Implantable drug delivery device for localized drug delivery - Patents.com

Abstract

Provided herein is a drug implant comprising a therapeutically active agent for treating a disease in a subject. In some cases, the drug implant may comprise a polymer matrix and a therapeutically active agent disposed therein. Also provided are methods for manufacturing the drug implant and methods for treating a disease using the implant. In some cases, the drug implant may comprise, for example, bicalutamide for use in treating prostate cancer.

Description

[Technical field]

[0001] Cross-reference to application Pursuant to 35 U.S.C. § 119(e), this application claims priority to the filing dates of U.S. Application No. 16 / 826,022, filed March 20, 2020, U.S. Application No. 16 / 826,043, filed March 20, 2020, and U.S. Application No. 16 / 826,064, filed March 20, 2020, the disclosures of which are incorporated herein by reference in their entireties. [Background technology]

[0002] The burden of prostate cancer in the United States is large. In 2009, approximately 192,000 men were diagnosed with prostate cancer, and 27,000 men were predicted to die from the disease. Approximately 2.2 million living American men have been diagnosed with prostate cancer, some surviving metastatic disease in a painful, functionally limiting stage. Prostate cancer is the most commonly diagnosed cancer among American men to date, and remains the second leading cause of cancer death in men. Hormonal therapy for prostate cancer includes a wide variety of treatments designed to affect cells whose normal functioning depends on androgens, including testosterone and dihydrotestosterone, among others. Prostate cancer cells are generally highly sensitive to treatments that lower androgen levels or affect the normal action of these hormones.

[0003] Bicalutamide is an antiandrogen that can be used to treat prostate cancer.Bicalutamide is a member of the nonsteroidal antiandrogen group of medicines, and acts by blocking androgen receptor.Bicalutamide is associated with some side effects, which may be partly due to the relatively large amount of bicalutamide that is administered systemically to achieve therapeutic benefit.Therefore, it may be possible that the local administration of a smaller amount of bicalutamide can achieve therapeutic benefit and prevent or reduce the side effects or toxicity of systemic administration of bicalutamide. Summary of the Invention

[0004] There is a need for improved drug implants that can be used to deliver therapeutically active agents (e.g., bicalutamide) directly to a target tissue of a subject. Provided herein is a drug implant that can deliver a therapeutically effective amount of drug directly to a target tissue. Provided herein is further a drug implant that, when implanted in a target tissue, results in a high concentration of drug in the target tissue and a low concentration of drug in the systemic circulation (e.g., in plasma). In some cases, the ability of the drug implants provided herein to deliver a therapeutically effective amount of drug directly to a target tissue while achieving a low concentration of drug in the systemic circulation can reduce or eliminate toxicity of the drug that would otherwise result from systemic administration. In addition, the drug implants described herein deliver the drug directly to the target tissue, ensuring that the target tissue receives a therapeutically effective amount of the drug. In a further aspect, the drug implants provided herein can be loaded with a large amount of drug, such that the drug implant can sustainably release the drug to the target tissue over an extended period of time.

[0005] In one embodiment, an implant is provided that includes bicalutamide dispersed in a polymer matrix, and provides sustained release of bicalutamide at a rate of at least 0.1 μg / day for at least 6 months after implantation of the implant into prostate tissue or tissue adjacent to the prostate. In some cases, the bicalutamide is in solid form. In some cases, the volume of the implant is at least 10 mm 3In some cases, the length of the implant is at least 1 mm. In some cases, the length of the implant is at least 3 mm. In some cases, the diameter of the implant is at least 0.1 mm. In some cases, the diameter of the implant is at least 0.8 mm. In some cases, the implant lacks at least one of a sheath, a scaffold, a retention member for retaining the implant in the target tissue, or a combination thereof. In some cases, the implant includes bicalutamide in an amount of at least 30% w / w. In some cases, the total dose of bicalutamide per implant is at least 1 mg. In some cases, the polymer matrix includes silicone. In some cases, the silicone has a Shore A hardness of at least 30 durometers. In some cases, the bicalutamide has a median particle size of less than 10 microns. In some cases, the bicalutamide has a D90 of less than 15 microns. In some cases, the cumulative release of bicalutamide in an in vitro model is at least one of the following: at least 100 μg on day 1, at least 1,500 μg on day 50, or at least 2,000 μg on day 100. In some cases, the implant is configured to be delivered to prostate tissue or tissue near the prostate through the lumen of a needle or catheter. In some cases, the implant consists essentially of a polymer matrix and bicalutamide dispersed in the polymer matrix.

[0006] In another aspect, a method for treating a subject in need of treatment is provided, the method comprises delivering any one of the above-mentioned implants to the subject's prostate tissue or tissue near the prostate, thereby treating the subject.In some cases, the subject has prostate proliferative disease.In some cases, the prostate proliferative disease is prostate cancer or benign prostatic hyperplasia.

[0007] In another aspect, a prostate implant is provided, comprising a polymer matrix and bicalutamide dispersed in the polymer matrix in an amount of at least 30% w / w. In some cases, the prostate implant releases at least 0.1 μg / day of bicalutamide 6 months after implantation in a subject. In some cases, the bicalutamide is in solid form. In some cases, the solid form has a median particle size of less than 10 microns. In some cases, the solid form has a D90 of less than 15 microns. In some cases, the prostate implant has a Shore A hardness of at least 30 durometers. In some cases, the polymer matrix is ​​silicone. In some cases, the silicone has one or more of the following properties: a Shore A hardness of at least 30 durometers and a cure temperature below the melting point of bicalutamide. In some cases, at least 50% of the bicalutamide remains in the polymer matrix 100 days after implantation. In some cases, the polymer matrix inhibits the regulation of bicalutamide in the prostate implant. In some cases, the regulation includes degradation. In some cases, degradation is determined by measuring the amount of bicalutamide in the eluate after incubating a prostate implant containing bicalutamide in a solution containing 1% SDS containing 0.05 N NaOH for 8 hours at 37° C. In some cases, the volume of the prostate implant is at least 10 mm 3 In some cases, the length of the prostate implant is between 1 mm and 30 mm. In some cases, the length of the prostate implant is between 5 mm and 25 mm. In some cases, the diameter of the prostate implant is between 0.1 mm and 1.5 mm. In some cases, the bicalutamide is dispersed in the polymer matrix in an amount of at least 40% w / w. In some cases, at least 50% of the outer surface of the prostate implant is configured to directly contact prostate tissue or tissue near the prostate. In some cases, the prostate implant is deliverable using the cannula of a prostate biopsy needle or Mick® needle. In some cases, the prostate implant consists essentially of a polymer matrix and bicalutamide dispersed in the polymer matrix.

[0008] In another aspect, a method for treating a prostate proliferative disease in a subject is provided, the method comprising implanting one or more implants into prostate tissue or tissue adjacent to the prostate, each of the one or more implants comprises a polymer matrix and bicalutamide, and the one or more implants provide a therapeutically effective amount of bicalutamide to the prostate for at least 6 months.In some cases, the prostate proliferative disease is prostate cancer or benign prostatic hyperplasia.In some cases, the bicalutamide is dispersed in the polymer matrix before implantation.In some cases, the implantation comprises deploying each of the one or more implants into prostate tissue or tissue adjacent to the prostate through a needle or catheter lumen.In some cases, the needle is a Mick® needle.In some cases, the implantation is performed by perineal administration.In some cases, the perineal administration comprises using a template guide needle.In some cases, the polymer matrix inhibits the degradation of bicalutamide. In some cases, the degradation is determined by measuring the amount of bicalutamide in the eluate after incubating one of the one or more implants in a solution containing 1% SDS containing 0.05 NaOH for 8 hours at 37°C. In some cases, the polymer matrix is ​​not substantially biodegradable. In some cases, the polymer matrix includes silicone. In some cases, the total dose of bicalutamide administered to the subject is less than the total dose of bicalutamide when administered to the subject by oral administration. In some cases, the total dose of bicalutamide administered to the subject is less than 100 mg over a 6 month period. In some cases, the implanting results in a plasma concentration of bicalutamide that is less than the plasma concentration of bicalutamide obtained when bicalutamide is administered to the subject by oral administration, and the implanting results in a steady state plasma concentration of (R)-bicalutamide that is less than 5 μg / mL. In some cases, the implanting includes transperineal implantation of at least three implants. In some cases, each of the one or more implants is at least 10 mm 3 It has a volume of.

[0009] In another aspect, a method for treating prostate proliferative disease of a subject is provided, the method comprises implanting one or more implants into prostate tissue or tissue near the prostate, each of the one or more implants comprises a polymer matrix and bicalutamide, and implanting produces a steady-state plasma concentration of (R)-bicalutamide that is less than 5 μg / mL.In some cases, implanting comprises deploying each of the one or more implants into prostate tissue or tissue near the prostate through a needle or catheter lumen.In some cases, the total dose of bicalutamide administered to the subject is less than the total dose of bicalutamide when administered to the subject by oral administration.In some cases, the total dose of bicalutamide administered to the subject is less than 100mg over a period of 6 months.

[0010] In one embodiment, an implant is provided that includes a biocompatible, substantially non-biodegradable polymer matrix and an antiandrogen dispersed throughout the polymer matrix. In another embodiment, an implant is provided that includes a biocompatible, substantially non-biodegradable polymer matrix and a therapeutically active agent dispersed throughout the polymer matrix, where when the implant is placed in a target tissue of a subject, the implant delivers a therapeutically effective amount of the therapeutically active agent to the target tissue of the subject for at least 24 months. In another embodiment, an implant is provided that includes a biocompatible, substantially non-biodegradable polymer matrix and an antiandrogen in crystalline form. In yet another embodiment, an implant is provided that includes a biocompatible, substantially non-biodegradable polymer matrix and an antiandrogen dispersed throughout the polymer matrix in an amount of 10-70% w / w.

