An alcohol-containing emulsion of 5α-reductase inhibitor and preparation method

Abstract

This invention discloses an alcohol-containing emulsion of a 5α-reductase inhibitor, its preparation method, and its application. The alcohol-containing emulsion comprises a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer. The alcohol-containing emulsion of this invention retains the refreshing feel of alcohol-containing preparations while solving the technical problem of ethanol damaging the stability of emulsions. It exhibits excellent stability and transdermal properties, making it suitable for use on the scalp for the treatment of androgenetic alopecia.

Description

Technical Field

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

[0002] This invention relates to the field of pharmaceutical technology, specifically to an alcoholic emulsion containing a 5α-reductase inhibitor, its preparation method, and its application. Prior Technology

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

[0004] Commercially available 5α-reductase inhibitors are primarily oral formulations used to treat benign prostatic hyperplasia (BPH) or androgenetic alopecia in men. Oral 5α-reductase inhibitors can cause numerous adverse reactions, including erectile dysfunction, decreased libido, ejaculation disorders, breast pain, and gynecomastia (male breast enlargement). Topical formulations, on the other hand, can effectively reduce the toxic side effects of systemic exposure, improving treatment safety and patient compliance. For example, finasteride spray (brand name: CARETOPIC®) is used to treat androgenetic alopecia in men and has similar clinical efficacy to oral finasteride.

[0005] Commercially available topical treatments for hair loss generally contain ethanol, such as minoxidil solution and minoxidil foam. After application, ethanol evaporates quickly on the scalp, resulting in rapid drying of the scalp and hair, a refreshing and non-greasy feel, and a good user experience. Most existing products are solutions, which have drawbacks such as easy dripping when applied to the scalp, difficulty in even application, short residence time on the skin, and limited transdermal absorption. Compared to homogeneous solutions, oil-in-water emulsions can increase the solubility of poorly soluble drugs and the residence time of the formulation on the skin. Micron-sized droplets dispersed in a continuous phase can effectively improve the transdermal absorption of active ingredients and reduce irritation. However, developing alcohol-containing emulsions suitable for the scalp presents significant technical challenges. First, ethanol reduces the surface tension at the oil-water interface, compromising the stability of the emulsion. Most commonly used emulsifiers are dissolved and extracted into the aqueous phase by ethanol, failing to distribute well at the oil-water interface to form a stable emulsion. Secondly, oil-in-water emulsions typically contain 10%-50% oil phase and the remainder water, a ratio that promotes a stable emulsion system. However, such a high oil phase concentration, when applied to the scalp, results in a significant amount of oil adhering to the hair after the water phase evaporates. Even with an oil phase concentration as low as 10%, this can create a greasy feeling and even cause the hair to stick, affecting patient adherence. Thirdly, topical emulsions are generally semi-solid, and their higher viscosity contributes to the stability of the emulsion system. However, formulations for scalp application require a thin, light consistency, meaning good fluidity and spreadability to avoid sticking to the hair. Developing low-viscosity, stable alcohol-based emulsions presents a greater challenge.

[0006] In addition, commercially available 5α-reductase inhibitors finasteride and dutasteride are highly lipid-soluble and have poor transdermal absorption. The formulations require the addition of penetration enhancers to achieve ideal transdermal absorption. However, penetration enhancers may interact with ethanol and emulsifiers, thereby affecting the stability of alcohol-containing emulsions and further increasing the difficulty of developing alcohol-containing emulsions.

[0007] Furthermore, the main shortcomings of the prior art and the improvements provided by the present invention are as follows:

[0008] 1. Existing topical hair growth medications for the scalp are almost all solution-based formulations, while this invention is an emulsion. Emulsions can provide a better skin feel and user experience than solutions, thereby improving medication adherence.

[0009] 2. Dutasteride has extremely low solubility. If traditional solution formulations are used, it is easy to precipitate and form at low temperatures, which will affect the accuracy of drug concentration and dosage. However, the emulsion of this invention will not produce drug crystals even under freeze-thaw conditions, which greatly improves the stability during storage and use.

[0010] 3. Existing lotion-type topical scalp cosmetics contain no more than 20% ethanol because ethanol is a demulsifier. Ordinary lotions will break down and separate when they come into contact with ethanol. However, the lotion 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 dosage of the present invention is as low as about 1.5%. The lower the emulsifier dosage, 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] Furthermore, this 5α-reductase inhibitor contains a topical hair growth medication for the scalp.

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

[0021] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.01% to 0.5% by weight, and more particularly 0.02% to 0.2% by weight of 5α-reductase inhibitor.

[0022] Furthermore, the alcohol is ethanol, such as anhydrous ethanol.

[0023] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 25% to 40% by weight, for example, about 33% by weight of alcohol.

[0024] Furthermore, the weight ratio of the alcohol to the diluent is not higher than (2.6~3.4):(1.6~2.4).

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

[0026] Furthermore, the hydrocarbon contains saturated alkanes and / or unsaturated alkanes with more than 18 carbon atoms per molecule.

[0027] Furthermore, the waxy substance includes oils and / or solid waxes containing more than 18 carbon atoms per molecule.

[0028] Furthermore, the waxy substance is either natural or synthetic.

[0029] Furthermore, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and fatty alcohols containing 18 or more carbon atoms.

[0030] Furthermore, the fatty alcohol containing more than 18 carbon atoms is stearyl alcohol and / or betaine alcohol.

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

[0032] Furthermore, the emulsifier is selected from one or more of the following: fatty alcohol polyethers, sucrose fatty acid esters, and sorbitol fatty acid esters.

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

[0034] Furthermore, the hydrophilic end of the fatty alcohol polyether contains 2 to 30 polyoxyethylene monomers, for example, 10 to 30 polyoxyethylene monomers, or for example, 10 to 25 polyoxyethylene monomers.

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

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

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

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

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

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

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

[0042] Furthermore, the benziol polyether is benziol polyether-30.

[0043] Furthermore, the benziol polyether is benziol polyether-20.

[0044] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains a total of 2.5% to 6% oil phase and emulsifier, for example, a total of 3% to 5% oil phase and emulsifier.

[0045] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.5% to 5% by weight, further 1% to 2.5% by weight, for example about 1.72% by weight, for example about 1.6% by weight, for example about 1.489% by weight.

[0046] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 1% to 2% by weight, further 1.3% to 1.8% by weight, for example about 1.511% by weight of emulsifier, for example about 1.3% by weight of emulsifier, for example about 1.4% by weight of emulsifier.

[0047] Furthermore, the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1, and more specifically 1:2 to 2:1.

[0048] Furthermore, the weight ratio between cetearyl alcohol polyether-20 and benzyl alcohol polyether-20 is 1:1 to 10:1, and more specifically 1:1 to 7:1.

[0049] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.5% to 2.0% by weight, more specifically 0.8% to 1.4% by weight, for example, about 1.254% by weight of cetearyl alcohol polyether-20, for example, about 1.117% by weight of cetearyl alcohol polyether-20, for example, about 1.03% by weight of cetearyl alcohol polyether-20.

[0050] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.1% to 0.8% by weight, more specifically 0.2% to 0.6% by weight, for example, about 0.257% by weight of benzyl alcohol polyether-20, for example, about 0.283% by weight of benzyl alcohol polyether-20, for example, about 0.414% by weight of benzyl alcohol polyether-20.

[0051] Furthermore, the diluent is water, such as purified water.

[0052] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 15% to 30% by weight, for example, about 23% by weight of water.

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

[0054] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 10% to 50% by weight, more specifically 30% to 50% by weight, for example, about 40% by weight of a penetration enhancer.

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

[0056] Furthermore, the alcohol-containing emulsion further contains other excipients.

[0057] Furthermore, the other excipients are selected from one or more of the following: thickeners, pH adjusters, antibacterial agents, and stabilizers.

[0058] Furthermore, the thickener is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hydroxypropyl methylcellulose.

[0059] Furthermore, this carbomer is a type A carbomer homopolymer.

[0060] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.1% to 0.4% by weight, for example, about 0.3% by weight of a thickener.

[0061] Furthermore, the pH adjuster is an alkaline substance, such as triethanolamine.

[0062] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.01% to 1% by weight, and more specifically 0.01% to 0.1% by weight, for example, about 0.033% by weight of a pH adjuster.

[0063] Furthermore, in this alcohol-containing emulsion, approximately 50% or more of the emulsion particles have a particle size of no more than 10 µm, and approximately 90% or more of the emulsion particles have a particle size of no more than 15 µm.

[0064] Furthermore, in this alcohol-containing emulsion, approximately 50% or more of the emulsion particles have a particle size of no more than 5 µm, and approximately 90% or more of the emulsion particles have a particle size of no more than 10 µm.

[0065] According to another aspect of the present invention, a method for preparing the above-mentioned alcohol-containing emulsion is provided, the method comprising the following steps: (1) Weigh appropriate amounts of 5α-reductase inhibitor, alcohol, oil phase, emulsifier, diluent, and penetration enhancer respectively. First, heat and melt the oil phase and emulsifier, then add the 5α-reductase inhibitor, alcohol, diluent, and penetration enhancer to emulsify, thus obtaining an emulsion; and (2) Cool the emulsion to obtain the alcohol-containing emulsion.

[0066] Furthermore, this emulsification is a homogeneous emulsification.

[0067] Furthermore, the emulsification temperature is 70℃~90℃, for example 75℃~85℃.

[0068] Furthermore, the water bath is a cold water bath, such as a low-temperature water bath or an ice water bath.

[0069] Furthermore, this 5α-reductase inhibitor contains a topical hair growth medication for the scalp.

[0070] Furthermore, the 5α-reductase inhibitor is dutasteride and / or finasteride.

[0071] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.01% to 0.5% by weight, and more particularly 0.02% to 0.2% by weight of 5α-reductase inhibitor.

[0072] Furthermore, the alcohol is ethanol, such as anhydrous ethanol.

[0073] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 25% to 40% by weight, for example, about 33% by weight of alcohol.

[0074] Furthermore, the weight ratio of the alcohol to the diluent is not higher than (2.6~3.4):(1.6~2.4).

[0075] Furthermore, the oil phase is a hydrocarbon or waxy substance that is not liquid at room temperature.

[0076] Furthermore, the hydrocarbon contains saturated alkanes and / or unsaturated alkanes with more than 18 carbon atoms per molecule.

[0077] Furthermore, the waxy substance includes oils and / or solid waxes containing more than 18 carbon atoms per molecule.

[0078] Furthermore, the waxy substance is either natural or synthetic.

[0079] Furthermore, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and fatty alcohols containing 18 or more carbon atoms.

[0080] Furthermore, the fatty alcohol containing more than 18 carbon atoms is stearyl alcohol and / or betaine alcohol.

[0081] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 1% to 2% by weight, further 1.3% to 1.8% by weight, further 1.4% to 1.8% by weight, for example about 1.72% by weight of oil phase, for example about 1.6% by weight of oil phase, for example about 1.489% by weight of oil phase.

[0082] Furthermore, the emulsifier is selected from one or more of the following: fatty alcohol polyethers, sucrose fatty acid esters, and sorbitol fatty acid esters.

[0083] Furthermore, the hydrophobic end of the fatty alcohol polyether contains at least 16 carbon atoms, for example, 16 to 22 carbon atoms.

[0084] Furthermore, the hydrophilic end of the fatty alcohol polyether contains 2 to 30 polyoxyethylene monomers, for example, 10 to 30 polyoxyethylene monomers, or for example, 10 to 25 polyoxyethylene monomers.

