IMPLANTABLE DEPOT HAVING CONTROLLABLE RELEASE PROFILE - Patent application

Abstract

Implantable depots for delivering therapeutic agents and related systems and methods are provided. In some embodiments, an implantable depot for treating pain in a subject after a surgical procedure includes a therapeutic agent region having a first polymer and an analgesic agent, a first control region including a second polymer, and a second control region including a third polymer. The first and second control regions can cover the first and second surfaces of the therapeutic agent region to inhibit the release of the analgesic agent from the surfaces. The depot can include one or more holes that extend across the first and second control regions and the therapeutic agent region to form one or more exposed portions. When implanted in a subject, the implantable depot can release the analgesic agent from the outer surface of the therapeutic agent region between the first and second surfaces and from the exposed portions of the therapeutic agent region.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 261,921, filed September 30, 2021, and U.S. Provisional Application No. 63 / 373,510, filed August 25, 2022, each of which is incorporated by reference in its entirety.

[0002] Technical Field TECHNICAL FIELD The present technology relates generally 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 methods. Devices made of biocompatible and / or biodegradable polymers and therapeutic agents can be implanted at clinically desirable anatomical locations, thereby resulting in localized delivery of selected agents. This localized delivery can allow a significant proportion of the agent to reach the intended target and avoid undesirable systemic side effects. However, these systems often suffer from the disadvantage of lacking a true controlled release mechanism, in that they typically release a burst of therapeutic agent upon contact with the surrounding physiological fluids, followed by the remainder of the drug release.

[0004] Controlled sustained release of a therapeutic agent can be of clinical benefit in certain circumstances. In particular, it may be desirable to implant a biodegradable carrier that holds a large dose of a therapeutic agent for controlled sustained release over time. This can be particularly valuable when the therapeutic agent-loaded carrier is implanted alongside or as part of an implantable medical device, as needed, in conjunction with an interventional or surgical procedure. Thus, there is a need for a biocompatible implantable system that can provide a highly controlled release of a therapeutic agent. Summary of the Invention [Means for solving the problem]

[0005] Many aspects of the present disclosure can be better understood with reference to the following figures. The components in the figures are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. [Brief description of the drawings]

[0006] [Figure 1A] FIG. 1A is a partial schematic diagram of an implantable depot constructed in accordance with an embodiment of the present technology.

[0007] [Figure 1B] FIG. 1B is a partial schematic diagram of another implantable depot constructed in accordance with an embodiment of the present technology.

[0008] [Figure 1C] FIG. 1C is a partial schematic diagram of yet another implantable depot constructed in accordance with an embodiment of the present technology.

[0009] [Figure 2A] FIG. 2A is a top view of a rectangular depot constructed in accordance with an embodiment of the present technology.

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

[0011] [Figure 3A] FIG. 3A is a top view of a triangular depot having holes configured in accordance with an embodiment of the present technology.

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

[0013] [Figure 4A] FIG. 4A is a top view of a triangular depot having holes configured in accordance with an embodiment of the present technology.

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

[0015] [Figure 4C] FIG. 4C is a top view of another triangular depot having holes configured in accordance with an embodiment of the present technology.

[0016] [Figure 4D] FIG. 4D is a top view of yet another triangular depot having holes configured in accordance with an embodiment of the present technology.

[0017] [Figure 4E] FIG. 4E is a top view of a triangular depot having holes configured in accordance with an embodiment of the present technology.

[0018] [Figure 4F] FIG. 4F is a top view of another triangular depot having holes configured in accordance with an embodiment of the present technology.

[0019] [Figure 4G] FIG. 4G is a top view of a triangular depot having holes configured in accordance with an embodiment of the present technology.

[0020] [Figure 4H]FIG. 4H is a top view of yet another triangular depot having holes configured in accordance with an embodiment of the present technology.

[0021] [Figure 5A] FIG. 5A is a top view of an arrowhead shaped depot constructed in accordance with an embodiment of the present technology.

[0022] [Figure 5B] FIG. 5B is a top view of a diamond shaped depot constructed in accordance with an embodiment of the present technology.

[0023] [Figure 5C] FIG. 5C is a top view of a rectangular depot constructed in accordance with an embodiment of the present technology.

[0024] [Figure 5D] FIG. 5D is a top view of a cruciform depot constructed in accordance with an embodiment of the present technology.

[0025] [Figure 5E] FIG. 5E is a top view of an L-shaped depot constructed in accordance with an embodiment of the present technology.

[0026] [Figure 5F] FIG. 5F is a top view of a circular depot constructed in accordance with an embodiment of the present technology.

[0027] [Figure 5G] FIG. 5G is a perspective view of a spherical depot constructed in accordance with an embodiment of the present technology.

[0028] [Figure 6] FIG. 6 is a scanning electron microscope image of a portion of the implantable depot.

[0029] [Figure 7A] FIG. 7A is a graph showing in vitro elution data for the implantable depot.

[0030] [Figure 7B] FIG. 7B is another graph showing in vitro elution data for the implantable depot.

[0031] [Figure 8A] FIG. 8A is a scanning electron microscope image of an implantable depot that is approximately 25% eluted.

[0032] [Figure 8B] FIG. 8B is a scanning electron microscope image of an implantable depot that is approximately 75% eluted.

[0033] [Figure 9A] FIG. 9A is a graph showing the mean bupivacaine plasma concentrations in subjects treated with the implantable depot versus other formulations following total knee arthroplasty.

[0034] [Figure 9B] FIG. 9B is a graph showing mean bupivacaine plasma concentrations overlaid with post-operative pain data in subjects treated with an implantable depot after total knee arthroplasty.

[0035] [Figure 9C] FIG. 9C is a graph showing the area under the curve (AUC) of bupivacaine plasma concentrations in subjects treated with the implantable depot following total knee arthroplasty versus other formulations.

[0036] [Figure 9D] FIG. 9D is a graph showing the mean bupivacaine plasma concentrations in subjects receiving various doses of bupivacaine from an implanted depot.

[0037] [Figure 9E] FIG. 9E is a graph showing the relationship between Cmax and bupivacaine dose for the implantable depot.

[0038] [Figure 9F] FIG. 9F is a graph showing the relationship between AUC0-14d and bupivacaine dose for the implantable depot.

[0039] [Figure 9G] FIG. 9G is a graph showing the in vivo bupivacaine release profile in subjects receiving an implanted depot.

[0040] [Figure 10] FIG. 10 is a graph showing the mean pain intensity scores for subjects treated with the implantable depot (not adjusted for opioid consumption).

[0041] [Figure 11A] FIG. 11A is a graph showing simulated bupivacaine plasma concentrations for subjects treated with an implantable depot versus actual bupivacaine plasma concentrations in subjects treated with other bupivacaine formulations following shoulder surgery.

[0042] [Figure 11B] FIG. 11B is a graph showing simulated bupivacaine plasma concentrations for subjects treated with an implantable depot versus actual bupivacaine plasma concentrations in subjects treated with another bupivacaine formulation following bunionectomy.

[0043] [Figure 11C] FIG. 11C is a graph showing simulated bupivacaine plasma concentrations for subjects treated with the implantable depot versus actual bupivacaine plasma concentrations in subjects treated with other bupivacaine formulations following open inguinal hernia repair.

[0044] [Figure 12] FIG. 12 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots formulated with bupivacaine free base without a control region.

[0045] [Figure 13] FIG. 13 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots having various control regions.

[0046] [Figure 14A] FIG. 14A is a graph showing the cumulative in vitro release of bupivacaine from implantable depots formulated with the free base and salt forms of bupivacaine.

[0047] [Figure 14B] FIG. 14B is a graph showing the cumulative in vitro release of bupivacaine from implantable depots having the free base and salt forms of bupivacaine.

[0048] [Figure 15] FIG. 15 is a semi-log graph showing the in vivo release of bupivacaine from implantable depots formulated with the free base and salt forms of bupivacaine in a rabbit subcutaneous model.

[0049] [Figure 16] FIG. 16 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots with various therapeutic agent loadings.

[0050] [Figure 17] FIG. 17 is a graph showing the cumulative in vitro release of bupivacaine from implantable depots formulated with various free base:salt ratios.

[0051] [Figure 18A-B] 18A and 18B show a Monte Carlo approach to modeling the travel distance for various depot geometries.

[0052] [Fig. 18C-D] 18C and 18D show a geometric / differential approach to modeling travel distance for various depot geometries. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] Detailed Description The present technology relates to implantable depots for sustained controlled release of therapeutic agents, and related systems and methods. For example, in some embodiments, an implantable depot for treating a subject includes a therapeutic agent region having a first surface, a second surface opposite the first surface, and an outer surface between the first surface and the second surface. The therapeutic agent region can include a polymer and a therapeutic agent (e.g., bupivacaine). The depot can also include a first control region including a polymer and covering the first surface of the therapeutic agent region to inhibit release of the therapeutic agent from the first surface. The depot can also include a second control region including a polymer and covering the second surface of the therapeutic agent region to inhibit release of the therapeutic agent from the second surface. Optionally, the depot can include one or more holes extending across the first and second control regions and the therapeutic agent region to form one or more exposed portions of the therapeutic agent region spaced from the outer surface. When implanted in a subject, the depot can release the therapeutic agent from the outer surface and one or more exposed portions of the therapeutic agent region. The release profile of the therapeutic agent can be adjusted by varying various parameters of the depot, such as the composition (e.g., amount and / or type of therapeutic agent, polymer, and / or other components, e.g., release agent) and / or geometry (e.g., thickness of the therapeutic agent region and / or control region, size, shape and / or location of the pore(s). Thus, the depots described herein can be adapted to provide sustained, controlled release of therapeutic agent for many different types of applications, such as for treating post-operative pain following a surgical procedure.

[0054] Embodiments of the present disclosure are more fully described below with reference to the accompanying drawings, in which like numerals represent like elements throughout the several views and in which example embodiments are shown. However, the claimed embodiments can be embodied in many different forms and should not be construed as being limited to the embodiments described herein. The examples described herein are non-limiting examples and are merely some examples among other possible examples.

[0055] As used herein, the terms "vertical," "outer (side)," "top," and "bottom" can refer to the relative direction or location of features of the embodiments disclosed herein given the orientation shown in the figures. For example, "top" or "top" can refer to a feature located closer to the top of a page than another feature. However, these terms should be interpreted broadly to include embodiments having other orientations, such as inverted or slanted orientations, and top / bottom, above / below, above / below, up / down, and left / right can be interchanged depending on the orientation.

[0056] The headings provided herein are provided merely for convenience and do not interpret the scope or meaning of the claimed inventive technology. Embodiments under any one heading may be used in combination with embodiments under any other heading. I. Implantable Depots for Delivery of Therapeutic Agents A. Overview

[0057] 1A is a partial schematic diagram of an implantable depot 100a configured in accordance with an embodiment of the present technology. The depot 100a is configured to be implanted at a treatment site in a patient's body and, upon implantation, 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 a disease or condition of the patient. For example, the therapeutic agent may be or include an analgesic drug (e.g., bupivacaine) for managing post-operative pain or other types of pain (e.g., chronic pain). Further examples and features of therapeutic agents that may be included in the depot 100a are provided in Section IC1. below.

[0058] The depot 100a can 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, pill, pellet, bead, scaffold, or combinations thereof. In an illustrative embodiment, the depot 100a is a multi-layered monolithic structure including a therapeutic agent region 102 juxtaposed between a first control region 104a and a second control region 104b. The therapeutic agent region 102 (also known as the "core region," "drug core," or "drug layer") contains the therapeutic agent, while the control regions 104a, 104b (also known as the "control layer") can modulate the release of the therapeutic agent from the therapeutic agent region 102. As discussed in detail below, the geometry and composition of the therapeutic agent region 102 and the control regions 104a, 104b can be configured to produce a desired release profile of the therapeutic agent.

[0059] In some embodiments, the therapeutic agent region 102 includes 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 polymer are separate phases within the therapeutic agent region 102, with the polymer acting as a "glue" to hold the therapeutic agent together. In such embodiments, the therapeutic agent can form separate crystals, particles, etc., which are adhered to one another by the polymer to form a unitary material. Alternatively, 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 bioresorbable polymer that is configured to degrade when exposed to physiological fluids. The degradation characteristics of the bioresorbable polymer can be selected to modulate the release rate of the therapeutic agent from the therapeutic agent region 102. Further examples and features of polymers that may be included in the therapeutic agent region 102 are provided below in section IC2.

[0060] Optionally, the therapeutic agent region 102 can include additional components, such as a release agent (e.g., polysorbate). The release agent can also affect the release rate of the therapeutic agent. In some embodiments, the release agent can have a dissolution rate that is faster than the degradation rate of the polymer in the therapeutic agent region 102 when exposed to a fluid (e.g., a physiological fluid). Thus, the release agent dissolves in the polymer surrounding the therapeutic agent region 102 when fluid contacts the therapeutic agent region 102 (e.g., after implantation of the depot 100a at the treatment site), thus forming openings (e.g., channels, voids, pores, etc.) in the surrounding polymer region that facilitate infiltration of fluid into the therapeutic agent region 102 and / or diffusion of the therapeutic agent out of the therapeutic agent region 102. Thus, increasing the amount of release agent in the therapeutic agent region 102 can increase the release rate of the therapeutic agent after implantation, as discussed in more detail elsewhere herein. Alternatively or in combination, the release agent may function as a surfactant to increase water uptake into the depot 100a or otherwise alter the interface between the therapeutic agent, polymer, and water to enhance the release rate. Optionally, the release agent may modulate the mechanical properties of the therapeutic agent region 102 (e.g., increase flexibility and / or decrease brittleness), thereby facilitating manufacture, storage, and / or handling of the depot 100a. Further examples and features of release agents that may be included in the therapeutic agent region 102 are provided below in section IC3. However, in other embodiments, the therapeutic agent region 102 may be provided without any release agent.

[0061] As shown in FIG. 1A, the therapeutic agent region 102 is aligned between the control regions 104a and 104b. The first control region 104a can partially or completely cover a first surface 106a (e.g., a top surface) of the therapeutic agent region 102. The second control region 104b can partially or completely cover a second surface 106b (e.g., a bottom surface) of the therapeutic agent region 102 opposite the first surface 106a. The therapeutic agent region 102 can include one or more outer surfaces 108 that are not covered by the control regions 104a, 104b. In an illustrative embodiment, for example, all four outer surfaces 108 of the therapeutic agent region 102 are exposed. Alternatively, in other embodiments, the therapeutic agent region 102 can include three, two, or a single exposed outer surface 108. Alternatively, the therapeutic agent region 102 can be entirely encapsulated by one or more control regions such that there are no exposed outer surfaces 108.

[0062] The control regions 104a, 104b can each include at least one polymer (e.g., PLGA). The first control region 104a can be made of the same polymer as the second control region 104b, or a different polymer. Additionally, the polymer used in the first and / or second control regions 104a, 104b can be the same or a different polymer than the polymer used in the therapeutic drug region 102. In some embodiments, the polymer in the first and / or second control regions 104a, 104b is a bioresorbable polymer. Further examples and features of polymers that may be included in the first and second control regions 104a, 104b are provided below in section IC2.

[0063] Optionally, the control regions 104a, 104b can include additional components, such as a release agent (e.g., polysorbate). The first control region 104a may include the same release agent as the second control region 104b, or may include a different release agent. Additionally, the release agent used in the first and / or second control regions 104a, 104b may be the same as or a different release agent than the release agent used in the therapeutic drug region 102. Further examples and features of release agents that may be included in the first and second control regions 104a, 104b are provided in Section IC3 below. However, in other embodiments, the first and / or second control regions 104a, 104b may be provided without any release agent.

[0064] The configuration (e.g., location and / or geometry) and composition of the control regions 104a, 104b can modulate the release profile of the therapeutic agent from the therapeutic drug region 102. For example, when the depot 100a is implanted at a treatment site, the control regions 104a, 104b can be located between the first and second surfaces 106a, 106b of the therapeutic drug region 102 and the physiological fluids at the treatment site. Thus, the control regions 104a, 104b can reduce or prevent diffusion of fluids toward the first and second surfaces 106a, 106b. In some embodiments, the polymer in the control regions 104a and 104b creates a partially or completely impermeable barrier to infiltration of fluids such that any additional components (e.g., release agents) in the control regions 104a, 104b are sequestered within the polymer and not exposed to the fluid.

[0065] The control regions 104a, 104b can reduce or prevent 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 drug region 102 only when the surface is exposed to a fluid, thus providing a path for the therapeutic agent to diffuse from the therapeutic drug region 102 to the surrounding environment. The control regions 104a, 104b can be configured to block release of all or substantially all of the therapeutic agent from the first and second surfaces 106a, 106b, such 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 drug region 102. For example, at least 80%, 85%, 90%, 95%, 99%, or 100% of the therapeutic agent delivered from the depot 100a may be released through the exterior surface 108, while less than 20%, 15%, 10%, 5%, or 1% of the therapeutic agent delivered from the depot 100a may be released through the first and second surfaces 106a, 106b. In some embodiments, the overall release rate of the therapeutic agent depends at least in part on the distance (e.g., maximum, minimum, and / or average distance) between individual molecules of the therapeutic agent and their nearest exposed surface of the therapeutic agent region 102, also referred to herein as the "travel distance" of the therapeutic agent. For example, therapeutic agent located on the periphery of the depot 100a near the exterior surface 108 may be released more rapidly than therapeutic agent located in the interior of the depot 100a away from the exterior surface 108, thus creating a sustained release profile, as described in more detail below.

[0066] In some embodiments, the control regions 104a, 104b serve other functions as well, such as increasing the mechanical integrity of the depot 100a. For example, the control regions 104a, 104b can have a higher tensile strength and / or fracture resistance than the therapeutic agent region 102. Thus, the presence of the control regions 104a, 104b can improve the handling and storage characteristics of the depot 100a.

[0067] Depot 100a is configured to release therapeutic agents in a highly controlled, predetermined manner that is specifically tailored to the 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 particular application by modifying one or more aspects of the composition and / or structure of the depot, such as any of the following: the geometry (e.g., size and / or shape) of depot 100a, therapeutic agent region 102, and / or control region 104a, 104b; the type of therapeutic agent, polymer, and / or release agent used; and the amount of therapeutic agent, polymer, and / or release agent included in depot 100a (e.g., in therapeutic agent region 102 and / or control region 104a, 104b).

[0068] 1B is a partial schematic diagram of another implantable depot 100b constructed in accordance with an embodiment of the present technology. Depot 100b is generally similar to depot 100a of FIG. 1A, except that depot 100b includes a single control region rather than two control regions. In an illustrative embodiment, depot 100b includes a first control region 104a covering a first surface 106a of depot 100b such that second surface 106b and outer surface 108 are exposed. Alternatively, depot 100b can include a second control region 104b covering a second surface 106b of depot 100b such that first surface 106a and outer surface 108 are exposed. Depot 100b can be used in embodiments where a more rapid release rate is desired (relative to the release rate of depot 100a) and / or where the therapeutic agent is relatively hydrophobic, as described further below.

[0069] Figure 1C is a partial schematic diagram of yet another implantable depot 100c constructed in accordance with an embodiment of the present technology. Depot 100c is generally similar to depot 100a of Figure 1A, except that depot 100c does not include any control regions such that first surface 106a, second surface 106b, and exterior surface 108 are exposed. Depot 100c can be used in embodiments where a more rapid release rate is desired (relative to the release rate of depot 100a or depot 100b) and / or where the therapeutic agent is relatively hydrophobic, as described further below. B. Geometric structure

[0070] 2A-5G show representative examples of depots 200-560 having various geometries configured in accordance with embodiments of the present technology. Features of depots 200-560 may be generally similar to features of depots 100a-100c of FIGS. 1A-1C. Accordingly, similar numbers (e.g., therapeutic drug region 102 and therapeutic drug region 202) are used to identify similar or identical components in FIGS. 1A-5G, and discussion of depots 200-560 of FIGS. 2A-5G is limited to features that differ from depots 100a-100c of FIGS. 1A-1C. Additionally, any of the features of depots 200-560 of FIGS. 2A-5G may be combined with each other and / or with features of depots 100a-100c of FIGS. 1A-1C. Although some embodiments of depots 200-560 in Figures 2A-5G are illustrated as having two control regions (similar to depot 100a in Figure 1A), in other embodiments, any of depots 200-560 may have a single control region (similar to depot 100b in Figure 1B) or no control region (similar to depot 100c in Figure 1C).

[0071] FIG. 2A is a top view of rectangular depot 200, and FIG. 2B is a side view of rectangular depot 200. As best seen in FIG. 2A, depot 200 has a generally rectangular shape with rounded corners. Depot 200 can have a length L1 in the range of 10 mm to 50 mm, 15 mm to 45 mm, 20 mm to 30 mm, or 25 mm to 35 mm. In some embodiments, 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, 40 mm, 42.5 mm, 45 mm, 47.5 mm, or 50 mm. The depot 200 can have a width W1 in the range of 5 mm to 30 mm, 10 mm to 25 mm, 10 mm to 20 mm, or 15 mm to 25 mm. In some embodiments, the width W1 is equal to or greater than 5 mm, 7.5 mm, 10 mm, 11 mm, 12 mm, 12.5 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 17.5 mm, 18 mm, 19 mm, 20 mm, 22.5 mm, 25 mm, 27.5 mm, or 30 mm.

