Tissue Penetrating and Biodegradable Drug Delivery Devices and Methods of Use Thereof

Abstract

A tissue-penetrating biodegradable drug delivery device is provided that is capable of directly delivering a pharmaceutical active ingredient (API) to a target tissue site. The drug delivery device can include multiple layers, and at least one of the multiple layers includes the API and a biodegradable polymer. When the device is placed directly or adjacent to the target tissue, the API layer can decompose to release the API to the target tissue from multiple directions.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 391,535, filed on July 22, 2022, and U.S. Provisional Application No. 63 / 501,986, filed on May 12, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] This relates to an implantable drug delivery device. Specifically, it relates to a tissue - penetrating and biodegradable drug delivery device for delivering a pharmaceutical active ingredient to a local tissue site.

Background Art

[0003] Cancer treatment has advanced significantly in recent years. However, problems remain, such as the limited ability of drugs to reach tumors effectively, short half - lives, and low retention rates at the site. The main limitation of existing chemotherapy effectiveness is due to systemic off - target toxicity. For example, only 1 - 5% of the chemotherapy dose administered systemically actually reaches the tumor site. In fact, even some of the most promising currently available chemotherapies are not tolerable in the long term for most patients.

Summary of the Invention

Means for Solving the Problems

[0004] The applicant has discovered an implantable and tissue-penetrating biodegradable drug delivery device that can directly deliver a pharmaceutical active ingredient (API) to a patient's target tissue. Since the drug delivery devices disclosed herein utilize local delivery methods, these devices can avoid the problem of systemic side effects, and due to their biodegradable nature, subsequent removal surgery is not required, and more direct site-specific treatment can be provided. Specifically, the drug devices disclosed herein can be flexibly applied via open surgery and minimally invasive surgery, enabling unidirectional, multidirectional, or omni-directional delivery of the API through a multi-layer configuration, acting as a barrier against intratumoral seeding, preventing systemic drug leakage, providing an adjustable release profile and degradation rate, being combinable with systemic therapy, and / or being transportable to a wide range of solid tumors, and can provide a consent-adaptive design.

[0005] In some embodiments, the drug delivery device can be flexible. In some embodiments, the drug delivery device can be flexible such that it can be placed within (i.e., within the tumor) and / or adjacent to the patient's target tissue using standard open surgical instruments, laparoscopic surgical instruments, endoscopic surgical instruments (e.g., bronchoscopic surgical instruments), percutaneous surgical instruments, or robotic surgical instruments. In some embodiments, the drug delivery device can be rigid. In some embodiments, if not flexible, the drug delivery device may not be able to pass through a tortuous path to the target tissue using a laparoscope, endoscope, bronchoscope, etc. In some embodiments, the drug delivery device can be partially or fully implanted at the target tissue site. In some embodiments, multiple drug delivery devices can be placed within and / or adjacent to (i.e., within the tumor) the patient's target tissue using standard open surgical instruments, laparoscopic surgical instruments, percutaneous surgical instruments, endoscopic surgical instruments, or robotic surgical instruments. In some embodiments, a second drug delivery device can be placed within and / or adjacent to the patient's target tissue after the first drug delivery device has already degraded or simultaneously with the first drug delivery device.

[0006] In some embodiments, the drug delivery devices disclosed herein may include at least two layers. In some embodiments, at least one of the layers may include an API and a biodegradable polymer. In some embodiments, at least one of the layers may include different APIs and biodegradable polymers. Biodegradable polymers having different APIs can degrade slower, faster, or in the same manner as the biodegradable polymers of at least one layer having a first API. In some embodiments, at least one of the layers includes a biodegradable polymer that does not contain an API. In some embodiments, the non-API layer may be a support layer for protecting the API layer, providing structural support to the drug delivery device, and / or providing strength to the drug delivery device. In some embodiments, all layers of the drug delivery device may include an API.

[0007] When the device is placed directly within the target tissue, the API layer(s) may degrade, thereby releasing the API(s) within the target tissue. In some embodiments, the non-API layer or non-API component(s) (e.g., the tip as discussed herein) of the drug delivery device can prevent the drug delivery device from being released from the target tissue (i.e., the non-API layer or non-API component can hold the drug delivery device in place). In some embodiments, the API layer or API layers can prevent the drug delivery device from being released from the target tissue.

[0008] In some embodiments, the non-API layer (or another non-API component such as the tip) can degrade more slowly than at least one of the API layers so that the non-API layer can continue to provide support for the drug delivery device and / or continue to hold the drug delivery device at the target tissue site. In this way, the non-API layer(s) or non-API component(s) may not completely degrade until the drug is completely released. Thus, the drug delivery device can be inserted into a patient to target a particular tissue without subsequent surgery to remove the device because all or most of it is absorbed in the patient's body.

[0009] The drug delivery devices disclosed herein can provide clinically appropriate delivery of the API to a tissue (e.g., a tumor), within a tissue, or adjacent to a tissue, with good tolerance and minimal systemic exposure of the API. This device, with all of the advantages associated above, can be used as a neoadjuvant therapy (and / or adjuvant therapy) for the treatment of many in vivo medical problems (e.g., cancer, other diseases, wounds, bulges, lacerations, non-cancerous growths, etc.), improving the complete resection rate, reducing the risk of local recurrence after resection, reducing and / or controlling the tumor volume, and / or improving the patient's survival rate.

[0010] In some embodiments, the drug delivery device includes a body comprising a plurality of layers, the plurality of layers including at least one first layer comprising a pharmaceutical active ingredient (API) and a biodegradable polymer, and the drug delivery device is configured to be inserted into a target tissue site of a patient. In some embodiments, the device includes a tip connected or integrated to the distal end of the body of the drug delivery device. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient from the tip first. In some embodiments, the target tissue site is a tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon. In some embodiments, the biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the biodegradable polymer is PLGA 50:50. In some embodiments, the at least one first layer comprises 1 to 15 wt% of the API. In some embodiments, the at least one first layer comprises a solvent. In some embodiments, the at least one first layer comprises 1 to 15 wt% of the solvent. In some embodiments, the plurality of layers includes at least one second layer comprising a second biodegradable polymer, the second biodegradable polymer having a slower degradation rate than the first biodegradable polymer. In some embodiments, the second biodegradable polymer is PLGA 75:25. In some embodiments, the plurality of layers includes at least one third layer comprising a second API and a third biodegradable polymer. In some embodiments, the plurality of layers includes at least one fourth layer comprising a third API and a fourth biodegradable polymer. In some embodiments, each of the plurality of layers has the same composition. In some embodiments, the drug delivery device is configured to be implanted in a patient using standard open surgical procedures and / or minimally invasive procedures. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient using a bronchoscope, forceps, trocar, or needle. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient by a robot.In some embodiments, at least one first layer is configured to release an API when inserted into a target tissue site of a patient. In some embodiments, at least one first layer is configured to release the API in multiple directions when inserted into a target tissue site of the patient. In some embodiments, the release of the API is controlled by in vivo degradation of a biodegradable polymer at the target tissue site. In some embodiments, the tip includes a fifth biodegradable polymer having a slower degradation rate than the first biodegradable polymer. In some embodiments, the tip includes PLGA 75:25. In some embodiments, the tip includes a tissue retention mechanism. In some embodiments, the tissue retention mechanism is configured to retain the drug delivery device within the target tissue when inserted into the target tissue of the patient. In some embodiments, the tissue retention mechanism extends outwardly from the tip. In some embodiments, the tissue retention mechanism comprises barbs and / or edges. In some embodiments, the tip has at least one apex at its distal end. In some embodiments, the body comprises a disengagement mechanism on the side of the proximal end of the body. In some embodiments, the flexible shaft is connected to the proximal end of the body. In some embodiments, the disengagement mechanism is configured to disengage the drug delivery device from the flexible shaft. In some embodiments, the disengagement mechanism is configured to disengage the drug delivery device from the flexible shaft by twisting. In some embodiments, the body of the drug delivery device is flexible.

[0011] In some embodiments, a method of preparing a drug delivery device includes adding a first solution comprising a first biodegradable polymer, a pharmaceutical active ingredient (API), and a solvent to a first substrate; drying the first solution on the first substrate to form a first layer; adding a second solution comprising a second biodegradable polymer and a second solvent to a second substrate; drying the second solution on the second substrate to form a second layer; and laminating the first layer and the second layer to form a laminated sheet. In some embodiments, the method includes cutting the laminated sheet to form the body of the drug delivery device. In some embodiments, the cutting is a die cut. In some embodiments, the second solution comprises a second API. In some embodiments, the first API and the second API are the same. In some embodiments, the method includes adding a third solution comprising a third biodegradable polymer and a third solvent to a third substrate; drying the third solution on the third substrate to form a third layer; and laminating the third layer to the laminated sheet to form a second laminated sheet. In some embodiments, applying the first solution to the entire first substrate with a film applicator; applying the second solution to the entire second substrate with a film applicator. In some embodiments, the applied first solution and the applied second solution have a desired thickness according to the film applicator. In some embodiments, the first substrate and / or the second substrate comprises a release liner. In some embodiments, the method includes heating the first layer and the second layer in an oven after drying the first solution and the second solution. In some embodiments, the method includes attaching a tip to the distal end of the body of the drug delivery device.

[0012] In some embodiments, a method of treating a patient's tissue comprises implanting a drug delivery device at a target tissue site of the patient, the drug delivery device comprising a body including a plurality of layers, the plurality of layers including at least one first layer comprising a pharmaceutical active ingredient (API) and a biodegradable polymer; and releasing the API from the at least one first layer, the release of the API being controlled by in vivo degradation of the biodegradable polymer at the target tissue site. In some embodiments, the drug delivery device comprises a tip connected to the distal end of the drug delivery device. In some embodiments, the drug delivery device is implanted into the patient's target tissue site with the tip first. In some embodiments, the target tissue site is a tumor in the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon. In some embodiments, the drug delivery device is implanted via an open surgery, laparoscopically, percutaneously, robotically, or endoscopically. In some embodiments, the drug delivery device is implanted via a bronchoscope. In some embodiments, releasing the API from the at least one first layer comprises releasing the API in multiple directions away from the drug delivery device. In some embodiments, the drug delivery device is implanted into the patient's target tissue site such that the tip is configured to hold the drug delivery device within the target tissue. In some embodiments, implanting the drug delivery device comprises using a tool for delivering the drug delivery device to the patient's target tissue site. In some embodiments, the tool includes a flexible shaft and is connected to the proximal end of the body of the drug delivery device. In some embodiments, implanting the drug delivery device into the target tissue site comprises disengaging the body of the drug delivery device from the flexible shaft. In some embodiments, disengaging the drug delivery device from the flexible shaft comprises turning the flexible shaft with respect to the drug delivery device. In some embodiments, the body of the drug delivery device includes an anatomical marker, and implanting the drug delivery device into the patient's target tissue site comprises monitoring the position of the anatomical marker.In some embodiments, the release of the API follows a delay period after implantation. In some embodiments, an amount of API below the therapeutically effective amount is released during the delay period. In some embodiments, after the delay period, the API is released at a substantially linear or linear release rate.

[0013] In some embodiments, the drug delivery device includes a body having a core containing a first biodegradable polymer and an outer layer surrounding at least a portion of the core and containing a pharmaceutical active ingredient (API) and a second biodegradable polymer, wherein the first biodegradable polymer has a slower degradation rate than the second biodegradable polymer, and a tip connected or integrated with the distal end of the body. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient from the tip first. In some embodiments, the target tissue site is a tumor in the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon. In some embodiments, the first biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the first biodegradable polymer is PLGA 75:25. In some embodiments, the second biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the second biodegradable polymer is PLGA 50:50. In some embodiments, the drug delivery device is configured to be implanted in a patient using standard laparotomy procedures and minimally invasive procedures. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient using a bronchoscope. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient by a robot. In some embodiments, the outer layer is configured to release the API when inserted into the target tissue site of the patient. In some embodiments, the outer layer is configured to release the API omnidirectionally when inserted into the target tissue site of the patient. In some embodiments, the release of the API is controlled by the in vivo degradation of the second biodegradable polymer at the target tissue site. In some embodiments, the body further includes a second outer layer surrounding at least a portion of the first outer layer and containing a third biodegradable polymer, wherein the third biodegradable polymer has a faster degradation rate than the second biodegradable polymer and / or the first biodegradable polymer. In some embodiments, the third biodegradable polymer is PLGA.In some embodiments, the tip comprises a third biodegradable polymer having a slower degradation rate than the second biodegradable polymer. In some embodiments, the tip comprises PLGA 75:25. In some embodiments, the tip comprises a tissue retention mechanism. In some embodiments, the tissue retention mechanism is configured to retain the drug delivery device within the target tissue when inserted into the patient's target tissue. In some embodiments, the tissue retention mechanism extends outwardly from the tip. In some embodiments, the tissue retention mechanism comprises barbs and / or edges. In some embodiments, the tip has at least one apex at its distal end. In some embodiments, the body comprises a disengagement mechanism on the proximal end side of the body. In some embodiments, the flexible shaft is connected to the proximal end of the body. In some embodiments, the disengagement mechanism is configured to disengage the drug delivery device from the flexible shaft. In some embodiments, the disengagement mechanism is configured to disengage the drug delivery device from the flexible shaft by twisting.

