CN1286529C - Skin targeting medicinal composition and its preparation and use - Google Patents

Skin targeting medicinal composition and its preparation and use Download PDF

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CN1286529C
CN1286529C CNB2004100132825A CN200410013282A CN1286529C CN 1286529 C CN1286529 C CN 1286529C CN B2004100132825 A CNB2004100132825 A CN B2004100132825A CN 200410013282 A CN200410013282 A CN 200410013282A CN 1286529 C CN1286529 C CN 1286529C
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skin
microemulsion
pharmaceutical composition
oil
targeting
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CN1583175A (en
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陈华兵
杨祥良
徐辉碧
杨亚江
刘卫
周小顺
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华中科技大学
武汉华中科大纳米药业有限公司
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Abstract

本发明提供了一种具有皮肤靶向性的药物组合物,包括0.5-10wt%的油、10-80wt%的表面活性剂、3-60wt%助表面活性剂、0-8wt%的渗透促进剂和0.05-8wt%的皮肤局部用活性药物鬼臼毒素或咪喹莫特及余量的水;组合物中微乳粒径小于150nm。 The present invention provides a pharmaceutical composition having a skin targeting, including 0.5-10wt% of oil, 10-80wt% surfactant, 3-60wt% co-surfactant, 0-8 wt% of a permeation enhancer and 0.05-8wt% of the topical skin active agent podophyllotoxin or imiquimod and the balance water; microemulsion compositions particle size less than 150nm. 其制备方法为:将油、表面活性剂、助表面活性剂、皮肤局部用活性药物、渗透促进剂、水混合制得微乳,即为微乳药物组合物。 The preparation process: the oil, surfactant, cosurfactant, topical skin active agent, penetration enhancer, prepared by mixing water microemulsion, microemulsion is the pharmaceutical composition. 将凝胶基质加入上述制得的微乳中,即得微乳凝胶药物组合物。 The gel matrix was added to the obtained microemulsion, microemulsion gel to obtain a pharmaceutical composition. 本发明提高了活性药物在表皮的吸收,增强药效,显著降低药物的全身性吸收带来的毒副作用,具有明显的皮肤靶向性。 The present invention improves the absorption of the active drug in the skin, enhance the efficacy, toxicity significantly lower systemic absorption of the drug caused, with obvious skin targeting. 可以用来治疗尖锐湿疣、皮肤的病毒感染、有效地治疗湿疹、皮肤真菌感染等。 Can be used to treat genital warts, viral infections of the skin, effectively treat eczema, fungal skin infections. 本发明刺激性小,可明显降低活性药物所致的局部轻度至中度的刺激性反应。 Irritation of the present invention, can significantly reduce the activity of drug-induced mild local reaction to moderate irritant.

Description

具有皮肤靶向性的药物组合物及其制备方法和用途 And pharmaceutical compositions having a skin preparation and use of targeting

发明领域本发明涉及到一种具有皮肤靶向性的微乳、微乳凝胶药物组合物及其制备方法和用途。 Field of the Invention The present invention relates to a microemulsion, microemulsion gel pharmaceutical composition and its preparation method and use thereof having a skin of targeting.

发明背景微乳是一种由油、表面活性剂、助表面活性剂和亲水相组成的体系,具有外观透明、热力学稳定、各向同性、分散相液滴平均粒径小于150nm等特性。 BACKGROUND OF THE INVENTION Microemulsions are systems consisting of oil, surfactant, co-surfactant and a hydrophilic phase having the appearance of a transparent, thermodynamically stable, isotropic, less than 150nm average droplet size of the dispersed phase characteristics. 微乳作为一种新型的给药体系具有稳定性好、溶解能力强、黏度低、制备简单、易工业化、等优点。 Microemulsion as a novel delivery system has good stability, solubility, low viscosity, prepared simple and easy to industrialize, and so on.

鬼臼毒素、咪喹莫特等皮肤局部用活性药物对皮肤具有明显的刺激性如局部搔痒、红斑、灼热感、刺激感、触痛、溃疡、糜烂及疼痛,当药物经皮吸收进入血液后会产生严重的全身性毒副作用,限制了其在临床中应用。 Podophyllotoxin, imiquimod and other topical skin active agent having a significant local irritation, such as itching, erythema, burning sensation, irritation, tenderness, ulceration, pain, and erosion, after percutaneous drug will be absorbed into the blood to the skin serious systemic side effects, limiting its clinical application.

本发明惊奇地发现,将鬼臼毒素、咪喹莫特等皮肤局部用活性药物制成微乳后,具有明显的皮肤靶向性,即可增加其在皮肤中的吸收,降低药物的全身性吸收,另外,还显著降低了药物对皮肤的刺激性。 The present inventors have surprisingly found that podophyllotoxin, imiquimod and other skin active agent is made after topical microemulsion, a clear skin targeting, to increase the absorption in the skin, reducing the systemic absorption of the drug in addition, the drug also significantly reduced the irritation to the skin. 另外,还意外地发现,将凝胶基质如卡波姆、角叉菜胶、黄原胶等加入到微乳中,可进一步制成微乳凝胶,在保持微乳上述优点的基础上,使微乳的黏度增加,便于使用。 Furthermore, also surprisingly been found that the gel matrix such as carbomer, carrageenan, xanthan gum and the like is added to the microemulsion, microemulsion gel can further be made, while maintaining the advantages of the above-described microemulsion, and the viscosity of the microemulsion increases ease of use. 另外,可将微乳或凝胶制成凝胶剂、贴剂等剂型。 In addition, microemulsion or gel can be prepared gel, paste or the like dosage forms.

发明内容 SUMMARY

本发明创造性地提供了一种具有皮肤靶向性的药物组合物及其制备方法和用途,将皮肤局部用活性药物包裹于微乳、微乳凝胶中,可降低对药物皮肤的刺激性,同时提高药物在皮肤中的滞留量,降低药物进入体内的药量,减小全身吸收带来的毒副作用,从而产生皮肤靶向性。 The present invention creatively provides a pharmaceutical composition and its preparation method and use of targeting skin having the skin topically active pharmaceutical wrapped in a microemulsion, microemulsion gels, the drug can reduce the irritation of the skin, while increasing the amount of drug retention in the skin, reduce the amount of medications into the body, reducing the side effects caused by systemic absorption to produce skin targeting.

本发明提供的技术方案是:具有皮肤靶向性的药物组合物,包括:0.5-10wt%的油、10-80wt%的表面活性剂、3-60wt%助表面活性剂、0-8wt%的渗透促进剂和0.05-8wt%的皮肤局部用活性药物及余量的水;皮肤局部用活性药物为鬼臼毒素或咪喹莫特;具有皮肤靶向性的药物组合物为微乳或微乳凝胶药物组合物,微乳或微乳凝胶药物组合物中微乳粒径小于150nm。 Aspect of the present invention is to provide: a drug having a skin targeting composition, comprising: 0.5 to 10 wt% of oil, 10-80wt% surfactant, 3-60wt% co-surfactant, 0-8 wt% of penetration enhancing agent and 0.05-8wt% of the topical skin active agent and the balance water; topical skin active agent is podophyllotoxin or imiquimod; pharmaceutical composition having a skin targeting of a microemulsion or microemulsion the pharmaceutical composition of gel, microemulsion or microemulsion gel pharmaceutical composition microemulsion particle size less than 150nm.

上述药物组合物还可含有0-5wt%的凝胶基质。 The above pharmaceutical composition may further contain 0-5 wt% of the gel matrix.

