CN101244027A治疗皮肤病的蒿甲醚经皮给药制剂---可用于多形性日光疹、 植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗｜CN101244027A: Artemether Transdermal Administration Formulation for Treating Skin Diseases - Suitable for Treating Skin Diseases Such as Polymorphic Light Eruption, Phytophotodermatitis, At
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CN101244027A治疗皮肤病的蒿甲醚经皮给药制剂---可用于多形性日光疹、 植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗
CN101244027A: Artemether Transdermal Administration Formulation for Treating Skin Diseases - Suitable for Treating Skin Diseases Such as Polymorphic Light Eruption, Phytophotodermatitis, Atopic Dermatitis, and Eczema
治疗皮肤病的蒿甲醚经皮给药制剂
本发明涉及一种蒿甲醚的经皮给药制剂，由主药蒿甲醚、透皮吸收促进剂或透皮吸收载体及其他药用辅料组成。研究表明，抗疟药蒿甲醚作为一种新型的免疫调节剂可用于某些皮肤类疾病的治疗。本发明所述经皮给药制剂中的蒿甲醚可直接作用于患处皮肤表面，并能透过表皮进入真皮层及皮下组织，与蒿甲醚其他给药途径相比，可大大增加蒿甲醚在患处皮肤中的药量，以提高疗效，减小剂量。本发明提供了一种蒿甲醚的新剂型，具有给药方便，靶向性强，无皮肤刺激性且制备简便等优点，可用于多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗。
治疗皮肤病的蒿甲醚经皮给药制剂
技术领域
本发明涉及药品技术领域，具体地说是治疗多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的蒿甲醚经皮给药制剂。
背景技术
青蒿素是我国药学工作者1971年从菊科植物黄花蒿叶中提取分离到的一种具有过氧桥的倍半萜内酯类化合物。在此基础上，我国医药界自主研发了青蒿素系列衍生药物如双氢青蒿素、蒿甲醚与青蒿琥酯。青蒿素类药具有高效、速效、低毒的抗疟活性，特别是对脑型疟和抗氯喹恶性疟的疗效尤为突出，被世界卫生组织称为“治疗疟疾的最大希望”。
近年来，药理研究发现青蒿素类药还具有免疫调节作用，可对朗格罕氏细胞产生影响。皮肤及皮下的朗格罕氏细胞具有摄取、加工、处理抗原的作用，作为特异性免疫的启动者，其在免疫过程中扮演着极为重要的角色，而青蒿素类药能抑制朗格罕氏细胞的活性，达到阻断皮肤过度免疫反应的效果。此外，青蒿素类药还可抑制成纤维细胞的增殖，并降低细胞外胶原合成量，使瘢痕明显软化、变平，从而发挥抗瘢痕作用。因此，青蒿素类药物有望增加新的适应症，即应用于一些皮肤类疾病的治疗。
相关临床研究已有报道，邓丹琪等通过口服蒿甲醚胶囊治疗多形性日光疹(32例，有效率84.4％)及慢性光化性皮炎(63例，有效率85.7％)，与阳性对照药硫酸羟氯喹片相比，疗效无显著性差异，且未发现副作用。进一步的实验研究也证实，蒿甲醚对紫外线照射后受损的永生化角质形成细胞株-HaCaT细胞具有一定的保护作用。
发明内容
本发明的目的是提供一种可直接作用于患处皮肤表面，并能透过表皮进入真皮层及皮下组织、提高疗效的治疗皮肤病的蒿甲醚经皮给药制剂。
本发明选择青蒿素衍生物中脂溶性较强(易透皮)且具有一定临床应用基础的蒿甲醚，将其制成经皮给药制剂。