[0085] Furthermore, the fatty alcohol polyether is selected from one or more of the following: stearyl alcohol polyether, cetearyl alcohol polyether, and benzyl alcohol polyether.

[0086] Furthermore, the hydrophilic end of the cetearyl alcohol polyether contains 10-30 repeating polyoxyethylene units.

[0087] Furthermore, the hydrophilic end of the sorghum alcohol polyether contains 10-30 repeating polyoxyethylene units.

[0088] Furthermore, the stearyl alcohol polyether is selected from one or more of the following: stearyl alcohol polyether-2, stearyl alcohol polyether-10, and stearyl alcohol polyether-20.

[0089] 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.

[0090] Furthermore, the sorbitol fatty acid ester is Span 60.

[0091] Furthermore, the benziol polyether is benziol polyether-5, benziol polyether-10, benziol polyether-20 and / or benziol polyether-30.

[0092] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains a total of 2.5% to 6% oil phase and emulsifier, for example, a total of 3% to 5% oil phase and emulsifier.

[0093] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.5% to 5% by weight, further 1% to 2.5% by weight, for example about 1.72% by weight, for example about 1.6% by weight, for example about 1.489% by weight.

[0094] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 1% to 2% by weight, further 1.3% to 1.8% by weight, for example about 1.511% by weight of emulsifier, for example about 1.3% by weight of emulsifier, for example about 1.4% by weight of emulsifier.

[0095] Furthermore, the weight ratio between the oil phase and the emulsifier is 1:2 to 5:1, and more specifically 1:2 to 2:1.

[0096] Furthermore, the weight ratio between cetearyl alcohol polyether-20 and benzyl alcohol polyether-20 is 1:1 to 10:1, and more specifically 1:1 to 7:1.

[0097] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.5% to 2.0% by weight, more specifically 0.8% to 1.4% by weight, for example, about 1.254% by weight of cetearyl alcohol polyether-20, for example, about 1.117% by weight of cetearyl alcohol polyether-20, for example, about 1.03% by weight of cetearyl alcohol polyether-20.

[0098] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.1% to 0.8% by weight, more specifically 0.2% to 0.6% by weight, for example, about 0.257% by weight of benzyl alcohol polyether-20, for example, about 0.283% by weight of benzyl alcohol polyether-20, for example, about 0.414% by weight of benzyl alcohol polyether-20.

[0099] Furthermore, the diluent is water, such as purified water.

[0100] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 15% to 30% by weight, for example, about 23% by weight of water.

[0101] Furthermore, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0102] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 10% to 50% by weight, more specifically 30% to 50% by weight, for example, about 40% by weight of a penetration enhancer.

[0103] Furthermore, the weight ratio of the alcohol, the penetration enhancer, and the diluent is (25~40):(30~50):(15~30), for example, about 33:about 40:about 23.

[0104] Furthermore, step (1) further includes the step of weighing an appropriate amount of other excipients.

[0105] Furthermore, step (2) further includes the step of adding the other excipients and mixing them.

[0106] Furthermore, the other excipients are selected from one or more of the following: thickeners, pH adjusters, antibacterial agents, and stabilizers.

[0107] Furthermore, the thickener is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hydroxypropyl methylcellulose.

[0108] Furthermore, this carbomer is a type A carbomer homopolymer.

[0109] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.1% to 0.4% by weight, for example, about 0.3% by weight of a thickener.

[0110] Furthermore, the pH adjuster is an alkaline substance, such as triethanolamine.

[0111] Furthermore, based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion contains 0.01% to 1% by weight, and more specifically 0.01% to 0.1% by weight, for example, about 0.033% by weight of a pH adjuster.

[0112] Furthermore, in this alcohol-containing emulsion, approximately 50% or more of the emulsion particles have a particle size of no more than 10 µm, and approximately 90% or more of the emulsion particles have a particle size of no more than 15 µm.

[0113] Furthermore, in this alcohol-containing emulsion, approximately 50% or more of the emulsion particles have a particle size of no more than 5 µm, and approximately 90% or more of the emulsion particles have a particle size of no more than 10 µm.

[0114] According to another aspect of the invention, the use of the above-mentioned alcohol-containing emulsion in the preparation of a medicament for the prevention and / or treatment of hair loss is provided.

[0115] Furthermore, the alcohol-containing emulsion further includes one or more drugs and / or extracts for the prevention and / or treatment of hair loss.

[0116] Furthermore, this hair loss is androgenetic alopecia.

[0117] Furthermore, the drug is minoxidil, hair growth capsules, hair growth pills, and / or cystine tablets.

[0118] Furthermore, this alcohol-containing emulsion is a topical scalp emulsion.

[0119] The beneficial effects of this invention:

[0120] This invention discloses an alcohol-containing emulsion containing a 5α-reductase inhibitor, creatively utilizing a combination of a solid oil phase and fatty alcohol polyethers to solve the technical problem of ethanol damaging emulsion stability, thus preparing a uniform and stable alcohol-containing emulsion. Existing emulsions generally contain liquid components in their oil phase. However, this invention unexpectedly discovered that oil phases and emulsifiers that are liquid at room temperature can damage the stability of alcohol-containing emulsions. Therefore, the oil phase and emulsifier of this invention are semi-solid or solid at room temperature. Most commonly used emulsifiers are dissolved by ethanol or interact with ethanol, resulting in poor emulsification. However, this invention unexpectedly discovered that when fatty alcohol polyethers are compounded with other emulsifiers, they can effectively emulsify the optimal oil phase of white beeswax / petrolatum in a system with an alcohol-to-water ratio not exceeding 3:2, forming a stable emulsion system. The emulsification effect is optimal when fatty alcohol polyethers containing 16-22 carbon atoms in the fatty chain and 10-30 (e.g., 10-25) polyoxyethylene monomers in the hydrophilic end are used in combination, resulting in round emulsion particles with a particle size not exceeding 15 µm.

[0121] In general, the oil phase content of water-in-oil emulsions is 10%-50%. However, according to the preferred formulation and proportion of this invention, the oil phase and emulsifier content of the alcohol-containing emulsion can be as low as 2.5%-6%, and the product viscosity is also much lower than that of commercially available emulsions and related patents. A stable emulsion system can still be obtained with such low oil phase and emulsifier content and such low viscosity, and the product can be stored at room temperature for a long time without any changes in its physicochemical properties. The alcohol-containing emulsion disclosed in this invention retains the refreshing feel of low-solids, alcohol-containing formulations, making it suitable for use on the scalp, while avoiding the greasiness and hair-adhesion disadvantages of conventional emulsions. It also fully utilizes the advantages of emulsions, such as improved solubility of active ingredients and transdermal absorption.

[0122] Furthermore, this invention preferentially selects propylene glycol and diethylene glycol monoethyl ether as suitable penetration enhancers, which neither affect the stability of the emulsion nor significantly improve the transdermal absorption of the 5α-reductase inhibitor. The active ingredient can effectively penetrate the stratum corneum barrier, resulting in a drug concentration at the site of action that is much higher than that of oral formulations, while systemic exposure is much lower, thus improving the efficacy and safety of the drug. Simple Explanation of the Diagram

[0123] To more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without exceeding the scope of protection claimed by the present invention.

[0124] Figure 1 shows photomicrographs of prescriptions 6, 7 and 8 of the present invention: (a) prescription 6, 0 days; (b) prescription 7, 0 days; (c) prescription 8, 0 days; (d) prescription 6, 5℃ for 15 days; (e) prescription 7, 5℃ for 15 days; (f) prescription 8, 5℃ for 15 days.

[0125] Figure 2 shows photomicrographs of alcoholic emulsions (Formulas 9-14) using different solid oil phases, namely (a) white petrolatum; (b) white beeswax; (c) octadecanol; (d) betaine alcohol; (e) hexadecyl palmitate; and (f) glyceryl betaine.

[0126] Figure 3 shows photomicrographs of alcoholic emulsions using different emulsifiers and their combinations: (a) Formula 20; (b) Formula 21; (c) Formula 22; (d) Formula 23; (e) Formula 24; (f) Formula 25.

[0127] Figure 4 shows photomicrographs of alcoholic emulsions with different solid contents: (a) Formula 26; (b) Formula 27; (c) Formula 29; (d) Formula 30.

[0128] Figure 5 shows the contour plots of (a) filtration residue prediction equations for alcohol-containing emulsions with different ratios of white beeswax, cetearyl alcohol polyether-20, and benzyl alcohol polyether-20; (b) initial particle size D50 prediction equations; (c) particle size D50 change rate prediction equations after being placed at 40℃ for 3 days; and (d) the optimal ratio range considering all factors.

[0129] Figure 6 shows photomicrographs of the alcohol-containing emulsion (Formula 56). (a) Initial sample; (b) Sample after freeze-thaw cycles; (c) Sample after 6 months at low temperature; (d) Sample after 6 months at high temperature.

[0130] Figure 7 shows the particle size and viscosity trends of the alcohol-containing emulsion (Formula 56) under high temperature conditions.

[0131] Figure 8 shows the particle size and viscosity trends of the alcohol-containing emulsion (Formula 56) under low temperature and freeze-thaw cycle conditions. Implementation

[0132] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0133] Unless otherwise stated, all technical and scientific terms and abbreviations used herein have the meanings commonly understood by one of ordinary skill in the field of this invention or the field of application of such terms. While any methods, conditions, substances, or materials similar to or equivalent to those disclosed herein may be used in the practice of this invention, preferred methods, conditions, substances, or materials are described herein.

[0134] This invention is intended to cover all options, variations, and equivalents that may be included in the field of prior art as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances.

[0135] The singular forms “a,” “an,” and “described” used in the specification and the appended claims include plural indicators unless the context clearly requires otherwise.

[0136] In this invention, the term "comprising" and "including" are synonymous. The terms "comprising," "including," "having," "containing," or any other variations thereof as used herein are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such a composition, step, method, article, or apparatus.

[0137] Experimental methods not specifically described in the embodiments of this specification are generally performed under conventional conditions in the art or under conditions recommended by the manufacturer. In this invention, unless otherwise specified, "above," "below," or "within" indicates that the number itself is included.

[0138] As described in the prior art section, existing topical formulations for treating hair loss suffer from poor stability and poor emulsification. To address these issues, the present invention provides an alcohol-containing emulsion of a 5α-reductase inhibitor, comprising a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer.

[0139] Specifically,

[0140] (1) The present invention has accomplished the following inventive work:

[0141] 1. Through saturation solubility experiments, liquid excipients with high saturation solubility, such as ethanol, propylene glycol, and diethylene glycol ethyl ether, were screened out. These excipients can greatly increase the concentration of dutasteride in the formulation.

[0142] 2. Through liquid matrix composition screening experiments, it was found that the liquid matrix with the ratio of "33% ethanol-40% propylene glycol-23% purified water" can successfully form an emulsion.

[0143] 3. Through single-factor screening experiments, white beeswax was selected as the oil phase, which can successfully form an emulsion.

[0144] 4. Through emulsification experiments, the specific oil phase types, emulsifiers, and their proportions that can successfully prepare stable emulsions in the "ethanol-propylene glycol-purified water" formulation system were screened as follows:

[0145] a) The oil phase is white beeswax.

[0146] b) The emulsifiers are benzyl alcohol polyether-20 and cetearyl alcohol ether-20.

