Alcohol-containing emulsion of 5α-reductase inhibitor, preparation method therefor, and use thereof

Abstract

Provided are an alcohol-containing emulsion of a 5α-reductase inhibitor, a preparation method therefor, and use thereof. The alcohol-containing emulsion comprises a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a permeation enhancer. The alcohol-containing emulsion not only retains the refreshing feel on the skin of alcohol-containing preparations, but also solves the technical problem of ethanol destroying the stability of the emulsion, has excellent stability and transdermal properties, and is suitable for use on the scalp area for the treatment of androgenetic alopecia.

Description

Alcoholic emulsion of 5α-reductase inhibitor and preparation method and application thereof

[0001] This application is a divisional application of Chinese Patent Application No. 202411281626.4, filed on September 12, 2024, entitled "Alcoholic emulsion of 5α-reductase inhibitor and preparation method and application thereof". TECHNICAL FIELD

[0002] The present application relates to the technical field of medicine, in particular to an alcoholic emulsion of 5α-reductase inhibitor and a preparation method and application thereof. BACKGROUND

[0003] Androgenetic alopecia, also known as seborrheic alopecia, is the most common progressive alopecia. The occurrence of androgenetic alopecia is closely related to the concentration of dihydrotestosterone in the body. 5α-reductase inhibitors such as finasteride and dutasteride inhibit the activity of 5α-reductase by forming an enzyme complex, inhibit the conversion of testosterone to dihydrotestosterone, thereby reducing the concentration of dihydrotestosterone, which can effectively treat androgenetic alopecia.

[0004] Commercially available 5α-reductase inhibitors are mainly oral preparations, which are used for the treatment of benign prostatic hyperplasia in men or androgenetic alopecia in men. Oral 5α-reductase inhibitors can cause erectile dysfunction, decreased libido, ejaculation disorders, breast pain, gynecomastia in men, and many other adverse reactions; while topical external preparations can effectively reduce the toxic side effects of systemic exposure, improve treatment safety and patient compliance. For example, finasteride spray (trade name: Propecia) is used for the treatment of androgenetic alopecia in men, and has similar clinical efficacy to oral finasteride.

[0005] ​The commercially available external preparations for treating alopecia generally contain ethanol, such as minoxidil tincture and minoxidil foam. After use, ethanol can volatilize quickly on the scalp, achieving quick drying of the scalp and hair, a clean and non-greasy skin feel, and a good patient experience. Most existing products are solutions, which have the disadvantages of easy dripping, uneven application, short drug residence time on the skin, and limited transdermal absorption. Compared with homogeneous solutions, oil-in-water emulsions can increase the solubility of poorly soluble drugs and the residence time of the preparation on the skin, and micrometer-sized emulsion droplets dispersed in the continuous phase can effectively improve the transdermal absorption of active ingredients and reduce irritation. However, there are great technical challenges in developing alcohol-containing emulsions suitable for the scalp. First, ethanol can reduce the surface tension of the oil-water interface and destroy the stability of the emulsion. Most commonly used emulsifiers are dissolved and extracted into the water phase by ethanol, and cannot be well distributed at the oil-water interface to form a stable emulsion. Second, oil-in-water emulsions generally contain 10%-50% oil phase and the remaining amount of water, which is conducive to the formation of a stable emulsion system. However, if such a high oil phase is used on the scalp, a large amount of oil phase will adhere to the hair after the water phase volatilizes. Even if the oil phase ratio is as low as 10%, it will also produce a greasy feeling, and even stick to the hair, affecting patient medication compliance. Third, external emulsions are generally semisolid, and their high viscosity is conducive to the stability of the emulsion system. However, formulations for the scalp need to be light and thin, i.e. have good flowability and spreadability, to avoid sticking to the hair, but the development of low-viscosity and stable alcohol-containing emulsions faces greater challenges.

[0006] In addition, the commercially available 5α-reductase inhibitors finasteride and dutasteride have strong liposolubility and poor transdermal absorption. The formulation needs to add a penetration enhancer to achieve ideal transdermal absorption, and the penetration enhancer may interact with ethanol and emulsifiers, thereby affecting the stability of the alcohol-containing emulsion, further increasing the difficulty of developing an alcohol-containing emulsion.

[0007] Further, the main defects of the prior art and the improvements provided by the present application are as follows:

[0008] 1. The existing scalp external hair growth drugs are almost all solution-type preparations, while the present application is an emulsion. The emulsion can provide a better skin texture and use experience than the solution, thereby improving medication compliance.

[0009] 2. Dutasteride has extremely low solubility. If a traditional solution dosage form is used, it is easy to precipitate at low temperatures, thereby affecting the drug concentration and dose accuracy. However, the emulsion of the present application does not have drug crystalline precipitates even under freeze-thaw conditions, greatly improving the stability during storage and use.

[0010] 3. Existing emulsion-type topical scalp cosmetics contain no more than 20% ethanol because ethanol is a demulsifier. Ordinary emulsions will break down and separate when they come into contact with ethanol. However, the emulsion of this invention contains as much as 33%–34% ethanol. At such a high concentration of ethanol, the product has the following advantages: (1) Higher concentration of ethanol can improve the transdermal absorption of drugs, thereby improving bioavailability; (2) High concentration of ethanol can also make the product evaporate and dry faster after being applied to the skin, quickly restoring the wet scalp and hair to a normal state, without affecting social activities, thereby improving medication compliance; (3) The prescription itself has antiseptic ability, and there is no need to add additional preservatives or adopt other antiseptic measures.

[0011] 4. Existing emulsion-type topical products require a high percentage (usually more than 10%) of emulsifier to maintain emulsion stability, while the emulsifier used in this invention is as low as about 1.5%. The lower the amount of emulsifier, the less irritation to the skin, making it very suitable for long-term daily use on the scalp.

[0012] 5. Dutasteride has extremely poor water solubility, being almost insoluble in water, and its solubility is also very low in some common solvent-based liquid excipients. However, for formulations intended for long-term daily use on the scalp, the ethanol content should not exceed 65%, otherwise it will cause significant cumulative skin irritation. The remaining percentage needs to be made up to 100% using other excipients. In this case, using water would greatly reduce the drug's solubility, while the "alcohol-oil" system obtained by using other liquid excipients miscible with ethanol would be difficult to emulsify. Summary of the Invention

[0013] Based on this, the present invention provides an alcohol-containing emulsion of a 5α-reductase inhibitor, the alcohol-containing emulsion comprising a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer.

[0014] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.005% to 0.5% by weight of a 5α-reductase inhibitor, 20% to 60% by weight of alcohol, 1.0% to 3.0% by weight of an oil phase, 1.0% to 3.0% by weight of an emulsifier, 10% to 35% by weight of a diluent, and 5% to 55% by weight of a penetration enhancer.

[0015] Furthermore, the oil phase is not liquid at room temperature.

[0016] Furthermore, the emulsifier is not in a liquid state at room temperature.

[0017] Furthermore, the emulsion does not contain an oil phase that is liquid at room temperature.

[0018] Furthermore, the emulsion does not contain emulsifiers that are liquid at room temperature.

[0019] Further, the 5a-reductase inhibitor comprises a scalp-applied hair growth medicine.

[0020] Further, the 5a-reductase inhibitor is dutasteride and / or finasteride.

[0021] Further, the alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt%, further 0.02 wt% to 0.2 wt% of the 5a-reductase inhibitor, based on the weight percentage of the alcohol-containing emulsion.

[0022] Further, the alcohol is ethanol, for example, anhydrous ethanol.

[0023] Further, the alcohol-containing emulsion comprises 25 wt% to 40 wt%, for example, about 33 wt% of the alcohol, based on the weight percentage of the alcohol-containing emulsion.

[0024] Further, the weight ratio between the alcohol and the diluent is not higher than (2.6 to 3.4):(1.6 to 2.4).

[0025] Further, the oil phase is a hydrocarbon or a wax substance that is not liquid at room temperature.

[0026] Further, the hydrocarbon substance comprises a saturated alkane and / or an unsaturated alkane having 18 or more carbon atoms per molecule.

[0027] Further, the wax substance comprises an oil and / or a solid wax having 18 or more carbon atoms per molecule.

[0028] Further, the wax substance is a natural or artificially synthesized wax substance.

[0029] Further, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and a fatty alcohol having 18 or more carbon atoms.

[0030] Further, the fatty alcohol having 18 or more carbon atoms is stearyl alcohol and / or behenyl alcohol.

[0031] Further, the alcohol-containing emulsion comprises 1 wt% to 2 wt%, further 1.3 wt% to 1.8 wt%, further 1.4 wt% to 1.8 wt%, for example, about 1.72 wt% of the oil phase, for example, about 1.6 wt% of the oil phase, for example, about 1.489 wt% of the oil phase, based on the weight percentage of the alcohol-containing emulsion.

[0032] Further, the emulsifier is selected from one or more of the following: a fatty alcohol polyether, a sucrose fatty acid ester, and a sorbitol fatty acid ester.

[0033] Further, the hydrophobic end of the fatty alcohol polyether comprises at least 16 carbon atoms, for example, from 16 to 22 carbon atoms.

[0034] Further, the hydrophilic end of the fatty alcohol polyether comprises from 2 to 30 polyoxyethylene monomers, for example, from 10 to 30 polyoxyethylene monomers, for example, from 10 to 25 polyoxyethylene monomers.

[0035] Further, the fatty alcohol polyether is selected from one or more of: stearyl alcohol polyether, cetearyl alcohol polyether, and behenyl alcohol polyether.

[0036] Further, the stearyl alcohol polyether is selected from one or more of: stearyl alcohol polyether-2, stearyl alcohol polyether-10, stearyl alcohol polyether-20. Further, the cetearyl alcohol polyether is selected from one or more of: cetearyl alcohol polyether-5, cetearyl alcohol polyether-10, cetearyl alcohol polyether-15, cetearyl alcohol polyether-20, cetearyl alcohol polyether-25.

[0037] Further, the cetearyl alcohol polyether is cetearyl alcohol polyether-20.

[0038] Further, the cetearyl alcohol polyether is cetearyl alcohol polyether-25.

[0039] Further, the sucrose fatty acid ester is sucrose stearate.

[0040] Further, the sorbitol fatty acid ester is Span 60.

[0041] Further, the behenyl alcohol polyether is selected from one or more of: behenyl alcohol polyether-5, behenyl alcohol polyether-10, behenyl alcohol polyether-20, behenyl alcohol polyether-30.

[0042] Further, the behenyl alcohol polyether is behenyl alcohol polyether-30.

[0043] Further, the behenyl alcohol polyether is behenyl alcohol polyether-20.

[0044] Further, the alcoholic-containing emulsion comprises from 2.5 wt% to 6 wt%, for example, from 3 wt% to 5 wt%, of the oil phase and emulsifier, based on the weight percentage of the alcoholic-containing emulsion.

[0045] Further, the alcoholic-containing emulsion comprises from 0.5 wt% to 5 wt%, further from 1 wt% to 2.5 wt%, for example, about 1.72 wt%, of the oil phase, for example, about 1.6 wt%, of the oil phase, for example, about 1.489 wt%, of the oil phase, based on the weight percentage of the alcoholic-containing emulsion.

[0046] Further, the alcoholic emulsion comprises 1 wt% to 2 wt%, further 1.3 wt% to 1.8 wt%, for example about 1.511 wt% of the emulsifier, for example about 1.3 wt% of the emulsifier, for example about 1.4 wt% of the emulsifier, based on the weight percentage of the alcoholic emulsion.

[0047] Further, the weight ratio between the oil phase and the emulsifier is 1 :2 to 5: 1, further 1 :2 to 2: 1.

[0048] Further, the weight ratio between the cetostearyl alcohol polyoxyl-20 and the behenyl alcohol polyoxyl-20 is 1 : 1 to 10: 1, further 1 : 1 to 7: 1.

[0049] Further, the alcoholic emulsion comprises 0.5 wt% to 2.0 wt%, further 0.8 wt% to 1.4 wt%, for example about 1.254 wt% of the cetostearyl alcohol polyoxyl-20, for example about 1.117 wt% of the cetostearyl alcohol polyoxyl-20, for example about 1.03 wt% of the cetostearyl alcohol polyoxyl-20, based on the weight percentage of the alcoholic emulsion.

