How to Treat Pancreatic Cancer

Abstract

An implantable, biodegradable drug delivery device capable of delivering an active pharmaceutical ingredient (API) directly to a target pancreatic tumor tissue is provided. The drug delivery device can include at least two layers. One of the layers can include the API and a biodegradable polymer, and the second layer can include another biodegradable polymer that degrades more slowly than the first biodegradable polymer. When the device is placed directly on the target tissue, the API layer degrades, thereby releasing the API toward the target tissue, while the non-API layer can prevent the release of the API into non-target tissue away from the target tissue.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 384,145, filed November 17, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to an implantable drug delivery device for treating pancreatic cancer. Specifically, the present invention relates to an implantable, biodegradable drug delivery device that delivers an active pharmaceutical ingredient to the local site of pancreatic cancer. [Background technology]

[0003] The majority of research in the field of oncology is based on new ways to use or package existing systemic chemotherapies. In other words, most researchers are testing chemotherapies approved for other cancers or new intravenous delivery methods, such as liposomes. However, a major limitation in the effectiveness of existing chemotherapies is systemic off-target toxicity. For example, only 1–5% of a systemically administered chemotherapy dose actually reaches the tumor site. In fact, even some of the most promising chemotherapies currently available are poorly tolerated in the long term by most patients. Summary of the Invention

[0004] Applicant has discovered implantable, biodegradable drug delivery devices capable of delivering active pharmaceutical ingredients (APIs) directly to target tissues in patients. Because the drug delivery devices disclosed herein utilize a localized delivery method, these devices can avoid the problem of systemic side effects, and their biodegradable nature can provide more direct, site-specific treatment without the need for subsequent surgical removal. Specifically, the drug devices disclosed herein can be flexibly applied via open and minimally invasive surgery, enable unidirectional, multidirectional, or omnidirectional delivery of APIs through multi-layered configurations, act as a barrier against tumor ingrowth, prevent systemic drug leakage, and offer tunable release profiles and degradation rates, and / or designs tailored to accommodate solid tumors.

[0005] The drug delivery device can be flexible so that it can be placed on a patient's target tissue (e.g., a peritumoral area of ​​an organ) using standard open surgery, laparoscopic surgery, endoscopic surgery, percutaneous surgery, or robotic surgical equipment. In addition, a flexible drug delivery device can flexibly conform to the shape of the underlying target tissue site. In some embodiments, multiple drug delivery devices can be placed on a patient's target tissue. In some embodiments, a second drug delivery device can be placed on a patient's target tissue after a first drug delivery device has already been degraded.

[0006] Specifically, the drug delivery devices disclosed herein can include at least two layers. One of the layers can include an API and a biodegradable polymer, and the second layer can include another biodegradable polymer that degrades more slowly than the first biodegradable polymer. When the device is placed directly on tissue (i.e., with the API layer facing the tissue), the API layer can degrade, thereby releasing the API toward the target tissue. In some embodiments, the non-API layer can prevent the release of the API onto non-target tissue away from the target tissue. In some embodiments, the non-API layer can prevent the drug delivery device from detaching from the target tissue (i.e., the non-API layer can hold the drug delivery device in place).

[0007] In some embodiments, the second layer can degrade more slowly than the first layer, so that the second layer can continue to prevent release of the API away from the target tissue and / or continue to hold the drug delivery device at the target tissue site. In this manner, the second layer may not be fully degraded until the drug is fully released. Thus, the drug delivery device can be inserted into a patient to target specific tissues without the need for subsequent surgery to remove the device, as it will be fully or largely absorbed by the patient's body.

[0008] The drug delivery devices disclosed herein enable clinically relevant delivery of APIs directly to tissues (e.g., tumors) with good tolerability and minimal systemic exposure of the API. The devices can be used as neoadjuvant (and / or adjuvant) therapy for the treatment of cancer, improving complete resection rates, reducing the risk of local recurrence, and / or improving patient survival.

[0009] In some embodiments, a method of treating pancreatic cancer comprises implanting a drug delivery device in a peritumor area of ​​the patient's pancreas, wherein the drug delivery device comprises a first layer comprising an API, a solvent, and at least 70% by weight of a first biodegradable polymer, and a second layer on one side of the first layer comprising a solvent and at least 85% by weight of a second biodegradable polymer, and further comprising releasing the API from the drug delivery device into the pancreatic tumor by in vivo degradation of the first biodegradable polymer, wherein the tumor reduces in size after implantation of the drug delivery device.

[0010] In some embodiments, a method of stabilizing pancreatic cancer comprises implanting a drug delivery device in a peritumor area of ​​the patient's pancreas, wherein the drug delivery device comprises a first layer comprising an API, a solvent, and at least 70% by weight of a first biodegradable polymer, and a second layer on one side of the first layer comprising a solvent and at least 85% by weight of a second biodegradable polymer, and further comprising releasing the API from the drug delivery device into the pancreatic tumor by in vivo degradation of the first biodegradable polymer, wherein the tumor volume, largest dimension of the tumor, and / or anterior / posterior diameter of the tumor perpendicular to the drug delivery device change by ±10% following implantation of the drug delivery device.

[0011] In some embodiments, the volume of the tumor decreases by at least 10% after implantation of the drug delivery device. In some embodiments, the volume of the tumor decreases by at least 40% after implantation of the drug delivery device. In some embodiments, the volume of the tumor decreases by at least 70% after implantation of the drug delivery device. In some embodiments, the largest dimension of the tumor decreases by 11% after implantation of the drug delivery device. In some embodiments, the largest dimension of the tumor decreases by at least 50% after implantation of the drug delivery device. In some embodiments, the anterior / posterior diameter of the tumor perpendicular to the drug delivery device on the tumor decreases by 15% after implantation of the drug delivery device. In some embodiments, the anterior / posterior diameter of the tumor perpendicular to the drug delivery device on the tumor decreases by at least 25% after implantation of the drug delivery device. In some embodiments, the anterior / posterior diameter is in the direction of API release from the drug delivery device. In some embodiments, both methods include administering systemic chemotherapy after implantation of the drug delivery device. In some embodiments, the drug delivery device improves penetration of the systemic chemotherapy into the tumor. In some embodiments, the clinical outcome after implantation of the drug delivery device is a RECIST partial response, a RECIST complete response, or RECIST stable disease. In some embodiments, no API is found in the patient's blood during treatment for pancreatic cancer. In some embodiments, the tumor is pancreatic ductal adenocarcinoma. In some embodiments, the drug delivery device improves the patient's quality of life. In some embodiments, the drug delivery device reduces the patient's pain. In some embodiments, the drug delivery device locally controls pancreatic cancer. In some embodiments, the drug delivery device extends the patient's progression-free survival (PFS). In some embodiments, the drug delivery device converts an unresectable tumor to a resectable tumor. In some embodiments, the drug delivery device improves the resection rate of pancreatic cancer in a patient. In some embodiments, the drug delivery device downstages pancreatic cancer. In some embodiments, the drug delivery device extends the patient's overall survival.In some embodiments, the drug delivery device reduces the patient's risk of metastasis. In some embodiments, the drug delivery device prevents metastasis in the patient. In some embodiments, two weeks after implantation of the drug delivery device, the tumor volume decreases by at least 5%. In some embodiments, two weeks after implantation of the drug delivery device, the tumor's greatest dimension decreases by at least 3%. In some embodiments, two weeks after implantation of the drug delivery device, the tumor's anterior / posterior diameter perpendicular to the drug delivery device decreases by at least 5%. In some embodiments, two weeks after implantation of the drug delivery device, the amount of CA19-9 protein in the patient's blood decreases by at least 20%. In some embodiments, any method includes administering systemic chemotherapy at least one week after implantation of the drug delivery device. In some embodiments, the tumor volume, greatest dimension, or anterior / posterior diameter of the tumor perpendicular to the drug delivery device changes by ±10% after implantation of the drug delivery device. In some embodiments, the tumor volume, greatest dimension, or anterior / posterior diameter of the tumor perpendicular to the drug delivery device changes by ±5% after implantation of the drug delivery device. In some embodiments, the first layer comprises 7.5-11% by weight of the API. In some embodiments, the API is paclitaxel. In some embodiments, the solvent comprises acetone, and the first layer comprises 3-11% by weight of acetone. In some embodiments, the second layer comprises 3-11% by weight of acetone. In some embodiments, the first biodegradable polymer comprises poly(lactic-co-glycolic acid) (PLGA) 50:50, and the second biodegradable polymer comprises PLGA 75:25. In some embodiments, the pancreatic cancer is immediately unresectable pancreatic cancer, non-metastatic pancreatic cancer, borderline resectable pancreatic cancer, resectable pancreatic cancer, locally advanced pancreatic cancer, metastatic pancreatic cancer, or metastatic spread to the pancreas.

[0012] Further advantages will be readily apparent to those skilled in the art from the following detailed description. The examples and descriptions herein should be considered as illustrative in nature and not as restrictive.

[0013] All publications, including patent documents, scientific articles, and databases, referenced in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication was individually incorporated by reference. To the extent that a definition set forth herein contradicts or is inconsistent with a definition set forth in a patent, application, published application, or other publication incorporated herein by reference, the definition set forth herein shall take precedence over the definition incorporated herein by reference. [Brief explanation of the drawings]

[0014] The present invention will now be described, by way of example only, with reference to the accompanying drawings.

[0015] [Figure 1] 1 illustrates a drug delivery device according to some embodiments disclosed herein.

[0016] [Figure 2] 1 shows an image of a drug delivery device showing a portion of a non-API layer extending beyond an API layer of some embodiments disclosed herein.

[0017] [Figure 3A] 1 shows an image of Film 1 disclosed herein before oven testing.

[0018] [Figure 3B] 1 shows an image of Film 1 disclosed herein prepared for oven testing.

[0019] [Figure 3C] 1 shows an image of Film 1 disclosed herein after 20 minutes in a 45° C. oven test.

[0020] [Figure 4A] 1 shows an image of Film 2 disclosed herein before oven testing.

[0021] [Figure 4B]1 shows an image of Film 2 disclosed herein prepared for oven testing.

[0022] [Figure 4C] 1 shows an image of Film 2 disclosed herein after 20 minutes in a 42° C. oven test.

[0023] [Figure 5A] 1 shows an image of Film 3 disclosed herein before oven testing.

[0024] [Figure 5B] 1 shows an image of Film 3 disclosed herein prepared for oven testing.

[0025] [Figure 5C] 1 shows an image of Film 3 disclosed herein after 20 minutes in a 37° C. oven test.

[0026] [Figure 6A] 1 shows an image of Film 4 disclosed herein before oven testing.

[0027] [Figure 6B] 1 shows an image of Film 4 disclosed herein prepared for oven testing.

[0028] [Figure 6C] 1 shows an image of Film 4 disclosed herein after 20 minutes of room temperature testing.

[0029] [Figure 7A] 1 shows an image of Film 5 disclosed herein before oven testing.

[0030] [Figure 7B] 1 shows an image of a film 5 disclosed herein prepared for oven testing.

[0031] [Figure 7C]1 shows an image of Film 5 disclosed herein after 20 minutes in a 40° C. oven test.

[0032] [Figure 8A] 1 shows an image of Film 6 disclosed herein before oven testing.

[0033] [Figure 8B] 1 shows an image of a film 6 disclosed herein prepared for oven testing.

[0034] [Figure 8C] 1 shows an image of Film 6 disclosed herein after 20 minutes in a 40° C. oven test.

[0035] [Figure 9A] 1 shows an image of Film 6 disclosed herein prepared for a second oven test.

[0036] [Figure 9B] 1 shows an image of Film 6 disclosed herein after 20 minutes at 42° C. in a second oven test.

[0037] [Figure 10A] 1 shows an image of Film 6 disclosed herein prepared for a third oven test.

[0038] [Figure 10B] 1 shows an image of Film 6 disclosed herein after 20 minutes at 45° C. in the third oven test.

[0039] [Figure 11A] 1 shows an image of a drug delivery device illustrating an orientation identifier of some embodiments disclosed herein.

[0040] [Figure 11B]1 illustrates proper (check mark on the left) and improper (x mark on the right) orientation of drug delivery devices according to some embodiments disclosed herein.

[0041] [Figure 12] 1 shows another view of a drug delivery device according to some embodiments disclosed herein.

[0042] [Figure 13A] 1 illustrates locations (X) for attaching a suture (eg, a fixation suture / cardinal suture) to a drug delivery device according to some embodiments disclosed herein.

[0043] [Figure 13B] 1 shows an image of a drug delivery device with sutures attached and ready for implantation according to some embodiments disclosed herein.

[0044] [Figure 14A] 1 illustrates an exemplary location ([O]) for attaching a direction-discriminating suture (eg, a prolene suture) to a drug delivery device according to some embodiments disclosed herein.

[0045] [Figure 14B] 1 shows an image of a drug delivery device with attached direction-discriminating sutures (e.g., prolene sutures) of some embodiments disclosed herein.

[0046] [Figure 15A] 1 illustrates a drug delivery device according to some embodiments disclosed herein rolled up for implantation.

[0047] [Figure 15B] 1 shows an image of a drug delivery device rolled up for implantation according to some embodiments disclosed herein.

[0048] [Figure 15C]10 shows another image of a drug delivery device rolled up for implantation according to some embodiments disclosed herein.

[0049] [Figure 15D] 1 shows an image of a drug delivery device of some embodiments disclosed herein rolled into a trocar for implantation.

[0050] [Figure 16A] 1 illustrates the correct orientation of a drug delivery device with a prolene suture (O) attached clockwise from the anchoring / cardinal suture X according to some embodiments disclosed herein.

[0051] [Figure 16B] 1 illustrates the incorrect orientation of a drug delivery device with a prolene suture (O) attached counterclockwise from a fixed / base suture X of some embodiments disclosed herein.

[0052] [Figure 17] 1 shows an example of a drug delivery device sutured in place according to some embodiments disclosed herein.

[0053] [Figure 18A] 1 shows the thickness measured at three different points on a first exemplary film of some embodiments disclosed herein before refrigeration.

[0054] [Figure 18B] 1 shows the thickness measured at three different points on a second exemplary film of some embodiments disclosed herein before refrigeration.

[0055] [Figure 18C] 1 shows thickness measured at three different points on a third exemplary film of some embodiments disclosed herein after four weeks of refrigeration.

