Patent Application
20250017847
The present technology relates generally to implantable depots, and in particular, to implantable depots for delivering therapeutic agents and associated systems, and methods.
Implantable systems for the 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 in clinically desirable anatomic locations, thereby providing localized delivery of select agents. This localized delivery enables a substantial proportion of the agent to reach the intended target and undesirable systemic side effects can be avoided. However, these systems often suffer from a lack of a true controlled release mechanism in that they typically provide a burst release of therapeutic agent upon contact with surrounding physiologic fluids, followed by a residual release of agent.
A 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 holding a large dose of a therapeutic agent for a controlled, sustained release over time. This may have particular value when the carrier loaded with therapeutic agent is implanted in conjunction with an interventional or surgical procedure and, optionally, alongside or as part of an implantable medical device. Thus, a need exists for biocompatible implantable systems capable of providing a highly controlled release of a therapeutic agent.
Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed on illustrating clearly the principles of the present disclosure.
The present technology relates to implantable depots for the sustained, controlled release of therapeutic agents, and associated systems and methods. For example, in some embodiments, an implantable depot for treating a subject includes a therapeutic region having a first surface, a second surface opposite the first surface, and a lateral surface between the first and second surfaces. The therapeutic 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 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 in second surface of the therapeutic region to inhibit release of the therapeutic agent from the second surface. Optionally, the depot can include one or more holes extending through the first and second control regions and the therapeutic region to form one or more exposed portions of the therapeutic region spaced apart from the lateral surface. When implanted in the subject, the depot can release the therapeutic agent from the lateral surface and the one or more exposed portions of the therapeutic region. The release profile of the therapeutic agent can be tuned by altering various parameters of the depot, such as the composition (e.g., amounts and/or types of therapeutic agent, polymer, and/or other components such as releasing agents) and/or geometry (e.g., thicknesses of the therapeutic region and/or control regions; size, shape, and/or locations of the hole(s)). Accordingly, the depots described herein can be adapted to provide sustained, controlled release of the therapeutic agent suitable for many different types of applications, such as treating postoperative pain following a surgical procedure.
Embodiments of the present disclosure will be described more fully hereinafter with reference to the accompanying drawings in which like numerals represent like elements throughout the several figures, and in which example embodiments are shown. Embodiments of the claims may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. The examples set forth herein are non-limiting examples and are merely examples among other possible examples.
As used herein, the terms “vertical,” “lateral,” “upper,” and “lower” can refer to relative directions or positions of features of the embodiments disclosed herein in view of the orientation shown in the Figures. For example, “upper” or “uppermost” can refer to a feature positioned closer to the top of a page than another feature. These terms, however, should be construed broadly to include embodiments having other orientations, such as inverted or inclined orientations where top/bottom, over/under, above/below, up/down, and left/right can be interchanged depending on the orientation.
The headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed present technology. Embodiments under any one heading may be used in conjunction with embodiments under any other heading.
The depot 100a can be any suitable structure or device suitable for carrying and controllably releasing the therapeutic agent, such as a film, sheet, strip, ribbon, capsule, coating, matrix, wafer, pill, pellet, bead, scaffold, or a combination thereof. In the illustrated embodiment, the depot 100a is a multilayered, monolithic structure including a therapeutic region 102 disposed between a first control region 104a and a second control region 104b. The therapeutic region 102 (also known as a “core region,” “drug core,” or “drug layer”) includes the therapeutic agent, while the control regions 104a, 104b (also known as the “control layers”) can modulate the release of the therapeutic agent from the therapeutic region 102. As discussed in detail below, the geometry and composition of the therapeutic region 102 and the control regions 104a, 104b can be configured to produce a desired release profile of the therapeutic agent.
In some embodiments, the therapeutic region 102 includes the therapeutic agent and at least one polymer (e.g., poly(lactide-co-glycolide) (PLGA)). The polymer can be combined with the therapeutic agent to form a solid central core of the depot 100a. In some embodiments, the therapeutic agent and the polymer are discrete phases within the therapeutic region 102, with the polymer acting as a “glue” to hold the therapeutic agent together. In such embodiments, the therapeutic agent can form discrete crystals, particles, etc., that are adhered to each other by the polymer to form a monolithic material. In other embodiments, however, the therapeutic agent can instead 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 physiologic fluids. The degradation characteristics of the bioresorbable polymer can be selected to modulate the release rate of the therapeutic agent from the therapeutic region 102. Additional examples and features of polymers that can be included in the therapeutic region 102 are provided in Section I.C.2 below.
Optionally, the therapeutic region 102 can include additional components, such as a releasing agent (e.g., polysorbate). The releasing agent can also affect the release rate of the therapeutic agent. In some embodiments, when exposed to a fluid (e.g., physiologic fluid), the releasing agent can have a dissolution rate that is faster than the degradation rate of the polymer in the therapeutic region 102. Accordingly, when a fluid contacts the therapeutic region 102 (e.g., after implantation of the depot 100a in a treatment site), the releasing agent dissolves within the surrounding polymer of the therapeutic region 102, thus forming openings (e.g., channels, voids, pores, etc.) in the surrounding polymer region that promote infiltration of fluid into the therapeutic region 102 and/or diffusion of the therapeutic agent out of the therapeutic region 102. Thus, increasing the amount of releasing agent in the therapeutic region 102 can increase the release rate of the therapeutic agent after implantation, as discussed in further detail elsewhere herein. Alternatively or in combination, the releasing agent can function as a surfactant to increase water uptake into the depot 100a, or otherwise alter the interfaces between the therapeutic agent, the polymer, and water to enhance release rate. Optionally, the releasing agent can modulate the mechanical properties of the therapeutic region 102 (e.g., increasing flexibility and/or reducing brittleness), which can facilitate manufacturing, storage, and/or handling of the depot 100a. Additional examples and features of releasing agents that can be included in the therapeutic region 102 are provided in Section I.C.3 below. In other embodiments, however, the therapeutic region 102 can be provided without any releasing agent.
As shown in
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 can be made of a different polymer. Additionally, the polymers used in the first and/or second control regions 104a, 104b can be the same as the polymer used in the therapeutic region 102, or can be different polymers. In some embodiments, the polymers of the first and/or second control regions 104a, 104b are bioresorbable polymers. Additional examples and features of polymers that can be included in the first and second control regions 104a, 104b are provided in Section I.C.2 below.
Optionally, the control regions 104a, 104b can include additional components, such as a releasing agent (e.g., polysorbate). The first control region 104a can include the same releasing agent as the second control region 104b, or can include a different releasing agent. Additionally, the releasing agent used in the first and/or second control regions 104a, 104b can be the same as the releasing agent used in the therapeutic region 102, or can be different releasing agents. Additional examples and features of releasing agents that can be included in the first and second control regions 104a, 104b are provided in Section I.C.3 below. In other embodiments, however, the first and/or second control regions 104a, 104b can be provided without any releasing agent.
The configuration (e.g., position and/or geometry) and composition of the control regions 104a, 104b can modulate the release profile of the therapeutic agent from the therapeutic region 102. For example, when the depot 100a is implanted at a treatment site, the control regions 104a, 104b can be positioned between the first and second surfaces 106a, 106b of the therapeutic region 102 and physiologic fluids at the treatment site. Accordingly, 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 within the control regions 104a and 104b creates a barrier that is partially or completely impenetrable to fluid infiltration, such that any additional components within the control regions 104a, 104b (e.g., releasing agent) are sequestered within the polymer and not exposed to fluids.
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 a surface of the therapeutic region 102 only if that surface is exposed to fluid, thus providing a route for the therapeutic agent to diffuse out of the therapeutic region 102 and into the surrounding environment. The control regions 104a, 104b can be configured to block all or substantially all release 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 lateral surfaces 108 of the therapeutic region 102. For example, at least 80%, 85%, 90%, 95%, 99%, or 100% of the therapeutic agent delivered from the depot 100a can be released through the lateral surfaces 108, while less than 20%, 15%, 10%, 5%, or 1% of the therapeutic agent delivered from the depot 100a can 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 the nearest exposed surface of the therapeutic region 102, also referred to herein as the “travel distance” of the therapeutic agent. For example, therapeutic agent located at the periphery of the depot 100a near the lateral surfaces 108 may release more quickly than therapeutic agent located within the interior of the depot 100a away from the lateral surfaces 108, thus creating a sustained release profile, as described in greater detail below.
In some embodiments, the control regions 104a, 104b also serve other functions, 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 region 102. Accordingly, the presence of the control regions 104a, 104b can improve the handling and storage characteristics of the depot 100a.
The depot 100a is configured to release a therapeutic agent in a highly controlled, predetermined manner that is specifically tailored to the medical condition being treated and/or the therapeutic agent used. As described in greater detail below, the release kinetics of the depot 100 can be customized for a particular application by varying one or more aspects of the depot's composition and/or structure, such as any of the following: the geometry (e.g., size and/or shape) of the depot 100a, therapeutic region 102, and/or control regions 104a, 104b; the types of therapeutic agent, polymer, and/or releasing agent used; and the amounts of therapeutic agent, polymer, and/or releasing agent included in the depot 100a (e.g., in the therapeutic region 102 and/or the control regions 104a, 104b).
Referring next to
The therapeutic region 202 can have a thickness that is greater than or equal to 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 98.8%, 99%, or 99.5% of the total thickness T1 of the depot 200. In some embodiments, the thickness of the therapeutic region 202 is within a range from 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 region 202 can be greater than or equal to 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, 1.92 mm, 1.93 mm, 1.94 mm, 1.95 mm, 1.96 mm, 1.97 mm, 1.98 mm, 1.99 mm, 2 mm, 2.1 mm, 2.2 mm, 2.25 mm, 2.3 mm, 2.4 mm, 2.5 mm, 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.
In the illustrated embodiment, the control regions 204a, 204b have the same thickness. In other embodiments, however, the control regions 204a, 204b can have different thicknesses (e.g., the first control region 204a can have a greater thickness than the second control region 204b, or vice-versa). The control regions 204a, 204b can each have a respective thickness that is less than or equal to 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 within a range from 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 less than or equal to 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, 13μ, 12 μm, 11μ, 10μ, 9μ, 8μ, 7μ, 6μ, 5 μm, 4μ, 3 μm, 2μ, or 1 μm. In some embodiments, thicker control regions are more resistant to fracture, cracking, or other damage during manufacturing, handling, and/or storage, and thus may produce a more consistent release profile of the therapeutic agent across different lots or batches. However, the control regions 204a, 204b can still be sufficiently thin so that the depot 200 still has a compact size suitable for placement in a treatment site.
The combined thickness of the control regions 204a, 204b can be less than or equal to 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 region 202. In some embodiments, the ratio of the combined thickness of the control regions 204a, 204b to the thickness of the therapeutic region 202 is no more than 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 within a range from 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 can be less than or equal to 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, the volume of the therapeutic region 202 is greater than or equal to 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 98.8%, 99%, or 99.5% of the total volume of the depot 200. The combined volume of the control regions 204a, 204b can be less than or equal to 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1.2%, 1%, or 0.5% of the total volume of the depot 200. In some embodiments, the depot 200 has a volume of at least 100 mm3, 150 mm3, 200 mm3, 250 mm3, 300 mm3, 350 mm3, 400 mm3, 450 mm3, or 500 mm3. The therapeutic region 202 can have a volume of at least 100 mm3, 150 mm3, 200 mm3, 250 mm3, 300 mm3, 350 mm3, 400 mm3, 450 mm3, or 500 mm3. The control regions 204a, 204b can collectively have a volume of no more than 100 mm3, 75 mm3, 50 mm3, 25 mm3, 10 mm3, 9 mm3, 8 mm3, 7 mm3, 6 mm3, 5 mm3, 4 mm3, 3 mm3, 2 mm3, or 1 mm3.
Referring to
In the illustrated embodiment, the depot 200 includes four notches 210, one at each of the four lateral 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 lateral 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 lateral surfaces 212 may not include any notches 210 (e.g., the notches 210 can be located at three, two, or a single lateral surface 212 of the depot 200). Additionally, although
In the illustrated embodiment, each notch 210 extends along the entire thickness T1 of the depot 200, e.g., from a first surface 214a (e.g., uppermost surface) of the depot 200, through the first control region 204a, therapeutic region 202, and second control region 204b, to a second surface 214b (e.g., lowermost 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., the notch 210 can be localized to the first control region 204a, the second control region 204b, the therapeutic region 202, the first control region 204a and the therapeutic region 202, the therapeutic region 202 and the second control region 204b, etc.).
