Tissue penetrating and biodegradable drug delivery devices and methods of use thereof

Abstract

Tissue penetrating and biodegradable drug delivery devices capable of delivering an active pharmaceutical ingredient (API) directly to a target tissue site are provided. The drug delivery device may include a plurality of layers, wherein at least one of the plurality of layers includes an API and a biodegradable polymer. Upon placement of the device directly into or adjacent to a target tissue, the API layer may degrade, thereby releasing the API in multiple directions into the target tissue.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] 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. Public domain

[0002] The present invention relates to implantable drug delivery devices. In particular, the present invention relates to tissue penetrating and biodegradable drug delivery devices for delivering active pharmaceutical ingredients to local tissue sites. Public background

[0003] In recent years, significant progress has been made in cancer treatment. However, challenges remain, including limited ability of drugs to successfully reach tumors, short half-lives, and low site retention. The main limitation to the effectiveness of existing chemotherapies is due to systemic off-target toxicity. For example, only 1-5% of chemotherapy doses administered systemically actually reach the tumor site. In fact, even some of the most promising currently available chemotherapies are not tolerable to most patients in the long term. Public Overview

[0004] Applicants have discovered an implantable, tissue-penetrating and biodegradable drug delivery device capable of delivering active pharmaceutical ingredients (API) directly to target tissues in a patient's body. Since the drug delivery devices disclosed herein utilize local delivery methods, these devices can overcome the problem of systemic side effects, and due to their biodegradable properties, site-specific treatment can be provided more directly without having to perform subsequent removal surgery. Specifically, the drug devices disclosed herein can be flexibly applied via open and minimally invasive surgery, allowing API to be delivered unidirectionally, multidirectionally or omnidirectionally via multilayer structures, acting as a barrier to tumor ingrowth and preventing systemic drug leakage, providing adjustable release profiles and degradation rates, can be combined with systemic treatments, and / or agree to be convertible into an adaptable design for a wide range of solid tumors.

[0005] In some embodiments, the drug delivery device can be flexible. In some embodiments, the drug delivery device can be flexible so that they can be placed in the target tissue of the patient (i.e., in the tumor) and / or near it using standard open, laparoscope, endoscope (e.g., bronchoscope), percutaneous or robotic surgical equipment. In some embodiments, the drug delivery device can be rigid. In some embodiments, in the absence of flexibility, the drug delivery device may not be able to reach the target tissue through a tortuous route using a laparoscope, endoscope, bronchoscope, etc. In some embodiments, the drug delivery device can be partially or completely embedded in the target tissue site. In some embodiments, standard open, laparoscope, percutaneous, endoscopic or robotic surgical equipment can be used to place multiple drug delivery devices in the target tissue in the patient (i.e., in the tumor) and / or near it. In some embodiments, the second drug delivery device can be placed in the target tissue of the patient and / or near it after the first drug delivery device has been degraded or simultaneously with the first drug delivery device.

[0006] In some embodiments, the drug delivery device 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 with different APIs may degrade slower, faster, or the same as the biodegradable polymers of at least one layer with the first API. In some embodiments, at least one of the layers includes a biodegradable polymer without an API. In some embodiments, a non-API layer may be a support layer for providing protection for the API layer, providing structural support for the drug delivery device, and / or providing strength for 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 in the target tissue, the API layer can degrade, thereby releasing the API in the target tissue. In some embodiments, the non-API layer or non-API component in the drug delivery device (e.g., a tip as discussed herein) 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, one or more 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 a tip) can degrade more slowly than at least one API layer, such that the non-API layer can continue to provide support for the drug delivery device and / or maintain the drug delivery device in the target tissue site. Thus, the non-API layer or non-API component may not fully degrade until the drug is fully released. Thus, the drug delivery device can be inserted into a patient to target a specific tissue without having to perform a subsequent surgery to remove the device because it can be completely or mostly absorbed by the patient's body.

[0009] The drug delivery device disclosed herein can provide clinically relevant delivery of API directly to tissues (e.g., tumors), in tissues, or near tissues, and has good tolerability and minimal systemic exposure to API. The device can be used as a neoadjuvant therapy (and / or adjuvant therapy) for the treatment of many medical problems (e.g., cancer, other diseases, wounds, sores, lacerations, non-cancerous growths, etc.), which can improve complete resection rates, reduce the risk of local recurrence after resection, reduce and / or control tumor mass, and / or improve patient survival, as well as all benefits associated with the above.

[0010] In some embodiments, the drug delivery device includes a main body, the main body includes a plurality of layers, wherein the plurality of layers include at least one first layer, the first layer includes an active pharmaceutical ingredient (API) and a biodegradable polymer, wherein the drug delivery device is configured to be inserted into a target tissue site of a patient. In some embodiments, the device includes a distal tip connected or integrated to the main body of the drug delivery device. In some embodiments, the drug delivery device is configured to insert the tip into the target tissue site of the patient 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 acid-co-glycolic acid) (PLGA). In some embodiments, the biodegradable polymer is PLGA 50:50. In some embodiments, the at least one first layer includes 1-15wt.% API. In some embodiments, the at least one first layer includes a solvent. In some embodiments, the at least one first layer includes 1-15wt.% solvent. In some embodiments, at least one of the multiple layers comprises a second layer of a second biodegradable polymer, wherein the second biodegradable polymer has a slower degradation rate than the first biodegradable polymer. In some embodiments, the second biodegradable polymer is PLGA 75:25. In some embodiments, the multiple layers include at least one third layer comprising a second API and a third biodegradable polymer. In some embodiments, the multiple layers include at least one fourth layer comprising a third API and a fourth biodegradable polymer. In some embodiments, each of the multiple layers has the same composition. In some embodiments, the drug delivery device is configured to be implanted in a patient using standard open and / or minimally invasive surgery. 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 robotically. In some embodiments, the at least one first layer is configured to release the API when inserted into the target tissue site of the patient. In some embodiments, the at least one first layer is configured to release the API in multiple directions when inserted into the target tissue site of the patient. In some embodiments, the release of the API is controlled by in vivo degradation of the biodegradable polymer in the target tissue site. In some embodiments, the tip comprises a fifth biodegradable polymer having a slower degradation rate than the first 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 in the target tissue when the drug delivery device is inserted into the target tissue of the patient. In some embodiments, the tissue retention mechanism extends outward from the tip. In some embodiments, the tissue retention mechanism includes a barb and / or an edge. In some embodiments, the tip has at least one vertex at its distal end. In some embodiments, the body includes a detachment mechanism toward the proximal end of the body. In some embodiments, a flexible shaft is connected to the proximal end of the body. In some embodiments, the detachment mechanism is configured to detach the drug delivery device from the flexible shaft. In some embodiments, the detachment mechanism is configured to detach 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, the method for preparing a drug delivery device includes adding a first solution comprising a first biodegradable polymer, an active pharmaceutical ingredient (API) and a solvent to a first matrix; drying the first solution on the first matrix to form a first layer; adding a second solution comprising a second biodegradable polymer and a second solvent to a second matrix; drying the second solution on the second matrix to form a second layer; laminating the first layer and the second layer together 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 die cutting. 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 matrix; drying the third solution on the third matrix to form a third layer; laminating the third layer to the laminated sheet to form a second laminated sheet. In some embodiments, the first solution is spread on the first matrix with a film applicator; and the second solution is spread on the second matrix with a film applicator. In some embodiments, the first solution and the second solution of the spreading have a desired thickness according to the film applicator. In some embodiments, the first matrix and / or the second matrix include 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 for treating a patient's tissue includes implanting a drug delivery device into a target tissue site of the patient, the drug delivery device comprising: a body comprising a plurality of layers, wherein the plurality of layers include at least one first layer comprising an active pharmaceutical ingredient (API) and a biodegradable polymer; and releasing the API from the at least one first layer in the target tissue site, wherein the release of the API is controlled by the in vivo degradation of the biodegradable polymer in the target tissue site. In some embodiments, the drug delivery device includes a tip connected to the distal end of the drug delivery device. In some embodiments, the tip of the drug delivery device is first implanted into the target tissue site of the patient. 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 drug delivery device is implanted via open surgery, laparoscopy, percutaneous, robotic or endoscopic. 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 includes releasing the API in multiple directions away from the drug delivery device. In some embodiments, the drug delivery device is implanted in a target tissue site of a patient so that the tip is configured to keep the drug delivery device in the target tissue. In some embodiments, implanting the drug delivery device includes delivering the drug delivery device to the target tissue site of the patient using a tool. 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 in the target tissue site includes disengaging the body of the drug delivery device from the flexible shaft. In some embodiments, disengaging the drug delivery device from the flexible shaft includes twisting the flexible shaft relative to the drug delivery device. In some embodiments, the body of the drug delivery device includes an anatomical landmark, and implanting the drug delivery device in the target tissue site of a patient includes monitoring the position of the anatomical landmark. In some embodiments, the release of the API is after a delay period after implantation. In some embodiments, a subtherapeutically effective amount of the API 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, the body including: a core comprising a first biodegradable polymer; and an outer layer surrounding at least a portion of the core, the outer layer comprising an active pharmaceutical 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 to 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. In some embodiments, the drug delivery device is configured to be inserted into a target tissue site of a patient with a 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 first biodegradable polymer is poly (lactic acid-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 acid-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 open and minimally invasive surgery. In some embodiments, the drug delivery device is configured to be inserted into a patient's target tissue site using a bronchoscope. In some embodiments, the drug delivery device is configured to be inserted into a patient's target tissue site robotically. In some embodiments, the outer layer is configured to release the API when inserted into the patient's target tissue site. In some embodiments, the outer layer is configured to release the API omnidirectionally when inserted into the patient's target tissue site. In some embodiments, the release of the API is controlled by the in vivo degradation of the second biodegradable polymer in the target tissue site. In some embodiments, the body also includes a second outer layer surrounding at least a portion of the first outer layer and comprising a third biodegradable polymer, wherein the third biodegradable polymer has a faster degradation rate than the second and / or first biodegradable polymer. In some embodiments, the third biodegradable polymer is PLGA. In some embodiments, the tip comprises a third biodegradable polymer, which has 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 in the target tissue when the drug delivery device is 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 a barb and / or an edge.In some embodiments, the tip has at least one vertex at its distal end. In some embodiments, the body includes a disengagement mechanism toward the proximal end of the body. In some embodiments, a 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, the outer layer comprising an active pharmaceutical 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 of 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 acid-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 acid-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 open and minimally invasive surgery. 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 robotically. 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 in the target tissue site.