[0072] Referring now to FIG. 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 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1 mm, 1.1 mm, 1.2 mm, 1.25 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.75 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.25 mm, 2.3 mm, 2.4 mm, 2.5 mm m, 2.6 mm, 2.7 mm, 2.75 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, or 5 mm.

[0073] The therapeutic agent region 202 can have a thickness 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 thickness T1 of the depot 200. In some embodiments, the thickness of the therapeutic agent region 202 is within 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 drug region 202 may be 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 910 μm, 920 μm, 930 μm, 940 μm, 950 μm, 960 μm, 970 μm, 980 μm, 990 μm, 1 mm, 1.1 mm, 1.2 mm, 1.25 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.61 mm, 1.62 mm, 1.63 mm, 1.64 mm, 1.65 mm, 1.66 mm, 1.67 mm, 1.68 mm, 1.69 mm, 1.7 mm, 1.75 mm, 1.8 mm, 1.9 mm, 1.91 mm, 1. The size may be equal to or greater than 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.

[0074] In an illustrative embodiment, the control regions 204a, 204b have the same thickness. However, in other embodiments, the control regions 204a, 204b can have different thicknesses (e.g., the first control region 204a can have a thickness greater than the second control region 204b, or vice versa). The control regions 204a, 204b can have respective thicknesses 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, each control region 204a, 204b has a thickness in the range 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 can 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, a thicker control region may be more resistant to breaking, cracking, or other damage during manufacturing, handling, and / or storage, and therefore may result in a more consistent release profile of the therapeutic agent between different lots or batches. However, the control regions 204a, 204b may remain thin enough such that the depot 200 still has a compact size suitable for placement at the treatment site.

[0075] The combined thickness 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 thickness T1 of the depot 200 and / or the thickness of the therapeutic drug region 202. In some embodiments, the ratio of the combined thickness of the control regions 204a, 204b to the thickness of the therapeutic agent region 202 is less than or equal to 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. The combined thickness of the control regions 204a, 204b can 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 the control regions 204a, 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.

[0076] In some embodiments, the volume of the therapeutic drug 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 is at least 100 mm 3 , 150mm 3 , 200mm 3 , 250mm 3 , 300mm 3 , 350mm 3 , 400mm 3 , 450mm 3 , or 500mm 3 The therapeutic drug region 202 has a volume of at least 100 mm 3 , 150mm 3 , 200mm 3 , 250mm 3 , 300mm 3 , 350mm 3 , 400mm 3 , 450mm 3 , or 500mm 3 The control regions 204a, 204b can have a combined volume of 100 mm 3 , 75mm 3 , 50mm 3 , 25mm 3 , 10mm 3 , 9mm 3 , 8mm 3 , 7mm 3 , 6mm 3 , 5mm 3 , 4mm 3 , 3mm 3 , 2mm 3 , or 1 mm 3 It may have the following volumes:

[0077] 2A and 2B together, in some embodiments, the depot 200 includes one or more notches 210 (e.g., cutouts, depressions, indentations, etc.) formed in one or more outer surfaces 212 of the depot 200. The notches 210 may be configured to modulate the release characteristics of the depot 200 by varying the amount of surface area exposed to fluid. Alternatively or in combination, the notches 210 may be configured to accommodate sutures or other fasteners to secure the depot 200 in place at the treatment site. However, in other embodiments, the depot 200 may be provided without any notches 210.

[0078] In an illustrative embodiment, the depot 200 includes four notches 210, one on each of the four outer surfaces 212 of the depot 200. Alternatively, the depot 200 can 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 can include more than one notch 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 can be located on three, two, or a single outer surface 212 of the depot 200). Additionally, although Figures 2A and 2B show each notch 210 as being located at or near the center of the corresponding outer surface 212, in other embodiments, some or all of the notches 210 may be in different locations (e.g., at or near the corners of the depot 200).

[0079] In an illustrative 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 the first control region 204a, the therapeutic agent region 202, and the second control region 204b, to a second surface 214b (e.g., the bottom surface) of the depot 200. Alternatively, some or all of the notches 210 can extend only partially along the thickness T1 of the depot 200 (e.g., notches 210 can be located in the first control region 204a, the second control region 204b, the therapeutic agent region 202, the first control region 204a and the therapeutic agent region 202, the therapeutic agent region 202 and the second control region 204b, etc.).

[0080] The geometry (e.g., size, shape) of the notches 210 can be varied as desired. For example, in the embodiment of FIG. 2A, each of the notches 210 has a semicircular shape. In other embodiments, some or all of the notches 210 can have different shapes, e.g., triangular, square, rectangular, semi-elliptical, or combinations thereof. All or a portion of some or all of the notches 210 can form a curved portion of a corresponding outer surface, and / or all or a portion of some or all of the notches 210 can form a straight portion of a corresponding outer surface. Each notch 210 can have a diameter or width (e.g., maximum width) within a 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 can have a diameter or width 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. In some embodiments, all of the notches 210 have the same size and / or shape. In other embodiments, some or all of the notches 210 can have different sizes and / or shapes.

[0081] The depot 200 can be manufactured in many different ways. In some embodiments, for example, the therapeutic drug region 202 is first formed using a thermocompression process. The thermocompression process can be performed at a temperature above room temperature (e.g., at least 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., or 120° C.) and 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. The control regions 204a, 204b can then be applied to the therapeutic drug region 202 using spray coating, dip coating, solvent casting, laser melting, or other suitable processes known to those of skill in the art. Notches 210 can then be cut into the depots 200 using a blade, laser cutting, ultrasonic cutting, air knife, or other suitable technique. In some embodiments, each depot 200 is individually formed. In other embodiments, the therapeutic drug region 202 and control regions 204a, 204b can be formed as a larger sheet of material that can then be cut into individual depots 200.

[0082] FIG. 3A is a top view of triangular depot 300, and FIG. 3B is a side view of triangular depot 300. As best seen in FIG. 3A, depot 300 has a generally triangular shape with rounded corners. The triangular shape may be advantageous to conform to the shape of certain surgical sites, such as the femoral gutter and / or the suprapatellar capsule of the knee. In an illustrative embodiment, depot 300 is shaped as an equilateral triangle such that all three sides of depot 300 have the same length L2. Length L2 may be within the range of 10 mm to 50 mm, 15 mm to 45 mm, 20 mm to 30 mm, or 25 mm to 35 mm. 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 can have different respective lengths. The depot 300 can 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 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 25 mm, 25.5 mm, 26 mm, 2.65 mm, 27 mm, 27.5 mm, 28 mm, 28.5 mm, 29 mm, 29.5 mm, 30 mm, 30.5 mm, 31 mm, 31.5 mm, 32 mm, 32.5 mm, 33 mm, 33.5 mm, 34 mm, 34.5 mm, or 35 mm.

[0083] 3B, the depot 300 can have a total thickness T2. The values ​​and ranges of thickness T2 of the depot 300, as well as the thicknesses of the therapeutic agent region 302 and the control regions 304a, 304b (and ratios between the various thicknesses) can be the same as or similar to the corresponding values ​​and ranges of the depot 200 of FIGS. 2A and 2B.

[0084] In some embodiments, the volume of the therapeutic agent region 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 regions 304a, 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 The therapeutic drug region 302 has a volume of 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 The control regions 304a, 304b can have a combined volume of 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 1 mm 3 It may have the following volumes:

[0085] As best seen in FIG. 3A, the depot 300 can include pores 316 (e.g., openings, apertures, channels) formed therein. The pores 316 can be configured to modulate the release characteristics of the depot 300, such as by varying the amount of surface area of ​​the therapeutic agent region 302 exposed to fluid. For example, the pores 316 can expose portions of the therapeutic agent region 302 located away from the periphery of the depot 300, thus facilitating infiltration of fluid to and / or release of therapeutic agent from the surface of the therapeutic agent region 302 exposed at the sidewalls of the pores 316. When the depot 300 is implanted, the pores 316 can also facilitate diffusion of therapeutic agent to target tissue located immediately above and / or below the depot 300. However, in other embodiments, the depot 300 can be provided without any pores 316.

[0086] In an illustrative embodiment, the depot 300 includes a single pore 316 at or near the center (e.g., center of gravity) of the depot 300. In other embodiments, the pore 316 may be in different locations of the depot 300. The location of the pore 316 may be selected 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 agent region 302 nearest 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.

[0087] The pores 316 can extend through the entire thickness T2 of the depot 300, for example, from a first surface 314a (e.g., the top surface) of the depot 300, through the first control region 304a, the therapeutic agent region 302, and the second control region 304b, to a second surface 314b (e.g., the bottom surface) of the depot 300. Alternatively, the pores 316 can extend only partially through the thickness T2 of the depot 300 (e.g., the pores 316 can extend only through the first control region 304a, only through the second control region 304b, only through the first control region 304a and the therapeutic agent region 302, only through the therapeutic agent region 302 and the second control region 304b, etc.).

[0088] The geometry (e.g., size, shape) of the holes 316 can be varied as desired. For example, as shown in FIG. 3A, the holes 316 can have a circular shape. In other embodiments, the holes 316 can have different shapes, such as an oval, triangular, square, or rectangular shape, or combinations thereof. The holes 316 can 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 holes 316 can have a diameter or width 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.

[0089] Alternatively or in combination, holes 316 can serve other functions, such as accommodating fasteners (e.g., sutures) for securing depot 300 in place at the treatment site. If desired, the presence of holes 316 can increase the overall flexibility of depot 300, thereby reducing the likelihood of inevitable fracturing during manufacture, storage, and / or handling of depot 300.

[0090] The depot 300 can be manufactured using techniques similar to those described above with respect to the depot 200 of Figures 2A and 2B. For example, the therapeutic agent region 302 can be formed using a thermocompression process, and the control regions 304a, 304b can be applied to the therapeutic agent region 302 using spray coating, dip coating, solvent casting, laser melting, etc. Holes 316 can then be cut into the depot 300 using a blade, laser cutting, ultrasonic cutting, air knife, or suitable techniques known to those of skill in the art.

[0091] 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 may be generally similar to depot 300 of Figures 3A and 3B. For example, the values ​​and ranges of dimensions 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 connection with depot 300. Thus, the discussion of depot 400 will be limited to features that differ from depot 300.

[0092] As best seen in FIG. 4A, the depot 400 includes a number of holes 416a-416d (e.g., openings, apertures, channels) formed therein. The holes 416a-416d can serve the same or similar functions as the holes 316 of the depot 300 of FIGS. 3A and 3B (e.g., modulating the release characteristics of the depot 400, accommodating fasteners for securing the depot 400, and / or increasing the flexibility of the depot 400). In an illustrative embodiment, the depot 400 includes four holes 416a-416d, namely, one hole 416a at the center or center of gravity of the depot 400 and three holes 416b-416d spaced from the central hole 416a and located near the three corners of the depot 400. Alternatively, the depot 400 can include a different number of holes (e.g., two, three, five, or more holes). For example, any of holes 416a-416d can be omitted, for example, depot 400 can include only central hole 416a, only peripheral holes 416b-416d, or can include one or more holes in addition to or as an alternative to holes 416a-416d. Further, any of holes 416a-416d can be located in various portions of depot 400, for example, at or near the ends of depot 400, or randomly distributed in depot 400.

[0093] The use of multiple holes 416a-416d can reduce the average and / or maximum migration distance of a therapeutic agent, for example, as compared to a depot with fewer or no pores (e.g., depot 300 of FIGS. 3A and 3B). In some embodiments, the average and / or maximum migration distance of a 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.

[0094] Each of the pores 416a-416d can extend through the entire thickness T3 of the depot 400, for example, from a first surface 414a (e.g., the top surface) of the depot 400, through the first control region 404a, the therapeutic drug region 402, and the second control region 404b, to a second surface 414b (e.g., the bottom surface) of the depot 400. Alternatively, some or all of the pores 416a-416d can extend only partially through the thickness T3 of the depot 400 (e.g., only through the first control region 404a, only through the second control region 404b, only through the first control region 404a and the therapeutic drug region 402, only through the therapeutic drug region 402 and the second control region 404b, etc.).

[0095] In an illustrative embodiment, each of the holes 416a-416d extends across and exposes a surface of the therapeutic agent region 402 such that the therapeutic agent can elute from the depot through the holes 416a-416d. In other embodiments, a barrier material can be located on the surface of the therapeutic agent region 402 of some or all of the holes 416a-416d to reduce or prevent release of the therapeutic agent from a particular hole or holes. The barrier material can be or include any material that inhibits the diffusion of the therapeutic agent, such as a polymeric layer or coating. For example, the barrier material can be made of the same or similar material as that of the control regions 404a, 404b. The barrier material can be placed only on the central hole 416a, only on the peripheral holes 416b-416d, or any other selected subset of the holes 416a-416d. For example, the barrier material can be placed on holes that are intended to be used for suturing, while holes that are intended to modulate the release profile of the therapeutic agent may not include any barrier agent.

[0096] The geometry (e.g., size, shape) of holes 416a-416d can be varied as desired. For example, as shown in FIG. 4A, holes 416a-416d can each have a circular shape. In other embodiments, some or all of holes 416a-416d can have a different shape, such as an oval, triangular, square, or rectangular shape, or a combination thereof. Holes 416a-416d can each have a diameter or width (e.g., maximum width) within a 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-416d can have a diameter or width 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, 2.25 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-416d have the same size and / or shape. In other embodiments, some or all of holes 416a-416d can have different sizes and / or shapes. For example, center hole 416a can have a different size and / or shape than surrounding holes 416b-416d.

[0097] The depot 400 can be manufactured using techniques similar to those described above with respect to the depot 300 of Figures 3A and 3B. For example, the therapeutic agent region 402 can be formed using a thermocompression process, and the control regions 404a, 404b can be applied to the therapeutic agent region 402 using spray coating, dip coating, solvent casting, laser melting, or the like. Holes 416a-416d can then be cut into the depot 400 using a blade, laser cutting, ultrasonic cutting, air knife, or any suitable technique known to one of skill in the art. In embodiments in which some or all of the holes 416a-416d include a barrier material, the holes can be formed in the therapeutic agent region 402 before the control regions 404a, 404b are applied, such that the material of the control regions 404a, 404b acts as a barrier material. Alternatively, the holes can be formed after the control regions 404a, 404b are applied, with the barrier material applied to the holes in a subsequent processing step.

[0098] As another example, depots 400 may be manufactured by first forming a large sheet or film of therapeutic agent region material. The sheet may then be coated (e.g., spray coated or dip coated) with the control region material. After the coating process, the top, bottom, and outer surfaces of the sheet may all be covered with the control region material. The sheet may then be cut into individual depots. In the resulting depots 400, the therapeutic agent region 402 may be exposed at the outer surface of the cut depot 400, and all other outer surfaces may remain covered with the control region material. Thus, depending on the location of the cut, each depot 400 may include one, two, or three outer surfaces on which the therapeutic agent region 402 is exposed. For example, a depot 400 produced by cutting a square sheet in half along a diagonal may have one outer surface on which the therapeutic agent region 402 is exposed, and two outer surfaces on which the therapeutic agent region 402 is covered.

[0099] Figures 4C-4H show further examples of triangular depots 420-470 configured in accordance with embodiments of the present technology. Features of depots 420-470 in Figures 4C-4H may generally be similar to corresponding features of depot 400 in Figures 4A and 4B. Accordingly, like numbers are used to identify similar or identical components in Figures 4A-4H, and discussion of depots 420-470 is limited to features that differ from depot 400 in Figures 4A and 4B. Additionally, any of the features of depots 420-470 may be combined with each other and / or with features of depot 400 in Figures 4A and 4B.

[0100] 4C is a top view of another triangular depot 420 configured in accordance with an embodiment of the present technology. Depot 420 includes only peripheral holes 416b-416d and no central hole. In other embodiments, depot 420 may include only a subset of holes 416b-416d, e.g., only hole 416b, only holes 416b and 416c, etc.

[0101] FIG. 4D is a top view of yet another triangular depot 430 configured in accordance with an embodiment of the present technology. In an illustrative embodiment, the central hole 416a of the depot 430 has a different geometry than the surrounding holes 416b-416d. For example, as shown in FIG. 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. Additionally, while the central hole 416a is shown as having the same shape as the surrounding holes 416b-416d, the central hole 416a may alternatively have a different shape than some or all of the surrounding holes 416b-416d.

[0102] 4E is a top view of a triangular depot 440 configured in accordance with an embodiment of the present technology. In an illustrative embodiment, depot 440 includes additional holes 416e-416g. For example, as shown in FIG. 4E, depot 440 includes three additional holes 416e-416g, each located near each side of depot 440 (e.g., near the midpoint of each side). In other embodiments, depot 440 can include a different number of additional holes, e.g., some of holes 416e-416g can be omitted and / or depot 440 can include additional holes in other locations. Alternatively or in combination, some or all of holes 416a-416d can be omitted.

[0103] 4F is a top view of another triangular depot 450 configured in accordance with an embodiment of the present technology. In an illustrative embodiment, the depot 450 includes a plurality of holes 416h that are randomly distributed. The holes 416h can each have the same geometry (e.g., size and / or shape), or some or all of the holes 416h can have different geometries. In some embodiments, the holes 416h can be localized in particular portions of the depot 450, such as only near the corners, only near the center, only near the sides, or in any other suitable configuration.

[0104] If desired, the control regions 404a, 404b of the depot 450 can extend across the outer surface (not visible in FIG. 4F) of the depot 450 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 holes 416h. In such embodiments, the depot 450 can include a relatively large number of holes 416h (e.g., tens, hundreds, or thousands of holes 416h) to allow release of the therapeutic agent.

[0105] 4G is a top view of a triangular depot 460 configured in accordance with an embodiment of the present technology. The depot 460 is shaped as an isosceles triangle such that one side (e.g., the base) of the depot 460 has a first length L4 and the other two sides each have a second length L5. In an illustrative embodiment, the second length L5 is greater than the first length L4, e.g., 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 can 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 can 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 20mm, 25mm, 30mm, 32.5mm, 35mm, 37.5mm, 40mm, 41mm, 42mm, 43mm, 44mm, 45mm, 47.5mm, 50mm, 55mm, or 60mm.

[0106] 4H is a top view of a triangular depot 470 configured in accordance with an embodiment of the present technology. The depot 470 is shaped as a right triangle, with a first side of the depot 470 having a first length L A and the second side of the depot 470 has a second length L B and a third side of the depot 470 has a third length L CFor example, the first length L A The second length L may be in the range of 5 mm to 25 mm, 7.5 mm to 22.5 mm, 10 mm to 15 mm, or 12.5 mm to 17.5 mm. B The third length L may be within the range of 8.5 mm to 35 mm, 13 mm to 30 mm, 17.5 mm to 26 mm, or 21.5 mm to 30 mm. C can be in the range of 10 mm to 50 mm, 15 mm to 45 mm, 20 mm to 30 mm, or 25 mm to 35 mm.

[0107] Figures 5A-5G show further examples of depots 500-560 having various geometries. The features of the depots 500-560 of Figures 5A-5G may generally be similar to other depots described herein (e.g., depot 400 of Figures 4A and 4B). Thus, the discussion of depots 500-560 is limited to features that differ from other embodiments of depots described herein. Additionally, any of the features of depots 500-560 may be combined with each other and / or with features of other embodiments described herein.

[0108] 5A is a top view of an arrowhead shaped depot 500 configured in accordance with an embodiment of the present technology. As shown in FIG. 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 chevron shape. This geometry can facilitate insertion of the depot 500 into a treatment site. For example, a surgeon can orient the apex 504 of the depot 500 toward the treatment site and then apply force to the end 502 of the depot 500 to press the depot 500 against the site. Although depot 500 is illustrated as including four holes 506a-506d configured similarly to holes 416a-416d in Figures 4A and 4B (e.g., including a central hole 506a and three peripheral holes 506b-506d near the corners of depot 500), the holes in depot 500 may instead be configured according to any of the other embodiments described herein or may be omitted entirely.

[0109] 5B is a top view of a diamond shaped depot 510 configured in accordance with an embodiment of the present technology. As shown in FIG. 5B, the depot 510 includes two corners 512a, 512b having a smaller angle (e.g., an angle equal to or less than 90°, 80°, 70°, 60°, 50°, 45°, 40°, 35°, 30°, 25°, 20°, 15°, or 10°) and two corners 512c, 512d having a larger angle (e.g., an angle 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 as having four sides of equal length, in other embodiments, some of the sides of the depot 510 can have different lengths (e.g., the two upper sides can be longer or shorter than the two lower sides). The depot 510 can have a height H6 in the range of 10 mm to 70 mm, 20 mm to 60 mm, 30 mm to 50 mm, 35 mm to 45 mm, or 40 mm to 45 mm. The depot 510 can have a width W6 in the range of 5 mm to 50 mm, 10 mm to 30 mm, 15 mm to 25 mm, or 20 mm to 25 mm.