[0011] In some cases, the implant, when placed in a target tissue of a subject, releases at least 0.1 μg / day of the therapeutically active agent or antiandrogen 24 months after implantation. In some cases, the therapeutically active agent or antiandrogen has a median particle size of less than 10 microns. In some cases, the implant has a Shore A hardness of at least 30 durometers when loaded with 60% w / w therapeutically active agent. In some cases, at least 99% of the polymer matrix remains in the target tissue of a subject for at least 600 days after implantation. In some cases, the implant is ultrasound visible when placed in the target tissue of a subject. In some cases, the therapeutically active agent or antiandrogen has a melting temperature higher than the hardening temperature of the polymer matrix. In some cases, the melting temperature is greater than 150° C. In some cases, the polymer matrix inhibits degradation of the therapeutically active agent or antiandrogen in the implant. In some cases, the polymer matrix inhibits degradation of the therapeutically active agent or antiandrogen by esterases or amidases. In some cases, degradation is determined by measuring the amount of therapeutically active agent or antiandrogen in the eluate after incubating the implant containing the therapeutically active agent or antiandrogen in a solution containing 1% SDS containing 0.05N NaOH for 8 hours at 37°C. In some cases, the implant is elongated. In some cases, the implant is cylindrical. In some cases, the implant is tubular. In some cases, the diameter of the implant is less than 1 mm. In some cases, the diameter of the implant is between 0.5 mm and 1.5 mm. In some cases, the diameter of the implant is between 0.7 mm and 1.3 mm. In some cases, the diameter of the implant is between 0.9 mm and 1.1 mm. In some cases, the diameter of the implant is about 1 mm. In some cases, the length of the implant is less than 20 mm. In some cases, the length of the implant is between 5 mm and 25 mm. In some cases, the length of the implant is between 10 mm and 20 mm. In some cases, the length of the implant is between 12 mm and 18 mm. In some cases, the length of the implant is about 15 mm. In some cases, the implant further comprises a coating. In some cases, the coating partially covers the implant.In some cases, the coating substantially covers the implant. In some cases, the coating covers the implant. In some cases, the therapeutically active agent is an antiandrogen. In some cases, the therapeutically active agent or antiandrogen is bicalutamide. In some cases, the implant is sterilized. In some cases, the implant is placed in a sterile package. In some cases, the polymer matrix is ​​at least 95% cured, at least 96% cured, at least 97% cured, at least 98% cured, at least 99% cured, or at least 99.9% cured. In some cases, the polymer matrix includes silicone. In some cases, the silicone is Silbione® LSR D370 manufactured by Elkem. In some cases, the silicone is DDU 4870 manufactured by NuSil™. In some cases, the implant is configured to be implanted into the prostate tissue of a subject. In some cases, the implant is devoid of metal.

[0012] In another aspect, a method of making an implant suitable for implantation into a subject's prostate is provided, the method comprising: (a) mixing an amount of an uncured biocompatible, substantially non-biodegradable polymer with an amount of an antiandrogen to form a mixture; (b) molding the mixture to produce a molded mixture; and (c) curing the molded mixture by heating the molded mixture for a period of time. In some cases, the amount of antiandrogen is 10% w / w to 70% w / w of the uncured biocompatible, substantially non-biodegradable polymer. In some cases, the antiandrogen is bicalutamide. In some cases, the biocompatible, substantially non-biodegradable polymer is a silicone. In some cases, the silicone is Silbione® LSR D370 manufactured by Elkem. In some cases, the silicone is DDU 4870 manufactured by NuSil™. In some cases, the curing in (c) further comprises heating the molded mixture at a temperature of about 150° C. to about 200° C. for 3 to 8 minutes. In some cases, the mixture further comprises a solvent. In some cases, the solvent is selected from the group consisting of pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. In some cases, the mixture is molded by a transfer molding process. In some cases, the method further comprises performing an analysis on the implant. In some cases, the analysis is selected from the group consisting of differential scanning calorimetry (DSC), development of the implant in a tissue substitute, dissolution testing, viscosity measurement, high pressure liquid chromatography (HPLC), and simulated in vivo stability assays.

[0013] In another aspect, a kit is provided, comprising a sterile package comprising any one of the implants described above, and instructions for implanting the implant into a target tissue of a subject. In some cases, the implant is configured to be delivered to a human prostate, tissue adjacent to the human prostate, or both. In some cases, the sterile package is formed from foil. In some cases, the kit further comprises one or more surgical tools for implanting the implant into a target tissue of a subject. In some cases, the one or more surgical tools comprise a needle, a forceps, a trocar, or a stylet.

[0014] In another aspect, a method is provided for treating a disease in a subject in need thereof, comprising implanting any one of the aforementioned implants into the prostate of the subject, thereby treating the disease.In another aspect, a method is provided for treating a disease in a subject in need thereof, comprising implanting a substantially non-biodegradable implant comprising a biocompatible polymer matrix and an antiandrogen drug dispersed throughout the biocompatible polymer matrix into the prostate of the subject, thereby treating the disease.

[0015] In some cases, the prostate includes prostate tissue, tissue adjacent to prostate tissue, or both. In some cases, the disease is a prostate proliferative disease or disorder (e.g., prostate cancer, benign prostatic hyperplasia). In some cases, the method further includes positioning a distal end of an elongated tube in the prostate or tissue adjacent to the prostate of the subject. In some cases, a portion of the elongated tube is positioned through a first portion of the grid such that a first position of the elongated tube in the subject is determined. In some cases, the elongated tube is a needle or a catheter. In some cases, a trocar is positioned within the lumen of the elongated tube. In some cases, the method further includes removing the trocar from the lumen of the elongated tube. In some cases, the method further includes positioning an implant within the lumen of the elongated tube after removing the trocar from the lumen of the elongated tube. In some cases, the method further includes pushing a stylet through the lumen of the elongated tube, thereby moving the implant to the distal end of the elongated tube. In some cases, the method further includes moving the elongated tube away from the subject, such that the implant remains within the subject. In some cases, the stylet is positioned in a portion of the lumen of the elongated tube that is a distal end of the stylet adjacent the implant, such that the implant remains within the subject. In some cases, a portion of a second elongated tube is positioned through a second portion of the grid such that a position of the second elongated tube in the subject is determined. [Brief description of the drawings]

[0016] Various aspects of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which:

[0017] [Figure 1] 1 illustrates a non-limiting example of a shaped implant according to an aspect of the present disclosure. [Figure 2A] 1 shows non-limiting examples of differential scanning calorimetry (DSC) thermograms of formulation components and molded rods according to embodiments of the present disclosure. [Figure 2B] 1 shows non-limiting examples of differential scanning calorimetry (DSC) thermograms of formulation components and molded rods according to embodiments of the present disclosure. [Figure 2C] 1 shows non-limiting examples of differential scanning calorimetry (DSC) thermograms of formulation components and molded rods according to embodiments of the present disclosure. [Figure 2D] 1 shows non-limiting examples of differential scanning calorimetry (DSC) thermograms of formulation components and molded rods according to embodiments of the present disclosure. [Figure 2E] 1 shows non-limiting examples of differential scanning calorimetry (DSC) thermograms of formulation components and molded rods according to embodiments of the present disclosure. [Figure 2F] 1 shows non-limiting examples of differential scanning calorimetry (DSC) thermograms of formulation components and molded rods according to embodiments of the present disclosure. [Figure 3A] 3A and 3B show non-limiting examples of ultrasound images of an implant in a dog prostate gland, as well as a photograph of an explant 8 weeks after implantation (FIG. 3C), according to embodiments of the present disclosure. [Figure 3B] 3A and 3B show non-limiting examples of ultrasound images of an implant in a dog prostate gland, as well as a photograph of an explant 8 weeks after implantation (FIG. 3C), according to embodiments of the present disclosure. [Figure 3C] 3A and 3B show non-limiting examples of ultrasound images of an implant in a dog prostate gland, as well as a photograph of an explant 8 weeks after implantation (FIG. 3C), according to embodiments of the present disclosure. [Figure 4A] 1 shows non-limiting examples of in vitro elution curves for 30% w / w, 45% w / w, and 60% w / w bicalutamide implants according to embodiments of the present disclosure. [Figure 4B] 1 shows non-limiting examples of in vitro elution curves of 30% w / w and 45% w / w bicalutamide using various silicone implants. [Figure 4C] 1 shows the predicted elution profile of bicalutamide-loaded implants for up to 24 months. [Figure 4D]FIG. 1 shows the cumulative release profile of implants containing 60% w / w bicalutamide in an in vitro model. [Figure 4E] FIG. 1 shows the release rate profile of implants containing 60% w / w bicalutamide in an in vitro model. [Figure 4F] 1 shows the predicted cumulative release profile of implants containing 60% w / w bicalutamide in an in vitro model. [Figure 4G] FIG. 1 shows the cumulative release profile of implants containing 60% w / w bicalutamide in an in vitro model. [Figure 4H] FIG. 1 shows the release rate profile of implants containing 60% w / w bicalutamide in an in vitro model. [Diagram 5] 1 shows non-limiting examples of results obtained from simulated in vivo stability assays. [Figure 6A] 1 shows a non-limiting example of bicalutamide levels in plasma after implantation of a device of the present disclosure into the prostate of a dog. [Figure 6B] 1 shows a non-limiting example of bicalutamide levels in plasma after implantation of a device of the present disclosure into the prostate of a dog. [Figure 7A] 1 shows a non-limiting example of bicalutamide levels in tissue after implantation of a device of the present disclosure into the prostate of a dog. [Figure 7B] 1 shows a non-limiting example of bicalutamide levels in tissue after implantation of a device of the present disclosure into the prostate of a dog. [Figure 8] 1 shows images and schematic diagrams of implant location and local distribution of R-bicalutamide (activity levels) in the rostral portion of the dog prostate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Provided herein are drug implants that can deliver a therapeutically effective amount of a drug directly to a target tissue. Further provided herein are drug implants that, when implanted in a target tissue, result in a high concentration of the drug in the target tissue and a low concentration of the drug in the systemic circulation (e.g., in the plasma). In some cases, the ability of the drug implants provided herein to deliver a therapeutically effective amount of a drug directly to a target tissue while achieving a low concentration of the drug in the systemic circulation can reduce or eliminate side effects or toxicity of the drug that would otherwise result from systemic administration. In addition, delivering the drug directly to the target tissue by the drug implants described herein ensures that the target tissue receives a therapeutically effective amount of the drug. In further embodiments, the drug implants provided herein can be loaded with a large amount of drug so that the drug implant can sustainably release the drug to the target tissue over an extended period of time. In some embodiments, the therapeutically active agent can be dispersed within the polymer matrix of the implant, which can provide certain advantages (e.g., faster elution time, higher drug loading within the implant, etc.). In certain embodiments, the drug implants provided herein may contain bicalutamide in high concentrations such that a therapeutically effective amount of bicalutamide can be administered directly to prostate tissue for extended periods of time (6 months or more) while maintaining low systemic concentrations of bicalutamide.

[0019] In various aspects, the drug implant disclosed herein may include a polymer matrix and a therapeutically active agent. In certain cases, the therapeutically active agent may be dispersed within the polymer matrix. The drug implant may be implanted into a target tissue and release a certain amount of the therapeutically active agent over time. The therapeutically active agent may be a drug or an active pharmaceutical ingredient (API) that may be effective in treating a disease or its symptoms. In some cases, the therapeutically active agent is bicalutamide, and the disease is a proliferative disease of the prostate (e.g., prostate cancer, benign prostatic hyperplasia). Further provided herein is a method of treating a disease by delivering the drug implant of the present disclosure to a target tissue of a subject in need thereof for long-term delivery of a therapeutically effective amount of the drug. Further provided is a method of manufacturing the drug implant and a kit including the drug implant.