[0056] [Figure 18D]1 shows the thickness measured at three different points on a fourth exemplary film of some embodiments disclosed herein after 11 weeks of refrigeration.

[0057] [Figure 19] 1 shows the average thickness of four exemplary films measured according to certain embodiments disclosed herein.

[0058] [Figure 20A] 1 shows the measured diameters of four exemplary films according to some embodiments disclosed herein.

[0059] [Figure 20B] 1 shows the average diameters of four exemplary films measured according to some embodiments disclosed herein.

[0060] [Figure 21A] 1 shows the measured dry versus wet thickness of three samples of some embodiments disclosed herein.

[0061] [Figure 21B] 1 shows the diameters of three samples measured dry versus wet for some embodiments disclosed herein.

[0062] [Figure 22] 1 shows a drug delivery device of some embodiments disclosed herein observed under a confocal microscope in fluorescence.

[0063] [Figure 23A] 1 shows the degradation of sample films of some embodiments disclosed herein after 1 day in buffer solution.

[0064] [Figure 23B] 1 shows the degradation of sample films of some embodiments disclosed herein after 3 days in buffer solution.

[0065] [Figure 23C] 1 shows the degradation of sample films of some embodiments disclosed herein after 5 days in buffer solution.

[0066] [Figure 23D] 1 shows the degradation of sample films of some embodiments disclosed herein after 7 days in buffer solution.

[0067] [Figure 23E] 1 shows the degradation of sample films of some embodiments disclosed herein after 2 weeks in buffer solution.

[0068] [Figure 23F] 1 shows the degradation of sample films of some embodiments disclosed herein after 3 weeks in buffer solution.

[0069] [Figure 23G] 1 shows the degradation of sample films of some embodiments disclosed herein after 4 weeks in buffer solution.

[0070] [Figure 23H] 1 shows the degradation of sample films of some embodiments disclosed herein after 6 weeks in buffer solution.

[0071] [Figure 23I] 1 shows the degradation of sample films of some embodiments disclosed herein after 8 weeks in buffer solution.

[0072] [Figure 23J] 1 shows the degradation of sample films of some embodiments disclosed herein after 10 weeks in buffer solution.

[0073] [Figure 24]1 shows a graph of percent mass remaining (dry mass / initial mass*100) over time for samples tested for degradation rate for several embodiments disclosed herein.

[0074] [Figure 25] 1 shows a graph of percent water absorption by the discs ((wet weight-dry weight) / dry weight*100) over time for samples tested for degradation rate of several embodiments disclosed herein.

[0075] [Figure 26] 1 shows an exemplary flow chart illustrating how the drug delivery device of some embodiments disclosed herein can attack tumor cells. Specifically, the elution layer can degrade to release the drug within the tumor (in the order of the left arrow), and then the backing layer can degrade (in the order of the right arrow).

[0076] [Figure 27A] 1 shows an image of a drug delivery device of some embodiments disclosed herein implanted on the abdominal wall of a pig.

[0077] [Figure 27B] 1 shows an image of a drug delivery device implanted on the pancreas of a pig according to some embodiments disclosed herein.

[0078] [Figure 28] Figure 1 shows weight gain from a pig study of several embodiments disclosed herein. Animals implanted in the abdominal wall only (left) and animals implanted in both the pancreas and abdominal wall (right) gained weight over a 30-day period. Body condition of all three animals was normal, i.e., tubular with slightly rounded sides, and ribs, hips, and spine palpated with firm pressure.

[0079] [Figure 29]1 shows histology of the abdominal wall from a porcine study of some embodiments disclosed herein, showing only mild hemorrhage (arrows) and adipose tissue necrosis (asterisk) in the lower abdominal wall.

[0080] [Figure 30] 1 shows histology of a pancreas from a porcine study of some embodiments disclosed herein, with a low magnification view of a cross section of the pancreas and implant (top) and a high magnification view of the boxed area (bottom) showing a thin capsule and fibrosis.

[0081] [Figure 31] 1 shows drug accumulation in tissues after 30 days in a pig study, demonstrating that the drug accumulates primarily beneath the implant, for some embodiments disclosed herein.

[0082] [Figure 32A] 1 shows the weight of drug delivery devices without oven drying or sterilization tested for drug release rate according to some embodiments disclosed herein.

[0083] [Figure 32B] 1 shows the cumulative drug release of some embodiments of drug delivery devices tested without oven drying or sterilization. The control is a single measurement, i.e., only one measurement per disk.

[0084] [Figure 33] 1 shows the cumulative drug release of oven-dried and sterilized drug delivery devices of some embodiments disclosed herein.

[0085] [Figure 34] 1 shows the cumulative drug release of a single oven-dried but non-sterilized drug delivery device of some embodiments disclosed herein.

[0086] [Figure 35A]1 shows a graph of the change in maximum tumor dimension over time in the first patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0087] [Figure 35B] 1 shows the tumor assessment of the first patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0088] [Figure 36A] A radiological image of the first patient's tumor at baseline from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line.

[0089] [Figure 36B] 1 shows a 3D rendering of the first patient's tumor at baseline from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0090] [Figure 37A] A radiological image of the first patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line two weeks after implantation and before chemotherapy.

[0091] [Figure 37B] 1 shows a 3D rendering of the first patient's tumor two weeks after implantation and before chemotherapy from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0092] [Figure 38A] A radiological image of the first patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 10 weeks after implantation and prior to chemotherapy cycle 5, is shown as a dashed line.

[0093] [Figure 38B]1 shows a 3D rendering of the first patient's tumor 10 weeks after implantation and prior to chemotherapy cycle 5 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0094] [Figure 39A] A radiological image of the first patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 16 weeks after implantation and prior to chemotherapy cycle 9, is shown as a dashed line.

[0095] [Figure 39B] 1 shows a 3D rendering of the first patient's tumor 16 weeks after implantation and prior to chemotherapy cycle 9 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0096] [Figure 40A] A radiological image of the first patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line 24 weeks after implantation and prior to chemotherapy cycle 12.

[0097] [Figure 40B] 1 shows a 3D rendering of the first patient's tumor 24 weeks after implantation and prior to chemotherapy cycle 12 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0098] [Figure 41A] 10 shows a graph of the change in maximum tumor dimension over time in a second patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0099] [Figure 41B] 1 shows tumor evaluation of a second patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0100] [Figure 42A]A radiological image of a second patient's tumor at baseline from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line.

[0101] [Figure 42B] 10 shows a 3D rendering of a second patient's tumor at baseline from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0102] [Figure 43A] A radiological image of a second patient's tumor two weeks after implantation from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line.

[0103] [Figure 43B] 10 shows a 3D rendering of a second patient's tumor two weeks after implantation from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0104] [Figure 44A] A radiological image of a second patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 10 weeks after implantation and prior to chemotherapy cycle 5, is shown as a dashed line.

[0105] [Figure 44B] 1 shows a 3D rendering of a second patient's tumor 10 weeks after implantation and prior to chemotherapy cycle 5 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0106] [Figure 45A] A radiological image of a second patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 16 weeks after implantation and prior to chemotherapy cycle 9, is shown as a dashed line.

[0107] [Figure 45B]1 shows a 3D rendering of a second patient's tumor 16 weeks after implantation and prior to chemotherapy cycle 9 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0108] [Figure 46A] 10 shows a graph of the change in maximum tumor dimension over time in a third patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0109] [Figure 46B] 1 shows tumor evaluation of a third patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0110] [Figure 47A] A radiological image of a third patient's tumor at baseline from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line.

[0111] [Figure 47B] 10 shows a 3D rendering of a third patient's tumor at baseline from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0112] [Figure 48A] A radiological image of a third patient's tumor two weeks after implantation from a clinical trial of a drug delivery device of some embodiments disclosed herein is shown as a dashed line.

[0113] [Figure 48B] 10 shows a 3D rendering of a third patient's tumor two weeks after implantation from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0114] [Figure 49A]A radiological image of a third patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 10 weeks after implantation and after five pre-chemotherapy cycles, is shown as a dashed line.

[0115] [Figure 49B] 1 shows a 3D rendering of a third patient's tumor 10 weeks after implantation and prior to chemotherapy cycle 5 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0116] [Figure 50A] A radiological image of a third patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 16 weeks after implantation and prior to chemotherapy cycle 9, is shown as a dashed line.

[0117] [Figure 50B] 1 shows a 3D rendering of a third patient's tumor 16 weeks after implantation and prior to chemotherapy cycle 9 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0118] [Figure 51A] A radiological image of a third patient's tumor from a clinical trial of a drug delivery device of some embodiments disclosed herein, 24 weeks after implantation and prior to chemotherapy cycle 12, is shown as a dashed line.

[0119] [Figure 51B] 1 shows a 3D rendering of a third patient's tumor 24 weeks after implantation and prior to chemotherapy cycle 12 from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0120] [Figure 52] 1 shows the overall procedure time for implanting a drug delivery device of some embodiments disclosed herein.

[0121] [Figure 53]1 shows the reduction in tumor size in the first patient from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0122] [Figure 54] 1 shows tumor volume reduction in three patients from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0123] [Figure 55] 1 shows anterior / posterior tumor shrinkage for three patients from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0124] [Figure 56A] 1 shows a graph of the amount of CA19-9 in the blood of three patients from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0125] [Figure 56B] 1 shows a table of the amount of CA19-9 in the blood of three patients from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0126] [Figure 57] 1 shows Kaplan-Meier curves of 12-month progression-free survival for three patients from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0127] [Figure 58] 1 shows Kaplan-Meier curves of 12-month overall survival for three patients from a clinical trial of a drug delivery device of some embodiments disclosed herein.

[0128] In the drawings, like reference numbers correspond to like elements unless otherwise stated. DETAILED DESCRIPTION OF THE INVENTION

[0129] Described herein are exemplary embodiments of biodegradable drug delivery devices that can be implanted into a patient to locally deliver a controlled, therapeutically effective amount of an API. Specifically, the drug delivery devices disclosed herein can be configured for controlled release of a therapeutically effective amount of an API directly to a target tissue site (e.g., a tumor) through in vivo degradation of a biodegradable polymer layer containing the API.

[0130] In some embodiments, the drug delivery device can be a film or patch having multiple biodegradable layers. In some embodiments, the drug delivery device can include at least one biodegradable layer. At least one layer can include an API that can be released in vivo by polymer biodegradation. In some embodiments, the second layer can be API-free. This non-API layer can be on one side of the API layer and prevent the release of the API toward the non-API layer. In other words, the non-API layer can help ensure that the API from the API layer during in vivo degradation is released from the non-API backing layer toward the target tissue, rather than toward non-target tissue. In addition, this non-API layer can hold the drug delivery device in place during degradation of the API layer. In some embodiments, the target tissue can be cancer tissue / cells or peritumor tissue / cells on an organ. For example, the target tissue can be cancer tissue / cells on the pancreas or peritumor tissue / cells.

[0131] Figure 1 shows a drug delivery device 100 including an API layer 101 and a non-API backing layer 102. The API-containing layer can include an API 103 embedded within and / or on the surface of the API layer 101. In use, the API layer faces the target tissue such that the API is released toward the target tissue during degradation, as indicated by the arrows in Figure 1. The non-API backing layer 102 can prevent the release of the API onto non-target tissue away from the target tissue.

[0132] Although the drug delivery device is shown in Figure 1 as a disk, the drug delivery devices disclosed herein can have many shapes, sizes, and geometries. In some embodiments, the drug delivery device can be circular, square, rectangular, oval, triangular, diamond-shaped, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), arc-shaped, trapezoidal, star-shaped, or a variety of other shapes and sizes. In some embodiments, the drug delivery device can be tubular, cylindrical, conical, pyramidal, triangular prism-shaped, cubic, spherical, rectangular prism-shaped, or a variety of other shapes and sizes.

[0133] In some embodiments, the drug delivery device can be made by solvent casting. As described in more detail below, at least one biodegradable polymer and at least one API can be dissolved in a solvent and poured into a mold. Once dried, a second layer having at least one biodegradable polymer can be poured over the first layer and then dried to form the device. This process can be repeated for as many additional API and / or non-API layers as needed. In some embodiments, the drug delivery device can be made by a continuous process. In some embodiments, the drug delivery device disclosed herein can be made by a continuous process (e.g., extrusion, continuous film evaporation, etc.) such as those employed in the polymer film manufacturing industry.

[0134] API layer In some embodiments, the drug delivery device may include at least one API-containing layer. 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 two or more APIs. As described above, the API layer may be configured to provide controlled release of the API through in vivo degradation of the biodegradable polymer at the target tissue site. In some embodiments, the API layer may also include one or more pharmaceutically acceptable excipients.

[0135] In some embodiments, the biodegradable polymer can be any suitable biodegradable polymer known in the art. For example, the biodegradable polymer can include synthetic polymers selected from poly(amides), poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudopoly(amino acids), poly(glycerol sebacate), copolymers thereof, and mixtures thereof. In addition, the biodegradable polymer can be formed from poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(caprolactone), and mixtures thereof. In some embodiments, the biodegradable polymer can be poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the PLGA can be PLGA 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 API-containing layer comprises PLGA 50:50.

[0136] PLGA degrades through hydrolysis or biodegradation, with its backbone ester bonds cleaved into oligomers and then monomers. The lactide-glycolide ratio determines the degradation rate of PLGA in aqueous media (e.g., water and water-containing environments such as the anatomical structures of humans or animals). Generally, the higher the lactic acid or lactide content, the slower the degradation behavior of PLGA, because lactide is hydrophobic and can prevent water from hydrolyzing the ester bonds of PLGA. Therefore, PLGA 50:50 degrades faster in water-containing environments than PLGA 65:35, which degrades faster than PLGA 75:25.

[0137] In some embodiments, the API-containing layer comprises at least about 50%, at least about 60%, at least about 70%, at least about 73%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% by weight of biodegradable polymer. In some embodiments, the API-containing layer comprises at most about 95%, at most about 90%, at most about 85%, at most about 80%, at most about 77%, or at most about 75% by weight of biodegradable polymer. In some embodiments, the API-containing layer comprises about 60-95%, about 70-95%, about 75-90%, about 75-89%, or about 79-89% by weight of biodegradable polymer.