[0110] In the illustrative 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 vary, e.g., the depot 510 can include fewer or more holes 514a-514d, the holes 514a-514d can be in different locations, etc. (e.g., at or near the center of the depot 510). The geometry (e.g., shape, size) and function of the holes 514a-514d 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 514a-514d can be omitted entirely.

[0111] 5C is a top view of a rectangular depot 520 configured in accordance with an embodiment of the present technology. The depot 520 can have a length L7 in the range of 10 mm to 50 mm, 20 mm to 40 mm, 25 mm to 35 mm, or 30 mm to 35 mm. The depot 520 can have a width W7 in the range of 5 mm to 25 mm, 10 mm to 20 mm, 10 mm to 15 mm, or 15 mm to 20 mm. In an illustrative embodiment, the depot 520 includes four holes 522a-522d evenly spaced along a central longitudinal axis of the depot 520. However, in other embodiments, the depot 520 can include fewer or more holes 522a-522d. Additionally, holes 522a-522d can be arranged differently, e.g., the spacing between holes 522a-522d can vary, holes 522a-522d can be spaced along a central horizontal axis of depot 520, holes 522a-522d can be located near the four corners of depot 520, etc. The geometry (e.g., shape, size) and function of holes 522a-522d can be the same as or similar to holes 416a-416d of Figures 4A and 4B. If desired, some or all of holes 522a-522d can be omitted entirely.

[0112] 5D is a top view of a cruciform depot 530 configured in accordance with an embodiment of the present technology. As shown in FIG. 5D, the depot 530 includes four arms 532a-532d extending from a central body 534. The depot 530 can be thought of as equivalent to a square with four cutouts 536a-536d on the four sides of the square. In an illustrative embodiment, all four sides of the depot 530 have the same length L8, for example, in the range of 10 mm to 40 mm, 15 mm to 35 mm, 20 mm to 30 mm, 20 mm to 25 mm, or 25 mm to 30 mm. In other embodiments, some of the sides of the depot 530 can have different lengths, for example, the horizontal sides can have a greater or lesser length than the vertical sides.

[0113] The geometry of cutouts 536a-536d can be varied as desired. In an illustrative embodiment, for example, cutouts 536a-536d each have a semicircular shape. However, in other embodiments, some or all of cutouts 536a-536d can have a different shape, for example, a square, rectangular, triangular, semi-oval, or other shape. Cutouts 536a-536d can each independently have any suitable size, for example, a diameter D8 or width within the range of 1 mm to 20 mm, 5 mm to 15 mm, or 8 mm to 12 mm.

[0114] In the illustrative 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 vary, e.g., the depot 530 can include fewer or more holes 538a-538d, the holes 538a-538d can be in different locations (e.g., at or near the center of the depot 530), etc. The geometry (e.g., shape, size) and function of the holes 538a-538d 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 538a-538d can be omitted entirely.

[0115] FIG. 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 an illustrative embodiment, the first and second elongated arms 542 are generally rectangular in construction 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. Width W9 can be in the range of 1 mm to 20 mm, 5 mm to 15 mm, 5 mm to 10 mm, or 10 mm to 15 mm. In other embodiments, first elongate arm 542 can have a different (e.g., longer or shorter) length and / or width than second elongate arm 544.

[0116] In the illustrative embodiment, the depot 540 includes three holes 546a-546c: one hole 546a located near the end of the first elongate arm 542, one hole 546b located near the end of the second elongate arm 544, and one hole 546c located near the junction between the first and second elongate arms 542, 544. In other embodiments, the number and location of holes 546a-546c can vary, e.g., depot 540 can include fewer or more holes 546a-546c, holes 546a-546c can be in different locations, etc. (e.g., spaced apart along the length of first elongate arm 542 and / or second elongate arm 544). The geometry (e.g., shape, size) and function of holes 546a-546c can be the same as or similar to holes 416a-416d of FIGS. 4A and 4B. If desired, some or all of holes 546a-546c can be omitted entirely.

[0117] 5F is a top view of a circular depot 550. Depot 550 has a diameter OD in 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, depot 550 can include a central hole 552. Hole 552 can increase the release rate of a therapeutic agent by increasing the surface area of ​​depot 550 exposed to physiological fluids and / or reducing the distance the therapeutic agent must travel to reach the exposed surface. In some embodiments, hole 552 has a diameter ID in 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 10may 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 the depot 550 may be 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 910 μm, 920 μm, 930 μm, 940 μm, 950 μm, 960 μm, 970 μm, 980 μm, 990 μm, 1 mm, 1.1 mm, 1.2 mm, 1.25 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.61 mm, 1.62 mm, 1.63 mm, 1.64 mm, 1.65 mm, 1.66 mm, 1.67 mm, 1.68 mm, 1.69 mm, 1.7 mm, 1.75 mm, 1.8 mm, 1.9 mm, 1.91 mm, 1.9 The size may be equal to or greater than 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 5mm.

[0118] 5G illustrates a depot 560 constructed in accordance with an embodiment of the present technology. The depot 560 has a body 562 having a spherical shape. The spherical shape increases the mechanical strength of the depot 560 and can be advantageous for packing into irregularly shaped spaces within a patient's body. The diameter D of the body 560 is 1.2 mm. 11In some embodiments, the diameter D may 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. 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 uniformly spaced along the circumference of the outer surface of the depot 560. In some embodiments, the holes 566 are aligned only in certain portions of the body 562, such as only in one hemisphere, only in certain quadrants, 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 uniformly 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 may be spaced apart from the diameter D of the body 562. 11 (e.g., hole 567 and hole 568). In such embodiments, the holes may have an opening in the surface of body 562 and may terminate at another opening in the surface of body 562 (e.g., hole 568) or may terminate within body 562 (e.g., hole 567). Additionally or alternatively, one, some, or all of holes 566 may be spaced apart from the diameter D of body 562. 11 (e.g., hole 569), such that the hole extends between two openings in diametrically opposed surfaces of body 562. In some embodiments, at least one hole has a depth equal to the diameter D of body 562. 11 and at least another hole has a diameter D of the body 562. 11 has a depth equivalent to

[0119] In some embodiments, the depots of the present technology are configured to be cut, broken, or otherwise divided into smaller pieces prior to use. For example, a depot shaped as an equilateral triangle (e.g., depot 300 in FIG. 3A) can be designed to be fractured into two smaller right triangles (e.g., similar to depot 470 in FIG. 4H). In such embodiments, the depot can include perforations, grooves, narrowings, etc. that define separation locations that facilitate controlled fracturing of the depot. This approach can make fracturing the depot easier while avoiding undesirable cracking of the controlled areas. Alternatively or in combination, a template can be provided to serve as a guide while simultaneously cutting the depot into smaller pieces (e.g., with a blade). C. Composition

[0120] The depots of the present technology (e.g., depots 100a-560 of Figures 1A-5G) can have a composition configured to provide a desired release profile of a therapeutic agent. As previously discussed, the depots described herein can include a therapeutic agent as well as one or more additional components, e.g., a polymer and / or a release agent. Each of these components is described in more detail below. 1. Therapeutic Agents

[0121] The therapeutic agent carried by the depots of the present technology (e.g., depots 100a-560 of Figures 1A-5G) can be any biologically active substance (or combination of substances) that provides a therapeutic benefit to a patient in need thereof. As used herein, "therapeutic agent" or "drug" can refer to a single therapeutic agent or can refer to a combination of therapeutic agents. In some embodiments, the therapeutic agent includes only a single therapeutic agent. In other embodiments, the therapeutic agent can include two or more therapeutic agents for simultaneous or sequential release.

[0122] In some embodiments, the therapeutic agent is or includes an analgesic. The term "analgesic" or "analgesic drug" includes one or more local or systemic agents administered to generally reduce, prevent, alleviate, or eliminate pain. Analgesics may include systemic and / or local anesthetics, narcotics, and / or anti-inflammatory agents. Analgesics may include pharmacologically active drugs or pharma- ceutically 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, carticaine, articaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, dexamethasone, tetrodotoxin, saxitoxin, neosaxitoxin, capsaicin, and combinations thereof.

[0123] 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 nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamic acid, mefenamic acid, and other COX-2 inhibitors, and combinations thereof.

[0124] In some embodiments, the therapeutic agent is or includes an antibiotic, antibacterial or antifungal agent, or a combination thereof. For example, suitable antibiotics and antibacterial agents include, but are not limited to, amoxicillin, amoxicillin / clavulanic acid, 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, antibacterial peptides, cecropin-mellitin, magainin, dermaseptin, cathelicidin, alpha-defensins, and alpha-protegrin. Antifungal agents include, but are not limited to, ketoconazole, clotrimazole, miconazole, econazole, intraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, voriconazole, terbinafine, amorolfine, naftifine, griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafine, and amphotericin B.

[0125] In some embodiments, the therapeutic agent is an adrenocorticostatic, a beta-antiadrenergic, an androgen or antiandrogenic, an antianemic, an anthelmintic, an anabolic, an anesthetic or analgesic, a stimulant, an antiallergic, an antiarrhythmic, an antiarteriosclerotic, an antibiotic, an antidiabetic, an antifibrinolytic, an anticonvulsant, an angiogenesis inhibitor, an anticholinergic, an enzyme, coenzyme or corresponding inhibitor, an antihistamine, an antihypertensive, an antihypotensive, an anticoagulant, an antifungal, an antiseptic, an antiinfective, an antihemorrhagic, a beta-receptor antagonist, a calcium channel antagonist, an antimyasthenic, an antiinflammatory, an antipyretic, an antirheumatic. , a cardiac inotropic agent, a chemotherapeutic agent, a coronary vasodilator, a cytostatic agent, a glucocorticoid, a hemostatic agent, an immunoglobulin or fragment thereof, a chemokine, a cytokine, a mitogen, a cell differentiation factor, a cytotoxic agent, a hormone, an immunosuppressant, an immunostimulant, a morphine antagonist, a muscle relaxant, a narcotic, a vector, a peptide, a (para)sympathicomimetic agent, a (para)sympatholytic agent, a protein, a cell, a selective estrogen receptor modulator (SERM), a sedative, an antispasmodic agent, a substance that inhibits bone resorption, a vasoconstrictor or vasodilator, a virustatic, or a wound healing agent. In some embodiments, the therapeutic agent may include a hemostatic agent (e.g., aluminum sulfate, fibrin, micronized gelfoam, etc.), which may be particularly beneficial when the depot is implanted in areas with high blood flow and potentially above average post-operative bleeding (e.g., chest, abdomen, anorectum, head and neck, etc.).

[0126] In some embodiments, the therapeutic agent is or comprises a drug or its pharmacologic acceptable salt used in the treatment of cancer.Such chemotherapeutic agents include antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavage agents, DNA crosslinking agents, DNA intercalating agents, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizing agents, 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, ansamitocin P3, auristatins, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribine, cytarabin, cryptophycin, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, cefotaxime ... These include, but are not limited to, nibs, gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferon, interleukin, beta-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, vindesine, and tamoxifen.

[0127] In some embodiments, the therapeutic agent is or includes a botulinum toxin or other neurotoxin used to treat various neuromuscular and / or neuroglandular disorders and neuropathy associated with pain. The botulinum toxin or other neurotoxin may include a pharmacologically active drug or a pharmaceutically acceptable salt thereof. The botulinum toxin may be selected from various strains of Clostridium botulinum and may include a pharmacologically active drug or a pharmaceutically acceptable salt thereof. In some embodiments, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G.

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

[0129] A pharma- ceutically acceptable salt may contain another molecule, such as water or another biologically compatible solvent (solvate), an acetate ion, a succinate ion, or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge of the parent compound. Optionally, a pharma- ceutically acceptable salt may contain multiple counter ions.

[0130] The therapeutic agent or its pharma- ceutically acceptable salt may be an essentially pure compound or may be formulated with a pharma- ceutical 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 of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. For example, diluents may include lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycine, and the like.

[0131] The therapeutic agent or pharma- ceutically acceptable salt form can be micronized, jet milled, or passed through a sieve to form a consistent particle size, which can further facilitate 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 (e.g., DS50 value) of the therapeutic agent is equal to or smaller 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.

[0132] Suitable dosage ranges utilizing the depot of the present technology will depend on the potency of the particular therapeutic agent, but may be in the range of about 0.001 mg to about 500 mg of drug per kilogram of body weight, for example, in the range of about 0.1 mg to about 200 mg of drug per kilogram of body weight, or in the range of about 1 to about 100 mg per kg of body weight. Dosage ranges can be readily determined by methods known to those of skill in the art. Unit dosage forms can contain between about 1 mg to about 500 mg of active ingredient.

[0133] In some embodiments, the therapeutic agent comprises 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 (also referred to herein as the "mass percent" or "weight percent" of the therapeutic agent in the depot). The mass percent of the therapeutic agent in the depot can be in the range of 25%-75%, 40%-80%, 50%-65%, or 60%-65%. In some embodiments, the therapeutic agent comprises 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 agent region. The mass percentage of the therapeutic agent in the therapeutic agent region can be in the range of 25%-75%, 40%-80%, 50%-65%, or 60%-65% of the total mass of the therapeutic agent region.

[0134] 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.

[0135] The total mass of therapeutic agent in the depot can be in the range of 100 mg to 1800 mg, 100 mg to 1500 mg, 100 mg to 1000 mg, 200 mg to 800 mg, 300 mg to 600 mg, 500 mg to 700 mg, 540 mg to 660 mg, or 570 mg to 630 mg. In some embodiments, the total mass of therapeutic agent in an individual depot can be in the range of 25 mg, 50 mg, 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, 640 mg, 660 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1000 mg, 1000 mg, 1000 mg, mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, 1600mg, 1700mg, or 1800mg.

[0136] The properties of the therapeutic agent can be selected to provide a desired release profile in vivo. For example, the therapeutic agent can be sufficiently hydrophobic to elute from the depot in a controlled and sustained manner at the treatment site in vivo when exposed to physiological fluids, even if the depot includes fewer control regions (e.g., depot 100b in FIG. 1B) or no control regions (e.g., depot 100c in FIG. 1C). In some embodiments, the therapeutic agent has multiple forms with different degrees of hydrophobicity, e.g., at least one hydrophobic form and at least one hydrophilic form. For example, the therapeutic agent can be or include an amine compound having a hydrophobic free base form and a hydrophilic salt form. The amine compound can be an amine-containing analgesic, such as an aminoamide local anesthetic (e.g., bupivacaine, ropivacaine, lidocaine, mepivacaine, prilocaine, etidocaine, levobupivacaine, trimecaine, articaine) or an aminoester local anesthetic (e.g., benzocaine, procaine, tetracaine, chloroprocaine). The amine-containing analgesic can have a free base form (e.g., bupivacaine free base) in which the amine group is deprotonated, and a salt form (e.g., bupivacaine hydrochloride, bupivacaine hydrochloride monohydrate) in which the amine is protonated and associated with a counterion (e.g., chloride, bromide, sulfate, phosphate, nitrate, acetate, oxalate, citrate, tartrate). As another example, the hydrophobic form can be the salt form of the therapeutic agent using a relatively hydrophobic salt (e.g., palmitate salt rather than chloride salt). The amine-containing analgesics can contain salt forms of various counterion combinations that alter the hydrophobicity and dissolution rate of the amine-containing analgesic.

[0137] The therapeutic agent in the implantable depot may be provided partially or entirely in hydrophobic (e.g., free base) form. For example, 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 by mass may be present in hydrophobic form. Alternatively or in combination, no more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 40%, 30%, or 20% of the therapeutic agent by mass may be present in hydrophobic form. Optionally, the implantable depot may include a combination of 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 form can produce a slower release rate, while increasing the relative amount of hydrophilic form can produce a more rapid release rate, in some embodiments, the ratio of the total mass of hydrophobic form to the total mass of hydrophilic form 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.

[0138] The use of hydrophobic forms of therapeutic agents can provide various benefits. For example, when hydrophobic forms are used, the depot can be fabricated with fewer or even no control regions, thus simplifying the manufacturing process and / or reducing the possibility of unavoidable uncontrolled release due to manufacturing defects in the control regions. This approach can also increase the amount of therapeutic agent that can be loaded into a single depot and / or reduce the depot size. Additionally, when hydrophobic forms of therapeutic agents are used in combination with control regions, the release duration of the therapeutic agent can be even further extended, thus allowing controlled release over extended periods that would otherwise be difficult or impossible with conventional systems. Furthermore, hydrophobic forms can exhibit a different melting point (e.g., lower melting point) and / or a different solubility (e.g., improved solubility in organic solvents) than hydrophilic forms. This can make the depot easier to manufacture and / or allow for additional manufacturing options, compared to depots formulated primarily or entirely from hydrophilic forms.

[0139] In some embodiments, the implantable depot is configured to release multiple therapeutic agents in a simultaneous or sequential manner, for example, to provide additional clinical benefits. For example, in a pain management situation, the depot can release a first analgesic agent (e.g., lidocaine) with a more rapid onset and a second analgesic agent (e.g., bupivacaine) with a slower onset. As another example, the depot can release a first therapeutic agent having a first type of therapeutic effect (e.g., an 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 the surrounding environment). The second therapeutic agent can enhance the effectiveness of the first therapeutic agent or can independently provide a therapeutic benefit to the patient. The implantable depots described herein can include any suitable number of therapeutic agents, for example, one, two, three, four, five, or more different therapeutic agents. 2. Polymers

[0140] The depots of the present technology (e.g., depots 100a-560 of Figures 1A-5G) may be made from one or more polymers. In some embodiments, the therapeutic agent region and the control region of the depot each comprise a polymer (or combination of polymers), which may be the same or different amounts, concentrations, and / or mass percentages of the same or different polymers (or combinations of polymers). In some embodiments, the control region comprises a polymer and the therapeutic agent region does not comprise a polymer. In some embodiments, the therapeutic agent region comprises a polymer and the control region does not comprise a polymer.

[0141] In some embodiments, the polymer(s) used in the depot of the present technology are bioresorbable polymers. The bioresorbable polymers used in the present technology can have a predetermined degradation rate. The term "bioresorbable" or "bioresorbable" can mean that the polymer is absorbed into the patient's body, for example, by cells or tissues. These polymers can be "biodegradable" in that all or a portion of the polymer breaks down over time by enzymatic action, by hydrolytic action, and / or other similar mechanisms in the patient's body. In some embodiments, the therapeutic agent is released as the bioresorbable polymer breaks down or degrades into non-toxic components in the body. The bioresorbable polymers used as the basic components of the depot of the present technology can break down or degrade after the therapeutic agent is completely released. The bioresorbable polymers can also be "bioerodible" in that they erode or degrade over time due at least in part to contact with substances found in the surrounding tissues, fluids, or by cellular action.

[0142] Suitable polymers for use in the depots of the present technology include polyglycolide (PGA), polylactide (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-glycolide) (PLGA) (e.g., poly(L-lactide-co-glycolide), 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), polyhydroxyalkanoates (PHA) ), polyhydroxybutyrate (PHB) (e.g., poly(4-hydroxybutyrate)), poly(phosphazenes) (e.g., ethyl glycinate poly(phosphazenes)), poly(phosphate esters), poly(amino acids), poly(depsipeptides), poly(butylene succinate) (PBS), poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), poly(ethylene glycol) (PEG), poloxamers (e.g., PEO-PPO-PEO), PEO-PPO-poly(acrylic acid) copolymers (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(methoxy ... ethyl 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 polycarbonates, poly(1,3-bis-(p-carboxyphenoxy)hexane-co-sebacic acid), poly(caprolactone co-butyl acrylate), copolymers of maleic anhydride, cellulose or cellulose derivatives (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose or salts thereof), copolymers of poly(ethylene glycol terephthalate) and poly(butylene terephthalate) (PEGT-PBT) (e.g., PolyActive), polysaccharides (e.g., hyaluronic acid, chitosan, starch, pregelatinized starch, alginates, dextran), sucrose acetate isobutyrate (SAIB), poly(aspirin), polymers incorporating 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.

[0143] If necessary, the polymers described herein can be modified to include functional side groups or side chains. For example, the polymers can be grafted, crosslinked, or otherwise covalently bonded with hydrophilic side chains, such as PEG. This approach can be advantageous to ensure consistent controlled release of therapeutic agents. In some situations, when therapeutic agents are eluted from the therapeutic agent region, voids or spaces in the polymer that were previously occupied by the therapeutic agent can collapse to form partially or completely impermeable polymer regions. If the collapse occurs near the portions of the therapeutic agent region that are contacted with physiological fluids, this can create a barrier that partially or completely inhibits further elution of therapeutic agents from those locations. However, polymers that include hydrophilic side chains can swell when exposed to fluids, thus reducing the likelihood of collapse and allowing for continued release of therapeutic agents.

