Microsphere-based injectable clascoterone formulation

Abstract

This invention provides biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 μm and a d90 value of 500 μm or less (e.g., 40 μm or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. This invention further provides related injectable formulations, methods for treating hair loss, and articles of manufacture.

Description

[0001] Dk. Avidence-7PCT MICROSPHERE-BASED INJECTABLE CLASCOTERONE FORMULATION This application claims the benefit of U.S. Provisional Application No.63 / 639,756, filed April 29, 2024, the contents of which are incorporated herein by reference. Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Field of the Invention The present invention relates to methods for treating hair loss via localized injection of clascoterone-containing biodegradable microspheres. Background of the Invention Alopecia Hair loss, also known as alopecia, is a common condition that affects both men and women. The most common types of hair loss, such as male-pattern baldness and female-pattern baldness, are associated with altered androgen levels and altered sensitivity to androgens in the hair follicles. Thus, they are known as androgenic alopecia or androgenetic alopecia. Inhibiting androgen signaling by blocking androgen receptors with anti-androgen drugs has shown clinical benefits in slowing hair loss or growing hair. FDA-approved androgen receptor blockers include clascoterone, enzalutamide, and apalutamide, among others, but they are only approved for indications such as acne and prostate cancer, and not hair loss. Clascoterone Oral administration of androgen receptor blockers carries potentially severe side effects such as seizure, cerebrovascular, and ischemic cardiovascular toxicity, fall and fracture and embryo-fetal toxicity (see, e.g., the FDA labels for XTANDI®and ERLEADA®). Topical delivery of androgen receptor blockers can reduce their systemic exposure and side effects. However, topical delivery carries the additional risk of transference through which the anti-androgen is unintentionally transferred from one person with topically applied drug to another person via direct contact or contact with a common surface, which causes side effects in the other person. These side effects can be addressed via localized delivery of anti-androgens through an injection into the skin or the scalp to act on the hair follicles directly. By bypassing the skin barrier, a direct injection is also more effective than topical treatment which relies on passive diffusion of the topical drug through the skin barrier. This approach maximizes local inhibition of androgen signaling, minimizes systemic side effects, and avoids the risk of transference. Ideally, an anti- androgen formulation should be long-acting and should be locally delivered using a thin needle. These features would reduce pain and injection frequency. Clascoterone is an androgen receptor blocker that is approved for topical treatment of acne at a concentration of 1%. In a clinical trial, 7.5% clascoterone applied to the scalp twice daily showed great promise for slowing down male-pattern baldness and regrowing hair. However, the high concentration of clascoterone required in the trial indicated poor penetration through the scalp into the hair follicles. Further increasing the amount of clascoterone delivered to the hair follicles by direct injections will likely increase its efficacy against hair loss. PLGA Microspheres Generally An important biodegradable material commonly used for extended-release drug delivery is polylactic co-glycolic acid copolymer (PLGA). PLGA is made of polylactic acid (PLA) units, polyglycolic acid (PGA) units, and typically both. As an FDA-approved polymer, it has been extensively investigated in many medical and pharmaceutical fields due to its biodegradability and biocompatibility. PLGA-containing microspheres have shown sustained release characteristics due to degradation and diffusion mechanisms. The drug release profile of a PLGA microsphere preparation is dependent on certain factors, such as the specific properties of the drug, the ratio of PLA to PGA, the type of end cap of the polymer (i.e., ester or acid), the molecular weight and inherent viscosity of the polymer, the loading ratio of drug to the polymer, and the size of the microspheres. Known Challenges As discussed by Bauer, et al. (2023), microsphere size is important for syringeability (i.e., the "ability to be transferred from a vial through a conventional needle into a syringe") and injectability (i.e., the ability of "transferring of contents [from] the syringe into the body"). Specifically, "[s]yringeability … and injectability … are [the] two most important quality attributes in [the] patient convenience related category. These two quality attributes play a significant part in the LAI [long-acting injectable] administration efficiency. Ideally, the product should be such that injection can be done through smaller needle size of conventional needles, reducing the local tissue damage and associated pain, and enhancing patient compliance. A high level of control over the particle size, shape, density, viscosity, and suspension concentration is required as large particles or aggregates in the formulation often cause needle clogging." (pages 1610 and 1611; citations omitted) Park, et al. (2019) describes how small microspheres are challenging to develop. Specifically, "[t]he important properties of microparticles for clinical applications (or microparticle properties) include a microparticle size small enough for injection, high drug loading, high drug loading efficiency, and long duration of drug release without the huge initial burst release ... One of the important properties to control is the microparticle size. The PLGA microparticle formulation currently in clinical use have large sizes, requiring large-diameter gauge needles for injection. For example, Trelstar and Risperidal Consta ... use 21-gauge needles. … Nutropin Depot … also used the 21-gauge needle. The size of Risperidal Consta microparticles ranges from 25 µm to 180 µm. … Delivery of the extended-release injectable formulation of naltrexone (marketed as Vivitrol) uses a 20-gauge needle. … In comparison, delivery of an insulin typically uses a 28-gauge needle. PLGA microparticles that can be administered using a 28-gauge needle or thinner needles will undoubtedly make clinical use more patient- friendly, although making smaller PLGA microparticles may come at the expense of other properties in Table 2 [drug loading, drug loading efficiency, initial burst release, drug release kinetics]." (pages 128 and 129; emphasis added; citations omitted) For large diameter particles, the small surface area per unit volume leads to reduced rate of water permeation and matrix degradation relative to smaller particles and so the maximum possible rate of encapsulated drug release is reduced. For drugs microencapsulated in larger microparticles, duration of action is potentially longer due to higher total drug loading and a longer particle degradation time. Simply put, small microspheres have higher surface area to volume ratios, which correlates to faster drug release and shorter drug release durations. See, e.g., Han, et al. (2016). Makadia and Siegel (2011) states that “[t]he ratio of surface area to volume has shown to be a significant factor for degradation of large devices [e.g., microspheres]. Higher surface area ratio leads to high degradation of the matrix. It has also been reported that bulk degradation is faster than pure surface degradation for PLGA, which makes the release of the drug faster from the devices with higher surface area to volume." (page 9; citations omitted) Berchane, et al. (2007) provides an example of this problem. Figure 4 of Berchane, et al. shows the release curves of piroxicam poly(lactide-co-glycolide) microspheres of different sizes. The 300-rpm group (mean diameter 33.5 µm from Table 1) has a duration over 30 days, whereas the 900-rpm group (mean diameter 13.5 µm from Table 1) released over 80% of drug in about 12 days. There remains a need for an injectable formulation of clascoterone microspheres that are long-lasting and that solve the problems of syringeability and injectability. Summary of the Invention This invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 m to 500 m (e.g., 40 m); (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical clascoterone; and (iv) when present intradermally, releases clascoterone for at least one month. This invention also provides a plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. This invention further provides an injectable formulation comprising (a) a pharmaceutically acceptable carrier and (b) a plurality of biodegradable microspheres wherein the microspheres (i) have a d10value of at least 1 m and a d90value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. This invention still further provides a method for treating hair loss in a subject comprising introducing biodegradable microspheres into an affected area of the subject’s skin, wherein the introducing is into skin at or around one or more hair follicles, and wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. This invention also provides an article of manufacture (kit) comprising, in separate compartments, (a) one of, and ideally both of, (i) a diluent and (ii) a label instructing the user to introduce the present biodegradable microspheres into the affected area of a subject’s skin, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. This invention further provides an article of manufacture comprising a syringe having therein the instant injectable formulation. Finally, this invention provides an article of manufacture comprising a dual chamber syringe having therein, in separate compartments, (a) a diluent, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co- glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month, wherein the diluent and microspheres can be admixed within the syringe to form an injectable formulation immediately prior to use. Brief Description of the Figures Figures 1A and 1B These figures show apalutamide release from microspheres made with a stir bar. Figures 1C and 1D These figures show enzalutamide release from microspheres made with a stir bar. Figure 2 This figure shows a mixer (Model L5MA, Silverson, Massachusetts, US) with an in-line mixing chamber and general-purpose disintegrating head that was used to continuously create oil-in-water emulsions and generate microspheres. Figures 3A and 3B These figures show drug release from apalutamide microspheres made in an in-line mixing chamber. Some formulations showed continuous apalutamide release over two months and other formulations showed gaps in release. Figures 3C and 3D These figures show drug release from enzalutamide microspheres made in an in-line mixing chamber. Some formulations showed continuous enzalutamide release over one month, two months, three months, six months, or twelve months. Figure 4 This figure shows that the effect of reducing particle size of enzalutamide microspheres on drug release was minimal. Figure 5 This figure shows the in vitro enzalutamide release profile for microspheres used in the rat study. Figure 6 This figure