上述油优选的是液态的C8-C16脂肪酸及其酯(如脂肪酸甘油酯、脂肪酸异丙酯等)、植物油及其甘油酯;更优选的是十四酸异丙酯、十六酸异丙酯、椰油酸辛酯、三辛酸癸酸甘油酯(如Myritol 318、德国Huls AG公司产品Miglyol 812)、玉米油、大豆油、花生油、橄榄油、油酸、亚油酸、油酸乙酯、亚油酸乙酯、三油酸甘油酯,以及玉米油、花生油或大豆油的甘油酯,酯化的玉米油与聚乙二醇反应得到的酯基转移的乙氧基植物油如Labrafil M 2125CS、Labrafil M 1944CS(Cattefossé公司产品、法国)等。 The oil liquid is preferably C8-C16 fatty acids and esters (e.g., fatty acid glycerides, fatty acid isopropyl ester, etc.), vegetable oils and their esters; more preferred are isopropyl myristate, isopropyl palmitic acid , octyl cocoate, glyceryl tricaprylate caprate (such as Myritol 318, Huls AG, Germany products Miglyol 812), corn oil, soybean oil, peanut oil, olive oil, oleic acid, linoleic acid, ethyl oleate, ethylene ethyl oleate, glyceryl trioleate, and corn oil, peanut oil or soybean oil glycerides, esterified corn oil with polyethylene glycol obtained by reaction of transesterification ethoxylated vegetable oils such as Labrafil M 2125CS, Labrafil M 1944CS (Cattefossé company's products, France) and so on.

首选的是Miglyol 812、十四酸异丙酯、十六酸异丙酯、玉米油甘油酯、油酸、油酸乙酯、Labrafil M 2125 CS。 Preferred is Miglyol 812, isopropyl myristate, isopropyl palmitic acid, corn oil glycerides, oleic acid, ethyl oleate, Labrafil M 2125 CS.

用于本发明的表面活性剂优选的是:(1)天然的或氢化的蓖麻油与环氧乙烷的反应产,包括聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油以及聚氧乙烯蓖麻油。 The surfactant is preferably used in the present invention are: (1) natural or hydrogenated castor oil with ethylene oxide reaction products, include polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor polyoxyethylene castor oil and sesame oil. 首先的是聚氧乙烯(40)氢化蓖麻油。 First of polyoxyethylene (40) hydrogenated castor oil.

(2)聚氧乙烯脱水山梨醇酯,如已知类型的商品名为吐温(Tween)的产品如:吐温20、吐温21、吐温40、吐温41、吐温60、吐温61、吐温65、吐温80、吐温81、吐温85等。 (2) polyoxyethylene sorbitan esters, such as the type known under the trade name Tween (Tween) products such as: Tween 20, Tween 21, Tween 40, Tween 41, Tween 60, Tween 61, Tween 65, Tween 80, Tween 81, Tween 85 and the like. 首选的是吐温80。 Tween 80 is preferred.

(3)聚氧乙烯脂肪酸酯。 (3) polyoxyethylene fatty acid esters. 此类产品中的聚氧乙烯或聚乙二醇的分子量为400-6000,亲水-亲油平衡值为10-25。 Polyoxyethylene such products or polyethylene glycol molecular weight of 400-6000, a hydrophilic - lipophilic balance value of 10-25. 优选的是硬脂酸聚氧乙烯(8)酯、硬脂酸聚氧乙烯(12)酯、硬脂酸聚氧乙烯(24)酯、硬脂酸聚氧乙烯(40)酯、硬脂酸聚氧乙烯(50)酯和硬脂酸聚氧乙烯(100)酯、硬脂酸聚氧乙烯(110)酯。 Preferred is stearic acid polyoxyethylene (8) stearate, polyoxyethylene (12) stearate, polyoxyethylene (24) stearate, polyoxyethylene (40) stearate polyoxyethylene (50) stearate, polyoxyethylene esters and (100) stearate, polyoxyethylene (110) ester. 此类产品中首选的是在市场上以Myrj 53命名的硬脂酸聚氧乙烯脂肪酸酯。 Preferred such products are marketed under the name of Myrj 53 stearate, polyoxyethylene fatty acid esters.

(4)聚氧乙烯脂肪醇醚。 (4) Polyoxyethylene fatty alcohol ethers. 该类产品是由醇类以摩尔比为1∶2-30与环氧乙烷进行加成反应制得。 Alcohols such products is carried out at a molar ratio of 1:2-30 addition reaction with ethylene oxide, too. 优选的是月桂醇聚氧乙烯(23)醚、硬脂醇聚氧乙烯(10)醚、鲸蜡醇聚氧乙烯(10)醚、硬脂醇聚氧乙烯(20)醚、油醇聚氧乙烯(10)醚等。 Preferred are lauryl alcohol polyoxyethylene (23) ether, stearyl polyoxyethylene (10) ether, cetyl alcohol, polyoxyethylene (10) ether, stearyl polyoxyethylene (20) ether, polyoxyethylene oleyl alcohol ethylene (10) ether. 首选的是月桂醇聚氧乙烯(23)醚、硬脂醇聚氧乙烯(20)醚。 Preferred are lauryl alcohol polyoxyethylene (23) ether, stearyl polyoxyethylene (20) ether.

(5)聚氧乙烯-聚氧丙烯共聚物和嵌段共聚物,商品名为Poloxamer或Pluronic,特别优选的是Poloxamer 188。 (5) Polyoxyethylene - polyoxypropylene copolymers and block copolymers, as Pluronic or Poloxamer tradename, particularly preferred is Poloxamer 188.

(6)卵磷脂。 (6) lecithin. 优选的是大豆卵磷脂和蛋黄卵磷脂。 Preferred are soybean lecithin and egg yolk lecithin.

(7)二-(2-乙基己基)琥珀酸酯磺酸钠。 (7) bis - (2-ethylhexyl) sodium sulfosuccinate.

所选择的单一的表面活性剂亲水-亲油平衡值至少为10。 Single hydrophilic surfactant is chosen - lipophilic balance value of at least 10. 混合的表面活性剂综合的亲水-亲油平衡值至少也应为8。 Integrated mixed surfactant hydrophilic - lipophilic balance value of at least 8 should be.

适合于本发明的助表面活性剂有乙醇、丙二醇、异丙醇、丙三醇、正丁醇、1.3-丁二醇,1,2-辛二醇、山梨醇、三醋酸甘油酯等。 Co-surfactants suitable for the present invention are ethanol, propylene glycol, isopropanol, glycerol, butanol, 1,3-butanediol, 1,2-octanediol, sorbitol, glycerol triacetate and the like. 优选的有乙醇、1,2-丙二醇、丙三醇、三醋酸甘油酯,首选的是1,2-丙二醇。 Preferred are ethanol, 1,2-propanediol, glycerol, triacetin, 1,2-propanediol is preferred.

适合于本发明中微乳凝胶中的凝胶基质有:(1)卡波姆系列包括卡波姆910、934、934P、940、941、971、974P、980、981、2020;(2)纤维素衍生物,如羧甲基纤维素及其钠盐、羟乙基纤维素、羟丙基甲基纤维素;(3)其它还有如黄原胶、阿拉伯胶、角叉菜胶、海藻酸钠等。 Microemulsion suitable for the present invention, the gel matrix has a gel: (1) Carbomer series including Carbopol 910,934,934P, 940,941,971,974P, 980,981,2020; (2) cellulose derivatives such as carboxymethyl cellulose and sodium salts thereof, hydroxyethyl cellulose, hydroxypropyl methyl cellulose; (3) there are other such as xanthan gum, gum arabic, carrageenan, alginic acid sodium.