本发明的蒿甲醚经皮给药制剂由主药蒿甲醚、透皮吸收促进剂或透皮吸收载体及其他药用辅料组成，蒿甲醚的重量百分比为0.1～20％。
制剂中蒿甲醚的重量百分比优选范围为0.2～10％。
本发明的蒿甲醚经皮给药制剂包括可供临床使用的各种外用剂型，如：软膏剂、贴剂、凝胶剂、气雾剂、粉雾剂、喷雾剂、散剂、洗剂、搽剂、涂剂、涂膜剂等。
本发明的蒿甲醚经皮给药制剂中所用透皮吸收促进剂包括表面活性剂、二甲基亚砜及其类似物、氮酮类化合物、脂肪酸及其酯、脂肪醇、角质保湿及软化剂、环糊精类、萜类、醇类化合物及植物挥发油中的一种或几种。
本发明的蒿甲醚经皮给药制剂中所用透皮吸收载体包括脂质体、传递体、醇质体、微乳、固体脂质纳米粒、环糊精包合物及非离子表面活性剂囊泡中的一种或几种。
本发明的蒿甲醚经皮给药制剂可根据制备的需要加入其他药用辅料，如：赋形剂、防腐剂等。
本发明的蒿甲醚经皮给药制剂可用于多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗。
本发明的蒿甲醚经皮给药制剂相关实验及结果如下：
1、不同透皮吸收促进剂对蒿甲醚经皮渗透的影响
采用改良Franz扩散池法进行体外透皮试验。将处理好的大鼠腹部皮肤固定于扩散池的接口处，有效扩散面积为2.8cm2，接受池容积7.0mL，30％乙醇为接受液，透皮扩散试验仪的磁力搅拌转速为200r·min-1，水浴温度为32±0.2℃。向供给池中加入2.0mL含不同促透剂(0.5％)的蒿甲醚SDS(1％十二烷基硫酸钠)饱和溶液。分别于1，2，4，6，8，10，12及24h从接受池中取样0.2mL，同时补加等温等体积接受介质。样品用HPLC法测定含量，计算累计透过量(Q)，将Q对渗透时间(t)作图得附图1，二者进行线性回归所得斜率即为渗透速率常数(Js)，24h累计透过量为Qr。24h时，取下皮肤，用棉签蘸取30％乙醇擦去皮肤内外表面残留药物，剪碎，再用无水乙醇提取，测定其中药物含量，得24h皮肤滞留量(Qs)。以蒿甲醚SDS饱和溶液(原药)为对照，不同透皮吸收促进剂对蒿甲醚经皮渗透的影响结果见表1，表明这几种常用促透剂可不同程度地增加蒿甲醚的经皮渗透速率、透过量及皮肤滞留量。
表1不同透皮吸收促进剂组的经皮渗透特性(n＝5)
2、不同透皮吸收载体对蒿甲醚经皮渗透的影响
体外透皮试验方法同上，供给池内分别加入蒿甲醚的各种透皮吸收载体，蒿甲醚SDS饱和溶液(原药)为对照，结果见附图2与表2，表明微乳、醇质体等透皮吸收载体也可使蒿甲醚的经皮渗透速率、透过量及皮肤滞留量显著提高。
表2不同透皮吸收载体组的经皮渗透特性(n＝5)
3、家兔皮肤刺激性试验
取健康雄性家兔12只，体重2.0～2.5kg，随机分为6组，分别为蒿甲醚SDS溶液组、蒿甲醚脂质体组、蒿甲醚传递体组、蒿甲醚醇质体组、蒿甲醚微乳组及蒿甲醚固体脂质纳米粒组。试验前24h，将家兔背部脊柱两侧毛剪短后用10％硫化钠脱去，每侧脱毛面积约为50cm2。分别于左侧皮肤涂以不含药基质作空白对照，右侧涂以等量含药供试制剂，然后用两层纱布覆盖，并用自制兔套固定。给药24h后，去除覆盖物并清除皮肤上残留物后，观察给药部位出现红斑和水肿情况，按表3，4中的标准进行评价，每日给药1次，连续7
d，结果见表5，表明供试蒿甲醚经皮给药制剂无明显的皮肤刺激性。
表3皮肤刺激反应评分标准
表4皮肤刺激强度分级
表5家兔皮肤刺激性试验
本发明的蒿甲醚经皮给药制剂给药后蒿甲醚可直接作用于患处皮肤表面，并能透过表皮进入真皮层及皮下组织，与蒿甲醚现有给药途径(口服与注射)相比，可大大增加蒿甲醚在患处皮肤(靶部位)中的药量，以提高疗效，减小剂量。
附图说明
图1是本发明的不同透皮吸收促进剂组的经皮渗透曲线。
图2是本发明的不同透皮吸收载体组的经皮渗透曲线。
具体实施方式
实施例1
处方：
蒿甲醚 10g 75％乙醇 加至100mL
制法：取蒿甲醚用75％乙醇溶解并定容，即得用于经皮给药的蒿甲醚搽剂，其中乙醇溶液既是溶剂也是消毒剂同时还具有促透作用。
实施例2
处方：
蒿甲醚 20g 氧化锌 20g
冰片 2g 滑石粉 加至100g
