes in vivo release from depots containing various forms of bupivacaine in a rabbit subcutaneous model. The composition and geometry of the depots are listed in Table 12 below.

[0329] [Table 12]

[0330] C100-FB-TR and C100-Hybrid-TR depots were prepared as described above in Example 9. The C100-Salt-2CR depot contained a therapeutic region with bupivacaine hydrochloride monohydrate (BUP-HCl) and two control regions (similar to depot 100a in Figure 1A). The therapeutic region of the C100-Salt-2CR depot was prepared as described above in Example 7, except that BUP-HCl was used instead of BUPFB for the therapeutic region. The control region of the C100-Salt-2CR depot was prepared via a dip-coating process using a formulation containing PLGA5050 and acetone in a mass ratio of 2:9. In this dip-coating process, a large disc manufactured using the hot-press method described in Example 7 was immersed entirely in a container containing the 2:9 PLGA:acetone dip-coating formulation. Targeted drug loading for C100-salt-2CR depot was 120 mg of BUP-HCl (equivalent to 100 mg of BUPFB).

[0331] Figure 15 is a semi-logarithmic graph showing the in vivo release of bupivacaine from depots in a rabbit subcutaneous model. Two depots were implanted in each of four rabbits in the subcutaneous space along the dorsal region. Only one subcutaneous pocket was created for each of the two depots. Blood samples were collected at predetermined time points (baseline, 1, 3, 8, 24, 48, 72, 120, 168, 216, 264, 336, 384, 432, 504, 600, and 672 hours). Bupivacaine assays were performed with a fixed amount of bupivacaine at each time point to quantify the plasma concentration of free bupivacaine base. As shown in Figure 15, the hybrid depot (C100-hybrid-TR, n=3) released more rapidly than the BUPFB depot (C100-FB-TR, n=4). The presence of a control region extended the release duration even when using the hydrophilic BUP-HCl form (C100-salt-2CR, n=4).

[0332] (Example 11) In vitro release from bupivacaine free base depot with various therapeutic loading capabilities. This example describes in vitro release from depots formulated with various amounts of BUPFB. The composition and geometry of the depots are listed in Table 13 below.

[0333] [Table 13]

[0334] The depot was prepared as described in Example 8 above, except that the therapeutic area of ​​the R300-FB2-TR depot contained a mixture of PS20, PLGA, BUPFB, and acetone in a mass ratio of 1:10:40:30.

[0335] Figure 16 is a graph showing the cumulative in vitro release of bupivacaine from the depot. The in vitro release test was performed at pH 7.4 using the method of Example 8. As shown in Figure 16, both depots exhibited controlled release over two weeks. The depot with higher BUPFB loading (R300-FB2-TR, 78.4% BUPFB, n=2) exhibited slightly slower release than the depot with lower BUPFB loading (R300-FB-TR, 64.5% BUPFB, n=2).

[0336] (Example 12) In vitro release from depots with various bupivacaine free base:salt ratios This example describes in vitro release from depots formulated with various BUPFB:BUP-HCl ratios. The composition and geometry of the depots are listed in Table 14 below.

[0337] [Table 14]

[0338] Depots were prepared as described in Example 7 above, except that (1) the therapeutic area of ​​the C100-1:1 hybrid-TR depot was formulated using a mixture of PS20, PLGA5050, BUP-HCl, BUPFB, and acetone in a mass ratio of 1:10:10:10:30, with targeted drug loading of 50 mg of BUPFB and 60 mg of BUP-HCl (equivalent to 100 mg of BUPFB), and (2) the therapeutic area of ​​the C100:1:2 hybrid-TR depot was formulated using a mixture of PS20, PLGA5050, BUP-HCl, BUPFB, and acetone in a mass ratio of 1:10:13.7:30, with targeted drug loading of 39 mg of BUPFB and 72.5 mg of BUP-HCl (equivalent to 100 mg of BUPFB).

[0339] Figure 17 is a graph showing the cumulative in vitro release of bupivacaine from the depot. The in vitro release test was performed at pH 7.4 using the method of Example 8. As shown in Figure 17, depots with a higher BUPFB:BUP-HCl ratio (C100-1:1 hybrid-TR, n=6) released more slowly than depots with a lower BUPFB:BUP-HCl ratio (C100-1:2 hybrid-TR, n=6).

[0340] (Example 13) Modeling of travel distance This embodiment describes a modeling technique for determining the travel distance of a therapeutic agent for various depot geometries.

[0341] In some embodiments, the depot described herein releases the therapeutic agent (e.g., bupivacaine) by first-order kinetics under sink conditions (e.g., PBS at pH 5.8), and therefore its half-life (t 1 / 2 ) is the equation t 1 / 2 =ln(2) / k obs The observed rate constant (k obs The relationship between the release rate and the travel distance was investigated. The half-life can be experimentally determined using the in vitro elution techniques described herein. The half-life is expected to vary with the geometry of the depot, including the average travel distance of the therapeutic agent to the exposed surface of the depot closest to the therapeutic agent. Two modeling methods, namely Monte Carlo statistical methods and geometric / calculus methods, were developed to investigate the relationship between the release rate and the travel distance.

[0342] Figures 18A and 18B show the Monte Carlo method applied to two depot geometries with control regions at the top and bottom: an equilateral triangle ("T500") (Figure 18A) and a right triangle ("T250") (Figure 18B). The Monte Carlo model was developed using Python and operated as follows: For each depot geometry, several pseudo-random points were added inside the depot. Next, the distance traveled from each point to the nearest edge was determined (three examples are shown in Figures 18A and 18B), and then the average distance traveled for all points was calculated. Next, the ratio of the average distance traveled for T500 and T250 was given by the ratio of the observed velocity constants (or t 1 / 2 The ratio of the values ​​was compared. Both ratios were approximately 1.4, which indicates that the average travel distance is directly proportional to the observed rate constant. This model can be used to predict the relative release rate of therapeutic agents from various depot geometries (e.g., different shapes, presence or absence of pores, presence or absence of control regions).

[0343] Figures 18C and 18D show the geometric / calculusal methods applied to the T500 (Figure 18C) and T250 (Figure 18D) depot geometries. The depot is geometrically divided into smaller areas using the point furthest from each end (incenter), and the integral is performed over each smaller area. The integrand is a known formula for the shortest distance from a given point to a given line. This integral outputs the average shortest distance to the ends for an infinite number of points. The output of the integral is expected to match the output of a Monte Carlo simulation.

[0344] (Example 14) In vitro release from implantable depots with different geometric shapes. In this example, we describe in vitro release from depots with different geometric shapes, as listed in Table 15 below.

[0345] [Table 15]

[0346] Each depot contained a therapeutic region and two control regions (similar to depot 100a in Figure 1A). The therapeutic region was formulated with PS20, PLGA5050, BUP-HCl monohydrate, and acetone in a mass ratio of 1:10:20:30. After mixing, the therapeutic region formulation was compressed and dried. The control regions were formulated with PLGA5050 and acetone in a mass ratio of 1:4 and applied to the therapeutic region by dip coating. The construct was then cut into the desired shape.

[0347] Figure 19 is a graph showing the cumulative in vitro release of bupivacaine from each depot geometry. Release data was obtained using accelerated in vitro release tests. Samples were immersed in phosphate buffer at pH 5.8 and 37°C while being agitated in a basket at 10 RPM. A fixed amount of buffer was taken at predetermined time points and analyzed at 263 nm using UV-Vis spectroscopy to quantify the amount of bupivacaine released. As shown in Figure 19, the depot geometry had a significant effect on the release rate of bupivacaine. Specifically, the release rate generally correlated with the travel distance, with the fastest release observed in the R267 depot, which had the shortest average travel distance (1.01 mm), while the slowest release was observed in the T500 depot, which had the longest average travel distance (1.56 mm). The technique used to cut the depot into its final shape also affected the release rate due to the "rollover" of the control region's edge to the sidewall of the therapeutic region after cutting. The T250 and T500 depots were cut using steel rule dies that produced more rollover, while the other depots were cut manually using blades that produced little to no rollover. Consequently, the T250 depot exhibited slower release than the R588 depot despite having a shorter travel distance (1.33 mm vs. 1.52 mm).

