WO2023201859A1 - 一种用于防治雄激素性脱发的爱普列特外用制剂 - Google Patents

一种用于防治雄激素性脱发的爱普列特外用制剂 Download PDF

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WO2023201859A1
WO2023201859A1 PCT/CN2022/097219 CN2022097219W WO2023201859A1 WO 2023201859 A1 WO2023201859 A1 WO 2023201859A1 CN 2022097219 W CN2022097219 W CN 2022097219W WO 2023201859 A1 WO2023201859 A1 WO 2023201859A1
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external preparation
preparation
epristeride
hair
preventing
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French (fr)
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牛犇
李家慧
吴叶鸣
游余文
黄坤
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江苏联环药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • the present invention belongs to the field of hair growth technology, and more specifically, relates to an external preparation of Aprelite for preventing and treating androgenic alopecia.
  • AGA Androgenetic alopecia
  • the main causes of AGA are genetic factors and abnormal androgen levels. Among them, abnormal androgen levels are mainly manifested in the type II 5 ⁇ reductase activity in hair loss areas that is significantly higher than in non-hair loss areas. Androgens are converted into dihydrotestosterone under the action of 5 ⁇ reductase. Increased dihydrotestosterone content can make hair follicles miniaturized. , the thick black terminal hair gradually turns into light-colored vellus hair, and eventually the hair follicles shrink and disappear, clinically manifesting as baldness.
  • Epristeride (chemical name: 17- ⁇ (N-tert-butyl-amino-formyl)androsta-3,5-diene-3-carboxylic acid) is a new type of non-competitive 5 ⁇ reductase Inhibitors.
  • Aprelite forms a ternary complex with 5 ⁇ reductase and NADP, which inhibits the conversion of testosterone into dihydrotestosterone (DHT), thereby reducing the content of dihydrotestosterone.
  • DHT dihydrotestosterone
  • the technical problem to be solved by the present invention is to provide a kind of external preparation of Ipremide for preventing and treating androgenic alopecia.
  • An external preparation of Ipremide for the prevention and treatment of androgenic alopecia including an active component and auxiliary materials for the preparation; the active ingredient is Apremide, and the auxiliary materials for the preparation include a cosolvent and a transdermal absorption accelerator , thickener, stabilizer.
  • the concentration of the active ingredient Aprelide in the external preparation of Aprelide is 0.1 to 10 w/v%.
  • the co-solvent is ethanol, propylene glycol, glycerol and water; and the volume ratio of ethanol, propylene glycol, glycerin and water is: 1-80:1-80:1-80:100.
  • the concentration of transdermal absorption accelerator is 0.05 ⁇ 20w/v%; the concentration of thickener is 0.05 ⁇ 10w/v%; the concentration of stabilizer is 0.05 ⁇ 10w/v% .
  • the transdermal absorption accelerator is selected from the group consisting of laurel azazone, menthol, 2-n-nonyl-1,3-dioxane, oleic acid, methyl or ethyl lauric acid and isopropyl myristate. .
  • the transdermal absorption enhancer is laurel azazone.
  • the thickener is one or more of natural polymer materials and their derivatives, and synthetic polymer materials.
  • the natural polymer materials and their derivatives include sodium alginate, agar, acacia gum, tragacanth, cellulose, chitosan and their derivatives
  • the synthetic polymer materials include fibers modified with various groups.
  • the thickening agent is sodium alginate.
  • the stabilizer is one or more of surfactants, soluble complexes, inorganic acids, organic amines and inorganic bases.
  • the surfactants include polysorbates, saturated or unsaturated C12-C18 linear hydrocarbon groups/cyclic aryl groups/naphthyl carboxylates/sulfates/sulfonates/phosphates, polyoxyethylene fats Alcohol ether, polyoxyethylene fatty acid ester, polyoxyethylene-polyoxypropylene copolymer.