[0015] In some embodiments, a method for treating a patient's tissue includes implanting a drug delivery device into a target tissue site of the patient, the drug delivery device comprising: a body, the body comprising: a core comprising a first biodegradable polymer; and an outer layer surrounding at least a portion of the core, the outer layer comprising an active pharmaceutical 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 to the distal end of the body; and releasing the API from the outer layer in the target tissue site, wherein the release of the API is controlled by the in vivo degradation of the second biodegradable polymer in the target tissue site. In some embodiments, the tip of the drug delivery device is first implanted into the target tissue site of the patient. 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 drug delivery device is implanted via open surgery, laparoscopy, robot, percutaneous or endoscopic. In some embodiments, the drug delivery device is implanted via a bronchoscope. In some embodiments, releasing the API from the outer layer includes releasing the API in all directions away from the outer layer. In some embodiments, the drug delivery device is implanted in a target tissue site of a patient so that the tip is configured to keep the drug delivery device in the target tissue. In some embodiments, implanting the drug delivery device includes using a tool to deliver the drug delivery device to the target tissue site of the patient. In some embodiments, the tool includes a flexible shaft and is connected to the proximal end of the body. In some embodiments, implanting the drug delivery device in a target tissue site includes disengaging the body of the drug delivery device from the flexible shaft. In some embodiments, disengaging the drug delivery device from the flexible shaft includes twisting the flexible shaft relative to the drug delivery device.

[0016] Additional advantages will be readily apparent to those skilled in the art from the following detailed description.The embodiments and descriptions herein are to be considered illustrative in nature and not restrictive.

[0017] All publications, including patent documents, scientific articles, and databases, mentioned in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication was individually incorporated by reference. If definitions set forth herein are contrary to or otherwise inconsistent with definitions set forth in patents, applications, published applications, and other publications incorporated herein by reference, the definitions set forth herein take precedence over definitions incorporated herein by reference. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0019] Figure 1A Shown is a top view of a drug delivery device according to some embodiments disclosed herein.

[0020] Figure 1B Shown is a side view of a drug delivery device according to some embodiments disclosed herein.

[0021] Figure 1C According to some embodiments disclosed herein, Figure 1B Cross section of line CC.

[0022] Figure 1D Another rectangular prismatic drug delivery device is shown according to some embodiments disclosed herein.

[0023] Figure 2A Another drug delivery device according to some embodiments disclosed herein is shown.

[0024] Figure 2B According to some embodiments disclosed herein, Figure 2A A cross section of line AA.

[0025] Figure 2C According to some embodiments disclosed herein, Figure 2A The cross section of line BB.

[0026] Figure 2D A clamp connected to a drug delivery device is shown according to some embodiments disclosed herein.

[0027] Figure 2E Shown is a cross-section of a drug delivery device having a hollow core according to some embodiments disclosed herein.

[0028] Figure 2F Another cross-section of a drug delivery device having a hollow core according to some embodiments disclosed herein is shown.

[0029] Figure 3 The application of a biodegradable polymer / API solution to a substrate using a film coater is shown according to some embodiments disclosed herein.

[0030] Figure 4A An image of a drug delivery device according to some embodiments disclosed herein is shown.

[0031] Figure 4B Additional images of drug delivery devices according to some embodiments disclosed herein are shown.

[0032] Figure 4CTwo additional images of drug delivery devices of various sizes are shown according to some embodiments disclosed herein.

[0033] Figure 5 Cumulative drug release from drug delivery devices tested according to some embodiments disclosed herein is shown.

[0034] In the drawings, like reference numerals correspond to like components unless otherwise specified. DETAILED DESCRIPTION OF THE INVENTION

[0035] Exemplary embodiments of biodegradable drug delivery devices that can be implanted in patients to locally deliver controlled therapeutically effective amounts of API are described herein. Specifically, the drug delivery device disclosed herein can be configured to provide controlled release of a therapeutically effective amount of API directly to or into and / or adjacent to a target tissue site (e.g., a tumor) by degrading a biodegradable polymer layer containing the API in vivo. In some embodiments, the drug delivery device may not be placed directly into the target tissue site (e.g., a tumor). Therefore, the drug delivery device can be delivered adjacent to the target tissue. For example, a tumor may be encapsulated in a scar capsule and / or it may not need to be "poked" to avoid destroying the tumor because it may discharge unwanted components. In these cases, the drug delivery device can be placed adjacent to the tumor site, such as near the edge or border of the tumor site and / or touch or contact the tumor site.

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

[0037] PCT Application No. PCT / US2022 / 079996 (which is incorporated herein by reference in its entirety) discloses a film or patch drug delivery device with multiple biodegradable layers. In use, the API layer disclosed in PCT / US2022 / 079996 will face the target tissue so that the API is released toward the target tissue during degradation, and the non-API backing layer can prevent the API from being released from the target tissue to the non-target tissue.

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

[0039] The drug delivery devices disclosed herein can have a variety of shapes, sizes, and geometries. In some embodiments, the drug delivery device can be circular, square, rectangular, elliptical, triangular, rhombus, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), arc, trapezoidal, star-shaped, or various other shapes and sizes. In some embodiments, the drug delivery device can be tubular, cylindrical, conical, pyramidal, triangular prism, cubic, spherical, spiral, rectangular prism, or various other shapes and sizes. For example, Figure 1A -D shows a rectangular prism-shaped drug delivery device 100, while Figure 2A -C shows 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 or more layers may include an API that can be released in vivo by polymer biodegradation. In some embodiments, at least one second layer or layers may not contain any API.

[0041] In some embodiments, the drug delivery device may include a body. In some embodiments, the body of the drug delivery device may be flexible or rigid. In some embodiments, the body may include multiple layers. In some embodiments, the drug delivery device may include at least one API layer or multiple API layers. The API layer may include an API embedded in 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 may also be API layers. These layers may include the same or different APIs. In some embodiments, at least one layer or multiple layers of the drug delivery device may be a non-API layer.

[0042] For example, the drug delivery device may include a body 204. In some embodiments, the body may include at least one API layer 101 (e.g., an outer layer). The API layer may include an API embedded in and / or on the surface of at least one API layer 101. In some embodiments, multiple layers of the drug delivery device (e.g., all other layers) may also be API layers. For example, layers 102 (e.g., an inner layer), 103, 104, and 105 may be layers that include API embedded in and / or on the surface of the layers. These layers may include the same or different APIs. In some embodiments, at least one layer of the drug delivery device may be a non-API layer. For example, the intermediate layer 103 may be a non-API layer to provide some additional structural support and / or strength to the entire drug delivery device. In use, the drug delivery device can be implanted within (i.e., intratumorally) and / or adjacent to a solid tumor, and the API layer can release the API within or adjacent to the tumor during degradation, such as Figure 1A -C and 2A-C as shown by arrow 301. Thus, the API layer can release the API in multiple directions and / or omnidirectionally (i.e., in each direction) 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 target tissue can be a tumor on or within 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., layers 101 and 105) can be non-API layers. In some embodiments, the body can be coated with a non-API coating, or can be covered on all sides with a non-API layer (e.g., a non-API shell). For example, in such an embodiment, Figure 1CThe cross section will include a non-API layer or coating (not shown) around the periphery of the cross section. In such an embodiment, the API layer 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 unintentional scratching and / or damage of the device during placement) until the non-API coating shell is first dissolved. In other words, the drug delivery device can have a protective non-API layer / coating so that the API layer is protected from any external elements. For example, in some embodiments, all sides (e.g., top, bottom, front, rear, each end) of the drug delivery device may have a non-API coating / layer / shell. In some embodiments, the non-API layer / coating / shell may include a biodegradable polymer (disclosed herein) having a slower, faster or the same degradation rate than the biodegradable polymer of the API layer. In some embodiments, when the outer layer contacts the environment of the degradable biodegradable polymer, regardless of the degradation rate of the layer, the outer layer can degrade faster than the inner layer of the drug delivery device, and the inner layer can be protected from the influence of such an environment. In some embodiments, the outer layer / shell of the device can be an API layer, so that once implanted in the target tissue, the API can be easily released without waiting for the non-API layer to degrade.

[0044] In some embodiments, the body of the drug delivery device may include at least one API layer and / or at least one non-API layer. As described above, the at least one API layer may be an outer layer, an inner layer, a shell layer, a core and / or a core layer. In addition, the at least one non-API layer may 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 may have the composition of any API layer or non-API layer disclosed herein. For example, Figure 2A -C shows a non-API core 202 with an API outer layer 201. In some embodiments, the core or core layer can provide strength to the drug delivery device when it is inserted into the patient's body. Figure 2B As shown, core 202 can provide longitudinal strength to the drug delivery device for implantation in and / or near a target tissue site in a patient. Figure 2COnly two layers are shown, but the drug delivery device disclosed herein may have additional layers, such as an API layer, a non-API layer, or a combination thereof. In some embodiments, the drug delivery device 200 may include an API layer 201 (i.e., an outer layer) and a non-API layer 202 (i.e., a core or core layer). The API-containing layer may include an API embedded in and / or on the surface of the API layer 201. In some embodiments, the API layer may surround at least a portion of the non-API core or core layer. In some embodiments, the non-API layer may surround at least a portion of the API core or core layer. In some embodiments, the drug delivery device may 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 prepared by a 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 in a mold and / or on a substrate. In some embodiments, after drying, the layer can be removed from the mold and / or the substrate, and the process can be repeated to produce as many API layers as possible required for the drug delivery device. In some embodiments, the layer can be retained on the substrate for further processing, such as lamination and / or cutting as described herein. In some embodiments, the second layer (that is, non-API layer) with at least one biodegradable polymer can be dissolved in a solvent, cast in a mold and / or on a substrate, dried and / or removed from a mold and / or substrate. The process can be repeated to produce as many API layers as possible required for the drug delivery device. In some embodiments, any combination and sequence of API and / or non-API layers can be laminated together to form a drug delivery device, or laminated together, then cut (e.g., die-cut) to form a 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, a non-API layer (e.g., a core or core layer) can be dissolved in a solvent and cast in a mold and / or on a substrate before casting an API layer (e.g., an outer layer or shell layer) on top of the non-API layer. The process can be repeated for as many additional API and / or non-API layers as desired.

[0047] In some embodiments, the drug delivery devices may be prepared by a continuous process.In some embodiments, the drug delivery devices disclosed herein may be prepared by a continuous process, such as those employed by the polymer film production industry (eg, extrusion, continuous film evaporation, etc.).

[0048] In some embodiments, for example Figure 1A -C and those shown in 2A-C, the drug delivery device is configured to be inserted into the target tissue site of the patient and / or adjacent to the target tissue site of the patient using standard open, laparoscopic, endoscopic (e.g., bronchoscope), percutaneous or robotic surgical equipment. In some embodiments, the drug delivery device can be inserted through the working channel of an endoscope (e.g., 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 by any of the above-mentioned administration routes.

[0049] Because the drug delivery device can be flexible, it is configured to be inserted through the working channel of an endoscope, a trocar, etc., so the diameter, width and / or height of the drug delivery device (the body and / or the tip) can be about 0.1-20mm, about 0.25-20mm, 0.25-12mm, 0.5-12mm, about 0.5-10mm, about 0.5-8mm, about 0.5-5mm, about 0.5-3mm, about 1-3mm or about 2mm. In some embodiments, the length of the body of the drug delivery device can be about 0.1-20mm, about 0.5-15mm, about 1-15mm, about 3-12mm, about 4-11mm or about 5-10mm. 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 205. In some embodiments, the drug delivery device may not include a tip. In some embodiments, the tip of the drug delivery device may be flexible or rigid. In some embodiments, the tip may be connected to the distal end of the body of the drug delivery device. In some embodiments, the tip and the body may be an integral unit. When the drug delivery device is guided to the tissue site of the patient, the drug delivery device may be guided by the tip first. In some embodiments, the tip may have at least one vertex at its distal end. The at least one vertex may allow the tip (and the drug delivery device) to penetrate into and / or near the target tissue site (e.g., a solid tumor). In some embodiments, the at least one vertex may be sharp. This may allow the drug delivery device tip to be first implanted in and / or near the target tissue site of the patient. In some embodiments, the drug delivery device does not include a tip.