[0014] In some embodiments, the drug delivery device includes a core comprising a first biodegradable polymer; and an outer layer surrounding at least a portion of the core and comprising a pharmaceutical active ingredient (API) and a second biodegradable polymer, wherein the first biodegradable polymer has a slower degradation rate than the second biodegradable polymer. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient. In some embodiments, the target tissue site is a solid tumor in the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon. In some embodiments, the first biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the first biodegradable polymer is PLGA 75:25. In some embodiments, the second biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the second biodegradable polymer is PLGA 50:50. In some embodiments, the drug delivery device is configured to be implanted into a patient using standard open surgical procedures and minimally invasive procedures. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient using a bronchoscope. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient by a robot. In some embodiments, the outer layer is configured to release the API when inserted into the target tissue site of the patient. In some embodiments, the outer layer is configured to release the API omnidirectionally when inserted into the target tissue site of the patient. In some embodiments, the release of the API is controlled by the in vivo degradation of the second biodegradable polymer at the target tissue site.

[0015] In some embodiments, a method of treating a patient's tissue comprises implanting a drug delivery device at a target tissue site of the patient, the drug delivery device comprising a body including a core containing a first biodegradable polymer and an outer layer surrounding at least a portion of the core, the outer layer containing a pharmaceutical active ingredient (API) and a second biodegradable polymer, wherein the degradation rate of the first biodegradable polymer is slower than the degradation rate of the second biodegradable polymer, the body; and a tip connected to the distal end of the body, implanting the drug delivery device; and releasing the API, wherein the release of the API is controlled by the in vivo degradation of the second biodegradable polymer at the target tissue site. In some embodiments, the drug delivery device is implanted into the patient's target tissue site first from the tip. In some embodiments, the target tissue site is a tumor in the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon. In some embodiments, the drug delivery device is implanted via an open surgery, laparoscopically, robotically, percutaneously, or endoscopically. In some embodiments, the drug delivery device is implanted via a bronchoscope. In some embodiments, releasing the API from the outer layer comprises releasing the API omnidirectionally away from the outer layer. In some embodiments, the drug delivery device is implanted into the patient's target tissue site such that the tip is configured to hold the drug delivery device within the target tissue. In some embodiments, implanting the drug delivery device comprises using a tool for delivering the drug delivery device to the patient's target tissue site. In some embodiments, the tool comprises a flexible shaft and is connected to the proximal end of the body. In some embodiments, implanting the drug delivery device into the target tissue site comprises disengaging the body of the drug delivery device from the flexible shaft. In some embodiments, disengaging the drug delivery device from the flexible shaft comprises screwing the flexible shaft relative to the drug delivery device.

[0016] Further advantages will be readily apparent to those skilled in the art from the following detailed description. The examples and descriptions in this specification should be considered to be illustrative in nature and not restrictive.

[0017] All publications, including patent documents, scientific papers, and databases, referred to in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were incorporated by reference separately. If the definitions set forth in this specification are contrary to or inconsistent with the definitions set forth in the patents, applications, published applications, and other publications incorporated by reference herein, the definitions set forth in this specification shall control.

[0018] The present invention will be described by way of example only with reference to the accompanying drawings.

Brief Description of the Drawings

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[0034] In the drawings, unless otherwise specified, like reference numerals correspond to like components.

[0035] **DETAILED DISCLOSURE** Described herein are exemplary embodiments of a biodegradable drug delivery device that can be implanted into a patient to locally deliver a controlled therapeutically effective amount of an API. Specifically, the drug delivery devices disclosed herein are configured to provide controlled release of a therapeutically effective amount of an API directly to a target tissue site (e.g., a tumor), into the target tissue site, and / or adjacent to the target tissue site by in vivo degradation of a biodegradable polymer layer containing the API. In some embodiments, it may not be possible to place the drug delivery device directly at the target tissue site (e.g., a tumor). Therefore, the drug delivery device can be delivered adjacent to the target tissue. For example, if the tumor is encapsulated by a scar capsule and / or if the tumor may excrete unwanted components and is thus instructed not to "poke" so as not to disrupt the tumor. In such situations, the drug delivery device can be placed adjacent to the tumor site, such as near the edge or boundary of the tumor site and / or in contact or close proximity to the tumor site.

[0036] In some embodiments, the target tissue can be cancerous tissue / cells on an organ or peritumoral tissue / cells. For example, the target tissue can be cancerous tissue / cells on the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon, or metastatic cancerous tissue / cells from a primary tumor or peritumoral tissue / cells.

[0037] PCT International Application No. PCT / US2022 / 079996 (which is hereby incorporated by reference in its entirety) discloses a film or patch drug delivery device having a plurality of biodegradable layers. In use, the API layer disclosed in PCT International Application No. PCT / US2022 / 079996 faces the target tissue such that the API is released towards the target tissue during degradation, and the non-API backing layer can prevent the API from being released from the target tissue onto non-target tissue.

[0038] As disclosed herein, in some embodiments, the drug delivery device can be a tissue (e.g., tumor) penetrating device (such as a bullet, arrow, plug, or other such device) having a plurality of biodegradable layers (e.g., a core layer, an inner layer, a shell layer, and / or an outer layer). At least one layer or a plurality of layers of the device can include an API that can be released in vivo by biodegradation of the polymer. In some embodiments, at least one layer may not include an API. In some embodiments, there may be no layer that does not include an API (i.e., all layers include at least some API). In some embodiments, the non-API layer(s) can be the core of the drug delivery device, or a core layer or an inner layer. In some embodiments, the non-API layer(s) can be an outer layer or a shell layer of the drug delivery device.

[0039] The drug delivery devices disclosed herein can have many shapes, sizes, and geometries. In some embodiments, the drug delivery device can be circular, square, rectangular, elliptical, triangular, rhombic, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), arcuate, trapezoidal, star-shaped, or various other shapes and sizes. In some embodiments, the drug delivery device can be tubular, cylindrical, conical, pyramidal, triangular prismatic, cubic, spherical, screw-shaped, square prismatic, or various other shapes and sizes. For example, FIGS. 1A - D show a square prismatic drug delivery device 100, and FIGS. 2A - C show a cylindrical drug delivery device 200.

[0040] In some embodiments, the drug delivery device may include multiple layers. In some embodiments, the drug delivery device may include at least one biodegradable layer. At least one layer or multiple layers may include an API that can be released in vivo by biodegradation of the polymer. In some embodiments, at least one second layer or multiple layers may not include an API.

[0041] In some embodiments, the drug delivery device may include a body. In some embodiments, the body of the drug delivery device can be flexible or rigid. In some embodiments, the body can include multiple layers. In some embodiments, the drug delivery device can include at least one API layer or multiple API layers. The API layer can include an API embedded within and / or on the surface of at least one API layer. In some embodiments, multiple layers (i.e., all other layers) of the drug delivery device can also be API layers. These layers can include the same or different APIs. In some embodiments, at least one of the layers or multiple layers of the drug delivery device can be a non-API layer.

[0042] For example, a drug delivery device can include a body 204. In some embodiments, the body can include at least one API layer 101 (e.g., an outer layer). The API layer can include APIs embedded within and / or on the surface of the at least one API layer 101. In some embodiments, multiple layers (e.g., all other layers) of the drug delivery device can also be API layers. For example, layer 102 (e.g., an inner layer), layer 103, layer 104, and layer 105 can be layers that include APIs embedded within the layer and / or on the layer surface. These layers can include the same or different APIs. In some embodiments, at least one of the layers of the drug delivery device can be a non-API layer. For example, the intermediate layer 103 can be a non-API layer to provide some additional structural support and / or strength to the overall drug delivery device. In use, the drug delivery device can be implanted within and / or adjacent to a solid tumor, and the API layer(s) can release the API within or adjacent to the tumor during degradation, as shown by the arrows 301 in FIGS. 1A-C and FIGS. 2A-C. Thus, the API layer(s) can release the API in a multi-directional and / or omnidirectional (i.e., in all directions) manner within the target tissue during degradation. In some embodiments, the target tissue can be a cancerous tumor (e.g., a solid tumor). For example, the targeted tissue can be a tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon, or a metastasis from a primary tumor.

[0043] In some embodiments, the outer layers of the device (e.g., layer 101 and layer 105) can be non-API layers. In some embodiments, the body can be coated with a non-API coating or can be entirely covered with a non-API layer (e.g., a non-API shell). For example, in such embodiments, the cross-section of FIG. 1C would include a non-API layer(s) or coating around the perimeter of the cross-section (not shown). In such embodiments, the API layer(s) can be inside the body of the drug delivery device so that the drug is not accidentally released, lost, and / or damaged (e.g., due to the device being scraped and / or damaged inadvertently during placement) until the non-API coating shell first dissolves. In other words, the drug delivery device can have a protective non-API layer(s) / coating such that the API layer is protected from any external elements. For example, in some embodiments, all sides (e.g., top, bottom, front, back, each end) of the drug delivery device can have a non-API coating / layer / shell. In some embodiments, the non-API layer / coating / shell can include a biodegradable polymer (disclosed herein) that has a slower, faster, or the same rate of degradation as the biodegradable polymer of the API layer(s). In some embodiments, the outer layer can degrade faster than the inner layer of the drug delivery device regardless of the rate of degradation of the layers because the outer layer is in contact with an environment that degrades the biodegradable polymer while the inner layer can be protected from such an environment. In some embodiments, the outer layer / shell of the device can be the API layer and can readily release the API when implanted in the target tissue without waiting for the layers other than the API to degrade.

[0044] In some embodiments, the body of the drug delivery device can include at least one API layer and / or at least one non-API layer. As described above, the at least one API layer can be an outer layer, an inner layer, a shell layer, a core, and / or a core layer. Further, the at least one non-API layer can be an outer layer, an inner layer, a shell layer, a core, and / or a core layer. In some embodiments, the core, core layer, outer layer, inner layer, and / or shell layer can have any API layer or non-API layer composition disclosed herein. For example, FIGS. 2A-C illustrate a non-API core 202 having an API outer layer 201. In some embodiments, the core or core layer can provide strength to the drug delivery device when the drug delivery device is inserted into a patient. As shown in FIG. 2B, the core 202 can provide longitudinal strength to the drug delivery device for embedding into and / or adjacent to the patient's target tissue site. Although only two layers are illustrated in FIG. 2C, the drug delivery devices disclosed herein can have additional layers such as API layers, non-API layers, or combinations thereof. In some embodiments, the drug delivery device 200 can include an API layer 201 (i.e., the outer layer) and a non-API layer 202 (i.e., the core or core layer). The API-containing layer can include an API embedded within and / or on the surface of the API layer 201. In some embodiments, the API layer can surround at least a portion of the non-API core or core layer. In some embodiments, the non-API layer can surround at least a portion of the API core or core layer. In some embodiments, the drug delivery device can have a hollow core as described below. The hollow core can be used to help guide and deliver the drug delivery device to its target tissue.

[0045] In some embodiments, the drug delivery device can be made by the solvent casting method. As described in more detail below, at least one biodegradable polymer and at least one API can be dissolved in a solvent and cast into a mold and / or onto a substrate. In some embodiments, after drying, the layer can be removed from the mold and / or substrate, and this process can be repeated to create the required number of API layers in the drug delivery device. In some embodiments, the layer can be left on the substrate for further processing such as lamination and / or cutting as described herein. In some embodiments, a second layer (i.e., a non-API layer) having at least one biodegradable polymer can be dissolved in a solvent, cast into a mold and / or onto a substrate, dried, and / or removed from the mold and / or substrate. This process can be repeated to create the required number of API layers in the drug delivery device. In some embodiments, any combination and order of API layers and / or non-API layers can be laminated together to form the drug delivery device, or can be laminated together and then cut (e.g., die cut) to form the drug delivery device.

[0046] In some embodiments, a second layer having at least one biodegradable polymer (and optionally an API) can be cast on top of the first layer and then dried (and repeated) to form the device. In some embodiments, the non-API layer (e.g., a core or core layer) can be dissolved in a solvent and cast into a mold and / or onto a substrate before the API layer (e.g., an outer layer or shell layer) is cast on top of the non-API layer. This process can be repeated for as many additional API layers and / or non-API layers as needed.