[0050] Further, the alcoholic emulsion comprises 0.1 wt% to 0.8 wt%, further 0.2 wt% to 0.6 wt%, for example about 0.257 wt% of the behenyl alcohol polyoxyl-20, for example about 0.283 wt% of the behenyl alcohol polyoxyl-20, for example about 0.414 wt% of the behenyl alcohol polyoxyl-20, based on the weight percentage of the alcoholic emulsion.

[0051] Further, the diluent is water, for example purified water.

[0052] Further, the alcoholic emulsion comprises 15 wt% to 30 wt%, for example about 23 wt% of the water, based on the weight percentage of the alcoholic emulsion.

[0053] Further, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0054] Further, the alcoholic emulsion comprises 10 wt% to 50 wt%, further 30 wt% to 50 wt%, for example about 40 wt% of the penetration enhancer, based on the weight percentage of the alcoholic emulsion.

[0055] Further, the weight ratio between the alcohol, the penetration enhancer and the diluent is (25-40):(30-50):(15-30), for example about 33: about 40: about 23.

[0056] Further, the alcoholic emulsion further comprises other excipients.

[0057] Further, the other excipient is selected from one or more of the following: a thickening agent, a pH adjusting agent, a bacteriostatic agent, and a stabilizing agent.

[0058] Further, the thickening agent is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hypromellose.

[0059] Further, the carbomer is carbomer homopolymer type A.

[0060] Further, the alcohol-containing emulsion comprises 0.1 wt% to 0.4 wt%, for example about 0.3 wt% of the thickening agent, based on the weight percentage of the alcohol-containing emulsion.

[0061] Further, the pH adjusting agent is a basic substance, for example triethanolamine.

[0062] Further, the alcohol-containing emulsion comprises 0.01 wt% to 1 wt%, further 0.01 wt% to 0.1 wt%, for example about 0.033 wt% of the pH adjusting agent, based on the weight percentage of the alcohol-containing emulsion.

[0063] Further, in the alcohol-containing emulsion, about 50% or more of the emulsion particle sizes are no more than 10 μm, and about 90% or more of the emulsion particle sizes are no more than 15 μm.

[0064] Further, in the alcohol-containing emulsion, about 50% or more of the emulsion particle sizes are no more than 5 μm, and about 90% or more of the emulsion particle sizes are no more than 10 μm.

[0065] According to another aspect of the present application, there is provided a method for preparing the above-mentioned alcohol-containing emulsion, the method comprising the following steps:

[0066] (1) separately weighing appropriate amounts of a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer, first heating and melting the oil phase with the emulsifier, and then adding the 5α-reductase inhibitor, the alcohol, the diluent, and the penetration enhancer for emulsification, to obtain an emulsion; and

[0067] (2) cooling the emulsion to obtain the alcohol-containing emulsion.

[0068] Further, the emulsification is homogenization emulsification.

[0069] Further, the temperature for the emulsification is 70°C to 90°C, for example 75°C to 85°C.

[0070] Further, the water bath is a cold water bath, for example a low-temperature water bath, for example an ice water bath.

[0071] Further, the 5α-reductase inhibitor comprises a scalp-external hair-growing drug.

[0072] Further, the 5α-reductase inhibitor is dutasteride and / or finasteride.

[0073] Further, the alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt%, further 0.02 wt% to 0.2 wt%, of the 5α-reductase inhibitor, based on the weight percentage of the alcohol-containing emulsion.

[0074] Further, the alcohol is ethanol, e.g. anhydrous ethanol.

[0075] Further, the alcohol-containing emulsion comprises 25 wt% to 40 wt%, e.g. about 33 wt%, of alcohol, based on the weight percentage of the alcohol-containing emulsion.

[0076] Further, the weight ratio between the alcohol and the diluent is not higher than (2.6 to 3.4):(1.6 to 2.4).

[0077] Further, the oil phase is a hydrocarbon or a wax material that is not liquid at room temperature.

[0078] Further, the hydrocarbon material comprises a saturated and / or an unsaturated alkane comprising more than 18 carbon atoms per molecule.

[0079] Further, the wax material comprises an oil and / or a solid wax comprising more than 18 carbon atoms per molecule.

[0080] Further, the wax material is a natural or artificially synthesized wax material.

[0081] Further, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and a fatty alcohol comprising more than 18 carbon atoms.

[0082] Further, the fatty alcohol comprising more than 18 carbon atoms is stearyl alcohol and / or behenyl alcohol.

[0083] Further, the alcohol-containing emulsion comprises 1 wt% to 2 wt%, further 1.3 wt% to 1.8 wt%, further 1.4 wt% to 1.8 wt%, e.g. about 1.72 wt%, of the oil phase, e.g. about 1.6 wt% of the oil phase, e.g. about 1.489 wt% of the oil phase, based on the weight percentage of the alcohol-containing emulsion.

[0084] Further, the emulsifier is selected from one or more of the following: a fatty alcohol polyether, a sucrose fatty acid ester, and a sorbitol fatty acid ester.

[0085] Further, the hydrophobic end of the fatty alcohol polyether comprises at least 16 carbon atoms, e.g. 16 to 22 carbon atoms.

[0086] Further, the hydrophilic end of the fatty alcohol polyether comprises 2 to 30 polyoxyethylene monomers, for example, 10 to 30 polyoxyethylene monomers, for example, 10 to 25 polyoxyethylene monomers.

[0087] Further, the fatty alcohol polyether is selected from one or more of: stearyl alcohol polyether, cetearyl alcohol polyether, and behenyl alcohol polyether.

[0088] Further, the hydrophilic end of the cetearyl alcohol polyether comprises 10 to 30 polyoxyethylene repeat units.

[0089] Further, the hydrophilic end of the behenyl alcohol polyether comprises 10 to 30 polyoxyethylene repeat units.

[0090] Further, the stearyl alcohol polyether is selected from one or more of: stearyl alcohol polyether-2, stearyl alcohol polyether-10, stearyl alcohol polyether-20.

[0091] Further, the cetearyl alcohol polyether is cetearyl alcohol polyether-20 and / or cetearyl alcohol polyether-25. Further, the sucrose fatty acid ester is sucrose stearate.

[0092] Further, the sorbitol fatty acid ester is Span 60.

[0093] Further, the behenyl alcohol polyether is behenyl alcohol polyether-5, behenyl alcohol polyether-10, behenyl alcohol polyether-20, and / or behenyl alcohol polyether-30.

[0094] Further, the alcoholic-containing emulsion comprises a total amount of 2.5 wt% to 6 wt% of the oil phase and the emulsifier, for example, 3 wt% to 5 wt% of the oil phase and the emulsifier, based on the weight percentage of the alcoholic-containing emulsion.

[0095] Further, the alcoholic-containing emulsion comprises 0.5 wt% to 5 wt%, further 1 wt% to 2.5 wt%, for example, about 1.72 wt% of the oil phase, for example, about 1.6 wt% of the oil phase, for example, about 1.489 wt% of the oil phase, based on the weight percentage of the alcoholic-containing emulsion.

[0096] Further, the alcoholic-containing emulsion comprises 1 wt% to 2 wt%, further 1.3 wt% to 1.8 wt%, for example, about 1.511 wt% of the emulsifier, for example, about 1.3 wt% of the emulsifier, for example, about 1.4 wt% of the emulsifier, based on the weight percentage of the alcoholic-containing emulsion.

[0097] Further, the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1, further 1:2 to 2:1.

[0098] Further, the weight ratio between the cetostearyl alcohol polyoxyl-20 and the behenyl alcohol polyoxyl-20 is 1:1 to 10:1, further 1:1 to 7:1.

[0099] Further, the alcohol-containing emulsion comprises 0.5% to 2.0%, further 0.8% to 1.4%, for example about 1.254% by weight of cetostearyl alcohol polyoxyl-20, for example about 1.117% by weight of cetostearyl alcohol polyoxyl-20, for example about 1.03% by weight of cetostearyl alcohol polyoxyl-20, based on the weight percentage of the alcohol-containing emulsion.

[0100] Further, the alcohol-containing emulsion comprises 0.1% to 0.8%, further 0.2% to 0.6%, for example about 0.257% by weight of behenyl alcohol polyoxyl-20, for example about 0.283% by weight of behenyl alcohol polyoxyl-20, for example about 0.414% by weight of behenyl alcohol polyoxyl-20, based on the weight percentage of the alcohol-containing emulsion.

[0101] Further, the diluent is water, for example purified water.

[0102] Further, the alcohol-containing emulsion comprises 15% to 30%, for example about 23% by weight of water, based on the weight percentage of the alcohol-containing emulsion.

[0103] Further, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0104] Further, the alcohol-containing emulsion comprises 10% to 50%, further 30% to 50%, for example about 40% by weight of penetration enhancer, based on the weight percentage of the alcohol-containing emulsion.

[0105] Further, the weight ratio between the alcohol, the penetration enhancer and the diluent is (25-40):(30-50):(15-30), for example about 33: about 40: about 23.

[0106] Further, in step (1), further comprising the step of weighing an appropriate amount of other excipients.

[0107] Further, in step (2), further comprising the step of adding the other excipients and mixing well.

[0108] Further, the other excipients are selected from one or more of the following: thickening agents, pH adjusting agents, bacteriostatic agents and stabilizing agents.

[0109] Further, the thickening agents are selected from one or more of the following: carbomer, hydroxyethyl cellulose and hypromellose.

[0110] Further, the carbomer is carbomer homopolymer type A.

[0111] Further, the alcohol-containing emulsion comprises 0.1 wt% to 0.4 wt%, for example about 0.3 wt% of the thickening agent, based on the weight percentage of the alcohol-containing emulsion.

[0112] Further, the pH adjusting agent is a basic substance, for example triethanolamine.

[0113] Further, the alcohol-containing emulsion comprises 0.01 wt% to 1 wt%, further 0.01 wt% to 0.1 wt%, for example about 0.033 wt% of the pH adjusting agent, based on the weight percentage of the alcohol-containing emulsion.

[0114] Further, in the alcohol-containing emulsion, about 50% or more of the emulsion particle size is no more than 10 μm, and about 90% or more of the emulsion particle size is no more than 15 μm.

[0115] Further, in the alcohol-containing emulsion, about 50% or more of the emulsion particle size is no more than 5 μm, and about 90% or more of the emulsion particle size is no more than 10 μm.

[0116] According to another aspect of the present application, there is provided a use of the above-mentioned alcohol-containing emulsion in the preparation of a medicament for preventing and / or treating alopecia.

[0117] Further, the alcohol-containing emulsion further comprises one or more medicaments and / or extracts for preventing and / or treating alopecia.

[0118] Further, the alopecia is androgenetic alopecia.

[0119] Further, the medicament is minoxidil, Yangxueshengfa Capsule, Shengfa Pill and / or Sulfocysteine Tablet.

[0120] Further, the alcohol-containing emulsion is a scalp external emulsion.

[0121] Advantages of the present application:

[0122] The present application discloses an alcohol-containing emulsion of 5alpha-reductase inhibitor, which creatively uses the combination of solid oil phase and fatty alcohol polyether to solve the technical problem of ethanol destroying the stability of emulsion. The oil phase of existing emulsion generally contains liquid components, but the present application surprisingly finds that the oil phase and emulsifier in liquid state at room temperature will destroy the stability of alcohol-containing emulsion, therefore, the oil phase and emulsifier of the present application are semi-solid or solid at room temperature. Most commonly used emulsifiers will be dissolved or interacted with ethanol, resulting in poor emulsification effect; while the present application surprisingly finds that when the fatty alcohol polyether is compounded with other emulsifiers, the preferred oil phase white beeswax / vaseline can be well emulsified to form a stable emulsion system in a system with alcohol / water ratio not more than 3:2. When the fatty alcohol polyether with fatty chain containing 16-22 carbon atoms and hydrophilic end containing 10-30, for example, 10-25 polyoxyethylene monomers, is compounded and used, the emulsification effect is best, and the obtained emulsion particle morphology is round and the particle size is not more than 15 μm.

[0123] The oil phase of general oil-in-water emulsion accounts for 10%-50%, while the oil phase and emulsifier of alcohol-containing emulsion according to the preferred prescription of the present application can be as low as 2.5%-6%, and the product viscosity is also much lower than that of commercial emulsion and related patents. A stable emulsion system can still be obtained under such low oil phase and emulsifier dosage and low viscosity, and the product can be stored at room temperature for a long time without changes in physical and chemical properties. The alcohol-containing emulsion disclosed in the present application not only retains the refreshing skin feeling of low solid content and alcohol-containing preparations suitable for use on the scalp, but also avoids the disadvantages of conventional emulsion such as greasiness and adhesion to hair, and fully utilizes the advantages of emulsion in improving the solubility and transdermal absorption of active ingredients.

