Topical formulations of 5-α-reductase inhibitors and uses thereof

Abstract

To provide a method for stimulating hair growth on the scalp of a human subject.SOLUTION: The present invention provides a method that includes the steps of: a) providing a topical composition comprising a therapeutically effective amount of dutasteride and / or finasteride, or pharmaceutically acceptable salts, esters, or derivatives thereof, and pharmaceutically acceptable topical excipients or carriers; and b) topically applying the composition to the scalp in an amount and for a duration sufficient to stimulate hair growth, wherein hair growth comprises an increase in scalp hair density, hair thickness, or scalp coverage.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to topical compositions for regulating hair growth and the treatment of various types of alopecia, such as female and male pattern androgenetic alopecia (AGA), alopecia areata, hair loss secondary to endocrine therapy in breast cancer patients (endocrine therapy-induced alopecia or ETIA), and hirsutism. [Background technology]

[0002] The background of the invention is now briefly described as an aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.

[0003] Hair loss or alopecia is a common and bothersome problem for many people. One of the most frequent types of alopecia is androgenetic alopecia, a common form of hair loss in both men and women. In men, this condition is also known as male-pattern baldness. The pattern of hair loss in women differs from male-pattern baldness. In women, hair thins over the entire head, but the hairline does not necessarily recede. Researchers have determined that this form of hair loss is linked to hormones called androgens, specifically an androgen called dihydrotestosterone (DHT).

[0004] Another common form of alopecia is hair loss secondary to endocrine therapy in breast cancer patients (endocrine therapy-induced alopecia or ETIA). Currently, selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have an important place as adjuvant endocrine therapy in patients with early invasive or noninvasive and / or advanced metastatic hormone receptor-positive breast cancer. A significant proportion of patients who use SERMs, such as tamoxifen for many years, report hair loss or thinning. See Gallicchio, L. et al., "Aromatase inhibitor therapy and hair loss among breast cancer survivors." Breast Cancer Res Treat (2013) 142: 435-43. A retrospective questioning of breast cancer patients about hair loss revealed that approximately 34% of patients who received endocrine therapy experienced hair loss or thinning. See ibid. The psychosocial importance of alopecia caused by cancer treatment cannot be underestimated. Approximately 58% of women undergoing treatment for breast cancer stated that alopecia was one of the most traumatic adverse events (AEs) during treatment, and 8% stated that this reaction alone would cause them to refuse treatment. See Saagar, V. et al., "Alopecia with Endocrine Therapies in Patients with Cancer." Oncologist (2013) 18(10): 1126-34. Reduced quality of life (QoL), social activities, self-esteem, and body image are all associated with hair loss. See Wang, J. et al., "Protection Against Chemotherapy-Induced Alopecia." Pharm Res. (2006) 23(11): 2505-14 and Shapiro, J., "Hair Loss in Women." N Engl J Med (2007) 357(16) 1620-30. These findings were attributed to severe alopecia occurring during treatment with cytotoxic agents. Endocrine therapy-induced alopecia (ETIA), occurring during treatment with endocrine agents, is less severe.However, ETIA can persist for the duration of treatment (typically 5-10 years), intensifying and extending the impact on patients' QoL. ETIA has a significant negative impact on QoL, often resulting in depression, concerns and dissatisfaction with appearance, and low self-esteem.

[0005] The characteristics of hair growth and the pathogenesis of AGA may help explain why SERMs and AIs cause ETIA. Animal (mouse) models treated with tamoxifen-loaded gel experienced hair growth arrest, which continued to fail to grow even after the treatment was discontinued. See Bhatia, A. et al., "Tamoxifen-loaded liposomal topical formulation arrests hair growth in mice." Br J Dermatol (2010) 163(2): 412-15. Furthermore, affected hair follicles were arrested in telogen. See ibid. Tamoxifen-associated alopecia has been shown to display a distribution similar to that of female-pattern AGA, primarily affecting the vertex and frontal scalp. See Linder, J. et al., "Hair shaft abnormalities after chemotherapy and tamoxifen therapy in patients with breast cancer evaluated by optical coherence tomography." Br J Dermatol (2012) 167(6): 1272-78. Both men and women with AGA have lower levels of aromatase in hair follicles located in the frontal area of ​​the scalp (see Sawaya, M. and Price, V., "Different Levels of 5α-Reductase Type I and II, Aromatase, and Androgen Receptor in Hair Follicles of Women and Men with Androgenetic Alopecia." J Invest Dermatol (1997) 109(3): 296-300). Thus, AIs may mimic the genetic defect typically seen in AGA.

[0006] Alopecia areata is a common autoimmune disorder that causes unpredictable hair loss. Hair often falls out in small pieces, about the size of a quarter. However, in more extreme cases, it can lead to complete hair loss on the scalp and even the entire body.

[0007] In addition to alopecia, hirsutism, which is excess facial and / or body hair growth, especially in women, is another common nuisance. Hirsutism can occur in women when the proportion of male hormones (androgens) is too high, resulting in an imbalance between female and male hormone levels.

[0008] Researchers have tried several treatment regimens to address various forms of alopecia and hirsutism with mixed results.For example, for the treatment of alopecia, vasodilators, such as minoxidil and minoxidil derivatives, such as potassium channel agonists, including diaminopyrimidine oxide, and oral formulations of inhibitors of the 5-α-reductase enzyme, which converts testosterone to DHT.The use of such oral formulations of such inhibitors, such as oral finasteride, has had mixed success and is associated with the risk of adverse side effects.

[0009] Avodart® (dutasteride) has been shown to be safe and effective for oral use both in extensive non-clinical studies and in data from 18 years of clinical use. Dutasteride reduces circulating levels of DHT by inhibiting both type 1 and type 2 5α-reductase isoenzymes (5α-reductase isoenzymes) responsible for the conversion of testosterone to DHT, known to be the most potent natural androgen in the human body. DHT is believed to potently regulate the transcription of androgen-sensitive genes in hair follicles, thereby influencing hair growth. See Jain, R. and De-Ekanumkul., "Potential targets in the discovery of new hair growth promoters for androgenic alopecia." Expert Opin Ther Targets (2014) 18(7): 787-086. Thus, specific and systemic treatment with anti-5α-reductase agents (e.g., oral Avodart® (dutasteride) soft gelatin capsules, 0.5 mg) has been shown to treat scalp hair loss in both men and women.The fact that patients with a congenital deficiency of 5α-reductase enzyme activity rarely develop AGA (see Herskovitz, I. and Tosti, A., "Female Pattern Hair Loss.", Int J Endocrinol Metab (2013) 11(4): e9860 (published online October 21, 2013)) and that patients using 5α-reductase enzyme inhibitors get significant improvement in hair loss (see Olsen, E. et al., "The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss: Results of a randomized placebo-controlled study of dutasteride versus finasteride.", J Am Acad Dermatol (2006) 55(6): 1014-23) is preliminary objective evidence for this proposed indication. In contrast, given the systemic side effects of taking these agents orally, topical 5α-reductase enzyme inhibitors can be applied locally (especially in the fronto-temporal region) or globally to the scalp skin.

[0010] Oral finasteride and oral dutasteride are two of the most widely known and widely used 5α-reductase inhibitors available today. Both drugs are designed to block the conversion of testosterone to DHT, an androgen known to be a contributing factor in AGA. Although oral finasteride and oral dutasteride share some important advantages, they are both unique drugs with slightly different purposes and effects.

[0011] Between oral finasteride and oral dutasteride, oral finasteride is the older drug. Oral finasteride was developed in the 1970s and was approved by the FDA for the treatment of BPH in 1992. Oral finasteride was finally approved for use as an AGA treatment in 1997 at a lower dose (1 mg) than the higher dose (5 mg) oral finasteride for the treatment of BPH. Meanwhile, dutasteride was only patented in 1996 and was approved by the FDA for the oral treatment of BPH in 2001 at a dose of 0.5 mg.

[0012] Oral dutasteride has been approved for the treatment of AGA in several other countries, but has not yet been FDA-approved for the treatment of AGA in the United States.

[0013] In a study of 399 subjects, researchers found that oral finasteride blocked 70.8±18.3% of DHT at a daily dose of 5 mg, while oral dutasteride blocked 98.4%±1.2% of DHT at the same dose. See Clark, RV et al., "Marked Suppression of Dihydrotestosterone in Men with Benign Prostatic Hyperplasia by Dutasteride, a Dual 5α-Reductase Inhibitor." J Clin Endocrinol Metab (2004) 89(5): 2179-84. This study was conducted on people with BPH, which means that much higher doses of oral dutasteride and oral finasteride were used than those used to treat hair loss. Nevertheless, it shows that oral dutasteride is more effective than oral finasteride on a milligram for milligram basis in lowering DHT. Oral dutasteride also shows more consistency in blocking DHT than oral finasteride. The level of variability in the oral dutasteride group was ±1.2%, indicating near-total disappearance of DHT, and the patient-to-patient variability was much smaller than the ±18.3% in the oral finasteride group. Data from the study also show that oral dutasteride is more effective than finasteride in promoting hair growth in people with male pattern baldness.