[0051] In some embodiments, the tip may be configured to retain or maintain the drug delivery device in the target tissue site. For example, in some embodiments, the tip may include (one or more) tissue retainers or (one or more) tissue retaining mechanisms 206. The tissue retaining mechanism may be configured to retain or maintain the drug delivery device in the target tissue site (i.e., in a solid tumor). In some embodiments, the tissue retaining mechanism may extend outward from the tip. In some embodiments, the tissue retaining mechanism may extend radially outward from the drug delivery device. In some embodiments, the tissue retaining mechanism may extend outward from the drug delivery device (or tip) and return toward the main body or proximal end of the drug delivery device. In some embodiments, the tissue retaining mechanism may include edges, barbs, lips or other similar aspects. In some embodiments, edges, barbs, lips or other similar aspects may be sharp. In some embodiments, the tip with a tissue retaining mechanism may be shaped like a broad arrow. Therefore, the tip (with a tissue retaining mechanism) may be configured to penetrate the target tissue site, embed the drug delivery device in or near the target tissue site, and retain / retain the drug delivery device in or near the target tissue site when the API is released from the API layer. In some embodiments, the body of the drug delivery device may include a tissue retention mechanism, such as a non-API or API layer 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 in the API layer, so that when the API is released from the API layer by in vivo degradation, the tip can keep the drug delivery device in the appropriate position in the tumor. Similar to the API and / or non-API layer, the tip can be configured / adjusted to have a specific desired degradation rate. In some embodiments, the tip can be made of any composition disclosed herein for the API layer and / or non-API layer. In some embodiments, the tip may have the same composition as any non-API layer disclosed herein. In some embodiments, the tip and body of the device can be an integral component or produced separately and then attached / adhered / connected to each other. In some embodiments, the tip can be created in the same manner as any API and / or non-API disclosed herein (e.g., solvent casting, lamination, cutting, etc.). In addition, because the tip can be made of a biodegradable material, the entire drug delivery device can be degradable, so that subsequent surgery may not be required to remove one aspect of the device. In some embodiments, the thickness of the layers and / or the size of the tip of the drug delivery device can be selected based on the desired degradation / API release kinetics.

[0053] In some embodiments, when the drug delivery device is implanted in and / or near the target tissue site, the drug delivery device can be configured to be disengaged or released from a component (e.g., a tool that can deliver the device, such as a flexible shaft 203). In some embodiments, in order to deliver, a flexible shaft (e.g., the distal end of the flexible shaft) can be connected to the body (e.g., the proximal end of the body) of the drug delivery device. The drug delivery device with a flexible shaft can then be inserted into the working channel of an endoscope (e.g., a standard or robotic endoscope) to be implanted in and / or near the target tissue site of the patient. In some embodiments, the proximal end of the flexible shaft can be connected or attached to a component of the endoscope, another tool for guiding 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 a delivery tool (e.g., a flexible shaft) may include twisting the delivery tool relative to the drug delivery device. The motion can release / disengage the drug delivery device from the delivery tool (e.g., a flexible shaft). In some embodiments, this motion can fatigue the portion of the drug delivery device connected to the delivery tool and separate the tool from the drug delivery device.

[0054] In some embodiments, the drug delivery device may have a hollow core so that the drug delivery device can serve as a shaft or handle for a central pin, staple, and / or mandrel (e.g., flexible shaft 203) to deliver the device to a target tissue site, e.g. Figure 2E-F shown in the drug delivery device. In some embodiments, the pin, nail and / or mandrel can then be removed from the drug delivery device so that the drug delivery device remains in its target tissue site. This will be similar to the case of rivet fastening mechanism or stent deployment. In some embodiments, the tip of the drug delivery device can be attached to the deployment mandrel by the core of the drug delivery device. When the mandrel is removed, the mandrel can be broken or disconnected from the tip, similar to a blind rivet mechanism. In some embodiments, the hollow core of the drug delivery device can have an inner diameter, and the inner diameter is configured to allow a delivery tool (e.g., a flexible shaft) to pass or translate through the hollow core. For example, the hollow core can have a diameter of at least about 0.1mm, at least about 0.5mm, at least about 1mm or at least about 2mm. In some embodiments, the hollow core can have a diameter of at most 10mm, at most 5mm, at most 2mm or at most 1mm. For example, in some embodiments, the distal end of the flexible shaft 203 can be attached / connected / adhered to the distal end (e.g., tip 205) of the drug delivery device by the hollow core of the drug delivery device. This can provide longitudinal support, strength and / or rigidity for the drug delivery device, for implantation in and / or near the target tissue site.In some embodiments, the proximal end of the flexible shaft can be connected or attached to an endoscopic assembly, another tool and / or a robotic assembly for guiding the drug delivery device to the target tissue site.In some embodiments, disengaging or releasing the drug delivery device from a delivery tool (e.g., a flexible shaft) may include twisting or ejecting the delivery tool relative to the drug delivery device. The motion can release / disengage the drug delivery device from the delivery tool (e.g., a flexible shaft).In some embodiments, this motion can fatigue the part 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 Figure 2D The forceps 210 shown (e.g., a standard lung biopsy forceps) can implant the drug delivery device in and / or near the target tissue site. In some embodiments, the forceps can be a biopsy forceps (e.g., a clamshell forceps). For example, the mouth of the forceps can be attached to the location where the release mechanism 207 is located, and the forceps can be used to place the drug delivery device at its target location. Once the drug delivery device is in place, the drug delivery device can be released by opening the forceps.

[0056] In some embodiments, the drug delivery device can be housed in an applicator. The applicator can include a plunger that can push the drug delivery device out of the applicator housing and into and / or adjacent to the target tissue site (i.e., similar to a tampon). The applicator can then be removed after use of the drug delivery device.

[0057] In some embodiments, the body can include a detachment mechanism 207 toward the proximal end of the body. In some embodiments, the body can include a detachment mechanism toward the distal end of the body. The detachment mechanism can be configured to detach the drug delivery device from the delivery tool. After the drug delivery device is implanted / embedded in the target tissue (e.g., a solid tumor), the delivery tool (e.g., a flexible shaft, forceps, etc.) can be withdrawn (in some embodiments, from the working channel of the endoscope) to leave the drug delivery device in the target tissue. In some embodiments, the tip of the drug delivery device can include a detachment mechanism, such as Figure 2E The disengagement mechanism shown in .

[0058] In some embodiments, the drug delivery device may include anatomical landmarks 208. In some embodiments, the anatomical landmarks may be in the API layer and / or non-API layer of the device. In some embodiments, the anatomical landmarks may be in the body and / or tip of the drug delivery device. In some embodiments, physicians can use anatomical landmarks to identify the drug delivery device in the patient using various imaging techniques. The physician can then monitor the progression and / or position of the drug delivery device relative to the tumor. In some embodiments, the anatomical landmarks may be radiopaque markers, X-ray markers, lead markers, or similar markers. In some embodiments, the anatomical landmarks may be embedded into the component after the component (e.g., layer, body, and / or tip) has been created.

[0059] As described above, the drug delivery device can be guided to the target tissue site by open surgery, laparoscopy, robotics, percutaneous, endoscopic or a combination thereof. Once at the target tissue site, the drug delivery device can be properly oriented using a camera or by other means to monitor anatomical landmarks. In some embodiments, a surgical camera can be used to ensure that the tip (at least one vertex) of the drug delivery device is directed to the target tissue site.

[0060] Once the correct placement and orientation of the drug delivery device have been confirmed, the drug delivery device can be inserted or implanted in and / or near the target tissue site. For example, the drug delivery device can be implanted so that at least a portion of the drug delivery device is in or near the target tissue site (e.g., solid tumor). In some embodiments, the entire drug delivery device can be implanted in the target tissue site. In some embodiments, after the drug delivery device is implanted in or near the target tissue, a delivery tool (e.g., flexible shaft, clamp, etc.) can be disengaged from the drug delivery device and then removed from the patient, thereby leaving the drug delivery device. API Layer

[0061] In some embodiments, the drug delivery device may include at least one or more layers containing API. In some embodiments, the at least one layer containing API may be an outer layer, an inner layer, a core, a core layer and / or a shell layer of a drug delivery device. In some embodiments, the API layer may include at least one active pharmaceutical ingredient (API) and at least one biodegradable polymer. In some embodiments, the API layer may include more than one biodegradable polymer. In some embodiments, the API layer may include more than one API. As described above, the API layer may be configured to provide controlled release of the API by degrading the biodegradable polymer in vivo at and / or in the target tissue site. In some embodiments, the API layer may 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 a synthetic polymer selected from poly(amides), poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudopoly(amino acids), poly(glycerol-sebate), copolymers thereof, and mixtures thereof. In addition, the biodegradable polymer can be formed by 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 with 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, PLGA85:15, PLGA 90:10 or other various ratios of PLGA. In some embodiments, the biodegradable polymer in the API-containing layer comprises PLGA 50:50.

[0063] PLGA can be degraded by hydrolysis or biodegradation, by cracking its backbone ester bond into oligomers, and then cracking into monomers. The lactide-glycolide ratio determines the degradation rate of PLGA in aqueous media (e.g., water and aqueous environments, such as in human or animal anatomical structures). Generally, the higher the lactic acid content or lactide content, the lower the degradation behavior of PLGA, because lactide has hydrophobicity, which can prevent water from hydrolyzing the ester bond in PLGA. Therefore, PLGA 50:50 degrades faster than PLGA 65:35 in aqueous environments, and PLGA 65:35 degrades faster than PLGA 75:25.

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

[0065] In some embodiments, the API can be an active pharmaceutical ingredient for treating human or veterinary diseases. The API can be one or more antibacterial agents, antifungal agents, antiprotozoal agents, antiviral agents, abortion inducing agents, spermicides, prostaglandins, steroids and microbicides, proteins / peptides and vaccine antigens.

[0066] Suitable APIs include, but are not limited to, analgesics and anti-inflammatory agents (e.g., ibuprofen), antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antianxiety agents, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraines, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoal agents, antirheumatic agents, antithyroid agents, antivirals, antianxiety agents, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropes, corticosteroids, cough suppressants, cytotoxins, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor agonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, 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 agent that effectively treats cancer by inhibiting the growth, invasion and / or inducing cytotoxicity through apoptosis or necrosis of malignant cells. The chemotherapeutic agent can be a taxane or a platinum drug. 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 may interfere with the mTOR or NfKb pathway. In some embodiments, the chemotherapeutic agent includes a STING agonist compound. In some embodiments, the chemotherapeutic agent may interfere with the STING pathway. In some embodiments, the chemotherapeutic agent includes genetic material such as mRNA, siRNA, etc. In some embodiments, the chemotherapeutic agent can be a siRNA-Alnylam type therapy.

