醇質(zhì)體促進(jìn)脂溶性藥物經(jīng)皮滲透的機(jī)制研究
發(fā)布時(shí)間：2018-12-06 15:04
【摘要】：研究背景細(xì)菌、真菌、病毒感染、紅斑鱗屑性等皮膚病的發(fā)病率逐漸升高,其所用的外用藥物劑型多為脂溶性藥物,劑型多為霜膏劑、乳劑等常規(guī)劑型,但由于角質(zhì)層的存在,易導(dǎo)致外用藥物的透皮吸收率低。近年來(lái),雖然出現(xiàn)了不少物理、化學(xué)方法以改善藥物透皮吸收不足,但由于存在如操作繁瑣、皮膚損傷、費(fèi)用偏高等問(wèn)題,因此,在臨床的有效應(yīng)用仍有較大限制。鑒于目前傳統(tǒng)皮膚外用劑型臨床療效在實(shí)際應(yīng)用上存在的不足,新型經(jīng)皮給藥在體的研發(fā)顯得極為迫切,目前也有不少新型制劑處于臨床前研究階段,其中,醇質(zhì)體作為新型經(jīng)皮給藥載體,首先由Touitou提出,其主要組分包括磷脂、高濃度乙醇、膽固醇、表面活性劑等,由于其獨(dú)特的藥效學(xué)特性已經(jīng)而成為經(jīng)皮載體熱點(diǎn)之一,然迄今為止,其經(jīng)皮機(jī)制仍未明確,尤其聚焦于以下三個(gè)問(wèn)題:1、醇質(zhì)體何種成分決定了其優(yōu)越的經(jīng)皮滲透性?2、醇質(zhì)體是否以完整的囊泡成分經(jīng)皮滲透?3、醇質(zhì)體攜帶藥物經(jīng)皮滲透的具體過(guò)程如何?我們相信,以上滲透機(jī)制問(wèn)題的闡明,將對(duì)醇質(zhì)體應(yīng)用于相關(guān)臨床疾病的經(jīng)皮給藥方面,如皮膚腫瘤的治療、皮膚美容的應(yīng)用,靶向藥物的前瞻性研究等都有重要的指導(dǎo)意義。研究目的研究和闡明醇質(zhì)體促脂溶性藥物經(jīng)皮滲透的三個(gè)重要問(wèn)題。研究方法采用Box-Behnken效應(yīng)面法篩選醇質(zhì)體制備的最優(yōu)配方后,比較羅丹明B在不同劑型中的經(jīng)皮滲透性,最后通過(guò)雙熒光標(biāo)記示蹤技術(shù),研究醇質(zhì)體促進(jìn)脂溶性藥物經(jīng)皮滲透的機(jī)制。研究結(jié)果1.醇質(zhì)體最優(yōu)處方篩選結(jié)果最優(yōu)處方為:羅丹明B為0.02%,蛋黃軟磷脂為2.45%,無(wú)水乙醇30%,超聲時(shí)間為8min。羅丹明B醇質(zhì)體外觀淡紅色,粒徑125.7±3.2nm,PDI0.199±0.014(n=3)。羅丹明B脂質(zhì)體外觀顏色深紅色,粒徑205.4±3.2nm,PDI0.368±0.034(n=3)。2.羅丹明B醇質(zhì)體、脂質(zhì)體、酊劑的在體經(jīng)皮滲透研究經(jīng)皮滲透1、4、8h后,羅丹明B醇質(zhì)體在經(jīng)皮滲透的平均熒光強(qiáng)度與脂質(zhì)體、酊劑相比均有統(tǒng)計(jì)學(xué)差異,羅丹明B酊劑與脂質(zhì)體比較無(wú)統(tǒng)計(jì)學(xué)差異。3.醇質(zhì)體促進(jìn)脂溶性藥物經(jīng)皮滲透的機(jī)制研究醇質(zhì)體經(jīng)皮滲透過(guò)程中,隨時(shí)間變化,綠色熒光一直滯留在表皮淺層、毛囊,紅色熒光分布在表皮、真皮層、毛囊。研究結(jié)論1.Box-Behnken效應(yīng)面法為篩選醇質(zhì)體的處方的較優(yōu)方法,所制備的醇質(zhì)體均一、穩(wěn)定。2.醇質(zhì)體促進(jìn)脂溶性藥物經(jīng)皮滲透的優(yōu)越性來(lái)源于乙醇、磷脂、囊泡系統(tǒng)與皮膚角質(zhì)層的協(xié)同作用,并非單純是一種或幾種成分的單獨(dú)效應(yīng)。3.醇質(zhì)體透皮機(jī)制的研究提示毛囊可作為皮膚外用制劑透皮的快速通道。4.醇質(zhì)體促進(jìn)脂溶性藥物經(jīng)皮滲透的機(jī)制可能為:醇質(zhì)體外用于皮膚后,由于其不同成分的協(xié)同作用,經(jīng)由皮膚附屬器毛囊途徑和角質(zhì)層途徑滲透。醇質(zhì)體無(wú)法以完整囊泡形態(tài)經(jīng)皮滲透,囊泡在表皮淺層破裂,釋放藥物,脂溶性藥物繼續(xù)往皮膚深層滲透,而脂質(zhì)成分則滯留在表皮淺層。
[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 鹵3.2 nm, PDI _ (0.199 鹵0.014) (n ~ (3). The appearance color of Rhodamine B liposome was dark red with a diameter of 205.4 鹵3.2nmPdI0.368 鹵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.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R986
[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 鹵3.2 nm, PDI _ (0.199 鹵0.014) (n ~ (3). The appearance color of Rhodamine B liposome was dark red with a diameter of 205.4 鹵3.2nmPdI0.368 鹵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.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R986
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