[0348] (Example 15) In vitro release from implantable depots containing bupivacaine of different particle sizes. This example describes in vitro release from a depot formulated with bupivacaine having different particle sizes.

[0349] Using the process described in Example 14, a triangular depot (similar to depot 400 in Figure 4A) ("T500") having a therapeutic region and two control regions (similar to depot 100a in Figure 1A) was formulated. Three different BUP-HCl powders were used to formulate the therapeutic region: (1) unground BUP-HCl powder with an average particle size greater than 300 μm, (2) BUP-HCl powder with a D50 value of 29 μm, and (3) BUP-HCl powder with a D50 value of 2 μm. The dose of bupivacaine in each therapeutic region was equivalent to 500 mg of BUPFB.

[0350] Figure 20 is a graph showing the cumulative in vitro release of bupivacaine from depots formulated with different particle sizes. The release data was obtained using the accelerated in vitro release test described in Example 14. As shown in Figure 20, the release rate of bupivacaine from the depot was affected by the particle size, with smaller particle sizes resulting in faster release.

[0351] (Example 16) In vitro release from bupivacaine hydrochloride depots with and without a control region This embodiment describes in vitro release from depots with and without a control region, formulated using BUP-HCl.

[0352] Figure 21A is a graph showing the cumulative in vitro release of bupivacaine at pH 5.8 from depots with a control region ("ATX101") and depots without a control region ("ATX102"). The ATX101 depot contained a therapeutic region and two control regions (similar to depot 100a in Figure 1A) and was formulated using the process of Example 14. The ATX102 depot contained a therapeutic region but lacked any control regions (similar to depot 100c in Figure 1C) and was formulated using the process of Example 14, except that the dip-coating procedure was omitted. The ATX101 and ATX102 depots in Figure 21A had a triangular shape containing a dose equivalent to 500 mg of BUPFB. Release data were obtained using the accelerated in vitro release test described in Example 14. As shown in Figure 21A, the ATX102 depot exhibited a significantly faster discharge rate than the ATX101 depot, with the ATX102 depot being 100% discharged in approximately 6 hours, compared to approximately 152 hours for the ATX101 depot.

[0353] Figure 21B is a graph showing the cumulative in vitro release of bupivacaine at pH 5.8 from ATX102 depots with different geometric shapes and thicknesses, as listed in Table 16 below. The ATX102 depots were prepared using the process of Example 14, except that the dip coating procedure was omitted. Release data were obtained using the accelerated in vitro release test at pH 5.8 described in Example 14.

[0354] [Table 16]

[0355] As shown in Figure 21B, the release rate was primarily influenced by the depot thickness, with thinner depots exhibiting faster release. Depot shape and bupivacaine content had little effect on the release rate, as revealed by the 2 mm thick T500, R250, and D167 depots, which had similar release profiles. These results are consistent with bupivacaine being released primarily from the exposed upper and lower surfaces of the depot.

[0356] Figure 21C is a graph showing the cumulative in vitro release of bupivacaine from ATX102 depots of different thicknesses at pH 7.4. ATX102 depots were formulated in rectangular shape and with an equivalent amount to 250 mg of BUPFB, at thicknesses of 2 mm, 1.5 mm, and 1 mm. Release data were obtained using samples immersed in phosphate buffer at pH 7.4 and 37°C. At predetermined time points, a fixed amount of buffer was withdrawn and analyzed using 263 nm UV-Vis spectroscopy to quantify the amount of bupivacaine released. As shown in Figure 21C, the release rate was affected by the depot thickness, with thinner depots generally exhibiting faster release, consistent with the trend observed in accelerated release tests at pH 5.8.

[0357] Figure 21D is a graph showing the cumulative in vitro release from ATX102 depots formulated with bupivacaine of different particle sizes at pH 5.8. Triangular ATX102 depots with a thickness of 2 mm were prepared using different BUP-HCl powders: (1) unground BUP-HCl powder with an average particle size greater than 300 μm, (2) BUP-HCl powder with a D50 value of 29 μm, (3) BUP-HCl powder with a D50 value of 14 μm, and (4) BUP-HCl powder with a D50 value of 2 μm. The bupivacaine dose in each depot was equivalent to 500 mg of BUPFB. Release data were obtained using the accelerated in vitro release test at pH 5.8 described in Example 14. As shown in Figure 21D, the bupivacaine release rate from the depot was affected by particle size, with smaller particle sizes resulting in faster release.

[0358] (Example 17) In vivo release from depots containing bupivacaine hydrochloride with and without a control region. This example describes in vivo release from depots formulated with bupivacaine hydrochloride having and not having a control region. ATX101 depot with two control regions and ATX102 depot without a control region were tested in rabbit subcutaneous implantation models, miniature pig abdominal hernia repair models, and canine subcutaneous implantation models.

[0359] In rabbit studies, the following depot configurations were tested: (1) a single ATX101 depot ("T500") (n=3) with an equilateral triangular shape containing the target dose equivalent to 500 mg of BUPFB, and (2) a single ATX102 depot ("D167") (n=3) with a rhomboid shape containing the target dose equivalent to 167 mg of BUPFB. The depots were implanted subcutaneously in the dorsal region for 28 days. Blood samples were collected at predetermined time points (before administration, after administration, 30 minutes, 1 hour, 3 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 216 hours, 264 hours, 336 hours, 384 hours, 456 hours, 528 hours, 600 hours, and 672 hours). Bupivacaine assays were performed for each fixed volume to quantify the plasma concentration of bupivacaine at each time point.

[0360] Figure 22A is a graph showing the mean bupivacaine plasma concentration over time in rabbits, and Table 17 below shows the selected pharmacokinetic parameters (C max and AUC last It is reported as mean ± standard deviation, T max and T last (This is reported as the median (minimum - maximum).) ATX102 depots have a higher C that occurs earlier compared to ATX101 depots. max The values ​​were lower, and excretion was faster.

[0361] [Table 17]

[0362] In the miniature pig study, the following depot configurations were tested: (1) four ATX101 depots (n=3) each containing a dose equivalent to 500 mg of BUPFB, for a triangular shape and a dose equivalent to the total target dose of 2000 mg of BUPFB; and (2) four ATX102 depots (n=3) each containing a dose equivalent to 500 mg of BUPFB, for a triangular shape and a dose equivalent to the total target dose of 2000 mg of BUPFB. These depots were implanted in the subcutaneous and preperitoneal layers of the abdominal region adjacent to the Prolenmesh for 28 days. Blood samples were taken at predetermined time points (post-administration, 30 minutes, 1 hour, 3 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 9 days, 11 days, 14 days, 16 days, 18 days, 21 days, 25 days, and 28 days). A bupivacaine assay was performed on each fixed volume to quantify the plasma concentration of bupivacaine at each time point.

[0363] Figure 22B is a graph showing the mean bupivacaine plasma concentration over time in miniature pigs, and Table 18 below shows the selected pharmacokinetic parameters (C max and AUC last It is reported as mean ± standard deviation, T max and T last (This is reported as the median (minimum - maximum).) ATX102 depots have a higher C that occurs earlier compared to ATX101 depots. max The values ​​were lower, and excretion was faster.

[0364] [Table 18]

[0365] In the canine study, the following depot configurations were tested: (1) two ATX101 depots (n=3) with an equilateral triangular shape and a dose equivalent to 500 mg of BUPFB, for the total target dose of 1000 mg; and (2) a single ATX102 depot (n=3) with an equilateral triangular shape and the target dose of 500 mg of BUPFB. These depots were implanted subcutaneously in the dorsal region for 28 days. Blood samples were taken at predetermined time points (before administration, after administration, 30 minutes, 1 hour, 3 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 216 hours, 264 hours, 336 hours, 384 hours, 432 hours, 504 hours, 600 hours, and 672 hours). Bupivacaine assays were performed on each fixed volume to quantify the plasma concentration of bupivacaine at each time point.