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

[0069] The API can be a single active pharmaceutical ingredient, such as a single chemical entity, or it can be a mixture of several active pharmaceutical ingredients. The active pharmaceutical ingredient can be any of many categories of active pharmaceutical ingredients. The active pharmaceutical ingredient can be selected from but not limited to paclitaxel, gemcitabine, nab-paclitaxel, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, vinorelbine, etoposide, mitomycin-C, cisplatin / carboplatin, fluorouracil, methotrexate, TAS-102 or a combination 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 a combination thereof. In some embodiments, the API can be an API for immunotherapy, such as nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, or a combination thereof.

[0071] In some embodiments, the API can be acyclovir, fluconazole, progesterone and its derivatives, nonoxyenol-9, terbutaline, lidocaine, testosterone and its derivatives, dinoprostone, lactobacillus, estrogen and its derivatives, naphthalene-2-sulfonate, lemitedan, 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 propyl axetil, 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 hydrochloride, dimenhydrinate, cefoperazone hydrochloride, enoxacin, sparfloxacin, aspirin, famotidine, amoxicillin trihydrate, pheniramine hydrochloride, amprilose hydrochloride, terfenadine, becamide, clarithromycin, roxithromycin, nizatidine, cetroxalate hydrochloride, ciprofloxacin, bifemel hydrochloride, cefuroxime axetil, perrenzepine and / or oxybutynin, diclofenac, nicorandil, levofloxacin, acriflavine, leuprolide acetate, metronidazole, benzydamine hydrochloride, chloramphenicol, oxybutynin, ethinyl estradiol, prostaglandins, insulin, calcitonin, and combinations thereof. The active pharmaceutical ingredient may also be a vaccine antigen, such as those used to treat hepatitis B, HIV, HPV, Chlamydia, gonococcal infections.

[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 to have the same activity as the active ingredient, although the activity level may be lower or higher. In some embodiments, the API may be in the form of microspheres. In some embodiments, the microspheres may release the API. In some embodiments, the API is encapsulated in microspheres.

[0073] When present, the API is used in the formulation in a therapeutically effective amount that is necessary to provide the desired dose, typically to produce at least one physiological effect determined by clinical studies. One of ordinary skill in the art can readily determine the appropriate amount of active pharmaceutical ingredient to include in a drug delivery device manufactured according to 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.% 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.% API. In some embodiments, the API-containing layer includes about 1-30 wt.%, about 1-25 wt.%, about 5-25 wt.%, about 10-20 wt.%, about 12-18 wt.%, about 12-15 wt.%, about 13-14 wt.%, about 1-15 wt.%, about 5-15 wt.%, about 7-12 wt.%, about 8-12 wt.%, or about 7.5-11 wt.% API. In some embodiments, the API-containing layer may include about 0.01-500 mg, about 0.01-50 mg, about 0.1-50 mg, or about 0.25-50 mg.

[0075] In order to prepare the API layer in some embodiments of the drug delivery device disclosed herein, a solution of a biodegradable polymer and API can be formed. Specifically, a certain amount of biodegradable polymer can be dissolved in a solvent. The biodegradable polymer / solvent solution can be stirred and / or heated to help dissolve the polymer in a solvent. In some embodiments, the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methyl ethyl ketone, dichloromethane, isopropanol, methyl isobutyl ketone, methyl propyl ketone, trichloroethylene, other substitutes of acetone or a combination thereof. In some embodiments, the biodegradable polymer and solvent solution can be about 0.1-0.3g biodegradable polymer, about 0.15-0.25g biodegradable polymer, about 0.175-0.225g biodegradable polymer, about 0.19-0.21g biodegradable polymer, about 0.198-0.202g biodegradable polymer or about 0.2g biodegradable polymer per 1mL solvent. In other words, 20g biodegradable polymers will be the biodegradable polymers and solvent solution of 0.2g biodegradable polymers per 1mL solvent in 100mL solvent.For the biodegradable polymers / API solution discussed below, the above concentration can also be real.For example, biodegradable polymers / API solution can have about 0.1-0.3g biodegradable polymers, about 0.15-0.25g biodegradable polymers, about 0.175-0.225g biodegradable polymers, about 0.19-0.21g biodegradable polymers, about 0.198-0.202g biodegradable polymers or about 0.2g biodegradable polymers per 1mL solvent.

[0076] In some embodiments, after the biodegradable polymer is dissolved in the solvent, the API can be added to the solution. In some embodiments, the API and the biodegradable polymer can be added to the solvent at the same time. In some embodiments, the API can be added to the solvent before the biodegradable polymer is added. 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 solution and the second solution 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 deteriorating in the polymer / solvent solution.

[0077] In some embodiments, the biodegradable polymer / API solution may have about 0.01-0.05 g API, about 0.01-0.045 g API, about 0.015-0.045 g API, about 0.02-0.04 g API, about 0.025-0.04 g API, or about 0.03-0.04 g API per 1 mL of solvent. The above concentrations are also true for API and solvent solutions (without biodegradable polymer). The biodegradable polymer / API solution may be stirred and / or heated until the API is fully mixed and / or dissolved in the solvent.

[0078] In some embodiments, after forming biodegradable polymer / API solution, the solution can be added to mold and / or substrate. In some embodiments, substrate can be release film or liner, such as medical release liner. In some embodiments, substrate can be made of polymer (such as polyester) or paper substrate, and can be coated with silicone or PTFE. In some embodiments, mold can be any container used to give API layer shape when API layer is formed. Therefore, mold can be circular, square, rectangular, elliptical, triangle, rhombus, polygon (such as pentagon, hexagon, octagon, etc.), arc, trapezoid, star, tubular, cylindrical, conical, pyramidal, triangular prism, cubic, spherical, rectangular prism or various other shapes and sizes. In addition to shape, mold can also determine the size (that is, width, length, diameter, height / thickness, etc.) of layer.

[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 subsequently modified (e.g., laminated and cut) to form the final API layer of the drug delivery device. In some embodiments, a biodegradable polymer / API solution can be added to a circular mold. In some embodiments, the mold can be an evaporating dish or a culture dish, etc. In addition, the amount added to the mold can depend on the desired thickness and / or API concentration of the API layer. In addition, the amount added to the mold can depend on the desired API release rate of the API layer. In some embodiments, about 1-20mL, about 1-10mL, about 4-6mL or about 5mL of a biodegradable polymer / API solution can be added to the mold.

[0080] In some embodiments, biodegradable polymer / API solution is added to substrate.As mentioned above, in some embodiments, substrate can be a release liner, and biodegradable polymer / API solution can be added to the peeling side of the release liner.In some embodiments, a film coater and / or a spiral rod coater can be used to produce a reproducible wet layer of a biodegradable polymer / API solution of a limited thickness.In some embodiments, a film coater and / or a spiral rod coater can be placed on a flat substrate with a selected desired thickness.In some embodiments, then a biodegradable polymer / API solution can be added to substrate.In some embodiments, the biodegradable polymer / API solution can be added before and / or in the reservoir of a film coater and / or a spiral rod coater.In some embodiments, the consistent pouring speed of the biodegradable polymer / API solution can produce a straighter leading edge.In some embodiments, the edge of the foot close to the film coater and / or the spiral rod coater, starting from more volume of biodegradable polymer / API solution, can produce a straighter trailing edge. In some embodiments, the biodegradable polymer / API solution 301 can be added between the legs 302a of the film coater 302 and / or the spiral rod coater, such as Figure 3 In some embodiments, once the biodegradable polymer / API solution is in place, a film coater and / or spiral rod coater may be moved across the substrate 303 at a steady speed in a given direction 304 (ie, knife coating).

[0081] In some embodiments, the film coater and / or spiral rod coater are moved on the substrate to guide the biodegradable polymer / API solution through the gap of the film coater and / or spiral rod coater, and the biodegradable polymer / API solution is spread on the substrate, thereby producing a wet layer of the biodegradable polymer / API solution of the desired thickness on the substrate. In some embodiments, the film coater and / or spiral rod coater can be a manual or automatic film coater. In some embodiments, the film coater can be a baker-type coater, a bird-type coater, a reservoir coater and / or a micrometer coater, 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, once spread on the substrate, then can dry biodegradable polymer / API solution.This drying can cause solvent evaporation, thereby leaving a solidified layer comprising biodegradable polymer, API and some residual solvents.In some embodiments, the residual solvent in the layer may be important, because it allows the layer to remain flexible and not crack during subsequent processing.Therefore, the API layer may also include a small amount of solvent, which will be discussed in further detail below.In some embodiments, once in a mold, then can dry biodegradable polymer / API solution.

[0084] In some embodiments, the biodegradable polymer / API solution can be dried in air, nitrogen or other gases at least at 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 with a humidity of 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 last 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 up to 6 days, up to 5 days, up to about 2 days, up to about 1 day, up to about 12 hours, up to about 6 hours, up to about 1 hour, or up to about 30 minutes. Non-API layer

[0085] In some embodiments, the drug delivery device may include at least one or more layers containing non-API. In some embodiments, the at least one layer containing non-API can be the outer layer, inner layer, core, core layer and / or shell layer of the drug delivery device. In some embodiments, the non-API layer may be free of API. In some embodiments, the non-API layer may include at least one or more biodegradable polymers. As described above, in some embodiments, the non-API layer can serve as a backing layer or support layer of the API layer and / or drug delivery device to provide strength (e.g., longitudinal strength) to the drug delivery device.

[0086] In some embodiments, the non-API layer may include a biodegradable polymer having a slower degradation rate than the biodegradable polymer in the API layer. As explained below, 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 because PLGA 75:25 degrades more slowly than PLGA 50:50. In some embodiments, the non-API layer may include a biodegradable polymer having the same or faster degradation rate as 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 in the API layer can degrade over the course of about 4 weeks, thereby releasing the API into and / or near the target tissue. The biodegradable polymer in the non-API layer can degrade over a longer period of time (e.g., 10 weeks). Therefore, 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 one or more API layers are completely degraded and the API has been completely released into the target tissue, one or more non-API layers can be completely degraded to be absorbed by the patient's body. In some embodiments, when the API layer is degrading, a portion of the non-API layer can be degraded, but the degradation rate of the non-API layer can be slower than the degradation rate of 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 degradation rate that is slower, faster, or the same as that of the biodegradable polymer in the API layer. For example, the biodegradable polymer may include a synthetic polymer selected from poly(amides), poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudopoly(amino acids), poly(glycerol-sebacic acid esters), copolymers thereof, and mixtures thereof. In addition, the biodegradable polymer can be formed by 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 with 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 non-API-containing layer includes 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.% 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.% biodegradable polymer. In some embodiments, the non-API-containing layer comprises about 80-99.9 wt.%, about 85-98 wt.%, about 86-97 wt.%, or about 88-96 wt.% biodegradable polymer.

