醇质体促进脂溶性药物经皮渗透的机制研究

发布时间：2018-12-06 15:04

【摘要】：研究背景细菌、真菌、病毒感染、红斑鳞屑性等皮肤病的发病率逐渐升高,其所用的外用药物剂型多为脂溶性药物,剂型多为霜膏剂、乳剂等常规剂型,但由于角质层的存在,易导致外用药物的透皮吸收率低。近年来,虽然出现了不少物理、化学方法以改善药物透皮吸收不足,但由于存在如操作繁琐、皮肤损伤、费用偏高等问题,因此,在临床的有效应用仍有较大限制。鉴于目前传统皮肤外用剂型临床疗效在实际应用上存在的不足,新型经皮给药在体的研发显得极为迫切,目前也有不少新型制剂处于临床前研究阶段,其中,醇质体作为新型经皮给药载体,首先由Touitou提出,其主要组分包括磷脂、高浓度乙醇、胆固醇、表面活性剂等,由于其独特的药效学特性已经而成为经皮载体热点之一,然迄今为止,其经皮机制仍未明确,尤其聚焦于以下三个问题:1、醇质体何种成分决定了其优越的经皮渗透性?2、醇质体是否以完整的囊泡成分经皮渗透?3、醇质体携带药物经皮渗透的具体过程如何?我们相信,以上渗透机制问题的阐明,将对醇质体应用于相关临床疾病的经皮给药方面,如皮肤肿瘤的治疗、皮肤美容的应用,靶向药物的前瞻性研究等都有重要的指导意义。研究目的研究和阐明醇质体促脂溶性药物经皮渗透的三个重要问题。研究方法采用Box-Behnken效应面法筛选醇质体制备的最优配方后,比较罗丹明B在不同剂型中的经皮渗透性,最后通过双荧光标记示踪技术,研究醇质体促进脂溶性药物经皮渗透的机制。研究结果1.醇质体最优处方筛选结果最优处方为:罗丹明B为0.02%,蛋黄软磷脂为2.45%,无水乙醇30%,超声时间为8min。罗丹明B醇质体外观淡红色,粒径125.7±3.2nm,PDI0.199±0.014(n=3)。罗丹明B脂质体外观颜色深红色,粒径205.4±3.2nm,PDI0.368±0.034(n=3)。2.罗丹明B醇质体、脂质体、酊剂的在体经皮渗透研究经皮渗透1、4、8h后,罗丹明B醇质体在经皮渗透的平均荧光强度与脂质体、酊剂相比均有统计学差异,罗丹明B酊剂与脂质体比较无统计学差异。3.醇质体促进脂溶性药物经皮渗透的机制研究醇质体经皮渗透过程中,随时间变化,绿色荧光一直滞留在表皮浅层、毛囊,红色荧光分布在表皮、真皮层、毛囊。研究结论1.Box-Behnken效应面法为筛选醇质体的处方的较优方法,所制备的醇质体均一、稳定。2.醇质体促进脂溶性药物经皮渗透的优越性来源于乙醇、磷脂、囊泡系统与皮肤角质层的协同作用,并非单纯是一种或几种成分的单独效应。3.醇质体透皮机制的研究提示毛囊可作为皮肤外用制剂透皮的快速通道。4.醇质体促进脂溶性药物经皮渗透的机制可能为:醇质体外用于皮肤后,由于其不同成分的协同作用,经由皮肤附属器毛囊途径和角质层途径渗透。醇质体无法以完整囊泡形态经皮渗透,囊泡在表皮浅层破裂,释放药物,脂溶性药物继续往皮肤深层渗透,而脂质成分则滞留在表皮浅层。
[Abstract]:Background the incidence of skin diseases such as bacteria, fungi, virus infection, erythema scale, etc., is gradually increasing. The drug formulations used for external use are mostly fat-soluble drugs, and the dosage forms are usually cream plasters, emulsions, etc., but due to the presence of the cuticle, It is easy to lead to low transdermal absorption rate of topical drugs. In recent years, although there are many physical and chemical methods to improve drug transdermal absorption deficiencies, but due to such problems as cumbersome operation, skin injury, high cost, etc., the effective application in clinic is still limited. In view of the deficiency of the clinical efficacy of the traditional skin topical dosage form, the research and development of the new transdermal drug in vivo is extremely urgent. At present, many new formulations are in the stage of preclinical research, among which, As a new type of transdermal drug delivery carrier, Alcohol was firstly proposed by Touitou. Its main components include phospholipid, high concentration ethanol, cholesterol, surfactant and so on. It has become one of the hot spots of transdermal carrier because of its unique pharmacodynamic properties. However, the transdermal mechanism is still unclear, especially focusing on the following three questions: 1. Which components of alcoholplasts determine their superior transdermal permeability? 2. What is the specific process of transdermal penetration of alcoholplasts carrying drugs? We believe that the elucidation of the above osmotic mechanism will be of great significance for the application of alcoholplasts in the transdermal administration of related clinical diseases, such as the treatment of skin tumors, the application of skin beauty, and the prospective study of targeted drugs. Objective to study and elucidate three important problems of transdermal penetration of lipophilic drugs. Methods after Box-Behnken effect surface method was used to screen the optimal formulation for the preparation of alcoholplasts, the transdermal permeability of Rhodamine B in different dosage forms was compared, and the double fluorescent tracer technique was used. To study the mechanism of alcohol plastids promoting the transdermal permeation of liposoluble drugs. Results 1. The optimum prescription was rhodamine B (0.02), egg yolk soft phospholipid (2.45), anhydrous ethanol (30%) and ultrasonic time (8 min). Rhodamine B alcoholplast was light red with a diameter of 125.7 卤3.2 nm, PDI _ (0.199 卤0.014) (n ~ (3). The appearance color of Rhodamine B liposome was dark red with a diameter of 205.4 卤3.2nmPdI0.368 卤0.034 (Nm3). Study on percutaneous permeation of rhodamine B alcoholplast, liposome and tincture the average fluorescence intensity of rhodamine B alcoholplast was significantly different from that of liposome and tincture. There was no significant difference between Rhodamine B tincture and liposome. Study on the Mechanism of Alcohol Plastids promoting Percutaneous Permeation of liposoluble drugs; during transdermal permeation of alcoholplasts, green fluorescence remained in the superficial layer of epidermis, hair follicle, red fluorescence in epidermis, dermis and hair follicle with the change of time. Conclusion 1.Box-Behnken effect surface method is the best method for the screening of alcoholplasts, and the prepared alcohols are uniform and stable. 2. The superiority of alcohol plastids in promoting the transdermal permeation of liposoluble drugs is derived from the synergistic effect of ethanol, phospholipid, vesicle system and skin keratinocytes, and is not a single effect of one or several components. The study of transdermal mechanism of alcoholplast suggests that hair follicles can be used as a fast transdermal pathway for skin preparation. 4. The mechanism of promoting lipophilic drug transdermal permeation may be: after the use of alcohol in skin in vitro, because of the synergistic effect of different components, it can be permeated through the hair follicle pathway and cuticle pathway of skin appendage. The alcoholplast could not penetrate through the skin in the form of intact vesicles, and the vesicles ruptured in the superficial layer of epidermis, released the drug, and the liposoluble drugs continued to permeate deeply into the skin, while the lipid component remained in the superficial layer of the epidermis.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R986

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