[0147] 5. Prescription Design (DOE) to establish the optimal proportional relationship of white beeswax, ceteth-20, and steareth-20. The method is as follows: Experimental variables A, B, and C are white beeswax, ceteth-20, and steareth-20 respectively. The variable ranges and constraints are set as 1.6 < A ≤ 2.2, 0.5 < B ≤ 1.3, 0.1 < C ≤ 0.6, and A + B + C = 3. A total of 12 prescriptions are designed, and the filter residue, particle size distribution of the samples, and the particle size change after storage at 40°C are investigated. Using the filter residue as the dependent variable and the dosages of the three components as the independent variables, the data is fitted, and it is found that the interval where the three components can form an emulsion is: the total amount of white beeswax and emulsifiers (ceteth-20 and steareth-20) in the prescription is 2.5%–5%, the ratio of white beeswax to emulsifiers is 2:1–1:2, and the ratio of ceteth-20 to steareth-20 in the emulsifiers is 1:1–7:1.

[0148] 6. The results of the comparative pharmacokinetic study of this emulsion and the commercially available oral dutasteride preparation on a piglet model show that after the emulsion of the present invention is applied to the local skin, a drug concentration 7 times higher than that of the oral dutasteride preparation is generated in the deep dermis (i.e., the hair follicle site), and the systemic exposure in the blood is much lower than that of the oral preparation. This indicates that the systemic exposure of the dutasteride-containing alcohol emulsion is much lower than that of the oral dutasteride soft capsule, which can effectively reduce the toxic and side effects of dutasteride.

[0149] (2) The innovative content of the present invention is as follows:

[0150] 1. To obtain a sufficiently high drug concentration and transdermal amount, excipients ethanol that can solubilize dutasteride and liquid excipient propylene glycol that can maximize the transdermal absorption amount (this excipient is also found to be able to solubilize dutasteride) are added to the preparation. Based on the combination of the two excipients, it is found that emulsification can be successful when adding water in a specific proportion (about 23%). Finally, a liquid matrix with a ratio of "33% ethanol - 40% propylene glycol - 23% purified water" is optimized. This matrix can dissolve a sufficiently high concentration (up to 0.2%) of dutasteride drug and obtain a significantly higher transdermal drug amount in the transdermal test simulating clinical use;

[0151] 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: benzyl alcohol polyether, an emulsion can be successfully prepared. Unexpectedly, it was also found that when the number of ethylene oxide monomers in the polyether chain of the benzyl 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.

[0152] 3. It was also unexpectedly discovered that in the liquid matrix of "33% ethanol-40% propylene glycol-23% purified water", in addition to benzyl 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.

[0153] 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 benzyl 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 benzyl alcohol polyether-20 in the emulsifier is 1:1–7:1.

[0154] 5. Maintaining stability of an emulsion requires high viscosity, but the emulsion of the present invention achieves stable emulsion 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.

[0155] 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 benzyl alcohol polyether-20 as the emulsifier.

[0156] (3) The advantages of the present invention over the prior art are as follows:

[0157] 1. Existing topical hair growth medications for the scalp are almost all solution-based formulations, while this invention is an emulsion. Emulsions can provide a better skin feel and user experience than solutions, thereby improving medication adherence.

[0158] 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. Previous technologies either dissolved sufficient amounts of dutasteride but failed to form an emulsion, or formed an emulsion but were unsuitable for use on the scalp. The formulation of this invention dissolves sufficient amounts 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 precipitate, greatly improving stability during storage and use.

[0159] 3. Existing emulsion-type topical products require a high percentage (usually more than 10%) of emulsifier to maintain emulsion stability, while the emulsifier dosage of the present invention is as low as about 1.5%. The lower the emulsifier dosage, the less irritation to the skin, making it very suitable for long-term daily use on the scalp.

[0160] 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.

[0161] 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 feel sticky.

[0162] 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 without dripping, thus avoiding the inaccurate dosage problem caused by dripping 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.

[0163] 7. The emulsion prepared according to this invention has a very small particle size, and is not only small but also very stable. It can stably maintain a particle size distribution with a D50 not exceeding 5µm and a D90 not exceeding 10µm at high temperatures (30°C). In contrast, existing emulsions either fail to emulsify into tiny particles in alcohol-containing systems, or the particles easily aggregate, or they are difficult to maintain particle size stability during high or low temperature storage. Surprisingly, the emulsion exhibits excellent stability, with its particle size remaining unchanged at both high and low temperatures.

[0164] 8. Currently, only one commercially available dutasteride formulation (dutasteride soft capsules) is available, which is an oral formulation. Oral administration results in high systemic drug exposure and significant side effects. The emulsion of this invention, when applied to the skin of piglets, produces a drug concentration in the target dermis (i.e., hair follicle layer) that is 8 times higher than that of the oral formulation, significantly improving the ability to target the dermis. Furthermore, the systemic drug exposure (AUC) is only 1.2% of that of the oral formulation, greatly reducing unnecessary systemic drug exposure. Therefore, compared with existing dutasteride-containing formulations, this invention has significant clinical advantages.

[0165] 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.

[0166] In this invention, when parts by weight, time, pressure, proportion, equivalent, concentration, or other values ​​or parameters are expressed as ranges, preferred ranges, or a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “10%~35%” is disclosed, the described range should be interpreted as including ranges “10%~35%”, “10%~30%”, “10%~25%”, “10%~20%”, “10%~15%”, “15%~35%”, “15%~30%”, “15%~25%”, “15%~20%”, “20%~35%”, “25%~30%”, “30%~35%”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0167] In a preferred embodiment, the oil phase is not in a liquid state at room temperature.

[0168] In a preferred embodiment, the emulsifier is not in a liquid state at room temperature.

[0169] In a preferred embodiment, the emulsion does not contain an oil phase that is liquid at room temperature.

[0170] In a preferred embodiment, the emulsion does not contain an emulsifier that is liquid at room temperature.

[0171] In a preferred embodiment, the 5α-reductase inhibitor comprises a topical hair growth medication for the scalp.

[0172] In a preferred embodiment, the 5α-reductase inhibitor is dutasteride and / or finasteride.

[0173] In a preferred embodiment, the alcohol-containing emulsion contains 0.01% to 0.5% by weight.

[0174] In a preferred embodiment, the 5α-reductase inhibitor is 0.02% to 0.2% by weight.

[0175] In a preferred embodiment, the alcohol is ethanol, such as anhydrous ethanol.

[0176] In a preferred embodiment, the alcohol-containing emulsion contains 25% to 40% by weight, for example, about 33% by weight of alcohol, based on the weight percentage of the alcohol-containing emulsion.

[0177] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 33%" includes 33% ± 5%, or from 31.35% to 34.65%.

[0178] In a preferred embodiment, the weight ratio of the alcohol to the diluent is not higher than (2.6~3.4):(1.6~2.4).

[0179] In a preferred embodiment, the oil phase is a hydrocarbon or wax substance that is not liquid at room temperature.

[0180] In a preferred embodiment, the hydrocarbon contains saturated alkanes and / or unsaturated alkanes with more than 18 carbon atoms per molecule.

[0181] In a preferred embodiment, the waxy substance comprises oils and / or solid waxes containing more than 18 carbon atoms per molecule.

[0182] In a preferred embodiment, the wax is a natural or synthetic wax.

[0183] In a preferred embodiment, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and fatty alcohols containing 18 or more carbon atoms.

[0184] In a preferred embodiment, the fatty alcohol containing 18 or more carbon atoms is octadecyl alcohol and / or betaine alcohol.

[0185] In a preferred embodiment, the alcohol-containing emulsion contains 1% to 2% by weight, further 1.3% to 1.8% by weight, for example about 1.72% by weight, for example about 1.6% by weight, for example about 1.489% by weight, based on the weight percentage of the alcohol-containing emulsion.

[0186] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.72%" includes 1.72% ± 5%, or from 1.634% to 1.806%; "about 1.6%" includes 1.6% ± 5%, or from 1.52% to 1.68%; "about 1.489%" includes 1.489% ± 5%, or from 1.41455% to 1.56345%.

[0187] In a preferred embodiment, the emulsifier is selected from one or more of the following: fatty alcohol polyethers, sucrose fatty acid esters, and sorbitol fatty acid esters.

[0188] In a preferred embodiment, the hydrophobic end of the fatty alcohol polyether contains at least 16 carbon atoms, for example, 16 to 22 carbon atoms.

[0189] In a preferred embodiment, the hydrophilic end of the fatty alcohol polyether contains 2 to 30 polyoxyethylene monomers, for example, 10 to 30 polyoxyethylene monomers, for example, 10 to 25 polyoxyethylene monomers.

[0190] In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the following: stearyl alcohol polyether, cetearyl alcohol polyether, and benzyl alcohol polyether.

[0191] In a preferred embodiment, the hydrophilic end of the cetearyl alcohol polyether comprises 10-30 repeating polyoxyethylene units.

[0192] In a preferred embodiment, the hydrophilic end of the benzyl alcohol polyether comprises 10-30 repeating polyoxyethylene units.

[0193] 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, and stearyl alcohol polyether-20.

[0194] 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, and cetearyl alcohol polyether-25.

[0195] In a preferred embodiment, the cetearyl alcohol polyether is cetearyl alcohol polyether-20.

[0196] In a preferred embodiment, the cetearyl alcohol polyether is cetearyl alcohol polyether-25.

[0197] In a preferred embodiment, the sucrose fatty acid ester is sucrose stearate.

[0198] In a preferred embodiment, the sorbitol fatty acid ester is Span 60.

[0199] In a preferred embodiment, the benzyl alcohol polyether is selected from one or more of the following: benzyl alcohol polyether-5, benzyl alcohol polyether-10, benzyl alcohol polyether-20, and benzyl alcohol polyether-30.

[0200] In a preferred embodiment, the benzyl alcohol polyether is benzyl alcohol polyether-30.

[0201] In a preferred embodiment, the benzyl alcohol polyether is benzyl alcohol polyether-20.

[0202] In a preferred embodiment, the alcohol-containing emulsion contains a total of 2.5% to 6% by weight of oil phase and emulsifier, for example, a total of 2.7% to 5% by weight of oil phase and emulsifier.

[0203] In a preferred embodiment, the alcohol-containing emulsion contains 0.5% to 5% by weight, further 1% to 2.5% by weight, for example about 1.72% by weight, for example about 1.6% by weight, for example about 1.489% by weight, based on the weight percentage of the alcohol-containing emulsion.

[0204] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.72%" includes 1.72% ± 5%, or from 1.634% to 1.806%; "about 1.6%" includes 1.6% ± 5%, or from 1.52% to 1.68%; "about 1.489%" includes 1.489% ± 5%, or from 1.41455% to 1.56345%.

[0205] In a preferred embodiment, the alcohol-containing emulsion contains 1% to 2% by weight, further 1.3% to 1.8% by weight, for example about 1.511% by weight, for example about 1.3% by weight, for example about 1.4% by weight, based on the weight percentage of the alcohol-containing emulsion.

[0206] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.511%" includes 1.511% ± 5%, or from 1.43545% to 1.58655%; "about 1.3%" includes 1.3% ± 5%, or from 1.235% to 1.365%; and "about 1.4%" includes 1.4% ± 5%, or from 1.33% to 1.47%.

[0207] In a preferred embodiment, the weight ratio of the oil phase to the emulsifier is 1:2 to 5:1, and more preferably 1:2 to 2:1.

[0208] In a preferred embodiment, the weight ratio between cetearyl alcohol polyether-20 and benzyl alcohol polyether-20 is 1:1 to 10:1, and more preferably 1:1 to 7:1.