shows clascoterone release from microspheres prepared with a stir bar. Figures 7A-7C These figures show that increasing the clascoterone:PLGA ratio did not affect total duration of drug release significantly. Figure 8 This figure shows clascoterone release from microspheres over two months. Figure 9 This figure shows clascoterone release from different PLGA types with formulations from PLGA75:25, 0.4 dl / g, ester-terminated showing prolonged gaps in drug release. Figures 10A and 10B These figures show over two months of clascoterone release from microspheres of mixed PLGA types. Figures 11A1-11A3, 11B1-11B3, 11C1 and 11C2 These figures illustrate the studies that identified the optimal clascoterone:PLGA ratio during microsphere preparation. Formulations in figures 11A1, 11B1, and 11C1 showed relatively uniform release kinetics suitable for chronic treatment of hair loss. Figures 12A-12C These figures show clascoterone release from microspheres over two to four months in vitro. Figure 13 These figures show clascoterone release from microspheres with a gap in release from day 30 to 60, which is undesirable for continuous treatment of hair loss. Figure 14 This figure shows over three months of in vitro release for clascoterone microspheres used in rat injection. Figures 15A and 15B These figures show over six months of in vitro release for un-irradiated clascoterone microspheres and four months of in vitro release for clascoterone microspheres after 15 kGy or 25 kGy E-beam irradiation. Detailed Description of the Invention This invention provides clascoterone-containing biodegradable microspheres and methods for using them to treat hair loss. Definitions In this application, certain terms are used which shall have the meanings set forth as follows. As used herein, a “biodegradable microsphere” comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix, which matrix can include solely polylactic acid (PLA), solely polyglycolic acid (PGA), or a polymeric combination of lactic acid and glycolic acid units. In general, for certain lactic acid to glycolic acid ratios (e.g., 50:50 to 100:0), the higher a microsphere’s lactic acid content, the slower it degrades and, thus, the more stable it is. Conversely, for such ratios, the higher a microsphere’s glycolic acid content, the faster it degrades and the less stable it is. In one embodiment, the biodegradable microsphere contains a combination of lactic acid and glycolic acid units wherein the molar ratio of lactic acid to glycolic acid units (i.e., the “lactic acid to glycolic acid ratio”, or “L:G ratio”) is 0:100, 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 95:5, or 100:0. In another embodiment, the biodegradable microsphere contains a combination of lactic acid and glycolic acid units wherein the molar ratio of lactic acid to glycolic acid is from 5:95 to 20:80, from 20:80 to 40:60, from 40:60 to 50:50, from 50:50 to 60:40, from 60:40 to 80:20, from 80:20 to 100:0, from 50:50 to 100:0, from 60:40 to 90:10, from 70:30 to 80:20, from 70:30 to 90:10, from 71:29 to 76:24, from 72:28 to 77:23, from 73:27 to 78:22, from 74:26 to 79:21, from 71:29 to 79:21, from 72:28 to 78:22, from 73:27 to 77:23, from 74:26 to 76:24, from 50:50 to 80:20, from 50:50 to 90:10, from 60:40 to 70:30, from 80:20 to 90:10, from 81:19 to 86:14, from 82:18 to 87:13, from 83:17 to 88:12, from 84:16 to 89:11, from 81:19 to 89:11, from 82:18 to 88:12, from 83:17 to 87:13, from 84:16 to 86:14, or from 90:10 to 100:00. The population of biodegradable microspheres used in this invention can be homogeneous or heterogeneous with respect to the microspheres’ molar ratio of lactic acid to glycolic acid. In one embodiment, the population of biodegradable microspheres is homogeneous with respect to the microspheres’ molar ratio of lactic acid to glycolic acid (e.g., the population includes only microspheres wherein the molar ratio of lactic acid to glycolic acid is 75:25 or 85:15). In another embodiment, the population of biodegradable microspheres is heterogeneous (e.g., the population includes both (i) microspheres wherein the molar ratio of lactic acid to glycolic acid is 70:30, and (ii) microspheres wherein the molar ratio of lactic acid to glycolic acid is 80:20). In a preferred embodiment, the instant microspheres contain PLGA having an inherent viscosity of 0.1 to 2.4 dl / g (e.g., 0.16 to 1.7 dl / g), and a molecular weight from 1,000 to 600,000 (e.g., from 7,000 to 240,000). In one embodiment, the biodegradable microsphere has an inherent viscosity of 0.1 dl / g, 0.2 dl / g, 0.3 dl / g, 0.4 dl / g, 0.5 dl / g, 0.6 dl / g, 0.7 dl / g, 0.8 dl / g, 0.9 dl / g, 1.0 dl / g, 1.1 dl / g, 1.2 dl / g, 1.3 dl / g, 1.4 dl / g, 1.5 dl / g, 1.6 dl / g, 1.7 dl / g, 1.8 dl / g, 1.9 dl / g, 2.0 dl / g, 2.1 dl / g, 2.2 dl / g, 2.3 dl / g, or 2.4 dl / g. In another embodiment, the biodegradable microsphere has an inherent viscosity of from 0.1 dl / g to 0.2 dl / g, from 0.2 dl / g to 0.3 dl / g, from 0.3 dl / g to 0.4 dl / g, from 0.4 dl / g to 0.5 dl / g, from 0.5 dl / g to 0.6 dl / g, from 0.6 dl / g to 0.7 dl / g, from 0.7 dl / g to 0.8 dl / g, from 0.8 dl / g to 0.9 dl / g, from 0.9 dl / g to 1.0 dl / g, from 1.0 dl / g to 1.1 dl / g, from 1.1 dl / g to 1.2 dl / g, from 1.2 dl / g to 1.3 dl / g, from 1.3 dl / g to 1.4 dl / g, from 1.4 dl / g to 1.5 dl / g, from 1.5 dl / g to 1.6 dl / g, from 1.6 dl / g to 1.7 dl / g, from 1.7 dl / g to 1.8 dl / g, from 1.8 dl / g to 1.9 dl / g, from 1.9 dl / g to 2.0 dl / g, from 2.0 dl / g to 2.1 dl / g, from 2.1 dl / g to 2.2 dl / g, from 2.2 dl / g to 2.3 dl / g, or from 2.3 dl / g to 2.4 dl / g. In a further embodiment, the biodegradable microsphere has an inherent viscosity of from 0.1 dl / g to 0.5 dl / g, from 0.5 dl / g to 1.0 dl / g, from 1.0 dl / g to 1.5 dl / g, from 1.5 dl / g to 2.0 dl / g, from 2.0 dl / g to 2.4 dl / g, from 0.3 dl / g to 0.5 dl / g, from 0.3 dl / g to 1.3 dl / g, or from 1.3 dl / g to 1.7 dl / g. Preferred embodiments of the present microspheres are PLGA75:25, 0.3-0.5 dl / g; PLGA85:15, 1.3-1.7 dl / g; and PLGA75:25, 0.3-0.5 dl / g mixed with PLGA85:15, 1.3-1.7 dl / g, with a d10 value of at least 3 m and a d90value of 28 m or less. In a further embodiment, the drug loading ratio for the present biodegradable microsphere is from 20% to 30%, from 25% to 35%, from 30% to 40%, from 35% to 45%, from 40% to 50%, from 41% to 50%, from 45% to 55%, from 50% to 60%, from 55% to 65%, from 60% to 70%, from 65% to 75%, from 20% to 35%, from 30% to 45%, from 40% to 55%, from 41% to 55%, from 50% to 65%, from 20% to 40%, from 30% to 50%, from 40% to 60%, from 41% to 60%, from 50% to 70%, from 20% to 50%, from 30% to 60%, from 40% to 70%, or from 41% to 70%. In the present plurality of biodegradable microspheres, the microspheres (i) have a d10 value of at least 1 m and a d90 value of 40 m or less; (ii) non-covalently carry a therapeutic agent (clascoterone); and (iii) depending on their polymeric composition, degrade over a period lasting, for example, from one month to over six months when present intradermally. Microsphere diameter ranges, set forth as ranges from d10to d90(as defined herein), include, for example, the following: from 1 m to 10 m, from 1 m to 15 m, from 1 m to 20 m, from 1 m to 25 m, from 1 m to 28 m, from 1 m to 35 m, from 1 m to 40 m, from 3 m to 10 m, from 3 m to 15 m, from 3 m to 20 m, from 3 m to 25 m, from 3 m to 28 m, from 3 m to 35 m, from 3 m to 40 m, from 5 m to 10 m, from 5 m to 15 m, from 5 m to 20 m, from 5 m to 25 m, from 5 m to 28 m, from 5 m to 35 m, from 5 m to 40 m, from 10 m to 15 m, from 10 m to 20 m, from 10 m to 25 m, from 10 m to 28 m, from 10 m to 35 m, from 10 m to 40 m, from 15 m to 20 m, from 15 m to 25 m, from 15 m to 28 m, from 15 m to 35 m, and from 15 m to 40 m. In a further embodiment, the d10values for the present microsphere diameters include the following: (i) 1.0 m, 1.5 m, 2.0 m, 2.5 m, 3.0 m, 3.5 m, 4.0 m, 4.5 m, 5.0 m, 5.5 m, 6.0 m, 6.5 m, 7.0 m, 7.5 m, 8.0 m, 8.5 m, 9.0 m, 9.5 m, 10.0 m, m, 11.0 m, 11.5 m, 12.0 m, 12.5 m, 13.0 m, 13.5 m, 14.0 m, 14.5 m, m, 15.5 m, 16.0 m, 16.5 m, 17.0 m, 17.5 m, 18.0 m, 18.5 m, 19.0 m,1 m, and 20.0 m; (ii) from 1.0 m to 2.0 m, from 2.0 m to 3.0 m, from 3.0 m tom, from 4.0 m to 5.0 m, from 5.0 m to 6.0 m, from 6.0 m to 7.0 m, from 7.0 m to 8.0 m, from 8.0 m to 9.0 m, from 9.0 m to 10.0 m, from 10.0 m to 11.0 m, from 11.0 m to 12.0 m, from 12.0 m to 13.0 m, from 13.0 m to 14.0 m, from 14.0 m to 15.0 m, from 15.0 m to 16.0 m, from 16.0 m to 17.0 m, from 17.0 m to1 m, from 18.0 m to 19.0 m, and from 19.0 m to 20.0 m; (iii) from 1.0 m to 3.0m, from 3.0 m to 5.0 m, from 5.0 m to 7.0 m, from 7.0 m to 9.0 m, from 9.0 m to 11.0 m, from 11.0 m to 13.0 m, from 13.0 m to 15.0 m, from 15.0 m to 17.0 m, from 17.0 m to 19.0 m, and from 19.0 m to 20.0 m; and (iv) from 1.0 m to 5.0 m, from 5.0 m to 10.0 m, from 10.0 m to 15.0 m, and from 15.0 m to 20.0 m. In a further embodiment, the d50values for the present microsphere diameters include the following: (i) 5.0 m, 5.5 m, 6.0 m, 6.5 m, 7.0 m, 7.5 m, 8.0 m, 8.5 m, 9.0 m, 9.5 m, 10.0 m, 10.5 m, 11.0 m, 11.5 m, 12.0 m, 12.5 m, 13.0 m, 13.5 m, m, 14.5 m, 15.0 m, 15.5 m, 16.0 m, 16.5 m, 17.0 m, 17.5 m, 18.0 m, m, 19.0 m, 19.5 m, 20.0 m, 20.5 m, 21.0 m, 21.5 m, 22.0 m, 22.5 m,2 m, 23.5 m, 24.0 m, 24.5 m, and 25.0 m; (ii) from 5.0 m to 6.0 m, from 6.0m to 7.0 m, from 7.0 m to 8.0 m, from 8.0 m to 9.0 m, from 9.0 m to 10.0 m, from 10.0 m to 11.0 m, from 11.0 m to 12.0 m, from 12.0 m to 13.0 m, from 13.0 m to 14.0 m, from 14.0 m to 15.0 m, from 15.0 m to 16.0 m, from 16.0 m to m, from 17.0 m to 18.0 m, from 18.0 m to 19.0 m, from 19.0 m to 20.0 m, from 20.0 m to 21.0 m, from 21.0 m to 22.0 m, from 22.0 m to 23.0 m, from 23.0 m to 24.0 m, and from 24.0 m to 25.0 m; (iii) from 5.0 m to 7.0 m, from 7.0 m to m, from 9.0 m to 11.0 m, from 11.0 m to 13.0 m, from 13.0 m to 15.0 m, from 15.0 m to 17.0 m, from 17.0 m to 19.0 m, from 19.0 m to 21.0 m, from 21.0 m to 23.0 m, and from 23.0 m to 25.0 m; and (iv) from 5.0 m to 10.0 m, from m to 15.0 m, from 15.0 m to 20.0 m, and from 20.0 m to 25.0 m. In a further embodiment, the d90 values for the present microsphere diameters include the following: (i) 10.0 m, 10.5 m, 11.0 m, 11.5 m, 12.0 m, 12.5 m, 13.0 m, 13.5 m, 14.0 m, 14.5 m, 15.0 m, 15.5 m, 16.0 m, 16.5 m, 17.0 m, 17.5 m, 18.0 m, 18.5 m, 19.0 m, 19.5 m, 20.0 m, 20.5 m, 21.0 m, 21.5 m, 22.0 m, 22.5 m, 23.0 m, 23.5 m, 24.0 m, 24.5 m, 25.0 m, 25.5 m, 26.0 m, 26.5 m, 27.0 m, 27.5 m, 28.0 m, 28.5 m, 29.0 m, 29.5 m, 30.0 m, 30.5 m, 31.0 m, 31.5 m, 32.0 m, 32.5 m, 33.0 m, 33.5 m, 34.0 m, 34.5 m, 35.0 m, 35.5 m, 36.0 m, 36.5 m, 37.0 m, 37.5 m, 38.0 m, 38.5 m, 39.0 m, 39.5 m, and 40.0 m; (ii) from 10.0 m to 11.0 m, from 11.0 m to 12.0 m, from 12.0 m to 13.0 m, from 13.0 m to 14.0 m, from 14.0 m to 15.0 m, from 15.0 m to 16.0 m, from 16.0 m to m, from 17.0 m to 18.0 m, from 18.0 m to 19.0 m, from 19.0 m to 20.0 m, from 20.0 m to 21.0 m, from 21.0 m to 22.0 m, from 22.0 m to 23.0 m, from 23.0 m to 24.0 m, from 24.0 m to 25.0 m, from 25.0 m to 26.0 m, from 26.0 m to m, from 27.0 m to 28.0 m, from 28.0 m to 29.0 m, from 29.0 m to 30.0 m, from 30.0 m to 31.0 m, from 31.0 m to 32.0 m, from 32.0 m to 33.0 m, from 33.0 m to 34.0 m, from 34.0 m to 35.0 m, from 35.0 m to 36.0 m, from 36.0 m to3 