[0366] Figure 22C is a graph showing the mean bupivacaine plasma concentration over time in dogs, and Table 19 below shows the selected pharmacokinetic parameters (C max and AUC last It is reported as mean ± standard deviation, T max and T last (This is reported as the median (minimum - maximum).) ATX102 depots have a higher C that occurs earlier compared to ATX101 depots. max The values ​​were lower, and excretion was faster.

[0367] [Table 19]

[0368] Figure 22D shows the cumulative AUC for various animal models. lastThis is a graph showing the profiles. The AUC data shown in Figure 22D are from the following test groups: (1) rabbits implanted with one ATX101 T500 depot (Figure 22A and Table 17), (2) rabbits implanted with one ATX102 D167 depot (Figure 22A and Table 17), (3) miniature pigs implanted with four ATX101 depots (Figure 22B and Table 18), (4) miniature pigs implanted with four ATX102 depots (Figure 22B and Table 18), (5) dogs implanted with two ATX101 depots (Figure 22C and Table 19), and (6) dogs implanted with one ATX102 depot (Figure 22C and Table 19). As shown in Figure 22D, across various animal models, the ATX102 depot exhibited faster release than the ATX101 depot.

[0369] (Example 18) In vivo release from combinations of different types of depots This embodiment describes in vivo release tests performed in a miniature pig hernia repair model implanted with a combination of two different types of depots: a depot with two control regions ("ATX101") and a depot without control regions ("ATX102").

[0370] The following depot configurations were tested: (1) 12 ATX101 T500 depots (n=3) for an equivalent dose of 6000 mg BUPFB, which is the total target dose; (2) 8 ATX101 T500 depots and 4 ATX102 T500 depots (n=3) for an equivalent dose of 6000 mg BUPFB, which is the total target dose; and (3) 4 ATX101 T500 depots, 8 ATX101 T250 depots, and 4 ATX102 T500 depots (n=3) for an equivalent dose of 6000 mg BUPFB, which is the total target dose. Implantation and blood collection were performed according to the procedure described in Example 17.

[0371] Figure 23 is a graph showing the mean bupivacaine plasma concentration over time in miniature pigs, and Table 20 below shows the selected pharmacokinetic parameters (C maxand AUC last It is reported as mean ± standard deviation, T max and T last (This is reported as the median (minimum - maximum).) In animals implanted with a combination of ATX101 and ATX102 depots, the ratio is higher than in animals implanted with ATX101 depot alone (T max Compared to C (approximately 11 days) max The value shifted earlier (T max (=6 hours to 2 days). The AUC values ​​of animals implanted with a combination of ATX101 and ATX102 depots were comparable to those of animals implanted with ATX101 depot alone.

[0372] [Table 20]

[0373] (Example 19) Toxicity study using high-dose bupivacaine free base depot This example describes toxicity testing conducted using a depot containing BUPFB without a control region.

[0374] Three depot configurations were tested: (1) an equilateral triangle containing 500 mg of BUPFB (similar to depot 400 in Figure 4A) ("T500"), (2) a right triangle containing 250 mg of BUPFB (similar to depot 470 in Figure 4H) ("T250"), and (3) a rhombus containing 167 mg of BUPFB (similar to depot 570 in Figure 5H) ("D167"). These depots were prepared by mixing PS20, PLGA5050, BUPFB, and acetone in a mass ratio of 1:10:20:30. This formulation was compressed using a hot press, dried, and then cut into the desired shape. The resulting depots contained only the therapeutic region and did not have a control region (similar to depot 100c in Figure 1C).

[0375] Depots were subcutaneously implanted along the dorsal region of male Sprague Dawley rats, as listed in Table 21 below. Blood samples were collected at predetermined time points (before administration, after administration, 30 minutes, 1 hour, 3 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, 216 hours, 264 hours, 336 hours, 384 hours, 432 hours, 504 hours, 600 hours, and 672 hours). Bupivacaine assays were performed on each fixed volume to quantify the plasma concentration of free bupivacaine base at each time point.

[0376] [Table 21]

[0377] Figure 24 is a graph showing the mean bupivacaine plasma concentration over time, and Table 22 below shows the selected pharmacokinetic parameters (C max and AUC last It is reported as mean ± standard deviation, T max and T last This is reported as the median (minimum - maximum).

[0378] [Table 22]

[0379] In all depot configurations, sustained and controlled delivery of bupivacaine was observed, and no clinical signs of acute toxicity were observed during the survival period, even at doses up to approximately 2000 mg / kg (LD50 for bupivacaine in rats). 50 The values ​​were 6 mg / kg (intravenous) or 43 mg / kg (subcutaneous). Plasma concentrations of bupivacaine peaked at approximately 2000 ng / ml.

[0380] (Example 20) plasticizer-containing depot This embodiment describes the preparation and characterization of depots formulated using various types of plasticizers.

[0381] Depots consisting solely of therapeutic agents were formulated using various plasticizer loading methods, as listed in Tables 23A-23E below. Eight plasticizers were tested, four of which were water-soluble (PEG400, propylene glycol (PG), triacetin, benzyl alcohol) and four were water-insoluble (benzyl benzoate, diethyl phthalate, tributyl O-acetylcitrate, and isopropyl myristate). The chemical structures of the plasticizers are shown in Figure 25. For each depot, the plasticizer was added to PLGA5050 and then mixed with acetone. The mixture was shaken overnight to obtain a homogeneous solution. Next, micronized bupivacaine hydrochloride monohydrate (BUP-HCl) (D50 value 6-12 μm) was added to the solution to create a dough-like consistency. The dough was subjected to a series of heat compression steps to remove most of the acetone to reach a specific thickness, and then cut into the shape of the final depot (Table 24). The dimensions of the depots were varied to maintain a consistent drug loading (300 mg of BUP-HCl per depot).

[0382] [Table 23A]

[0383] [Table 23B]

[0384] [Table 23C]

[0385] [Table 23D]

[0386] [Table 23E]

[0387] [Table 24]

[0388] In the in vitro release test at pH 7.4, the depot was immersed in 100 mL of pH 7.4 PBS buffer in a 37°C water bath (standing). Buffer samples were collected at 0.5 hours, 1 hour, 1.5 hours, 2.5 hours, 4 hours, 6 hours, and 24 hours over a 168-hour period and replaced with fresh buffer. The amount of released bupivacaine was quantified by analyzing the buffer samples using UV-Vis spectroscopy.

[0389] In the in vitro release test at pH 5.8, the depot was immersed in 750 mL of pH 5.8 buffer in a 37°C water bath, and a spindle attached to the container was rotated at 10 RPM. Buffer samples were collected at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 1 hour over a 24-hour period. The amount of released bupivacaine was quantified by analyzing the buffer samples using UV-Vis spectroscopy.

[0390] Figures 26A–26C show graphs illustrating the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 26A), diethyl phthalate (Figure 26B), and benzyl benzoate (Figure 26C) with a 14 wt% loading (n=3 for each plasticizer). All depots were rectangles with a thickness of 2 mm. The release amount was normalized to 100% based on the total initial drug loading in the depot (300 mg of BUP-HCl). With a 14 wt% loading, only three of the eight plasticizers tested (triacetin, diethyl phthalate, and benzyl benzoate) produced depots with improved flexibility (see Table 25B below) and exhibited controlled drug release over time. The other five plasticizers (PEG400, propylene glycol, benzyl alcohol, tributyl acetylcitrate, and isopropyl myristate) resulted in depots with lower flexibility or precipitation of the plasticizers over time. While not strictly theoretical, it is assumed that improved flexibility generally correlates with the miscibility and low volatility of the plasticizers in PLGA5050. The estimated RED for triacetin and diethyl phthalate in PLGA5050 is less than 1 (0.68 for triacetin and 0.80 for diethyl phthalate), while the estimated RED for propylene glycol and isopropyl myristate is greater than 1 (1.49 for propylene glycol and 1.44 for isopropyl myristate). Triacetin, benzyl benzoate, and diethyl phthalate have relatively low vapor pressures at 25°C (0.33 Pa for triacetin, 0.03 Pa for benzyl benzoate, and 0.28 Pa for diethyl phthalate), while benzyl alcohol and PEG400 have relatively high vapor pressures (12.53 Pa for benzyl alcohol and less than 10 Pa for PEG400).

