Drug implant containing darolutamide and method of using the same

Abstract

Disclosed herein are drug implants comprising darolutamide for the treatment of a disease in a subject. In some cases, the drug implant may comprise a polymeric matrix and darolutamide disposed therein. Further provided are methods for manufacturing the drug implant and methods of treating a disease with the implant. In some cases, the drug implant may be used for the treatment of a proliferative disease of the prostate.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 368,922, filed Jul. 20, 2022, the entire disclosure of which is incorporated herein by reference.

Background Art

[0002] The burden of prostate cancer in the United States is significant. In 2009, approximately 192,000 men were diagnosed with prostate cancer and an estimated 27,000 men died from the disease. Approximately 2.2 million living American men have been diagnosed with prostate cancer, some of whom are living with metastatic disease, pain, and functionally limiting stages. Prostate cancer has been the most commonly diagnosed cancer among American men and continues to be the second leading cause of cancer death in men. Hormonal therapies for prostate cancer include a wide variety of treatments designed to affect cells whose normal function is androgen-dependent, including testosterone and dihydrotestosterone. Prostate cancer cells are generally very sensitive to treatments that reduce androgen levels or affect the normal action of these hormones.

[0003] Darolutamide is an antiandrogen that can be used in the treatment of prostate cancer. Darolutamide is a member of the pharmaceutical class of non-steroidal antiandrogens (NSAAs) and acts by blocking the androgen receptor. Darolutamide has been associated with several side effects that may be partially due to the relatively large amounts of darolutamide that are administered systemically to obtain a therapeutic benefit. Thus, local administration of lower amounts of darolutamide may be able to achieve a therapeutic benefit and prevent or reduce the side effects or toxicity of systemic darolutamide administration.

Summary of the Invention

[0004] There is an unmet need for an improved drug implant that can be used to directly deliver a therapeutic agent (e.g., darolutamide) to a target tissue of interest. This disclosure meets this unmet need.

[0005] In one aspect, there is provided a drug implant comprising: a) a biocompatible non-biodegradable polymer matrix; and b) darolutamide dispersed within the biocompatible non-biodegradable polymer matrix. In some cases, darolutamide is present in the drug implant in an amount of about 10% w / w to about 80% w / w. In some cases, the total dosage of darolutamide in the drug implant is from about 1 mg to about 10 mg. In some cases, the drug implant releases at least about 0.1 μg / day of darolutamide 6 months after implantation into a subject. In some cases, the cumulative release of darolutamide in an in vitro model is (i) 2000 micrograms or less by day 1, 12,000 micrograms or less by day 60, and 16,000 micrograms or less by day 120, and (ii) at least 10 micrograms by day 1, at least 200 micrograms by day 60, and at least 300 micrograms by day 120, and the in vitro model comprises incubating the drug implant in 1% sodium dodecyl sulfate in water at 37° C. with continuous agitation. In some cases, the biocompatible non-biodegradable polymer matrix is silicone. In some cases, the silicone is acetoxy-cured silicone or platinum-cured silicone. In some cases, the biocompatible non-biodegradable polymer matrix is thermoplastic polyurethane or poly(ethylene vinyl acetate). In some cases, at least 50% of the darolutamide remains within the biocompatible non-biodegradable polymer matrix 100 days after implantation. In some cases, at least 99 weight % of the biocompatible non-biodegradable polymer matrix remains within the target tissue of the subject for at least 600 days after implantation. In some cases, darolutamide is in solid form. In some cases, darolutamide is in crystalline form, semi-crystalline form, or amorphous form. In some cases, the drug implant has a Shore A hardness of at least 20 durometers when loaded with 60% w / w of darolutamide. In some cases, when disposed within the target tissue of the subject, the drug implant is visible by ultrasound. In some cases, darolutamide has a melting temperature higher than the molding or curing temperature of the polymer matrix.In some cases, the drug implant inhibits the modulation of darolutamide within the drug implant. In some cases, modulation includes degradation. In some cases, the drug implant is elongated. In some cases, the drug implant is cylindrical. In some cases, the drug implant is tubular. In some cases, the drug implant is rod-shaped. In some cases, the diameter of the drug implant is from about 0.1 mm to about 1.5 mm. In some cases, the length of the drug implant is from about 1 mm to about 30 mm. In some cases, the volume of the drug implant is about 0.1 mm. 3 ~ about 30 mm 3 In some cases, at least 50% of the outer surface of the drug implant is configured to directly contact the target tissue. In some cases, the drug implant is configured to be implanted into the target tissue, or a tissue near or adjacent to the target tissue. In some cases, the target tissue is prostate tissue. In some cases, the drug implant is configured to be delivered to the target tissue using the lumen of a needle or catheter. In some cases, the drug implant lacks at least one of a sheath, a scaffold, a retention member, or a combination thereof for retaining the drug implant within the target tissue. In some cases, the drug implant further includes a coating. In some cases, the coating partially covers the drug implant. In some cases, the coating substantially covers the drug implant. In some cases, the coating covers the drug implant. In some cases, the drug implant is sterilized. In some cases, the drug implant is disposed within a sterilized package. In some cases, the drug implant consists essentially of a biocompatible non-biodegradable polymer matrix and darolutamide dispersed within the biocompatible non-biodegradable polymer matrix.

[0006] In another aspect, a method for treating a proliferative disorder of the prostate of a subject is provided, the method comprising implanting one or more drug implants as recited in any one of the preceding claims into prostate tissue or tissue adjacent to the prostate. In some cases, the one or more drug implants deliver a therapeutically effective amount of darolutamide to the prostate for at least 6 months. In some cases, the proliferative disorder of the prostate is prostate cancer or benign prostatic hyperplasia. In some cases, the prostate cancer is castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer. In some cases, darolutamide is dispersed within a biocompatible non-biodegradable polymer matrix prior to implantation. In some cases, implantation comprises placing each of the one or more drug implants into prostate tissue or tissue adjacent to the prostate through the lumen of a needle or catheter. In some cases, implantation is performed by transperineal administration. In some cases, transperineal administration comprises using a template-guided needle. In some cases, the total dose of darolutamide administered to the subject is less than the total dose of darolutamide that would be administered to the subject by oral administration. In some cases, the total dose of darolutamide administered to the subject is less than 100 mg over a 6-month period. In some cases, implantation results in a plasma concentration of darolutamide that is less than the plasma concentration of darolutamide obtained when darolutamide is administered to the subject by oral administration. In some cases, implantation results in a steady-state plasma concentration of darolutamide of less than about 4.79 mg / L. In some cases, the one or more drug implants comprise 2 to 16 drug implants.

[0007] In yet another aspect, a method of manufacturing any one of the foregoing drug implants is provided, the method comprising: (a) mixing an amount of uncured polymer with an amount of darolutamide to form a mixture; (b) shaping the mixture to produce a shaped mixture; and (c) curing the shaped mixture by heating the shaped mixture for a period of time. In some cases, the amount of darolutamide is from 10% w / w to 80% w / w of the uncured polymer. In some cases, the polymer is silicone or thermoplastic polyurethane or poly(ethylene vinyl acetate). In some cases, curing in (c) further comprises heating the shaped mixture at a temperature of about 150°C to about 200°C for about 3 to about 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 shaped by a transfer molding process or by extrusion through a tube. In some cases, shaping comprises extruding the mixture using a ram extruder or a twin screw extruder. In some cases, shaping comprises injection molding. In some cases, the method further comprises performing an analysis on the drug implant. In some cases, the analysis is selected from the group consisting of differential scanning calorimetry (DSC), placement of the drug implant in surrogate tissue, elution testing, rheology, high performance liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).

