Topical composition containing dutasteride and minoxidil for alopecia

Abstract

The present invention relates to a composition comprising minoxidil and dutasteride and one or more pharmaceutically acceptable excipients. The present invention also relates to a method for preparing such a composition. Furthermore, the present invention relates to the topical application of a composition for preventing hair loss and / or promoting hair growth. Additionally, the present invention relates to achieving acceptable pharmacokinetic parameters to provide beneficial therapeutic effects while minimizing side effects.

Description

Technology Field

[0001] Related applications

[0002] This application claims the benefit of Indian provisional patent No. 202321086964 filed on December 19, 2023, the full text of which is incorporated herein by reference.

[0003] Technology field

[0004] The present invention relates to a composition comprising minoxidil and dutasteride and one or more pharmaceutically acceptable excipients. The present invention also relates to a method for preparing such a composition. Furthermore, the present invention relates to the topical application of a composition for the prevention of hair loss and / or the promotion of hair growth. Additionally, the present invention relates to achieving acceptable pharmacokinetic parameters to provide a beneficial therapeutic effect while minimizing side effects. Background Technology

[0005] Hair loss is a natural phenomenon. Hair growth follows a cycle that includes the creation and development of hair follicles, a resting phase, and the final stage of shedding. This cycle between the growth phase, the regression phase, and the resting phase is driven by specific secretions from hair follicles acting as glands; the follicles gradually produce clumps of keratin, which are shed after the resting phase and replaced with new keratin.

[0006] This cycle begins with the development of the hair follicle originating from the dermis, which contains numerous mesenchymal cells, leading to the formation of the dermal papilla. In the final stage (the growth phase), the cells surrounding the dermal papilla divide actively every 12 hours, producing cells that line up, grow longer, and begin to keratinize. This is hair growth. During the regression phase, mitosis no longer occurs, and the hair bulb detaches from the papilla and rises toward the surface. In the resting phase, the hair becomes fully keratinized and ready to be shed. After three to four months, another cell division cycle begins in the hair's germination zone, and another hair follicle is formed.

[0007] As male pattern baldness depends on male hormones, it is directly related to the amount of male hormones. Therefore, extensive research aimed at preventing and treating hair loss by inhibiting the activity of male hormones has recently been reported. The mechanism of hair loss related to male hormones is briefly explained below. Testosterone, a male hormone, is converted into the active male hormone dihydrotestosterone by 5α-reductase. This active male hormone binds to specific receptors and produces proteins that induce hair loss, thereby causing hair loss. Furthermore, this mechanism leads to the excessive production of sebum, causing acne or seborrheic dermatitis, which ultimately results in hair loss accompanied by inflammation of the scalp. Therefore, the cause of male pattern baldness is the excessive synthesis of dihydrotestosterone; consequently, male pattern baldness can be effectively prevented and treated by competitively inhibiting the binding of androgen dihydrotestosterone to androgen receptors in the sebaceous glands and hair follicles.

[0008] Treatments for various forms of hair loss have achieved only limited success. Three drugs with evidence supporting their use in male pattern baldness are oral finasteride (PROPECIA®, Merck), oral dutasteride, and topical minoxidil (ROGAINE®, Pfizer / Johnson & Johnson). These treatments require long-term use of the medication, and if treatment is discontinued, the effects gained are lost and hair thickness returns to the level seen when treatment was not received. Reversible side effects associated with the use of these androgen inhibitors have been reported, including decreased libido, erectile dysfunction, and skin discomfort.

[0009] The mechanism of action of minoxidil, which was approved by the U.S. Food and Drug Administration (FDA) as a hair loss treatment in 1979, has not been clearly elucidated. However, the mechanism of action has been explained by two hypotheses: one that minoxidil promotes hair growth by increasing blood flow to hair follicles, and another that it induces hair growth by acting directly on the follicular epithelium. However, hair restoration agents containing minoxidil must be applied several times a day to maintain the hair growth effect, which is very cumbersome and easy to forget. Consequently, in many cases, the hair growth effect is not fully achieved due to irregular application and the arbitrary discontinuation of treatment. Furthermore, if topical application of minoxidil is interrupted or discontinued, the subject gradually loses the regrowthed hair.

[0010] IN 378724 discloses a topical composition comprising one or more hair growth promoters, at least one acidifying agent, and a suitable carrier system.

[0011] US 10993934 B2 discloses a topical composition of dutasteride for preventing hair loss and androgenetic alopecia (AA) and for promoting hair growth. The topical composition for preventing hair loss and promoting hair growth provides equivalent or superior hair loss prevention and hair growth promotion effects at a much lower dose than existing compositions (oral administration forms) using finasteride and dutasteride.

[0012] US 2012 / 0258972A1 discloses a method for treating hair loss caused by androgenetic alopecia and / or male pattern baldness.

[0013] Androgenetic alopecia is a common type of hair loss in both men and women. In men, this condition is known as male pattern baldness. Some of the current challenges facing AGA include the following:

[0014] Understanding the underlying causes. Despite significant progress in understanding the genetics and biology of AGA, there are still many aspects of this pathological condition that are not fully understood. Researchers are still working to identify the precise genetic and environmental factors that contribute to AGA.

[0015] Development of effective treatments. Although several treatments for AGA are available, including medication and hair transplant surgery, a fundamental cure for this condition still does not exist. Current treatments are often expensive, time-consuming, and may have side effects.

[0016] Addressing Psychological Impacts. AGA can have a significant psychological impact on individuals suffering from the condition, potentially leading to anxiety, depression, and low self-esteem. Further research is needed to better understand the psychological aspects of AGA and develop effective intervention strategies to address these issues.

[0017] Hair Loss Prevention. While treatments exist to slow down or even reverse hair loss in some cases, completely preventing it remains a difficult task. Lifestyle changes, such as reducing stress and maintaining a healthy diet, can be helpful, but more research is needed to identify the most effective methods for preventing hair loss.

[0018] Overall, the issues of AGA highlight the need for continuous research and development of new and more effective treatments, as well as the need for increased attention to the psychological impact of this condition.

[0019] The method described herein constitutes a major improvement over currently available treatments for alopecia, particularly AGA, and enables physicians to obtain an effective, valuable, and safe treatment for alopecia, particularly AGA.

[0020] The present invention relates to a composition comprising a. a pharmaceutically effective amount of a 5α-reductase inhibitor, b. a pharmaceutically effective amount of a vasodilator, and c. a pharmaceutically acceptable vehicle.

[0021] The present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. a pharmaceutically effective amount of a 5α-reductase inhibitor, b. a pharmaceutically effective amount of a vasodilator, and c. a pharmaceutically acceptable vehicle.

[0022] The present invention relates to a composition comprising a. a pharmaceutically effective amount of dutasteride, b. a pharmaceutically effective amount of minoxidil, and c. a pharmaceutically acceptable vehicle.

[0023] The present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. a pharmaceutically effective amount of dutasteride, b. a pharmaceutically effective amount of minoxidil, and c. a pharmaceutically acceptable vehicle.

[0024] Surprisingly, the inventors of the present invention discovered that a combination therapy using dutasteride and minoxidil is an effective approach for treating androgenetic alopecia (AGA).

[0025] Combining dutasteride and minoxidil can target different modes of the hair loss process, potentially providing a more comprehensive and effective treatment for AGA. However, it should be noted that combination therapy may increase the risk of side effects such as scalp irritation, dizziness, and sexual dysfunction.

[0026] The present invention relates to a composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein at least one of the active ingredients is partially solubilized.

[0027] In another embodiment, the present invention relates to a composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein dutasteride is partially solubilized, supersaturated, or suspended.

[0028] In another embodiment, the present invention relates to a composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein minoxidil is partially solubilized, supersaturated, or suspended.

[0029] In another embodiment, the present invention relates to a composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein dutasteride and minoxidil are completely solubilized.

[0030] In another embodiment, the present invention relates to a stable composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle.

[0031] In another embodiment, the present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein dutasteride is partially solubilized and minoxidil is solubilized.

[0032] In another embodiment, the present invention relates to a composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein minoxidil is partially solubilized and dutasteride is solubilized.

[0033] In another embodiment, the present invention relates to a sol-gel technology-based in situ (in which a phase transition from liquid to gel occurs upon exposure to a physiological environment) in situ This relates to a gel-forming formulation. This technology provides the advantages of being convenient to administer to patients while simultaneously extending drug delivery.

[0034] In another embodiment, the present invention relates to a stable composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein the composition is stable at room temperature for a period of at least about one month.

[0035] In another embodiment, the present invention relates to a stable composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein the composition is stable at room temperature for a period of at least about 2 months.

[0036] In another embodiment, the present invention relates to a stable composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein the composition is stable at room temperature for a period of at least about 3 months.

[0037] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more penetration enhancers.

[0038] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more solubilizing agents.

[0039] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more stabilizers.

[0040] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more surfactants.

[0041] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more viscosity modifiers.

[0042] In another aspect, the present invention relates to a topical composition comprising a. dutasteride, b. minoxidil, and c. one or more solvent(s) and a pharmaceutically acceptable vehicle.

[0043] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more acidifying agents.

[0044] In another aspect, the present invention relates to a topical composition comprising a pharmaceutically acceptable vehicle comprising a. dutasteride, b. minoxidil, and c. one or more emulsifiers.

[0045] In another aspect, the present invention relates to a topical composition comprising a. about 0.001% w / w to about 1% w / w of dutasteride or a pharmaceutically acceptable salt thereof, b. about 1% w / w to about 20% w / w of minoxidil or a pharmaceutically acceptable salt thereof, and c. a pharmaceutically acceptable vehicle.

[0046] In another aspect, the present invention relates to a topical composition comprising a. about 0.01% w / w to about 0.1% w / w of dutasteride or a pharmaceutically acceptable salt thereof, b. about 2% w / w to about 15% w / w of minoxidil or a pharmaceutically acceptable salt thereof, and c. a pharmaceutically acceptable vehicle.

[0047] In another aspect, the present invention relates to a topical composition comprising a. about 0.02% w / w to about 0.08% of dutasteride or a pharmaceutically acceptable salt thereof, b. about 5% w / w to about 10% w / w of minoxidil or a pharmaceutically acceptable salt thereof, and c. a pharmaceutically acceptable vehicle.

[0048] In another aspect, the present invention relates to a topical composition comprising a. about 0.04% w / w to about 0.06% of dutasteride or a pharmaceutically acceptable salt thereof, b. about 5% w / w to about 10% w / w of minoxidil or a pharmaceutically acceptable salt thereof, and c. a pharmaceutically acceptable vehicle.

[0049] In another aspect, the present invention relates to a topical composition comprising a. about 0.05% w / w of dutasteride or a pharmaceutically acceptable salt thereof, b. about 5% w / w of minoxidil or a pharmaceutically acceptable salt thereof, and c. a pharmaceutically acceptable vehicle.

[0050] In another aspect, the present invention relates to a method for treating hair loss and / or promoting hair growth in a subject requiring the application of a formulation in the form of a composition for external application selected from the group consisting of hair tonics, solutions, dispersions, suspensions, emulsions, microemulsions, colloidal solutions, creams, ointments, lotions, hair dyes, shampoos, rinses, gels, patches, hair serums, foams, and sprays.

[0051] In another aspect, the present invention relates to a composition for external application selected from the group consisting of hair tonics, solutions, dispersions, suspensions, emulsions, microemulsions, colloidal solutions, creams, ointments, lotions, hair dyes, shampoos, rinses, gels, patches, hair serums, foams, and sprays. Brief explanation of the drawing

[0052] Fig. 1a . Effect of hair growth formulations on hair coverage rate. The line graph shows the hair coverage rate scores by date. Fig. 1b . Effect of hair growth formulations on hair coverage rate. The bar graph shows the terminal hair coverage rate score. Fig. 2 Effect of hair growth formulations on entry into the anagen phase. The line graph shows the number of mice in the anagen phase by day. Fig. 3 . Final macroscopic image of the mouse. Local placebo. Fig. 4 Final macroscopic image of the mouse: Topical dutasteride 0.05% Fig. 5 . Final macroscopic image of the mouse. Topical minoxidil 5% Fig. 6 Final macroscopic image of a mouse: Combination composition of topical dutasteride 0.05% and topical minoxidil 5%. Specific details for implementing the invention

[0053] Detailed descriptions of specific embodiments of the present invention in the form of topical compositions in the form of creams, ointments, gels, lotions, hair tonics, patches, hair serums, emulgels, emulsions, aerosol foams, solutions, sprays, suspensions, swabs, sponges, powders, or pastes are disclosed herein. It should be understood that the disclosed embodiments are merely examples of ways in which specific embodiments of the present application may be implemented and do not encompass all ways in which the present application may be implemented.

[0054] A. Dutasteride

[0055] Dutasteride is the chemical name ( It has )-N-{2,5-bis(trifluoromethyl)phenyl}-3-oxo-4-aziandrost-1-en-17-carboxamide. It has a structural formula similar to chemical formula I.