[0138] In some embodiments, the API can be an active pharmaceutical ingredient for the treatment of a human or animal disease. In some embodiments, the API can be a chemotherapeutic agent, such as any drug formulation effective for treating cancer by inhibiting malignant cell proliferation, invasiveness, and / or inducing cytotoxicity through apoptosis or necrosis of malignant cells. The chemotherapeutic agent can be a taxane drug 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 can interfere with the mTOR or NFkB pathway. In some embodiments, the chemotherapeutic agent includes a STING agonist compound. In some embodiments, the chemotherapeutic agent can interfere with the STING pathway. In some embodiments, the chemotherapeutic agent includes genetic material, such as mRNA or siRNA. In some embodiments, the chemotherapeutic agent can be an siRNA-Alnylam type therapy. In some embodiments, the API can include a vaccine antigen. In some embodiments, the API can be an mRNA vaccine antigen, such as an mRNA cancer vaccine antigen.

[0139] The API may be a single active pharmaceutical ingredient, such as a single chemical entity, or may be a mixture of several active pharmaceutical ingredients. The active pharmaceutical ingredient may be any of many categories of active pharmaceutical ingredients. The active pharmaceutical ingredient may be selected from the group consisting of, but not limited to, paclitaxel, gemcitabine, nab-paclitaxel, 5-fluorouracil, oxaliplatin, irinotecan, docetaxel, vinorelbine, etoposide, mitomycin-C, cisplatin / carboplatin, fluorouracil, methotrexate, TAS-102, or a combination thereof. In some embodiments, the API is paclitaxel. In some embodiments, the paclitaxel is manufactured by Phyton Biotech.

[0140] In some embodiments, the API can be an API for a 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 an immunotherapy such as nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, or a combination thereof.

[0141] The API may include salts, esters, hydrates, solvates, and derivatives of any of the aforementioned active ingredients. Suitable derivatives are known to those skilled in the art to have the same activity as the active ingredient, although at a lower or higher activity level. In some embodiments, the API may be in the form of a microsphere. In some embodiments, the microsphere can release the API. In some embodiments, the API is encapsulated within the microsphere.

[0142] If present, the API is used in the formulation in a therapeutically effective amount necessary to provide the required dosage, typically resulting in at least one physiological effect established by clinical trials. One of ordinary skill in the art can readily determine the appropriate amount of active pharmaceutical ingredient to include in a drug delivery device made in accordance with the present disclosure.

[0143] 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%, or at least about 15 wt% of the API. In some embodiments, the API-containing layer comprises at most about 30 wt%, at most about 20 wt%, at most about 15 wt%, at most about 12 wt%, at most about 11 wt%, at most about 10 wt%, at most about 9 wt%, at most about 8 wt%, at most about 7 wt%, or at most about 5 wt% of the API. In some embodiments, the API-containing layer comprises about 1-15 wt%, about 5-15 wt%, about 7-12 wt%, about 8-12 wt%, or about 7.5-11 wt% of the API. In some embodiments, the API-containing layer may comprise about 1-500 mg, about 25-450 mg, about 30-400 mg, about 40-350 mg, about 50-300 mg, about 60-250 mg, about 70-200 mg, about 80-150 mg, about 85-125 mg, about 90-105 mg, about 95-105 mg, or about 100 mg of API.

[0144] In some embodiments of the drug delivery device disclosed herein, the API layer can be prepared by forming a solution of the biodegradable polymer and the API. Specifically, a certain amount of the biodegradable polymer can be dissolved in a solvent. The biodegradable polymer / solvent solution can be stirred and / or heated to aid in dissolving the polymer in the solvent. In some embodiments, the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methyl ethyl ketone, methylene chloride, isopropyl alcohol, methyl isobutyl ketone, methyl propyl ketone, trichloroethylene, other substitutes for acetone, or combinations thereof. In some embodiments, the biodegradable polymer and solvent solution may contain about 0.1-0.3 g of biodegradable polymer, about 0.15-0.25 g of biodegradable polymer, about 0.175-0.225 g of biodegradable polymer, about 0.19-0.21 g of biodegradable polymer, about 0.198-0.202 g of biodegradable polymer, or about 0.2 g of biodegradable polymer per mL of solvent. In other words, if 20 g of biodegradable polymer is contained in 100 mL of solvent, the resulting biodegradable polymer and solvent solution will contain 0.2 g of biodegradable polymer per mL of solvent. The above concentrations may also apply to the biodegradable polymer / API solutions described below. For example, the biodegradable polymer / API solution can have about 0.1-0.3 g of biodegradable polymer, about 0.15-0.25 g of biodegradable polymer, about 0.175-0.225 g of biodegradable polymer, about 0.19-0.21 g of biodegradable polymer, about 0.198-0.202 g of biodegradable polymer, or about 0.2 g of biodegradable polymer per mL of solvent.

[0145] After the biodegradable polymer is dissolved in the solvent, the API can be added to the solution. In some embodiments, the API and biodegradable polymer can be added to the solvent simultaneously. In some embodiments, the API can be added to the solvent before the addition of the biodegradable polymer. In some embodiments, the API can be added to the solvent to form a first solution, the biodegradable polymer can be added to the solvent to form a second solution, and the first and second solutions can be combined to form a biodegradable polymer / API solution. In some embodiments, when the API is incorporated into the biodegradable polymer layer, the API can be in the form of microspheres. In some embodiments, the microspheres can help prevent dissolution and / or degradation of the API in the polymer / solvent solution.

[0146] In some embodiments, the biodegradable polymer / API solution can have about 0.01-0.05 g of API, about 0.01-0.04 g of API, about 0.015-0.035 g of API, about 0.02-0.03 g of API, about 0.023-0.027 g of API, or about 0.025 g of API per mL of solvent. The above concentrations also apply to solutions of API and solvent (without the biodegradable polymer). The biodegradable polymer / API solution can be stirred and / or heated until the API is thoroughly mixed and / or dissolved in the solvent.

[0147] After the biodegradable polymer / API solution is formed, the solution can be added to a mold. The mold can be any container used to impart shape to the API layer as it is formed. Thus, the mold can be circular, square, rectangular, oval, triangular, diamond-shaped, polygonal (e.g., pentagonal, hexagonal, octagonal, etc.), arc-shaped, trapezoidal, star-shaped, or a variety of other shapes and sizes. In addition to shape, the mold can also determine the size (i.e., width, length, diameter, etc.) of the layer.

[0148] Thus, if the drug delivery device is circular in shape, the biodegradable polymer / API solution can be added to a circular mold. In some embodiments, the mold can be an evaporating dish, a Petri dish, or the like. Furthermore, the amount added to the mold can depend on the desired thickness and / or API concentration of the API layer. Furthermore, the amount added to the mold can depend on the desired API release rate of the API layer. In some embodiments, about 1-20 mL, about 1-10 mL, about 4-6 mL, or about 5 mL of the biodegradable polymer / API solution can be added to the mold.

[0149] Once in the mold, the biodegradable polymer / API solution can be dried. This drying can evaporate the solvent, leaving a solidified layer containing the biodegradable polymer, API, and some residual solvent. Residual solvent in the layer can be important because it allows the layer to remain flexible and not crack during subsequent folding / rolling. As such, the API layer may also contain small amounts of solvent, as described in more detail below. In some embodiments, the biodegradable polymer / API solution can be dried in the mold at room temperature (e.g., 20-25°C) in air, nitrogen, or other gases. In some embodiments, the biodegradable polymer / API solution can be dried in an environment with humidity 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, drying can be for about 1-6 days, about 1-4 days, about 1-3 days, or about 1.5-2.5 days.

[0150] Non-API layer In some embodiments, the drug delivery device may include at least one non-API-containing layer. In some embodiments, the non-API layer may not contain an API. In some embodiments, the non-API layer may include at least one biodegradable polymer. As explained above, in some embodiments, the non-API layer may function as a backing layer for the API layer and help prevent release of the API from the target tissue site onto non-target tissue. In some embodiments, the non-API layer may include a biodegradable polymer that degrades slower than the biodegradable polymer in the API layer. As explained below, PLGA 75:25 degrades slower than PLGA 50:50, so PLGA 50:50 can be the biodegradable polymer in the API layer and PLGA 75:25 can be the biodegradable polymer in the second layer. In some embodiments, the non-API layer may include a biodegradable polymer that has a degradation rate that is the same as or faster than the biodegradable polymer in the API layer. In some embodiments, the non-API layer may also include one or more pharmaceutically acceptable additives.

[0151] For example, a biodegradable polymer in the API layer can degrade over approximately 4 weeks to release the API toward the target tissue. A biodegradable polymer in the non-API layer can degrade over a longer period (e.g., 10 weeks). Thus, in some embodiments, the non-API backing layer can be used to hold the drug delivery device at its target location (e.g., on a tumor) while the API layer degrades to release the API. After the API layer has completely degraded and the API has been completely released into the target tissue, the non-API layer can completely degrade and be absorbed into the patient's body. In some embodiments, although a portion of the non-API layer may degrade while the API layer degrades, the degradation rate of the non-API layer is slower than that of the API layer, and therefore the non-API layer can prevent the API from being released from the target tissue site and / or hold the drug delivery device in place at the target tissue site. Thus, in some embodiments, the non-API layer enables unidirectional delivery of the API toward the target tissue site.

[0152] 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 has a slower degradation rate than the biodegradable polymer in the API layer. For example, the biodegradable polymer can include synthetic polymers selected from poly(amides), poly(esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudopoly(amino acids), poly(glycerol sebacate), copolymers thereof, and mixtures thereof. In addition, the biodegradable polymer can be formed from poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(caprolactone), and mixtures thereof. In some embodiments, the biodegradable polymer can be poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the PLGA can be PLGA 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, PLGA 85:15, PLGA 90:10, or other various ratios of PLGA. In some embodiments, the biodegradable polymer in the non-API-containing layer comprises PLGA 75:25.

[0153] In some embodiments, the non-API-containing layer comprises at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% by weight of biodegradable polymer. In some embodiments, the non-API-containing layer comprises at most about 99.9%, at most about 99%, at most about 98%, at most about 97%, at most about 95%, or at most about 90% by weight of biodegradable polymer. In some embodiments, the non-API-containing layer comprises about 80-99.9%, about 85-98%, about 86-97%, or about 88-96% by weight of biodegradable polymer.

[0154] A second solution of a biodegradable polymer can be formed to prepare a non-API layer for a drug delivery device. Specifically, a certain amount of the biodegradable polymer can be dissolved in a solvent. The second biodegradable polymer / solvent solution can be stirred and / or heated to aid in dissolving the polymer in the solvent. In some embodiments, the solvent can be acetone, chloroform, tetrahydrofuran, ethyl acetate, methyl acetate, xylene, toluene, methyl ethyl ketone, methylene chloride, isopropyl alcohol, methyl isobutyl ketone, methyl propyl ketone, trichloroethylene, other substitutes for acetone, or a combination thereof. In some embodiments, the biodegradable polymer and solvent solution can contain about 0.1-0.3 g of biodegradable polymer, about 0.15-0.25 g of biodegradable polymer, about 0.175-0.225 g of biodegradable polymer, about 0.19-0.21 g of biodegradable polymer, about 0.198-0.202 g of biodegradable polymer, or about 0.2 g of biodegradable polymer per mL of solvent. In other words, 20 g of biodegradable polymer in 100 mL of solvent results in a biodegradable polymer and solvent solution containing 0.2 g of biodegradable polymer per mL of solvent.

[0155] In some embodiments, after the second biodegradable polymer solution is formed, the solution can be added to the mold containing the API layer. In this manner, the second biodegradable polymer solution can be added over the API layer in the mold so as to coat or form a covering over the API layer. The amount added to the mold can depend on the desired thickness (and degradation rate) of the non-API layer. In some embodiments, about 1-20 mL, about 1-10 mL, about 4-6 mL, or about 5 mL of the second solution of biodegradable polymer can be added to the mold with the API layer. In some embodiments, the non-API biodegradable solution can be added to the mold first to form the non-API layer (in a manner similar to that described above for the API layer), and then the API layer can be formed over the non-API layer in the mold.

[0156] Once in the mold, the second biodegradable polymer solution can be dried. In some embodiments, this drying can evaporate the solvent, leaving a second solidified layer on one side of the first solidified API layer. The second layer can be adhered to the first layer by a welding process. In other words, the first layer can be slightly dissolved upon application and then redried together with the second layer to form a solid second layer on one side of the solid first layer, thereby adhering the second layer to the first layer. This second layer can include a biodegradable polymer (having a slower degradation rate than the biodegradable polymer of the first API layer) and some residual solvent. Thus, the non-API layer can also include a small amount of solvent, as described in more detail below. In some embodiments, the non-API biodegradable polymer solution can be dried in the mold at room temperature (e.g., 20-25°C) in air, nitrogen, or other gases. In some embodiments, the non-API biodegradable polymer solution can be dried in an environment with humidity less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1%. In some embodiments, drying can be for about 1-6 days, about 1-4 days, about 1-3 days, or about 1.5-2.5 days. The layer of the drug delivery device can have a uniform consistency and be homogeneous.

[0157] The above process for preparing an API layer and a non-API layer adhered to an API layer can be repeated for additional layers, as well as for other API layers, non-API layers adhered to one side of the API layer, other API layers, non-API layers, and / or other non-API layers. In other words, the drug delivery devices disclosed herein can include any number of API and non-API layers in any order, such as API / non-API, non-API / API, API / non-API / API, non-API / API / non-API, API / API / non-API, API / non-API / API, API / non-API / API / non-API, API / API / non-API, API / API / non-API, API / API / non-API, API / API / non-API, non-API / API / non-API, non-API / API / API / non-API configurations. These additional API and / or non-API layers can have any API or non-API layer composition disclosed herein and can be made by the same processes as the API or non-API layers disclosed herein.

[0158] In some embodiments, a drug delivery device may include two or more API layers. In some embodiments, a drug delivery device may include a non-API layer sandwiched between two API layers. In some embodiments, a drug delivery device may include two API layers on top of each other and a non-API layer on one side of one of the API layers. For example, in some embodiments, a drug delivery device may include a second API layer on one side of a first API layer and a non-API layer on one side of the second API layer opposite the first API layer. In some embodiments, the second API layer may have the same composition (i.e., API) as the first API layer. In some embodiments, there may be three or more API layers before the non-API layer. These API layers may have the same or different compositions or the same or different APIs. Furthermore, these additional layers can be added to a drug delivery device by the same methods disclosed herein.