[0391] As shown in Figures 26A-26C, the release rates observed for depots formulated with triacetin, diethyl phthalate, and benzyl benzoate were slower than those for depots formulated without plasticizers. While not strictly theoretical, it can be assumed that the presence of hydrophobic benzene rings in diethyl phthalate and benzyl benzoate reduced water penetration into the depot, thus slowing the release rate (the logP of benzyl benzoate is 3.97, and the logP of diethyl phthalate is 2.47).

[0392] Figures 27A–27C show graphs illustrating the in vitro release at pH 7.4 for depots formulated with triacetin (Figure 27A), diethyl phthalate (Figure 27B), and benzyl benzoate (Figure 27C) at a 3.2 wt% loading (n=6 for each plasticizer). All depots were rectangles with a thickness of 2 mm. The release amount was normalized to 100% based on the total initial drug loading in the depot (300 mg of BUP-HCl). An increase in release rate was observed at a 3.2 wt% loading, but the resulting depots did not exhibit improved flexibility (see Table 25C below).

[0393] Figures 28A–28C are graphs showing in vitro release at pH 5.8 for depots with various plasticizer loadings and thicknesses. The depots were rectangles with thicknesses of 2 mm, 1 mm, or 0.6 mm. The depots were formulated with 0 wt%, 7 wt%, 10 wt%, or 14 wt% triacetin (n=3 for the 0 wt% depot and n=2 for all other depots). For the 1 mm and 0.6 mm depots, the release amount was normalized to 100% at t=24 hours (based on the assumption that 100% of the drug had eluted by 24 hours). For the 2 mm depot, the release amount was normalized to 100% based on the amount of drug remaining in the depot quantified by HPLC at 24 hours ("HPLC extractable dose"). The addition of triacetin resulted in slower release rates for depots of comparable thickness. Thinner depots had faster release rates, independently of the amount of triacetin loading. The flexibility of the depot depended on its thickness, with thinner depots exhibiting greater flexibility than thicker ones. In 2mm thick depots, flexibility decreased with lower triacetin loading. These results demonstrate that the drug release profile can be controlled by varying plasticizer loading and depot thickness.

[0394] Figure 29 is a graph showing in vitro release at pH 5.8 for depots without plasticizers, depots with a single plasticizer, and depots with two plasticizers. The depots were rectangles with a thickness of 2 mm. The depots were formulated without plasticizers, with 7 wt% triacetin ("single plasticizer"), or with 7 wt% triacetin / 1 wt% glycerol ("two plasticizers"). In the two-plasticizer depots, the mass ratio of plasticizer:PLGA5050:BUP-HCl:acetone was 2.64:10:20:30, and the mass ratio of glycerol:triacetin was 0.33:2.31. The release amount was normalized to 100% at t=16 hours for the plasticizer-free depot, to 100% at t=160 hours for the two-plasticizer depot, and based on the HPLC extraction dose for the single-plasticizer depot. As indicated by the arrows in Figure 29, the addition of glycerol increased the release rate while maintaining the flexibility of the depot. While not strictly theoretical, it can be hypothesized that the absence of hydroxyl groups and ionizable groups in triacetin reduces its polarity, thereby decreasing water penetration into the depot and slowing the release rate. The addition of glycerol, which contains three hydroxyl groups capable of forming hydrogen bonds with water molecules, may promote water penetration into the depot and increase the release rate.

[0395] Figure 30 is a graph showing the in vitro release at pH 5.8 for depots without plasticizers, depots with a single plasticizer, depots with two plasticizers, or depots with three plasticizers. The depots were rectangles with a thickness of 2 mm or 1 mm. The depots were formulated without plasticizers, with 7 wt% triacetin ("single plasticizer"), with 7 wt% triacetin / 1 wt% glycerol ("two plasticizers"), or with 1.4 wt% triacetin / 1.4 wt% benzyl benzoate / 0.4 wt% glycerol ("three plasticizers"). In the three-plasticizer depots, the mass ratio of plasticizer:PLGA5050:BUP-HCl:acetone was 1:10:20:30, and the mass ratio of benzyl benzoate:triacetin:glycerol was 0.44:0.44:0.125. The release rate was normalized to 100% at t=16 hours for depots without plasticizers, to 100% at t=24 hours for depots with three plasticizers, to 100% at t=160 hours for depots with two plasticizers, and to the HPLC extraction rate for single-plasticizer depots. As shown in Figure 30, the single-plasticizer depot (triacetin only) exhibited the slowest release rate. Adding glycerol to the two-plasticizer depot increased the release rate. Adding benzyl benzoate to the three-plasticizer depot slowed the release rate. The two-plasticizer and three-plasticizer depots maintained flexibility for up to one month (see Figures 35 and 36 below), while the single-plasticizer depot was no longer flexible after 10 days (see Figure 35 below).

[0396] Figure 31 is a graph showing in vitro release at pH 5.8 for depots without plasticizers or depots containing two plasticizers. The depots were rectangles with a thickness of 2 mm or 1 mm. The depots were formulated without plasticizers, with 7 wt% triacetin / 1 wt% glycerol ("dual plasticizer 1"), or with 2.8 wt% triacetin / 0.4 wt% glycerol ("dual plasticizer 2"). In the depots containing dual plasticizer 2, the mass ratio of plasticizer:PLGA5050:BUP-HCl:acetone was 1:10:20:30, and the mass ratio of triacetin:glycerol was 0.88:0.125. The depots containing dual plasticizer 2 were formulated using unground BUP-HCl, while all other depots were formulated using micronized BUP-HCl. The release rate was normalized to 100% at t=16 hours for depots without plasticizers, to 100% at t=24 hours for depots with two types of plasticizers 2, and to 100% at t=160 hours for depots with two types of plasticizers 1. As shown in Figure 31, the depots with two types of plasticizers 2 using unground BUP-HCl exhibited a slower release rate up to one month compared to the depots with three types of plasticizers, and also showed slightly lower flexibility.

[0397] Figure 32A shows the setup 3200 for Depot's mechanical testing. A three-point bending test was performed by placing the test specimen 3202 longitudinally between the upper jig 3204 and the U-shaped lower jig 3206. The distance between the two supports of the lower jig 3206 was approximately 15.5 mm. During the test, the test specimen 3202 was bent by applying a downward force by lowering the upper jig 3204 at a speed of 0.5 mm / min. The upper jig 3204 was mounted on a tensile testing machine and the force exerted as the displacement increased was recorded. The test was performed at room temperature (20-25°C). Depot's flexural modulus was derived from the initial straight portion of the force-displacement curve using the formula

number

[0398] Figure 32B shows an image of a depot loaded with plasticizers during mechanical testing. The depot contained three plasticizers formulated with 1.4 wt% triacetin, 1.4 wt% benzyl benzoate, and 0.4 wt% glycerol. As shown in Figure 32B, this depot exhibited highly flexible behavior and could be bent significantly without breaking.

[0399] Figures 33A–33H show force-displacement curves for depots formulated with benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), tributyl acetylcitrate (Figure 33C), isopropyl myristate (Figure 33D), PEG400 (Figure 33E), triacetin (Figure 33F), benzyl alcohol (Figure 33G), and propylene glycol (Figure 33H) at a 14 wt% loading. Depots without plasticizers were also tested as a control. The depots were rectangular with a thickness of 2 mm. Tests were performed before subjecting the depots to in vitro release testing ("pre-elution") and after subjecting them to in vitro release testing at pH 5.8 for 16–24 hours ("post-elution"). As shown in Figures 33A–33H, the depots without plasticizers were inflexible and broke with a displacement of less than 1 mm (see also Table 25A below). All plasticizers in the 14 wt% loading resulted in increased flexibility compared to depots without plasticizers; however, only benzyl benzoate (Figure 33A), diethyl phthalate (Figure 33B), and triacetin (Figure 33F) showed the highest flexibility both before and after dissolution, with no plasticizer leaching or drug precipitation after preparation (see also Table 25B below). Post-dissolved triacetin depots were observed to be remarkably flexible immediately after removal from a 37°C water bath, and decreased in flexibility upon drying and cooling to room temperature during the mechanical testing procedure. Therefore, although the mechanical testing data for the post-dissolved triacetin depot in Figure 33F showed decreased flexibility compared to the pre-dissolved depot, experimental observations of the post-dissolved depots at 37°C suggested that these depots maintained their flexibility under physiological conditions.