The geometry (e.g., size, shape) of the notches 210 can be varied as desired. For example, in the embodiment of
The depot 200 can be manufactured in many different ways. In some embodiments, for example, the therapeutic region 202 is formed first using a heat compression process. The heat compression 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 within a range from about 0.01 MPa to about 1 MPa, or about 0.1 MPa to about 0.8 MPa, or about 0.3 MPa to about 0.6 MPa. Subsequently, the control regions 204a, 204b can be applied to the therapeutic region 202 using spray coating, dip coating, solvent casting, laser melting, or other suitable processes known to those of skill in the art. The notches 210 can then be cut into the depot 200 using a blade, laser cutting, ultrasonic cutting, air knife, or other suitable techniques. In some embodiments, each depot 200 is formed individually. In other embodiments, the therapeutic region 202 and control regions 204a, 204b can be formed as a larger material sheet, which can then be cut into individual depots 200.
Referring next to
In some embodiments, the volume of the therapeutic region 302 of the depot 300 is greater than or equal to 50%, 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 98.8%, 99%, or 99.5% of the total volume of the depot 300. The combined volume of the control regions 304a, 304b can be less than or equal to 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 has a volume of at least 100 mm3, 200 mm3, 300 mm3, 400 mm3, 500 mm3, 550 mm3, 600 mm3, 650 mm3, 700 mm3, 750 mm3, 800 mm3, 850 mm3, 900 mm3, 950 mm3, or 1000 mm3. The therapeutic region 302 can have a volume of at least 100 mm3, 200 mm3, 300 mm3, 400 mm3, 500 mm3, 550 mm3, 600 mm3, 650 mm3, 700 mm3, 750 mm3, 800 mm3, 850 mm3, 900 mm3, 950 mm3, or 1000 mm3. The control regions 304a, 304b can collectively have a volume of no more than 100 mm3, 75 mm3, 50 mm3, 45 mm3, 40 mm3, 35 mm3, 30 mm3, 25 mm3, 20 mm3, 25 mm3, 15 mm3, 10 mm3, 9 mm3, 8 mm3, 7 mm3, 6 mm3, 5 mm3, 4 mm3, 3 mm3, 2 mm3, or 1 mm3.
As best seen in
In the illustrated embodiment, the depot 300 includes a single hole 316 at or near the center (e.g., centroid) of the depot 300. In other embodiments, the hole 316 can be at a different location in the depot 300. The location of the hole 316 can be selected to reduce (e.g., minimize) the average and/or maximum travel distance between individual molecules of the therapeutic agent and the nearest exposed surface of the therapeutic region 302. For example, the average and/or maximum travel distance of the therapeutic agent in the depot 300 can be less than or equal to 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.
The hole 316 can extend through the entire thickness T2 of the depot 300, e.g., from a first surface 314a (e.g., uppermost surface) of the depot 300, through the first control region 304a, therapeutic region 302, and second control region 304b, to a second surface 314b (e.g., lowermost surface) of the depot 300. Alternatively, the hole 316 can extend only partially through the thickness T2 of the depot 300 (e.g., the hole 316 can extend through the first control region 304a only, the second control region 304b only, the first control region 304a and the therapeutic region 302 only, the therapeutic region 302 and the second control region 304b only, etc.).
The geometry (e.g., size, shape) of the hole 316 can be varied as desired. For example, as shown in
Alternatively or in combination, the hole 316 can serve other functions, such as accommodating fasteners (e.g., sutures) for securing the depot 300 in place at a treatment site. Optionally, the presence of the hole 316 can increase the overall flexibility of the depot 300, which can reduce the likelihood of inadvertent breakage during manufacturing, storage, and/or handling of the depot 300.
The depot 300 can be manufactured using techniques similar to those described above with respect to the depot 200 of
As best seen in
The use of multiple holes 416a-416d can reduce the average and/or maximum travel distance for the therapeutic agent, e.g., compared to depots having fewer or no holes (e.g., the depot 300 of
Each of the holes 416a-416d can extend through the entire thickness T3 of the depot 400, e.g., from a first surface 414a (e.g., uppermost surface) of the depot 400, through the first control region 404a, therapeutic region 402, and second control region 404b, to a second surface 414b (e.g., lowermost surface) of the depot 400. Alternatively, some or all of the holes 416a-416d can extend only partially through the thickness T3 of the depot 400 (e.g., through the first control region 404a only, the second control region 404b only, the first control region 404a and the therapeutic region 402 only, the therapeutic region 402 and the second control region 404b only, etc.).
In the illustrated embodiment, each of the holes 416a-416d extends through the therapeutic region 402 and exposes a surface thereof, such that the therapeutic agent can elute out of the depot via the holes 416a-416d. In other embodiments, a barrier material can be positioned over the surfaces of the therapeutic region 402 at some or all of the holes 416a-416d to reduce or prevent release of the therapeutic agent from a certain hole or holes. The barrier material can be or include any material that inhibits diffusion of therapeutic agent, such as a polymer layer or coating. For example, the barrier material can be made of a material identical or similar to the material of the control regions 404a, 404b. The barrier material can be located at the central hole 416a only, the peripheral holes 416b-416d only, or any other selected subset of the holes 416a-416d. For example, the barrier material can be located at holes that are intended to be used for suturing, while holes intended to modulate the release profile of the therapeutic agent may not include any barrier agent.
The geometry (e.g., size, shape) of the holes 416a-416d can be varied as desired. For example, as shown in
The depot 400 can be manufactured using techniques similar to those described above with respect to the depot 300 of
As another example, the depot 400 can be manufactured by first forming a large sheet or film of therapeutic region material. The sheet can then be coated (e.g., spray coated or dip coated) with control region material. After the coating process, the upper, lower, and lateral surfaces of the sheet can all be covered with the control region material. The sheet can then be cut into individual depots. In the resulting depot 400, the therapeutic region 402 can be exposed at the lateral surfaces of the depot 400 where the cuts were made, and can remain covered with the control region material at all other lateral surfaces. Accordingly, depending on the locations of the cuts, each depot 400 can include one, two, or three lateral surfaces where the therapeutic region 402 is exposed. For example, a depot 400 produced by cutting a square sheet in half along the diagonal can have one lateral surface where the therapeutic region 402 is exposed, and two lateral surfaces where the therapeutic region 402 is covered.
Optionally, the control regions 404a, 404b of the depot 450 can extend over the lateral surfaces of the depot 450 (not visible in
In the illustrated embodiment, the depot 510 includes four holes 514a-514d near the four corners 512a-512d. In other embodiments, the number and locations of the holes 514a-514d can be varied, e.g., the depot 510 can include fewer or more holes 514a-514d, the holes 514a-514d can be at different locations (e.g., at or near the center of the depot 510), etc. The geometry (e.g., shape, size) and function of the holes 514a-514d can be identical or similar to the holes 416a-416d of
The geometry of the cutouts 536a-536d can be varied as desired. In the illustrated embodiment, for example, the cutouts 536a-536d each have a semi-circular shape. In other embodiments, however, some or all of the cutouts 536a-536d can have a different shape, such as a square, rectangular, triangular, semi-oval, or other shape. The cutouts 536a-536d can each independently have any suitable size, such as a diameter D8 or width within a range from 1 mm to 20 mm, 5 mm to 15 mm, or 8 mm to 12 mm.
In the illustrated 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 locations of the holes 538a-538d can be varied, e.g., the depot 530 can include fewer or more holes 538a-538d, the holes 538a-538d can be at 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 identical or similar to the holes 416a-416d of
In the illustrated embodiment, the depot 540 includes three holes 546a-546c: one hole 546a near the end of the first elongate arm 542, one hole 546b located near the end of second elongate arm 544, and one hole 546c located near the connection between the first and second elongate arms 542, 544. In other embodiments, the number and locations of the holes 546a-546c can be varied, e.g., the depot 540 can include fewer or more holes 546a-546c, the holes 546a-546c can be at different locations (e.g., spaced along the length of the first elongate arm 542 and/or second elongate arm 544, etc. The geometry (e.g., shape, size) and function of the holes 546a-546c can be identical or similar to the holes 416a-416d of
In some embodiments, the depots of the present technology are configured to be cut, fractured, or otherwise divided into smaller pieces before use. For example, a depot shaped as an equilateral triangle (e.g., the depot 300 of
The depots of the present technology (e.g., the depots 100a-560 of
The therapeutic agent carried by the depots of the present technology (e.g., the depots 100a-560 of
In some embodiments, the therapeutic agent is or includes an analgesic agent. The term “analgesic agent” or “analgesic” includes one or more local or systemic agents that are administered to reduce, prevent, alleviate, or remove pain entirely. The analgesic agent may comprise a systemic and/or local anesthetic, narcotics, and/or anti-inflammatory agents. The analgesic agent can include the pharmacologically active drug or a pharmaceutically acceptable salt thereof. Suitable analgesic agents 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.
In some embodiments, the therapeutic agent includes narcotics, for example, cocaine or anti-inflammatory agents. Examples of appropriate anti-inflammatory agents include steroids, such as prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, and methylprednisolone. Other appropriate anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen sodium, diclofenac, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate, mefenamic acid, and other COX-2 inhibitors, and combinations thereof.
In some embodiments, the therapeutic agent is or includes an antibiotic, an antimicrobial or antifungal agent, or combinations thereof. For example, suitable antibiotics and antimicrobials include, but are not limited to, amoxicillin, amoxicillin/clavulanate, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole/trimethoprim, tetracycline, minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin, aminoglycides, quinolones, fluoroquinolones, vancomycin, gentamycin, cephalosporin, carbapenem, imipenem, ertapenem, antimicrobial peptides, cecropin-mellitin, magainin, dermaseptin, cathelicidin, α-defensins, and α-protegrins. Antifungal agents include, but are not limited to, ketoconazole, clortrimazole, 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.
In some embodiments, the therapeutic agent is or includes an adrenocorticostatic, a β-adrenolytic, an androgen or antiandrogen, an antianemic, an antiparasitic, an anabolic, an anesthetic or analgesic, an analeptic, an antiallergic, an antiarrhythmic, an anti-arteriosclerotic, an antibiotic, an antidiabetic, an antifibrinolytic, an anticonvulsive, an angiogenesis inhibitor, an anticholinergic, an enzyme, a coenzyme or a corresponding inhibitor, an antihistaminic, an antihypertensive, an antihypotensive, an anticoagulant, an antimycotic, an antiseptic, an anti-infective, an antihemorrhagic, a β-receptor antagonist, a calcium channel antagonist, an antimyasthenic, an antiphlogistic, an antipyretic, an antirheumatic, a cardiotonic, a chemotherapeutic, a coronary dilator, a cytostatic, a glucocorticoid, a hemostatic, an immunoglobulin or its fragment, a chemokine, a cytokine, a mitogen, a cell differentiation factor, a cytotoxic agent, a hormone, an immunosuppressant, an immunostimulant, a morphine antagonist, an muscle relaxant, a narcotic, a vector, a peptide, a (para) sympathicomimetic, a (para) sympatholytic, a protein, a cell, a selective estrogen receptor modulator (SERM), a sedating agent, an antispasmodic, a substance that inhibits the resorption of bone, a vasoconstrictor or vasodilator, a virustatic, or a wound-healing agent. In some embodiments, the therapeutic agent can include a hemostatic agent (e.g., aluminum sulfate, fibrin, micronized gelfoam, etc.), which can be especially beneficial when implanting the depot in areas with high vascular flow and potentially above-average post-operative bleeding (e.g., thoracic, abdominal, anorectal, head and neck, etc.).
In some embodiments, the therapeutic agent is or includes a drug used in the treatment of cancer or a pharmaceutically acceptable salt thereof. Such chemotherapeutic agents include antibodies, alkylating agents, angiogenesis inhibitors, antimetabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine/threonine kinase inhibitors. Specific therapeutic agents include, but are not limited to, adalimumab, ansamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribin, cytarabin, cryptophycins, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferons, interleukins, 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.
In some embodiments, the therapeutic agent is or includes a botulinum toxin or other neurotoxin used in the treatment of various neuromuscular and/or neuroglandular disorders and neuropathies associated with pain. The botulinum toxin or other neurotoxin can include the pharmacologically active drug or a pharmaceutically acceptable salt thereof. The botulinum toxin can be selected from a variety of strains of Clostridium botulinum and may comprise the pharmacologically active drug or a pharmaceutically acceptable salt thereof. In some embodiment, the botulinum toxin is selected from the group consisting of botulinum toxin types A, B, C, D, E, F, and G.
A pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of neutral therapeutic agents and that are not otherwise unacceptable for pharmaceutical use. Pharmaceutically acceptable salts include salts of acidic or basic groups, which groups may be present in the therapeutic agents. The therapeutic agents used in the present technology that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts of basic therapeutic agents used in the present technology can include those that form non-toxic acid addition salts, i.e., salts comprising pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The therapeutic agents of the present technology that include an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Suitable base salts can be formed from bases which form non-toxic salts, and can include aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or diethanolamine salts.
A pharmaceutically acceptable salt can include another molecule, such as water or another biologically compatible solvent (a solvate), an acetate ion, a succinate ion, or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Optionally, a pharmaceutically acceptable salt can include multiple counterions.
The therapeutic agent or pharmaceutically acceptable salt thereof can be an essentially pure compound, or can be formulated with a pharmaceutically acceptable carrier such as diluents, adjuvants, excipients, or vehicles known to one skilled in the art. The carrier(s) can be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. For example, diluents can include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, and the like.
The therapeutic agent or pharmaceutically acceptable salt form can be micronized, jet milled, or passed through a sieve to form consistent particle sizes, which can further facilitate the controlled release of the therapeutic agent. This process can be helpful for highly insoluble therapeutic agents, for example. In some embodiments, the particle size of the therapeutic agent (e.g., the DS50 value) is less than or equal to 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.
Suitable dosage ranges utilizing the depot of the present technology are dependent on the potency of the particular therapeutic agent, but can be within a range from about 0.001 mg to about 500 mg of drug per kilogram body weight, for example, within a range from about 0.1 mg to about 200 mg of drug per kilogram body weight, or within a range from about 1 to about 100 mg per kg body weight. Dosage ranges may be readily determined by methods known to one skilled in the art. Dosage unit forms can contain between about 1 mg to about 500 mg of active ingredient.
In some embodiments, the therapeutic agent constitutes at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total mass of the depot (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 within a range from 25% to 75%, 40% to 80%, 50% to 65%, or 60% to 65%. In some embodiments, the therapeutic agent constitutes at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the total mass of the therapeutic region. The mass percent of the therapeutic agent in the therapeutic region can be within a range from 25% to 75%, 40% to 80%, 50% to 65%, or 60% to 65% of the total mass of the therapeutic region.
In some embodiments, the depots described herein have a total mass (e.g., total dry mass) within a range from 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 can be greater than or equal to 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.
The total mass of the therapeutic agent within the depot can be within a range from 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 the therapeutic agent within an individual depot is greater than or equal to 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, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg.
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, sustained manner when exposed to physiologic fluids at a treatment site in vivo, even when the depot includes fewer control regions (e.g., the depot 100b of
The therapeutic agent in the implantable depot can be provided partially or entirely in the 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 can be in the 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 can be in the hydrophobic form. Optionally, the implantable depot can include a combination of a hydrophobic form and a hydrophilic form of the therapeutic agent. The relative amounts of the hydrophobic form and the hydrophilic form can be selected to produce a desired release profile, e.g., increasing the relative amount of the hydrophobic form can produce a slower release rate, while increasing the relative amount of the hydrophilic form can produce a faster release rate. In some embodiments, the ratio of the total mass of the hydrophobic form to the total mass of the hydrophilic form is greater than or equal to 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.
The use of the hydrophobic form of the therapeutic agent can provide various benefits. For example, when the hydrophobic form is used, the depot can be fabricated with fewer control regions or even no control regions, thus simplifying the manufacturing process and/or reducing the likelihood of inadvertent 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 decrease the depot size. Additionally, when the hydrophobic form of the therapeutic agent is used in combination with control regions, the release duration of the therapeutic agent can be extended even further, thus allowing for controlled release over extended time periods that would otherwise be difficult or impossible with conventional systems. Moreover, the hydrophobic form may exhibit a different melting point (e.g., a lower melting point) and/or different solubility (e.g., improved solubility in organic solvents) than the hydrophilic form. This may make manufacturing of the depot easier and/or allow for additional manufacturing options, compared to depots formulated primarily or entirely out of the hydrophilic form.
In some embodiments, the implantable depot is configured to release multiple therapeutic agents in a simultaneous or sequential manner, e.g., to provided added clinical benefits. For example, in the context of pain management, the depot can release a first analgesic having a faster onset (e.g., lidocaine) and a second analgesic having a slower onset (e.g., bupivacaine). 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 within the depot and/or in the surrounding environment). The second therapeutic agent can enhance the efficacy of the first therapeutic agent or can independently provide a therapeutic benefit for the patient. The implantable depots described herein can include any suitable number of therapeutic agents, such as one, two, three, four, five, or more different therapeutic agents.
The depots of the present technology (e.g., the depots 100a-560 of
In some embodiments, the polymer(s) used in the depots of the present technology are bioresorbable polymers. The bioresorbable polymers used in the present technology can have a predetermined degradation rate. The terms “bioresorbable” or “bioabsorbable” can mean that a polymer will be absorbed within the patient's body, for example, by a cell or tissue. These polymers can be “biodegradable” in that all or parts of the polymer will degrade over time by the action of enzymes, by hydrolytic action, and/or by other similar mechanisms in the patient's body. In some embodiments, the bioresorbable polymer breaks down or degrades within the body to non-toxic components while a therapeutic agent is being released. Bioresorbable polymers used as base components of the depots of the present technology may break down or degrade after the therapeutic agent is fully released. The bioresorbable polymers can also be “bioerodible,” in that they will erode or degrade over time due, at least in part, to contact with substances found in the surrounding tissue, fluids or by cellular action.
Suitable polymers for use in the depots of the present technology include, but are not limited to: 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), polyhydroxyalkanoate (PHA), polyhydroxybutyrate (PHB) (e.g., poly(4-hydroxy butyrate)), poly(phosphazene) (e.g., ethyl glycinate poly(phosphazene)), poly(phosphate ester), poly(amino acid), poly(depsipeptide), poly(butylene succinate) (PBS), poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), poly(ethylene glycol) (PEG), a poloxamer (e.g., PEO—PPO-PEO), a PEO-PPO-poly(acrylic acid) copolymer (PEO—PPO-PAA), PLGA-PEO-PLGA, PEG-PLG, PEG-PLGA-PEG, poly(vinylpyrrolidone) (PVP), polyvinyl alcohol (PVA), PVA-grafted PLGA (PVA-g-PLGA), poly(N-isopropylacrylamide), poly(methacrylate), poly(hydroxyethylmethacrylate), poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate), polymethylmethacrylate (PMMA), poly(propylene fumarate), poly(iminocarbonate), poly(glycolide-co-trimethylene carbonate), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly(1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid), poly(caprolactone co-butylacrylate), a copolymer of maleic anhydride, cellulose or a cellulose derivative (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose or a salt thereof), a copolymer of poly(ethylene glycol terephthalate) and poly(butylene terephthalate) (PEGT-PBT) (e.g., PolyActive), a polysaccharide (e.g., hyaluronic acid, chitosan, starch, pre-gelatinized starch, alginate, dextran), sucrose acetate isobutyrate (SAIB), poly(aspirin), a polymer incorporating vitamin E or a vitamin E analog (e.g., alpha tocopheryl acetate, D-alpha tocopheryl succinate), Carbopol®, or a protein (e.g., gelatin, collagen, albumin), or a copolymer derivative, or combination thereof.
Optionally, the polymers described herein can be modified to include functional side groups or chains. For example, the polymer can be grafted with, crosslinked to, or otherwise covalently bonded to a hydrophilic side chain, such as PEG. This approach can be advantageous for ensuring consistent, controlled release of the therapeutic agent. In some situations, when the therapeutic agent elutes from the therapeutic region, the voids or spaces in the polymer that were previously occupied by the therapeutic agent may collapse to form partially or completely impermeable polymer regions. If the collapse occurs near the portions of the therapeutic region that are in contact with physiologic fluid, this can create a barrier that partially or completely inhibits further elution of therapeutic agent from those locations. However, polymers including hydrophilic side chains can swell when exposed to fluid, thus reducing the likelihood of collapse and allowing continued release of the therapeutic agent.
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 may impact water uptake into the depot, which in turn can alter the release rate of the therapeutic agent. More hydrophilic polymers (e.g., PLGA with a higher glycolic acid content, polymers incorporating PEG covalently into the polymer backbone) may produce higher release rates than more hydrophobic polymers. In some embodiments, the different end groups of the polymer can be selected to affect the hydrophilicity of the polymer. For example, polymers having an acid terminal group can be more hydrophilic than polymers having an ester terminal group.
In some embodiments, the mass percent of the polymer in the depot is no more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. The mass percent of the polymer in the depot can be within a range from 10% to 60%, 20% to 50%, 25% to 40%, or 30% to 35%. In some embodiments, the mass percent of the polymer in the therapeutic region is no more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%. The mass percent of the polymer in the therapeutic region can be within a range from 10% to 60%, 20% to 50%, 25% to 40%, or 30% to 35%. In some embodiments, the mass percent of the polymer in an individual 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 mass percent of the polymer in the control region can be within a range from 25% to 75%, 40% to 80%, 50% to 65%, 60% to 65%, 50% to 75%, or 75% to 100%.
The total mass of the polymer within the depot can be within a range from 100 mg to 1000 mg, 100 mg to 500 mg, 150 mg to 350 mg, 250 mg to 350 mg, or 300 mg to 350 mg. In some embodiments, the total mass of the polymer is 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.
In some embodiments, the ratio of the mass of the therapeutic agent in the depot to the mass of the polymer in the depot is at least 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, or 16:1. In some embodiments, the ratio of the mass of the polymer in the therapeutic region to the mass of the therapeutic agent in the therapeutic 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.
In some embodiments, the polymers disclosed herein are configured to degrade at a sufficiently slow rate so that the depot maintains sufficient flexural strength and/or mechanical integrity in vivo for at least a predetermined period of time or until a predetermined proportion of therapeutic agent has been released from the depot. The depot can be considered to maintain its structural integrity if the depot remains largely intact with only partial or gradual reduction due to elution of therapeutic agent or dissolution of the control regions or releasing agent. The depot can be considered to lose its structural integrity if it separates (e.g., fractures) into multiple component pieces, for example, with two or more of the resulting pieces being at least 5% of the previous size of the depot. Alternatively, or additionally, the depot can be considered to lose its structural integrity if the release rate of the therapeutic agent increases by more than a factor of three as compared to the release rate of therapeutic agent in a control depot submerged in a buffered solution. In some embodiments, the molecular weight of the polymer can be selected to account for a loss in molecular weight that occurs during the manufacturing process such that the post-manufacturing molecular weight remains above a minimum weight required to achieve a desired sustained release profile.
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 proportion of therapeutic agent payload has been released from the depot. For example, the depot can be configured to maintain its structural integrity in vivo until at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the original mass of the therapeutic agent in the depot has been released.
The depots of the present technology (e.g., the depots 100a-560 of
In some embodiments, the releasing agent is a polysorbate, such as Polysorbate 80, Polysorbate 60, Polysorbate 40, or Polysorbate 20 (Tween 20™). Other releasing agents suitable for use in the present technology include polyethylene glycol (e.g., PEG 3000, PEG 6000, PEG 10,000, etc.), polyvinyl alcohols, sorbitan fatty acid esters (e.g., sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), sorbitane trioleate (Span 85), sorbitan monooleate (Span 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 oils (e.g., polyethoxylated castor oil, polyoxyl hydrogenated castor oil, Polyoxyl 35 castor oil, Polyoxyl 40 Hydrogenated castor oil, Polyoxyl 40 castor oil, Cremophor® RH60, Cremophor® RH40), polyethylene glycol ester glycerides (e.g., Labrasol®, Labrifil® 1944), poloxamers, polyoxyethylene polyoxypropylene 1800, polyoxyethylene fatty acid esters (e.g., Polyoxyl 20 Stearyl Ether, diethylene glycol octadecyl ether, glyceryl monostearate, triglycerol monostearate, Polyoxyl 20 stearate, Polyoxyl 40 stearate, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate), oleic acid, sodium desoxycholate, sodium lauryl sulfate, myristic acid, stearic acid, vitamin E 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.
