WO2020019927A1 - 壬二酸凝胶剂及其制备方法和应用 - Google Patents

壬二酸凝胶剂及其制备方法和应用 Download PDF

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WO2020019927A1
WO2020019927A1 PCT/CN2019/093004 CN2019093004W WO2020019927A1 WO 2020019927 A1 WO2020019927 A1 WO 2020019927A1 CN 2019093004 W CN2019093004 W CN 2019093004W WO 2020019927 A1 WO2020019927 A1 WO 2020019927A1
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azelaic acid
acne
propanediol
solution
water
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PCT/CN2019/093004
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English (en)
French (fr)
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王广基
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成都卓阳生物科技有限公司
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Priority to US16/960,025 priority Critical patent/US11026907B2/en
Priority to EP19840552.4A priority patent/EP3708152B1/en
Publication of WO2020019927A1 publication Critical patent/WO2020019927A1/zh

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61K47/30—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the invention relates to azelaic acid gel, a preparation method and application thereof, and belongs to the technical field of skin medicine.
  • Acne is a chronic inflammatory skin disease of the sebaceous gland units of the hair follicles. It occurs mainly in adolescents and has a great psychological and social impact on adolescents. However, it can often be reduced or healed naturally after adolescence. Clinical manifestations are characterized by polymorphous skin lesions such as acne, pimples, pustules, and nodules.
  • Azelaic acid also known as azalea acid, has white to slightly yellow monoclinic prisms, needle-like crystals, or powder. It has an antibacterial effect, which can directly inhibit and kill bacteria on the skin surface and in the hair follicles; competitively inhibit the enzymatic process of producing dihydrotestosterone, reduce excessive skin fat caused by dihydrotestosterone factors; inhibit the production of reactive oxygen free radicals and Effect, conducive to anti-inflammatory.
  • azelaic acid products are often made into plasters.
  • an invention patent with an application number of 201610786026.2 discloses an acne cream and a method for preparing the same.
  • Second raw material and cream base the second raw material is composed of 10% azelaic acid, 0.1% adapalene, 1% clindamycin, 1% salicylic acid, 1.5% oleazone and 0.2% Nepal Gold methyl ester.
  • the invention patent with the application number 201210230433.7 discloses an ointment for treating acne. It consists of 3% oxymatrine, 1% vitamin E, 2% azelaic acid, menthol 0.5%, and 2901 5% by mass percentage. Boric acid 3%, Azone 2% and cream base 83.5% by mass are mixed to make a paste.
  • the technical problem solved by the present invention is to provide a new formulation of azelaic acid, that is, azelaic acid gel. Compared with creams, this gel has no oily ingredients added to prevent or treat acne. The effect is good.
  • the azelaic acid gel agent of the present invention is composed of the following weight percentage components: 10-20% azelaic acid, 0.5-2% salicylic acid, 1-3% ZEN, 60-74% 1,3-propanediol, The rest is water.
  • the azelaic acid gel is composed of the following weight percentages: 12-18% azelaic acid, 0.8-1.5% salicylic acid, 1.5-2.5% ZEN, and 1,3-propanediol 65-72 %, The rest is water. .
  • the azelaic acid gel is composed of the following weight percentage components: 15% azelaic acid, 2% ZEN, 1% salicylic acid, 70% 1,3-propanediol, and 12% water.
  • the water is deionized water.
  • the second technical problem solved by the present invention is to provide a method for preparing the azelaic acid gel agent according to the present invention.
  • the method for preparing azelaic acid gel according to the present invention comprises the following steps:
  • Step a, step b, or step c may be performed first, or the three steps may be performed simultaneously. Just mix solution A, solution B and solution C at the end.
  • the invention also provides the application of the azelaic acid gel agent of the invention in the preparation of a medicine for preventing or treating acne.
  • the azelaic acid gel agent of the present invention can be used in the treatment or prevention of acne, improve the cure rate of acne patients, reduce the facial skin damage caused by acne, and reduce the physical and psychological pain caused by acne. At the same time reduce the cost of patient treatment and reduce medical expenses.
  • the present invention has the following beneficial effects:
  • the invention uses specific raw materials to prepare azelaic acid into a gel.
  • the product is transparent without precipitation, can penetrate the skin better, and can be used in the treatment or prevention of acne to improve the cure rate of acne patients.