  • Soluble complexes include disodium edetate; inorganic acids include hydrochloric acid, acetic acid, and phosphoric acid; organic amines include ethylamine and triethanolamine; and inorganic bases include sodium hydroxide, potassium hydroxide, and calcium hydroxide.
  • the stabilizer is disodium edetate.
  • the preparation form is any one of solution, spray, gel, liniment, and lotion.
  • the invention provides a new type of external preparation for preventing and treating androgenetic alopecia. Compared with the existing external preparation finasteride, it can significantly extend the hair anagen phase and promote the growth of new hair follicles with longer length. It is effective in treating hair loss and promoting hair growth. The growth effect is remarkable.
  • Figure 1 is a diagram of the back hair growth of mice of the present invention.
  • Day-1 is the day before administration
  • Day 12 is the 12th day after administration
  • Day 20 is the 20th day after administration.
  • Optional transdermal absorption enhancers for the above-mentioned anti-hair loss external preparations are azadron and its analogs, menthol, SEPA (2-n-nonyl-1,3-dioxane), and terpenes.
  • Optional thickeners are one or more of natural polymer materials and their derivatives, and synthetic polymer materials.
  • natural polymer materials and their derivatives include sodium alginate, agar, gum arabic, tragacanth, cellulose, chitosan and their derivatives
  • synthetic polymer materials include cellulose modified with various groups.
  • the thickening agent is preferably sodium alginate.
  • Optional stabilizers are surfactants, soluble complexes (such as disodium edetate), inorganic acids (such as hydrochloric acid, acetic acid, phosphoric acid), organic amines (triethylamine, triethanolamine) and inorganic bases (such as hydrogen One or more of sodium oxide, potassium hydroxide, calcium hydroxide).
  • soluble complexes such as disodium edetate
  • inorganic acids such as hydrochloric acid, acetic acid, phosphoric acid
  • organic amines triethylamine, triethanolamine
  • inorganic bases such as hydrogen
  • sodium oxide, potassium hydroxide, calcium hydroxide such as sodium oxide, potassium hydroxide, calcium hydroxide.
  • surfactants include polysorbates, saturated or unsaturated C12-C18 linear hydrocarbon group/cyclic aryl/naphthyl carboxylate (R-COOM)/sulfate (R-OSO 3 M) /Sulfonate (R-OPO 3 M)/Phosphate (R-OPO 3 M), polyoxyethylene fatty alcohol ether, polyoxyethylene fatty acid ester, polyoxyethylene-polyoxypropylene copolymer (poloxamer ).
  • the stabilizer is preferably disodium edetate.
  • additives such as solubilizers, emulsifiers, non-aqueous excipients, and preservatives.
  • solubilizers such as solubilizers, emulsifiers, non-aqueous excipients, and preservatives.
  • mice C57BL/6 female mice about 8 weeks old (purchased from Beijing Vitong Lever Company) were adaptively fed in separate cages for 1 week.
  • Day-1 of the test (the day before drug administration), they were anesthetized by intraperitoneal injection of Avertin solution. After shaving the hair on the back of the mice with an electric razor, apply depilatory cream to remove the hair.
  • mice After all mice were depilated, they were randomly divided into groups according to the condition of their back skin after depilation, with 5 mice in each group.
  • the modeling group was subcutaneously injected with a modeling agent (1mg testosterone, suspended in 10% polysorbate 80 solution). Modeling was performed every seven days for five days, and the control group was injected with the corresponding solvent control.
  • mice were smeared with 0.1 mL of the corresponding drug every day as planned.
  • mice were weighed twice a week, and photos were taken on Day-1, Day 12, and Day 20 to record the hair growth status on the back of the mice.
  • the animal grouping is shown in Table 3 below:
  • SPSS13.0 statistical software was used for analysis of variance, and the statistical mean ⁇ standard deviation (Mean ⁇ SD) was used.