制法：取蒿甲醚、氧化锌、薄荷脑及滑石粉细粉(过100目筛)，采用等量递增法充分混合，即得用于经皮给药的蒿甲醚散剂。
实施例3
处方：
蒿甲醚 1g 聚乙烯醇-124 30g
薄荷脑 10g 乙醇 500mL
甘油 100mL 纯化水 加至1000mL
制法：取聚乙烯醇-124加入甘油和水中充分膨胀后，加热使完全溶解；另取蒿甲醚与薄荷脑用乙醇溶解，并在搅拌下缓缓加至聚乙烯醇-124溶液中，再加水至全量，搅匀后迅速分装，密闭，即得用于经皮给药的蒿甲醚涂膜剂。
实施例4
处方：
蒿甲醚 50g 硬脂酸甘油酯 70g
硬脂酸 100g 白凡士林 120g
液状石蜡 100g 甘油 120g
十二烷基硫酸钠 10g 羟苯乙酯 1g
纯化水 480mL
制法：取硬脂酸甘油酯、硬脂酸、白凡士林及液状石蜡加热熔化为油相；另将甘油及水加热至90℃，再加入十二烷基硫酸钠及羟苯乙酯溶解为水相；然后将水相缓缓倒入油相中，边加边搅，直至冷凝；最后将蒿甲醚细粉(过100目筛)加入上述基质中，搅拌均匀，即得用于经皮给药的蒿甲醚乳膏剂。
实施例5
处方：
蒿甲醚 2g 聚丙烯酸树脂Eudragit E100 30g
琥珀酸 2g 癸二酸二丁酯 10g
肉豆蔻酸异丙酯 6g
制法：取处方中的药物及辅料，用适量丙酮-乙醇(2∶1)溶解，将混合液均匀涂布于背衬材料上，自然挥干溶媒，在60℃烘箱中固化10min，冷却后盖上防粘材料，切片，即得用于经皮给药的蒿甲醚贴片。
实施例6
处方：
蒿甲醚 5g 卵磷脂 20g
胆固醇 5g 纯化水 500mL
制法：取蒿甲醚、卵磷脂、胆固醇用适量乙醚溶解，并置于圆底烧瓶中，37℃下减压蒸去乙醚，再加入水，37℃下旋转水合30min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚脂质体。
实施例7
处方：
蒿甲醚 5g 卵磷脂 14g
去氧胆酸钠 4g 纯化水 500mL
制法：取蒿甲醚、卵磷脂、去氧胆酸钠用适量乙醚溶解，并置于圆底烧瓶中，37℃下减压蒸去乙醚，再加入水，37℃下旋转水合30min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚传递体。
实施例8
处方：
蒿甲醚 5g 卵磷脂 15g
乙醇 200mL 纯化水 300mL
制法：取蒿甲醚、卵磷脂溶于乙醇中，将该乙醇液在搅拌下缓慢滴入水中，滴完后持续搅拌10min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚醇质体。
实施例9
处方：
蒿甲醚 16g 油酸 25g
吐温-80 90g 乙醇 135g
纯化水 250mL
制法：取蒿甲醚、油酸、吐温-80及乙醇，充分混匀，搅拌下滴入水，即得用于经皮给药的蒿甲醚微乳。
实施例10
处方：
蒿甲醚 5g 硬脂酸 10g
大豆磷脂 11g 纯化水 500mL
制法：取蒿甲醚、硬脂酸、大豆磷脂，于70℃水浴中用适量无水乙醇溶解得有机相；另取水作为水相，加热至相同温度，将有机相注入水相中，80℃搅拌2h，形成初乳；然后将初乳冰浴探头超声300s，即得用于经皮给药的蒿甲醚固体脂质纳米粒。
实施例11
处方：
蒿甲醚 5g 羟丙基-β-环糊精 30g
制法：取羟丙基-β-环糊精用60mL纯化水溶解，蒿甲醚用适量无水乙醇溶解后在搅拌下滴入羟丙基-β-环糊精溶液中，包合温度为45℃，恒温搅拌5h后停止加热，继续搅拌冷却至室温得包合物溶液，冷冻干燥后研细，过80目筛，即得用于经皮给药的蒿甲醚羟丙基-β-环糊精包合物。
实施例12
处方：
蒿甲醚 1g 司盘-80 20g
胆固醇 10g 纯化水 500mL
制法：将蒿甲醚、司盘-80、胆固醇用适量乙醚溶解，并置于圆底烧瓶中，37℃下减压蒸去乙醚，再加入水，37℃下旋转水合30min，冰浴探头超声60s，即得用于经皮给药的蒿甲醚非离子表面活性剂囊泡。
发明效果
鉴于建立动物模型的困难，以及蒿甲醚注射、口服制剂几十年临床应用的安全性，采用自愿受试者对本发明产品进行试验，结果如下：
