卢立康唑醇质体的研制及局部药效学研究

发布时间：2018-02-21 12:19

本文关键词： 醇质体卢立康唑透皮吸收最小抑菌浓度　出处：《中国人民解放军医学院》2014年博士论文　论文类型：学位论文

【摘要】：研究背景卢立康唑是一种新型的咪唑类抗真菌新药。它通过抑制麦角固醇的生物合成，，发挥抗真菌作用。因其具有优秀的抗菌活性，近年受到临床研究的广泛关注。另一方面，在药物传递系统中，醇质体作为一种新的药物载体，也越来越受到关注。醇质体是由脂质体中添加乙醇演变而来，特有的理化性质使其能更有效的携带药物通过角质层释放至皮肤各层。因此，新型药物卢立康唑的醇质体制剂可成为扩大皮肤科抗真菌药物经皮给药的理想选择。研究卢立康唑醇质体的处方配比及理化性质为本课题研究目的之一。同时进一步分析卢立康唑醇质体体外透皮效果及体外抗菌活性为本课题研究目的之二。目的 1、卢立康唑优秀的抗菌活性和醇质体制剂透皮性好、载药量高等优点结合，使得本研究以制备卢立康唑醇质体为研究切入点，以期充分发挥卢立康唑的局部药理作用，为皮肤科临床抗菌药物的选择提供研发新思路。 2、本研究通过对醇质体制备工艺、评价方法的筛选，为今后其他醇质体制剂的研发提供实验室依据和思路选择。 3、为了科学、准确的评价卢立康唑醇质体局部药效机制，体外透皮效果采用Franz扩散池检测，并进行体外抗菌活性MIC的测定，研究卢立康唑醇质体的透皮性能和抗菌能力，为该药的外用制剂临床研究提供科学的数据。 4、为评价卢立康唑醇质体制备的可行性，将从制备方法到检测手段进行有效数据评价，并考察最优处方醇质体的理化性质，为临床应用的大规模制备提供实验室依据。实验方法 1、醇质体的制备：醇质体制备采用薄膜法与注入法的比较。 2、醇质体粒径分析：激光动态散射仪检测并分析醇质体粒径。 3、醇质体的包封率(EE%)：未包封的部分采用超速离心法及透析法分离，后进行高效液相色谱法（HPLC）检测药物含量，并进行数据比较。 4、药物的HPLC检测：均在室温下进行，以乙腈-0.1%磷酸二氢胺为流动相，紫外分光光度计测量数据为检测波长，进行精密度及回收率等方法学的研究。 5、醇质体的形态学观察：采用透射电镜进行观察分析。 6、体外大鼠皮肤透皮实验：采用Franz扩散池进行离体大鼠皮肤透皮实验。 7、卢立康唑醇质体体外抗菌活性研究：微量液基稀释法。实验结果 1、卢立康唑醇质体的制备研究中发现，薄膜分散法在药物包封率、粒径等方面优于文献中常应用的注入法；且评价工艺中超速离心法较透析法更简洁、快速。 2、本研究结果发现乙醇浓度和磷脂量对卢立康唑醇质体的包封率有正相关；而乙醇浓度与醇质体的粒径有负相关，醇质体的粒径随磷脂量增加而增大。采用粒径、包封率为指标进行选择最优化处方，发现醇质体制剂在卵磷脂为5%(w/v)、乙醇为45%(v/v)、超声时间8min处方配比下，粒径小、粒径分布均匀和包封率高，卢立康唑醇质体中药物包封率达到了70%。 3、卢立康唑醇质体及非醇质体制剂体外透皮实验比较，结果显示：透皮速率卢立康唑醇质体软膏制剂脂质体水醇溶液，24小时透皮量醇质体优于其他剂型，48小时皮肤全层滞留量醇质体与软膏相当，优于脂质体及水醇溶液。 4、卢立康唑不同制剂的体外抑菌实验结果表示，卢立康唑醇质体的抑菌效果优于脂质体及水醇溶液，且对毛癣菌属较念珠菌属敏感程度更高。结论 1、采用薄膜法技术制备的醇质体，具有包封率高、透皮率好的优点。 2、最优化处方显示，在卵磷脂为5%(w/v)、乙醇为45%(v/v)、超声时间8分钟的处方配比下，卢立康唑醇质体制剂粒径较小、包封率高。且具有刺激性小、稳定性好等特点。 3、醇质体较脂质体、水醇溶液及即将上市的软膏透皮性能好。 4、体外实验，卢立康唑醇质体的抗菌性能优于脂质体及水醇溶液。
[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.

【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R943;R96

【参考文献】