[0056]

[0057] Chemical Formula I

[0058] Dutasteride is a synthetic 4-azasteroid compound that selectively inhibits both type I and type II isoforms of steroid 5α-reductase (5AR), an intracellular enzyme that converts testosterone into 5α-dihydrotestosterone (DHT), and is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men. A drug containing dutasteride as the active ingredient is marketed by GlaxoSmithKline under the trade name AVODART®, which is in the form of a soft gelatin capsule for oral administration and contains 0.5 mg of the active ingredient.

[0059] The literature [R. Clerk et al., Journal of Clinical Endocrinology and Metabolism, Vol. 89, pp. 2179-2184, 2004] demonstrated that dutasteride has about 3 times higher efficacy in inhibiting type II 5α-reductase compared to finasteride, and more than 100 times higher efficacy in inhibiting type I isoforms.

[0060] Type I 5α-reductase is reported to be present primarily in the skin—specifically in both hair follicles and sebaceous glands—as well as in the liver, prostate, and kidneys, whereas Type II 5α-reductase is found in the male genitalia, prostate, and hair follicles. Due to the distribution of both isoforms of 5α-reductase in the skin, it has been hypothesized that dutasteride, a dual inhibitor, would be more useful in the treatment of AA compared to selective type 11 inhibitors such as finasteride. [Reference (S. Marihart et. al., Reviews in Urology, Vol. 7, pages 203-210, 2005)].

[0061] Dutasteride (0.5 mg / day) is approved in Korea, Japan, and Taiwan for the treatment of androgenetic alopecia. However, efficacy and safety data for dutasteride have been mostly derived from short-term clinical trials and post-marketing surveillance studies. Long-term real-world evidence regarding the efficacy of dutasteride in androgenetic alopecia is limited.

[0062] Orally administered dutasteride works by blocking the conversion of testosterone into DHT in the body, thereby preventing DHT from reaching the hair follicles. Due to oral use, it carries potential side effects associated with sexual dysfunction and neuropsychiatric adverse effects. Side effects include depression, chest pain, edema, sexual dysfunction, and suicidal thoughts.

[0063] When used topically, dutasteride can provide a local effective concentration while minimizing systemic concentration. When applied topically, it acts by blocking the conversion of DHT in the hair follicle, the site of action.

[0064] In addition, topical use of dutasteride targeting hair follicles helps reduce the concentration of dutasteride compared to oral administration, which is more helpful in reducing side effects.

[0065] The therapeutically effective amount of dutasteride is about 0.001% w / w to 1% w / w or about at least 0.01% w / w to about 0.5% w / w based on the total weight of the composition, or preferably about at least 0.01% w / w to about 0.07% w / w, or preferably about 0.03% w / w, most preferably about 0.05% w / w.

[0066] 특정 양태에서, 조성물 중 두타스테리드의 농도는 약 0.001 % w / w, 0.002 % w / w, 0.003 % w / w, 0.004 % w / w, 0.005 % w / w, 0.006 % w / w, 0.007 % w / w, 0.008 % w / w, 0.009 % w / w, 0.01 % w / w, 0.02 % w / w, 0.03 % w / w, 0.04 % w / w, 0.05 % w / w, 0.06 % w / w, 0.07 % w / w, 0.08 % w / w, 0.09 % w / w, 0.1 % w / w, 0.11 % w / w, 0.12 % w / w, 0.13 % w / w, 0.14 % w / w, 0.15 % w / w; 0.16 % w / w, 0.17 % w / w, 0.18 % w / w, 0.19 % w / w, 0.2 % w / w, 0.21 % w / w, 0.22 % w / w, 0.23 % w / w, 0.24 % w / w, 0.25 % w / w, 0.26 % w / w, 0.27 % w / w, 0.28 % w / w, 0.29 % w / w, 0.3 % w / w, 0.31 % w / w, 0.32 % w / w, 0.33 % w / w, 0.34 % w / w, 0.35 % w / w, 0.36 % w / w, 0.37 % w / w, 0.38 % w / w, 0.39 % w / w, 0.4 % w / w, 0.41 % w / w, 0.42 % w / w, 0.43 % w / w, 0.44 % w / w, 0.45 % w / w, 0.46 % w / w, 0.47 % w / w, 0.48 % w / w, 0.49 % w / w, 0.5 % w / w, 0.51 % w / w, 0.52 % w / w, 0.53 % w / w, 0.54 % w / w, 0.55 % w / w, 0.56 % w / w, 0.57 % w / w, 0.58 % w / w, 0.59 % w / w, 0.6 % w / w, 0.61 % w / w, 0.62 % w / w, 0.63 % w / w, 0.64 % w / w 0.65 %, 0.66 % w / w, 0.67 % w / w, 0.68 % w / w, 0.69 % w / w, 0.7 % w / w, 0.71 % w / w, 0.72 % w / w, 0.73 % w / w, 0.74 % w / w, 0.75 % w / w, 0.76 % w / w, 0.77 % w / w, 0.78 % w / w, 0.79 % w / w, 0.80 % w / w, 0.80 % w / w, 0.80 % w / w, 0.81 % w / w, 0.82 % w / w, 0.83 % w / w, 0.84 % w / w, 0.85 % w / w, 0.86 % w / w, 0.87 % w / w, 0.88 % w / w, 0.89 % w / w, 0.9 % w / w, 0.91 % w / w, 0.92 % w / w, 0.93 % w / w, 0.94 % w / w, 0.95 % It is selected from w / w, 0.96 % w / w, 0.97 % w / w, 0.98 % w / w, 0.99 % w / w, or 1 % w / w.

[0067] B. Minoxidil

[0068]

[0069] Chemical Formula II

[0070] Minoxidil is known to open adenosine triphosphate (ATP)-sensitive potassium channels and dilate blood vessels, thereby allowing more nutrients, blood, and oxygen to be supplied to the hair follicles. In the late resting phase of the hair follicle growth cycle, stem cells located in the bulge region differentiate to re-enter the growth phase. In patients with androgenetic alopecia, hair follicles become smaller and the growth phase is shortened. Minoxidil [involves] intracellular Ca 2+It increases the amount of, which can promote stem cell differentiation by upregulating adenosine triphosphate (ATP) synthase independently of its role in ATP synthesis. Minoxidil-induced Ca2+ influx can increase stem cell differentiation and has been theorized to be a factor in the mechanism by which minoxidil promotes hair growth [Mechanism of Action of Minoxidil in the Treatment of Androgenetic Alopecia, A. Gren et al., J Biol Regul Homeost Agents 31(4):1049-1053 (2017)].

[0071] There is some evidence that minoxidil can cause hair in the resting phase to fall out, and that this hair is replaced by newer, thicker hair in the growth phase. Minoxidil is a prodrug that is converted to minoxidil sulfate by the sulfotransferase enzyme SULT1A1.

[0072]

[0073] Furthermore, compared to minoxidil, minoxidil sulfate is a much more potent hair growth agent. Some studies speculate that the amount of the SULT1A1 enzyme present inside and outside the hair follicles is a factor determining whether an individual responds well to minoxidil.

[0074] The therapeutically effective amount of minoxidil is about 1% w / w to 20% w / w based on the total weight of the composition, or about at least 2% w / w to about 15% w / w, or preferably about at least 5% w / w to about 10% w / w, or most preferably about 5% w / w. In certain embodiments, the concentration of minoxidil in the composition is about 1% w / w, 1.1% w / w, 1.2% w / w, 1.3% w / w, 1.4% w / w, 1.5% w / w, 1.6% w / w, 1.7% w / w, 1.8% w / w, 1.9% w / w, 2% w / w, 2.1% w / w, 2.2% w / w, 2.3% w / w, 2.4% w / w, 2.5% w / w, 2.6% w / w, 2.7% w / w, 2.8% w / w, 2.9% w / w, 3% w / w, 3.1% w / w, 3.2% w / w, 3.3% w / w, 3.4% w / w, 3.5% based on the total weight of the composition. w / w, 3.6 % w / w, 3.7 % w / w, 3.8 % w / w, 3.9 % w / w, 4 % w / w, 4.1 % w / w, 4.2 % w / w, 4.3 % w / w, 4.4 % w / w, 4.5 % w / w, 4.6 % w / w, 4.7 % w / w, 4.8 % w / w, 4.9 % w / w, 5 % w / w, 5.1 % w / w, 5.2 % w / w, 5.3 % w / w, 5.4 % w / w, 5.5 % w / w, 5.6 % w / w, 5.7 % w / w, 5.8 % w / w, 5.9 % w / w, 6 % w / w, 6.1 % w / w, 6.2 % w / w, 6.3 % w / w, 6.4 % w / w, 6.5 % w / w, 6.6 % w / w, 6.7 % w / w, 6.8 % w / w, 6.9 % w / w, 7 % w / w, 7.1 % w / w, 7.2 % w / w, 7.3 % w / w, 7.4 % w / w, 7.5 % w / w, 7.6 % w / w, 7.7 % w / w, 7.8 % w / w, 7.9 % w / w, 8 % w / w, 8.1 % w / w, 8.2 % w / w, 8.3 % w / w, 8.4 % w / w, 8.5 % w / w, 8.6 % w / w, 8.7 % w / w, 8.8 % w / w, 8.9 % w / w, 9 % w / w, 9.1 % w / w, 9.2 % w / w, 9.3 % w / w, 9.4 % w / w, 9.5 % w / w, 9.6 % w / w, 9.7 % w / w, 9.8 % w / w, 9.9 % w / w, 10 % w / w, 10.1 % w / w, 10.2 % w / w, 10.3 % w / w, 10.4 % w / w, 10.5 % w / w, 10.6 % w / w, 10.7 % w / w, 10.8 % w / w, 10.9 % w / w, 11 % w / w, 11.1 % w / w, 11.2 % w / w, 11.3 % w / w, 11.4 % w / w, 11.5 % w / w, 11.6 % w / w, 11.7 % w / w, 11.8 % w / w, 11.9 % w / w, 12 % w / w, 12.1 % w / w, 12.2 % w / w, 12.3 % w / w, 12.4 % w / w, 12.5 % w / w, 12.6 % w / w, 12.7 % w / w, 12.8 % w / w, 12.9 % w / w, 13 % w / w, 13.1 % w / w, 13.2 % w / w, 13.3 % w / w, 13.4 % w / w, 13.5 % w / w, 13.6 % w / w, 13.7 % w / w, 13.8 % w / w, 13.9 % w / w, 14 % w / w, 14.1 % w / w, 14.2 % w / w, 14.3 % w / w, 14.4 % w / w, 14.5 % w / w, 14.6 % w / w, 14.7 % w / w, 14.8 % w / w, 14.9 % w / w, 15 % w / w, 15.1 % w / w, 15.2 % w / w, 15.3 % w / w, 15.4 % w / w, 15.5 % w / w, 15.6 % w / w, 15.7 % w / w, 15.8 % w / w, 15.9 % w / w, 16 % w / w, 16.1 % w / w, 16.2 % w / w, 16.3 % w / w, 16.4 % w / w, 16.5 % w / w, 16.6 % w / w, 16.7 % w / w, 16.8 % w / w, 16.9 % w / w, 17 % w / w, 17.1 % w / w, 17.2 % w / w, 17.3 % w / w, 17.4 % w / w, 17.5 % w / w, 17.6 % w / w, 17.7 % w / w, 17.8 % w / w, 17.9 % w / w, 18 % w / w, 18.1 % w / w, 18.2 % w / w, 18.3 % w / w, 18.4 % w / w, 18.5 % w / w, 18.6 % w / w, 18.7 % w / w, 18.8 % w / w, 18.9 % w / w, 19 % w / w, 19.1 % w / w, 19.2 % w / w, 19.3 % w / w, 19.4 It is selected from % w / w, 19.5 % w / w, 19.6 % w / w, 19.7 % w / w, 19.8 % w / w, 19.9 % w / w, or 20 % w / w.

[0075] definition :

[0076] As used herein, the terms 'active' and 'active agent' refer to therapeutic agents used in the treatment of diseases or disorders. For example, therapeutic agents used herein are useful for the treatment, alleviation, or prevention of hair loss and / or the promotion of hair growth. Exemplary agents are hair growth promoters, and / or hair growth promoters and / or hair density increasers and / or anti-hair loss agents.

[0077] For example, the active agent may be dutasteride or minoxidil or a combination thereof.

[0078] The term "effective amount" refers to a sufficient amount to achieve a desired modification of the physical properties of a composition or substance. For example, the "effective amount" of a therapeutic agent refers to a sufficient amount to achieve a desired level of improvement in a clinical condition controlled by the formulation component, for example, hair growth or alleviation of hair loss. A therapeutic agent should be understood to include a neutral form of the drug and a pharmaceutically acceptable form thereof. "Pharmaceutically acceptable" refers to such a compound, substance, composition, salt, and / or form of administration that is suitable for administration to a patient without excessive toxicity, irritation, allergic reaction, or other problems or complications corresponding to a reasonable benefit / risk ratio when used in the composition of the present invention, including when the composition is applied topically according to the method described herein.

[0079] The term 'solution state stability' refers to the chemical and physical stability of a formulation; for example, physical stability means a state in which there are no visible particulate matter or dispersed particles within the formulation, while chemical stability means a state in which degradation products or impurities are maintained within acceptable limits.