特别适合的凝胶基质是卡波姆940、934、黄原胶、角叉菜胶、阿拉伯胶、海藻酸钠。 Particularly suitable gel matrix is ​​940,934 carbomer, xanthan gum, carrageenan, acacia gum, sodium alginate. 首选的是卡波姆940和黄原胶。 The preferred is Carbomer 940 and xanthan gum.

适合于本发明的渗透促进剂包括烯萜类、脂肪酸及其酯,优选的有氮酮、油酸、油酸乙酯、薄荷脑、樟脑、冰片、柠檬油精。 Suitable for the present invention include penetration enhancers alkenyl terpenes, fatty acids and esters, preferred are azone, oleic acid, ethyl oleate, menthol, camphor, borneol, limonene. 特别适合的是水溶性氮酮、薄荷脑、冰片、柠檬油精,首选的是薄荷脑。 Particularly suitable water-soluble azone, menthol, borneol, limonene, menthol is preferred.

本发明的药物组合pH控制在5-8,超出该范围时,可用pH调节剂进行调节,pH调节剂包括氢氧化钠、三乙醇胺、氨水等,优选三乙醇胺。 The pharmaceutical compositions of the present invention controls the pH at 5-8, while outside this range can be used to adjust pH adjusting agents, pH adjusting agents include sodium hydroxide, triethanolamine, ammonia and the like, preferably triethanolamine.

本发明还进一步包括一些添加剂,如抗氧剂(丁羟基苯甲醚、丁羟基甲苯、维生素E、茶多酚等)、防腐剂(羟苯乙酯、三氯叔丁醇等)、保湿剂(甘油和丙二醇)。 The present invention further includes additives such as an antioxidant (butylhydroxyanisole, butylated hydroxytoluene, vitamin E, polyphenols, etc.), a preservative (ethylparaben, chlorobutanol, etc.), humectants (glycerol and propylene glycol). 这些添加剂可占微乳总重量的0-0.5wt%。 These additives can comprise 0-0.5 wt% of the total weight of the microemulsion.

本发明提供的具有皮肤靶向性的药物组合物,包括微乳和微乳凝胶的药物组合物,其制备方法是:(1)具有皮肤靶向性的微乳的药物组合物的制备将皮肤局部用活性药物、渗透促进剂溶解于由油、表面活性剂、助表面活性剂的混合液中,形成油相,在搅拌状态下,向油相中加入水,制得微乳;或者将皮肤局部用活性药物、渗透促进剂溶解于油、表面活性剂的混合液中,制成油相,将助表面活性剂与水混合后,在搅拌的条件下加入油相,制得微乳;或者将油、表面活性剂、助表面活性剂混合,形成油相,在搅拌的条件下加入水,制成未载药的微乳后,再加入皮肤局部用活性药物和渗透促进剂,搅拌至完全溶解后得到的微乳即为具有皮肤靶向性的药物组合物。 The present invention provides a pharmaceutical composition having a skin targeting of a pharmaceutical composition comprising a microemulsion and microemulsion gel preparation method is: (1) Preparation of pharmaceutical composition of the microemulsion targeting the skin topical skin active agent, a permeation enhancer dissolved in a mixture of oil, surfactant, co-surfactant, the oil phase is formed, under stirring, water was added to the oil phase, a microemulsion was obtained; or after topical skin active agent, penetration enhancer dissolved in oil, surfactant mixture, the oil phase is formed, the co-surfactant is mixed with water, added to the oil phase under stirring to prepare a microemulsion; or oil, a surfactant, co-surfactant are mixed to form an oil phase, water was added under stirring, the formed microemulsion did not contain the drug, then added to the topical skin active drug and permeation enhancer, stirred until after complete dissolution the resulting microemulsion having a skin that is targeted pharmaceutical composition.

(2)具有皮肤靶向性的微乳凝胶的药物组合物的制备将油、表面活性剂、助表面活性剂、皮肤局部用活性药物、渗透促进剂、水混合制得微乳(按上述制备具有皮肤靶向性的微乳的药物组合物的方法),将凝胶基质加入上述制得的微乳中,搅拌溶胀后,得到微乳凝胶;或将皮肤局部用活性药物、渗透促进剂溶解于由油、表面活性剂、助表面活性剂的混合液中,形成油相,再将水和凝胶基质混合制成水溶胀体,将油相与水溶胀体混合均匀后制得微乳凝胶;或将皮肤局部用活性药物、渗透促进剂溶解于由油、表面活性剂、助表面活性剂的混合液中,形成油相,将水按1∶0.2~5的比例分成两分,一份与油相制成微乳,另一分与凝胶基质混合制成水溶胀体,将微乳与水溶胀体混合均匀后制得具有皮肤靶向性的微乳凝胶的药物组合物。 (2) Preparation of a pharmaceutical composition having a skin targeting microemulsion gels of the oil, surfactant, cosurfactant, topical skin active agent, penetration enhancer, water microemulsion prepared by mixing (as described above the method of preparing a pharmaceutical composition having a microemulsion targeting skin), the gel matrix was added to the microemulsion obtained after stirring swollen to give a gel microemulsion; or topical skin active drug, permeation enhancer is dissolved in a mixture of oil, surfactant, co-surfactant, the oil phase is formed, then water and water-swellable hydrogel matrix prepared by mixing thereof, the oil phase to prepare a water-swellable material evenly mixed microstructure curdlan; or topical skin active agent, a permeation enhancer dissolved in a mixture of oil, surfactant, co-surfactant, the oil phase is formed, the water proportion of 0.2 to 5 minutes into two , a microemulsion made with the oil phase, and the other sub prepared by mixing water-swellable gel matrix body, the microemulsion mixed with water-swellable composition having a skin-targeted pharmaceutical microemulsion gel uniformly prepared thereof.

本发明可以制备的制剂是:具有皮肤靶向性的活性药物的微乳凝胶可直接作为凝胶剂应用,同时微乳和微乳凝胶各种外用液、乳膏剂、贴剂、霜剂等各种局部皮肤制剂。 Formulations of the present invention can be prepared are: skin active pharmaceutical microemulsion gel with a targeting agent may be directly applied as a gel, while a variety of microemulsions and microemulsion gels external liquid, creams, patches, creams and other topical skin preparations. 上述制剂可以用于治疗尖锐湿疣、皮肤的病毒感染、真菌感染。 Above formulations may be used in the treatment of genital warts, viral skin infection, fungal infection. 特别是用于尖锐湿疣的治疗。 Especially for the treatment of genital warts.

本发明由于采用了微乳和微乳凝胶,与现有技术(酊剂和乳膏)相比显示出如下优越性:第一,活性药物在表皮的吸收,增强药效,显著降低药物的全身性吸收带来的毒副作用,具有明显的皮肤靶向性。 As a result of the present invention microemulsions and microemulsion gels, as compared with the prior art (tinctures and creams) show the following advantages: First, absorption of the active drug in the epidermis, to enhance efficacy, a significant reduction in the systemic drug side effects caused by absorption, with a clear skin targeting. 可以用来治疗皮肤的病毒感染,如单纯性疱疹感染;可以有效地治疗湿疹、皮肤真菌感染等。 It can be used to treat viral skin infections, such as herpes simplex infections; effective in treating eczema, fungal skin infections. 第二,由于无刺激性的辅料和微乳的O/W结构,使活性药物不能大量地直接接触皮肤,避免了活性药物对皮肤的严重刺激性。 Second, since the O / W structure and non-irritating excipients microemulsion, a large amount of the active drug is not in direct contact with the skin, the active agent to avoid serious skin irritation. 可明显降低活性药物所致的局部轻度至中度的炎症反应,如烧灼、搔痒、疼痛、糜烂等。 Can significantly reduce the activity of drug-induced localized mild to moderate inflammatory reaction, such as burning, itching, pain, erosion and the like. 第三,微乳凝胶提供了较高的黏性,同时还保持了较好的皮肤靶向性,便于定量给药以及作为各种剂型的基础。 Third, microemulsion gel provides high viscosity, while maintaining a good skin targeting, dosing convenience, and as the basis of various dosage forms.