[0008] In yet another aspect, a kit is provided that includes a sterilized package containing any one of the drug implants recited in any of the preceding claims and instructions for implanting the drug implant into a target tissue of a subject.

[0009] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the present disclosure are described in detail in the appended claims. A better understanding of the features and advantages of the present disclosure can be obtained by referring to the following detailed description, which describes exemplary embodiments in which the principles of the present disclosure are utilized, and the accompanying drawings.

[0011]

Figure 1A

Figure 1B

Mode for Carrying Out the Invention

[0012] Provided herein are drug implants that can directly deliver a therapeutically effective amount of darolutamide to a target tissue. Also provided herein are drug implants that, when implanted into a target tissue, result in a high concentration of darolutamide within the target tissue and a low concentration of darolutamide in the systemic circulation (e.g., in plasma). In some cases, the ability of the drug implants provided herein to directly deliver a therapeutically effective amount of darolutamide to a target tissue can reduce or eliminate the side effects or toxicities of darolutamide treatment that would otherwise result from systemic administration while achieving a low concentration of darolutamide in the systemic circulation. Additionally, direct delivery of darolutamide to a target tissue by the drug implants described herein ensures that the target tissue receives a therapeutically effective amount of darolutamide. In a further aspect, the drug implants provided herein can be loaded with a large amount of darolutamide such that the drug implant can sustainably release darolutamide to the target tissue over a long period of time. In some aspects, darolutamide can be dispersed within a polymeric matrix of the implant that provides certain advantages (e.g., faster elution time, higher drug loading within the implant, etc.). In certain aspects, the drug implants provided herein can contain darolutamide at a high concentration such that a therapeutically effective amount of darolutamide can be directly administered to prostate tissue for a long period of time (e.g., for six months or more) while maintaining a low systemic concentration of darolutamide.

[0013] In various aspects, the drug implants disclosed herein can comprise a polymeric matrix and darolutamide. In certain cases, darolutamide can be dispersed within the polymeric matrix. Preferably, the polymeric matrix is biocompatible and non-biodegradable. The drug implant can be implanted into a target tissue and can release an amount of darolutamide over time. The drug implant containing darolutamide can be effective in treating a disease or its symptoms. The disease can be, for example, a proliferative disease of the prostate such as prostate cancer or benign prostatic hyperplasia. In some cases, the prostate cancer is castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer.

[0014] In this specification, a method of treating a disease is further provided by delivering a drug implant of the present disclosure (e.g., containing darolutamide) to a target tissue of a subject in need thereof to deliver a therapeutically effective amount of darolutamide over a long period of time. Further provided are a method of manufacturing a drug implant and a kit comprising the drug implant.

[0015] Drug implant In this specification, a drug implant (also referred to herein as an "implant") suitable for delivering darolutamide to a target tissue is provided. In some aspects of the present disclosure, the implant comprises a polymeric matrix (e.g., biocompatible, non-biodegradable), and darolutamide dispersed therein. The implant may be suitable for treating a proliferative disease of the prostate, such as, for example, prostate cancer or benign prostatic hyperplasia. In some cases, the prostate cancer is castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer.

[0016] The polymeric matrix can include any polymeric material. Generally, the polymeric material is biocompatible. The term "biocompatible" as used herein refers to the property of a material that allows for long-term contact with tissues in a subject without causing toxicity or significant damage. In some cases, the "biocompatible" polymeric material complies with the guidelines defined by the International Organization for Standardization (ISO) 10993-1:2018.

[0017] In some embodiments, the polymeric material can be "non-biodegradable" or "substantially non-biodegradable". The terms "non-biodegradable" or "substantially non-biodegradable", when used with respect to the implants of the present disclosure, generally refer to implants that cannot be degraded, or are substantially non-degradable, over the intended lifetime of the implant (e.g., by microorganisms, by enzymes (such as esterases), by oxidation). For example, at least 99 weight % of the polymeric material can remain after two years of implanting the device into the target tissue for the substantially non-biodegradable implants of the present disclosure. In some cases, "non-biodegradable" implants or polymers may comply with the guidelines defined by the Standard Guide for the Evaluation of Absorbable Polymer Implants (ASTM F2902-16) by ASTM International.

[0018] In certain aspects of the present disclosure, the polymer matrix may include polysiloxane (silicone). The silicone can be any biocompatible silicone. In some cases, the silicone can be a medical grade silicone. In some cases, the silicone can be hydrophobic. In some cases, the silicone can be a United States Pharmacopeia (USP) Class V or USP Class VI certified silicone. In various aspects, the silicone can be an acetoxy-curing silicone. In some cases, the silicone can be a Silbione® silicone adhesive manufactured by Elkem (e.g., Silbione® Biomedical ADH1 M200, as of September 1, 2020, accessible from silicone.elkem.com / EN / our_offer / Product / 90061907 / _ / SILBIONE-BIO-ADH1-M200). In some cases, the silicone can be a platinum-curing silicone. In various aspects, the silicone can be any liquid silicone rubber (LSR). In some cases, the silicone can be a Silbione® liquid silicone rubber (LSR) manufactured by Elkem.In some cases, the Silbione® LSR can be one or more of Silbione® LSR 4301, Silbione® LSR 4305, Silbione® LSR 4310, Silbione® LSR 4325, Silbione® LSR 4330, Silbione® LSR 4340, Silbione® LSR 4350, Silbione® LSR 60, Silbione® LSR 4360, Silbione® LSR 4370, Silbione® LSR 4745, Silbione® LSR 4755, Silbione® LSR 4765, Silbione® LSR 4125, Silbione® LSR 4130, Silbione® LSR 4140, 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 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.

[0019] In various other embodiments, the polymeric material can be a thermoplastic polyurethane. In some cases, the polyurethane can be one or more of the following polyurethanes manufactured by Lubrizol. PY-PT72AE, PY-PT87AE, PY-PT87AS, PY-PT83AL, and PY-PT43DE20.

[0020] In various other embodiments, the polymeric material can be poly(ethylene vinyl acetate) (PEVA). In some cases, the PEVA can be one or more PEVAs manufactured by Celanese (e.g., under the brand names ATEVA® or VitalDose®). The vinyl acetate content of the PEVA can be from 9% to 40%. In certain embodiments, the vinyl acetate content is 10%. In other certain embodiments, the vinyl acetate content is 28%. In still other certain embodiments, the vinyl acetate content is 40%.

[0021] The hardness of the rubber is measured by the Shore A hardness scale. Higher numbers on the scale refer to harder materials, while lower numbers on the scale refer to softer materials. Generally, the polymeric material within a drug implant has a Shore A hardness of at least 30 durometers. For example, the polymeric material can have a Shore A hardness of at least 30 durometers, at least 40 durometers, at least 50 durometers, at least 60 durometers, or at least 70 durometers. In one embodiment, the uncured polymeric material can have a Shore A hardness of 30 durometers and the cured polymeric material can have a Shore A hardness of 70 durometers.

[0022] The implant may further contain a therapeutic agent (e.g., darolutamide). In some cases, darolutamide is dispersed or distributed within the polymeric matrix. In some cases, darolutamide is dispersed or distributed throughout the polymeric matrix. In some cases, darolutamide is uniformly or homogeneously dispersed or distributed within the polymeric matrix. In other cases, darolutamide is heterogeneously dispersed or distributed within the polymeric matrix. In other cases, darolutamide is gradient-dispersed or distributed within the polymeric matrix. In certain embodiments, darolutamide is dispersed or distributed within the polymeric matrix during the manufacture of the implant (e.g., darolutamide is mixed with the polymeric material prior to the curing of the polymeric material as disclosed herein). In some cases, dispersing darolutamide within the polymeric matrix may be advantageous over other drug implants (e.g., those in which the drug is encapsulated in a capsule or within the lumen of a tube). For example, dispersing darolutamide within the polymeric matrix may enable higher darolutamide loading within the implant, faster elution rates, etc.