[0144] 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, which in turn can change the release rate of the therapeutic agent. A more hydrophilic polymer (e.g., PLGA with a higher glycolic acid content, a polymer with PEG covalently incorporated into the polymer backbone) can produce a higher release rate than a more hydrophobic polymer. In some embodiments, different end groups of the polymer can be selected to affect the hydrophilicity of the polymer. For example, a polymer with an acid end group can be more hydrophilic than a polymer with an ester end group.

[0145] In some embodiments, the weight percent of polymer in the depot is less than or equal to 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. The weight percent of polymer in the depot can be in the range of 10%-60%, 20%-50%, 25%-40%, or 30%-35%. In some embodiments, the weight percent of polymer in the therapeutic agent region is less than or equal to 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. The weight percent of polymer in the therapeutic drug region may be in the range of 10%-60%, 20%-50%, 25%-40%, or 30%-35%. In some embodiments, the weight percent of polymer in each control region is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. The weight percent of polymer in the control region may be in the range of 25%-75%, 40%-80%, 50%-65%, 60%-65%, 50%-75%, or 75%-100%.

[0146] The total mass of 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 polymer is less than or equal to 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.

[0147] In some embodiments, the ratio of the mass of therapeutic agent in the depot to the mass of polymer in the depot is at least 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, or 16:1. In some embodiments, the ratio of the mass of polymer in the therapeutic agent region to the mass of therapeutic agent in the therapeutic agent region is no more than 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.

[0148] In some embodiments, the polymers disclosed herein are configured to degrade at a rate slow enough that the depot maintains sufficient bending 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, only partially or gradually decreasing due to elution of the therapeutic agent or dissolution of the control region or release agent. A depot can be considered to lose its structural integrity if it separates (e.g., breaks down) into multi-component pieces, for example, when two or more of the resulting pieces are at least 5% of the previous size of the depot. Alternatively or additionally, a depot can be considered to lose its structural integrity if the release rate of the therapeutic agent increases by more than three-fold compared to the release rate of the therapeutic agent in a control depot submerged in a buffer solution. In some embodiments, the molecular weight of the polymer can be selected to account for the loss of molecular weight that occurs during the manufacturing process, such that the molecular weight after manufacturing remains greater than the minimum weight necessary to achieve the desired sustained release profile.

[0149] In some embodiments, the depot is configured to maintain its structural integrity in vivo for 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 therapeutic agent in the depot has been released. 3. Release agent

[0150] Depots of the present technology (e.g., depots 100a-560 of Figures 1A-5G) can optionally include one or more release agents. In some embodiments, the therapeutic agent region and the control region each include a release agent (or combination of release agents), which can be the same or different amounts, concentrations, and / or mass percentages of the same or different release agents (or combinations of release agents). 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.

[0151] 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 glycols (e.g., PEG 3000, PEG 6000, PEG 10,000, etc.), polyvinyl alcohol, sorbitan fatty acid esters (e.g., sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), sorbitan trioleate (Span 85), sorbitan monooleate (Span 86), sorbitan tert-butyl ether (Span 87), sorbitan tert-butyl ether (Span 88), sorbitan tert-butyl ether (Span 89), sorbitan tert-butyl ether (Span 90), sorbitan tert-butyl ether (Span 91), sorbitan tert-butyl ether (Span 92), sorbitan tert-butyl ether (Span 93), sorbitan tert-butyl ether (Span 94), sorbitan tert-butyl ether (Span 95), sorbitan tert-butyl ether (Span 96), sorbitan tert-butyl ether (Span 97), sorbitan tert-butyl ether (Span 98), sorbitan tert-butyl ether (Span 9 ...5), sorbitan tert-butyl ether (Span 96), sorbitan tert-butyl ether (Span 97), sorbit 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 40 castor oil, Cremophor® RH 60, Cremophor® RH 40), 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 Included are D-alpha-tocopherol polyethylene glycol succinate (vitamin E-TPGS), saturated polyglycolized glycerides (e.g., Gelucire® 44 / 14, Gelucire® 50 / 13), polypropoxylated stearyl alcohols (e.g., Acconon® MC-8, Acconon® CC-6), or derivatives or combinations thereof.

[0152] 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 can be in the range of 0.1%-20%, 0.5%-10%, or 1%-5%. In some embodiments, the mass percentage of the release agent in the therapeutic agent region 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 drug region can be in the range of 0.1%-20%, 0.5%-10%, or 1%-5%. In some embodiments, the mass percentage of the release agent in each control region 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 region can be in the range of 0.1%-20%, 0.5%-10%, 1%-5%, 10%-50%, 20%-40%, or 30%-35%.

[0153] The total mass of the release agent in the depot can 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 less than or equal to 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.

[0154] In some embodiments, the ratio of the mass of the release agent to the mass of polymer in the therapeutic agent region 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 agent 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 agent region may not include any release agent.

[0155] In some embodiments, the ratio of mass of release agent to mass of polymer in each controlled 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 controlled regions may not include any release agent. II. Release Profile and Pharmacokinetics

[0156] The depots of the present technology (e.g., depots 100a-560 of Figures 1A-5G) can be configured to deliver a therapeutic agent according to a desired release profile. As described elsewhere herein, the release profile of the depot can be controlled by adjusting the geometry and / or composition of the depot. The release profile can provide for a sustained, continuous release of the therapeutic agent over a desired treatment period or duration (e.g., the period after the depot is implanted in the body and / or immersed in a fluid). The treatment period can 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. 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., mass) of therapeutic agent in the depot over the treatment period.

[0157] The release profile of the depot can be measured using in vitro or in vivo techniques. Any description herein of the release profile of the depot can refer to in vitro release, in vivo release, or both, unless otherwise specified. The release profile of the depot can be measured in vitro by immersing the depot in a suitable dissolution medium (e.g., phosphate buffered saline) at 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 dissolution can 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 dissolution can be selected based on other considerations. For example, an accelerated in vitro release process can be developed to facilitate, for example, quality control testing, when the product proceeds to development or manufacturing. Accelerated in vitro release can be achieved through temperature increase, addition of surfactants or organic co-solvents to the aqueous buffer, and / or change in pH. For example, the accelerated in vitro release can be measured at pH 5.8.

[0158] The release profile of the depot can be measured in vivo by implanting the depot at a treatment site in a subject (e.g., an animal or human subject), collecting local and / or systemic samples (e.g., blood samples, plasma samples, 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). Optionally, the release profile of the depot can be measured by measuring the total area under the curve (AUC 0~inf ) is assumed to correspond to 100% release of the total therapeutic dose in the depot, and then the AUC 0~t1 vs. AUC 0~infA cumulative in vivo release profile can be estimated from the concentration data by calculating the cumulative release percentage of therapeutic agent at each study time point t1 from the ratio of t1 / t2 / t1. 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 immersed in an extraction medium (e.g., 5:3 v / v acetonitrile:methanol) to dissolve the depot and release any remaining therapeutic agent. The extraction medium can be allowed to evaporate completely and the therapeutic agent can be reconstituted using a suitable solvent (e.g., methanol). The reconstituted samples can be analyzed via high performance liquid chromatography (HPLC) to measure the amount of therapeutic agent in the samples.

[0159] In some embodiments, the depot herein is configured to release therapeutic agent at different rates over a treatment period.For example, the depot herein can release therapeutic agent at a first rate during a first treatment period, and then at a second rate during a second treatment period.For example, the first period can 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 can 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 of time can be the first 1 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 can be 1 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 after the first period of treatment. The first rate can be the same as the second rate or can be different (e.g., smaller or larger than the second rate). In some embodiments, the first rate is at least 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times the second rate, or vice versa.

[0160] In some embodiments, the depot releases a first amount of therapeutic agent over a first period of time and a second amount of therapeutic agent over a second period of time. The first amount can be at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% of the initial amount of therapeutic agent in the depot (e.g., by mass), and / or the first amount can be no more than 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30% or 25% of the initial amount of 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 therapeutic agent in the depot, and / or the second amount may be no more than 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the initial amount of therapeutic agent in the depot. Optionally, the depot can release a third amount of therapeutic agent over a third period of time after the second period of time. The third amount may be at least 1%, 2%, 5%, 10%, 15%, 20%, 25% or 30% of the initial amount of therapeutic agent in the depot, and / or the third amount may be no more than 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5% of the initial amount of therapeutic agent in the depot.

[0161] For example, the depot may exhibit the following release profiles when measured in vitro at pH 5.8: the depot may release 10%-35% of the therapeutic agent over the first 5-10 hours of the treatment period, the depot may release 5%-65% of the therapeutic agent over the next 25-35 hours of the treatment period, and / or the depot may release 1%-60% of the therapeutic agent over the next 115-130 hours of the treatment period.

[0162] 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 within 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 within 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.

[0163] In some embodiments, the depot exhibits the following release profiles 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. 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 hours, and at least 50% of the therapeutic agent in the depot is released within the first 10, 11, 12, 13, 14, 14.5, 15, 15.5, 16, or 24 hours of the treatment period. , 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours or 20 hours, and at least 60% of the therapeutic agent in the depot is released during the first 15 hours, 20 hours, 21 hours, 22 hours, 22.5 hours, 23 hours, 23.5 hours, 24 hours, 24.5 hours, 25 hours, 25.5 hours, 26 hours, 26.5 hours, 27 hours or 28 hours of the treatment period.5, 28, 29 or 30 hours, at least 70% 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, 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.

[0164] In some embodiments, the depot exhibits the following release profiles 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 within the range of 1%-25%, 1%-10%, or 1%-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 within the range of 1%-30%, 5%-20%, or 5%-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 within the range of 10%-35%, 10%-25%, or 15%-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 within the range of 15%-50%, 10%-40%, or 10%-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 within the range of 1%-25%, 1%-30%, or 1%-40%, or 1%-50%, of the initial amount of therapeutic agent in the depot. the cumulative amount of 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 therapeutic agent in the depot; the cumulative amount of 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 therapeutic agent in the depot; the cumulative amount of 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 therapeutic agent in the depot; and / or the cumulative amount of 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 therapeutic agent in the depot.

[0165] 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, 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, and up to 10% 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 therapeutic agent is released over the first 7, 8, 9 or 10 days of the treatment period, up to 60% of the therapeutic agent in the depot is released over the first 10, 11, 12 or 13 days of the treatment period, up to 70% of the therapeutic agent in the depot is released over the first 13, 14, 15 or 16 days of the treatment period, up to 80% of the therapeutic 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 therapeutic agent in the depot is released over the first 19, 20, 21 or 22 days of the treatment period.

[0166] In some embodiments, the release profile of the therapeutic agent is a first order release profile (which can be represented by the equation

number

[0167] The depots described herein can be configured to release a greater amount of therapeutic agent per day over a first period of time than over a second, longer period of time. In some embodiments, the depots are configured to release therapeutic agent for at least 14 days after implantation (or immersion in a fluid), where a controlled burst of about 20% to about 50% of the therapeutic agent payload is released over the first 3 to 5 days, with at least 80% of the remaining therapeutic agent payload being released at a slower rate over the final 10 to 11 days. In some embodiments, at least 90% of the therapeutic agent payload is released by the end of the 14 days.

[0168] A two-phase release profile may be particularly advantageous in the context of treating pain resulting from total knee arthroplasty ("TKA"). TKA patients typically experience the greatest pain within the first 1-3 days after surgery (clinically referred to as "acute pain"), which gradually decreases over the next 7-10 days (clinically referred to as "subacute pain"). The acute period often overlaps or coincides with the patient's inpatient care (usually 1-3 days), and the subacute period generally begins when the patient is discharged and returns home. A two-phase release profile may also be beneficial in other surgical applications, such as other orthopedic applications (e.g., ligament repair / replacement and other injuries to the knee, shoulder, ankle, etc.) or non-orthopedic surgical applications, as described in more detail below. Excessive pain after any surgical procedure can prolong inpatient care, cause psychological distress, increase opioid consumption, and / or impair patient engagement in physical therapy, all of which can prolong and / or reduce the extent of patient recovery. Pain relief during the subacute period can be particularly complex to manage as patients transition from the inpatient to the home environment, with poor patient compliance with prescribed pain management regimens.

[0169] To address the aforementioned challenges in post-surgical pain management, the depot of the present technology can have release profiles tailored to meet the unique pain management needs of the acute and subacute periods. For example, to address the greater acute pain that is present immediately following surgery, the depot can be configured to release the therapeutic agent at a more rapid rate over the first 3-5 days after implantation compared to the subsequent 9-11 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 the diminishing pain during the subacute period, the depot can be configured to release the therapeutic agent at a slower rate over the remaining 9-11 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 is continually diminished throughout the first period and / or the second period.

[0170] The release profile of the depot can be tailored to release the therapeutic agent for 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 the entire release duration. In some embodiments, the depot will release the therapeutic agent at a constant rate for a first period of time and at a non-constant rate for a second period of time (which may occur before or after the first period of time).

[0171] In some embodiments, the depot is configured to release no more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% of the therapeutic agent over the first 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, or 13 days of the release duration, with at least 75%, 80%, 85%, 90%, 95%, or 100% of the remaining therapeutic agent being released over the remaining days of the release duration. The intended duration of release can be 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, or 30 days.

[0172] In some embodiments, the depot is configured to release 50 mg / day to 600 mg / day, 100 mg / day to 500 mg / day, 100 mg / day to 400 mg / day, or about 100 mg / day to 300 mg / day of therapeutic agent to the treatment site. In general, the release rate can be selected to deliver a desired dosage to provide the degree of pain relief required at a given time after the surgical procedure, control toxicity, and deliver the therapeutic agent for a period of time sufficient 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 therapeutic agent within any number of days of release duration.

[0173] In some embodiments, the depot is configured to release 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 of the therapeutic agent to the treatment site within a first release period. The depot may be further configured to release 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 of the therapeutic agent to the treatment site within a second release period. The release rate during the first period may be the same or different, or may be less than or greater than the release rate during the second period. Additionally, the first period may be longer or shorter than the second period. The first period may occur before or after the second period.

[0174] In some embodiments, the depot is configured to release up to 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, 1000 mg of a therapeutic agent within a first release period of any number of days. Alternatively or in combination, 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, or 300 mg of therapeutic agent within a first release period of any number of days, which may be useful for providing different degrees of pain relief at different times following a surgical procedure and may also be useful for controlling toxicity. In such embodiments, the depot can 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 therapeutic agent within a second release period of any number of days. The first period and / or the second period can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days.

[0175] One or more depots of the present technology can be implanted at a treatment site to produce a desired level of therapeutic agent in vivo, e.g., at or above the therapeutic threshold and / or below the toxic threshold. For example, one or more depots of the present technology when implanted can be at or above the therapeutic threshold and / or below the toxic threshold, e.g., 5ng / ml, 10ng / ml, 15ng / ml, 20mg / ml, 25ng / ml, 30ng / ml, 40ng / ml, 50ng / ml, 60ng / ml, 70ng / ml, 80ng / ml, 90ng / ml, 100ng / ml, 110ng / ml, 120ng / ml, 130ng / ml, 140ng / ml, 150ng / ml, 160ng / ml, 170ng / ml, 180ng / ml, 190ng / ml, , 200ng / ml, 210ng / ml, 220ng / ml, 230ng / ml, 240ng / ml, 250ng / ml, 300ng / ml, 400ng / ml, 500ng / ml, 600ng / ml, 700ng / ml, 800ng / ml, 900ng / ml, or 1000ng / ml can result in a mean plasma concentration of the therapeutic agent that is equal to or greater than a therapeutic threshold of 200ng / ml, 210ng / ml, 220ng / ml, 230ng / ml, 240ng / ml, 250ng / ml, 300ng / ml, 400ng / ml, 500ng / ml, 600ng / ml, 700ng / ml, 800ng / ml, 900ng / ml, or 1000ng / ml. Alternatively or in combination, the depot(s) may produce a mean plasma concentration of the therapeutic agent that is equal to or less than the toxicity threshold of 9000ng / ml, 8000ng / ml, 7000ng / ml, 6000ng / ml, 5000ng / ml, 4000ng / ml, 3000ng / ml, 2500ng / ml, 2400ng / ml, 2300ng / ml, 2200ng / ml, 2100ng / ml, 2000ng / ml, 1900ng / ml, 1800ng / ml, 1700ng / ml, 1600ng / ml, 1500ng / ml, 1400ng / ml, 1300ng / ml, 1200ng / ml, 1100ng / ml, or 1000ng / ml.The mean plasma concentration of the therapeutic agent may be maintained above the therapeutic threshold and / or below the toxic threshold 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.

[0176] In some embodiments, the depot(s), when implanted, has a mean C of therapeutic agent less than or equal to 1000ng / ml, 900ng / ml, 800ng / ml, 700ng / ml, 600ng / ml, 500ng / ml, 400ng / ml, 300ng / ml, 200ng / ml, 100ng / ml, or 50ng / ml. max The depot(s) may be administered for a mean t of the therapeutic agent 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. 1 / 2 The depot(s) may provide a mean t of the therapeutic agent that is 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. max The depot(s) may provide a mean t of the therapeutic agent that is at least 7, 8, 9, 10, 12, 13, 14, 15, 16, 20, 25, 30, 35, 40, or 45 days. last may result.

[0177] In some embodiments, the depot(s), when implanted, have a mean AUC of the therapeutic agent that is 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. t1~t2 and the period t1 to t2 can be any of the following: 0 to 7 days, 0 to 14 days, 0 to 21 days, 0 to 30 days, 3 to 7 days, 7 to 14 days, 7 to 21 days, 7 to 30 days, 14 to 21 days, 14 to 30 days, or 21 to 30 days. The depot(s) have a mean AUC of the therapeutic agent that is 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. last may result. III. System and Method of Use

[0178] The depots of the present technology (e.g., depots 100a-560 of Figs. 1A-5G) 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 specific areas of the patient's body depending on the medical condition being treated. The depots of the present technology can be positioned in vivo in proximity to target tissues (e.g., bone, soft tissue, etc.) within the patient's body to provide controlled, sustained release of therapeutic agent for treatment of a particular condition. This implantation can be associated with a surgery or intervention to acutely treat a particular condition, whereby the depot provides long-term sustained pharmacological treatment after completion of the surgery or intervention. The depot can be a stand-alone element or can be connected to or integrated as part of an implantable device or prosthesis associated with the intervention or surgery.

[0179] The amount or dosage of therapeutic agent that is effective in patients who need 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 can be used as necessary to help identify optimal dosage ranges.The specific dosage level for any particular individual varies depending on a variety of factors, including drug activity, age, weight, general physical and mental health, genetic factors, environmental influences, sex, diet, administration timing, administration site, excretion rate, and / or the severity of the particular problem being treated.

[0180] Some aspects of the present technology include a system that includes one or more depots (each of which can be any of the depots described herein) provided for implantation by a clinician. For example, the system can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more implanted depots. Each depot can be configured to control-release a therapeutic agent to tissues adjacent to the implantation site of the depot. Thus, the depots, when combined, can 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, A dose of 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 can be provided. The dose provided by an individual depot or series of depots can be expressed in terms of the mass of therapeutic agent used in the depot(s) or in terms of the mass of therapeutic agent in another form (e.g., active moiety form or established salt form). For example, the dose of bupivacaine in a depot formulated with bupivacaine hydrochloride monohydrate can be expressed in terms of the equivalent mass of bupivacaine free base (e.g., 595 mg of bupivacaine hydrochloride monohydrate is equivalent to 500 mg of bupivacaine free 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).

[0181] In embodiments in which 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 differ from one another (e.g., with respect to geometry, composition, and / or release profile). For example, the system may include at least one depot having a release profile that provides for immediate release of the therapeutic agent and at least one other depot having a release profile that provides for delayed release of the therapeutic agent.

[0182] Many depots of the present technology are configured to be implanted at a surgical site to treat postoperative pain at or near the site. As used herein, the term "pain" includes nociception and pain sensation, both of which can be objectively and subjectively assessed using pain scores and other methods known in the art, such as opioid use methods, as described in more detail below. Pain can include allodynia (e.g., increased response to normally non-noxious stimuli) or hyperalgesia (e.g., increased response to normally noxious or unpleasant stimuli), which in turn can be thermal or mechanical (tactile) in nature. In some embodiments, pain is characterized by thermal sensitivity, mechanical sensitivity, and / or rest pain. Pain can be primary or secondary pain, as known in the art. Exemplary types of pain that can be reduced, prevented or treated by the methods and compositions disclosed herein include, but are not limited to, postoperative pain, for example, from the lower back (lumbar pain) or neck region (cervical pain), leg pain, radicular pain (experienced in the lower back and legs from lumbar surgery, and in the neck and arms from cervical surgery), or abdominal pain from abdominal surgery, and neuropathic pain in the arms, neck, back, lower back, legs and associated pain distribution resulting from disc or spinal surgery.Neuropathic pain can include pain resulting from surgery on nerve roots, dorsal root ganglion, or peripheral nerves.