In some embodiments, the mass percent of the releasing agent in the depot is no more than 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%. The mass percent of the releasing agent in the depot can be within a range from 0.1% to 20%, 0.5% to 10%, or 1% to 5%. In some embodiments, the mass percent of the releasing agent in the therapeutic region is no more than 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%. The mass percent of the releasing agent in the therapeutic region can be within a range from 0.1% to 20%, 0.5% to 10%, or 1% to 5%. In some embodiments, the mass percent of the releasing agent in an individual control region is no more than 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%. The mass percent of the releasing agent in the control region can be within a range from 0.1% to 20%, 0.5% to 10%, 1% to 5%, 10% to 50%, 20% to 40%, or 30% to 35%.
The total mass of the releasing agent in the depot can be within a range from 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 releasing 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.
In some embodiments, the ratio of the mass of the releasing agent to the mass of the polymer in therapeutic region is no more than 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. In some embodiments, the ratio of the mass of the releasing agent to the mass of the polymer to the mass of the therapeutic agent in the therapeutic region is within a range from 0.1:10:20 to 2:10:20, from 0.1:10:20 to 1:10:20, from 0.1:10:20 to 0.5:10:20, from 0.5:10:20 to 0.1:10:20, from 0.5:10:20 to 1:10:20, from 1:10:20 to 10:10:20, from 1:10:20 to 5:10:20, from 2:10:20 to 5:10:20, or from 5:10:20 to 10:10:20. In other embodiments, the therapeutic region may not include any releasing agent.
In some embodiments, the ratio of the mass of the releasing agent to the mass of the polymer in an individual control region is at least 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, or 1:25. In other embodiments, the control region may not include any releasing agent.
The depots of the present technology (e.g., the depots 100a-560 of
The release profile of a depot can be measured using in vitro or in vivo techniques. Any description herein of a release profile of a depot can refer to in vitro release, in vivo release, or both, unless otherwise specified. The release profile of a depot can be measured in vitro by immersing the depot in a suitable elution medium (e.g., phosphate-buffered saline) at a controlled temperature (e.g., 37° C.) and pH (e.g., 7.4, 5.8), and measuring the amount of released therapeutic agent at various time points (e.g., using spectrophotometric techniques). When measuring in vitro release, the elution pH and/or other parameters can be configured to approximate in vivo physiologic conditions (e.g., release is measured at pH 7.4). Alternatively, the elution pH and/or other parameters can be selected based on other considerations. For example, as a product advances in development or manufacturing, an accelerated in vitro release process can be developed, e.g., to facilitate quality control testing. The accelerated in vitro release can be accomplished through an increase in temperature, the addition of a surfactant or organic co-solvent to the aqueous buffer, and/or by a change in pH. For example, accelerated in vitro release can be measured at pH 5.8.
The release profile of a 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 from the subject at various time points (e.g., blood samples, plasma samples, synovial fluid samples), and measuring the amount of therapeutic agent in the sample (e.g., using liquid chromatography tandem mass spectrometry). Optionally, a cumulative in vivo release profile can be estimated from concentration data by assuming that the total area under the curve (AUC0-inf) of the concentration data corresponds to 100% release of the total therapeutic agent dose in the depot, then calculating the cumulative percentage release of the therapeutic agent at each study time point t1 from the ratio of AUC0-t1 to AUC0-inf normalized to 100%. 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 fully evaporated, and the therapeutic agent can be reconstituted using a suitable solvent (e.g., methanol). The reconstituted sample can be analyzed via high-performance liquid chromatography (HPLC) to measure the amount of therapeutic agent in the sample.
In some embodiment, the depots herein are configured to release the therapeutic agent at different rates over the treatment period. For example, the depots herein can release the therapeutic agent at a first rate during a first time period of the treatment, and a second rate during a second, subsequent time period of the treatment. For example, the first period can be the first 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days of the treatment period; and the second period can be the next 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days after the first period. Stated differently, the first period 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; and the second period can be the next 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 after the first treatment period. The first rate may be the same as or different than (e.g., less than or greater than) the second rate. In some embodiments, the first rate is at least 2-fold, 3-fold, 4-old, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the second rate, or vice-versa.
In some embodiments, the depot releases a first amount of the therapeutic agent over the first time period and a second amount of the therapeutic agent over the second time period. The first amount can be least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of the initial amount (e.g., by mass) of the therapeutic agent in the depot; 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 the therapeutic agent in the depot. The second amount can be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the initial amount of the therapeutic agent in the depot; and/or the second amount can be no more than 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, or 10% of the initial amount of the therapeutic agent in the depot. Optionally, the depot can release a third amount of the therapeutic agent over a third time period subsequent to the second time period. The third amount can be at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 30% of the initial amount of the therapeutic agent in the depot; and/or the third amount can be no more than 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial amount of the therapeutic agent in the depot.
For example, when measured in vitro at pH 5.8, the depot can exhibit the following release profile: the depot can release from 10% to 35% of the therapeutic agent over the first 5 hours to 10 hours of the treatment period; the depot can release from 5% to 65% of the therapeutic agent over the next 25 hours to 35 hours of the treatment period; and/or the depot can release from 1% to 60% of the therapeutic agent over the next 115 hours to 130 hours of the treatment period.
In some embodiments, when measured in vitro at pH 5.8, the depot exhibits the following release profile: the cumulative amount of therapeutic agent released over the first 6 hours to 8 hours of the treatment period is within a range from 5% to 40%, from 10% to 35%, or from 15% to 30% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 35 hours to 42 hours of the treatment period is within a range from 35% to 80%, from 37% to 77%, from 40% to 75%, or from 42% to 72% of the initial amount of the therapeutic agent in the depot; and/or the cumulative amount of therapeutic agent released over the first 159 hours to 161 hours of the treatment period is at least 60%, 70%, or 80% of the initial amount of the therapeutic agent in the depot.
In some embodiments, when measured in vitro at pH 5.8, the depot exhibits the following release profile: 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; at least 40% of the therapeutic agent in the depot is released over the first 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, or 15 hours of the treatment period; at least 50% of the therapeutic agent in the depot is released over the first 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, or 20 hours of the treatment period; at least 60% of the therapeutic agent in the depot is released over 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, 27.5 hours, 28 hours, 29 hours, or 30 hours of the treatment period; at least 70% of the therapeutic agent is released over the first 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours or 40 hours of the treatment period; at least 80% of the therapeutic agent is released over the first 50 hours, 52 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 62 hours, 64 hours, 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 hours, 105 hours, 110 hours, 115 hours, 120 hours, 125 hours, 130 hours, 135 hours, 140 hours, 145 hours, or 150 hours of the treatment period.
In some embodiments, when measured in vitro at pH 7.4 and/or in vivo, the depot exhibits the following release profile: the cumulative amount of therapeutic agent released over the first 24 hours of the treatment period is within a range from 1% to 25%, 1% to 10%, or 1% to 5% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 48 hours of the treatment period is within a range from 1% to 30%, 5% to 20%, or 5% to 15% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 72 hours of the treatment period is within a range from 10% to 35%, 10% to 25%, or 15% to 25% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 96 hours of the treatment period is within a range from 15% to 50%, 10% to 40%, or 10% to 30% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 120 hours of the treatment period is within a range from 20% to 60%, 25% to 50%, or 30% to 40% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 144 hours of the treatment period is within a range from 25% to 70%, 30% to 50%, or 35% to 45% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 7 days to 8 days of the treatment period is within a range from 30% to 70%, or 35% to 55% of the initial amount of the therapeutic agent in the depot; the cumulative amount of therapeutic agent released over the first 14 days of the treatment period is within a range from 50% to 90%, or 60% to 80% of the initial amount of the 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 a range from 70% to 99%, or 85% to 95% of the initial amount of the therapeutic agent in the depot.
In some embodiments, when measured in vitro at pH 7.4 and/or in vivo, the depot exhibits the following release profile: up to 10% of the therapeutic agent in the depot is released over the first 4 hours, 12 hours, 24 hours, or 48 hours of the treatment period; up to 20% of the therapeutic agent in the depot is released over the first 24 hours, 48 hours, 72 hours, or 84 hours of the treatment period; up to 30% of the therapeutic agent in the depot is released over the first 48 hours, 72 hours, 120 hours, or 144 hours of the treatment period; up to 40% of the therapeutic agent in the depot is released over the first 120 hours, 144 hours, 168 hours, or 192 hours of the treatment period; up to 50% of the therapeutic agent in the depot is released over the first 7 days, 8 days, 9 days, or 10 days of the treatment period; up to 60% of the therapeutic agent in the depot is released over the first 10 days, 11 days, 12 days, or 13 days of the treatment period; up to 70% of the therapeutic agent in the depot is released over the first 13 days, 14 days, 15 days, or 16 days of the treatment period; up to 80% of the therapeutic agent in the depot is released over the first 16 days, 17 days, 18 days, 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 days, 20 days, 21 days, or 22 days of the treatment period.
In some embodiments, the release profile of the therapeutic agent is a first order release profile (which can be modeled by the equation Qt=Q0e−kt where Qt is amount of therapeutic agent released at time t, Q0 is the initial amount of therapeutic agent in the depot, and k is the rate constant). Alternatively, the release profile can be a zero order release profile, a second order release profile, or any other suitable release profile known to those of skill in the art.
The depots described herein can be configured to release a larger amount of the therapeutic agent per day for a first time period than for a longer second time period. In some embodiments, the depot is configured to release the therapeutic agent for at least 14 days post-implantation (or post-immersion in a fluid), where a controlled burst of about 20% to about 50% of the therapeutic agent payload is released in the first 3 days to 5 days, and at least 80% of the remaining therapeutic agent payload is released at a slower rate over the last 10 days to 11 days. In some embodiments, at least 90% of the therapeutic agent payload is released by the end of 14 days.
A two-stage release profile may be especially beneficial in the context of treating pain resulting from a total knee arthroplasty (“TKA”). TKA patients typically experience the greatest pain within the first 1 day to 3 days following surgery (clinically referred to as “acute pain”) with increasingly less pain over the next 7 days to 10 days (clinically referred to as “subacute pain”). The acute period often overlaps or coincides with the patient's inpatient care (usually 1 day to 3 days), and the subacute period generally begins when the patient is discharged and returns home. The two-stage release profile can also be beneficial for other surgical applications, such as other orthopedic applications (e.g., ligament repair/replacement and other damage to the knee, shoulder, ankle, etc.) or non-orthopedic surgical applications, as described in greater detail below. Excessive pain following any surgery may extend inpatient care, cause psychological distress, increase opioid consumption, and/or impair patient participation in physical therapy, any of which may prolong the patient's recovery and/or mitigate the extent of recovery. Pain relief during the subacute period may be particularly complicated to manage, as patient compliance with the prescribed pain management regimen drops off when patients transition from an inpatient to home environment.
To address the foregoing challenges in post-surgical pain management, the depots of the present technology may have a release profile tailored to meet the pain management needs specific to the acute and subacute periods. For example, to address the greater acute pain that occurs immediately following surgery, the depot can be configured to release the therapeutic agent at a faster rate for the first 3 days to 5 days after implantation compared to the subsequent 9 days to 11 days. In some embodiments, the depot delivers a local anesthetic at a rate from 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 for the remaining 9 days to 11 days. In some embodiments, the depot delivers a local anesthetic at a rate from about 50 mg/day to about 250 mg/day during this second, subacute period. In some embodiments, the rate of release continuously decreases throughout the first period and/or the second period.
The release profile of the depot can be tuned to release a therapeutic agent for other durations and/or at other release rates by adjusting the structure, composition, and/or the 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 duration of release. In some embodiments, the depot is to release the therapeutic agent at a constant rate for a first time period and at a non-constant rate for a second time period (which may occur before or after the first time period).
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 in the first day, 2 days, 3 days, 4 days, 5 days, 6 days, 8 days, 9 days, 10 days, 11 days, 12 days, or 13 days of the duration of release, and at least 75%, 80%, 85%, 90%, 95%, or 100% of the remaining therapeutic agent is released in the remaining days of the duration of release. The intended duration of release may 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.
In some embodiments, the depot is configured to release from 50 mg/day to 600 mg/day, from 100 mg/day to 500 mg/day, from 100 mg/day to 400 mg/day, or from about 100 mg/day to 300 mg/day of the therapeutic agent to the treatment site. In general, the release rate can be selected to deliver the desired dosage to provide the extent of pain relief needed at a given time after the surgical procedure, control toxicity, and deliver the therapeutic agent for a sufficient period of time for pain relief. In some embodiments, the depot is configured to release 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of therapeutic agent within any day of the duration of release.