[0023] In various aspects of the present disclosure, the implant may contain a therapeutic agent (e.g., darolutamide) in an amount of from about 0.5% w / w to about 80% w / w. For example, the implant may contain a therapeutic agent (e.g., darolutamide) in an amount of about 0.5% w / w, about 1% w / w, about 5% w / w, 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, about 70% w / w, about 75% w / w, or about 80% w / w. In various aspects, the implant may contain a therapeutic agent (e.g., darolutamide) in an amount of at least about 0.5% w / w, at least about 1% w / w, at least about 5% w / w, 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, at least about 70% w / w, at least about 75% w / w, or at least about 80% w / w. In certain aspects, darolutamide is present in the implant in an amount of about 0.5% w / w, about 1% w / w, about 5% w / w, about 10% w / w, about 30% w / w, about 45% w / w, or about 60% w / w. In some cases, the present disclosure provides a drug implant loaded with a high concentration of darolutamide (e.g., about 60% w / w or more). In some cases, the implant may contain darolutamide in an amount of at least about 30% w / w. In some cases, the implant may contain darolutamide in an amount of at least about 45% w / w.

[0024] In various aspects of the present disclosure, the implant may contain a therapeutically active agent (e.g., darolutamide) in an amount of from about 5% volume / volume (v / v) to about 60% v / v. For example, the implant may contain a therapeutically active agent (e.g., darolutamide) 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 aspects, the implant may contain a therapeutically active agent (e.g., darolutamide) 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 aspects, darolutamide is present in the implant in an amount of at least about 30% v / v.

[0025] In various embodiments, the implant of the present disclosure can contain a total amount of darolutamide of at least about 1 mg, for example, from about 1 mg to about 10 mg. In some cases, the total amount of darolutamide in the implant can be from about 8 mg to about 10 mg. For example, the implant can contain a total amount of darolutamide of 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 3.3 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 6.8 mg, about 6.9 mg, about 7.0 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, 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.

[0026] In various aspects of the present disclosure, the polymeric material can be cured with darolutamide present therein. Without wishing to be bound by theory, curing refers to a chemical process that effects curing of the polymeric material by crosslinking polymer chains. Any method including the use of an electron beam, heating, and / or addition of an additive can be used to cure the polymers of the present disclosure. In various aspects of the present disclosure, darolutamide can be mixed with the uncured polymeric material prior to curing. In some aspects, the polymer matrix can be cured to at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or 100%.

[0027] Generally, the polymeric material has a molding or curing temperature lower than the melting temperature of darolutamide, for example, to prevent melting and / or decomposition of a drug. In some cases, the polymeric material can have a molding or curing temperature of less than 195°C, 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.

[0028] In some cases, the polymer is a thermally fusible or thermoplastic (e.g., polyurethane) that can be molded at elevated temperature and cured upon cooling. In certain embodiments, darolutamide can have a melting temperature of about 169°C to about 177°C, and the polymer can have a molding or curing temperature of less than about 175°C (e.g., about 150°C). In some cases, the polymer is a thermosetting material (e.g., silicone) that is irreversibly cured by curing that can be facilitated by addition of a catalyst and / or application of heat. In some cases, the polymeric material can be cured at room temperature (e.g., about 25°C). In some cases, the polymer requires exposure to air to cure.

[0029] In various aspects of the present disclosure, darolutamide can be present in the implant in solid form. In some cases, solid darolutamide can dissolve upon contact with biological fluids (e.g., after implantation into tissue) and diffuse from the implant and into the target tissue. In some cases, darolutamide is present in the implant in crystalline, semi-crystalline, or amorphous form. Generally, the particle size of darolutamide in the implant can be important for the uniformity of the drug content within the implant. Without wishing to be bound by theory, small particle sizes can ensure a uniform distribution within the formulation and between implants during shaping of the formulation. In some cases, the darolutamide present in the implant can have a median particle size (e.g., D50 particle size) of less than about 10 μm. In some cases, the darolutamide present in the implant can have a D90 particle size of less than about 15 μm.

[0030] Generally, the implants of the present disclosure have mechanical properties such that the implant can be successfully positioned in the target tissue. For example, the implants of the present disclosure can be sufficiently rigid so that they can be successfully positioned in the target tissue, but not so rigid that they break during placement. It should be understood that the mechanical properties of the devices described herein can vary depending on the polymeric material used and can be determined empirically. In some aspects, an implant containing darolutamide can have a Shore A hardness of at least 30 durometers.

[0031] In various aspects, the implant can have a three-dimensional shape. The three-dimensional shape can be any suitable shape. In some cases, the implant can be cylindrical or substantially cylindrical. In some cases, the implant can be tubular or substantially tubular. In some cases, the implant can be elongated (e.g., can have a length greater than its width). In some cases, the implant can be non-hollow. In some cases, the implant can be rod-shaped or rod-like.

[0032] In various aspects, the implant may have a certain diameter. In some cases, the diameter of the implant may be from about 0.1 mm to about 1.5 mm. In some cases, the diameter of the implant may be from about 0.7 mm to about 1.3 mm. In some cases, the diameter of the implant may be from 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, for example, 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.

[0033] In various aspects, the implant can have a certain length. In some cases, the length of the implant can be from about 1 mm to about 30 mm. In some cases, the length of the implant can be from about 5 mm to about 25 mm. In some cases, the length of the implant can be from about 10 mm to about 20 mm. In some cases, the length of the implant can be from about 12 mm to about 18 mm. In some cases, the length of the implant can 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 is less than about 30 mm, for example, 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.

[0034] In various aspects, the implant can have a certain volume. In some cases, the volume of the implant is from about 0.1 mm 3 to about 30 mm 3It can be. For example, the volume of the implant is about 0.1 mm 3 , about 0.5 mm 3 , about 1 mm 3 , about 5 mm 3 , about 10 mm 3 , about 15 mm 3 , about 20 mm 3 , about 25 mm 3 , or about 30 mm 3 It can be. In some cases, the volume of the implant can be about 10 mm 3 It can be.

[0035] In various aspects, the implant may lack a coating, covering, or sheath. For example, in some cases, a portion of the outer surface of the implant may not be coated or covered 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 examples, the entire outer surface or substantially the entire outer surface of the implant may not be covered or coated 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 about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 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, at least about 50% 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 within the target tissue. In some cases, the implant may consist essentially of a polymeric matrix and a therapeutically active agent (e.g., darolutamide) dispersed therein.

[0036] 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 is metal-free.

[0037] In various aspects, the implant may prevent modulation of darolutamide contained therein when the implant is implanted into a subject. Modulation may include, but is not limited to, degradation, chemical modification, etc. For example, the biological environment of the tissue may include degrading agents (e.g., esterases, amidases) that can degrade the drug. In some cases, the implant may protect the therapeutic agent from degradation by preventing degrading agents from entering the implant. In various aspects, in vitro stability tests may be performed to determine the protective effect of the implant on the therapeutic agent contained therein. In such cases, the therapeutic agent may be able to diffuse from the implant while maintaining in vivo stability within the implant. In various aspects, the ability of degrading agents to degrade the therapeutic agent within the implant may be determined by a simulated in vivo stability assay. In a non-limiting example, the implant of the present disclosure containing a therapeutic agent may be incubated in a solution containing degrading agents (known to degrade the therapeutic agent). After a period of incubation, the therapeutic agent can be extracted from the implant and the degradation peak can be measured (e.g., by high performance liquid chromatography (HPLC)).