[0159] In some embodiments, the drug delivery device may include two or more non-API layers. 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 one side of the API layer opposite 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 than the first non-API layer. In some embodiments, the second non-API layer may degrade faster, slower, or at the same rate as the API layer. In some embodiments, the first non-API layer may degrade faster, slower, or at the same rate as the API layer. In some embodiments, the first non-API layer may degrade faster, slower, or at the same rate as the second non-API layer. In some embodiments, there may be three or more non-API layers before the API layer. Furthermore, these additional layers can be added to the drug delivery device by the same methods disclosed herein.

[0160] In some embodiments, a drug delivery device can include a second API layer on one side of a first API layer configured to degrade at a slower rate than the first API layer, and a non-API layer on the opposite side of the second API layer, configured to degrade at a slower rate than the second API layer. In other words, a first solution of a first biodegradable polymer and a first API can be added to a mold and dried to form a first layer. A second solution of a second biodegradable polymer (having a slower degradation rate than the first biodegradable polymer) and a second API can then be added to the mold on top of the first layer and dried to form a second layer. A third solution of a third biodegradable polymer (having a slower degradation rate than the second biodegradable polymer) can then be added to the mold on top of the second layer and dried to form a third non-API layer. For example, a drug delivery device may include a first layer having an API and PLGA50:50, a second layer having the same or a different API and PLGA65:35, and a non-API layer containing PLGA75:25, where the first PLGA50:50 layer degrades first to release the first API, then the second PLGA65:35 layer degrades to release the second API, and finally the non-API PLGA75:25 layer degrades.

[0161] After the desired amounts of API and non-API layers are added to the mold and allowed to dry, the drug delivery film can be removed from the mold. In some embodiments, the periphery of a first layer (e.g., API layer) can be inset against the periphery of a second layer (e.g., non-API layer) formed on the first layer, such that a portion of the second layer extends beyond the first layer. This is shown in Figure 2, which shows an image of a drug delivery device having an API layer 101 and a non-API layer 102, where a portion of the non-API layer extends beyond the first layer to serve as a boundary, rim, or edge 104 around the API layer.

[0162] There are many ways to form this boundary around the API layer. In some embodiments, the composition (and viscosity) of the non-API layer is different from that of the API layer, so that the non-API layer can adhere and climb up the edge or side of the mold (e.g., evaporating dish) when added to the mold. Thus, during drying, a portion of the non-API layer can form on the edge or side of the mold, but not directly on the API layer. This portion that forms on the edge or side of the mold can be a boundary, rim, or edge that is defined around the API layer.

[0163] Oven drying Because the drug delivery devices disclosed herein can be placed directly into a target tissue region using minimally invasive, standard surgical techniques, such as open, laparoscopic, endoscopic, percutaneous, or robotic surgery, the drug delivery device must be sufficiently flexible to be used with standard surgical equipment (e.g., trocars used in laparoscopic surgery, catheters in endoscopic surgery, bronchoscopes, robotic bronchoscopes, etc.). In some embodiments, the drug delivery device can be rolled and / or folded to be inserted through trocars measuring 3 mm to 12 mm (e.g., 3, 5, 8, 10, 12 mm trocars) and larger. Thus, once inside the patient's body, the drug delivery device can be unfolded and placed at the target tissue site (e.g., a tumor) using standard surgical equipment. In some embodiments, the drug delivery device is placed on the target tissue so that it covers the target tissue and adheres to tissue adjacent to the target tissue. For example, if the target tissue is a tumor in an organ, the drug delivery device can be placed on the organ so that the tumor area is covered with the API layer of the drug delivery device (i.e., the API layer is in contact with the tumor or the area around the tumor) and the device can be adhered to the non-tumor portion of the organ.

[0164] In initial testing, applicant discovered that when some drug delivery devices are inserted into a patient's body, the high body temperatures cause the devices to adhere to themselves, melt, or flow, preventing them from properly unfolding for placement at the target tissue site. Applicant discovered that this is at least in part due to excessive solvent remaining in the drug delivery device. The solvent can be important for the layers (and the device as a whole) to remain flexible and prevent cracking during subsequent folding / rolling. However, too much solvent can cause the layers to stick / adhere to themselves at elevated temperatures. Therefore, applicant discovered a method to remove more solvent, as well as a more optimal amount of solvent in the drug delivery device, so that the drug delivery device is properly implantable in the patient (i.e., maintains adequate flexibility / softness for surgery but does not stick / adhere to itself).

[0165] Specifically, six films containing a first layer of 0.8–1 g PLGA 50:50 (and acetone) and a second layer consisting of 0.8–1 g PLGA 75:25 (and acetone) on one side of the first layer were tested in an oven to determine whether manufacturing variations affected the film's tendency to adhere to itself. Film 1 was rolled and folded once, held in place using a rubber band, and placed in a HeraTherm high-temperature oven at 45°C for 20 minutes. After 20 minutes, Film 1 was completely adhered and could not be unrolled by any means, as shown in Figures 3A–3C. Film 2 was rolled and folded in the same manner as Film 1 and placed in an oven at 42°C for 20 minutes. After 20 minutes, Film 2 could still be unrolled but was partially stuck at the tightest wound portion, as shown in Figures 4A–4C. Films 3, 4, and 5 were tested to confirm that the test results were consistent with those obtained during method development. Film 3 was folded in the same manner as in the previous test and placed in a 37°C oven for 20 minutes. Film 4 was similarly folded and held at room temperature for 20 minutes. Film 5 was similarly folded and placed in a 40°C oven for 20 minutes. After 20 minutes at 37°C, Film 3 was unable to be fully unfolded due to some adhesive spots, as shown in Figures 5A-5C. This occurred at a lower temperature than observed with previous batches. Film 4 showed no signs of sticking, as shown in Figures 6A-6C. Film 5 was completely adhesive and could not be unfolded at all, as shown in Figures 7A-7C.

[0166] After initial preparation, Film 6 was dried in a Binder convection oven at 40°C for three days. After removal from the oven, Film 6 felt stiff at room temperature, suggesting that additional solvent may have been removed. Film 6 was rolled, folded, and placed in a 40°C oven for 20 minutes. After removal, it was not tacky, so Film 6 was retested at 42°C for 20 minutes and finally at 45°C for 20 minutes. As shown in Figures 8A-8C, 9A-9B, and 10A-10B, Film 6 did not adhere to itself at any time during either test. Thus, undried films may not function properly at temperatures that drug delivery devices may be exposed to when implanted in human / animal studies. However, Applicant discovered that adding an oven drying step sufficiently removed excess solvent so that drug delivery device performance was not compromised even at 45°C, a temperature outside the clinically expected range.

[0167] Thus, after the drug delivery device is removed from the mold (or, in some embodiments, while still in the mold), it can be placed in an oven to further dry. In some embodiments, the drug delivery device is placed in an oven at a temperature of 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, or at least about 42°C. In some embodiments, the drug delivery device is placed in an oven at a temperature of 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, or at most about 36°C. In some embodiments, the drug delivery device is placed in an oven at 30-45°C, 32-45°C, 35-45°C, 35-42°C, 35-41°C, 36-40°C, 37-39°C, or 38°C. In some embodiments, the drug delivery device is placed in an oven for about 1-5 days, about 2-4 days, about 2.5-3.5 days, about 2.75-3.25 days, about 68-80 hours, or about 3 days.

[0168] Thus, the drug delivery device may have a solvent content of less than about 12 wt%, or about 1-15 wt%, about 2-12 wt%, or about 3-11 wt%. In some embodiments, the API layer of the drug delivery device may have at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 3.5 wt%, at least about 5 wt%, at least about 7 wt%, or at least about 10 wt% solvent. In some embodiments, the API layer of the drug delivery device may have at most about 15 wt%, at most about 12 wt%, at most about 10 wt%, or at most about 5 wt% solvent. In some embodiments, the API layer of the drug delivery device may have at most about 1-15 wt%, at most about 2-12 wt%, at most about 3-11 wt%, or at most about 3.5-10 wt% solvent. In some embodiments, the non-API layers of the drug delivery device may have at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 3.5 wt%, at least about 5 wt%, at least about 7 wt%, or at least about 10 wt% solvent. In some embodiments, the non-API layers of the drug delivery device may have at most about 15 wt%, at most about 12 wt%, at most about 11 wt%, at most about 10 wt%, or at most about 5 wt% solvent. In some embodiments, the non-API layers of the drug delivery device may have about 1-15 wt%, about 2-12 wt%, about 3-11 wt%, or about 3.5-11 wt% solvent. The amount of solvent in the drug delivery device can be measured by gas chromatography.

[0169] In some embodiments, the drug delivery device can be sterilized, such as by electron beam irradiation. Additionally, the drug delivery device can be sterilized sealed in a pouch, such as a Tyvek pouch, and stored in a refrigerator.

[0170] Directional Indicators and Sutures As described above, the periphery of the API layer can be inset relative to the periphery of the non-API layer, causing a portion of the non-API layer to extend beyond the first layer, as shown in FIG. 2. Because the biodegradable polymers utilized in the layers can have similar colors and / or similar transparencies, it can be difficult to distinguish which side of the drug delivery device the API and non-API layers are on. Therefore, in some embodiments, the non-API layer can be marked with an orientation identifier. In some embodiments, the portion of the non-API layer that extends beyond the API layer (i.e., the rim) can include an orientation identifier. In some embodiments, the API layer can be marked with an orientation identifier. In some embodiments, the orientation identifier can be applied with a gemstone stamp. In some embodiments, there are two or more orientation identifiers. These orientation identifiers can be applied in multiple locations on the non-API or API layer. The orientation identifier can be any type of identifying mark, such as a letter, number, word, image, shape, etc. In some embodiments, the orientation identifier is a stamp on the layer. For example, FIG. 11A shows an image of a drug delivery device showing an orientation identifier 105 (e.g., "PT"). In this way, a surgeon can identify the orientation identifier within a patient during surgery to determine which side of the drug delivery device the drug-containing layer is on. For example, when the API layer faces away from the reader (i.e., toward the target tissue), the orientation identifier (e.g., "PT") will also be oriented appropriately, as shown in FIG. 11B. In other words, when the drug delivery device is properly positioned at the target tissue site with the API layer side facing the target tissue, the orientation identifier (e.g., "PT") can be legible and correctly oriented so that the surgeon can identify the orientation identifier.

[0171] In addition to the directional identifier, the portion of the non-API layer extending beyond the API layer can also be used to suture the drug delivery device to the target tissue of the patient. Figure 12 shows another example of a non-API layer in which a rim 104 extends beyond the API layer. For example, after locating the directional identifier of the drug delivery device and properly orienting the drug delivery device, a resorbable suture such as 3-0 Vicryl or equivalent suture with an SH needle can be attached to the portion of the non-API layer extending beyond the API layer (i.e., the rim). Additionally, Lapra-Ty® and absorbable suture clips may also be used. This potentially reduces the time required to place the patch on the target tissue, as the suture can be sutured in place and then secured with a clip without tying a knot. In some embodiments, the sutures can be spaced approximately evenly around the rim. For example, four sutures can be placed at four approximately evenly spaced positions around the rim, representing the four cardinal directions. 13A and 13B are images showing the locations for attaching four sutures (FIG. 13A) and a sample sutured drug delivery device ready for implantation (FIG. 13B). This technique allows the surgeon to avoid the need to suture the patch inside the body, allowing for faster implantation. In some embodiments, another suture (e.g., a different colored suture, such as prolene or equivalent) can be placed near one of the primary sutures as an additional directional identifier. For example, a different colored suture can be placed clockwise near the primary suture as an additional directional identifier, as shown in FIGS. 14A-14B. This directional identifier suture does not need to be used for anchoring to the target tissue. If the implant feels cold or stiff before attaching the sutures, it can be warmed by hand or soaked in warm saline before attaching the sutures.

[0172] In some embodiments, the drug delivery device may include an anatomical marker. In some embodiments, the API layer and / or the non-API layer may include an anatomical marker. In some embodiments, the anatomical marker may be adhered or connected to the drug delivery device. In some embodiments, the anatomical marker may be adhered or connected to the API layer and / or the non-API layer. Using the anatomical marker, a physician can identify the drug delivery device in a patient using various imaging techniques. The physician can then monitor the progress and / or position of the drug delivery device relative to the tumor. In some embodiments, the anatomical marker may be a radiopaque marker, an x-ray marker, a lead marker, or a similar marker.

[0173] embedded The suture-primed drug delivery device (with the suture and intact needle already tied) can then be folded and / or rolled into a tubular (e.g., cigar) shape just below the diameter of the trocar (3 mm to 12 mm (e.g., 3, 5, 8, 10, 12 mm)). In some embodiments, the drug delivery device can be folded and / or rolled just below the diameter of the trocar (3 mm to 12 mm (e.g., 3, 5, 8, 10, 12 mm trocar) depending on the trocar utilized. For example, if a 10 mm trocar is used during surgery, the suture-primed drug delivery device can be rolled into a tubular shape just under 10 mm in diameter. In some embodiments, the drug side can be on the inside or outside of the tubular roll. Figures 15A-15D show a rolled drug delivery device. If the implant feels cold or stiff before rolling, it can be warmed by hand or soaked in warm saline before rolling.

[0174] After being rolled, the drug delivery device can be inserted through the desired trocar port. The drug delivery device typically unfolds and flattens upon passing through the trocar. However, the drug delivery device can also be flattened using typical surgical tools, such as laparoscopic intestinal grasping forceps. After flattening, the drug delivery device can be guided onto the target tissue. After reaching the target area, a camera can be used to verify that the drug delivery device is properly oriented. In other words, a surgical camera can be used to verify that the API layer is facing the target tissue. The surgeon can determine the proper orientation by looking for an orientation identifier on the drug delivery device. For example, when the drug delivery device is properly positioned on the target tissue with the API layer against the target tissue, "PT" will be legible and correctly oriented so that the surgeon can identify the orientation identifier. Thus, the orientation identifier can be viewed during open, laparoscopic, endoscopic, or robotic surgery. In some embodiments, the surgeon can use a camera to view the suture orientation identifier on the drug delivery product to verify that the non-API layer is facing away from the target tissue. For example, referring back to Figure 14A, if the surgeon confirms that the direction identifiers on the sutures are mirror-imaged and oriented counterclockwise, the surgeon can flip the drug delivery device over before suturing in place so that the direction identifiers on the sutures are clockwise from the anchoring suture. Figures 16A-16B illustrate this point. Failure to confirm proper orientation could result in release of the API to non-target sites.

