Dacrostamide-containing pharmaceutical implants and methods of use thereof

Abstract

Provided herein are pharmaceutical implants comprising dalotamide for use in the treatment of a disease in a subject. In some instances, a pharmaceutical implant may include a polymer matrix and dalotamide disposed therein. Additionally, methods for making the pharmaceutical implants and methods of treating diseases with the implants are provided. In some instances, the pharmaceutical implants may be used to treat prostate proliferative diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 368,922, filed on July 20, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] The burden of suffering from prostate cancer is remarkable in the U.S. In 2009, about 192,000 males were diagnosed as prostate cancer, and it is expected that 27,000 males will die from the disease. About 2.2 million American males alive have been diagnosed as prostate cancer, and some are experiencing the disease of transfer (pain and functional limitation stage of the disease). Prostate cancer is the most common diagnosis cancer in American males and is the second leading cause of cancer death in men all the time. The hormone therapy of prostate cancer includes a variety of treatments, and it is designed to affect the cell that normal function depends on androgen (it especially includes testosterone and dihydrotestosterone). Prostate cancer cells are generally very susceptible to the treatment that reduces androgen levels or affects the normal effects of these hormones.

[0004] Darolutamide (darolutamide) is an antiandrogen that can be used to treat prostate cancer. Darolutamide is a member of the nonsteroidal antiandrogen (NSAA) drug class and works by blocking androgen receptors. Darolutamide has been associated with many side effects, which may be partly due to the systemic administration of relatively high amounts of darolutamide to obtain therapeutic benefits. Thus, local administration of smaller amounts of darolutamide may be able to achieve therapeutic benefits and prevent or reduce the side effects or toxicity of systemic darolutamide administration. SUMMARY OF THE INVENTION

[0005] There is an unmet need for improved drug implants that can be used to deliver therapeutically active agents, such as darolutamide, directly to a target tissue in a subject. The present disclosure meets this unmet need.

[0006] In one aspect, a drug implant is provided, comprising: a) a biocompatible, non-biodegradable polymer matrix; and b) darolutamide dispersed in 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 dose of darolutamide in the drug implant is 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 in a subject. In some cases, the cumulative release of darolutamide in an in vitro model is (i) no more than 2000 micrograms at day 1, no more than 12,000 micrograms at day 60, and no more than 16,000 micrograms at day 120; and is (ii) at least 10 micrograms at day 1, at least 200 micrograms at day 60, and at least 300 micrograms at day 120, wherein the in vitro model comprises incubating the drug implant with continuous agitation at 37°C in 1% sodium dodecyl sulfate / water. 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 darolutamide remains in the biocompatible, non-biodegradable polymer matrix after 100 days of implantation. In some cases, at least 99% by weight of the biocompatible, non-biodegradable polymer matrix remains in the target tissue of the subject after implantation for at least 600 days. In some cases, darolutamide is in solid form. In some cases, darolutamide is in crystalline, semi-crystalline 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 darolutamide. In some cases, the drug implant is visible by ultrasound when arranged in the target tissue of the subject. In some cases, darolutamide has a melting temperature greater than the molding or curing temperature of the polymer matrix. In some cases, the drug implant inhibits the adjustment of darolutamide within the drug implant. In some cases, the adjustment 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 about 0.1 mm to about 1.5 mm. In some cases, the length of the drug implant is about 1 mm to about 30 mm. In some cases, the volume of the drug implant is about 0.1 mm 3 To about 30mm 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 in 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 by the lumen of a needle or catheter. In some cases, the drug implant lacks at least one of a retaining element, a stent, a sheath, or a combination thereof for keeping the drug implant in the target tissue. In some cases, the drug implant also 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 sterile. In some cases, the drug implant is arranged in a sterile package. In some cases, the drug implant is essentially composed of: a biocompatible, non-biodegradable polymer matrix and darolamide dispersed in the biocompatible, non-biodegradable polymer matrix.

[0007] On the other hand, a method for treating a prostate proliferative disease of a subject is provided, the method comprising implanting one or more drug implants according to any one of the aforementioned aspects or situations into prostate tissue or tissue near the prostate. In some cases, one or more drug implants deliver a therapeutically effective amount of daroltamide 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, prostate cancer is castration-sensitive prostate cancer or castration-resistant prostate cancer that has not metastasized. In some cases, daroltamide is dispersed in a biocompatible, non-biodegradable polymer matrix before implantation. In some cases, implantation includes configuring each of one or more drug implants to prostate tissue or tissue near the prostate through the lumen of a pin or catheter. In some cases, implantation occurs via perineal administration. In some cases, perineal administration includes using a template guide needle. In some cases, the total dose of daroltamide given to a subject is less than the total dose of daroltamide given to a subject by oral administration. In some cases, the total dose of daroltamide given to a subject during 6 months is less than 100mg. In some cases, implantation results in a darolutamide plasma concentration that is less than the darolutamide plasma concentration obtained when darolutamide is administered to a subject by oral administration. In some cases, implantation results in a darolutamide steady-state plasma concentration that is less than about 4.79 mg / L. In some cases, the one or more drug implants comprise 2 to 16 drug implants.

[0008] In yet another aspect, a method for preparing a drug implant of any of the preceding aspects or situations is provided, the method comprising: (a) mixing an amount of an uncured polymer with an amount of darolutamide 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 darolutamide is 10% w / w to 80% w / w of the uncured polymer. In some cases, the polymer is a silicone or a thermoplastic polyurethane or a poly(ethylene-vinyl acetate). In some cases, curing of (c) further comprises heating the molded 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: pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane. In some cases, the mixture is molded by a transfer molding method or by extrusion through a tube. In some cases, molding comprises extruding the mixture with a plunger extruder or a twin screw extruder. In some cases, molding includes injection molding. In some cases, the method further includes analyzing the drug implant. In some cases, the analysis is selected from: differential scanning calorimetry (DSC), configuring the drug implant in a surrogate tissue, elution testing, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability testing, and dynamic mechanical analysis (DMA).

[0009] In yet another aspect, a kit is provided, comprising: a sterile package containing the drug implant of any of the preceding aspects or conditions; and instructions for implanting the drug implant into a target tissue of a subject.

[0010] Join by reference

[0011] All publications, patents, and patent applications mentioned in this specification are herein 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

[0012] 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 will be obtained by referring to the following detailed description and accompanying drawings which describe exemplary embodiments in which the principles of the present disclosure are applied, wherein:

[0013] Figure 1A Cumulative release data for drug implants containing various loadings of darolutamide and various polymers, consistent with the embodiments provided herein, are described.