[0020] Drug implants Provided herein is a drug implant (also referred to herein as "implant") suitable for delivering a therapeutically active agent to a target tissue. In some aspects of the present disclosure, the implant comprises a polymer matrix and a therapeutically active agent dispersed therein. The therapeutically active agent or drug can be bicalutamide. The implant can be suitable for treating prostate proliferative diseases (e.g., prostate cancer, benign prostatic hyperplasia).

[0021] The polymer matrix can include any polymeric material. In general, the polymeric material can be biocompatible. As used herein, the term "biocompatible" refers to the property of a material that allows for prolonged contact with tissues in a subject without causing toxicity or significant damage.

[0022] In some embodiments, the polymeric material may be "non-biodegradable" or "substantially non-biodegradable." The terms "non-biodegradable" or "substantially non-biodegradable," when used with respect to implants of the present disclosure, generally refer to implants that cannot be degraded or substantially degraded by microorganisms over the intended lifespan of the implant. For example, a substantially non-biodegradable implant of the present disclosure may have at least 99% of the polymeric material remaining two years after the device is implanted in a target tissue.

[0023] In certain embodiments of the present disclosure, the polymer matrix may include polysiloxane (silicone). The silicone may be any biocompatible silicone. In some cases, the silicone may be medical grade silicone. In some cases, the silicone may be United States Pharmacopoeia (USP) Class V or USP Class VI certified silicone. In various embodiments, the silicone may be any liquid silicone rubber (LSR). In some cases, the silicone may be Silbione® Liquid Silicone Rubber (LSR) manufactured by Elkem. In some cases, Silbione® LSR may be Silbione® LSR4301, Silbione® LSR4305, Silbione® LSR4310, Silbione® LSR4325, Silbione® LSR4330, Silbione® LSR4340, Silbione® LSR4350, Silbione® LSR60, Silbione® LSR4360, Silbione® LSR4370, Silbione® LSR4745, Silbione® LSR4755, Silbione® LSR4765, Silbione® LSR4125, Silbione® LSR4130, Silbione® LSR4140, Silbione® LSR M301, Silbione® LSR M305, Silbione® LSR M310, Silbione® LSR M325, Silbione® LSR M330, Silbione® LSR M340, Silbione® LSR M350, Silbione® LSR M360, Silbione® LSR M365, Silbione® LSR M370, Silbione® LSR M125, Silbione® LSR M130, Silbione® LSR M140. In various embodiments, the silicone can be Silbione® LSR D370.In some cases, the silicone can be a silicone manufactured by NuSil™. In various embodiments, the silicone can be DDU 4870 manufactured by NuSil™. In some cases, the silicone can be one or more of the following silicones manufactured by NuSil™: MED-4801, MED-4805, MED-4810, MED-5820, MED-5830, MED-5840, MED-5850, MED-5860, MED-5870, MED-4880, MED50-5338, MED-5440, MED-4842, and MED1-4855.

[0024] Additional non-biodegradable polymers that may be used herein include, but are not limited to, silicone materials, acrylates, polyethylene, polyurethanes, hydrogels, polyesters, polypropylene, polytetrafluoroethylene (PTFE), expanded PTFE (ePTFE), polyetheretherketone (PEEK), nylon, extruded collagen, polymer foams, silicone rubber, polyethylene terephthalate, ultra-high molecular weight polyethylene, polycarbonate urethanes, polyurethanes, and polyimides.

[0025] The Shore A hardness scale measures the hardness of rubber. A higher number on the scale refers to a harder material, while a lower number on the scale refers to a softer material. Generally, the polymeric material in the drug implant has a Shore A hardness of at least 30 durometer. For example, the polymeric material can have a Shore A hardness of at least 30 durometer, at least 40 durometer, at least 50 durometer, at least 60 durometer, or at least 70 durometer. In one embodiment, the uncured polymeric material can have a Shore A hardness of 30 durometer, and the cured polymeric material can have a Shore A hardness of 70 durometer.

[0026] The implant may further comprise a therapeutically active agent (also referred to herein as a "drug"). In certain embodiments, the therapeutically active agent is bicalutamide. In some cases, the therapeutically active agent may be dispersed or distributed within the polymer matrix. In some cases, the therapeutically active agent may be dispersed or distributed throughout the polymer matrix. In some cases, the therapeutically active agent may be uniformly or homogeneously dispersed or distributed within the polymer matrix. In other cases, the therapeutically active agent may be heterogeneously dispersed or distributed within the polymer matrix. In other cases, the therapeutically active agent may be dispersed or distributed in a gradient within the polymer matrix. In certain embodiments, the therapeutically active agent may be dispersed or distributed within the polymer matrix during manufacture of the implant (e.g., the therapeutically active agent may be mixed with the polymer material prior to curing of the polymer material disclosed herein). In some cases, providing a drug dispersed within the polymer matrix may be advantageous over other drug implants (e.g., those in which the drug is encapsulated within a capsule or within the lumen of a tube). For example, dispersing the drug within a polymer matrix may allow for higher loading of the drug within the implant, faster elution rates, and the like.

[0027] In various embodiments of the present disclosure, the implant may include a therapeutically active agent (e.g., bicalutamide) in an amount of about 10% w / w to about 70% w / w. For example, the implant may include a therapeutically active agent (e.g., bicalutamide) in an amount of about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, or about 70% w / w. In various embodiments, the implant may include a therapeutically active agent (e.g., bicalutamide) in an amount of at least about 10% w / w, at least about 15% w / w, at least about 20% w / w, at least about 25% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, at least about 50% w / w, at least about 55% w / w, at least about 60% w / w, at least about 65% w / w, or at least about 70% w / w. In certain embodiments, the therapeutically active agent is bicalutamide and is present in the implant in an amount of about 10% w / w, about 30% w / w, about 45% w / w, or about 60% w / w. In some cases, the present disclosure provides drug implants loaded with a high concentration of bicalutamide (e.g., 60% w / w). In some cases, the implant may contain bicalutamide in an amount of at least 30% w / w. In some cases, the implant may contain bicalutamide in an amount of at least 40% w / w.

[0028] In various embodiments of the present disclosure, the implant may include a therapeutically active agent (e.g., bicalutamide) in an amount of about 5% volume / volume (v / v) to about 60% v / v. For example, the implant may include a therapeutically active agent (e.g., bicalutamide) in an amount of about 5% v / v, about 10% v / v, about 15% v / v, about 20% v / v, about 25% v / v, about 30% v / v, about 35% v / v, about 40% v / v, about 45% v / v, about 50% v / v, about 55% v / v, or about 60% v / v. In various embodiments, the implant may comprise a therapeutically active agent (e.g., bicalutamide) in an amount of at least about 5% v / v, at least about 10% v / v, at least about 15% v / v, at least about 20% v / v, at least about 25% v / v, at least about 30% v / v, at least about 35% v / v, at least about 40% v / v, at least about 45% v / v, at least about 50% v / v, at least about 55% v / v, or at least about 60% v / v. In certain embodiments, the therapeutically active agent is bicalutamide and is present in the implant in an amount of at least 30% v / v.

[0029] In various embodiments, the implants of the present disclosure may contain at least 1 mg of bicalutamide, for example, about 1 mg to about 10 mg in total. In some cases, the total amount of bicalutamide in the implant may be about 8 mg to about 10 mg. For example, the implants may contain about 1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 ... About 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6 .8mg, about 6.9mg, about 7.0mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7mg, about 7.8mg, about 7.9mg, The pharmaceutical composition may contain bicalutamide in a total amount of about 8.0 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10.0 mg.

[0030] In various embodiments of the present disclosure, the polymeric material can be cured with bicalutamide present therein. Without wishing to be bound by theory, curing refers to a chemical process that hardens the polymeric material by crosslinking the polymer chains. Any method can be used to harden the polymer of the present disclosure, including the use of electron beams, heating, and / or adding additives. In various embodiments of the present disclosure, bicalutamide can be mixed with the uncured polymeric material before curing. In some embodiments, the polymeric matrix can be at least 95% cured, at least 96% cured, at least 97% cured, at least 98% cured, at least 99% cured, at least 99.9% cured, or 100% cured.

[0031] Generally, the polymeric material has a curing temperature lower than the melting temperature of the therapeutically active agent, for example, to prevent melting and / or degradation of the drug. For example, the polymeric material may have a curing temperature lower than the melting temperature of bicalutamide. In some cases, the polymeric material may have a curing temperature that is less than 190°C, less than 185°C, less than 180°C, less than 175°C, less than 170°C, less than 165°C, less than 160°C, less than 155°C, or less than 150°C. In a particular example, bicalutamide may have a melting temperature of about 180°C to 190°C, and the polymer may have a curing temperature of less than about 190°C (e.g., about 170°C).

[0032] In various embodiments of the present disclosure, bicalutamide may be present in the implant in solid form. In some cases, solid bicalutamide may dissolve when contacted with biological fluid (e.g., after implantation into tissue) and may diffuse from the implant into target tissue. In some cases, bicalutamide is present in the implant in crystalline form. In general, the particle size of bicalutamide in the implant may be important for the uniformity of drug content in the implant. Without wishing to be bound by theory, small particle size may ensure uniform distribution within the formulation and between implants when molding the formulation. In some cases, the bicalutamide present in the implant may have a median particle size (e.g., D50 particle size) of less than 10 μm. In some cases, the bicalutamide present in the implant may have a D90 particle size of less than 15 μm.

[0033] In various aspects of the present disclosure, the implant may further comprise additional molecules that cannot be dissolved from the implant. In some cases, these additional molecules may result in a faster dissolution rate of the drug. Non-limiting examples of additional molecules that may be present in the implant include sugars (e.g., lactose), salts, fused silica, cellulose, and high molecular weight polyethylene glycol (PEG).

[0034] Generally, the implant of the present disclosure has mechanical properties that allow the implant to be deployed normally in target tissue.For example, the implant of the present disclosure can be sufficiently rigid so that it can be deployed normally in target tissue, but not so rigid that it breaks during deployment.It should be understood that the mechanical properties of the device described herein can vary depending on the polymeric material used and can be experimentally determined.In some embodiments, the implant containing bicalutamide can have a Shore A hardness of at least 30 durometer.

[0035] In various aspects, the implant may have a three-dimensional shape. The three-dimensional shape may be any suitable shape. In some cases, the implant may be cylindrical or substantially cylindrical. In some cases, the implant may be tubular or substantially tubular. In some cases, the implant may be elongated (e.g., may have a length greater than its width). In some cases, the implant may not be hollow. In some cases, the implant may be rod or rod-like.