m, from 37.0 m to 38.0 m, from 38.0 m to 39.0 m, and from 39.0 m to 40.0m; (iii) from 10.0 m to 12.0 m, from 12.0 m to 14.0 m, from 14.0 m to 16.0 m, from 16.0 m to 18.0 m, from 18.0 m to 20.0 m, from 20.0 m to 22.0 m, from 22.0 m to 24.0 m, from 24.0 m to 26.0 m, from 26.0 m to 28.0 m, from 28.0 m to m, from 30.0 m to 32.0 m, from 32.0 m to 34.0 m, from 34.0 m to 36.0 m, from 36.0 m to 38.0 m, and from 38.0 m to 40.0 m; and (iv) from 10.0 m to 15.0 m, from 15.0 m to 20.0 m, from 20.0 m to 25.0 m, from 25.0 m to 28.0 m, from28 m to 35.0 m, and from 35.0 m to 40.0 m.The subject biodegradable microspheres can further comprise polyethylene glycol (PEG). Biodegradable PLGA microspheres (including homogeneous and heterogeneous populations thereof having defined molar ratios of lactic acid to glycolic acid units) are commercially available from, among other sources, Millipore-Sigma in the form of Degradex®products (Burlington, MA) and Evonik Industries in the form of Resomer®products (Essen, Germany). As used herein, the term “carry”, with respect to pharmaceutical clascoterone and a biodegradable microsphere, means that the pharmaceutical clascoterone is non- covalently bound to, or otherwise contained in or on, the biodegradable microsphere in a manner permitting release from the microsphere during its biodegradation.As used herein, the term “clascoterone” is also known as, for example, cortexolone-17propionate, Breezula, 11-Deoxycortisol 17 -propionate, 17 -(Propionyloxy)-deoxycorticosterone, and 21-Hydroxy-3,20-dioxopregn-4-en-17-yl propionate. Clascoterone has CAS number 19608-29-8. Clascoterone is an androgen receptor inhibitor. It is commercially known and is sold by Sun Dermatology, a division of Sun Pharmaceutical Industries, Inc., under the trade name Winlevi®. As used herein, the term “diluent” includes, without limitation, sodium chloride, carboxymethylcellulose sodium, polysorbate 80, mannitol (which can optionally be incorporated on and / or into the microspheres to improve suspendability), water, and medium-chain fatty acids. As used herein, the term “d90value”, with respect to the present microspheres, means the 90thpercentile diameter in the microsphere population on a volume-weighted basis. The term “d50 value” means the 50thpercentile diameter in the microsphere population on a volume-weighted basis. The term “d10 value” means the 10thpercentile diameter in the microsphere population on a volume-weighted basis. As used herein, “intradermally”, includes, without limitation, (i) situated within one or more layers of the skin or (ii) situated between two or more layers of the skin. These layers of skin include, for example, the epidermis (e.g., the stratum corneum, the stratum lucidum, the stratum granulosum, the stratum spinosum, and / or the stratum basale), the dermis, and the hypodermis. In a preferred embodiment, intradermally means situated in the dermis. In another embodiment, intradermally means situated in the epidermis. In a further embodiment, intradermally means situated in the hypodermis. As used herein, “introducing”, with respect to biodegradable microspheres, means delivering to a specified part of the body, such as skin, scalp, or subcutaneous tissue. Methods of introducing biodegradable microspheres to the subcutaneous tissue are known and include, for example, Lupron Injection. See, e.g., the Lupron®label. Methods of introducing drugs to the scalp are known and include, for example, Botox injection for chronic migraine. See, e.g., the Botox®label. The present biodegradable microspheres can be delivered to the skin, scalp, or subcutaneous tissue through one or multiple injections at a time to cover a larger area under treatment. For example, Botox®Cosmetic is delivered to treat wrinkles through multiple injections. See, e.g., the Botox®Cosmetic label. As used herein, “hair loss” includes, without limitation, androgenic alopecia, male- pattern baldness, female-pattern baldness, drug-induced hair loss (e.g., chemotherapy- induced hair loss), radiotherapy-induced hair loss, alopecia areata, alopecia universalis, traction alopecia, frontal fibrosing alopecia, central centrifugal cicatricial alopecia, anagen effluvium, telogen effluvium, scarring alopecia, tinea capitis, and involutional alopecia. As used herein, the term “pharmaceutical clascoterone” includes, without limitation, clascoterone and pharmaceutical salts and esters thereof. “Pharmaceutically acceptable carriers” are well known and include, without limitation, the diluents described herein. As used herein, a biodegradable microsphere “releases” clascoterone when some or all of the clascoterone contained by the microsphere is freed into the microsphere’s surrounding milieu. Preferably, the release is continuous. For example, in a plurality of clascoterone-carrying biodegradable microspheres having an average release per day of X mg, the clascoterone released per day is, e.g., from 0.1X mg to 10X mg, from 0.2X mg to 10X mg, from 0.3X mg to 10X mg, from 0.4X mg to 10X mg, from 0.5X mg to 10X mg, from 0.1X mg to 9X mg, from 0.2X mg to 9X mg, from 0.3X mg to 9X mg, from 0.4X mg to 9X mg, from 0.5X mg to 9X mg, from 0.1X mg to 8X mg, from 0.2X mg to 8X mg, from 0.3X mg to 8X mg, from 0.4X mg to 8X mg, from 0.5X mg to 8X mg, from 0.1X mg to 7X mg, from 0.2X mg to 7X mg, from 0.3X mg to 7X mg, from 0.4X mg to 7X mg, from 0.5X mg to 7X mg, from 0.1X mg to 6X mg, from 0.2X mg to 6X mg, from 0.3X mg to 6X mg, from 0.4X mg to 6X mg, from 0.5X mg to 6X mg; from 0.1X mg to 5X mg, from 0.2X mg to 5X mg, from 0.3X mg to 5X mg, from 0.4X mg to 5X mg, from 0.5X mg to 5X mg, from 0.1X mg to 4X mg, from 0.2X mg to 4X mg, from 0.3X mg to 4X mg, from 0.4X mg to 4X mg, from 0.5X mg to 4X mg, from 0.1X mg to 3X mg, from 0.2X mg to 3X mg, from 0.3X mg to 3X mg, from 0.4X mg to 3X mg, from 0.5X mg to 3X mg, from 0.1X mg to 2X mg, from 0.2X mg to 2X mg, from 0.3X mg to 2X mg, from 0.4X mg to 2X mg, or from 0.5X mg to 2X mg. In another example, in a plurality of clascoterone- carrying biodegradable microspheres having an average release per week of X mg, the clascoterone released per week is, e.g., from 0.1X mg to 10X mg, from 0.2X mg to 10X mg, from 0.3X mg to 10X mg, from 0.4X mg to 10X mg, from 0.5X mg to 10X mg, from 0.1X mg to 9X mg, from 0.2X mg to 9X mg, from 0.3X mg to 9X mg, from 0.4X mg to 9X mg, from 0.5X mg to 9X mg, from 0.1X mg to 8X mg, from 0.2X mg to 8X mg, from 0.3X mg to 8X mg, from 0.4X mg to 8X mg, from 0.5X mg to 8X mg, from 0.1X mg to 7X mg, from 0.2X mg to 7X mg, from 0.3X mg to 7X mg, from 0.4X mg to 7X mg, from 0.5X mg to 7X mg, from 0.1X mg to 6X mg, from 0.2X mg to 6X mg, from 0.3X mg to 6X mg, from 0.4X mg to 6X mg, from 0.5X mg to 6X mg; from 0.1X mg to 5X mg, from 0.2X mg to 5X mg, from 0.3X mg to 5X mg, from 0.4X mg to 5X mg, from 0.5X mg to 5X mg, from 0.1X mg to 4X mg, from 0.2X mg to 4X mg, from 0.3X mg to 4X mg, from 0.4X mg to 4X mg, from 0.5X mg to 4X mg, from 0.1X mg to 3X mg, from 0.2X mg to 3X mg, from 0.3X mg to 3X mg, from 0.4X mg to 3X mg, from 0.5X mg to 3X mg, from 0.1X mg to 2X mg, from 0.2X mg to 2X mg, from 0.3X mg to 2X mg, from 0.4X mg to 2X mg, or from 0.5X mg to 2X mg. As used herein, the term “subject” includes, without limitation, a mammal such as a human. As used herein, the term “therapeutically effective amount”, with respect to pharmaceutical clascoterone carried in biodegradable microspheres, refers to the amount of pharmaceutical clascoterone collectively carried by the total dose of biodegradable microspheres introduced into an affected area of the subject’s skin (e.g., the scalp or subcutaneous tissue). In one embodiment, the effective amount is 1 g, 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 40 g, 50 g, 60 g, 70 g, 80 g, 90 g, 100 g, 150 g, 200 g, 250 g, 300 g, 350 g, 400 g, 450 g, 500 g, 550 g, 600 g, 650 g, 700 g, 750 g, 800 g, 850 g, 900 g, 950 g, 1mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg, 2,600 mg, 2,700 mg, 2,800 mg, 2,900 mg, 3,000 mg, 3,100 mg, 3,200 mg, 3,300 mg, 3,400 mg, 3,500 mg, 3,600 mg, 3,700 mg, 3,800 mg, 3,900 mg, 4,000 mg, 4,100 mg, 4,200 mg, 4,300 mg, 4,400 mg, 4,500 mg, 4,600 mg, 4,700 mg, 4,800 mg, 4,900 mg, 5,000 mg, 5,100 mg, 5,200 mg, 5,300 mg, 5,400 mg, 5,500 mg, 5,600 mg, 5,700 mg, 5,800 mg, 5,900 mg, 6,000 mg, 6,100 mg, 6,200 mg, 6,300 mg, 6,400 mg, 6,500 mg, 6,600 mg, 6,700 mg, 6,800 mg, 6,900 mg, 7,000 mg, 7,100 mg, 7,200 mg, 7,300 mg, 7,400 mg, 7,500 mg, 7,600 mg, 7,700 mg, 7,800 mg, 7,900 mg, 8,000 mg, 8,100 mg, 8,200 mg, 8,300 mg, 8,400 mg, 8,500 mg, 8,600 mg, 8,700 mg, 8,800 mg, 8,900 mg, 9,000 mg, 9,100 mg, 9,200 mg, 9,300 mg, 9,400 mg, 9,500 mg, 9,600 mg, 9,700 mg, 9,800 mg, 9,900 mg, or 10,000 mg. In another embodiment, the effective amount is from 1 g to 10 g, from 10 g to 50 g, from 50 g to 100 g, from 100 g to 150 g, from 150 g to 200 g, from 200 g to 250 g, from 250 g to 300 g, from 300 g to 350 g, from 350 g to 400 g, from 400 g to 450 g, from 450 g to 500 g, from 500 g to 550 g, from 550 g to 600 g, from 600 g to 650 g, from 650 g to 700 g, from 700 g to 750 g, from 750 g to 800 g, from 800 g to 850 g, from 850 g to 900 g, from 900 g to 950 g, from 950 g to 1 mg, 1 mg to 10 mg, from 10 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 150 mg, from 150 mg to 200 mg, from 200 mg to 250 mg, from 250 mg to 300 mg, from 300 mg to 350 mg, from 350 mg to 400 mg, from 400 mg to 450 mg, from 450 mg to 500 mg, from 500 mg to 550 mg, from 550 mg to 600 mg, from 600 mg to 650 mg, from 650 mg to 700 mg, from 700 mg to 750 mg, from 750 mg to 800 mg, from 800 mg to 850 mg, from 850 mg to 900 mg, from 900 mg to 950 mg, from 950 mg to 1,000 mg, from 1,000 mg to 1,100 mg, from 1,100 mg to 1,200 mg, from 1,200 mg to 1,300 mg, from 1,300 mg to 1,400 mg, from 1,400 mg to 1,500 mg, from 1,500 mg to 1,600 mg, from 1,600 mg to 1,700 mg, from 1,700 mg to 1,800 mg, from 1,800 mg to 1,900 mg, from 1,900 mg to 2,000 mg, from 2,000 mg to 2,100 mg, from 2,100 mg to 2,200 mg, from 2,200 mg to 2,300 mg, from 2,300 mg to 2,400 mg, from 2,400 mg to 2,500 mg, from 2,500 mg to 2,600 mg, from 2,600 mg to 2,700 mg, from 2,700 mg to 2,800 mg, from 2,800 mg to 2,900 mg, from 2,900 mg to 3,000 mg, from 3,000 mg to 3,100 mg, from 3,100 mg to 3,200 mg, from 3,200 mg to 3,300 mg, from 3,300 mg to 3,400 mg, from 3,400 mg to 3,500 mg, from 3,500 mg to 3,600 mg, from 3,600 mg to 3,700 mg, from 3,700 mg to 3,800 mg, from 3,800 mg to 3,900 mg, from 3,900 mg to 4,000 mg, from 4,000 mg to 4,100 mg, from 4,100 mg to 4,200 mg, from 4,200 mg to 4,300 mg, from 4,300 mg to 4,400 mg, from 4,400 mg to 4,500 mg, from 4,500 mg to 4,600 mg, from 4,600 mg to 4,700 mg, from 4,700 mg to 4,800 mg, from 4,800 mg to 4,900 mg, from 4,900 mg to 5,000 mg, from 5,000 mg to 5,100 mg, from 5,100 mg to 5,200 mg, from 5,200 mg to 5,300 mg, from 5,300 mg to 5,400 mg, from 5,400 mg to 5,500 mg, from 5,500 mg to 5,600 mg, from 5,600 mg to 5,700 mg, from 5,700 mg to 5,800 mg, from 5,800 mg to 5,900 mg, from 5,900 mg to 6,000 mg, from 6,000 mg to 6,100 mg, from 6,100 mg to 6,200 mg, from 6,200 mg to 6,300 mg, from 6,300 mg to 6,400 mg, from 6,400 mg to 6,500 mg, from 6,500 mg to 6,600 mg, from 6,600 mg to 6,700 mg, from 6,700 mg to 6,800 mg, from 6,800 mg to 6,900 mg, from 6,900 mg to 7,000 mg, from 7,000 mg to 7,100 mg, from 7,100 mg