[0014] A 2006 study of 416 men indicates that oral dutasteride produced better hair count results than oral finasteride over a 12-24 week period. See Olsen, E. et al., 2006, supra. The researchers used a panel of experts and before-and-after photographs to compare and evaluate the effects of the two drugs. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Gallicchio, L. et al., “Aromatase inhibitor therapy and hair loss among breast cancer survivors.” Breast Cancer Res Treat (2013) 142: 435~43 [Non-Patent Document 2] Saagar, V. et al., “Alopecia with Endocrine Therapies in Patients with Cancer.” Oncologist (2013) 18(10): 1126~34 [Non-Patent Document 3] Wang, J. et al., "Protection Against Chemotherapy-Induced Alopecia.", Pharm Res. (2006) 23(11): 2505~14 [Non-Patent Document 4] Shapiro, J., “Hair Loss in Women.”, N Engl J Med (2007) 357(16) 1620~30 [Non-Patent Document 5] Bhatia, A. et al., “Tamoxifen-loaded liposomal topical formulation arrests hair growth in mice.” Br J Dermatol (2010) 163(2): 412~15 [Non-Patent Document 6] Linder, J. et al., “Hair shaft abnormalities after chemotherapy and tamoxifen therapy in patients with breast cancer evaluated by optical coherence tomography.” Br J Dermatol (2012) 167(6): 1272~78 [Non-Patent Document 7] Sawaya, M. and Price, V., "Different Levels of 5α-Reductase Type I and II, Aromatase, and Androgen Receptor in Hair Follicles of Women and Men with Androgenetic Alopecia.", J Invest Dermatol (1997) 109(3): 296~300 [Non-Patent Document 8] Jain, R. and De-Ekanumkul. "Potential targets in the discovery of new hair growth promoters for androgenic alopecia." Expert Opin Ther Targets (2014) 18(7): 787-086 [Non-Patent Document 9] Herskovitz, I. and Tosti, A., "Female Pattern Hair Loss." Int J Endocrinol Metab (2013) 11(4): e9860 (Published online October 21, 2013) [Non-Patent Document 10] Olsen, E. et al., “The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss: Results of a randomized-controlled study of dutasteride versus finasteride.” J Am Acad Dermatol (2006) 55(6): 1014~23 [Non-Patent Document 11] Clark, RV et al., “Marked Suppression of Dihydrotestosterone in Men with Benign Prostatic Hyperplasia by Dutasteride, a Dual 5α-Reductase Inhibitor.” J Clin Endocrinol Metab (2004) 89(5): 2179~84 Summary of the Invention [Problem to be solved by the invention]

[0016] The present disclosure provides topical compositions of 5-alpha reductase inhibitors, such as dutasteride or finasteride, or pharma- ceutically acceptable salts, esters, or derivatives thereof, for the treatment of hair loss secondary to endocrine therapy (endocrine therapy-induced alopecia or ETIA), androgenetic alopecia (AGA), alopecia areata, and / or hirsutism in breast cancer patients. Specifically included within the scope of the invention are the compositions and formulations described in the Examples. [Means for solving the problem]

[0017] In one aspect, the present disclosure provides a topical composition comprising a therapeutically effective amount of a 5-alpha reductase inhibitor, such as dutasteride or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative thereof, and a suitable pharma- ceutically acceptable topical excipient or carrier.

[0018] In another aspect of the present invention, the present disclosure provides methods for preparing the 5-alpha reductase inhibitor (e.g., dutasteride) formulations described in the Examples.

[0019] In another aspect, the present disclosure provides a method for stimulating hair growth in the scalp of a human subject suspected of suffering from alopecia due to endocrine therapy from breast cancer treatment.The method includes the steps of: a) preparing a topical composition comprising a therapeutically effective amount of a 5-alpha reductase inhibitor, such as dutasteride or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative thereof, and a suitable pharma- ceutically acceptable topical excipient or carrier; and b) topically applying the composition to the subject's skin or scalp in and / or adjacent to the area where hair growth is desired.An increase in scalp hair density, hair diameter, or scalp coverage in the human subject receiving the topical composition compared to an untreated individual indicates stimulation of hair growth in the scalp of the human subject.

[0020] In another aspect, the present disclosure provides a method for stimulating hair growth in the scalp of a human subject suspected of suffering from androgenetic alopecia.The method includes the steps of: a) preparing a topical composition comprising a therapeutically effective amount of a 5-alpha reductase inhibitor, such as dutasteride or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative thereof, and a suitable pharma- ceutically acceptable topical excipient or carrier; and b) topically applying the composition to the subject's skin or scalp in and / or adjacent to the area where hair growth is desired.An increase in scalp hair density, hair diameter, or scalp coverage in the human subject receiving the topical composition compared to an untreated individual indicates stimulation of hair growth in the scalp of the human subject.

[0021] In another aspect, the present disclosure provides a method for reducing facial hair growth in a human subject suspected of suffering from hirsutism. The method includes the steps of: a) preparing a topical composition comprising a therapeutically effective amount of a 5-alpha reductase inhibitor, such as dutasteride or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative thereof, and a suitable pharma- ceutically acceptable topical excipient or carrier; and b) topically applying the composition to the subject's facial or body skin in and / or adjacent to the area where reduced hair growth is desired. A reduction in facial hair density, hair diameter, or coverage in the human subject receiving the topical composition compared to an untreated individual indicates a reduction in facial hair growth in the human subject.

[0022] In another aspect, the present disclosure provides a topical formulation comprising a therapeutically effective amount of dutasteride, or its pharma- ceutically acceptable salt, ester, or derivative, dissolved in an oil phase, and a pharma- ceutically acceptable topical excipient or carrier.The topical formulation can be an emulsion.The oil phase can comprise at least one oil, or at least two oils.The formulation can further comprise a moisturizer, a thickener, an emulsifier, and a preservative.

[0023] In another aspect, the present disclosure provides a topical formulation comprising a therapeutically effective amount of dutasteride, or a pharma- ceutically acceptable salt, ester, or derivative thereof, dissolved in an oil phase, and a pharma- ceutically acceptable topical excipient or carrier. The formulation may be free of ethyl alcohol and / or polypropylene glycol.

[0024] In another aspect, the present disclosure provides a topical formulation comprising a therapeutically effective amount of dutasteride, or a pharma- ceutically acceptable salt, ester, or derivative thereof, dissolved in an aqueous phase, and a pharma- ceutically acceptable topical excipient or carrier. The topical formulation may be an emulsion. The aqueous phase may optionally include a solubilizer. The aqueous phase may optionally include a penetration enhancer. The formulation may further include a thickener, an emollient, a pH adjuster, a preservative, and / or a conditioning agent.

[0025] In another aspect, the disclosure provides a method of preparing a topical formulation comprising the steps of mixing a conditioning agent and water to form a conditioning solution; mixing a first emulsifier, a first preservative, and a solvent to obtain an emulsifier solution; mixing dutasteride, at least one oil, and at least one solvent to obtain a dutasteride solution; mixing the dutasteride solution and the emulsifier solution to obtain a combined solution; mixing the combined solution and the conditioning solution to form a dutasteride conditioning mixture; and mixing a second emulsifier and a second preservative into the dutasteride conditioning mixture.

[0026] In another aspect, the disclosure provides a method of preparing a topical formulation comprising mixing a humectant and water to form a humectant solution, mixing a thickener and a first solvent to form a thickener solution, mixing the thickener solution and the humectant solution to form a combined solution, mixing a preservative into the combined solution to form a combined preservative solution, mixing dutasteride and a second solvent to form a dutasteride solution, mixing at least one oil into the dutasteride solution to form a dutasteride oil mixture, mixing at least one emulsifier into the dutasteride oil mixture to form a second dutasteride oil mixture, and mixing the second dutasteride oil mixture with the combined preservative solution in a container.