[0209] In a preferred embodiment, the alcohol-containing emulsion contains 0.5% to 2.0% by weight, more specifically 0.8% to 1.4% by weight, for example, about 1.254% by weight of cetearyl alcohol polyether-20, for example, about 1.117% by weight of cetearyl alcohol polyether-20, for example, about 1.03% by weight of cetearyl alcohol polyether-20.

[0210] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.254%" includes 1.254% ± 5%, or from 1.1913% to 1.3167%; "about 1.17%" includes 1.17% ± 5%, or from 1.1115% to 1.2285%; "about 1.03%" includes 1.03% ± 5%, or from 0.9785% to 1.0815%.

[0211] In a preferred embodiment, the alcohol-containing emulsion contains 0.1% to 0.8% by weight, more specifically 0.2% to 0.6% by weight, for example, about 0.257% by weight of benzyl alcohol polyether-20, for example, about 0.283% by weight of benzyl alcohol polyether-20, for example, about 0.414% by weight of benzyl alcohol polyether-20.

[0212] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.257%" includes 0.257% ± 5%, or from 0.24415% to 0.26985%; "about 0.283%" includes 0.283% ± 5%, or from 0.26885% to 0.29715%; "about 0.414%" includes 0.414% ± 5%, or from 0.3933% to 0.4347%.

[0213] In a preferred embodiment, the diluent is water, such as purified water.

[0214] In a preferred embodiment, the alcohol-containing emulsion contains 15% to 30% by weight, for example, about 23% by weight, of water.

[0215] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 23%" includes 23% ± 5%, or from 21.85% to 24.15%.

[0216] In a preferred embodiment, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0217] In a preferred embodiment, the alcohol-containing emulsion contains 10% to 50% by weight, more specifically 30% to 50% by weight, for example, about 40% by weight of a penetration enhancer, based on a weight percentage of the alcohol-containing emulsion.

[0218] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 40%" includes 40% ± 5%, or from 38% to 42%.

[0219] In a preferred embodiment, the weight ratio of the alcohol, the penetration enhancer, and the diluent is (25-40):(30-50):(15-30), for example, about 33:about 40:about 23.

[0220] In this invention, “about” refers to a value within a range of ±5% of a specific 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; and “about 23” includes ±5% of 23, or from 21.85 to 24.15.

[0221] In a preferred embodiment, the alcohol-containing emulsion further comprises other excipients.

[0222] In a preferred embodiment, the other excipients are selected from one or more of the following: thickeners, pH adjusters, antibacterial agents, and stabilizers.

[0223] In a preferred embodiment, the thickener is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hydroxypropyl methylcellulose.

[0224] In a preferred embodiment, the carbomer is a carbomer homopolymer type A.

[0225] In a preferred embodiment, the alcohol-containing emulsion contains 0.1% to 0.4% by weight, for example, about 0.3% by weight, of a thickener.

[0226] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.3%" includes 0.3% ± 5%, or from 0.285% to 0.315%.

[0227] In a preferred embodiment, the pH adjuster is an alkaline substance, such as triethanolamine.

[0228] In a preferred embodiment, the alcohol-containing emulsion contains 0.01% to 1% by weight, more specifically 0.01% to 0.1% by weight, for example, about 0.033% by weight of a pH adjuster.

[0229] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.033%" includes 0.033% ± 5%, or from 0.03135% to 0.03465%.

[0230] 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.

[0231] 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.

[0232] 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%.

[0233] According to another aspect of the present invention, a method for preparing the above-mentioned alcohol-containing emulsion is provided, the method comprising the following steps: (1) Weigh appropriate amounts of 5α-reductase inhibitor, alcohol, oil phase, emulsifier, diluent, and penetration enhancer respectively. First, heat and melt the oil phase and emulsifier, then add the 5α-reductase inhibitor, alcohol, diluent, and penetration enhancer to emulsify, thus obtaining an emulsion; and (2) Cool the emulsion to obtain the alcohol-containing emulsion.

[0234] In a preferred embodiment, the emulsification is a homogenized emulsification.

[0235] In a preferred embodiment, the emulsification temperature is 70°C to 90°C, for example, 75°C to 85°C.

[0236] In a preferred embodiment, the water bath is a cold water bath, such as a low-temperature water bath or an ice water bath.

[0237] In a preferred embodiment, the 5α-reductase inhibitor comprises a topical hair growth medication for the scalp. In a preferred embodiment, the 5α-reductase inhibitor is dutasteride and / or finasteride.

[0238] In a preferred embodiment, the alcohol-containing emulsion contains 0.01% to 0.5% by weight.

[0239] In a preferred embodiment, 0.02% to 0.2% by weight of a 5α-reductase inhibitor is used.

[0240] In a preferred embodiment, the alcohol is ethanol, such as anhydrous ethanol.

[0241] In a preferred embodiment, the alcohol-containing emulsion contains 25% to 40% by weight, for example, about 33% by weight of alcohol, based on the weight percentage of the alcohol-containing emulsion.

[0242] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 33%" includes 33% ± 5%, or from 31.35% to 34.65%.

[0243] In a preferred embodiment, the weight ratio of the alcohol to the diluent is not higher than (2.6~3.4):(1.6~2.4).

[0244] In a preferred embodiment, the oil phase is a hydrocarbon or wax substance that is not liquid at room temperature.

[0245] In a preferred embodiment, the hydrocarbon contains saturated alkanes and / or unsaturated alkanes with more than 18 carbon atoms per molecule.

[0246] In a preferred embodiment, the waxy substance comprises oils and / or solid waxes containing more than 18 carbon atoms per molecule.

[0247] In a preferred embodiment, the wax is a natural or synthetic wax.

[0248] In a preferred embodiment, the oil phase is selected from one or more of the following: petrolatum, white petrolatum, white beeswax, and fatty alcohols containing 18 or more carbon atoms.

[0249] In a preferred embodiment, the fatty alcohol containing 18 or more carbon atoms is octadecyl alcohol and / or betaine alcohol.

[0250] In a preferred embodiment, the alcohol-containing emulsion contains 1% to 2% by weight, more preferably 1.3% to 1.8% by weight, more preferably 1.4% to 1.8% by weight, for example about 1.72% by weight, for example about 1.6% by weight, for example about 1.489% by weight, based on the weight percentage of the alcohol-containing emulsion.

[0251] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.72%" includes 1.72% ± 5%, or from 1.634% to 1.806%; "about 1.6%" includes 1.6% ± 5%, or from 1.52% to 1.68%; "about 1.489%" includes 1.489% ± 5%, or from 1.41455% to 1.56345%.

[0252] In a preferred embodiment, the emulsifier is selected from one or more of the following: fatty alcohol polyethers, sucrose fatty acid esters, and sorbitol fatty acid esters.

[0253] In a preferred embodiment, the hydrophobic end of the fatty alcohol polyether contains at least 16 carbon atoms, for example, 16 to 22 carbon atoms.

[0254] In a preferred embodiment, the hydrophilic end of the fatty alcohol polyether contains 2 to 30 polyoxyethylene monomers, for example, 10 to 30 polyoxyethylene monomers, for example, 10 to 25 polyoxyethylene monomers.

[0255] In a preferred embodiment, the fatty alcohol polyether is selected from one or more of the following: stearyl alcohol polyether, cetearyl alcohol polyether, and benzyl alcohol polyether.

[0256] 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, and stearyl alcohol polyether-20.

[0257] In a preferred embodiment, the cetearyl alcohol polyether is cetearyl alcohol polyether-20 and / or cetearyl alcohol polyether-25.

[0258] In a preferred embodiment, the sucrose fatty acid ester is sucrose stearate.

[0259] In a preferred embodiment, the sorbitol fatty acid ester is Span 60.

[0260] In a preferred embodiment, the benzyl alcohol polyether is benzyl alcohol polyether-5, benzyl alcohol polyether-10, benzyl alcohol polyether-20 and / or benzyl alcohol polyether-30.

[0261] In a preferred embodiment, the alcohol-containing emulsion contains a total of 2.5% to 6% by weight of oil phase and emulsifier, for example, a total of 3% to 5% by weight of oil phase and emulsifier.

[0262] In a preferred embodiment, the alcohol-containing emulsion contains 0.5% to 5% by weight, further 1% to 2.5% by weight, for example about 1.72% by weight, for example about 1.6% by weight, for example about 1.489% by weight, based on the weight percentage of the alcohol-containing emulsion.

[0263] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.72%" includes 1.72% ± 5%, or from 1.634% to 1.806%; "about 1.6%" includes 1.6% ± 5%, or from 1.52% to 1.68%; and "about 1.634%" includes 1.634% ± 5%, or from 1.5523% to 1.7157%.

[0264] In a preferred embodiment, the alcohol-containing emulsion contains 1% to 2% by weight, further 1.3% to 1.8% by weight, for example about 1.511% by weight, for example about 1.3% by weight, for example about 1.4% by weight, based on the weight percentage of the alcohol-containing emulsion.

[0265] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.511%" includes 1.511% ± 5%, or from 1.43545% to 1.58655%; "about 1.3%" includes 1.3% ± 5%, or from 1.235% to 1.365%; and "about 1.4%" includes 1.4% ± 5%, or from 1.33% to 1.47%.

[0266] In a preferred embodiment, the weight ratio of the oil phase to the emulsifier is 1:2 to 5:1, and more preferably 1:2 to 2:1.

[0267] In a preferred embodiment, the weight ratio between cetearyl alcohol polyether-20 and benzyl alcohol polyether-20 is 1:1 to 10:1, and more preferably 1:1 to 7:1.

[0268] In a preferred embodiment, the alcohol-containing emulsion contains 0.5% to 2.0% by weight, more specifically 0.8% to 1.4% by weight, for example, about 1.254% by weight of cetearyl alcohol polyether-20, for example, about 1.117% by weight of cetearyl alcohol polyether-20, for example, about 1.03% by weight of cetearyl alcohol polyether-20.

[0269] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 1.254%" includes 1.254% ± 5%, or from 1.1913% to 1.3167%; "about 1.117%" includes 1.117% ± 5%, or from 1.06115% to 1.17285%; "about 1.03%" includes 1.03% ± 5%, or from 0.9785% to 1.0815%.

[0270] In a preferred embodiment, the alcohol-containing emulsion contains 0.1% to 0.8% by weight, more specifically 0.2% to 0.6% by weight, for example, about 0.257% by weight of benzyl alcohol polyether-20, for example, about 0.283% by weight of benzyl alcohol polyether-20, for example, about 0.414% by weight of benzyl alcohol polyether-20.

[0271] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.257%" includes 0.257% ± 5%, or from 0.24415% to 0.26985%; "about 0.283%" includes 0.283% ± 5%, or from 0.26885% to 0.29715%; "about 0.414%" includes 0.414% ± 5%, or from 0.3933% to 0.4347%.

[0272] In a preferred embodiment, the diluent is water, such as purified water.

[0273] In a preferred embodiment, the alcohol-containing emulsion contains 15% to 30% by weight, for example, about 23% by weight, of water.

[0274] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 23%" includes 23% ± 5%, or from 21.85% to 24.15%.

[0275] In a preferred embodiment, the penetration enhancer is diethylene glycol monoethyl ether and / or propylene glycol.

[0276] In a preferred embodiment, the alcohol-containing emulsion contains 10% to 50% by weight, more specifically 30% to 50% by weight, for example, about 40% by weight of a penetration enhancer, based on a weight percentage of the alcohol-containing emulsion.

[0277] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 40%" includes 40% ± 5%, or from 38% to 42%.