[0175] After confirming the correct placement and orientation of the drug delivery device, the drug delivery device can be sutured into place. For example, the drug delivery devices can be sutured into place one by one using sutures pre-attached to the area surrounding the target tissue and / or to the target tissue itself. Figure 17 shows an example of a drug delivery device sutured into place with sutures 106.

[0176] Drug delivery device characteristics In some embodiments, the drug delivery devices disclosed herein can be transparent, medium to light brown in color, with a clean rim that shows two sides. The drug delivery device can have no visible foreign particles or cracks on the surface. Additionally, a directional indicator can be clearly marked on the clean rim to allow the surgeon to distinguish between the non-API side and the API side.

[0177] In some embodiments, the drug delivery device may be essentially circular when formed from a circular mold, such as an evaporating dish or Petri dish. In some embodiments, the diameter of the drug delivery device may be at least about 1 cm, at least about 3 cm, at least about 5 cm, or at least about 6 cm. In some embodiments, the diameter of the drug delivery device may be at most about 10 cm, at most about 8 cm, at most about 7 cm, or at most about 6 cm. In some embodiments, the diameter of the drug delivery device may be about 3-9 cm, about 4-8 cm, about 5-7 cm, about 5.5-6.5 cm, or about 6.1-6.3 cm.

[0178] In some embodiments, the periphery of the API layer can be inset relative to the periphery of the non-API layer such that a portion (i.e., a rim) of the non-API layer extends beyond the API layer by an average of about 0.1-10 mm, about 0.5-8 mm, or about 1-5 mm around the periphery of the API layer, which can be measured with a micrometer and is the average of n=5 measurements at 5 randomly selected points around the rim of the non-API layer of the drug delivery device.

[0179] Film thickness was measured using the following protocol: (1) the API layer (first layer) was placed face down; (2) the device was reoriented so that three lines at 25%, 50%, and 75% down the device could be consistently determined; (3) the micrometer was calibrated to zero when the device was fully closed (not clamped); (4) the micrometer was used to measure the device at five different points along each line; (5) step 4 was repeated three times for a total of 15 measurements for each line. Four films were tested, each containing a first layer of 0.8–1 g PLGA 50:50 and 40–100 mg acetone, and a second layer on either side of the first layer consisting of 0.8–1 g PLGA 75:25 and 40–100 mg acetone. FIG. 18A shows thicknesses measured at three different points on a first device before refrigeration, FIG. 18B shows thicknesses measured at three different points on a second device before refrigeration, FIG. 18C shows thicknesses measured at three different points on a third device after 4 weeks of refrigeration, and FIG. 18D shows thicknesses measured at three different points on a fourth device after 11 weeks of refrigeration. Refrigeration temperatures were approximately 2-8°C. FIG. 19 shows the average thicknesses of four exemplary devices measured according to some embodiments disclosed herein.

[0180] In some embodiments, the average thickness of the drug delivery device can be at least 10 microns, at least 25 microns, at least 50 microns, at least 100 microns, at least 200 microns, at least 300 microns, at least 400 microns, at least 500 microns, at least 550 microns, at least 600 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, at least 4500 microns, or at least 5000 microns. In some embodiments, the drug delivery device can be at most 5000 microns thick, at most 4500 microns thick, at most 4000 microns thick, at most 3500 microns thick, at most 3000 microns thick, at most 2500 microns thick, at most 2000 microns thick, at most 1500 microns thick, at most 1000 microns thick, at most 900 microns thick, at most 750 microns thick, at most 600 microns thick, at most 500 microns thick, at most 300 microns thick, at most 200 microns thick, or at most 100 microns thick. In some embodiments, the average thickness of the drug delivery device can be about 100-1500 microns, about 200-900 microns, about 300-900 microns, about 400-800 microns, about 430-730 microns, about 500-600 microns, or about 580 microns.

[0181] In some embodiments, the average thickness of the API and / or non-API layers 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 layers 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 layers 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 thickness of the drug delivery device can be selected based on the desired degradation / API release rate. The average thickness can be measured with a micrometer at five randomly selected points on the drug delivery device, with n=5 measurements being the average.

[0182] The diameter of a drug delivery device can be measured by the following protocol: (1) the outer diameter (i.e., the diameter of the non-API layer) can be measured by placing a ruler along the diameter, including the outer rim of the non-API layer, and carefully reading the ruler; (2) step 1 was repeated 15 times, moving the device each time, for a total of 15 readings; (3) the inner diameter (i.e., the diameter of the API layer) was measured similarly, but without including the outer rim. Figures 20A-20B show the diameters and average diameters of four exemplary devices measured according to some embodiments disclosed herein. Therefore, the average thickness and diameter of a drug delivery device do not change significantly over a period of time under intended storage conditions (e.g., about 2-8°C).

[0183] The diameter and thickness of three films containing a first layer of 0.8–1 g PLGA 50:50 and 40–100 mg acetone, and a second layer consisting of 0.8–1 g PLGA 75:25 and 40–100 mg acetone on either side of the first layer, were tested and their dry versus wet measurements were compared. The films were measured on day 0 (before being placed in buffer) and then again at 1, 7, and 14 days after being placed in 60 mL Sørensen buffer. Figure 21A shows the average thickness of the films measured dry versus wet, and Figure 21B shows the average diameter of the films measured dry versus wet.

[0184] To determine whether the API is contained exclusively in the API layer and uniformly distributed throughout the API layer, a drug delivery device containing a first layer of 0.8-1 g PLGA 50:50, 100 mg paclitaxel, 300 micrograms of fluorescently labeled paclitaxel, and 40-100 mg acetone, and a second layer on either side of the first layer composed of 0.8-1 g PLGA 75:25 and 40-100 mg acetone, as shown in Figure 22, was observed under a confocal microscope. As seen in Figure 22, the API layer and non-API layer are very distinct, indicating that paclitaxel may be contained exclusively in the API layer and may be dispersed throughout the API layer. Thus, in the API layer of the drug delivery device disclosed herein, the API is uniformly and homogeneously dispersed throughout the layer.

[0185] A set of 30 films containing a first layer of 0.8–1 g of PLGA 50:50 (and acetone) and a second layer consisting of 0.8–1 g of PLGA 75:25 (and acetone) on either side of the first layer was degraded in an aqueous medium to determine the degradation rate of the polymer and the water absorbed by the polymer. The films were placed in 15 mL of Sørensen buffer (0.2 M, pH 7.4) and incubated at 37°C on a shaker set at 50 rpm. Samples were removed, dried, and weighed at time points ranging from 1 day to 10 weeks to document the mass loss at various time points. Results of testing under these conditions showed that the device gradually degraded during the first week. At that point, the rate of mass loss increased, and the device mass decreased linearly. Thus, the layers of the drug delivery device (and the drug delivery device itself) can degrade substantially linearly or linearly. After 10 weeks, only 10% of the initial polymer mass remained. Images of the discs taken at different time points also showed that PLGA 50:50 degraded faster than PLGA 75:25, appearing completely degraded by week 6, suggesting complete release of the API by week 6. All test samples were weighed and imaged prior to testing. Each was then placed in 15 mL of Sørensen buffer (pH 7.4). The sample containers were sealed with parafilm and placed in an incubation shaker set at 37°C and 50 rpm. The pH of the samples was titrated weekly with 1.0 N NaOH to return them to an acceptable pH range (7.4 ± 0.3). Samples were removed at predetermined time points (1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, and 10 weeks). The removed samples were imaged, weighed, and then placed in a Petri dish covered with Kimwipes. The Petri dish was then placed in a vacuum desiccator for up to 1 week to dry. The dried samples were imaged a third time and weighed, allowing the polymer's mass loss and water absorption to be measured during the test. At 8 and 10 weeks, the sample solutions were also filtered through Grade 1 filter paper to collect any visible particulates in the solution. The filter paper was pre-weighed and placed in a Petri dish along with the intact sample to dry.The weight of the particulate matter was included in the remaining weight of the sample. Images of the degraded samples before degradation, after removal from the solution, and after drying are shown in Figures 23A-23J. Over the first week (Figures 23A-23D), the samples hydrated but did not appear to change significantly from their initial appearance after drying. By week 2 (Figure 23E), there was a slight change in the appearance of the film, and by week 3 (Figure 23F), visible degradation of the PLGA was evident. The PLGA 50:50 layer was typically light to medium brown, while the PLGA 75:25 was typically clear or white. In Figure 23F, the PLGA 50:50 layer had significantly degraded at week 3; by week 4 (Figure 23G), most of the PLGA 50:50 had disappeared, and in one sample, the PLGA 75:25 also appeared to have begun to degrade. By week 6 (Figure 23H), the remaining samples were very thin and brittle, and some samples cracked upon drying. At 8 and 10 weeks (Figures 23I-23J), very little intact sample remained, and particulate matter was recovered from solution by filtration (not shown). Figure 24 shows a graph of the percent mass remaining (dry mass / initial mass * 100) over time. While loss was slow over the first 2 weeks, with approximately 90% mass remaining, the sample rapidly degraded over the next 8 weeks, with approximately 10% remaining mass. Figure 25 shows the percent water absorption ((wet mass - dry mass) / dry mass * 100) by the disks over time. Water appears to be absorbed slowly over the first 2 weeks, then rapidly increases as the polymer degrades. Thus, the film appears to degrade slowly over the first 2 weeks, degrade linearly after 2 weeks, and only 10% remains after 10 weeks. PLGA 50:50 appears to degrade first, becoming nearly completely degraded by week 4 and completely degraded by week 6. PLGA75:25 degrades to approximately 10% of the original device mass by 10 weeks.

[0186] In some embodiments, the drug delivery device can be configured to release the API according to a defined release rate profile. In some embodiments, release of the API can be delayed (or only a subtherapeutically effective amount of the API can be released during the delay period) after the device is implanted at the target tissue site to allow the patient's body to recover from the implantation procedure before the drug is released. This delay may allow some healing of the implantation site before release of the API, thereby reducing the risks associated with swelling, perforation, bleeding, infection, and other potential problems. In some embodiments, the delayed release period of the API 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 delayed release period of the API can be at most 28 days, at most 25 days, at most 21 days, at most 18 days, at most 15 days, at most 14 days, at most 12 days, at most 10 days, at most 8 days, at most 7 days, at most 5 days, or at most 3 days. In some embodiments, the delayed release period of the API can be from 1 to 28 days, from 1 to 21 days, from 1 to 14 days, or from 7 to 14 days. After the delay period, the API can have a substantially linear or linear release rate.

[0187] Therefore, the API layer with PLGA50:50 can begin to release the API at the target tissue approximately one week after implantation, with complete release by four weeks after implantation. This is in good agreement with the degradation data; although polymer hydration takes time, most of the PLGA50:50 has disappeared by four weeks, indicating that most of the API has been released. In addition, the non-API layer made of PLGA75:25 may serve as a mechanism for releasing the API from only one side of the device. Although the PLGA75:25 layer thinned over four to six weeks, only one sample developed small holes before the PLGA50:50 layer completely degraded. This prevents API leakage away from the target tissue site and anchors the device to the target site.

[0188] The degradation of the biodegradable polymer in the API layer can control the release of the API from the API layer during use. Thus, the degradation of the API layer in the drug delivery device can be tailored based on the biodegradable polymer in the API layer as well as the thickness of the API layer, because the thicker the API layer, the longer it takes to degrade. In some embodiments, the API layer can be configured to completely degrade within at least 3 days, at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 3.5 weeks, at least 4 weeks, at least 30 days, at least 4.5 weeks, at least 5 weeks, at least 6 weeks, at least 2 months, at least 3 months, at least 4 months, at least 6 months, at least 8 months, or at least 10 months after implantation. In some embodiments, the API layer can be configured to completely degrade within at most 2 years, at most 1 year, at most 10 months, at most 8 months, at most 6 months, at most 4 months, at most 3 months, at most 2 months, at most 6 weeks, at most 5 weeks, at most 4.5 weeks, at most 30 days, at most 4 weeks, at most 3.5 weeks, at most 3 weeks, at most 2 weeks, or at most 1 week after implantation. In some embodiments, the API layer can be configured to completely degrade within about 3 days to 10 months, 1 week to 6 months, 1 to 6 weeks, about 2 to 6 weeks, about 3 to 5 weeks, about 3.5 to 4.5 weeks, or about 4 weeks (about 30 days) after implantation. As used herein, "completely degrade" or "sufficiently degrade" refers to the layer or device degrading to less than 10% of its original mass within that period. In some embodiments, the API can be released from the API layer at a rate of at least about 1 mg API / day. In some embodiments, the API can be released from the API layer at a rate of about 1-10 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 at a rate of about 7-70 mg / week, about 7-35 mg / week, about 14-35 mg / week, or about 21-28 mg / week after implantation. In some embodiments, the degradation profile of the API layer (and API release profile) after implantation can include a lag period of about 1 day to 2 weeks.After the lag period, the degradation of the API layer (and API release) can be substantially linear or linear.

[0189] Drug release (i.e., API release) was tested in vitro in a paddle-over-disk (USP 5) apparatus (SOTAX). While this configuration is typically designed for transdermal patches, this was the most appropriate configuration because it was designed to measure unidirectional release from the patch. Specifically, a drug delivery device containing a first layer of 0.8–1 g PLGA 50:50, 100 mg paclitaxel, and 40–100 mg acetone, and a second layer on either side of the first layer consisting of 0.8–1 g PLGA 75:25 and 40–100 mg acetone, was placed in a SOTAX container, PLGA 50:50 side up, in 900 mL of 1.75 M sodium salicylate in 1x PBS. The water bath was set to 37 °C, and the paddle was set to a stirring speed of 100 rpm. The control container, containing 104.67 mg paclitaxel, did not contain a disk holder. Paclitaxel for the positive control (+CTRL) was weighed into a glass scintillation vial and placed in a dry container. 2 mL samples were taken at the following time points: 4 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, and 10 weeks. After each sample, 2 mL of 1.75% sodium salicylate in 1X PBS was added. Samples were analyzed by HPLC using a diode array detector at 229 nm. The expected drug concentration in each disk segment was based on 100 mg of drug per device. A calibration curve relating the area under the curve of the paclitaxel peak (or peak corresponding to thermal decomposition) to concentration was generated prior to sample testing. A linear equation was generated from the data to calculate the concentration for samples with concentrations within the curve range. The AUC of the paclitaxel sample was then measured, and the concentration was calculated from the equation. If the sample concentration exceeded the curve range, the sample was diluted to fall within the curve to ensure accuracy. The weights of the three drug delivery devices (i.e., discs that were not sterilized or oven-dried) and the positive control are shown in Figure 32A. Figure 32B shows the average release of drug from the three drug delivery devices, as well as the drug content of the positive control over time.Additional samples were also tested that were oven-dried (three samples) and sterilized (two samples), but this time 3 mL samples were taken instead of 2 mL samples. The oven-dried samples were placed in a 38°C oven for three days. The sterilized samples were sterilized by electron beam irradiation. The drug release of the oven-dried and sterilized drug delivery devices compared to the positive control is shown in Figure 33, and the drug release of an individual oven-dried, but not sterilized, drug delivery device is shown in Figure 34. The results showed a delay in API release of 1-2 weeks, followed by a steady, linear release over 9 weeks.