[0038] In various aspects of the present disclosure, the implants of the present disclosure can be configured to be delivered directly to a target tissue of a subject. In some cases, the target tissue can be prostate tissue. In some cases, the implants of the present disclosure can be configured to be delivered to tissue adjacent to or in the vicinity of the target tissue. In some cases, a therapeutic agent can diffuse from the implant in a controlled manner and act directly on the target tissue.

[0039] In various aspects, the implants of the present disclosure can be configured to remain within the target tissue for a period of time. In some cases, the implants of the present disclosure can be configured to remain within the target tissue indefinitely (e.g., never removed). In some cases, two or more implants of the present disclosure can be implanted into 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 into the target tissue. In some cases, two or more implants can be implanted at different sites of the target tissue (e.g., to deliver a drug to different sites of the target tissue). In some cases, two or more implants can be implanted in close proximity to each other within 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 been depleted from the initial implants. For example, one or more additional implants can be implanted after or substantially after the drug has stopped eluting from one or more initial implants. In some cases, the implants of the present disclosure can be visible by ultrasound when disposed within the target tissue of the subject. In such cases, the position of the implant can be monitored non-invasively. In some cases, the implant can be sterilized prior to implantation into the subject. In some cases, the implant is sterilized by gamma sterilization.

[0040] In various aspects, the implants of the present disclosure may be capable of delivering sustained release of darolutamide for a period of time. For example, the implants of the present disclosure may be capable of sustained release of darolutamide. "Sustained release", as used herein, refers to the ability of an implant to release an amount of drug over an extended period of time after implantation into a target tissue. In some cases, the implants of the present disclosure may be capable of delivering an amount of drug to a 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 implants of the present disclosure may be capable of delivering at least 0.5 μg / day of darolutamide to a target tissue (e.g., prostate tissue, or tissue adjacent to or in the vicinity of the prostate) for at least 6 months after implantation. In some cases, the implants of the present disclosure may be capable of delivering at least 0.1 μg / day of darolutamide to a target tissue (e.g., prostate tissue, or tissue adjacent to or in the vicinity of the prostate) for up to 24 months (e.g., to the target tissue) after implantation.

[0041] In some cases, the drug implants of the present disclosure may exhibit one or more, or all, of the following characteristics: cumulative release of darolutamide in an in vitro model of 2,000 micrograms or less by day 1, cumulative release of darolutamide in an in vitro model of 12,000 micrograms or less by day 60, and cumulative release of darolutamide in an in vitro model of 16,000 micrograms or less by day 120. In some cases, the drug implants of the present disclosure may exhibit one or more, or all, of the following characteristics: cumulative release of darolutamide in an in vitro model of at least 10 micrograms by day 1, cumulative release of darolutamide in an in vitro model of at least 200 micrograms by day 60, and cumulative release of darolutamide in an in vitro model of at least 300 micrograms by day 120. The in vitro model may include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37°C for a specified period with continuous agitation.

[0042] Method for manufacturing a drug implant In the present specification, a method for manufacturing the implant described herein is further provided. Non-limiting examples of the method for manufacturing the drug implant of the present disclosure may be those provided in Examples 1 to 4.

[0043] In some embodiments, the method may include mixing an amount of uncured polymer material with an amount of darolutamide to form a mixture. In some cases, the polymer is a thermosetting substance and the darolutamide is mixed into the uncured polymer material. In some cases, the polymer is thermoplastic and the darolutamide is mixed into a solution or melt of the polymer material. The method may further include shaping the mixture to produce a shaped structure. The shaped structure may be formed by shaping the mixture in a mold (e.g., a transfer molding process), by extruding the mixture (e.g., through a tube), or by any other process. In the case of a thermosetting substance, the method may further include curing the shaped mixture for a period of time, with or without high temperature. In some cases, the polymer material may be any biocompatible silicone provided herein. In an exemplary embodiment, the silicone may be Silbione® ADH1 M200. In another exemplary embodiment, the silicone may be a platinum-cured silicone, e.g., Silbione® D370. In the case of a thermoplastic resin, the mixture may be shaped as described at high temperature and cooled to solidify the polymer. In some cases, the thermoplastic resin may be any biocompatible polyurethane provided herein. In some cases, shaping includes extruding the mixture using a ram extruder or a twin-screw extruder. In some cases, shaping includes an injection molded body.

[0044] In some embodiments, the mixture may further comprise a solvent. Non-limiting examples of solvents that can be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. The solvent can be used, for example, to reduce the viscosity of the liquid polymer. In some embodiments, the mixture can be shaped by a transfer molding process or by extrusion (e.g., through a tube).

[0045] A therapeutic active agent (e.g., darolutamide) can be provided in the mixture in an amount such that the total amount of the active agent in the implant can be from about 0.5% w / w to about 80% w / w, such as about 0.5% w / w, about 1% w / w, about 5% w / w, 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, about 70% w / w, about 75% w / w, or about 80% w / w. In some cases, the total amount of the active agent (e.g., darolutamide) in the implant can be at least about 0.5% w / w, at least about 1% w / w, at least about 5% w / w, 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, at least about 70% w / w, at least about 75% w / w, or at least about 80% w / w. Darolutamide can be provided in the mixture in an amount such that the total amount of darolutamide in the implant can be from about 1 mg to about 10 mg.

[0046] In some embodiments, thermoforming includes heating and shaping a mixture (e.g., transfer molding, extrusion, or another process) at a temperature of about 100°C to about 175°C, such as about 150°C, about 155°C, about 160°C, about 165°C, about 170°C, or about 175°C. The forming temperature generally depends on the polymer material selected. Generally, the forming temperature of the polymer material is selected to be lower than the melting temperature of the therapeutic agent. In the case of a thermoplastic resin, the mixture is heated for a time sufficient to achieve a formable state prior to shaping. In some cases, the mixture is heated for about 3 minutes to about 8 minutes, such as about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes. In some cases, the melting temperature of darolutamide (e.g., about 169°C to about 177°C) may be higher than the forming temperature of the silicone.

[0047] In some embodiments, the mixture may further include a solvent. Non-limiting examples of solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane. The solvent can be used, for example, to reduce the viscosity of the liquid polymer. In some embodiments, the mixture can be shaped by a transfer molding process or by extrusion (e.g., through a tube).

[0048] After manufacturing an 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) (e.g., to determine the curing rate of the implant and / or to evaluate the properties of the drug). In some cases, the one or more analyses may be placement of the implant into a surrogate tissue. In some cases, the one or more analyses may be an elution test (e.g., to evaluate the rate of drug elution from the implant). In some cases, the one or more analyses may be an in vivo stability test (e.g., to evaluate the ability of the implant to degrade through). In some cases, the one or more analyses may be viscometry. In some cases, the one or more analyses may be the use of a rheometer (e.g., to evaluate the viscosity and curing profile of the formulation). In some cases, the one or more analyses may be high performance liquid chromatography (e.g., to confirm the uniformity of content and to evaluate impurities in the drug formulation and the molded implant). In some cases, the one or more analyses may be dynamic mechanical analysis (DMA) (e.g., to evaluate the mechanical properties of the implant to ensure that it can be properly positioned).

[0049] Treatment method Disclosed herein is a method of treating a disease (or its symptoms) in a subject. The terms "treating," "treatment," or "treat" are used interchangeably herein and may refer to providing a therapeutic benefit to a subject in need thereof. For example, treating a disease or disorder may include ameliorating, suppressing, reducing, alleviating, or curing the disease or disorder. Treating a disease or disorder may also include ameliorating, suppressing, reducing, alleviating, or curing one or more symptoms associated with the disease or disorder. When used with respect to a tumor, treating may include shrinking or reducing the size of the tumor or tumor mass.