[0080] His ‘pharmaceuticalally acceptable form’ means any pharmaceutically acceptable derivative or variant, including stereoisomers, mixtures of stereoisomers, enantiomers, solvates, hydrates, isomorphs, polymorphs, pseudomorphs, salt forms, and prodrugs. Preferably, in some embodiments, the pharmaceutically acceptable form includes the salt form. In other preferred embodiments, the pharmaceutically acceptable form includes any stereoisomer or mixture of stereoisomers of the therapeutic agent. The specific level regarding % w / w in the composition required as an effective amount will vary depending on various factors, including the amount and type of the therapeutic agent and the formulation, e.g., solution, emulsion, suspension, spray, ointment, cream, gel, etc.

[0081] The term 'comprising' is interpreted as specifying the existence of the described feature, integer, step, or component as referred to, but does not exclude the existence or addition of one or more features, integers, steps, or components or groups thereof. Additionally, the terms 'by,' 'comprising,' 'comprises,' 'comprised of,' 'including,' 'includes,' 'included,' 'accomprising,' 'accomprising,' and 'e.g.' are used in their respective open, non-restrictive senses and may be used interchangeably. Furthermore, the term 'comprising' is intended to include the examples and modes covered by the terms 'essentially composed' and 'comprised.' Similarly, the term 'essentially composed' is intended to include the examples covered by the term 'comprised.'

[0082] As used herein, the term "safe effective amount" means an amount of a compound or composition sufficient to induce a positive benefit, e.g., significant hair growth, but sufficiently small to avoid serious side effects; that is, an amount of a compound or composition to provide a reasonable benefit-risk ratio within the reasonable judgment of a person skilled in the art.

[0083] The terms 'hair growth', 'regulating hair growth', 'regulating hair growth', and 'regulating hair growth' mean stimulating hair growth, promoting hair growth, stimulating hair to thicken, preventing, reducing, stopping and / or delaying hair loss, preventing, reducing, stopping and / or delaying hair thinning or hair loss, increasing the rate of hair growth, inducing the formation of more hair strands, increasing the diameter of hair strands, extending hair strands, changing vellus hair follicles or small hair follicles into large and thick hair follicles, and inducing the formation of vellus hair and terminal hair follicles.

[0084] The terms 'stability' or 'stable' as used herein include both chemical stability and physical / polymorphic stability of the topical composition of the present invention, wherein the composition is maintained within established specifications to maintain its identity, strength, quality and purity throughout the entire storage, retesting, or expiration period, and is not altered or degraded due to internal reactions or due to the influence of oxygen, heat, light, moisture or pressure, wherein the drug is present in an amount of at least about 95% to about 100% of the originally specified amount for at least about 1 month when stored at 2-8°C or 25°C / 60% relative humidity (RH), 30°C / 65% RH or 40°C / 75% RH, and the amount of total impurities is about 5.0% or less.

[0085] As used in this specification and the appended claims, the singular forms ('a,' 'an,' and 'the') include multiple referents unless the context otherwise clearly indicates. Thus, references to, for example, 'silicone base,' 'gel base for gel-cream emulsion,' or 'heavy cream base' include, without limitation, two or more of such silicone bases, gel bases for gel-cream emulsion, or heavy cream bases.

[0086] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in the form of ranges in this specification. It will also be understood that both endpoints of each of such ranges are important in relation to and independently of other endpoints. Additionally, there are various values ​​disclosed in this specification, and each value is also understood to be described in this specification as 'about' such a specific value in addition to the value itself. For example, where a value '10' is disclosed, 'about 10' is also disclosed. Ranges may be expressed in this specification as 'about' from one specific value and / or 'about' another specific value. Similarly, where a value is expressed as an approximation by the use of a preceding 'about', it will be understood that a specific value forms an additional embodiment. For example, where a value 'about 10' is disclosed, '10' is also disclosed.

[0087] It should be understood that such range formats are used for convenience and conciseness, and therefore should be interpreted in a flexible manner to include not only the numeric values ​​explicitly mentioned as limits of the range, but also all individual numeric values ​​or sub-ranges included within the range as explicitly mentioned. For example, the numeric range 'about 0.1% to 5%' should be interpreted to include not only the explicitly mentioned values ​​of about 0.1% to about 5%, but also individual values ​​within the indicated range (e.g., about 1%, about 2%, about 3%, and about 4%) and sub-ranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges).

[0088] As used herein, the term 'alopecia' refers to androgenetic alopecia (AGA), alopecia areata (including diffuse alopecia areata, solitary alopecia areata, multiple alopecia areata, filamentous alopecia, frontal alopecia, and generalized alopecia), telogen effluvium, anagenous alopecia, and traction alopecia, as collectively or individually specified.

[0089] As used herein, the terms “about,” “approximately,” “at or about,” and “substantially” mean that the quantity or value in question may be an exact value or a value that provides an equivalent result or effect to that listed in the claims or taught herein. That is, it should be understood that quantity, size, formulation, parameter, and other quantities and characteristics are not exact and do not need to be exact, and may be and / or larger or smaller than desired, taking into account tolerances, conversion factors, rounding, measurement errors, and other factors known to a person skilled in the art to obtain an equivalent result or effect as needed. In some situations, a value that provides an equivalent result or effect cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” are generally understood to mean a range of ±20% variation of the indicated nominal value, unless otherwise specified or inferred. Generally, a quantity, size, formulation, parameter, or other quantity or characteristic is 'about,' 'approximately,' or 'at or to that extent,' regardless of whether it is explicitly stated. Where 'about,' 'approximately,' or 'at or to that extent' is used before a quantitative value, the parameter is also understood to include the specific quantitative value itself, unless otherwise specifically stated.

[0090] As used herein, the terms 'optional' or 'optional' mean that an event or environment described subsequently may or may not occur, and that the description includes cases where said event or environment occurs and cases where it does not occur.

[0091] As used herein, the term "administration" refers to the act of administering a drug, a prodrug or other active agent, or a therapeutic treatment (e.g., a composition of the present invention) to a subject. An exemplary route of administration into the human body may be on the skin, e.g., the scalp. Administration may consist of one or more administrations, applications, or doses, and is not intended to be limited to a specific period. "Administered" and "applied" are used to describe the act of "administration" and are used as synonyms.

[0092] In this specification, the term 'oil-based' refers to a composition in which the main component is oil.

[0093] As used herein, the term 'aqueous-based' refers to a composition in which the main component is water or a water-miscible or soluble excipient.

[0094] The phrase 'alcohol-free' means that the composition does not contain short-chain alcohols.

[0095] The phrase 'propylene glycol-free' means that the composition does not contain propylene glycol.

[0096] The term “substantially absent” means that the content of a component in the composition is less than about 10% w / w. For example, a composition that is substantially free of petrolatum has a petrolatum content of less than about 10% in the final composition. In some embodiments, the term “substantially absent” refers to a component that is less than about 10% w / w, less than about 1% w / w, less than about 5% w / w, about 1% w / w, or about 0% w / w in the composition based on the total weight of the composition.

[0097] As used herein, the term 'substantially solubilized' means that the therapeutic agent is dissolved within the composition and exists at a concentration lower than the solubility limit within the composition.

[0098] As used herein, the term 'partially solubilized' means that the therapeutic agent is in an insoluble state within the composition and exists at a concentration lower than the solubility limit within the composition.

[0099] With respect to the administration or application of a composition or product, the terms “topical” or “topically” mean administration or application to the epidermis or administration onto the surface of the skin. As used herein, the term “topical active agent” refers to a compound effective for the treatment of skin diseases when administered topically. With respect to a composition, formulation, or product, the term “topical” refers to a composition or product formulated for topical application. “Formulation” and “composition” may be interchangeable.

[0100] As used herein, the term 'pharmaceutical composition' refers to a composition comprising a 5α-reductase inhibitor and a vasodilator together with one or more pharmaceutically acceptable excipients as necessary to prepare a dosage form for effective delivery of the active agent. Such pharmaceutical compositions may be in the form of a solution, ointment, cream, gel, lotion, suspension, spray, foam, microsphere, microemulsion, nanoemulsion, nanoparticle, nanosuspension, derma stick, roll-on, pump, patch, tape, etc.

[0101] According to the present invention, the 'scalp' refers to the skin covering the head, and is defined by the face in the front and by the neck on the sides and back.

[0102] As used herein, the term 'treatment period' means that the composition is prescribed, used, or administered for the corresponding period (e.g., 1 month, 2 months, 6 months, 1 year, or 2 years).

[0103] As used herein, the term "solvent" refers to a substance that solubilizes an active agent and provides a uniform distribution of the active agent throughout the composition. As used herein, "solvent" and "solubilizing agent" may be interchangeable.

[0104] "Penetration enhancement" or "permeation enhancement" refers to increasing the permeability of a biological membrane (e.g., skin or mucous membrane) to a drug, thereby increasing the rate at which the drug passes through the membrane. "Permeation enhancer," "accelerator," "penetration enhancer," or similar terms refer to a substance that enhances such permeation or penetration, and the "effective amount" of an accelerator refers to an amount effective in enhancing the penetration of a selected formulation through the skin or mucous membrane to a desired degree.

[0105] As used in this specification, the term 'object' refers to a human object or an animal including mammals (e.g., monkeys, guinea pigs, companion animals, e.g., cats and dogs).

[0106] As used in this specification, the term 'silicone excipient' refers to a silicone-based material used in compositions for various functions, such as gelling agents(s), solvent(s), emulsifier(s), volatile solvent(s), polymer(s), and wax(s).

[0107] The pharmaceutically acceptable vehicle according to the present invention is a C8-C such as paraffin oil and isopropyl myristate. 18 esters of organic acids, C8-C 30Fatty alcohols, silicone oils, vegetable oils, fractions or hydrogenated vegetable oils, monoglycerides, diglycerides, triglycerides, phospholipids, dimethyl isosorbide, volatile solvents, alcohols such as N-methylpyrrolidone, N,N-dimethylacetamide and N,N-dimethylformamide, dimethyl sulfoxide, ethanol and isopropyl alcohol, glycols such as propylene glycol, polyethylene glycol and glycerol, cyclodextrins such as beta-cyclodextrin, beta-hydroxycyclodextrin, gamma-cyclodextrin and hydroxypropyl cyclodextrin, and mixtures thereof, but are not limited thereto.

[0108] Pharmaceutically acceptable excipient(s) are selected from solvents, emulsifiers, co-emulsifiers, gelling agents, polymers, thickeners, viscosity enhancers, co-solvents, softeners, pH adjusters, penetration promoters, antioxidants, preservatives, and any combination thereof.

[0109] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, comprising the step of administering an effective amount of a pharmaceutical formulation topically to a subject once daily.

[0110] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, comprising the step of administering an effective amount of a pharmaceutical formulation topically to a subject twice daily.

[0111] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, comprising the step of locally administering an effective amount of a pharmaceutical formulation to a subject every two days.

[0112] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of administering an effective amount of a topical pharmaceutical formulation topically to a subject in need thereof, wherein the topical administration of the formulation for 6 months does not result in systemic side effects associated with dutasteride and / or minoxidil.

[0113] In another embodiment, the subject has no systemic adverse effects associated with dutasteride and / or minoxidil for at least one month, or at least two months, or at least three months, or at least four months, or at least five months.

[0114] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of administering an effective amount of a topical pharmaceutical formulation topically to a subject in need thereof, wherein administering the formulation topically once a day for at least one month achieves hair growth equivalent to that observed when a commercially available topical minoxidil formulation is administered for the same period.

[0115] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of locally administering an effective amount of a topical pharmaceutical formulation to a subject in need thereof, wherein locally administering the formulation twice a day for at least one month achieves hair growth equivalent to that observed when a commercially available topical minoxidil formulation is administered for the same period.

[0116] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of administering an effective amount of a topical pharmaceutical formulation topically to a subject in need thereof, wherein administering the formulation topically once a day for at least two months achieves hair growth equivalent to that observed when a commercially available topical minoxidil formulation is administered for the same period.

[0117] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of locally administering an effective amount of a topical pharmaceutical formulation to a subject in need thereof, wherein locally administering the formulation twice a day for at least two months achieves hair growth equivalent to that observed when a commercially available topical minoxidil formulation is administered for the same period.

[0118] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of administering an effective amount of a topical pharmaceutical formulation topically to a subject in need thereof, wherein administering the formulation topically once a day for at least 6 months achieves hair growth equivalent to that observed when administering a commercially available topical minoxidil formulation for the same period.

[0119] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of administering an effective amount of a topical pharmaceutical formulation topically to a subject in need thereof, wherein administering the formulation topically twice a day for at least 6 months achieves hair growth equivalent to that observed when administering a commercially available topical minoxidil formulation for the same period.

[0120] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, comprising the step of locally administering an effective amount of a pharmaceutical formulation during a treatment period, wherein, after discontinuation of administration of the pharmaceutical formulation, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least one month.

[0121] In another embodiment, the treatment period is at least 1 month or at least 2 months or at least 3 months or at least 4 months or at least 5 months or at least 6 months or at least 7 months or at least 8 months or at least 9 months or at least 10 months or at least 11 months or at least 1 year or at least 2 years.

[0122] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least one month, or at least two months, or at least three months, or at least four months, or at least five months, or at least six months after a treatment period of at least one month.