[0027] In some embodiments of the above aspects, the therapeutically effective amount of dutasteride is about 0.001% to about 1% (w / w). In some embodiments, the therapeutically effective amount of a 5-α reductase inhibitor, such as dutasteride or finasteride, is about 0.001% to about 0.5% (w / w). In some embodiments, the therapeutically effective amount of a 5-α reductase inhibitor, such as dutasteride or finasteride, is about 0.002% to about 0.1% (w / w). In some embodiments, the therapeutically effective amount of dutasteride is about 0.001%, 0.005%, 0.010%, 0.025%, 0.050%, 0.075%, 0.100%, 0.150%, 0.200%, 0.250%, 0.300%, 0.350%, 0.400%, 0.500%, 0.600%, 0.700%, 0.800%, 0.900% or about 1% (w / w). In some embodiments, the amount of 5-alpha reductase inhibitor, e.g., dutasteride or finasteride, administered in a single topical application is about: 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg. In some embodiments, the amount of 5-alpha reductase inhibitor, e.g., dutasteride or finasteride, administered in a single topical application is about 0.1 to about 3.0 mg, or about 0.3 mg to about 2.5 mg, or about 0.5 mg to about 2.5 mg, or about 0.5 mg to about 2.0 mg, or about 0.5 mg to about 1.5 mg, or about 0.5 mg to about 1.0 mg.

[0028] In some embodiments, the dutasteride of the composition is in the form of nanoparticles. In some embodiments, the nanoparticles are coated with a 5-alpha reductase inhibitor, such as dutasteride or finasteride. In some embodiments, the 5-alpha reductase inhibitor, such as dutasteride or finasteride, is sustained-released to the skin or scalp when the topical composition is applied to the skin or scalp of a human subject. In some embodiments, the nanoparticles have a diameter of about 25 nm to about 500 nm. In some embodiments, the nanoparticles have a diameter of about 100 nm to about 500 nm. In some embodiments, the nanoparticles have a diameter of about 500 nm.

[0029] In some embodiments of the above aspects, the topical composition comprises a surfactant, a co-surfactant, a penetration enhancer, an antioxidant, a buffering agent, a preservative, a viscosity modifier, a chelating or complexing agent, a colorant, a fragrance, a polymer, a gelling agent, an alcohol, a liquid or semi-solid oily component, or any combination thereof.

[0030] In some embodiments, the topical composition comprises at least two of an API (a 5-alpha reductase inhibitor, e.g., dutasteride or finasteride), a cationic emulsifier, a conditioning agent, an emollient, an emulsifier, a moisturizing solvent, a non-ionic emulsifier, a penetration enhancer, a pH adjuster, a preservative, a solvent, a thickener, a viscosity enhancer, or any combination thereof.

[0031] In some embodiments, the topical composition is a cream and includes a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a penetration enhancer.

[0032] In some embodiments, the topical composition is a lotion and includes a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a penetration enhancer.

[0033] In some embodiments, the topical composition is a lotion and includes a solvent, a humectant, a thickening agent, a preservative, an emollient, an emulsifier, a pH adjuster, and a penetration enhancer.

[0034] In some embodiments, the topical composition is a lotion conditioner and includes a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a conditioning agent.

[0035] In some embodiments, the topical composition is a lotion serum and includes a solvent, a humectant, a thickening agent, a preservative, an emollient, an emulsifier, a pH adjuster, a penetration enhancer, and a conditioning agent.

[0036] In some embodiments, the topical composition is a gel and comprises a solvent, a thickener, an emollient, and a penetration enhancer.

[0037] In some embodiments, the topical composition is a gel and comprises a solvent, a thickening agent, and a penetration enhancer.

[0038] In some embodiments, the topical composition is a gel and / or serum and includes a solvent, a viscosity enhancer, an emollient, and a penetration enhancer.

[0039] In some embodiments of the above aspects, the pharma- ceutically acceptable topical carrier is a hydrophilic, hydrophobic, lipophilic, or amphiphilic carrier, or a mixture thereof. In some embodiments, the pharma- ceutically acceptable carrier is paraffin oil, C8-C 18 Esters of organic acids, C8-C 30 Hydrophobic or lipophilic substances include fatty alcohols, silicone oils, vegetable oils, fractionated or hydrogenated vegetable oils, monoglycerides, diglycerides, triglycerides, phospholipids, dimethylisosorbide, volatile solvents, N-methylpyrrolidone, dimethylacetamide, dimethylformamide; dimethylsulfoxide, or any combination thereof. In some embodiments, the pharma- ceutically acceptable topical excipient or carrier comprises ethanol, polypropylene glycol, purified water, or a combination thereof.

[0040] In some embodiments of the above aspects, the topical composition is in the form of a foam, cream, paste, gel, aerosol, powder, oil, serum, or liquid. In some embodiments, the topical composition further comprises a therapeutically effective amount of finasteride, minoxidil, or a combination thereof. In some embodiments, the amount of finasteride can be about 0.01 mg to about 5 mg. In some embodiments, the amount of finasteride can be about: 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, or 5 mg. In some embodiments, the amount of minoxidil can be about: 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, or 7.5 mg. In some embodiments, the topical composition comprises a propellant. Non-limiting examples of propellants include dichloromethane, dimethyl ether, butane, propane, nitrogen, fluorocarbons, and carbon dioxide.

[0041] In some embodiments, the topical composition is applied to the skin or scalp of the human subject for one day. In some embodiments, the topical composition is applied to the skin or scalp of the human subject for multiple days. In some embodiments, the topical composition is applied daily for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 21 days or more (22 days or more). In some embodiments, the topical composition is applied daily for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or more (17 weeks or more). In some embodiments, the topical formulation of the 5-alpha reductase inhibitor is applied once a day, twice a day, three times a day, four times a day, or more frequently (five times a day or more). In some embodiments, the topical composition is applied multiple times daily for multiple days or weeks, or months. In some embodiments, the skin is abdominal skin. In some embodiments, the skin is skin of the limbs, forehead, throat, or back.

[0042] In some embodiments, stimulating hair growth comprises increasing hair count. In some embodiments, stimulating hair growth comprises increasing hair diameter. In some embodiments, increasing hair diameter comprises increasing in the frontal, central, parietal regions of the scalp of a human subject, or a combination thereof. In some embodiments, stimulating hair growth comprises improved scalp coverage and improved hair structure.

[0043] In some embodiments of the above aspects, the human subject can be male or female. In some embodiments, the human subject suspected of having androgenetic alopecia is male. In some embodiments, the male suspected of having androgenetic alopecia has a male baldness pattern.

[0044] As used herein, the singular forms "a," "an," and "the" include the plural unless specifically stated otherwise. Thus, for example, reference to "a protein" includes a plurality of protein molecules.

[0045] As used herein, the term "about" in a quantitative sense refers to plus or minus 10%. For example, "about 3%" includes 2.7-3.3%, and "about 10%" includes 9-11%. Furthermore, when "about" is used in connection with a quantitative term herein, it is understood that it also intends and describes the exact value of the quantitative term in addition to the value of plus or minus 10%. For example, the term "about 3%" expressly intends, describes and includes exactly 3%.

[0046] The above summary of the present disclosure is non-limiting, and other features and advantages of the disclosed devices and methods will be apparent from the following detailed description of the present disclosure and the claims. It should be understood that other 5-alpha reductase inhibitors, such as finasteride, may be used in place of dutasteride in any of the formulations and methods. [Brief description of the drawings]

[0047] [Figure 1] FIG. 1 shows the chemical structure of dutasteride. [Diagram 2] FIG. 1 shows the results of a dutasteride / excipient binary compatibility study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] The present disclosure is directed to topical compositions of 5-alpha reductase inhibitors, such as dutasteride or finasteride, or pharma- ceutically acceptable salts, esters, or derivatives thereof, for the treatment of hair loss secondary to endocrine therapy (endocrine therapy-induced alopecia or ETIA), androgenetic alopecia (AGA), alopecia areata (AA), and hirsutism in breast cancer patients. Topical compositions of 5-alpha reductase inhibitors are advantageous over any oral formulation of 5-alpha reductase inhibitors, as they may allow for sustained release of the active ingredient, better penetration at therapeutically effective doses of the 5-alpha reductase inhibitor, and an improved safety profile by not having to travel through the bloodstream to be effective, thereby minimizing the risk of systemic side effects.

[0049] The chemical name of dutasteride is (5α,17β)-N-{2,5-bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C 27 H 30 It is F6N2O2, exhibits a molecular weight of 528.53 kDa, and has the following structural formula as shown in FIG. 1. Dutasteride is a selective inhibitor of both type 1 and type 2 5α-reductase isoenzymes, which are intracellular enzymes that convert testosterone to DHT. Moreover, since dutasteride inhibits both type 1 and type 2 5α-reductase isoenzymes, it may be more effective than another known type 1 5α-reductase inhibitor, finasteride.