下面以实施例方式对本发明中具有皮肤靶向性的微乳及微乳凝胶的药物组合物进行说明。 The pharmaceutical composition having the following manner in Example of targeting skin microemulsion and microemulsion gels of the present invention will be described.

实施例1具有皮肤靶向性的鬼臼毒素微乳的药物组合物将3g十六酸异丙酯,40g聚氧乙烯(40)氢化蓖麻油,20g丙二醇混合,形成混合溶液后,使鬼臼毒素0.5g和樟脑2g溶解于该混合溶液,制得油相。 After a pharmaceutical composition having a skin microemulsion embodiment podophyllotoxin targeting of Example 1 3g of palmitic acid, isopropyl, 4Og polyoxyethylene (40) hydrogenated castor oil, 20g of propylene glycol mixed to form a mixed solution, so that podophyllotoxin toxins and camphorsulfonic 2g 0.5g were dissolved in the mixed solution to prepare an oil phase. 在搅拌的条件下缓缓将蒸馏水加入油相中,使总量达100g,搅拌均匀后得到透明微乳即为具有皮肤靶向性的药物组合物。 Under stirring slowly added to the oil phase and distilled water to make the whole 100g, transparent microemulsion obtained after mixing with the skin is the targeting of pharmaceutical compositions. 用激光粒度仪(Nano ZS90型,英国马尔文公司)25℃时测定其有效粒径,有效粒径为70.81nm。 With a laser particle size analyzer (Nano ZS90 type, Malvern UK) effective particle size was measured 25 ℃, the effective particle size of 70.81nm.

实施例2具有皮肤靶向性的鬼臼毒素微乳凝胶的药物组合物将3g十四酸异丙酯,30g吐温80,30g丙二醇混合,形成混合溶液后,使0.5g鬼臼毒素和2g薄荷脑溶解于该混合溶液,制得油相。 The pharmaceutical composition of the microemulsion gel with 2 podophyllotoxin skin targeting of Example 3g of isopropyl myristate, propylene glycol 30g Tween 80,30g mixed to form a mixed solution, so that podophyllotoxin and 0.5g 2g menthol were dissolved in the mixed solution to prepare an oil phase. 取0.375g卡波姆940与水混合,溶胀后加入0.5g三乙醇胺,搅拌均匀后与油相混合,搅拌至使完全均匀,得到具有皮肤靶向性的鬼臼毒素微乳凝胶的药物组合物。 Take 0.375g Carbomer 940 is mixed with water, was added 0.5g triethanolamine after swelling, even after mixing with the oil phase mixture, stirring until completely uniform so, to obtain a pharmaceutical composition having a gel microemulsion podophyllotoxin targeting of skin thereof. 用激光粒度仪在25℃时测定1ml水和0.05mg微乳凝胶并存的稀释液中颗粒的粒径分布,最大颗粒小于150nm。 1ml water was measured and was diluted microemulsion 0.05mg coexist in the gel particles at 25 ℃ size distribution with a laser particle size analyzer, the largest particles less than 150nm.

实施例3具有皮肤靶向性的鬼臼毒素微乳的药物组合物将5g中链三酸甘油酯(Miglyol 812),30g吐温,5g Poloxamer 188,30g丙二醇,15g乙醇混合,形成混合溶液后,加入0.5g鬼臼毒素和3g樟脑,搅拌溶解后,制得油相。 After 3 podophyllotoxin pharmaceutical composition having a skin targeting microemulsion of Example 5g of medium-chain triglyceride (Miglyol 812), 30g Tween, 5g Poloxamer 188,30g propylene glycol, 15g of ethanol mixed to form a mixed solution after addition of 0.5g 3g podophyllotoxin and camphor, stirred to dissolve, to prepare an oil phase. 在搅拌的条件下将蒸馏水缓缓加入油相中,使总量达100g,搅拌均匀后,得到透明均一的微乳即为具有皮肤靶向性的药物组合物。 Under stirring in distilled water was added slowly to the oil phase, to make the whole 100g, stirred uniformly to obtain a transparent homogeneous microemulsion having a skin that is targeted pharmaceutical composition. 激光粒度仪测得该微乳的粒径为83.08nm。 Measured by laser diffraction particle size of the microemulsion 83.08nm.

实施例4具有皮肤靶向性的鬼臼毒素微乳凝胶的药物组合物将6g中链三酸甘油酯(Miglyol 812),35g吐温,20g丙二醇,10g异丙醇混合,形成混合溶液后,加入鬼臼毒素0.15g和柠檬油精2g,搅拌溶解后,制得油相。 After 4 podophyllotoxin pharmaceutical composition having a skin gel microemulsion targeting of Example 6g the medium-chain triglyceride (Miglyol 812), 35g Tween, 20g of propylene glycol, 10g isopropyl alcohol were mixed to form a mixed solution after addition of 0.15g podophyllotoxin and limonene 2g, stirred to dissolve, to prepare an oil phase. 取黄原胶2.0g,加入适量水中,形成均匀的水凝胶基质后与油相混合,搅拌均匀后制得总量为100g的具有皮肤靶向性的鬼臼毒素微乳凝胶,即为具有皮肤靶向性的药物组合物。 After taking xanthan gum 2.0g, was added an appropriate amount of water to form a homogeneous hydrogel matrix mixed with the oil phase, after stirring uniformly to prepare a total amount of 100g of podophyllotoxin microemulsion gel having a skin targeting, namely having a skin targeting pharmaceutical compositions. 测定0.07g微乳凝胶的20倍水稀释液的有效粒径,有效粒径为93.85nm。 Determination of the effective size of 0.07g microemulsion gel 20-fold aqueous dilution of the effective diameter of 93.85nm.

实施例5具有皮肤靶向性的鬼臼毒素微乳的药物组合物取10g油酸,30g硬脂酸聚氧乙烯(50)酯,5g二-(2-乙基己基)琥珀酸酯磺酸钠,35g丙二醇,5g正丁醇混合形成混合溶剂后,再加入0.15g鬼臼毒素和5g冰片,溶解后制得油相。 The pharmaceutical composition of embodiment 5 having a skin podophyllotoxin microemulsion according targeting taken 10g oleic acid, 30g of stearic acid polyoxyethylene (50) esters, 5g two - (2-ethylhexyl) succinate sulfonate sodium, 35g propylene glycol, 5g of n-butanol are mixed to form a mixed solvent, and then added 0.15g podophyllotoxin borneol 5g, prepared by dissolving the oil phase. 在搅拌的条件下将蒸馏水缓缓加入油相中,使总量达100g,搅拌均匀后制得均匀透明的微乳液,即为具有皮肤靶向性的药物组合物。 Under stirring in distilled water was added slowly to the oil phase, to make the whole 100g, after stirring uniformly to prepare a uniform transparent microemulsion having a skin that is targeted pharmaceutical composition.