[0400] Figure 34 shows the force-displacement curves for depots formulated with 3.2 wt% loading of various plasticizers. The depots were rectangular with a thickness of 2 mm and were pre-dissolved. Depots with lower 3.2 wt% plasticizer loading were less flexible compared to depots with 14 wt% plasticizer loading (Figures 33A-33H) (see also Table 25C below).

[0401] Figure 35 is a graph showing force-displacement curves for depots containing a single or dual plasticizer at various time points after manufacturing. Depots were formulated using 14 wt% triacetin ("single plasticizer") or 7 wt% triacetin / 1 wt% glycerol ("dual plasticizer"). The depots were rectangular with a thickness of 2 mm. Tests were performed immediately after manufacturing ("t=0"), 5 days after manufacturing ("t=5d"), 10 days after manufacturing ("t=10d"), 14 days after manufacturing ("t=14d"), or 1 month after manufacturing ("t=1m"). Depots were stored at room temperature (20-25°C) for the specified periods after manufacturing. As shown in Figure 35, the single plasticizer depot was no longer flexible after 10 days, despite the higher 14 wt% loading. In the depots with the two plasticizers, flexibility decreased slightly after one month post-manufacturing, but the depots as a whole still maintained their flexibility (see also Table 25D below). These results demonstrate that the secondary plasticizer (glycerol) was beneficial in providing flexibility over a long period after manufacturing.

[0402] Figure 36 is a graph showing the force-displacement curves for depots containing three different plasticizers at various post-manufacturing time points. The depots were formulated using 1.4 wt% triacetin / 1.4 wt% benzyl benzoate / 0.4% glycerol. The depots were rectangular with a thickness of 2 mm. Tests were conducted immediately after manufacturing ("t=0"), 7 days after manufacturing ("t=7d"), or 14 days after manufacturing ("t=14d"). All depots maintained their flexibility throughout the 14-day post-manufacturing period (see also Table 25E below).

[0403] Tables 25A to 25G below summarize the results of mechanical tests on depots with various compositions and structures.

[0404] [Table 25A]

[0405] [Table 25B]

[0406] [Table 25C]

[0407] [Table 25D]

[0408] [Table 25E]

[0409] [Table 25F]

[0410] [Table 25G]

[0411] The accelerated aging data in Tables 25F and 25G were obtained by storing the depots in a stable chamber at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The results shown in Tables 25F and 25G demonstrate that the depots formulated with plasticizers maintained their flexibility even after storage at room temperature for up to one month, and some formulations were even able to maintain their flexibility under accelerated aging conditions.

[0412] Overall, these results demonstrate that certain plasticizers (triacetin, benzyl benzoate, diethyl phthalate) and depot compositions can provide improved flexibility compared to depots without plasticizers, while also delivering the desired drug release profile. Using formulations with two or three plasticizers allowed for the maintenance of flexibility and controlled release over extended periods.

[0413] Further example (I) Some aspects of the technology of the present invention are described in the following examples.

[0414] Example I-1. An implantable depot for treating pain, comprising a therapeutic area containing a polymer, an analgesic, and a plasticizer, wherein, when implanted in vivo, the therapeutic area is configured to release the analgesic for a treatment period of at least 3 days. The implanted depot has a flexural modulus in the range of 1 MPa to 400 MPa. Planted depot.

[0415] Example I-2. The planted depot described in Example I-1, wherein the plasticizer is hydrophilic.

[0416] Example I-3. The planted depot described in Example I-1, wherein the plasticizer is hydrophobic.

[0417] Example I-4. An implantable depot according to any one of Examples I-1 to I-3, wherein the plasticizer comprises one or more of the following: triglycerides, fatty acid esters, lactic acid esters, citrates, phthalates, glycerol esters, sebacates, monoglyceride esters, benzyl derivatives, polyethylene glycol, polysorbates, diols, or triols.

[0418] Example I-5. An implantable depot according to any one of Examples I-1 to I-4, wherein the plasticizer comprises one or more of triacetin, diethyl phthalate, benzyl benzoate, or glycerol.

[0419] Example I-6. An implantable depot according to any one of Examples I-1 to I-5, wherein the relative energy difference (RED) between the plasticizer and the polymer is equal to or less than 1.

[0420] Example I-7. A planted depot according to any one of Examples I-1 to I-6, wherein the vapor pressure of the plasticizer is equal to or less than 0.5 Pa at 25°C.

[0421] Example I-8. An implantable depot according to any one of Examples I-1 to I-7, wherein the logP value of the plasticizer is in the range of -1.5 to 6, 0 to 4, or 2 to 4.

[0422] Example I-9. An implantable depot according to any one of Examples I-1 to I-8, wherein the plasticizer constitutes 0.1% to 20% of the total mass of the therapeutic agent.

[0423] Example I-10. An implantable depot according to any one of Examples I-1 to I-9, wherein the plasticizer constitutes 0.1% to 20% of the total mass of the implantable depot.

[0424] Example I-11. An implantable depot according to any one of Examples I-1 to I-10, wherein the therapeutic area contains only a single plasticizer.

[0425] Example I-12. An implantable depot according to any one of Examples I-1 to I-10, wherein the plasticizer is a first plasticizer and the therapeutic area further comprises a second plasticizer.

[0426] Example I-13. The implantable depot described in Example I-12, wherein the first plasticizer is triacetin and the second plasticizer is glycerol.

[0427] Example I-14. An implantable depot according to Example I-12 or 13, wherein the therapeutic agent further comprises a third plasticizer.

[0428] Example I-15. The implantable depot described in Example I-14, wherein the first plasticizer is triacetin, the second plasticizer is glycerol, and the third plasticizer is benzyl benzoate.

[0429] Example I-16. An implantable depot according to any one of Examples I-1 to I-15, wherein the therapeutic area has a first surface, a second surface opposite to the first surface, and an outer surface between the first surface and the second surface.

[0430] Example I-17. An implantable depot according to Example I-16, wherein the first surface, second surface, and outer surface of the therapeutic area are exposed.

[0431] Example I-18. The implantable depot according to Example I-16, further comprising a first control region covering a first surface of a therapeutic area, wherein the first control region comprises a polymer.

[0432] Example I-19. The implantable depot according to Example I-18, wherein the first control region is free of any plasticizer.

[0433] Example I-20. The implantable depot according to Example I-18, wherein the first control region contains a plasticizer.

[0434] Example I-21. An implantable depot according to any one of Examples I-18 to 20, further comprising a second control region covering a second surface of a therapeutic area, wherein the second control region comprises a polymer.

[0435] Example I-22. The implantable depot according to Example I-21, wherein the second control region is free of any plasticizer.

[0436] Example I-23. The implantable depot according to Example I-21, wherein the second control region contains a plasticizer.

[0437] Example I-24. An implantable depot according to any one of Examples I-1 to I-23, wherein the analgesic constitutes at least 50% of the total mass of the implantable depot.

[0438] Example I-25. An implantable depot according to any one of Examples I-1 to I-24, wherein the analgesic contains bupivacaine.

[0439] Example I-26. An implantable depot according to any one of Examples I-1 to I-25, wherein the polymer comprises poly(lactide-co-glycolide).

[0440] Example I-27. An implantable depot described in any one of Examples I-1 to I-26, wherein the treatment period is 7 days or less.

[0441] Example I-28. An implantable depot according to any one of Examples I-1 to I-26, wherein the treatment period is at least 7 days.