  • the azelaic acid gel of the present invention is an oil-free formula (relative cream). After using oily skin, it will not increase the burden on the skin and block pores, so there is no hidden danger of acne. For already acne-prone skin, due to the strong penetration of azelaic acid itself, gel-like azelaic acid is better than cream It is simpler and easier to penetrate, and does not require more oil for solubilization and penetration, so as to avoid the corresponding side effects caused by excessive introduction of oily substances; in the late stage of anti-acne, the need for unblocked hair follicle tubes is conducive to the discharge of oil and other metabolites Azelaic acid is anti-inflammatory and sterilized, smooth the hair follicle tube, smoothly solve the problem of discharge, and reduce the possibility of recurrence of acne.
  • the azelaic acid gel agent of the present invention has simple components, can be antibacterial without adding a preservative, and has a simple preparation method and low cost.
  • the azelaic acid gel agent of the present invention is composed of the following weight percentage components: 10-20% azelaic acid, 0.5-2% salicylic acid, 1-3% ZEN, 60-74% 1,3-propanediol, The rest is water.
  • ZEN is a polyacrylate cross-linked polymer-6, which is produced by the French company SABIC under the trade name SepiMAX ZEN.
  • Zinc is an associative polymer with excellent resistance to electrolysis. It can resist the damage to the formula caused by the electrolyte to the greatest extent. At the same time, it also has a good suspension stability ability. It can produce a transparent hydrogel product with a moist and elegant touch and a velvet texture.
  • ZEN can azelaic acid gel be successfully formulated. If the amount of ZEN added is too low, the product obtained will be thin and fluid, and cannot be prepared into a gel. If the amount of ZEN added is too large, the product will be too dry and affect the use.
  • azelaic acid has no effect on the structure of ZEN.
  • water is used as a solvent
  • the transparency of the product is too low, and after returning to room temperature, azelaic acid crystals will precipitate, and absolute ethanol or 1, 3-Propanediol can change the phenomenon of azelaic acid precipitation, but absolute ethanol cannot change the transparency of the product, and the use of 1,3-propanediol can not only solve the problem of azelaic acid precipitation, but also change the transparency of the product and obtain alcohol-free Scented clear gel. Therefore, in the present invention, a certain amount of 1,3-propanediol and water are mixed as a solvent, and the obtained product is a transparent gel without crystal precipitation, a moderate consistency, no fluidity, and no alcohol taste.
  • Salicylic acid can soften and exfoliate keratin, reduce pore blockage, and has better effects on adolescent acne and acne vulgaris.
  • the amount of salicylic acid in the present invention is preferably 0.5 to 2%. Mixing a specific amount of salicylic acid with azelaic acid has a synergistic effect and can improve the treatment of acne.
  • the azelaic acid gel is composed of the following weight percentages: 12-18% azelaic acid, 0.8-1.5% salicylic acid, 1.5-2.5% ZEN, and 1,3-propanediol 65-72 %, The rest is water.
  • the azelaic acid gel is composed of the following weight percentage components: 15% azelaic acid, 2% ZEN, 1% salicylic acid, 70% 1,3-propanediol, and 12% water.
  • the water is deionized water.
  • the second technical problem solved by the present invention is to provide a method for preparing the azelaic acid gel agent according to the present invention.
  • the method for preparing azelaic acid gel according to the present invention comprises the following steps:
  • Step a, step b, or step c may be performed first, or the three steps may be performed simultaneously. Just mix solution A, solution B and solution C at the end.
  • the invention also provides the application of the azelaic acid gel agent of the invention in the preparation of a medicine for preventing or treating acne.
  • the azelaic acid gel agent of the present invention can be used in the treatment or prevention of acne, improve the cure rate of acne patients, reduce the facial skin damage caused by acne, and reduce the physical and psychological pain caused by acne. At the same time reduce the cost of patient treatment and reduce medical expenses.
  • ZEN purchased from Sebic, France
  • Azelaic acid purchased from Shanghai Kunen Technology Development Co., Ltd .;
  • Salicylic acid purchased from Shandong Xinhua Pharmaceutical Co., Ltd .;
  • 1,3-propanediol source of corn, purchased from DuPont, USA;
  • An azelaic acid gel was prepared according to the method described in Example 1, wherein the total amount of each raw material is shown in Table 3.