实施例6具有皮肤靶向性的鬼臼毒素微乳凝胶的药物组合物取2g十四酸异丙酯、1g Labrafil M 2125CS,40g吐温80,15g丙二醇,混合形成混合溶剂后,再加入鬼臼毒素0.15g、冰片2g和2g薄荷脑,溶解后制得油相。 After 6 podophyllotoxin pharmaceutical composition having a skin gel microemulsion targeting of Example 2g taken isopropyl myristate, 1g Labrafil M 2125CS, 40g Tween 80,15g propylene glycol and mixed to form a mixed solvent, then add podophyllotoxin 0.15g, borneol 2g of menthol and 2g, and dissolved to prepare an oil phase. 在搅拌的条件下缓缓加入水17.85g,搅拌均匀后制成均匀的微乳,再加入1.0g卡波姆934和1g三乙醇胺,搅拌均匀后制得鬼臼毒素微乳凝胶,即为具有皮肤靶向性的药物组合物。 Under stirring 17.85 g of water was added slowly, to prepare a homogeneous microemulsion Stir, then add 1.0g 1g Carbopol 934 and triethanolamine, stir to obtain podophyllotoxin gel microemulsion, i.e. having a skin targeting pharmaceutical compositions.

实施例7具有皮肤靶向性的鬼臼毒素微乳的药物组合物取6g油酸,2g三油酸甘油酯,10g大豆卵磷脂,30g吐温80,15g丙二醇,10g乙醇,混合均匀后制成混合溶剂,加入鬼臼毒素1.0g,搅拌溶解后制成油相。 7 podophyllotoxin microemulsion having a skin targeting pharmaceutical compositions of Example 6g taken oleate, 2g after triolein, soybean lecithin 10g, 30g Tween 80,15g propylene glycol, 10g of ethanol, mixed system a mixed solvent, podophyllotoxin was added 1.0g, prepared oil phase and stirred to dissolve. 在搅拌的条件下缓缓水加入油相中,搅拌均匀后制成微乳,即为具有皮肤靶向性的药物组合物。 Under stirring slowly added to the oil in the aqueous phase microemulsion made after mixing, having a skin that is targeted pharmaceutical composition.

实施例8具有皮肤靶向性的鬼臼毒素微乳凝胶的药物组合物取油酸乙酯10g,30g的吐温80,丙二醇30g,丙三醇15g,混合后形成混合溶剂,再加入鬼臼毒素0.5g,溶解后制成油相。 8 podophyllotoxin pharmaceutical composition having a skin gel microemulsion of Example targeting taken as ethyl oleate 10g, 30g of polysorbate 80, propylene glycol 30g, glycerin 15g, mixed to form a mixed solvent, adding a ghost mortar toxin 0.5g, after dissolved by the oil phase. 在搅拌的条件下向油相中缓缓加入蒸馏水13g。 Phase, 13g of distilled water was slowly added to the oil under stirring. 加入角叉菜胶1.5g,搅拌至均匀后制得总量为100g的鬼臼毒素微乳凝胶,即为具有皮肤靶向性的药物组合物。 Carrageenan was added 1.5g, and stirred until homogeneous to obtain a total amount of 100g of podophyllotoxin microemulsion gels, i.e. having a skin targeting pharmaceutical compositions.

实施例9取玉米油甘油酯40g,30g聚氧乙烯氢化蓖麻油40,丙二醇10g,三醋酸甘油酯5g,混合后制成混合溶液,加入咪喹莫特8g,溶解后制成油相,在搅拌的条件加入蒸馏水,使总量达100g,搅拌均匀后得均一透明的微乳液,即为具有皮肤靶向性的药物组合物。 Example 9 after taking corn oil glycerides 40g, 30g of polyoxyethylene hydrogenated castor oil 40, propylene glycol 10g, glyceryl triacetate 5g, mixed to prepare a mixed solution, adding imiquimod 8g, an oil phase prepared by dissolving, in stirring to distilled water was added to make the whole 100g, to obtain a uniform transparent microemulsion after mixing, having a skin that is targeted pharmaceutical composition.

实施例10取实施例9的微乳液50g,加入阿拉伯胶1.75g,搅拌均匀后制得鬼臼毒素的微乳凝胶,即为具有皮肤靶向性的药物组合物。 Example 10 50g microemulsion embodiment taken Example 9, gum arabic was added 1.75g, after stirring uniformly to prepare a gel microemulsion podophyllotoxin, i.e. having a skin targeting pharmaceutical compositions.

实施例11稳定性考察采用长期留样法观察。 Sample was observed to stay long stability of Example 11 using the embodiment. 取十四酸甘油酯2g,35g吐温80,25g丙二醇,制成混合溶液后加入鬼臼毒素0.5g和薄荷脑,溶解后形成油相。 Take myristic acid glyceride 2g, 35g Tween 80,25g propylene glycol, after a mixed solution prepared was added 0.5g of podophyllotoxin and menthol, form an oil phase dissolved. 向油相中缓缓加入蒸馏水,使总量达100g,搅拌均匀后即得鬼臼毒素微乳,即为具有皮肤靶向性的药物组合物。 Distilled water was added slowly to the oil phase, to make the whole 100g, after stirring uniformly to obtain podophyllotoxin microemulsion, i.e. having a skin targeting pharmaceutical compositions. 取适量鬼臼毒素微乳,密封于试管中,置于室温下保存12个月,定期观察样品的含量、外观、性状以及是否出现分层、絮凝等现象。 Take appropriate podophyllotoxin microemulsion, sealed in a test tube, was placed under room temperature storage for 12 months, the content of the sample was observed periodically, appearance, character and whether delamination, flocculation phenomena.

在室温下,鬼臼毒素微乳在12个月内未出现分层、絮凝现象,含量、粒径外观均无明显改变。 At room temperature, podophyllotoxin microemulsion stratification does not appear within 12 months, flocculation, content, particle size had no significant changes in appearance.

实施例12稳定性考察采用长期留样法观察。 12 stay long sample observation method Stability embodiment employs. 取十六酸异丙酯10g,30g的吐温80,10g硬脂醇聚氧乙烯(20)醚。 Take palmitic acid, isopropyl 10g, 30g of Tween 80,10g stearyl polyoxyethylene (20) ether. 丙二醇15g,混合形成混合溶剂后,再加入鬼臼毒素0.15g和冰片3g,溶解后制得油相。 After the propylene glycol 15g, mixed to form a mixed solvent, and then added 0.15g podophyllotoxin borneol 3g, to give an oil phase was prepared by dissolving. 在搅拌的条件下缓缓加入水17.85g,搅拌均匀后制成均匀的微乳,再加入1.0g卡波姆934和1g三乙醇胺,搅拌均匀后制得鬼臼毒素微乳凝胶,即为具有皮肤靶向性的药物组合物。 Under stirring 17.85 g of water was added slowly, to prepare a homogeneous microemulsion Stir, then add 1.0g 1g Carbopol 934 and triethanolamine, stir to obtain podophyllotoxin gel microemulsion, i.e. having a skin targeting pharmaceutical compositions. 取适量鬼臼毒素微乳凝胶,密封于试管中,置于室温下保存12个月,定期观察样品的含量、外观、性状以及是否出现分层、絮凝等现象。 Take appropriate podophyllotoxin microemulsion gel, sealed in a test tube, was placed under room temperature storage for 12 months, the content of the sample was observed periodically, appearance, character and whether delamination, flocculation phenomena.