[0123] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 2 months.

[0124] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 3 months.

[0125] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 4 months.

[0126] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 5 months.

[0127] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 6 months.

[0128] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 1 year.

[0129] In another embodiment, the reversal of the hair loss prevention and / or hair growth promotion effect is delayed for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after a treatment period of at least 2 years.

[0130] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, comprising the step of locally administering an effective amount of a pharmaceutical formulation, wherein, after discontinuation of administration of the pharmaceutical formulation, the effect of preventing hair loss and / or promoting hair growth is maintained for at least one month.

[0131] In another embodiment, the hair loss prevention and / or hair growth promotion effect is maintained for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months after discontinuation of administration of the pharmaceutical formulation.

[0132] In an embodiment, the topical pharmaceutical composition according to the present invention provides improved topical delivery of an active agent, i.e., a 5α-reductase inhibitor, e.g., dutasteride, which improves bioavailability and is substantially equivalent to an oral or injectable formulation of a 5α-reductase inhibitor in terms of effect.

[0133] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of topically administering an effective amount of a topical pharmaceutical formulation comprising one or more active ingredients selected from dutasteride, minoxidil, and at least one acidifying agent to a subject in need thereof, wherein the active ingredients are present in a ratio of about 1:0.1 to about 1:0.4, preferably in a ratio of about 1:0.2 to about 1:0.3.

[0134] In one aspect of the above embodiment, the dutasteride and the acidifying agent are present in a ratio of about 1:10 to about 1:40.

[0135] In one aspect of the above embodiment, the dutasteride and the acidifying agent are present in a ratio of about 1:15 to about 1:35.

[0136] In one aspect of the above embodiment, the dutasteride and the acidifying agent are present in a ratio of about 1:20 to about 1:30.

[0137] In one aspect of the above embodiment, the dutasteride and the acidifying agent are present in a ratio of about 1:28.

[0138] In one aspect of the above embodiment, the minoxidil and acidifying agent are present in a ratio of about 1:0.1 to about 1:0.4.

[0139] In one aspect of the above embodiment, the minoxidil and acidifying agent are present in a ratio of about 1:20 to about 1:30.

[0140] In one aspect of the above embodiment, the minoxidil and acidifying agent are present in a ratio of about 1:28.

[0141] In another embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth, the method comprising the step of topically administering an effective amount of a topical pharmaceutical formulation comprising one or more active ingredients selected from dutasteride, minoxidil, and at least one thermoreversible polymer to a subject in need thereof, wherein the active ingredients are present in a ratio of about 1:0.5 to about 1:0.4, preferably in a ratio of about 1:0.1 to about 1:0.3, and most preferably in a ratio of about 1:0.15 to about 1:0.25.

[0142] In one aspect of the above embodiment, the dutasteride and poloxamer are present in a ratio of about 1:5 to about 1:40.

[0143] In one aspect of the above embodiment, the dutasteride and poloxamer are present in a ratio of about 1:10 to about 1:35.

[0144] In one aspect of the above embodiment, the dutasteride and poloxamer are present in a ratio of about 1:15 to about 1:30.

[0145] In one aspect of the above embodiment, the dutasteride and poloxamer are present in a ratio of about 1:15 to about 1:25.

[0146] In one aspect of the above embodiment, the dutasteride and poloxamer are present in a ratio of about 1:20.

[0147] In one aspect of the above embodiment, the minoxidil and poloxamer are present in a ratio of about 1:0.5 to about 1:0.4.

[0148] In one aspect of the above embodiment, the minoxidil and poloxamer are present in a ratio of about 1:0.1 to about 1:0.3.

[0149] In one aspect of the above embodiment, the minoxidil and poloxamer are present in a ratio of about 1:0.15 to about 1:0.25.

[0150] In one aspect of the above embodiment, the minoxidil and poloxamer are present in a ratio of about 1:0.2.

[0151] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.05% w / w of dutasteride, about 5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0152] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.02% w / w of dutasteride, about 5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0153] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.01% w / w of dutasteride, about 5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0154] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.05% w / w of dutasteride, about 2% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0155] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.02% w / w dutasteride, about 2% w / w minoxidil, and a pharmaceutically acceptable vehicle.

[0156] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.1% w / w dutasteride, about 5% w / w minoxidil, and a pharmaceutically acceptable vehicle.

[0157] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.1% w / w dutasteride, about 2% w / w minoxidil, and a pharmaceutically acceptable vehicle.

[0158] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.01% w / w of dutasteride, about 2% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0159] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.05% w / w of dutasteride, about 7.5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0160] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.02% w / w dutasteride, about 7.5% w / w minoxidil, and a pharmaceutically acceptable vehicle.

[0161] In one embodiment, the present invention provides a method for preventing hair loss and / or promoting hair growth in a patient requiring this, comprising the step of topically administering to a subject a pharmaceutical formulation comprising about 0.01% w / w of dutasteride, about 7.5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0162] In one embodiment, the present invention relates to a synergistic composition for preventing hair loss and / or promoting hair growth in patients requiring it, comprising about 0.01% w / w to 0.2% w / w of dutasteride, about 2% w / w to about 10% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0163] In one embodiment, the present invention relates to a synergistic composition for preventing hair loss and / or promoting hair growth in patients requiring it, comprising about 0.05% w / w of dutasteride, about 5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0164] In one embodiment, the present invention relates to a synergistic composition for preventing hair loss and / or promoting hair growth in patients requiring it, comprising about 0.05% w / w of dutasteride, about 5% w / w of minoxidil, and a pharmaceutically acceptable vehicle.

[0165] In another embodiment, the oil phase may comprise one or more oils having long-chain triglycerides, such as vegetable oil, fish oil, animal fat, hydrogenated vegetable oil, partially hydrogenated vegetable oil, semi-synthetic triglycerides, synthetic triglycerides, or mixtures thereof. Fractionated, refined, or pure refined oils of this type may also be used. The oil may be present in an amount of about 1% w / w to about 95% w / w.

[0166] Specific examples of oils containing long-chain triglycerides suitable for use in the composition of the present invention include almond oil, castor oil, coconut oil, corn oil, cottonseed oil, emu oil, evening primrose oil, flaxseed oil, grapeseed oil, peanut oil, mustard seed oil, olive oil, palm oil, palm kernel oil, peanut oil, rapeseed oil, safflower oil, sesame oil, shark liver oil, soybean oil, sunflower oil, hydrogenated castor oil, hydrogenated coconut oil, hydrogenated palm oil, hydrogenated soybean oil, hydrogenated vegetable oil, a mixture of hydrogenated cottonseed oil and hydrogenated castor oil, partially hydrogenated soybean oil, a mixture of partially hydrogenated soybean oil and partially hydrogenated cottonseed oil, oils containing glyceryl trioleate, glyceryl trilinoleate, glyceryl trilinolenate, and Ω3 polyunsaturated fatty acid triglycerides, and mixtures thereof.

[0167] Preferably, long-chain triglyceride-containing oils include coconut oil, corn oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, hydrogenated coconut oil, partially hydrogenated soybean oil, glyceryl trioleate, glyceryl trilinoleate, glyceryl trilinolenate, Ω3 polyunsaturated fatty acid triglyceride-containing oils, and mixtures thereof. Most preferably, the long-chain triglyceride-containing oils include coconut oil and hydrogenated castor oil. The oils may be present in an amount of about 1% w / w to about 95% w / w, preferably about 5% w / w to about 50%, most preferably about 1% w / w to about 20% w / w.

[0168] In certain embodiments, the antioxidant of the present invention comprises one or more ascorbic acid, monothioglycerol, potassium metabisulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium sulfite, sodium thiosulfate, tocopherol or its derivatives, such as dl-alpha tocopherol, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, propyl gallate, acai oil, alpha lipoic acid, green tea extract, retinol, vitamin C, coenzyme Q10 (Co Q-10), isoflavones, polyphenols, curcumin, turmeric, pomegranate, rosemary extract, glutathione, selenium, zinc, chelating molecules, ethylenediaminetetraacetic acid (EDTA), disodium EDTA, tetrasodium EDTA, pentanodium phenetate, sodium metasilicate, and phosphate derivatives. The antioxidant is selected from etidronic acid and / or its derivatives, and / or galactaric acid. The antioxidant may be present in an amount of about 0.01% w / w to about 5% w / w, preferably about 0.01% w / w to about 1%, most preferably about 0.01% w / w to about 0.05% w / w.

[0169] In some embodiments, the antioxidant enhances the activity of at least one active ingredient.

[0170] In some embodiments, antioxidants enhance the activity of dutasteride.

[0171] In some embodiments, antioxidants enhance the activity of minoxidil.

[0172] In certain embodiments, the preservative of the present invention is selected from one or more sodium benzoate, benzoic acid, phenol, cresol, alcohol, chlorbutanol, benzalkonium chloride, methyl paraben or its salt, propyl paraben or its salt, methyl paraben or its salt. The preservative may be present in an amount of about 0.01% w / w to about 5% w / w, preferably about 0.01% w / w to about 1%, most preferably about 0.01% w / w to about 0.05% w / w.

[0173] In one embodiment, the present invention relates to a method for delivering a topical composition for treating hair loss in a human user, the method comprising the step of providing a topical composition comprising a hair growth component comprising about 0.01% w / w to about 0.2% w / w of dutasteride, about 1% w / w to about 20% w / w of minoxidil, and at least one penetration promoter, wherein the penetration promoter is present at a concentration sufficient to help the one or more active compounds penetrate the surface of the skin to a depth of about the depth of the hair bulb.

[0174] In one embodiment, the present invention relates to a method for delivering a topical composition for treating hair loss in a human user, the method comprising the step of providing a topical composition comprising a hair growth component comprising about 0.01% w / w to about 0.1% w / w of dutasteride, about 1% w / w to about 15% w / w of minoxidil, and at least one antioxidant, wherein the antioxidant is present at a concentration sufficient to enhance the therapeutic benefit of the one or more active compounds compared to a composition without the antioxidant.

[0175] In one embodiment, the present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, substantially free of ethanol and propylene glycol.

[0176] In certain embodiments, the present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein the composition is substantially free of ethanol.

[0177] In certain embodiments, the present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, wherein the composition is substantially free of propylene glycol.

[0178] In certain embodiments, the present invention relates to a composition for treating hair loss and / or promoting hair growth comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable vehicle, substantially free of ethanol and propylene glycol.

[0179] In one embodiment, the present invention relates to a composition comprising a. dutasteride, b. minoxidil, and c. a pharmaceutically acceptable carrier comprising one or more penetration promoters, one or more solubilizing agents, one or more stabilizing agents, or a mixture thereof.

[0180] In certain embodiments, the solubilizing agent of the present invention is selected from one or more alcohol(s), one or more polyhydric alcohol(s) such as propylene glycol, polypropylene glycol, pentylene glycol, and glycerin, ethyl acetate, phenoxyethanol, diisopropyl adipate, isopropyl myristate, diethyl sebacate, dibutyl sebacate, dimethyl isosorbide, dimethyl sulfoxide, and mixtures thereof. In certain embodiments, the solubilizing agent comprises ethanol, isopropanol, pentylene glycol, propylene glycol, ethyl acetate, polyethylene glycol, and mixtures thereof. The solubilizing agent may be present in an amount of about 1% w / w to about 50% w / w, preferably about 5% w / w to about 30%, most preferably about 10% w / w to about 25% w / w.

[0181] In some embodiments, the solubilizing agent of the present invention is a glycol selected from ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene glycol, hexylene glycol, propylene glycol dipellagonate, diethylene glycol monoethyl ether, propylene laurate glycol dicaprylate dicaprate propylene glycol, and diethylene glycol monoethyl ether, ethanol, dimethyl isosorbide, methylpyrrolidone, oleic acid, capric / caprylic glyceride, and any combination of any of the foregoing. The solubilizing agent may be present in an amount of about 1% w / w to about 50% w / w, preferably about 5% w / w to about 30%, most preferably about 10% w / w to about 25% w / w.

[0182] In one embodiment, the present invention relates to a composition comprising a pharmaceutically acceptable carrier comprising a. dutasteride, b. minoxidil, and c. one or more crystal growth inhibitors.

[0183] In some embodiments, the crystal growth inhibitor is a glycol or a derivative thereof selected from ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene 20 glycol, hexylene glycol, propylene glycol dipellagonate, diethylene glycol monoethyl ether, propylene laurate glycol dicaprylate dicaprate propylene glycol, and diethylene glycol monoethyl ether.

[0184] The present invention relates to adding hexylene glycol to a pharmaceutical composition comprising a. dutasteride and b. minoxidil, containing a pharmaceutically acceptable solvent including water, to inhibit the growth of at least one of the active ingredients in the composition. For a topical solution product designed to contain a composition in which the active ingredients are solubilized, adding hexylene glycol to the composition inhibits the crystal growth of the precipitated active ingredient during the product's shelf life or during any period of temperature deviation from the product's indicated storage conditions during transport or distribution, thereby ensuring consistent bioavailability. Inhibiting crystal growth causes the precipitated active ingredient to rapidly return to a completely dissolved state when the product returns to a controlled room temperature.

[0185] Preferably, hexylene glycol is added to a composition containing 2% w / w to about 15% w / w.