[0036] In various embodiments, the implant may have a diameter. In some cases, the diameter of the implant may be about 0.1 mm to about 1.5 mm. In some cases, the diameter of the implant may be about 0.7 mm to about 1.3 mm. In some cases, the diameter of the implant may be about 0.9 mm to about 1.1 mm. In some cases, the diameter of the implant may be at least about 0.1 mm, for example, at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.0 mm, at least about 1.1 mm, at least about 1.2 mm, at least about 1.3 mm, at least about 1.4 mm, or at least about 1.5 mm. In some cases, the diameter of the implant may be less than about 1 mm, e.g., less than about 1 mm, less than about 0.9 mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6 mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3 mm, less than about 0.2 mm, or less than about 0.1 mm. In some cases, the diameter of the implant may be at least about 0.1 mm. In some cases, the diameter of the implant may be at least about 0.8 mm. In some cases, the diameter of the implant may be about 1 mm.

[0037] In various embodiments, the implant may have a length. In some cases, the length of the implant may be about 1 mm to about 30 mm. In some cases, the length of the implant may be about 5 mm to about 25 mm. In some cases, the length of the implant may be about 10 mm to about 20 mm. In some cases, the length of the implant may be about 12 mm to about 18 mm. In some cases, the length of the implant may be at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 7 mm, at least about 8 mm, at least about 9 mm, at least about 10 mm, at least about 11 mm, at least about 12 mm, at least about 13 mm, at least about 14 mm, at least about 15 mm, at least about 16 mm, at least about 17 mm, at least about 18 mm, at least about 19 mm, at least about 20 mm, at least about 21 mm, at least about 22 mm, at least about 23 mm, at least about 24 mm, at least about 25 mm, at least about 26 mm, at least about 27 mm, at least about 28 mm, at least about 29 mm, or at least about 30 mm. In some cases, the length of the implant is at least about 1 mm. In some cases, the length of the implant is at least about 3 mm. In some cases, the length of the implant is about 15 mm. In some cases, the length of the implant may be less than about 30 mm, e.g., less than about 30 mm, less than about 29 mm, less than about 28 mm, less than about 27 mm, less than about 26 mm, less than about 25 mm, less than about 24 mm, less than about 23 mm, less than about 22 mm, less than about 21 mm, less than about 20 mm, less than about 19 mm, less than about 18 mm, less than about 17 mm, less than about 16 mm, less than about 15 mm, less than about 14 mm, less than about 13 mm, less than about 12 mm, less than about 11 mm, less than about 10 mm, less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm, less than about 3 mm, less than about 2 mm, or less than about 1 mm.

[0038] In various embodiments, the implant can have a volume. In some cases, the volume of the implant is about 0.1 mm. 3 ~about 30mm 3For example, the volume of the implant may be about 0.1 mm 3 , about 0.5mm 3 , about 1mm 3 , about 5mm 3 , about 10mm 3 , about 15mm 3 , about 20mm 3 , about 25mm 3 , or about 30 mm 3 In some cases, the volume of the implant may be about 10 mm 3 It could be.

[0039] In various embodiments, the implant may lack a coating, cover, or sheath. For example, in some cases, a portion of the outer surface of the implant may be uncoated or uncovered, such that the outer surface of the uncoated or uncovered portion of the implant is directly exposed to or in direct contact with the biological environment (e.g., target tissue, biological fluid) after implantation. In some instances, the entire outer surface or substantially the entire outer surface of the implant is uncovered or uncoated, such that the entire outer surface or substantially the entire outer surface of the implant is directly exposed to or in direct contact with the biological environment after implantation. In other cases, less than the entire outer surface of the implant is directly exposed to or in direct contact with the biological environment after implantation. For example, in some cases, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the outer surface of the implant is directly exposed to or in direct contact with the biological environment after implantation. In some cases, the implant may lack a sheath, scaffold, retention member, retention frame, or any other additional means for retaining the implant in the target tissue. In some cases, the implant may consist essentially of a polymer matrix and a therapeutically active agent (eg, bicalutamide) dispersed therein.

[0040] In some cases, the implant may include a coating. In some cases, the coating may cover the implant. In some cases, the coating may partially cover the implant. In some cases, the coating may substantially cover the implant. In some cases, the implant may include a core made of a first polymeric material and a coating of a second polymeric material. In a non-limiting example, the implant of the present disclosure may include a non-silicone core surrounded by a silicone coating. In some cases, the implant of the present disclosure does not include metal.

[0041] In various embodiments, when the implant is implanted in a subject, the implant can prevent the modulation of the bicalutamide contained therein. Modulation can include, but is not limited to, degradation, chemical modification, and the like. For example, the biological environment of the tissue can include degradants (e.g., esterase, amidase) that can degrade the drug. In some cases, the implant can protect the therapeutically active agent from degradation by preventing degradants from entering the implant. In various embodiments, an in vitro stability test can be performed to determine the protective effect of the implant on the therapeutically active agent contained in the implant. For example, if the therapeutically active agent is bicalutamide, the degradation can be determined by incubating the implant containing bicalutamide in a solution containing 1% SDS containing 0.05N NaOH at 37°C for 8 hours, and then measuring the amount of bicalutamide in the eluate (e.g., in vivo stability test, a non-limiting example of which is provided in Example 2). In such a case, the therapeutically active agent can be allowed to diffuse out of the implant while maintaining in vivo stability within the implant. In various embodiments, the ability of a degradant to degrade a therapeutically active agent within an implant can be determined by a simulated in vivo stability assay, for example, as described in Example 2. In a non-limiting example, an implant of the present disclosure containing a therapeutically active agent can be incubated in a solution containing a degradant (known to degrade the therapeutically active agent). After a period of incubation, the therapeutically active agent can be extracted from the implant and degradation peaks can be measured (e.g., by high performance liquid chromatography (HPLC)).

[0042] In various aspects of the present disclosure, the implants of the present disclosure may be configured to be delivered directly to a target tissue of a subject. In some cases, the target tissue may be prostate tissue. In some cases, the implants of the present disclosure may be configured to be delivered to tissue adjacent to or near the target tissue. In some cases, the therapeutically active agent may diffuse from the implant in a controlled manner and act directly on the target tissue.

[0043] In various embodiments, the implants of the present disclosure can be configured to remain in the target tissue for a period of time. In some cases, the implants of the present disclosure can be configured to remain in the target tissue indefinitely (e.g., never removed). In some cases, two or more implants of the present disclosure can be implanted in the target tissue. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 implants can be implanted in the target tissue. In some cases, two or more implants can be implanted in different sites of the target tissue (e.g., to deliver drugs to different sites of the target tissue). In some cases, two or more implants can be implanted in close proximity to each other in the target tissue. In some cases, one or more initial implants can be implanted, and additional implants can be implanted later after the drug has depleted from the initial implants. For example, one or more additional implants can be implanted after the drug has stopped or substantially stopped eluting from the one or more initial implants. In some cases, the implants of the present disclosure may be visible by ultrasound when placed in the target tissue of a subject. In such cases, the position of the implant may be non-invasively monitored. In some cases, the implants may be sterilized prior to implantation into a subject. In some cases, the implants are sterilized by gamma sterilization.

[0044] In various embodiments, the implant of the present disclosure may be capable of delivering sustained release of therapeutically active agent for a period of time. For example, the implant of the present disclosure may be capable of sustained release of therapeutically active agent. As used herein, "sustained release" refers to the ability of the implant to release a certain amount of drug for an extended period of time after implantation into the target tissue. In some cases, the implant of the present disclosure may be capable of delivering a certain amount of drug to the target tissue for at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months. In certain cases, the implant of the present disclosure may be capable of delivering at least 0.1 μg / day of bicalutamide for at least 6 months after implantation into the prostate tissue or tissue adjacent or adjacent to the prostate. In some cases, the implant of the present disclosure may be capable of delivering at least 0.1 μg / day of bicalutamide (e.g., to the prostate) for up to 24 months after implantation into the prostate tissue or tissue adjacent or adjacent to the prostate.

[0045] Methods for Producing Drug Implants - Patent application Further provided herein is a method for producing the implant described herein. A non-limiting example of the method for producing the drug implant of the present disclosure may be provided in Example 1.

[0046] In some embodiments, the method may include mixing an amount of uncured polymeric material with an amount of therapeutically active agent to form a mixture. The method may further include molding the mixture to create a molded structure. The method may further include curing the molded mixture by heating the molded mixture for a period of time. In some cases, the uncured polymeric material may be any biocompatible silicone provided herein. In exemplary embodiments, the silicone may be Silbione® LSR D370 or DDU 4870 (manufactured by NuSil™). In some cases, the therapeutically active agent may be an antiandrogen, examples of which are provided herein. In exemplary embodiments, the therapeutically active agent may be bicalutamide.

[0047] The therapeutically active agent (e.g., bicalutamide) may be provided in the hardening mixture in an amount such that the total amount of active agent in the implant may be about 10% w / w to about 70% w / w, for example, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, or about 70% w / w. In some cases, the total amount of active agent in the implant can be at least about 10% w / w, at least about 15% w / w, at least about 20% w / w, at least about 25% w / w, at least about 30% w / w, at least about 35% w / w, at least about 40% w / w, at least about 45% w / w, at least about 50% w / w, at least about 55% w / w, at least about 60% w / w, at least about 65% w / w, or at least about 70% w / w. In some cases, the therapeutic active agent is bicalutamide. Bicalutamide can be present in the hardening mixture such that the total amount of bicalutamide in the implant is at least 10% w / w, at least 30% w / w, at least 40% w / w, at least 45% w / w, or at least 60% w / w. Bicalutamide can be provided in the setting mixture in an amount such that the total amount of bicalutamide in the implant can be from about 1 mg to about 10 mg.

[0048] In some embodiments, curing involves heating the molded mixture at 150°C to 200°C, e.g., 150°C, 155°C, 160°C, 165°C, 170°C, 175°C, 180°C, 185°C, 190°C, 195°C, or 200°C. The curing temperature generally depends on the polymeric material selected. Generally, the curing temperature of the polymeric material is selected such that it is lower than the melting temperature of the therapeutic active agent. In some cases, curing involves heating the molded mixture for 3 minutes to 8 minutes, e.g., 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, or 8 minutes. In some cases, the silicone and active agent can be selected based on the cure temperature of the silicone and the melting temperature of the active agent, such that the melting temperature of the active agent can be higher than the cure temperature of the silicone.

[0049] In some embodiments, the mixture may further comprise a solvent. Non-limiting examples of solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. In some embodiments, the mixture may be molded by a transfer molding process.

[0050] After manufacturing the implant as provided herein, the method may further include performing one or more analyses on the implant. In some cases, the one or more analyses may be differential scanning calorimetry (DSC), a non-limiting example of which is provided in Example 2. In some cases, the one or more analyses may be deploying the implant in a substitute tissue, a non-limiting example of which is provided in Example 2. In some cases, the one or more analyses may be dissolution testing, a non-limiting example of which is provided in Example 2. In some cases, the one or more analyses may be in vivo stability testing, a non-limiting example of which is provided in Example 2. In some cases, the one or more analyses may be viscosity measurements. In some cases, the one or more analyses may be high pressure liquid chromatography.