[0047] In some embodiments, the drug delivery device can be made via a continuous process. In some embodiments, the drug delivery devices disclosed herein can be manufactured by continuous processes (e.g., extrusion, continuous film evaporation, etc.) such as those employed in the polymer film manufacturing industry.

[0048] In some embodiments, such as those shown in FIGS. 1A-C and FIGS. 2A-C, the drug delivery device is configured to be inserted into and / or adjacent to a target tissue site of a patient using standard open surgical instruments, laparoscopic surgical instruments, endoscopic surgical instruments (e.g., bronchoscopic surgical instruments), percutaneous surgical instruments, or robotic surgical instruments. In some embodiments, the drug delivery device can be inserted through the working channel of an endoscope (e.g., a bronchoscope), a trocar, or a needle (for percutaneous delivery). For example, the drug delivery device can be guided to the target tissue site through the working channel of an endoscope (or a robotic endoscope). In some embodiments, the device is flexible so that it can be delivered to the target tissue via any of the above administration routes.

[0049] Since the drug delivery device can be flexible such that it is configured to be inserted through the working channels of endoscopes, trocars, etc., the diameter, width, and / or height of the drug delivery device (of the body and / or the tip) can be in the range of about 0.1 - 20 mm, about 0.25 - 20 mm, about 0.25 - 12 mm, about 0.5 - 12 mm, about 0.5 - 10 mm, about 0.5 - 8 mm, about 0.5 - 5 mm, about 0.5 - 3 mm, about 1 - 3 mm, or about 2 mm. In some embodiments, the length of the body of the drug delivery device can be about 0.1 - 20 mm, about 0.5 - 15 mm, about 1 - 15 mm, about 3 - 12 mm, about 4 - 11 mm, or about 5 - 10 mm. In some embodiments, the device can have a smaller diameter, width, and / or height for percutaneous insertion.

[0050] In some embodiments, the drug delivery device may include a tip portion 205. In some embodiments, the drug delivery device may not include a tip portion. In some embodiments, the tip portion of the drug delivery device may be flexible or rigid. In some embodiments, the tip portion may be connected to the distal end of the body of the drug delivery device. In some embodiments, the tip portion and the body may be an integral unit. When the drug delivery device is guided to a tissue site of a patient, the tip of the drug delivery device may be guided first. In some embodiments, the tip portion may have at least one apex at its distal end. The at least one apex may enable the tip portion (and the drug delivery device) to penetrate and / or be adjacent to a target tissue site (e.g., a solid tumor). In some embodiments, the at least one apex may be sharp. Thereby, the drug delivery device can be implanted into and / or adjacent to the patient's target tissue site from the tip first. In some embodiments, the drug delivery device does not include a tip portion.

[0051] In some embodiments, the distal end may be configured to hold or retain the drug delivery device at the target tissue site. For example, in some embodiments, the distal end can include one or more tissue holders or tissue retention mechanisms 206. The tissue retention mechanism(s) may be configured to hold or retain the drug delivery device at the target tissue site (i.e., within the solid tumor). In some embodiments, the tissue retention mechanism(s) can extend outwardly from the distal end. In some embodiments, the tissue retention mechanism(s) can extend radially outwardly from the drug delivery device. In some embodiments, the tissue retention mechanism(s) can extend outwardly from the drug delivery device (or distal end) and return towards the body or proximal end of the drug delivery device. In some embodiments, the tissue retention mechanism(s) can include edges, barbs, lips, or other similar aspects. In some embodiments, the edges, barbs, lips, or other similar aspects can be sharp. In some embodiments, the distal end having the tissue retention mechanism(s) can resemble the shape of a broadhead arrow. Thus, the distal end (having the tissue retention mechanism) can be configured to penetrate the target tissue site, embed the drug delivery device within or adjacent to the target tissue site, and hold / retain the drug delivery device within or adjacent to the target tissue site when the API is released from the API layer(s). In some embodiments, the body of the drug delivery device can include tissue retention mechanisms (plural possible) such as non-API layers or API layer(s) of the body.

[0052] In some embodiments, the tip may also include a biodegradable polymer. In some embodiments, the biodegradable polymer of the tip has a slower degradation rate than the biodegradable polymer of the API layer(s), such that when the API is released from the API layer(s) by in vivo degradation, the tip can hold the drug delivery device in a predetermined position within the tumor. Similar to the API layer and / or non-API layer, the tip can be configured / adjusted to have a particular desired degradation rate. In some embodiments, the tip can be made from any of the compositions disclosed herein for the API layer and / or non-API layer. In some embodiments, the tip can have the same composition as any of the non-API layers disclosed herein. In some embodiments, the tip and the body of the device can be integral components or can be created separately and later attached / adhered / connected to each other. In some embodiments, the tip can be created in the same manner as any of the APIs and / or non-APIs disclosed herein can be created (e.g., solvent casting, lamination, cutting, etc.). Additionally, since the tip can be made of a biodegradable material, the entire drug delivery device can be degradable and subsequent surgery to remove a portion of the device may not be required. In some embodiments, the thickness of the layers of the drug delivery device and / or the size of the tip can be selected based on the desired degradation / API release rate.

[0053] In some embodiments, when implanting a drug delivery device at and / or adjacent to a target tissue site, the drug delivery device can be configured to disengage or release from a component (e.g., a tool capable of delivering a device such as a flexible shaft 203). In some embodiments, for delivery, a flexible shaft (e.g., the distal end of the flexible shaft) can be connected to the body of the drug delivery device (e.g., the proximal end of the body). The drug delivery device having the flexible shaft can then be inserted into the working channel of an endoscope (e.g., a standard endoscope or a robotic endoscope) and implanted at and / or adjacent to the patient's target tissue site. In some embodiments, the proximal end of the flexible shaft can be connected or attached to an endoscope component, another tool used to guide the drug delivery device to the target tissue site, and / or a robotic component. In some embodiments, disengaging or releasing the drug delivery device from the delivery tool (e.g., the flexible shaft) can include screwing the delivery tool relative to the drug delivery device. This operation can liberate / disengage the drug delivery device from the delivery tool (e.g., the flexible shaft). In some embodiments, this operation can fatigue a portion of the drug delivery device connected to the delivery tool, allowing the tool to be separated from the drug delivery device.

[0054] In some embodiments, the drug delivery device can have a hollow core, whereby the drug delivery device can function as a shaft or shank for a central pin, peg, and / or mandrel (e.g., flexible shaft 203) such as the drug delivery devices shown in FIGS. 2E - F, and can deliver the device to a target tissue site. In some embodiments, the pin, peg, and / or mandrel can then be removed from the drug delivery device such that the drug delivery device remains at its target tissue site. This could be similar to a riveting mechanism or stent deployment. In some embodiments, the tip of the drug delivery device can be attached to a deployment mandrel through the core of the drug delivery device. When the mandrel is removed, similar to a pop - rivet mechanism, the mandrel can break off and separate from the tip or be severed. In some embodiments, the hollow core of the drug delivery device can have an inner diameter configured to pass or translate a delivery tool (e.g., flexible shaft) through the hollow core. For example, the hollow core can have a diameter of at least about 0.1 mm, at least about 0.5 mm, at least about 1 mm, or at least about 2 mm. In some embodiments, the hollow core can have a diameter of at most 10 mm, at most 5 mm, at most 2 mm, or at most 1 mm. For example, in some embodiments, the distal end of the flexible shaft 203 can be attached / connected / adhered etc. to the distal end (e.g., tip 205) of the drug delivery device through the hollow core of the drug delivery device. This can provide longitudinal support, strength, and / or rigidity to the drug delivery device for implantation within the target tissue site and / or implantation adjacent to the target tissue site. In some embodiments, the proximal end of the flexible shaft can be connected or attached to an endoscopic component, another tool used to direct the drug delivery device to the target tissue site, and / or a robotic component. In some embodiments, disengaging or releasing the drug delivery device from the delivery tool (e.g., flexible shaft) can include turning or springing the delivery tool with respect to the drug delivery device.This operation enables the release / disengagement of the drug delivery device from the delivery tool (e.g., a flexible shaft). In some embodiments, this operation can fatigue a portion of the drug delivery device connected to the delivery tool and separate the tool from the drug delivery device.

[0055] In some embodiments, the drug delivery device can be attached to forceps 210 (e.g., standard lung biopsy forceps) as shown in FIG. 2D that can embed the drug delivery device within and / or adjacent to the target tissue site. In some embodiments, the forceps can be biopsy forceps (e.g., clam shell forceps). For example, the mouth of the forceps can be attached at the location where the disengagement mechanism 207 is disposed, and the forceps can be used to position the drug delivery device at its target location. Once the drug delivery device is positioned, the forceps can be opened to release the drug delivery device.

[0056] In some embodiments, the drug delivery device can be housed in an applicator. The applicator can include a plunger (i.e., similar to the mechanism of a tampon) that can extrude the drug delivery device from the applicator housing into and / or adjacent to the target tissue site. And the applicator can be removed after the drug delivery device has been applied.

[0057] In some embodiments, the body can include a disengaging mechanism 207 on the proximal end side of the body. In some embodiments, the body can include a disengaging mechanism on the distal end side of the body. The disengaging mechanism can be configured to disengage the drug delivery device from the delivery tool. After the drug delivery device is implanted / embedded in a target tissue (e.g., a solid tumor), the delivery tool (e.g., a flexible shaft, forceps, etc.) can be withdrawn leaving the drug delivery device in the target tissue (in some embodiments, from the working channel of an endoscope). In some embodiments, the distal end portion of the drug delivery device can include a disengaging mechanism(s) as shown in FIG. 2E.

[0058] In some embodiments, the drug delivery device can include an anatomical marker(s) 208. In some embodiments, the anatomical marker(s) can be in the API layer and / or non-API layer of the device. In some embodiments, the anatomical marker can be on the body and / or distal end portion of the drug delivery device. In some embodiments, the anatomical marker can be used with various imaging techniques for a physician to identify the drug delivery device within a patient. The physician can then monitor the progression and / or position of the drug delivery device relative to the tumor. In some embodiments, the anatomical marker can be a radiopaque marker, an X-ray marker, a lead marker, or a similar marker(s). In some embodiments, the anatomical marker can be embedded in a component (e.g., a layer, body, and / or distal end portion) after its components have already been fabricated.

[0059] As described above, the drug delivery device can be guided to the target tissue site via open surgery, laparoscopically, robotically, percutaneously, endoscopically, or a combination thereof. Once the target tissue site is reached, the proper orientation of the drug delivery device can be confirmed by monitoring anatomical markers with a camera or other means. In some embodiments, a surgical camera can be utilized to confirm that the (at least one) tip (apex) of the drug delivery device is directed towards the target tissue site.

[0060] Once the correct placement and orientation of the drug delivery device are confirmed, the drug delivery device can be inserted or implanted within and / or adjacent to the target tissue site. For example, the drug delivery device can be implanted such that at least a portion of the drug delivery device is within or adjacent to the target tissue site (e.g., a solid tumor). In some embodiments, the entire drug delivery device can be implanted within the target tissue site. In some embodiments, after the drug delivery device is implanted within or adjacent to the target tissue, the delivery tool (e.g., a flexible shaft, forceps, etc.) can be removed from the drug delivery device and then the patient can be removed leaving the drug delivery device behind.

[0061] In some embodiments of the API layer, the drug delivery device can include at least one or a plurality of API-containing layers. In some embodiments, at least one API-containing layer can be an outer layer, an inner layer, a core, a core layer, and / or a shell layer of the drug delivery device. In some embodiments, the API layer can include at least one active pharmaceutical ingredient (API) and at least one biodegradable polymer. In some embodiments, the API layer can include one or more biodegradable polymers. In some embodiments, the API layer can include one or more APIs. As described above, the API layer can be configured to provide controlled release of the API by in vivo degradation of the biodegradable polymer at the target tissue site and / or within the target tissue site. In some embodiments, the API layer can also include one or more pharmaceutically acceptable excipients.

[0062] In some embodiments, the biodegradable polymer can be any suitable biodegradable polymer known in the art. For example, the biodegradable polymer can include synthetic polymers selected from poly(amides), poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo-poly(amino acids), poly(glycerol sebacate), copolymers thereof, and mixtures thereof. In addition, the biodegradable polymer can be formed from poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(caprolactone), and mixtures thereof. In some embodiments, the biodegradable polymer can be poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the PLGA can be PLGA having various ratios of lactic acid to glycolic acid, such as PLGA 50:50, PLGA 60:40, PLGA 65:35, PLGA 70:30, PLGA 75:25, PLGA 80:20, PLGA 85:15, PLGA 90:10, or other various ratios of PLGA. In some embodiments, the biodegradable polymer in the API-containing layer includes PLGA 50:50.