[0124] In addition, the present application preferably selects suitable penetration enhancers propylene glycol and diethylene glycol monoethyl ether, which can significantly improve the transdermal absorption of 5alpha-reductase inhibitor without affecting the stability of emulsion. The active ingredient can effectively penetrate the stratum corneum barrier, and the drug concentration at the action site is much higher than that of oral preparations, while the systemic exposure is much lower than that of oral preparations, thereby improving the efficacy and safety of the drug. BRIEF DESCRIPTION OF DRAWINGS

[0125] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art according to these drawings without exceeding the scope of the present application.

[0126] Figure 1 is a micrograph of the present application, prescription 6, prescription 7 and prescription 8 (a) prescription 6, 0 days; (b) prescription 7, 0 days; (c) prescription 8, 0 days; (d) prescription 6, 5℃ 15 days; (e) prescription 7, 5℃ 15 days; (f) prescription 8, 5℃ 15 days.

[0127] Figure 2 is a micrograph of alcohol-containing emulsions using different solid oil phases (formulations 9-14), the oil phases are (a) white petrolatum; (b) white beeswax; (c) octadecanol; (d) behenyl alcohol; (e) cetyl palmitate; (f) glyceryl behenate.

[0128] Figure 3 is a micrograph of alcohol-containing emulsions using different emulsifiers and their combinations (a) prescription 20; (b) prescription 21; (c) prescription 22; (d) prescription 23; (e) prescription 24; (f) prescription 25.

[0129] Figure 4 is a micrograph of alcohol-containing emulsions with different solid contents (a) prescription 26; (b) prescription 27; (c) prescription 29; (d) prescription 30.

[0130] Figure 5 is a micrograph of alcohol-containing emulsions with different ratios of white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether 20 (a) filter residue prediction equation contour map; (b) initial particle size D50 prediction equation contour map; (c) particle size D50 change rate prediction equation contour map after 3 days at 40℃; (d) optimal ratio range contour map considering comprehensively.

[0131] Figure 6 is a micrograph of alcohol-containing emulsions (prescription 56). Among them, (a) initial sample; (b) sample after freeze-thaw cycle; (c) low-temperature 6-month sample; (d) high-temperature 6-month sample.

[0132] Figure 7 is a graph of the particle size and viscosity change trend of alcohol-containing emulsions (prescription 56) under high-temperature conditions.

[0133] Figure 8 is a graph of the particle size and viscosity change trend of alcohol-containing emulsions (prescription 56) under low-temperature and freeze-thaw cycle conditions. DETAILED DESCRIPTION

[0134] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0135] Unless otherwise indicated, all technical and scientific terms and abbreviations used herein have the meanings that would be understood by one of ordinary skill in the art in the field of the application, or by consulting the entire disclosure of this application. Although any methods, conditions, materials, or articles similar or equivalent to those described herein can be used in the practice of the present application, the preferred methods, conditions, materials, or articles are described herein.

[0136] The present application is intended to embrace all options, variations, and equivalents that can be contained within the present art as defined by the claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The application is not limited to the embodiments described.

[0137] As used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0138] In this application, the term "comprising" is synonymous with "including," "containing," or "characterized by." As used herein, the term "comprising," "including," "containing," "characterized by," or any other variation thereof, is intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

[0139] Unless otherwise indicated, the experimental methods in the specification examples were conducted under conventional conditions in the art or as suggested by the manufacturer. In the present application, unless otherwise specified, "above", "below", "within" means inclusive.

[0140] As described in the background section, the existing external preparations for treating alopecia have problems of poor stability and emulsification. To solve the above problems, the present application provides an alcoholic emulsion of 5α-reductase inhibitor, which comprises 5α-reductase inhibitor, alcohol, oil phase, emulsifier, diluent, and penetration enhancer.

[0141] Specifically,

[0142] (1) The present application has accomplished the following invention:

[0143] 1. By saturated solubility experiment, liquid excipients such as ethanol, propylene glycol, diethylene glycol ethyl ether with high saturated solubility were screened out, which can greatly increase the concentration of dutasteride in the preparation.

[0144] 2. By liquid matrix composition screening experiment, it was found that the liquid matrix with a ratio of "33% ethanol-40% propylene glycol-23% purified water" can be successfully emulsified.

[0145] 3. White beeswax was selected as the oil phase by single factor screening experiment to successfully form emulsion.

[0146] 4. Through emulsification test, the specific oil phase type and emulsifier and their ratio that can successfully prepare stable emulsion in the "ethanol-propylene glycol-purified water" prescription system were selected as follows:

[0147] a) The oil phase is white beeswax.

[0148] b) The emulsifier is behenyl alcohol polyether-20 and cetylstearyl alcohol ether-20.

[0149] 5. Prescription design (DOE) to establish the optimal ratio of white beeswax, cetylstearyl alcohol ether-20 and behenyl alcohol polyether-20, the method is as follows: the experimental variables A, B and C are white beeswax, cetylstearyl alcohol ether-20 and behenyl alcohol polyether-20 respectively, the variable range and constraint condition are 1.6 < A ≤ 2.2, 0.5 < B ≤ 1.3, 0.1 < C ≤ 0.6, A + B + C = 3. A total of 12 prescriptions are designed, and the filtration residue, particle size distribution and particle size change after 40℃ storage of the samples are observed. Taking the filtration residue as the dependent variable and the amount of the three components as the independent variable, the data is fitted, and it is found that the emulsion-forming range of the amount of the three components is: the total amount of white beeswax and emulsifier (cetylstearyl alcohol ether-20 and behenyl alcohol polyether-20) in the prescription is 2.5%-5%, the ratio of white beeswax to emulsifier is 2:1-1:2, and the ratio of cetylstearyl alcohol ether-20 to behenyl alcohol polyether-20 in the emulsifier is 1:1-7:1.

[0150] 6. The comparative pharmacokinetic test results of the present solution and the commercially available oral dutasteride preparation on a piglet model show that, after being applied to the local skin, the emulsion of the present application produces a drug concentration in the deep dermis (i.e. the hair follicle site) that is 7 times higher than that of the oral dutasteride preparation, and the systemic exposure in the blood is much lower than that of the oral preparation, which indicates that the systemic exposure of the dutasteride alcohol-containing emulsion is much lower than that of the oral dutasteride soft capsule, and can effectively reduce the toxic side effects of dutasteride.

[0151] (2) The innovative content of the present application is as follows:

[0152] 1. In order to obtain a high enough drug concentration and transdermal amount, solubilizing aids for dutasteride, such as ethanol and liquid aids propylene glycol (which is also found to solubilize dutasteride) that can maximize the transdermal absorption amount, are added to the preparation, and on the basis of the combination of the two aids, it is found that emulsification can be successfully carried out when a specific proportion (about 23%) of water is added. Finally, a liquid base with a ratio of "33% ethanol-40% propylene glycol-23% purified water" is optimized, which can dissolve a high enough concentration (up to 0.2%) of dutasteride drug, and significantly higher transdermal drug amount is obtained in the transdermal test simulating clinical use;

[0153] 2. Generally, the higher the proportion of solvent-based excipients, the more difficult emulsification becomes. Emulsification in the liquid matrix of this invention, where the organic solvent content is as high as 73% (33% ethanol and 40% propylene glycol), is almost impossible. However, this invention has creatively discovered that when the emulsifier used has a saturated aliphatic chain with no less than 22 carbons (C22), such as using an uncommon emulsifier: behenyl alcohol polyether, an emulsion can be successfully prepared. It was also unexpectedly discovered that when the number of ethylene oxide monomers in the polyether chain of the behenyl alcohol polyether used must be between 5 and 25, a stable emulsion can be successfully prepared in this liquid matrix. The resulting emulsion has very uniform and fine particles, with a D50 as low as 5 μm and a D90 as low as 10 μm.

[0154] 3. It was also unexpectedly discovered that in the liquid matrix of "33% ethanol-40% propylene glycol-23% purified water", in addition to behenyl alcohol polyether, the use of a second emulsifier with "saturated fatty chain length of 16-18 carbons", such as cetearyl alcohol ether-20, can also produce emulsions with more uniform and stable particles.

[0155] 4. Through experimental design, a range of dosages that can successfully emulsify was found, namely, the total amount of white beeswax and emulsifier (cetear stearyl alcohol ether-20 and behenyl alcohol polyether-20) in the formulation is 2.5%–5%, the ratio of white beeswax to emulsifier is 2:1–1:2, and the ratio of cetearyl alcohol ether-20 to behenyl alcohol polyether-20 in the emulsifier is 1:1–7:1.

[0156] 5. Maintaining stability of an emulsion requires high viscosity, but the emulsion of the present invention achieves stable maintenance even at ultra-low viscosity. This is because, through experimental design, the type and amount of oil phase-emulsifier that can be fully emulsified in the system were unexpectedly obtained in this system.

[0157] In summary, this invention protects an emulsion based on "33% ethanol-40% propylene glycol-23% purified water". This emulsion is a "water-ethanol-polyol oil-in-oil" type emulsion prepared by high-shear emulsification using white beeswax (or other waxes, oils, or hydrocarbons containing more than 18 carbon atoms per molecule) as the oil phase and a mixture of cetearyl alcohol ether-20 and behenyl alcohol polyether-20 as the emulsifier.

[0158] (3) The advantages of the present invention over the prior art are as follows:

[0159] 1. Existing topical hair growth medications for the scalp are almost all solution-based formulations, while this invention is an emulsion. Emulsions provide a better skin feel and user experience than solutions, thereby improving medication adherence.

[0160] 2. Dutasteride has extremely low solubility. If traditional solution formulations are used, it is prone to precipitation at low temperatures, leading to a decrease in drug concentration and consequently affecting the accuracy of drug concentration and dosage. Existing technologies can either dissolve a sufficient amount of dutasteride but fail to form an emulsion, or form an emulsion but are unsuitable for use on the scalp. The formulation of this invention dissolves a sufficient amount of dutasteride and allows for adequate transdermal absorption of the drug, while also successfully emulsifying to produce a fine emulsion. Even under freezing conditions, no drug crystals will precipitate, greatly improving stability during storage and use.

[0161] 3. Existing emulsion-type topical products require a high percentage (usually more than 10%) of emulsifier to maintain emulsion stability, while the emulsifier used in this invention is as low as about 1.5%. The lower the amount of emulsifier, the less irritation to the skin, making it very suitable for long-term daily use on the scalp.

[0162] 4. Existing emulsion-type topical scalp cosmetics contain no more than 20% ethanol, because ethanol is a demulsifier. Ordinary emulsions will break down and separate when they come into contact with ethanol. The present invention contains as much as 33%-34% ethanol, but its stability is far superior to existing ethanol-containing emulsions. It can remain stable even after long-term storage at high or low temperatures and will not undergo changes in physicochemical properties. Compared with existing emulsions, the product with such a high ethanol concentration also has the following advantages: (1) Higher concentration of ethanol can improve the transdermal absorption of drugs, thereby improving bioavailability; (2) High concentration of ethanol can also make the product evaporate and dry faster after being applied to the skin, quickly restoring the wet scalp and hair to a normal state, without affecting social activities, thereby improving medication compliance; (3) The prescription itself has antiseptic ability, and there is no need to add additional preservatives or adopt other antiseptic measures.

[0163] 5. The total amount of non-volatile solid components in the formulation of the present invention is very low, down to about 3%. Its advantage for use on the scalp is that there is very little solid residue after use, the skin feels very light and refreshing, and it does not cause the hair to become sticky.

[0164] 6. The formulation of this invention has a low viscosity, between 50 and 300 cp, making it ideal for scalp application. With a viscosity higher than 50 cp, it can remain on the scalp surface during application without dripping, thus avoiding the problem of inaccurate dosage caused by dripping after application of currently available solution-type ointments. Furthermore, ordinary high-viscosity creams applied to the scalp tend to cause hair to clump together, making it impossible to maintain a hairstyle and hindering social interactions, severely impacting patient compliance. In contrast, the low viscosity (below 300 cp) and thinness of this invention prevent hair from clumping together during application, significantly improving patient compliance.