[0014] Figure 1B Cumulative release data for drug implants containing various loadings of darolutamide and EVA with varying percentages of vinyl acetate, consistent with the embodiments provided herein, are described. DETAILED DESCRIPTION OF THE INVENTION

[0016] Provided herein is a drug implant that can deliver a therapeutically effective amount of daroltamide directly to a target tissue. Also provided herein is a drug implant that, when implanted into a target tissue, causes a high concentration of daroltamide in the target tissue, as well as a low concentration of daroltamide in the systemic circulation (e.g., in plasma). In some cases, the ability of a drug implant provided herein to deliver a therapeutically effective amount of daroltamide directly to the target tissue and simultaneously achieve a low concentration of daroltamide in the systemic circulation can reduce or eliminate the side effects or toxicity of daroltamide treatment that would occur with systemic administration. In addition, daroltamide is delivered directly to the target tissue by the drug implant described herein to ensure that the target tissue receives a therapeutically effective amount of daroltamide. On the other hand, provided herein is a drug implant that can load a large amount of daroltamide so that the drug implant can continuously release daroltamide to the target tissue for a long period of time. In some aspects, daroltamide can be dispersed in a polymer matrix of an implant, which can provide special advantages (e.g., faster elution time, higher drug loading in the implant, etc.). In particular aspects, the drug implants provided herein can contain high concentrations of darolutamide so as to enable administration of therapeutically effective amounts of darolutamide directly to prostate tissue for extended periods of time (e.g., 6 months or longer) while maintaining low systemic concentrations of darolutamide.

[0017] In various aspects, the drug implant disclosed herein may comprise a polymer matrix and darolutamide. In particular cases, darolutamide may be dispersed within the polymer matrix. Preferably, the polymer matrix is ​​biocompatible and non-biodegradable. The drug implant may be implanted into a target tissue and may release an amount of darolutamide over time. The drug implant containing darolutamide may effectively treat a disease or its symptoms. The disease may be, for example, a prostate proliferative disease, 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.

[0018] Also provided herein are methods of treating a disease by delivering a drug implant of the present disclosure (e.g., containing darolutamide) to a target tissue of a subject in need thereof so as to deliver a therapeutically effective amount of darolutamide over a prolonged period of time. Additionally, methods of preparing a drug implant and kits comprising a drug implant are provided.

[0019] Drug implants

[0020] Provided herein are drug implants (also referred to herein as "implants") suitable for delivering darolutamide to target tissues. In certain aspects of the present disclosure, the implant comprises a polymer matrix (e.g., a biocompatible, non-biodegradable polymer matrix) and darolutamide dispersed therein. The implant may be suitable for treating, for example, prostate proliferative diseases, 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.

[0021] The polymer matrix may comprise any polymeric substance. Generally, the polymeric substance is biocompatible. The term "biocompatible" as used herein refers to a property of a substance that allows long-term contact with tissues in a subject without causing toxicity or significant damage. In some cases, a "biocompatible" polymeric substance complies with the guidelines described in International Organization for Standardization (ISO) 10993-1:2018.

[0022] In certain aspects, the polymer material can be "non-biodegradable" or "substantially non-biodegradable". The term "non-biodegradable" or "substantially non-biodegradable", when used to refer to the implants of the present disclosure, generally refers to an implant that cannot or substantially cannot be decomposed (e.g., by microorganisms, enzymes (e.g., esterases), oxidation) within the expected life of the implant. For example, two years after the device is implanted in the target tissue, the substantially non-biodegradable implant of the present disclosure can have at least 99% by weight of residual polymer material. In some cases, the "non-biodegradable" implant or polymer can meet the guidelines described in the Standard Guide for Assessment of Absorbable Polymeric Implants (ASTM F2902-16) of ASTM International.

[0023] In certain aspects of the present disclosure, the polymer matrix can 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 cured silicone. In some cases, the silicone can be a silicone manufactured by Elkem. Silicone adhesives (e.g. Biomedical ADH1 M200; available at silicones.elkem.com / EN / our_offer / Product / 90061907 / _ / SILBIONE-BIO-ADH1-M200 on September 1, 2020). In some cases, the silicone can be a platinum-cured silicone. In various aspects, the silicone can be any liquid silicone rubber (LSR). In some cases, the silicone can be a silicone made by Elkem. Liquid Silicone Rubber (LSR). In some cases, LSR can be one or more of the following: LSR 4301, LSR 4305, LSR 4310, LSR 4325, LSR 4330, LSR 4340, LSR 4350, LSR 60, LSR4360, LSR 4370, LSR 4745, LSR 4755, LSR4765, LSR 4125, LSR 4130, LSR 4140, LSRM301, LSR M305, LSR M310, LSR M325, LSRM330, LSR M340, LSR M350, LSR M360, LSRM365, LSR M370, LSR M125, LSR M130, LSRM140. In various aspects, silicone can be LSR D370. In some cases, silicone can be NuSil TM In various aspects, the organosilicon can be NuSil TMPrepared DDU 4870. In some cases, silicone can be NuSil TM One or more of the following silicones were prepared: 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] In various other aspects, the polymeric material can be a thermoplastic polyurethane. In some cases, the polyurethane can be one or more of the following polyurethanes produced by Lubrizol: PY-PT72AE, PY-PT87AE, PY-PT87AS, PY-PT83AL, and PY-PT43DE20.

[0025] In various other aspects, 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 trade name or ). The vinyl acetate content of PEVA can be 9% to 40%. In particular embodiments, the vinyl acetate content is 10%. In other particular embodiments, the vinyl acetate content is 28%. In still other particular embodiments, the vinyl acetate content is 40%.

[0026] The Shore A hardness scale measures the hardness of the rubber. Higher rating numbers refer to harder materials, while lower rating numbers refer to softer materials. 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 the following Shore A hardness: at least 30-durometer, at least 40-durometer, at least 50-durometer, at least 60-durometer, or at least 70-durometer. In one aspect, the uncured polymeric material can have a Shore A hardness of 30-durometer, while the cured polymeric material can have a Shore A hardness of 70-durometer.

[0027] The implant may further comprise a therapeutically active agent (e.g., darolutamide). In some cases, darolutamide is dispersed or distributed in a polymer matrix. In some cases, darolutamide is dispersed or distributed throughout the polymer matrix. In some cases, darolutamide is uniformly or evenly dispersed or distributed in the polymer matrix. In other cases, darolutamide is unevenly dispersed or distributed in the polymer matrix. In other cases, darolutamide is gradient dispersed or distributed in the polymer matrix. In particular aspects, darolutamide is dispersed or distributed in a polymer matrix when preparing the implant (e.g., darolutamide is mixed with a polymer substance before the polymer substance solidifies, as disclosed herein). In some cases, dispersing darolutamide in a polymer matrix can be advantageous relative to other drug implants (e.g., those encapsulated in a capsule or in the lumen of a tube). For example, dispersing darolutamide in a polymer matrix can allow for a higher loading of darolutamide in the implant, a faster elution rate, etc.

[0028] In various aspects of the present disclosure, the implant can include a therapeutically active agent (e.g., darolamide) in an amount of about 0.5% w / w to about 80% w / w. For example, the implant can include a therapeutically active agent (e.g., darolamide) 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 can comprise a therapeutically active agent (e.g., darolamide) 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 particular aspects, darolutamide is present in an implant in an amount of about 0.5% w / w, about 1% w / w, about 5% w / w, 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 higher). 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.

[0029] In various aspects of the present disclosure, the implant can include a therapeutically active agent (e.g., darolamide) in an amount of about 5% volume / volume (v / v) to about 60% v / v. For example, the implant can include a therapeutically active agent (e.g., darolamide) 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 can include 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 particular, darolutamide is present in the implant in an amount of at least about 30% v / v.