[0063] PLGA degrades by hydrolysis or biodegradation, and its backbone ester bonds are cleaved into oligomers and subsequently monomers. The lactide-glycolide ratio determines the degradation rate of PLGA in an aqueous medium (e.g., water and water-containing environments such as within human or animal anatomical structures). Generally, the higher the lactic acid content or lactide content, the lower the degradation behavior of PLGA. This is because lactide has hydrophobicity and water can prevent the hydrolysis of the ester bonds of PLGA. Therefore, PLGA 50:50 degrades faster in a water-containing environment than PLGA 65:35, and PLGA 65:35 degrades faster than PLGA 75:25.

[0064] In some embodiments, the API-containing layer comprises at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 73 wt%, at least about 75 wt%, at least about 80 wt%, at least about 85 wt%, or at least about 90 wt% of a biodegradable polymer. In some embodiments, the API-containing layer comprises at most about 95 wt%, at most about 90 wt%, at most about 85 wt%, at most about 80 wt%, at most about 77 wt%, or at most about 75 wt% of a biodegradable polymer. In some embodiments, the API-containing layer comprises about 60 - 95 wt%, about 70 - 95 wt%, about 75 - 90 wt%, about 75 - 89 wt%, or about 79 - 89 wt% of a biodegradable polymer.

[0065] In some embodiments, the API can be a pharmaceutical active ingredient for the treatment of human or animal diseases. The API can be one or more of an antibacterial agent, an antifungal agent, an antiprotozoal agent, an antiviral agent, a labor inducer, a spermicide, a prostaglandin, a steroid and a microbicide, a protein / peptide and a vaccine antigen.

[0066] Suitable APIs include, but are not limited to, analgesics and anti-inflammatory agents (e.g., ibuprofen), antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, anxiolytics and antidepressants, antidiabetic agents, antidiarrheals, antiepileptics, antifungal agents, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antitumor agents and immunosuppressants, antiprotozoals, antirheumatics, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics and anxiolytics, beta blockers, cardiotonics, corticosteroids, antitussives, cytotoxics, venotonic agents, diuretics, enzymes, antiparkinson agents, gastrointestinal agents, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates and antianginals, nutraceuticals, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, smoking cessation products, and combinations thereof.

[0067] In some embodiments, the API can be a chemotherapeutic agent such as any pharmaceutical formulation effective to treat cancer by inhibiting the growth and invasiveness of malignant cells and / or inducing cytotoxicity by apoptosis or necrosis of malignant cells. The chemotherapeutic agent can be a taxane agent or a platinum agent. In some embodiments, the chemotherapeutic agent includes a MEK inhibitor, a KRAS inhibitor, a PI3K inhibitor, a hedgehog inhibitor, a Wnt inhibitor, or a combination thereof. In some embodiments, the chemotherapeutic agent can interfere with the mTOR or NFkB pathway. In some embodiments, the chemotherapeutic agent includes a STING agonist compound. In some embodiments, the chemotherapeutic agent can interfere with the STING pathway. In some embodiments, the chemotherapeutic agent includes genetic material such as mRNA, siRNA. In some embodiments, the chemotherapeutic agent can be a siRNA-Alnylam type therapy.

[0068] In some embodiments, the API can include a vaccine antigen. In some embodiments, the API can be an mRNA vaccine antigen such as an mRNA cancer vaccine antigen.

[0069] The API can be a single pharmaceutical active ingredient such as a single chemical substance, or it can be a mixture of several pharmaceutical active ingredients. The pharmaceutical active ingredient can be any of many categories of pharmaceutical active ingredients. The pharmaceutical active ingredient can be selected from the group consisting of, but not limited to, paclitaxel, gemcitabine, nab-paclitaxel, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, vinorelbine, etoposide, mitomycin-C, cisplatin / carboplatin, fluorouracil, methotrexate, TAS-102, or combinations thereof. In some embodiments, the API is paclitaxel. In some embodiments, the paclitaxel is from Phyton Biotech.

[0070] In some embodiments, the API can be an API for targeted therapy such as bevacizumab, ramucirumab, erlotinib, afatinib, gefitinib, osimertinib, dacomitinib, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, dabrafenib, trametinib, sunitinib, regorafenib, or combinations thereof. In some embodiments, the API can be an API for immunotherapy such as nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, or combinations thereof.

[0071] In some embodiments, the API may be acyclovir, fluconazole, progesterone and its derivatives, nonoxynol-9, terbutaline, lidocaine, testosterone and its derivatives, dinoprostone, lactic acid bacteria, estrogen and its derivatives, naphthalene 2-sulfonate, lesmitidan, doxycycline, droxidopa, sapropterin, butoconazole, clindamycin nitrate / phosphate, neomycin sulfate, polymyxin sulfate, nystatin, clotrimazole, dextrin sulfate, glyminox, miconazole nitrate, benzalkonium chloride, sodium lauryl sulfate, tenofovir, insulin, calcitonin, danazol, ibuprofen, acetaminophen, cefpodoxime proxetil, desloratadine, dextromethorphan, diphenhydramine hydrochloride, vitamins and / or minerals, adipic acid, ascorbic acid, macrolide antibiotics, NS-AIDS, cefuroxime axetil, amobarbital, ciprofloxacin hydrochloride, sildenafil citrate, pinaverium bromide, propantheline bromide, triprolidine HCl, dimenhydrinate, cefeneloxamate HCl, enoxacin, sparfloxacin, aspirin, famotidine, amoxicillin trihydrate, morphine HCl, amylopride HCl, terfenadine, beclamide, clarithromycin, roxithromycin, nizatidine, cetraxate HCl, ciprofloxacin, bifenemelene HCl, cefuroxime axetil, pirenzepine and / or oxybutynin, diclofenac, nicorandil, levofloxacin, acriflavine, leuprorelin acetate, metronidazole, benzydamine hydrochloride, chloramphenicol, oxybutynin, ethinyl estradiol, prostaglandin, insulin, calcitonin, and combinations thereof. The pharmaceutical active ingredient may also be a vaccine antigen such as for the treatment of hepatitis B, HIV, HPV, chlamydia, gonorrhea infection, etc.

[0072] The API may include salts, esters, hydrates, solvates and derivatives of any of the aforementioned active ingredients. Suitable derivatives are those known to those skilled in the art that may have a low or high activity level but have the same activity as the active ingredient. In some embodiments, the API can be in the form of microspheres. In some embodiments, the microspheres can release the API. In some embodiments, the API is encapsulated within the microspheres.

[0073] When present, the API is employed in the formulation at a therapeutically effective amount necessary to provide the required dosage and typically results in at least one physiological effect established by clinical trials. A person skilled in the art can readily determine the appropriate amount of the pharmaceutical active ingredient to include in a drug delivery device made in accordance with the present disclosure.

[0074] In some embodiments, the API-containing layer comprises at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 5 wt%, at least about 7 wt%, at least about 8 wt%, at least about 9 wt%, at least about 10 wt%, at least about 11 wt%, at least about 12 wt%, at least about 13 wt%, at least about 14 wt%, or at least about 15 wt% of the API. In some embodiments, the API-containing layer comprises at most about 30 wt%, at most about 25 wt%, at most about 20 wt%, at most about 18 wt%, at most about 15 wt%, at most about 14 wt%, at most about 13 wt%, at most about 12 wt%, at most about 11 wt%, at most about 10 wt%, at most about 9 wt%, at most about 8 wt%, at most about 7 wt%, or at most about 5 wt% of the API. In some embodiments, the API-containing layer comprises from about 1 to 30 wt%, from about 1 to 25 wt%, from about 5 to 25 wt%, from about 10 to 20 wt%, from about 12 to 18 wt%, from about 12 to 15 wt%, from about 13 to 14 wt%, from about 1 to 15 wt%, from about 5 to 15 wt%, from about 7 to 12 wt%, from about 8 to 12 wt%, or from about 7.5 to 11 wt% of the API. In some embodiments, the API-containing layer may comprise from about 0.01 to 500 mg, from about 0.01 to 50 mg, from about 0.1 to 50 mg, or from about 0.25 to 50 mg.

[0075] In some embodiments of the drug delivery devices disclosed herein, to prepare the API layer, a solution of a biodegradable polymer and an API can be formed. Specifically, an amount of the biodegradable polymer can be dissolved in a solvent. The biodegradable polymer / solvent solution can be stirred and / or heated to assist in dissolving the polymer in the solvent. In some embodiments, the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methyl ethyl ketone, methylene chloride, isopropyl alcohol, methyl isobutyl ketone, methyl propyl ketone, trichloroethylene, other alternatives to acetone, or combinations thereof. In some embodiments, the biodegradable polymer and solvent solution can be about 0.1 - 0.3 g of biodegradable polymer per mL of solvent, about 0.15 - 0.25 g of biodegradable polymer, about 0.175 - 0.225 g of biodegradable polymer, about 0.19 - 0.21 g of biodegradable polymer, about 0.198 - 0.202 g of biodegradable polymer, or about 0.2 g of biodegradable polymer. In other words, if 20 g of biodegradable polymer is contained in 100 mL of solvent, it becomes a biodegradable polymer and solvent solution containing 0.2 g of biodegradable polymer per mL of solvent. The above concentrations can also apply to the biodegradable polymer / API solution described later. For example, the biodegradable polymer / API solution can have about 0.1 - 0.3 g of biodegradable polymer per mL of solvent, about 0.15 - 0.25 g of biodegradable polymer, about 0.175 - 0.225 g of biodegradable polymer, about 0.19 - 0.21 g of biodegradable polymer, about 0.198 - 0.202 g of biodegradable polymer, or about 0.2 g of biodegradable polymer.

[0076] In some embodiments, after dissolving the biodegradable polymer in a solvent, the API can be added to the solution. In some embodiments, the API and the biodegradable polymer can be added simultaneously to the solvent. In some embodiments, the API can be added to the solvent prior to the addition of the biodegradable polymer. In some embodiments, the API can be added to the solvent to form a first solution, the biodegradable polymer can be added to the solvent to form a second solution, and the first and second solutions can be combined to form a biodegradable polymer / API solution. In some embodiments, when the API is incorporated into the biodegradable polymer layer, the API can be in the form of microspheres. In some embodiments, the microspheres can help prevent the API from dissolving and / or degrading in the polymer / solvent solution.

[0077] In some embodiments, the biodegradable polymer / API solution can have from about 0.01 to 0.05 g of API, from about 0.01 to 0.045 g of API, from about 0.015 to 0.045 g of API, from about 0.02 to 0.04 g of API, from about 0.025 to 0.04 g of API, or from about 0.03 to 0.04 g of API per mL of solvent. The above concentrations also apply to the API and the solvent solution (without the biodegradable polymer). The biodegradable polymer / API solution can be stirred and / or heated until the API is well mixed and / or dissolved in the solvent.

[0078] In some embodiments, after the biodegradable polymer / API solution is formed, the solution can be added to a mold and / or a substrate. In some embodiments, the substrate can be a release film or liner such as a medical release liner. In some embodiments, the substrate can be formed from a polymer (e.g., polyester) or a paper substrate and can be coated with silicone or PTFE. In some embodiments, the mold can be any container used to impart a shape to the API layer when the API layer is formed. Thus, the mold can be circular, square, rectangular, oval, triangular, rhombic, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), arcuate, trapezoidal, star-shaped, tubular, cylindrical, conical, pyramidal, triangular prism-shaped, cubic, spherical, cuboid-shaped, or various other shapes and sizes. In addition to the shape, the mold can also determine the size of the layer (i.e., width, length, diameter, height / thickness, etc.).

[0079] In some embodiments, the mold can determine the shape of the final API layer. In other embodiments, the mold forms a precursor API layer, which is later modified (e.g., laminated and cut) to form the final API layer of the drug delivery device. In some embodiments, the biodegradable polymer / API solution can be added to a circular mold. In some embodiments, the mold can be an evaporating dish, a Petri dish, etc. Additionally, the amount added to the mold can depend on the desired thickness and / or API concentration of the API layer. Additionally, the amount added to the mold can depend on the desired API release rate of the API layer. In some embodiments, about 1 - 20 mL, about 1 - 10 mL, about 4 - 6 mL, or about 5 mL of the biodegradable polymer / API solution can be added to the mold.