本发明不限于以上实施例。
1、一种治疗皮肤病的蒿甲醚经皮给药制剂，其特征在于所述制剂由主药蒿甲醚、透皮吸收促进剂或透皮吸收载体及其他药用辅料组成，蒿甲醚的重量百分比为0.1～20％。
2、根据权利要求1所述的治疗皮肤病的蒿甲醚经皮给药制剂，其特征在于所述的制剂中蒿甲醚的重量百分比为0.2～10％。
3、根据权利要求1或2所述的治疗皮肤病的蒿甲醚经皮给药制剂，其特征在于该制剂包括可供临床使用的各种外用剂型：软膏剂、贴剂、凝胶剂、气雾剂、粉雾剂、喷雾剂、散剂、洗剂、搽剂、涂剂、涂膜剂。
4、根据权利要求1或2所述的蒿甲醚经皮给药制剂，其特征在于该制剂中所用透皮吸收促进剂包括表面活性剂、二甲基亚砜及其类似物、氮酮类化合物、脂肪酸及其酯、脂肪醇、角质保湿及软化剂、环糊精类、萜类、醇类化合物及植物挥发油中的一种或几种。
5、根据权利要求1或2所述的蒿甲醚经皮给药制剂，其特征在于该制剂中所用透皮吸收载体包括脂质体、传递体、醇质体、微乳、固体脂质纳米粒、环糊精包合物及非离子表面活性剂囊泡中的一种或几种。
6、权利要求1或2所述的蒿甲醚经皮给药制剂，其特征在于可用于多形性日光疹、植物日光性皮炎、异位性皮炎及湿疹等皮肤疾病的治疗。
Artemether percutaneous drug administration preparation for treating dermatosis
The invention relates to a transdermal medication preparation of artemether, which comprises artemether as the main drug, transdermal absorption enhancer or percutaneous absorption carrier and other pharmaceutical adjuvants. Antimalarial artemether can be used as a new immunomodulator and can be used for treating certain skin disease as studies show. The artemether of the transdermal medication preparation can directly act on skin surface of patients and enter dermis layer and subcutaneous tissue through penetrating through epidermis. The transdermal medication preparation of artemether can greatly increase dosage of artemether in skin of patients to increase therapeutic effect at lower dosage compared with other administration mode of artemether. The transdermal medication preparation of artemether has the advantages of convenient administration, strong targeting, no skin irritation and simple preparation. The transdermal medication preparation of artemether can be used for treating skin diseases such as polymorphous light eruption, vegetable-solar dermatitis, atopic dermatitis and eczema.