[0051] Treatment method: Disclosed herein is a method of treating a disease (or a symptom thereof) in a subject. The terms "treating", "treatment" or "treating" may be used interchangeably herein and refer to providing a therapeutic benefit to a subject in need of treatment. For example, treating a disease or disorder includes improving, inhibiting, reducing, alleviating, or curing the disease or disorder. Treating a disease or disorder also includes improving, inhibiting, reducing, alleviating, or curing one or more symptoms associated with the disease or disorder. When used in reference to a tumor, treating includes reducing or decreasing the size of the tumor or tumor volume.

[0052] In various aspects, the subject may be diagnosed with a disease, may be suspected of having a disease, or may be at risk of having a disease. In some cases, the method includes implanting an implant of the present disclosure into a target tissue of the subject. The implant of the present disclosure may be implanted into the target tissue by any method. In some cases, the implant may be implanted into the target tissue by surgical or non-surgical methods. In some cases, the implant may be implanted using standard surgical tools, such as tools commonly used for biopsy or brachytherapy. In some cases, the implant may be implanted into the target tissue by using, for example, a needle, forceps, catheter (e.g., having a lumen). For example, in one embodiment, the implant may be implanted into the target tissue by deployment from the lumen of a needle or catheter. In some cases, the implant may be implanted into the target tissue using the cannula of a prostate biopsy needle. In some cases, the implant may be implanted into the target tissue using a Mick® needle. In some cases, the deployment of the implant may be guided by ultrasound. In some cases, the implant may be implanted by transperineal implantation (e.g., by using a template guide needle). In some cases, the implant may be sterilized and placed in packaging.

[0053] In a non-limiting example, a method of deploying an implant of the present disclosure in a target tissue may include placing a distal end of an elongated tube in the target tissue (e.g., the prostate or tissue adjacent to the prostate). In some cases, the elongated tube may be a needle having a lumen. The elongated tube may have a sharp end such that the distal end of the elongated tube can penetrate the target tissue. In some cases, the distal end of the elongated tube may be placed through a first portion of a grid (e.g., a guide template) such that a first position of the elongated tube in the subject is determined. The grid may allow the implant to be properly placed in the target tissue. In some cases, a trocar is placed in the lumen of the elongated tube. The method may include inserting the elongated tube (with or without the trocar placed in the lumen of the elongated tube) into the target tissue. If a trocar is used, the method may further include removing the trocar from the lumen of the elongated tube while maintaining the distal end of the elongated tube in the target tissue. The method may further include placing an implant of the present disclosure in the lumen of the elongated tube. The implant may be pushed through the lumen of the elongated tube by a blunt ended rod (e.g., a stylet) sized to fit within the lumen of the elongated tube. The stylet may be used to push the implant from the proximal end of the elongated tube to the distal end of the elongated tube. The method may further include removing the elongated tube from the target tissue while maintaining the stylet in place. Once the elongated tube is removed from the target tissue, the stylet may push the implant from the elongated tube into the target tissue. The method may further include removing both the stylet and the elongated tube together from the target tissue.

[0054] In some embodiments, the method may include implanting two or more implants into a target tissue of a subject. For example, the method may include implanting a first implant into a first portion of the target tissue and a second implant into a second portion of the target tissue. In some cases, the first portion of the target tissue and the second portion of the target tissue may be different. In some cases, the first implant may include a first therapeutic active agent and the second implant may include a second therapeutic active agent. In some cases, the first therapeutic active agent and the second therapeutic active agent may be the same. In other cases, the first therapeutic active agent and the second therapeutic active agent may be different. In some cases, a grid (e.g., a guide template) may be used to place the first implant into the first portion of the target tissue and the second implant into the second portion of the target tissue. In some cases, the first implant and / or the second implant may be placed using ultrasound guidance.

[0055] In some embodiments, the method may further include implanting additional implants into the target tissue. For example, the method may further include implanting a third implant into a third portion of the target tissue, implanting a fourth implant into a fourth portion of the target tissue, implanting a fifth implant into a fifth portion of the target tissue, implanting a sixth implant into a sixth portion of the target tissue, implanting a seventh implant into a seventh portion of the target tissue, implanting an eighth implant into an eighth portion of the target tissue, etc. The third, fourth, fifth, sixth, seventh, eighth, or more therapeutic active agents may each be the same, different, or a combination thereof. In some cases, at least three implants are implanted into the target tissue. For example, at least three implants may be implanted into the prostate or tissue adjacent or proximal to the prostate by transperineal administration.

[0056] In some embodiments, one or more implants can be implanted in the prostate or tissue adjacent or adjacent to the prostate before surgical treatment for treating prostate cancer.For example, one or more implants can be implanted in the prostate or tissue adjacent or adjacent to the prostate before performing prostatectomy (e.g., 1 week, 2 weeks, 3 weeks, etc.).In such cases, prostatectomy can remove the prostate or a part thereof.In some cases, prostatectomy can remove one or more of the implants from the subject.In other cases, one or more implants can be implanted in the prostate or tissue adjacent or adjacent to the prostate and can remain in the prostate indefinitely.For example, one or more implants can provide a therapeutically effective amount of bicalutamide to prostate tissue for a period of time, so that the subject is in remission or cure of prostate cancer.

[0057] As used herein, the term "subject" generally refers to a vertebrate, such as a mammal, e.g., a human. Mammals include, but are not limited to, mice, monkeys, humans, research animals, farm animals, sports animals, and pets. In some cases, the methods described herein may be used on tissues derived from a subject and the progeny of such tissues. The tissues may be obtained in vivo from a subject. In some cases, the tissues may be cultured in vitro.

[0058] In some embodiments, the methods provided herein can be used to treat a subject in need of treatment. In some cases, the subject may be suffering from a disease. In some cases, the subject may be a human. In some cases, the human may be a patient in a hospital or clinic. In some cases, the subject may be a non-human animal, such as a non-human primate, a livestock animal, a household pet, or an experimental animal. For example, the non-human animal may be an ape (e.g., a chimpanzee, a baboon, a gorilla, or an orangutan), an Old World monkey (e.g., a rhesus monkey), a New World monkey, a dog, a cat, a bison, a camel, a cow, a deer, a pig, a donkey, a horse, a mule, a llama, a sheep, a goat, a buffalo, a reindeer, a yak, a mouse, a rat, a rabbit, or any other non-human animal.

[0059] Where the subject may be a human, the subject may be of any age. In some cases, the subject may be about 50 years old or older. In some cases, the subject may be about 55 years old or older. In some cases, the subject may be about 60 years old or older. In some cases, the subject may be about 65 years old or older. In some cases, the subject may be about 70 years old or older. In some cases, the subject may be about 75 years old or older. In some cases, the subject may be about 80 years old or older. In some cases, the subject may be about 85 years old or older. In some cases, the subject may be about 90 years old or older. In some cases, the subject may be about 95 years old or older. In some cases, the subject may be about 100 years old or older. In some cases, the subject may be about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or over 100 years old. In some cases, the subject may be about 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, 17 years old, 18 years old, 19 years old, 20 years old, or more than 20 years old.

[0060] In some cases, the methods provided herein can treat a disease in a subject. In some cases, the methods provided herein can alleviate or reduce symptoms of a disease. In some cases, the methods provided herein can result in a reduction in the severity of one or more symptoms associated with a disease. In some cases, the methods provided herein can slow, stop, or reverse the progression of one or more symptoms associated with a disease. In some cases, the methods provided herein can prevent the occurrence of one or more symptoms associated with a disease. In some cases, the methods provided herein can slow, stop, or reverse the progression of a disease, as measured by the number and severity of symptoms experienced.

[0061] In some cases, the disease may be a proliferative disease or disorder. In some cases, the proliferative disease or disorder may be cancer. In some cases, the subject may have a tumor. In some cases, the method may reduce the size of the tumor. In some cases, the method may reduce the size of the tumor by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.

[0062] In some embodiments, the proliferative disease or disorder can be a prostate proliferative disease or disorder.In one non-limiting example, the prostate proliferative disease or disorder can be prostate cancer.Prostate cancer can be adenocarcinoma, sarcoma, neuroendocrine tumor, small cell carcinoma, transitional cell carcinoma, or squamous cell carcinoma.In another non-limiting example, the prostate proliferative disease or disorder can be benign prostatic hyperplasia.

[0063] This method can be utilized to deliver a therapeutically effective amount of a drug to a target tissue. In some cases, this method can include delivering a drug implant to a target tissue (or tissue adjacent to the target tissue) of a subject. Any tissue can be suitable for delivery of the drug implant of the present disclosure. In an exemplary case, the target tissue can be the prostate, tissue adjacent to the prostate, or both. Non-limiting examples of target tissues include breast, pancreas, bladder, brain, skin, kidney, lung, liver, tongue, esophagus, stomach, intestine, gallbladder, heart, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, eye, bone, fallopian tube, uterus, ovary, sinus, inner ear (eustachian tube), testis, and cervix.

[0064] In various aspects of the present disclosure, a method is provided for implanting a drug implant of the present disclosure into a target tissue (or adjacent tissue) of a subject, where the implant delivers a therapeutically effective amount of drug to the target tissue. As used herein, when used in reference to a drug or therapeutically active agent, "therapeutically effective amount" refers to an amount of drug or therapeutically active agent that can induce a therapeutic response in a subject. In various aspects of the present disclosure, the implant can deliver a therapeutically effective amount of drug to a tissue of a subject for 6 to 24 months. In some cases, the implant can deliver a therapeutically effective amount of drug to a tissue of a subject for 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months. In some cases, the implant may deliver a therapeutically effective amount of drug to a tissue of a subject for at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months.