  • the independent sample t test was used for comparison between the two groups, and p ⁇ 0.05 was considered statistically different.
  • hair growth scoring index 0 points, no growth; 1 points, ⁇ 20% growth; 2 points, 20–40% growth; 3 points, 40–60% growth; 4 points, 60–80% growth; 5 points, Score 80–100% growth.
  • mice can effectively promote hair growth in mice, and its efficacy is better than that of the control drug finasteride and equivalent to that of the control drug minoxidil. . No adverse reactions were seen in mice during the test, indicating that the drug is safe.

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Abstract

本发明公开了一种用于防治雄激素性脱发的爱普列特外用制剂，属于生发技术领域。其药物活性成分为爱普列特，助溶剂为乙醇、丙二醇、甘油和水，可选地添加透皮吸收促进剂、稳定剂、增稠剂。本发明药物制剂与现有外用制剂非那雄胺相比，能显著延长毛发生长期，促进新生毛囊生长，长度更长，在治疗脱发、促进毛发生长方面效果显著。具有疗效好，见效快，安全性高等优点；其制备方法简便易行，稳定性好，可操作性强，适于工业化生产。

Description

一种用于防治雄激素性脱发的爱普列特外用制剂 技术领域
本发明属于生发技术领域，更具体地说，涉及一种用于防治雄激素性脱发的爱普列特外用制剂。
背景技术
雄激素性秃发(androgeneticalopecia，AGA)是最常见的一种渐进性脱发类型。在我国男性和女性AGA的患病率分别为21.3％和6.0％，其多发生于青春期和青春期后，主要表现为毛发进行性减少和毛囊的微小化。AGA发病原因主要为遗传因素和雄激素水平异常。其中，雄激素水平异常主要表现在脱发区II型5α还原酶活性明显高于非脱发区，雄激素在5α还原酶的作用下转化为双氢睾酮，双氢睾酮含量升高可使毛囊微小化，粗黑的终毛逐渐变为淡色的毳毛，最终毛囊萎缩消失，临床上表现为秃发。
爱普列特(Epristeride，化学名为17-β(N-叔丁基-氨基-甲酰基)雄甾-3,5-二烯-3-羧酸)是一种新型非竞争性5α还原酶抑制剂。爱普列特与5α还原酶、NADP形成三元复合物，抑制睾酮向双氢睾酮(DHT)的转化，从而使其双氢睾酮含量下降。目前国内临床上用于良性前列腺增生的治疗，为口服片剂，推荐剂量为每天2次，每次5mg。长期服用可使前列腺体积缩小，排尿阻力降低，从而减轻膀胱流出道梗阻以提高尿流率，减少残余尿量，达到症状改善的目的。
结合爱普列特的作用机制及雄激素性秃发的致病原因，推测爱普列特具有潜在治疗雄激素性秃发的作用，故对此进行验证。同时，考虑到系统给药可能带来的不良反应，拟开发局部用药制剂，减少系统用药带来的全身副反应。局部定向给药，可直接作用于脱发部位，用量少且起效快，安全有效且易耐受，适宜长期使用。鉴于此，提出了本发明。