[0442] Example I-29. An implantable depot for treating pain, comprising a therapeutic area containing a polymer and an analgesic, wherein the therapeutic area has a first surface, a second surface opposite to the first surface, and an outer surface between the first surface and the second surface. When implanted in vivo, the therapeutic area is configured to release analgesics from its first surface, second surface, and outer surface for a treatment period of 7 days or less. Planted depot.

[0443] Example I-30. An implantable depot as described in Example I-29, wherein the first surface, second surface, and outer surface of the therapeutic area are exposed.

[0444] Example I-31. An implantable depot as described in Example I-29 or 30, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first day of the treatment period.

[0445] Example I-32. An implantable depot according to any one of Examples I-29 to 31, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first two days of the treatment period.

[0446] Example I-33. An implantable depot according to any one of Examples I-29 to I-32, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first three days of the treatment period.

[0447] Example I-34. An implantable depot according to any one of Examples I-29 to 33, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first four days of the treatment period.

[0448] Example I-35. An implantable depot as described in any one of Examples I-29 to 34, which, when implanted in vivo, produces an average plasma concentration of an analgesic equal to or greater than the therapeutic threshold within the first 12 hours, 1 day, 2 days, 3 days, or 4 days of the treatment period.

[0449] Example I-36. An implantable depot as described in Example I-35, with a therapeutic threshold of 200 ng / ml.

[0450] Example I-37. When implanted in vivo, the average T is 96 hours, 72 hours, 36 hours, 48 ​​hours, 24 hours, or 12 hours or less. max An implantable depot as described in any one of Examples I-29 to I-36, which produces the following.

[0451] Example I-38. When implanted in vivo, the average T duration was 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day or less. last An implantable depot as described in any one of Examples I-29 to I-37, which produces the following.

[0452] Example I-39. An implantable depot according to any one of Examples I-29 to 38, wherein the analgesic constitutes at least 50% of the total mass of the implantable depot.

[0453] Example I-40. An implantable depot according to any one of Examples I-29 to I-39, wherein the analgesic contains bupivacaine.

[0454] Example I-41. An implantable depot according to any one of Examples I-29 to 40, wherein the polymer comprises poly(lactide-co-glycolide).

[0455] Example I-42. An implantable depot according to any one of Examples I-29 to I-41, wherein the analgesic and polymer are separate phases within the therapeutic agent.

[0456] Example I-43. An implantable depot according to any one of Examples I-29 to I-42, wherein the therapeutic area includes a releasing agent.

[0457] Example I-44. The implantable depot described in Example I-43, wherein the release agent constitutes 5% or less of the total mass of the implantable depot.

[0458] Example I-45. An implantable depot according to Example I-43 or Example I-44, wherein the release agent comprises polysorbate.

[0459] Example I-46. An implantable depot according to any one of Examples I-29 to I-45, wherein the therapeutic agent further comprises a plasticizer.

[0460] Example I-47. The planted depot described in Example I-46, wherein the plasticizer is hydrophilic.

[0461] Example I-48. The planted depot described in Example I-46, wherein the plasticizer is hydrophobic.

[0462] Example I-49. An implantable depot according to any one of Examples I-46 to 48, wherein the plasticizer comprises one or more of the following: triglycerides, fatty acid esters, lactic acid esters, citrates, phthalates, glycerol esters, sebacates, monoglyceride esters, benzyl derivatives, polyethylene glycol, polysorbates, diols, or triols.

[0463] Example I-50. An implantable depot according to any one of Examples I-46 to 49, wherein the plasticizer comprises one or more of triacetin, diethyl phthalate, benzyl benzoate, or glycerol.

[0464] An embedded depot according to any one of Examples I-29 to 50, having a flexural modulus in the range of 1.1 MPa to 400 MPa.

[0465] Example I-52. A method for treating pain in a subject after a surgical procedure, comprising placing one or more implantable depots described in any one of Examples I-1 to I-51 into the subject.

[0466] Example I-53. The mass of analgesic in each depot is 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, The method described in Example I-52, which is equal to or greater than 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg.

[0467] Example I-54. The method according to Example I-52 or Example I-53, wherein, when implanted in vivo, each depot continuously releases an analgesic for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or less.

[0468] Example I-55. When implanted in vivo, one or more depots contain 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 mg / ml, 25 ng / ml, 30 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, 100 ng / ml, 110 ng / ml, 120 ng / ml, 130 ng / ml, 140 ng / ml, 150 ng / ml, 160 ng / ml, 170 ng / ml, 180 The method according to any one of Examples I-52 to 54, which produces an average plasma concentration of an analgesic equal to or greater than ng / ml, 190 ng / ml, 200 ng / ml, 210 ng / ml, 220 ng / ml, 230 ng / ml, 240 ng / ml, 250 ng / ml, 300 ng / ml, 400 ng / ml, 500 ng / ml, 600 ng / ml, 700 ng / ml, 800 ng / ml, 900 ng / ml, or 1000 ng / ml.

[0469] Example I-56. The method of Example I-55, wherein the mean plasma concentration is maintained over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days or less.

[0470] Example I-57. When implanted in vivo, one or more depots contain an average C of analgesic equal to or less than 5000 ng / ml, 4000 ng / ml, 3000 ng / ml, 2000 ng / ml, 1000 ng / ml, 900 ng / ml, 800 ng / ml, 700 ng / ml, 600 ng / ml, 500 ng / ml, 400 ng / ml, 300 ng / ml, 200 ng / ml, 100 ng / ml, or 50 ng / ml. max A method according to any one of Examples I-52 to I-56, which produces the result.

[0471] Example I-58. When implanted in vivo, one or more depots have an average AUC of at least 500-day-ng / ml, 1000-day-ng / ml, 1500-day-ng / ml, 2000-day-ng / ml, 2500-day-ng / ml, 3000-day-ng / ml, 3500-day-ng / ml, 4000-day-ng / ml, 4500-day-ng / ml, 5000-day-ng / ml, 5500-day-ng / ml, 6000-day-ng / ml, 6500-day-ng / ml, 7000-day-ng / ml, 7500-day-ng / ml, or 8000-day-ng / ml of analgesic. 0~14d A method according to any one of Examples I-52 to I-57, which produces the result.

[0472] Example I-59. The method according to any one of Examples I-52 to 58, wherein the mean NRS score of a treatment group treated with one or more implantable depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the mean NRS score of a control group not treated with one or more implantable depots.

[0473] Example I-60. The method according to Example I-59, wherein the mean NRS score of the treatment group and the mean NRS score of the control group are assessed at 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days after the surgical procedure.

[0474] Example I-61. The method according to any one of Examples I-52 to 60, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of a treatment population treated with one or more implantable depots are pain-free at some point after the surgical procedure.

[0475] Example I-62. The method as described in Example I-61, wherein the time point is 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days after the surgical procedure.

[0476] Example I-63. The method according to any one of Examples I-52 to I-62, wherein the mean NRS AUC of a treatment population treated with one or more implantable depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the mean NRS AUC of a control population not treated with one or more implantable depots.

[0477] Example I-64. The mean NRS AUC of the treatment group and the mean NRS AUC of the control group were observed at the following times after the surgical procedure: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0 hours-7 days, 0 hours-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12 hours-7 days, 12 hours-14 days, 12 hours-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days, 2-7 days, 2-1 The method as described in Example I-63, which is evaluated over a period of 4 days, 3-4 days, 3-7 days, 3-14 days, 4-5 days, 4-7 days, 4-14 days, 5-6 days, 5-7 days, 5-14 days, 6-7 days, 6-14 days, 7-8 days, 7-14 days, 8-9 days, 9-10 days, 10-11 days, 11-12 days, 12-13 days, or 13-14 days.

[0478] Example I-65. The method according to any one of Examples I-52 to 64, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the treatment population treated with one or more implantable depots have not used opioids for a period of time following the surgical procedure.

[0479] Example I-66. Period after surgical procedure: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0 hours-7 days, 0 hours-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12 hours-7 days, 12 hours-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days, 2-7 days, 2 days The method as described in Example I-65, which is ~14 days, 3-4 days, 3-7 days, 3-14 days, 4-5 days, 4-7 days, 4-14 days, 5-6 days, 5-7 days, 5-14 days, 6-7 days, 6-14 days, 7-8 days, 7-14 days, 8-9 days, 9-10 days, 10-11 days, 11-12 days, 12-13 days, or 13-14 days.