  • azelaic acid gel is designed as: CP-940 (Shanghai Yanglong Industrial Co., Ltd.), azelaic acid (Shanghai Kunen Technology Development Co., Ltd.), hydrogen Sodium oxide (analytical pure AR, Chengdu Kelong Chemical Reagent Factory), water (self-produced deionized water).
  • CP-940 is a high-molecular polymer whose aqueous solution is acidic and slowly swells in water. The curled molecules will expand due to the electric repulsive force to achieve thickening effect.
  • Sodium hydroxide and triethanolamine are Commonly used neutralizers, taking into account the acidic properties of azelaic acid, increase the proportion of CP-940 on the basis of past gel formulations. Based on the amount of CP-940 added at 0.5%, 1.0%, 1.5%, and 2.0%, 15% azelaic acid was added. The results are shown in Table 4.
  • azelaic acid is slightly soluble in cold water, it has a great influence on the structure of CP-940.
  • CP-940 is neutralized or not, azelaic acid will destroy the structure of CP-940. Therefore, it is not feasible to use CP-940 as the matrix component of the gel.
  • Examples 1 to 4 were used to perform acne with azelaic acid cream (the formula of azelaic acid cream: 15% azelaic acid, 1% salicylic acid, and 84% cream base) as a comparative example.
  • azelaic acid cream the formula of azelaic acid cream: 15% azelaic acid, 1% salicylic acid, and 84% cream base
  • the specific experimental methods are:
  • Acne classification criteria improved Pillsbury classification: grade 0: very small acne or small pimples (not included in the test criteria); grade I (mild): scattered pimples, acne, small pustules, lesions in 10 ⁇ 25; Grade II (moderate): piles of pimples, acne, with small pustules, lesions in 25 to 50; Grade III (severe): pimple, acne, with small pustules, number of lesions is greater 50; nodules less than 5; grade IV (very severe): severe piles of pimples, acne, small pustules, nodules, cysts and scars.
  • Exclusion criteria those who have used topical acne medication within 2 weeks; those who have used antibiotics or other acne medication systemically within 4 weeks; those with open wounds or erosions on the acne affected area; acceptance of acne due to other diseases Pharmacotherapeutic women; pregnant or lactating women; people with other skin diseases that may affect the efficacy of the observation, such as psoriasis, lupus erythematosus, hormone-dependent dermatitis, etc .; people who are allergic to azelaic acid.
  • Administration method apply a thin layer of medicine to the facial acne area in the morning and evening, and avoid applying it to the eyes and mucous membranes. No other topical drugs and antibiotics were used during the trial. The course of treatment was 6 weeks, and the patients were revisited every 2 weeks.
  • Observation indicators Observe and record the efficacy indicators and adverse reactions during the initial diagnosis and the follow-up visits at 2, 4, and 6 weeks after treatment.
  • Efficacy indicators include inflammatory damage; inflammatory pimples and pustules; non-inflammatory damage: whiteheads and blackheads.
  • the main efficacy parameter is the reduction in the number of total inflammatory lesions (the sum of pimples and pustules), and the total efficacy evaluation is performed at week 6.
  • Adverse reactions Patients applying the product of the present invention mainly have burning pain, itching, erythema, edema, dryness, desquamation, and all of them are mild. Most of them have not been treated and do not affect treatment.