Treat dermopathic artemether percutaneous drug administration preparation
Technical field
The present invention relates to field of pharmaceutical technology, specifically treat the artemether percutaneous drug administration preparation of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.
Background technology
Arteannuin be China pharmacy worker 1971 from feverfew Hemerocallis citrina Baroni mugwort extraction separation to a kind of sesquiterpene lactones compounds with peroxide bridge.On this basis, the independent research of China the world of medicine arteannuin series derivatives medicine such as dihydroarteannuin, Artemether and artesunate.That arteannuin medicine has is efficient, quick-acting, the antimalarial active of low toxicity, and particularly the curative effect to cerebral malaria and anti-chloroquine subtertian malaria is particularly outstanding, is called " maximum of treatment malaria is wished " by World Health Organization (WHO).
In recent years, pharmacological research finds that arteannuin medicine also has immunoregulation effect, can exert an influence to langerhans' cells.Skin and subcutaneous langerhans' cells have picked-up, process, handle antigenic effect, startup person as specific immunity, it is playing the part of very important role in immunologic process, and arteannuin medicine can suppress the activity of langerhans' cells, reaches the excessive immunoreactive effect of blocking-up skin.In addition, arteannuin medicine also can suppress fibroblasts proliferation, and reduces extracellular collagen synthetic quantity, makes cicatrix obviously soften, flatten, thereby brings into play anti-cicatrix effect.Therefore, artemisinin-based drug is expected to increase new indication, promptly is applied to some skin class treatment of diseases.
The existing report of relevant clinical research, Deng Danqi etc. are by oral Artemether capsule for treating polymorphous light eruption (32 examples, effective percentage 84.4%) and farmersskin (63 examples, effective percentage 85.7%), compare with positive control drug hydroxychloroquine sulfate sheet, the curative effect there was no significant difference, and do not find side effect.Further experimentation also confirms, Artemether to ultraviolet radiation after impaired immortalization keratinocyte strain-HaCaT cell have the certain protection effect.
Summary of the invention
The purpose of this invention is to provide a kind of illing skin surface that directly acts on, and can see through the dermopathic artemether percutaneous drug administration preparation of treatment that epidermis enters skin corium and subcutaneous tissue, raising curative effect.
The present invention selects fat-soluble strong (easily transdermal) in the artemisinin derivative and has the Artemether on certain clinical practice basis, is made into percutaneous drug administration preparation.
Artemether percutaneous drug administration preparation of the present invention is made up of principal agent Artemether, Percutaneous absorption enhancer or Transdermal absorption carrier and other pharmaceutic adjuvants, and the percentage by weight of Artemether is 0.1～20%.
The percentage by weight preferable range of Artemether is 0.2～10% in the preparation.
Artemether percutaneous drug administration preparation of the present invention comprises can be for the various exterior-applied formulations of clinical use, as: ointment, patch, gel, aerosol, powder spray, spray, powder, lotion, liniment, varnish, liniment etc.
Used Percutaneous absorption enhancer comprises surfactant, dimethyl sulfoxide and analog thereof, azone compounds, fatty acid and ester thereof, aliphatic alcohol in the artemether percutaneous drug administration preparation of the present invention, cutin is preserved moisture and softening agent, cyclodextrin, terpenoid, alcohol compound and plant volatile oil in one or more.