In some embodiments, the depot is configured to release from 50 mg/day to 600 mg/day, from 100 mg/day to 500 mg/day, from 100 mg/day to 400 mg/day, or from 100 mg/day to 300 mg/day of the therapeutic agent to the treatment site within a first time period of release. The depot can further be configured to release from 500 mg/day to 600 mg/day, from 100 mg/day to 500 mg/day, from 100 mg/day to 400 mg/day, or from 100 mg/day to 300 mg/day of the therapeutic agent to the treatment site within a second time period of release. The release rate during the first time period can be the same as, different than, less than, or greater than the release rate during the second time period. Moreover, the first time period can be longer or shorter than the second time period. The first time period can occur before or after the second time period.
In some embodiments, the depot is configured to release no more than 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 the therapeutic agent within any day of a first time period of release. Alternatively or in combination, 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, or 300 mg of the therapeutic agent within any day of the first time period of release. This may be useful for providing different degrees of pain relief at different times after the surgical procedure, and it may also be useful to control 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 the therapeutic agent within any day of a second time period of release. The first time period and/or the second time 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.
One or more depots of the present technology can be implanted at a treatment site in order to produce a desired level of therapeutic agent in vivo, such as a level at or above a therapeutic threshold and/or below a toxicity threshold. For example, when implanted, one or more depots of the present technology can produce a mean plasma concentration of the therapeutic agent greater than or equal to a therapeutic threshold of 5 ng/ml, 10 ng ml, 15 ng/ml, 20 mg/ml, 25 ng/ml, 30 ng/ml, 40 ng/ml, 50 ng/ml, 60 ng/ml, 70 ng/ml, 80 ng/ml, 90 ng/ml, 100 ng/ml, 110 ng/ml, 120 ng/ml, 130 ng/ml, 140 ng/ml, 150 ng/ml, 160 ng/ml, 170 ng/ml, 180 ng/ml, 190 ng/ml, 200 ng/ml, 210 ng/ml, 220 ng/ml, 230 ng/ml, 240 ng/ml, 250 ng/ml, 300 ng/ml, 400 ng/ml, 500 ng/ml, 600 ng/ml, 700 ng/ml, 800 ng/ml, 900 ng/ml, or 1000 ng/ml. Alternatively or combination, the depot(s) can produce a mean plasma concentration of the therapeutic agent less than or equal to a toxicity threshold of 9000 ng/ml, 8000 ng/ml, 7000 ng/ml, 6000 ng/ml, 5000 ng/ml, 4000 ng/ml, 3000 ng/ml, 2500 ng/ml, 2400 ng/ml, 2300 ng/ml, 2200 ng/ml, 2100 ng/ml, 2000 ng/ml, 1900 ng/ml, 1800 ng/ml, 1700 ng/ml, 1600 ng/ml, 1500 ng/ml, 1400 ng/ml, 1300 ng/ml, 1200 ng/ml, 1100 ng/ml, or 1000 ng/ml. The mean plasma concentration of the therapeutic agent can be maintained above the therapeutic threshold and/or below the toxicity threshold 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, when implanted, the depot(s) produce a mean Cmax of the therapeutic agent that is less than or equal to 1000 ng/ml, 900 ng/ml, 800 ng/ml, 700 ng/ml, 600 ng/ml, 500 ng/ml, 400 ng/ml, 300 ng/ml, 200 ng/ml, 100 ng/ml, or 50 ng/ml. The depot(s) can produce a mean t1/2 of the therapeutic agent that is greater than or equal to 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. The depot(s) can produce a mean tmax 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. The depot(s) can produce a mean tlast of the therapeutic agent that is at least 7 days, 8 days, 9 days, 10 days, 12 days, 13 days, 14 days, 15 days, 16 days, 20 days, 25 days, 30 days, 35 days, 40 days, or 45 days.
In some embodiments, when implanted, the depot(s) produce a mean AUCt1-t2 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; where the time period t1-t2 can be any of the following: 0 days to 7 days, 0 days to 14 days, 0 days to 21 days, 0 days to 30 days, 3 days to 7 days, 7 days to 14 days, 7 days to 21 days, 7 days to 30 days, 14 days to 21 days, 14 days to 30 days, or 21 days to 30 days. The depot(s) can produce a mean AUClast 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.
The depots of the present technology (e.g., the depots 100a-560 of
The amount or dose of the therapeutic agent that will be effective in a patient in need thereof can depend on the specific nature of the condition, and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The specific dose level for any particular individual will depend upon a variety of factors including the activity of the drug, the age, body weight, general physical and mental health, genetic factors, environmental influences, sex, diet, time of administration, location of administration, rate of excretion, and/or the severity of the particular problem being treated.
Some aspects of the present technology include a system including one or more depots (each of which could be any of the depots described herein) provided for implantation by a clinical practitioner. For example, a system can include one, two, three, four, five, six, seven, eight, nine, ten, or more implanted depots. Each depot can be configured for controlled release of a therapeutic agent to tissue proximate to the implantation site of the depot. Accordingly, the depots can collectively provide a desired dose of the therapeutic agent, such as a dose greater than or equal to 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, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, or 1800 mg. The dose provided by an individual depot or a set of depots can be expressed in terms of the mass of the therapeutic agent used in the depot(s), or in terms of the mass of another form of the therapeutic agent (e.g., the form of the active moiety or the established salt form). For example, the dose of bupivacaine in a depot formulated with bupivacaine hydrochloride monohydrate may 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 bupivacaine hydrochloride monohydrate is equivalent to 563 mg of bupivacaine hydrochloride).
In embodiments where the system includes multiple depots, some or all of the depots in the system can be identical and/or some or all of the depots can differ from each other (e.g., with respect to geometry, composition, and/or release profile). For example, the system can include at least one depot having a release profile that provides for an immediate release of a therapeutic agent, and at least one other depot having a release profile that provides for a delayed release of the therapeutic agent.
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 the sensation of pain, both of which can be assessed objectively and subjectively, using pain scores and other methods well-known in the art, such as opioid usage, as described in further detail below. Pain can include allodynia (e.g., increased response to a normally non-noxious stimulus) or hyperalgesia (e.g., increased response to a normally noxious or unpleasant stimulus), which can in turn be thermal or mechanical (tactile) in nature. In some embodiments, pain is characterized by thermal sensitivity, mechanical sensitivity, and/or resting pain. The pain can be primary or secondary pain, as is well-known in the art. Exemplary types of pain reducible, preventable or treatable by the methods and compositions disclosed herein include, without limitation, postoperative pain, for example, from the back in the lumbar regions (lower back pain) or cervical region (neck pain), leg pain, radicular pain (experienced in the lower back and leg from lumbar surgery in the neck and arm from cervical surgery), or abdominal pain from abdominal surgery, and neuropathic pain of the arm, neck, back, lower back, leg, and related pain distributions resulting from disk or spine surgery. Neuropathic pain may include pain arising from surgery to the nerve root, dorsal root ganglion, or peripheral nerve.
In some embodiments, the pain includes “post-surgical pain,” “postoperative pain,” or “surgery-induced pain,” which are used herein interchangeably, and refer to pain arising in the recovery period of seconds, minutes, hours, days or weeks following a surgical procedure (e.g., hernia repair, orthopedic or spine surgery, etc.). Surgical procedures can include any procedure that penetrates beneath the skin and causes pain and/or inflammation to the patient. Surgical procedures can be performed at various sites in a patient's body. For example, surgery may be performed at a patient's knees, hips, upper extremities, lower extremities, neck, spine, shoulders, chest, nasal/sinus region, abdomen, and/or pelvic region.
Some embodiments of the present technology include one or more depots (e.g., having the same or different configuration and/or dosing) that are positioned at or near a surgical site of a knee joint to treat pain associated with a total knee replacement surgery, also known as TKA. In some instances, 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 pouch, specifically under the periosteum and attached to the quadriceps tendon. Additional areas for placement of one or more depots may include generally the medial and lateral gutters (including optional fixation to tissue at the medial or lateral side of the respective gutter), on the femur, on the tibia (e.g., posterior attachment to the tibial plateau, at or near the anterior tibia to anesthetize infrapatellar branches of the saphenous nerve). In some embodiments, one or more depots are positioned adjacent to at least one of a posterior capsule of the knee, a superior region of the patella, and/or the arthrotomy incision into the knee capsule. In some embodiments, one or more depots are positioned at or near the saphenous nerve, the adductor canal, and/or the femoral nerve. In some embodiments, one or more depots are positioned at or near an infrapatellar branch of the saphenous nerve, one or more genicular nerves of the knee, a superior region of the patella. It may be desirable to position the depot(s) within the knee capsule but away from any articulating portions of the knee joint itself.
In some embodiments, one or more depots are positioned at or near one or more nerves innervating an anterior knee capsule. For example, the depot(s) may be configured to be positioned at or near a superolateral genicular branch from the vastus lateralis, a superomedial genicular branch from the vastus medialis, a medial (retinacular) genicular branch from the vastus intermedius, an inferolateral genicular branch from the common peroneal nerve, an inferomedial genicular branch from the saphenous nerve, and/or a lateral (retinacular) genicular branch from the common peroneal nerve. Instead of or in addition to the placement of depots within the intracapsular space, one or more depots may be placed at an extracapsular position. In some embodiments, the depot(s) are implanted adjacent to one or more extracapsular nerves. In some embodiments, one or more depots are positioned along or adjacent the subcutaneous skin incision.
So as not to interfere or overlap with a peripheral nerve block administered perioperatively to the patient, one or more of the depots may optionally include a delayed release capability for 6 hours to 24 hours following implantation. In some embodiments, one or more depots placed in the adductor canal and knee capsule are configured to have a delay in the release of therapeutic agent of at least 24 hours.
In some embodiments, the depots of the present technology utilize regional procedures for controlling pain following TKA. Such procedures can include local anesthetic infiltration between the popliteal artery and capsule of the knee (IPACK) block. An IPACK block procedure typically involves scanning the popliteal fossa using a probe proximal the popliteal crease, and injecting an analgesic (e.g., 20 ml of 0.25% ropivacaine) between the patient's popliteal artery and femur. Unlike other known procedures (e.g., adductor canal block (ACB) and femoral nerve catheter (FNC) block) for treating postoperative pain following TKA, IPACK block targets only the terminal branches of the sciatic nerve. In doing so, analgesia and/or other therapeutic agents can be provided to the posterior knee region without causing distal neurologic deficits. In some embodiments, the depots of the present technology are implanted using a combination of the IPACK block procedure and the ACB or FNC block procedures. For example, patients can preoperatively receive one or more depots utilizing an FNC block, and then receive one or more additional depots utilizing a postoperative IPACK block. Utilizing the IPACK block procedure with depots of the present technology can advantageously provide adequate analgesia following TKA, promote improved physical therapy performance, reduce the incident of foot drop, reduce opioid consumption, and/or better control posterior knee pain following TKA, e.g., relative to ACB, FNC block, or other known techniques for pain management following TKA, often allowing for earlier hospital discharge.
The depots disclosed herein can be used to treat postoperative pain associated with other knee surgeries. For example, one or more depots may be used to treat postoperative pain associated with an ACL repair surgery, a medial collateral ligament (“MCL”) surgery, and/or a posterior cruciate ligament (“PCL”) surgery. For ACL repair, one or more depots may be positioned to delivery analgesic the femoral and/or sciatic nerves, while for PCL repair surgery, one or more depots may be positioned parasacral to deliver analgesic to the sciatic nerve. The one or more depots may be used to treat postoperative pain associated with a partial knee replacement surgery, total knee replacement surgery, and/or a revision surgery of a knee replacement surgery. In such procedures, one or more depots can be placed contiguous to the joint or repair site to provide a local block, or else may suitably positioned to provide a regional block by delivering an analgesic to one or more of the femoral nerve or the sciatic nerve, for example via placement in the adductor canal.
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, legs, or arms. For at least some of these surgical procedures, an analgesic can be provided to deliver a local block or a regional block to treat postoperative pain. For a local block, one or more depots can be attached under direct vision in open surgery, for example during joint arthroplasty, open reduction and internal fixation (ORIF) surgery, ligament reconstruction, etc. In procedures involving a joint, one or more depots can be positioned at the joint capsule (e.g., at or near the intracapsular and/or extracapsular space of the joint) and/or adjacent soft tissues spaced apart from articulating surfaces to avoid the depot interfering with joint movement or being damaged by contact with articulating surfaces. In procedures involving fracture repair or ligament repair, one or more depots can be positioned at or adjacent to the repair site to provide a local block. For a regional block, one or more depots can be deposited at a treatment site adjacent to the target nerve via ultrasound guidance using a blunt trocar catheter or other suitable instrument. In some embodiments, it can be beneficial to combine delivery of an analgesic or other therapeutic agents via the depot(s) with delivery of NSAIDs, a long-acting narcotic delivered pre-operatively, and/or acetaminophen. The sustained, controlled, release of an analgesic via the 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.