[0050] Dutasteride may be more potent than finasteride in inhibiting the 5α-reductase enzyme, but both have reported adverse effects. Oral formulations of finasteride and dutasteride have been shown by researchers to be effective in treating androgenetic alopecia (AGA) and have been proposed as treatments for hair loss secondary to endocrine therapy in breast cancer patients (endocrine therapy-induced alopecia or ETIA). Oral dutasteride is not approved for the treatment of any form of alopecia or hirsutism in the United States.

[0051] The present invention provides topical formulations of 5-alpha reductase inhibitors, such as dutasteride or finasteride, or pharma- ceutically acceptable salts, esters, or derivatives thereof, for the treatment of hair loss secondary to endocrine therapy (endocrine therapy-induced alopecia or ETIA), androgenetic alopecia (AGA), and hirsutism in breast cancer patients, which are safe and effective as they may allow for sustained release of the active ingredient; better penetration at therapeutically effective amounts of the 5-alpha reductase inhibitor; and an improved safety profile as it does not need to travel via the bloodstream to be effective, thereby minimizing the risk of systemic side effects.

[0052] As used herein, the term "regulating hair growth" refers to increasing or decreasing the number, diameter, or structure of hair on the scalp or face.

[0053] As used herein, the term "therapeutically effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom(s) of a disease. Reduction of a symptom(s) (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of the symptom(s) or elimination of the symptom(s).

[0054] As used herein, when the amount of dutasteride is expressed as "%", it refers to % (w / w) unless otherwise indicated.

[0055] As used herein, the phrase "pharmacologically acceptable" is used in reference to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0056] As used herein, the terms "permeation enhancing" or "penetration enhancing" refer to increasing the permeability of a biological membrane (i.e., skin or mucosa) to a drug and increasing the rate at which the drug is transported across the membrane. "Permeation enhancer," "enhancer," "penetration enhancer," or similar terms refer to a material that achieves such penetration or permeation enhancement, and an "effective amount" of an enhancer refers to an amount effective to enhance the desired degree of penetration of a selected agent through the skin or mucosa.

[0057] Suitable penetration enhancers that can be used in the present invention include, but are not limited to, sulfoxides, such as dimethyl sulfoxide (DMSO) and decyl methyl sulfoxide (C 10MSO; ethers such as diethylene glycol monoethyl ether (commercially available as Transcutol® P) and diethylene glycol monomethyl ether; 1-substituted azacycloheptan-2-ones such as 1-n-dodecyl-cyclazacycloheptan-2-one; alcohols such as propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid, and valeric acid; fatty acid esters such as isopropyl myristate, palmitic acid. Examples of suitable penetration enhancers include isopropyl, methyl propionate, and ethyl oleate; polyol esters such as butanediol and polyethylene glycol monolaurate, amides and other nitrogen compounds such as urea, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes and terpinoids; alkanones; organic acids such as salicylic acid and salicylates, citric acid and succinic acid, and the like; and mixtures of any thereof. Suitable penetration enhancers also include, but are not limited to, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, diethylene glycol monoethyl ether (Transcutol® P), oleyl alcohol, dehydrated alcohol, benzyl alcohol, laureth-4, diethyl sebacate, and dimethyl isosorbide.

[0058] Suitable solvents that can be used in the present invention include, but are not limited to, sterile water, glycerin, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, olive oil, castor oil, coconut oil, light mineral oil, diethylene glycol monoethyl ether (Transcutol® P), diethyl sebacate, benzyl alcohol, cyclomethicone, PEG 400, dehydrated alcohol, and dimethyl isosorbide.

[0059] Suitable moisturizing agents that can be used in the present invention include, but are not limited to, sodium hyaluronate, glycerin, sorbitol solution 70%, and methyl gluceth-20 (Glucam E20).

[0060] Suitable thickening agents that can be used in the present invention include, but are not limited to, xanthan gum, cetearyl alcohol, Promulgen D, Carbopol 974P NF polymer, Pemulen TR-2, Pemulen TR-1, Klucel HG Pharm, Carbopol 980 NF, polymer, and Sepineo P 600.

[0061] Suitable preservatives that can be used in the present invention include, but are not limited to, methylparaben and propylparaben.

[0062] Suitable emollients that can be used in the present invention include, but are not limited to, olive oil, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, castor oil, light mineral oil, cyclomethicone, diethyl sebacate, benzyl alcohol, PEG-35 castor oil, and coconut oil.

[0063] Suitable emulsifiers that can be used in the present invention include, but are not limited to, Brij L4, Arlacel 165, Tween 20, Brij S721, Brij S2, Promulgen D, stearalkonium chloride, Pemulen TR-2, Pemulen TR-1, sodium monostearate, Sepineo P 600, laureth-4, polysorbate 20, sorbitan monostearate, and PEG-35 castor oil.Non-ionic emulsifiers include, but are not limited to, Brij L4, Arlacel 165, sodium monostearate, laureth-4, polysorbate 20, and PEG-35 castor oil.Cationic surfactants include, but are not limited to, stearalkonium chloride.

[0064] Suitable pH adjusting agents that can be used in the present invention include, but are not limited to, solutions of NaOH and HCl.

[0065] Suitable conditioning agents that can be used in the present invention include, but are not limited to, stearalkonium chloride and polyquaternium-10.

[0066] Suitable solubilizers that can be used in the present invention include, but are not limited to, Laureth-4.

[0067] Suitable viscosity enhancing agents that can be used in the present invention include, but are not limited to, PEG 3350. EXAMPLES

[0068] [Example 1] Topical formulations containing dutasteride A 0.10% w / v topical formulation may be prepared as follows.

[0069] [Table 1]

[0070] [Example 2] Topical cream formulations containing dutasteride (dutasteride dissolved in the oil phase) A. A 0.05% w / w topical formulation may be prepared as follows:

[0071] [Table 2]

[0072] The ingredients of Phase A were combined in the main vessel until a solution was obtained. Phase B was sprinkled into the main vessel with high agitation and mixed until a homogenous gel was obtained. Phase C was premixed in a separate vessel until evenly dispersed and added to the main vessel. The batch was then heated to 70-75°C. Phase D was then added to the main vessel and mixed until Phase D was solubilized. The ingredients of Phase E were combined in a separate vessel and mixed until a solution was obtained. Phase F was then added to Phase E in the separate vessel and the mixture was heated until it was at 70-75°C.

[0073] Once the mixture in the main vessel and the mixture of Phase E+F were both at 70-75°C, Phase E+F was added to the main vessel and homogenized. The batch was then cooled to below 30°C.

[0074] The hydrophilic-lipophilic balance (HLB), which is the balance between the size and strength of the hydrophilic and lipophilic parts of a surfactant molecule, was calculated.

[0075] [Table 3]

[0076] B. A 0.05% w / w topical formulation may be prepared as follows: (2019-045-31R)

[0077] [Table 4]

[0078] The ingredients of Phase A were mixed in the main vessel until a solution was obtained. Phase B was sprinkled into the main vessel with high agitation and mixed until a homogenous gel was obtained. Phase C was premixed in a separate vessel until uniformly dispersed and added to the main vessel. The batch was then heated to 70-75°C. Phase D was then added to the main vessel and mixed until Phase D was solubilized. The ingredients of Phase E were mixed in a separate vessel and mixed until a solution was obtained. Phase F was then added to Phase E in a separate vessel and the mixture was heated until the mixture was 70-75°C. Once the mixture in the main vessel and the mixture of Phase E+F were both at 70-75°C, Phase E+F was added to the main vessel and homogenized. The batch was then cooled to less than 30°C.

[0079] The hydrophilic-lipophilic balance (HLB), which is the balance between the size and strength of the hydrophilic and lipophilic parts of a surfactant molecule, was calculated.

[0080] [Table 5]

[0081] [Example 3] Topical cream formulations containing dutasteride (dutasteride dissolved in the aqueous phase) A 0.05% w / w topical formulation may be prepared as follows.

[0082] [Table 6]

[0083] The Phase A ingredients were combined in the main vessel. The Phase B ingredients were combined in a separate vessel and mixed until a solution was obtained. Phase B was then added to the main vessel and mixed until a solution was obtained. The main vessel was then heated to 70-75°C. The Phase C ingredients were combined in a separate vessel and heated to 70-75°C. Phase C was then added to the main vessel with homogenization. The contents of the main vessel were mixed until the oil phase was completely combined. Phase D was then added to the main vessel and homogenized until the batch temperature was 60°C. The main vessel was cooled to <30°C. Phase E was combined in a separate vessel until a solution was obtained. Phase E was then added to the main vessel and mixed.

[0084] The HLB was calculated.

[0085] [Table 7]

[0086] [Example 4] Topical lotions ("conditioners") containing dutasteride (dutasteride dissolved in the oil phase) A 0.05% w / w topical formulation for leave-in conditioner may be prepared as follows.

