本文關(guān)鍵詞： 醇質(zhì)體 盧立康唑 透皮吸收 最小抑菌濃度　出處：《中國(guó)人民解放軍醫(yī)學(xué)院》2014年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：研究背景 盧立康唑是一種新型的咪唑類(lèi)抗真菌新藥。它通過(guò)抑制麥角固醇的生物合成，，發(fā)揮抗真菌作用。因其具有優(yōu)秀的抗菌活性，近年受到臨床研究的廣泛關(guān)注。另一方面，在藥物傳遞系統(tǒng)中，醇質(zhì)體作為一種新的藥物載體，也越來(lái)越受到關(guān)注。醇質(zhì)體是由脂質(zhì)體中添加乙醇演變而來(lái)，特有的理化性質(zhì)使其能更有效的攜帶藥物通過(guò)角質(zhì)層釋放至皮膚各層。因此，新型藥物盧立康唑的醇質(zhì)體制劑可成為擴(kuò)大皮膚科抗真菌藥物經(jīng)皮給藥的理想選擇。研究盧立康唑醇質(zhì)體的處方配比及理化性質(zhì)為本課題研究目的之一。同時(shí)進(jìn)一步分析盧立康唑醇質(zhì)體體外透皮效果及體外抗菌活性為本課題研究目的之二。 目的 1、盧立康唑優(yōu)秀的抗菌活性和醇質(zhì)體制劑透皮性好、載藥量高等優(yōu)點(diǎn)結(jié)合，使得本研究以制備盧立康唑醇質(zhì)體為研究切入點(diǎn)，以期充分發(fā)揮盧立康唑的局部藥理作用，為皮膚科臨床抗菌藥物的選擇提供研發(fā)新思路。 2、本研究通過(guò)對(duì)醇質(zhì)體制備工藝、評(píng)價(jià)方法的篩選，為今后其他醇質(zhì)體制劑的研發(fā)提供實(shí)驗(yàn)室依據(jù)和思路選擇。 3、為了科學(xué)、準(zhǔn)確的評(píng)價(jià)盧立康唑醇質(zhì)體局部藥效機(jī)制，體外透皮效果采用Franz擴(kuò)散池檢測(cè)，并進(jìn)行體外抗菌活性MIC的測(cè)定，研究盧立康唑醇質(zhì)體的透皮性能和抗菌能力，為該藥的外用制劑臨床研究提供科學(xué)的數(shù)據(jù)。 4、為評(píng)價(jià)盧立康唑醇質(zhì)體制備的可行性，將從制備方法到檢測(cè)手段進(jìn)行有效數(shù)據(jù)評(píng)價(jià)，并考察最優(yōu)處方醇質(zhì)體的理化性質(zhì)，為臨床應(yīng)用的大規(guī)模制備提供實(shí)驗(yàn)室依據(jù)。 實(shí)驗(yàn)方法 1、醇質(zhì)體的制備：醇質(zhì)體制備采用薄膜法與注入法的比較。 2、醇質(zhì)體粒徑分析：激光動(dòng)態(tài)散射儀檢測(cè)并分析醇質(zhì)體粒徑。 3、醇質(zhì)體的包封率(EE%)：未包封的部分采用超速離心法及透析法分離，后進(jìn)行高效液相色譜法（HPLC）檢測(cè)藥物含量，并進(jìn)行數(shù)據(jù)比較。 4、藥物的HPLC檢測(cè)：均在室溫下進(jìn)行，以乙腈-0.1%磷酸二氫胺為流動(dòng)相，紫外分光光度計(jì)測(cè)量數(shù)據(jù)為檢測(cè)波長(zhǎng)，進(jìn)行精密度及回收率等方法學(xué)的研究。 5、醇質(zhì)體的形態(tài)學(xué)觀察：采用透射電鏡進(jìn)行觀察分析。 6、體外大鼠皮膚透皮實(shí)驗(yàn)：采用Franz擴(kuò)散池進(jìn)行離體大鼠皮膚透皮實(shí)驗(yàn)。 7、盧立康唑醇質(zhì)體體外抗菌活性研究：微量液基稀釋法。 實(shí)驗(yàn)結(jié)果 1、盧立康唑醇質(zhì)體的制備研究中發(fā)現(xiàn)，薄膜分散法在藥物包封率、粒徑等方面優(yōu)于文獻(xiàn)中常應(yīng)用的注入法；且評(píng)價(jià)工藝中超速離心法較透析法更簡(jiǎn)潔、快速。 2、本研究結(jié)果發(fā)現(xiàn)乙醇濃度和磷脂量對(duì)盧立康唑醇質(zhì)體的包封率有正相關(guān)；而乙醇濃度與醇質(zhì)體的粒徑有負(fù)相關(guān)，醇質(zhì)體的粒徑隨磷脂量增加而增大。采用粒徑、包封率為指標(biāo)進(jìn)行選擇最優(yōu)化處方，發(fā)現(xiàn)醇質(zhì)體制劑在卵磷脂為5%(w/v)、乙醇為45%(v/v)、超聲時(shí)間8min處方配比下，粒徑小、粒徑分布均勻和包封率高，盧立康唑醇質(zhì)體中藥物包封率達(dá)到了70%。 