[0186] In one embodiment, the present invention relates to a composition comprising a pharmaceutically acceptable carrier comprising a. dutasteride, b. minoxidil, and c. one or more solubilizing agents, wherein the solubilizing agent is water, a C1-C3 alcohol (e.g., methanol, ethanol, n-propanol, isopropyl alcohol), n-butanol, e.g., 1-butanol, n-hexanol, 2-ethyl-1-hexanol, polyhydric alcohol (e.g., ethylene glycol, propylene glycol, polypropylene glycol [e.g., polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400)]), pentylene glycol, butanediol isomer, 1,5-pentanediol, 1,2,6-trihydroxyhexane, 1,2-ethyl-1,3-hexanediol, 1,7-hepatandiol, or glycerin; Ether alcohols, e.g., 1-methoxy-2-propanol, 3-ethyl-3-hydroxymethyloxetane, tetrahydrofurfuryl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol or dipropylene glycol, xylene, chlorobenzene, ethyl acetate, butyl acetate, diethylene glycol dimethyl ether, dipropylene glycol dimethyl ether, ethylene glycol monomethyl or monoethyl ether acetate, diethylene glycol ethyl and butyl ether acetate, propylene glycol monomethyl ether acetate, 1-methoxypropyl-2-acetate, 3-methoxy-n-butyl acetate, propylene glycol diacetate, Polymeric solubilizers selected from the group consisting of N-methylpyrrolidone and N-methylcaprolactam, dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycol succinate (TPGS), dimethylformamide (DMF), dimethylacetamide (DMA), capryl-caproyl macrogol 8-glyceride (labrasol); and vinyl polymers such as cyclodextrin and ethylene-vinyl acetate;It is selected from monohydric or polyhydric alcohols, including but not limited to ethylene vinyl acetate, polyvinyl alcohol, povidone, copovidone, or any combination thereof.

[0187] In certain embodiments, one or more solubilizing agents are present in the composition in an amount of about 0.1% to about 60%, optionally about 0.1% to about 50%, or optionally about 0.1% to about 40% by weight of the total composition.

[0188] One aspect of the present invention relates to a composition comprising at least one cyclodextrin.

[0189] In one embodiment, the cyclodextrin of the composition of the present invention is α-cyclodextrin, -Cyclodextrin, - Selected from the group consisting of cyclodextrin or mixtures thereof. Preferably, the cyclodextrin in the above list is hydroxypropyl-cyclodextrin.

[0190] In some embodiments, the topical composition comprises one or more water-immiscible material(s) selected from mineral oil, wax(s), paraffin(s), petrolatum, vegetable oil(s), fatty alcohol(s), fatty acid(s), fatty alcohol ether(s), fatty acid ester(s), mono or diester(s) of fatty acid(s), and any combination of any of the foregoings. The water-immiscible material(s) may be present in an amount of about 1% w / w to about 95% w / w, preferably about 5% w / w to about 50%, most preferably about 1% w / w to about 20% w / w.

[0191] In some aspects of the present invention, the topical foam composition comprises one or more aromatic alcohols. In one embodiment, the aromatic alcohol is benzyl alcohol. The composition further comprises one or more foam structuring agents, such as one or more fatty alcohols. One or more fatty alcohols included in the composition of the present invention have a linear or branched carbon skeleton having 6 to 22 carbon atoms.

[0192] In one embodiment, the fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, lauryl alcohol, stearyl alcohol, octyldodecanol, and combinations thereof.

[0193] In one embodiment, fatty alcohols such as cetyl alcohol and / or stearyl alcohol are included in the composition at about 0.2-2% w / w, 0.04-1.8% w / w, 0.6-1.6% w / w, and 0.8-1.4% w / w.

[0194] In another embodiment, the composition further comprises one or more foam structuring agents, such as one or more nonionic surfactants. Nonionic surfactants that can be used in the composition of the present invention generally include ethoxylated alcohols. The nonionic surfactants that can be used in the composition of the present invention are glyceryl stearate, PEG 100-stearate, polyoxyl-20-cetostearyl ether, glyceryl monooleate, glyceryl palmitostearate, polyoxyl-20-stearate, polyoxyl-40-stearate, polyoxyl-60-stearate, polyoxyl-80-stearate, polyoxyl-20-oleate, polyoxyl-40-oleate, polyoxyl-60-oleate, polyoxyl-20-palmitate, polyoxyl-40-palmitate, polyoxyl-60-palmitate, polyoxyl-80-palmitate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan It includes monostearate, polyoxyethylene (20) sorbitan monooleate, lauret-2, lauret-4, lauret-6, and lauret-8. However, other nonionic surfactants will be obvious to a person skilled in the art. In a preferred embodiment, the nonionic surfactant is polyoxyethylene (20) sorbitan monostearate. In an embodiment, a nonionic surfactant, such as polyoxyethylene (20) sorbitan monostearate, is included in the composition in an amount between about 0.05-1.0% w / w, 0.06-0.95% w / w, 0.07-0.9% w / w, 0.08-0.75% w / w, 0.09-0.7% w / w, 0.1-0.65% w / w, 0.15-0.6% w / w, and 0.2-0.5% w / w, or in an amount between about 0.15% w / w, 0.16% w / w, 0.17% w / w, 0.18% w / w, 0.19% w / w, 0.2% w / w, 0.21% w / w, 0.22% w / w, 0.23% w / w, and 0.24% w / w. w / w, 0.25 % w / w, 0.26 % w / w, 0.27 % w / w, 0.28 % w / w, 0.29 % w / w, 0.3 % w / w, 0.31 % w / w, 0.32 % w / w, 0.33 % w / w, 0.34 % w / w, 0.35 % w / w, 0.36 % w / w, 0.37 % w / w, 0.38 % w / w, 0.39 % w / w, 0.40 % w / w, 0.41 % w / w, 0.42 % w / w, 0.43 % w / w, 0.44 % w / w, 0.45 % w / w, 0.46 % w / w, 0.47 % w / w, 0.48 % w / w, It is included in the composition in an amount of 0.49% w / w, 0.50% w / w.

[0195] In another embodiment, the composition further comprises one or more pH adjusters. The pH of the formulation plays an important role in stabilizing the formulation and solubilizing the drug. The use of acidifying and basicizing agents to adjust the pH essential for solubilizing the drug may not be suitable for topical application to the scalp or skin and may cause itching or irritation at the application site.

[0196] Suitable examples of acidifying agents that may be used in this application include, but are not limited to, citric acid, citric anhydride, citric acid monohydrate, DL-lactic acid, DL-malic acid, DL-tartaric acid, fumaric acid, L-malic acid, L-tartaric acid, salicylic acid, glycolic acid, potassium tartrate, potassium citrate, DL-potassium gluconate, sodium lactate, sodium L-tartarate, sodium citrate, ascorbic acid, sorbic acid, methanesulfonic acid, or any combination thereof.

[0197] In one embodiment, the present application relates to an aqueous-based topical composition comprising one or more hair growth promoters and at least one acidifying agent, wherein the acidifying agent is present in an amount of about 0.1% to about 5% based on the total weight of the composition.

[0198] In one embodiment, the acidifying agent is lactic acid.

[0199] In some aspects of the above embodiments, the acidifying agent is malic acid.

[0200] In some aspects of the above embodiments, the acidifying agent is tartaric acid.

[0201] In some aspects of the above embodiments, the acidifying agent is fumaric acid.

[0202] In some aspects of the above embodiments, the acidifying agent is citric acid.

[0203] In some embodiments of the above examples, the pH of the composition is in the range of about 3 to about 8.

[0204] In some embodiments of the above examples, the pH of the composition is in the range of about 3.5 to about 7.5.

[0205] In some embodiments of the above examples, the pH of the composition is in the range of about 4 to about 7.

[0206] In some embodiments of the above examples, the pH of the composition is in the range of about 4.5 to about 6.5.

[0207] In some embodiments of the above examples, the pH of the composition is in the range of about 5 to about 6.

[0208] Minoxidil is a base and is very slightly soluble in water. Minoxidil dissolves under acidic conditions. Lactic acid helps to solubilize minoxidil within the formulation without affecting the overall pH of the formulation. Without being bound by any theory, the inventors surprisingly discovered that dutasteride, which is highly sensitive to acids and bases, is stabilized by an acidic environment.

[0209] In one embodiment, lactic acid is a preferred acidifying agent. Lactic acid has the ability to exfoliate the scalp and remove buildup. Lactic acid can also help increase hair elasticity and prevent breakage. Lactic acid has moisturizing properties, which means it promotes a healthy hydration level that helps draw moisture into the hair shaft and prevents dryness and frizz.

[0210] In one embodiment, the formulation of the present invention contains a thickener (viscosity modifier) ​​that provides viscosity, so that the formulation may be provided in the form of a solution, serum, lotion, gel, cream, or ointment. Preferably, but not necessarily, the thickener is miscible or soluble in an aqueous fluid. Examples of suitable thickeners include acacia, alginate, bentonite, carbomer also known as carboxyvinyl polymer, such as the product sold under the trade name Carbopol® (Lubrizol, Wycliffe, Ohio), carboxymethylcellulose, ethylcellulose, Sepineo P 600 (acrylamide / acryloyldimethyltaurate copolymer / isohexadecane and polysorbate 80) polymer, which is a pH-independent thickener, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum, etc. Thickeners may also be present in the oil or lipophilic portion of the formulation. Examples of suitable lipophilic thickeners include cetyl alcohol, stearyl alcohol, glyceryl stearate, white beeswax, microcrystalline wax, hydrogenated polyisobutane polymer, and emulsified wax. The thickener may be present in an amount of about 0.1% w / w to about 20% w / w, preferably about 1% w / w to about 15%, most preferably about 2% w / w to about 10% w / w.

[0211] In one embodiment, the viscosity modifier is cyclopentasiloxane, polysilicon-11, C30 - 45 The polymers are alkyl cetearyl dimethicone crosslinked polymer, dimethiconol, phenyl trimethicone, PEG PPG dimethicone, cyclomethicone, and simethicone.

[0212] In some embodiments, surfactants or emulsifiers may be included if necessary or desirable to obtain the desired formulation. The emulsifiers are preferably nonionic emulsifiers, such as sorbitan esters, polyoxyethylene derivatives of sorbitan esters, or glyceryl esters; polymeric emulsifiers, such as acrylate / C10-C30 alkyl acrylate cross-linked polymers, such as those sold under the trade name PEMULEN® (Lubrizol Corporation, Wycliffe, Ohio, USA); or anionic emulsifiers, such as alkali soaps, such as sodium or potassium oleate; amine soaps, such as triethanolamine stearate; detergents, such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium docusate. Cationic emulsifiers, such as quaternary ammonium salts, are less preferred. Specific examples of suitable anionic and nonionic emulsifiers include glyceryl monostearate, polyoxyethylene monooleate, polyoxyethylene monostearate, polyoxyethylene monolaurate, potassium oleate, sodium lauryl sulfate, sodium oleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, triethanolamine oleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, and polyoxyethylene sorbitan trioleate. The surfactant or emulsifier may be present in an amount of about 0.1% w / w to about 50% w / w or about 0.5% w / w to about 40%, preferably about 1% w / w to about 15%, most preferably about 2% w / w to about 10% w / w.

[0213] The formulation may include other pharmaceutically acceptable excipients, and preferably, the formulation includes a wetting agent, such as glycerin, sorbitol, hexylene glycol, urea, or propylene glycol. Preferably, the formulation contains a softening agent such as petrolatum, lanolin, mineral oil, light mineral oil, stearic acid, cyclomethicone, or dimethicone, a pH adjuster such as sodium hydroxide, a chelating agent such as EDTA and a salt thereof, and a buffer.

[0214] The formulation of the present invention may be prepared by any known method used to prepare single-phase or multi-phase pharmaceutical formulations for topical administration. To prepare a multi-phase formulation such as an emulsion, for example, the components of the aqueous phase and the oil phase may be individually combined and mixed until a homogeneous solution is obtained, and then the aqueous solution and the oil solution may be combined and mixed, for example by shear mixing, to form the formulation. The oil phase may be added to the aqueous phase, or the aqueous phase may be added to the oil phase. The phases may be combined and mixed, for example, at an elevated temperature of 35-90 °C or at room temperature between 20-30 °C, or between room temperature and the elevated temperature.

[0215] In one embodiment, the composition according to the present invention comprises a. dutasteride, b. minoxidil, and c. water, a pharmaceutically acceptable carrier comprising one or more penetration promoters, one or more solubilizers, one or more stabilizers, or a mixture thereof, wherein the pharmaceutically acceptable carrier is non-irritating when applied to the surface of the skin or scalp of a recipient, and the active agent penetrates the dermis of the skin to a minimum systemic blood level.

[0216] In one embodiment, the present invention relates to a topical composition comprising a. dutasteride, b. minoxidil, and c. water, a pharmaceutically acceptable carrier comprising one or more penetration promoters, one or more solubilizing agents, one or more stabilizing agents, or a mixture thereof, wherein the composition is substantially free of systemic blood levels.