[0165] 7、The emulsion prepared according to the present application has very small particle size, which is not only small but also stable, and can keep the D50 of the particle size distribution of the emulsion stable at high temperature (30℃) to be no more than 5 μm and the D90 to be no more than 10 μm. In contrast, the existing emulsion cannot be emulsified into small particles in an alcohol-containing system, or the particles are easy to coalesce into clusters, or it is difficult to maintain the particle size stable at high or low temperature. Surprisingly, the emulsion has very good stability, and the particle size remains unchanged at high and low temperatures.

[0166] 8、At present, there is only one commercially available dutasteride preparation (dutasteride soft capsules), which is an oral preparation. After oral administration, the systemic drug exposure is high, and the side effects are large. The emulsion of the present application generates a drug concentration in the target dermis (i.e., the hair follicle layer) that is 8 times higher than that of the oral preparation after being applied to the skin of a piglet, greatly improving the ability to target the target skin layer, and the drug exposure (AUC) in the systemic blood circulation is only 1.2% of that of the oral preparation, greatly reducing unnecessary systemic drug exposure. Therefore, compared with the existing dutasteride-containing preparation, the present application has great clinical advantages.

[0167] Further, the alcohol-containing emulsion comprises 0.005% to 0.5% by weight of the 5α-reductase inhibitor, 20% to 60% by weight of the alcohol, 1.0% to 3.0% by weight of the oil phase, 1.0% to 3.0% by weight of the emulsifier, 10% to 35% by weight of the diluent, and 5% to 55% by weight of the penetration enhancer, based on the weight percentage of the alcohol-containing emulsion.

[0168] In the present application, when the weight parts, time, pressure, ratio, equivalent, concentration, or other values or parameters are expressed in ranges, preferred ranges, or ranges defined by a series of upper and lower preferred values, it should be understood that all ranges formed by any pair of upper or lower values of any range are specifically disclosed, regardless of whether the range is disclosed separately. For example, when the range "10% to 35%" is disclosed, the described range should be interpreted to include the range "10% to 35%", "10% to 30%", "10% to 25%", "10% to 20%", "10% to 15%", "15% to 35%", "15% to 30%", "15% to 25%", "15% to 20%", "20% to 35%", "25% to 30%", "30% to 35%", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its end values and all integers and fractions within the range.

[0169] In a preferred embodiment, the oil phase is not in a liquid state at room temperature.

[0170] In a preferred embodiment, the emulsifier is not in a liquid state at room temperature.

[0171] In a preferred embodiment, the emulsion does not comprise an oil phase that is liquid at room temperature.

[0172] In a preferred embodiment, the emulsion does not comprise an emulsifier that is liquid at room temperature.

[0173] In a preferred embodiment, the 5α-reductase inhibitor comprises a topical scalp hair growth agent.

[0174] In a preferred embodiment, the 5α-reductase inhibitor is dutasteride and / or finasteride.

[0175] In a preferred embodiment, the alcohol-containing emulsion comprises 0.01% to 0.5% by weight, based on the weight of the alcohol-containing emulsion.

[0176] In a preferred embodiment, the 5α-reductase inhibitor is 0.02% to 0.2% by weight.

[0177] In a preferred embodiment, the alcohol is ethanol, e.g., anhydrous ethanol.

[0178] In a preferred embodiment, the alcohol-containing emulsion comprises 25% to 40% by weight, e.g., about 33% by weight, of alcohol, based on the weight of the alcohol-containing emulsion.

[0179] In the present application, "about" means a value within ±5% of a specified value. For example, "about 33%" includes ±5% of 33%, or from 31.35% to 34.65%.

[0180] In a preferred embodiment, the ratio by weight between the alcohol and the diluent is not higher than (2.6-3.4):(1.6-2.4).

[0181] In a preferred embodiment, the oil phase is a hydrocarbon or a wax that is not liquid at room temperature.

[0182] In a preferred embodiment, the hydrocarbon comprises a saturated and / or unsaturated alkane having more than 18 carbon atoms per molecule.

[0183] In a preferred embodiment, the wax comprises an oil and / or a solid wax having more than 18 carbon atoms per molecule.

[0184] In a preferred embodiment, the wax is a natural or synthetic wax.

[0185] In a preferred embodiment, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and a fatty alcohol having more than 18 carbon atoms.

[0186] In a preferred embodiment, the fatty alcohol containing 18 or more carbon atoms is octadecanol and / or behenyl alcohol.

[0187] In a preferred embodiment, the alcohol-containing emulsion comprises from 1 wt% to 2 wt%, further from 1.3 wt% to 1.8 wt%, for example about 1.72 wt%, of an oil phase, for example about 1.6 wt% of an oil phase, for example about 1.489 wt% of an oil phase, based on the weight percentage of the alcohol-containing emulsion.

[0188] In the present application, "about" means a value within ±5% of a specified value. For example, "about 1.72%" includes ±5% of 1.72%, or from 1.634% to 1.806%; "about 1.6%" includes ±5% of 1.6%, or from 1.52% to 1.68%; "about 1.489%" includes ±5% of 1.489%, or from 1.41455% to 1.56345%.

[0189] In a preferred embodiment, the emulsifier is selected from one or more of the following: fatty alcohol polyether, sucrose fatty acid ester, and sorbitol fatty acid ester.

[0190] In a preferred embodiment, the hydrophobic end of the fatty alcohol polyether comprises at least 16 carbon atoms, for example from 16 to 22 carbon atoms.

[0191] In a preferred embodiment, the hydrophilic end of the fatty alcohol polyether comprises from 2 to 30 polyoxyethylene monomers, for example from 10 to 30 polyoxyethylene monomers, for example from 10 to 25 polyoxyethylene monomers.

[0192] In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the following: stearyl alcohol polyether, cetearyl alcohol polyether, and behenyl alcohol polyether.

[0193] In a preferred embodiment, the hydrophilic end of the cetearyl alcohol polyether comprises from 10 to 30 polyoxyethylene repeat units.

[0194] In a preferred embodiment, the hydrophilic end of the behenyl alcohol polyether comprises from 10 to 30 polyoxyethylene repeat units.

[0195] In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the following: stearyl alcohol polyether-2, stearyl alcohol polyether-10, stearyl alcohol polyether-20.

[0196] In a preferred embodiment, the cetearyl alcohol polyether is selected from one or more of the following: cetearyl alcohol polyether-5, cetearyl alcohol polyether-10, cetearyl alcohol polyether-15, cetearyl alcohol polyether-20, cetearyl alcohol polyether-25.

[0197] In a preferred embodiment, the cetearyl alcohol is cetearyl alcohol.

[0198] In a preferred embodiment, the cetearyl alcohol is cetearyl alcohol.

[0199] In a preferred embodiment, the sucrose fatty acid ester is sucrose stearate.

[0200] In a preferred embodiment, the sorbitol fatty acid ester is Span 60.

[0201] In a preferred embodiment, the behenyl alcohol polyether is selected from one or more of: behenyl alcohol polyether-5, behenyl alcohol polyether-10, behenyl alcohol polyether-20, behenyl alcohol polyether-30.

[0202] In a preferred embodiment, the behenyl alcohol polyether is behenyl alcohol polyether-30.

[0203] In a preferred embodiment, the behenyl alcohol polyether is behenyl alcohol polyether-20.

[0204] In a preferred embodiment, the alcoholic-containing emulsion comprises a total amount of 2.5 wt% to 6 wt% of oil phase and emulsifier, for example a total amount of 2.7 wt% to 5 wt% of oil phase and emulsifier, by weight percentage of the alcoholic-containing emulsion.

[0205] In a preferred embodiment, the alcoholic-containing emulsion comprises 0.5 wt% to 5 wt%, further 1 wt% to 2.5 wt%, for example about 1.72 wt% of oil phase, for example about 1.6 wt% of oil phase, for example about 1.489 wt% of oil phase, by weight percentage of the alcoholic-containing emulsion.

[0206] In the present application, "about" means a value within ±5% of a specified value. For example, "about 1.72%" includes ±5% of 1.72%, or from 1.634% to 1.806%; "about 1.6%" includes ±5% of 1.6%, or from 1.52% to 1.68%; "about 1.489%" includes ±5% of 1.489%, or from 1.41455% to 1.56345%.

[0207] In a preferred embodiment, the alcoholic-containing emulsion comprises 1 wt% to 2 wt%, further 1.3 wt% to 1.8 wt%, for example about 1.511 wt% of emulsifier, for example about 1.3 wt% of emulsifier, for example about 1.4 wt% of emulsifier, by weight percentage of the alcoholic-containing emulsion.

[0208] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 1.511%" includes ±5% of 1.511%, or from 1.43545% to 1.58655%; "about 1.3%" includes ±5% of 1.3%, or from 1.235% to 1.365%; "about 1.4%" includes ±5% of 1.4%, or from 1.33% to 1.47%.

[0209] In a preferred embodiment, the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1, further 1:2 to 2:1.

[0210] In a preferred embodiment, the weight ratio between the cetostearyl alcohol polyoxyl-20 and the behenyl alcohol polyoxyl-20 is 1:1 to 10:1, further 1:1 to 7:1.

[0211] In a preferred embodiment, the alcohol-containing emulsion comprises 0.5% to 2.0% by weight, further 0.8% to 1.4% by weight, for example about 1.254% by weight of cetostearyl alcohol polyoxyl-20, for example about 1.117% by weight of cetostearyl alcohol polyoxyl-20, for example about 1.03% by weight of cetostearyl alcohol polyoxyl-20, based on the weight of the alcohol-containing emulsion.

[0212] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 1.254%" includes ±5% of 1.254%, or from 1.1913% to 1.3167%; "about 1.17%" includes ±5% of 1.17%, or from 1.1115% to 1.2285%; "about 1.03%" includes ±5% of 1.03%, or from 0.9785% to 1.0815%.

[0213] In a preferred embodiment, the alcohol-containing emulsion comprises 0.1% to 0.8% by weight, further 0.2% to 0.6% by weight, for example about 0.257% by weight of behenyl alcohol polyoxyl-20, for example about 0.283% by weight of behenyl alcohol polyoxyl-20, for example about 0.414% by weight of behenyl alcohol polyoxyl-20, based on the weight of the alcohol-containing emulsion.

[0214] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 0.257%" includes ±5% of 0.257%, or from 0.24415% to 0.26985%; "about 0.283%" includes ±5% of 0.283%, or from 0.26885% to 0.29715%; "about 0.414%" includes ±5% of 0.414%, or from 0.3933% to 0.4347%.

[0215] In a preferred embodiment, the diluent is water, such as purified water.

[0216] In a preferred embodiment, the alcohol-containing emulsion comprises 15% to 30% by weight, such as about 23% by weight, of water.

[0217] In the present application, "about" means a value within ±5% of a specified value. For example, "about 23%" includes ±5% of 23%, or from 21.85% to 24.15%.

[0218] In a preferred embodiment, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0219] In a preferred embodiment, the alcohol-containing emulsion comprises 10% to 50% by weight, further 30% to 50% by weight, such as about 40% by weight, of penetration enhancer.

[0220] In the present application, "about" means a value within ±5% of a specified value. For example, "about 40%" includes ±5% of 40%, or from 38% to 42%.

[0221] In a preferred embodiment, the weight ratio between the alcohol, the penetration enhancer, and the diluent is (25-40):(30-50):(15-30), such as about 33: about 40: about 23.

[0222] In the present application, "about" means a value within ±5% of a specified value. For example, "about 33" includes ±5% of 33, or from 31.35 to 34.65; "about 40" includes ±5% of 40, or from 38 to 42; "about 23" includes ±5% of 23, or from 21.85 to 24.15.

[0223] In a preferred embodiment, the alcohol-containing emulsion further comprises other excipients.

[0224] In a preferred embodiment, the other excipients are selected from one or more of the following: thickening agents, pH adjusting agents, bacteriostatic agents, and stabilizing agents.

[0225] In a preferred embodiment, the thickening agent is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hypromellose.

[0226] In a preferred embodiment, the carbomer is carbomer homopolymer type A.

[0227] In a preferred embodiment, the alcohol-containing emulsion comprises 0.1% to 0.4% by weight, such as about 0.3% by weight, of thickening agent.

[0228] In the present application, "about" means a value within ±5% of a specified value. For example, "about 0.3%" includes ±5% of 0.3%, or from 0.285% to 0.315%.

[0229] In a preferred embodiment, the pH adjusting agent is a basic substance, such as triethanolamine.

[0230] In a preferred embodiment, the alcohol-containing emulsion comprises 0.01% to 1% by weight, further 0.01% to 0.1% by weight, for example about 0.033% by weight of the pH adjusting agent, based on the weight of the alcohol-containing emulsion.