[0065] In various embodiments of the present disclosure, the therapeutically effective amount of the drug can be at least 0.1 μg / day. In some cases, the therapeutically effective amount of the drug is at least 0.1 μg / day, 0.2 μg / day, 0.3 μg / day, 0.4 μg / day, 0.5 μg / day, 0.6 μg / day, 0.7 μg / day, 0.8 μg / day, 0.9μg / day, 1μg / day, 2μg / day, 3μg / day, 4μg / day, 5μg / day, 6μg / day, 7μg / day, 8μg / day, 9μg / day, 10μg / day, 15μg / day, 20μg / day, 25μg / day, 30μg / day, 35μg / day, 40μg / day, 45μg / day, 50μg / day, 55μg / day, 60μg / day, 65μg / day, 70μg / day, 75μg / day, 80μg / day, 85μg / day, 90μg / day, 95μg / day, 100μg / day, 110μg / day, 120μg / day, 130μg / day, 140μg / day, 150μ g / day, 160μg / day, 170μg / day, 180μg / day, 190μg / day, 200μg / day, 210μg / day, 220μg / day, 230μg / day, 240μg / day, 250μg / day, 260μg / day, 270μg / day, 280μg / day, 290μg / day , 300μg / day, 310μg / day, 320μg / day, 330μg / day, 340μg / day, 350μg / day, 360μg / day, 3 70μg / day, 380μg / day, 390μg / day, 400μg / day, 410μg / day, 420μg / day, 430μg / day, 440 μg / day, 450μg / day, 460μg / day, 470μg / day, 480μg / day, 490μg / day, 500μg / day, 510μg / day, 520μg / day, 530μg / day, 540μg / day, 550μg / day, 560μg / day, 570μg / day, 580μg / day, 590μg / day, 600μg / day, 610μg / day, 620μg / day, 630μg / day, 640μg / day, 650μg / day, 660μg / day, 670μg / day, 680μg / day, 690μg / day, 700μg / day, 710μg / day, 720μg / day, It may be 30μg / day, 740μg / day, 750μg / day, 760μg / day, 770μg / day, 780μg / day, 790μg / day, 800μg / day, 810μg / day, 820μg / day, 830μg / day, 840μg / day, 850μg / day, 860μg / day, 870μg / day, 880μg / day, 890μg / day, 900μg / day, 910μg / day, 920μg / day, 930μg / day, 940μg / day, 950μg / day, 960μg / day, 970μg / day, 980μg / day, 990μg / day, 1000μg / day or more. It is understood that a therapeutically effective amount of a drug may vary based on the drug and / or the disease being treated and may be empirically determined.

[0066] In various embodiments, the implant can provide a cumulative release of therapeutically active agent from the implant to the target tissue. In some cases, the cumulative in vitro release of bicalutamide from the implant can be at least 100 μg on day 1. In some cases, the cumulative in vitro release of bicalutamide from the implant can be at least 1,500 μg on day 50. In some cases, the cumulative in vitro release of bicalutamide from the implant can be at least 2,000 μg on day 100. In some cases, at least 50% of the total amount of bicalutamide present in the implant at the time of implantation remains in the polymer matrix at day 100 after implantation.

[0067] In various aspects of the present disclosure, the implant may be configured to remain in the target tissue for a period of time. In some cases, the implant may be configured to remain in the target tissue for an extended period of time (e.g., months to years) or indefinitely (e.g., never to be removed). For example, after the implant has delivered all of the therapeutically active agent contained therein to the subject, the implant (without the therapeutically active agent) may remain in the target tissue. In some cases, if additional treatment is required, one or more additional implants can be delivered to the target tissue (without removing the first implant). In some cases, the implant may be composed of a non-biodegradable and / or non-absorbable polymeric material such that the polymeric material remains substantially intact in the target tissue for an extended period of time or indefinitely.

[0068] Advantageously, the implant of the present disclosure can deliver therapeutically effective amount of bicalutamide to prostate tissue or tissue adjacent or close to prostate for a long period of time (for example, at least 6 months).In addition, the implant of the present disclosure can deliver high concentration of bicalutamide locally to prostate while maintaining low systemic concentration of bicalutamide.In some cases, the implant of the present disclosure can reduce or prevent toxicity caused by high systemic concentration of bicalutamide.

[0069] In various embodiments, the total dose of bicalutamide administered to subject by the implant of the present disclosure is less than the total dose of bicalutamide administered to subject by systemic (e.g., oral) administration.Standard oral administration regimens of bicalutamide include 150mg / day bicalutamide monotherapy for early stage prostate cancer, and 50mg / day combined with other therapies for advanced prostate cancer.Advantageously, the implant of the present disclosure provides a lower total dose of bicalutamide compared to oral administration regimens.In some cases, the total amount of bicalutamide administered to subject is less than 100mg over a period of 6 months.

[0070] In various embodiments, the present disclosure's drug implant can be implanted in prostate or tissue adjacent to or close to prostate, and can obtain a plasma concentration of bicalutamide that is substantially lower than the plasma concentration of bicalutamide that is obtained when bicalutamide is administered to a subject by systemic (e.g., oral) administration.For example, the steady-state plasma concentration of the R-enantiomer of bicalutamide is reported to be about 9 μg / ml.In some cases, the present disclosure's implant can be implanted in prostate or tissue adjacent to or close to prostate, and can obtain a steady-state plasma concentration of R-bicalutamide that is less than 9 μg / ml, for example, less than 5 μg / ml.

[0071] kit Further provided herein is a kit. In some embodiments, the kit can include one or more implants described herein. For example, the kit can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 implants. In some cases, one or more implants can include a therapeutically active agent contained therein. In some cases, each of the one or more implants can include the same therapeutically active agent. In other cases, each of the one or more implants can include one or more different therapeutically active agents.

[0072] In some embodiments, the kit may include one or more surgical tools, such as a needle or forceps. In some embodiments, the kit may be packaged in a sterile package. In some cases, the sterile package includes a foil. In some embodiments, the kit may further include instructions for implanting the implant into the tissue of a subject.

[0073] Specific Terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter.

[0074] In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0075] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Thus, "about 5 μL" also means "about 5 μL" and "5 μL". In general, the term "about" includes amounts that are expected to be within experimental error, for example, within 15%, 10%, or 5%.

[0076] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0077] Non-Limiting List of Exemplary Embodiments In addition to the aspects and embodiments described and provided elsewhere in this disclosure, the following non-limiting list of specific embodiments are specifically contemplated. 1. An implant comprising: a biocompatible, substantially non-biodegradable polymer matrix; and An implant comprising an antiandrogen dispersed throughout a polymer matrix. 2. An implant comprising: a biocompatible polymer matrix, and An implant comprising a therapeutically active agent dispersed throughout a polymeric matrix, wherein when the implant is placed within a target tissue of a subject, the implant delivers a therapeutically effective amount of the therapeutically active agent to the target tissue of the subject for at least 24 months. 3. An implant comprising: a biocompatible, substantially non-biodegradable polymer matrix; and An implant comprising an antiandrogen in crystalline form. 4. An implant comprising: a biocompatible, substantially non-biodegradable polymer matrix; and An implant comprising an antiandrogen dispersed throughout a polymer matrix in an amount of 10-70% w / w. 5. An implant according to any one of embodiments 1-4, wherein the implant, when placed within the target tissue of a subject, releases at least 0.1 μg / day of the therapeutically active agent or antiandrogen 24 months after implantation. 6. An implant according to any one of embodiments 1 to 5, wherein the therapeutically active agent or antiandrogen has a median particle size of less than 10 microns. 7. An implant according to any one of the preceding embodiments, wherein the implant has a Shore A hardness of at least 30 durometers when loaded with 60% w / w of a therapeutically active agent. 8. An implant according to any one of embodiments 1 to 7, wherein at least 99% of the polymer matrix remains within the target tissue of the subject for at least 600 days after implantation. 9. An implant according to any one of embodiments 1 to 8, wherein the implant is ultrasound visible when placed within the target tissue of a subject. 10. An implant according to any one of the preceding embodiments, wherein the therapeutically active agent or antiandrogen has a melting temperature higher than the curing temperature of the polymer matrix. 11. The implant of embodiment 10, having a melting temperature above 150° C. 12. An implant according to any one of the preceding embodiments, wherein the polymer matrix inhibits degradation of the therapeutically active agent or antiandrogen in the implant. 13. The implant of embodiment 12, wherein the polymer matrix inhibits degradation of the therapeutically active agent or antiandrogen by esterases or amidases. 14. An implant according to embodiment 12 or 13, wherein the degradation is determined by measuring the amount of therapeutically active agent or antiandrogen in the eluate after incubating the implant containing the therapeutically active agent or antiandrogen in a solution containing 1% SDS containing 0.05N NaOH for 8 hours at 37°C. 15. An implant according to any one of embodiments 1 to 14, wherein the implant is elongated. 16. An implant according to any one of the preceding embodiments, wherein the implant is cylindrical. 17. An implant according to any one of the preceding embodiments, wherein the implant is tubular. 18. An implant according to any one of the preceding embodiments, wherein the diameter of the implant is less than 1 mm. 19. An implant according to any one of the preceding embodiments, wherein the diameter of the implant is between 0.5 mm and 1.5 mm. 20. An implant according to any one of the preceding embodiments, wherein the diameter of the implant is between 0.7 mm and 1.3 mm. 21. An implant according to any one of the preceding embodiments, wherein the diameter of the implant is between 0.9 mm and 1.1 mm. 22. An implant according to any one of embodiments 1 to 18, wherein the diameter of the implant is about 1 mm. 23. An implant according to any one of embodiments 1 to 22, wherein the length of the implant is less than 20 mm. 24. An implant according to any one of the preceding embodiments, wherein the length of the implant is between 5 mm and 25 mm. 25. An implant according to any one of the preceding embodiments, wherein the length of the implant is between 10 mm and 20 mm. 26. An implant according to any one of the preceding embodiments, wherein the length of the implant is between 12 mm and 18 mm. 27. An implant according to any one of embodiments 1 to 22, wherein the length of the implant is about 15 mm. 28. An implant according to any one of the preceding embodiments, wherein the implant further comprises a coating. 29. The implant of embodiment 28, wherein the coating partially covers the implant. 30. The implant of embodiment 28, wherein the coating substantially covers the implant. 31. The implant of embodiment 28, wherein the coating covers the implant. 32. The implant of embodiment 2, wherein the therapeutically active agent is an antiandrogen. 33. An implant according to any one of embodiments 1 to 32, wherein the therapeutically active agent or antiandrogen is bicalutamide. 34. An implant according to any one of the preceding embodiments, wherein the implant is sterilized. 35. An implant according to any one of embodiments 1 to 34, wherein the implant is placed in a sterile package. 36. An implant according to any one of embodiments 1 to 35, wherein the polymer matrix is ​​at least 95% cured, at least 96% cured, at least 97% cured, at least 98% cured, at least 99% cured, or at least 99.9% cured. 37. An implant according to any one of the preceding embodiments, wherein the polymer matrix comprises silicone. 38. An implant according to embodiment 37, wherein the silicone is Silbione® LSR D370, manufactured by Elkem. 39. The implant of embodiment 37, wherein the silicone is DDU 4870 manufactured by NuSil™. 40. An implant according to any one of embodiments 1 to 39, wherein the implant is configured to be implanted into the prostate tissue of a subject. 41. An implant according to any one of the preceding embodiments, wherein the implant is devoid of metal. 42. A method of manufacturing an implant suitable for implantation into the prostate of a subject, the method comprising: (a) combining an amount of an uncured biocompatible, substantially non-biodegradable polymer with an amount of an antiandrogen to form a mixture; (b) shaping the mixture to form a shaped mixture; (c) curing the molded mixture by heating the molded mixture for a period of time. 43. The method of embodiment 42, wherein the amount of antiandrogen is 10% w / w to 70% w / w of the uncured biocompatible, substantially non-biodegradable polymer. 44. The method of embodiment 42 or 43, wherein the antiandrogen is bicalutamide. 45. The method according to any one of embodiments 42 to 44, wherein the biocompatible, substantially non-biodegradable polymer is a silicone. 46. ​​The method of embodiment 45, wherein the silicone is Silbione® LSR D370 manufactured by Elkem. 47. The method of embodiment 45, wherein the silicone is DDU 4870 manufactured by NuSil™. 48. The method of any one of embodiments 42-47, wherein curing (c) further comprises heating the molded mixture at a temperature of about 150° C. to about 200° C. for 3 to 8 minutes. 49. The method of any one of embodiments 42 to 48, wherein the mixture further comprises a solvent. 50. The method of embodiment 49, wherein the solvent is selected from the group consisting of pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. 51. The method of any one of embodiments 42-50, wherein the mixture is molded by a transfer molding process. 52. The method of any one of embodiments 42-51, further comprising performing an analysis on the implant. 53. The method according to embodiment 54, wherein the analysis is selected from the group consisting of differential scanning calorimetry (DSC), development of the implant in a surrogate tissue, dissolution testing, viscosity measurement, high pressure liquid chromatography (HPLC), and simulated in vivo stability assays. 54. A kit comprising: A sterile package containing an implant according to any one of embodiments 1 to 41; and instructions for implanting the implant into a target tissue of a subject. 55. The kit of embodiment 54, wherein the implant is configured to be delivered to the human prostate, tissue adjacent to the human prostate, or both. 56. The kit according to embodiment 54 or 55, wherein the sterile package is formed from foil. 57. A kit described in any one of embodiments 54 to 56, further comprising one or more surgical tools for implanting the implant into the target tissue of the subject. 58. The kit of embodiment 57, wherein the one or more surgical tools include a needle, forceps, trocar, or stylet. 59. A method of treating a disease in a subject in need thereof, comprising: A method comprising implanting an implant according to any one of embodiments 1 to 41 into the prostate of a subject, thereby treating a disease. 60. A method of treating a disease in a subject in need thereof, comprising: A method comprising implanting a substantially non-biodegradable implant comprising a biocompatible polymer matrix and an anti-androgenic drug dispersed throughout the biocompatible polymer matrix into the prostate of a subject, thereby treating the disease. 61. The method of embodiment 60, wherein the prostate comprises prostate tissue, tissue adjacent to prostate tissue, or both. 62. The method of embodiment 60 or 61, wherein the disease is a proliferative disease or disorder of the prostate (e.g., prostate cancer, benign prostatic hyperplasia). 63. The method of any one of embodiments 60 to 62, further comprising placing a distal end of the elongate tube within the subject's prostate gland or tissue adjacent to the prostate gland. 64. The method of embodiment 63, wherein a portion of the elongated tube is placed through a first portion of the grid such that a first position of the elongated tube in the subject is determined. 65. The method of embodiment 63 or 64, wherein the elongated tube is a needle or a catheter. 66. The method of embodiment 65, wherein the trocar is placed within the lumen of the elongated tube. 67. The method of embodiment 66, further comprising removing the trocar from the lumen of the elongate tube. 68. The method of embodiment 67, further comprising disposing an implant within the lumen of the elongated tube after removing the trocar from the lumen of the elongated tube. 69. The method of embodiment 68, further comprising pushing the stylet through the lumen of the elongated tube, thereby moving the implant to the distal end of the elongated tube. 70. The method of embodiment 69, further comprising moving the elongated tube away from the subject, such implant remaining within the subject. 71. The method of embodiment 70, wherein the stylet is positioned in a portion of the lumen of the elongated tube, the distal end of the stylet adjacent to the implant, such that the implant remains within the subject. 72. The method of any one of embodiments 60 to 71, wherein a portion of a second elongated tube is positioned through a second portion of the grid such that a position of the second elongated tube in the subject is determined. EXAMPLES