[0217] In one embodiment, the composition according to the present invention relates to a topical composition comprising an active ingredient comprising a. dutasteride at a concentration of about 0.05% w / w of the composition, b. minoxidil at a concentration of about 5% w / w of the composition by weight, and c. a pharmaceutically acceptable carrier, wherein the composition is an aqueous solution and the solution comprises a solvent, and the composition comprising dutasteride and minoxidil at said concentrations may provide synergistic efficacy and a synergistic reduction of at least one of dutasteride and minoxidil.

[0218] In another embodiment, the sol-gel technology is particularly a thermoreversible gel. The use of an aqueous liquid that can be applied as a liquid at room temperature but forms a semi-solid gel when heated to body temperature is utilized as a vehicle for drug delivery, because this system offers not only ease of application but also allows the aqueous composition to remain at the site requiring treatment longer than when it is not converted into a gel.

[0219] A useful polymer that provides the sol-gel properties of the pharmaceutical composition of the present invention is preferably an ethylene oxide / propylene oxide triblock copolymer. A preferred family of hydrogel polymers is a group of triblock copolymers designated as PEG-PPG-PEG (PEG = polyethylene glycol and PPG = polypropylene glycol) and called poloxamers, which produces a reverse thermal gelation composition, that is, a composition having the property that viscosity increases as temperature increases and then decreases again above a certain temperature.

[0220] In particular, Poloxamer 407 has a gelation temperature above 10°C but below the human body temperature of 37°C. Thanks to these characteristics, Poloxamer 407 (PF-127) can be used as a carrier in most routes of administration, including oral, topical, nasal, vaginal, rectal, ocular, and parenteral administration. Poloxamer 407 (PF-127) is a nonionic surfactant composed of a polyoxyethylene-polyoxypropylene triblock copolymer at concentrations ranging from 20 to 30%. At low concentrations (10-4 Monomolecular micelles are formed at -10-5%), but as the concentration increases, polymolecular aggregates consisting of a hydrophobic central core with hydrophilic polyoxyethylene chains facing the external medium are generated. Micellization occurs in diluted solutions of block copolymers in selected solvents exceeding the critical micelle concentration at a given temperature. At high concentrations above the critical gel concentration, micelles can be aligned into a lattice.

[0221] Aqueous solutions of poloxamer are stable in the presence of acids, alkalis, and metal ions. Commonly used poloxamers include types 88 (Class F-68), 237 (Class F-87), 338 (Class F-108), and 407 (Class F-127), which are freely soluble in water. The 'F' designation refers to the flake form of the product. PF-127 possesses excellent solubilization ability and low toxicity, and is therefore considered an excellent carrier for topical drug delivery.

[0222] PF-127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E101 P56 E101 with an average molar mass of 13,000. It contains approximately 70% ethylene oxide, which explains its hydrophilicity. It is one of a series of poloxamer ABA block copolymers. As mentioned above, an aqueous solution of PF-127 at 20 to 30% w / w exhibits the interesting characteristic of reverse thermal gelation; that is, it is liquid at refrigerated temperatures (4–5 °C) but gels upon heating to room temperature. Gelation is reversible upon cooling. Therefore, this phenomenon suggests that when applied to the skin, the gel formulation will form a solid artificial barrier and a sustained-release depot. Furthermore, PF-127 is known to have the lowest toxicity among commercially available copolymers.

[0223] In one of the embodiments, the poloxamer polymer is preferably present in an amount of about 1 to about 10% w / w. Preferably, the drug delivery vehicle may also contain, in addition to the drug and buffer, preservatives, cosolvents, suspending agents, viscosity enhancers, osmotic pressure regulators, coloring agents, and other excipients. Suitable water-soluble preservatives that can be used in the drug delivery vehicle include sodium bisulfite, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric borate, parabens, benzyl alcohol, and phenyl ethanol. These agents may be present in an amount of about 0.001% to about 5% by weight, preferably about 0.01% to about 2% by weight.

[0224] In a preferred embodiment, the composition of the present invention can be delivered to an application area requiring a low-viscosity liquid at room temperature, which forms a semi-solid gel having high viscosity upon contact with the body of the subject.

[0225] In one embodiment, an amount of ethylene oxide / propylene oxide block copolymer effective for producing a composition having a sufficiently low viscosity at room temperature, to be dispensed from a dispensing device or applicator to a scalp area. At body temperature, the material exhibits a much higher viscosity and adheres stably to the scalp. As the material dissolves, the therapeutic agent contained therein is slowly released into the hair follicles.

[0226] One embodiment of the present invention, the use of a thermoreversible hydrogel composition for the delivery of a therapeutic agent for treating hair loss and / or promoting hair growth, is that said thermoreversible hydrogel composition has a viscosity of less than 200 Pa·s over a temperature range of 4 °C to 12 °C and 10 at 37 °C 3 It is characterized by including a thermoreversible hydrogel characterized by a viscosity greater than Pa·s.

[0227] In one embodiment of the present invention, the use of a thermoreversible hydrogel composition for the delivery of a therapeutic agent for treating hair loss and / or promoting hair growth is characterized in that the thermoreversible hydrogel composition comprises a thermoreversible hydrogel characterized by a viscosity of less than 50 cP over a temperature range of 5 °C to 25 °C. In one specific embodiment, the viscosity is less than 30 cP. In one specific embodiment, the viscosity is less than 20 cP. In one specific embodiment, the viscosity is less than 10 cP. In one specific embodiment, the viscosity is about 5 cP to less than 15 cP. In one embodiment, the composition is a fluid liquid or solution composition, wherein such composition uses a hydrogel, in particular a thermoreversible hydrogel such as one or more poloxamers.

[0228] In one embodiment of the present invention, the use of a thermoreversible hydrogel composition for the delivery of a therapeutic agent for treating hair loss and / or promoting hair growth is such that the thermoreversible hydrogel composition has a viscosity of less than 5 Pa.s over a temperature range of 4 °C to 12 °C and 10 at 37 °C 3 It is characterized by including a thermoreversible hydrogel characterized by excess viscosity.

[0229] In some embodiments of the present invention, the thermoreversible hydrogel is further characterized by a viscosity of less than 5 Pa·s over a temperature range of 4 °C to 12 °C. In some embodiments of the present invention, the thermoreversible hydrogel is further characterized by a viscosity of less than 0.5 Pa·s over a temperature range of 4 °C to 12 °C. In some embodiments of the present invention, the thermoreversible hydrogel is 3X10 at 37 °C 3 It is additionally characterized by excess viscosity.

[0230] In one embodiment, the present invention discloses a hydrophilic sustained-release material comprising an amount of poloxamer effective for producing a hydrogel composition having a sufficiently low viscosity to be applied to the scalp at room temperature.

[0231] In one embodiment, the composition according to the present invention relates to a topical composition comprising an active ingredient comprising a. dutasteride at a concentration of about 0.05% w / w of the composition, b. minoxidil at a concentration of about 5% w / w of the composition by weight, and c. a pharmaceutically acceptable carrier, wherein the composition is an aqueous solution and the solution comprises a solvent, and the composition comprising dutasteride and minoxidil at said concentrations may provide synergistic efficacy and a synergistic reduction of at least one of dutasteride and minoxidil.

[0232] In one embodiment, the composition according to the present invention comprises a composition for treating alopecia and / or promoting hair regrowth, said composition comprising (a) at least one therapeutic agent selected from 5α-reductase inhibitors and vasodilators, (b) at least one solubilizing agent, and (c) water, said composition substantially free of grease.

[0233] In one embodiment, the composition according to the present invention comprises a composition suitable for preventing hair loss and / or promoting hair growth, wherein the composition comprises (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w minoxidil, (ii) about 0.02 to about 0.07% w / w dutasteride—, and (b) means for solubilizing one or more activators to provide sufficient solution stability, and the composition provides a pH of about 3 to about 7.

[0234] In one aspect of the above embodiment, the means for solubilization comprises one or more solvents, one or more solubilizing agents, and one or more crystal growth inhibitors.

[0235] In one aspect of the above embodiment, the solvent is selected from ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol, N-methylpyrrolidone and N-methylcaprolactam, dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycol succinate (TPGS), dimethylformamide (DMF), dimethylacetamide (DMA), and capryl-caproyl macrogol 8-glyceride.

[0236] In one embodiment of the above example, the solubilizing agent is selected from one or more of glycerol, aliphatic alcohol or aromatic alcohol containing four or more carbon atoms, polyoxyl castor oil, polyoxyl hydrogenated castor oil, cyclodextrin, ethylene vinyl acetate, polyvinyl alcohol, povidone, copovidone, or any combination thereof.

[0237] In one embodiment of the above example, the stabilizer or antioxidant is selected from sodium sulfite, sodium thiosulfate, tocopherol or its derivatives, such as dl-alpha tocopherol, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbyl palmitate.

[0238] In one aspect of the above embodiment, the crystal growth inhibitor is selected from glycols or derivatives thereof selected from ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene 20 glycol, hexylene glycol, propylene glycol dipellagonate, diethylene glycol monoethyl ether, propylene laurate glycol dicaprylate dicaprate propylene glycol, and diethylene glycol monoethyl ether.

[0239] In one aspect of the above embodiment, the composition further comprises an acidifying agent selected from citric acid, citric anhydride, citric acid monohydrate, DL-lactic acid, DL-malic acid, DL-tartaric acid, fumaric acid, L-malic acid, L-tartaric acid, salicylic acid, glycolic acid, potassium tartrate, potassium citrate, DL-potassium gluconate, sodium lactate, sodium L-tartaric acid, sodium citrate, ascorbic acid, sorbic acid, methanesulfonic acid, or any combination thereof.

[0240] In one embodiment of the above example, the composition further comprises a thermoreversible polymer.

[0241] In one embodiment, the composition according to the present invention comprises a composition suitable for preventing hair loss and / or promoting hair growth, wherein the composition comprises (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w minoxidil, (ii) about 0.02 to about 0.07% w / w dutasteride—and (b) an acidifying agent, wherein the ratio of the activator to the acidifying agent is in the range of about 1:0.1 to about 1:0.4.

[0242] In one aspect of the above embodiment, the ratio of dutasteride to acidifying agent is in the range of about 1:10 to about 1:40.

[0243] In one embodiment, the composition according to the present invention comprises a composition suitable for preventing hair loss and / or promoting hair growth, wherein the composition comprises (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w minoxidil, (ii) about 0.02 to about 0.1% w / w dutasteride—, (b) means for solubilizing one or more activators to provide sufficient solution stability, and the composition provides a pH of about 3 to about 7.

[0244] In one aspect of the above embodiment, the means for solubilization comprises one or more solvents, one or more solubilizing agents, and one or more crystal growth inhibitors.

[0245] In one aspect of the above embodiment, the solvent is selected from ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol, N-methylpyrrolidone and N-methylcaprolactam, dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycol succinate (TPGS), dimethylformamide (DMF), dimethylacetamide (DMA), and capryl-caproyl macrogol 8-glyceride.

[0246] In one embodiment of the above example, the solubilizing agent is selected from one or more of glycerol, aliphatic alcohol or aromatic alcohol containing four or more carbon atoms, polyoxyl castor oil, polyoxyl hydrogenated castor oil, cyclodextrin, ethylene vinyl acetate, polyvinyl alcohol, povidone, copovidone, or any combination thereof.

[0247] In one aspect of the above embodiment, the crystal growth inhibitor is selected from glycols or derivatives thereof selected from ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene 20 glycol, hexylene glycol, propylene glycol dipellagonate, diethylene glycol monoethyl ether, propylene laurate glycol dicaprylate dicaprate propylene glycol, and diethylene glycol monoethyl ether.

[0248] In one aspect of the above embodiment, the composition further comprises an acidifying agent selected from citric acid, citric anhydride, citric acid monohydrate, DL-lactic acid, DL-malic acid, DL-tartaric acid, fumaric acid, L-malic acid, L-tartaric acid, salicylic acid, glycolic acid, potassium tartrate, potassium citrate, DL-potassium gluconate, sodium lactate, sodium L-tartaric acid, sodium citrate, ascorbic acid, sorbic acid, methanesulfonic acid, or any combination thereof.

[0249] In one embodiment of the above example, the composition further comprises a thermoreversible polymer.

[0250] In one embodiment, the composition according to the present invention comprises a composition suitable for preventing hair loss and / or promoting hair growth, wherein the composition comprises (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w of minoxidil, (ii) about 0.02 to about 0.07% w / w of dutasteride—and (b) an acidifying agent, wherein the ratio of the activator to the acidifying agent is in the range of about 1:0.1 to about 1:0.4.

[0251] In one aspect of the above embodiment, the ratio of dutasteride to acidifying agent is in the range of about 1:10 to about 1:40.

[0252] In one embodiment, the composition according to the present invention comprises a composition for treating hair loss and / or promoting hair growth, wherein the composition comprises a. dutasteride at a concentration of about 0.05% w / w of the composition, b. minoxidil at a concentration of about 5% w / w of the composition by weight, and c. a pharmaceutically acceptable carrier, wherein the composition comprises means for penetration of at least dutasteride or minoxidil.