[0030] In various aspects, the implants of the present disclosure can include darolutamide in a total amount of at least about 1 mg, for example, about 1 mg to about 10 mg. In some cases, the total amount of darolutamide in the implant can be about 8 mg to about 10 mg. For example, the implant can include darolamide in the following total amounts: 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

[0032] 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0mg, about 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, about 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, about 7.1mg, about 7.2mg, about 7.3mg g, 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.

[0033] In various aspects of the present disclosure, a polymeric substance may be cured with darolutamide present therein. Without being limited by theory, curing refers to a chemical process that causes hardening of a polymeric substance by cross-linking polymer chains. Any method may be used to cure the polymers of the present disclosure, including the use of electron beams, heating, and / or the addition of additives. In various aspects of the present disclosure, darolutamide may be mixed with an uncured polymeric substance prior to curing. In certain aspects, the polymer matrix may 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.

[0034] Typically, the polymeric material has a molding or curing temperature that is lower than the melting temperature of darolutamide, for example, to prevent melting and / or degradation of the drug. In some cases, the polymeric material may 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.

[0035] In some cases, the polymer is a hot melt polymer or a thermoplastic polymer that becomes moldable at elevated temperatures and hardens after cooling (e.g., polyurethane). In a particular example, darolamide 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 polymer that hardens irreversibly (e.g., silicone) by curing (which can be accelerated by the addition of catalysts and / or heat). In some cases, the polymer substance can be cured at room temperature (e.g., about 25°C). In some cases, the polymer needs to be exposed to air to cure.

[0036] In various aspects of the present disclosure, darolutamide can be present in the implant in solid form. In some cases, solid darolutamide can dissolve when contacting biological fluid (e.g., after implantation of tissue), and can diffuse out from the implant and enter the target tissue. In some cases, darolutamide is present in the implant in a crystalline form, in a semi-crystalline form, or in an amorphous form. Generally, the particle size of darolutamide in the implant can be important for the uniformity of the drug content in the implant. Not limited by theory, small particle size can ensure uniform distribution between implants in the formulation and when the formulation is molded. In some cases, darolutamide present in the implant can have a median particle size (e.g., D50 particle size) less than about 10 μm. In some cases, darolutamide present in the implant can have a D90 particle size less than about 15 μm.

[0037] Generally, the mechanical properties of the implants disclosed herein enable the implants to be successfully configured into the target tissue. For example, the implants disclosed herein can be sufficiently rigid so that they can be successfully configured into the target tissue, but not too rigid to break during configuration. It should be understood that the mechanical properties of the device described herein can vary depending on the polymer material used, and can be determined empirically. In some aspects, the implant containing darolutamide can have a Shore A hardness of at least 30 durometers.

[0038] 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 the width). In some cases, the implant may not be hollow. In some cases, the implant can be rod-shaped or rod-like.

[0039] In various aspects, the implant can have a diameter. In some cases, the diameter of the implant can be about 0.1mm to about 1.5mm. In some cases, the diameter of the implant can be about 0.7mm to about 1.3mm. In some cases, the diameter of the implant can be about 0.9mm to about 1.1mm. In some cases, the diameter of the implant can be at least about 0.1mm, for example, at least about 0.1mm, at least about 0.2mm, at least about 0.3mm, at least about 0.4mm, at least about 0.5mm, at least about 0.6mm, at least about 0.7mm, at least about 0.8mm, at least about 0.9mm, at least about 1.0mm, at least about 1.1mm, at least about 1.2mm, at least about 1.3mm, at least about 1.4mm, or at least about 1.5mm. In some cases, the diameter of the implant can be less than about 1mm, for example, less than about 1mm, less than about 0.9mm, less than about 0.8mm, less than about 0.7mm, less than about 0.6mm, less than about 0.5mm, less than about 0.4mm, less than about 0.3mm, less than about 0.2mm, or less than about 0.1mm. In some cases, the diameter of the implant can be at least about 0.1mm. In some cases, the diameter of the implant can be at least about 0.8mm. In some cases, the diameter of the implant can be about 1mm.

[0040] In various aspects, implant can have length. In some cases, the length of implant can be about 1mm to about 30mm. In some cases, the length of implant can be about 5mm to about 25mm. In some cases, the length of implant can be about 10mm to about 20mm. In some cases, the length of implant can be about 12mm to about 18mm. In some cases, the length of implant can be at least about 1mm, at least about 2mm, at least about 3mm, at least about 4mm, at least about 5mm, at least about 6mm, at least about 7mm, at least about 8mm, at least about 9mm, at least about 10mm, at least about 11mm, at least about 12mm, at least about 13mm, at least about 14mm, at least about 15mm, at least about 16mm, at least about 17mm, at least about 18mm, at least about 19mm, at least about 20mm, at least about 21mm, at least about 22mm, at least about 23mm, at least about 24mm, at least about 25mm, at least about 26mm, at least about 27mm, at least about 28mm, at least about 29mm, or at least about 30mm. In some cases, the length of implant is at least about 1mm. In some cases, the length of implant is at least about 3mm. In some cases, the length of implant is about 15mm. In some cases, the length of the implant can be 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.

[0041] In various aspects, the implant can have a volume. In some cases, the volume of the implant can be about 0.1 mm 3 To about 30mm 3 For 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 30mm 3 In some cases, the volume of the implant may be about 10 mm3 .

[0042] In various aspects, implant can lack coating, covering layer, or sheath.For example, in some cases, a part of implant outer surface can not be coated or cover thereby the outer surface of the uncoated or uncovered part of implant directly exposed to or directly contact biological environment (for example target tissue, biological fluid) after implantation.In some instances, whole outer surfaces of implant or substantially whole outer surfaces are uncovered or uncoated thereby whole outer surfaces of implant or substantially whole outer surfaces directly exposed to or directly contact biological environment after implantation.In other cases, implant is less than whole outer surface directly exposed to or directly contact 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 directly contacts the biological environment after implantation. In some cases, at least about 50% of the outer surface of the implant is directly exposed to or directly contacts the biological environment after implantation. In some cases, the implant can lack a sheath, a support, a retaining element, a retaining frame, or any other additional means for keeping the implant in the target tissue. In some cases, the implant can be substantially composed of: a polymer matrix and a therapeutically active agent (e.g., darolamide) dispersed therein.

[0043] 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 consisting of a first polymer substance and a coating of a second polymer substance. 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.

[0044] In various aspects, the implant can prevent the adjustment of the darolamide contained therein when the implant is implanted into the subject. Adjustment can include, but is not limited to, degradation, chemical modification, etc. For example, the biological environment of the tissue can include degradants (e.g., esterases, amidases) that can degrade the drug. In some cases, the implant can protect the therapeutically active agent from degradation by preventing the degradants from penetrating the implant. In various aspects, an in vitro stability test can be performed to determine the protective effect of the implant on the therapeutically active agent contained therein. In this case, the therapeutically active agent can be diffused out from the implant and simultaneously maintain in vivo stability in the implant. In various aspects, the ability of the degradant to degrade the therapeutically active agent in the implant can be determined by simulating in vivo stability tests. In a non-limiting example, the implant of the present disclosure containing the therapeutically active agent can be incubated in a solution including a degradant (known to degrade the therapeutically active agent). After the incubation period, the therapeutically active agent can be extracted from the implant and the degradation peak can be measured (e.g., by high performance liquid chromatography (HPLC)).