3、盧立康唑醇質(zhì)體及非醇質(zhì)體制劑體外透皮實(shí)驗(yàn)比較，結(jié)果顯示：透皮速率盧立康唑醇質(zhì)體軟膏制劑脂質(zhì)體水醇溶液，24小時(shí)透皮量醇質(zhì)體優(yōu)于其他劑型，48小時(shí)皮膚全層滯留量醇質(zhì)體與軟膏相當(dāng)，優(yōu)于脂質(zhì)體及水醇溶液。 4、盧立康唑不同制劑的體外抑菌實(shí)驗(yàn)結(jié)果表示，盧立康唑醇質(zhì)體的抑菌效果優(yōu)于脂質(zhì)體及水醇溶液，且對(duì)毛癬菌屬較念珠菌屬敏感程度更高。 結(jié)論 1、采用薄膜法技術(shù)制備的醇質(zhì)體，具有包封率高、透皮率好的優(yōu)點(diǎn)。 2、最優(yōu)化處方顯示，在卵磷脂為5%(w/v)、乙醇為45%(v/v)、超聲時(shí)間8分鐘的處方配比下，盧立康唑醇質(zhì)體制劑粒徑較小、包封率高。且具有刺激性小、穩(wěn)定性好等特點(diǎn)。 3、醇質(zhì)體較脂質(zhì)體、水醇溶液及即將上市的軟膏透皮性能好。 4、體外實(shí)驗(yàn)，盧立康唑醇質(zhì)體的抗菌性能優(yōu)于脂質(zhì)體及水醇溶液。
[Abstract]:Research background
Lu voriconazole is a new type of imidazole antifungal drug. It through inhibiting the biosynthesis of ergosterol, play anti fungal effect. Because of its excellent antibacterial activity in recent years has attracted extensive attention in clinical research. On the other hand, in the drug delivery system, ethosomes as a novel drug carrier, and more attention. Ethosomes is by adding ethanol in the liposome evolution, unique physicochemical properties make it more effective to carry drugs through the layers of cuticle release to the skin. Therefore, alcohol quality system agent of new drug voriconazole Lu can be formed by the expansion of the Department of Dermatology antifungal drug transdermal delivery ideal. Study on Lu Likang with ethosomes formula and physicochemical properties is one of the purposes of this research. At the same time, further analysis of Lu voriconazole ethosomes in vitro antibacterial activity for the purpose of this study and in vitro transdermal effect Two.
objective
1, Lu voriconazole excellent antibacterial activity and preparation of ethosomes transdermal drug loading, the advantages of combination, make the research on the preparation of Lu voriconazole ethosomes as a point of entry, in order to give full play to local pharmacological effects of Lu voriconazole, provide new ideas for clinical research in Department of dermatology in the choice of antibiotics.