[0231] In the present application, "about" means a value within ±5% of a specified value. For example, "about 0.033%" includes ±5% of 0.033%, or from 0.03135% to 0.03465%.

[0232] In a preferred embodiment, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 10 μm, and about 90% or more of the emulsion particles have a particle size of no more than 15 μm.

[0233] In a preferred embodiment, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 5 μm, and about 90% or more of the emulsion particles have a particle size of no more than 10 μm.

[0234] In the present application, "about" means a value within ±5% of a specified value. For example, "about 50%" includes ±5% of 50%, or from 47.5% to 52.5%; "about 90%" includes ±5% of 90%, or from 85.5% to 94.5%.

[0235] According to another aspect of the present application, there is provided a method for preparing the above-mentioned alcohol-containing emulsion, the method comprising the steps of:

[0236] (1) separately weighing appropriate amounts of a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent and a penetration enhancer, first heating and melting the oil phase with the emulsifier, then adding the 5α-reductase inhibitor, the alcohol, the diluent and the penetration enhancer to emulsify, to obtain an emulsion; and

[0237] (2) cooling the emulsion to obtain the alcohol-containing emulsion.

[0238] In a preferred embodiment, the emulsification is homogenization emulsification.

[0239] In a preferred embodiment, the temperature for the emulsification is 70°C to 90°C, for example 75°C to 85°C.

[0240] In a preferred embodiment, the water bath is a cold water bath, e.g., a low temperature water bath, e.g., an ice water bath.

[0241] In a preferred embodiment, the 5a-reductase inhibitor comprises a topical scalp hair growth medication.

[0242] In a preferred embodiment, the 5a-reductase inhibitor is dutasteride and / or finasteride.

[0243] In a preferred embodiment, the alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt% of the alcohol, based on the weight of the alcohol-containing emulsion.

[0244] In a preferred embodiment, the 5a-reductase inhibitor is present in an amount of 0.02 wt% to 0.2 wt%.

[0245] In a preferred embodiment, the alcohol is ethanol, e.g., anhydrous ethanol.

[0246] In a preferred embodiment, the alcohol-containing emulsion comprises 25 wt% to 40 wt% of the alcohol, e.g., about 33 wt%, based on the weight of the alcohol-containing emulsion.

[0247] In the present application, "about" means a value within ±5% of a specified value. For example, "about 33%" includes ±5% of 33%, or from 31.35% to 34.65%.

[0248] In a preferred embodiment, the ratio by weight between the alcohol and the diluent is not higher than (2.6-3.4):(1.6-2.4).

[0249] In a preferred embodiment, the oil phase is a hydrocarbon or a wax substance that is not liquid at room temperature.

[0250] In a preferred embodiment, the hydrocarbon substance comprises a saturated and / or an unsaturated alkane comprising more than 18 carbon atoms per molecule.

[0251] In a preferred embodiment, the wax substance comprises an oil and / or a solid wax comprising more than 18 carbon atoms per molecule.

[0252] In a preferred embodiment, the wax substance is a natural or synthetic wax substance.

[0253] In a preferred embodiment, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and a fatty alcohol comprising more than 18 carbon atoms.

[0254] In a preferred embodiment, the fatty alcohol comprising more than 18 carbon atoms is stearyl alcohol and / or behenyl alcohol.

[0255] In a preferred embodiment, the alcohol-containing emulsion comprises from 1 wt% to 2 wt%, further from 1.3 wt% to 1.8 wt%, further from 1.4 wt% to 1.8 wt%, for example about 1.72 wt%, further about 1.6 wt%, further about 1.489 wt% of the oil phase, based on the weight percent of the alcohol-containing emulsion.

[0256] In the present application, "about" means a value within ±5% of a specified value. For example, "about 1.72%" includes ±5% of 1.72%, or from 1.634% to 1.806%; "about 1.6%" includes ±5% of 1.6%, or from 1.52% to 1.68%; "about 1.489%" includes ±5% of 1.489%, or from 1.41455% to 1.56345%.

[0257] In a preferred embodiment, the emulsifier is selected from one or more of the following: a fatty alcohol polyether, a sucrose fatty acid ester, and a sorbitol fatty acid ester.

[0258] In a preferred embodiment, the hydrophobic end of the fatty alcohol polyether comprises at least 16 carbon atoms, for example from 16 to 22 carbon atoms.

[0259] In a preferred embodiment, the hydrophilic end of the fatty alcohol polyether comprises from 2 to 30 polyoxyethylene monomers, for example from 10 to 30 polyoxyethylene monomers, for example from 10 to 25 polyoxyethylene monomers.

[0260] In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the following: a stearyl alcohol polyether, a cetyl stearyl alcohol polyether, and a behenyl alcohol polyether.

[0261] In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the following: a stearyl alcohol polyether-2, a stearyl alcohol polyether-10, a stearyl alcohol polyether-20.

[0262] In a preferred embodiment, the cetyl stearyl alcohol polyether is a cetyl stearyl alcohol polyether-20 and / or a cetyl stearyl alcohol polyether-25.

[0263] In a preferred embodiment, the sucrose fatty acid ester is a sucrose stearate.

[0264] In a preferred embodiment, the sorbitol fatty acid ester is Span 60.

[0265] In a preferred embodiment, the behenyl alcohol polyether is a behenyl alcohol polyether-5, a behenyl alcohol polyether-10, a behenyl alcohol polyether-20, and / or a behenyl alcohol polyether-30.

[0266] In a preferred embodiment, the alcohol-containing emulsion comprises 2.5% to 6% by weight of the alcohol-containing emulsion of the oil phase and emulsifier, for example 3% to 5% by weight of the alcohol-containing emulsion of the oil phase and emulsifier.

[0267] In a preferred embodiment, the alcohol-containing emulsion comprises 0.5% to 5% by weight of the alcohol-containing emulsion of the oil phase, further 1% to 2.5%, for example about 1.72% by weight of the alcohol-containing emulsion of the oil phase, for example about 1.6% by weight of the alcohol-containing emulsion of the oil phase, for example about 1.489% by weight of the alcohol-containing emulsion of the oil phase.

[0268] In the present application, "about" means a value in the range of ±5% of a specified value. For example, "about 1.72%" includes ±5% of 1.72%, or from 1.634% to 1.806%; "about 1.6%" includes ±5% of 1.6%, or from 1.52% to 1.68%; "about 1.634%" includes ±5% of 1.634%, or from 1.5523% to 1.7157%.

[0269] In a preferred embodiment, the alcohol-containing emulsion comprises 1% to 2% by weight of the alcohol-containing emulsion of the emulsifier, further 1.3% to 1.8%, for example about 1.511% by weight of the alcohol-containing emulsion of the emulsifier, for example about 1.3% by weight of the alcohol-containing emulsion of the emulsifier, for example about 1.4% by weight of the alcohol-containing emulsion of the emulsifier.

[0270] In the present application, "about" means a value in the range of ±5% of a specified value. For example, "about 1.511%" includes ±5% of 1.511%, or from 1.43545% to 1.58655%; "about 1.3%" includes ±5% of 1.3%, or from 1.235% to 1.365%; "about 1.4%" includes ±5% of 1.4%, or from 1.33% to 1.47%.

[0271] In a preferred embodiment, the weight ratio between the oil phase and the emulsifier is 1 :2 to 5: 1, further 1 :2 to 2: 1.

[0272] In a preferred embodiment, the weight ratio between the ceteareth-20 and the beheneth-20 is 1 : 1 to 10: 1, further 1 : 1 to 7: 1.

[0273] In a preferred embodiment, the alcohol-containing emulsion comprises 0.5% to 2.0% by weight of the alcohol-containing emulsion of the ceteareth-20, further 0.8% to 1.4%, for example about 1.254% by weight of the alcohol-containing emulsion of the ceteareth-20, for example about 1.117% by weight of the alcohol-containing emulsion of the ceteareth-20, for example about 1.03% by weight of the alcohol-containing emulsion of the ceteareth-20.

[0274] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 1.254%" includes ±5% of 1.254%, or from 1.1913% to 1.3167%; "about 1.117%" includes ±5% of 1.117%, or from 1.06115% to 1.17285%; "about 1.03%" includes ±5% of 1.03%, or from 0.9785% to 1.0815%.

[0275] In a preferred embodiment, the alcohol-containing emulsion comprises from 0.1% to 0.8%, further from 0.2% to 0.6%, for example about 0.257% by weight of the alcohol- containing emulsion of behenyl alcohol polyether-20, for example about 0.283% by weight of the alcohol-containing emulsion of behenyl alcohol polyether-20, for example about 0.414% by weight of the alcohol-containing emulsion of behenyl alcohol polyether-20.

[0276] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 0.257%" includes ±5% of 0.257%, or from 0.24415% to 0.26985%; "about 0.283%" includes ±5% of 0.283%, or from 0.26885% to 0.29715%; "about 0.414%" includes ±5% of 0.414%, or from 0.3933% to 0.4347%.

[0277] In a preferred embodiment, the diluent is water, for example purified water.

[0278] In a preferred embodiment, the alcohol-containing emulsion comprises from 15% to 30%, for example about 23% by weight of the alcohol-containing emulsion of water.

[0279] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 23%" includes ±5% of 23%, or from 21.85% to 24.15%.

[0280] In a preferred embodiment, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0281] In a preferred embodiment, the alcohol-containing emulsion comprises from 10% to 50%, further from 30% to 50%, for example about 40% by weight of the alcohol-containing emulsion of penetration enhancer.

[0282] In the present application, "about" means a value that is ±5% of a specified value. For example, "about 40%" includes ±5% of 40%, or from 38% to 42%.

[0283] In a preferred embodiment, the weight ratio between the alcohol, the penetration enhancer and the diluent is (25-40):(30-50):(15-30), for example about 33: about 40: about 23.

[0284] In the present application, "about" means a value within ±5% of a specified value. For example, "about 33" includes ±5% of 33, or from 31.35 to 34.65; "about 40" includes ±5% of 40, or from 38 to 42; "about 23" includes ±5% of 23, or from 21.85 to 24.15.

[0285] In a preferred embodiment, in step (1), further comprising the step of weighing an appropriate amount of other excipients.

[0286] In a preferred embodiment, in step (2), further comprising the step of adding the other excipients and mixing.

[0287] In a preferred embodiment, the other excipients are selected from one or more of the following: thickening agent, pH adjusting agent, bacteriostatic agent and stabilizing agent.

[0288] In a preferred embodiment, the thickening agent is selected from one or more of the following: carbomer, hydroxyethyl cellulose and hypromellose.

[0289] In a preferred embodiment, the carbomer is carbomer homopolymer type A.

[0290] In a preferred embodiment, the alcohol-containing emulsion comprises 0.1-0.4% by weight, for example about 0.3% by weight, of the thickening agent, based on the weight percentage of the alcohol-containing emulsion.

[0291] In the present application, "about" means a value within ±5% of a specified value. For example, "about 0.3%" includes ±5% of 0.3%, or from 0.285% to 0.315%.

[0292] In a preferred embodiment, the pH adjusting agent is a basic substance, for example triethanolamine.

[0293] In a preferred embodiment, the alcohol-containing emulsion comprises 0.01-1% by weight, further 0.01-0.1% by weight, for example about 0.033% by weight, of the pH adjusting agent, based on the weight percentage of the alcohol-containing emulsion.

[0294] In the present application, "about" means a value within ±5% of a specified value. For example, "about 0.033%" includes ±5% of 0.033%, or from 0.03135% to 0.03465%.

[0295] In a preferred embodiment, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 10 μm, and about 90% or more of the emulsion particles have a particle size of no more than 15 μm.

[0296] In a preferred embodiment, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 5 μm, and about 90% or more of the emulsion particles have a particle size of no more than 10 μm.

[0297] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 50%" includes 50% ± 5%, or from 47.5% to 52.5%; "about 90%" includes 90% ± 5%, or from 85.5% to 94.5%.

[0298] According to another aspect of the invention, the use of the above-described alcohol-containing emulsion in the preparation of a medicament for the prevention and / or treatment of hair loss is provided.

[0299] In a preferred embodiment, the alcohol-containing emulsion further comprises one or more drugs and / or extracts for the prevention and / or treatment of hair loss.

[0300] In a preferred embodiment, the hair loss is androgenetic alopecia.

[0301] In a preferred embodiment, the drug is minoxidil, hair growth capsules, hair growth pills, and / or cystine tablets.

[0302] In a preferred embodiment, the alcohol-containing emulsion is a topical scalp emulsion.