[0278] In a preferred embodiment, the weight ratio of the alcohol, the penetration enhancer, and the diluent is (25-40):(30-50):(15-30), for example, about 33:about 40:about 23.

[0279] In this invention, “about” refers to a value within a range of ±5% of a specific 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; and “about 23” includes ±5% of 23, or from 21.85 to 24.15.

[0280] In a preferred embodiment, step (1) further includes the step of weighing an appropriate amount of other excipients.

[0281] In a preferred embodiment, step (2) further includes the step of adding the other excipients and mixing them.

[0282] In a preferred embodiment, the other excipients are selected from one or more of the following: thickeners, pH adjusters, antibacterial agents, and stabilizers.

[0283] In a preferred embodiment, the thickener is selected from one or more of the following: carbomer, hydroxyethyl cellulose, and hydroxypropyl methylcellulose.

[0284] In a preferred embodiment, the carbomer is a carbomer homopolymer type A.

[0285] In a preferred embodiment, the alcohol-containing emulsion contains 0.1% to 0.4% by weight, for example, about 0.3% by weight, of a thickener.

[0286] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.3%" includes 0.3% ± 5%, or from 0.285% to 0.315%.

[0287] In a preferred embodiment, the pH adjuster is an alkaline substance, such as triethanolamine.

[0288] In a preferred embodiment, the alcohol-containing emulsion contains 0.01% to 1% by weight, more specifically 0.01% to 0.1% by weight, for example, about 0.033% by weight of a pH adjuster.

[0289] In this invention, "about" refers to a value within a range of ±5% of a specific value. For example, "about 0.033%" includes 0.033% ± 5%, or from 0.03135% to 0.03465%.

[0290] 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.

[0291] 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.

[0292] 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%.

[0293] According to another aspect of the invention, the use of the above-mentioned alcohol-containing emulsion in the preparation of a medicament for the prevention and / or treatment of hair loss is provided.

[0294] 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.

[0295] In a preferred embodiment, the hair loss is androgenetic alopecia.

[0296] In a preferred embodiment, the drug is minoxidil, hair growth capsules, hair growth pills, and / or cystine tablets.

[0297] In a preferred embodiment, the alcohol-containing emulsion is a topical scalp emulsion.

[0298] 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 that do not specify specific conditions are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0299] 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.

[0300] 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.

[0301] Example

[0302] In this invention, all materials and reagents used are commercially available products and are conventional reagents that can be obtained through commercial purchase.

[0303] Preparation of alcohol-containing emulsions

[0304] Unless otherwise specified, the following examples are prepared according to the following methods:

[0305] Oil phase preparation: Weigh the oil phase and emulsifier, heat to melt and mix evenly, and keep warm at 75℃–85℃ for later use;

[0306] Aqueous phase preparation: In a separate container, add anhydrous ethanol (if there is an active ingredient, dissolve it in anhydrous ethanol), purified water, and penetration enhancer, mix well, and heat to 75℃–85℃ for later use;

[0307] Total mixing: The aqueous phase and oil phase are mixed and homogenized using a stator-rotor type emulsifying homogenizer at 6000–15000 rpm;

[0308] Cooling: After homogenization, place the sample in a cold water bath to cool; and

[0309] 5. Add thickener and mix well.

[0310] Example 1: Selection of Penetration Enhancer

[0311] As a poorly soluble drug, dutasteride requires optimal solubility in topical formulations to ensure sufficient molecular weight for absorption through the skin. Table 1 shows that dutasteride exhibits no transdermal absorption in an ethanol-water solution (60:40), but transdermal absorption significantly increases with the addition of a penetration enhancer. The solubility of dutasteride varies considerably among different penetration enhancers; only excipients that can effectively dissolve a sufficient amount of dutasteride and are miscible with water can function effectively in the emulsion system of this invention.

[0312] Table 1 Selection of Penetration Enhancers Penetration enhancer API solubility in excipients (%) Miscibility with water IVPT Study Results (Using a vertical diffusion cell and an ex vivo piglet skin model, with 0.5% Tween 80 solution as the receiving medium, the API concentration in the receiving cell was investigated after 24 hours of transdermal absorption) Examine the prescription (by weight). API concentration in prescription (%) 24-hour receiver cell concentration (ng / ml) Propylene glycol 0.76 Miscible Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.26 0.285 Polyethylene glycol 400 0.29 Miscible Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.39 0.445 Diethylene glycol monoethyl ether 2.46 Miscible Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.21 0.31 Propylene glycol monooctanoate 3.03 Immiscible Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.25 0.28 Caprylic and caprylic acid mono- and diglycerides 1.88 Immiscible Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.37 0.505 Propylene glycol monolauric acid 1 Immiscible / / / monolinoleic glycerides 0.52 Immiscible / / / Caprylic / Capric Acid / Capric Acid Polyethylene Glycol Glycerides 0.42 Immiscible Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.22 0.205 Oleic acid 0.2 Immiscible 100% penetration enhancer 0.2 0.50 Isopropyl myristate 0.04 Immiscible 100% penetration enhancer 0.04 0.225 Isooctyl salicylate 0.19 Immiscible / / / Isopropyl palmitate 0.06 Immiscible / / / 15-hydroxystearic acid polyethylene glycol ester not applicable soluble Anhydrous ethanol:penetration enhancer:water (60:20:20) 0.36 0.655 Menthol not applicable Slightly soluble Anhydrous ethanol:penetration enhancer:water (78:2:20) 0.56 0.61 Control group without penetration enhancer Anhydrous ethanol:water (60:40) 0.31 Not detected

[0313] Emulsions were prepared using ethanol and water as the aqueous phase, and different penetration enhancers were screened. The study found that most penetration enhancers affected the stability of alcohol-containing emulsions. For example, propylene glycol monooctanoate, propylene glycol monolauric acid, caprylic / capric acid mono- and diglycerides, and polyethylene glycol 15-hydroxystearate dissolved or partially dissolved in ethanol, leading to oil-water phase separation and failure to form an emulsion. Polyethylene glycol 400, isopropyl palmitate, and menthol may interact with the oil phase or emulsifiers, affecting the emulsification effect and causing emulsion particle aggregation or precipitation. Unexpectedly, diethylene glycol monoethyl ether and propylene glycol were found to be miscible with ethanol and water, without affecting the stability of the emulsion system, and the resulting emulsions were stable and did not separate.

[0314] Alcoholic emulsions containing diethylene glycol monoethyl ether or propylene glycol (some formulations were compounded with menthol or caprylic / caprylic acid mono- and diglycerides) were prepared according to the formulations shown in Table 2, and the centrifugal stability and in vitro transdermal absorption (IVPT) of the emulsions were investigated. The results showed that when the above formulation samples were centrifuged at 12000 rpm for 10 minutes, the formulations containing diethylene glycol monoethyl ether and propylene glycol did not separate after centrifugation, while the emulsions containing menthol or caprylic / caprylic acid mono- and diglycerides showed decreased stability and separated after centrifugation. The transdermal absorption of the above formulations was studied using a vertical diffusion cell and excised pig skin. The receiving medium was 0.5% Tween 80 solution. Forty-eight hours after administration, the stratum corneum was removed with tape, and the cumulative transdermal drug amount (µg / g) in the epidermis and dermis was measured. The results indicated that the addition of diethylene glycol monoethyl ether or propylene glycol to the formulations allowed the drug to penetrate the stratum corneum and reach the site of action. Compared to the traditional solutions shown in Table 1, alcohol-containing emulsions exhibit better transdermal absorption, allowing the drug to form reservoirs in the epidermis and dermis, achieving a long-lasting sustained-release effect. Propylene glycol demonstrates better penetration enhancement than diethylene glycol monoethyl ether. When the amount of propylene glycol increases from 20% to 50%, the cumulative drug penetration in the epidermis and dermis increases from 7.5 µg / g to 8.7 µg / g, indicating that transdermal absorption increases with increasing penetration enhancer dosage. Adding menthol or caprylic / capric acid mono- or diglycerides to the formulation does not significantly increase transdermal absorption compared to using propylene glycol or diethylene glycol monoethyl ether alone.

[0315] Table 2 Screening of penetration enhancers prescription 1 2 3 4 5 Prescription composition (weight %) Dutasteride 0.2 0.2 0.2 0.2 0.2 Anhydrous ethanol 51.96 51.96 42.4 47.28 29.28 water 34.64 34.64 28.2 31.52 19.52 Shanyu Chun 0.34 0.34 0.34 0.34 0.34 Sorghum alcohol polyether-5 0.66 0.66 0.66 0.66 0.66 Vaseline 0.2 0.2 0.2 Diethylene glycol monoethyl ether 10 Propylene glycol 10 20 20 50 Menthol 2 2 Caprylic and caprylic acid mono- and diglycerides 8 Centrifugation stability and IVPT results Centrifugal stability Slight layering Slight layering Layering Unlayered Unlayered 24h receiving cell concentration 0.7 1.5 0.8 1.6 1.8 48h receiving cell concentration 4.8 9.8 6.6 11.6 15.4 48hr cumulative transdermal dose µg / g* 6.4 7.9 6.0 7.5 8.7

[0316] In summary, the penetration enhancer in this invention is selected from diethylene glycol monoethyl ether or propylene glycol, with propylene glycol being preferred. The dosage of the penetration enhancer is 10%–50%, preferably 30%–50%.

[0317] Example 2 Selection of Oil Phase

[0318] Alcohol-containing emulsions with different oil phases were prepared according to the formulations shown in Table 3. The emulsifier was benzyl alcohol polyether-5, and the oil phase consisted of benzyl alcohol and squalene (Formula 6) / light liquid paraffin (Formula 7) / white beeswax (Formula 8). The study found that all three formulations were uniform and fine viscous emulsions, with uniformly distributed fine particles observed under a microscope (Fig. 1a, Fig. 1b, Fig. 1c). However, after the samples were placed at 5°C for 15 days, formulations 6 and 7 showed a pearlescent appearance, indicating crystal precipitation, with clustered crystals visible under a microscope (Fig. 1d, Fig. 1e). Formulation 8 showed no significant changes in appearance or microstructure (Fig. 1f). These results indicate that when the formulation contains liquid oil, the oil phase precipitates and separates during emulsion storage; while when the oil phase is solid, the emulsion stability is significantly improved. Therefore, the alcohol-containing emulsions of this invention should not contain an oil phase that is liquid at room temperature.

[0319] Table 3 Comparison of solid oil phase and liquid oil phase prescription 6 7 8 Anhydrous ethanol 59.3 59.3 59.3 Purified water 39.6 39.6 39.6 Sorghum alcohol polyether-5 0.58 0.58 0.58 Shanyu Chun 0.42 0.42 0.42 Squalene 0.1 Lightweight liquid paraffin 0.1 White beeswax 0.1

[0320] Using propylene glycol, ethanol, and water as the aqueous phase, and stearyl alcohol polyether-2 and cetearyl alcohol polyether-20 as emulsifiers, alcohol-containing emulsions were prepared according to the formulations shown in Table 4. The emulsification effects of different oil phases were further investigated. The results are shown in Figure 2. When the oil phase was white petrolatum (Figure 2a) and white beeswax (Figure 2b), the oil phase could be emulsified into uniformly distributed fine particles. When the oil phase was octadecyl alcohol (Figure 2c) and betaine alcohol (Figure 2d), although a white viscous emulsion could be obtained, the oil phase and emulsifier would form liquid crystals (sheet-like or fibrous structures in the figure), resulting in precipitation of the sample. Moreover, the liquid crystal structure was sensitive to environmental temperature and shear force, and the liquid crystal structure may change during long-term storage, thus affecting the stability of the emulsion. When the oil phase was hexadecyl palmitate (Figure 2e) and glyceryl betaine (Figure 2f), the emulsification effect of the oil phase was poor, the oil and water phases separated, and a large number of unemulsified oil phase clumps could be seen under a microscope.