to 7,200 mg, from 7,200 mg to 7,300 mg, from 7,300 mg to 7,400 mg, from 7,400 mg to 7,500 mg, from 7,500 mg to 7,600 mg, from 7,600 mg to 7,700 mg, from 7,700 mg to 7,800 mg, from 7,800 mg to 7,900 mg, from 7,900 mg to 8,000 mg, from 8,000 mg to 8,100 mg, from 8,100 mg to 8,200 mg, from 8,200 mg to 8,300 mg, from 8,300 mg to 8,400 mg, from 8,400 mg to 8,500 mg, from 8,500 mg to 8,600 mg, from 8,600 mg to 8,700 mg, from 8,700 mg to 8,800 mg, from 8,800 mg to 8,900 mg, from 8,900 mg to 9,000 mg, from 9,000 mg to 9,100 mg, from 9,100 mg to 9,200 mg, from 9,200 mg to 9,300 mg, from 9,300 mg to 9,400 mg, from 9,400 mg to 9,500 mg, from 9,500 mg to 9,600 mg, from 9,600 mg to 9,700 mg, from 9,700 mg to 9,800 mg, from 9,800 mg to 9,900 mg, or from 9,900 mg to 10,000 mg. In a further embodiment, the effective amount is from 1 g to 250 g, from 250 g to 500 g, from 500 g to 750 g, from 750 g to 1 mg, 1 mg to 250 mg, from 250 mg to 500 mg, from 500 mg to 750 mg, from 750 mg to 1,000 mg, from 1,000 mg to 1,250 mg, from 1,250 mg to 1,500 mg, from 1,500 mg to 1,750 mg, from 1,750 mg to 2,000 mg, from 2,000 mg to 2,250 mg, from 2,250 mg to 2,500 mg, from 2,500 mg to 2,750 mg, from 2,750 mg to 3,000 mg, from 3,000 mg to 3,250 mg, from 3,250 mg to 3,500 mg, from 3,500 mg to 3,750 mg, from 3,750 mg to 4,000 mg, from 4,000 mg to 4,250 mg, from 4,250 mg to 4,500 mg, from 4,500 mg to 4,750 mg, from 4,750 mg to 5,000 mg, from 5,000 mg to 5,250 mg, from 5,250 mg to 5,500 mg, from 5,500 mg to 5,750 mg, from 5,750 mg to 6,000 mg, from 6,000 mg to 6,250 mg, from 6,250 mg to 6,500 mg, from 6,500 mg to 6,750 mg, from 6,750 mg to 7,000 mg, from 7,000 mg to 7,250 mg, from 7,250 mg to 7,500 mg, from 7,500 mg to 7,750 mg, from 7,750 mg to 8,000 mg, from 8,000 mg to 8,250 mg, from 8,250 mg to 8,500 mg, from 8,500 mg to 8,750 mg, from 8,750 mg to 9,000 mg, from 9,000 mg to 9,250 mg, from 9,250 mg to 9,500 mg, from 9,500 mg to 9,750 mg, or from 9,750 mg to 10,000 mg. In yet a further embodiment, the effective amount is from 1 g to 500 g, from 500 g to 1 mg, from 1 mg to 500 mg, from 10 mg to 500 mg, from 500 mg to 1,000 mg, from 1,000 mg to 1,500 mg, from 1,500 mg to 2,000 mg, from 2,000 mg to 2,500 mg, from 2,500 mg to 3,000 mg, from 3,000 mg to 3,500 mg, from 3,500 mg to 4,000 mg, from 4,000 mg to 4,500 mg, from 4,500 mg to 5,000 mg, from 5,000 mg to 5,500 mg, from 5,500 mg to 6,000 mg, from 6,000 mg to 6,500 mg, from 6,500 mg to 7,000 mg, from 7,000 mg to 7,500 mg, from 7,500 mg to 8,000 mg, from 8,000 mg to 8,500 mg, from 8,500 mg to 9,000 mg, from 9,000 mg to 9,500 mg, or from 9,500 mg to 10,000 mg. As used herein, “treating” a subject afflicted with hair loss shall include, without limitation, (i) slowing, stopping, or reversing the progression of hair loss, (ii) reducing the likelihood of the recurrence of hair loss, and / or (iii) preventing the occurrence of hair loss before its onset. In the preferred embodiment, treating a subject afflicted with hair loss means reversing the progression of hair loss, ideally to the point of eliminating the hair loss. Embodiments of the Invention This invention solves an unmet need in the art by providing an unexpectedly superior way to treat hair loss using clascoterone. The invention does this via clascoterone- carrying microspheres that can be injected into the affected area with an acceptably thin needle and release clascoterone over time. Specifically, this invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 m to 500 m (e.g., 40 m); (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical clascoterone; and (iv) when present intradermally, releases clascoterone for at least one month. In one embodiment of the instant biodegradable microsphere, the microsphere has a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50. In another embodiment, the microsphere (i) has a diameter of from 3 m to 28 m; (ii) has a lactic acid to glycolic acid molar ratio of 75:25, or 85:15, or between 75:25 and 85:15; and (iii) has a clascoterone loading ratio of 40% to 70%. In another embodiment, the microsphere further comprises polyethylene glycol (PEG). In a further embodiment, the microsphere, when present intradermally, releases clascoterone for longer than one month. Preferably, the microsphere, when present intradermally, releases clascoterone for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. This invention also provides a plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 m and a d90value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. In an embodiment of the instant plurality of biodegradable microspheres, the microspheres further comprise polyethylene glycol (PEG). The PEG can be any type suitable for use in forming biodegradable microspheres (e.g., PEG1450 (Polysciences, Inc., Warrington, PA)). Moreover, the ratio of PEG to PLGA can be any ratio suitable for use in forming biodegradable microspheres (e.g., 25:100, 50:100, 75:100 or 100:100). In another embodiment of the instant plurality of biodegradable microspheres, the microspheres, when present intradermally (e.g., in the skin, scalp, or subcutaneous tissue), release clascoterone for longer than one month. Preferably, the microspheres, when present intradermally, release clascoterone for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In a further embodiment of the instant plurality of biodegradable microspheres, the microspheres (i) have a d10value of at least 3 m and a d90value of 28 m or less; (ii) have a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50; and (iii) carry from 1 g to 10,000 mg of pharmaceutical clascoterone. This invention further provides an injectable formulation comprising (a) a pharmaceutically acceptable carrier and (b) a plurality of biodegradable microspheres wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. In an embodiment of the instant injectable formulation, the microspheres further comprise polyethylene glycol (PEG). In another embodiment of the instant injectable formulation, the microspheres, when present intradermally, release clascoterone for longer than one month. Preferably, the microspheres, when present intradermally, release clascoterone for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. This invention still further provides a method for treating hair loss in a subject comprising introducing biodegradable microspheres into an affected area of the subject’s skin, wherein the introducing is into skin at or around one or more hair follicles, and wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month. In the preferred embodiment, the affected area of the subject’s skin is the subject’s scalp. In another embodiment, the affected area of the subject’s skin is the subject’s face. Skin at or around a hair follicle includes, without limitation, skin within 1 cm of the hair follicle, within 9 mm of the hair follicle, within 8 mm of the hair follicle, within 7 mm of the hair follicle, within 6 mm of the hair follicle, within 5 mm of the hair follicle, within 4 mm of the hair follicle, within 3 mm of the hair follicle, within 2 mm of the hair follicle, within 1 mm of the hair follicle, within 0.9 mm of the hair follicle, within 0.8 mm of the hair follicle, within 0.7 mm of the hair follicle, within 0.6 mm of the hair follicle, within 0.5 mm of the hair follicle, within 0.4 mm of the hair follicle, within 0.3 mm of the hair follicle, within 0.2 mm of the hair follicle, or within 0.1 mm of the hair follicle. In an embodiment of the instant therapeutic method, the microspheres further comprise polyethylene glycol (PEG). In the preferred embodiment of the instant therapeutic method, the subject is human. In another preferred embodiment of the instant therapeutic method, the hair loss is androgenic alopecia (e.g., in men or in women). In another embodiment of the instant therapeutic method, the microspheres (i) have a d10 value of at least 3 m and a d90 value of 28 m or less; (ii) have a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50; and (iii) carry from 1 g to 10,000 mg of pharmaceutical clascoterone. Preferably, the microspheres have an average lactic acid to glycolic acid molar ratio of 75:25, or 85:15, or between 75:25 and 85:15. Preferably, the clascoterone loading ratio in the microspheres is from 40% to 70%. In another embodiment of the instant therapeutic method, the microspheres, when present intradermally, release clascoterone for longer than one month. Preferably, the microspheres, when present intradermally, release clascoterone for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months. In this invention, the biodegradable microspheres can be introduced into the affected area of the subject’s skin (e.g., the subject’s scalp, face, or subcutaneous tissue) using any known method appropriate for the tissue in question. For example, in a preferred embodiment of the instant method where the tissue is the scalp, the method comprises injecting the biodegradable microspheres into the scalp. The microspheres can be introduced via a single injection or, preferably, via multiple injections (e.g., at least 5, at least 10, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 300, at least 400, or at least 500 injections) to cover a larger area under treatment. In another embodiment, the instant method is performed a plurality of times (e.g., two times, three times, four times, five times, or more). In that embodiment, each subsequent time the method is performed, it is performed after a suitable period has lapsed since the preceding time the method was performed. This suitable time can be, for example, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or longer. Microsphere-based drug products and methods of delivering them are known, at least generally (e.g., Lupron®(leuprolide acetate microspheres for depot suspension (Abbvie)); and Sandostatin LAR®Depot (octreotide acetate for injectable suspension) (Novartis)). This invention also provides an article of manufacture (kit) comprising, in separate compartments, (a) one of, and ideally both of, (i) a diluent and (ii) a label instructing the user to introduce the present biodegradable microspheres into the affected area of a subject’s skin (e.g., the subject’s scalp, face, or subcutaneous tissue), and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 m and a d90 value of 500 m or less (e.g., 40 m or less) (e.g., a d10 value of least 3 m and a d90value of 28 m or less); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix (preferably having a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50 (e.g., 75:25, or 85:15, or between 75:25 and 85:15)); (iii) carry a therapeutically effective amount of pharmaceutical clascoterone (e.g., from 1 g to 10,000 mg of pharmaceutical clascoterone); and (iv) when present intradermally, release clascoterone for at least one month (and optionally release clascoterone for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months). In one embodiment of the instant kit, the microspheres further comprise polyethylene glycol (PEG). Where applicable, the embodiments described above for the instant method are also envisioned for this article of manufacture. In a preferred embodiment, the instant kit is supplied as a single-dose kit and contains (i) a single dose vial of clascoterone-carrying biodegradable microspheres, and (ii) a single dose vial of diluent (e.g., sterile, clear liquid solution of 0.9% w / w sodium chloride, 0.5% - 1% w / w sodium carboxymethylcellulose, and 0.1% w / w polysorbate-80, or sterile liquid of medium-chain fatty acids). This invention further provides an article of manufacture comprising a syringe having therein the instant injectable formulation. Ideally, this article of manufacture is ready for use without further manipulation. Preferably, this syringe has a needle at least as thin as a 29 Gauge or 30 Gauge needle. This invention still further provides an article of manufacture comprising a dual chamber syringe having therein, in separate compartments, (a) a diluent, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 m and a d90value of 500 m or less (e.g., 40 m or less); (ii) comprise a polylactic-co- glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month, wherein the diluent and microspheres can be admixed within the syringe to form an injectable formulation immediately prior to use (e.g., within 30 minutes, 20 minutes, 10 minutes, five minutes, or one minute of use). Preferably, this dual chamber syringe has a needle at least as thin as a 29 Gauge or 30 Gauge needle. Where applicable, the embodiments described above for the instant method and instant kit are also envisioned for the above two syringe-based articles of manufacture. This invention will be better understood by reference to the examples which follow, but those skilled in the art will readily appreciate that the specific examples detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Examples Example 1. Preparing apalutamide and enzalutamide microspheres with a stir bar PLGA refers to poly-lactic-co-glycolic acid; PDLA refers to poly-D-lactic acid, which is one kind of poly-lactic acid (PLA); DMSO refers to dimethyl sulfoxide; PVA refers to polyvinyl alcohol; PBS refers to phosphate buffered saline, pH 7.4; and MW refers to molecular weight. (i)_PLGA50:50, 0.2 dl / g, acid-terminated: Intrinsic viscosity = 0.16-0.24 dl / g. MW:7,000- 17,000; (ii) PLGA50:50, 0.2 dl / g, ester-terminated: Intrinsic viscosity = 0.16-0.24 dl / g. MW:7,000-17,000; (iii) PLGA50:50, 0.4 dl / g, acid-terminated: Intrinsic viscosity = 0.32- 0.44 dl / g. MW:24,000-38,000; (iv) PLGA50:50, 0.4 dl / g, ester-terminated: Intrinsic viscosity = 0.32-0.44 dl / g. MW:24,000-38,000; (v) PLGA50:50, 0.5 dl / g, acid-terminated: Intrinsic viscosity = 0.45-0.6 dl / g. MW:38,000-54,000; (vi) PLGA50:50, 0.5 dl / g, ester- terminated: Intrinsic viscosity = 0.45-0.6 dl / g. MW:38,000-54,000; (vii) PLGA50:50, 0.6 dl / g, ester-terminated: Intrinsic viscosity = 0.50-0.65 dl / g; (viii) PLGA50:50, 0.7 dl / g, ester-terminated: Intrinsic viscosity = 0.61-0.74 dl / g. MW:54,000-69,000; (ix) PLGA65:35, 0.4 dl / g, acid-terminated: Intrinsic viscosity = 0.32-0.44 dl / g. MW:24,000- 38,000; (x) PLGA75:25, 0.2 dl / g, acid-terminated: Intrinsic viscosity = 0.14-0.22 dl / g. MW: 4,000-15,000; (xi) PLGA75:25, 0.2 dl / g, ester-terminated: Intrinsic viscosity = 0.16- 0.24 dl / g. MW: 4,000-15,000; (xii) PLGA75:25, 0.4 dl / g, acid-terminated: Intrinsic viscosity = 0.32-0.44 dl / g. MW: 15,000-35,000; (xiii) PLGA75:25, 0.4 dl / g, ester- terminated: Intrinsic viscosity = 0.32-0.44 dl / g. MW: 15,000-35,000; (xiv) PLGA75:25, 0.6 dl / g, ester-terminated: Intrinsic viscosity = 0.5-0.7 dl / g. MW: 35,000-76,000 with average about 61,100; (xv) PLGA75:25, 0.65 dl / g, ester-terminated: Intrinsic viscosity = 0.55-0.75 dl / g. MW: about 97,000; (xvi) PLGA75:25, 0.9 dl / g, ester-terminated: Intrinsic viscosity = 0.71-1.0 dl / g. MW:76,000-115,000; (xvii) PLGA75:25, 1.1 dl / g, ester- terminated: Intrinsic viscosity = 0.9-1.3 dl / g. MW: 115,000-190,000; (xviii) PLGA85:15, 1.5 dl / g, ester-terminated: Intrinsic viscosity = 1.3-1.7 dl / g. MW: 190,000-240,000. In experiments described herein, one type of PVA (i.e., of one molecular weight and degree of hydrolysis) at one concentration (i.e., 1%) is used to produce microspheres. However, in this invention, other types of PVA and other PVA concentrations are also envisioned to yield the same microspheres. For example, where 0.11% PVA4-88, 200 l dichloromethane, and 1,400 rpm stirring, is used to produce a certain population of microspheres, 0.05% PVA4-88, 300 l dichloromethane, and 1,000 rpm stirring, may also be used to produce essentially the same population of microspheres. Surfactants other than PVA can also be used in this invention to produce microspheres. These other surfactants include, for example, the commonly known surfactants vitamin E, Tween-20, Tween-80, poloxamers, poloxamines, pluronic polymers (such as F68 and F127), and sodium cholate. Similarly, in some experiments described herein, dichloromethane is used to produce microspheres. However, in this invention, other types of organic solvents (e.g., ethyl acetate, chloroform, acetone, propylene carbonate, and tetrahydrofuran) may be used instead of dichloromethane to yield essentially the same microspheres, assuming other experimental parameters are adjusted accordingly. Moreover, in this invention, any of a plurality of physical methods for preparing PLGA microspheres (e.g., spinning disk, spray drying, and microfluidics) may be used to yield the subject microspheres. 1 mg PLGA75:25, 0.4 dl / g, acid-terminated and 1-2 mg apalutamide or enzalutamide were dissolved in 200 µl dichloromethane (DCM) to form the oil phase and injected into 50 ml 0.11% polyvinyl alcohol 4-88 (PVA 4-88, Millipore Sigma, Darmstadt, Germany) to form an emulsion with a stir bar at 1,400 rpm for 2 minutes. Microspheres solidified after stirring at 500 rpm for another 30 minutes. Microspheres were collected and the supernatants were analyzed for amount of drug leaked from the microspheres by measuring UV absorption at 230 nm. The encapsulation efficiency was calculated as 1 minus the percentage leaked. The drug loading ratio was calculated as the theoretical drug loading based on input raw materials multiplied by encapsulation efficiency. All prepared microspheres showed high encapsulation efficiency and drug loading (Table 1). Table 1. Encapsulation efficiency and drug loading of apalutamide and enzalutamide microspheres. release from apalutamide and enzalutamide 1 mg PLGA and 1-2 mg apalutamide or enzalutamide were dissolved in 200 µl DCM to form the oil phase and injected into 50 ml 0.11% PVA4-88 to form an emulsion with a stir bar at 1,400 rpm for 2 minutes. Microspheres solidified after stirring at 500 rpm for another 60 minutes. Microspheres were collected by centrifugation at 3,000 g for 2 minutes and washed with water twice. To monitor drug release, microspheres were added to 250 ml phosphate buffered saline (PBS, pH=7.4) and shaken at 60 rpm at 37 C. The concentration of released drug into PBS was determined with UV absorption at 230 nm. Every 2-3 weeks, 200 ml of release solution was replaced with 200 ml of fresh PBS to maintain sink condition. PLGA used in this study included: PLGA50:50, 0.4 dl / g, acid-terminated; PLGA65:35, 0.4 dl / g, acid-terminated; PLGA75:25, 0.4 dl / g, acid- terminated; PLGA75:25, 0.6 dl / g, ester-terminated. In figures 1A-D, microspheres from 2 mg apalutamide or enzalutamide and 1 mg PLGA showed strong burst release of over 10% over 3 days, which increases the risk of toxicity for patients. For microspheres from 1 mg apalutamide or enzalutamide and 1 mg PLGA, some formulations showed over two months of continuous drug release (PLGA65:35, 0.4 dl / g, acid-terminated and PLGA75:25, 0.4 dl / g, acid-terminated). Example 3. Preparing apalutamide and enzalutamide microspheres in a mixing chamber 200 mg PLGA and 200 mg apalutamide or enzalutamide were dissolved in 4 ml DCM to form the oil phase and pumped into a Silverson L5MA in-line mixing chamber at a rate of 4 ml / min (Silverson, Massachusetts, US) (Figure 2). The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 2,800 rpm or 3,600 rpm and collected on top of 800 ml water under stirring at 500 rpm for 1.5 hours. The solidified microspheres were filtered through a 63 µm sieve to remove large particulates and collected on a 5 µm PTFE membrane in a vacuum filter flask. The microspheres were washed with water twice, lyophilized and irradiated with 15 kGy E-beam. PLGA used in this study is shown in table 2. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US) (Table 2). Apalutamide and enzalutamide content in microspheres was analyzed with HPLC with a Zorbax SB- Phenyl 5-micron, 4.6 x 250 mm column (Agilent Technologies, California, US). About 20 mg of microspheres were dissolved in 25 ml acetonitrile for injection into HPLC (mobile phase: 50% acetonitrile in water; column temperature: 30 C; detection wavelength: 230 nm; flow rate: 3.5 ml / min; injection volume: 15 µl) (Table 2). To monitor drug release, 5 mg microspheres were added to 250 ml PBS and shaken at 60 rpm at 37 C continuously. The concentration of released apalutamide or enzalutamide in the solution was determined with UV absorption at 230 nm. Every 2-3 weeks, 200 ml of release solution was replaced with 200 ml of fresh PBS to maintain sink condition. In figures 3A-D, some apalutamide formulations showed continuous drug release over two months (PLGA65:35, 0.4 dl / g, acid-terminated and PLGA75:25, 0.4 dl / g, acid- terminated). Surprisingly, some enzalutamide formulations showed continuous drug release over three months (PLGA75:25, 0.4 dl / g, acid-terminated), over five months (PLGA75:25, 0.4 dl / g, ester-terminated), over six months (PLGA75:25, 0.6 dl / g, ester- terminated; PLGA75:25, 0.9 dl / g, ester-terminated; PLGA75:25, 1.1 dl / g, ester- terminated) and over one year (PLGA85:15, 1.5 dl / g, ester-terminated). Table 2. Particle size and drug loading of apalutamide and enzalutamide microspheres Example 4. Effect of reducing particle size of enzalutamide microspheres 200 mg enzalutamide and 200 mg PLGA were dissolved in 4 ml DCM to form the oil phase and pumped into a Silverson L5MA in-line mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 3,600 rpm or 4,400 rpm and collected on top of 800 ml water under stirring at 500 rpm for 1 hour. The solidified microspheres were filtered through a 63 µm sieve and collected on a 5 µm PTFE membrane in a vacuum filter flask. The microspheres were washed with water twice, lyophilized and irradiated with 15 kGy E-beam. PLGA used in this study is shown in table 3. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US) (Table 3). To monitor drug release, 5 mg microspheres were added to 250 ml PBS and shaken at 60 rpm at 37 C continuously. The concentration of released enzalutamide in the solution was determined with UV absorption at 230 nm. Every 2-3 weeks, 200 ml of release solution was replaced with 200 ml of fresh PBS to maintain sink condition. In figure 4, all formulations showed continuous enzalutamide release over at least two months. Unexpectedly, reducing the particle size by increasing the speed of the mixing blade did not affect the total release duration. Table 3. Particle size of enzalutamide microspheres Example 5. In vivo release of enzalutamide in Sprague Dawley rats 1 g PLGA75:25, 0.4 dl / g, acid-terminated or PLGA75:25, 0.4 dl / g, ester-terminated and 1 g enzalutamide were dissolved in 20 ml DCM to form the oil phase and pumped into a Silverson L5MA mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4- 88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 3,600 rpm and collected on top of 2 L water under stirring at 500 rpm for one hour. The solidified microspheres were filtered through a 63 µm sieve and collected on a 5 µm PTFE membrane in a vacuum filter flask. The microspheres were washed with water twice, lyophilized and irradiated with 15 kGy E-beam. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US). The d10, d50, and d90values for the acid-terminated formulation were 8.9 µm, 14.8 µm, and 22.1 µm. The d10, d50, and d90values for the ester-terminated formulation were 8.8 µm, 15.0 µm, and 23.0 µm. To monitor enzalutamide release, 5 mg microspheres were added to 250 ml PBS and shaken at 60 rpm at 37 C continuously. The concentration of released enzalutamide in the solution was determined with UV absorption at 230 nm. Every 2-3 weeks, 200 ml of release solution was replaced with 200 ml of fresh PBS to maintain sink condition. Figure 5 shows continuous release over three months for the acid-terminated formulation and over five months for the ester-terminated formulation in vitro. 200 mg of each microsphere was injected subcutaneously into the scalp of a male Sprague Dawley rat. Plasma samples were collected to determine enzalutamide concentrations in the plasma with an LC-MS / MS system (SHIMADZU LC40, Triple Quad 6500+ with Analyst 1.7.2 AB Sciex). Table 4 shows continuous enzalutamide release over 4 to 6 months in vivo. Table 4. In vivo release of enzalutamide microspheres in rats Example 6. Preparing clascoterone microsphere with a stir bar 1 mg clascoterone and 1 mg PLGA were dissolved in 200 µl DCM to form the oil phase and injected into 50 ml 0.11% PVA4-88 to form an emulsion with stir bar at 1,400 rpm for 2 minutes. The emulsion was then stirred at 500 rpm for one hour to solidify. Microspheres were collected, washed with water twice and added to 250 ml water with shaking at 60 rpm at 37 C. Clascoterone release into water was monitored with measuring UV absorption of the release solution at 230 nm. The residual PVA from the emulsion was also collected to measure UV absorption at 230 nm to determine the quantity of leaked clascoterone during microsphere formation. Encapsulation efficiency was calculated as 1 minus percentage of leaked clascoterone. Drug loading ratios were calculated as encapsulation efficiency multiplied by the theoretical loading of 50%. PLGA used in this study, encapsulation efficiency and actual drug loading are shown in table 5. Figure 6 shows continuous clascoterone release over three weeks for all microspheres and as long as three months for PLGA75:25, 0.6 dl / g, ester-terminated. Table 5. Drug loading and encapsulation efficiency of clascoterone microspheres Example 7. Effect of increasing clascoterone:PLGA ratio on drug release 1 mg clascoterone and 0.6-1 mg PLGA (mixture of PLGA75:25, 0.4 dl / g, acid-terminated and PLGA75:25, 0.6 dl / g, ester-terminated) were dissolved in 200 µl DCM to form an emulsion and injected into 50 ml 0.11% PVA4-88 with a stir bar at 1,400 rpm for 2 minutes. The emulsions were then stirred at 500 rpm for one hour to solidify into microspheres, which were washed in water twice and added to 250 ml water with shaking at 60 rpm at 37 C. Clascoterone release into water was monitored with measuring UV absorption of the release solution at 230 nm. Figure 7 shows that increasing clascoterone:PLGA ratio did not affect total duration of release significantly. Example 8. Effect of increasing clascoterone loading in microspheres prepared in a mixing chamber 100 mg clascoterone and 80 mg or 60 mg or 40 mg PLGA75:25, 0.6 dl / g, ester- terminated were dissolved in 2 ml DCM to form the oil phase, and pumped into the Silverson L5MA in-line mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 3,200 rpm, 3,600 rpm, or 4,000 rpm and collected on top of 300 ml water under stirring at 500 rpm for one hour. The solidified microspheres were lyophilized. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US) (Table 6). Clascoterone content in microspheres was analyzed with HPLC with a Zorbax SB-Phenyl 5-micron, 4.6 x 250 mm column (Agilent Technologies, California, US). About 10 mg of microspheres were dissolved in 1ml DMSO and precipitated in 9 ml methanol for injection into HPLC (mobile phase: 50% acetonitrile in water; column temperature: 30 C; detection wavelength: 230 nm; flow rate: 3.5 ml / min; injection volume: 15 µl) (Table 6). To monitor drug release, 10 mg microspheres were added to 250 ml water and shaken at 60 rpm at 37 C continuously. The concentration of released enzalutamide in the solution was determined with UV absorption at 230 nm. Figure 8 shows continuous clascoterone release over at least two months for all microspheres. Table 6. Particle size and drug loading of clascoterone microspheres on clasctorone release from 100 mg clascoterone and 80 mg PLGA were dissolved in 2 ml DCM to form the oil phase and pumped into the Silverson L5MA in-line mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. The emulsions were created by the mixing blade at 3,200 rpm or 3,600 rpm and collected on top of 250 ml water under stirring at 500 rpm for one hour. Microspheres were collected by centrifugation at 4,000 g for 5 minutes and lyophilized. PLGA studied in this experiment included: PLGA50:50, 0.4 dl / g, ester-terminated; PLGA50:50, 0.5 dl / g, ester-terminated; PLGA50:50, 0.7 dl / g, ester-terminated; PLGA75:25, 0.2 dl / g, ester-terminated; PLGA75:25, 0.4 dl / g, ester-terminated. To monitor drug release, 10 mg microspheres were added to 250 ml water and shaken at 60 rpm at 37 C continuously. The concentration of released clascoterone in the solution was determined with UV absorption at 230 nm. In figure 9, the total duration of release was less than one month for PLGA50:50, 0.4 dl / g, ester-terminated and PLGA75:25, 0.2 dl / g, ester-terminated. PLGA75:25, 0.4 dl / g, ester-terminated showed a prolonged gap in clascoterone release from day 30 to day 55, which is unsuitable for continuous treatment of hair loss. Example 10. Effect of mixing different PLGA polymers on clascoterone release from microspheres 200 mg clascoterone and 160 mg or 120 mg mixed PLGA (between PLGA75:25, 0.4 dl / g, acid-terminated and PLGA75:25, 0.6 dl / g, ester-terminated) were dissolved in 4 ml DCM and pumped into the Silverson L5MA in-line mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. The emulsions were created by the mixing blade at 3,600 rpm and collected on top of 800 ml water under stirring at 500 rpm for one hour. Microspheres were filtered with a 63 µm sieve to remove large particulates, washed with water twice, and lyophilized. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US) (Table 7). Clascoterone content in microspheres was analyzed with HPLC with a Zorbax SB-Phenyl 5-micron, 4.6 x 250 mm column (Agilent Technologies, California, US). About 10 mg of microspheres were dissolved in 1ml DMSO and precipitated in 9 ml methanol for injection into HPLC (mobile phase: 50% acetonitrile in water; column temperature: 30 C; detection wavelength: 230 nm; flow rate: 3.5 ml / min; injection volume: 15 µl) (Table 7). To monitor drug release, 10 mg microspheres were added to 250 ml water and shaken at 60 rpm at 37 C continuously. The concentration of released clascoterone in the solution was determined with UV absorption at 230 nm. Figures 10A and 10B show continuous clascoterone release over two months for all tested microspheres. Table 7. Drug loading and particle sizes of clascoterone microspheres Example 11. Identifying the optimal ratio of clascoterone:PLGA for continuous drug release 200 mg clascoterone and 160 mg or 120 mg or 100 mg mixed PLGA (between PLGA75:25, 0.4 dl / g, acid-terminated and PLGA75:25, 0.6 dl / g, ester-terminated or PLGA75:25, 1.1 dl / g, ester-terminated or PLGA85:15, 1.5 dl / g, ester-terminated) were dissolved in 4 ml DCM to form the oil phase and pumped into the Silverson L5MA mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. The emulsions were created by the mixing blade at 3,600 rpm and collected on top of 800 ml water under stirring at 500 rpm for one hour. Microspheres were filtered with a 63 µm sieve to remove large particulates and collected on a 5 µm PTFE membrane in a vacuum filter flask. The microspheres were washed with water twice, lyophilized and irradiated with 15 kGy E-beam. To monitor drug release, 10 mg microspheres were added to 250 ml water and shaken at 60 rpm at 37 C continuously. The concentration of released clascoterone in the solution was determined with UV absorption at 230 nm. In figures 11A1-3, 200 mg clascoterone+160 mg PLGA showed the most uniform release profile of clascoterone day-to-day. As the ratio of clascoterone:PLGA increased, initial release in the first 10 days greatly increased and the release rate between day 10 and 20 greatly decreased. This non-uniform release profile is prone to cause side effects in patients and thus undesirable as a treatment for hair loss. Similarly, in figures 11B1-3, 200 mg clascoterone+160 mg PLGA showed the most uniform release profile of clascoterone day-to-day. As the ratio of clascoterone:PLGA increased, initial release in the first 10 days increased and the release rate between day 20 and 30 decreased. This non- uniform release profile is undesirable as a treatment for hair loss. Similarly, in figures 11C1 and 11C2, 200 mg clascoterone+160 mg PLGA showed a more uniform release profile than 200 mg clascoterone+120 mg PLGA. For microspheres from mixing PLGA75:25, 0.4 dl / g, acid-terminated and PLGA85:15, 1.5 dl / g, ester-terminated, 200 mg clascoterone+100 mg PLGA caused severe burst release above 30% in the first day of release, which is unsuitable for treatment of hair loss. Example 12. In vivo release of clascoterone microspheres in Sprague Dawley rats 400 mg clascoterone and 400 mg or 320 mg PLGA were dissolved in 8 ml DCM to form the oil phase and pumped into a Silverson L5MA in-line mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 3,600 rpm or 4,400 rpm and collected on top of 800 ml water under stirring at 500 rpm for one hour. Solidified microspheres were filtered with a 63 µm sieve to remove large particulates and collected on a 5 µm PTFE membrane in a vacuum filter flask, washed with water twice, lyophilized, and irradiated with 15 kGy E-beam. PLGA used in this study are shown in table 8. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US) (Table 8). To monitor drug release, 10 mg microspheres were added to 250 ml water and shaken at 60 rpm at 37 C continuously. The concentration of released clascoterone in the solution was determined with UV absorption at 230 nm. In figures 12A-C, all microspheres showed 2-4 months of continuous clascoterone release in vitro. 200 mg microspheres of #12-13, #12-17, #12-19, and #12-23 were injected subcutaneously into the scalp of a male Sprague Dawley rat and plasma samples were collected to measure clascoterone concentration over 182 days with an LC-MS / MS system (SHIMADZU LC40, Triple Quad 6500+ with Analyst 1.7.2 AB Sciex). Table 9 shows continuous clascoterone release from microspheres over at least four months for these microspheres.