在室温下,鬼臼毒素微乳在12个月内未出现分层、絮凝现象,含量、粒径外观均无明显改变。 At room temperature, podophyllotoxin microemulsion stratification does not appear within 12 months, flocculation, content, particle size had no significant changes in appearance.

实施例1-12所述的任何组合物中的鬼臼毒素可以用另一种药物咪喹莫特代替。 Podophyllotoxin composition according to any embodiment 1-12 embodiment may be another drug imiquimod instead. 下面以实施例的方式加以说明。 Below by way of example will be described.

实施例13-18按实施例1-10所述的微乳及微乳凝胶的制备方法均能得到均匀的具有皮肤靶向性的眯喹莫特微乳和微乳凝胶药物组合物。 Examples 13-18 and microemulsion prepared in Example 1-10 microemulsion method can obtain a homogeneous gel having a skin Mi quinolin targeting Mott microemulsion and microemulsion gel pharmaceutical composition. 实施例13和17所制得的微乳凝胶的20倍稀释液的最大粒径为150nm,实施例14、15、16、18所制得的微乳有效粒径均小于100nm。 Maximum particle size of 20-fold dilutions of Examples 13 and 17 prepared microemulsion gels embodiment is 150nm, prepared in Example 14,15,16,18 microemulsion effective particle size less than 100nm.

对实施例17、18进行了长期稳定性考察,在12个月内未出现分层、絮凝现象,含量、粒径外观均无明显改变。 The embodiments 17 and 18 long-term stability of stratified not appear within 12 months, flocculation, content, particle size no significant changes appearance.

实施例19皮肤滞留实验研究对实施例11,12,15,17所得具有皮肤靶向性的鬼臼毒素和咪喹莫特的微乳及微乳凝胶药物组合物进行皮肤靶向性考察。 Example 19 Experimental study of the retention of the skin obtained in Example 11,12,15,17 embodiment of podophyllotoxin having a skin targeting and imiquimod microemulsion and microemulsion gel pharmaceutical composition targeting a skin inspection.

将体重为15±0.5kg幼猪腹部脱毛,空气栓塞法处死后取下腹部皮肤,去掉皮下脂肪,用蒸馏水洗净皮肤。 15 ± 0.5kg body weight of young pigs epilation abdomen, abdominal skin is removed by air embolism after death, to remove subcutaneous fat, the skin washed with distilled water. 再用生理盐水清洗皮肤,用滤纸吸干后备用。 Skin and then rinsing with physiological saline, blotted dry with filter paper after use. 受试物分别为具有皮肤靶向性的鬼臼毒素微乳药物组合物(简称鬼臼毒素微乳组)、鬼臼毒素微乳凝胶药物组合物(简称鬼臼毒素微乳凝胶组)、咪喹莫特微乳药物组合物(简称咪喹莫特微乳组)、咪喹莫特微乳凝胶药物组合物(简称咪喹莫特微乳凝胶组)、市售鬼臼毒素酊、市售咪喹莫特乳膏。 Respectively, having a skin test was targeted podophyllotoxin microemulsion pharmaceutical composition (referred to as microemulsions podophyllotoxin), podophyllotoxin microemulsion gel pharmaceutical composition (referred to as microemulsion gels podophyllotoxin group) imiquimod microemulsion pharmaceutical composition (referred to as imiquimod microemulsions), imiquimod microemulsion gel pharmaceutical composition (referred to as microemulsion gels imiquimod group), a commercially available podophyllotoxin tincture, commercial imiquimod cream. 采用改进Franz扩散池进行透皮试验,扩散池用一个恒温(37℃)循环水套保温,皮肤固定在供给室和接收池之间,皮肤表层面向供给室,有效渗透面积S为2.8cm2,接收池容积为7.0ml,接收液为生理盐水,将1.0g的受试物均匀涂布于供给室中的皮肤表面,开启电磁搅拌器以300r/min的速度搅拌。 The improved transdermal Franz diffusion cell experiment, the diffusion cell with a thermostat (37 ℃) circulating water jacket insulation, the skin is fixed between the supply chamber and the receiving tank, the supply chamber facing the skin surface, the effective permeation area S of 2.8cm2, reception tank 7.0 ml of volume, receiving physiological saline solution, 1.0g of the test was uniformly applied to the skin surface in the supply chamber, open the electromagnetic stirrer at a speed of 300r / min of stirring. 于1,2,4,6,8,24h取出接收液0.5ml(每次取样后均补加等量的生理盐水),将取得的样品进行离心,取上清液,测定鬼臼毒素和咪喹莫特的含量。 1,2,4,6,8,24h receiving liquid extracted in 0.5ml (after each sample were supplemented with normal saline), the obtained sample was centrifuged, the supernatant was measured and microphone podophyllotoxin quinoline content Mott. 并计算单位面积累积透皮释药量Q,药物在各时间点的累积透皮量如表1所示。 And calculates the cumulative transdermal delivery amount per unit area Q, the amount of drug in the cumulative penetration at each time point as shown in Table 1. 透皮实验完毕后,取下皮肤,洗去皮肤两面的残留物后,从皮肤中提取出药物,得各受试物的皮肤滞留量,如表2所示。 After completion of the transdermal experiment, the skin is removed, the residue was washed on both surfaces of the skin, the drug is extracted from the skin to give each test substance hold the skin, as shown in Table 2.

表1表明本发明具有皮肤靶向性的鬼臼毒素药物组合物和咪喹莫特药物组合物的累积透皮量显著小于市售的鬼臼毒素酊剂和咪喹莫特乳膏(P<0.001),在前8h时,微乳和微乳凝胶组均未透皮,而仅在第24h时,有少量药物透过,而酊剂和乳膏剂透皮速率快,透皮量大。 Table 1 shows the present invention having a skin targeting pharmaceutical compositions of podophyllotoxin and imiquimod cumulative penetration amount of the pharmaceutical composition is significantly less than the commercially available podophyllotoxin and imiquimod cream tinctures (P <0.001 ), when the front 8h, microemulsions and microemulsion gel group were not transdermally, but only during the first 24h, a small amount of the drug through, tinctures, and the permeation rate faster creams, transdermal large. 同时从表2可知,本发明药物组合物能大大提高药物在皮肤中的滞留量,远高于酊剂和乳膏剂。 Meanwhile seen from Table 2, the pharmaceutical compositions of the invention can greatly increase the amount of drug retention in the skin, much higher than tinctures and creams. 这显示出本发明微乳和微乳凝胶药物组合物有很好的皮肤靶向性。 This shows that the present invention is a microemulsion and microemulsion gel pharmaceutical compositions have good skin targeting.

表1 本发明鬼臼毒素、咪喹莫特的微乳及微乳凝胶药物组合物的累积透皮吸收透皮量(μg/cm2) Table 1 Invention podophyllotoxin, cumulative penetration of imiquimod microemulsion and microemulsion gel pharmaceutical composition for transdermal absorption amount (μg / cm2)

表2 在第24h时各受试物在皮肤中的滞留量 Table 2 At the time of each test was 24h holdup in the skin

实施例20本发明鬼臼毒素、咪喹莫特的微乳、微乳凝胶药物组合物皮肤刺激性研究。 Toxin podophyllotoxin invention, imiquimod microemulsion, microemulsion gel pharmaceutical composition Skin Irritation Example 20 embodiment.

对实施例11,12,15,17所得鬼臼毒素和咪喹莫特的微乳及微乳凝胶药物组合物进行家兔皮肤刺激性考察。 Examples of the obtained 11,12,15,17 podophyllotoxin and imiquimod microemulsion and microemulsion gel pharmaceutical composition irritation to rabbit skin.