For example, one or more depots can be used to treat postoperative pain associated with foot and/or ankle surgeries, such as ankle arthroplasty (including ankle revision, ankle replacement, and total ankles replacement), ankle fusion, hindfoot fusion, ligament reconstruction, corrective osteotomies (e.g., bunionectomy, pes planus surgery), or ORIF of ankle or foot 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 local block. Additionally or alternatively, one or more depots can be placed parasacral or at another suitable location to target one or more of the subgluteal sciatic nerve, popliteal sciatic nerve, deep peroneal nerve, or the superficial peroneal nerve. In some embodiments, depots positioned to treat postoperative pain associated with ankle or foot surgeries have a release profile configured to deliver therapeutically beneficial levels of analgesic for a period of 3 days to 7 days.
In another example, one or more depots can be used to treat postoperative pain associated with hip surgeries, such as hip arthroplasty (including hip revision, partial hip replacement, and total hip replacement) or ORIF of hip 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 local block. Additionally or alternatively, a regional block can be provided by placing depots in the psoas compartment, lumbar paravertebral space, fascia iliaca, or other suitable location to target one or more of the lumbar plexus, sacral plexus, femoral nerve, sciatic nerve, superior gluteal nerve, or obturator nerve. In some embodiments, it may be beneficial to secure the one or more depot(s) (e.g., using sutures, fasteners, or other fixation mechanisms) to maintain an anterior position of the depot, thereby preventing or reducing exposure of analgesic to motor nerves (e.g., sciatic or femoral nerves). In some embodiments, depots positioned to treat postoperative pain associated with hip surgeries have a release profile configured to deliver therapeutically beneficial levels of analgesic for a period of 5 days to 7 days, or 7 days to 10 days, depending on the particular surgical procedure.
Postoperative pain associated with shoulder and upper-arm surgeries can likewise be treated using one or more depots as disclosed herein. Examples of such surgeries include shoulder arthroplasty (including shoulder revision, partial shoulder replacement, and total shoulder replacement), upper-arm fracture repair (e.g., scapular, humerus), ligament/tendon repair (e.g., rotator cuff, labrum, biceps, etc.), or ORIF of fractures of the shoulder or upper arm. 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 local 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, interscalene, or supraclavicular space. In some embodiments, interscalene placement of the depots can avoid exposure of analgesic to native cartilage, thereby reducing the risk of chondrotoxicity. In some embodiments, depots positioned to treat postoperative pain associated with shoulder or upper-arm related surgeries have a release profile configured to deliver therapeutically beneficial levels of analgesic for a period of 3 days to 7 days.
In another example, one or more depots as described herein can be used to treat postoperative pain associated with elbow surgeries, such as elbow arthroplasty (including elbow revision, partial elbow replacement, and total elbow replacement), ligament reconstruction, or ORIF of fractures of the elbow. In treating postoperative pain associated with such surgeries, one or more depots can be positioned adjacent to the joint or repair site to provide a local block. Additionally or alternatively, one or more depots can be configured and positioned to target the brachial plexus nerves, for example by being placed at or near the cervical paravertebral space, infraclavicular, or axillary position, or other suitable location. In some embodiments, depots positioned to treat postoperative pain associated with elbow surgeries have a release profile configured to deliver therapeutically beneficial levels of analgesic for a period of 3 days to 7 days.
Postoperative pain associated with wrist and hand surgeries can also be treated using one or more depots as described herein. Examples of wrist and hand surgeries include wrist arthroplasty (including wrist revision, partial wrist replacement, and total wrist replacement), wrist fusion, carpal tunnel surgery, and ORIF of fractures of the wrist. In treating postoperative pain associated with such surgeries, one or more depots can be configured and positioned adjacent to the wrist joint or repair site to provide a local block. Additionally or alternatively, one or more depots can be configured and positioned to target the target the ulnar, median, radial, and cutaneous forearm nerves, for example via placement at the antecubital fossa, cervical paravertebral space, infraclavicular, or axillary position. In some embodiments, depots positioned to treat postoperative pain associated with wrist and hand surgeries have a release profile configured to deliver therapeutically beneficial levels of analgesic for a period of 3 days to 7 days.
The depots disclosed herein can likewise be used to treat postoperative pain from other orthopedic surgeries, such as spine surgeries (e.g., laminectomy, spinal fusion), procedures to treat bone fractures (e.g., hip fracture, radius fracture, ulna fracture, tibial fracture, fibular fracture, ankle fracture). For example, postoperative pain associated with spinal fusion can be treated via placement of one or more depots subcutaneously or in the paravertebral space. In treatment of postoperative pain associated with fibular fracture repair, one or more depots can be configured and placed to target the sciatic nerve and/or the popliteal sciatic nerve, for example, being placed parasacral. Various other placements and configurations are possible to provide therapeutic relief from postoperative pain associated with orthopedic surgical procedures.
The depots disclosed herein may be used to treat postoperative pain associated with other types of surgeries besides orthopedic surgeries. For example, the depots may be used to treat postoperative pain for chest-related surgery; breast-related surgery; gynecological or obstetric surgery; general surgery; abdominal surgery; urological surgery; ear, nose, and throat (ENT) surgery; oral and maxillofacial surgery; oncological surgery; or cosmetic surgery. For particular surgeries or classes of surgeries, one or more depots can be positioned at a treatment site to treat postoperative pain. The treatment site can be at or near the surgical site, or can be spaced apart from the surgical site (e.g., proximate to a target nerve or nerve bundle that innervates the surgical site).
For example, one or more depots as described herein can be used to treat postoperative pain associated with chest-related surgeries, such as a thoracotomy, sternotomy, esophageal surgery, cardiac surgery, lung resection, thoracic surgery, or other such procedure. In treating postoperative pain associated with such surgeries, one or more depots can be configured and positioned to target the intercostal nerves, for example, by being placed at or near the thoracic paravertebral space or other suitable location. Analgesics delivered to the intercostal nerves can reduce pain in a patient's chest area, thereby relieving postoperative pain associated with the above-noted chest-related surgical procedures.
In another example, one or more depots disclosed herein can be used to treat postoperative pain associated with breast-related surgeries, such as a mastectomy, breast augmentation (mammoplasty), breast reduction, breast reconstruction procedure, or other such procedures. To treat postoperative pain from such procedures, one or more depots can be positioned and configured to deliver analgesics or other therapeutic agents to the intercostal nerves, for example via placement at or near the patient's infraclavicular space or other suitable location. Additionally or alternatively, one or more depots can be positioned and configured to deliver analgesics or other therapeutic agents to the lateral pectoral nerve and/or the medial pectoral nerve, for example, via placement between the serratus anterior muscle and the latissimus dorsi muscle or other suitable location. As noted above, analgesics delivered to the intercostal nerves can reduce pain in a patient's chest area, while analgesics delivered to the lateral and/or medial pectoral nerves can reduce pain in the pectoralis major and pectoralis minor, thereby reducing postoperative pain associated with the above-noted chest-related surgical procedures.
As another example, one or more depots can be used to treat postoperative pain associated with general, 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 surgeries, small bowel resection, splenectomy, laparotomy, laparoscopy, hernia repair (e.g., inguinal, ventral, umbilical, incisional), sigmoidectomy, colorectal resection, liver resection, enterostomy, rectum resection, kidney stone removal, cystectomy procedures, and gender reassignment surgeries. For such operations, postoperative pain can be treated by placing one or more depots to target nerves at the transverse abdominis plane (TAP). Analgesics delivered to the TAP can anesthetize the nerves that supply the anterior abdominal wall, thereby reducing postoperative pain in this region. In some embodiments, one or more depots are disposed between the internal oblique and transverse abdominis muscles. In some embodiments, one or more depots can be disposed at or adjacent to the abdominal wall, for example, being secured in place via sutures, fasteners, or other fixation mechanisms.
In some embodiments, one or more depots are used to treat postoperative pain associated with gynecological and obstetric surgeries, such as myomectomy, Caesarian section, hysterectomy (e.g., transvaginal hysterectomy), oophorectomy, pelvic floor reconstruction, or other such surgical procedures. For such procedures, the depot(s) can be configured and positioned to deliver analgesics or other therapeutic agents to one or more of the nerves innervating the pelvic and/or genital area, for example, the pudendal nerve, intercostal nerve, or other suitable nerve.
In some embodiments, one or more depots can be used to treat postoperative pain associated with ENT surgical procedures, for example, tonsillectomy, submucosal resection, rhinoplasty, sinus surgery, inner ear surgery, parotidectomy, submandibular gland surgery, or other such procedures. Similarly, one or more depots can be used to treat postoperative pain associated with oral and maxillofacial surgeries, for example, dentoalveolar surgery, dental implant surgery, orthognathic surgery, temporomandibular joint (TMJ) surgery, dental reconstruction surgeries, or other such procedures. For 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 innervating regions affected by the surgical procedure, for example, the mandibular nerve, the mylohyoid nerve, lingual nerve, inferior alveolar nerve, buccal nerve, auriculotemporal nerve, anterior ethmoidal nerve, or other suitable nerve.
One or more depots can also be used to treat postoperative pain for other surgical procedures, for example oncological surgeries (e.g., tumor resection), cosmetic surgeries (e.g., liposuction, abdominoplasty), amputations, or other surgical procedures resulting in postoperative pain. Optionally, one or more depots can be used to treat pain for indications that may not be associated with a surgical procedure, such as treatment of neuromas or phantom limb pain.
The number of depots and the characteristics of individual depots (e.g., geometry, composition, release profile) can be selected to deliver the desired therapeutic benefits for the particular condition to be treated. For example, while a patient recovering from hard tissue surgeries (e.g., knee replacement surgery) may benefit from delivery of analgesics for a relatively long time period (e.g., at least 7 days, 14 days, or 21 days post-surgery), a patient recovering from other types of surgeries may not require the same level or duration of analgesic drug delivery. In some embodiments, a patient recovering from a soft tissue surgery (e.g., tonsillectomy, hernia repair, abdominoplasty, mammoplasty) may benefit from delivery of analgesics for a shorter time period, such as up to 4 days, 5 days, 6 days, or 7 days post-surgery. As such, depots delivered to a patient for treatment of postoperative pain following soft tissue surgeries may require fewer depots, or depots having a smaller payload of therapeutic agent, or depot(s) having a faster release profile, etc. In another example, the systemic therapeutic threshold of the therapeutic agent that correlates to the desired amount of pain relief may vary depending on the condition to be treated, and the number and characteristics of the depot(s) selected for implantation can be selected to provide therapeutic agent delivery at or above the systemic therapeutic threshold for the appropriate time period after surgery. Additionally, the number and characteristics of the depot(s) selected for implantation can be tailored to accommodate the target anatomical region for placement in the patient's body.
The efficacy of the depots of the present technology (e.g., the depots 100a-560 of
The Numeric Rating Scale (NRS) is a pain scoring system in which the patient assesses their pain on a scale from 0 (no pain) to 10 (worst possible pain). Pain can be measured at rest (NRS-R) or with activity (NRS-A). Any reference herein to an NRS score can encompass an NRS-R score, an NRS-A score, or a combination thereof. The NRS scores described herein can be measured at a time of day before the patient has consumed any opioids or other pain management medications, and/or at a time of day when the patient has not consumed any opioids or other pain management medications. In some embodiments, the NRS score of a patient who has received one or more depots of the present technology (“treatment patient”) is significantly lower than the NRS score of a patient who has not received any depots (“control patient”) at one or more time points after surgery. The time point can be 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after surgery. The NRS score of the treatment patient can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the NRS score of the control patient at the same time point.
In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of treatment patients are pain-free based on the NRS score (e.g., a NRS score of 0 or 1) at one or more time points after surgery, such as 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after surgery. A treatment patient may achieve a pain-free state faster than a control patient, e.g., by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 28 days, or 30 days.
In some embodiments, postoperative pain is evaluated by comparing the NRS-R score to the NRS-A score of a patient at one or more time points. In the context of TKA, activity can redistribute the anesthetic within the synovial space of the knee, which may reduce the NRS-A score. Accordingly, the difference between the NRS-A score and the NRS-R score at a particular time point may be smaller for treatment patients versus control patients (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% smaller).