[0321] In summary, the alcohol-containing emulsion described in this invention 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 an aqueous matrix (composed of ethanol, water, and propylene glycol), resulting in smaller and more uniformly distributed emulsion particles.

[0322] Table 4 Screening of solid oil phases prescription 9 10 11 12 13 14 Propylene glycol 40 40 40 40 40 40 Anhydrous ethanol 34.2 34.2 34.2 34.2 34.2 34.2 Purified water 22.8 22.8 22.8 22.8 22.8 22.8 Stearyl alcohol polyether 2 0.8 0.8 0.8 0.8 0.8 0.8 Cetearyl alcohol polyether 20 0.2 0.2 0.2 0.2 0.2 0.2 Vaseline 2 White beeswax 2 Stearyl alcohol 2 Shanyu Chun 2 palmitic acid hexadecyl 2 Glyceryl betaine 2

[0323] Example 3 Selection of Emulsifier Type

[0324] Alcoholic emulsions containing different emulsifiers and combinations of emulsifiers were prepared according to the formulations shown in Tables 5 and 6. The appearance and microstructure of the products were examined, and the combination with the best emulsification effect was selected.

[0325] The evaluation criteria for emulsification effect are as follows:

[0326] Good: It forms a uniform white emulsion with no particulate sediment. Microscopic observation shows that the emulsion particles are evenly distributed and small in size.

[0327] Good: Forms a uniform white emulsion with no or only a few particles of sediment; microscopic observation reveals irregular particle shapes or agglomeration.

[0328] Medium: Can form a white emulsion, but with a significant amount of particulate sediment; microscopic observation reveals some unemulsified oil phase.

[0329] Poor: Oil-water phase separation or a large amount of precipitate visible to the naked eye.

[0330] Table 5. Emulsion formulations and emulsification effects using different emulsifiers prescription 15 16 17 18 19 20 twenty one Propylene glycol 40 40 40 40 40 40 40 Anhydrous ethanol 34.2 34.2 34.2 34.2 34.2 34.2 34.2 Purified water 22.8 22.8 22.8 22.8 22.8 22.8 22.8 White beeswax 2 2 2 2 2 2 2 Polyethylene glycol 7 stearate 1 Sorghum alcohol polyether-5 1 Sorghum alcohol polyether-10 1 Span 60 1 Polyoxyethylene fatty acid esters 1 Sucrose stearate 1 Cetearyl alcohol polyether-20 1 Emulsification effect Difference better better medium Difference medium medium

[0331] Table 6. Emulsion formulations and emulsification effects using compound emulsifiers prescription twenty two twenty three twenty four 25 Dutasteride 0.1 0.1 Propylene glycol 40 40 50 50 Anhydrous ethanol 34.2 34.2 28.74 28.74 Purified water 22.8 22.8 19.16 19.16 White beeswax 2 2 0.14 0.14 Shanyu Chun 0.55 0.55 Sorghum alcohol polyether-5 1.31 1.21 Span 60 0.1 Cetearyl alcohol polyether-20 0.8 0.8 Sucrose stearate 0.2 Sorghum alcohol polyether-10 0.2 Emulsification effect good good better good

[0332] The effects of different emulsifiers on the emulsification of white beeswax in an ethanol-water-propylene glycol matrix were investigated (Table 5). It was found that fatty alcohol polyether emulsifiers had the best emulsification effect, with uniform distribution and small particle size. Span 60 and sucrose stearate had the second best emulsification effect. Although they could emulsify white beeswax, microscopic observation showed that the emulsion particles agglomerated, resulting in precipitation at the bottom of the sample. Polyethylene glycol 7 stearate and polyoxyethylene fatty acid esters could not emulsify white beeswax well, and the oil and water phases of the sample separated. Microscopic observation showed a large number of unemulsified oil phase clumps.

[0333] An unexpected discovery was made that fatty alcohol polyether emulsifiers, when combined with any other emulsifier, significantly improved the emulsification effect. As shown in Tables 5 and 6 and Figure 3, in formulations using sucrose stearate (Figure 3a, Formulation 20) or cetearyl alcohol polyether-20 (Figure 3b, Formulation 21) as emulsifiers, the emulsion particles were prone to agglomeration; however, when the two were used in combination (Figure 3c, Formulation 22), the emulsification effect was significantly improved, and no agglomeration of emulsion particles was observed under a microscope. After the emulsion passed through an 80-mesh filter, almost no solid particles remained on the filter, indicating that there was no unemulsified oil phase or agglomerated precipitated emulsion particles in the product. Similarly, formulation 24, using benzyl alcohol polyether-5 as an emulsifier, yielded a uniform, fine, white emulsion with no particulate sediment after filtration. However, microscopic observation revealed a fibrous liquid crystal structure (Figure 3e), which may affect the long-term stability of the sample. Formulation 25, with the same amounts of other components as formulation 24, only changed the emulsifier to a combination of benzyl alcohol polyether-5 and Span 60. The resulting emulsion had rounded particles, the liquid crystal structure was almost completely eliminated, and the microstructure of the emulsion was significantly improved (Figure 3f). After storing formulation 25 at 40°C for one month, its appearance and microstructure remained unchanged, indicating good sample stability.

[0334] The study also found that combining two emulsifiers, both of which are fatty alcohol polyethers, yielded the best emulsification effect. Formulas 22 and 23 were formulated with sucrose stearate and betaine-10, respectively, combined with cetearyl alcohol polyether-20. Microscopic observation showed that the emulsion particles of Formula 23 (Figure 3d) were more rounded, without agglomeration, and the particle size was significantly smaller than that of Formula 22 (Figure 3c). Both samples were centrifuged at 25°C and 4000 rpm for 6 hours using a Lumisizer dispersion analyzer (simulating 2 years of room temperature storage stability). After centrifugation, the emulsion particles of Formula 22 precipitated, while those of Formula 23 remained well dispersed in the aqueous matrix with almost no sedimentation. This indicates that the emulsion stability of Formula 23, which uses a combination of two fatty alcohol polyethers, is significantly better than that of Formula 22, which uses both fatty alcohol polyethers and sucrose stearate.

[0335] In summary, the emulsifier of the alcohol-containing emulsion of the present invention uses a compound of two or more emulsifiers. One emulsifier is preferably a fatty alcohol polyether, and the other emulsifier is selected from sorbitan fatty acid esters, sucrose stearate, or fatty alcohol polyethers; more preferably, the emulsifier is a combination of fatty alcohol polyethers.

[0336] Example 4: Amounts of oil phase and emulsifier

[0337] Using propylene glycol, ethanol, and water as the aqueous phase, and stearyl alcohol polyether-2 and cetearyl alcohol polyether-20 as emulsifiers, alcohol-containing emulsions were prepared according to the formulations shown in Table 7. The effects of the oil phase and the total amount of active agents (hereinafter referred to as solid content) on the physicochemical properties of the formulations were investigated. The study found that the ratio of oil phase to emulsifier in both formulations 26 (Figure 4a) and 27 (Figure 4b) was 3:1, and the ratio of stearyl alcohol polyether-2 to cetearyl alcohol polyether-20 was 4:1, while the solid contents were 2% and 2.67%, respectively. The particle size distribution and microstructure of the two formulations were similar. However, when the samples were centrifuged at 25℃ and 4000 rpm for 6 hours (simulating 2 years of stability at room temperature), formulation 26 with a solid content of 2% showed stratification after centrifugation, while no stratification was observed in formulation 27, and the emulsion remained stable. This indicates that when the solid content is too low, the emulsion is prone to sedimentation, requiring the addition of a thickener to stabilize the emulsion. Formula 28 and Formula 27 have the same surfactant composition ratio and similar oil phase to surfactant ratio, but the solid content increased from 2.67% to 5%, with no significant difference in centrifugal stability, particle size distribution, and microstructure. Formula 29 (Figure 4c) showed good emulsification when the solid content increased to 6%, but the particle size increased significantly. Formula 30 (Figure 4d) had larger particles and incomplete emulsification when the solid content increased to 6.67%, and the oil phase precipitated to form a sediment.

[0338] The above studies show that the suitable total amount of oil phase and emulsifier in the alcohol-containing emulsion of the present invention is 2.5%-6%, and more preferably, the amount of oil phase and emulsifier is 3%-5%.

[0339] Table 7 Formulations with different amounts of oil phase and emulsifier prescription 26 27 28 29 30 White beeswax 1.50 2.00 4.00 4.90 5.00 Stearyl alcohol polyether 2 0.40 0.53 0.80 0.79 1.25 Cetearyl alcohol polyether 20 0.10 0.13 0.20 0.37 0.42 Dutasteride 0.20 0.20 0.00 0.00 0.00 Propylene glycol 40.00 40.00 40.00 40.00 40.00 Anhydrous ethanol 34.68 34.28 33.00 32.36 32.00 water 23.12 22.86 22.00 21.58 21.33 Centrifugation stability and particle size distribution results Centrifugal stability Layering Unlayered Unlayered Unlayered Oil phase precipitation occurs Particle size distribution D10 (µm) 2.61 2.90 2.91 3.84 Particle size distribution D50 (µm) 5.46 5.20 5.24 11.7 Particle size distribution D90 (µm) 12.3 9.47 10.10 31.4

[0340] Example 5: Chain lengths of the aliphatic chain and the polyoxyethylene chain of the emulsifier

[0341] Previous studies have found that the fatty chain portion (hydrophobic end) of fatty alcohol polyethers should contain at least 16 carbon atoms. This ensures that the emulsifier is evenly distributed on the surface of the emulsion particles, preventing the emulsifier from being extracted into the aqueous phase by ethanol, thus compromising the stability of the emulsion. Therefore, fatty alcohol polyethers with fatty chains containing 16–22 carbon atoms were selected for compounding. Emulsions were prepared according to the formulations shown in Table 8, and the appearance, microstructure, emulsification effect, and particle size distribution of the emulsions were investigated.

[0342] To examine the emulsification effect, a certain amount of emulsion was filtered through a 500-mesh filter. The filter was then dried in a 50°C oven and weighed. The percentage of residue (unemulsified oil phase or agglomerated emulsion particles) on the filter was calculated relative to the oil phase and emulsifier dosage, and the filtration residue percentage was reported (see Table 8). Furthermore, the particle size distribution of the emulsion was examined using a laser particle size analyzer, and the results are shown in Table 8.