家兔背部脊柱两侧脱毛(脱毛面积约为体表面积10%),分一次给药或多次给药(连续给药)一周两种方法,每种方法又分完整皮肤组和破损皮肤组两组,每组3只家兔,每只家兔背部皮肤分四区:空白区、鬼臼毒素微乳(本发明药物组合物)区、鬼臼毒素微乳凝胶(本发明药物组合物)区、咪喹莫特微乳(本发明药物组合物)区、咪喹莫特微乳凝胶(本发明药物组合物)区,鬼臼毒素酊(市售产品)区、咪喹莫特乳膏(市售产品)区。 Depilatory rabbit back sides of the spine (depilatory area of ​​approximately 10% body surface area), divided one or multiple administration (continuous administration) one week two methods, each method is divided into groups and the intact skin damaged skin two groups groups, three rabbits per group, each rabbit skin of the back is divided into four regions: the blank area, microemulsions podophyllotoxin (pharmaceutical composition of the present invention) region, podophyllotoxin microemulsion gel (pharmaceutical compositions of the invention) area, microemulsions imiquimod (pharmaceutical composition of the present invention) region, imiquimod microemulsion gels (according to the present invention, a pharmaceutical composition) region, podophyllotoxin tincture (commercial product) region, imiquimod milk cream (commercial product) area. 分别将各受试物分别涂于相应区域。 Respectively were each applied to each respective test area. 24小时后用温水去除残留受试物,观察去除受试物后1、24、48和72小时涂抹部位有无红斑和水肿等情况,以及上述变化的恢复情况和时间。 After 24 hours with warm water to remove residual test substance, where the presence or absence of erythema was observed 24, 48 is removed and 72 hours after test substance application area and edema, as well as the recovery and the time of the change. 根据皮肤刺激反应的类型进行评分(红斑:0:无红斑,1:勉强可见红斑,2:中度红斑,3:严重红斑,4:紫红色红斑并有焦痂生成;水肿:0:无红肿,1:勉强可见红肿,2:轻度可见,3:皮肤隆起约1cm,轮廓清楚,4:水肿隆起约1cm以上并范围扩大)。 Score (erythema response depending on the type of skin irritation: 0: No erythema, 1: barely visible erythema, 2: moderate erythema 3: severe erythema 4: erythema and eschar purple generated; Edema: 0: No swelling , 1: barely visible swelling, 2: slightly visible 3: about 1cm skin swells, clear outline, 4: edema and raised above the range of about 1cm to expand). 根据平均分值计算刺激强度,若平均分值小于0.4,为无刺激性;0.5~1.9为轻度刺激性;2.0~5.9为中度刺激性;6.0~8.0为强刺激性。 Stimulation intensity is calculated based on the average value, if the average value is smaller than 0.4, is non-irritating; mild irritation 0.5 to 1.9; 2.0 to 5.9 Moderate irritant; 6.0-8.0 is strong irritant.

表3 鬼臼毒素和咪喹莫特的微乳、微乳凝胶对家兔皮肤的刺激性 Table 3 podophyllotoxin and imiquimod microemulsion, microemulsion gel on rabbit skin irritation

结果如表3所示,本发明中的鬼臼毒素和咪喹莫特的微乳、微乳凝胶药物组合物对皮肤无刺激性,而鬼臼毒素酊和咪喹莫特乳膏对皮肤的刺激性明显。 The results are shown in Table 3, in the present invention, podophyllotoxin and imiquimod microemulsion, microemulsion gel pharmaceutical composition is non-irritating to the skin, and tincture podophyllotoxin and imiquimod cream on the skin irritation obvious. 这表明,本发明微乳、微乳凝胶药物组合物安全性明显优于上市制剂(和空白比较:*P<0.01)。 This indicates that the present invention is a microemulsion, microemulsion gel pharmaceutical composition formulation listed security significantly better than (and blank comparison: * P <0.01).

实施例21本发明的鬼臼毒素、咪喹莫特的微乳、微乳凝胶药物组合物皮肤耐受性研究及因全身性吸收产生的毒副反应观察。 Podophyllotoxin Example 21 of the present invention is observed imiquimod microemulsion, microemulsion gel Tolerance pharmaceutical compositions and skin toxicity by systemic absorption produced.

对实施例11,12,15,17所得鬼臼毒素和咪喹莫特的微乳及微乳凝胶药物组合物进行家兔皮肤耐受性考察及因全身性吸收产生的毒性反应观察。 Examples of the obtained 11,12,15,17 podophyllotoxin and imiquimod microemulsion and microemulsion gel pharmaceutical compositions investigated and the resistance to toxicity by systemic absorption observed rabbit skin produced.

观察成年家兔完整皮肤和破损皮肤短期内接触市售鬼臼毒素酊剂、市售咪喹莫特乳膏剂、鬼臼毒素和咪喹莫特的微乳和微乳凝胶药物组合物所产生的全身性毒性反应。 Observation and adult rabbits intact skin contacting commercially available short term podophyllotoxin damaged skin tinctures, creams commercially imiquimod, podophyllotoxin and imiquimod microemulsion and microemulsion gel pharmaceutical composition produced systemic toxicity. 各受试样品以5g样品/kg家兔的剂量给药。 Each test sample was administered at a dose of 5g samples / kg in rabbits. 市售鬼臼毒素酊剂、市售咪喹莫特乳膏给药24h后,动物产生了严重的皮肤刺激性如红斑、糜烂等,动物同时出现了呕吐、腹泻等系统性毒性反应。 Commercially available podophyllotoxin tincture, Mott cream imiquimod administration commercially available 24h after the animals had severe skin irritation, such as erythema, erosion, and other animals at the same time there has been vomiting, diarrhea and other systemic toxicity. 而鬼臼毒素和咪喹莫特的微乳和微乳凝胶药物组合物给药24h后,家兔无死亡现象,动物体重、皮肤、毛发、眼睛、粘膜、循环、四肢活动等无明显变化,动物无呕吐、腹泻、血小板减少、外周神经麻痹等全身性毒性反应。 Whereas podophyllotoxin and imiquimod administration of microemulsion and microemulsion gel pharmaceutical composition for 24h, rabbits no mortality, no significant change in animal body weight, skin, hair, eyes, mucous membranes, circulation, limbs, etc. animal no vomiting, diarrhea, thrombocytopenia, peripheral nerve palsy systemic toxicity. 这表明,本发明鬼臼毒素和咪喹莫特的微乳、微乳凝胶药物组合物的安全性较好,能够耐受较高的药物用量,无明显的皮肤毒性,无因系统性吸收而产生的毒副反应,具有明显的皮肤靶向性。 This indicates that the present invention podophyllotoxin and imiquimod microemulsion, microemulsion safety of the pharmaceutical composition is preferably a gel, capable of withstanding higher drug dosage, no significant skin toxicity, due to no systemic absorption the toxicity produced, having a significant skin targeting.

实施例22本发明具有皮肤靶向的微乳和微乳凝胶药物组合物其特别之处在于,可以按照常规的方法制成鬼臼毒素和咪喹莫特微乳、微乳凝胶药物组合物的各种外用液、凝胶剂、贴剂、霜剂、喷剂、溶液剂、软膏剂。 Example 22 embodiment of the present invention having a skin-targeted microemulsion and microemulsion gel pharmaceutical composition is unique in that it can be prepared according to conventional methods podophyllotoxin and imiquimod microemulsion, microemulsion gel pharmaceutical compositions various topical liquid, gel material, patches, creams, sprays, solutions, ointments. 以鬼臼毒素的以上各种制剂治疗尖锐湿疣时,鬼臼毒素的含量为0.15-0.5%,每日用药2次,3天为一个疗程。 In preparation for the treatment of genital warts or higher various podophyllotoxin, podophyllotoxin an amount of 0.15-0.5%, medication twice daily 3 days a course of treatment. 咪喹莫特以上的各种制剂治疗尖锐湿疣时,其药物含量为2-5%,每日一次,每周三次,共使用6-8周。 When the above various formulations of imiquimod treatment of genital warts, drug content of 2-5% thereof, once daily, three times a week for 6-8 weeks.