Optionally, postoperative pain can be assessed by comparing the AUC of the NRS score (“NRS AUC”) of a treatment patient versus the NRS AUC of a control patient over one or more time periods after surgery. The time period can be from 0 hours to 12 hours, from 0 hours to 24 hours, from 0 hours to 72 hours, from 0 hours to 96 hours, from 0 hours to 7 days, from 0 hours to 14 days, 0 hours to 15 days, from 0 hours to 30 days, from 12 hours to 24 hours, from 12 hours to 36 hours, from 12 hours to 72 hours, from 12 hours to 96 hours, from 12 hours to 7 days, from 12 hours to 10 days, from 12 hours to 14 days, from 12 hours to 21 days, from 12 hours to 30 days, from 1 day to 2 days, from 1 day to 4 days, from 1 day to 7 days, from 1 day to 14 days, from 1 day to 15 days, from 1 day to 21 days, from 1 day to 30 days, from 2 days to 3 days, from 2 days to 4 days, from 2 days to 7 days, from 2 days to 14 days, from 2 days to 15 days, from 2 days to 21 days, from 2 days to 30 days, from 3 days to 4 days, from 3 days to 7 days, from 3 days to 14 days, from 3 days to 15 days, from 3 days to 21 days, from 3 days to 30 days, from 4 days to 5 days, from 4 days to 7 days, from 4 days to 14 days, from 4 days to 15 days, from 4 days to 21 days, from 4 days to 30 days, from 5 days to 6 days, from 5 days to 7 days, from 5 days to 14 days, from 5 days to 15 days, from 5 days to 21 days, from 5 days to 30 days, from 6 days to 7 days, from 6 days to 14 days, from 6 days to 15 days, from 6 days to 21 days, from 6 days to 30 days, from 7 days to 8 days, from 7 days to 14 days, from 7 days to 15 days, from 7 days to 21 days, from 7 days to 30 days, from 8 days to 9 days, from 9 days to 10 days, from 10 days to 11 days, from 11 days to 12 days, from 12 days to 13 days, from 13 days to 14 days, from 14 days to 15 days, from 14 days to 21 days, from 14 days to 30 days, from 15 days to 21 days, from 15 days to 30 days, from 16 days to 21 days, from 16 days to 30 days, or from 21 days to 30 days after surgery. The NRS AUC of the treatment patient can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the NRS AUC of the control patient over the same time period.
The efficacy of the depots of the present technology in treating pain can also be assessed based on consumption of supplemental opioid medications prescribed to the patient for pain management. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of treatment patients remain opioid-free over one or more time periods after surgery. Alternatively or in combination, the total amount of opioids consumed by a treatment patient can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to the total amount of opioids consumed by a control patient over the same time period after surgery. The total amount of opioids consumed by the treatment patient can be no more than 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 time period. The time period for assessing postoperative opioid consumption can be from 0 hours to 12 hours, from 0 hours to 24 hours, from 0 hours to 72 hours, from 0 hours to 96 hours, from 0 hours to 7 days, from 0 hours to 14 days, 0 hours to 15 days, from 0 hours to 30 days, from 12 hours to 24 hours, from 12 hours to 36 hours, from 12 hours to 72 hours, from 12 hours to 96 hours, from 12 hours to 7 days, from 12 hours to 10 days, from 12 hours to 14 days, from 12 hours to 21 days, from 12 hours to 30 days, from 1 day to 2 days, from 1 day to 4 days, from 1 day to 7 days, from 1 day to 14 days, from 1 day to 15 days, from 1 day to 21 days, from 1 day to 30 days, from 2 days to 3 days, from 2 days to 4 days, from 2 days to 7 days, from 2 days to 14 days, from 2 days to 15 days, from 2 days to 21 days, from 2 days to 30 days, from 3 days to 4 days, from 3 days to 7 days, from 3 days to 14 days, from 3 days to 15 days, from 3 days to 21 days, from 3 days to 30 days, from 4 days to 5 days, from 4 days to 7 days, from 4 days to 14 days, from 4 days to 15 days, from 4 days to 21 days, from 4 days to 30 days, from 5 days to 6 days, from 5 days to 7 days, from 5 days to 14 days, from 5 days to 15 days, from 5 days to 21 days, from 5 days to 30 days, from 6 days to 7 days, from 6 days to 14 days, from 6 days to 15 days, from 6 days to 21 days, from 6 days to 30 days, from 7 days to 8 days, from 7 days to 14 days, from 7 days to 15 days, from 7 days to 21 days, from 7 days to 30 days, from 8 days to 9 days, from 9 days to 10 days, from 10 days to 11 days, from 11 days to 12 days, from 12 days to 13 days, from 13 days to 14 days, from 14 days to 15 days, from 14 days to 21 days, from 14 days to 30 days, from 15 days to 21 days, from 15 days to 30 days, from 16 days to 21 days, from 16 days to 30 days, or from 21 days to 30 days after surgery.
In some embodiments, the time to first opioid consumption after surgery (e.g., time to rescue opioid) for a treatment patient is delayed compared to a control patient, such as 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. A treatment patient may 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. Treatment patients may also experience fewer or no opioid-related adverse events (e.g., nausea, vomiting, constipation, ileus) compared to control patients. In some embodiments, the percentage of treatment 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.
The efficacy of the depots of the present technology in treating pain can also be assessed based on a movement parameter, such as range of motion and/or other activity. For example, for TKA, range of motion can be assessed based on degrees of flexion and/or extension of the knee after surgery. In some embodiments, the time for a treatment patient to achieve a target degree of flexion and/or extension after surgery is reduced compared to a control patient, e.g., by at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 28 days, or 30 days. The target degree of flexion and/or extension can vary based on the activity being assessed (e.g., walking, sitting, going up stairs, etc.), and can be determined in accordance with standards known to those of skill in the art. The treatment patient can achieve the target degree of flexion and/or extension within 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. As another example, treatment patients may resume normal physical activity faster than control patients after surgery, such as at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 28 days, or 30 days. Other suitable movement parameters include overall activity levels (e.g., number of steps, time spent walking, time spent running, six-minute walk distance, etc.), gait (e.g., time to recovery of normal gait), and/or other metrics. Movement parameter measurements can be assessed based on change or rate of change in the measured values over time and/or comparison of the measured value to a control patient value, a value of healthy individuals (e.g., of a similar age, having a similar activity profile to the patient pre-surgery, etc.), and/or a particular patient's pre-operative level. In some embodiments, a patient's physical activity is tracked and assessed using a wearable or sensor, such as a fitness monitor.
In some embodiments, the efficacy of the depots of the present technology in treating pain is assessed based on compliance with a prescribed physical therapy regimen. Patients experiencing considerable postoperative pain will often miss or skip physical therapy sessions (e.g., onsite or virtual) and/or give considerably less effort as quantified by time, repetitions, flexion/extension, and/or other parameters. Treatment patients may, therefore, demonstrate greater compliance with physical therapy as compared to control patients based on one or more of these metrics. Poor compliance with physical therapy can result in the formation of adhesions and/or scar tissue that causes stiffness in the surgical area (e.g., the knee joint), which may require return to the hospital for a surgical manipulation of the knee. As such, rate or incidence of surgical manipulation can be another clinical endpoint for demonstrating benefit, e.g., the rate of surgical manipulation in treatment patients can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients.
The efficacy of the depots of the present technology in treating pain can alternatively or additionally be assessed based on other factors. For example, treatment patients may be discharged from the hospital sooner than control patients, e.g., by at least 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 60 hours, or 96 hours. The discharge time may be related to the amount of pain that the patient is experiencing, in that patients experiencing more postoperative pain may be discharged later than patients experiencing less postoperative pain. In a further example, the rehospitalization rate of treatment patients can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients. Rehospitalization may occur if the patient is experiencing prolonged and/or severe pain, if surgical revisions are needed, and/or other factors. In yet another example, the percentage of treatment patients who contact their surgeon or physician after discharge to seek treatment for postoperative pain can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% compared to control patients.
As another example, treatment patients may exhibit improved recovery after surgery compared to control patients, as measured by one or more quality of recovery (QoR) scores. QoR scores allow the patient to provide a self-reported rating on recovery-related measures such as pain, physical comfort, physical independence, psychological support, emotional state, and mental well-being. QoR scores can be assessed using a longer form 40-item score (QoR-40) or a shorter-form 15-item score (QoR-15) derived from the QoR-40. In some embodiments, treatment patients exhibit improved QoR scores compared to control patients at one or more time points after surgery, such as 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after surgery.
In some embodiments, the efficacy of the depots of the present technology is evaluated using the WOMAC index, which is a set of standardized questionnaires used by health professionals to evaluate the condition of patients with joint pain from a variety of sources. The WOMAC measures five items for pain (score range 0-20), two for stiffness (score range 0-8), and 17 for functional limitation (score range 0-68). Physical functioning questions cover everyday activities such as stair use, standing up from a sitting or lying position, standing, bending, walking, getting in and out of a car, shopping, putting on or taking off socks, lying in bed, getting in or out of a bath, sitting, and heavy and light household duties. The questions on the WOMAC are a subset of the questions of the Hip disability and Osteoarthritis Outcome score (HOOS). Thus, a HOOS survey may also be used to determine a WOMAC score.
Some embodiments of the present technology include a method for treating a patient suffering from postsurgical pain at an anatomical region of the patient's body. The pain may be associated with a surgery at or near the anatomical region. In some embodiments, the method includes improving a WOMAC index total score of the patient by implanting one or more of the depots disclosed herein at a surgical site at the anatomical region. The method can include improving a WOMAC index pain sub-score, stiffness sub-score, and/or physical function sub-score. The WOMAC index total score and/or one or more of the sub-scores may be evaluated at set time intervals (weekly, monthly, bi-monthly, etc.) and compared to the patient's previous scores, the patient's pre-operative score, and/or the score of a patient of similar age, fitness, and health that underwent the same surgery but was not treated with one of the depots of the present technology.
The KOOS was developed as an extension of the WOMAC Index with the purpose of evaluating short-term and long-term symptoms and function in subjects with knee injury and osteoarthritis. The KOOS holds five separately scored subscales: pain, other symptoms, function in daily living (ADL), function in sport and recreation (sport/rec), and knee-related quality of life (QOL). The KOOS has been validated for several orthopedic interventions such as anterior cruciate ligament reconstruction, meniscectomy and total knee replacement. The effect size is generally largest for the subscale QOL followed by the subscale pain. In some embodiments, the method includes improving a KOOS score of the patient by implanting one or more of the depots disclosed herein at a surgical site at the anatomical region. The method can include improving a KOOS sub-score, including at least one of pain, other symptoms, function in daily living (ADL), function in sport and recreation (sport/rec), and/or knee-related quality of life (QOL). The KOOS score and/or one or more of the sub-scores may be evaluated at set time intervals (weekly, monthly, bi-monthly, etc.) and compared to the patient's previous scores, the patient's pre-operative score, and/or the score of a control patient (e.g., a patient of similar age, fitness, and health that underwent the same surgery but was not treated with one of the depots of the present technology).
In some embodiments, a method of treating a subject suffering from pain after a surgical procedure (e.g., a 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 the depots 100a-560 of
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 technology.
This example describes three configurations for depots designed for implantation in a surgical site to treat postoperative pain: (1) a rectangular depot with notches, similar to the depot 200 illustrated in
Tables 2 and 3 below provide the dry mass compositions for the therapeutic region and control regions, respectively, in the R300, T600, and T500 depots. 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 (releasing agent).
Table 4 provides the theoretical dry mass compositions of the components in the R300, T600, and T500 depots. The theoretical percent composition of each component was calculated on a mass basis derived from on the respective thicknesses of the therapeutic and control regions, and the percent composition in each formulation. The calculation assumed that all component densities are equivalent (i.e., 1.0 g/cm3).
This example describes the preparation and characterization of the R300, T600, and T500 depots. The therapeutic region in all three depots was formulated with PS20, PLGA5050, BUP—HCl, and acetone in a 1:10:20:30 ratio by mass. The control regions in R300 and T600 were formulated with PS20, PLGA5050, and acetone in a 1:2:6 ratio by mass. The control regions in T500 were formulated with PLGA5050 and acetone in a 1:4 ratio by mass.
The therapeutic regions for R300, T600, and T500 were manufactured 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 portioned out into smaller quantities and stirred. Each portion underwent a series of heat compression steps to form a disk of the desired thickness. The disks were then dried.