Used Transdermal absorption carrier comprises one or more in liposome, carrier, ethosome, microemulsion, solid lipid nanoparticle, cyclodextrin clathrate and the nonionic surfactant vesicle in the artemether percutaneous drug administration preparation of the present invention.
Artemether percutaneous drug administration preparation of the present invention can add other pharmaceutic adjuvants according to the needs of preparation, as: excipient, antiseptic etc.
Artemether percutaneous drug administration preparation of the present invention can be used for the treatment of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.
Artemether percutaneous drug administration preparation related experiment of the present invention and result are as follows:
1, different Percutaneous absorption enhancers are to the influence of artemether percutaneous infiltration
Adopt improvement Franz diffusion cell method to carry out the transdermal test in vitro test.The rat abdomen skin of handling well is fixed in the seam of diffusion cell, and effectively diffusion area is 2.8cm 2, accept pool volume 7.0mL, 30% ethanol is acceptable solution, the magnetic agitation rotating speed of transdermal diffusion test instrument is 200rmin -1, bath temperature is 32 ± 0.2 ℃.In supply pool, add Artemether SDS (1% sodium lauryl sulphate) saturated solution that 2.0mL contains different penetration enhancer (0.5%).Respectively at 1,2,4,6,8,10,12 and the 24h 0.2mL that from accept the pond, takes a sample, add the isothermal equal-volume simultaneously and accept medium.Sample is measured content with the HPLC method, calculates accumulative total transit dose (Q), with Q to time of penetration (t) map accompanying drawing 1, the two carries out linear regression gained slope and is infiltration rate constant (Js), 24h accumulative total transit dose is Qr.During 24h, take off skin, dip in cotton swab and get 30% ethanol and wipe skin surfaces externally and internally left drug, shred, the reuse dehydrated alcohol extraction is measured wherein medicament contg, 24h skin hold-up (Qs).With Artemether SDS saturated solution (former medicine) is contrast, different Percutaneous absorption enhancers the results are shown in Table 1 to the influence of artemether percutaneous infiltration, show that these several penetration enhancer commonly used can increase transdermal penetration speed, transit dose and the skin hold-up of Artemether to some extent.
The transdermal penetration characteristic (n=5) of the different Percutaneous absorption enhancer groups of table 1
2, different Transdermal absorption carriers are to the influence of artemether percutaneous infiltration
The transdermal test in vitro test method is the same, the various Transdermal absorption carriers that add Artemether in the supply pool respectively, Artemether SDS saturated solution (former medicine) is contrast, the results are shown in accompanying drawing 2 and table 2, show that Transdermal absorption carriers such as microemulsion, ethosome also can make transdermal penetration speed, transit dose and the skin hold-up of Artemether significantly improve.
The transdermal penetration characteristic (n=5) of the different Transdermal absorption vehicle group of table 2
3, rabbit skin irritation test
Get 12 of healthy male rabbits, body weight 2.0～2.5kg is divided into 6 groups at random, is respectively Artemether SDS solution group, Artemether liposome group, Artemether carrier group, Artemether ethosome group, Artemether microemulsion group and Artemether solid lipid nanoparticle group.24h before the test cuts short the back with tame rabbit back spinal column diamond wool and sloughs with 10% sodium sulfide, and every side depilation area is about 50cm 2Be coated with pastille substrate not respectively at left side skin and make blank, the right side is coated with the equivalent pastille for test preparation, covers with two-layer gauze then, and overlaps with the self-control rabbit and to fix.Behind the administration 24h, dismantle and remove on the skin behind the residue, observe medicine-feeding part and erythema and edema situation occur, press table 3, the standard in 4 is estimated administration every day 1 time, continuous 7
D the results are shown in Table 5, and showing for the examination artemether percutaneous drug administration preparation does not have tangible skin irritation.