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Abstract

一种壬二酸凝胶剂及其制备方法和应用。该壬二酸凝胶剂由以下重量百分比的组分组成：壬二酸10-20%，水杨酸0.5-2%，聚丙烯酸酯交联聚合物-6 1-3%，1,3-丙二醇60-74%，其余为水。该壬二酸凝胶剂用于制备预防或治疗痤疮的药物。

Description

壬二酸凝胶剂及其制备方法和应用 技术领域
本发明涉及壬二酸凝胶剂及其制备方法和应用，属于皮肤药物技术领域。
背景技术
痤疮是毛囊皮脂腺单位的一种慢性炎症性皮肤病，主要好发于青少年，对青少年的心理和社交影响很大，但青春期后往往能自然减轻或痊愈。临床表现以好发于面部的粉刺、丘疹、脓疱、结节等多形性皮损为特点。
据我国皮肤病协会、我国青少年联合会联合调查显示：我国痤疮的发病率呈逐年上升趋势，80％以上的人不同程度的碰到过痤疮问题。病情较严峻痤疮发病率占青年人的1/3以上。其中中学生痤疮患者为2.94亿，大学生痤疮患者人数为1.33亿，25岁以上的上班族白领痤疮患者1.27亿多，三大部分人群总共达5.5亿多人。
据不完全统计，我国祛痘消费者正以每年400-600万人次增长，我国的祛痘市场正在经历前所未有的急速上升。以每位有意愿治疗的长痘者年均500的祛痘费用来算，祛痘市场的规模已经超过700亿。
对于痤疮的治疗，轻中度的痤疮患者一般选择不治疗和自行选用市面上的祛痘产品进行治疗，重度的痤疮患者会到医院和祛痘机构进行治疗。目前市面上的祛痘机构与产品并不能彻底祛痘，而且有副作用。医院祛痘不专一、美容院祛痘不专业，据我国卫生部权威统计，在我国痤疮完全治愈率只有32.95％。因此，急需一种能够提高痤疮治愈率的药物。
壬二酸，又名杜鹃花酸，外观为白色至微黄色单斜棱晶、针状结晶或粉末。具有抗菌的作用，可以直接抑制和杀灭皮肤表面和毛囊内的细菌；竞争性抑制产生二氢睾酮的酶过程，减少二氢睾酮因素诱发的皮肤油脂过多；抑制活性氧自由基的产生和作用，有利于抗炎。常用于痤疮、玫瑰痤疮，色素沉着紊乱等的治疗。对皮肤有较好的渗透性，可增加皮肤的吸收功能。但受高温易分解，因此，在使用时不宜高温加入。易溶于热水、酒精及部分多元醇，微溶于冷水、醚和苯。
目前，对于壬二酸产品，常做成膏剂，比如，申请号为201610786026.2的发明专利公开了一种痤疮膏及其制备方法，由早用膏剂和晚用膏剂组成，其中的晚用膏剂包括第二原料和乳膏基质，第二原料由以下物质组成：10％壬二酸，0.1％阿达帕林，1％ 克林霉素，1％水杨酸，1.5％油脂性氮酮和0.2％尼泊尔金甲酯。又如，申请号为201210230433.7的发明专利公开了一种治疗痤疮的药膏，按质量百分比由氧化苦参碱3％，维生素E 1％，壬二酸2％，薄荷脑0.5％，2901 5％，硼酸3％，氮酮2％与乳膏基质83.5％质量百分比混合制成膏剂。
以上专利均是将壬二酸做成膏剂，而目前市场中的壬二酸产品，也常做成膏剂，目的是为增加其溶解性和渗透性。通过油性的原料来溶解壬二酸，同时加入助渗透剂(一般为油性原料)促进它在皮肤中的渗透，这样就使得产品只能是含油的膏霜或者乳液。壬二酸的用量大则油性原料用量则多，渗透性强助渗剂量也越大，副作用也越大。因此，膏霜型的壬二酸相对油感厚重，透气性差，副作用较大，有效物含量不高。
发明内容
针对以上缺陷，本发明解决的技术问题是提供一种壬二酸的新剂型，即壬二酸凝胶剂，相对于膏霜来讲，该凝胶剂无油性成分添加，预防或治疗痤疮的效果好。
本发明壬二酸凝胶剂，由以下重量百分比的组分组成：壬二酸10～20％，水杨酸0.5～2％，ZEN 1～3％，1,3-丙二醇60～74％，其余为水。
优选的，所述壬二酸凝胶剂由以下重量百分比的组分组成：壬二酸12～18％，水杨酸0.8～1.5％，ZEN 1.5～2.5％，1,3-丙二醇65～72％，其余为水。。