[0190] Furthermore, the degradation of the non-API layers in the drug delivery device can be tailored based on the biodegradable polymers in the non-API layers as well as the thickness of the non-API layers. In some embodiments, the non-API layers can be configured to degrade at a slower rate than the API layers so that the API is released toward the target tissue. In some embodiments, the non-API layers can be configured to degrade at the same rate as the API layers. In some embodiments, the non-API layers can be configured to degrade at a faster rate than the API layers. For example, in some embodiments, there can be a non-API layer on one side of the API layer facing the tumor (and another non-API layer (i.e., a backing layer) on the opposite side of the API layer opposite the first non-API layer). This first non-API layer can degrade faster than the API layer, resulting in a delay period in the release of the API as the non-API layers (i.e., layers that are not the backing layer) degrade first.

[0191] In some embodiments, the non-API layer can be configured to completely degrade within at least 5 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, or at least 1 year after implantation. In some embodiments, the non-API layer can be configured to completely degrade within at most 3 years, at most 2 years, at most 1 year, at most 10 months, at most 8 months, at most 6 months, at most 4 months, at most 3 months, at most 12 weeks, at most 11 weeks, at most 10 weeks, at most 8 weeks, at most 6 weeks, at most 5 weeks, at most 4 weeks, at most 3 weeks, or at most 2 weeks after implantation. In some embodiments, the non-API layer can be configured to completely degrade in about 1 week to 2 years, 1 week to 1 year, 1 week to 6 months, about 4 to 14 weeks, about 6 to 12 weeks, about 8 to 12 weeks, about 9 to 11 weeks, or about 10 weeks after implantation.

[0192] As described above, for open, laparoscopic, robotic, or endoscopic implantation, drug delivery devices must be sufficiently flexible and / or small enough to pass through a trocar or other working channel of an endoscope (e.g., a robotic endoscope). A study was conducted to determine whether passing through a trocar altered the device's surface or its API content. Specifically, a drug delivery device containing a first layer of 0.8–1 g PLGA 50:50, 90–105 mg paclitaxel, and 40–100 mg acetone, and a second layer on either side of the first layer composed of 0.8–1 g PLGA 75:25 and 40–100 mg acetone, was passed through a 10 mm trocar 10 times. The samples were observed before and after the procedure, their thickness was measured before and after the procedure, and the drug content of the samples was measured and compared to that of samples not passed through a trocar. Microscopic examination revealed slight surface scratches, but no difference in drug content was observed. During handling, the drug delivery devices passed easily through the trocar. No differences were observed between the group of devices measured, weighed, and imaged and the group of devices handled through the trocar and then measured, weighed, and imaged. Most images showed no visible changes, such as scratches on the surface. The most obvious damage to any device appeared to occur in the control drug delivery device during micrometer measurement. There was no change in the dimensions or weight of the drug delivery device. Finally, there was no difference in drug content between groups, indicating leakage of the drug content in the trocar, as measured by dissolving the devices in acetonitrile and diluting 1:1000 for HPLC analysis on an Agilent HPLC.

[0193] Cancer treatment In some embodiments, the target tissue may be pancreatic tissue. For example, the target tissue may be cancerous tissue / cells (e.g., a tumor or tumors) on the pancreas. Accordingly, the drug delivery devices disclosed herein can be used to treat tumors of the pancreas. Specifically, various cancers that the drug delivery devices may be useful in treating include, but are not limited to, pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the drug delivery devices can be used to treat resectable and / or unresectable cancers. In some embodiments, the drug delivery devices herein can be used to treat cancers ranging from immediately unresectable to non-metastatic. In some embodiments, the drug delivery devices can be used to treat patients after cancer resection to prevent recurrence. For example, the drug delivery devices can be used to treat patients with borderline resectable or locally advanced pancreatic adenocarcinoma. In some embodiments, the cancer in the pancreas treated by the drug delivery device can be a primary pancreatic tumor or a pancreatic tumor that has metastasized and spread to the pancreas. In some embodiments, the drug delivery device can be used to treat patients with immediately unresectable pancreatic cancer, non-metastatic pancreatic cancer, borderline resectable pancreatic cancer, resectable pancreatic cancer, locally advanced pancreatic cancer, metastatic pancreatic cancer, and / or cancer that has metastasized and spread to the pancreas.

[0194] In some embodiments, the drug delivery devices disclosed herein can be placed in the peritumor area of ​​interest (with the API layer facing and in contact with the peritumor area of ​​interest) and biodegrade within the patient's body within about 1 week to 2 years, about 1 to 52 weeks, about 1 to 26 weeks, about 1 to 24 weeks, about 1 to 20 weeks, about 1 to 15 weeks, about 4 to 12 weeks, about 6 to 12 weeks, about 8 to 12 weeks, about 9 to 11 weeks, or about 10 weeks after implantation. In some embodiments, the tumor may be located inside (i.e., not on) the surface of an organ, and the drug delivery device is placed on the peritumor surface of the organ. As described above, the drug delivery device can be placed directly in the peritumor area of ​​interest (e.g., around a pancreatic tumor) using minimally invasive, standard surgical techniques during routine staging evaluations. In some embodiments, multiple drug delivery devices can be placed directly in the peritumor area of ​​interest. In some embodiments, the drug delivery device can be rolled into a tubular shape, inserted via a surgical procedure, positioned over the area around the tumor of interest, and sutured into place. In some embodiments, the size (e.g., diameter or surface area) of the drug delivery device allows the surgeon to cover the targeted tissue site (e.g., the pancreatic head and neck, and edges that drape the area near the superior mesenteric artery and superior mesenteric vein).

[0195] In some embodiments, degradation of the API layer can control the release of the API for 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, degradation of the API layer can control the release of the API for at most 2 years, at most 1 year, at most 10 months, at most 8 months, at most 6 months, at most 4 months, at most 3 months, at most 2 months, at most 6 weeks, at most 5 weeks, at most 4.5 weeks, at most 30 days, at most 4 weeks, at most 3.5 weeks, at most 3 weeks, at most 2 weeks, or at most 1 week after implantation. In some embodiments, degradation of the API layer can control the release of the API for about 3 days to 10 months, 1 week to 6 months, 1 to 6 weeks, about 2 to 6 weeks, about 3 to 5 weeks, about 3.5 to 4.5 weeks, or about 4 weeks (about 30 days) after implantation. In some embodiments, a biodegradable polymer in the API layer can provide a controlled, sustained release of the API over this period while the cancer-facing side of the device is absorbed by the body. In some embodiments, the non-cancer-facing side of the device (non-API layer) can help ensure that the drug delivery device maintains contact with the target tissue (e.g., tumor) during drug release and can also help prevent the drug delivery device from escaping from the intended area. This non-API layer can then be fully degraded after the API layer has fully degraded and released all of the API. Figure 26 shows an exemplary flowchart illustrating how the drug delivery devices disclosed herein can attack live tumor cells in some embodiments. In some embodiments, the non-API layer can be fully degraded simultaneously with or faster than the API layer.

[0196] Studies in large animals (i.e., pigs) and human cadavers have shown that the drug delivery device disclosed herein can be successfully deployed on the peritumoral surface of the pancreas via standard laparoscopic procedures. Specifically, two 30-day studies were conducted in pig models to evaluate safety, toxicity, and biodistribution. Parameters included body weight, hematology, urinalysis, drug concentrations in the blood and at the implantation site, and histological evaluation of major organs. In both studies, the drug delivery device was designed to locally deliver paclitaxel for 30 days. In the first study, the drug delivery device was implanted laparoscopically on the peritoneal surface to test the feasibility and tolerability of paclitaxel. In the second study, the drug delivery device was placed directly on the ventral surface of a healthy pig pancreas via open surgery, as shown in Figures 27A-27B. Blood samples for paclitaxel analysis were collected on day 0 (pre-implantation and post-implantation), twice weekly thereafter, and on day 31 (pre-necropsy), processed to plasma, stored frozen, and sent for analysis of paclitaxel concentrations. Animals were euthanized on day 31, and limited necropsies were performed. All frozen plasma and designated tissue samples were processed according to appropriate laboratory and standard operating procedures and analyzed for paclitaxel content by LC-MS. Protein precipitation extraction was used for plasma and tissue samples, and tissue samples were homogenized. For device testing, all samples were immersed in 0.5% formic acid in 9:1 (v:w) methanol and sonicated in an ice bath for 30 minutes. The solution was transferred to a new container on ice. This process was repeated two more times. A final 9:1 (v:w) rinse was added and transferred to the final vial. Implants and tissue samples were paraffinized and stained with H&E for histological evaluation. Light microscopy was used to characterize the host response, using standard nomenclature of pathology, including type of inflammation, fibrosis, collagen deposition / content, and vascularity / vascular integration.

[0197] Animals appeared healthy throughout the 30 days in both studies and did not exhibit the debilitating effects typically associated with IV chemotherapy (weight gain would be expected in healthy pigs not receiving chemotherapy, but weight loss would be expected in IV chemotherapy, as shown in Figure 28). After 30 days of in vivo paclitaxel release, the non-API backing layer was still present at the implantation site and showed no signs of migration. Visible redness was observed in the underlying tissue of the abdominal wall, but histology showed minimal bleeding and necrosis, as shown in Figure 29. A thin capsule and fibrosis were observed in the underlying tissue of the pancreas, as shown in Figure 30, but there was minimal impact on surrounding structures. The drug was released and accumulated primarily beneath the drug delivery device at concentrations up to 40 μM (as shown in Figure 31). Serum paclitaxel concentrations remained below the limit of quantification throughout the 30-day treatment period, verifying the ability of the drug delivery device to deliver drug only to its intended site. Therefore, there appears to be no diffusion outside the intended area.

[0198] To verify the feasibility of minimally invasive surgical insertion, the drug delivery device disclosed herein was placed directly onto the pancreas of three human cadavers under laparoscopy. The drug delivery device was consistently and effectively placed during minimally invasive surgery without significantly extending procedure time. More specifically, the time required for laparoscopic visualization of the pancreas was approximately 25 minutes, and the time required for placement and suturing of the drug delivery device into the pancreas was approximately 10-25 minutes, approximately 10-20 minutes, or approximately 15-20 minutes. Therefore, placement of the drug delivery device at the target site only slightly extended procedure time. The drug delivery device perfectly conformed to pancreatic tissue, allowing for intimate contact with the intended tissue for drug delivery and covering areas of the pancreas where critical tumor and vasculature connections are often present.

[0199] Finally, the drug delivery device disclosed herein was used in a Phase I clinical trial in three patients with locally advanced pancreatic ductal adenocarcinoma (PDAC) and treated with a drug delivery device in the form of a circular patch containing a first layer of 1 g of PLGA 50:50, 90-105 mg of paclitaxel, and 40-100 mg of acetone, and a second layer (backing layer) on either side of the first layer, consisting of 1 g of PLGA 75:25 and 40-100 mg of acetone.

[0200] Prior to implantation, the surgeon prepared each drug delivery device by suturing four evenly spaced sutures around the edge of the second layer, near the four cardinal directions of the circular drug delivery device. After confirming that the subject was negative for visual metastatic disease by diagnostic laparoscopy, the patch was placed directly onto the surface of the pancreas overlying the tumor with a trocar using standard laparoscopic instruments. The implantation procedure took 18 to 32 minutes in all three patients treated to date. The device was correctly oriented on the pancreas and successfully positioned with the paclitaxel layer facing the pancreas in all cases. No adverse events or device failures were reported during any of the procedures. The ease of preparation was rated as very easy for all procedures, and placement was rated as very easy or not difficult.

[0201] Tumor volume, lateral, and anterior / posterior measurements were taken for each patient at various time points before and after implantation. Specifically, the lateral (T) measurement can be the length of the tumor's largest dimension. The anterior / posterior (AP) dimension or diameter can be the length of the tumor perpendicular to the drug delivery device. In some embodiments, the anterior / posterior dimension or diameter can be the length of the tumor in the direction of drug release / delivery. In some embodiments, the anterior / posterior dimension can be the largest dimension of the tumor perpendicular to the drug delivery device. The lateral dimension can be measured manually by the reader on the longest diameter tumor slice in the CT software. The anterior-posterior diameter can be measured manually by the reader on the longest diameter tumor slice perpendicular to the drug delivery device in the CT software. Tumor volume can be measured manually by the reader by measuring the lesion depicted on the axial image for each tumor slice calculated by the 3D software.

[0202] Additionally, patient blood can be tested for CA19-9 using standard laboratory tests and for paclitaxel using a pharmacokinetic assay. Standard RECIST (Response Evaluation Criteria in Solid Tumors) assessments were used to determine clinical outcomes (e.g., partial response, remained unresectable, metastatic, primary stable / progressive, stable disease, etc.).

[0203] All patients began modified FOLFIRINOX (oxaliplatin, leucovorin, fluorouracil, and irinotecan) 21 days (±7 days) after device implantation. The third patient had their dose increased after the first cycle of treatment, and the first patient also underwent radiation therapy approximately 7 months after device implantation to treat their tumor after completing systemic chemotherapy.

[0204] This phase I clinical trial demonstrated local responses in the initial cohort of patients, an excellent safety profile (e.g., well tolerated with no SAEs in all patients, no peritonitis, pancreatitis, infections, hematologic toxicities, and no systemically detectable levels of paclitaxel), and minimal increase in operating room time (i.e., less than approximately 20 minutes) due to use of the drug delivery device.