发明内容
针对现有技术存在的上述问题，本发明所要解决的技术问题在于提供一种一种用于防治雄激素性脱发的爱普列特外用制剂。
为了解决上述技术问题，本发明所采用的技术方案如下：
一种用于防治雄激素性脱发的爱普列特外用制剂，包括活性组分和制剂用辅 料；所述活性成分为爱普列特，所述制剂用辅料包括助溶剂、透皮吸收促进剂、增稠剂、稳定剂。
进一步的，爱普列特外用制剂中活性成分爱普列特的浓度为0.1～10w/v％。
进一步的，所述助溶剂为乙醇、丙二醇、甘油和水；且乙醇、丙二醇、甘油和水的体积比为：1-80:1-80:1-80:100。
进一步的，爱普列特外用制剂中，透皮吸收促进剂的浓度为0.05～20w/v％；增稠剂的浓度为0.05～10w/v％；稳定剂的浓度为0.05～10w/v％。
其中，透皮吸收促进剂选自月桂氮卓酮、薄荷醇、2-n-壬基-1,3-二噁烷、油酸、月桂酸的甲酯或乙酯及肉豆蔻酸异丙酯。
作为优选，透皮吸收促进剂为月桂氮卓酮。
增稠剂为天然高分子材料及其衍生物、合成高分子材料其中的一种或多种。所述天然高分子材料及其衍生物包括海藻酸钠、琼脂、阿拉伯胶、西黄蓍胶、纤维素、壳聚糖及其衍生物，所述合成高分子材料包括各种基团修饰的纤维素及纤维素钠盐、聚维酮、聚乙烯醇、聚乙二醇、卡波姆、聚丙烯酸树脂及其衍生物。
作为优选，增稠剂为海藻酸钠。
稳定剂为表面活性剂、可溶性络合物、无机酸、有机胺和无机碱中的一种或多种其中的一种。
所述表面活性剂包括聚山梨酯类、饱和或不饱和的C12～C18的直链烃基/环状芳基/萘基的羧酸盐/硫酸盐/磺酸盐/磷酸盐、聚氧乙烯脂肪醇醚、聚氧乙烯脂肪酸酯、聚氧乙烯-聚氧丙烯共聚物。
可溶性络合物包括依地酸二钠；无机酸包括盐酸、醋酸、磷酸；有机胺包括乙胺、三乙醇胺；无机碱包括氢氧化钠、氢氧化钾、氢氧化钙。
作为优选，稳定剂为依地酸二钠。
进一步的，制剂剂型为溶液剂、喷雾剂、凝胶剂、搽剂、洗剂中任意一种。
所述的爱普列特外用制剂在防治雄激素性脱发中的应用。
相比于现有技术，本发明的有益效果为：
本发明提供了一种新型防治雄激素性脱发的外用制剂，与现有外用制剂非那雄胺相比，能显著延长毛发生长期，促进新生毛囊生长，长度更长，在治疗脱发、促进毛发生长方面效果显著。
附图说明
图1为本发明的小鼠背部毛发生长情况图；图中，Day-1为给药前一天，Day 12为给药后的第12天，Day 20为给药后的第20天。
具体实施方式
下面将结合具体实施方式对本发明的技术方案进行清楚、完整地描述，但是本领域技术人员将会理解，下列所描述的实施例是本发明一部分实施例，而不是全部的实施例，仅用于说明本发明，而不应视为限制本发明的范围。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。根据本发明的技术方案及构思加以等同替换或改变，都应涵盖在本发明权利要求的保护范围之内。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1防脱生发外用制剂的制备
配制1000ml所述防脱生发外用制剂需使用爱普列特20g、乙醇300ml、丙二醇300ml、甘油30ml、月桂氮卓酮25ml、依地酸二钠0.5g，海藻酸钠2g。具体组分及其比例如下表1所示。
表1
组分 功能 每单位的量 ％
爱普列特 活性成分 20g 2％
乙醇 溶剂 300ml 30％
丙二醇 溶剂 300ml 30％
甘油 溶剂 30ml 3％
月桂氮卓酮 透皮吸收促进剂(PE) 25ml 2.5％