[0303] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0304] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0305] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this patent specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features.

[0306] Example

[0307] The materials and reagents used in the present application are commercially available, are conventional reagents, and can be obtained by commercially available methods.

[0308] Preparation of alcohol-containing emulsion

[0309] The following examples were prepared according to the following method unless otherwise stated:

[0310] 1. Oil phase preparation: weigh the oil phase and emulsifier, melt and mix uniformly, and keep at 75-85°C for standby;

[0311] 2. Water phase preparation: take another container, add anhydrous ethanol (if there is an active ingredient, dissolve it in anhydrous ethanol), purified water, penetration enhancer, mix uniformly, and heat to 75-85°C for standby;

[0312] 3. Total mixing: mix the water phase and oil phase, and use a fixed rotor type emulsifying homogenizer at 6000-15000 rpm for homogenization;

[0313] 4. Cooling: after homogenization, place the sample in a cold water bath for cooling; and

[0314] 5. Add thickening agent, mix well.

[0315] Selection of penetration enhancer in Example 1

[0316] As a poorly soluble drug, dutasteride should be as soluble as possible in topical formulations to ensure that sufficient drug is in a molecular state for absorption by the skin. As shown in Table 1, dutasteride has no transdermal absorption in ethanol-water solution (60:40), and the transdermal absorption increases significantly after the addition of penetration enhancer. The solubility of dutasteride in different penetration enhancers varies greatly, and only the penetration enhancer auxiliary material that can well dissolve a sufficient amount of dutasteride and is miscible with water can play a role in the emulsion system of the present application.

[0317] Selection of penetration enhancer in Table 1

[0318] Ethanol and water were used as the water phase, and different penetration enhancers were used to prepare emulsions for the selection of penetration enhancers. It was found that most penetration enhancers would affect the stability of the alcohol-containing emulsion. For example, propylene glycol monooctanoate, propylene glycol monolaurate, caprylic acid and capric acid monoglyceride, 15-hydroxystearic acid polyethylene glycol ester, etc. would dissolve or partially dissolve in ethanol, causing oil and water phase separation and failing to form emulsion; and polyethylene glycol 400, isopropyl palmitate and menthol might interact with the oil phase or emulsifier, affecting the emulsification effect, leading to aggregation or precipitation of the emulsion particles. It was unexpectedly found that diethylene glycol monoethyl ether and propylene glycol were miscible with ethanol and water, and would not affect the stability of the emulsion system, and the obtained emulsion was stable and did not separate.

[0319] The alcohol-containing emulsion containing diethylene glycol monoethyl ether or propylene glycol (some of the prescriptions are compounded with menthol or caprylic capric acid monoglyceride and double glyceride) is prepared according to the prescription shown in Table 2, and the centrifugal stability of the emulsion and the in vitro percutaneous absorption (IVPT) of the drug are investigated. The results show that after centrifugation at 12000 rpm for 10 minutes, the prescription containing diethylene glycol monoethyl ether and propylene glycol does not separate after centrifugation, while the prescription emulsion containing menthol or caprylic capric acid monoglyceride and double glyceride has decreased stability and separates after centrifugation. The percutaneous absorption of the above prescriptions is studied using a vertical diffusion cell and an isolated pig skin, and the receiving medium is 0.5% Tween 80 solution. After 48 hours of administration, the stratum corneum is removed by tape stripping, and the cumulative percutaneous amount of drug in the epidermis and dermis (μg / g) is determined. The results show that after the addition of diethylene glycol monoethyl ether or propylene glycol in the prescription, the drug can penetrate the stratum corneum and reach the target site. Compared with the traditional solution shown in Table 1, the percutaneous absorption of the alcohol-containing emulsion is better, and the drug distributed in the epidermis and dermis can form a reservoir to achieve a long-acting and slow-release effect. Propylene glycol has a better penetration effect than diethylene glycol monoethyl ether. When the amount of propylene glycol increases from 20% to 50%, the cumulative percutaneous amount of drug in the epidermis and dermis increases from 7.5 μg / g to 8.7 μg / g, and the percutaneous absorption of the drug increases with the increase of the amount of penetration enhancer. After adding menthol or caprylic capric acid monoglyceride and double glyceride in the prescription, the percutaneous absorption of the drug does not increase significantly compared with the use of propylene glycol or diethylene glycol monoethyl ether alone.

[0320] Table 2 Screening of penetration enhancer

[0321] Based on the above research, the penetration enhancer in the present application is selected from diethylene glycol monoethyl ether or propylene glycol, and preferably propylene glycol. The amount of penetration enhancer is 10%-50%, and preferably 30%-50%.

[0322] Example 2 Selection of oil phase

[0323] The alcohol-containing emulsion containing different oil phases is prepared according to the prescription shown in Table 3, and the emulsifier is behenyl alcohol polyether-5. The oil phases are behenyl alcohol and squalene (prescription 6), light liquid paraffin (prescription 7), and white beeswax (prescription 8). It is found that the three prescriptions are uniform and fine viscous emulsions, and microscopic observation shows uniform distribution of fine emulsion particles (Fig. 1a, Fig. 1b, Fig. 1c). However, after the samples are placed at 5℃ for 15 days, the appearance of prescription 6 and prescription 7 is pearlescent, indicating that crystals are precipitated in the samples, and cluster-shaped crystals can be observed under a microscope (Fig. 1d, Fig. 1e). The appearance and microscopic structure of prescription 8 do not change significantly (Fig. 1f). The above results show that when the prescription contains a liquid oil, the oil phase precipitates and separates during the storage of the emulsion. When the oil phase is solid, the stability of the emulsion is significantly improved. Therefore, the alcohol-containing emulsion described in the present application should not contain an oil phase that is liquid at room temperature.

[0324] Table 3 Comparison of solid oil phase and liquid oil phase

[0325] The alcohol-containing emulsion was prepared according to the prescription shown in Table 4 with propylene glycol, ethanol and water as the water phase, and stearyl alcohol polyether-2 and cetyl alcohol polyether-20 as the emulsifier, and the emulsification effect of different oil phases was further investigated. The research results are shown in Figure 2. When the oil phase is white petrolatum (Figure 2a) and white beeswax (Figure 2b), the oil phase can be emulsified into fine and uniformly distributed emulsion particles; when the oil phase is octadecanol (Figure 2c) and behenyl alcohol (Figure 2d), although a white and viscous emulsion can be obtained, the oil phase and the emulsifier can form a liquid crystal (sheet-like or fibrous structure in the figure), which leads to the precipitation of the sample, and the liquid crystal structure is sensitive to environmental temperature and shear force, and the liquid crystal structure may change during long-term storage, thereby affecting the stability of the emulsion; when the oil phase is cetyl palmitate (Figure 2e) and glyceryl behenate (Figure 2f), the emulsification effect of the oil phase is poor, and the oil and water phases are separated, and a large number of unemulsified oil phase lumps can be seen under a microscope.

[0326] Based on the above research, the alcohol-containing emulsion described in the present application should not contain an oil phase that is liquid at room temperature. In particular, white petrolatum or white beeswax performs significantly better than other solid oil phases in the water phase matrix (consisting of ethanol, water and propylene glycol), and the obtained emulsion particles are smaller in size and more uniformly distributed.

[0327] Table 4 Screening of solid oil phase

[0328] Example 3 Selection of emulsifier type

[0329] The alcohol-containing emulsion containing different emulsifiers and emulsifier combinations was prepared according to the prescription shown in Table 5 and Table 6, and the appearance and microscopic properties of the product were investigated, and the combination with the best emulsification effect was selected.

[0330] The evaluation criteria for emulsification effect are as follows:

[0331] Good: Formed a white emulsion with uniform appearance, no particle precipitation, and the emulsion particles were uniformly distributed and small in size under microscopic observation

[0332] Better: Formed a white emulsion with uniform appearance, no particle precipitation or only a small amount of particle precipitation, and the emulsion particles were irregular in shape or aggregated under microscopic observation

[0333] Medium: Formed a white emulsion, but there were a lot of particle precipitations, and part of the unemulsified oil phase could be seen under microscopic observation

[0334] Poor: Oil and water phases were separated or a large amount of precipitations could be seen visually

[0335] Table 5 Emulsion prescription and emulsification effect using different emulsifiers

[0336] Table 6 Emulsion formulation and emulsification effect using complex emulsifiers

[0337] The effect of different emulsifiers on the emulsification of white beeswax in the "ethanol-water-propylene glycol" base was investigated (Table 5), and it was found that the fatty alcohol polyether emulsifier had the best emulsification effect, with uniform and small particle size; the emulsification effect of Span 60 and sucrose stearate was second, although they could emulsify white beeswax, but microscopical observation showed that the emulsion particles aggregated, resulting in the appearance of precipitate at the bottom of the sample; polyethylene glycol 7 stearate and polyoxyethylene fatty acid ester could not well emulsify white beeswax, and the sample oil-water phase separated, and microscopical observation showed that there were a large number of unemulsified oil phase lumps.

[0338] It was unexpectedly found that the complex of fatty alcohol polyether emulsifier and other emulsifiers could significantly improve the emulsification effect. As shown in Table 5, Table 6 and Figure 3, the emulsion particles of the formulations using sucrose stearate (Figure 3a, formulation 20) or cetyl stearyl alcohol polyether-20 (Figure 3b, formulation 21) as emulsifiers were prone to aggregation; when the two were used in combination (Figure 3c, formulation 22), the emulsification effect was significantly improved, and microscopical observation showed that the emulsion particles did not aggregate, and almost no solid particles were left on the filter screen after the emulsion was filtered through an 80-mesh filter screen, indicating that there was no unemulsified oil phase or aggregated and precipitated emulsion particles in the product. Similarly, formulation 24 used behenyl alcohol polyether-5 as the emulsifier, and a uniform and fine white emulsion without particle precipitation after filtration was obtained, but microscopical observation showed that there was a fibrous liquid crystal structure (Figure 3e), which might affect the long-term stability of the sample; while formulation 25 had the same amount of other components as formulation 24, only the emulsifier was changed to a combination of behenyl alcohol polyether-5 and Span 60, and the obtained emulsion had round emulsion particles, the liquid crystal structure basically disappeared, and the micro-morphology of the emulsion was significantly improved (Figure 3f). After formulation 25 was stored at 40°C for 1 month, the appearance and microstructure did not change, and the sample had good stability.

[0339] It was also found that the complex of two fatty alcohol polyether emulsifiers could achieve the best emulsification effect. Formulation 22 and formulation 23 used sucrose stearate and behenyl alcohol polyether-10, respectively, in combination with cetyl stearyl alcohol polyether-20, and microscopical observation showed that the emulsion particle morphology of formulation 23 (Figure 3d) was more round, there was no emulsion particle aggregation, and the emulsion particle size was significantly lower than that of formulation 22 (Figure 3c). The two samples were placed in a Lumisizer dispersion analyzer and centrifuged at 25°C, 4000 rpm for 6 hours (simulating 2-year stability at room temperature), and the emulsion particles of formulation 22 settled after centrifugation, while the emulsion particles of formulation 23 were well dispersed in the aqueous phase matrix after centrifugation, and almost no settlement occurred, indicating that the emulsion stability of formulation 23 using two fatty alcohol polyether emulsifiers was significantly better than that of formulation 22 using a fatty alcohol polyether and sucrose stearate.

[0340] In summary, the emulsifier of the alcohol-containing emulsion of the present application is compounded with two or more emulsifiers. One of the emulsifiers is preferably a fatty alcohol polyether, and the other emulsifier is selected from sorbitan fatty acid ester, sucrose stearate, or fatty alcohol polyether; more preferably, the emulsifier is a combination of fatty alcohol polyether.