[0253] In one embodiment, the composition according to the present invention comprises a composition for treating hair loss and / or promoting hair growth, wherein the composition comprises (a) an active ingredient—the active ingredient being composed of (i) dutasteride at a concentration of about 0.05% w / w of the composition, (ii) minoxidil at a concentration of about 5% w / w of the composition by weight—and (b) a pharmaceutically acceptable carrier, wherein the composition is a solution.

[0254] In one embodiment, the composition according to the present invention comprises a composition for treating hair loss and / or promoting hair growth, wherein the composition comprises (a) an active ingredient—the active ingredient being composed of (i) dutasteride at a concentration of about 0.05% w / w of the composition, (ii) minoxidil at a concentration of about 5% w / w of the composition by weight—and (b) a pharmaceutically acceptable carrier, wherein the composition is a dispersion.

[0255] In one embodiment, the present invention comprises a composition for treating alopecia and / or promoting hair regrowth, said composition comprising (a) at least one therapeutic agent selected from 5-alpha reductase inhibitors and vasodilators, (b) at least one solvent, (c) a viscosity modifier, and (d) water, said composition substantially free of alcohol and propylene glycol.

[0256] In one embodiment, the composition according to the present invention comprises a solution formulation comprising about 0.01 to 0.05% w / w of dutasteride, about 2.0 to 5.0% w / w of minoxidil, about 5.0-50.0% w / w of diethylene glycol monoethyl ether, about 1.0-10.0% w / w of glycerin, about 0.5-2.0% w / w of lactic acid, about 0.2-2.0% w / w of polysorbate 60, about 0.5-3.0% w / w of benzyl alcohol, about 15-30.0% w / w of purified water; and up to 100% w / w of isopropyl alcohol.

[0257] In one embodiment, the composition according to the present invention comprises a thermoreversible sol-gel spray formulation comprising about 0.01 to 0.05% w / w of dutasteride, about 2.0 to 5.0% w / w of minoxidil, about 5.0-50.0% w / w of diethylene glycol monoethyl ether, about 1.0-5.0% w / w of poloxamer, about 1.0-10.0% w / w of glycerin, about 0.5-2.0% w / w of lactic acid, about 0.2-2.0% w / w of polysorbate 60, about 0.5-3.0% w / w of benzyl alcohol, and up to about 100% w / w of purified water.

[0258] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 5.0-50.0% w / w diethylene glycol monoethyl ether, about 1.0-10.0% w / w glycerin, about 0.5-2.0% w / w lactic acid, about 0.2-2.0% w / w polysorbate 60, about 0.5-3.0% w / w benzyl alcohol, about 0.5-2.5% w / w cetyl alcohol, about 0.2-1.5% w / w stearyl alcohol, about 20-50% w / w purified water, and a foam formulation of about 1.0-5.0 gm / 60 gm can of propellant (NIP-70). Includes.

[0259] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 0.01-0.1% w / w citric acid anhydride, about 0.05-0.5% w / w cetrimonium chloride, about 1-5% w / w cetyl alcohol, about 1-5% w / w cyclomethicone, about 0.01-0.2% w / w disodium edetate, about 1.0-10.0% w / w glycerin, about 5.0-50.0% w / w diethylene glycol monoethyl ether, about 0.5-2.0% w / w lactic acid, about 1.0-5.0% w / w macrogol stearate type I, about 1.0-10. It comprises a microspherical formulation of % w / w mono- and di-glycerides, about 0.5-5.0% w / w phenoxyethanol, about 2.0-10.0% w / w silicon dioxide, about 0.5-5.0% polyquaternium-7, sodium hydroxide for pH adjustment, and up to 100% w / w purified water.

[0260] In one embodiment, the composition according to the present invention comprises a solution formulation comprising about 0.01 to 0.05% w / w of dutasteride, about 2.0 to 5.0% w / w of minoxidil, about 5.0-50.0% w / w of diethylene glycol monoethyl ether, about 1.0-10.0% w / w of glycerin, about 0.5-2.0% w / w of lactic acid, about 0.2-2.0% w / w of polysorbate 60, about 0.5-3.0% w / w of benzyl alcohol, about 15-40.0% w / w of purified water; and up to 100% w / w of isopropyl alcohol.

[0261] In one embodiment, the composition according to the present invention comprises a thermoreversible sol-gel spray formulation comprising about 0.01 to 0.05% w / w of dutasteride, about 2.0 to 5.0% w / w of minoxidil, about 5.0-50.0% w / w of diethylene glycol monoethyl ether, about 1.0-5.0% w / w of poloxamer, about 1.0-10.0% w / w of glycerin, about 0.5-2.0% w / w of lactic acid, about 0.2-2.0% w / w of polysorbate 60, about 0.5-3.0% w / w of benzyl alcohol, and up to about 100% w / w of purified water.

[0262] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 5.0-50.0% w / w diethylene glycol monoethyl ether, about 1.0-10.0% w / w glycerin, about 0.5-2.0% w / w lactic acid, about 0.2-2.0% w / w polysorbate 60, about 0.5-3.0% w / w benzyl alcohol, about 0.5-2.5% w / w cetyl alcohol, about 0.2-1.5% w / w stearyl alcohol, about 20-50% w / w purified water, and a foam formulation of about 1.0-5.0 gm / 60 gm can of propellant (NIP-70). Includes.

[0263] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 0.01-0.1% w / w citric acid anhydride, about 0.05-0.5% w / w cetrimonium chloride, about 1-5% w / w cetyl alcohol, about 1-5% w / w cyclomethicone, about 0.01-0.2% w / w disodium edetate, about 1.0-10.0% w / w glycerin, about 5.0-50.0% w / w diethylene glycol monoethyl ether, about 0.5-2.0% w / w lactic acid, about 1.0-5.0% w / w macrogol stearate type I, about 1.0-10. It comprises a microspherical formulation of % w / w mono- and di-glycerides, about 0.5-5.0% w / w phenoxyethanol, about 2.0-10.0% w / w silicon dioxide, about 0.5-5.0% polyquaternium-7, sodium hydroxide for pH adjustment, and up to 100% w / w purified water.

[0264] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 15.0-35.0% w / w diethylene glycol monoethyl ether, about 1.0-10.0% w / w glycerin, about 0.5-2.0% w / w lactic acid, about 0.2-2.0% w / w phenoxyethanol, about 0.001-0.01% w / w dl-alpha tocopherol acetate, about 10-30% w / w isopropyl alcohol, about 0.1-5% w / w polyoxyl 40 hydrogenated castor oil, about 5-20% w / w hexylene glycol, about 0.1-5% poloxamer, It includes a solution formulation containing up to 100% w / w of purified water.

[0265] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 10.0-50.0% w / w diethylene glycol monoethyl ether, about 1.0-10.0% w / w glycerin, about 0.5-2.0% w / w lactic acid, about 0.2-2.0% w / w phenoxyethanol, about 0.001-0.01% w / w dl-alpha tocopherol acetate, about 15-40% w / w isopropyl alcohol, about 0.1-5% w / w polyoxyl 40 hydrogenated castor oil, about 5-20% w / w hexylene glycol, about 0.1-5% poloxamer, It includes a solution formulation containing up to 100% w / w of purified water.

[0266] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 15.0-35.0% w / w diethylene glycol monoethyl ether, about 1.0-10.0% w / w glycerin, about 0.5-2.0% w / w lactic acid, about 0.2-2.0% w / w phenoxyethanol, about 0.001-0.01% w / w dl-alpha tocopherol acetate, about 10-30% w / w isopropyl alcohol, about 0.1-5% w / w polyoxyl 40 hydrogenated castor oil, about 5-20% w / w hexylene glycol, about 0.1-5% poloxamer, It includes a solution formulation containing up to 100% w / w of purified water.

[0267] In one embodiment, the composition according to the present invention comprises about 0.01 to 0.05% w / w dutasteride, about 2.0 to 5.0% w / w minoxidil, about 10.0-50.0% w / w diethylene glycol monoethyl ether, about 1.0-10.0% w / w glycerin, about 0.5-2.0% w / w lactic acid, about 0.2-2.0% w / w phenoxyethanol, about 0.001-0.01% w / w dl-alpha tocopherol acetate, about 15-40% w / w isopropyl alcohol, about 0.1-5% w / w polyoxyl 40 hydrogenated castor oil, about 5-20% w / w hexylene glycol, about 0.1-5% poloxamer, It includes a solution formulation containing up to 100% w / w of purified water.

[0268] In one embodiment, the present invention relates to reducing the amount of at least one of the active ingredients that may enter systemic circulation after local administration of dutasteride and minoxidil.

[0269] In some embodiments, the concentration of minoxidil is at the same level, namely 2% w / w or 5% w / w, 10% w / w, 15% w / w or 20% w / w.

[0270] In some embodiments, the concentration of minoxidil is at the same level, i.e., 2% w / w or 5% w / w or higher, but at least one of the side effects associated with minoxidil is further reduced compared to the same concentration of minoxidil in the comparative composition.

[0271] In some embodiments, the concentration of minoxidil is at the same level, i.e., 2% w / w or 5% w / w or higher, but the efficacy is further enhanced compared to the same concentration of minoxidil in the comparative composition, and at the same time, at least one of the side effects associated with minoxidil is reduced compared to the same concentration of minoxidil in the comparative composition.

[0272] Example-1 : Dutasteride + Minoxidil Cream

[0273]

[0274] manufacturing process The oil phase is prepared by mixing cetyl alcohol, cyclomethicone, macrogol stearate type I, mono- and di-glycerides, and phenoxyethanol in an SS container and heating. Separately, diethylene glycol monoethyl ether, purified water, citric anhydride, glycerin, lactic acid, and disodium EDTA are added to an SS container and heated, and minoxidil is added to the above phase under stirring to obtain a clear drug phase. Separately, a sodium hydroxide solution is prepared in purified water. Separately, dutasteride microspheres are prepared by loading polyquaternium-7 microspheres onto a silicone base. The minoxidil drug phase is transferred to a main preparation container, the oil phase is transferred to the main preparation container under homogenization, homogenized, and dutasteride microspheres are added to the above phase under homogenization. The mixture is cooled under stirring, and if necessary, the pH of the cream is adjusted with a sodium hydroxide solution.

[0275] Examples- 2: Dutasteride + Minoxidil Thermoreversible Spray

[0276]

[0277] Manufacturing method : Diethylene glycol monoethyl ether, glycerin, lactic acid, polysorbate 60, benzyl alcohol, and purified water were added to an SS container and heated; minoxidil was added to the mixture and dissolved under stirring; the minoxidil drug phase was cooled; dutasteride was added and dissolved in the above phase under stirring. Purified water was added to a separate SS container, and poloxamer was added to the mixture under stirring to obtain a uniform gel dispersion without lumps; the drug phase was added to this gel under stirring and mixed.

[0278] Example-3 : Dutasteride + Minoxidil Foam

[0279]

[0280] Manufacturing method Diethylene glycol monoethyl ether, glycerin, lactic acid, polysorbate 60, benzyl alcohol, and purified water were added to an SS container, cetyl alcohol was added to this phase under stirring to obtain a clear phase, stearyl alcohol was added under stirring to obtain a clear phase, minoxidil was added to this under stirring, the phase was cooled under stirring, dutasteride was added and dissolved in the above phase under stirring. Mixing was performed under stirring. Aluminum cans were filled with pre-forms, and finally, the filled cans were crimped and filled with propellant (NIP-70).

[0281] Example-4 : Dutasteride + Minoxidil solution

[0282]

[0283] Manufacturing method : A drug phase of minoxidil is prepared by adding it to a mixture of diethylene glycol monoethyl ether, glycerin, lactic acid, polysorbate 60, benzyl alcohol, and purified water while stirring at 45-55°C, then cooling the temperature, adding isopropyl alcohol to the minoxidil drug phase, and then adding dutasteride. Mixing is performed under stirring to obtain a clear solution.

[0284] Example-5 : Dutasteride + Minoxidil solution

[0285]

[0286] Manufacturing methodPurified water, a certain amount of diethylene glycol monoethyl ether, glycerin, lactic acid, polyoxyl 40 hydrogenated castor oil, phenoxyethanol, and hexylene glycol were mixed and heated. Minoxidil was added under stirring. Separately, a dutasteride drug phase was prepared by adding a portion of the diethylene glycol monoethyl ether under stirring, and this was added to the minoxidil drug phase under stirring. Vitamin E acetate was mixed in a portion of the isopropyl alcohol under stirring, added to the minoxidil phase, and mixed. The remaining amount of isopropyl alcohol was added to obtain a clear colorless to pale yellow solution. Poloxamer was added to the above phase under stirring and mixed to obtain a transparent colorless to pale yellow solution.

[0287] Example-6 : Dutasteride + Minoxidil solution

[0288]

[0289] Manufacturing method : Purified water, a certain amount of diethylene glycol monoethyl ether, glycerin, lactic acid, polyoxyl 40 hydrogenated castor oil, phenoxyethanol, and hexylene glycol. Minoxidil was added to the above mixture under stirring. Separately, a dutasteride drug phase was prepared by adding a portion of the diethylene glycol monoethyl ether under stirring and added to the dutasteride drug phase. Vitamin E acetate was mixed with a portion of the isopropyl alcohol under stirring and added to the minoxidil drug phase. The remaining amount of isopropyl alcohol was added to the above mixture under stirring. Poloxamer was added to the above mixture under stirring and mixed to obtain a transparent colorless to pale yellow solution.