Table 3 skin irritation reaction standards of grading
Table 4 skin irritation strength grading
Table 5 rabbit skin irritation test
Artemether can directly act on the illing skin surface after the artemether percutaneous drug administration preparation administration of the present invention, and can enter skin corium and subcutaneous tissue through epidermis, compare with the existing route of administration of Artemether (oral with inject), can increase the dose of Artemether in illing skin (target site) greatly, to improve curative effect, reduce dosage.
Description of drawings
Fig. 1 is the transdermal penetration curve of different Percutaneous absorption enhancer groups of the present invention.
Fig. 2 is the transdermal penetration curve of different Transdermal absorption vehicle group of the present invention.
The specific embodiment
Embodiment 1
Prescription:
Artemether 10g 75% ethanol adds to 100mL
Method for making: get Artemether with 75% dissolve with ethanol and standardize solution, promptly get the Artemether liniment that is used for percutaneous dosing, wherein alcoholic solution be solvent also be that disinfectant also has transdermal enhancing effect simultaneously.
Embodiment 2
Prescription:
Artemether 20g zinc oxide 20g
Borneolum Syntheticum 2g Pulvis Talci adds to 100g
Method for making: get Artemether, zinc oxide, Mentholum and Pulvis Talci fine powder (crossing 100 mesh sieves), adopt the equivalent incremental method fully to mix, promptly get the Artemether powder that is used for percutaneous dosing.
Embodiment 3
Prescription:
Artemether 1g polyvinyl alcohol-124 30g
Mentholum 10g ethanol 500mL
Glycerol 100mL purified water adds to 1000mL
Method for making: get polyvinyl alcohol-124 add fully expand in the G ﹠ W after, heating makes dissolving fully; Other gets Artemether and Mentholum dissolve with ethanol, and under agitation slowly adds in polyvinyl alcohol-124 solution, adds water to full dose again, stirs evenly back packing rapidly, and is airtight, promptly gets the Artemether liniment that is used for percutaneous dosing.
Embodiment 4
Prescription:
Artemether 50g tristerin 70g
Stearic acid 100g white vaseline 120g
Liquid Paraffin 100g glycerol 120g
Sodium lauryl sulphate 10g ethyl hydroxybenzoate 1g
Purified water 480mL
Method for making: getting tristerin, stearic acid, white vaseline and liquid Paraffin heat fused is oil phase; In addition glycerol and water are heated to 90 ℃, add sodium lauryl sulphate again and ethyl hydroxybenzoate is dissolved as water; Then water is slowly poured in the oil phase, the limit edged stirs, until condensation; At last Artemether fine powder (crossing 100 mesh sieves) is added in the above-mentioned substrate, stir, promptly get the Artemether ointment that is used for percutaneous dosing.
Embodiment 5
Prescription:
Artemether 2g polyacrylic resin Eudragit E 10030g
Succinic acid 2g dibutyl sebacate 10g
Isopropyl myristate 6g
Method for making: get medicine and adjuvant in the prescription,, evenly coat mixed liquor on the back lining materials with proper amount of acetone-ethanol (2: 1) dissolving, naturally volatilize solvent, in 60 ℃ of baking ovens, solidify 10min, adhesive on the cooling bonnet, section promptly gets the Artemether paster that is used for percutaneous dosing.
Prescription:
Artemether 5g lecithin 20g
Cholesterol 5g purified water 500mL
Method for making: get Artemether, lecithin, an amount of ether dissolution of cholesterol, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether add entry again, and 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether liposome that is used for percutaneous dosing.
Embodiment 7
Prescription:
Artemether 5g lecithin 14g
Sodium deoxycholate 4g purified water 500mL
Method for making: get Artemether, lecithin, an amount of ether dissolution of sodium deoxycholate, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether, add entry again, 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether carrier that is used for percutaneous dosing.
Embodiment 8
Prescription:
Artemether 5g lecithin 15g
Ethanol 200mL purified water 300mL
Method for making: get Artemether, lecithin is dissolved in the ethanol, and this ethanol liquid is under agitation slowly splashed in the water, drip off the back and continue to stir 10min, the ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether ethosome that is used for percutaneous dosing.