[0183] In some embodiments, pain includes "post-surgical pain," "post-operative pain," or "surgery-induced pain," which are used interchangeably herein and refer to pain that occurs during the seconds, minutes, hours, days, or weeks of recovery following a surgical procedure (e.g., hernia repair, orthopedic or spinal surgery, etc.). Surgical procedures may include any procedure that penetrates below the skin and causes pain and / or inflammation to the patient. Surgical procedures may be performed at various sites within the patient's body. For example, surgery may be performed on the patient's knee, hip, upper leg, lower leg, neck, spine, shoulder, chest, nasal / sinus area, abdominal, and / or pelvic area.

[0184] Some embodiments of the present technology include one or more depots (e.g., having the same or different configurations and / or dosages) positioned at or near the surgical site of the knee joint to treat pain associated with total knee arthroplasty surgery, also known as TKA. In some cases, it may be beneficial to position one or more of the depots within the joint capsule. In some embodiments, one or more depots are positioned at or near the suprapatellar capsule, particularly under the periosteum and attached to the quadriceps tendon. Additional areas for placing one or more depots may generally include the medial and lateral grooves (including fixation to tissues on the medial or lateral sides of the respective grooves as required), 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 positioned adjacent to at least one of the posterior knee capsule, the region above the patella, and / or the arthrotomy incision to the knee capsule. In some embodiments, the depot(s) are located at or near the saphenous nerve, adductor canal, and / or femoral nerve. In some embodiments, the depot(s) are located at or near the infrapatellar branch of the saphenous nerve, one or more genicular nerves in the knee, or the superior region of the patella. It may be desirable to locate the depot(s) within the knee capsule, but away from any articulating portions of the knee joint itself.

[0185] In some embodiments, one or more depots are located at or near one or more nerves that innervate the anterior knee joint capsule. For example, the depot(s) can be configured to be located at or near the superior lateral genicular branch from the vastus lateralis, the superior medial genicular branch from the vastus medialis, the medial (retinacular) genicular branch from the vastus intermedius, the inferior lateral genicular branch from the common peroneal nerve, the inferior medial genicular branch from the saphenous nerve, and / or the lateral (retinacular) genicular branch from the common peroneal nerve. Instead of or in addition to placing the depot in the intra-articular space, one or more depots can be located in an extra-articular position. In some embodiments, the depot(s) are implanted adjacent to one or more extra-articular nerves. In some embodiments, one or more depots are located along or adjacent to a subcutaneous incision in the skin.

[0186] One or more of the depots may include the ability to provide delayed release 6 to 24 hours after implantation, as needed, so as not to interfere with or overlap with peripheral nerve blocks administered to the patient perioperatively. In some embodiments, one or more depots placed within the adductor canal and knee capsule are configured to provide delayed release of therapeutic agent for at least 24 hours.

[0187] In some embodiments, the depot of the present technology utilizes a localized procedure to control pain after TKA. Such a procedure can include infiltrating a local anesthetic between the popliteal artery and the knee joint capsule (IPACK) block. An IPACK block procedure typically involves scanning the popliteal fossa with a probe proximal to the popliteal crease 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 can provide analgesics and / or other therapeutic agents to the posterior knee region without causing distal neurological deficits. In some embodiments, the depot of the present technology is implanted using a combination of an IPACK block procedure and an ACB or FNC block procedure. For example, a patient may receive one or more depots using an FNC block prior to surgery, and then one or more additional depots using an IPACK block postoperatively. Utilizing an IPACK block procedure in conjunction with the depots of the present technology may advantageously provide adequate analgesia after TKA, promote improved physical therapy performance, reduce the incidence of foot drop, reduce opioid consumption, and / or better control posterior knee pain after TKA relative to, for example, ACB, FNC block, or other known techniques for pain management after TKA, and often expedite discharge from the hospital.

[0188] 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 surgery, total knee replacement surgery, and / or revision knee replacement surgery. In such procedures, one or more depots can be placed adjacent to a joint or repair site to provide a local block, or can otherwise be suitably positioned to provide a regional block, for example, by delivering an analgesic to one or more of the femoral or sciatic nerves via placement in the adductor canal.

[0189] In addition to the knee-related surgeries described above, embodiments of the depots disclosed herein can be used to treat postoperative pain associated with other orthopedic surgeries, such as procedures involving the ankle, hip, shoulder, wrist, hand, spine, leg, or arm. For at least some of these surgical procedures, analgesics can be provided to deliver a local or regional block to treat postoperative pain. For a regional block, one or more depots can be attached under direct vision in open surgical procedures, such as during arthroplasty, open reduction and internal fixation (ORIF) surgery, ligament reconstruction, etc. For procedures involving joints, one or more depots can be located in the joint capsule (e.g., in or near the intra-articular and / or extra-articular space of the joint) and / or in adjacent soft tissue spaced from the articular surface to avoid the depot being hindered by articular movement or damaged by contact with the articular surface. In procedures involving fracture or ligament repair, one or more depots can be placed at or adjacent to the repair site to provide local block. For local block, one or more depots can be placed at the treatment site adjacent to the target nerve via ultrasound guidance using a blunt trocar catheter or other suitable device. In some embodiments, it may be beneficial to combine the delivery of analgesics or other therapeutic agents via the depot(s) with NSAIDs, long-acting narcotics delivered preoperatively, and / or acetaminophen. The sustained controlled release of analgesics via one or more depots can work in concert with these other therapeutic agents to provide a reduction in postoperative pain associated with orthopedic and other surgical procedures.

[0190] For example, one or more depots can be used to treat post-operative pain associated with foot and / or ankle surgery, such as ankle arthroplasty (including ankle revision, ankle replacement, and total ankle replacement), ankle fusion, hindfoot fusion, ligament reconstruction, corrective osteotomy (e.g., bunionectomy, flatfoot surgery), or ORIF of ankle or foot fractures. In treating post-operative pain associated with such surgery, one or more depots can be configured and positioned adjacent to a joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be placed parasacral or in another location suitable for targeting one or more of the subgluteal sciatic nerve, popliteal sciatic nerve, deep peroneal nerve, or superficial peroneal nerve. In some embodiments, the depot placed to treat post-operative pain associated with ankle or foot surgery has a release profile configured to deliver therapeutically beneficial levels of analgesia over a period of 3 to 7 days.

[0191] In another example, one or more depots can be used to treat post-operative pain associated with hip surgery, such as hip arthroplasty (including hip revision, partial hip replacement, and total hip replacement) or ORIF of hip fracture. In treating post-operative pain associated with such surgery, one or more depots can be configured and positioned adjacent to the joint or repair site to provide local block. Additionally or alternatively, local block can be provided by placing the depot in the psoas groove, lumbar paravertebral space, under the fascia iliaca, or other location 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 depot, thereby preventing or reducing exposure of analgesic to motor nerves (e.g., sciatic nerve or femoral nerve). In some embodiments, the depot placed for treating post-operative pain associated with hip surgery has a release profile configured to deliver therapeutically beneficial levels of analgesia over a period of 5 to 7 days or 7 to 10 days, depending on the particular surgical procedure.

[0192] Postoperative pain associated with shoulder and upper arm surgery can also be treated using one or more depots disclosed herein. Examples of such surgeries include shoulder arthroplasty (including shoulder revision, partial shoulder replacement, and total shoulder replacement), humeral fracture repair (e.g., scapula, humerus), ligament / tendon repair (e.g., rotator cuff, labrum, biceps, etc.), or ORIF of shoulder or upper arm fractures. In treating postoperative pain associated with such surgeries, one or more depots can be configured and positioned adjacent to the joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be configured and positioned to target the brachial plexus by placing one or more depots in the cervical paravertebral space, the interscalene space, or the supraclavicular space. In some embodiments, placement of the depot in the interscalene space can avoid exposure of the analgesic to the natural cartilage, thereby reducing the risk of chondrotoxicity. In some embodiments, the depot positioned to treat post-operative pain associated with shoulder or upper arm related surgery has a release profile configured to deliver therapeutically beneficial levels of analgesia over a period of 3 to 7 days.

[0193] In another example, one or more depots described herein can be used to treat post-operative pain associated with elbow surgery, such as elbow arthroplasty (including elbow revision, partial elbow replacement, and total elbow replacement), ligament reconstruction, or ORIF of an elbow fracture. In treating post-operative pain associated with such surgery, one or more depots can be positioned adjacent to the joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be configured and positioned to target the brachial plexus nerves, for example, by placement in or near the cervical paravertebral space, subclavian, or axillary location, or other suitable location. In some embodiments, the depots positioned to treat post-operative pain associated with elbow surgery have a release profile configured to deliver therapeutically beneficial levels of analgesia over a period of 3 to 7 days.

[0194] Postoperative pain associated with wrist and hand surgery can also be treated using one or more depots described herein. Examples of wrist and hand surgery include wrist arthroplasty (including wrist revision, partial wrist replacement, and total wrist replacement), wrist fusion, carpal tunnel surgery, and ORIF of wrist fractures. In treating postoperative pain associated with such surgery, one or more depots can be configured and positioned adjacent to the wrist joint or repair site to provide a regional block. Additionally or alternatively, one or more depots can be configured and positioned to target the ulnar, median, radial, and cutaneous antebrachial nerves, for example, via placement in the antecubital fossa, cervical paravertebral space, subclavian, or axillary location. In some embodiments, the depot positioned 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.

[0195] The depots disclosed herein can be used to treat post-operative pain from other orthopedic surgical procedures, such as spinal surgery (e.g., laminectomy, spinal fusion), procedures for treating fractures (e.g., hip fracture, radius fracture, ulna fracture, tibia fracture, fibula fracture, ankle fracture). For example, post-operative pain associated with spinal fusion can be treated via placement of one or more depots in the subcutaneous or paravertebral space. For the treatment of post-operative pain associated with fibula fracture repair, one or more depots can be configured and placed to target the sciatic nerve and / or popliteal sciatic nerve, for example, by placing them parasacral. Various other placements and configurations are also possible to provide therapeutic relief from post-operative pain associated with orthopedic surgical procedures.

[0196] The depot disclosed herein can be used to treat postoperative pain associated with other types of surgery in addition to orthopedic surgery.For example, the depot can be used to treat postoperative pain of chest-related surgery; breast-related surgery; gynecologic or obstetric surgery; general surgery; abdominal surgery; urological surgery; ear, nose, and throat (ENT) surgery; oral and maxillofacial surgery; oncological surgery; or cosmetic surgery.In a particular surgery or class of surgery, one or more depots can be placed at the treatment site to treat postoperative pain.The treatment site can be at or near the surgical site, or can be spaced from the surgical site (e.g., close to the target nerve or nerve bundle that innervates the surgical site).

[0197] For example, one or more depots described herein can be used to treat post-operative pain associated with chest-related surgery, such as thoracotomy, sternotomy, esophageal surgery, cardiac surgery, lung resection, chest surgery, or other such procedures.In treating post-operative pain associated with such surgery, one or more depots can be configured and positioned to target the intercostal nerves, for example, by placing them in or near the thoracic paravertebral space or other suitable location.The analgesic delivered to the intercostal nerves can reduce the pain in the patient's chest region, thereby relieving the post-operative pain associated with the chest-related surgical procedures described above.

[0198] In another example, one or more depots disclosed herein can be used to treat post-operative pain associated with breast-related surgical procedures, such as mastectomy, augmentation (mammoplasty), breast reduction, breast reconstruction procedures, or other such procedures. To treat post-operative pain from such procedures, one or more depots can be positioned and configured to deliver an analgesic or other therapeutic agent to the intercostal nerves, for example, via placement in or near the subclavian space or other suitable location of the patient. Additionally or alternatively, one or more depots can be positioned and configured to deliver an analgesic or other therapeutic agent to the lateral and / or medial pectoral nerves, for example, via placement between the serratus anterior and latissimus dorsi muscles or other suitable location. As previously mentioned, an analgesic delivered to the intercostal nerves can reduce pain in the patient's chest region, while an analgesic delivered to the lateral and / or medial pectoral nerves can reduce pain in the pectoralis major and minor muscles, thereby reducing post-operative pain associated with the chest-related surgical procedures described above.

[0199] As another example, one or more depots can be used to treat postoperative pain associated with systemic, abdominal, pelvic, and / or urological procedures. Examples of such procedures include proctocolectomy, colectomy, pancreatectomy, appendectomy, hemorrhoidectomy, cholecystectomy, kidney transplant, nephrectomy, radical prostatectomy, nephrectomy, gastrectomy, gastric surgery, small bowel resection, splenectomy, laparotomy, laparoscopy, hernia repair (e.g., groin, abdominal wall, umbilicus, scar), sigmoid resection, colorectal resection, liver resection, enterostomy, rectal resection, nephrolithotomy, cystectomy, and gender reassignment surgery. In such procedures, postoperative pain can be treated by placing one or more depots to target the nerves of the transversus abdominis plane (TAP). Analgesics delivered to the TAP can anesthetize the nerves supplying the anterior abdominal wall, thereby reducing postoperative pain in this region. In some embodiments, one or more depots are aligned between the internal oblique and transverse abdominis muscles. In some embodiments, one or more depots can be aligned to or near the abdominal wall, for example, by being secured in place via sutures, fasteners, or other fixation mechanisms.

[0200] In some embodiments, the depot or depots are used to treat post-operative pain associated with gynecological and obstetric surgery, such as myomectomy, cesarean section, hysterectomy (e.g., vaginal hysterectomy), oophorectomy, pelvic floor reconstruction, or other such surgical procedures, in which the depot(s) can be configured and positioned to deliver analgesic or other therapeutic agents to one or more of the nerves that innervate the pelvic and / or genital regions, such as the pudendal nerve, intercostal nerve, or other suitable nerve.

[0201] In some embodiments, one or more depots can be used to treat post-operative pain associated with ENT surgical procedures, such as tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, submandibular gland surgery, or other such procedures. Similarly, one or more depots can be used to treat post-operative pain associated with oral and maxillofacial surgery, such as alveolar surgery, dental implant surgery, orthognathic 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) can be configured and positioned to deliver analgesics or other therapeutic agents to one or more of the nerves that innervate the area affected by the surgical procedure, such as the mandibular nerve, mylohyoid nerve, lingual nerve, inferior alveolar nerve, buccal nerve, auriculotemporal nerve, anterior ethmoidal nerve, or other suitable nerves.

[0202] The depot or depots may also be used to treat post-operative pain from other surgical procedures, such as oncological surgery (e.g., tumor resection), cosmetic surgery (e.g., liposuction, abdominoplasty), amputation, or other surgical procedures that result in post-operative pain. Optionally, the depot or depots may be used to treat pain for indications that may not be associated with a surgical procedure, such as for treating neuromas or phantom limb pain.

[0203] The number of depots and the characteristics of each individual depot (e.g., geometry, composition, release profile) can be selected to deliver the desired therapeutic benefit to the particular condition being treated. For example, a patient recovering from hard tissue surgery (e.g., knee replacement surgery) may benefit from delivery of analgesic drug over a relatively long period of time (e.g., at least 7, 14, or 21 days after surgery), while a patient recovering from other types of surgery may not require the same level or duration of analgesic drug delivery. In some embodiments, a patient recovering from soft tissue surgery (e.g., tonsillectomy, hernia repair, abdominoplasty, mammaplasty) may benefit from delivery of analgesic drug for a shorter period of time, e.g., up to 4, 5, 6, or 7 days after surgery. Thus, depots delivered to a patient for treatment of postoperative pain after soft tissue surgery may require fewer depots, or depots with a smaller payload of therapeutic agent, or depot(s) with a more rapid release profile, etc. In another example, the systemic therapeutic threshold of a therapeutic agent that correlates with a 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 can be selected to deliver the therapeutic agent at or above the systemic therapeutic threshold for an appropriate period of time following surgery. Additionally, the number and characteristics of the depot(s) selected for implantation can be tailored to accommodate the target anatomical region for placement within the patient's body. IV. Clinical outcomes

[0204] The effectiveness of the depots of the present technology (e.g., depots 100a-560 of Figures 1A-5G) in providing therapeutic benefit can be evaluated using a variety of metrics. For example, the effectiveness of one or more depots in providing pain relief via delivery of analgesic drugs 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) index, and Knee Injury and Osteoarthritis Outcome Score (KOOS), among others.

[0205] The Numeric Rating Scale (NRS) is a pain scoring system in which patients assess their pain on a scale of 0 (no pain) to 10 (worst pain imaginable). Pain can be measured at rest (NRS-R) or with activity (NRS-A). Any reference to an NRS score herein can encompass an NRS-R score, an NRS-A score, or a combination thereof. The NRS scores described herein can be measured during a period before the patient consumes any opioids or other pain management medications and / or during a period when the patient is not consuming any opioids or other pain management medications. In some embodiments, the NRS scores of patients who have 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 have not received any depots ("control patients"). The time point may 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 treated patients may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the NRS score of control patients at the same time point.

[0206] In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of treated patients are pain free based on NRS score (e.g., an NRS score of 0 or 1) at one or more time points following surgery, for example, 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 following surgery. Treated patients may achieve pain freedom, for example, at least 1, 2, 3, 4, 5, 6, 7, 14, 28, or 30 days sooner than control patients.

[0207] 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 TKA, activity may redistribute anesthetic into the knee's synovial space, thereby reducing the NRS-A score. Thus, the difference between the NRS-A score and the NRS-R score at a particular time point may be smaller (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% smaller) in treated patients compared to control patients.

[0208] Optionally, postoperative pain can be assessed by comparing the AUC of the NRS score of treated patients ("NRS AUC") to the NRS AUC of control patients over one or more time periods after surgery. The time periods include: 0 hours to 12 hours, 0 hours to 24 hours, 0 hours to 72 hours, 0 hours to 96 hours, 0 hours to 7 days, 0 hours to 14 days, 0 hours to 15 days, 0 hours to 30 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 7 days, 12 hours to 10 days, 12 hours to 14 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 7 days, 12 hours to 10 days, 12 hours to 14 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 24 days, 12 hours to 24 days, 12 hours to 36 hours ... 1 day, 12 hours to 30 days, 1 day to 2 days, 1 day to 4 days, 1 day to 7 days, 1 day to 14 days, 1 day to 15 days, 1 day to 21 days, 1 day to 30 days, 2 days to 3 days, 2 days to 4 days, 2 days to 7 days, 2 days to 14 days, 2 days to 15 days, 2 days to 21 days, 2 days to 30 days, 3 days to 4 days, 3 days to 7 days, 3 days to 14 days, 3 days to 15 days, 3 days to 21 days , 3-30 days, 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 to 15 days, 7 to 21 days, 7 to 30 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, 13 to 14 days, 14 to 15 days, 14 to 21 days, 14 to 30 days, 15 to 21 days, 15 to 30 days, 16 to 21 days, 16 to 30 days, or 21 to 30 days. The NRS AUC of treated patients may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the NRS AUC of control patients over the same period.

[0209] The effectiveness of the depot of the technology of the present invention in treating pain can also be assessed based on the consumption of supplemental opioid medicines 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 remain opioid-free for one or more periods after surgery.As an alternative or in combination, the total amount of opioid consumed by treated patients can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the total amount of opioid consumed by control patients for the same period after surgery. The total amount of opioid consumed by a treated patient can be less than or equal to 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 over a specified period of time.The time periods for assessing postoperative opioid consumption were 0 hours to 12 hours, 0 hours to 24 hours, 0 hours to 72 hours, 0 hours to 96 hours, 0 hours to 7 days, 0 hours to 14 days, 0 hours to 15 days, 0 hours to 30 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 7 days, 12 hours to 10 days, and 12 hours after surgery. 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 days, 3-21 days, 3-30 days, 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- It can be 14 days, 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.

[0210] In some embodiments, the time to first opioid consumption (e.g., time to rescue opioid) of treated patients after surgery is delayed, for example, 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 control patients. Treated patients do not consume any opioids until 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 less 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.

[0211] The effectiveness of the depot of the present technology in treating pain can also be assessed based on motion parameters, such as range of motion and / or other activities.For example, for TKA, range of motion can be assessed based on the flexion and / or extension of the knee after surgery.In some embodiments, the time for treated patients to achieve target flexion and / or extension after surgery is reduced, for example, by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 28 days, or 30 days, compared to control patients.Target flexion and / or extension can vary based on the activity being assessed (e.g., walking, sitting, climbing stairs, etc.) and can be determined according to criteria known to those skilled in the art. Treated patients can achieve target 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, treated patients can resume normal physical activity, e.g., at least 1, 2, 3, 4, 5, 6, 7, 14, 28, or 30 days after surgery, sooner than control patients. Other suitable performance parameters include overall activity level (e.g., step counts, time spent walking, time spent running, 6-minute walk distance, etc.), gait (e.g., time to return to normal gait), and / or other metrics. Performance parameter measurements can be assessed based on change or rate of change of the measurements over time and / or comparison of the measurements to values ​​in control patients, values ​​in healthy individuals (e.g., individuals of a similar age to the patient pre-surgery, individuals with a similar activity profile, etc.), and / or pre-operative levels for the particular patient. In some embodiments, the patient's physical activity is tracked and assessed using wearables or sensors, e.g., fitness monitors.