[0080] In some embodiments, the biodegradable polymer / API solution is added to a substrate. As described above, in some embodiments, the substrate can be a release liner and the biodegradable polymer / API solution can be added to the release surface of the release liner. In some embodiments, a film applicator and / or a spiral bar coater can be used to form a reproducible wet layer of the biodegradable polymer / API solution having a certain thickness. In some embodiments, the film applicator and / or the spiral bar coater can be disposed on a flat substrate where the desired thickness is selected. In some embodiments, the biodegradable polymer / API solution can then be added to the substrate. In some embodiments, the biodegradable polymer / API solution can be added in front of the film applicator and / or the spiral bar coater and / or within a reservoir of the film applicator and / or the spiral bar coater. In some embodiments, a more straight leading edge can be created by a consistent injection rate of the biodegradable polymer / API solution. In some embodiments, a more straight trailing edge can be created by starting with a greater amount of the biodegradable polymer / API solution at the end near the feet of the film applicator and / or the spiral bar coater. In some embodiments, as shown in FIG. 3, the biodegradable polymer / API solution 301 can be added between the film applicator 302 and / or the feet 302a of the spiral bar coater. In some embodiments, once the biodegradable polymer / API solution is in place, the film applicator and / or the spiral bar coater can be moved on the substrate 303 at a steady rate in a given direction 304 (i.e., drawdown).

[0081] In some embodiments, moving the film applicator and / or the spiral bar coater over the substrate guides the biodegradable polymer / API solution through the gap of the film applicator and / or the spiral bar coater, spreads the biodegradable polymer / API solution over the substrate, thereby forming a wet layer of the biodegradable polymer / API solution of a desired thickness on the substrate. In some embodiments, the film applicator and / or the spiral bar coater can be a manual or automatic film applicator. In some embodiments, the film applicator can be a baker-type applicator, a bird-type applicator, a reservoir applicator, and / or a micrometric applicator, etc.

[0082] In some embodiments, the thickness of the wet layer of the biodegradable polymer / API solution on the substrate can be at least about 0.1 mm, at least about 0.25 mm, at least about 0.5 mm, at least about 0.75 mm, at least about 1 mm, at least about 1.25 mm, at least about 1.5 mm, at least about 1.75 mm, or at least about 2 mm thick. In some embodiments, the thickness of the wet layer of the biodegradable polymer / API solution on the substrate can be at most about 5 mm, at most about 4 mm, at most about 3 mm, at most about 2 mm, at most about 1.5 mm thick, or at most about 1 mm thick.

[0083] In some embodiments, after being spread over the substrate, the biodegradable polymer / API solution can be dried. This drying causes the solvent to evaporate, leaving a solidified layer containing the biodegradable polymer, the API, and some residual solvent. In some embodiments, the solvent remaining in the layer can be important because it can keep the layer(s) flexible and prevent cracking during subsequent processing. Thus, the API layer can also contain a small amount of solvent, which will be described in more detail below. In some embodiments, after being placed in a mold, the biodegradable polymer / API solution can be dried.

[0084] In some embodiments, the biodegradable polymer / API solution can be dried in air, nitrogen, or another gas at at least room temperature (e.g., 20 - 25 °C). In some embodiments, the biodegradable polymer / API solution can be dried at at least about 20 °C, at least about 25 °C, or at least about 30 °C. In some embodiments, the biodegradable polymer / API solution can be dried in an environment where the humidity is less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than 1%. In some embodiments, the drying can be for at least about 1 minute, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 12 hours, or at least about 1 day. In some embodiments, the drying can be for at most 6 days, at most 5 days, at most about 2 days, at most about 1 day, at most about 12 hours, at most about 6 hours, at most about 1 hour, or at most about 30 minutes.

[0085] Non - API layer In some embodiments, the drug delivery device can include at least one or more non - API - containing layers. In some embodiments, at least one non - API - containing layer can be an outer layer, an inner layer, a core, a core layer, and / or a shell layer of the drug delivery device. In some embodiments, the non - API layer may not contain an API. In some embodiments, the non - API layer can include at least one or more biodegradable polymers. As described above, in some embodiments, the non - API layer functions as a backing layer or a support layer for the API layer and / or the drug delivery device and can impart strength (e.g., longitudinal strength) to the drug delivery device.

[0086] In some embodiments, the non-API layer may include a biodegradable polymer that degrades at a slower rate than the biodegradable polymer in the API layer. As described below, since PLGA 75:25 degrades more slowly than PLGA 50:50, PLGA 50:50 can be the biodegradable polymer in the API layer and PLGA 75:25 can be the biodegradable polymer in the non-API layer. In some embodiments, the non-API layer may include a biodegradable polymer that has the same or a faster degradation rate than the biodegradable polymer in the API layer. In some embodiments, the non-API layer may also include one or more pharmaceutically acceptable excipients.

[0087] As an example, the biodegradable polymer of the API layer can degrade over about four weeks and release the API within and / or adjacent to the target tissue. The biodegradable polymer of the non-API layer can degrade over a longer period (e.g., ten weeks). Thus, in some embodiments, the non-API layer can be used to provide strength, structure, and / or support to the API layer and / or the drug delivery device at its target location while the API layer degrades to release the API.

[0088] After the API layer has completely degraded and the API has been completely released into the target tissue, the non-API layer can completely degrade and be absorbed into the patient's body. In some embodiments, a portion of the non-API layer can degrade while the API layer is degrading, but the non-API layer can have a slower degradation rate than the API layer.

[0089] In some embodiments, the biodegradable polymer can be any suitable biodegradable polymer known in the art. As described above, the biodegradable polymer in the non-API layer can have a slower, faster, or the same degradation rate as the biodegradable polymer in the API layer. For example, the biodegradable polymer can include synthetic polymers selected from poly(amides), poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo-poly(amino acids), poly(glycerol sebacate), copolymers thereof, and mixtures thereof. In addition, the biodegradable polymer can be formed from poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(caprolactone), and mixtures thereof. In some embodiments, the biodegradable polymer can be poly(lactic acid-co-glycolic acid) (PLGA). In some embodiments, the PLGA can be PLGA having various lactic acid to glycolic acid ratios such as PLGA 50:50, PLGA 60:40, PLGA 65:35, PLGA 70:30, PLGA 75:25, PLGA 80:20, PLGA 85:15, PLGA 90:10, or other various ratios of PLGA. In some embodiments, the biodegradable polymer in the non-API-containing layer comprises PLGA 75:25.

[0090] In some embodiments, the non-API-containing layer comprises at least about 70 wt%, at least about 75 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, or at least about 95 wt% of the biodegradable polymer. In some embodiments, the non-API-containing layer comprises at most about 99.9 wt%, at most about 99 wt%, at most about 98 wt%, at most about 97 wt%, at most about 95 wt%, or at most about 90 wt% of the biodegradable polymer. In some embodiments, the non-API-containing layer comprises from about 80 to 99.9 wt%, from about 85 to 98 wt%, from about 86 to 97 wt%, or from about 88 to 96 wt% of the biodegradable polymer.

[0091] To prepare a non-API layer for a drug delivery device, a second solution of a biodegradable polymer can be formed. Specifically, an amount of biodegradable polymer can be dissolved in a solvent. The second biodegradable polymer / solvent solution can be stirred and / or heated to assist in dissolving the polymer in the solvent. In some embodiments, the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methyl ethyl ketone, methylene chloride, isopropyl alcohol, methyl isobutyl ketone, methyl propyl ketone, trichloroethylene, other alternatives to acetone, or combinations thereof. In some embodiments, the biodegradable polymer and solvent solution can be about 0.1 to 0.3 g of biodegradable polymer per mL of solvent, about 0.15 to 0.25 g of biodegradable polymer, about 0.175 to 0.225 g of biodegradable polymer, about 0.19 to 0.21 g of biodegradable polymer, about 0.198 to 0.202 g of biodegradable polymer, or about 0.2 g of biodegradable polymer. In other words, if 20 g of biodegradable polymer is included in 100 mL of solvent, it becomes a biodegradable polymer and solvent solution containing 0.2 g of biodegradable polymer per mL of solvent.

[0092] In some embodiments, after the second biodegradable polymer solution is formed, the solution can be added to a mold and / or a substrate and made in the same manner (such as drying, removal, etc.) as the API layer is made in the mold and / or the substrate. In some embodiments, the substrate can be any of the substrates described above with respect to the API layer. In some embodiments, the mold can be any of the molds described above with respect to the API layer. In some embodiments, the mold and / or the substrate can define the shape of the final non-API layer. In other embodiments, the mold and / or the substrate form a precursor non-API layer that can be modified later. In some embodiments, after the second biodegradable polymer solution is formed, the solution can be added to a mold and / or a substrate that includes an API layer(s) (or another non-API layer(s)). Thus, the second biodegradable polymer solution can be added onto the API layer (or another non-API layer) in the mold and / or the substrate, such as a coating or a covering on the API layer.

[0093] In some embodiments, the amount added to the mold and / or the substrate can depend on the desired thickness (and degradation rate) of the non-API layer. In some embodiments, a second solution of the biodegradable polymer of about 1 - 20 mL, about 1 - 10 mL, about 4 - 6 mL, or about 5 mL can be added to the mold. In some embodiments, the biodegradable polymer solution can be added to the substrate, and a film applicator and / or a spiral bar coater can determine the thickness of the wet biodegradable polymer solution. In some embodiments, the thickness of the wet layer of the biodegradable polymer solution on the substrate can be at least about 0.1 mm, at least about 0.25 mm, at least about 0.5 mm, at least about 0.75 mm, at least about 1 mm, at least about 1.25 mm, at least about 1.5 mm, at least about 1.75 mm, or at least about 2 mm thick. In some embodiments, the thickness of the wet layer of the biodegradable polymer solution on the substrate can be at most about 5 mm, at most about 4 mm, at most about 3 mm, at most about 2 mm, at most about 1.5 mm thick, or at most about 1 mm thick.

[0094] In some embodiments, a non-API biodegradable solution can be first added to a mold or substrate to form a non-API layer (in a manner similar to the API layer described above for the API layer), and then the API layer can be formed on top of the non-API layer within the mold or on the substrate. In some embodiments, a non-API biodegradable solution can be first added to the mold and / or substrate to form a non-API layer (e.g., a core or core layer), and then an API layer can be formed on top of the non-API layer within the mold and / or substrate or in another mold so as to surround at least a portion of the non-API layer.

[0095] After being disposed on a substrate or within a mold, the second biodegradable polymer solution can be dried. In some embodiments, this drying causes the solvent to evaporate, thereby leaving a solidified layer that contains the biodegradable polymer and some residual solvent. In some embodiments, this drying causes the solvent to evaporate, thereby leaving a non-API layer. In some embodiments, this drying causes the solvent to evaporate, thereby leaving a first solidified API layer or a second solidified layer on one side of the non-API layer. In some embodiments, the second layer can adhere to the first layer by a welding process. In other words, when the second layer is applied, the first layer is slightly dissolved, and together with the second layer, it can be re-dried to form a solid second layer on one side of the solid first layer, so that the second layer can adhere to the first layer.

[0096] In some embodiments, the non-API layer can also contain a small amount of solvent, which will be described in more detail below. In some embodiments, the non-API biodegradable polymer solution can be dried in air, nitrogen, or other gas at least at room temperature (e.g., 20-25 °C). In some embodiments, the non-API biodegradable polymer solution can be dried at at least about 20 °C, at least about 25 °C, or at least about 30 °C. In some embodiments, the non-API biodegradable polymer solution can be dried in an environment where the humidity is less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1%. In some embodiments, the drying can be at least about 1 minute, at least about 5 minutes, at least about 10 minutes, or at least about 15 minutes. In some embodiments, the drying can be at least about 1 minute, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 12 hours, or at least about 1 day. In some embodiments, the drying can be at most about 6 days, at most about 5 days, at most about 2 days, at most about 1 day, at most about 12 hours, at most about 6 hours, at most about 1 hour, or at most about 30 minutes. In some embodiments, the layers of the drug delivery device (API layer, non-API layer, and / or both the API layer and the non-API layer) can have a uniform viscosity and be homogeneous.

[0097] In some embodiments, after the individual layers (API, non-API) are added and dried, the layers can be removed. In some embodiments, after the desired amount of API layer and / or non-API layer is added and dried together, the API layer, non-API layer, and / or drug delivery film can be removed from the mold or substrate. In some embodiments, the API layer(s) and non-API layer(s) can be left in the mold or on the substrate for further processing (e.g., drying, lamination, cutting, etc.).

[0098] In some embodiments, the above-described steps of preparing the API layer and the non-API layer can be repeated as many times as the number of additional layers required for the drug delivery device. In some embodiments, the drug delivery device can include multiple layers instead of one large layer due to manufacturing constraints for one large layer. For example, the thicker the individual layer, the higher the likelihood of having impurities such as bubbles that can affect the degradation rate. Additionally, there is a limit to the layer thickness for the solvent to evaporate to form such a layer. Thus, in some embodiments, the drug delivery device can be formed from multiple layers rather than one layer.