[0050] In various aspects, a subject may be diagnosed with a disease, may be suspected of having a disease, or may be at risk of having a disease (one or more of its symptoms). 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 a surgical or non-surgical method. 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 placement 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 placement 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-guided needle). In some cases, the implant may be sterilized and disposed within a packaging.

[0051] In a non-limiting example, a method of placing an implant of the present disclosure in a target tissue may include disposing a distal end of an elongate tube in the target tissue (e.g., the prostate or tissue adjacent to the prostate). In some cases, the elongate tube may be a needle having a lumen. The elongate tube may have a sharpened end such that the distal end of the elongate tube can penetrate the target tissue. In some cases, the distal end of the elongate tube may be disposed through a first portion of a grid (e.g., a guide template) such that a first position of the elongate tube in the subject is determined. The grid may enable proper placement of the implant in the target tissue. In some cases, a trocar is disposed within the lumen of the elongate tube. The method may include inserting the elongate tube (with or without the trocar disposed within the lumen of the elongate tube) into the target tissue. The method may further include, when using the trocar, removing the trocar from the lumen of the elongate tube while maintaining the distal end of the elongate tube within the target tissue. The method may further include placing an implant of the present disclosure within the lumen of the elongate tube. The implant may be pushed through the lumen of the elongate tube by a smooth-ended rod (e.g., a stylet) sized to fit within the lumen of the elongate tube. The implant can be pushed from the proximal end of the elongate tube to the distal end of the elongate tube using the stylet. The method may further include removing the elongate tube from the target tissue while maintaining the stylet in a predetermined position. When the elongate tube is removed from the target tissue, the stylet can push the implant from the elongate tube into the target tissue. The method may further include removing both the stylet and the elongate tube from the target tissue together.

[0052] In some embodiments, the method can include implanting two or more implants into a target tissue of interest. For example, the method can include implanting a first implant into a first portion of the target tissue and implanting 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 can be different. In some cases, the first implant can include a first therapeutic agent (e.g., darolutamide), and the second implant can include a second therapeutic agent. In some cases, the first therapeutic agent (e.g., darolutamide) and the second therapeutic agent can be the same. In other cases, the first therapeutic agent (e.g., darolutamide) and the second therapeutic agent can be different. In some cases, a grid (e.g., a guide template) can be used to position the first implant within the first portion of the target tissue and to position the second implant within the second portion of the target tissue. In some cases, the first implant and / or the second implant can be positioned using ultrasound guidance.

[0053] In some embodiments, the method can further include implanting additional implants into the target tissue. For example, the method can 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, and so on. The third, fourth, fifth, sixth, seventh, eighth, or more, therapeutic agents can 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 can be implanted into the prostate, or into tissue adjacent to or near the prostate, by transperineal administration.

[0054] In some embodiments, one or more implants can be implanted into the prostate, or into tissue adjacent to or in the vicinity of the prostate, before a surgical procedure for treating prostate cancer. For example, one or more implants can be implanted into the prostate, or into tissue adjacent to or in the vicinity of the prostate, before performing a prostatectomy (e.g., one week before, two weeks before, three weeks before, etc.). In such cases, the prostatectomy can remove the prostate or a portion thereof. In some cases, the prostatectomy can remove one or more of the implants from the subject. In other cases, one or more implants can be implanted into the prostate, or into tissue adjacent to or in the vicinity of the prostate, and can remain within the prostate without limitation. For example, one or more implants can provide a therapeutically effective amount of darolutamide to prostate tissue for a period of time such that the subject is in remission or cured of prostate cancer.

[0055] As used herein, the term "subject" generally refers to a mammal, e.g., a vertebrate such as a human. Mammals include, but are not limited to, mice, monkeys, humans, research animals, farm animals, sport animals, and pets. In some cases, the methods described herein can be used with tissues derived from a subject and progeny of such tissues. Tissues can be obtained in vivo from a subject. In some cases, tissues can be cultured in vitro.

[0056] 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 at risk of having a disease. In some cases, the subject can be a human. In some cases, the human can be a patient in a hospital or clinic. In some cases, the subject can be a non-human animal, e.g., a non-human primate, a farm animal, a household pet, or a laboratory animal. For example, the non-human animal can 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 llama, a sheep, a goat, a water buffalo, a reindeer, a yak, a mouse, a rat, a rabbit, or any other non-human animal.

[0057] When the subject can be a human, the subject can be of any age. In some cases, the subject can be about 50 years old or older. In some cases, the subject can be about 55 years old or older. In some cases, the subject can be about 60 years old or older. In some cases, the subject can be about 65 years old or older. In some cases, the subject can be about 70 years old or older. In some cases, the subject can be about 75 years old or older. In some cases, the subject can be about 80 years old or older. In some cases, the subject can be about 85 years old or older. In some cases, the subject can be about 90 years old or older. In some cases, the subject can be about 95 years old or older. In some cases, the subject can be about 100 years old or older. In some cases, the subject can 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 years old, or older than 100 years old. In some cases, the subject can be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 years old, or older than 20 years old

[0058] 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 the 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.

[0059] In some cases, the disease can be a proliferative disease or disorder. In some cases, the proliferative disease or disorder can be cancer. In some cases, the subject can have a tumor. In some cases, this method can reduce the size of the tumor. In some cases, this method can reduce the size of the tumor by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.

[0060] In some embodiments, the proliferative disease or disorder can be a proliferative disease or disorder of the prostate. In one non-limiting example, the proliferative disease or disorder of the prostate can be prostate cancer. Prostate cancer can be adenocarcinoma, sarcoma, neuroendocrine tumor, small cell cancer, transitional cell cancer, or squamous cell cancer. In some cases, prostate cancer is castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer. In another non-limiting example, the proliferative disease or disorder of the prostate can be benign prostatic hyperplasia.

[0061] This method can be utilized to deliver a therapeutically effective amount of darolutamide to the target tissue. In some cases, this method can include delivering a drug implant to the target tissue (or tissue adjacent to the target tissue) of the 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 neck.

[0062] In various aspects of the present disclosure, provided is a method for implanting a drug implant of the present disclosure into a target tissue (or adjacent tissue) of a subject, the implant delivering a therapeutically effective amount of darolutamide to the target tissue. As used herein, "therapeutically effective amount" refers to the amount of a drug or therapeutic agent that can induce a therapeutic response in a subject when used with respect to the drug or therapeutic agent. In various aspects of the present disclosure, the implant can deliver a therapeutically effective amount of the drug to the subject's tissue for 6 to 24 months. In some cases, the implant can deliver a therapeutically effective amount of the drug to the subject's tissue for 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months. In some cases, the implant can deliver a therapeutically effective amount of the drug to the subject's tissue 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.