[0205] The first patient had locally advanced disease. The implantation procedure took 25 minutes for the first patient, and the clinical outcome was a partial response, remaining unresectable. Figure 35A shows a graph of the first patient's tumor's maximum dimension over 23 weeks, and Figure 35B shows data collected regarding tumor volume and size over 23 weeks. As shown in Figure 35B, the first patient's tumor volume decreased by 11% 2 weeks after implantation, before the start of systemic chemotherapy, and by more than 70% 23 weeks after implantation. In addition, the maximum tumor dimension decreased by 50% 23 weeks after implantation, and the anterior / posterior tumor dimensions decreased by 27% over the same period. Figures 36A-40B show radiographic images (dashed lines) of the first patient's tumor at baseline, before chemotherapy 2 weeks after implantation, before cycle 5 10 weeks after implantation, before cycle 9 16 weeks after implantation, and before cycle 12 24 weeks after implantation, as well as 3D renderings of the tumor. The first patient's last visit was at 12 months, and the clinical outcome was RECIST progression.

[0206] The second patient had locally advanced disease. The implant procedure time for the second patient was 18 minutes, and the clinical outcomes were metastatic, primary stable, or progressive disease. The second patient presented with a large tumor, and distant metastases were diagnosed at the 3-month visit. It is possible that the subject already had undiagnosed metastatic disease at the time of presentation. Despite the progression of distant metastatic disease, the second patient experienced anterior-posterior tumor shrinkage, and the tumor remained stable, indicating that the patient benefited from local treatment. Figure 41A shows a graph of the maximum tumor dimension for the second patient. An "*" in the graph indicates that systemic chemotherapy failed and the patient developed metastatic disease. Figure 41B shows the collected data regarding tumor volume and size. As shown in Figure 41B, the anterior-posterior length of the tumor still shrank by 16%. Figures 42A-45B show radiographic images (dashed lines) of the second patient's tumor at baseline, before chemotherapy 2 weeks after implantation, before cycle 5 10 weeks after implantation, and before cycle 9 16 weeks after implantation, as well as 3D renderings of the tumor. The second patient's last visit was at 6 months, with clinical outcomes of RECIST metastatic, primary stable / progressive.

[0207] The third patient also had locally advanced disease. The implantation procedure took 32 minutes for the third patient, and the clinical outcome was stable disease. Figure 46A shows a graph of the maximum tumor dimension for the third patient, and Figure 46B shows the collected data for tumor volume and size. The "*" in Figure 46A indicates that the analysis of transverse dimensions used data from week 2 due to baseline uncertainty. Figures 47A-51B show radiographic images (dashed lines) of the third patient's tumor at baseline, before chemotherapy 2 weeks after implantation, before cycle 5 10 weeks after implantation, before cycle 9 16 weeks after implantation, and before cycle 12 24 weeks after implantation, as well as 3D renderings of the tumor. The third patient's last visit was at 12 months, and the clinical outcome was RECIST progression (metastatic).

[0208] From the three patients in the clinical trial, the drug delivery device was easily incorporated into laparoscopic procedures. The device was successfully implanted using standard laparoscopic configurations with only a small increase in procedure time, and there are opportunities for further time reduction through robotic procedures and / or optimization, as shown in Figure 52.

[0209] Figure 53 shows the reduction in tumor size for the first patient from the clinical trial. As previously mentioned, the first patient's tumor shrank by more than 70% from baseline. In addition, a significant response in the anterior-posterior direction (direction of drug release) measured in the axial plane was observed prior to cycle 5, accompanied by a significant reduction in the swelling effect of the pancreatic lesion, which was confirmed at the next visit.

[0210] Figure 54 shows the change in tumor volume from baseline for three patients in a clinical trial. Dramatic tumor volume reductions for the first patient (approximately 70%) and the third patient (approximately 40%) were confirmed at the final scan. In addition, the second patient, who failed systemic treatment and progressed to metastatic disease, experienced minimal local volume change. Thus, the drug device disclosed herein can stabilize and / or reduce tumor size (e.g., volume, lateral dimension, or anterior / posterior dimension).

[0211] Figure 55 shows the anterior / posterior shrinkage of tumors in three patients. This strong shrinkage response in the anterior / posterior diameter supports the ability of the drug delivery device to unidirectionally release API onto the tumor. This is also shown in Figure 53, where the implant is shown as a dashed-dotted line, the tumor 2 weeks after implantation is shown as a short-dashed line, and the tumor 24 weeks after implantation is shown as a long-dashed line. As can be seen from the arrows in Figure 53, the tumor shrank in the anterior-posterior direction (i.e., perpendicular to the drug delivery device).

[0212] Figures 56A-B show the change in the amount of CA19-9 in the blood of three patients from the clinical trial over time. As shown in the figures, patients 1 and 3 experienced a 28-37% decline from baseline to day 21. Patient 2, who had metastatic disease, showed a slight decline of 21% from days 7 to 14. The "*" in Figure 56A indicates that the data for day 14 for patient 3 was the same as day 7 for continuity.

[0213] Additionally, no SAEs were reported in any patient during or after the 28-day safety window. There was no evidence of pancreatitis, peritonitis, or infection. Paclitaxel was not detected in peripheral blood sampling in any patient. For example, Table 1 below of the modified ITT population shows that no patients from the clinical trial had detectable paclitaxel in peripheral blood sampling. [Table 1]

[0214] The lower limit of detection for the pharmacokinetic assay was 40 ng / mL. An undetectable result indicates that paclitaxel was below 40 ng / mL at all time points for all patients. The percentages indicate how many patients had undetectable paclitaxel in their peripheral blood samples. For example, in the third column, 100% indicates that no detectable paclitaxel was found in the peripheral blood samples of both patient 2 and patient 3. The 66.7% in the final column was due to the absence of measurements for patient 1 at a given time point. As shown in the table above, throughout the clinical research study, paclitaxel was undetectable in the peripheral blood samples of any patient.

[0215] The overall response rates for the three patients are shown in Table 2 below for the modified ITT population. [Table 2]

[0216] The best overall response rate is not dependent on time point, and can refer to the best response of each patient to treatment according to standard RECIST assessment during clinical trial.For example, the best response of the first patient is stable disease response, and the same applies to one of the second and third patients.The other of the best responses of the second and third patients to treatment is partial response.The overall response rate indicates that, except for stable disease response, only one of the patients has a response that is partial response.

[0217] Furthermore, there was no delay in the initiation of planned systemic therapy. Thus, the drug delivery device disclosed herein performs as predicted in preclinical studies and can promote local disease control in a progressive cohort.

[0218] The drug delivery devices disclosed herein can stabilize and / or reduce tumor size after implantation onto a tumor. Specifically, the drug delivery devices disclosed herein can reduce tumor volume by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% after implantation (100% reduction is tumor disappearance). The drug delivery devices disclosed herein can reduce the largest dimension of a tumor by at least 5%, at least 10%, at least 25%, at least 40%, or at least 50% after implantation. The drug delivery devices disclosed herein can reduce the anterior / posterior dimension of a tumor (i.e., the orthogonal dimension from the drug delivery device) by at least 10%, at least 15%, at least 20%, or at least 25% after implantation. In some embodiments, the change in tumor volume, largest dimension, and / or anterior / posterior dimension of a tumor can be within ±10% or ±5% after implantation of the drug delivery device. In some embodiments, the reduction in tumor size, reduction in tumor volume, reduction in the largest dimension of the tumor, and / or reduction in the anterior / posterior diameter perpendicular to the drug delivery device can occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body.

[0219] In some embodiments, the drug delivery devices disclosed herein can reduce the size of cancerous tissue (e.g., a tumor) in a patient. In some embodiments, the tumor size is reduced 1 day, 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 23 weeks, or 24 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume decreases 1 day, 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 23 weeks, or 24 weeks after implantation of the drug delivery device. In some embodiments, the tumor's greatest dimension decreases 1 day, 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 23 weeks, or 24 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior diameters perpendicular to the drug delivery device decrease 1 day, 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 23 weeks, or 24 weeks after implantation of the drug delivery device. In some embodiments, the stabilization and / or reduction in tumor size, stabilization and / or reduction in tumor volume, stabilization and / or reduction in largest tumor dimension, and / or reduction in the anterior / posterior diameters perpendicular to the drug delivery device can occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body.

[0220] In some embodiments, the size of the tumor (e.g., volume, lateral dimension, anterior / posterior dimension, etc.) stabilizes and / or decreases after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the volume of the tumor decreases by at least about 1%, at least about 2%, at least about 5%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 34%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 59%, at least about 60%, at least about 65%, at least about 68%, at least about 70%, at least about 72%, at least about 75%, or at least about 80% after implantation of the drug delivery device. In some embodiments, the tumor volume decreases by up to about 100%, up to about 95%, up to about 90%, up to about 85%, up to about 80%, up to about 75%, up to about 70%, up to about 65%, up to about 60%, up to about 55%, up to about 50%, up to about 40%, up to about 35%, up to about 30%, or up to about 25% after implantation of the drug delivery device. In some embodiments, the change in tumor volume may be within ±25%, ±20%, ±15%, ±10%, ±5%, ±2%, or ±1% after implantation of the drug delivery device. In some embodiments, the stabilization and / or reduction in tumor volume in this paragraph may occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body. In some embodiments, the volume of the tumor in this paragraph stabilizes and / or shrinks after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the volume of the tumor in this paragraph stabilizes and / or shrinks after implantation of the drug delivery device with systemic chemotherapy.

[0221] In some embodiments, the tumor volume is reduced by at least about 1%, at least about 2%, at least about 5%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, or at least about 15% 2 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by about 1-20% or about 5-15% 2 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 59%, at least about 60%, or at least about 65% 9 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 34%, at least about 35%, or at least about 40% 11 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 68%, at least about 70%, or at least about 75% 15 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45% 16 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 72%, at least about 75%, or at least about 80% 23 weeks after implantation of the drug delivery device. In some embodiments, the tumor volume is reduced by at least about 20%, at least about 25%, at least about 30%, at least about 34%, at least about 35%, at least about 40%, or at least about 45% 24 weeks after implantation of the drug delivery device.In some embodiments, the reduction in tumor volume in this paragraph can occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body. In some embodiments, the reduction in tumor volume in this paragraph occurs after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the reduction in tumor volume in this paragraph occurs after implantation of the drug delivery device with systemic chemotherapy.

[0222] In some embodiments, the maximum dimension of the tumor is reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 8%, at least about 10%, at least about 11%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 55% after implantation of the drug delivery device. In some embodiments, the maximum dimension of the tumor is reduced by up to 100%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 40%, up to 30%, or up to 25% after implantation of the drug delivery device. In some embodiments, the change in the tumor's maximum dimension may be within ±25%, ±20%, ±15%, ±10%, ±5%, ±2%, or ±1% after implantation of the drug delivery device. In some embodiments, the stabilization and / or reduction in the tumor's maximum dimension in this paragraph may occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body. In some embodiments, the tumor's maximum dimension in this paragraph stabilizes and / or reduces after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the tumor's maximum dimension in this paragraph stabilizes and / or reduces after implantation of the drug delivery device with systemic chemotherapy.

[0223] In some embodiments, the largest dimension of the tumor is reduced by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, or at least about 10% 2 weeks after implantation of the drug delivery device. In some embodiments, the largest dimension of the tumor is reduced by about 1-10% or about 1-5% 2 weeks after implantation. In some embodiments, the largest dimension of the tumor is reduced by at least about 5%, at least about 8%, at least about 10%, at least about 12%, at least about 15%, or at least about 20% 9 weeks after implantation of the drug delivery device. In some embodiments, the largest dimension of the tumor is reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 50% 15 weeks after implantation of the drug delivery device. In some embodiments, the maximum dimension of the tumor is reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 55% 23 weeks after implantation of the drug delivery device. In some embodiments, the maximum dimension of the tumor is reduced by at least about 5%, at least about 8%, at least about 10%, at least about 11%, at least about 12%, at least about 15%, or at least about 20% between 2 and 11 weeks after implantation of the drug delivery device. In some embodiments, the maximum dimension of the tumor in this paragraph is reduced after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the maximum dimension of the tumor in this paragraph is reduced after implantation of the drug delivery device in conjunction with systemic chemotherapy.

[0224] In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by up to about 100%, up to about 90%, up to about 75%, up to about 50%, up to about 40%, up to about 35%, up to about 30%, or up to about 25% after implantation of the drug delivery device. In some embodiments, the change in the anterior / posterior dimension perpendicular to the drug delivery device on the tumor can be within ±25%, ±20%, ±15%, ±10%, ±5%, ±2%, or ±1% after implantation of the drug delivery device. In some embodiments, the stabilization and / or reduction of the anterior / posterior dimensions perpendicular to the drug delivery device on the tumor in this paragraph can occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body. In some embodiments, the anterior / posterior dimensions perpendicular to the drug delivery device on the tumor in this paragraph stabilize and / or reduce after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the anterior / posterior dimensions perpendicular to the drug delivery device on the tumor in this paragraph stabilize and / or reduce after implantation of the drug delivery device with systemic chemotherapy.

[0225] In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% two weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% three weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by about 5-40%, about 10-35%, about 15-30%, 20-30%, or about 25-30% two or three weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor is reduced by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 9 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor is reduced by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 11 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor is reduced by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 15 weeks after implantation of the drug delivery device.In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor is reduced by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 16 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor is reduced by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 17 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 23 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor decreases by at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 21%, at least about 25%, at least about 27%, at least about 30%, or at least about 35% 24 weeks after implantation of the drug delivery device. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor in this paragraph decreases after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the anterior / posterior dimension perpendicular to the drug delivery device on the tumor in this paragraph decreases after implantation of the drug delivery device together with systemic chemotherapy.

[0226] In some embodiments, the amount of CA19-9 protein in the patient's blood is reduced by at least about 20%, at least about 25%, at least about 28%, at least about 30%, or at least about 33%, at least about 35%, at least about 36%, or at least about 40% after implantation of the drug delivery device. In some embodiments, the amount of CA19-9 protein in the patient's blood is reduced by up to about 100%, up to about 75%, up to about 50%, up to about 40%, up to about 35%, or up to about 30% after implantation. In some embodiments, the change in the amount of CA19-9 protein in the patient's blood can be within ±25%, ±20%, ±15%, ±10%, ±5%, ±2%, or ±1% after implantation of the drug delivery device. In some embodiments, the stabilization and / or reduction in the amount of CA19-9 protein in the patient's blood in this paragraph can occur after the drug delivery device has completely dissolved in the patient's body, after the drug delivery device has partially dissolved in the patient's body, and / or after a portion of the drug delivery device (e.g., the API layer) has completely dissolved in the patient's body. In some embodiments, the amount of CA19-9 protein in the patient's blood in this paragraph stabilizes and / or decreases after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the amount of CA19-9 protein in the patient's blood in this paragraph stabilizes and / or decreases after implantation of the drug delivery device together with systemic chemotherapy.