[0078] Example 1 Method for Making Implants The manufacture of the implant involved two major steps: formulation of the active pharmaceutical ingredient (API) (e.g., bicalutamide) with an elastomer (e.g., heat-cured silicone) to ensure uniform mixing of the API within the polymer matrix, and molding of the implant to ensure that the product can be deployed in the organ as intended.

[0079] formulation The implant formulations contained medical grade silicone as an excipient mixed with the API, using a solvent to reduce the viscosity of the silicone, if necessary, to incorporate the desired API loading.

[0080] A 60% w / w bicalutamide formulation was made using a centrifugal mixer (FlackTek DAC400-VAC). The required amount of silicone part A and part B were added to a mixing cup, and an equal weight of solvent (dissolves the silicone; e.g., pentane) was added. The silicone and solvent were mixed at high speed until the viscosity of the silicone was reduced so that the silicone could flow. The API powder was then incorporated into the mixing cup and mixed at high speed until a visibly smooth mixture was obtained with no dry API spots. The solvent was then removed under vacuum, leaving a paste of silicone and API. Table 1 below shows the formulation for 60% w / w bicalutamide using Silbione® LSR D370 as the silicone and pentane as the solvent for 10 grams of the mixture. Table 2 below lists a set of solvent removal parameters that can be repeated until the desired amount of solvent is removed, as confirmed by weight.

[0081] Other methods to achieve the same mixing uniformity with less solvent can be used, such as shear mixing. Other solvents that help reduce viscosity and dissolve silicones (e.g., dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, etc.) can also be used in the formulation. [Table 1] [Table 2]

[0082] molding The implant rods were fabricated using an aluminum mold by a transfer molding process. The mold was assembled and a pre-weighed amount of the formulation was injected into the mold. After the formulation was injected, the rods were cured at a specific temperature (150-200°C) for a predetermined time (3-8 minutes) based on the silicone supplier's curing recommendation. After curing, the mold was cooled and the rods were removed from the mold for characterization. Figure 1 shows an example of a molded implant according to Example 1.

[0083] Example 2. Characterization of bicalutamide-containing formulations and implants Various analytical techniques were used to characterize the formulations and molded implants. Differential scanning calorimetry (DSC) was used to measure the hardening rate of the implants and to ensure that the crystalline properties of the drug were not affected. Implants were deployed in bovine tongues to assess proper deployment of the implants with tissue properties comparable to the prostate. Methods for deployment have been described. Dissolution testing was used to assess the elution rate of the drug from the implants. Viscometers were used to assess the viscosity and hardening profile for the formulations and to ensure that the process parameters used were capable of molding hardened rods. High pressure liquid chromatography (HPLC) was used to confirm content uniformity and to assess impurities in the drug formulations and molded rods. A simulated in vivo stability assay was used to assess the ability of degradants to enter the implants.

[0084] Differential Scanning Calorimetry (DSC) Samples were run on a TA Instruments Model Q2000 (V24.11 Build 124) DSC equipped with a nitrogen flow sample chamber. Samples were prepared by loading approximately 5-15 mg of material into a sealed aluminum T-zero pan. Samples were placed in the DSC sampler and run under nitrogen purge (50 mL / min) at a rate of 10 °C / min from 20 °C to 220 °C. Figures 2A-2F show a set of DSC thermograms generated during development. Comparing the thermogram of the uncured silicone (Figure 2A) to the in-process formulation mixture (Figure 2C) and molded rods (Figures 2B and 2D) indicates that the molded rods were fully cured and the API was mixed into the formulation. Comparison of the thermograms for API alone (Figure 2E) with the molded rods at 45% w / w API (Figure 2F) and 60% w / w API (Figure 2D) showed no change in the melting range for the API (191-193 °C), indicating that the crystalline structure of the API was likely not altered during formulation and molding.

[0085] Implant deployment The drug implants were deployed in the canine prostate. To date, two preclinical studies have been conducted in dogs, and data from these studies indicate that the implants can be successfully implanted in the prostate and remain within the prostate for at least 8 weeks (Figures 3A-3C).

[0086] Dissolution Test Dissolution tests were performed to analyze the in vitro performance of the molded implants. The implants were placed in 1% w / w sodium lauryl sulfate (SDS) solution and the dissolution medium was changed periodically. The elution of API was quantified at each time point by UV / Vis spectroscopy or HPLC. Comparison of the dissolution curves for 30% w / w, 45% w / w, and 60% w / w bicalutamide formulations with the predicted profiles over approximately 2 years are shown in Figures 4A-4C.

[0087] Figure 4D shows the cumulative release (μg / day) of bicalutamide from implants containing 60% w / w bicalutamide in an in vitro model. Figure 4E shows the release rate profile of bicalutamide from implants containing 60% w / w bicalutamide in an in vitro model. Figure 4F shows the predicted cumulative release (ug / day) profile of implants containing 60% w / w bicalutamide, demonstrating that the implants are loaded with enough bicalutamide to provide a therapeutically effective dose of drug for two years. The dotted line indicates the total amount of drug loaded into the implant (approximately 8.4 mg).

[0088] Figure 4G shows the effect of age, storage conditions, and sterilization on the cumulative release profile of implants containing 60% w / w bicalutamide in an in vitro model. Figure 4G demonstrates that different storage conditions, sterilization techniques, and age of the implants do not affect the cumulative release profile of these implants in an in vitro model. Figure 4H shows the release rate of bicalutamide from these implants, again demonstrating that it is not affected by different storage conditions, sterilization techniques, or age of the implants in an in vitro model.

[0089] Simulated in vivo stability assay Simulated in vivo stability was performed to analyze the in vivo stability of the active agent within the implants. Implants containing 0% w / w, 30% w / w, 45% w / w, and 60% w / w bicalutamide were placed in 1% SDS solution containing 0.05N NaOH (a degradant known to degrade bicalutamide) for approximately 8 hours at 37°C. Experimental controls included 0% w / w, 30% w / w, 45% w / w, and 60% w / w bicalutamide implants in 1% SDS without NaOH, as well as bicalutamide solutions in 1% SDS with and without NaOH. Bicalutamide extracted from the elution medium and implants was analyzed using reversed-phase high pressure liquid chromatography (RP-HPLC). Results demonstrated that bicalutamide eluates in all samples containing NaOH, including bicalutamide solutions, showed degradation (25%-40% by area) (see Figure 5). In contrast, no degradation peaks were observed for the extracted samples. Thus, the implants prevented NaOH from entering the device, thereby protecting the bicalutamide within the implant from degradation.