[0063] In various aspects of the present disclosure, a therapeutically effective amount of the drug can be at least about 0.1 μg / day. In some cases, a therapeutically effective amount of the drug is at least about 0.1 μg / day, about 0.2 μg / day, about 0.3 μg / day, about 0.4 μg / day, about 0.5 μg / day, about 0.6 μg / day, about 0.7 μg / day, about 0.8 μg / day, about 0.9 μg / day, about 1 μg / day, about 2 μg / day, about 3 μg / day, about 4 μg / day, about 5 μg / day, about 6 μg / day, about 7 μg / day, about 8 μg / day, about 9 μg / day, about 10 μg / day, about 15 μg / day, about 20 μg / day, about 25 μg / day, about 30 μg / day, about 35 μg / day, about 40 μg / day, about 45 μg / day, about 50 μg / day, about 55 μg / day, about 60 μg / day, about 65 μg / day, about 70 μg / day, about 75 μg / day, about 80 μg / day, about 85 μg / day, about 90 μg / day, about 95 μg / day, about 100 μg / day, about 110 μg / day, about 120 μg / day, about 130 μg / day, about 140 μg / day, about 150 μg / day, about 160 μg / day, about 170 μg / day, about 180 μg / day, about 190 μg / day, about 200 μg / day, about 210 μg / day, about 220 μg / day, about 230 μg / day, about 240 μg / day, about 250 μg / day, about 260 μg / day, about 270 μg / day, about 280 μg / day, about 290 μg / day, about 300 μg / day, about 310 μg / day, about 320 μg / day, about 330 μg / day, about 340 μg / day, about 350 μg / day, about 360 μg / day, about 370 μg / day, about 380 μg / day, about 390 μg / day, about 400 μg / day, about 410 μg / day, about 420 μg / day, about 430 μg / day, about 440 μg / day, about 450 μg / day, about 460 μg / day, about 470 μg / day, about 480 μg / day, about 490 μg / day, about 500 μg / day, about 510 μg / day, about 520 μg / day, about 530 μg / day, about 540 μg / day, about 550 μg / day, about 560 μg / day, about 570 μg / day, about 580 μg / day, about 590 μg / day, about 600 μg / day, about 610 μg / day, about 620 μg / day, about 630 μg / day, about 640 μg / day, about 650 μg / day, about 660 μg / day, about 670 μg / day, about 680 μg / day, about 690 μg / day, about 700 μg / day, about 710 μg / day, about 720 μg / day, about 730 μg / day, about 740 μg / day, about 750 μg / day, about 760 μg / day, about 770 μg / day, about 780 μg / day, about 790 μg / day, about 800 μg / day, about 810 μg / day,It can be an amount of about 820 μg / day, about 830 μg / day, about 840 μg / day, about 850 μg / day, about 860 μg / day, about 870 μg / day, about 880 μg / day, about 890 μg / day, about 900 μg / day, about 910 μg / day, about 920 μg / day, about 930 μg / day, about 940 μg / day, about 950 μg / day, about 960 μg / day, about 970 μg / day, about 980 μg / day, about 990 μg / day, about 1000 μg / day or more. It should be understood that the therapeutically effective amount of the drug can vary based on the drug and / or the disease being treated and can be determined empirically.,

[0064] In various embodiments, the implant can effect a cumulative release of darolutamide from the implant to the target tissue. In some cases, the in vitro cumulative release of darolutamide from the implant can be at least 140 μg on day 1. In some cases, the in vitro cumulative release of darolutamide from the implant can be at least 1,000 μg on day 60. In some cases, the in vitro cumulative release of darolutamide from the implant can be at least 1,500 μg on day 120. In some cases, at least 50% of the total amount of darolutamide present in the implant at the time of implantation remains within the polymeric matrix on day 100 after implantation. In various embodiments, the implant can effect a cumulative release of darolutamide in one or more in vitro models of 2,000 micrograms or less by day 1, 12,000 micrograms or less by day 60, and 16,000 micrograms or less by day 120. In various embodiments, the implant can effect a cumulative release of darolutamide in one or more in vitro models of at least 10 micrograms by day 1, at least 200 micrograms by day 60, and at least 300 micrograms by day 120. The in vitro model can include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37° C. for a specified period with continuous agitation.,

[0065] In various aspects of the present disclosure, the implant can be configured to remain in the target tissue for a certain period of time. In some cases, the implant can be configured to remain in the target tissue for a long period of time (e.g., several months to several years) or indefinitely (e.g., can never be removed). For example, after the implant has delivered all of the therapeutic active agent contained therein to the subject, the implant (without the therapeutic active agent) may remain in the target tissue. In some cases, if additional treatment is needed, one or more additional implants can be delivered to the target tissue (without removing the initial implant). In some cases, the implant can be composed of a non-biodegradable and / or non-absorbable polymer material such that the polymer material remains substantially intact in the target tissue for a long period of time or indefinitely.

[0066] Advantageously, the implant of the present disclosure can deliver a therapeutically effective amount of darolutamide to the prostate tissue, or tissue adjacent to or near the prostate, for a long period of time (e.g., at least 6 months). Further, the implant of the present disclosure can deliver a high concentration of darolutamide locally to the prostate while maintaining a low systemic concentration of darolutamide. In some cases, the implant of the present disclosure can reduce or prevent toxicity resulting from a high systemic concentration of darolutamide.

[0067] In various aspects, the total dose of darolutamide administered to a subject by the implant of the present disclosure is less than the total dose of darolutamide when administered to the subject by systemic (e.g., oral) administration. Standard oral dosing regimens of darolutamide include a 600 mg / day monotherapy of darolutamide for prostate cancer. Advantageously, the implant of the present disclosure provides administration of a lower total dose of darolutamide compared to an oral dosing regimen. In some cases, the total amount of darolutamide administered to the subject is less than 100 mg over a 6-month period.

[0068] In various aspects, when the drug implant of the present disclosure is implanted into the prostate, or into tissue adjacent to or in the vicinity of the prostate, it results in a plasma concentration of darolutamide that is substantially lower than the plasma concentration of darolutamide obtained when darolutamide is administered to a subject by systemic (e.g., oral) administration. For example, the steady-state plasma concentration of darolutamide (assuming a daily dose of 600 mg) has been reported to be about 4.79 mg / L. In some cases, implanting the implant of the present disclosure into the prostate, or into tissue adjacent to or in the vicinity of the prostate, results in a steady-state plasma concentration of darolutamide that is less than 4.79 mg / L.

[0069] Kit As used herein, kits are further provided. In some aspects, a kit can include one or more implants as described herein. For example, a 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 the therapeutic active agent contained therein. In some cases, each of the one or more implants can include darolutamide. In other cases, each of the one or more implants can include one or more different therapeutic active agents.

[0070] In some aspects, a kit can include one or more surgical tools such as needles or forceps. In some aspects, a kit can be packaged in a sterile package. In some cases, the sterile package includes foil. In some aspects, a kit can further include instructions for implanting the implant into the tissue of a subject.

[0071] Specific terms Unless defined otherwise, 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 summary and the following detailed description are merely illustrative and explanatory and are not restrictive of any claimed subject matter.

[0072] In this application, the use of the singular form includes the plural form unless otherwise specified. It should be noted that when 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 otherwise specified. Further, the use of the term "including", as well as other forms such as "include", "includes", and "included", is not limiting.

[0073] When used in this specification, ranges and amounts can be expressed as "about" with respect to a particular value or range. About also includes the exact amount. Thus, "about 5 μL" also means "about 5 μL" and "5 μL". Generally, the term "about" includes amounts that are expected to be within experimental error, for example, within 15%, 10%, or 5%.

[0074] The section headings used in this specification are for organizational purposes only and should not be construed as limiting the subject matter described.

Examples

[0075] Example 1 Method for fabricating an implant - Platinum-cured silicone The manufacture of the implant includes two main steps: the formulation of an active pharmaceutical ingredient (API) (e.g., darolutamide) with an elastomer (e.g., pharmaceutical-grade platinum-cured silicone) to ensure a uniform mixing of the API within the polymer matrix, and the shaping of the implant to ensure that the product can be placed in the organ as intended.

[0076] Formulation The implant formulation includes medical-grade silicone as an excipient mixed with the API. A solvent is used to reduce the viscosity of the silicone as needed to incorporate the desired API loading.

[0077] The darolutamide formulation is prepared using a centrifugal mixer. Add the required amounts of silicone parts A and B to a mixing cup, and add an equal weight of a solvent (which dissolves silicone; for example, pentane). Mix the silicone and the solvent at high speed until the viscosity of the silicone is reduced so that the silicone can flow. Then, incorporate the API powder into the mixing cup and mix at high speed until a smooth mixture is obtained with no dry API spots visible to the eye. Then, remove the solvent under vacuum, leaving a paste of silicone and API. Table 1 below shows an example of a formulation of darolutamide prepared at a 10 wt% load.