[0091] In order to prepare the non-API layer for drug delivery device, the second solution of biodegradable polymer can be formed. Specifically, a certain amount of biodegradable polymer can be dissolved in a solvent. The second biodegradable polymer / solvent solution can be stirred and / or heated to help dissolve the polymer in a solvent. In some embodiments, the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methyl ethyl ketone, methylene chloride, isopropanol, methyl isobutyl ketone, methyl propyl ketone, trichloroethylene, other substitutes of acetone or its combination. In some embodiments, the biodegradable polymer and solvent solution can be about 0.1-0.3g biodegradable polymer, about 0.15-0.25g biodegradable polymer, about 0.175-0.225g biodegradable polymer, about 0.19-0.21g biodegradable polymer, about 0.198-0.202g biodegradable polymer or about 0.2g biodegradable polymer in every 1mL solvent. In other words, 20 g of biodegradable polymer in 100 mL of solvent would be a biodegradable polymer and solvent solution of 0.2 g of biodegradable polymer per 1 mL of solvent.

[0092] In some embodiments, after forming the second biodegradable polymer solution, the solution can be added to the mold and / or substrate and produced in the same manner (drying, removing, etc.) as the API layer is prepared in the mold and / or substrate. In some embodiments, the substrate can be any substrate previously described for the API layer. In some embodiments, the mold can be any mold previously described for the API layer. In some embodiments, the mold and / or substrate can determine the shape of the final non-API layer. In other embodiments, the mold and / or substrate form a precursor non-API layer that can be subsequently modified. In some embodiments, after forming the second biodegradable polymer solution, the solution can be added to the mold and / or substrate containing the API layer (or another non-API layer). Therefore, the second biodegradable polymer solution can be added to the API layer (or another non-API layer) of the mold and / or substrate, such as a covering or coating on the API layer (or another non-API layer).

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

[0094] In some embodiments, a non-API biodegradable solution may be first added to a mold and / or matrix to form a non-API layer (in a manner similar to the API layer explained above with respect to the API layer), and then the API layer may be formed on top of the non-API layer in the mold and / or matrix. In some embodiments, a non-API biodegradable solution may be first added to a mold and / or matrix to form a non-API layer (e.g., a core or core layer), and then the API layer may be formed on top of the non-API layer in the mold and / or matrix or a different mold so as to surround at least a portion of the non-API layer.

[0095] Once on the substrate or in the mold, the second biodegradable polymer solution can be dried. In some embodiments, the drying can cause the solvent to evaporate, thereby leaving a solidified layer comprising a biodegradable polymer and some residual solvent. In some embodiments, the drying can cause the solvent to evaporate, thereby leaving a non-API layer. In some embodiments, the drying can cause the solvent to evaporate, thereby leaving a second solidified layer on one side of the first solidified API or non-API layer. In some embodiments, the second layer can be adhered to the first layer via a solvent welding process. In other words, the second layer can be adhered to the first layer because the first layer can be slightly dissolved when the second layer is applied, and can be dried again with the second layer to form a solid second layer on one side of the solid first layer.

[0096] In some embodiments, the non-API layer may also include a small amount of solvent, which will be discussed in further detail below. In some embodiments, the non-API biodegradable polymer solution can be dried in air, nitrogen or other gases at at least 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 with a humidity of less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than 5%, or less than about 1%. In some embodiments, the drying can last for 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 last 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 up to 6 days, up to 5 days, up to about 2 days, up to about 1 day, up to about 12 hours, up to about 6 hours, up to about 1 hour, or up to about 30 minutes. In some embodiments, the layers of the drug delivery device (API layer, non-API layer and / or both API and non-API layers) can have a uniform consistency and be homogeneous.

[0097] In some embodiments, after the individual layers (API, non-API) have been added and dried, these layers can be removed. In some embodiments, after the desired amount of API and / or non-API layers have been 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 and non-API layer can be retained in the mold or on the substrate for further processing (e.g., drying, lamination, cutting, etc.).

[0098] In some embodiments, the above process of preparing API layer and non-API layer can be repeated because the drug delivery device requires many additional layers. In some embodiments, the drug delivery device may include multiple layers rather than a large layer due to the manufacturing constraints of a large layer. For example, the thicker the single layer, the more likely the layer is to have impurities that may affect the degradation rate, such as bubbles. In addition, for the solvent to evaporate to form such a layer, there is a limit to the thickness of the layer. Therefore, in some embodiments, the drug delivery device can be formed by multiple layers rather than one layer.

[0099] In some embodiments, the desired API layer and / or non-API layer can be laminated together to form a laminate. For example, if a layered drug delivery device of API / API / API is desired, three separate API layers (having the same and / or different compositions) can be laminated together in the desired order. For example, Figures 1A-1C Can be made by laminating layers 101, 102, 103, 104 and 105 in order.In some embodiments, the laminated sheet is the main body of a drug delivery device or a drug delivery device.In some embodiments, the lamination process is a single step.In some embodiments, each layer can be laminated one layer at a time until final laminated sheet is produced.In some embodiments, a standard laminating machine can be used for the lamination process, such as a laboratory laminating machine or an industrial laminating machine.In some embodiments, the laminating machine may include a roller (e.g., a roll), and the roller includes a heated roller.

[0100] In some embodiments, the speed, temperature, pressure and / or gap parameters of the laminator can be set to the desired parameters. In some embodiments, the speed can be set to at least about 0.5ft / min, at least about 1ft / min, at least about 3ft / min, at least about 5ft / min, at least about 10ft / min, or at least about 15ft / min. In some embodiments, the speed can be set to at most about 20ft / min, at most about 15ft / min, at most about 10ft / min, or at most about 5ft / min. 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, pressure can be set to at least about 1psi, at least about 5psi, at least about 10psi, at least about 15psi, at least about 20psi, at least about 30psi, at least about 40psi, at least about 50psi or at least about 75psi. In some embodiments, pressure can be set to at most about 200psi, at most about 150psi, at most about 100psi, at most about 75psi, at most about 50psi, at most about 40psi or at most about 30psi. In some embodiments, the roller gap of laminating machine can be at most about 1 inch, at most about 0.5 inch, at most about 0.25 inch, at most about 0.1 inch, at most about 0.075 inch or at most about 0.05 inch. In some embodiments, roller can not have gap (for example, roller is completely 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 an interlayer. In some embodiments, at least two layers can be pressed together so that the matrix of the two layers is on the outside (i.e., will contact the rollers of the laminator). In some embodiments, the matrix of the layer (e.g., release liner) contacts the rollers of the laminator. In some embodiments, the interlayer of the layers can be fed into the laminator (e.g., the rollers of the laminator) to form a laminated sheet.

[0102] Once leaving laminator, other layers can be added to laminated sheet.In some embodiments, depending on the overall layer structure required for drug delivery device, substrate can be removed from one side of laminated sheet and the process can be repeated.For example, if two layers are laminated together, substrate (for example, release liner) can be removed from one side of laminated sheet, and additional layers (for example, API, non-API layer) can be pressed together with the non-substrate side of laminated sheet to form another interlayer.In some embodiments, the new additional layers can be pressed together so that the substrate of the new layer is outside (that is, the roller of the contact laminator).In some embodiments, the substrate of the new layer (for example, release liner) and the substrate of the old laminated sheet can contact the roller of the laminator.Then the new layer interlayer can be fed to laminator to form a new laminated sheet.For multiple additional layers required in required layer structure / orientation / thickness, the process can be repeated.In some embodiments, once all layers have been added, remaining substrate can be removed from laminated sheet.

[0103] Any combination and / or any order of API and / or non-API layers can be created. In some embodiments, any combination and / or any order of API and / or non-API layers can be laminated together. In some embodiments, the drug delivery device 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, API / API / non-API / non-API, API / API / non-API / non-API, API / API / non-API / non-API, API / API / non-API / non-API, API / API / non-API, non-API / API / non-API, non-API / API / API / non-API constructions, etc. These API layers and / or non-API layers may have the composition of any API layer or non-API layer disclosed herein and be prepared by the same method as any API layer or non-API layer disclosed herein.

[0104] In some embodiments, laminated sheet can be cut into the size and / or shape required for drug delivery device.In some embodiments, laminated sheet can be cut when one or more substrates are still on laminated sheet.In some embodiments, the drug delivery device can be cut into circle, square, rectangle, ellipse, triangle, rhombus, polygon (for example, pentagon, hexagon, octagon, etc.), arc, trapezoid, star or various other shapes and sizes.In some embodiments, the drug delivery device can be cut into tubular, cylindrical, conical, pyramidal, triangular prism, cubic, spherical, rectangular prism or various other shapes and sizes.In some embodiments, the laminated sheet can be cut by die-cutting, manual cutting, laser cutting, manual punching, water jet cutting or similar types of cutting laminated sheet to form the main body of drug delivery device or drug delivery device.For example, a mold can be used to punch out the main body of drug delivery device or drug delivery device from laminated sheet. In some embodiments, the drug delivery film formed by solvent casting multiple layers in a mold and / or matrix can be cut into the size and / or shape required for the drug delivery device (i.e., if lamination is not used). In some embodiments, one or more layers can be cut into the desired size and / or shape before lamination. In some embodiments, lamination can occur after the layers are cut into the desired size and / or shape.

[0105] In some embodiments, the process of preparing API layers and / or non-API layers that adhere to each other can be repeated for additional layers and other API layers and non-API layers, other API layers, non-API layers, and / or other non-API layers that adhere to one side of the API layer. Any combination (see the above example combinations) and / or any order of API and / or non-API layers can be obtained by solvent casting methods. In addition, other components of the drug delivery device, such as a tip, can be created similarly to the creation of any layer discussed herein.

[0106] In some embodiments, the drug delivery device may include more than one API layer. 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 one of the API layers. For example, in some embodiments, the drug delivery device may include a second API layer on one side of the first API layer and a non-API layer on one side of the second API layer opposite to 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 the same as the second API layer. In some embodiments, the first API layer may degrade faster, slower, or the same as the non-API layer. In some embodiments, more than two API layers may exist 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 may have the same or different composition or the same or different API as another API layer. In addition, these additional layers can be added to the drug delivery device by the same method disclosed herein.

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

[0108] Because the drug delivery devices disclosed herein can be placed directly on and / or in and / or near a target tissue area using minimally invasive standard surgical techniques (e.g., open, laparoscopic, endoscopic, percutaneous, or robotic surgery), the drug delivery device should be flexible enough to be used with standard surgical equipment (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 3 mm to 12 mm (e.g., 3, 5, 8, 10, 12 mm trocars) and larger trocars.

[0109] In some embodiments, the drug delivery device can be inserted into the working channel of an endoscope or a robotic endoscope (e.g., a bronchoscope or a robotic bronchoscope). Once in the patient's body, the drug delivery device can be implanted in and / or near the target tissue site (e.g., a tumor) using standard or robotic surgical equipment. In some embodiments, the drug delivery device is placed or implanted in the target tissue so that it resides completely or partially in the target tissue (i.e., completely or partially embedded in the target tissue).