[0087] [Table 8]

[0088] Phase A components were combined in a main vessel while heating to 70-75°C. Components were mixed until uniform. Phase B components were combined in a separate vessel and mixed until a solution was obtained. Phase C components were added to Phase B while heating to 70-75°C. The combined Phases B and C were added to the main vessel while heating at 70-75°C and mixed until uniform. The main vessel was then cooled to 40°C. Phase D components were combined in a separate vessel. Phase D was then added to the main vessel and the main vessel was then cooled to <30°C.

[0089] A 0.05% w / w topical formulation for leave-in conditioner may be prepared as follows. (2019-045-34R)

[0090] [Table 9]

[0091] The Phase A components were combined in a main vessel while heating to 70-75°C. The components were mixed until uniform. The Phase B components were combined in a separate vessel and mixed until a solution was obtained. The Phase C components were combined in a separate vessel and mixed until a solution was obtained. The Phase C components were added to Phase B while heating to 70-75°C. The combined Phases B and C were added to the main vessel while heating at 70-75°C and mixed until uniform. The main vessel was then cooled to 40°C. The Phase D components were combined in a separate vessel. Phase D was then added to the main vessel and the main vessel was then cooled to <30°C.

[0092] [Example 5] Topical lotion formulations containing dutasteride (dutasteride dissolved in the aqueous phase) A 0.05% w / w topical formulation for application may be prepared as follows.

[0093] [Table 10]

[0094] Phase A components were combined in the main vessel and mixed until a solution was obtained. Phase B components were sprinkled into the main vessel with vigorous mixing for up to 30 minutes. Phase C components were combined in a separate vessel and mixed until a solution was obtained. Phase C was added to the main vessel and mixed until uniform. Phase D components were premixed and then added to the main vessel with vigorous mixing and mixed until fully incorporated. Phase E was used to adjust the pH of the mixture in the main vessel to pH 6.5-7.0. Phase F components were combined in a separate vessel and mixed until a solution was obtained, added to the main vessel and mixed until uniform.

[0095] [Example 6] Topical lotion formulations containing dutasteride (2019-045-71) A 0.05% w / w topical formulation for application may be prepared as follows.

[0096] [Table 11]

[0097] Phase A components were combined in the main manufacturing vessel and heated to 70-75°C if necessary to dissolve the methylparaben. Phase B was sprinkled into the main vessel and mixed until no fish eyes were present. The main vessel was then heated to 75-80°C. Phase C components were combined in a separate vessel and homogenized until a solution was obtained. Phase C components were heated to 75-80°C if necessary to dissolve the dutasteride. Phase D components were added to Phase C while heating to 75-80°C and mixed until Phase D was completely melted. Phase C+D were added to the main manufacturing vessel at 75-80°C and homogenized until the oil phase was completely combined. Phase E was used to rinse the Phase C+D vessel. The main manufacturing vessel was cooled to ≦30°C. Phase F was used to neutralize the batch to pH 5.5-6.0. To the main manufacturing vessel was added sufficient Phase G to bring the total to 100% w / w.

[0098] [Example 7] Topical lotion formulations containing dutasteride (2019-045-76) A 0.05% w / w topical formulation for application may be prepared as follows.

[0099] [Table 12]

[0100] Phase A components were mixed in the main manufacturing vessel with high agitation until a homogenous gel was obtained. Phase B components were mixed in a separate vessel. Phase B was added to the main manufacturing vessel and mixed until evenly dispersed. Phase C was added to the main manufacturing vessel and mixed until dissolved. The main manufacturing vessel was then heated to 70-75°C. Phase D was mixed in a separate vessel with homogenization until a solution was obtained. That phase was heated to 70-75°C if necessary to dissolve the dutasteride. Phase E components were added to Phase D one at a time to obtain a solution. Phase F components were added to Phase D+E while heating to 70-75°C until Phase F was completely melted. Phase D+E+F was added to the main manufacturing vessel at 70-75°C and homogenized until the oil phase was completely combined. Phase G was used to rinse the Phase D+E+F vessel. The main manufacturing vessel was cooled to ≦30°C.

[0101] [Example 8] Topical lotion (conditioner) formulations containing dutasteride (2019-045-63) A 0.05% w / w topical formulation for application may be prepared as follows.

[0102] [Table 13]

[0103] Phase A components were combined in the main manufacturing vessel, heated to 70-75°C, and mixed until uniform. Phase B components were combined in a separate vessel with homogenization until a solution was obtained. Phase B components were heated to 70-75°C, if necessary, to dissolve the dutasteride. Phase C components were added to Phase B with heating to 70-75°C, and mixed until Phase C was completely melted and combined. Phases B+C were added to the main manufacturing vessel with homogenization at 70-75°C, and mixed until the oil phase was completely combined. Phase D was used to rinse the Phase B+C vessel. The main manufacturing vessel was cooled to ≦40°C. Phase E components were combined in a separate vessel, then added to the main manufacturing vessel and mixed until uniform. The main manufacturing vessel was cooled to ≦30°C. Sufficient Phase F was added to the batch to bring the total to 100% w / w.

[0104] [Example 9] Topical lotion "serum" formulations containing dutasteride (dutasteride dissolved in the oil phase) A 0.05% w / w topical formulation for application may be prepared as follows.

[0105] [Table 14]

[0106] The Phase A components were combined in the main vessel and mixed until a solution was obtained. The Phase B components were sprinkled into the main vessel with vigorous mixing until no fish eyes were present. The Phase C components were combined in a separate vessel and mixed until a solution was obtained. The Phase D components were then added to Phase C and mixed until a solution was obtained. Phase E was then dispersed into the combined Phase C+D. The combined Phase C+D+E was then added to the main vessel with vigorous propeller mixing for 20-30 minutes. The batch was then homogenized at 6,000 rpm for 1 minute. The pH of the batch was adjusted to pH 5.5-6.0 using Phase F.

[0107] A 0.05% w / w topical lotion (serum) formulation for application may be prepared as follows: (2019-045-25R)

[0108] [Table 15]

[0109] Phase A components were combined in the main vessel and mixed until a solution was obtained. Phase B components were sprinkled into the main vessel with vigorous mixing until no fish eyes were present. Phase C components were combined in a separate vessel and mixed until a solution was obtained. Phase D components were then added to Phase C and mixed until a solution was obtained. Phase E was then dispersed into the combined Phase C+D. The combined Phase C+D+E was then added to the main vessel with vigorous propeller mixing for 20-30 minutes. The batch was then homogenized at 6,000 rpm for 1 minute. The pH of the batch was adjusted to pH 5.5-6.0 using Phase F.

[0110] [Example 10] Topical gel formulations containing dutasteride A 0.05% w / w topical formulation for application may be prepared as follows: Advantageously, a lightweight gel with a non-sticky finish can be applied to the scalp / hair and does not leave much residue after setting.

[0111] [Table 16]

[0112] The Phase A components were combined in the main vessel and mixed until a solution was obtained. The Phase B components were added to the main vessel and mixed until a solution was obtained. Phase C was sprinkled into the main vessel and mixed until a uniform gel was obtained.

[0113] [Example 11] Topical gel formulations containing dutasteride A 0.05% w / w topical formulation for application may be prepared as follows: (2019-045-53)

[0114] [Table 17]

[0115] The ingredients of Phase A were mixed in the main manufacturing vessel until a solution was obtained. Phase B was slowly added to the main manufacturing vessel with mixing until a homogenous gel was obtained. A sufficient amount of Phase C was added to the main manufacturing vessel to bring the total to 100% w / w.

[0116] A 0.05% w / w topical formulation for application may be prepared as follows.

[0117] [Table 18]

[0118] The ingredients of Phase A were mixed in the main manufacturing vessel until a solution was obtained. Phase B was slowly added to the main manufacturing vessel with mixing until a homogenous gel was obtained.

[0119] [Example 12] Topical gel formulations containing dutasteride A 0.05% w / w topical formulation for application may be prepared as follows:

[0120] [Table 19]

[0121] The ingredients of Phase A were mixed in the main manufacturing vessel until a solution was obtained. Phase B was added to the main manufacturing vessel with homogenization and mixed until a uniform gel was obtained.

[0122] [Example 13] Topical gel (serum) formulations containing dutasteride A 0.05% w / w topical formulation for application may be prepared as follows: (2019-045-61)

[0123] [Table 20]

[0124] The ingredients of Phase A were mixed in the main manufacturing vessel until a solution was obtained. Phase A was then heated to 60-65° C. Phase B was weighed into a separate vessel and heated to 60-65° C. Phase B was then slowly added to the main manufacturing vessel and mixed until a homogenous gel was obtained and the temperature was ≦30° C.