[0045] In various aspects of the present disclosure, 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, implants of the present disclosure may be configured to be delivered to tissue adjacent to or near the target tissue. In some cases, therapeutically active agents may diffuse out of the implant in a controlled manner and act directly on the target tissue.

[0046] In various aspects, implants of the present disclosure may be configured to retain a period of time in the target tissue. In some cases, implants of the present disclosure may be configured to retain (e.g., never remove) indefinitely in the target tissue. In some cases, two or more implants of the present disclosure may 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 may be implanted in the target tissue. In some cases, two or more implants may be implanted in the target tissue in close proximity to each other. In some cases, one or more initial implants may be implanted, and additional implants may be subsequently implanted after the medicine has been consumed from the initial implant. For example, one or more additional implants may be implanted after the medicine has stopped or substantially stopped eluting from one or more initial implants. In some cases, implants of the present disclosure may be visible by ultrasound when arranged in the subject's target tissue. In this case, the position of the implant can be monitored non-invasively. In some cases, the implant can be sterilized prior to implantation in a subject. In some cases, the implant is sterilized via gamma sterilization.

[0047] In various aspects, implants of the present disclosure may be able to deliver sustained-release darolutamide for a period of time. For example, implants of the present disclosure may be able to sustainably release darolutamide. "Sustained release" as used herein refers to the ability of an implant to release a certain amount of medicine for a prolonged period of time after implantation of a target tissue. In some cases, implants of the present disclosure may be able to deliver a certain amount of medicine 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 special cases, implants of the present disclosure may be able to deliver at least 0.5 μg / day of darolutamide for at least 6 months after implantation of a target tissue (such as prostate tissue or tissue adjacent or near the prostate). In some cases, implants of the present disclosure may be able to deliver at least 0.1 μg / day of darolutamide (such as to the target tissue) for up to 24 months after implantation of a target tissue (such as prostate tissue or tissue adjacent or near the prostate).

[0048] In some cases, the drug implants of the present disclosure may exhibit one or more or all of the following characteristics: a cumulative release of darolutamide at day 1 of no more than 2,000 micrograms in an in vitro model, a cumulative release of darolutamide at day 60 of no more than 12,000 micrograms in an in vitro model, and a cumulative release of darolutamide at day 120 of no more than 16,000 micrograms in an in vitro model. In some cases, the drug implants of the present disclosure may exhibit one or more or all of the following characteristics: a cumulative release of darolutamide at day 1 of at least 10 micrograms in an in vitro model, a cumulative release of darolutamide at day 60 of at least 200 micrograms in an in vitro model, and a cumulative release of darolutamide at day 120 of at least 300 micrograms in an in vitro model. The in vitro model may include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) / water at 37° C. with continuous agitation for a specified time interval.

[0049] Method for preparing a pharmaceutical implant

[0050] Also provided herein are methods for making the implants described herein.Non-limiting examples of methods for making the pharmaceutical implants of the present disclosure can be as provided in Examples 1-4.

[0051] In certain aspects, the method may involve mixing an amount of a polymeric substance with an amount of darolutamide to form a mixture. In some cases, the polymer is a thermosetting polymer and darolutamide is mixed into the uncured polymeric substance. In some cases, the polymer is a thermoplastic polymer and darolutamide is mixed into a solution or melt of the polymeric substance. The method may further involve molding the mixture to produce a molded structure. The molded structure may be formed by molding the mixture in a mold (e.g., a transfer molding process), extruding the mixture (e.g., through a tube), or any other method. In the case of a thermosetting substance, the method may further involve allowing the molded mixture to cure for a period of time, with or without elevated temperatures. In some cases, the polymeric substance may be any biocompatible silicone provided herein. In exemplary aspects, the silicone may be ADH1M200. In yet another exemplary aspect, the silicone can be a platinum-cured silicone, such as D370. In the case of thermoplastics, the mixture can be molded at an elevated temperature as described and cooled to solidify the polymer. In some cases, the thermoplastic polymer can be any biocompatible polyurethane provided herein. In some cases, molding includes extruding the mixture with a plunger extruder or a twin screw extruder. In some cases, molding includes injection molding.

[0052] In some aspects, the mixture can also include a solvent. Non-limiting examples of operable solvents include pentane, heptane, toluene, methylene chloride, tetrahydrofuran, and hexane. The solvent can be used to, for example, reduce the viscosity of the liquid polymer. In some aspects, the mixture can be molded by transfer molding or by (for example, through a tube) extrusion.

[0053] The therapeutically active agent (e.g., darolutamide) can be provided in the mixture in an amount such that the total amount of active agent in the implant can be about 0.5% w / w to about 80% w / w, for example, 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 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.

[0054] In some aspects, heat molding includes heating and molding the mixture (e.g., transfer molding, extrusion, or another method) at 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 molding temperature generally depends on the selected polymeric substance. Generally, the molding temperature of the polymeric substance is selected to be lower than the melting temperature of the therapeutically active agent. For thermoplastic polymers, the mixture is heated for a sufficient time to achieve a moldable state before molding. 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 darolamide (e.g., about 169°C to about 177°C) can be greater than the molding temperature of silicone.

[0055] In some aspects, the mixture can also include a solvent. Non-limiting examples of operable solvents include pentane, heptane, toluene, methylene chloride, tetrahydrofuran, and hexane. The solvent can be used to, for example, reduce the viscosity of the liquid polymer. In some aspects, the mixture can be molded by transfer molding or by (for example, through a tube) extrusion.

[0056] After preparing the implant as provided herein, the method may also include one or more analyses to the implant. In some cases, one or more analyses may be differential scanning calorimetry (DSC) (e.g., determining the characteristic of the implant solidification rate and / or evaluating the drug). In some cases, one or more analyses may be configuring the implant into a surrogate tissue. In some cases, one or more analyses may be elution tests (e.g., evaluating the elution rate of the drug from the implant). In some cases, one or more analyses may be in vivo stability tests (e.g., evaluating the ability of the degradation product to penetrate the implant). In some cases, one or more analyses may be viscometry. In some cases, one or more analyses may be using a rheometer (e.g., evaluating the viscosity and solidification characteristics of the formulation). In some cases, one or more analyses may be high pressure liquid chromatography (e.g., confirming the uniformity of the contents and evaluating the impurities in the drug formulation and the molded implant). In some cases, one or more analyses may be dynamic mechanical analysis (DMA) (e.g., evaluating the mechanical properties of the implant to ensure that it can be correctly configured).

[0057] Treatment

[0058] Disclosed herein are methods for treating a disease (or its symptoms) in a subject. The terms "therapeutic," "therapy," or "treatment" may be used interchangeably herein and refer to providing a therapeutic benefit to a subject in need thereof. For example, treating a disease or disorder includes improving, eliminating, reducing, alleviating, or curing the disease or disorder. Treating a disease or disorder also includes improving, eliminating, reducing, alleviating, or curing one or more symptoms associated with the disease or disorder. In the case of a tumor, treating includes reducing or decreasing tumor size or tumor volume.