作为优选方案，所述壬二酸凝胶剂由以下重量百分比的组分组成：壬二酸15％，ZEN 2％，水杨酸1％，1,3-丙二醇70％，水12％。
优选的，所述水为去离子水。
本发明解决的第二个技术问题是提供本发明所述壬二酸凝胶剂的制备方法。
本发明壬二酸凝胶剂的制备方法，包括如下步骤：
a、将ZEN均匀分散于1,3-丙二醇中后再与水混合均匀，得到溶液A；
b、将壬二酸均匀分散于1,3-丙二醇中，加热至65～80℃，得到溶液B；
c、将水杨酸均匀分散于1,3-丙二醇中，得到溶液C；
d、将溶液A、溶液B和溶液C混合，55～65℃搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。
其中，步骤a、步骤b和步骤c之间没有时间顺序，可以先进行步骤a，也可以先进行步骤b，也可以先进行步骤c，也可以这三个步骤同时进行。仅需在最后将溶液A、溶液B和溶液C混合搅匀即可。
本发明还提供本发明所述的壬二酸凝胶剂在制备预防或者治疗痤疮药物中的应用。
本发明的壬二酸凝胶剂，可用于痤疮的治疗或者预防中，提高痤疮患者的治愈率，减少患者由于痤疮带来面部皮肤损伤，从而减轻患者由于痤疮带来的生理和心理痛苦。同时降低患者治疗费用，减少医疗开支。
与现有技术相比，本发明具有如下有益效果：
本发明采用特定的原料，将壬二酸制备成凝胶剂，产品透明无沉淀，能较好的渗透皮肤，可用于痤疮的治疗或者预防中，提高痤疮患者的治愈率。
本发明的壬二酸凝胶剂，是无油分添加的配方(相对膏霜)。油性皮肤使用后，不会增加皮肤上的负担和堵塞毛孔，从而没有产生痘痘的隐患；对于已经长痘痘肌肤，由于壬二酸本身较强的渗透，凝胶状的壬二酸比膏状的渗透更简单容易，不需要更多油脂进行助溶和助渗，从而避免因油性物质过度引入而产生相应的副作用；在抗痘后期，需要毛囊管畅通有利于油脂及其他代谢物的排出，壬二酸消炎灭菌，畅通毛囊管，顺利解决排出问题，减少痘痘的复发可能。
本发明的壬二酸凝胶剂，其组分简单，无需加入防腐剂依然能够抗菌，且制备方法简单，成本低廉。
具体实施方式
本发明壬二酸凝胶剂，由以下重量百分比的组分组成：壬二酸10～20％，水杨酸0.5～2％，ZEN 1～3％，1,3-丙二醇60～74％，其余为水。
其中，ZEN为聚丙烯酸酯交联聚合物-6，为法国赛比克公司生产，商品名为SepiMAX ZEN。壬二酸电解出来电解质，能够破坏卡波姆的结构，而ZEN是一种具有优良耐电解能力的缔合聚合物。可以最大程度的抵御电解质给配方带来的破坏，同时，还具有很好的悬浮稳定能力，可以生产具有滋润优雅触感，赋予天鹅绒质感的透明水凝胶产品。通过研究发现，只有采用ZEN，才能成功配制得到壬二酸凝胶剂。ZEN加入量过低的话，得到的产品较稀，有流动性，无法制备成凝胶，而加入量过多的话，产品太干影响使用。
发明人研究发现，壬二酸对ZEN的结构没有影响，但是，如果只采用水作为溶剂，产品透明度太低，并且恢复室温后，壬二酸晶体会析出，而采用了无水乙醇或者1,3-丙二醇能够改变壬二酸析出的现象，但是，无水乙醇无法改变产品的透明度，而采用1,3-丙二醇不仅能解决壬二酸析出的问题，也能改变产品的透明度，得到无酒精味的透 明凝胶。因此，本发明采用一定量的1,3-丙二醇和水混合作为溶剂，得到的产品为透明凝胶，无晶体析出，稠度适中，无流动性，无酒精味。
水杨酸能够使角质软化脱落，减少毛孔阻塞，对于青春期粉刺、寻常性痤疮有较好效果，根据研究，本发明水杨酸的用量优选为0.5～2％。特定量的水杨酸与壬二酸混合，具有协同增效作用，能够提高痤疮的治疗效果。
优选的，所述壬二酸凝胶剂由以下重量百分比的组分组成：壬二酸12～18％，水杨酸0.8～1.5％，ZEN 1.5～2.5％，1,3-丙二醇65～72％，其余为水。
作为优选方案，所述壬二酸凝胶剂由以下重量百分比的组分组成：壬二酸15％，ZEN 2％，水杨酸1％，1,3-丙二醇70％，水12％。
优选的，所述水为去离子水。