[0343] Table 8. Emulsion formulations and evaluation results for different combinations of fatty alcohol polyethers. prescription 31 32 33 34 35 36 Anhydrous ethanol 34.2 34.2 34.2 34.2 34.2 34.2 water 22.8 22.8 22.8 22.8 22.8 22.8 Propylene glycol 40 40 40 40 40 40 White beeswax 2 2 2 2 1.8 1.8 Cetearyl alcohol polyether-25 0.96 0.96 Cetearyl alcohol polyether-20 0.8 0.7 0.7 0.7 Sorghum alcohol polyether-10 0.2 0.15 0.24 Sorghum alcohol polyether-20 0.15 0.3 0.24 Sorghum alcohol polyether-30 0.3 Filter residue 0.55% 0.49% 0.24% 0.29% 0.17% 0.43% Particle size distribution D10 (µm) 2.45 2.22 1.67 1.22 1.59 1.92 Particle size distribution D50 (µm) 4.58 4.42 3.28 2.60 2.83 4.23 Particle size distribution D90 (µm) 8.74 8.97 7.56 11.8 5.15 9.71

[0344] Based on the research results of Examples 3, 4, and 5, it can be seen that when fatty alcohol polyethers contain 2-5 polyoxyethylene monomers, the emulsion is prone to forming liquid crystals, thus affecting the stability and user experience of the product. For example, formulations 10 and 27 used stearyl alcohol polyether-2, and formulations 16, 24, and 25 used benzyl alcohol polyether-5. Microscopic observation revealed a large number of fibrous liquid crystal structures, which may affect the stability of the emulsion. In contrast, formulations 31-36 used emulsifiers containing 10-30 polyoxyethylene monomers, resulting in emulsions with a fine and uniform appearance, filtration residue of less than 1%, and, under microscopic observation, basically round emulsion particles with a particle D90 of less than 15 µm. More preferably, when the number of polyoxyethylene monomers is 10-25, the particle D90 is less than 10 µm. Even more preferably, when cetearyl alcohol polyether-25 and benzyl alcohol polyether-20 are selected, the filtration residue and particle size distribution D90 are the lowest, at only 0.17% and 5.15 µm, respectively.

[0345] In summary, the fatty alcohol polyether emulsifier used in the alcohol-containing emulsion of the present invention should have at least 16 carbon atoms at its hydrophobic end, more preferably, 16-22 carbon atoms at its hydrophobic end; and should have 5-30 polyoxyethylene monomers at its hydrophilic end, more preferably, 10-30 polyoxyethylene monomers at its hydrophilic end, and even more preferably, 10-25 polyoxyethylene monomers at its hydrophilic end.

[0346] Example 6: Composition ratio of oil phase and emulsifier

[0347] Using propylene glycol, ethanol, and water as the aqueous phase, white beeswax as the oil phase, and cetearyl alcohol polyether-20 and benzyl alcohol polyether-20 as emulsifiers, with the total amount of oil phase and emulsifier set at 3%, a 0.2% dutasteride emulsion was prepared according to the formulation shown in Table 9. 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.

[0348] Table 9. Emulsion formulations and evaluation results containing different proportions of oil phase and emulsifier. prescription 37 38 39 40 41 42 Dutasteride 0.2 0.2 0.2 0.2 0.2 0.2 White beeswax 0.85 1.55 2 2.5 2.02 1.84 Cetearyl alcohol polyether-20 2 0.73 0.55 0.23 0.13 1.06 Sorghum alcohol polyether-20 0.15 0.72 0.45 0.27 0.85 0.1 Propylene glycol 40 40 40 40 40 40 Anhydrous ethanol 34 34 34 34 34 34 Purified water 22.8 22.8 22.8 22.8 22.8 22.8 Results of Filter Residue and Particle Size Distribution Investigation *Filter residue 0.04% 0.06% 0.22% 0.60% 0.42% 0.13% Initial particle size distribution D10(µm) 0.88 1.70 2.08 2.56 2.18 1.91 D50(µm) 2.88 4.24 3.91 4.69 4.47 3.35 D90(µm) 8.17 9.19 7.22 8.19 8.47 5.67 Particle size distribution at 40℃ for 3 days D10(µm) 1.03 1.61 2.09 2.53 2.06 1.94 D50(µm) 2.87 3.80 3.96 5.04 4.45 3.60 D90(µm) 191 10.1 7.57 10.1 9.97 6.99

[0349] As shown in Table 9, the white beeswax dosage in Formulations 38 - 42 was 1% - 2.5%, that is, the ratio of the oil phase to the emulsifier was 1:2 - 5:1. The obtained emulsions were uniform and delicate, with almost no particle precipitation, the particle size was less than 10 µm, and there was no significant change in the particle size after being placed at 40°C for 3 days. The white beeswax dosage in Formulation 37 was less than 1%. Although the initial particle size was less than 10 µm, the emulsion particles aggregated and flocculated after being placed at 40°C for 3 days, and the particle size increased to 191 µm. The filtration residue of Formulation 40 with a white beeswax dosage of 2.5% was significantly higher than that of other formulations, and a small amount of incompletely emulsified white beeswax crystals could be seen microscopically, indicating that when the white beeswax dosage was greater than 2%, the emulsification effect decreased. Therefore, the preferable white beeswax dosage was 1% - 2%.

[0350] The white beeswax dosages in Formulations 41, 39 and 42 were similar, while the ratios of ceteth-20 to steareth-20 were approximately 1:7, 1:1 and 10:1 from small to large respectively, and uniform emulsions with almost no particle precipitation and a particle size less than 10 µm could be obtained. There was no significant change in the particle size after being placed at 40°C for 3 days. However, the ratio of ceteth-20 to steareth-20 in Formulation 41 was less than 1:1, and the filtration residue was significantly higher than that of Formulations 39 and 42, indicating that when the dosage of ceteth-20 in the formulation was higher than that of steareth-20, the emulsification effect was better. Therefore, the preferable ratio of ceteth-20 to steareth-20 was 1:1 - 10:1.

[0351] According to the above research, a formulation design (DOE) was carried out to establish the optimal ratio relationship of white beeswax, ceteth-20 and steareth-20. The method was as follows: The experimental variables A, B, and C were white beeswax, ceteth-20 and steareth-20 respectively. The variable ranges and constraint conditions were set as 1.6 < A ≤ 2.2, 0.5 < B ≤ 1.3, 0.1 < C ≤ 0.6, and A + B + C = 3. A total of 12 formulations were designed, and the filtration residue, particle size distribution and particle size change after being placed at 40°C of the samples were investigated. The component ratios and investigation results of each formulation are shown in detail in Table 10 and Figure 5.

[0352] Table 10 Emulsion formulations with different ratios of white beeswax, ceteth-20 and steareth-20 and investigation results Formulation 43 44 45 46 47 48 49 50 51 52 53 54 White beeswax 2.035 1.765 1.600 1.947 2.188 1.985 1.786 2.200 1.600 1.600 1.863 1.742 Cetearyl alcohol polyether 20 0.703 0.635 0.800 0.526 0.712 0.915 1.114 0.540 1.117 1.300 0.722 0.919 Sorghum alcohol polyether 20 0.262 0.600 0.600 0.526 0.100 0.100 0.100 0.260 0.283 0.100 0.414 0.339 Dutasteride 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 Anhydrous ethanol 34 34 34 34 34 34 34 34 34 34 34 34 water 22.8 22.8 22.8 22.8 22.8 22.8 22.8 22.8 22.8 22.8 22.8 22.8 Propylene glycol 40 40 40 40 40 40 40 40 40 40 40 40 Filter residue (%) 0.22 0.10 0.02 0.16 0.44 0.17 0.09 0.25 0.07 0.07 0.10 0.07 initial D10(µm) 2.23 1.83 1.69 2.04 2.15 2.06 1.89 2.20 1.78 1.81 2.04 1.78 D50(µm) 4.04 3.82 3.92 4.02 4.14 3.92 3.63 4.16 3.41 3.36 3.79 3.44 D90(µm) 7.09 8.04 9.71 8.11 8.02 8.04 8.67 7.96 6.49 6.25 6.76 6.59 40℃ 3 days D10(µm) 2.29 1.80 1.63 2.03 2.31 2.19 1.97 2.27 1.79 1.93 2.05 1.78 D50(µm) 4.6 3.8 3.76 4.11 5.14 4.63 4.12 4.41 3.62 4.32 4.19 3.64 D90(µm) 9.57 8.21 8.84 8.58 13 11.1 10.2 8.81 7.62 13.6 9.7 8.21

[0353] Using filtration residue as the dependent variable and the amounts of the three components as independent variables, the data in Table 10 were fitted (Figure 5a). The prediction results showed a linear relationship between filtration residue and the amount of white beeswax in the formulation. The lower the amount of white beeswax, the less filtration residue, indicating fewer unemulsified oil phases or agglomerated precipitates. Using the initial particle size D50 as the dependent variable and the amounts of the three components as independent variables, the results showed that the lower the amount of white beeswax, the higher the proportion of cetearyl 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 cetearyl alcohol polyether-20 to benzyl 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 3 days at 40℃ was fitted as the dependent variable (Figure 5c). The results showed that the particle size change was mainly related to the amount of betaine-20. The higher the amount of betaine-20, the smaller the particle size change. When the amount of betaine-20 was greater than 0.2%, the particle size change after high-temperature storage did not exceed 5%, indicating better emulsion stability. That is, more preferably, the ratio of cetearyl alcohol polyether-20 to betaine-20 in the formulation should not be greater than 6:1. Taking into account the above factors (Figure 5d), the optimal composition of the oil phase and emulsifier in the formulation is 1.4%-1.8% white beeswax, 0.8%-1.4% cetearyl alcohol polyether-20, and 0.2%-0.6% betaine-20.

[0354] Therefore, the preferred ratio of white beeswax to emulsifier in the formulation is 2:1–1:2, and the preferred ratio of cetearyl alcohol polyether-20 to benzyl alcohol polyether-20 is 1:1–7:1.

[0355] Example 7: Alcohol-containing emulsions with different ethanol dosages and specifications

[0356] Dutasteride exhibits good solubility in ethanol; the higher the proportion of ethanol in the formulation, the better the solubility of dutasteride, and the faster the formulation evaporates, resulting in a refreshing feel on the skin. However, a high proportion of ethanol can compromise the stability of the emulsion, leading to demulsification. Previous studies have shown that when the ratio of ethanol to water in the formulation is not higher than 3:2, the effect of ethanol on emulsion stability is relatively small. The solubility of dutasteride in mixed solvents of propylene glycol, ethanol, and water in different proportions is shown in Table 11. The 0.02% dutasteride emulsion formulation should contain at least 20% ethanol, and if the specification is increased to 0.2%, the formulation should contain at least 30% ethanol. Increasing the amount of propylene glycol can promote drug dissolution and transdermal absorption, 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 formulation, the solubility of dutasteride, and transdermal absorption, the optimal weight ratio of ethanol, water, and propylene glycol in the matrix of this invention is approximately 33:approximately 23:approximately 40.

[0357] Table 11 Solubility of dutasteride in a mixed solvent of propylene glycol, ethanol and water solvent Solubility (mg / ml) Anhydrous ethanol-water (30:70) 0.011 Anhydrous ethanol-water (40:60) 0.036 Anhydrous ethanol-water (50:50) 0.27 Anhydrous ethanol-water (60:40) 0.99 Anhydrous ethanol-water (70:30) 2.8 Anhydrous ethanol-propylene glycol-water (54:10:36) 1.6 Anhydrous ethanol-propylene glycol-water (48:20:32) 1.7 Anhydrous ethanol-propylene glycol-water (42:30:28) 2.0 Anhydrous ethanol-propylene glycol-water (35:40:25) 2.2 Anhydrous ethanol-propylene glycol-water (30:50:20) 2.6 Anhydrous ethanol-propylene glycol-water (24:60:16) 3.1 Anhydrous ethanol-propylene glycol-water (10:40:50) 0.068 Anhydrous ethanol-propylene glycol-water (20:40:40) 0.20 Anhydrous ethanol-propylene glycol-water (25:40:35) 0.50 Anhydrous ethanol-propylene glycol-water (30:40:30) 1.2

[0358] Dutasteride emulsions in 0.2% and 0.05% concentrations were prepared according to the formulations in Table 12, with ethanol content of 34% and 25%, respectively. The results showed that the emulsions with different ethanol concentrations exhibited good emulsification, minimal filtration residue, and emulsion particle size less than 10 µm. Lower ethanol concentrations resulted in smaller emulsion particle sizes. After placing both samples at 40℃ for 3 days, no significant changes in particle size or microstructure were observed. Furthermore, when the samples were placed at 2℃-8℃, their microstructure remained unchanged, and no needle-like dutasteride crystals precipitated, indicating that dutasteride dissolves well in the emulsion and does not precipitate even at low temperatures.