[0099] In some embodiments, the desired API layer(s) and / or non-API layer(s) can be laminated together to form a laminated sheet. For example, if a drug delivery device with an API / API / API layer is required, three individual API layers (having the same composition and / or different compositions) can be laminated together in the desired order. For example, FIGS. 1A - 1C can be made by laminating layers 101, 102, 103, 104, and 105 together in sequence. In some embodiments, the laminated sheet is the drug delivery device or the body of the drug delivery device. In some embodiments, the lamination process is a single process. In some embodiments, each layer can be laminated one at a time until the final laminated sheet is created. In some embodiments, a standard laminator such as a laboratory laminator or an industrial laminator can be used for the lamination process. In some embodiments, the laminator can include rolls (e.g., nip rolls) including heating rolls.

[0100] In some embodiments, the speed, temperature, pressure, and / or gap parameters of the laminator can be set to desired parameters. In some embodiments, the speed can be set to at least about 0.5 feet per minute (about 0.1524 meters per minute), at least about 1 foot per minute (about 0.3048 meters per minute), at least about 3 feet per minute (about 0.9144 meters per minute), at least about 5 feet per minute (about 1.524 meters per minute), at least about 10 feet per minute (about 3.048 meters per minute), or at least about 15 feet per minute (about 4.572 meters per minute). In some embodiments, the speed can be set to at most about 20 feet per minute (about 6.096 meters per minute), at most about 15 feet per minute (about 4.572 meters per minute), at most about 10 feet per minute (about 3.048 meters per minute), or at most about 5 feet per minute (about 1.524 meters per minute). In some embodiments, the temperature can be set to at least about 50°C, at least about 75°C, at least about 100°C, at least about 110°C, at least about 125°C, at least about 150°C, or at least about 200°C. In some embodiments, the temperature can be set to at most about 500°C, at most about 400°C, at most about 300°C, at most about 200°C, at most about 175°C, at most about 150°C, or at most about 125°C. In some embodiments, the pressure can be set to at least about 1 psi (about 6.895 kPa), at least about 5 psi (about 34.474 kPa), at least about 10 psi (about 68.948 kPa), at least about 15 psi (about 103.421 kPa), at least about 20 psi (about 137.895 kPa), at least about 30 psi (about 206.843 kPa), at least about 40 psi (about 275.790 kPa), at least about 50 psi (about 344.738 kPa), or at least about 75 psi (about 517.107 kPa).In some embodiments, the pressure can be set to at most about 200 psi (about 1,378.95 kPa), at most about 150 psi (about 1,034.21 kPa), at most about 100 psi (about 689.48 kPa), at most about 75 psi (about 517.11 kPa), at most about 50 psi (about 344.74 kPa), at most about 40 psi (about 275.79 kPa), or at most about 30 psi (about 206.84 kPa). In some embodiments, the roller gap of the laminator can be at most about 1 inch (about 25.4 millimeters), at most about 0.5 inch (about 12.7 millimeters), at most about 0.25 inch (about 6.35 millimeters), at most about 0.1 inch (about 2.54 millimeters), at most about 0.075 inch (about 1.905 millimeters), or at most about 0.05 inch (about 1.27 millimeters). In some embodiments, the roller(s) can have no gap (e.g., the nip roller is fully closed).

[0101] In some embodiments, for the lamination process, at least two layers (e.g., API / API, non - API / non - API, API / non - API) can be pressed together to form a sandwich. In some embodiments, at least two layers can be pressed together such that the two layer substrates are on the outside (i.e., in contact with the rollers of the laminator). In some embodiments, the layer substrates (e.g., release liner) are in contact with the rollers of the laminator. In some embodiments, the layer sandwich can be supplied to the laminator (e.g., to the rollers of the laminator) to form a laminated sheet.

[0102] After removal from the laminator, additional layers can be added to the laminate sheet. In some embodiments, depending on the overall layer structure desired for the drug delivery device, the substrate can be removed from one side of the laminate sheet and the process repeated. For example, if two layers are laminated together, the substrate (e.g., release liner) can be removed from one side of the laminate sheet and an additional layer (e.g., API, non-API layer) pressed together with the non-substrate side of the laminate sheet to form another sandwich. In some embodiments, this newly added layer can be pressed together such that the substrate of the new layer is on the outside (i.e., in contact with the roll of the laminator). In some embodiments, the substrate of the new layer (e.g., release liner) and the substrate of the old laminate sheet can be in contact with the roll of the laminator. Next, this new layer sandwich can be fed into the laminator to form a new laminate sheet. This process can be repeated for the desired number of additional layers with the desired layer structure / orientation / thickness. In some embodiments, once all layers have been added, the remaining substrate can be removed from the laminate sheet.

[0103] API layers and / or non-API layers can be created in any combination and / or in any order. In some embodiments, API layers and / or non-API layers in any combination and / or in any order can be stacked together. In some embodiments, the drug delivery devices disclosed herein can include any number of API layers and / or non-API layers in any order, such as API / API, API / API / API, API / API / API / API, API / API / API / API / API, API / API / non-API / API / API, non-API / non-API / non-API, non-API / API, API / non-API / API, non-API / API / non-API, API / API / non-API, non-API / API / API, API / non-API / API / non-API, API / API / non-API / non-API, API / API / API / non-API, non-API / API / non-API / API, non-API / API / API / non-API configurations. These additional API layers and / or non-API layers can have the composition of the API layers or non-API layers disclosed herein and can be fabricated by the same processes as the API layers or non-API layers disclosed herein.

[0104] In some embodiments, the laminated sheet can be cut to a desired size and / or shape for the drug delivery device. In some embodiments, the laminated sheet can be cut with the substrate or substrates remaining on the laminated sheet. In some embodiments, the drug delivery device can be cut into a circular, square, rectangular, elliptical, triangular, rhombic, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), arcuate, trapezoidal, star-shaped, or other various shapes and sizes. In some embodiments, the drug delivery device can be cut to be tubular, cylindrical, conical, pyramidal, triangular prismatic, cubic, spherical, quadrangular prismatic, or other various shapes and sizes. In some embodiments, the laminated sheet can be die-cut, hand-cut, laser-cut, hand-punched, waterjet-cut, or cut by a similar type to form the drug delivery device or the body of the drug delivery device. For example, the drug delivery device or the body of the drug delivery device can be punched out from the laminated sheet using a mold. In some embodiments, the drug delivery film formed by solvent casting of a mold and / or multiple layers in the substrate can be cut to a desired size and / or shape for the drug delivery device (i.e., when lamination is not employed). In some embodiments, the layer or layers can be cut to a desired size and / or shape prior to lamination. In some embodiments, lamination can be performed after the layer or layers have been cut to a desired size and / or shape.

[0105] In some embodiments, the step of preparing the API layer(s) and / or non-API layer(s) adhered to each other can be repeated for not only additional layers but also other API layers, other non-API layers, and other API layers and non-API layers adhered to one side of the API layer, other API layer, non-API layer, and / or other non-API layer. API layers and / or non-API layers in any combination (see the above combination examples) and / or in any order can be obtained by the solvent casting method. Further, other components of the drug delivery device, such as the tip, can also be fabricated in the same manner as any layer fabrication discussed herein.

[0106] In some embodiments, the drug delivery device may include two or more API layers. In some embodiments, the drug delivery device may include a non-API layer sandwiched between two API layers. In some embodiments, the drug delivery device may include two API layers on top of each other and then a non-API layer on one side of the API layers. For example, in some embodiments, the drug delivery device may include a second API layer on a side of a first API layer and a non-API layer on a side of the second API layer opposite the first API layer. In some embodiments, the second API layer may have the same composition (i.e., API) as the first API layer. In some embodiments, the first API layer may degrade faster, slower, or at the same rate as the second API layer. In some embodiments, the first API layer may degrade faster, slower, or at the same rate as the non-API layer. In some embodiments, there may be more than two API layers before the non-API layer. In some embodiments, the drug delivery device may not include a non-API layer. In some embodiments, the API layer(s) may have the same or different composition, or the same or different APIs, as another API layer(s). Further, these additional layers can be added to the drug delivery device in the same manner as disclosed herein.

[0107] In some embodiments, the drug delivery device can include two or more non-API layers. In some embodiments, the drug delivery device can include an API layer sandwiched between two non-API layers. For example, in some embodiments, the drug delivery device can include a first non-API layer on a side of the API layer and a second non-API layer on a side of the API layer opposite the first non-API layer. In some embodiments, the second non-API layer can have the same composition as the first non-API layer. In some embodiments, the second non-API layer can have a different composition from the first non-API layer. In some embodiments, the second non-API layer can degrade faster, slower, or at the same rate as the API layer. In some embodiments, the first non-API layer can degrade faster, slower, or at the same rate as the API layer. In some embodiments, the first non-API layer can degrade faster, slower, or at the same rate as the second non-API layer. In some embodiments, there may be more than two non-API layers in front of the API layer. In some embodiments, the non-API layer(s) can have the same or different composition from another non-API layer(s). Further, these additional layers can be added to the drug delivery device by the same methods disclosed herein

[0108] Oven drying The drug delivery devices disclosed herein can be placed directly on, within, and / or adjacent to a target tissue region using minimally invasive standard surgical techniques such as open surgery, laparoscopic surgery, endoscopic surgery, percutaneous surgery, or robotic surgery. Thus, the drug delivery device needs to be flexible enough to be used in combination with standard surgical instruments (e.g., trocars used in laparoscopic surgery, catheters in endoscopic surgery, bronchoscopes, robotic bronchoscopes, needles for percutaneous delivery, etc.). In some embodiments, the drug delivery device can be inserted through trocars of 3 mm to 12 mm (e.g., 3, 5, 8, 10, 12 mm trocars) and above

[0109] In some embodiments, the drug delivery device can be inserted into the working channel of an endoscope or robotic endoscope, such as a bronchoscope or robotic bronchoscope. After entering the patient, the drug delivery device can be implanted into and / or adjacent to a target tissue site (e.g., a tumor) using standard or robotic surgical instruments. In some embodiments, the drug delivery device is positioned or implanted in the target tissue such that it is fully or partially within the target tissue (i.e., fully or partially embedded within the target tissue).

[0110] The solvent can be important to ensure that the layer(s) (and the device as a whole) retain flexibility and do not crack during subsequent processing (e.g., lamination, cutting, implantation, etc.). In some embodiments, if there is too much solvent, the layer(s) or device may stick / attach to themselves or to other devices, such as a delivery tool (e.g., an endoscope), at warm temperatures. In some embodiments, after removal from the mold and / or substrate, or in some embodiments, while still in the mold and / or on the substrate, the layer(s) (e.g., API layer, non-API layer) can be placed in an oven for additional drying. In some embodiments, after removing the drug delivery film (e.g., multiple layers made from solvent casting) from the mold, or in some embodiments, while still in the mold, the drug delivery film can be placed in an oven for additional drying. In some embodiments, layers laminated together can be placed in an oven for additional drying. In some embodiments, layers laminated together and / or layers cut to fit the shape of the drug delivery device can be placed in an oven for additional drying. In some embodiments, this additional oven drying can cure the polymer in the layer. In some embodiments, this curing can prevent separation of the drug in the API layer.

[0111] In some embodiments, the layer, plurality of layers, drug delivery film, laminated sheet, or drug delivery device is placed in an oven at at least about 30°C, at least about 35°C, at least about 36°C, at least about 37°C, at least about 38°C, at least about 39°C, at least about 40°C, at least about 45°C, at least about 50°C, at least about 55°C, at least about 60°C, at least about 65°C, at least about 70°C, or at least about 75°C. In some embodiments, the layer, plurality of layers, drug delivery film, laminated sheet, or drug delivery device is placed in an oven at at most about 100°C, at most about 90°C, at most about 85°C, at most about 80°C, at most about 75°C, at most about 70°C, at most about 65°C, at most about 60°C, at most about 55°C, at most about 50°C, at most about 45°C, at most about 42°C, at most about 40°C, at most about 39°C, at most about 38°C, at most about 37°C, at most about 36°C, or at most about 30°C. In some embodiments, the layer, plurality of layers, drug delivery film, laminated sheet, or drug delivery device is placed in an oven for at least about 30 minutes, at least about 1 hour, at least about 4 hours, at least about 5 hours, at least about 8 hours, at least about 9 hours, at least about 12 hours, at least about 1 day, or at least about 2 days. In some embodiments, the layer, plurality of layers, drug delivery film, laminated sheet, or drug delivery device is placed in an oven for at most about 5 days, at most about 4 days, at most about 3 days, at most about 2 days, at most about 1 day, at most about 12 hours, at most about 10 hours, at most about 9 hours, at most about 5 hours, at most about 2 hours, or at most about 1 hour.