[0059] In various aspects, the subject may have been diagnosed with, may be suspected of having, or may be at risk for the disease (or one or more symptoms thereof). In some cases, the method comprises 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 with standard surgical tools (e.g., tools typically used for biopsy or brachytherapy). In some cases, the implant may be implanted into the target tissue by using, for example, a needle, forceps, or a catheter (e.g., having a lumen). For example, in one embodiment, the implant may be implanted into the target tissue by being configured 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 cannula of a prostate biopsy needle. The needle is implanted into the target tissue. In some cases, the configuration of the implant can be guided by ultrasound. In some cases, the implant can be implanted by perineal implantation (e.g., using a template to guide the needle). In some cases, the implant can be sterile and arranged in a package.

[0060] In a non-limiting example, a method of configuring an implant of the present invention into a target tissue may involve arranging the distal end of an elongated tube into a target tissue (e.g., a prostate or prostate adjacent tissue). In some cases, the elongated tube may be a needle with a lumen. The elongated tube may have a tip so 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 arranged by a first portion of a grid (e.g., a guide template) so that the first position of the elongated tube in the subject is determined. The grid may allow for suitable placement of the implant into the target tissue. In some cases, a trocar is arranged in the lumen of the elongated tube. The method may involve inserting the elongated tube (with or without a trocar arranged in the lumen of the elongated tube) into the target tissue. The method may also involve (in the case of using a trocar) removing the trocar from the lumen of the elongated tube while keeping the distal end of the elongated tube in the target tissue. The method may also involve placing the implant of the present invention in the lumen of the elongated tube. The implant can be pushed through the lumen of the elongated tube by a blunt-ended rod (e.g., a stylet) whose size matches the lumen of the elongated tube. The stylet can be used to push the implant from the proximal end of the elongated tube to the distal end of the elongated tube. The method can also involve removing the elongated tube from the target tissue while maintaining the stylet position. As the elongated tube is removed from the target tissue, the stylet can push the implant out of the elongated tube and into the target tissue. The method can also involve removing both the stylet and the elongated tube from the target tissue together.

[0061] In some aspects, the method may involve implanting more than one (individual) implant into a target tissue of a subject. For example, the method may involve implanting a first implant into a first portion of a target tissue, and implanting a second implant into a second portion of a 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 therapeutically active agent (e.g., darolamide) and the second implant may include a second therapeutically active agent. In some cases, the first therapeutically active agent (e.g., darolamide) and the second therapeutically active agent may be the same. In other cases, the first therapeutically active agent (e.g., darolamide) and the second therapeutically active agent may be different. In some cases, a grid (e.g., a guide template) may be used to position the first implant in the first portion of the target tissue, and the second implant may be positioned in the second portion of the target tissue. In some cases, the first implant and / or the second implant may be positioned with ultrasound guidance.

[0062] In some aspects, method can also include extra implants implanted into target tissue.For example, method can also include the third implant implanted into the third part of target tissue, the fourth implant implanted into the fourth part of target tissue, the fifth implant implanted into the fifth part of target tissue, the sixth implant implanted into the sixth part of target tissue, the seventh implant implanted into the seventh part of target tissue, the eighth implant implanted into the eighth part of target tissue, etc. The third, fourth, fifth, sixth, seventh, eighth or more therapeutically active agents can be identical, different or their combination separately.In some cases, at least three kinds (individual) implants are implanted into target tissue.For example, at least three kinds (individual) implants can be implanted into prostate or prostate adjacent or nearby tissue by perineum administration.

[0063] In some aspects, one or more implants can be implanted into prostate or prostate adjacent or nearby tissue before performing surgical operation treatment prostate cancer. For example, one or more implants can be implanted into prostate or prostate adjacent or nearby tissue before performing prostatectomy (for example one week before, two weeks before, three weeks before, etc.). In this case, prostatectomy can remove prostate or its part. In some cases, prostatectomy can remove one or more in implant from experimenter. In other cases, one or more implants can be implanted into prostate or prostate adjacent or nearby tissue, and can be retained in prostate indefinitely. For example, one or more implants can provide darolutamide of therapeutic effective amount to prostate tissue for a period of time so that experimenter's prostate cancer is alleviated or cured.

[0064] The term "subject" as used herein 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 can be used on tissues from a subject and the progeny of the tissues. The tissue can be obtained from the subject in vivo. In some cases, the tissue can be cultured in vitro.

[0065] In some aspects, the methods provided herein can be used to treat subjects in need. In some cases, the subject can suffer from a disease. In some cases, the subject can be a person. In some cases, a person can be a patient in a hospital or clinic. In some cases, the subject can be a non-human animal, such as a non-human primate, livestock animal, domestic pet, or laboratory animal. For example, the non-human animal can be an ape (e.g., chimpanzee, baboon, gorilla, or orangutan), an old world monkey (e.g., macaque), a new world monkey, a dog, a cat, a bison, a camel, a cow, a deer, a pig, a donkey, a horse, a mule, an American rhea, a sheep, a goat, a buffalo, a reindeer, a yak, a mouse, a rat, a rabbit, or any other non-human animal.

[0066] In the case where 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 or older. 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 or older.

[0067] 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 cause a reduction in the severity of one or more symptoms associated with a disease. In some cases, the methods provided herein can slow down, stop or reverse the progress of one or more symptoms associated with a disease. In some cases, the methods provided herein can prevent the development of one or more symptoms associated with a disease. In some cases, the methods provided herein can slow down, stop or reverse the progress of a disease, as measured by the number and severity of symptoms experienced.

[0068] 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, the method can reduce the size of the tumor. In some cases, the 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%.

[0069] In some aspects, the proliferative disease or disorder can be a proliferative disease or disorder of the prostate. In a 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 carcinoma, transitional cell carcinoma, or squamous cell carcinoma. 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.

[0070] Methods can be used to deliver a therapeutically effective amount of darolutamide to a target tissue. In some cases, methods may involve delivering a drug implant to a target tissue (or a tissue adjacent to the target tissue) of a subject. Any tissue may be suitable for delivery of a drug implant of the present disclosure. In exemplary cases, the target tissue may be the prostate, a 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), testicle, and neck.

[0071] In various aspects of the present disclosure, the method provides implanting a drug implant of the present disclosure into a target tissue (or adjacent tissue) of a subject, wherein the implant delivers a therapeutically effective amount of darolutamide to the target tissue. As used herein, "therapeutically effective amount" refers to the amount of a drug or therapeutically active agent when used to refer to a drug or therapeutically active agent, which can cause a therapeutic response in a subject. 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 may 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.