[0110] Solvent may be important because it allows layer (and whole device) to remain flexible and not crack during subsequent processing (e.g., lamination, cutting, implantation, etc.). In some embodiments, too much solvent may cause layer or device to adhere / adhere to itself or itself or other devices such as delivery tools (e.g., endoscope) at warm temperatures. In some embodiments, after removing from mold and / or substrate, or in some embodiments, when still in mold and / or on substrate, one or more layers (e.g., API layer, non-API layer) can be placed in an oven for additional drying. In some embodiments, after removing drug delivery film (e.g., multiple layers made by solvent casting on one another) from mold, or in some embodiments, when still in mold, drug delivery film can be placed in an oven for additional drying. In some embodiments, the layer laminated together can be placed in an oven for additional drying. In some embodiments, the layer laminated together and / or cut into the shape of a drug delivery device can be placed in an oven for additional drying. In some embodiments, this additional oven drying can harden the polymer in the layer. In some embodiments, the hardening can prevent drug separation in the API layer.

[0111] In some embodiments, a layer, multiple layers, drug delivery film, laminate, 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, at least about 75°C. In some embodiments, the layer, layers, drug delivery films, laminates, or drug delivery devices are placed in an oven at a temperature of 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, layers, drug delivery films, laminates, or drug delivery devices are 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, a layer, multiple layers, drug delivery film, laminate, or drug delivery device is placed in an oven for up to about 5 days, up to about 4 days, up to about 3 days, up to about 2 days, up to about 1 day, up to about 12 hours, up to about 10 hours, up to about 9 hours, up to about 5 hours, up to about 2 hours, or up to about 1 hour.

[0112] Therefore, a layer, a plurality of layers, a drug delivery film, a laminated sheet or a drug delivery device may have a solvent content of less than about 12wt.%, or about 1-15wt.%, about 2-12wt.%, about 3-11wt.%, or about 5-8wt.%. In some embodiments, the API layer of the drug delivery device may have at least about 1wt.%, at least about 2wt.%, at least about 3wt.%, at least about 3.5wt.%, at least about 5wt.%, at least about 6wt.%, at least about 7wt.%, at least about 8wt.%, or at least about 10wt.% solvent. In some embodiments, the API layer of the drug delivery device may have at most about 15wt.%, at most about 12wt.%, at most about 10wt.%, at most about 8wt.%, at most about 7wt.%, at most about 6wt.%, or at most about 5wt.% solvent. In some embodiments, the API layer of the drug delivery device may have about 1-15wt.%, about 2-12wt.%, about 3-11wt.%, about 3.5-10wt.%, or about 5-8wt.% solvent. In some embodiments, the non-API layer of the drug delivery device may have at least about 1wt.%, at least about 2wt.%, at least about 3wt.%, at least about 3.5wt.%, at least about 5wt.%, at least about 6wt.%, at least about 7wt.%, at least about 8wt.%, or at least about 10wt.% solvent. In some embodiments, the non-API layer of the drug delivery device may have at most about 15wt.%, at most about 12wt.%, at most about 11wt.%, at most about 10wt.%, at most about 8wt.%, at most about 7wt.%, at most about 6wt.%, or at most about 5wt.% 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.% 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, for example, by electron beam radiation. In addition, the drug delivery device can be sealed in a bag, such as a Tyvek bag, for sterilization and stored in a refrigerator. Azimuth indicator

[0114] As described above, in some embodiments, the drug delivery device may include anatomical landmarks. In some embodiments, the API layer and / or non-API layer may include anatomical landmarks. In some embodiments, anatomical landmarks may be adhered to, connected to, or within a drug delivery device. In some embodiments, anatomical landmarks may be adhered to, connected to, or within an API layer and / or non-API layer. In some embodiments, (one or more) anatomical landmarks may be adhered to, connected to, or within another component (e.g., the tip of a drug delivery device) or within another component (e.g., the tip of a drug delivery device). Doctors may use anatomical landmarks to identify drug delivery devices in patients using various imaging techniques. The physician may then monitor the progression and / or position of a drug delivery device relative to a tumor. In some embodiments, anatomical landmarks may be radiopaque landmarks, x-ray landmarks, lead landmarks, or similar landmarks. Implantation

[0115] In some embodiments, once the target tissue site (e.g., a 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, hands, grasping instruments, shafts attached through the working channel of an endoscope, and the like.

[0116] Failure to confirm proper implantation may result in the release of API to non-target sites. For example, if the drug delivery device is not fully embedded within the target tissue (e.g., a solid tumor), the portion of the device outside the target tissue may release API to non-target sites, which may be potentially harmful. Drug delivery device properties

[0117] In some embodiments, the drug delivery devices disclosed herein can be transparent and / or medium to light brown.The drug delivery device can have no visible foreign particulate matter on the surface or crevices. Figure 4A -C shows an image of a drug delivery device prepared herein where multiple layers are laminated together and die cut.

[0118] In some embodiments, the average thickness of the API and / or 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 and / or 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 and / or 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 kinetics. The average thickness can be measured by a micrometer, the average 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 0.1mm, at least about 0.5mm, at least about 0.75mm, at least about 1mm, at least about 1.25mm, at least about 1.5mm, at least about 1.75mm, at least about 2mm, at least about 2.5mm, or at least about 3mm. In some embodiments, the height of the drug delivery device can be at most about 10mm, at most about 5mm, at most about 4mm, at most about 3mm, at most about 2.5mm, at most about 2mm, at most about 1.75mm, at most about 1.5mm, at most about 1.25mm, or at most about 1mm. In some embodiments, the height of the drug delivery device is about 0.1-10mm, about 0.5-5mm, about 0.75-2.5mm, or about 1-2mm. 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 about 0.1-10 cm, about 0.5-5 cm, about 0.75-2.5 cm, or about 1-2 cm. In some embodiments, a ruler or similar measuring tool can be used to measure the length of the drug delivery device.

[0121] In some embodiments, the drug delivery device can be configured to release API according to a limited release kinetic curve. In some embodiments, after the device is implanted in the target tissue site and / or in the target tissue site, the release of API can be delayed (or only the API of the sub-therapeutic effective amount can be released during the delay period), so that the patient's body can recover from the implantation operation before releasing the drug. Delay can allow some healing at the implantation site before the API is released, thereby potentially reducing the risk 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 on all sides of the drug delivery device, so that when the patient heals from the implantation operation, the API will not be released. On the contrary, only the 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 up to 28 days, up to 25 days, up to 21 days, up to 18 days, up to 15 days, up to 14 days, up to 12 days, up to 10 days, up to 8 days, up to 7 days, up to 5 days or up to 3 days. In some embodiments, the API delayed release period can be 1-28 days, 1-21 days, 1-14 days or 7-14 days. After the delay period, the API can have a substantially linear or linear release rate.

[0122] In some embodiments, an API layer with PLGA 50:50 can begin releasing the API at the target tissue about 1 week after implantation, and the API can be completely released 4 weeks after implantation. This can be well consistent with the degradation data - polymer hydration takes time, but at 4 weeks, most of the PLGA 50:50 is gone, so most of the API will be released. In addition, the non-API layer made with PLGA75:25 can be used as a mechanism to maintain the structure, strength and / or support of the drug delivery device because it can degrade more slowly. This can help anchor 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, because the thicker the API layer, the longer the time required for degradation. In some embodiments, the API layer can be configured to be completely degraded within a time 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 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, at least 10 months after implantation. In some embodiments, the API layer can be configured to completely degrade within a time period of up to 2 years, up to 1 year, up to 10 months, up to 8 months, up to 6 months, up to 4 months, up to 3 months, up to 2 months, up to 10 weeks, up to 9 weeks, up to 8 weeks, up to 6 weeks, up to 5 weeks, up to 4.5 weeks, up to 30 days, up to 4 weeks, up to 3.5 weeks, up to 3 weeks, up to 2 weeks, or up to 1 week after implantation. In some embodiments, the API layer can be configured to completely degrade within a time period of about 3 days to 10 months, 1 week to 6 months, 1-6 weeks, about 2-6 weeks, about 3-5 weeks, about 3.5-4.5 weeks, or about 4 weeks (about 30 days) after implantation. "Complete degradation" or "thorough degradation" as used herein refers to a layer or device that degrades to less than 10% of the original mass within the time 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 0.01-10 mg / day, about 0.1-10 mg / day, about 0.1-5 mg / day, about 0.1-3 mg / day, about 0.1-1 mg / day, about 1-5 mg / day, about 2-5 mg / day, or about 3-4 mg / day after implantation. In some embodiments, the API can be released from the API layer after implantation at a rate of about 0.5-70 mg / week, about 0.5-35 mg / week, about 0.5-20 mg / week, about 0.5-10 mg / week, about 0.5-5 mg / week, about 0.5-1 mg / week, about 7-70 mg / week, about 7-35 mg / week, about 14-35 mg / week, or about 21-28 mg / week.In some embodiments, the degradation curve (and API release curve) of the API layer after implantation may include a delay period of about 1 day to 2 weeks. After the delay period, the degradation (and API release) of the API layer may be substantially linear or linear. In some embodiments, the outer layer (e.g., Figures 1A-1C Layers 101 and 105 ) of the drug delivery device may degrade at a faster rate than the inner layers (eg, layers 102 , 103 , 104 ) of the drug delivery device because more surface area of ​​these layers is exposed to the degradation environment.

[0124] Drug release (i.e., API release) of the drug delivery device disclosed herein is tested in vitro. Specifically, a drug delivery device containing four layers of about 0.7g PLGA 50:50, 100mg paclitaxel and 4mg acetone is prepared, and the drug release rate is tested. All four layers are produced separately, and then the drug delivery device is laminated together one layer at a time. The laminated sheet is punched to form a drug delivery device of about 1.5mm thickness, about 1.25mm width and about 2cm length. The drug delivery device is prepared so that 6 products can be used for testing at each time point (1, 2, 3, 4 and 6 weeks). Each sample is placed in a scintillation vial with 20mL 1.75M sodium salicylate (release solution). The sample is kept in a water bath at 37C until their time point. Once pulled, the release solution is discarded, and the sample is completely dissolved in acetonitrile. Paclitaxel is measured on HPLC to determine the remaining drug content, which is used to determine the amount of the released drug. Samples are taken at the 1st, 2, 4, 6 and 8 weeks. Figure 5 The total percentage of drug released from the drug delivery device over time is shown. The results show that the API release is delayed for 1-2 weeks, followed by a stable linear release until the 8th week.

[0125] In addition, 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 toward 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 all sides of the drug delivery device. This non-API layer / coating can degrade faster than the API layer, so that there may be a delayed API release period due to the non-API layer / coating being degraded first.