[0112] Accordingly, a layer, multiple layers, a drug delivery film, a laminated sheet, or a drug delivery device can have a solvent content of less than about 12 wt%, or about 1-15 wt%, about 2-12 wt%, about 3-11 wt%, or about 5-8 wt%. In some embodiments, the API layer of the drug delivery device can have at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 3.5 wt%, at least about 5 wt%, at least about 6 wt%, at least about 7 wt%, at least about 8 wt%, or at least about 10 wt% of solvent. In some embodiments, the API layer of the drug delivery device can have at most about 15 wt%, at most about 12 wt%, at most about 10 wt%, at most about 8 wt%, at most about 7 wt%, at most about 6 wt%, or at most about 5 wt% of solvent. In some embodiments, the API layer of the drug delivery device can have about 1-15 wt%, about 2-12 wt%, about 3-11 wt%, about 3.5-10 wt%, or about 5-8 wt% of solvent. In some embodiments, the non-API layer of the drug delivery device can have at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 3.5 wt%, at least about 5 wt%, at least about 6 wt%, at least about 7 wt%, at least about 8 wt%, or at least about 10 wt% of solvent. In some embodiments, the non-API layer of the drug delivery device can have at most about 15 wt%, at most about 12 wt%, at most about 11 wt%, at most about 10 wt%, at most about 8 wt%, at most about 7 wt%, at most about 6 wt%, or at most about 5 wt% of solvent. In some embodiments, the non-API layer of the drug delivery device can have about 1-15 wt%, about 2-12 wt%, about 3-11 wt%, about 3.5-11 wt%, or about 5-8 wt% of solvent. The amount of solvent in the drug delivery device can be measured by gas chromatography.

[0113] In some embodiments, the drug delivery device can be sterilized by, for example, electron beam irradiation. Further, the drug delivery device can be sealed in a pouch such as a Tyvek pouch for sterilization and stored in a refrigerator.

[0114] Direction indicator As described above, in some embodiments, the drug delivery device can include an anatomical marker(s). In some embodiments, the API layer and / or non-API layer can include an anatomical marker(s). In some embodiments, the anatomical marker can be attached to, connected to, or placed within the drug delivery device. In some embodiments, the anatomical marker(s) can be attached to, connected to, or within the API layer and / or non-API layer. In some embodiments, the anatomical marker(s) can be attached to, connected to, or within another component such as the tip of the drug delivery device. The anatomical marker(s) can be used with various imaging techniques for a physician to identify the drug delivery device within a patient. The physician can then monitor the progression and / or position of the drug delivery device relative to the tumor. In some embodiments, the anatomical marker can be a radiopaque marker, an x-ray marker, a lead marker, or similar marker(s).

[0115] Implantation In some embodiments, once the target tissue site (e.g., tumor) is identified and visualized, the drug delivery device can be implanted within or adjacent to the tumor mass using various delivery methods including, but not limited to, a hand, a grasping instrument, a shaft attached via the working channel of a scope, etc.

[0116] If proper implantation is not confirmed, there is a possibility that the API could be released to non-target sites. For example, if the drug delivery device is not fully implanted within the target tissue (e.g., solid tumor), the portion of the device outside of the target tissue can release the API to non-target sites, which can potentially be harmful.

[0117] Characteristics of the drug delivery device In some embodiments, the drug delivery devices disclosed herein can be transparent and / or light brown to medium brown. The drug delivery devices may not have visible foreign particles or cracks on the surface. Figures 4A - C show images of drug delivery devices prepared herein that together comprise a plurality of layers that are laminated and die cut.

[0118] In some embodiments, the average thickness of the API layer and / or the non-API layer can be at least 1 micron, at least 10 microns, at least 25 microns, at least 50 microns, at least 100 microns, at least 250 microns, at least 300 microns, at least 400 microns, at least 500 microns, at least 750 microns, at least 1000 microns, at least 1500 microns, at least 2000 microns, at least 2500 microns, at least 3000 microns, at least 3500 microns, at least 4000 microns, or at least 4500 microns. In some embodiments, the average thickness of the API layer and / or the non-API layer can be at most 5000 microns, at most 4500 microns, at most 4000 microns, at most 3500 microns, at most 3000 microns, at most 2500 microns, at most 2000 microns, at most 1500 microns, at most 1000 microns, at most 750 microns, at most 600 microns, at most 500 microns, at most 400 microns, at most 350 microns, at most 300 microns, at most 250 microns, at most 200 microns, at most 150 microns, at most 100 microns, at most 50 microns, at most 25 microns, or at most 10 microns. In some embodiments, the average thickness of the API layer and / or the non-API layer can be about 50-500 microns, about 100-450 microns, about 150-450 microns, about 200-400 microns, about 215-365 microns, about 250-300 microns, or about 290 microns. In some embodiments, the size of the drug delivery device can be selected based on the desired degradation / API release rate. The average thickness can be measured in micrometers as the average value of n = 5 measurements at 5 randomly selected points on the surface of the API and / or non-API layer.

[0119] In some embodiments, the width / thickness of the drug delivery device can be at least about 0.1 mm, at least about 0.5 mm, at least about 0.75 mm, at least about 1 mm, at least about 1.25 mm, at least about 1.5 mm, at least about 1.75 mm, at least about 2 mm, at least about 2.5 mm, or at least about 3 mm. In some embodiments, the width / thickness of the drug delivery device can be at most about 10 mm, at most about 5 mm, at most about 4 mm, at most about 3 mm, at most about 2.5 mm, at most about 2 mm, at most about 1.75 mm, at most about 1.5 mm, at most about 1.25 mm, or at most about 1 mm. In some embodiments, the width / thickness of the drug delivery device is about 0.1 - 10 mm, about 0.5 - 5 mm, about 0.75 - 2.5 mm, or about 1 - 2 mm. In some embodiments, the height of the drug delivery device can be at least about 0.1 mm, at least about 0.5 mm, at least about 0.75 mm, at least about 1 mm, at least about 1.25 mm, at least about 1.5 mm, at least about 1.75 mm, at least about 2 mm, at least about 2.5 mm, or at least about 3 mm. In some embodiments, the height of the drug delivery device can be at most about 10 mm, at most about 5 mm, at most about 4 mm, at most about 3 mm, at most about 2.5 mm, at most about 2 mm, at most about 1.75 mm, at most about 1.5 mm, at most about 1.25 mm, or at most about 1 mm. In some embodiments, the height of the drug delivery device is about 0.1 - 10 mm, about 0.5 - 5 mm, about 0.75 - 2.5 mm, or about 1 - 2 mm. In some embodiments, the width, thickness, and / or height of the drug delivery device can be measured by a micrometer.

[0120] In some embodiments, the length of the drug delivery device can be at least about 0.1 cm, at least about 0.5 cm, at least about 0.75 cm, at least about 1 cm, at least about 1.25 cm, at least about 1.5 cm, at least about 1.75 cm, at least about 2 cm, at least about 2.5 cm, or at least about 3 cm. In some embodiments, the length of the drug delivery device can be at most about 10 cm, at most about 5 cm, at most about 4 cm, at most about 3 cm, at most about 2.5 cm, at most about 2 cm, at most about 1.75 cm, at most about 1.5 cm, at most about 1.25 cm, or at most about 1 cm. In some embodiments, the length of the drug delivery device is from about 0.1 to 10 cm, from about 0.5 to 5 cm, from about 0.75 to 2.5 cm, or from about 1 to 2 cm. In some embodiments, the length of the drug delivery device can be measured using a ruler or similar measuring tool.

[0121] In some embodiments, the drug delivery device can be configured to release the API according to a defined release rate profile. In some embodiments, after the device is implanted into and / or within the target tissue site, the release of the API can be delayed (or only an amount of the API below the therapeutically effective amount can be released during the delay period) so that the patient's body can recover from the implantation surgery before the drug is released. This delay allows for some healing of the implantation site prior to the release of the API, thereby potentially reducing the risks associated with swelling, perforation, bleeding, infection, and other potential problems. For example, in some embodiments, the drug delivery device can have a layer and / or coating of a non-API composition over the entire surface of the drug delivery device such that the API is not released while the patient heals from the implantation surgery. Alternatively, only this layer and / or coating of the non-API coating can be degraded. In some embodiments, the API delayed release period can be at least 1 day, at least 3 days, at least 7 days, at least 9 days, at least 10 days, at least 12 days, at least 14 days, at least 16 days, at least 18 days, or at least 21 days. In some embodiments, the API delayed release period can be at most 28 days, at most 25 days, at most 21 days, at most 18 days, at most 15 days, at most 14 days, at most 12 days, at most 10 days, at most 8 days, at most 7 days, at most 5 days, or at most 3 days. In some embodiments, the API delayed release period can be 1 to 28 days, 1 to 21 days, 1 to 14 days, or 7 to 14 days. After the delay period, the API can have a substantially linear or linear release rate.

[0122] In some embodiments, the API layer having PLGA 50:50 can start releasing the API in the target tissue about 1 week after implantation and can be completely released by 4 weeks after implantation. This can be in good agreement with the degradation data. That is, although the hydration of the polymer takes time, most of the PLGA 50:50 has disappeared after 4 weeks, so most of the API will have been released. Further, the non-API layer made of PLGA 75:25 functions as a mechanism to maintain the structure, strength, and support of the drug delivery device due to its slow degradation. This helps to fix the device to the target site.

[0123] The degradation of the biodegradable polymer in the API layer can control the release of the API from the API layer during use. Therefore, the degradation of the API layer in the drug delivery device can be adjusted based on the biodegradable polymer in the API layer and the thickness of the API layer. This is because the thicker the API layer, the longer the time required for degradation. In some embodiments, the API layer can be configured to completely degrade within at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks, at least 4 weeks, at least 30 days, at least 4.5 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 2 months, at least 3 months, at least 4 months, at least 6 months, at least 8 months, or at least 10 months after implantation. In some embodiments, the API layer can be configured to completely degrade within at most 2 years, at most 1 year, at most 10 months, at most 8 months, at most 6 months, at most 4 months, at most 3 months, at most 2 months, at most 10 weeks, at most 9 weeks, at most 8 weeks, at most 6 weeks, at most 5 weeks, at most 4.5 weeks, at most 30 days, at most 4 weeks, at most 3.5 weeks, at most 3 weeks, at most 2 weeks, or at most 1 week after implantation. In some embodiments, the API layer can be configured to completely degrade within a period of about 3 days to 10 months, 1 week to 6 months, 1 to 6 weeks, about 2 to 6 weeks, about 3 to 5 weeks, about 3.5 to 4.5 weeks, or about 4 weeks (about 30 days) after implantation. As used herein, "completely degrade" or "sufficiently degrade" means that the layer or device degrades to less than 10% of its original mass within the period. In some embodiments, the API can be released from the API layer at a rate of at least about 0.01 mg / day, at least about 0.05 mg / day, at least about 0.1 mg / day, at least about 0.5 mg / day, at least about 0.75 mg / day, or at least about 1 mg API / day. In some embodiments, the API can be released from the API layer at a rate of at least about 0.1 mg / week, at least about 0.5 mg / week, at least about 0.75 mg / week, or at least about 1 mg API / week.In some embodiments, the API can be released from the API layer at a rate of about 0.01 to 10 mg / day, about 0.1 to 10 mg / day, about 0.1 to 5 mg / day, about 0.1 to 3 mg / day, about 0.1 to 1 mg / day, about 1 to 5 mg / day, about 2 to 5 mg / day, or about 3 to 4 mg / day after implantation. In some embodiments, the API can be released from the API layer at a rate of about 0.5 to 70 mg / week, about 0.5 to 35 mg / week, about 0.5 to 20 mg / week, about 0.5 to 10 mg / week, about 0.5 to 5 mg / week, about 0.5 to 1 mg / week, about 7 to 70 mg / week, about 7 to 35 mg / week, about 14 to 35 mg / week, or about 21 to 28 mg / week after implantation. In some embodiments, the degradation profile (and API release profile) of the API layer after implantation can include a lag period of about 1 day to 2 weeks. After the lag period, the degradation (and API release) of the API layer can be substantially linear or linear. In some embodiments, the outer layers (e.g., layers 101 and 105 of FIGS. 1A-1C) can degrade at a faster rate than the inner layers (e.g., layers 102, 103, 104) of the drug delivery device because more surface area of these layers is exposed to the degradation environment.