[0002] Table 8. Particle sizes of clascoterone microspheres. rom microspheres g, ester-terminated the Silverson L5MA .11% PVA4-88 was . created by a mixing blade at 4,400 rpm and collected on top of 800 ml water under stirring at 500 rpm for one hour. The solidified microspheres were filtered with a 100 µm sieve to remove large particulates and collected on a 5 µm PTFE membrane in a vacuum filter flask. The microspheres were washed with water twice, lyophilized and irradiated with 15 kGy E- Example 10. The % for the 1,200 mg ded to 250 ml water leased 30 nm. In figure 13, n day 25 and day 5 dl / g, ester- t r e Dawley rats en smaller ne and 480 mg and pumped into t e S verson n- ne mxng c amber a a rae o m / mn. e waer phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 4,400 rpm and collected on top of 2 L water under stirring at 500 rpm for 30 minutes. The solidified microspheres were filtered with a 45 µm sieve and collected on a 5 µm PTFE membrane in a vacuum filter flask, washed with water twice, lyophilized, and irradiated with 15 kGy E-beam. Particle sizes of microspheres were determined with a laser-diffraction particle size analyzer (Beckman Coulter LS13320, New Jersey, US) (Table 10). Clascoterone content in microspheres was analyzed with HPLC with a Zorbax SB-Phenyl 5-micron, 4.6 x 250 mm column (Agilent Technologies, California, US). About 10 mg of microspheres were dissolved in 1 ml DMSO and precipitated in 9 ml methanol for injection into HPLC (mobile phase: 50% acetonitrile in water; column temperature: 30 C; detection wavelength: 230 nm; flow rate: 3.5 ml / min; injection volume: 10 µl). To monitor drug release, 10 mg microspheres were added to 250 ml water and shaken at 60 rpm at 37 C continuously. The concentration of released clascoterone in the solution was determined with UV absorption at 230 nm. Figure 14 shows continuous clascoterone release in vitro for three to four months. 200 mg microspheres were injected subcutaneously into a male Sprague Dawley rat and plasma samples were collected to measure clascoterone concentration over 168 days with an LC-MS / MS system (SHIMADZU LC40, Triple Quad 6500+ with Analyst 1.7.2 AB Sciex). Figure 14 shows that all microsphere formulations exhibited continuous clascoterone release over three, four, or five months. Table 10. Particle size and drug loading of clascoterone microspheres for rat injection. Table 11. Plasma concentration of clascoterone from release of microspheres after injection to rats Example 15. Syringeability and injectability test of clascoterone microspheres Smaller needle sizes cause less injection site pain. The scalp is rich in sensory nerves, which makes a small needle size crucial for improving patient experience and compliance to long-term treatment of hair loss. A diluent for the microsphere was prepared as 0.9% sodium chloride, 0.5% sodium carboxymethyl cellulose, and 0.1% polysorbate 80 in water. When 200 mg of microspheres from Example 14 was resuspended in 0.5 ml to 1 ml of diluent, the suspension was easily able to be withdrawn and injected with a 29 Gauge or 30 Gauge needle (external diameter of 0.34- 0.31 mm) without clogging. These needle sizes are FDA-approved for Botox injections to the scalp to treat chronic migraine and for Botox injections to the face to treat wrinkles and are thus widely accepted by healthcare professionals and patients. In this Example the clascoterone microspheres passed through 29-gauge and 30- may also be used clinically. microspheres in Sprague erminated were dissolved in 48 ml DCM to form the oil phase and pumped into the Silverson in-line mixing chamber at a rate of 4 ml / min. The water phase of 0.11% PVA4-88 was pumped into the mixing chamber at 800 ml / min. Emulsions were created with the mixing blade at 4,400 rpm The 5 µm PTFE . A portion of icle size , d50: 14.6 µm, and d90: 22.0 µm. Clascoterone loading in microspheres was analyzed with the HPLC method in Example 14 to be 51.9%. Drug release was monitored with the same method in Example 14. Figures 15A and 15B show continuous clascoterone release of over six months in un-irradiated microspheres and of four months in microspheres irradiated with 15 kGy or 25 kGy E-beam. The un-irradiated microspheres were injected subcutaneously into two male Sprague Dawley rats (at 200 mg microspheres per rat) and two male Beagle dogs (at 1,000 mg microspheres per dog). Plasma samples were collected to measure clascoterone concentration over 280 days with an LC-MS / MS system (SHIMADZU LC40, Triple Quad 6500+ with Analyst 1.7.2 AB Sciex). The un-irradiated microspheres showed continuous clascoterone release over 8 months in the rat and the dog. months.