依地酸二钠 稳定剂 0.5g 0.05％
海藻酸钠 增稠剂 2g 0.2％
水 溶剂 QS 1000ml 100％
该实施例防脱生发外用制剂的一种制备方法包括以下步骤：
1)按配方分别称取爱普列特、乙醇、丙二醇、甘油、月桂氮卓酮和依地酸 二钠；
2)将爱普列特加入乙醇中，充分溶解，得到溶液A；
3)将月桂氮卓酮和甘油加入丙二醇中，混合均匀，用适量水充分溶解依地酸二钠和海藻酸钠后与之混合，得到溶液B；
4)将步骤1)得到的溶液A加入到步骤2)得到的溶液B中，得到溶液C，加纯化水定容至1000ml，充分混合，即得。
该实施例防脱生发外用制剂的另一种制备方法包括以下步骤：
1)按配方用量分别称取爱普列特、乙醇、丙二醇、月桂氮卓酮和依地酸二钠；
2)将乙醇与部分丙二醇以体积比9：1-1：1混合均匀，向其中加入爱普列特，使其充分溶解，得到溶液A；
3)用适量的纯化水将依地酸二钠和海藻酸钠溶解，加入月桂氮卓酮和甘油，再与剩余的丙二醇混匀，得到溶液B；
4)将上述得到的溶液A和溶液B混合均匀，加水定容至1000ml，充分混合，即得。
实施例2防脱生发外用制剂的制备
配制1000ml所述防脱生发外用制剂需使用爱普列特50g、乙醇300ml、丙二醇100ml、甘油30ml、月桂氮卓酮25ml、三乙醇胺0.5g、卡波姆1g。具体组分及其比例如下表2所示。
表2
组分 功能 每单位的量 ％
爱普列特 活性成分 50g 5％
乙醇 溶剂 300ml 30％
丙二醇 溶剂 100ml 10％
甘油 溶剂 30ml 3％
月桂氮卓酮 透皮吸收促进剂(PE) 25ml 2.5％
三乙醇胺 稳定剂 0.5g 0.05％
卡波姆 增稠剂 1g 0.1％
水 溶剂 QS 1000ml 100％
该实施例防脱生发外用制剂的制备方法包括以下步骤：
1)按配方用量分别称取爱普列特、乙醇、丙二醇、月桂氮卓酮和卡波姆；
2)将乙醇与部分丙二醇以体积比9：1-1：1混合均匀，向其中加入爱普列特，使其充分溶解，得到溶液A；
3)将卡波姆用适量的纯化水充分溶胀，用三乙醇胺调节pH后，加入月桂氮卓酮和甘油，再与剩余的丙二醇混匀，得到混合物B；
4)将上述得到的溶液A和混合物B搅拌均匀，加水定容至1000ml，充分混合，即得。
上述防脱生发外用制剂可选的透皮吸收促进剂为月桂氮卓酮及其类似物、薄荷醇、SEPA(2-n-壬基-1,3-二噁烷)、萜(烯)类化合物或含萜(烯)类的挥发油、短链或中长链饱和/不饱和脂肪酸、油酸、油酸或月桂酸的甲酯或乙酯及肉豆蔻酸异丙酯，优选为月桂氮卓酮。
可选的增稠剂为天然高分子材料及其衍生物、合成高分子材料其中的一种或多种。其中，天然高分子材料及其衍生物包括海藻酸钠、琼脂、阿拉伯胶、西黄蓍胶、纤维素类、壳聚糖及其衍生物；合成高分子材料包括各种基团修饰的纤维素及纤维素钠盐、聚维酮、聚乙烯醇、卡波姆、聚丙烯酸树脂及其衍生物；增稠剂优选海藻酸钠。
可选的稳定剂为表面活性剂、可溶性络合物(如依地酸二钠)、无机酸(如盐酸、醋酸、磷酸)、有机胺(三乙胺、三乙醇胺)和无机碱(如氢氧化钠、氢氧化钾、氢氧化钙)中的一种或多种其中的一种。其中，表面活性剂包括聚山梨酯类、饱和或不饱和的C12～C18的直链烃基/环状芳基/萘基的羧酸盐(R-COOM)/硫酸盐(R-OSO 3M)/磺酸盐(R-OPO 3M)/磷酸盐(R-OPO 3M)、聚氧乙烯脂肪醇醚、聚氧乙烯脂肪酸酯、聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆)。稳定剂优选依地酸二钠。