[0212] In some embodiments, the effectiveness of the depot of the technology of the present invention in treating pain is assessed based on compliance with the prescribed physical therapy regimen. Patients who experience significant postoperative pain often fail to attend or miss physical therapy sessions (e.g., on-site or virtual), and / or put in a lot of effort as quantified by time, repetition, flexion / extension, and / or other parameters. Therefore, treated patients may demonstrate higher compliance with physical therapy compared to control patients based on one or more of these metrics. Reduced compliance with physical therapy may lead to the formation of adhesions and / or scar tissue that cause stiffness in the surgical area (e.g., knee joint), which may require a return to hospital for knee surgical manipulation. Thus, the rate or incidence of surgical manipulation may be another clinical endpoint to demonstrate benefit, for example, the rate of surgical manipulation in treated patients may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients.

[0213] The effectiveness of the depot of the present technology in treating pain can be assessed based on other factors, alternatively or additionally.For example, treated patients can be discharged from the hospital, for example, at least 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 60 hours, or 96 hours earlier than control patients. The time of discharge can be related to the amount of pain the patient is experiencing, in that patients experiencing more postoperative pain can be discharged later than patients experiencing less postoperative pain.In a further example, the re-admission rate of treated patients can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients.Re-admission can occur when patients experience prolonged and / or severe pain, when revision surgery is required, and / or when there are other factors. In yet another example, the percentage of treated patients who contact their surgeon or physician after discharge to seek treatment for post-operative pain may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients.

[0214] As another example, treated patients may exhibit improved post-surgical recovery compared to control patients, as measured by one or more quality of recovery (QoR) scores. The QoR score allows 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. The QoR score can be assessed using a longer form of the 40-item score (QoR-40) or a shorter form of the 15-item score (QoR-15) derived from the QoR-40. In some embodiments, treated patients exhibit improved QoR scores compared to control patients at one or more time points following surgery, for example, 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 following surgery.

[0215] In some embodiments, the efficacy of the depot of the technology of the present invention is evaluated using the WOMAC index, which is a set of standardized questionnaires used by medical professionals to evaluate the condition of patients with joint pain from various origins. WOMAC measures 5 items for pain (score range 0-20), 2 items for stiffness (score range 0-8), and 17 items for functional limitations (score range 0-68). The questions about physical function cover daily activities such as climbing stairs, rising from a sitting or lying position, standing, bending, 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 simple household chores. The WOMAC questions are a subset of the Hip disability and Osteoarthritis Outcome score (HOOS) questions. Thus, the HOOS survey can also be used to determine the WOMAC score.

[0216] Some embodiments of the present technology include a method for treating a patient suffering from post-surgical pain in an anatomical region of the patient's body. The pain may be associated with surgery at or near the anatomical region. In some embodiments, the method includes improving the patient's WOMAC index total score by implanting one or more of the depots disclosed herein in the anatomical region at the surgical site. The method may include improving the WOMAC index pain subscore, stiffness subscore, and / or physical function subscore. The WOMAC index total score and / or one or more of the subscores may be evaluated at predetermined time intervals (weekly, monthly, bimonthly, etc.) and compared to 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 surgical procedure but have not been treated with one of the depots of the present technology.

[0217] KOOS was developed as an extension of the WOMAC index for the purpose of assessing short-term and long-term symptoms and function in subjects with knee injury and osteoarthritis. KOOS includes five subscales that are scored separately: pain, other symptoms, function in daily living (ADL), function in sports and recreation (Sports / Rec), 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 arthroplasty. The effect size is generally largest for the subscale QOL, followed by the pain subscale. In some embodiments, the method includes improving the KOOS score of a patient by implanting one or more of the depots disclosed herein in the anatomical region of the surgical site. The method can include improving the KOOS subscores, including at least one of pain, other symptoms, function in daily living (ADL), function in sports and recreation (Sports / Rec), and / or knee-related quality of life (QOL). The KOOS score and / or one or more of the subscores may be assessed at predetermined time intervals (weekly, monthly, bimonthly, etc.) and compared to the patient's past scores, the patient's pre-operative scores, and / or scores of control patients (patients of similar age, physical health and health status who underwent the same surgical procedure but were not treated with one of the depots of the present technology).

[0218] In some embodiments, a method of treating a subject suffering from pain after a surgical procedure (e.g., TKA or any of the other surgical procedures described herein) includes placing one or more of the depots described herein (e.g., one or more of depots 100a-560 of FIGS. 1A-5G) in the subject (e.g., at or near the surgical site or another treatment site). The depot(s) may be configured such that a population of patients treated with the depot(s) (a "treated population") exhibits at least one improved clinical outcome compared to a population of patients not treated with the depot(s) (a "control population"). The improved clinical outcome may include any of the metrics described herein. For example, the treated population may exhibit one or more of the following improved outcomes compared to the control population: lower mean NRS score, lower mean difference between NRS-A and NRS-R scores, lower mean NRS AUC, greater percentage of patients free of pain, lower mean opioid consumption, greater percentage of patients free of opioids, longer mean time to first opioid consumption, lower incidence of opioid-related adverse events, improved mean flexion and / or extension, shorter mean time to achieve target flexion and / or extension, shorter mean time to discharge from hospital, lower hospitalization rate, greater mean QoR score, greater mean WOMAC score, and / or greater mean KOOS score. Improved clinical outcomes can be assessed at any of the time points and / or time periods following the surgical procedure described herein. EXAMPLES

[0219] The following examples are included to further describe some aspects of the present technology and should not be used to limit the scope of the present technology. Example 1 Construction of an implantable depot for treating post-operative pain - Patents.com

[0220] This example describes three configurations of depots designed for implantation at a surgical site to treat post-operative 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 drug region located between two control regions. The dimensions of each depot are provided in Table 1 below.

[0221] [Table 1-1] [Table 1-2]

[0222] Tables 2 and 3 below provide the compositions by dry weight for the therapeutic drug and control regions in the R300, T600, and T500 depots, respectively. In Examples 1-3 and the accompanying figures, "BUP-HCl" refers to bupivacaine hydrochloride monohydrate (therapeutic agent), "PLGA5050" refers to PLGA 50:50 (polymer), and "PS20" refers to Polysorbate 20 (release agent).

[0223] [Table 2]

[0224] [Table 3]

[0225] Table 4 provides the theoretical composition by dry weight of the components of the R300, T600, and T500 depots. The theoretical percent composition of each component was calculated on a mass basis derived from the respective thicknesses of the therapeutic drug and control regions, and the percent composition of each formulation. For the calculations, the densities of all components were assumed to be equivalent (i.e., 1.0 g / cm 3 ) was assumed.

[0226] [Table 4] Example 2 Preparation and characterization of implantable depots

[0227] This example describes the preparation and characterization of the R300, T600, and T500 depots. The therapeutic drug regions of all three depots were formulated with a 1:10:20:30 ratio by mass of PS20, PLGA5050, BUP-HCl, and acetone. The control regions of R300 and T600 were formulated with a 1:2:6 ratio by mass of PS20, PLGA5050, and acetone. The control region of T500 was formulated with a 1:4 ratio by mass of PLGA5050 and acetone.

[0228] The therapeutic drug regions of R300, T600, and T500 were fabricated by combining PS20, PLGA5050, and acetone and mixing until the PLGA5050 was completely dissolved. BUP-HCl was then 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 a disk of the desired thickness. The disks were then dried.

[0229] After the disks were dried, control regions were applied to both sides of the disks. For the R300 and T600 depots, the control regions were formed by dissolving PLGA5050 and PS20 in acetone and then casting the polymer solution into a thin film of the desired thickness. The thin film was then bonded to each side of the disk using heat compression. For the T500 depot, the control regions were formed by dissolving PLGA5050 in acetone and then immersing the disk in the polymer solution. After the control regions were applied, individual depots were cut from the disks.

[0230] Figure 6 is a scanning electron microscope (SEM) image of a portion of the R300 depot. The depot was freeze-milled and sputter coated before imaged. As can be seen in Figure 6, the therapeutic drug region is a biphasic structure with BUP-HCl crystals held together by PLGA5050. The control region is an approximately 10 μm thick layer over the therapeutic drug region. Example 3 In vitro release profile

[0231] This example describes in vitro release data for the T500 depot. In vitro dissolution studies were performed in phosphate buffered saline (PBS) at pH 5.8. The depot was placed in a basket rotating at 10 RPM at 37° C. in 750 mL of dissolution medium. The dissolution medium was periodically analyzed spectrophotometrically at 262 nm and the BUP-HCl concentration was quantified in a stand-alone sealed cuvette using a USP reference standard.

[0232] Figure 7A is a graph showing the percentage of BUP-HCl released from the T500 depot over time. The release profiles were highly consistent among the different depot samples tested (n=12), with a standard deviation of less than 10% for the first 80 hours of release.

[0233] FIG. 7B is a semi-logarithmic graph showing the percentage of BUP-HCl remaining in the T500 depot over time. As can be seen, the in vitro elution of BUP-HCl from the T500 depot follows first order release kinetics (R 2 = 0.9979), with an observed rate constant of 0.023 h -1 and the half-life is 30 hours.

[0234] FIG. 8A is an SEM image at 50x magnification of a T500 depot that is approximately 25% eluted, and FIG. 8B is an SEM at 50x magnification of a T500 depot that is approximately 75% eluted. The depot was sectioned with a microtome prior to imaging. In the 75% eluted sample, portions of the depot near the periphery and periphery of the pores are significantly thinner compared to the 25% eluted sample, indicating that the BUP-HCl payload in those portions has been released. In contrast, the interior portions of the depot away from the periphery and pores maintain their original thickness, indicating that the BUP-HCl payload is still present. These results indicate that the BUP-HCl release rate correlates to the distance traveled, in that BUP-HCl molecules placed closer to the exposed surface of the depot are eluted more rapidly than BUP-HCl molecules placed further away from the exposed surface. Example 4 In vivo pharmacokinetics of implantable depots

[0235] This example describes in vivo pharmacokinetic data for R300 and T600 depots implanted in human subjects for the treatment of postoperative pain following TKA. The safety and pharmacokinetics of the R300 and T600 depots were investigated in a 22-patient open-label study. Patients were adult subjects between 18-80 years of age undergoing unilateral primary TKA. One or more depots were placed in the knee capsule of each subject after the TKA procedure and prior to surgical closure of the knee capsule. Depending on the dosage level, the depot(s) were placed in one or more of the following locations: suprapatellar capsule, medial sulcus lateral to the capsular tissue, and / or lateral sulcus lateral to the capsular tissue. Table 5 below provides the depot configurations and bupivacaine doses by cohort (in Examples 4-6 and the accompanying figures, "BUP" or "bupivacaine" refers to bupivacaine free base).

[0236] [Table 5]

[0237] Venous blood samples (4 mL) for plasma pharmacokinetic analysis were collected at various time intervals during surgery and within the first 24 hours after surgery, then approximately every 4 hours from 24 to 96 hours after surgery, then daily thereafter until day 15, and at follow-up visits on days 30, 45, and 60 (subjects in cohort 3C additionally visited on days 18, 21, 24, and 27). Bupivacaine was extracted from human plasma by protein precipitation with acetonitrile. Prior to extraction, bupivacaine-d9 was added as an internal standard. A portion of the organic supernatant was transferred to a new 96-well plate and diluted with water. 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.

[0238] Figure 9A is a graph showing mean bupivacaine plasma concentrations over time in subjects receiving R300 or T600 depots (line 902) after TKA compared to subjects treated with other bupivacaine formulations (lines 904-910). Line 902 shows data from subjects in cohorts 3A-3C (days 1-14 and 30 data are from all cohorts 3A-3C subjects, days 18, 21, 24, and 27 data are from cohort 3C subjects 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, Lachiewiczet al., The Journal of Arthroplasty 35 (2020) 2843-2851).

[0239] As shown in Figure 9A, the mean bupivacaine plasma concentrations (line 902) in subjects treated with the R300 or T600 depots remained near or above the therapeutic threshold of 200 ng / ml through day 21. In contrast, the mean bupivacaine plasma concentrations in subjects treated with the other formulations fell below the therapeutic threshold within the first 3-5 days. This data demonstrates that implantable depots can provide a continuous, sustained release of bupivacaine at therapeutic levels for a significantly longer period than conventional formulations.

[0240] FIG. 9B is a graph showing mean bupivacaine plasma concentrations over time in subjects receiving R300 or T600 depots (line 902, left vertical axis) overlaid with NRS-R postoperative pain scores (line 912, right vertical axis) for primary TKA patients from the Force Therapeutics database (n=103,818-296,286). As shown in FIG. 9B, pain scores rise immediately after TKA and gradually decrease over the next 30 days. In some cases, local anesthetic should be present until pain scores are lowered to below 4 (approximately 21 days after TKA) to allow for gentle recuperation and rehabilitation. The release profiles of the R300 and T600 depots are aligned with the development of pain scores over time by providing higher bupivacaine levels during the acute pain period (0-4 days) and sustained lower bupivacaine levels throughout the entire recuperation period (4-30 days).

[0241] FIG. 9C is a graph showing the AUC of bupivacaine plasma concentrations over various time periods in subjects receiving R300 or T600 depot (bars 914-918) compared to subjects treated with other bupivacaine formulations (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 in bars 914-918 for days 14-30 indicate that these AUC values ​​were calculated over a longer interval (2 weeks) compared to the other AUC values ​​shown in FIG. 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 Exparel and Marcaine, and bar 926 shows data from subjects receiving Zynrelef. Data for the other formulations were obtained from the same source as in Figure 9A. As shown in Figure 9B, AUC values ​​for subjects treated with R300 or T600 depot were comparable to those of the other formulations during the acute period (days 0-4) and superior to the other formulations throughout the recovery period (days 4-30).

[0242] Figure 9D is a graph showing the mean bupivacaine plasma concentrations in subjects receiving various doses of bupivacaine from an implanted 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 the mean bupivacaine plasma concentrations in subjects receiving various doses of bupivacaine from an implanted depot. max FIG. 9F is a graph showing the relationship between AUC 0~14d 9D-9F are graphs showing the relationship between pharmacokinetic parameters of the R300 and T600 depots and bupivacaine dose. The data in Figures 9D-9F show that the pharmacokinetic parameters of the R300 and T600 depots exhibit a linear dose response.

[0243] FIG. 9G is a graph showing the in vivo bupivacaine release profile in subjects receiving an implanted depot. The release profile shown in FIG. 9G was extrapolated from bupivacaine plasma concentration levels in subjects receiving 1512 mg of bupivacaine (Cohorts 3A-3C). Briefly, the total area under the curve (AUC 0~inf ) was assumed to correspond to 100% release of the total bupivacaine dose in the depot. The cumulative percentage of bupivacaine released over time was calculated as the AUC 0~t1 vs. AUC 0~inf was calculated at each study time point t1 from the ratio of bupivacaine to bupivacaine. As shown in Figure 9G, the depot exhibited sustained release of bupivacaine for over 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 indicates that the implantable depot can maintain sustained release of bupivacaine during the acute and recuperative periods after surgery. Example 5 Clinical Efficacy of Implantable Depots

[0244] This example describes postoperative pain and opioid consumption in patients treated with an implantable depot after TKA (subjects in 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 relation to the NRS-R.

[0245] Intraoperative and postoperative medications for all cohort 1 subjects included intrathecal morphine; adductor canal block; local infiltration cocktail consisting of ropivacaine, clonidine, ketorolac, and epinephrine; a long-acting opioid (Targin); and rescue opioids (most often oxycodone) when needed, in addition to the implantable depot. These subjects also consumed acetaminophen and celecoxib for various durations during the study. These subjects could use up to 255 mg of ropivacaine in the local infiltration cocktail, adductor canal block, and / or spinal anesthesia.

[0246] Intraoperative and postoperative medications for all Cohort 2 subjects included intrathecal morphine, adductor canal block, local infiltration cocktail consisting of ropivacaine, clonidine, ketorolac, and epinephrine, a long-acting opioid (Targin), and rescue opioids (most often oxycodone) when needed, in addition to the implantable depot. These subjects also consumed acetaminophen and celecoxib for various durations during the study. These subjects could use up to 165 mg of ropivacaine in the local infiltration cocktail, adductor canal block, and / or spinal anesthesia.

[0247] Intraoperative and postoperative medications for subjects in Cohorts 3A-3C (collectively, "Cohort 3 subjects") included, in addition to the implantable depot, intrathecal morphine in 6 of 15 subjects; a local infiltration cocktail consisting of clonidine, ketorolac, and epinephrine in 6 of 15 subjects and no local infiltration in the remaining 9 subjects; a long-acting opioid (Targin) in 3 of 15 subjects; and rescue opioids (most often oxycodone) when needed. These subjects also consumed acetaminophen and celecoxib for various durations during the trial. Only ropivacaine was permitted as spinal anesthesia in these subjects. Adductor canal block and local infiltration of anesthetic agents were not permitted.

[0248] NRS-Rs were 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 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 30 days, 45 days, and 60 days. In addition, due to a protocol amendment, NRS-Rs for pain intensity were also performed on days 18, 21, 24, and 27 for subjects in Cohort 3C. Subjects were asked to complete the NRS-R for pain intensity before consuming any opioids until day 15 following the surgical procedure.

[0249] FIG. 10 is a graph showing the mean NRS-R pain scores for each of the cohorts (not adjusted for opioid consumption). There were no significant differences in pain scores between the cohorts. However, comparing the total amount of opioids consumed (64% less in cohort 3 vs. cohort 1, see Table 8 below) and the limited set of pain scores, it appears that patients consume opioids to try to maintain a tolerable pain intensity level during the first two weeks after TKA surgery. Overall, patients' pain was manageable, with pain intensity scores generally at or below 3.

[0250] The AUC of the NRS-R for pain intensity adjusted for opioid use was calculated cumulatively for each day to the end of the day using the trapezoidal method. Table 6 below shows the AUC for the first 72 hours. The AUC was comparable between cohorts 1 and 3, except that all subjects in cohort 1, cohort 2, and 6 of 15 subjects in cohort 3 received intrathecal morphine, which reduced the AUC for those subjects for approximately the first 24 hours.

[0251] [Table 6]

[0252] Table 7 below shows the AUC over the first 15 days (2 weeks after surgery). The AUC was comparable between cohorts 1 and 3, however cohort 3 subjects consumed 64% less opioids over the 2 week period compared to cohort 1 subjects (see Table 8 below) and did not receive adjunctive anesthetics during surgery (adductor canal block, or local infiltration of anesthetic).

[0253] [Table 7]

[0254] Table 8 below shows the patients' opioid consumption over the first 2 weeks after surgery. All cases of opioid consumption were tracked from the day of the TKA surgical procedure (day 1) to day 15. A preliminary interim analysis showed that 80% (12 / 15) of subjects in cohort 3 on the 1,512 mg dose discontinued all opioid use for TKA-induced knee pain within the first 2 weeks after TKA surgery (Table 1), compared to 52.8% according to the literature (Runner et al., The Journal of Arthroplasty 35 (2020), S158-S162). No subjects in cohort 2 (756 mg) consumed opioids after day 15, and half (50%) of subjects in cohort 1 (252 mg) continued to consume opioids beyond day 15.

[0255] [Table 8]

[0256] Results showed that as bupivacaine doses were increased, post-surgical opioid consumption (MME) decreased during the first 2 weeks after surgery. The literature indicates that the average MME consumed after TKA ranges from 428 MME to nearly 700 MME (Runner et al.; Ruddell et al., The Journal of Bone and Joint Surgery103 (2021), 106-114). Cohort 3 subjects consumed less than half the total opioids reported in the literature (176.77 MME vs. 428 MME). Although 20% (3 / 15) of cohort 3 subjects actually consumed additional opioids as needed for knee pain after the first 2 weeks, these additional opioids (over 2 weeks) are not captured in the 176.77 MME reported in Table 8.

[0257] Of the 15 subjects in cohort 3, one subject never consumed opioids (6.7%). Among the remaining subjects who did consume opioids, the time to first consumption was 6.283 hours (95% CI; 3.117, 22.533) calculated by Kaplan-Meyer. Example 6 Simulated pharmacokinetics of implantable depots

[0258] This example describes simulated pharmacokinetic data for an implantable depot for treating postoperative pain following shoulder surgery, bunionectomy, and inguinal hernia repair. Pharmacokinetic data for other bupivacaine formulations using the same bupivacaine dose in the treatment of TKA and another indication of interest ("new indication") are presented. max and T max The simulated data were generated by calculating the scale factors. Specifically, the C max C of pharmacokinetic data for new indications max By taking the ratio of max The scale factor was then computed. max The scale factor was multiplied with the bupivacaine plasma concentration data for Cohort 3 across all time points to obtain scaled bupivacaine plasma concentration data for the new indication. Similarly, the T max T of pharmacokinetic data for new indications max By taking the ratio of max The scale factor was then computed. max The scale factor was multiplied with the bupivacaine time data for Cohort 3 across all bupivacaine plasma concentration data to derive scaled time data for the new indication. The bupivacaine plasma concentration data was multiplied with the linear C maxFurther scaling based on the dose relationship allowed simulation of the resulting pharmacokinetics of various bupivacaine doses. The resulting data provide a rough simulation of the pharmacokinetics of the implantable depot when implanted in other anatomical locations to treat other indications.