[0125] [Example 14] Analysis of Dutasteride / Excipient Binary Compatibility Studies Samples were weighed out (approximately 500mg-100mg sample in 40mL VOA vials). Samples were thoroughly dispersed in 5.0mL hexane by vortexing. Sonication was also used, if necessary, to thoroughly disperse the sample. 10mL of diluent (water / acetonitrile: 40 / 60) was added to the VOA vial and mixed by vortexing. Aliquots were filtered through 0.45μm PTFE filters into autosampler vials for HPLC analysis. A six-point calibration curve was prepared with dutasteride ranging from 10μg / mL-200μg / mL in diluent as a standard.

[0126] The samples were analyzed by HPLC for the following parameters:

[0127] [Table 21]

[0128] Various combinations of dutasteride with excipients were tested at T=0 and T=14 days after storage at 50° C. to determine their stability and compatibility of dutasteride with different excipients. The results of the study are reported in FIG.

[0129] [Example 15] Treatment of human subjects suffering from alopecia with a topical composition of dutasteride Topical compositions of dutasteride, such as those described in Examples 1-13, can be applied for multiple days to the scalp of a human subject suffering from alopecia.

[0130] A two-group randomized, parallel-group comparative study can be conducted: Group I: 10 human subjects can receive 1 mL (1 mg) of the topical formulation of Example 1 applied to the scalp once daily (qd) or twice daily (bid) for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0131] The second group can receive a placebo without dutasteride applied to the scalp once daily (qd) or twice daily (bid) for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0132] For each of both groups, hair diameter increase, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), scalp coverage, hair structure, and target area hair density (TAHD) can be measured every 2 weeks, or every 4 weeks, or every 8 weeks, or every 12 weeks.

[0133] An increase in hair diameter, target area hair count (TAHC), target area hair width (TAHW), scalp coverage, hair structure, or target area hair density (TAHD) in Group 1 individuals compared to Group 2 individuals indicates a positive response to topical treatment with dutasteride for alopecia.

[0134] [Example 16] Treatment of women suffering from hirsutism with a topical dutasteride composition Two randomized parallel group comparative studies can be conducted: Group I: 10 women suffering from hirsutism can receive 1 mL (1 mg) of a topical formulation of dutasteride, such as those described in Examples 1-13, applied to the face once daily (qd) or twice daily (bid) for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0135] The second group can receive a placebo without dutasteride applied to the face once daily (qd) or twice daily (bid) for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0136] For each of both groups, hair diameter reduction, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), hair structure, and target area hair density (TAHD) can be measured every 2 weeks, or every 4 weeks, or every 8 weeks, or every 12 weeks.

[0137] The reduction in facial hair diameter, target area hair count (TAHC), facial hair width (TAHW), hair structure, and facial hair density (TAHD) in women in group 1 compared to group 2 indicates a positive response to topical treatment with dutasteride for hirsutism.

[0138] [Example 17] Treatment of Men Suffering from Hirsutism with a Topical Dutasteride Composition Two randomized parallel group comparative studies can be conducted: Group I: 10 men suffering from hirsutism can receive 1 mL (1 mg) of a topical formulation of dutasteride, such as those described in Examples 1-13, applied to the face once daily (qd) or twice daily (bid) for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0139] The second group can receive a placebo without dutasteride applied to the face once daily (qd) or twice daily (bid) for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0140] For each of both groups, hair diameter reduction, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), hair structure, and target area hair density (TAHD) can be measured every 2 weeks, or every 4 weeks, or every 8 weeks, or every 12 weeks.

[0141] The reduction in facial hair diameter, target area hair count (TAHC), facial hair width (TAHW), hair structure, and facial hair density (TAHD) in women in group 1 compared to group 2 indicates a positive response to topical treatment with dutasteride for hirsutism.

[0142] [Example 18] Treatment of women with hair loss secondary to endocrine therapy in breast cancer patients Two randomized parallel group comparative studies can be conducted. Group I: 20 women suffering from hair loss secondary to endocrine therapy in breast cancer patients can receive dutasteride 0.5 mg in a topical formulation, such as those described in Examples 1-13, applied once daily (qd) or twice daily (bid) to the affected areas of the scalp for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0143] The second group may receive a placebo without dutasteride applied to the affected areas of the scalp once daily (qd) or twice daily (bid) for at least 1 week, or up to 12 weeks.

[0144] For each of both groups, hair diameter increase, hair count in the target area (TAHC), hair growth assessment (HGA), hair width in the target area (TAHW), scalp coverage, hair structure, and hair density in the target area (TAHD) can be measured.

[0145] An increase in hair diameter, target area hair count (TAHC), target area hair width (TAHW), scalp coverage, hair structure, or target area hair density (TAHD) in Group 1 individuals compared to Group 2 individuals indicates a positive response to topical treatment with dutasteride for alopecia.

[0146] [Example 19] Treatment of human subjects suffering from alopecia with a topical composition of dutasteride A patient suffering from alopecia may apply a dose of a topical formulation of dutasteride. The topical formulation of dutasteride may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The topical formulation of dutasteride may be administered to the affected area once, hourly, twice a day, three times a day, four times a day, or daily (once a day), for one day, or every two days, or every three days, or every four days, or every five days, or every six days, or every week, for at least four weeks, or at least eight weeks, or at least twelve weeks, or at least sixteen weeks.

[0147] [Example 20] Treatment of women suffering from hirsutism with a topical dutasteride composition A patient suffering from hirsutism may apply a dose of a topical formulation of dutasteride. The topical formulation of dutasteride may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The topical formulation of dutasteride may be administered to the affected area once, hourly, twice a day, three times a day, four times a day, or daily (once a day), for one day, or every two days, or every three days, or every four days, or every five days, or every six days, or weekly, for at least four weeks, or at least eight weeks, or at least twelve weeks, or at least sixteen weeks.

[0148] [Example 21] Treatment of Men Suffering from Hirsutism with a Topical Dutasteride Composition A patient suffering from hirsutism may apply a dose of a topical formulation of dutasteride. The topical formulation of dutasteride may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The topical formulation of dutasteride may be administered to the affected area once, hourly, twice a day, three times a day, four times a day, or daily (once a day), every day, or every second day, or every third day, or every fourth day, or every fifth day, or every sixth day, or every week, for at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks.

[0149] [Example 22] Treatment of women with hair loss secondary to endocrine therapy in breast cancer patients Patients suffering from breast cancer and hair loss secondary to endocrine therapy may apply a dose of a topical formulation of dutasteride. The topical formulation of dutasteride may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The topical formulation of dutasteride may be administered to the affected area once, hourly, twice a day, three times a day, four times a day, or daily (once a day), for one day, or every two days, or every three days, or every four days, or every five days, or every six days, or weekly, for at least four weeks, or at least eight weeks, or at least twelve weeks, or at least sixteen weeks.

[0150] The invention has been described broadly and generically herein. Each narrower species and subgeneric grouping that falls within the scope of the generic disclosure is also part of the method. This includes the general description of the method, but with a proviso or negative limitation that removes any subject matter from the genus, whether or not the deleted material is specifically described herein.

[0151] Other embodiments are within the scope of the following claims. Furthermore, when features or aspects of the methods are described in terms of a Markush group, one of skill in the art will recognize that the invention is thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims

1. 1. A method of stimulating hair growth in the scalp of a human subject, comprising: a) providing a topical composition comprising a therapeutically effective amount of dutasteride and / or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative of dutasteride and / or finasteride, and a pharma- ceutically acceptable topical excipient or carrier; and b) topically applying the composition to the scalp in an amount and for a time sufficient to stimulate hair growth. Including, The method, wherein hair growth comprises an increase in hair density, hair diameter, or scalp coverage.

2. 13. The method of claim 1, wherein the human subject is suffering from a condition selected from the group consisting of androgenetic alopecia (AGA), alopecia areata, and endocrine therapy-induced alopecia (ETIA).

3. 3. The method of claim 2, wherein the ETIA is hair loss secondary to endocrine therapy for breast cancer.

4. 4. The method of any one of claims 1 to 3, wherein the composition is applied to the scalp in areas including the frontal, central, and parietal regions of the scalp, or a combination thereof.

5. 5. The method of any one of claims 1 to 4, wherein the hair growth further comprises improved scalp coverage and improved hair structure.