此外，还可以添加其他药学可接受的添加剂，如增溶剂、乳化剂、非水性赋形剂以及防腐剂。制备这些组合物的常用技术及方法广为人知，可参考《现代药物制剂丛书》何仲贵等主编，2008年，人民卫生出版社。
实施例3动物药效对比试验
8周龄左右的C57BL/6雌鼠(购自北京维通利华公司)分笼适应性喂养1周后，在试验的Day-1(给药前一天)，采用腹腔注射阿佛丁溶液麻醉；电动剃刀剃去小鼠背部毛发后，再涂抹脱毛膏脱毛；所有小鼠脱毛后，按脱毛后背部皮肤情况随机分组，每组5只小鼠。Day 1(给药当天)开始，造模组皮下注射造模剂(1mg睾酮，混悬于10％聚山梨酯80溶液)，每七天造模五天，对照组注射相应溶剂对照。给药组按计划每天涂抹给予小鼠0.1mL相应药物。
小鼠每周称量2次体重，并在Day-1、Day 12、Day 20天拍照记录小鼠背部毛发生长状态。
动物分组情况如下表3所示：
表3
Figure PCTCN2022097219-appb-000001
Figure PCTCN2022097219-appb-000002
注：空白对照组、模型组与对照组所用溶剂同供试品组溶剂
采用SPSS13.0统计软件进行方差分析，统计平均值±标准差(Mean±SD)，两组间比较采用独立样本t检验，p<0.05具有统计学差异。
根据毛发生长评分指标：0分，no growth；1分，<20％growth；2分，20–40％growth；3分，40–60％growth；4分，60–80％growth；5分，80–100％growth进行评分。
各组小鼠背部毛发生长情况如图1及表4所示；
表4
Figure PCTCN2022097219-appb-000003
注：#，p<0.05vs空白对照组；###，p<0.001vs空白对照组；*，p<0.05vs模型组；***，p<0.001vs模型组。
结果表明：连续给予雄激素性脱发模型小鼠爱普列特外用制剂后，能有效促进小鼠毛发生长，且药效优于对照药物非那雄胺，与对照药物米诺地尔药效相当。在试验过程中未见小鼠出现任何不良反应，说明药物安全性良好。

Claims (7)

  1. 一种用于防治雄激素性脱发的爱普列特外用制剂，其特征在于，包括活性组分和制剂用辅料；所述活性成分为爱普列特，所述制剂用辅料包括助溶剂、透皮吸收促进剂、增稠剂、稳定剂。
  2. 根据权利要求1所述的用于防治雄激素性脱发的爱普列特外用制剂，其特征在于，爱普列特外用制剂中活性成分爱普列特的浓度为0.1～10w/v％。
  3. 根据权利要求1所述的用于防治雄激素性脱发的爱普列特外用制剂，其特征在于，所述助溶剂为乙醇、丙二醇、甘油和水。
  4. 根据权利要求3所述的用于防治雄激素性脱发的爱普列特外用制剂，其特征在于，乙醇、丙二醇、甘油和水的体积比为：1-80:1-80:1-80:100。
  5. 根据权利要求1所述的用于防治雄激素性脱发的爱普列特外用制剂，其特征在于，爱普列特外用制剂中，透皮吸收促进剂的浓度为0.05～20w/v％；增稠剂的浓度为0.05～10w/v％；稳定剂的浓度为0.05～10w/v％。
  6. 根据权利要求1所述的用于防治雄激素性脱发的爱普列特外用制剂，其特征在于，制剂剂型为溶液剂、喷雾剂、凝胶剂、搽剂、洗剂中任意一种。
  7. 权利要求1-6任一项所述的爱普列特外用制剂在防治雄激素性脱发中的应用。
PCT/CN2022/097219 2022-04-20 2022-06-24 一种用于防治雄激素性脱发的爱普列特外用制剂 WO2023201859A1 (zh)

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