本发明解决的第二个技术问题是提供本发明所述壬二酸凝胶剂的制备方法。
本发明壬二酸凝胶剂的制备方法，包括如下步骤：
a、将ZEN均匀分散于1,3-丙二醇中后再与水混合均匀，得到溶液A；
b、将壬二酸均匀分散于1,3-丙二醇中，加热至65～80℃，得到溶液B；
c、将水杨酸均匀分散于1,3-丙二醇中，得到溶液C；
d、将溶液A、溶液B和溶液C混合，55～65℃搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。
其中，步骤a、步骤b和步骤c之间没有时间顺序，可以先进行步骤a，也可以先进行步骤b，也可以先进行步骤c，也可以这三个步骤同时进行。仅需在最后将溶液A、溶液B和溶液C混合搅匀即可。
本发明还提供本发明所述的壬二酸凝胶剂在制备预防或者治疗痤疮药物中的应用。
本发明的壬二酸凝胶剂，可用于痤疮的治疗或者预防中，提高痤疮患者的治愈率，减少患者由于痤疮带来面部皮肤损伤，从而减轻患者由于痤疮带来的生理和心理痛苦。同时降低患者治疗费用，减少医疗开支。
下面结合实施例对本发明的具体实施方式做进一步的描述，并不因此将本发明限制在所述的实施例范围之中。实施例中所用原料为：
ZEN：购自法国赛比克；
壬二酸：购自上海凛恩科技发展有限公司；
水杨酸：购自山东新华制药股份有限公司；
1,3-丙二醇：玉米来源，购自美国杜邦公司；
水：自产去离子水。
实施例1
按如下步骤制备得到壬二酸凝胶剂：
a、将ZEN均匀分散于1,3-丙二醇中后再与水混合均匀，得到溶液A；
b、将壬二酸均匀分散于1,3-丙二醇中，加热至75℃，搅拌至透明，得到溶液B；
c、将水杨酸均匀分散于1,3-丙二醇中，得到溶液C；
d、将溶液A、溶液B和溶液C混合，60℃搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。
其中，各原料的配方见表1。
表1
Figure PCTCN2019093004-appb-000001
在该配方基础上，人为引入一定量的细菌(18000cfu/g或霉菌8700cfu/g液体)，再取定量的该样品测定其抑菌效果，结果见表2。
表2
Figure PCTCN2019093004-appb-000002
Figure PCTCN2019093004-appb-000003
从表2可以看出，虽然体系中没有加入防腐剂，但依然能够抗菌。
实施例2～4
按照实施例1所述的方法制备得到壬二酸凝胶剂，其中，各原料的总用量见表3。
表3
Figure PCTCN2019093004-appb-000004
测定上述产品的抗菌性能，发现实施例2～4的产品也具有抗菌性能。
对比例1
借鉴以往开发啫喱类产品的实际配方经验，将壬二酸凝胶的基质配方成分设计为：CP-940(上海阳珑实业有限公司)、壬二酸(上海凛恩科技发展有限公司)、氢氧化钠(分析纯AR，成都市科龙化工试剂厂)、水(自产去离子水)。
CP-940是一种高分子聚合物，其水溶液呈酸性，在水中慢慢溶胀，其卷曲的分子会因电斥力而张开，从而达到增稠的作用，而氢氧化钠和三乙醇胺则是常用的中和剂，考虑到壬二酸的酸性特性，将CP-940的比例在以往做凝胶类配方的基础上加大。我们将CP-940的量分别以0.5％、1.0％、1.5％、2.0％的添加量作为基础，加入15％的壬二酸，其结果如表4。
表4
Figure PCTCN2019093004-appb-000005
Figure PCTCN2019093004-appb-000006
可见，壬二酸虽然微溶于冷水，但对于CP-940的结构影响很大。
考虑到壬二酸的电解质性质，我们决定不用碱中和CP-940，再次配置基础凝胶，结果见表5。
表5
Figure PCTCN2019093004-appb-000007
可见，CP-940无论中和或者不中和，壬二酸都会破坏CP-940的结构，因此，用CP-940来作为凝胶的基质组分是行不通的。