[0003] References Bauer, et al., Current State and Opportunities with Long-acting Injectables: Industry Perspectives from the Innovation and Quality Consortium “Long-Acting Injectables” Working Group, Pharmaceutical Research (2023) 40:1601-1631. Berchane, et al., Effect of mean diameter and polydispersity of PLG microspheres on drug release: Experiment and theory, International Journal of Pharmaceutics 337 (2007) 118-126. FDA label for XTANDI®. FDA label for ERLEADA®. FDA label for WINLEVI®(clascoterone). FDA labels for Botox®and Botox®Cosmetic. FDA label for Lupron®. Han, et al., Bioerodable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading, Frontiers in Pharmacology, June 2016, Vol.7, Article 185, 1-11. Makadia and Siegal, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier, Polymers (Basel) 2011 September 1; 3(3): 1377-97. Park, et al., Injectable, long-acting PLGA formulations: Analyzing PLGA and understanding microparticle formation, Journal of Controlled Release 304 (2019) 125- 134. Table 12. In vivo clascoterone release from un-irradiated microspheres over 8 months.

[0004] References

[0005] Bauer, et al., Current State and Opportunities with Leng-acting Injectables: Industry Perspectives from the Innovation and Quality Consortium “Long-Acting Injectables" Working Group, Pharmaceutical Research (2023) 40:1601-1631.

[0006] Berchane, et al., Effect of mean diameter and polydispersity of PLG microspheres on drug release: Experiment and theory, International Journal of Pharmaceutics 337 (2007) 118-126.

[0007] FDA label for XTANDI®.

[0008] FDA label for ERLEADA®.

[0009] FDA label for WINLEVI® (clascoterone).

[0010] FDA labels for Botox® and Botox® Cosmetic.

[0011] FDA label for Lupron®.

[0012] Han, et al. , Bioerodable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading, Frontiers in Pharmacology, June 2016, Vol. 7, Article 185, 1-11.

[0013] Makadia and Siegal, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier, Polymers (Basel) 2011 September 1 ; 3(3): 1377-97.

[0014] Park, et al., Injectable, long-acting PLGA formulations: Analyzing PLGA and understanding microparticle formation, Jour al of Controlled Release 304 (2019) 125- 134.

Claims

Claims What is claimed is:

1. A biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 m to 500 m; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries pharmaceutical clascoterone; and (iv) when present intradermally, releases clascoterone for at least one month.

2. The biodegradable microsphere of claim 1, wherein the microsphere has a lactic acid to glycolic acid molar ratio of from 100:0 to 50:

50.

3. The biodegradable microsphere of claim 1 or 2, wherein the microsphere (i) has a diameter of from 3 m to 28 m; and (ii) has a lactic acid to glycolic acid molar ratio of 75:25, or 85:15, or between 75:25 and 85:

15.

4. The biodegradable microsphere of any of claims 1-3, wherein the microsphere further comprises polyethylene glycol (PEG).

5. The biodegradable microsphere of any of claims 1-4, wherein the microsphere, when present intradermally, releases clascoterone for longer than one month.

6. A plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 40 m or less; (ii) comprise a polylactic-co- glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month.

7. The plurality of biodegradable microspheres of claim 6, wherein the microspheres further comprise polyethylene glycol (PEG).

8. The plurality of biodegradable microspheres of claim 6 or 7, wherein the microspheres, when present intradermally, release clascoterone for at least two months.

9. The plurality of biodegradable microspheres of any of claims 6-8, wherein the microspheres (i) have a d10 value of at least 3 m and a d90 value of 28 m or less; (ii) 40have a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50; and (iii) carry from 1 g to 10,000 mg of pharmaceutical clascoterone.

10. An injectable formulation comprising (a) a pharmaceutically acceptable carrier and (b) a plurality of biodegradable microspheres wherein the microspheres (i) have a d10value of at least 1 m and a d90value of 40 m or less; (ii) comprise a polylactic-co- glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month.

11. The formulation of claim 10, wherein the microspheres further comprise polyethylene glycol (PEG).

12. The formulation of claim 10 or 11, wherein the microspheres, when present intradermally, release clascoterone for at least two months.

13. A method for treating hair loss in a subject comprising introducing biodegradable microspheres into an affected area of the subject’s skin, wherein the introducing is into skin at or around one or more hair follicles, and wherein the microspheres (i) have a d10 value of at least 1 m and a d90 value of 40 m or less; (ii) comprise a polylactic-co- glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month.

14. The method of claim 13, wherein the microspheres further comprise polyethylene glycol (PEG).

15. The method of claim 13 or 14, wherein the subject is human.

16. The method of any of claims 13-15, wherein the microspheres (i) have a d10 value of at least 3 m and a d90value of 28 m or less; (ii) have a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50; and (iii) carry from 1 g to 10,000 mg of pharmaceutical clascoterone. 4117. The method of any of claims 13-16, wherein the microspheres have an average lactic acid to glycolic acid molar ratio of 75:25, or 85:15, or between 75:25 and 85:

15.

18. The method of any of claims 13-17, wherein the microspheres release clascoterone for at least two months.

19. The method of any of claims 13-18, wherein the microspheres release clascoterone for at least three months.

20. The method of any of claims 13-19, wherein the microspheres release clascoterone for at least six months.

21. A kit comprising, in separate compartments, (a) a diluent, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10 value of at least 1 m and a d90value of 40 m or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month.

22. An article of manufacture comprising a syringe having therein the injectable formulation of any of claims 10-12.

23. An article of manufacture comprising a dual chamber syringe having therein, in separate compartments, (a) a diluent, and (b) plurality of biodegradable microspheres, wherein the microspheres (i) have a d10value of at least 1 m and a d90value of 40 m or less; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of pharmaceutical clascoterone; and (iv) when present intradermally, release clascoterone for at least one month, wherein the diluent and microspheres can be admixed within the syringe to form an injectable formulation immediately prior to use. 42

Images