After the disks dried, the control regions were applied to both sides of the disk. For the R300 and T600 depots, the control regions were formed by dissolving PLGA5050 and PS20 in acetone, then casting the polymer solution into thin films of the desired thickness. The thin films were then bonded to each side of the disk using heat compression. For the T500 depots, the control regions were formed by dissolving PLGA5050 in acetone, then dipping the disks into the polymer solutions. After the control regions were applied, individual depots were cut from the disks.
This example describes in vitro release data for the T500 depot. In vitro elution studies were performed at pH 5.8 in phosphate-buffered saline (PBS). Depots were placed in baskets rotating at 10 RPM in 750 mL of elution media at 37° C. The elution media was periodically analyzed spectrophotometrically at 262 nm and the BUP—HCl concentration was quantified with a USP reference standard in a standalone sealed cuvette.
This example describes in vivo pharmacokinetic data for R300 and T600 depots implanted in human subjects for treatment of postoperative pain after TKA. The safety and pharmacokinetics of R300 and T600 depots were investigated in an open-label 22 patient study. The patients were adult subjects between 18- and 80-years old undergoing primary unilateral TKA. One or more depots were placed in the knee capsule of each subject following the TKA procedure and before surgical closure of the knee capsule. Depending on dosage levels the depot(s) were placed in one or more of the following locations: the suprapatellar pouch, the medial gutter alongside the capsular tissue, and/or the lateral gutter alongside the capsular tissue. Table 5 below provides the depot configurations and bupivacaine dose for each cohort (in Examples 4-6 and the accompanying Figures, “BUP” or “bupivacaine” refers to bupivacaine free base).
Venous blood samples (4 mL) for plasma pharmacokinetic analysis were taken at various time intervals during surgery and within the first 24 hours post-surgery, then approximately every 4 hours from 24 to 96 hours post-surgery, then daily thereafter through Day 15, and at follow-up visits on Days 30, 45, and 60 (the Cohort 3C subjects had additional visits on Days 18, 21, 24, and 27). Bupivacaine was extracted from human plasma by protein precipitation with acetonitrile. Before the 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. The samples were injected into a liquid chromatography tandem mass spectrometry (LC-MS/MS) system using an Agilent Zorbax SB-C18 column with a gradient mobile phase containing acetonitrile, water, and formic acid.
As shown in
This example describes postoperative pain and opioid consumption in patients treated with implantable depots following TKA (the Cohort 1-3C subjects of Example 4). While the primary endpoint of the study was bupivacaine concentration, exploratory analysis of clinical efficacy was also evaluated in in terms of NRS-R for pain intensity and opioid consumption.
Operative and postoperative medications for all Cohort 1 subjects, in addition to the implantable depots, included intrathecal morphine; an adductor canal block; a local infiltration cocktail consisting of ropivacaine, clonidine, ketorolac, and epinephrine; a long-acting opioid (Targin); and rescue opioids as needed (mostly oxycodone). These subjects also consumed acetaminophen and celecoxib for varying durations during the trial. In these subjects, no more than 255 mg of ropivacaine could be used in the local infiltration cocktail, adductor canal block, and/or in spinal anesthesia.
Operative and postoperative medications for all Cohort 2 subjects, in addition to the implantable depots, included intrathecal morphine; an adductor canal block; a local infiltration cocktail consisting of ropivacaine, clonidine, ketorolac, and epinephrine; a long-acting opioid (Targin); and rescue opioids as needed (mostly oxycodone). These subjects also consumed acetaminophen and celecoxib for varying durations during the trial. In these subjects, no more than 165 mg of ropivacaine could be used in the local infiltration cocktail, adductor canal block, and/or in spinal anesthesia.
Operative and post-operative medications for Cohort 3A-3C subjects (collectively, “Cohort 3 subjects”), in addition to the implantable depots, included 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) for 3 of 15 subjects; and rescue opioids as needed (mostly oxycodone). These subjects also consumed acetaminophen and celecoxib for varying durations during the trial. In these subjects, ropivacaine was only permitted as the spinal anesthesia. No adductor canal blocks and no local infiltration with anesthetic was permitted.
NRS-R were conducted before surgery and after surgery at 30 minutes, 1, 2, 3, 4, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, 48 52, 56, 60, 64, 68, 72, 76, 80, 84, 90, and 96 hours as well as at Days 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 30, 45, and 60. In addition, due to a protocol amendment, NRS-R for pain intensity was also conducted on Days 18, 21, 24, and 27 for the Cohort 3C subjects. Subjects were asked to complete an NRS-R for pain intensity prior to consuming any opioid from the surgical procedure through Day 15.
The AUC of the NRS-R for pain intensity adjusted for opioid use was calculated for each day and cumulatively through the end of each 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; however, all subjects in Cohort 1, Cohort 2, and 6 of 15 subjects in Cohort 3 received intrathecal morphine, which lowered the AUC in those subjects in the first approximately 24 hours.
Table 7 below shows the AUC for the first 15 days (two weeks post-surgery). The AUC was comparable between Cohorts 1 and 3; however, Cohort 3 subjects consumed 64% less opioids over two weeks (see Table 8 below) and received no operative adjunct anesthetics (adductor canal block, or local infiltration of anesthetic) compared to Cohort 1 subjects.
Table 8 below shows patient opioid consumption through the first two weeks after surgery. Every instance of opioid consumption was tracked from the day of the TKA surgical procedure (Day 1) through Day 15. The preliminary interim analysis showed that 80% of subjects (12/15) in Cohort 3 at the 1,512 mg dose discontinued use of all opioids for TKA knee pain within the first two weeks after TKA surgery (Table 1) compared to the literature of 52.8% (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 of the Cohort 1 (252 mg) subjects (50%) continued consuming opioids beyond Day 15.
The results showed that as the bupivacaine dose increased, the postsurgical opioid consumption in MME decreased in the first two weeks after surgery. Literature indicates the average MME consumed after a TKA is between 428 MME and nearly 700 MME (Runner et al.; Ruddell et al., The Journal of Bone and Joint Surgery 103 (2021), 106-114). The Cohort 3 subjects consumed less than half of the total opioids reported in the literature (176.77 MME vs 428 MME). 20% of the Cohort 3 subjects (3/15) did consume additional opioids, as needed for knee pain, after the first two weeks and these additional opioids (beyond two weeks) are not captured in the 176.77 MME reported in Table 8.
Of the 15 Cohort 3 subjects, one subject did not consume any opioids (6.7%). Of the remaining subjects that did consume opioids, the time to first consumption was 6.283 hours (95% CI; 3.117, 22.533) as calculated by Kaplan-Meyer.
This example describes simulated pharmacokinetic data of implantable depots for treating postoperative pain after shoulder surgery, bunionectomy, and inguinal hernia repair. The simulated data was generated by calculating Cmax and Tmax scaling factors from pharmacokinetic data for other bupivacaine formulations that used the same bupivacaine dosages in treating TKA and another indication of interest (“new indication”). Specifically, the Cmax scaling factor was computed by taking the ratio of the Cmax in the TKA pharmacokinetic data to the Cmax in the pharmacokinetic data for the new indication. The Cmax scaling factor was then multiplied with the Cohort 3 bupivacaine plasma concentration data across all time points to obtain scaled bupivacaine plasma concentration data for the new indication. Similarly, the Tmax scaling factor was computed by taking the ratio of the Tmax in the TKA pharmacokinetic data to the Tmax in the pharmacokinetic data for the new indication. The Tmax scaling factor was then multiplied with the Cohort 3 bupivacaine time data across all bupivacaine plasma concentration data to derive scaled time data for the new indication. The bupivacaine plasma concentration data could be scaled further based on the linear Cmax-dose relationship obtained in Example 4 above to simulate the pharmacokinetics resulting from different bupivacaine dosages. The resulting data provides a rough simulation of the pharmacokinetics of the implantable depots when implanted at other anatomical locations for treating other indications.
This example describes in vitro release from a depot containing bupivacaine free base (“BUPFB”). The depot included a therapeutic region only, without any control regions (similar to the depot 100c of
The therapeutic region was prepared by mixing PS20, PLGA5050, BUPFB, and acetone in a 1:10:20:30 ratio by mass. A thermal press was used to compress and dry the formulation into large circular discs. The larger discs were subsequently cut into smaller circular discs (similar to the depot 550 of
This example describes in vitro release from BUPFB depots including 2, 1, and no control regions. The compositions and geometry of the depots are listed in Table 10 below.
The therapeutic regions of the R300-FB-TR, R300-FB-1CR, and R300-FB-2CR were prepared according to the process of Example 7, except that the therapeutic regions were cut into rectangles.
The R300-FB-TR depot did not include any control regions, the R300-FB-1CR depot included a single control region (similar to the depot 100b of
This example describes 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 geometry of the depots are listed in Table 11 below.
The depots were prepared according to the methods described in Example 7 above, except for the following changes: (1) for the C100-hybrid-TR depot, the therapeutic region was formulated using a mixture of PS20, PLGA5050, BUP—HCl, BUPFB, and acetone in a 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) for the T400-salt-TR depot, the therapeutic region was formulated using a mixture of PS20, PLGA5050, BUP—HCl, and acetone in a 1:10:20:30 ratio by mass, with a targeted drug loading of 480 mg BUP—HCl (equivalent to 400 mg BUPFB), and cut into a triangular shape.
This example describes in vivo release in a rabbit subcutaneous model from depots with different forms of bupivacaine. The compositions and geometry of the depots are listed in Table 12 below.
The C100-FB-TR and C100-hybrid-TR depots were prepared as described above in Example 9. The C100-salt-2CR depot contained a therapeutic region with bupivacaine hydrochloride monohydrate (BUP—HCl) and two control regions (similar to the depot 100a of
This example describes in vitro release from depots formulated with varying amounts of BUPFB. The compositions and geometry of the depots are listed in Table 13 below.
The depots were prepared as described in Example 8 above, except that the therapeutic region of the R300-FB2-TR depot included a mixture of PS20, PLGA, BUPFB, and acetone in a 1:10:40:30 ratio by mass.
This example describes in vitro release from depots formulated with varying BUPFB:BUP—HCl ratios. The compositions and geometry of the depots are listed in Table 14 below.
The depots were prepared as described in Example 7 above, except that (1) the therapeutic region of the C100-1:1hybrid-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 region of the C100:1:2hybrid-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).
This example describes modeling techniques for determining the travel distance of a therapeutic agent for various depot geometries.
In some embodiments, the depots described herein release the therapeutic agent (e.g., bupivacaine) with first order kinetics under sink conditions (e.g., PBS at pH 5.8), such that the half-life (t1/2) is related to the observed rate constant (kobs) by the equation t1/2=ln(2)/kobs. The half-life can be determined experimentally using the in vitro elution techniques described herein. The half-life is expected to vary with the geometry of the depot, including the mean travel distance of the therapeutic agent to the nearest exposed surface of the depot. Two modeling approaches were developed to validate the relationship between release rates and travel distance: a Monte Carlo statistical approach and a geometric/calculus approach.
Several aspects of the present technology are set forth in the following examples.
Although many of the embodiments are described above with respect to systems, devices, and methods for treating postoperative pain, the technology is applicable to other applications and/or other approaches. For example, the depots of the present technology may be used to treat postoperative pain associated with a veterinary procedure and/or surgery. Moreover, other embodiments in addition to those described herein are within the scope of the technology. Additionally, several other embodiments of the technology can have different configurations, components, or procedures than those described herein. A person of ordinary skill in the art, therefore, will accordingly understand that the technology can have other embodiments with additional elements, or the technology can have other embodiments without several of the features shown and described above with reference to
The descriptions of embodiments of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include the plural or singular term, respectively. Although specific embodiments of, and examples for, the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative embodiments may perform steps in a different order. The various embodiments described herein may also be combined to provide further embodiments.
As used herein, the terms “generally,” “substantially,” “about,” and similar terms are used as terms of approximation and not as terms of degree, and are intended to account for the inherent variations in measured or calculated values that would be recognized by those of ordinary skill in the art.
Moreover, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and/or additional types of other features are not precluded. As used herein, the phrase “and/or” as in “A and/or B” refers to A alone, B alone, and A and B.
To the extent any materials incorporated herein by reference conflict with the present disclosure, the present disclosure controls.
It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Further, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.
The present application claims the benefit of priority to U.S. Provisional Application No. 63/261,921, filed Sep. 30, 2021, and U.S. Provisional Application No. 63/373,510, filed Aug. 25, 2022, each of which is incorporated by reference herein in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/077351 | 9/30/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63373510 | Aug 2022 | US | |
| 63261921 | Sep 2021 | US |