[0480] Example I-67. The method according to any one of Examples I-52 to 66, wherein the mean total opioid consumption of a treatment population treated with one or more implantable depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the mean total opioid consumption of a control population not treated with one or more depots.

[0481] Example I-68. Mean total opioid consumption in the treatment group and the control group compared after the surgical procedure: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0 hours-7 days, 0 hours-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12 hours-7 days, 12 hours-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days. The method as described in Example I-67, which is evaluated over a period of 2 to 7 days, 2 to 14 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 6 to 7 days, 6 to 14 days, 7 to 8 days, 7 to 14 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, or 13 to 14 days.

[0482] Example I-69. The method according to any one of Examples I-52 to 68, wherein the mean total opioid consumption of a treatment population treated with one or more implantable depots is 600 morphine milligram equivalents (MME), 550 MME, 500 MME, 450 MME, 400 MME, 350 MME, 300 MME, 250 MME, 200 MME, 150 MME, 100 MME, or 50 MME or less.

[0483] Example I-70. The mean total opioid consumption of the treatment group was as follows: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0 hours-7 days, 0 hours-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12 hours-7 days, 12 hours-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days, 2-7 days, 2 The method described in Example I-69, which is evaluated over a period of 1 to 14 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 6 to 7 days, 6 to 14 days, 7 to 8 days, 7 to 14 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 d...

Claims

1. An implantable depot for treating pain comprises a therapeutic area containing a polymer, an analgesic, and a plasticizer, and is configured to release the analgesic over a treatment period of at least three days when implanted in vivo. The implantable depot has a flexural modulus in the range of 1 MPa to 400 MPa. Planted depot.

2. The planting-type depot according to claim 1, wherein the plasticizer is hydrophilic.

3. The planting-type depot according to claim 1, wherein the plasticizer is hydrophobic.

4. The implantable depot according to any one of claims 1 to 3, wherein the plasticizer comprises one or more of triglycerides, fatty acid esters, lactic acid esters, citrates, phthalates, glycerol esters, sebacates, monoglyceride esters, benzyl derivatives, polyethylene glycol, polysorbates, diols, or triols.

5. The implantable depot according to any one of claims 1 to 4, wherein the plasticizer comprises one or more of triacetin, diethyl phthalate, benzyl benzoate, or glycerol.

6. The implantable depot according to any one of claims 1 to 5, wherein the relative energy difference (RED) between the plasticizer and the polymer is equal to or less than 1.

7. The implantable depot according to any one of claims 1 to 6, wherein the vapor pressure of the plasticizer is equal to or less than 0.5 Pa at 25°C.

8. The implantable depot according to any one of claims 1 to 7, wherein the logP value of the plasticizer is in the range of -1.5 to 6, 0 to 4, or 2 to 4.

9. The implantable depot according to any one of claims 1 to 8, wherein the plasticizer constitutes 0.1% to 20% of the total mass of the therapeutic agent region.

10. The implantable depot according to any one of claims 1 to 9, wherein the plasticizer constitutes 0.1% to 20% of the total mass of the implantable depot.

11. The implantable depot according to any one of claims 1 to 10, wherein the therapeutic agent area comprises only a single plasticizer.

12. The implantable depot according to any one of claims 1 to 10, wherein the plasticizer is a first plasticizer, and the therapeutic area further comprises a second plasticizer.

13. The implantable depot according to claim 12, wherein the first plasticizer is triacetin and the second plasticizer is glycerol.

14. The implantable depot according to claim 12 or 13, wherein the therapeutic agent area further comprises a third plasticizer.

15. The implantable depot according to claim 14, wherein the first plasticizer is triacetin, the second plasticizer is glycerol, and the third plasticizer is benzyl benzoate.

16. The implantable depot according to any one of claims 1 to 15, wherein the therapeutic agent region has a first surface, a second surface opposite to the first surface, and an outer surface between the first surface and the second surface.

17. The implantable depot according to claim 16, wherein the first surface, the second surface, and the outer surface of the therapeutic agent region are exposed.

18. The implantable depot according to claim 16, further comprising a first control region covering the first surface of the therapeutic agent region, wherein the first control region comprises a polymer.

19. The implantable depot according to claim 18, wherein the first control region does not contain any plasticizer.

20. The implantable depot according to claim 18, wherein the first control region contains a plasticizer.

21. The implantable depot according to any one of claims 18 to 20, further comprising a second control region covering the second surface of the therapeutic agent region, wherein the second control region comprises a polymer.

22. The implantable depot according to claim 21, wherein the second control region does not contain any plasticizer.

23. The implantable depot according to claim 21, wherein the second control region contains a plasticizer.

24. The implantable depot according to any one of claims 1 to 23, wherein the analgesic constitutes at least 50% of the total mass of the implantable depot.

25. The implantable depot according to any one of claims 1 to 24, wherein the analgesic agent comprises bupivacaine.

26. The implantable depot according to any one of claims 1 to 25, wherein the polymer comprises poly(lactide-co-glycolide).

27. The implantable depot according to any one of claims 1 to 26, wherein the treatment period is 7 days or less.

28. The implantable depot according to any one of claims 1 to 26, wherein the treatment period is at least 7 days.

29. An implantable depot for treating pain, comprising a therapeutic region containing a polymer and an analgesic, wherein the therapeutic region has a first surface, a second surface opposite to the first surface, and an outer surface between the first surface and the second surface. When implanted in vivo, the therapeutic area is configured to release the analgesic from the first surface, the second surface, and the outer surface of the therapeutic area for a treatment period of 7 days or less. Planted depot.

30. The implantable depot according to claim 29, wherein the first surface, the second surface, and the outer surface of the therapeutic agent region are exposed.

31. The implantable depot according to claim 29 or 30, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first day of the treatment period.

32. An implantable depot according to any one of claims 29 to 31, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first two days of the treatment period.

33. An implantable depot according to any one of claims 29 to 32, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first three days of the treatment period.

34. An implantable depot according to any one of claims 29 to 33, wherein at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the analgesic is released within the first four days of the treatment period.

35. The implantable depot according to any one of claims 29 to 34, wherein, when implanted in vivo, it produces an average plasma concentration of the analgesic equal to or greater than the therapeutic threshold within the first 12 hours, 1 day, 2 days, 3 days, or 4 days of the treatment period.

36. The implantable depot according to claim 35, wherein the treatment threshold is 200 ng / ml.

37. When implanted in vivo, the average T is 96 hours, 72 hours, 36 hours, 48 ​​hours, 24 hours, or 12 hours or less. ｍａｘ A planted depot according to any one of claims 29 to 36, which produces the following.

38. When implanted in vivo, the average T is 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day or less. ｌａｓｔ A planted depot according to any one of claims 29 to 37, which produces the following.

39. The implantable depot according to any one of claims 29 to 38, wherein the analgesic constitutes at least 50% of the total mass of the implantable depot.

40. The implantable depot according to any one of claims 29 to 39, wherein the analgesic comprises bupivacaine.

41. The implantable depot according to any one of claims 29 to 40, wherein the polymer comprises poly(lactide-co-glycolide).

42. The implantable depot according to any one of claims 29 to 41, wherein the analgesic and the polymer are separate phases within the therapeutic agent.

43. The implantable depot according to any one of claims 29 to 42, wherein the therapeutic agent area includes a releasing agent.

44. The implantable depot according to claim 43, wherein the release agent constitutes 5% or less of the total mass of the implantable depot.

45. The implantable depot according to claim 43 or claim 44, wherein the release agent comprises polysorbate.

46. The implantable depot according to any one of claims 29 to 45, wherein the therapeutic agent area further comprises a plasticizer.