[0259] FIG. 11A is a graph showing simulated mean bupivacaine plasma concentrations over time for subjects treated with an implantable depot following shoulder surgery (lines 1102 and 1104) versus actual mean bupivacaine plasma concentrations in subjects treated with other bupivacaine formulations (lines 1106 and 1108). Specifically, line 1102 shows simulated bupivacaine levels for a subject treated with a depot containing a 1000 mg dose of bupivacaine (e.g., two T500 depots), line 1104 shows simulated bupivacaine levels for a subject treated with a depot containing a 750 mg dose of bupivacaine (e.g., three R300 depots), line 1106 shows bupivacaine levels in a subject treated with Exparel (266 mg of bupivacaine, Patel et al., Pain Medicine 21 (2020), 387-400), and line 1108 shows bupivacaine levels in a subject treated with Posimir (bupivacaine extended release solution, 660 mg of bupivacaine, FDA Briefing Document, Meeting of Anesthetic and Analgesic Drug Products Advisory Committee (2020)). As shown in Figure 11A, the implanted depot produces bupivacaine plasma levels above the therapeutic threshold of 200 ng / ml for over 10 days, thus expected to cover the acute and subacute pain period following shoulder surgery. In contrast, bupivacaine plasma levels in subjects treated with the Exparel and Posimir formulations fall below the therapeutic threshold for the first 3-4 days after surgery.

[0260] 11B is a graph showing simulated mean bupivacaine plasma concentrations over time for subjects treated with an implantable depot (line 1110) versus actual mean bupivacaine plasma concentrations in subjects treated with another bupivacaine formulation (line 1112) following bunionectomy. Specifically, line 1110 shows simulated bupivacaine levels for subjects treated with a depot containing a 250 mg dose of bupivacaine (e.g., one R300 depot), while line 1112 shows bupivacaine levels in subjects treated with Zynrelef (60 mg bupivacaine, Viscusi et al., ASRA poster (2017), Viscusi et al., ESRA poster(2017)). Zynrelef is approved for postoperative analgesia for up to 72 hours following bunionectomy. As shown in FIG. 11B, the implantable depot maintained bupivacaine plasma levels at or above the levels produced by Zynrelef at 72 hours for more than 12 days and maintained bupivacaine plasma levels at or above the estimated therapeutic threshold of 5 ng / ml, thus expected to cover the acute and subacute pain periods following bunionectomy.

[0261] Figure 11C is a graph showing simulated mean bupivacaine plasma concentrations over time for subjects treated with the implantable depot (lines 1114 and 1116) versus the actual mean bupivacaine plasma concentrations in subjects treated with other bupivacaine formulations (lines 1118 and 1120) following open inguinal hernia repair. Specifically, line 1118 shows simulated bupivacaine levels for a subject treated with a depot containing a 1500 mg dose of bupivacaine (e.g., three T500 depots), line 1116 shows simulated bupivacaine levels for a subject treated with a depot containing a 1000 mg dose of bupivacaine (e.g., two T500 depots), line 1118 shows bupivacaine levels in a subject 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 a subject treated with Zynrelef (300 mg bupivacaine, Viscusi et al., ESRA poster (2017)). As shown in Figure 11C, the implantable depot produces bupivacaine plasma levels above the therapeutic threshold of 200 ng / ml for more than 7 days, thus expected to cover the acute and subacute pain period following open inguinal hernia repair. In contrast, bupivacaine plasma levels in subjects treated with the Exparel and Posimir formulations fall below the therapeutic threshold during the first 1-2 days after surgery. Example 7 In vitro release from depots containing no control region

[0262] This example describes the in vitro release from a depot containing bupivacaine free base ("BUPFB"). The depot contained only a therapeutic drug region and no control region (similar to depot 100c in Figure 1C). The composition and geometry of the depot are listed in Table 9 below.

[0263] [Table 9]

[0264] The therapeutic drug region was prepared by mixing PS20, PLGA5050, BUPFB, and acetone in a 1:10:20:30 ratio by mass. The formulation was compressed using a hot press and dried into a large circular disk. The large disk was then cut into smaller circular disks (similar to depot 550 in FIG. 5F) with an outer diameter of 14 mm and a targeted drug loading of 100 mg BUPFB.

[0265] Figure 12 is a graph showing the cumulative in vitro release of bupivacaine from C100-FB-TR depots (n=3). Release data was obtained using an accelerated in vitro release study. Samples were immersed in phosphate buffer at pH 5.8. At predetermined time points, aliquots of the buffer were removed 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 release of payload over a period of six days. Example 8 In vitro release from depots containing various control regions

[0266] This example describes the in vitro release from BUPFB depots containing two, one and no control regions. The composition and geometry of the depots are listed in Table 10 below.

[0267] [Table 10]

[0268] The therapeutic drug 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 drug regions were cut into rectangles.

[0269] The R300-FB-TR depot contained no control region, the R300-FB-1CR depot contained a single control region (similar to depot 100b in FIG. 1B), and the R300-FB-2CR depot contained two control regions (similar to depot 100a in FIG. 1A). The control region was prepared by mixing PS20, PLGA5050, and acetone in a 1:2:6 ratio by mass. The control region was then formed using a solvent casting process in which the formulation was spread thinly across a polytetrafluoroethylene block (PTFE) block and the acetone was flashed off. The control region was then applied to the therapeutic drug region via heat compression using a heat compression machine.

[0270] Figure 13 is a graph showing the cumulative in vitro release of bupivacaine from the depots (n=2 per 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 into fresh pH 7.4 buffer. The buffer was analyzed using UV-Vis spectroscopy to quantify the amount of bupivacaine released at each time point. As shown in Figure 13, all three depots exhibited controlled release over a 14 day period. The release rate slowed with increasing number of control regions. Example 9 In vitro release from free base, salt, and hybrid depots

[0271] This example describes the in vitro and in vivo release from depots formulated with BUPFB, bupivacaine hydrochloride monohydrate ("BUP-HCl"), or a mixture of BUPFB and BUP-HCl ("hybrid" depots). The compositions and geometries of the depots are listed in Table 11 below.

[0272] [Table 11]

[0273] 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 drug region was formulated with a targeted drug loading of 50 mg BUPFB and 60 mg BUP-HCl (equivalent to 100 mg BUPFB) using a mixture of PS20, PLGA5050, BUP-HCl, BUPFB, and acetone in a 1:10:10:10:30 ratio by mass, and (2) for the T400-Salt-TR depot, the therapeutic drug region was formulated with a targeted drug loading of 480 mg BUP-HCl (equivalent to 400 mg BUPFB) using a mixture of PS20, PLGA5050, BUP-HCl, and acetone in a 1:10:20:30 ratio by mass and cut into a triangular shape.

[0274] Figure 14A is a graph showing the cumulative in vitro release of bupivacaine from C100-FB-TR and C100-Hybrid-TR depots (n=3 per depot type). Release data was obtained using the accelerated in vitro release study described in Example 7 above. As shown in Figure 14A, the hybrid depots exhibited a more rapid release than the depots formulated with BUPFB.

[0275] Figure 14B is a graph showing the cumulative in vitro release of bupivacaine from all three depots. Release data was obtained using the accelerated in vitro release study 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), then the depot formulated with BUPFB alone (C100-FB-TR, n=3). Example 10 In vivo release from free base, salt, and hybrid depots

[0276] This example describes the in vivo release from depots with various forms of bupivacaine in a rabbit subcutaneous model. The composition and geometry of the depots are listed in Table 12 below.

[0277] [Table 12]

[0278] C100-FB-TR and C100-Hybrid-TR depots were prepared as described above in Example 9. The C100-salt-2CR depot contained a therapeutic drug region with bupivacaine hydrochloride monohydrate (BUP-HCl) and two control regions (similar to depot 100a in FIG. 1A). The therapeutic drug region of the C100-salt-2CR depot was prepared as described above in Example 7, except that BUP-HCl was used for the therapeutic drug region instead of BUPFB. The control region of the C100-salt-2CR depot was prepared via a dip-coating process using a formulation including PLGA5050 and acetone in a mass ratio of 2:9. In this dip-coating process, a large disk produced using the hot compression method described in Example 7 was submerged in its entirety into a vessel containing a dip-coating formulation of 2:9 PLGA:acetone. The targeted drug loading of the C100-salt-2CR depot was 120 mg of BUP-HCl (equivalent to 100 mg of BUPFB).

[0279] Figure 15 is a semi-logarithmic graph showing the in vivo release of bupivacaine from the depots in a rabbit subcutaneous model. Four rabbits were implanted with two depots each in the subcutaneous space along the dorsal region. Only one subcutaneous pocket was created for the two depots. Blood was collected at predefined 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 on each aliquot to quantify the plasma concentration of bupivacaine free base at each time point. 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 the control region extended the release duration even when the hydrophilic BUP-HCl form (C100-salt-2CR, n=4) was used. Example 11 In vitro release from depots with different therapeutic drug loadings

[0280] This example describes the in vitro release from depots formulated with various amounts of BUPFB. The compositions and geometries of the depots are listed in Table 13 below.

[0281] [Table 13-1] [Table 13-2]

[0282] The depot was prepared as described in Example 8 above, except that the therapeutic agent region of the R300-FB2-TR depot contained a mixture of PS20, PLGA, BUPFB, and acetone in a 1:10:40:30 ratio by mass.

[0283] Figure 16 is a graph showing the cumulative in vitro release of bupivacaine from the depots. In vitro release studies were performed at pH 7.4 using the method of Example 8. As shown in Figure 16, both depots exhibited controlled release over a two week period. The depot with the higher BUPFB loading (R300-FB2-TR, 78.4% BUPFB, n=2) exhibited slightly slower release than the depot with the lower BUPFB loading (R300-FB-TR, 64.5% BUPFB, n=2). Example 12 In vitro release from depots with various free base:salt ratios

[0284] This example describes the in vitro release from depots formulated with various BUPFB:BUP-HCl ratios. The depot compositions and geometries are listed in Table 14 below.

[0285] [Table 14]

[0286] The depots were prepared as described in Example 7 above, except that (1) the therapeutic drug region of the C100-1:1 hybrid-TR depot was formulated using a mixture of PS20, PLGA5050, BUP-HCl, BUPFB, and acetone in a 1:10:10:10:30 ratio by mass with a targeted drug loading of 50 mg BUPFB and 60 mg BUP-HCl (equivalent to 100 mg BUPFB), and (2) the therapeutic drug region of the C100:1:2 hybrid-TR depot was formulated using a mixture of PS20, PLGA5050, BUP-HCl, BUPFB, and acetone in a 1:10:13.7:30 ratio by mass with a targeted drug loading of 39 mg BUPFB and 72.5 mg BUP-HCl (equivalent to 100 mg BUPFB).

[0287] Figure 17 is a graph showing the cumulative in vitro release of bupivacaine from the depots. In vitro release studies were performed at pH 7.4 using the method of Example 8. As shown in Figure 17, depots with higher BUPFB:BUP-HCl ratios (C100-1:1 Hybrid-TR, n=6) released slower than depots with lower BUPFB:BUP-HCl ratios (C100-1:2 Hybrid-TR, n=6). (Example 13) Modeling travel distance

[0288] This example describes a modeling technique for determining the travel distance of a therapeutic agent for various depot geometries.

[0289] In some embodiments, the depots described herein release a therapeutic agent (e.g., bupivacaine) with first order kinetics under sink conditions (e.g., PBS at pH 5.8) and therefore have a short half-life (t 1 / 2 ) is the observed rate constant (k obs ) into the equation t 1 / 2 =ln(2) / k obs The half-life is related by: The half-life can be experimentally determined using the in vitro dissolution techniques described herein. The half-life is expected to vary with the geometry of the depot, including the average migration distance of the therapeutic agent to the exposed surface of the depot closest to the therapeutic agent. Two modeling approaches were developed to examine the relationship between release rate and migration distance: a Monte Carlo statistical approach and a geometric / differential approach.

[0290] Figures 18A and 18B show the Monte Carlo approach applied to two depot geometries: an equilateral triangle ("T500") (Figure 18A) and a right-angled triangle ("T250") (Figure 18B). The Monte Carlo model was developed using Python and operated as follows: for each depot geometry, a number of random points were added to the interior of the depot. The travel distance from each point to the nearest edge was then determined (three examples are shown in Figures 18A and 18B), and then the average travel distance for all points was calculated. The ratio of the average travel distances for T500 and T250 was then calculated as the ratio of the observed rate constants (or t 1 / 2 The ratio of the mean distance traveled was compared to the mean release rate (ratio of values). Both ratios were approximately 1.4, indicating that the mean distance traveled is directly proportional to the observed rate constant. This model can be used to predict the relative release rates of therapeutic agents from various depot geometries (e.g., different shapes, presence or absence of pores).

[0291] Figures 18C and 18D show the geometric / differential approach 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 all edges (the incenter) and the integral of each smaller area is taken. The integrand is the known formula for the shortest distance from a point to a line. This integration outputs the average shortest distance to the edge for an infinite number of points. The output of the integration is expected to match the output of the Monte Carlo simulation. Further examples