[0359] Table 12 Dutasteride emulsions in 0.2% and 0.05% strengths prescription 55 56 Dutasteride 0.2 0.05 White beeswax 2 2 Cetearyl alcohol polyether-20 0.7 0.7 Sorghum alcohol polyether-20 0.3 0.3 Propylene glycol 40 40 Anhydrous ethanol 34 25 Purified water twenty two 32 Filter residue 0.37% 0.09% Initial particle size distribution D10(µm) 2.22 0.08 D50(µm) 3.94 2.05 D90(µm) 6.77 6.15 40℃ for 3 days Particle size distribution D10(µm) 2.19 0.94 D50(µm) 4.04 2.77 D90(µm) 7.37 6.39

[0360] Example 8: Formulation containing thickener and its stability

[0361] Dutasteride alcoholic solutions with different thickener dosages were prepared according to the formulations in Table 13. When the carbomer dosage was 0.2%, 0.3%, and 0.4%, the viscosities of the formulations were 92.2 cP, 166.8 cP, and 260.4 cP, respectively, indicating good emulsion flowability. When the carbomer dosage was higher than 0.5%, the viscosity of the formulation was higher, and the flowability was poor. Taking formulation 57 as an example, the stability of the alcoholic emulsion under high temperature (30℃), low temperature (2℃~8℃), and freeze-thaw cycles (stored at -20℃ and 25℃ for approximately 48 hours, cyclicated three times) was investigated. As shown in Figure 6, the microstructure of the sample did not change significantly after freeze-thaw cycles or after being placed under high and low temperature conditions for 6 months. The emulsion particles were round and without agglomeration. At the same time, no needle-shaped dutasteride crystals were observed to precipitate under microscopic observation, indicating that dutasteride can dissolve well in the emulsion and will not precipitate under various conditions. As shown in Figures 7 and 8, after the samples underwent freeze-thaw cycles or were placed under high and low temperature conditions for 6 months, there were no significant changes in particle size and viscosity.

[0362] In summary, the thickener used in this invention, at a dosage of 0.1%-0.4%, produces an emulsion with a viscosity significantly lower than other alcohol-containing emulsions and related patents, maintaining good fluidity and making it suitable for use on the scalp. Furthermore, the alcohol-containing emulsion exhibits no significant changes in its physicochemical properties under high temperature, low temperature, and freeze-thaw conditions, demonstrating significantly superior stability compared to previous technologies.

[0363] Table 13. Formulations of alcohol-containing emulsions using different thickeners and results of viscosity and particle size analysis. prescription 57 58 59 Dutasteride 0.2 0.2 0.2 White beeswax 1.489 1.489 1.489 Cetearyl alcohol polyether-20 1.254 1.254 1.254 Sorghum alcohol polyether-20 0.257 0.257 0.257 Propylene glycol 40 40 40 Purified water twenty three twenty three twenty three Carbomer Homopolymer Type A 0.3 0.2 0.4 Anhydrous ethanol 33.467 33.585 33.15 Triethanolamine Adjust to pH 6.0 Investigation results Viscosity (cP) 166.8 92.2 260.4 Particle size distribution D10 (µm) 1.34 1.34 1.22 Particle size distribution D50 (µm) 2.09 2.09 2.00 Particle size distribution D90 (µm) 3.36 3.35 3.30

[0364] Example 9 Transdermal absorption of alcohol-containing emulsions

[0365] Using 1-3 month old Bama piglets as a model, the pharmacokinetics of dutasteride alcohol-containing emulsions administered transdermally at strengths of 0.02%, 0.06%, and 0.2% were studied. In the experimental group, 0.5 mL was administered daily to the skin on the back of the piglets for 14 consecutive days, covering an area of ​​200 cm², as shown in Table 14. The control group received oral dutasteride commercially available soft capsules (trade name: Anfuda, strength 0.5 mg / capsule) once daily, one capsule each time.

[0366] Table 14. Dutasteride alcoholic emulsions in 0.02%, 0.06%, and 0.2% strengths. prescription 60 61 62 Dutasteride 0.02 0.06 0.2 White beeswax 1.72 1.72 1.72 Cetearyl alcohol polyether-20 1.03 1.03 1.03 Sorghum alcohol polyether-20 0.25 0.25 0.25 Propylene glycol 40 40 40 Anhydrous ethanol 34 34 34 Purified water 22.78 22.74 22.6 Carbomer 0.2 0.2 0.2 Triethanolamine Adjust to pH 6.0 Adjust to pH 6.0 Adjust to pH 6.0

[0367] The blood drug concentrations on days 1 and 14, and the content of dutasteride in skin tissue after 14 days, were measured. The results are shown in Table 15. The study found that the drug concentration in the dermis after topical administration of dutasteride alcohol-containing emulsion was significantly higher than that after oral administration. After 14 days of administration of 0.02% dutasteride alcohol-containing emulsion (0.1 mg / day), the drug concentration in the dermis was 787.5 ng / g, approximately eight times that of oral administration. This indicates that dutasteride in the alcohol-containing emulsion can effectively penetrate the skin barrier and reach the site of action, achieving better local drug concentrations at a dose one-fifth that of oral administration. On the other hand, the blood drug concentrations on days 1 and 14 of all concentration groups were significantly lower than those after oral administration. The daily dose of 0.02% dutasteride alcohol-containing emulsion (1 mg / day) was twice that of the daily dose of oral administration (0.5 mg / day), but the area under the curve (AUC(0-t)) after 14 days of administration was only 1.2% of that after oral administration. These data indicate that the systemic exposure to dutasteride alcohol emulsion is far lower than that of oral dutasteride soft capsules, which can effectively reduce the toxic side effects of dutasteride.

[0368] Table 15 Drug distribution of different strengths of the composition in the blood and skin at the administration site of Bama piglets Day 1 AUC(0-t)(h×ng / ml) Day 14 AUC(0-t)(h×ng / ml) Average blood drug concentration on day 14 (ng / ml) Drug concentration in dermis on day 14 (ng / g) Oral administration of 0.5 mg 607 3780 79.768 92.9 Topical application 0.1 mg 0.02% specification 1.71 15 0.316 787.5 Topical application 0.3 mg 0.06% specification 0.777 23.8 0.505 523.2 Topical application 1 mg 0.2% specification 1.43 48.3 1.018 3277.5

[0369] The embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of the present invention. Furthermore, any changes or modifications made by those skilled in the art based on the ideas of the present invention, and on the specific implementation methods and application scope of the present invention, are all within the scope of protection of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.

[0370] none

Claims

1. An alcohol-containing emulsion of a 5α-reductase inhibitor, said alcohol-containing emulsion comprising a 5α-reductase inhibitor, an alcohol, an oil phase, an emulsifier, a diluent, and a penetration enhancer; wherein, Based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.005 wt% to 0.5 wt% of a 5α-reductase inhibitor, 25 wt% to 40 wt% of an alcohol, 1.3 wt% to 1.8 wt% of an oil phase, 1.0 wt% to 2.0 wt% of an emulsifier, 15 wt% to 30 wt% of a diluent, and 30 wt% to 50 wt% of a penetration enhancer; wherein the 5α-reductase inhibitor is dutasteride, the alcohol is ethanol, the oil phase is white petrolatum and / or white beeswax, the emulsifier is benzyl alcohol polyether and cetearyl alcohol polyether, the diluent is water, and the penetration enhancer is propylene glycol; wherein the weight ratio of the alcohol, the penetration enhancer, and the diluent is (25~40):(30~50):(15~30); wherein the weight ratio of the oil phase to the emulsifier is 1:2 to 2:1; The hydrophilic end of the benzyl alcohol polyether contains 10-30 repeating polyoxyethylene units; the hydrophilic end of the cetearyl alcohol polyether contains 10-30 repeating polyoxyethylene units.

2. The alcohol-containing emulsion as described in claim 1, wherein, The cetearyl alcohol polyether is selected from one or more of the following: cetearyl alcohol polyether-10, cetearyl alcohol polyether-15, cetearyl alcohol polyether-20, and cetearyl alcohol polyether-25.

3. The alcohol-containing emulsion as described in claim 2, wherein, The benzyl alcohol polyether is selected from one or more of the following: benzyl alcohol polyether-10, benzyl alcohol polyether-20, and benzyl alcohol polyether-30.

4. The alcohol-containing emulsion as described in claim 3, wherein, The weight ratio between cetearyl alcohol polyether-20 and benzyl alcohol polyether-20 is 1:1 to 10:

1.

5. The alcohol-containing emulsion as described in claim 2, wherein, The alcohol-containing emulsion contains 0.8% to 1.4% by weight of cetearyl alcohol polyether-20.

6. The alcohol-containing emulsion as described in claim 3, wherein, The alcohol-containing emulsion contains 0.2% to 0.6% by weight of benzyl alcohol polyether-20.

7. The alcohol-containing emulsion as described in claim 1, wherein, The weight ratio of the alcohol, the penetration enhancer, and the diluent is approximately 33:approximately 40:approximately 23.

8. The alcohol-containing emulsion as described in claim 1, wherein, The alcohol-containing emulsion further includes other excipients.

9. The alcohol-containing emulsion as described in claim 8, wherein, The other excipients are selected from one or more of the following: thickeners, pH adjusters, antibacterial agents, and stabilizers.

10. A method for preparing an alcohol-containing emulsion, the method comprising the following steps: (1) weighing appropriate amounts of 5α-reductase inhibitor, alcohol, oil phase, emulsifier, diluent, and penetration enhancer respectively; first heating and melting the oil phase and emulsifier; then adding the 5α-reductase inhibitor, alcohol, diluent, and penetration enhancer for emulsification to obtain an emulsion; and (2) cooling the emulsion in a water bath to obtain the alcohol-containing emulsion; wherein, Based on the weight percentage of the alcohol-containing emulsion, the alcohol-containing emulsion comprises 0.005 wt% to 0.5 wt% of a 5α-reductase inhibitor, 25 wt% to 40 wt% of an alcohol, 1.3 wt% to 1.8 wt% of an oil phase, 1.0 wt% to 2.0 wt% of an emulsifier, 15 wt% to 30 wt% of a diluent, and 30 wt% to 50 wt% of a penetration enhancer; wherein the 5α-reductase inhibitor is dutasteride, the alcohol is ethanol, the oil phase is white petrolatum and / or white beeswax, the emulsifier is benzyl alcohol polyether and cetearyl alcohol polyether, the diluent is water, and the penetration enhancer is propylene glycol; wherein the weight ratio of the alcohol, the penetration enhancer, and the diluent is (25~40):(30~50):(15~30); wherein the weight ratio of the oil phase to the emulsifier is 1:2 to 2:1; The hydrophilic end of the benzyl alcohol polyether contains 10-30 repeating polyoxyethylene units; the hydrophilic end of the cetearyl alcohol polyether contains 10-30 repeating polyoxyethylene units.

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