6. 1. A method for reducing facial hair growth in a human subject diagnosed with hirsutism, comprising: a) providing a topical composition comprising a therapeutically effective amount of dutasteride and / or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative of dutasteride and / or finasteride, and a pharma- ceutically acceptable topical excipient or carrier; and b) topically applying the composition to the subject's skin at the site of facial hair growth in an amount and for a time sufficient to reduce facial hair density, facial hair diameter, or both. The method includes:

7. 7. The method of claim 6, wherein the reduction in facial hair growth comprises a decrease in at least one of facial hair diameter, target area hair count (TAHC), facial hair width (TAHW), hair structure, and facial hair density (TAHD).

8. 1. A method for reducing excess facial or bodily hair growth in a human subject diagnosed with hirsutism, comprising: a) providing a topical composition comprising a therapeutically effective amount of dutasteride and / or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative of dutasteride and / or finasteride, and a pharma- ceutically acceptable topical excipient or carrier; and b) topically applying the composition to the skin of the subject at the site of facial or body hair growth in an amount and for a time sufficient to reduce facial or body hair density, facial or body hair diameter, or both. The method includes:

9. 9. The method of claim 8, wherein the reduction in facial or body hair growth comprises a decrease in at least one of facial or body hair diameter, target area hair count (TAHC), facial or body hair width (TAHW), hair structure, and facial or body hair density (TAHD).

10. 10. The method of any one of claims 1 to 9, wherein the human subject is female, male, transgender or non-binary.

11. 11. The method of any one of claims 1 to 10, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.001% to about 1% (w / w).

12. 12. The method of claim 11, wherein the therapeutically effective amount of dutasteride or finasteride is about 0.002% to about 0.1% (w / w).

13. 13. The method of claim 12, wherein the therapeutically effective amount of dutasteride or finasteride is about 0.075% (w / w).

14. 14. The method of any one of claims 1 to 13, wherein the topical composition further comprises a surfactant, a penetration enhancer, an antioxidant, a buffering agent, a preservative, a viscosity modifier, a chelating agent, a colorant, a fragrance, a polymer, a gelling agent, an alcohol, a liquid or semi-solid oily component, or any combination thereof.

15. 15. The method of any one of claims 1 to 14, wherein the pharma- ceutically acceptable topical excipient or carrier comprises ethanol, polypropylene glycol, purified water, or a combination thereof.

16. 16. The method of any one of claims 1 to 15, wherein the dutasteride or finasteride is in the form of nanoparticles.

17. 17. The method of any one of claims 1 to 16, wherein the topical composition further comprises at least one of a solvent, a humectant, a thickening agent, a preservative, an emollient, an emulsifier, a pH adjuster, a penetration enhancer, a conditioning agent, and combinations thereof.

18. 18. The method of any one of claims 1 to 17, wherein the topical composition further comprises at least one of a solvent, a moisturizing solvent, a thickening agent, a preservative, an emollient, a cationic emulsifier, an emulsifier, a non-ionic emulsifier, a pH adjuster, a penetration enhancer, a conditioning agent, a preservative, a thickening agent, a viscosity enhancer, and combinations thereof.

19. 19. The method of any one of claims 1 to 18, further comprising a therapeutically effective amount of minoxidil.

20. 20. The method of any one of claims 1 to 19, wherein the composition is in the form of a lotion, serum, foam, cream, paste, gel, aerosol, powder, oil, or liquid.

21. A topical composition comprising a therapeutically effective amount of dutasteride and / or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative of dutasteride and / or finasteride, and a pharma- ceutically acceptable topical excipient or carrier.

22. 22. The composition of claim 21, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.001% to about 1% (w / w).

23. 22. The composition of claim 21, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.002% to about 0.1% (w / w).

24. 22. The composition of claim 21, wherein the therapeutically effective amount of dutasteride or finasteride is about 0.075% (w / w).

25. 25. The composition of any one of claims 21 to 24, wherein the dutasteride or finasteride is in the form of nanoparticles.

26. 26. The composition of any one of claims 21 to 25, in the form of a lotion, serum, foam, cream, paste, gel, aerosol, powder, oil, or liquid.

27. 27. The composition of any one of claims 21 to 26, further comprising a therapeutically effective amount of minoxidil.

28. 28. The composition of any one of claims 21 to 27, which does not contain ethyl alcohol, polypropylene glycol, or both.

29. 29. The composition of any one of claims 21 to 28, further comprising a surfactant, a co-surfactant, a penetration enhancer, an antioxidant, a buffering agent, a solubilizing agent, a preservative, a viscosity modifier, a chelating or complexing agent, a colorant, a fragrance, a polymer, a gelling agent, an alcohol, a liquid or semi-solid oily component, or any combination thereof.

30. The pharma- ceutically acceptable topical carrier may be paraffin oil, C 8 ~C 18 Esters of organic acids, C 8 ~C 30 30. The composition of any one of claims 21 to 29, comprising a lipophilic material comprising a fatty alcohol, a silicone oil, a vegetable oil, a fractionated or hydrogenated vegetable oil, a monoglyceride, a diglyceride, a triglyceride, a phospholipid, dimethylisosorbide, a volatile solvent, N-methylpyrrolidone, dimethylacetamide, dimethylformamide; dimethylsulfoxide, or any combination thereof.

31. 31. The composition of any one of claims 21 to 30, wherein the pharma- ceutically acceptable topical excipient or carrier comprises ethanol, polypropylene glycol, purified water, or a combination thereof.

32. 32. The composition of any one of claims 21 to 31, further comprising at least one of a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, a pH adjuster, a penetration enhancer, a conditioning agent, and combinations thereof.

33. 33. The composition of any one of claims 21 to 32, further comprising at least two of a cationic emulsifier, a conditioning agent, an emollient, an emulsifier, a moisturizing solvent, a non-ionic emulsifier, a penetration enhancer, a pH adjuster, a preservative, a solvent, a thickener, a viscosity enhancer, and any combination thereof.

34. 34. The composition of any one of claims 21 to 33, further comprising a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a penetration enhancer.

35. 35. The composition of any one of claims 21 to 34, further comprising a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, a pH adjuster, and a penetration enhancer.

36. 36. The composition of any one of claims 21 to 35, further comprising a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a conditioning agent.

37. 37. The composition of any one of claims 21 to 36, further comprising a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, a pH adjuster, a penetration enhancer, and a conditioning agent.

38. 38. The composition of any one of claims 21 to 37, further comprising a solvent, a thickener, an emollient, and a penetration enhancer.

39. 39. The composition of any one of claims 21 to 38, further comprising a solvent, a viscosity enhancer, an emollient, and a penetration enhancer.

40. 40. The composition of any one of claims 21-39, further comprising a penetration enhancer selected from the group consisting of medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, diethylene glycol monoethyl ether, oleyl alcohol, dehydrated alcohol, benzyl alcohol, laureth-4, and dimethyl isosorbide.

41. 41. The composition of any one of claims 21 to 40, further comprising a solvent selected from the group consisting of sterile water, glycerin, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, olive oil, castor oil, coconut oil, light mineral oil, diethylene glycol monoethyl ether, diethyl sebacate, benzyl alcohol, cyclomethicone, PEG 400, dehydrated alcohol, and dimethyl isosorbide.

42. 42. The composition of any one of claims 21 to 41, further comprising a moisturizer selected from the group consisting of sodium hyaluronate, glycerin, sorbitol solution 70%, and methyl gluceth-20.

43. 43. The composition of any one of claims 21 to 42, further comprising a thickening agent selected from the group consisting of xanthan gum, cetearyl alcohol, Promulgen D, Carbopol 974P NF polymer, Pemulen TR-2, Pemulen TR-1, Klucel HG Pharm, Carbopol 980 NF, polymer, and Sepineo P 600.

44. 44. The composition of any one of claims 21 to 43, further comprising a preservative selected from the group consisting of methylparaben and propylparaben.

45. 45. The composition of any one of claims 21 to 44, further comprising an emollient selected from the group consisting of olive oil, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, castor oil, light mineral oil, cyclomethicone, diethyl sebacate, benzyl alcohol, PEG-35 castor oil, and coconut oil.

46. 46. ​​The composition of any one of claims 21 to 45, further comprising an emulsifier selected from the group consisting of Bridge L4, Arlacel 165, Tween 20, Bridge S721, Bridge S2, Promulgen D, Stearalkonium Chloride, Pemulen TR-2, Pemulen TR-1, Sodium Monostearate, Sepineo P 600, Laureth-4, Polysorbate 20, and PEG-35 Castor Oil.

47. 47. The composition of any one of claims 21 to 46, further comprising a pH adjuster selected from the group consisting of solutions of NaOH and HCl.

48. 48. The composition of any one of claims 21 to 47, further comprising a conditioning agent selected from the group consisting of stearalkonium chloride and polyquaternium-10.

49. 49. The composition of any one of claims 21 to 48, further comprising Laureth-4.