[0124] For the drug delivery device disclosed in this specification, drug release (i.e., API release) was tested in vitro. Specifically, a drug delivery device containing four layers of approximately 0.7 g of PLGA 50:50, 100 mg of paclitaxel, and 4 mg of acetone was fabricated and tested for drug release rate. After fabricating all four layers individually, the drug delivery device was laminated layer by layer. The laminated sheet was die-cut to produce a drug delivery device with a thickness of approximately 1.5 mm, a width of approximately 1.25 mm, and a length of approximately 2 cm. The drug delivery device was fabricated such that 6 products were available for testing at each time point (1, 2, 3, 4, and 6 weeks). Each sample was placed in a scintillation vial with 20 ml of 1.75 M sodium salicylate (release solution). The samples were placed in a water bath at 37 °C and held at that temperature. After withdrawal, the release solution was discarded and the samples were completely dissolved in acetonitrile. The dissolved samples were assayed for paclitaxel by HPLC to measure the remaining drug content and used to determine the amount of drug released. Samples were taken at 1 week, 2 weeks, 4 weeks, 6 weeks, and 8 weeks. Figure 5 shows the total percent drug release from the drug delivery device over time. The results showed that the release of the API was delayed by 1 - 2 weeks, followed by a stable linear release until 8 weeks.

[0125] Furthermore, the degradation of the non - API layer in the drug delivery device can be adjusted based on the biodegradable polymer in the non - API layer and the thickness of the non - API layer. In some embodiments, the non - API layer can be configured to degrade at a slower rate than the API layer so that the API is released towards the target tissue. In some embodiments, the non - API layer can be configured to degrade at the same rate as the API layer. In some embodiments, the non - API layer can be configured to degrade at a faster rate than the API layer. For example, in some embodiments, there may be a non - API layer or non - API coating covering the entire surface of the drug delivery device. This non - API layer / coating can degrade faster than the API layer, and a delay period in API release can occur because the non - API layer / coating degrades first.

[0126] In some embodiments, the non-API layer can be configured to completely decompose within at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, or at least 1 year after implantation. In some embodiments, the non-API layer can be configured to completely decompose within at most 3 years, at most 2 years, at most 1 year, at most 10 months, at most 8 months, at most 6 months, at most 4 months, at most 3 months, at most 12 weeks, at most 11 weeks, at most 10 weeks, at most 8 weeks, at most 6 weeks, at most 5 weeks, at most 4 weeks, at most 3 weeks, or at most 2 weeks after implantation. In some embodiments, the non-API layer can be configured to completely decompose within about 1 week to 2 years, 1 week to 1 year, 1 week to 6 months, about 4 to 14 weeks, about 6 to 12 weeks, about 8 to 12 weeks, about 9 to 11 weeks, or about 10 weeks after implantation.

[0127] Cancer treatment In some embodiments, the target tissue can be tissue associated with various organs throughout the body, including but not limited to the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon, or metastases from a primary tumor. For example, the target tissue can be cancerous tissue / cells (e.g., one or more tumors) on the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon, or metastases from a primary tumor. Thus, the drug delivery devices disclosed herein can be used to treat many diseases, including tumors of various organs throughout the body, including metastases from the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon, or a primary tumor. Specifically, various cancers for which the drug delivery device can be useful include, but are not limited to, pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, gallbladder cancer, lymphoma, non-small cell lung cancer, or metastatic tumors. In some embodiments, the drug delivery device can be used to treat resectable and / or unresectable cancers. In some embodiments, the drug delivery devices herein can be used to treat non-metastatic cancers from initially unresectable cancers. In some embodiments, the drug delivery device can be used to treat patients after cancer resection to prevent recurrence. For example, the drug delivery device can be used to treat patients with resectable borderline or locally advanced pancreatic adenocarcinoma or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancers treated by the drug delivery device can be tumors within the primary tissue or metastatic spread to the tissue. In some embodiments, the drug delivery device can be used to treat patients with initially unresectable cancer, non-metastatic cancer, resectable borderline cancer, resectable cancer, locally advanced cancer, metastatic cancer, and / or metastases from a primary tumor.

[0128] In some embodiments, the drug delivery devices disclosed herein can be placed within and / or adjacent to (i.e., intratumorally) the target tumor and can biodegrade in a patient's body over about 1 week to 2 years, about 1 to 52 weeks, about 1 to 26 weeks, about 1 to 24 weeks, about 1 to 20 weeks, about 1 to 15 weeks, about 4 to 12 weeks, about 6 to 12 weeks, about 8 to 12 weeks, about 9 to 11 weeks, or about 10 weeks of implantation. In some embodiments, the tumor may be inside (i.e., not on the surface) an organ and the drug delivery device is placed inside the tumor. As described above, the drug delivery device can be placed directly within and / or adjacent to the tumor using minimally invasive standard surgical techniques during a routinely performed staging assessment. In some embodiments, multiple drug delivery devices can be placed directly and / or adjacent to (e.g., simultaneously and / or sequentially after one has finished degrading) within the target tissue. In some embodiments, the drug delivery device can be inserted into the working channel of an endoscope, guided to the target tumor, and inserted within and / or adjacent to the target tumor.

[0129] In some embodiments, the degradation of the API layer can control the release of the API for a period of at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks, at least 4 weeks, at least 30 days, at least 4.5 weeks, at least 5 weeks, at least 6 weeks, at least 2 months, at least 3 months, at least 4 months, at least 6 months, at least 8 months, or at least 10 months after implantation. In some embodiments, the degradation of the API layer can control the release of the API for a period of at most 2 years, at most 1 year, at most 10 months, at most 8 months, at most 6 months, at most 4 months, at most 3 months, at most 2 months, at most 6 weeks, at most 5 weeks, at most 4.5 weeks, at most 30 days, at most 4 weeks, at most 3.5 weeks, at most 3 weeks, at most 2 weeks, or at most 1 week after implantation. In some embodiments, the degradation of the API layer can control the release of the API for a period of about 3 days to 10 months, 1 week to 6 months, 1 to 6 weeks, about 2 to 6 weeks, about 3 to 5 weeks, about 3.5 to 4.5 weeks, or about 4 weeks (about 30 days) after implantation. In some embodiments, the biodegradable polymer in the API layer can provide controlled sustained release of the API over this period during which the side of the device facing the cancer is absorbed into the body. In some embodiments, the non-API layer(s) of the device and / or tip can help ensure that the drug delivery device maintains contact with the target tissue (e.g., tumor) during drug release and can help prevent the drug delivery device from detaching or releasing from the area of interest. This non-API layer(s) and / or tip can completely degrade after the API layer has completely degraded and released all of the API. In some embodiments, the non-API layer can completely degrade at the same time as or faster than the API layer.

[0130] In some embodiments, the drug delivery devices disclosed herein can stabilize and / or reduce the size of a tumor after implantation onto the tumor. In some embodiments, reduction in tumor size, reduction in tumor volume, reduction in the maximum dimension of the tumor, and / or reduction in the anterior / posterior diameter orthogonal to the drug delivery device can occur after the drug delivery device has completely dissolved in the patient, after the drug delivery device has partially dissolved in the patient, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient.

[0131] In some embodiments, the drug delivery devices and methods disclosed herein can be used in conjunction with systemic chemotherapy, radiation therapy, and / or surgery. In some embodiments, the drug delivery devices and methods disclosed herein can improve the tumor penetration of systemic chemotherapy in a patient. In some embodiments, systemic chemotherapy can be administered (or initiated) after implantation of the drug delivery device (e.g., 2 weeks, 3 weeks, 4 weeks, etc. after implantation). In some embodiments, systemic chemotherapy can be administered (or initiated) at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 3 months, at least 6 months, or at least 1 year after implantation of the drug delivery device.

[0132] The drug delivery devices disclosed herein can alter the route of administration to target only the area of interest, thereby increasing the amount of drug reaching the tumor for the purpose of enhancing therapeutic efficacy. Thus, the drug delivery device can be applied to patients with lung cancer (among other cancers) (i) as neoadjuvant therapy before surgery to inhibit progression and reduce size, and improve resectability and / or clinical benefit (i.e., ease of breathing, pain reduction); (ii) after resection to reduce the local recurrence rate; or (iii) in metastatic patients to control local progression and improve quality of life.

[0133] Additional Definitions Unless otherwise defined, all terms, notations, and other technical and scientific terms used in this specification are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms having a generally understood meaning are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference from what is generally understood in the art.

[0134] When referring in this specification to a value or parameter as "about", variations directed to that value or parameter itself are included and described. For example, a description referring to "about X" includes a description of "X". Additionally, references to the phrases "less than", "more than", "at most", "at least", "below", "above", or other similar phrases that are followed by a series of values or parameters are meant to apply that phrase to each value or parameter in the series of values or parameters. For example, a description that a layer has a thickness of at least about 5 cm, about 10 cm, or about 15 cm means that the layer has a thickness of at least about 5 cm, at least about 10 cm, or at least about 15 cm.

[0135] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, the term "and / or" as used herein refers to and is understood to cover any and all possible combinations of one or more of the associated listed items. Further, the terms "includes", "including", "comprises", and / or "comprising" as used herein are used to specify the presence of the stated feature, integer, step, operation, element, component, and / or unit, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, units, and / or groups thereof.

[0136] As used herein, "treatment" or "treating" is an approach for obtaining a beneficial or desired result, including clinical outcomes. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from a disease, reducing the degree of a disease, stabilizing a disease (e.g., preventing or delaying the worsening of a disease), preventing or delaying the spread (e.g., metastasis) of a disease, preventing or delaying the recurrence of a disease, delaying or decelerating the progression of a disease, improving the disease state, providing remission (partial or complete) of a disease, reducing the dosage of one or more other pharmaceuticals required for the treatment of a disease, delaying the progression of a disease, improving the quality of life, and / or extending the survival period. "Treatment" also encompasses reducing the pathological consequences of cancer. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0137] This application discloses several numerical ranges in the text and drawings. Since the present disclosure can be implemented over the entire disclosed numerical range, even if the exact range limitations are not recited verbatim in this specification, the disclosed numerical ranges inherently support any range or value within the disclosed numerical range, including the endpoints.

[0138] The foregoing description has been presented for purposes of enabling a person skilled in the art to make and use the present disclosure, and is provided in the context of a particular application and its requirements. Various modifications to the preferred embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the present disclosure. Accordingly, the present disclosure is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features disclosed herein.

Claims

1. A drug delivery device, A body (204) comprising multiple layers of polymer, wherein the multiple layers include (i) at least one first layer (101, 201) comprising a pharmaceutical active ingredient (API) and a first biodegradable polymer, and (ii) a second layer (103, 202) located on one side of the first layer, The second layer (103) does not contain the API and contains a second biodegradable polymer that degrades more slowly in vivo than the first biodegradable polymer. A drug delivery device configured to be inserted into a target tissue site in a patient.

2. The drug delivery device according to claim 1, further comprising a tip (205) connected to or integrated with the distal end of the main body (204) of the drug delivery device, wherein the drug delivery device is configured to be inserted first from the target tissue site of the patient's tip (205).

3. The drug delivery device according to claim 1 or claim 2, wherein the target tissue site is a tumor of the pancreas, biliary tract, gallbladder, esophagus, liver, stomach, peritoneum, small intestine, lung, or colon.

4. The drug delivery device according to claim 1, wherein the first biodegradable polymer is poly(lactic acid-co-glycolic acid) (PLGA), and in particular, the first biodegradable polymer is PLGA 50:

50.

5. The drug delivery device according to claim 1, wherein at least one of the first layers comprises 1 to 30% by weight of the API, and the first layer (101, 201) comprises 1 to 15% by weight of a solvent, the solvent being acetone.

6. The drug delivery device according to claim 1, wherein the plurality of layers include a third layer (102) containing a second API and a third biodegradable polymer, and the plurality of layers include a fourth layer (104) containing a third API and a fourth biodegradable polymer.

7. The drug delivery device according to claim 1, wherein each of the plurality of layers has the same composition.

8. The drug delivery device according to claim 1, wherein the drug delivery device is configured to be inserted into the target tissue site of a patient using a bronchoscope, forceps, trocar, or needle.

9. The drug delivery device according to claim 1, wherein the first layer (101, 201) is configured to release the API in multiple directions when inserted into the target tissue site of a patient.

10. The drug delivery device according to claim 1, wherein the release of the API is controlled by the in vivo degradation of the biodegradable polymer at the target tissue site.

11. The drug delivery device according to claim 2, wherein the tip portion (205) comprises a fifth biodegradable polymer having a slower degradation rate than the first biodegradable polymer, and in particular, the tip portion comprises PLGA 75:

25.

12. The drug delivery device according to claim 2, wherein the tip portion (205) includes a tissue retention mechanism (206), and the tissue retention mechanism (206) extends outward from the tip portion (205).

13. The drug delivery device according to claim 2, wherein the tip portion (205) has at least one vertex at its distal end.

14. The drug delivery device according to claim 1, wherein the main body is provided with a release mechanism (207) on the proximal end side of the main body (204).

15. The drug delivery device according to claim 14, wherein a flexible shaft (203) is connected to the proximal end of the main body, and in particular, the disengagement mechanism (207) is configured to disengage the drug delivery device from the flexible shaft (203).

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