[0227] In some embodiments, the amount of CA19-9 protein in the patient's blood is reduced by at least about 20%, at least about 25%, at least about 30%, or at least about 33% two weeks after implantation of the drug delivery device. In some embodiments, the amount of CA19-9 protein in the patient's blood is reduced by about 15-45%, about 20-40%, about 25-35%, or about 30-35% two weeks after implantation of the drug delivery device. In some embodiments, the amount of CA19-9 protein in the patient's blood is reduced by at least about 20%, at least about 25%, at least about 28%, at least about 30%, at least about 33%, at least about 35%, at least about 36%, or at least about 40% three weeks after implantation of the drug delivery device. In some embodiments, the amount of CA19-9 protein in the patient's blood in this paragraph is reduced after implantation of the drug delivery device without systemic chemotherapy. In some embodiments, the amount of CA19-9 protein in the patient's blood in this paragraph is reduced after implantation of the drug delivery device in conjunction with systemic chemotherapy.

[0228] In some embodiments, methods of treating tissue (e.g., cancer) with a drug delivery device disclosed herein may result in no serious adverse effects (SAEs). In some embodiments, methods of treating tissue (e.g., cancer) with a drug delivery device disclosed herein may result in no evidence of at least one selected from the group consisting of pancreatitis, peritonitis, and infection. In some embodiments, methods of treating tissue (e.g., cancer) with a drug delivery device disclosed herein may result in no detectable API from the drug delivery device in a peripheral blood sample of a patient implanted with the drug delivery device. In some embodiments, methods of treating tissue (e.g., cancer) with a drug delivery device disclosed herein may elicit at least one of a RECIST outcome of partial response, complete response, or stable disease in a patient implanted with the drug delivery device. In some embodiments, the RECIST outcome may be after the drug delivery device has completely dissolved in the patient's body. In some embodiments, the RECIST outcome may be after the drug delivery device has partially dissolved in the patient's body. In some embodiments, RECIST outcomes may be at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, or at least about 1 year after implantation of the drug delivery device.

[0229] In some embodiments, methods of treating tissue (e.g., cancer) with a drug delivery device disclosed herein may not result in toxicity to the patient from the drug delivery device. In some embodiments, methods of treating tissue with a drug delivery device disclosed herein may result in at least one of improved quality of life, pain relief, and local disease control in patients implanted with the drug delivery device. In some embodiments, the drug delivery device may extend a patient's progression-free survival (PFS). Figure 57 shows Kaplan-Meier curves of PFS within 12 months for three patients from the clinical trial described above. This curve indicates the likelihood that a patient will survive without tumor or cancer progression after initiating treatment with a drug delivery device (i.e., implantation of a drug delivery device) based on standard RECIST assessments for defining tumor or cancer progression (e.g., growth of the primary tumor and / or metastatic lesions according to RECIST). As shown in Figure 57, patients have a 1 / 3 chance of surviving without progression within 12 months of implantation of the drug delivery device. The first step in the Kaplan-Meier curve around the 3-month time point is because one patient progressed at that time, and the second step around the 9-month time point is because one patient progressed at that time, but the final patient showed no signs of progression for the entire 12 months.

[0230] In some embodiments, progression-free survival within 12 months of implantation of the drug delivery device is at least about a 5% chance, at least about a 10% chance, at least about a 15% chance, at least about a 20% chance, at least about a 25%, at least about a 30% chance, at least about a 1 / 3 chance, at least about a 35% chance, at least about a 40% chance, at least about a 45% chance, at least about a 50% chance, at least about a 55% chance, at least about a 60% chance, at least about a 65% chance, or at least about a 2 / 3 chance. In some embodiments, progression-free survival within 9 months of implantation of the drug delivery device is at least about a 25% chance, at least about a 30% chance, at least about a 35% chance, at least about a 40% chance, at least about a 45%, at least about a 50% chance, at least about a 55% chance, at least about a 60% chance, at least about a 65% chance, at least about a ⅔ chance, at least about a 70% chance, at least about a 75% chance, at least about an 80% chance, at least about an 85% chance, or at least about a 90% chance. In some embodiments, progression-free survival within 3 months of implantation of the drug delivery device is at least about a 50% chance, at least about a 55% chance, at least about a 60% chance, at least about a 65% chance, at least about a ⅔ chance, at least about a 70% chance, at least about a 75% chance, at least about an 80% chance, at least about an 85% chance, at least about a 90% chance, at least a 95% chance, or at least a 100% chance.

[0231] Figure 58 shows Kaplan-Meier curves for overall survival within 12 months for three patients from the clinical trial of the drug delivery device described above. As shown in Figure 58, the curves indicate a 100% probability of survival within 12 months of implantation, as all patients survived the course of the study after implantation. One of the patients in Figure 58 has a censored observation because the patient did not sign on for the long-term 12-month follow-up. Instead, the patient completed the 6-month study.

[0232] In some embodiments, the drug delivery device can convert an unresectable tumor to a resectable tumor. In other words, the drug delivery device can improve tumor resection rates. In some embodiments, the drug delivery device can downstage the disease (i.e., downstage the cancer). In some embodiments, the drug delivery device can extend the overall survival of a patient. In some embodiments, the drug delivery device can reduce the patient's risk of metastasis. In some embodiments, the drug delivery device can prevent metastasis in a patient. In some embodiments, the drug delivery device can prevent metastasis for at least 6 months, at least 1 year, or at least 2 years.

[0233] In some embodiments, the drug delivery devices and methods disclosed herein can be used in conjunction with systemic chemotherapy, radiation therapy, and / or surgery. In some embodiments, the drug delivery devices and methods disclosed herein can improve tumor penetration of systemic chemotherapy in patients. In some embodiments, systemic chemotherapy can be administered (or administration can begin) after implantation of the drug delivery device (e.g., 2 weeks, 3 weeks, 4 weeks, etc. after implantation). In some embodiments, systemic chemotherapy can be administered (or administration can begin) at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 3 months, at least 6 months, or at least 1 year after implantation of the drug delivery device.

[0234] The drug delivery device disclosed herein can alter the route of administration to target only the desired area, thereby increasing the amount of drug reaching the tumor for the purpose of enhancing the efficacy of treatment. Thus, the drug delivery device can be applied to PDAC patients (i) as neoadjuvant treatment before surgery to control progression and downsize local progression and marginal anatomy to improve resectability, (ii) after resection to reduce the local recurrence rate, and (iii) in metastatic patients to control local progression and improve quality of life.

[0235] Additional definitions Unless otherwise defined, all terminology, notations, and other technical and scientific terms 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 pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from that generally understood in the art.

[0236] Reference herein to "about" a value or parameter includes (describes) variations on the value or parameter itself. For example, a reference to "about X" includes a reference to "X." Furthermore, reference to the terms "less than," "greater than," "at most," "at least," "less than or equal to," "greater than or equal to," or other similar terms following a series of values ​​or parameters means that the term applies to each value or parameter in the series. 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.

[0237] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term "and / or," as used herein, refers to and encompasses any and all possible combinations of one or more of the associated listed items. It should further be understood that, as used herein, the terms "includes," "including," "comprises," and / or "comprising" 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.

[0238] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from a disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, slowing or slowing the progression of the disease, improving the disease state, providing remission (partial or total) of the disease, reducing the dosage of one or more other pharmaceutical agents required to treat the disease, slowing the progression of the disease, improving quality of life, and / or prolonging survival. "Treatment" also encompasses alleviating the pathological consequences of cancer. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0239] This application discloses several numerical ranges in the text and figures, and because the disclosure can be practiced throughout the disclosed numerical ranges, the disclosed numerical ranges inherently support any range or value within the disclosed numerical range, including the endpoints, even if an exact range limitation is not literally stated herein.

[0240] The above description is presented to enable any person skilled in the art to make and use the disclosure, and is provided in the context of a particular application and its requirements. Various modifications to the preferred embodiment will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the disclosure. Thus, the disclosure is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features disclosed herein.

Claims

1. 1. A method of treating pancreatic cancer, comprising: implanting a drug delivery device in a peri-tumoral region of the patient's pancreas, wherein the drug delivery device comprises: a first layer comprising an API, a solvent, and at least 70% by weight of a first biodegradable polymer; a second layer on one side of the first layer, the second layer comprising a solvent and at least 85% by weight of a second biodegradable polymer; and releasing the API from the drug delivery device into the pancreatic tumor by in vivo degradation of the first biodegradable polymer; wherein the tumor shrinks in size after implantation of the drug delivery device.

2. 10. The method of claim 1, wherein the tumor volume is reduced by at least 10% after implantation of the drug delivery device.

3. 3. The method of claim 2, wherein the tumor volume is reduced by at least 40% after implantation of the drug delivery device.

4. 4. The method of claim 3, wherein the tumor volume is reduced by at least 70% after implantation of the drug delivery device.

5. The method of any one of claims 1 to 4, wherein the largest dimension of the tumor is reduced by 11% after implantation of the drug delivery device.

6. 7. The method of claim 6, wherein the greatest dimension of the tumor is reduced by at least 50% after implantation of the drug delivery device.

7. 7. The method of any one of claims 1 to 6, wherein the anterior / posterior diameter of the tumor perpendicular to the drug delivery device on the tumor is reduced by 15% after implantation of the drug delivery device.

8. 8. The method of claim 7, wherein the anterior / posterior diameter of the tumor perpendicular to the drug delivery device on the tumor is reduced by at least 25% after implantation of the drug delivery device.

9. 9. The method of claim 8, wherein the anterior / posterior diameter is in the direction of API release from the drug delivery device.

10. 10. The method of any one of claims 1 to 9, further comprising administering systemic chemotherapy after implantation of the drug delivery device.

11. 11. The method of claim 10, wherein the drug delivery device improves tumor penetration of systemic chemotherapy.

12. The method of any one of claims 1 to 11, wherein the clinical outcome after implantation of the drug delivery device is RECIST partial response, RECIST complete response, or RECIST stable disease.

13. 13. The method of any one of claims 1-12, wherein no API is found in the patient's blood throughout the treatment of pancreatic cancer.

14. The method of any one of claims 1 to 13, wherein the tumor is pancreatic ductal adenocarcinoma.

15. The method of any one of claims 1 to 14, wherein the drug delivery device improves the quality of life of the patient.

16. The method of any one of claims 1 to 15, wherein the drug delivery device relieves pain in the patient.

17. The method of any one of claims 1 to 16, wherein the drug delivery device locally controls the pancreatic cancer.

18. The method of any one of claims 1 to 17, wherein the drug delivery device extends the progression-free survival (PFS) of the patient.

19. The method of any one of claims 1 to 18, wherein the drug delivery device converts an unresectable tumor into a resectable tumor.

20. 20. The method of claim 19, wherein the drug delivery device improves resection rates for pancreatic cancer in the patient.

21. The method of any one of claims 1 to 20, wherein the drug delivery device downstages the pancreatic cancer.

22. The method of any one of claims 1 to 21, wherein the drug delivery device increases the overall survival of the patient.

23. The method of any one of claims 1 to 22, wherein the drug delivery device reduces the risk of metastasis in the patient.

24. 24. The method of claim 23, wherein the drug delivery device prevents metastases in the patient.

25. 25. The method of any one of claims 1 to 24, wherein the tumor volume is reduced by at least 5% two weeks after implantation of the drug delivery device.

26. 26. The method of any one of claims 1 to 25, wherein the greatest dimension of the tumor is reduced by at least 3% two weeks after implantation of the drug delivery device.

27. 27. The method of any one of claims 1 to 26, wherein the anterior / posterior diameter of the tumor perpendicular to the drug delivery device on the tumor is reduced by at least 5% two weeks after implantation of the drug delivery device.

28. 28. The method of any one of claims 1 to 27, wherein the amount of CA19-9 protein in the patient's blood is reduced by at least 20% two weeks after implantation of the drug delivery device.

29. 29. The method of any one of claims 25 to 28, further comprising administering systemic chemotherapy at least one week after implantation of the drug delivery device.

30. 30. The method of any one of claims 1 to 29, wherein the change in the volume of the tumor, the largest dimension of the tumor, or the anterior / posterior diameter of the tumor perpendicular to the drug delivery device is ±10% after implantation of the drug delivery device.

31. 31. The method of claim 30, wherein the change in the volume of the tumor, the largest dimension of the tumor, or the anterior / posterior diameter of the tumor perpendicular to the drug delivery device is ±5% after implantation of the drug delivery device.

32. 31. The method of any one of claims 1 to 30, wherein the first layer comprises 7.5 to 11 wt% API.

33. 33. The method of claim 32, wherein the API is paclitaxel.

34. The method of any one of claims 1 to 33, wherein the solvent comprises acetone and the first layer comprises 3 to 11 wt% acetone.

35. 35. The method of claim 34, wherein the second layer comprises 3 to 11 weight percent acetone.

36. 36. The method of any one of claims 1-35, wherein the first biodegradable polymer comprises poly(lactic-co-glycolic acid) (PLGA) 50:50 and the second biodegradable polymer comprises PLGA 75:

25.

37. 37. The method of any one of claims 1 to 36, wherein the pancreatic cancer is immediately unresectable pancreatic cancer, non-metastatic pancreatic cancer, borderline resectable pancreatic cancer, resectable pancreatic cancer, locally advanced pancreatic cancer, metastatic pancreatic cancer, or metastatic spread to the pancreas.

38. 1. A method of stabilizing pancreatic cancer, comprising: implanting a drug delivery device in a peri-tumoral region of the patient's pancreas, wherein the drug delivery device comprises: a first layer comprising an API, a solvent, and at least 70% by weight of a first biodegradable polymer; a second layer on one side of the first layer, the second layer comprising a solvent and at least 85% by weight of a second biodegradable polymer; and releasing the API from the drug delivery device into the pancreatic tumor by in vivo degradation of the first biodegradable polymer; wherein the change in the volume of the tumor, the largest dimension of the tumor, and / or the anterior / posterior diameter of the tumor perpendicular to the drug delivery device is ±10% after implantation of the drug delivery device.

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