2, this study provides laboratory basis and ideas for the research and development of other alcohols preparation in the future through the preparation of the alcohols system and the screening of evaluation methods.
3, in order to scientific, accurate evaluation of Lu voriconazole ethosomes local pharmacodynamic mechanism, in vitro transdermal effect by using Franz diffusion cell detection and determination of in vitro antibacterial activity of MIC on Lu Likang with ethosomes transdermal performance and antibacterial ability, provide scientific data for clinical study of topical formulations of this drug.
4, in order to evaluate the feasibility of the preparation of loziconazole, we will evaluate the effective data from the preparation methods to the detection methods, and investigate the physicochemical properties of the best prescription, and provide a laboratory basis for large-scale preparation of clinical application.
Experimental method
1, preparation of alcohol plastids: the preparation of alcohol plastids is compared with the film method and the injection method.
2, the particle size analysis of the alcohol plastid: the laser dynamic scatterometer was used to detect and analyze the particle size of the plastid.
3, the encapsulation efficiency of alcohol body (EE%): the unencapsulated part was separated by ultracentrifugation and dialysis. Then the content of the drug was detected by high performance liquid chromatography (HPLC), and the data were compared.
4, HPLC detection of drugs: they are all carried out at room temperature, with acetonitrile, -0.1% phosphoric acid, two hydrogen amine as mobile phase, UV spectrophotometer data for wavelength detection, precision and recovery methods.
5, the morphological observation of the alcohol plastids: observation and analysis by transmission electron microscope.
6, skin transdermal experiment of rats in vitro: the skin transdermal experiment of rats in vitro was carried out by Franz diffusion pool.
7, the in vitro antibacterial activity of Lu Likang zolzol plastid: microdilution based dilution method.
experimental result
1, the preparation of Lu Likang azolium was found to be superior to the commonly used injection method in the drug entrapment efficiency and particle size in the study of drug entrapment efficiency and particle size. Moreover, the ultracentrifugation method is simpler and faster than the dialysis method in the evaluation process.
2, the results of this study found that ethanol concentration and amount of phospholipid Lu voriconazole ethosome encapsulation rate have positive correlation; and ethanol concentration and particle size of ethosomes was negatively related, ethosomes size increases with increasing amount of phospholipid. The particle size, encapsulation efficiency as the index of choosing the optimum prescription found, ethosome preparation in lecithin was 5% (w/v), ethanol is 45% (v/v), ultrasonic time 8min formula, small particle size, uniform particle size distribution and high encapsulation efficiency, Lu Likang with ethosome encapsulation rate reached 70%.
3, skin penetration experiments, Lu Likang with ethosomes and non alcohol plastid preparations in vitro results showed that the permeation rate of Lu Likang ethosomes ointment liposome water alcohol solution, 24 hours of transdermal ethosomes than other formulations, 48 hours of full-thickness skin retention of ethosomes and ointment is better than that of liposome and phase when. Water alcohol solution.
4, in vitro antibacterial experiment results of different preparations of lupinazole indicated that the antibacterial effect of Lu Likang azole alcohol body was better than that of liposomes and water alcohol solution, and it was more sensitive to Trichophyton than Candida.
conclusion
1, the alcohol plastids prepared by thin film technology have the advantages of high encapsulation efficiency and good transdermal rate.
2, the optimized prescription showed that when the lecithin was 5% (w/v), the ethanol was 45% (v/v), and the ultrasonic time was 8 minutes, the Lu Likang azole liposome preparation had smaller particle size, higher entrapment efficiency and less irritation and good stability.
3, the polythol is better than the liposome, the aqueous alcohol solution and the ointment that will be listed on the market.
4, in vitro, the antiseptic performance of Lu Likang azolol was better than that of liposome and aqueous alcohol solution.

【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R943;R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 呂立華;呂林華;張玉碧;;正交試驗(yàn)設(shè)計(jì)優(yōu)化銀杏內(nèi)酯B醇質(zhì)體的制備工藝[J];齊齊哈爾醫(yī)學(xué)院學(xué)報(bào);2012年16期

本文編號(hào)：1521955