50. 50. The composition of any one of claims 21 to 49, further comprising PEG 3350.

51. dutasteride and / or finasteride, or pharma- ceutically acceptable salts, esters, or derivatives of dutasteride and / or finasteride, dissolved in an oil phase comprising at least one oil; and Pharmaceutically acceptable topical excipient or carrier 13. A topical formulation comprising:

52. 52. The formulation of claim 51, which is an emulsion.

53. 53. A formulation according to claim 51 or 52, wherein the oil phase comprises a medium chain triglyceride oil.

54. 54. The formulation of any one of claims 51 to 53, wherein at least one oil is olive oil.

55. 55. The formulation of any one of claims 51 to 54, wherein the oil phase comprises oleyl alcohol, isopropyl myristate, diethyl sebacate, and combinations thereof.

56. 56. The formulation of any one of claims 51 to 55, wherein the oil phase comprises at least 2, 3, 4, or 5 or more oils.

57. 57. A formulation according to any one of claims 51 to 56, wherein the oil phase comprises a medium chain triglyceride oil and olive oil.

58. 58. A formulation according to any one of claims 51 to 57, wherein the oil phase further comprises at least one solvent.

59. 59. The formulation of claim 58, wherein the at least one solvent is benzyl alcohol, diisopropyl acetate, isopropyl palmitate, and combinations thereof.

60. 60. The formulation of any one of claims 51 to 59, further comprising a humectant, a thickener, an emulsifier, and a preservative.

61. 61. The formulation of any one of claims 51 to 60, which does not contain ethyl alcohol, polypropylene glycol, or both.

62. 62. The composition of any one of claims 51 to 61, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.001% to about 1% (w / w).

63. 63. The composition of any one of claims 51 to 62, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.002% to about 0.1% (w / w).

64. 64. The composition of any one of claims 51 to 63, wherein the therapeutically effective amount of dutasteride or finasteride is about 0.075% (w / w).

65. 1. A method of preparing a topical formulation comprising the steps of: mixing a first conditioning agent and a first preservative with a first solvent to form a conditioning solution; mixing dutasteride or finasteride, at least one oil, and at least one solvent to obtain a dutasteride / finasteride solution; mixing the first emulsifier and the second preservative with the dutasteride / finasteride solution to obtain a dutasteride / finasteride emulsion solution; mixing the dutasteride / finasteride emulsifier solution and the conditioning solution to obtain a combined solution; mixing a second conditioning agent and a solvent to form a second conditioning solution; and Mixing the second conditioning solution and the combined solution to form a combined dutasteride / finasteride solution. The method includes:

66. 66. The method of claim 65, wherein the first preservative is methylparaben.

67. 67. The method of claim 65 or 66, wherein the first conditioning agent is stearalkonium chloride.

68. 68. The method of any one of claims 65 to 67, wherein the first preservative and the second preservative comprise a paraben.

69. 69. The method of any one of claims 65 to 68, wherein the first preservative and the second preservative are each independently selected from the group consisting of methylparaben and propylparaben.

70. 70. The method of any one of claims 65 to 69, wherein the first solvent is water, glycerin, or a combination thereof.

71. 71. The method of any one of claims 65 to 70, wherein the at least one oil is selected from the group consisting of olive oil, medium chain triglycerides, and combinations thereof.

72. 72. The method of any one of claims 65 to 71, wherein the at least one solvent is benzyl alcohol, diisopropyl adipate, or a combination thereof.

73. 73. The method of any one of claims 65 to 72, wherein the first emulsifier is Promulgen D.

74. 74. The method of any one of claims 65 to 73, wherein the second conditioning agent is polyquaternium-10.

75. 75. The method of any one of claims 65 to 74, wherein the step of combining the first conditioning agent and the first solvent comprises heating to 70-75°C.

76. 76. The method of any one of claims 65 to 75, wherein the step of mixing dutasteride or finasteride, at least one oil, and at least one solvent to obtain a dutasteride / finasteride solution comprises heating to 70-75°C.

77. 77. The method of any one of claims 65 to 76, wherein the step of combining the first emulsifier and the second preservative with the dutasteride / finasteride solution to obtain a dutasteride / finasteride emulsifier solution comprises heating to 70-75°C.

78. 78. The method of any one of claims 65 to 77, wherein the step of mixing the dutasteride / finasteride emulsifier solution and the conditioning solution to obtain a combined solution comprises heating to 70-75°C and homogenizing.

79. 79. The method of any one of claims 65-78, further comprising cooling the combined dutasteride / finasteride solution to less than about 30°C after mixing the combined solution with the second conditioning solution.

80. 80. The method of any one of claims 65-79, further comprising adding sterile water to the combined dutasteride / finasteride solution after cooling to below about 30°C.

81. 1. A method of preparing a topical formulation comprising the steps of: mixing a humectant with water to form a humectant solution; mixing a thickening agent and a first solvent to form a thickening agent solution; mixing a thickener solution with a humectant solution to form a combined solution; mixing a preservative into the combined solution to form a combined preservative solution; mixing dutasteride or finasteride and a second solvent to form a dutasteride / finasteride solution; mixing at least one oil into the dutasteride / finasteride solution to form a dutasteride / finasteride oil mixture; mixing at least one emulsifier with the dutasteride / finasteride oil mixture to form a second dutasteride / finasteride oil mixture; and mixing the second dutasteride / finasteride oil mixture with the combined preservative solution in a container. The method includes:

82. 82. The method of claim 81, wherein the moisturizer is mixed with the water with agitation to form a moisturizer solution.

83. 83. The method of claim 81 or 82, wherein dutasteride and the second solvent are mixed together under homogenization to form a dutasteride / finasteride solution.

84. 84. The method of any one of claims 81 to 83, wherein the step of combining the second solvent and dutasteride or finasteride comprises heating to about 70-75°C.

85. 85. The method of any one of claims 81 to 84, wherein the step of mixing at least one emulsifier and the dutasteride / finasteride oil mixture to form a second dutasteride / finasteride oil mixture comprises heating.

86. 86. The method of any one of claims 81 to 85, wherein the second dutasteride / finasteride oil mixture is mixed with the combined preservative solution while heating to about 70-75°C.

87. 87. The method of any one of claims 81 to 86, further comprising cooling the container to less than about 30°C after mixing the second dutasteride / finasteride oil mixture and the combined preservative solution.

88. 88. The method of any one of claims 81 to 87, wherein the moisturizing agent is selected from the group consisting of sodium hyaluronate and glycerin.

89. 89. The method of any one of claims 81 to 88, wherein the thickening agent is selected from the group consisting of xanthan gum and cetearyl alcohol.

90. 90. The method of any one of claims 81 to 89, wherein the preservative is selected from the group consisting of paraben, methylparaben, and propylparaben.

91. 91. The method of any one of claims 81 to 90, wherein at least one oil is a medium chain glyceride.

92. 92. The method of any one of claims 81 to 91, wherein the at least one emulsifier is selected from the group consisting of Arlacel 165, sodium monostearate, and combinations thereof.

93. a therapeutically effective amount of dutasteride and / or finasteride, or a pharma- ceutically acceptable salt, ester, or derivative of dutasteride and / or finasteride, dissolved in an aqueous phase; and Pharmaceutically acceptable topical excipient or carrier 13. A topical formulation comprising:

94. 94. The formulation of claim 93, which is an emulsion.

95. 95. The formulation of claim 93 or 94, wherein the aqueous phase further comprises a penetration enhancer.

96. 96. The formulation of any one of claims 93 to 95, wherein the aqueous phase further comprises a solubilizing agent.

97. 97. The formulation of any one of claims 93 to 96, wherein the aqueous phase further comprises diisopropyl adipate.

98. 98. The formulation of any one of claims 93 to 97, further comprising a thickening agent, a softening agent, a pH adjusting agent, a preservative, and a conditioning agent.

99. 99. The formulation of any one of claims 93 to 98, further comprising an oil phase.

100. 100. The formulation of claim 99, wherein the oil phase comprises a medium chain triglyceride.

101. 101. The formulation of claim 99 or 100, wherein the oil phase further comprises an emulsifier.

102. 102. The formulation of any one of claims 99 to 101, wherein the oil phase further comprises a thickening agent and a preservative.

103. 103. The composition of any one of claims 93 to 102, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.001% to about 1% (w / w).

104. 103. The composition of any one of claims 93 to 102, wherein the therapeutically effective amount of dutasteride or finasteride is from about 0.002% to about 0.1% (w / w).

105. 103. The composition of any one of claims 93 to 102, wherein the therapeutically effective amount of dutasteride or finasteride is about 0.075% (w / w).

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