[0072] In various aspects of the present disclosure, the therapeutically effective amount of the drug may be at least about 0.1 μg / day. In some cases, the therapeutically effective amount of the drug can be 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. / day, about 60μg / day, about 65μg / day, about 70μg / day, about 75μg / day, about 80μg / day, about 85μg / day, about 90μg / day, about 95μg / day, about 100μg / day, about 110μg / day, about 120μg / day, about 130μg / day, about 140μg / day, about 150μg / day, about 160μg / day, about 170μg / day, about 180μg / day, about 190μg / day, about 200μg / day, about 210μg / day, about 220μg / day, about 230μg / day, about 240μg / day, about 250μg / day, about 260μg / day, about 270μg / day, about 280μg / day, about 29 0μg / day, about 300μg / day, about 310μg / day, about 320μg / day, about 330μg / day, about 340μg / day, about 350μg / day, about 360μg / day, about 370μg / day, about 380μg / day, about 390μg / day, about 400μg / day, about 410μg / day, about 420μg / day, about 430μg / day, about 440μg / day, about 450μg / day, about 460μg / day, about 470μg / day, about 480μg / day, about 490μg / day, about 500μg / day, about 510μg / day, about 520μg / day, about 530μg / day, about 540μg / day, about 550μg / day, about 560μg / day, about 570μg / day, about 580μg / day, about 590μg / day, about 600μg / day, about 610μg / day, about 620μg / day, about 630μg / day, about 640μg / day, about 650μg / day, about 660μg / day, about 670μg / day, about 680μg / day, about 690μg / day, about 700μg / day, about 710μg / day, about 720μg / day, about 730μg / day, about 740μg / day, about 750μg / day, about 760μg / day, about 770μg / day, about 780μg / day, about 790μg / day, about 800μg / day, about 810μg / day, about 820μg / 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 a drug can vary based on the drug and / or the disease to be treated and can be determined empirically. ,

[0073] In various aspects, the implant can cause 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 100 days after implantation, at least 50% of the total amount of darolutamide present in the implant at the time of implantation remains in the polymer matrix. In various aspects, the implant can cause a cumulative release of one or more of darolutamide in an in vitro model: no more than 2,000 micrograms on day 1, no more than 12,000 micrograms on day 60, and no more than 16,000 micrograms on day 120. In various aspects, the implant can cause a cumulative release of darolutamide of one or more of at least 10 micrograms at day 1, at least 200 micrograms at day 60, and at least 300 micrograms at day 120 in an in vitro model. The in vitro model can include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) / water at 37° C. with continuous agitation for designated time intervals.

[0074] In various aspects of the present disclosure, implant can be configured to retain a period of time in target tissue. In some cases, implant can be configured to retain in target tissue with long time period (such as several months to several years) or infinitely (such as can never remove). For example, after implant has delivered whole therapeutic active agents contained therein to experimenter, implant (not containing therapeutic active agents) can remain in target tissue. In some cases, if additional treatment is needed, one or more additional implants can be delivered to target tissue (not removing initial implant). In some cases, implant can be constituted by non-biodegradable and / or non-absorbable polymeric material so that described polymeric material is substantially unchanged in target tissue with long time period or infinitely retain.

[0075] Advantageously, the implants disclosed herein are capable of delivering a therapeutically effective amount of darolutamide to prostate tissue, or tissue adjacent to or near the prostate, for a prolonged period of time (e.g., at least 6 months). Additionally, the implants disclosed herein are capable of delivering high concentrations of darolutamide locally to the prostate while maintaining low systemic concentrations of darolutamide. In some cases, the implants disclosed herein can reduce or prevent the toxicity caused by high systemic concentrations of darolutamide.

[0076] In various aspects, the total dose of darolutamide administered to a subject via an implant of the present disclosure is less than the total dose of darolutamide administered to a subject by systemic (e.g., oral) administration. Standard oral dosing regimens for darolutamide include 600 mg / day of darolutamide monotherapy for prostate cancer. Advantageously, implants of the present disclosure provide administration of a lower total dose of darolutamide relative to an oral dosing regimen. In some cases, the total amount of darolutamide administered to a subject over a 6-month period is less than 100 mg.

[0077] In various aspects, implantation of the disclosed drug implant into the prostate or tissue adjacent or near the prostate results in a darolutamide plasma concentration that is substantially less than the darolutamide plasma concentration 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 600 mg daily dose) has been reported to be about 4.79 mg / L. In some cases, implantation of the disclosed implant into the prostate or tissue adjacent or near the prostate results in a darolutamide steady-state plasma concentration of less than 4.79 mg / L.

[0078] Reagent test kit

[0079] Kits are also provided herein. In some aspects, the kit can include one or more implants as 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 therapeutically active agents contained therein. In some cases, each of one or more implants can include darolamide. In other cases, each of one or more implants can include one or more different therapeutically active agents.

[0080] In some aspects, the test kit can include one or more surgical tools, such as a needle or forceps. In some aspects, the test kit can be packaged in a sterile package. In some cases, the sterile package includes foil. In some aspects, the test kit can also include instructions for implanting the implant into the subject's tissue.

[0081] Some nomenclature / terminology

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. It should be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and do not limit any subject matter claimed.

[0083] In this application, the use of the singular includes the plural unless otherwise specifically stated. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "an" include plural referents unless the context clearly indicates otherwise. In this application, the use of "or", "means" and / or" unless otherwise stated. In addition, the use of the term "comprise" as well as other forms, such as "contains", "includes" and "comprising" is non-limiting.

[0084] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes exact amounts. Thus, "about 5 μL" means "about 5 μL" as well as "5 μL." Generally, the term "about" includes amounts that would be expected to be within experimental error, such as within 15%, 10%, or 5%.

[0085] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Example

[0086] Example 1. Method of making implants - platinum-cured silicone

[0087] The preparation of the implant involves two main steps: formulating the active pharmaceutical ingredient (API) (e.g., darolutamide) with an elastomer (e.g., medical-grade platinum-cured silicone) to ensure uniform mixing of the API within the polymer matrix, and molding the implant to ensure that the product can be deployed to the organ as desired.

[0088] Preparation

[0089] The implant formulation includes medical grade silicone as an excipient and the API mixed therewith. The solvent is used to reduce the viscosity of the silicone (if necessary) to incorporate the desired API load.

[0090] The darolutamide formulation is prepared using a centrifugal mixer. The required amounts of silicone part A and part B are added to a mixing cup, and an equal weight of solvent (which dissolves the silicone; for example, pentane) is added. The silicone and solvent are mixed at high speed until the viscosity of the silicone is reduced to the point where it flows. The API powder is then added to the mixing cup and mixed at high speed until a visually uniform mixture is obtained with no spots of dry API. The solvent is then removed (with or without vacuum), leaving a paste of silicone and API. Table 1 below shows an example of a darolutamide formulation, prepared at 10% weight loading.

[0091] This method can be used to formulate active pharmaceutical ingredients (eg, darolutamide) and elastomers (eg, platinum-cured silicones) from as low as 10% loading to greater than 70% loading.

[0092] Other solvent-free methods of achieving the same mixing uniformity may be used, such as shear mixing. Other solvents that help reduce viscosity and dissolve silicones (e.g., methylene chloride, tetrahydrofuran, hexane, pentane, heptane, toluene, etc.) may also be used in formulation.

[0093] Table 1. Example formulation compositions

[0094]

[0095] Table 2. Example solvent removal conditions

[0096]

[0097] Molding

[0098] Implant rods are prepared using (e.g., aluminum) molds (e.g., via transfer molding) or by extruding apalutamide formulations (e.g., through tubes). The molded rods are cured at a temperature (e.g., about 125° C. to 175° C.) for a predetermined time (e.g., about 3 to 8 minutes) based on the silicone supplier's recommended cure. After curing, the mold is cooled and the rods are demolded for characterization.