[0126] In some embodiments, the non-API layer can be configured to completely degrade within a time period of 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 degrade within a time period of up to 3 years, up to 2 years, up to 1 year, up to 10 months, up to 8 months, up to 6 months, up to 4 months, up to 3 months, up to 12 weeks, up to 11 weeks, up to 10 weeks, up to 8 weeks, up to 6 weeks, up to 5 weeks, up to 4 weeks, up to 3 weeks, or up to 2 weeks after implantation. In some embodiments, the non-API layer can be configured to completely degrade within a time period of about 1 week to 2 years, 1 week to 1 year, 1 week to 6 months, about 4-14 weeks, about 6-12 weeks, about 8-12 weeks, about 9-11 weeks, or about 10 weeks after implantation. Cancer treatment

[0127] In some embodiments, the target tissue can be tissue associated with various organs of the whole body, including but not limited to pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon or metastasis from primary tumor. For example, the target tissue can be cancerous tissue / cell (e.g., one or more tumors) on pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon or metastasis from primary tumor. Therefore, the drug delivery device disclosed herein can be used to treat a variety of diseases, including tumors of various organs of the whole body (including pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, colon) or metastasis from primary tumor. Specifically, the drug delivery device can help treat various cancers including but 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 cancer and / or unresectable cancer. In some embodiments, the drug delivery device herein can be used to treat non-metastatic cancers that cannot be removed immediately. In some embodiments, the drug delivery device can be used to treat patients after resection of cancer to prevent recurrence. For example, the drug delivery device can be used to treat patients with border resectable or locally advanced pancreatic cancer or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancer treated by the drug delivery device can be a tumor in the tissue of the primary source or a tumor that metastasizes to the tissue. In some embodiments, the drug delivery device can be used to treat patients with cancer that cannot be removed immediately, non-metastatic cancer, marginal resectable cancer, resectable cancer, locally advanced cancer, metastatic cancer and / or metastasis from primary tumors.

[0128] In some embodiments, the drug delivery device disclosed herein can be placed in a tumor of interest and / or adjacent to a tumor of interest (i.e., intratumorally), and can be implanted in about 1 week to 2 years, about 1-52 weeks, about 1-26 weeks, about 1-24 weeks, about 1-20 weeks, about 1-15 weeks, about 4-12 weeks, about 6-12 weeks, about 8-12 weeks, about 9-11 weeks or about 10 weeks in the patient's body. Biodegradable. In some embodiments, the tumor can be inside an organ (i.e., not on the surface), and the drug delivery device is placed in the tumor. As described above, during the routine staging assessment, minimally invasive standard surgical techniques can be used to place the drug delivery device directly in the tumor and / or adjacent to the tumor. In some embodiments, multiple drug delivery devices can be placed directly in the target tissue and / or adjacent to the target tissue (e.g., simultaneously and / or in series after a drug delivery device has completed degradation). In some embodiments, the drug delivery device can be inserted into the working channel of an endoscope, guided to the tumor of interest, and inserted into the tumor of interest and / or adjacent to the tumor of interest.

[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 up to 2 years, up to 1 year, up to 10 months, up to 8 months, up to 6 months, up to 4 months, up to 3 months, up to 2 months, up to 6 weeks, up to 5 weeks, up to 4.5 weeks, up to 30 days, up to 4 weeks, up to 3.5 weeks, up to 3 weeks, up to 2 weeks, or up to 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, 1-6 weeks, about 2-6 weeks, about 3-5 weeks, about 3.5-4.5 weeks, or about 4 weeks (about 30 days) after implantation. In some embodiments, the biodegradable polymer in the API layer can provide controlled and sustained release of the API during the period, during which the cancer-facing side of the device is absorbed into the body. In some embodiments, the non-API layer of the device and / or tip can help ensure that the drug delivery device remains in contact with the target tissue (e.g., a tumor) during drug release, and can help prevent the drug delivery device from leaving the area of ​​interest or being released from the area of ​​interest. Then, after the API layer is completely degraded and the entire API is released, the non-API layer and / or tip can be completely degraded. In some embodiments, the non-API layer can be completely degraded at the same time or faster than the API layer.

[0130] In some embodiments, the drug delivery device disclosed herein can stabilize and / or reduce the size of the tumor after implantation on the tumor. In some embodiments, the reduction in tumor size, the reduction in tumor volume, the reduction in the maximum size of the tumor, and / or the reduction in the front / rear diameter orthogonal to the drug delivery device can be after the drug delivery device has been completely dissolved in the patient, after the drug delivery device has been partially dissolved in the patient, and / or after a portion of the drug delivery device (e.g., an API layer) has been completely dissolved in the patient.

[0131] In some embodiments, drug delivery devices and methods disclosed herein can be used together with systemic chemotherapy, radiotherapy and / or surgery. In some embodiments, drug delivery devices and methods disclosed herein can improve the tumor penetration of systemic chemotherapy in patients. In some embodiments, systemic chemotherapy can be applied (or started) after implantation of drug delivery device (for example, two weeks, 3 weeks, 4 weeks, etc. after implantation). In some embodiments, systemic chemotherapy can be applied (or started) 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 one year after implantation of drug delivery device.

[0132] The drug delivery device disclosed herein can change the route of administration to target only the area of ​​interest, thereby increasing the amount of drug that reaches the tumor, with the goal of enhancing the therapeutic efficacy. Therefore, the drug delivery device can be applied to patients with lung cancer (and other cancers): (i) preoperatively as a neoadjuvant therapy to control progression and reduce size to improve resectability and / or clinical benefits (i.e., ease of breathing, pain relief); (ii) post-resection to reduce local recurrence rates; or (iii) to control local progression and improve quality of life in metastatic patients. Other definitions

[0133] Unless otherwise defined, all technical terms, symbols and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ease of reference, and the inclusion of such definitions herein should not be construed as representing a substantial difference from what is generally understood in the art.

[0134] Reference herein to "about" a value or parameter includes (and describes) variations for the value or parameter itself. For example, a description referring to "about X" includes a description of "X". In addition, references to phrases "less than," "greater than," "at most," "at least," "less than or equal to," "greater than or equal to," or other similar phrases followed by a string of values ​​or parameters are intended to apply the phrases to each value or parameter in the string of values ​​or parameters. For example, a statement 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] Unless the context clearly indicates otherwise, the singular forms "a", "an" and "the" as used herein are intended to include the plural forms as well. It should also be understood that the term "and / or" used herein refers to and encompasses any and all possible combinations of one or more of the relevant listed items. It should also be understood that when used herein, the terms "include" and / or "comprise" specify the presence of stated features, integers, steps, operations, elements, components and / or units, but do not exclude 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" is a method of obtaining a beneficial or desired result (including a clinical result). For the purposes of the present invention, a beneficial or desired clinical result includes, but is not limited to, one or more of the following: alleviating one or more symptoms caused by the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the deterioration of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, improving the disease state, providing relief (partial or complete) of the disease, reducing the dosage of one or more other drugs required to treat the disease, delaying the progression of the disease, improving the quality of life and / or prolonging survival. "Treatment" also includes reducing the pathological consequences of cancer. The method of the present invention contemplates any one or more of these treatment aspects.

[0137] This application discloses several numerical ranges in the text and drawings. The disclosed numerical ranges inherently support any range or value within the disclosed numerical ranges, including endpoints, even if the precise range limitations are not stated verbatim in the specification, because the present disclosure can be practiced throughout the disclosed numerical ranges.

[0138] The above description is to enable those skilled in the art to make and use the present disclosure, and is provided in the context of a specific application and its requirements. Various modifications to the preferred embodiments will be 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. Therefore, the present disclosure is not intended to be limited to the embodiments shown, but rather to the widest scope consistent with the principles and features disclosed herein.

Claims

1. A drug delivery device comprising: A body comprising a plurality of layers, wherein the plurality of layers comprises at least one first layer comprising an active pharmaceutical ingredient (API) and a biodegradable polymer, Wherein the drug delivery device is configured to be inserted into a target tissue site of a patient.

2. The drug delivery device of claim 1, further comprising a tip connected or integrated to the distal end of the body of the drug delivery device.

3. The drug delivery device of claim 2, wherein the drug delivery device is configured to be inserted tip first into a target tissue site of a patient.

4. The drug delivery device according to any one of claims 1-3, wherein the target tissue site is a tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung or colon.

5. The drug delivery device according to any one of claims 1-4, wherein the biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA).

6. The drug delivery device of claim 5, wherein the biodegradable polymer is PLGA 50:

50.

7. The drug delivery device according to any one of claims 1 to 6, wherein the at least one first layer comprises 1-15 wt.% API.

8. The drug delivery device according to any one of claims 1-7, wherein the at least one first layer comprises a solvent.

9. The drug delivery device according to claim 8, wherein the at least one first layer comprises 1-15 wt.% solvent.

10. The drug delivery device of claim 9, wherein the solvent is acetone.

11. The drug delivery device according to any one of claims 1-10, wherein the plurality of layers comprises at least one second layer comprising a second biodegradable polymer, wherein the second biodegradable polymer has a slower degradation rate than the first biodegradable polymer.

12. The drug delivery device of claim 11, wherein the second biodegradable polymer is PLGA75:

25.

13. The drug delivery device according to any one of claims 1-12, wherein the plurality of layers comprises at least one third layer comprising a second API and a third biodegradable polymer.

14. The drug delivery device according to any one of claims 1-13, wherein the plurality of layers comprises at least one fourth layer comprising a third API and a fourth biodegradable polymer.

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

16. The drug delivery device of any one of claims 1-15, wherein the drug delivery device is configured to be implanted in a patient using standard open and / or minimally invasive surgery.

17. The drug delivery device of any one of claims 1-16, wherein the drug delivery device is configured to be inserted into a target tissue site of a patient using a bronchoscope, forceps, trocar, or needle.

18. The drug delivery device of any one of claims 1-17, wherein the drug delivery device is configured to be robotically inserted into a target tissue site of a patient.

19. The drug delivery device of any one of claims 1-18, wherein the at least one first layer is configured to release the API when inserted into a target tissue site of a patient.

20. The drug delivery device of claim 19, wherein the at least one first layer is configured to release the API multi-directionally when inserted into a target tissue site of a patient.

21. The drug delivery device according to any one of claims 19-20, wherein the release of the API is controlled by in vivo degradation of the biodegradable polymer in the target tissue site.

22. The drug delivery device of any one of claims 2-21, wherein the tip comprises a fifth biodegradable polymer having a slower degradation rate than the first biodegradable polymer.

23. The drug delivery device of claim 22, wherein the tip comprises PLGA 75:

25.

24. The drug delivery device of any one of claims 2-23, wherein the tip comprises a tissue retaining mechanism.

25. The drug delivery device of claim 24, wherein the tissue retaining mechanism is configured to retain the drug delivery device in a target tissue of a patient when the drug delivery device is inserted into the target tissue.

26. The drug delivery device of claim 25, wherein the tissue retaining mechanism extends outwardly from the tip.

27. The drug delivery device of claim 26, wherein the tissue retaining mechanism comprises barbs and / or edges.

28. The drug delivery device of any one of claims 2-27, wherein the tip has at least one apex at its distal end.

29. The drug delivery device of any one of claims 1-28, wherein the body includes a breakaway mechanism toward a proximal end of the body.