[0341] Example 4 Oil phase and the amount of emulsifier

[0342] The alcohol-containing emulsion was prepared according to the prescription shown in Table 7 with propylene glycol, ethanol and water as the water phase, and stearyl alcohol polyether-2 and cetyl stearyl alcohol polyether-20 as the emulsifier, and the effect of the oil phase and the total amount of the surfactant (hereinafter referred to as solid content) on the physical and chemical properties of the preparation was investigated. It was found that the ratio of the oil phase to the emulsifier in prescription 26 (Figure 4a) and prescription 27 (Figure 4b) was both 3:1, the ratio of stearyl alcohol polyether-2 to cetyl stearyl alcohol polyether-20 was both 4:1, and the solid content was 2% and 2.67%, respectively. The particle size distribution and microscopic morphology of the two prescriptions were similar. However, when the samples were centrifuged at 25°C and 4000 rpm for 6 hours (simulating 2-year stability at room temperature), prescription 26 with a solid content of 2% showed stratification after centrifugation, while prescription 27 did not show stratification and the emulsion remained stable; this indicated that when the solid content was too low, the emulsion was prone to sedimentation, and a thickening agent needed to be added to stabilize the emulsion. Prescription 28 had the same ratio of surfactants as prescription 27, and the ratio of the oil phase to the surfactant was similar, but the solid content increased from 2.67% to 5%. There was no significant difference in centrifugal stability, particle size distribution and microscopic morphology. When the solid content of prescription 29 (Figure 4c) increased to 6%, the emulsification effect was good, but the particle size of the emulsion increased significantly. When the solid content of prescription 30 (Figure 4d) increased to 6.67%, the emulsion particles were large and the emulsification was incomplete, and the oil phase precipitated to form a sediment.

[0343] The above study showed that the suitable total amount of the oil phase and the emulsifier in the alcohol-containing emulsion of the present application was 2.5%-6%, more preferably, the amount of the oil phase and the emulsifier was 3%-5%.

[0344] Table 7 Prescriptions with different amounts of oil phase and emulsifier

[0345] Example 5 Chain length of the fatty chain and the polyoxyethylene chain of the emulsifier

[0346] Previous studies have found that the fatty chain part (hydrophobic end) of the fatty alcohol polyether should contain at least 16 carbon atoms, so that the emulsifier can be evenly distributed on the surface of the emulsion particles, avoiding the extraction of the emulsifier into the water phase by ethanol, thereby destroying the stability of the emulsion. Therefore, fatty alcohol polyethers with fatty chains containing 16-22 carbon atoms were selected for compounding, and emulsions were prepared according to the prescriptions shown in Table 8, and the appearance, microscopic properties, emulsification effect and particle size distribution of the emulsions were investigated.

[0347] To investigate the emulsification effect, a certain amount of emulsion was filtered with a 500 mesh filter, then the filter was placed in a 50°C oven to dry, weighed, and the ratio of the residue (unemulsified oil phase or agglomerated precipitated milk particles) on the oil phase and emulsifier dosage was calculated, and the filtration residue % was reported (see Table 8). In addition, the particle size distribution of the emulsion was investigated using a laser particle size analyzer, and the results are shown in Table 8.

[0348] Table 8 Emulsion formulation and investigation results of different fatty alcohol polyether combinations

[0349] Based on the research results of Examples 3, 4, and 5, when the fatty alcohol polyether contains 2-5 polyoxyethylene monomers, the emulsion is prone to form liquid crystals, which affects the stability of the product and the use experience. For example, formulations 10 and 27 use stearyl alcohol polyether-2, and formulations 16, 24, and 25 use behenyl alcohol polyether-5, microscopic observation shows a large number of fibrous liquid crystal structures, which may affect the stability of the emulsion. Formulations 31-36 use emulsifiers containing 10-30 polyoxyethylene monomers, the resulting emulsion is fine and uniform in appearance, the filtration residue is less than 1%, and microscopic observation shows that the emulsion is basically round and the D90 of the emulsion particles is less than 15 μm. More preferably, when the number of polyoxyethylene monomers is 10-25, the D90 of the emulsion particles is less than 10 μm. More preferably, when cetylstearyl alcohol polyether-25 and behenyl alcohol polyether-20 are selected, the filtration residue and particle size distribution D90 are the lowest, respectively only 0.17% and 5.15 μm.

[0350] Based on the above research, the fatty alcohol polyether emulsifier used in the alcohol-containing emulsion of the present application should have a hydrophobic end containing at least 16 carbon atoms, more preferably a hydrophobic end containing 16-22 carbon atoms; and a hydrophilic end containing 5-30 polyoxyethylene monomers, more preferably a hydrophilic end containing 10-30 polyoxyethylene monomers, more preferably a hydrophilic end containing 10-25 polyoxyethylene monomers.

[0351] Example 6 Composition ratio of oil phase and emulsifier

[0352] A 0.2% dutasteride emulsion was prepared according to the formulations shown in Table 9 using propylene glycol, ethanol, and water as the water phase, white beeswax as the oil phase, cetylstearyl alcohol polyether-20 and behenyl alcohol polyether-20 as the emulsifiers, and setting the total amount of oil phase and emulsifier to 3%. The microscopic properties, emulsification effect (filtration residue), and particle size distribution of the samples were investigated to determine the optimal ratio of oil phase and emulsifier.

[0353] Table 9 Emulsion formulation and investigation results of different ratios of oil phase and emulsifier

[0354] As shown in Table 9, the white beeswax dosage of the prescriptions 38-42 is 1%-2.5%, i.e. the ratio of oil phase to emulsifier is 1:2-5:1, the obtained emulsion is uniform and fine, almost no particle precipitates, the particle size is less than 10 μm, and the particle size has no significant change after 3 days of storage at 40°C. The white beeswax dosage of the prescription 37 is less than 1%, although the initial particle size is less than 10 μm, but after 3 days of storage at 40°C, the emulsion particles agglomerate and flocculate, the particle size increases to 191 μm. The filtration residue of the prescription 40 with a white beeswax dosage of 2.5% is significantly higher than that of other prescriptions, and a small amount of white beeswax crystals that are not completely emulsified can be seen under a microscope, indicating that when the white beeswax dosage is greater than 2%, the emulsification effect is reduced. Therefore, the white beeswax dosage is preferably 1%-2%.

[0355] The white beeswax dosages of the prescriptions 41, 39 and 42 are similar, and the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 is about 1:7, 1:1 and 10:1, respectively, from small to large, and almost no particle precipitates, the particle size is less than 10 μm, and the particle size has no significant change after 3 days of storage at 40°C. But the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 in the prescription 41 is less than 1:1, and the filtration residue is significantly higher than that of the prescriptions 39 and 42, indicating that when the dosage of cetostearyl alcohol polyether-20 is higher than that of behenyl alcohol polyether-20 in the prescription, the emulsification effect is better. Therefore, the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 is preferably 1:1-10:1.

[0356] According to the above research, the prescription design (DOE) is carried out to establish the optimal ratio relationship of white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20, the method is as follows: the experimental variables A, B and C are white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20, respectively, and the variable range and constraint condition is 1.6

[0357] Table 10 Emulsion prescription of different white beeswax, cetostearyl alcohol polyether-20 and behenyl alcohol polyether-20 ratio and observation results

[0358] The data in Table 10 was fitted (Figure 5a) with the filtration residue as the dependent variable and the amount of the three components as the independent variable. The prediction results showed that the filtration residue was linearly related to the amount of white beeswax in the prescription. The lower the amount of white beeswax, the less the filtration residue, indicating that the less the oil phase that was not emulsified or the less the aggregated and precipitated emulsion particles. The initial particle size D50 was fitted (Figure 5b) with the amount of the three components as the independent variable. The results showed that the lower the amount of white beeswax, the higher the proportion of cetostearyl alcohol polyether-20 in the emulsifier, and the smaller the initial particle size. When the amount of white beeswax was less than 1.8% and the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 was higher than 2:1, the initial particle size D50 was less than 3.5 μm. The change rate of D50 after being placed at 40°C for 3 days was fitted (Figure 5c) as the dependent variable. The results showed that the change in particle size was mainly related to the amount of behenyl alcohol polyether-20. The higher the amount of behenyl alcohol polyether-20, the smaller the change in particle size. When the amount of behenyl alcohol polyether-20 was greater than 0.2%, the change in particle size after being placed at high temperature was not more than 5%, indicating that the emulsion had better stability. That is, more preferably, the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 in the prescription should be not more than 6:1. Considering the above factors (Figure 5d) comprehensively, the optimal composition of the oil phase and the emulsifier in the prescription was that the amount of white beeswax was 1.4%-1.8%, the amount of cetostearyl alcohol polyether-20 was 0.8%-1.4%, and the amount of behenyl alcohol polyether-20 was 0.2%-0.6%.

[0359] Therefore, the ratio of white beeswax to emulsifier in the prescription is preferably 2:1-1:2, and the ratio of cetostearyl alcohol polyether-20 to behenyl alcohol polyether-20 is preferably 1:1-7:1.

[0360] Example 7 Alcohol-containing emulsions with different amounts of ethanol and different specifications

[0361] Dutasteride has good solubility in ethanol. The greater the proportion of ethanol in the prescription, the better the solubility of dutasteride, and at the same time, the preparation can be quickly dried and has a refreshing skin feel. However, a high proportion of ethanol can damage the stability of the emulsion and cause demulsification. Previous studies have shown that when the ratio of ethanol to water in the prescription is not higher than 3:2, the effect of ethanol on the stability of the emulsion is small. The solubility of dutasteride in different proportions of propylene glycol, ethanol, and water mixed solvents is shown in Table 11. The prescription of a 0.02% specification of dutasteride emulsion should contain at least 20% of ethanol. If the specification is increased to 0.2%, the prescription should contain at least 30% of ethanol. Increasing the amount of propylene glycol can promote the dissolution and transdermal absorption of the drug, but a higher amount of propylene glycol can also increase skin irritation. As shown in Example 1, the optimal amount of propylene glycol is 30%-50%. Considering the stability of the preparation, the solubility and transdermal absorption of dutasteride, the optimal weight ratio of ethanol, water, and propylene glycol in the matrix of the present application is about 33:about 23:about 40.

[0362] Table 11 Solubility of dutasteride in propylene glycol, ethanol, and water mixed solvents

[0363] The dutasteride emulsions of 0.2% and 0.05% specifications were prepared according to the prescriptions in Table 12, and the amount of ethanol in the prescriptions was 34% and 25% respectively. The results of the investigation showed that the alcohol-containing emulsions with different amounts of ethanol had good emulsification effect, little filtration residue, and the particle size of the emulsion was less than 10 μm. The lower the amount of ethanol, the smaller the particle size of the obtained emulsion. The particle size and microscopic properties of the two samples did not change significantly after being placed at 40°C for 3 days. In addition, the microscopic properties remained unchanged after the samples were placed at 2°C-8°C, and no needle-shaped dutasteride crystals were precipitated, indicating that dutasteride could be well dissolved in the emulsion and would not precipitate at low temperature.

[0364] Table 12 Dutasteride emulsions of 0.2% and 0.05% specifications

[0365] Example 8 Prescription with thickening agent and its stability

[0366] The dutasteride alcohol-containing solutions with different amounts of thickening agent were prepared according to the prescriptions in Table 13. When the amount of carbomer was 0.2%, 0.3% and 0.4%, the viscosity of the preparation was 92.2 cP, 166.8 cP and 260.4 cP respectively, and the emulsion had good flowability; when the amount of carbomer was higher than 0.5%, the viscosity of the preparation was high and the flowability was poor. Taking prescription 57 as an example, the stability of the alcohol-containing emulsion was investigated under the conditions of high temperature (30°C), low temperature (2°C-8°C) and freeze-thaw cycle (stored at-20°C and 25°C for about 48 hours respectively, and cycled for three times). As shown in Figure 6, the microscopic morphology of the sample did not change significantly after the freeze-thaw cycle or after being placed at high temperature and low temperature for 6 months, the emulsion particles were round and had no aggregation, and no needle-shaped dutasteride crystals were precipitated under microscopic observation, indicating that dutasteride could be well dissolved in the emulsion and would not precipitate under various conditions. As shown in Figures 7 and 8, the particle size and viscosity of the sample did not change significantly after the freeze-thaw cycle or after being placed at high temperature and low temperature for 6 months.

[0367] Based on the above research, the amount of thickening agent in the present application is 0.1%-0.4%, and the viscosity of the emulsion is much lower than that of other alcohol-containing emulsions and related patents, which can maintain good flowability and is suitable for use on the scalp. At the same time, the physicochemical properties of the alcohol-containing emulsion do not change significantly under the conditions of high temperature, low temperature and freeze-thaw, and the stability is significantly better than that of the prior art.

[0368] Table 13 Prescription of alcohol-containing emulsion using different thickening agents and viscosity and particle size investigation results

[0369] Example 9 Transdermal absorption of alcohol-containing emulsion

[0370] The pharmacokinetics of 0.02%, 0.06% and 0.2% dutasteride alcoholic emulsion was studied in 1-3 month old Bama piglets. The test group was administered 0.5 mL of the drug on the back skin of the piglets every day for 14 days, and the administration area was 200 cm 2 , and the prescription is shown in Table 14. The control group was administered orally with commercially available soft capsules of dutasteride (trade name: Anfuda, specification 0.5 mg / pill), once a day, and one pill each time.