Embodiment 9
Prescription:
Artemether 16g oleic acid 25g
Tween 80 90g ethanol 135g
Purified water 250mL
Method for making: get Artemether, oleic acid, tween 80 and ethanol, fully mixing splashes into water under stirring, and promptly gets the Artemether microemulsion that is used for percutaneous dosing.
Embodiment 10
Prescription:
Artemether 5g stearic acid 10g
Soybean phospholipid 11g purified water 500mL
Method for making: get Artemether, stearic acid, soybean phospholipid, in 70 ℃ of water-baths, get organic facies with an amount of anhydrous alcohol solution; Water intaking is heated to uniform temp as water in addition, and organic facies is injected aqueous phase, and 80 ℃ are stirred 2h, form colostrum; The ultrasonic 300s that then the colostrum ice bath popped one's head in promptly gets the Artemether solid lipid nanoparticle that is used for percutaneous dosing.
Embodiment 11
Prescription:
Artemether 5g HP-30g
Method for making: get HP-and dissolve with the 60mL purified water, Artemether under agitation splashes in the HP-solution after with an amount of anhydrous alcohol solution, the enclose temperature is 45 ℃, constant temperature stops heating after stirring 5h, the continuation stirring is cooled to room temperature and gets inclusion complex in solution, porphyrize after the lyophilization is crossed 80 mesh sieves, promptly gets the Artemether hydroxypropyl-beta-cyclodextrin inclusion that is used for percutaneous dosing.
Embodiment 12
Prescription:
Artemether 1g Arlacel-80 20g
Cholesterol 10g purified water 500mL
Method for making: with an amount of ether dissolution of Artemether, Arlacel-80, cholesterol, and place round-bottomed flask, 37 ℃ of following pressure reducing and steaming ether, add entry again, 37 ℃ of following rotation hydration 30min, ice bath ultrasonic 60s that pops one's head in promptly gets the Artemether nonionic surfactant vesicle that is used for percutaneous dosing.
The invention effect
In view of the difficulty of setting up animal model, and Artemether is injected, the safety of oral formulations clinical practice decades, adopts the volunteer that product of the present invention is tested, and the result is as follows:
The invention is not restricted to above embodiment.
1, the dermopathic artemether percutaneous drug administration preparation of a kind of treatment is characterized in that described preparation is made up of principal agent Artemether, Percutaneous absorption enhancer or Transdermal absorption carrier and other pharmaceutic adjuvants, and the percentage by weight of Artemether is 0.1～20%.
2, the dermopathic artemether percutaneous drug administration preparation of treatment according to claim 1, the percentage by weight that it is characterized in that Artemether in the described preparation is 0.2～10%.
3, the dermopathic artemether percutaneous drug administration preparation of treatment according to claim 1 and 2, it is characterized in that said preparation comprises can be for the various exterior-applied formulation of clinical use: ointment, patch, gel, aerosol, powder spray, spray, powder, lotion, liniment, varnish, liniment.
4, artemether percutaneous drug administration preparation according to claim 1 and 2, it is characterized in that used Percutaneous absorption enhancer comprises surfactant, dimethyl sulfoxide and analog thereof, azone compounds, fatty acid and ester thereof, aliphatic alcohol in the said preparation, cutin is preserved moisture and softening agent, cyclodextrin, terpenoid, alcohol compound and plant volatile oil in one or more.
5, artemether percutaneous drug administration preparation according to claim 1 and 2 is characterized in that used Transdermal absorption carrier in the said preparation comprises one or more in liposome, carrier, ethosome, microemulsion, solid lipid nanoparticle, cyclodextrin clathrate and the nonionic surfactant vesicle.
6, claim 1 or 2 described artemether percutaneous drug administration preparations is characterized in that can be used for the treatment of dermatosis such as polymorphous light eruption, Phytophotodermatitis, atoipc dermatitis and eczema.
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