[0078] This method can be used to formulate a pharmaceutical active ingredient (e.g., darolutamide) having an elastomer (e.g., platinum-cured silicone) from a low load of 10 wt% up to a load exceeding 70 wt%.

[0079] Other methods to achieve the same mixing uniformity with less solvent, such as shear mixing, may be used. Other solvents that assist in reducing viscosity and dissolve silicone (e.g., dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, etc.) can also be used in the formulation. [Table 1] [Table 2]

[0080] Molding The implant rod is prepared using a mold (e.g., made of aluminum) (e.g., via a transfer molding process), or by extruding the apalutamide formulation (e.g., through a tube). Cure the molded rod at a specific temperature (e.g., about 125 °C to 175 °C) for a predetermined time (e.g., 3 to 8 minutes) based on the recommendations of the silicone supplier for curing. After curing, cool the mold and separate the rod from the mold for characterization.

[0081] Example 2. Method for Preparing an Implant - Acetoxy - Curing Silicone In this example, the implant formulation comprises a medical - grade silicone having a curing chemistry alternative to platinum - curing, acetoxy - curing silicone, which is used as an excipient mixed with the API.

[0082] Formulation The implant formulation comprises a medical - grade silicone as an excipient mixed with the API. A solvent for reducing the viscosity of the silicone is used as needed to incorporate the desired API loading.

[0083] The darolutamide formulation is prepared using a centrifugal mixer. The required amount of silicone is added to a mixing cup, and an equal weight of a solvent (which dissolves the silicone; for example, pentane) is added. The silicone and the solvent are mixed at high speed until the viscosity of the silicone is reduced such that the silicone flows. Then, the API powder is incorporated into the mixing cup and mixed at high speed until a smooth mixture is obtained visually free of dry API spots. Then, the solvent is removed under vacuum, leaving a paste of silicone and API. A portion of the solvent (up to 50% w / w) can be left in the mixture to slow down the curing process, extend the pot life, and lower the viscosity to aid in molding or extrusion. Table 3 below shows an example of a darolutamide formulation made at a 10 - weight% load.

[0084] This method can be used to formulate pharmaceutical active ingredients (e.g., darolutamide) with elastomers (e.g., acetoxy - curing silicone) having loadings from as low as 10 weight% to over 70 weight%.

[0085] Other methods for achieving the same mixing uniformity with less solvent, such as shear mixing, may be used. Other solvents that aid in viscosity reduction and dissolve the silicone (e.g., dichloromethane, tetrahydrofuran, hexane, pentane, heptane, toluene, etc.) can also be used in the formulation.

Table 3

[0086] Forming The implant rod is made by extruding the darolutamide formulation (e.g., through a tube). To ensure that the silicone has cured, the formed rod is cured at ambient temperature for a predetermined time (about 1 - 3 days). After curing, the rod is withdrawn from the tube, cut to a certain length, and its properties are evaluated.

[0087] Example 3. Method for Making an Implant - Thermoplastic Polyurethane Solvent Process In this example, the implant formulation contains thermoplastic polyurethane as an excipient mixed with the API.

[0088] Formulation A solvent is used to dissolve the polyurethane, enabling it to combine with the API and creating a uniform dispersion with the desired loading. After combination, the solvent is removed, and the resulting polyurethane - API pellets are formed into implant rods by transfer molding or extrusion.

[0089] The polyurethane pellets are added to a mixing cup together with a solvent (e.g., dichloromethane) and incubated at 37°C with stirring for several hours until dissolution of the polyurethane is achieved. The ratio of the polyurethane to the solvent is selected to achieve complete dissolution of the polyurethane into a solution with a sufficiently low viscosity (e.g., about 20 wt% solids content) for mixing. Then, the API powder is added to the solvent and mixed at high speed until a smooth mixture is obtained with no visible dry API spots. The following Table 4 shows an example of a formulation made with 30% API w / w. Then, the solvent is removed under vacuum, leaving large pellets consisting of polyurethane, API, and residual solvent that can be used for thermoforming. The following Table 5 shows an exemplary set of solvent removal conditions. Other solvents for dissolving the polyurethane (e.g., tetrahydrofuran, dimethylformamide, dimethylacetamide, etc.) can also be used in the formulation.

Table 4

Table 5

[0090] Forming The implant rod is made using a mold (e.g., aluminum) (e.g., via a transfer molding process) or by extruding the darolutamide formulation (e.g., through a tube). The formulation is melted at a specific temperature (about 150°C - 200°C) for several minutes (about 3 - 8 minutes) before injection or extrusion. After curing, the mold is cooled and the rod is separated from the mold for characterization.

[0091] Example 4. Method for Making an Implant - Thermoplastic Polyurethane and Polyethylene Vinyl Acetate Extrusion Process In this example, the implant formulation contains thermoplastic polyurethane or polyethylene vinyl acetate as excipients mixed with the API.

[0092] Formulation The ground excipient powder (thermoplastic polyurethane or polyethylene vinyl acetate) is added to a mixing cup together with the API (darolutamide). The cup is mixed at high speed until the powder is fully incorporated. The following Table 6 shows typical measurements for a 2 - gram powder mixture at a 50 wt% API load. The ratios are adjusted according to different target loads.

Table 6

[0093] Forming The implant rod is fabricated in an extrusion process using either a ram or a twin-screw extruder. An aliquot of the powder mixture (0.5 - 10 g) is placed into the extruder cavity and heated to approximately 150 °C for 1 - 3 minutes. A plunger or rotating screw is actuated to force the molten powder mixture through an extrusion nozzle or die. As the extruded rope exits the fixture, it is collected by hand or using a conveyor system. By adjusting the diameter of the nozzle or die and the conveyor speed, an implant of a specific diameter can be obtained. After it has cooled for a few seconds, it can be cut to the desired length for the implant rod.

[0094] An alternative method is to use a twin-screw extruder (e.g., ThermoFisher HAAKE MiniCTW) to melt and extrude the darolutamide polymer powder mixture for a larger batch size. The mixture is introduced into the barrel of the extruder heated to 150 - 200 °C, and the molten mixture is extruded through a die to produce an extruded strand of the desired diameter. A conveyor belt transports the extruded strand, which is cooled and then cut to the desired length for the implant rod.

[0095] This process can also be completed with a powder mixture containing comminuted excipient and API powder, or pellets from the solvent mixtures described herein.

[0096] Example 5. Characterization of Darolutamide-Containing Formulations and Implants Various analytical techniques are used to characterize the formulations and the molded implants. For example, differential scanning calorimetry (DSC) is used to determine the curing rate of the implant and to evaluate the properties of the drug. Dissolution tests are used to evaluate the rate of drug elution from the implant. For example, high-performance liquid chromatography (HPLC) is used to confirm the uniformity of content and to evaluate impurities in the drug formulations and the molded rods.

[0097] Example 6. Dissolution Tests of Various Drug Implants of the Present Disclosure In accordance with the embodiments provided herein, elution tests were performed on various drug implants. Three groups of polymers, namely, silicone with a platinum curing system (Silbione D370), thermoplastic polyurethane (Lubrizol Pathway), and ethylene vinyl acetate (Celanese ATEVA and VitalDose), were tested with darolutamide according to Table 7 below. Some percentages of vinyl acetate were tested (28% and 40%). The drug implants were fabricated according to Examples 1-4 above.

Table 7

[0098] The drug implants were incubated in 1% sodium dodecyl sulfate in water at 37 °C for up to 240 days. Figures 1A and 1B show the cumulative release of darolutamide from various drug implants. The data shown in the figures indicate that the darolutamide release rate from the implant can be adjusted via the total loading of the drug within the matrix and the type of polymer matrix used in the implant.