[0090] Example 3 Analysis of Drug Implants of the Present Disclosure Implanted in the Prostate of Dogs Three dogs, at least 15 months of age, were recruited in this study. Each dog received two active implant devices containing 60% bicalutamide (approximately 8.4 mg) by weight / Silbione Biomedical LSR D370 silicone on rods measuring 15 mm in length by 0.95 mm in diameter. An 18-gauge brachytherapy needle (OD 1.27 mm) was used for device implantation. Clinical observations and body weights were recorded. Blood was collected at frequent intervals for determination of plasma bicalutamide concentrations and clinical chemistry evaluation. After 55 days of observation, the animals were euthanized, a full body necropsy was performed, the implanted devices were retrieved, and tissues (including the prostate) were harvested for histopathological examination and bicalutamide quantification.

[0091] Live animal ingredients During surgical implantation, a single device was placed in each lobe of the prostate to avoid complications. Device placement was confirmed by transrectal ultrasound during implantation and 1, 7, 14, and 28 days after implantation. Mild to moderate swelling was observed around the surgical incision site in all three test animals, which resolved with anti-inflammatory (carprofen) treatment. Blood was collected for clinical chemistry evaluation and bicalutamide quantification. During the 55-day observation period, the test animals showed no signs of distress or adverse effects from the test device.

[0092] Complete autopsy and histopathological interpretation At 55 days after implantation, the test animals were euthanized and a full body necropsy was performed. No pathology associated with the test device was noted during the necropsy. Organs were sampled for histopathological evaluation and bicalutamide quantification. The prostate was trimmed and cut into three sections perpendicular to the urethra: a cranial (rostral) section, a 3-5 mm transverse section, and a caudal section. From the rostral section, two 5 mm punch biopsies were obtained surrounding the implant, and the remainder of the rostral and caudal sections were divided into four sections each and sent for bicalutamide quantification. The entire transverse section was sent for histopathological evaluation.

[0093] Histopathological evaluation revealed no device-related lesions in tissues other than the prostate. Minimal nephrocalcinosis was observed but was considered consistent with background findings in the study dogs. The prostate, testes, and epididymis were mature and did not demonstrate device-related pathology. No device ducts were visible, and no fibrous encapsulation was seen. Mild interglandular fibrosis and lymphocytic infiltration was observed in some animals but was considered consistent with the intended breeding study dogs.

[0094] Plasma Drug Quantitation Plasma total, R-, and S-bicalutamide levels were comparable across all three test animals, peaking between 12-24 ng / mL (FIGS. 6A and 6B). Steady state continued through day 55, with mean median levels of total, R-, and S-bicalutamide reaching 13.2±1.7, 9.1±1.3, and 5.0±0.5, respectively, by approximately day 4. The ratio of R-bicalutamide to S-bicalutamide was approximately 2:1. Note that the plasma levels shown in FIGS. 6A and 6B are in micrograms for the oral dose, while the scale is in ng / mL for the device plasma levels.

[0095] Solid Tissue Drug Quantitation Bicalutamide was quantified in major organs and prostate-related tissues collected during necropsy. Bicalutamide levels were highest in the removed organs (liver and kidney) and in the lungs. Consistent with the plasma findings, the ratio of R-bicalutamide to S-bicalutamide was approximately 2:1. Compared to plasma levels, mean accumulation was evident only in the liver (47±16, 28±9, and 19±7 ng / g versus 13±2, 9±1, and 5±1 ng / g for total, R-bicalutamide, and S-bicalutamide), but was very low compared to prostate exposure.

[0096] Prostate Drug Assay Quantification of prostatic bicalutamide showed that the total, R-bicalutamide, and S-bicalutamide levels in the whole gland were 172±21, 86±10, and 87±11 ng / g, respectively. 5 mm diameter punch biopsies around the device implants yielded averages of 1426±501, 698±242, and 727±259 ng / g total, R-bicalutamide, and S-bicalutamide, respectively (FIGS. 7A and 7B). Unlike plasma and other organs, the ratio of R-bicalutamide to S-bicalutamide in the prostate was approximately 1:1. As seen in FIG. 8, the levels of R-bicalutamide were higher on average per quadrant (black numbers) showing elution across the prostate than around the implant (red numbers in circles).

[0097] Overview of the study This study aimed to evaluate the safety, toxicity, and tissue distribution of bicalutamide in dogs when two 60 wt% bicalutamide devices were implanted in the prostate. No significant safety or toxicity findings were observed in the live animal portion of the study. Consistently, gross and histopathological analysis of major organs and prostate-related tissues revealed no pathology attributable to the test device, including foreign body reactions, that could compromise bicalutamide delivery to the prostate. Comparison of bicalutamide levels in plasma, organs, and prostate demonstrated that significantly greater local (e.g., prostate) exposure was achieved. The whole prostate levels achieved for the active R-bicalutamide isomer (84.6 ± 10.1 ng / g or 196.6 ± 23.5 nM) are sufficient to inhibit the androgen receptor in a cell-free androgen binding assay (IC 50 Prostate tissue within approximately 5 mm of the device achieved R-bicalutamide levels (698 ± 242 ng / g or 1623 ± 562 nM) that were shown to inhibit prostate cancer cells (IC 50 Approximately 1000 nM). The equal distribution of R-bicalutamide and S-bicalutamide (approximately 1:1) found in the prostate favors device delivery rather than systemic recirculation as the isomeric formulation within the device is approximately 1:1, while hepatic metabolism results in a systemic ratio of 2:1 in this dog model.

[0098] The prostate was divided into three pieces to allow for a more thorough evaluation of bicalutamide delivery while maintaining the ability to assess histopathology. Although limited to a relatively thin cross-section of the prostate, this centrally located slice was in contact with or in close proximity to the implanted device, allowing for histopathological analysis of the effects of the device and delivered bicalutamide on the tissue. Furthermore, the central cross-section of the prostate was sent for histopathology, and its contribution to the bicalutamide levels throughout the prostate was not included. This would likely result in an underestimation of bicalutamide throughout the gland, as the mean levels may have been higher in the proximal portion of the device than in other parts of the gland that were more distant from the device (e.g., the caudal piece).

[0099] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It is understood that various alternatives to the embodiments of the present disclosure described herein may be used in the practice of the present disclosure. The following claims define the scope of the disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. An implant comprising bicalutamide dispersed in a liquid silicone rubber matrix, the liquid silicone rubber matrix comprises Silbione® LSR D370; the liquid silicone rubber matrix having a Shore A hardness of at least 30 durometer; said implant comprising said bicalutamide in an amount of at least 30% w / w; said bicalutamide having a D90 of less than 15 microns; An implant, wherein the liquid silicone rubber matrix releases bicalutamide at a rate of 0.1 μg / day to 95 μg / day for at least six months after implantation of the implant into prostatic or prostatic tissue.

2. 2. The implant of claim 1, wherein the bicalutamide is in a solid form.

3. The implant has a volume of at least 10 mm ３ 3. The implant of claim 1 or 2,

4. 4. The implant of claim 1, wherein the length of the implant is at least 1 mm.

5. 5. The implant of claim 1, wherein the length of the implant is at least 3 mm.

6. 6. The implant of claim 1, wherein the diameter of the implant is at least 0.1 mm.

7. 7. The implant of claim 1, wherein the diameter of the implant is at least 0.8 mm.

8. The implant of claim 1 , wherein the implant lacks a sheath.

9. 9. The implant of claim 1, wherein the total dose of bicalutamide per implant is at least 1 mg.

10. 10. The implant of any one of claims 1 to 9, wherein the bicalutamide has a median particle size of less than 10 microns.

11. 11. The implant of claim 1, wherein the implant is configured to be delivered to the prostate tissue or the tissue adjacent to the prostate via a lumen of a needle or catheter.

12. 12. The implant of any one of claims 1 to 11, consisting essentially of said liquid silicone rubber matrix and said bicalutamide dispersed in said liquid silicone rubber matrix.

13. 13. The implant of any one of claims 1 to 12, wherein the implant comprises the bicalutamide in an amount of about 30% w / w, and the cumulative release of the bicalutamide in a 1% w / w sodium lauryl sulfate (SDS) solution at 60 days is less than 500 μg.

14. 14. The implant of any one of claims 1 to 13, wherein the implant comprises the bicalutamide in an amount of about 45% w / w, and the cumulative release of the bicalutamide in a 1% w / w sodium lauryl sulfate (SDS) solution at 60 days is less than 700 μg.

15. 15. The implant of any one of claims 1 to 14, wherein the implant comprises the bicalutamide in an amount of about 60% w / w, and the cumulative release of the bicalutamide in a 1% w / w sodium lauryl sulfate (SDS) solution at 60 days is less than 2000 μg.

16. 1. A drug / polymer composite prostate implant comprising: a silicone rubber matrix comprising Silbione® LSR D370 and having a Shore A hardness of at least 30 durometer; and bicalutamide having a D90 of less than 15 microns dispersed in said silicone matrix in an amount of at least 30% w / w, wherein said prostate implant releases 0.1 μg / day to 10 μg / day of said bicalutamide six months after implantation in a subject.

17. 17. The prostatic implant of claim 16, wherein the bicalutamide is in a solid form.

18. 20. The prostatic implant of claim 17, wherein the solid form has a median particle size of less than 10 microns.

19. A prostate implant according to any one of claims 16 to 18, wherein the silicone has a curing temperature below the melting point of bicalutamide.

20. 20. The prostate implant of any one of claims 16 to 19, wherein at least 50% of the bicalutamide remains in the silicone matrix 100 days after implantation.

21. A prostate implant according to any one of claims 16 to 20, wherein the silicone rubber matrix is ​​liquid silicone rubber.

22. The prostate implant has a volume of at least 10 mm ３ 22. The prostate implant of claim 16, wherein

23. A prostate implant according to any one of claims 16 to 22, wherein the length of the prostate implant is between 1 mm and 30 mm.

24. A prostate implant according to any one of claims 16 to 23, wherein the length of the prostate implant is between 5mm and 25mm.

25. A prostate implant according to any one of claims 16 to 24, wherein the diameter of the prostate implant is between 0.1 mm and 1.5 mm.

26. A prostate implant according to any one of claims 16 to 25, wherein the bicalutamide is dispersed in the polymer matrix in an amount of at least 40% w / w.

27. A prostate implant according to any one of claims 16 to 26, wherein at least 50% of the outer surface of the polymer matrix is ​​uncoated.

28. The prostate implant of any one of claims 16 to 27, wherein the prostate implant is deliverable using a needle cannula.

29. 29. The prostate implant of any one of claims 16 to 28, consisting essentially of the polymer matrix and the bicalutamide dispersed in the polymer matrix.

30. The prostate implant of any one of claims 16 to 29, wherein the bicalutamide is in a crystalline form.

31. The prostate implant of any one of claims 16 to 30, wherein the bicalutamide is in a solid amorphous form.

32. The prostate implant of any one of claims 16 to 31, wherein the outer surface of the prostate implant polymer matrix is ​​coated.

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