30. The drug delivery device of claim 29, wherein a flexible shaft is connected to the proximal end of the body.

31. The drug delivery device of claim 30, wherein the detachment mechanism is configured to detach the drug delivery device from the flexible shaft.

32. The drug delivery device according to any one of claims 30-31, wherein the disengagement mechanism is configured to disengage the drug delivery device from the flexible shaft by twisting.

33. A method of preparing a drug delivery device, the method comprising: adding a first solution comprising a first biodegradable polymer, an active pharmaceutical ingredient (API), and a solvent to the first matrix; 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 the second matrix; drying the second solution on the second substrate to form a second layer; The first layer and the second layer are laminated together to form a laminated sheet.

34. The method of claim 33, cutting the laminated sheet to form a body of a drug delivery device.

35. The method of claim 34, wherein the cutting is die cutting.

36. The method of any one of claims 33-35, wherein the second solution comprises a second API.

37. The method of claim 34, wherein the first API and the second API are the same.

38. The method according to any one of claims 33 to 37, further comprising: adding a third solution comprising a third biodegradable polymer and a third solvent to the third matrix; drying the third solution on the third substrate to form a third layer; The third layer is laminated to the laminated sheet to form a second laminated sheet.

39. The method of claim 38, wherein the third solution comprises a third API.

40. The method according to any one of claims 33-39, further comprising: spreading the first solution on the first substrate using a film applicator; and The second solution is spread on the second substrate using a film applicator.

41. The method of claim 40, wherein the spread first solution and the spread second solution have a desired thickness according to the film coater.

42. The method of any one of claims 33-41, wherein the first substrate and / or the second substrate comprises a release liner.

43. The method of any one of claims 33-42, further comprising heating the first layer and the second layer in an oven after drying the first solution and the second solution.

44. The method of any one of claims 34-43, attaching a tip to the distal end of the body of the drug delivery device.

45. A method of treating tissue in a patient, the method comprising: A drug delivery device is implanted into a target tissue site of a patient, the drug delivery device comprising: a body comprising a plurality of layers, wherein the plurality of layers comprises at least one first layer comprising an active pharmaceutical ingredient (API) and a biodegradable polymer; and The API is released from the at least one first layer in the target tissue site, wherein the release of the API is controlled by in vivo degradation of the biodegradable polymer in the target tissue site.

46. ​​The method of claim 45, wherein the drug delivery device comprises a tip connected to a distal end of the drug delivery device.

47. The method of claim 46, wherein the drug delivery device tip is first implanted into a target tissue site in a patient.

48. The method of any one of claims 45-47, wherein the target tissue site is a tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon.

49. The method of any one of claims 45-48, wherein the drug delivery device is implanted via open surgery, laparoscopy, percutaneous, robotic, or endoscopy.

50. The method of claim 49, wherein the drug delivery device is implanted via a bronchoscope.

51. The method of any one of claims 45-50, wherein releasing the API from the at least one first layer comprises releasing the API in a plurality of directions away from a drug delivery device.

52. The method of any one of claims 46-51, wherein the drug delivery device is implanted in a target tissue site of a patient such that the tip is configured to retain the drug delivery device in the target tissue.

53. The method of any one of claims 45-52, wherein implanting the drug delivery device comprises using a tool to deliver the drug delivery device to the target tissue site of the patient.

54. The method of claim 53, wherein the tool comprises a flexible shaft and is connected to a proximal end of the body of the drug delivery device.

55. The method of claim 54, wherein implanting the drug delivery device into a target tissue site comprises detaching the body of the drug delivery device from the flexible shaft.

56. The method of claim 55, wherein decoupling the drug delivery device from the flexible shaft comprises twisting the flexible shaft relative to the drug delivery device.

57. The method of any one of claims 45-56, wherein the body of the drug delivery device comprises an anatomical landmark, and implanting the drug delivery device into a target tissue site of a patient comprises monitoring a position of the anatomical landmark.

58. A drug delivery device comprising: A subject, the subject comprising: a core comprising a first biodegradable polymer; and an outer layer surrounding at least a portion of the core, the outer layer comprising an active pharmaceutical 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 is connected or integrated to the distal end of the body.

59. The drug delivery device of claim 58, wherein the drug delivery device is configured to be inserted into a target tissue site of a patient.

60. The drug delivery device of claim 59, wherein the drug delivery device is configured for tip first insertion into a target tissue site of a patient.

61. The drug delivery device of any one of claims 59-60, wherein the target tissue site is a tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon.

62. The drug delivery device of any one of claims 58-61, wherein the first biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA).

63. The drug delivery device of claim 62, wherein the first biodegradable polymer is PLGA 75:

25.

64. The drug delivery device of any one of claims 58-63, wherein the second biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA).

65. The drug delivery device of claim 64, wherein the second biodegradable polymer is PLGA 50:

50.

66. The drug delivery device of any one of claims 58-65, wherein the drug delivery device is configured to be implanted in a patient using standard open and minimally invasive surgery.

67. The drug delivery device of any one of claims 58-66, wherein the drug delivery device is configured to be inserted into a target tissue site of a patient using a bronchoscope.

68. The drug delivery device of any one of claims 58-67, wherein the drug delivery device is configured to be robotically inserted into a target tissue site of a patient.

69. The drug delivery device of any one of claims 58-68, wherein the outer layer is configured to release the API when inserted into a target tissue site of a patient.

70. The drug delivery device of claim 69, wherein the outer layer is configured to release the API omnidirectionally when inserted into a target tissue site of a patient.

71. The drug delivery device according to any one of claims 69-70, wherein the release of the API is controlled by in vivo degradation of the second biodegradable polymer in the target tissue site.

72. The drug delivery device of any one of claims 58-71, wherein the body further comprises a second outer layer surrounding at least a portion of the first outer layer and comprising a third biodegradable polymer, wherein the third biodegradable polymer has a faster degradation rate than the second and / or first biodegradable polymers.

73. The drug delivery device of claim 72, wherein the third biodegradable polymer is PLGA.

74. The drug delivery device of any one of claims 58-73, wherein the tip comprises a third biodegradable polymer having a slower degradation rate than the second biodegradable polymer.

75. The drug delivery device of claim 74, wherein the tip comprises PLGA 75:

25.

76. The drug delivery device of any one of claims 58-75, wherein the tip comprises a tissue retaining mechanism.

77. The drug delivery device of claim 76, wherein the tissue retention mechanism is configured to retain the drug delivery device in a target tissue of a patient when the drug delivery device is inserted into the target tissue.

78. The drug delivery device of claim 77, wherein the tissue retaining mechanism extends outwardly from the tip.

79. The drug delivery device of claim 78, wherein the tissue retention mechanism comprises barbs and / or edges.

80. The drug delivery device of any one of claims 58-79, wherein the tip has at least one apex at its distal end.

81. The drug delivery device of any one of claims 58-80, wherein the body includes a breakaway mechanism toward a proximal end of the body.

82. The drug delivery device of claim 81, wherein a flexible shaft is connected to the proximal end of the body.

83. The drug delivery device of claim 82, wherein the detachment mechanism is configured to detach the drug delivery device from the flexible shaft.

84. The drug delivery device of any one of claims 82-83, wherein the detachment mechanism is configured to detach the drug delivery device from the flexible shaft by twisting.

85. A drug delivery device comprising: a core comprising a first biodegradable polymer; and An outer layer surrounds at least a portion of the core, the outer layer comprising an active pharmaceutical ingredient (API) and a second biodegradable polymer, wherein the first biodegradable polymer has a slower degradation rate than the second biodegradable polymer.

86. The drug delivery device of claim 85, wherein the drug delivery device is configured to be inserted into a target tissue site of a patient.

87. The drug delivery device of claim 86, wherein the target tissue site is a solid tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon.

88. The drug delivery device of any one of claims 85-87, wherein the first biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA).

89. The drug delivery device of claim 88, wherein the first biodegradable polymer is PLGA75:

25.

90. The drug delivery device of any one of claims 85-89, wherein the second biodegradable polymer is poly(lactic-co-glycolic acid) (PLGA).

91. The drug delivery device of claim 90, wherein the second biodegradable polymer is PLGA 50:

50.

92. The drug delivery device of any one of claims 85-91, wherein the drug delivery device is configured to be implanted in a patient using standard open and minimally invasive surgery.

93. The drug delivery device of any one of claims 85-92, wherein the drug delivery device is configured to be inserted into a target tissue site of a patient using a bronchoscope.

94. The drug delivery device of any one of claims 85-93, wherein the drug delivery device is configured to be robotically inserted into a target tissue site of a patient.

95. The drug delivery device of any one of claims 85-94, wherein the outer layer is configured to release the API when inserted into a target tissue site of a patient.

96. The drug delivery device of claim 95, wherein the outer layer is configured to release the API omnidirectionally when inserted into a target tissue site of a patient.

97. The drug delivery device according to any one of claims 95-96, wherein the release of the API is controlled by in vivo degradation of the second biodegradable polymer in the target tissue site.

98. A method of treating tissue in a patient, the method comprising: A drug delivery device is implanted into a target tissue site of a patient, the drug delivery device comprising: A subject, the subject comprising: a core comprising a first biodegradable polymer; and an outer layer surrounding at least a portion of the core, the outer layer comprising an active pharmaceutical 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 to the distal end of the body; and The API is released from the outer layer in the target tissue site, wherein the release of the API is controlled by in vivo degradation of the second biodegradable polymer in the target tissue site.

99. The method of claim 98, wherein the drug delivery device tip is first implanted into a target tissue site in a patient.

100. The method of any one of claims 98-99, wherein the target tissue site is a tumor of the pancreas, biliary system, gallbladder, esophageal system, liver, stomach, peritoneum, small intestine, lung, or colon.

101. The method of any one of claims 98-100, wherein the drug delivery device is implanted via open surgery, laparoscopy, robotics, percutaneously, or endoscopically.

102. The method of claim 101, wherein the drug delivery device is implanted via bronchoscope.

103. The method of any one of claims 98-102, wherein releasing the API from the outer layer comprises releasing the API in all directions away from the outer layer.

104. The method of any one of claims 98-103, wherein the drug delivery device is implanted in a target tissue site of a patient such that the tip is configured to retain the drug delivery device in the target tissue.

105. The method of any one of claims 98-104, wherein implanting the drug delivery device comprises using a tool to deliver the drug delivery device to the target tissue site of the patient.

106. The method of claim 105, wherein the tool comprises a flexible shaft and is connected to the proximal end of the body.

107. The method of claim 106, wherein implanting the drug delivery device into a target tissue site comprises detaching the body of the drug delivery device from the flexible shaft.

108. The method of claim 107, wherein decoupling the drug delivery device from the flexible shaft comprises twisting the flexible shaft relative to the drug delivery device.

109. The method of any one of claims 45-57, wherein release of the API is after a delay period following implantation.

110. The method of claim 109, wherein a subtherapeutically effective amount of the API is released during the delay period.

111. The method of any one of claims 109-110, wherein after the delay period, the API is released at a substantially linear or linear release rate.

112. The drug delivery device of any one of claims 1-32, wherein the body of the drug delivery device is flexible.

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