Claims

1. a) A biocompatible, non-biodegradable polymer matrix, b) A drug implant comprising darolutamide dispersed in the biocompatible, non-biodegradable polymer matrix.

2. The drug implant according to claim 1, wherein the darolutamide is present in the drug implant in an amount of about 10% w / w to about 80% w / w.

3. The drug implant according to claim 1, wherein the total dose of darolutamide in the drug implant is about 1 mg to about 10 mg.

4. The drug implant according to claim 1, wherein the drug implant releases at least about 0.1 μg / day of darolutamide six months after implantation in a subject.

5. The cumulative release of darolutamide in the in vitro model was (i) No more than 2,000 micrograms by day 1, No more than 12,000 micrograms by day 60, and No more than 16,000 micrograms by day 120, and (ii) at least 10 micrograms by day 1, at least 200 micrograms by day 60, and at least 300 micrograms by day 120. The drug implant according to claim 1, wherein the in vitro model comprises incubating the drug implant in 1% sodium dodecyl sulfate water at 37°C with continuous stirring.

6. The drug implant according to claim 1, wherein the biocompatible, non-biodegradable polymer matrix is ​​silicone.

7. The drug implant according to claim 6, wherein the silicone is acetoxy-cured silicone or platinum-cured silicone.

8. The drug implant according to any one of claims 1 to 5, wherein the biocompatible, non-biodegradable polymer matrix is ​​thermoplastic polyurethane or poly(ethylene vinyl acetate).

9. The drug implant according to claim 1, wherein at least 50% of the darolutamide remains in the biocompatible, non-biodegradable polymer matrix 100 days after implantation.

10. The drug implant according to claim 1, wherein at least 99% by weight of the biocompatible, non-biodegradable polymer matrix remains in the target tissue for at least 600 days after implantation.

11. The drug implant according to claim 1, wherein the darolutamide is in solid form.

12. The drug implant according to claim 1, wherein the darolutamide is in crystalline, semicrystalline, or amorphous form.

13. The drug implant according to claim 1, wherein the drug implant has a Shore A hardness of at least 20 durometers when loaded with 60% w / w of darolutamide.

14. The drug implant according to claim 1, wherein the drug implant is visible by ultrasound when placed within the target tissue.

15. The drug implant according to claim 1, wherein the darolutamide has a melting temperature higher than the molding or curing temperature of the polymer matrix.

16. The drug implant according to claim 1, wherein the drug implant inhibits the modulation of the darolutamide within the drug implant.

17. The drug implant according to claim 16, wherein the modulation includes decomposition.

18. The drug implant according to claim 1, wherein the drug implant is elongated.

19. The drug implant according to claim 1, wherein the drug implant is cylindrical.

20. The drug implant according to claim 1, wherein the drug implant is tubular.

21. The drug implant according to claim 1, wherein the drug implant is rod-shaped.

22. The drug implant according to claim 1, wherein the diameter of the drug implant is approximately 0.1 mm to approximately 1.5 mm.

23. The drug implant according to claim 1, wherein the length of the drug implant is approximately 1 mm to approximately 30 mm.

24. The volume of the drug implant is approximately 0.1 mm ３ ~Approx. 30mm ３ The drug implant according to claim 1.

25. The drug implant according to claim 1, wherein at least 50% of the outer surface of the drug implant is configured to be in direct contact with the target tissue.

26. The drug implant according to claim 1, wherein the drug implant is configured to be implanted in a target tissue, or in tissue near or adjacent to the target tissue.

27. The drug implant according to claim 26, wherein the target tissue is prostate tissue.

28. The drug implant according to claim 1, wherein the drug implant is configured to be delivered to target tissue using the lumen of a needle or catheter.

29. The drug implant according to claim 1, wherein the drug implant lacks at least one of a sheath, scaffold, retaining member, or a combination thereof for holding the drug implant within target tissue.

30. The drug implant according to claim 1, wherein the drug implant further comprises a coating.

31. The drug implant according to claim 30, wherein the coating partially covers the drug implant.

32. The drug implant according to claim 30, wherein the coating substantially covers the drug implant.

33. The drug implant according to claim 30, wherein the coating covers the drug implant.

34. The drug implant according to claim 1, wherein the drug implant is sterilized.

35. The drug implant according to claim 1, wherein the drug implant is disposed within a sterile package.

36. The drug implant according to claim 1, comprising essentially the biocompatible non-biodegradable polymer matrix and the darolutamide dispersed within the biocompatible non-biodegradable polymer matrix.

37. A drug implant according to claim 1 for use in a method for treating a target proliferative disorder of the prostate, the method comprising implanting one or more drug implants according to claim 1 into prostate tissue or tissue near the prostate.

38. The drug implant according to claim 37, wherein one or more drug implants deliver a therapeutically effective amount of darolutamide to the prostate for at least six months.

39. The drug implant according to claim 37 or 38, wherein the proliferative disorder of the prostate is prostate cancer or benign benign prostatic hyperplasia.

40. The drug implant according to claim 39, wherein the prostate cancer is castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer.

41. The drug implant according to claim 37, wherein the darolutamide is dispersed in the biocompatible, non-biodegradable polymer matrix prior to implantation.

42. The drug implant according to claim 37, wherein the implantation comprises placing each of the one or more drug implants through the lumen of a needle or catheter into the prostate tissue or the tissue near the prostate.

43. The drug implant according to claim 37, wherein the transplantation is performed by transperineal administration.

44. The drug implant according to claim 37, wherein the transperineal administration includes the use of a template guide needle.

45. The drug implant according to claim 37, wherein the total dose of darolutamide administered to the subject is less than the total dose of darolutamide administered to the subject by oral administration.

46. The drug implant according to claim 37, wherein the total dose of darolutamide administered to the subject is less than 100 mg over a period of six months.

47. The drug implant according to claim 37, wherein the implantation results in a plasma concentration of darolutamide that is less than the plasma concentration of darolutamide obtained when darolutamide is administered orally to the subject.

48. The drug implant according to claim 37, wherein the implantation results in a steady-state plasma concentration of darolutamide less than approximately 4.79 mg / L.

49. The drug implant according to claim 37, wherein the one or more drug implants include 2 to 16 drug implants.

50. A method for manufacturing a drug implant according to claim 1, (a) Mixing a certain amount of uncured polymer with a certain amount of darolutamide to form a mixture, (b) Molding the mixture to produce a molded mixture, (c) A method comprising heating the molding mixture for a certain period of time to cure the molding mixture.

51. The method according to claim 50, wherein the amount of darolutamide is 10% w / w to 80% w / w of the uncured polymer.

52. The method according to claim 50, wherein the polymer is silicone, thermoplastic polyurethane, or poly(ethylene vinyl acetate).

53. The method according to claim 50, wherein the curing in (c) further comprises heating the molding mixture at a temperature of about 100°C to about 175°C for about 3 to about 8 minutes.

54. The method according to claim 50, wherein the mixture further comprises a solvent.

55. The method according to claim 54, wherein the solvent is selected from the group consisting of pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane.

56. The method according to claim 50, wherein the mixture is formed by a transfer molding process or by extrusion through a tube.

57. The method according to claim 50, wherein the molding includes extruding the mixture using a ram extruder or a twin-screw extruder.

58. The method according to claim 50, wherein the molding includes injection molding.

59. The method according to claim 50, further comprising performing an analysis on the drug implant.

60. The method according to claim 59, wherein the analysis is selected from the group consisting of differential scanning calorimetry (DSC), placement of the drug implant in a surrogate tissue, dissolution testing, rheology, high-pressure liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).

61. A sterile package containing the drug implant described in claim 1, A kit comprising instructions for implanting the drug implant into the target tissue.

Images