[0099] Example 2. Method of making implants - acetoxy-cured silicone

[0100] In this example, the implant formulation includes medical grade silicone and API mixed therewith, wherein silicone with acetoxy cure (with an alternative cure chemistry of platinum cure) is to be used as the excipient.

[0101] Preparation

[0102] The implant formulation includes medical grade silicone as an excipient and the API mixed therewith. The solvent is used to reduce the viscosity of the silicone (if necessary) to incorporate the desired API load.

[0103] 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 solvent (which dissolves the silicone; for example, pentane) is added. The silicone and solvent are mixed at high speed until the viscosity of the silicone is reduced to the point where it flows. The API powder is then added to the mixing cup and mixed at high speed until a visually uniform mixture is obtained with no spots of dry API. The solvent is then removed (with or without vacuum), leaving a paste of silicone and API. Some of the solvent (up to 50% w / w) may be left in the mixture to slow the curing process and extend the pot life as well as to reduce viscosity to aid molding or extrusion. Table 3 below shows an example of a darolutamide formulation, prepared at 10% loading.

[0104] This method can be used to formulate active pharmaceutical ingredients (eg, darolutamide) and elastomers (eg, acetoxy-cured silicones) from as low as 10% loading to greater than 70% loading.

[0105] Other solvent-free methods of achieving the same mixing uniformity may be used, such as shear mixing. Other solvents that help reduce viscosity and dissolve silicones (e.g., methylene chloride, tetrahydrofuran, hexane, pentane, heptane, toluene, etc.) may also be used in formulation.

[0106] Table 3. Example formulation compositions

[0107]

[0108] Molding

[0109] Implant rods are prepared by extruding the darolutamide formulation (e.g., through a tube). The molded rods are cured at ambient temperature for a predetermined time (about 1-3 days) to ensure that the silicone has cured. After curing, the rods are pulled from the tube and cut to length and characterized.

[0110] Example 3. Method for preparing implants - Thermoplastic polyurethane solvent method

[0111] In this example, the implant formulation includes thermoplastic polyurethane as an excipient and an API mixed therewith.

[0112] Preparation

[0113] The solvent used to dissolve the polyurethane is mixed with the API to form a uniform dispersion of the desired loading. After mixing, the solvent is removed and the resulting polyurethane-API pellet is molded into an implant rod by transfer molding or extrusion.

[0114] Polyurethane pellets are added to a mixing cup with a solvent (e.g., dichloromethane) and incubated with stirring at 37°C for several hours until polyurethane dissolution is achieved. The ratio of polyurethane to solvent is selected to achieve complete dissolution of the polyurethane and a sufficiently low viscosity solution for mixing (e.g., about 20% by weight solids content). The API powder is then added to the solution and mixed at high speed until a visually uniform mixture is obtained and there are no dry API spots. Table 4 below shows an example of a formulation prepared as 30% API w / w. The solvent is then removed under vacuum to leave a large pellet consisting of polyurethane, API and residual solvent that can be used for thermal molding. Table 5 below shows an example group of solvent removal conditions. Other solvents that dissolve polyurethane (e.g., tetrahydrofuran, dimethylformamide, dimethylacetamide, etc.) can also be used for formulation.

[0115] Table 4. Example formulation compositions

[0116] Components Added weight (g) Lubrizol Pathway PT-87AS 1g Solvents 6g Darolamide ground powder 0.45g

[0117] Table 5. Example solvent removal conditions

[0118]

[0119] Molding

[0120] Implant rods are prepared using (e.g., aluminum) molds (e.g., via transfer molding) or by extruding the darolutamide formulation (e.g., through a tube). Prior to injection or extrusion, the formulation is melted at a temperature (about 150° C. to 200° C.) for several minutes (about 3 to 8 minutes). After solidification, the mold is cooled and the rod is demolded for characterization.

[0121] Example 4. Method of making implants - thermoplastic polyurethane and polyethylene-vinyl acetate extrusion process

[0122] In this example, the implant formulation includes thermoplastic polyurethane or polyethylene-vinyl acetate as an excipient and an API mixed therewith.

[0123] Preparation

[0124] Add the milled excipient powder (thermoplastic polyurethane or polyethylene-vinyl acetate) and API (darolutamide) to the mixing cup. Mix the cup at high speed until the powder is fully incorporated. Table 6 below shows typical metrics for a 2-gram powder mix at 50% API loading. Adjust the ratio for different target loadings.

[0125] Table 6. Example Formulation Composition - 50% Daroltamide Loading

[0126] Components Added weight (g) Cryogenically ground Lubrizol Pathway PT-87AE 1g Darolamide ground powder 1g

[0127] Molding

[0128] Implant rod is prepared by extrusion method, using plunger type or double screw extruder.Aliquots (0.5-10g) of powder mixture are placed in extruder chamber and heated to about 150 ℃ for 1-3 minutes.Activate plunger or rotating screw to force molten powder mixture to pass through extrusion nozzle or die.Leave fixture with the extruded band, collect manually or with conveyor belt system.Can adjust nozzle or die diameter and conveyor belt speed to obtain implant of certain diameter.After it cools for a few seconds, it can be cut into the desired length of implant rod.

[0129] For larger batches, an alternative method uses a twin screw extruder (e.g., ThermoFisher HAAKEMiniCTW) to melt and extrude the darolamide polymer powder mixture. The mixture is introduced into an extruder barrel heated to 150-200°C and the molten mixture is pushed through a die to produce an extruded strip of the desired diameter. The conveyor carries the extruded strip, which is allowed to cool and then cut into the desired length of the implant rod.

[0130] This process can produce a powder mixture containing milled excipients and API powder, or even pellets from a solvent mixture, as described herein.

[0131] Example 5. Characterization of formulations and implants containing darolutamide

[0132] Various analytical techniques are used to characterize formulations and molded implants. Differential scanning calorimetry (DSC) is used, for example, to determine the solidification rate of implants and to evaluate the properties of the drug. Elution tests are used to evaluate the elution rate of the drug from the implant. High pressure liquid chromatography (HPLC) is used, for example, to confirm content homogeneity and to evaluate impurities in drug formulations and molded rods.

[0133] Example 6. Elution test of various drug implants disclosed herein

[0134] Elution tests were performed on various drug implants according to the embodiments provided herein. Three groups of polymers were tested with darolutamide according to Table 7 below: silicone with a platinum curing system (Silbione D370), thermoplastic polyurethane (Lubrizol Pathway), and ethylene-vinyl acetate (Celanese ATEVA and VitalDose). Several percentages of vinyl acetate (28% and 40%) were tested. Drug implants were prepared according to Examples 1-4 above.

[0135] Table 7. Overview of polymers and darolamide loading used for elution testing

[0136] polymer Darolamide loading Silicone (D370) 30％ TPU 16HRLN 50％ PEVA 28% Vinyl Acetate 50％，70％ PEVA 40% Vinyl Acetate 50％

[0137] Drug implants were incubated in 1% sodium dodecyl sulfate / water at 37°C for up to 240 days. Figure 1A and 1B Depicting the cumulative release of darolutamide from various drug implants. The data presented in the figure show that the release rate of darolutamide from implants can be tailored via the total drug loading in the matrix and the type of polymer matrix used for the implant.