上述具有皮肤靶向的药物组合物及其制剂可以用其它皮肤局部用的活性药物代替,可得到类似的皮肤靶向性效果。 Having the above-described pharmaceutical compositions and formulations of the skin can be targeted by other topical skin active agent instead, obtained similar results targeting skin.

Claims (7)

1.具有皮肤靶向性的药物组合物,包括:0.5-10wt%的油、10-80wt%的表面活性剂、3-60wt%助表面活性剂、0-8wt%的渗透促进剂和0.05-8wt%的皮肤局部用活性药物及余量的水;皮肤局部用活性药物为鬼臼毒素或咪喹莫特;具有皮肤靶向性的药物组合物为微乳或微乳凝胶药物组合物,微乳或微乳凝胶药物组合物中微乳粒径小于150nm。 1. having a skin targeting drug composition, comprising: 0.5-10wt% of oil, 10-80wt% surfactant, 3-60wt% co-surfactant, 0-8 wt% of the permeation accelerator and 0.05 8wt% of the topical skin active agent and the balance water; topical skin active agent is podophyllotoxin or imiquimod; pharmaceutical composition having a skin targeting of a microemulsion or microemulsion gel pharmaceutical composition, microemulsion or microemulsion gel pharmaceutical composition microemulsion particle size less than 150nm.
2.根据权利要求1所述的具有皮肤靶向性的药物组合物,其特征在于:还含有0-5wt%的凝胶基质;所述的凝胶基质为卡波姆、纤维素衍生物、黄原胶、阿拉伯胶、角叉菜胶或海藻酸钠中的一种或多种的混合物。 2. A pharmaceutical composition having a skin targeting according to claim 1, characterized by: further containing 0-5wt% of the gel matrix; the gel matrix carbomer, cellulose derivatives, xanthan gum a gum arabic, carrageenan or sodium alginate or more thereof.
3.根据权利要求1或2所述的具有皮肤靶向性的药物组合物,其特征在于:油为液态的C8-C16脂肪酸及其酯、植物油及其甘油酯、酯化的玉米油与聚乙二醇反应得到的酯基转移的乙氧基植物油的一种或者多种的混合物。 3. The pharmaceutical composition having a skin targeting of claim 1 or claim 2, wherein: the liquid oil is a C8-C16 fatty acids and esters, glycerides and vegetable oils, esterified corn oil with polyethylene an ethoxylated vegetable oil transesterification reaction of ethylene glycol or a mixture of more thereof.
4.根据权利要求1或2所述的具有皮肤靶向性的药物组合物,其特征在于:表面活性剂为聚氧乙烯失水山梨醇脂肪酸酯、聚氧乙烯脂肪酸酯、聚氧乙烯氢化蓖麻油、卵磷脂、聚氧乙烯脂肪醇醚、聚氧乙烯-聚氧丙烯共聚物和嵌段共聚物、二-(2-乙基己基)琥珀酸酯磺酸钠;助表面活性剂为乙醇、丙二醇、异丙醇、丙三醇、正丁醇、三醋酸甘油酯中的一种或者多种的混合物。 4. The pharmaceutical composition having a skin targeting of claim 1 or claim 2, wherein: the surfactant is a polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene hydrogenated castor oil, lecithin, polyoxyethylene fatty alcohol ethers, polyoxyethylene - polyoxypropylene copolymers and block copolymers, di - (2-ethylhexyl) sodium sulfosuccinate; co-surfactants ethanol, propylene glycol, isopropanol, glycerol, butanol, a mixture of one or more of glycerol triacetate.
5.根据权利要求1或2所述的具有皮肤靶向性的组合物,其特征在于:渗透促进剂为氮酮、薄荷脑、冰片、樟脑、柠檬油精中的一种或多种的混合物。 The targeting composition having a skin of claim 1 or claim 2, wherein: permeation enhancer is Azone A menthol, borneol, camphor, limonene or a mixture of more .
6.权利要求2所述的具有皮肤靶向性的药物组合物的制备方法,其特征在于:将油、表面活性剂、助表面活性剂、皮肤局部用活性药物、渗透促进剂、水混合制得微乳,将凝胶基质加入微乳中,搅拌溶胀后,得到具有皮肤靶向性的药物组合物;或者将油、表面活性剂、助表面活性剂混合得到混合液,将皮肤局部用活性药物、渗透促进剂溶解于混合液中,形成油相,再将水和凝胶基质混合制成水溶胀体,将油相与水溶胀体混合均匀后制得具有皮肤靶向性的药物组合物;或者将皮肤局部用活性药物、渗透促进剂溶解于由油、表面活性剂、助表面活性剂制成的混合液中,形成油相,另将水按1∶0.2~5的比例分成两份,一份加入油相后制成微乳,另一份与凝胶基质混合制成水溶胀体,将微乳与水溶胀体混合均匀后制得具有皮肤靶向性的药物组合物;上述油、 The method of preparing a pharmaceutical composition having a skin of the targeting of claim 2, wherein: the oil, surfactant, cosurfactant, topical skin active agent, penetration enhancer, prepared by mixing water obtained microemulsion, the microemulsion gel matrix was added, stirred swollen to give a pharmaceutical composition having a skin of targeting; or oil, a surfactant, co-surfactant mixture was obtained by mixing the topical skin active drugs, permeation enhancer is dissolved in the mixture to form an oil phase, and the aqueous and mixed to form a water-swellable hydrogel matrix material, the oil phase after water-swellable material having a skin uniformly mixed to prepare a pharmaceutical composition targeted ; or topical skin active drug, permeation enhancer is dissolved in a mixture made of oil, surfactant, co-surfactant, to form an oil phase, and the aqueous further proportion of 0.2 to 5 into two after addition of the oil phase of a microemulsion formed, another blend of water-swellable gel matrix body and the microemulsion mixed with water-swellable prepare pharmaceutical compositions having uniform skin after targeting; of the oil , 面活性剂、助表面活性剂、皮肤局部用活性药物、渗透促进剂、凝胶基质、水的加入量按制得的药物组合物含0.5-10wt%的油、10-80wt%的表面活性剂、3-60wt%助表面活性剂、0-8wt%的渗透促进剂和0.05-8wt%的皮肤局部用活性药物、0-5wt%的凝胶基质及余量的水的比例确定。 Surfactants, co-surfactants, topical skin active agent, penetration enhancers, gel matrix, water is added in an amount according to the obtained pharmaceutical compositions containing 0.5 to 10 wt% of oil, 10-80wt% surfactant , 3-60wt% co-surfactant, 0-8 wt% of permeation enhancer and 0.05-8wt% of the topical skin active agent, the ratio of gel matrix 0-5wt% and the balance of water is determined.
7.权利要求1或2所述的具有皮肤靶向的药物组合物在制备皮肤给药的凝胶剂中的应用。 A pharmaceutical composition having a targeted skin of claim 1 or claim 2 in the preparation of the gelling agent in the dermal administration.
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