[0371] Table 14 0.02%, 0.06% and 0.2% dutasteride alcoholic emulsion

[0372] The blood drug concentration on the first day and the 14th day and the content of dutasteride in the skin tissue after 14 days were detected, and the results are shown in Table 15. It was found that after the local administration of dutasteride alcoholic emulsion, the drug concentration in the dermis was significantly higher than that of oral administration. After 14 days of administration of 0.02% dutasteride alcoholic emulsion (0.1 mg / day), the drug concentration in the dermis was 787.5 ng / g, which was about 8 times that of oral administration. This shows that the dutasteride in the alcoholic emulsion can effectively penetrate the skin barrier and reach the action site, and the dosage is 1 / 5 of the oral administration, which can still achieve better local drug concentration. On the other hand, the blood drug concentration of each concentration specification test group on the first day and the 14th day was significantly lower than that of oral administration. The daily dose of 0.02% dutasteride alcoholic emulsion (1 mg / day) was 2 times that of oral administration (0.5 mg / day), but the area under the curve AUC (0-t) of the drug-time curve after 14 days of administration was only 1.2% of that of oral administration. These data show that the systemic exposure of dutasteride alcoholic emulsion is much lower than that of oral dutasteride soft capsules, which can effectively reduce the toxic side effects of dutasteride.

[0373] Table 15 Drug distribution of different specification compositions in Bama piglets blood and skin at the administration site

[0374] The above describes the embodiments of the present application in detail, and the specific examples are applied to explain the principles and implementation modes of the present application. The above description of the embodiments is only used to help understand the method and core idea of the present application. Meanwhile, the changes or deformations made by the skilled in the art according to the idea of the present application, based on the specific implementation mode and application range of the present application, all belong to the scope of protection of the present application. In summary, the content of the specification should not be understood as a limitation of the present application.

Claims

An alcoholic emulsion of a 5a-reductase inhibitor, characterized in that, The alcohol-containing emulsion comprises a 5a-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer; wherein the alcohol-containing emulsion comprises 0.005 wt% to 0.5 wt% of the 5a-reductase inhibitor, 25 wt% to 40 wt% of the alcohol, 1.3 wt% to 1.8 wt% of the oil phase, 1.0 wt% to 2.0 wt% of the emulsifier, 15 wt% to 30 wt% of the diluent, and 30 wt% to 50 wt% of the penetration enhancer, all based on the weight percentage of the alcohol-containing emulsion; wherein the 5a-reductase inhibitor is dutasteride and / or finasteride, the alcohol is ethanol, the oil phase is white petrolatum and / or white beeswax, the emulsifier is a mixture of a behenyl alcohol polyether and a cetylstearyl alcohol polyether, the diluent is water, and the penetration enhancer is propylene glycol. The alcohol-containing emulsion according to claim 1, characterized in that The alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt%, preferably 0.02 wt% to 0.2 wt% of the 5a-reductase inhibitor, all based on the weight percentage of the alcohol-containing emulsion. The alcohol-containing emulsion according to claim 1, characterized in that The ethanol is anhydrous ethanol; Preferably, the alcohol-containing emulsion comprises about 33 wt% of the ethanol, all based on the weight percentage of the alcohol-containing emulsion. Preferably, the weight ratio between the ethanol and the diluent is no more than (2.6-3.4):(1.6-2.4). The alcohol-containing emulsion according to claim 1, characterized in that The alcohol-containing emulsion comprises about 1.72 wt% of the oil phase, such as about 1.6 wt% of the oil phase, such as about 1.489 wt% of the oil phase, all based on the weight percentage of the alcohol-containing emulsion. Preferably, the cetylstearyl alcohol polyether is selected from one or more of cetylstearyl alcohol polyether-5, cetylstearyl alcohol polyether-10, cetylstearyl alcohol polyether-15, cetylstearyl alcohol polyether-20, and cetylstearyl alcohol polyether-25; Preferably, the cetylstearyl alcohol polyether is cetylstearyl alcohol polyether-20. Preferably, the cetylstearyl alcohol polyether is cetylstearyl alcohol polyether-25. Preferably, the behenyl alcohol polyether is selected from one or more of behenyl alcohol polyether-5, behenyl alcohol polyether-10, behenyl alcohol polyether-20, and behenyl alcohol polyether-30. Preferably, the behenyl alcohol polyether is behenyl alcohol polyether-30. Preferably, the behenyl alcohol polyether is behenyl alcohol polyether-20. Preferably, the alcohol-containing emulsion comprises 1.3 wt% to 1.8 wt%, such as about 1.511 wt%, such as about 1.3 wt%, such as about 1.4 wt% of the emulsifier, all based on the weight percentage of the alcohol-containing emulsion. Preferably, the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1, preferably 1:2 to 2:

1. Preferably, the weight ratio between the cetylstearyl alcohol polyether-20 and the behenyl alcohol polyether-20 is 1:1 to 10:1, preferably 1:1 to 7:

1. Yet preferably, the alcohol-containing emulsion comprises 0.8 wt% to 1.4 wt%, for example about 1.254 wt% of ceteareth-20, for example about 1.117 wt% of ceteareth-20, for example about 1.03 wt% of ceteareth-20, by weight percentage of the alcohol-containing emulsion; Yet preferably, the alcohol-containing emulsion comprises 0.2 wt% to 0.6 wt%, for example about 0.257 wt% of beheneth-20, for example about 0.283 wt% of beheneth-20, for example about 0.414 wt% of beheneth-20, by weight percentage of the alcohol-containing emulsion; Yet preferably, the diluent is purified water; Yet preferably, the alcohol-containing emulsion comprises about 23 wt% of water, by weight percentage of the alcohol-containing emulsion; Especially preferably, the alcohol-containing emulsion comprises about 40 wt% of the penetration enhancer, by weight percentage of the alcohol-containing emulsion; Particularly preferably, the weight ratio between the alcohol, the penetration enhancer and the diluent is about 33: about 40: about 23. The alcohol-containing emulsion according to claim 1, characterized in that The alcohol-containing emulsion further comprises other excipients; Preferably, the other excipients are selected from one or more of the following: thickening agents, pH adjusting agents, bacteriostatic agents and stabilizers; Preferably, the thickening agents are selected from one or more of the following: carbomer, hydroxyethyl cellulose and hypromellose; Preferably, the carbomer is carbomer homopolymer type A; Preferably, the alcohol-containing emulsion comprises 0.1 wt% to 0.4 wt%, for example about 0.3 wt% of thickening agents, by weight percentage of the alcohol-containing emulsion; More preferably, the pH adjusting agent is a basic substance, for example triethanolamine; Yet preferably, the alcohol-containing emulsion comprises 0.01 wt% to 1 wt%, preferably 0.01 wt% to 0.1 wt%, for example about 0.033 wt% of pH adjusting agents, by weight percentage of the alcohol-containing emulsion; Yet preferably, in the alcohol-containing emulsion, about 50% or more of the emulsion particle size is no more than 10 μm, and about 90% or more of the emulsion particle size is no more than 15 μm; Yet preferably, in the alcohol-containing emulsion, about 50% or more of the emulsion particle size is no more than 5 μm, and about 90% or more of the emulsion particle size is no more than 10 μm. A process for the preparation of an alcohol-containing emulsion according to any one of claims 1 to 5, characterized in that The method comprises the following steps: (1) separately weigh appropriate amounts of 5α-reductase inhibitor, alcohol, oil phase, emulsifier, diluent and penetration enhancer, first melt the oil phase and the emulsifier, then add the 5α-reductase inhibitor, alcohol, diluent and penetration enhancer for emulsification, to obtain an emulsion; and (2) cool the emulsion in a water bath to obtain the alcohol-containing emulsion. The method according to claim 6, characterized in that The emulsification is homogeneous emulsification; Preferably, the temperature of the emulsification is 70°C to 90°C, for example 75°C to 85°C; Preferably, the water bath is a cold water bath, for example a low-temperature water bath, for example an ice water bath. The method according to claim 6, characterized in that The alcohol-containing emulsion comprises 0.01 wt% to 0.5 wt%, preferably 0.02 wt% to 0.2 wt% of 5α-reductase inhibitor, by weight percentage of the alcohol-containing emulsion; Preferably, the ethanol is anhydrous ethanol; Preferably, the alcohol-containing emulsion comprises about 33% by weight of ethanol, based on the weight percentage of the alcohol-containing emulsion; Preferably, the weight ratio between the ethanol and the diluent is not higher than (2.6-3.4):(1.6-2.4); Preferably, the alcohol-containing emulsion comprises about 1.72% by weight of oil phase, such as about 1.6% by weight of oil phase, such as about 1.489% by weight of oil phase, based on the weight percentage of the alcohol-containing emulsion; Preferably, the ceteareth is ceteareth-20; Preferably, the ceteareth is ceteareth-25; Preferably, the behenyl alcohol polyether is behenyl alcohol polyether-5, behenyl alcohol polyether-10, behenyl alcohol polyether-20 and / or behenyl alcohol polyether-30; Preferably, the alcohol-containing emulsion comprises 1.3-1.8% by weight, such as about 1.511% by weight of emulsifier, such as about 1.3% by weight of emulsifier, such as about 1.4% by weight of emulsifier, based on the weight percentage of the alcohol-containing emulsion; Preferably, the weight ratio between the oil phase and the emulsifier is 1:2-5:1, preferably 1:2-2:1; Preferably, the weight ratio between the ceteareth-20 and the behenyl alcohol polyether-20 is 1:1-10:1, preferably 1:1-7:1; Preferably, the alcohol-containing emulsion comprises 0.8-1.4% by weight, such as about 1.254% by weight of ceteareth-20, such as about 1.117% by weight of ceteareth-20, such as about 1.03% by weight of ceteareth-20, based on the weight percentage of the alcohol-containing emulsion; Preferably, the alcohol-containing emulsion comprises 0.2-0.6% by weight, such as about 0.257% by weight of behenyl alcohol polyether-20, such as about 0.283% by weight of behenyl alcohol polyether-20, such as about 0.414% by weight of behenyl alcohol polyether-20, based on the weight percentage of the alcohol-containing emulsion; Preferably, the diluent is purified water; Preferably, the alcohol-containing emulsion comprises about 23% by weight of water, based on the weight percentage of the alcohol-containing emulsion; Preferably, the alcohol-containing emulsion comprises about 40% by weight of penetration enhancer, based on the weight percentage of the alcohol-containing emulsion; Preferably, the weight ratio between the alcohol, the penetration enhancer and the diluent is about 33:about 40:about 23. The method according to claim 6, characterized in that In step (1), further comprising the step of weighing an appropriate amount of other auxiliary materials; Preferably, in step (2), further comprising the step of adding the other auxiliary materials and mixing well; Preferably, the other auxiliary materials are selected from one or more of the following: thickening agent, pH adjusting agent, bacteriostatic agent and stabilizer; Preferably, the thickening agent is selected from one or more of the following: carbomer, hydroxyethyl cellulose and hypromellose; Preferably, the carbomer is carbomer homopolymer type A; Preferably, the alcohol-containing emulsion comprises 0.1-0.4% by weight, such as about 0.3% by weight of thickening agent, based on the weight percentage of the alcohol-containing emulsion; More preferably, the pH adjusting agent is a basic substance, for example triethanolamine; More preferably, the alcohol-containing emulsion comprises 0.01% to 1%, preferably 0.01% to 0.1%, for example about 0.033% by weight of the alcohol-containing emulsion of the pH adjusting agent; More preferably, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 10 μm, and about 90% or more of the emulsion particles have a particle size of no more than 15 μm; More preferably, in the alcohol-containing emulsion, about 50% or more of the emulsion particles have a particle size of no more than 5 μm, and about 90% or more of the emulsion particles have a particle size of no more than 10 μm. Use of the alcohol-containing emulsion of any one of claims 1 to 5 in the preparation of a medicament for preventing and / or treating hair loss; Preferably, the alcohol-containing emulsion further comprises one or more drugs and / or extracts for preventing and / or treating hair loss; More preferably, the hair loss is androgenetic alopecia; More preferably, the drug is minoxidil, Yangxueshengfa Capsule, Shengfa Pill and / or Cysteine Tablets; Especially preferably, the alcohol-containing emulsion is a scalp external emulsion.

Images