Claims

1. Drug implants, including: a) a biocompatible, non-biodegradable polymer matrix; and b) darolutamide dispersed in said biocompatible, non-biodegradable polymer matrix.

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

3. The drug implant of any one of the preceding claims, wherein the total dose of darolutamide in the drug implant is from about 1 mg to about 10 mg.

4. The drug implant of any of the preceding claims, wherein the drug implant releases at least about 0.1 μg / day of darolutamide six months after implantation in a subject.

5. The drug implant according to any one of the preceding claims, wherein the cumulative release of darolutamide in an in vitro model is (i) not more than 2000 micrograms on day 1, not more than 12,000 micrograms on day 60, and not more than 16,000 micrograms on day 120; and (ii) at least 10 micrograms on day 1, at least 200 micrograms on day 60, and at least 300 micrograms on day 120, The in vitro model involves incubation of drug implants in 1% sodium dodecyl sulfate / water at 37°C with continuous agitation.

6. The pharmaceutical implant of any of the preceding claims, wherein the biocompatible, non-biodegradable polymer matrix is ​​silicone.

7. The drug implant of claim 6, wherein the silicone is an acetoxy-cured silicone or a platinum-cured silicone.

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

9. The pharmaceutical implant of any of the preceding claims, wherein at least 50% of darolutamide remains in the biocompatible, non-biodegradable polymer matrix after 100 days of implantation.

10. The pharmaceutical implant of any of the preceding claims, wherein at least 99% by weight of the biocompatible, non-biodegradable polymer matrix remains in the target tissue of the subject at least 600 days after implantation.

11. The pharmaceutical implant of any of the preceding claims, wherein darolutamide is in solid form.

12. The drug implant according to any one of the preceding claims, wherein darolutamide is in crystalline, semi-crystalline or amorphous form.

13. The drug implant of any of the preceding claims, wherein the drug implant has a Shore A hardness of at least 20 Durometer at a loading of 60% w / w darolamide.

14. The drug implant of any of the preceding claims, wherein the drug implant is visible by ultrasound when deployed in a target tissue of a subject.

15. The pharmaceutical implant of any of the preceding claims, wherein darolutamide has a melting temperature greater than the molding or solidification temperature of the polymer matrix.

16. The drug implant of any of the preceding claims, wherein the drug implant inhibits the modulation of darolutamide within the drug implant.

17. The pharmaceutical implant of claim 16, wherein said modifying comprises degradation.

18. The drug implant according to any one of the preceding claims, wherein the drug implant is elongated.

19. The drug implant according to any one of the preceding claims, wherein the drug implant is cylindrical.

20. The drug implant according to any one of the preceding claims, wherein the drug implant is tubular.

21. The drug implant according to any one of the preceding claims, wherein the drug implant is in the shape of a rod.

22. The drug implant of any one of the preceding claims, wherein the drug implant has a diameter of about 0.1 mm to about 1.5 mm.

23. The drug implant of any one of the preceding claims, wherein the length of the drug implant is from about 1 mm to about 30 mm.

24. The drug implant of any one of the preceding claims, wherein the volume of the drug implant is about 0.1 mm 3 To about 30mm 3 .

25. The drug implant of any of the preceding claims, wherein at least 50% of an outer surface of the drug implant is configured to directly contact a target tissue.

26. The drug implant of any one of the preceding claims, wherein the drug implant is configured to be implanted into a target tissue or a tissue near or adjacent to the target tissue.

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

28. The drug implant of any one of the preceding claims, wherein the drug implant is configured to be delivered to a target tissue using the lumen of a needle or catheter.

29. The drug implant of any of the preceding claims, wherein the drug implant lacks at least one of a retaining element, a scaffold, a sheath, or a combination thereof for retaining the drug implant within the target tissue.

30. The drug implant of any one of the preceding claims, wherein the drug implant further comprises a coating.

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

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

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

34. The pharmaceutical implant according to any one of the preceding claims, wherein the pharmaceutical implant is sterile.

35. The pharmaceutical implant according to any one of the preceding claims, wherein the pharmaceutical implant is arranged in a sterile package.

36. The drug implant of claim 1, consisting essentially of a biocompatible, non-biodegradable polymer matrix and darolutamide dispersed in said biocompatible, non-biodegradable polymer matrix.

37. A method of treating a prostatic proliferative disorder in a subject, the method comprising implanting one or more pharmaceutical implants according to any one of the preceding claims into prostate tissue or tissue adjacent to the prostate.

38. The method of claim 37, wherein the one or more drug implants deliver a therapeutically effective amount of darolutamide to the prostate for at least 6 months.

39. The method of claim 37 or 38, wherein the prostatic proliferative disease is prostate cancer or benign prostatic hyperplasia.

40. The method of claim 39, wherein the prostate cancer is castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer.

41. The method of any one of claims 37-40, wherein darolutamide is dispersed within a biocompatible, non-biodegradable polymer matrix prior to implantation.

42. The method of any of the preceding claims, wherein the implanting comprises deploying each of the one or more drug implants into the prostate tissue or tissue adjacent to the prostate through the lumen of a needle or catheter.

43. The method of any of the preceding claims, wherein the implanting occurs via transperineal administration.

44. The method of any of the preceding claims, wherein the transperineal administration comprises using a template to guide the needle.

45. The method of any one of the preceding claims, wherein the total dose of darolutamide administered to the subject is less than the total dose of darolutamide if administered to the subject by oral administration.

46. ​​The method of any one of the preceding claims, wherein the total dose of darolutamide administered to the subject over a period of 6 months is less than 100 mg.

47. The method of any one of the preceding claims, wherein the implantation results in a darolutamide plasma concentration that is less than the darolutamide plasma concentration obtained if darolutamide is administered to the subject by oral administration.

48. The method of any of the preceding claims, wherein the implantation results in a steady-state plasma concentration of darolutamide of less than about 4.79 mg / L.

49. The method of any one of the preceding claims, wherein the one or more drug implants comprises 2 to 16 drug implants.

50. A method of preparing a pharmaceutical implant according to any one of the preceding claims, the method comprising: (a) mixing an amount of an uncured polymer with an amount of darolutamide 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.

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

52. The method of claim 50 or 51, wherein the polymer is silicone or thermoplastic polyurethane or poly(ethylene vinyl acetate).

53. The method of any one of claims 50-52, wherein the curing of (c) further comprises heating the molded mixture at a temperature of about 100°C to about 175°C for about 3 to about 8 minutes.

54. The method of any one of claims 50-53, wherein the mixture further comprises a solvent.

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

56. The process according to any one of claims 50 to 55, wherein the mixture is moulded by means of a transfer moulding process or by means of extrusion through a tube.

57. The method of any one of claims 50-53, wherein the molding comprises extruding the mixture with a ram extruder or a twin screw extruder.

58. The method of any one of claims 50-53, wherein the molding comprises injection molding.

59. The method of any one of claims 50-58, further comprising analyzing the pharmaceutical implant.

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

61. A kit comprising: A sterile package comprising the pharmaceutical implant of any one of the preceding claims; and Instructions for implanting the pharmaceutical implant into a target tissue of a subject.

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