47. The planting-type depot according to claim 46, wherein the plasticizer is hydrophilic.

48. The planting-type depot according to claim 46, wherein the plasticizer is hydrophobic.

49. The implantable depot according to any one of claims 46 to 48, wherein the plasticizer comprises one or more of triglycerides, fatty acid esters, lactic acid esters, citrates, phthalates, glycerol esters, sebacates, monoglyceride esters, benzyl derivatives, polyethylene glycol, polysorbates, diols, or triols.

50. The implantable depot according to any one of claims 46 to 49, wherein the plasticizer comprises one or more of triacetin, diethyl phthalate, benzyl benzoate, or glycerol.

51. An implantable depot according to any one of claims 29 to 50, having a flexural modulus in the range of 1 MPa to 400 MPa.

52. A method for treating pain in a subject after a surgical procedure, comprising placing one or more implantable depots described in any one of claims 1 to 51 in the subject.

53. The mass of the analgesic in each depot is 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 70 mg The method according to claim 52, which is equal to or greater than 0 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg.

54. The method according to claim 52 or claim 53, wherein, when implanted in vivo, each depot continuously releases the analgesic for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days or less.

55. When implanted in vivo, one or more depots contain 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 mg / ml, 25 ng / ml, 30 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, 100 ng / ml, 110 ng / ml, 120 ng / ml, 130 ng / ml, 140 ng / ml, 150 ng / ml, 160 ng / ml, 170 ng / ml, 180 The method according to any one of claims 52 to 54, which produces an average plasma concentration of the analgesic equal to or greater than ng / ml, 190 ng / ml, 200 ng / ml, 210 ng / ml, 220 ng / ml, 230 ng / ml, 240 ng / ml, 250 ng / ml, 300 ng / ml, 400 ng / ml, 500 ng / ml, 600 ng / ml, 700 ng / ml, 800 ng / ml, 900 ng / ml, or 1000 ng / ml.

56. The method according to claim 55, wherein the average plasma concentration is maintained over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days or less.

57. When implanted in vivo, one or more depots have an average C of the analgesic equal to or less than 5000 ng / ml, 4000 ng / ml, 3000 ng / ml, 2000 ng / ml, 1000 ng / ml, 900 ng / ml, 800 ng / ml, 700 ng / ml, 600 ng / ml, 500 ng / ml, 400 ng / ml, 300 ng / ml, 200 ng / ml, 100 ng / ml, or 50 ng / ml. ｍａｘ The method according to any one of claims 52 to 56, which produces the following.

58. When implanted in vivo, one or more depots have an average AUC of the analgesic at least 500-day-ng / ml, 1000-day-ng / ml, 1500-day-ng / ml, 2000-day-ng / ml, 2500-day-ng / ml, 3000-day-ng / ml, 3500-day-ng / ml, 4000-day-ng / ml, 4500-day-ng / ml, 5000-day-ng / ml, 5500-day-ng / ml, 6000-day-ng / ml, 6500-day-ng / ml, 7000-day-ng / ml, 7500-day-ng / ml, or 8000-day-ng / ml. ０～１４ｄ The method according to any one of claims 52 to 57, which produces the following.

59. The method according to any one of claims 52 to 58, wherein the mean NRS score of a treatment group treated with the one or more implantable depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the mean NRS score of a control group not treated with the one or more implantable depots.

60. The method according to claim 59, wherein the mean NRS score of the treatment group and the mean NRS score of the control group are evaluated 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days after the surgical procedure.

61. The method according to any one of claims 52 to 60, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the treatment population treated with the one or more implantable depots are pain-free at some point after the surgical procedure.

62. The method according to claim 61, wherein the aforementioned time is 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days after the surgical procedure.

63. The method according to any one of claims 52 to 62, wherein the mean NRS AUC of a treatment population treated with the one or more implantable depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the mean NRS AUC of a control population not treated with the one or more implantable depots.

64. The mean NRS AUC of the treatment group and the mean NRS AUC of the control group are as follows: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0 hours-7 days, 0-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12-7 days, 12-14 days, 12-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days, 2-7 days, 2- The method according to claim 63, wherein the evaluation is performed over a period of 14 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 6 to 7 days, 6 to 14 days, 7 to 8 days, 7 to 14 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, or 13 to 14 days.

65. The method according to any one of claims 52 to 64, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the treatment population treated with the one or more implantable depots have not used opioids for a period of time following the surgical procedure.

66. The aforementioned period is as follows: 0 to 12 hours, 0 to 24 hours, 0 to 72 hours, 0 to 96 hours, 0 to 7 days, 0 to 14 days, 12 to 24 hours, 12 to 36 hours, 12 to 72 hours, 12 to 96 hours, 12 to 7 days, 12 to 14 days, 1 to 2 days, 1 to 4 days, 1 to 7 days, 1 to 14 days, 2 to 3 days, 2 to 4 days, 2 to 7 days, 2 to The method according to claim 65, wherein the duration is 14 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 6 to 7 days, 6 to 14 days, 7 to 8 days, 7 to 14 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, or 13 to 14 days.

67. The method according to any one of claims 52 to 66, wherein the mean total opioid consumption of a treatment population treated with the one or more implantable depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the mean total opioid consumption of a control population not treated with the one or more depots.

68. The average total opioid consumption of the treatment group and the average total opioid consumption of the control group were as follows: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0-7 days, 0-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12-7 days, 12-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days The method according to claim 67, wherein the evaluation is performed over a period of 1 day, 2 to 7 days, 2 to 14 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 6 to 7 days, 6 to 14 days, 7 to 8 days, 7 to 14 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, or 13 to 14 days.

69. The method according to any one of claims 52 to 68, wherein the average total opioid consumption of the treatment population treated with one or more implantable depots is 600 morphine milligram equivalents (MME), 550 MME, 500 MME, 450 MME, 400 MME, 350 MME, 300 MME, 250 MME, 200 MME, 150 MME, 100 MME, or 50 MME or less.

70. The average total opioid consumption of the treatment group was as follows: 0-12 hours, 0-24 hours, 0-72 hours, 0-96 hours, 0-7 days, 0-14 days, 12-24 hours, 12-36 hours, 12-72 hours, 12-96 hours, 12-7 days, 12-14 days, 1-2 days, 1-4 days, 1-7 days, 1-14 days, 2-3 days, 2-4 days, 2-7 days, 2 The method according to claim 69, wherein the evaluation is performed over a period of 1 to 14 days, 3 to 4 days, 3 to 7 days, 3 to 14 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 6 to 7 days, 6 to 14 days, 7 to 8 days, 7 to 14 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, or 13 to 14 days.

71. The method according to any one of claims 52 to 70, wherein the average time to first opioid consumption in a treatment population treated with the one or more implantable depots is delayed by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 96 hours, 5 days, 6 days, or 7 days compared to the average time to first opioid consumption in a control population not treated with the one or more implantable depots.

72. The method according to any one of claims 52 to 71, wherein the surgical procedure is a soft tissue repair procedure.

73. The method according to claim 72, wherein the soft tissue repair procedure is open inguinal hernia repair, abdominal wall reconstruction, abdominal surgery, mastoplasty, or abdominal wall hernia repair.

74. The method according to any one of claims 52 to 71, wherein the surgical procedure is an orthopedic procedure.

75. The method according to claim 74, wherein the orthopedic procedure is total shoulder arthroplasty or total hip arthroplasty.

76. The method according to any one of claims 52 to 71, wherein the surgical procedure is a procedure on the foot or ankle joint.

77. The method according to claim 76, wherein the procedure on the foot or ankle is a bunion resection, ankle fracture repair, or hindfoot fixation.

78. The method according to any one of claims 52 to 71, wherein the surgical procedure is a gynecological or pelvic procedure.

79. The method according to claim 78, wherein the gynecological or pelvic procedure is a cesarean section, a hysterectomy, or an oophorectomy.

80. The method according to any one of claims 52 to 71, wherein the surgical procedure is a thoracic procedure.

81. The method according to claim 80, wherein the thoracic procedure is a sternotomy or a thoracotomy.

82. The method according to any one of claims 52 to 71, wherein the surgical procedure is a gastrointestinal procedure.

83. The method according to claim 82, wherein the gastrointestinal procedure is a colectomy.

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