实施例5 痤疮治疗试验
采用实施例1～4的产品，同时以壬二酸膏霜(壬二酸膏霜的配方为：壬二酸15％，水杨酸1％，乳膏基质84％)作为对比例，进行痤疮治疗疗效测定，其具体的实验方法为：
选择14～40岁的寻常性痤疮患者，性别不限，皮损根据Pillsbury分级分为1～4级的患者进行试验。
痤疮分类标准(改良pillsbury分级法)：0级：非常小的粉刺或小丘疹(不纳入受试标准)；Ⅰ级(轻度)：散在性丘疹、粉刺，有小脓疱，病损在10～25个；Ⅱ级(中度)：成堆的丘疹、粉刺，有小脓疱，病损在25～50个；Ⅲ级(重度)：丘疹、粉刺，有小脓 疱，病损数大于50个；结节小于5个；Ⅳ级(极重度)：严重成堆的丘疹、粉刺，有小脓疱、结节、囊肿和疤痕。
排除病例标准：2周内局部使用过治疗痤疮的药物者；4周内系统使用过抗生素或其他治疗痤疮的药物者；痤疮患处有开放性创口或糜烂面者；因其他疾病接受对痤疮有影响的药物治疗者；妊娠期或哺乳期妇女；患有其他可能影响观察疗效的皮肤疾病者，如银屑病、红斑狼疮、激素依赖性皮炎等；已知对壬二酸过敏者。
给药方法：早晚各1次用一薄层的药涂在面部痤疮区域，避免涂在眼睛和粘膜部位。试验期间不使用其他外用药及抗生素。疗程6周，每2周复诊1次。
观察指标：初诊及治疗后2、4、6周复诊时观察、记录疗效指标及不良反应。疗效指标包括炎性损害；炎性丘疹、脓疱；非炎性损害:白头及黑头粉刺。观察指标：炎性损害计数：治疗前对面部丘疹、脓疱、结节和囊肿单独计数，在第2、第4和第6周复诊时再分别计数；非炎性损害计数：治疗前对面部白头和黑头粉刺单独计数，在第2、第4和第6周复诊时再分别计数；
实验室检查：在治疗前后分别检查血、尿常规，其中12例作肝功能(TI，ALT)、肾功能(BUN、Cr)检查。
疗效标准：主要的疗效参数是总炎性损害数的减少(丘疹和脓疱的总和)，第6周时进行总疗效评价。
标准如下：
治愈：损害减少≥90％；
显效：损害减少60％～89％；
好转：损害减少20％～59％；
无效：病情无变化，或损害减少结果。
各个产品均选用30例患者，观察其疗效和不良反应，结果见表6。
表6
Figure PCTCN2019093004-appb-000008
Figure PCTCN2019093004-appb-000009
不良反应：应用本发明产品的患者，不良反应主要为灼痛、瘙痒、红斑、水肿、干燥、脱屑，程度均较轻，大多数未作处理，不影响治疗。

Claims (6)

  1. 壬二酸凝胶剂，其特征在于：由以下重量百分比的组分组成：壬二酸10～20％，水杨酸0.5～2％，ZEN 1～3％，1,3-丙二醇60～74％，其余为水。
  2. 根据权利要求1所述的壬二酸凝胶剂，其特征在于：由以下重量百分比的组分组成：壬二酸12～18％，水杨酸0.8～1.5％，ZEN 1.5～2.5％，1,3-丙二醇65～72％，其余为水。
  3. 根据权利要求1所述的壬二酸凝胶剂，其特征在于：由以下重量百分比的组分组成：壬二酸15％，ZEN 2％，水杨酸1％，1,3-丙二醇70％，水12％。
  4. 根据权利要求1～3任一项所述的壬二酸凝胶剂，其特征在于：所述水为去离子水。
  5. 权利要求1～4任一项所述的壬二酸凝胶剂的制备方法，其特征在于，包括如下步骤：
    a、将ZEN均匀分散于1,3-丙二醇中后再与水混合均匀，得到溶液A；
    b、将壬二酸均匀分散于1,3-丙二醇中，加热至65～80℃，得到溶液B；
    c、将水杨酸均匀分散于1,3-丙二醇中，得到溶液C；
    d、将溶液A、溶液B和溶液C混合，55～65℃搅拌混匀，然后冷却至室温，得到壬二酸凝胶剂。
  6. 权利要求1～4任一项所述的壬二酸凝胶剂在制备预防或者治疗痤疮药物中的应用。
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