[0290] Example-7 The results of the stability study of Example 6 at 25 ℃ / 60 % RH and 40 ℃ / 75 % RH are shown in Table 1 below.

[0291]

[0292] Example 6 - The impurity profile of the results of the stability study of the minoxidil component at 25 ℃ / 60 % RH and 40 ℃ / 75 % RH is shown in Table 2.

[0293]

[0294] Example 6 - The impurity profile of the dutasteride component as a result of the stability study at 25 ℃ / 60 % RH and 40 ℃ / 75 % RH is shown in Table 3.

[0295]

[0296] Example-8 : Animal dermal toxicity study

[0297] According to Example 6, a study was conducted to determine the dermal concentration, plasma concentration, dermal stimulation, and sensitization potential of the dutasteride and minoxidil formulations according to the present invention.

[0298] A. 14-Day Dermal Toxicity Study Using Dutasteride + Minoxidil Topical Solution in Rats .

[0299] Research Design :

[0300] Test species: Male Sprague Dawley rat

[0301]

[0302] exposure The test formulation and placebo were applied to 10% of the body surface area (BSA) of depilated rats. The exposure period was 6 hours / day.

[0303] parameters The formulation was evaluated using toxicity parameters (plasma: days 1, 14, 30, and 90; skin: days 14 and 90) and histopathological examination of the application site. In addition, skin reaction scores for edema / erythema were evaluated after daily exposure.

[0304] result: No local reactions or any clinical signs were observed. No treatment-related effects were observed on body weight, hematological markers, clinical chemical markers, organ weights, or gross pathological findings. Up to five times the maximum recommended human dose (MRHD), no histopathological findings were observed at the application site or in any tissue / organ.

[0305] AUC, C at NOAEL (No Adverse Event Level) dose of dutasteride + minoxidil topical solution 0.25 / 25 mg / kg / day 최대 and skin concentration parameters are presented below (Table 5).

[0306]

[0307] In a 14-day dermal study in rats, the NOAEL dose was 0.25 / 25 mg / kg / day (mg / m²) of dutasteride + minoxidil topical solution. 2 It was 5 times the reference MRHD [1 ml applied once daily]. Plasma exposure of dutasteride was low, while plasma exposure of minoxidil was higher compared to dutasteride. For both dutasteride (~70 times) and minoxidil (~260 times), skin concentrations at the application site were significantly higher than their plasma exposures. Higher skin concentrations were not associated with local dermal toxicity.

[0308] B. 14-Day Dermal Toxicity Study Using Dutasteride + Minoxidil Topical Solution in Rabbits .

[0309] Research Design:

[0310] Test species: Male New Zealand white rabbit

[0311]

[0312] exposure The test formulation and placebo were applied to 10% of the body surface area (BSA) of shaved rabbits. The exposure period was 6 hours / day.

[0313] parametersThe formulation was evaluated using toxicity parameters (plasma: days 1, 14, 30, and 90; skin: days 14 and 90) and histopathological examination of the application site. In addition, skin reaction scores for edema / erythema were evaluated after daily exposure.

[0314] result : No local reactions or any clinical signs were observed. No treatment-related effects were observed on body weight, hematological markers, clinical chemical markers, organ weights, or gross pathological findings. Up to five times the maximum recommended human dose (MRHD), no histopathological findings were observed at the application site or in any tissue / organ.

[0315] AUC, C at NOAEL (No Adverse Event Level) dose of dutasteride + minoxidil topical solution 0.125 / 12.5 mg / kg / day 최대 and skin concentration parameters are presented below (Table 7).

[0316]

[0317] In a 14-day dermal study in rabbits, the NOAEL dose was 0.125 / 12.5 mg / kg / day (mg / m²) of dutasteride + minoxidil topical solution. 2 It was 5 times the reference MRHD [1 ml applied once daily]. Plasma exposure of dutasteride was low, while plasma exposure of minoxidil was higher compared to dutasteride. For both dutasteride (~245 times) and minoxidil (~7460 times), skin concentrations at the application site were significantly higher than their plasma exposures. Higher skin concentrations were not associated with local dermal toxicity.

[0318] Example-9 : Preclinical test for evaluating hair growth

[0319] Hair growth measurements to be performed on C3H mice (6-7 weeks old). C3H mice were divided into 8 groups, with approximately 7 animals in each group as provided in Table 8. The study on C3H mice is planned for a sufficient number of days.

[0320] Formulation:

[0321] 1) Placebo vehicle

[0322] 2) Dutasteride 0.05%

[0323] 3) Minoxidil 5%

[0324] 4) Topical Dutasteride 0.05% + Topical Minoxidil 5%

[0325]

[0326] procedure:

[0327] Mice were housed in cages of similar size in an environment-controlled room with a light-to-dark cycle of approximately 12 hours and 12 hours, and food and water were provided freely. Animal care was based on NIH Publication No. 85-23, 'Guidelines for the Care and Use of Experimental Animals'. Once all mice entered the long resting / dormant phase of the hair cycle, their dorsal areas were depilated (Wahl Clippers KM10 series, Blade # 40). Ten female mice per group were depilated while sedated with isoflurane anesthesia.

[0328] Determination of the onset of accelerated growth:

[0329] At the start of the study, the dorsal hair of the mice was completely removed by shaving with short clippers based on visual inspection. The test item was applied to the depilated area of ​​the mice once daily at a dose of 0.2 ml. Both the hair growth phase and hair coverage rate were observed by visual inspection, and the hair condition of each mouse was recorded for 5 days over 1 week (Telogen: Resting phase of the hair growth cycle—no dark-colored follicles / roots visible on shaved skin; Growth phase: Growing follicles, i.e., follicles in the growth state of the hair growth cycle—dark-colored follicles / roots visible on shaved skin). A study log (or growth phase log) was recorded documenting daily observations of mice entering the growth phase (gray skin, the first visual sign of new hair growth). Treatment was continued for 8 weeks.

[0330] The groups were ranked from the group with the highest hair coverage to the group with the lowest hair coverage according to the following hair coverage scoring system.

[0331]

[0332] Histological analysis :

[0333] At the end of the experiment, mice were euthanized by CO2 asphyxiation, and the skin was surgically removed to investigate histological characteristics at the end of the treatment period. Skin samples were fixed in 10% phosphate-buffered formalin for 24 hours. The samples were embedded in paraffin blocks. Paraffin sections were processed for histological analysis. Histological examination was performed using hematoxylin-eosin staining. The number of hair follicles was counted, and subcutaneous tissue thickness was measured.

[0334] Statistical analysis :

[0335] All statistical analyses were performed using Prism 8 software (GraphPad Software, San Diego, California, USA). Hair growth sites were evaluated using a two-way repeated measures ANOVA followed by a Tukey multiple comparison post-hoc test.

[0336] result :

[0337] Hair Coverage Score

[0338] Healthy female C3H mice aged 6 to 7 weeks were used. The mice were depilated on their backs to ensure they were hairless. The following day, the mice were randomized by body weight. Hair coverage scoring and application of the composition of Example 6 were initiated. The composition of Example 6 was applied for 48 days, and scoring was also performed throughout the study. As shown in Fig. 1a, topical application of the composition of Example 6 containing dutasteride 0.05% w / w and minoxidil 5% w / w resulted in faster hair growth compared to the single treatment group and placebo. As shown in Fig. 1b, topical application of the composition of Example 6 containing dutasteride 0.05% w / w and minoxidil 5% w / w resulted in a final significantly increased hair coverage score compared to the single treatment group and placebo (Table 9 - Average Hair Coverage Scores).

[0339]

[0340]

[0341] Growth Phase Initiation Log

[0342] After the initiation of application of the hair growth formulation, the number of mice transitioning from the resting phase to the growth phase was recorded in the growth phase log. On day 3 of treatment application, a significantly higher number of mice in the combination group exhibited the growth phase compared to the single treatment and placebo vehicles (Fig. 2, Table 10).

[0343]

[0344]

[0345] The results of the embodiments show that the combination formulation of minoxidil and dutasteride in the present invention has superior efficacy compared to a single minoxidil composition or a dutasteride composition.

[0346] The results of Example 6 indicate that, compared to a single minoxidil preparation or dutasteride preparation, the topical composition of minoxidil and dutasteride of the present invention has better efficacy when compared to a composition of minoxidil alone or dutasteride alone.

[0347] Therefore, it is clear that patients with androgenetic alopecia can dramatically benefit from combination therapy adding minoxidil to dutasteride.

[0348] The terms or expressions used in this document are for illustrative purposes only and are not intended to be restrictive. Accordingly, the terms and / or phrases of this specification should be interpreted by those skilled in the art in light of the teachings and guidelines of this specification.

[0349] The scope and range of the present invention shall not be limited by any of the exemplary embodiments described above, but shall be defined only by the following claims and their equivalents.

Claims

Claim 1 A pharmaceutical composition comprising: (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w minoxidil, and (ii) about 0.02 to about 0.07% w / w dutasteride—, and (b) means for solubilizing one or more activators to provide solution state stability, and (c) an acidifying agent, wherein the composition provides a pH of about 3 to about 7, and the pharmaceutical composition prevents hair loss and / or promotes hair growth. Claim 2 A pharmaceutical composition according to claim 1, wherein the means for solubilization comprises one or more solvents, one or more solubilizing agents, and one or more crystal growth inhibitors. Claim 3 A pharmaceutical composition according to claim 2, wherein the solvent comprises ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol, N-methylpyrrolidone and N-methylcaprolactam, dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycol succinate (TPGS), dimethylformamide (DMF), dimethylacetamide (DMA), and capryl-caproyl macrogol 8-glyceride. Claim 4 A pharmaceutical composition according to claim 2, wherein the solubilizing agent comprises one or more of glycerol, an aliphatic alcohol or an aromatic alcohol containing four or more carbon atoms, polyoxyl castor oil, polyoxyl hydrogenated castor oil, cyclodextrin, ethylene vinyl acetate, polyvinyl alcohol, povidone, copovidone, or any combination thereof. Claim 5 A pharmaceutical composition according to claim 2, wherein the crystal growth inhibitor comprises a glycol or a derivative thereof selected from ethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, pentylene 20 glycol, hexylene glycol, propylene glycol dipellagonate, diethylene glycol monoethyl ether, propylene laurate glycol dicaprylate dicaprate propylene glycol, and diethylene glycol monoethyl ether. Claim 6 A pharmaceutical composition according to claim 1, further comprising a stabilizer. Claim 7 A pharmaceutical composition according to claim 6, wherein the stabilizer comprises sodium sulfite, sodium thiosulfate, tocopherol or derivatives thereof such as dl-alpha tocopherol, sodium metabisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and ascorbyl palmitate. Claim 8 A pharmaceutical composition according to claim 1, wherein the acidifying agent comprises citric acid, citric anhydride, citric acid monohydrate, dl-lactic acid, dl-malic acid, dl-tartaric acid, fumaric acid, l-malic acid, l-tartaric acid, salicylic acid, glycolic acid, potassium tartrate, potassium citrate, dl-potassium gluconate, sodium lactate, sodium l-tartarate, sodium citrate, ascorbic acid, sorbic acid, methanesulfonic acid, or any combination thereof. Claim 9 The pharmaceutical composition according to claim 1, wherein the composition is selected from the group consisting of hair tonic, solution, dispersion, suspension, emulsion, microemulsion, colloidal solution, cream, ointment, lotion, hair dye, shampoo, rinse, gel, patch, hair serum, foam, and spray. Claim 10 A pharmaceutical composition according to claim 1, further comprising a thermoreversible polymer. Claim 11 A pharmaceutical composition according to claim 1, wherein the ratio of dutasteride to acidifying agent is in the range of about 1:10 to about 1:

40. Claim 12 A pharmaceutical composition according to claim 1, wherein the acidifying agent is lactic acid. Claim 13 A pharmaceutical composition comprising: (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w minoxidil, (ii) about 0.02 to about 0.07% w / w dutasteride—, (b) means for solubilizing one or more activators to provide solution state stability, and (c) an acidifying agent, wherein the composition can provide a synergistic effect for preventing hair loss and / or promoting hair growth. Claim 14 A pharmaceutical composition according to claim 13, further comprising a dermatologically acceptable carrier comprising about 1.0% and about 5.0% w / w of an ethylene oxide / propylene oxide triblock copolymer. Claim 15 A pharmaceutical composition according to claim 13, wherein the pH of the composition is about 3 to about 7. Claim 16 In claim 13, the above composition is a pharmaceutical composition having a pH of about 5 to about 6.

5. Claim 17 A pharmaceutical composition according to claim 13, wherein the composition provides a viscosity of less than 50 cP at a temperature of about 5 ℃ to 25 ℃. Claim 18 A method for preventing hair loss and / or promoting hair growth, comprising: (a) an activator—the activator comprises (i) about 2% w / w to about 7% w / w minoxidil, (ii) about 0.02 to about 0.07% w / w dutasteride—, and (c) an acidifying agent, and (b) means for solubilizing one or more activators to provide sufficient solution stability, wherein the composition provides a pH of about 3 to about 7, and the method comprises administering to a subject once or twice a day.

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