[0292] Certain aspects of the present technology are described in the following examples. 1. An implantable depot for treating pain in a subject following a surgical procedure, the implantable depot comprising: a medicament region having a first surface, a second surface opposite the first surface, and an exterior surface between the first surface and the second surface, the medicament region comprising a first polymer and a pain relieving agent; a first control region covering a first surface of the therapeutic drug region and inhibiting release of the analgesic agent from the first surface, the first control region comprising a second polymer; a second control region covering a second surface of the therapeutic drug region and inhibiting release of the analgesic agent from the second surface, the second control region comprising a third polymer; one or more holes extending across the first and second control regions and the medicament region to form one or more exposed portions of the medicament region spaced from the outer surface; Including, the implantable depot is configured to release the analgesic agent from an outer surface of the therapeutic agent region and from one or more exposed portions when implanted in a subject; Implantable depot. 2. The implantable depot of Example 1, wherein the one or more holes are configured such that the maximum migration distance of the therapeutic agent is 5 mm or less. 3. The implantable depot of example 1 or example 2, having a triangular shape. 4. The implantable depot of any one of Examples 1-3, comprising a plurality of holes. 5. The implantable depot of Example 4, containing 4 holes. 6.4 holes, a central hole located at or near the center of the implantable depot; and Three peripheral holes spaced apart from a central hole The implantable depot of Example 5, comprising: 7. The implantable depot of any one of Examples 1-6, wherein at least a portion of the one or more pores have different sizes. 8. The implantable depot of any one of Examples 1-7, wherein at least a portion of the one or more pores have a different shape. 9. The implantable depot of any one of Examples 1-6, wherein the one or more holes each have the same size and shape. 10. The implantable depot of any one of Examples 1-3, comprising a single hole. 11. The implantable depot of any one of Examples 1-10, wherein at least a portion of the one or more holes have a circular shape. 12. The implantable depot of any one of Examples 1-11, wherein at least some of the holes have a width in the range of 1 mm to 5 mm. 13. The implantable depot of any one of Examples 1-12 having a total thickness within the range of 1.8 mm to 2.2 mm. 14. The implantable depot of any one of Examples 1-13, wherein the therapeutic drug region has a first thickness and the first and second control regions, combined, have a second thickness that is less than the first thickness. 15. The implantable depot of example 14, wherein the first thickness is at least 95% of the total thickness of the implantable depot. 16. The implantable depot of example 14 or example 15, wherein the second thickness is 5% or less of the total thickness of the implantable depot. 17. The implantable depot of any one of examples 14-16, wherein the ratio of the second thickness to the first thickness is 1 / 35 or less. 18. The implantable depot of any one of examples 14-17, wherein the first thickness is in the range of 1.75 mm to 2.25 mm and the second thickness is in the range of 40 μm to 60 μm. 19. The implantable depot of any one of Examples 1-18, wherein the therapeutic drug region has a first volume and the first and second control regions, combined, have a second volume that is smaller than the first volume. 20. The implantable depot of example 19, wherein the first volume is at least 95% of the total volume of the implantable depot. 21. The implantable depot of example 19 or example 20, wherein the second volume is 5% or less of the total volume of the implantable depot. 22. The first volume is at least 850 mm 3 and the second volume is 25 mm 3 The implantable depot of any one of Examples 19 to 21, which is: 23. The implantable depot of any one of examples 1-22, wherein the implantable depot includes at least three sides, each side having a length within the range of 25 mm to 35 mm. 24. The implantable depot of any one of examples 1 to 23, wherein the analgesic agent constitutes at least 60% of the total mass of the depot. 25. The implantable depot of any one of examples 1-24, wherein the analgesic agent constitutes at least 60% of the total mass of the therapeutic agent region. 26. The implantable depot of any one of Examples 1 to 25, wherein the total mass of the analgesic in the implantable depot is in the range of 540 mg to 660 mg. 27. The implantable depot of any one of examples 1 to 26, wherein the analgesic comprises bupivacaine or ropivacaine. 28. The implantable depot of any one of examples 1-27, wherein the first, second, and third polymers together constitute 35% or less of the total mass of the depot. 29. The implantable depot of any one of Examples 1-28, wherein the first polymer constitutes 35% or less of the total mass of the therapeutic agent. 30. The implantable depot of any one of examples 1-29, wherein the second polymer constitutes at least 95% of the total mass of the first control region and the third polymer constitutes at least 95% of the total mass of the second control region. 31. The implantable depot of any one of Examples 1 to 30, wherein the total mass of the first, second, and third polymers in the implantable depot is in the range of 300 mg to 350 mg. 32. The implantable depot of any one of examples 1-31, wherein the first, second, and third polymers are the same polymer. 33. The implantable depot of any one of examples 1-32, wherein the first, second, and third polymers are bioresorbable polymers. 34. The implantable depot of any one of examples 1-33, wherein one or more of the first, second, or third polymers is poly(lactide-co-glycolide). 35. The implantable depot of any one of Examples 1-34, wherein the analgesic agent and the first polymer are separate phases within the therapeutic agent region. 36. The implantable depot of any one of examples 1 to 35, wherein the therapeutic drug region comprises a release agent. 37. The implantable depot of example 36, wherein the release agent constitutes 5% or less of the total mass of the implantable depot. 38. The implantable depot of example 36 or example 37, wherein the release agent constitutes 5% or less of the total mass of the therapeutic agent region. 39. The implantable depot of any one of examples 36 to 38, wherein the total mass of the release agent in the implantable depot is in the range of 20 mg to 40 mg. 40. The implantable depot of any one of examples 36 to 39, wherein the release agent is a polysorbate. 41. The implantable depot of any one of Examples 1 to 40, configured to continuously release the analgesic agent for a period of at least 7 days, 14 days, 21 days, or 30 days when implanted in vivo. 42. The implantable depot of any one of Examples 1-41, wherein the implantable depot is configured to release the analgesic agent at a first rate over a first period of time and at a second rate over a second period of time, the first rate being greater than the second rate. 43. The implantable depot of any one of Examples 1 to 42, configured to release up to 20% of the analgesic over the first 72 hours after implantation. 44. The implantable depot of any one of Examples 1 to 43, configured to release up to 50% of the analgesic agent over the first 7 days after implantation. 45. The implantable depot of any one of Examples 1 to 44, configured to release at least 70% of the analgesic agent over the first 14 days after implantation. 46. ​​A system for treating pain in a subject following a surgical procedure, the system comprising one or more of the implantable depots of any one of Examples 1-45. 47. The system of example 46, comprising a plurality of implantable depots. 48. The system of Example 47, comprising three implantable depots. 49. The system of example 46, including a single implantable depot. 50. When one or more implantable depots are implanted in vivo, the following concentrations are acceptable: 5ng / ml, 10ng ml, 15ng / ml, 20mg / ml, 25ng / ml, 30ng / ml, 40ng / ml, 50ng / ml, 60ng / ml, 70ng / ml, 80ng / ml, 90ng / ml, 100ng / ml, 110ng / ml, 120ng / ml, 130ng / ml, 140ng / ml, 150ng / ml, 160ng / ml, 170ng / ml, 180ng / ml, 190ng / ml, 200ng / ml, 210ng / ml, 220ng / ml, 230ng / ml, 240ng / ml, 250ng / ml, 260ng / ml, 270ng / ml, 280ng / ml, 290ng / ml, 300ng / ml, 310ng / ml, 320ng / ml, 330ng / ml, 340ng / ml, 350ng / ml, 360ng / ml, 370ng / ml, 380ng / ml, 390ng / ml, 400ng / ml, 410ng / ml, 420ng / ml, 430ng / ml, 440ng / ml, 450ng / ml, 460ng / ml, 470ng / ml, 480ng / ml, 490ng / ml, 500ng / ml, 510ng / ml, 520ng / ml, 530ng / ml, 540ng / ml, 550ng / ml, 560ng / ml, 570ng / ml, 580ng / ml, 590ng / ml, 600 50 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. 51. The system of example 50, wherein the average plasma concentration is maintained for a period of 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. 52. One or more implantable depots, when implanted in vivo, have a mean C of analgesic equal to or less than 1000ng / ml, 900ng / ml, 800ng / ml, 700ng / ml, 600ng / ml, 500ng / ml, 400ng / ml, 300ng / ml, 200ng / ml, 100ng / ml, or 50ng / ml. max The system of any one of Examples 46 to 51, 53. One or more implantable depots, when implanted in vivo, have a mean AUC of analgesic 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. 0~14d The system of any one of Examples 46 to 52, 54. A method for treating pain in a subject following a surgical procedure, comprising placing within the subject a system according to any one of examples 46-53. 55. A method for treating pain in a subject following a surgical procedure, the method comprising: placing one or more depots within the subject, each depot comprising: a medicament region having a first surface, a second surface opposite the first surface, and an exterior surface between the first surface and the second surface, the medicament region comprising a first polymer and a pain relieving agent; a first control region covering a first surface of the therapeutic drug region and inhibiting release of the analgesic agent from the first surface, the first control region comprising a second polymer; a second control region covering a second surface of the therapeutic drug region and inhibiting release of the analgesic agent from the second surface, the second control region comprising a third polymer; one or more holes extending across the first and second control regions and the medicament region to form one or more exposed portions of the medicament region spaced from the outer surface; Including, each depot is configured to release an analgesic agent from an outer surface of the therapeutic agent region and one or more exposed portions; method. 56. The method of example 55, wherein the one or more depots include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 depots. 57. The method of Example 55 or Example 56, wherein the mass of analgesic in each depot is in the range of 540 mg to 660 mg. 58. The mass of analgesic in each depot is 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg g, 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. 59. The method of any one of Examples 55-58, wherein each depot, when implanted in vivo, continuously releases the analgesic agent for a period of 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. 60. When one or more depots are implanted in vivo, the following concentrations are acceptable: 5ng / ml, 10ng ml, 15ng / ml, 20mg / ml, 25ng / ml, 30ng / ml, 40ng / ml, 50ng / ml, 60ng / ml, 70ng / ml, 80ng / ml, 90ng / ml, 100ng / ml, 110ng / ml, 120ng / ml, 130ng / ml, 140ng / ml, 150ng / ml, 160ng / ml, 170ng / ml, 180ng / ml, 190ng / ml, 20 60. The method of any one of Examples 55-59, which results in an average plasma concentration of the analgesic agent that is greater than or equal to 0 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. 61. The method of example 60, wherein the average plasma concentration is maintained for a period of 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. 62. When one or more depots are implanted in vivo, the mean C of analgesic agent is equal to or less than 1000ng / ml, 900ng / ml, 800ng / ml, 700ng / ml, 600ng / ml, 500ng / ml, 400ng / ml, 300ng / ml, 200ng / ml, 100ng / ml, or 50ng / ml. max The method of any one of Examples 55 to 61, 63. When one or more depots are implanted in vivo, a mean AUC of analgesic 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 0~14d The method of any one of Examples 55 to 62, 64. The method of any one of Examples 55-63, wherein the mean NRS score of a treatment population treated with one or more 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 population not treated with one or more depots. 65. The method of Example 64, wherein the mean NRS score of the treated population and the mean NRS score of the control population are assessed 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 the surgical procedure. 66. The method of any one of Examples 55-65, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of a treated population treated with one or more depots is pain free at some point following the surgical procedure. 67. The method of Example 66, 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, 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 the surgical procedure. 68. The method of any one of Examples 55-67, wherein the mean NRS AUC of a treatment population treated with the one or more 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 depots. 69. Mean NRS AUC of the treated population and the control population after the surgical procedure: 0 hrs to 12 hrs, 0 hrs to 24 hrs, 0 hrs to 72 hrs, 0 hrs to 96 hrs, 0 hrs to 7 days, 0 hrs to 14 days, 0 hrs to 15 days, 0 hrs to 30 days, 12 hrs to 24 hrs, 12 hrs to 36 hrs, 12 hrs to 72 hrs, 12 hrs to 96 hrs, 12 hrs to 7 days, 12 hrs to 14 days, 12 hrs to 14 days, 12 hrs to 30 days, 1 day to 2 days, 1 day to 4 days, 1 day to 7 days, 1 day to 14 days, 1 day to 15 days, 1 day to 30 days, 2 days to 3 days, 2 days to 4 days, 2 days to 7 days, 2 days to 14 days, 2 days to 15 days, 2 days to 30 days, 3 days to 4 days, 3 days to 7 days, 3 days 68. The method of Example 68, wherein the method is evaluated over a period of 14 days, 3 days to 15 days, 3 days to 30 days, 4 days to 5 days, 4 days to 7 days, 4 days to 14 days, 4 days to 15 days, 4 days to 30 days, 5 days to 6 days, 5 days to 7 days, 5 days to 14 days, 5 days to 15 days, 5 days to 30 days, 6 days to 7 days, 6 days to 14 days, 6 days to 15 days, 6 days to 30 days, 7 days to 8 days, 7 days to 14 days, 7 days to 15 days, 7 days to 30 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, 14 days to 15 days, 14 days to 30 days, 15 days to 30 days, or 16 days to 30 days. 70. The method of any one of Examples 55-69, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the treated population treated with the one or more depots are opioid-free for a period of time following the surgical procedure. 71. The period after the surgical procedure is: 0 hours to 12 hours, 0 hours to 24 hours, 0 hours to 72 hours, 0 hours to 96 hours, 0 hours to 7 days, 0 hours to 14 days, 0 hours to 15 days, 0 hours to 30 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 7 days, 12 hours to 14 days, 12 hours to 14 days, 12 hours to 30 days, 1 day to 2 days, 1 day to 4 days, 1 day to 7 days, 1 day to 14 days, 1 day to 15 days, 1 day to 30 days, 2 days to 3 days, 2 days to 4 days, 2 days to 7 days, 2 days to 14 days, 2 days to 15 days, 2 days to 30 days, 3 days to 4 days, 3 days to The method of Example 70, wherein the period of time is 7 days, 3 days to 14 days, 3 days to 15 days, 3 days to 30 days, 4 days to 5 days, 4 days to 7 days, 4 days to 14 days, 4 days to 15 days, 4 days to 30 days, 5 days to 6 days, 5 days to 7 days, 5 days to 14 days, 5 days to 15 days, 5 days to 30 days, 6 days to 7 days, 6 days to 14 days, 6 days to 15 days, 6 days to 30 days, 7 days to 8 days, 7 days to 14 days, 7 days to 15 days, 7 days to 30 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, 14 days to 15 days, 14 days to 30 days, 15 days to 30 days, or 16 days to 30 days. 72. The method of any one of Examples 55-71, wherein the average total opioid consumption of a treatment population treated with the one or more depots is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the average total opioid consumption of a control population not treated with the one or more depots. 73. Mean total opioid consumption in the treated population and the control population after the surgical procedure: 0 hours to 12 hours, 0 hours to 24 hours, 0 hours to 72 hours, 0 hours to 96 hours, 0 hours to 7 days, 0 hours to 14 days, 0 hours to 15 days, 0 hours to 30 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 7 days, 12 hours to 14 days, 12 hours to 14 days, 12 hours to 30 days, 1 day to 2 days, 1 day to 4 days, 1 day to 7 days, 1 day to 14 days, 1 day to 15 days, 1 day to 30 days, 2 days to 3 days, 2 days to 4 days, 2 days to 7 days, 2 days to 14 days, 2 days to 15 days, 2 days to 30 days , 3 to 4 days, 3 to 7 days, 3 to 14 days, 3 to 15 days, 3 to 30 days, 4 to 5 days, 4 to 7 days, 4 to 14 days, 4 to 15 days, 4 to 30 days, 5 to 6 days, 5 to 7 days, 5 to 14 days, 5 to 15 days, 5 to 30 days, 6 to 7 days, 6 to 14 days, 6 to 15 days, 6 to 30 days, 7 to 8 days, 7 to 14 days, 7 to 15 days, 7 to 30 days, 8 to 9 days, 9 to 10 days, 10 to 11 days, 11 to 12 days, 12 to 13 days, 13 to 14 days, 14 to 15 days, 14 to 30 days, 15 to 30 days, or 16 to 30 days. 74. The method of any one of Examples 55-73, wherein the mean total opioid consumption of the treatment population treated with one or more depots is less than or equal to 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. 75. Mean total opioid consumption in the treated population was measured at 0 hours to 12 hours, 0 hours to 24 hours, 0 hours to 72 hours, 0 hours to 96 hours, 0 hours to 7 days, 0 hours to 14 days, 0 hours to 15 days, 0 hours to 30 days, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 72 hours, 12 hours to 96 hours, 12 hours to 7 days, 12 hours to 14 days, 12 hours to 14 days, 12 hours to 30 days, 1 day to 2 days, 1 day to 4 days, 1 day to 7 days, 1 day to 14 days, 1 day to 15 days, 1 day to 30 days, 2 days to 3 days, 2 days to 4 days, 2 days to 7 days, 2 days to 14 days, 2 days to 15 days, 2 days to 30 days, 3 days to 4 days, 3 days to 5 days, 3 days to 6 days, 3 days to 7 days, 3 ... The method of Example 74, wherein the method is evaluated over a period of days to 7 days, 3 days to 14 days, 3 days to 15 days, 3 days to 30 days, 4 days to 5 days, 4 days to 7 days, 4 days to 14 days, 4 days to 15 days, 4 days to 30 days, 5 days to 6 days, 5 days to 7 days, 5 days to 14 days, 5 days to 15 days, 5 days to 30 days, 6 days to 7 days, 6 days to 14 days, 6 days to 15 days, 6 days to 30 days, 7 days to 8 days, 7 days to 14 days, 7 days to 15 days, 7 days to 30 days, 8 days to 9 days, 9 days to 10 days, 10 days to 11 days, 11 days to 12 days, 12 days to 13 days, 13 days to 14 days, 14 days to 15 days, 14 days to 30 days, 15 days to 30 days, or 16 days to 30 days. 76. The method of any one of Examples 55-75, wherein the mean time to first opioid consumption of a treatment population treated with the one or more 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 mean time to first opioid consumption of a control population not treated with the one or more depots. 77. The method of any one of Examples 55-76, wherein the surgical procedure is a total knee arthroplasty (TKA), a total shoulder arthroplasty, a total hip arthroplasty, an inguinal hernia repair, a bunionectomy, a mammoplasty, or an abdominoplasty. 78. An implantable depot for treating pain in a subject, the implantable depot comprising: a therapeutic drug region having a first surface, a second surface opposite the first surface, and an exterior surface between the first surface and the second surface, the therapeutic drug region comprising a polymer and an analgesic agent, at least a portion of the analgesic agent being present in a free base form; Including, the implantable depot is configured, when implanted in a subject, to release an analgesic agent from at least an outer surface of the therapeutic agent region for a release period of at least three days; Implantable depot. 79. The implantable depot of example 78, wherein the analgesic comprises bupivacaine and the free base form comprises bupivacaine free base. 80. The implantable depot of example 78 or 79, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the analgesic is present in free base form. 81. The implantable depot of any one of Examples 78 to 80, wherein 100% of the analgesic is present in free base form. 82. The implantable depot of any one of examples 78 to 80, wherein at least a portion of the analgesic is present in salt form. 83. The implantable depot of example 82, wherein the analgesic comprises bupivacaine and the salt form comprises bupivacaine hydrochloride. 84. The implantable depot of example 82 or 83, wherein the ratio by weight of the salt form to the free base form is equal to or greater than 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, or 5:1. 85. The implantable depot of any one of examples 78-84, wherein the therapeutic agent region comprises a release agent. 86. The implantable depot of example 85, wherein the release agent is a polysorbate. 87. The implantable depot of any one of Examples 78-86, wherein the polymer is a first polymer and the depot further comprises a control region covering a first surface of the therapeutic agent region and inhibiting release of the analgesic agent from the first surface, the control region comprising a second polymer that is the same as or different from the first polymer. 88. The implantable depot of example 87, wherein the control region is a first control region, and the implantable depot further comprises a second control region covering a second surface of the therapeutic drug region and inhibiting release of the analgesic agent from the second surface, the second control region comprising a third polymer that is the same as or different from one or both of the first polymer and the second polymer. 89. The implantable depot of example 88, wherein the first, second, and third polymers are the same polymer. 90. The implantable depot of example 88 or 89, wherein one or more of the first, second, or third polymers is poly(lactide-co-glycolide). 91. The implantable depot of any one of examples 78 to 90, wherein the release period is at least 14 days, 21 days, 28 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 110 days, or 120 days. 92. A system for treating pain in a subject, the system comprising one or more of the implantable depots of any one of Examples 78-91. 93. A method for treating pain, comprising: implanting a depot in a subject, wherein the depot comprises a therapeutic drug region having a first surface, a second surface opposite the first surface, and an exterior surface between the first surface and the second surface, the therapeutic drug region comprising a first polymer and a pain relieving agent, at least a portion of the pain relieving agent being present in free base form; releasing a pain relieving agent from at least an outer surface of the therapeutic agent for a release period of at least 3 days; A method comprising: 94. The method of example 93, wherein the pain comprises post-operative pain associated with a surgical procedure. 95. The method of example 94, wherein the surgical procedure comprises knee surgery, hip surgery, shoulder surgery, hernia repair surgery, bunionectomy, breast surgery, abdominal surgery, spinal surgery, or hemorrhoidectomy. 96. The method of any one of Examples 93-95, wherein the analgesic agent comprises bupivacaine and the free base form comprises bupivacaine free base. 97. The method of any one of Examples 93-96, wherein at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the analgesic agent is present in free base form. 98. The method of any one of Examples 93-98, wherein 100% of the analgesic is present in free base form. 99. The method of any one of Examples 93-98, wherein at least a portion of the analgesic is present in a salt form. 100. The method of example 99, wherein the analgesic comprises bupivacaine and the salt form comprises bupivacaine hydrochloride. 101. The method of example 99 or 100, wherein the ratio by weight of the salt form to the free base form is equal to or greater than 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, or 5:1. 102. The method of any one of examples 93-101, wherein the therapeutic drug region comprises a release agent. 103. The method of any one of examples 93-102, wherein the depot comprises a control region covering a first surface of the therapeutic drug region and inhibiting release of the analgesic agent from the first surface, the control region comprising a second polymer. 104. The method of example 103, wherein the control region is a first control region and the depot further comprises a second control region covering a second surface of the therapeutic drug region and inhibiting release of the analgesic agent from the second surface, the second control region comprising a third polymer. 105. The method of example 104, wherein the first, second, and third polymers are the same polymer. 106. The method of any one of Examples 93-105, wherein the release period is at least 14 days, 21 days, 28 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 110 days, or 120 days. 107. An implantable depot for treating pain in a subject, the implantable depot comprising: a therapeutic drug region having an outer surface, the therapeutic drug region comprising a first polymer and an analgesic agent, at least a portion of the analgesic agent being present in a free base form; a control region covering at least a portion of the surface of the medicament region and inhibiting release of the analgesic agent from the surface, the control region comprising a second polymer that is the same or different from the first polymer; Including, the implantable depot is configured, when implanted in a subject, to release the analgesic agent from at least a surface of the therapeutic agent region over a release period of at least 3 days; Implantable depot. 108. The implantable depot of Example 107, wherein the depot includes an aperture extending through at least a portion of the thickness of the depot such that a portion of the therapeutic agent region is exposed through the control region, and the implantable depot is configured to release the analgesic agent through the aperture when implanted in a subject. conclusion

[0293] Although many of the embodiments are described above with respect to systems, devices, and methods for treating post-operative pain, the technology of the present invention can be applied to other uses and / or other procedures. For example, the depot of the technology of the present invention can be used to treat post-operative pain associated with veterinary procedures and / or surgery. Furthermore, other embodiments are included within the scope of the technology of the present invention in addition to those described herein. Additionally, some other embodiments of the technology of the present invention can have different configurations, components, or procedures than those described herein. Thus, one skilled in the art will understand that the technology of the present invention can have other embodiments that include additional elements, or that the technology of the present invention can have other embodiments that do not include some of the features shown and described above with reference to Figures 1A-18D.

[0294] The description of the embodiments of the technology of the present invention is not intended to be exhaustive or to limit the technology of the present invention to the precise form disclosed above. Wherever the context requires, terms indicating singular or plural number may also include the respective terms indicating plural or singular number. Specific embodiments and examples of the technology of the present invention are described above for illustrative purposes, but various equivalent modifications are possible within the scope of the technology of the present invention, as will be recognized by those skilled in the relevant art. For example, while several steps are presented in a given order, alternative embodiments may perform the steps in a different order. Various embodiments described herein may be combined to provide further embodiments.

[0295] As used herein, the terms "generally," "substantially," "about," and similar terms are used as terms of approximation, not degree, and are intended to account for inherent variations in measurements or calculations that will be recognized by one of ordinary skill in the art.

[0296] Further, unless the word "or" is expressly limited to refer to a list of two or more items to mean only a single item exclusively from the other items, the use of "or" in such a list should be interpreted as including (a) any single item in that list, (b) all of the items in that list, or (c) any combination of the items in that list. Additionally, the term "comprising" is used throughout to mean the inclusion of at least the recited feature(s), so as not to the exclusion of any more of the same feature and / or other features of additional types. As used herein, the phrase "and / or," such as in "A and / or B," refers to A alone, B alone, and A and B.

[0297] To the extent that any material incorporated by reference herein conflicts with the present disclosure, the present disclosure controls.

[0298] Also, while specific embodiments have been described herein for illustrative purposes, it will be understood that various modifications may be made without departing from the teachings of the present invention. Moreover, while advantages associated with certain embodiments of the present technology are described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages to be within the scope of the present technology. Thus, the present disclosure and related technology may encompass other embodiments not expressly shown or described herein.

Claims

1. 1. An implantable depot for treating pain in a subject following a surgical procedure, said implantable depot comprising: a therapeutic drug region having a first surface, a second surface opposite the first surface, and an exterior surface between the first surface and the second surface, the therapeutic drug region comprising a first polymer and an analgesic agent; a first control region covering the first surface of the therapeutic drug region and inhibiting release of the analgesic agent from the first surface, the first control region comprising a second polymer; a second control region covering the second surface of the therapeutic drug region and inhibiting release of the analgesic agent from the second surface, the second control region comprising a third polymer; and one or more holes extending across the first and second control regions and the therapeutic agent region to form one or more exposed portions of the therapeutic agent region spaced from the outer surface; Including, the implantable depot is configured, when implanted in the subject, to release the analgesic agent from the outer surface of the therapeutic agent region and the one or more exposed portions. Implantable depot.

2. 10. The implantable depot of claim 1, wherein the one or more holes are configured to allow a maximum migration distance of a therapeutic agent of 5 mm or less.

3. An implantable depot as described in claim 1, wherein the implantable depot has a triangular shape.

4. An implantable depot as described in claim 1, wherein the implantable depot comprises a plurality of holes.

5. An implantable depot as described in claim 4, wherein the implantable depot comprises four holes.

6. The four holes are a central hole located at or near the center of the implantable depot; and Three peripheral holes spaced from the central hole 6. The implantable depot of claim 5, comprising:

7. 10. The implantable depot of claim 1, wherein at least some of said one or more pores have different sizes.

8. 10. The implantable depot of claim 1, wherein at least some of said one or more holes have different shapes.

9. 10. The implantable depot of claim 1, wherein said one or more holes each have the same size and shape.

10. An implantable depot as described in claim 1, wherein the implantable depot comprises a single hole.

11. 10. The implantable depot of claim 1, wherein at least some of said one or more holes have a circular shape.

12. 10. The implantable depot of claim 1, wherein at least some of said holes have a width in the range of 1 mm to 5 mm.

13. The implantable depot of claim 1, wherein the implantable depot has a total thickness in the range of 1.8 mm to 2.2 mm.

14. 10. The implantable depot of claim 1, wherein the therapeutic drug region has a first thickness, and the first and second control regions collectively have a second thickness that is less than the first thickness.

15. 15. The implantable depot of claim 14, wherein said first thickness is at least 95% of the total thickness of said implantable depot.

16. 15. The implantable depot of claim 14, wherein said second thickness is no more than 5% of the total thickness of said implantable depot.

17. 10. The implantable depot of claim 1, wherein the therapeutic drug region has a first volume and the first and second control regions collectively have a second volume that is smaller than the first volume.

18. 18. The implantable depot of claim 17, wherein said first volume is at least 95% of the total volume of said implantable depot.

19. 18. The implantable depot of claim 17, wherein said second volume is no more than 5% of the total volume of said implantable depot.

20. 10. The implantable depot of claim 1, wherein the implantable depot comprises at least three sides, each side having a length in the range of 25 mm to 35 mm.

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