和厚朴酚自微乳化给药系统及固体化研究

发布时间：2018-04-12 22:26

本文选题：和厚朴酚 + 自微乳化给药系统　；参考：《重庆医科大学》2014年硕士论文

【摘要】：厚朴属木兰科，为我国传统中药，已用于多种疾病的治疗，和厚朴酚是其主要活性成分之一，但其在水中的溶解度极低，因此目前未见上市产品。自微乳化给药系统（Self-microemulsifying drug delivery systems，SMEDDS）由四种组分构成，表面活性剂、助表面活性剂、油相与药物，轻微搅拌，即可在水中自发形成细小的乳滴。SMEDDS能够增加水难溶性药物在胃肠道的溶出度，利于药物的吸收。目前可以通过不同的方法和手段将自微乳制剂同固体材料结合，形成固体自乳化片，微丸和微球等，跟传统自微乳制剂相比，固体自微乳制剂携带更方便，稳定性更高，患者顺应性更好。本课题为了提高和厚朴酚的溶解度和口服生物利用度，将和厚朴酚制备成自微乳化给药系统，对处方进行了优化，对其质量进行了初步评价，并研究它在大鼠体内的药动学特征，再进一步探索与多糖类高分子材料结合制成固体制剂，为开发难溶性药物的临床应用提供一定的理论基础。具体研究内容包括以下两个部分：第一部分和厚朴酚自微乳化给药系统的研究 1建立紫外分光光度法测定和厚朴酚的含量，和厚朴酚的最大紫外检测波长为294nm，和厚朴酚在4.0～28.0μg/ml浓度范围内，吸光度与浓度线性关系良好，标准曲线方程为A=0.0292C-0.0038，r=0.9996。同时，精密度、回收率均满足方法学要求。 2考察和厚朴酚在各辅料中的溶解度，筛选对和厚朴酚溶解度较大的辅料，初步确定油相、表面活性剂、助表面活性剂；然后通过处方配伍实验选择乳化效果较好且处方稳定的辅料，再采用水滴定法绘制伪三元相图，以微乳区域大小为指标，确定以MCT作为油相，Cremophor RH40为表面活性剂，Transcutol P为助表面活性剂，表面活性剂与助表面活性剂的比值（Km）为2，最后以体外释放及粒径考察结果得到各组分的最佳比例为MCT∶Cremophor RH40∶Transcutol P=20.0∶53.3∶26.7。 3采用染色法鉴别和厚朴酚自微乳制剂乳化后的微乳类型，并对制剂的自乳化速率和初步稳定性进行考察。结果表明和厚朴酚自微乳制剂乳化后为O/W型微乳，自乳化时间短且稳定性好。 4建立HPLC方法测定和厚朴酚在体内的药物浓度，血浆中和厚朴酚在0.0355～9.0909μg/ml浓度范围内，线性关系良好，其回归方程为：Y=0.3890C+0.0249，r=0.9996，，该方法准确度高，专属性强且重现性好，满足血药浓度分析的要求。大鼠口服灌胃和厚朴酚SMEDDS和混悬液后，前者生物利用度是后者的1.25倍，因此和厚朴酚SMEDDS对提高和厚朴酚的生物利用度有效果。第二部分和厚朴酚自微乳化给药系统结冷胶钙微丸的制备及特性研究 1采用离子凝胶法制备载和厚朴酚SMEDDS的结冷胶钙微丸(calcium-gellan beads containing honokiol self-microemulsifying drugdelivery system, GB-HSMEDDS)，以结冷胶浓度，氯化钙浓度，交联时间，自微乳与结冷胶溶液质量比值(g/g)为变量，采用单因素实验设计，以GB-HSMEDDS的包封率作为考察指标，当结冷胶浓度为1.25%，CaCl2浓度为8%，和厚朴酚SMEDDS与结冷胶溶液质量比为0.15，交联时间15min为制备条件时，GB-HSMEDDS包封率和形态较好。 2对优化后的GB-HSMEDDS在pH1.2HCl溶液及pH6.8PBS中的溶胀及释放特性进行研究。结果表明GB-HSMEDDS在pH6.8PBS中的溶胀度显著大于在pH1.2HCl溶液中的(p＜0.01)，药物在HCl溶液中2h的累积释放超过50%，而在PBS中的不足20%。
[Abstract]:Magnoliaceae, Magnolia, is a traditional Chinese medicine which has been applied to many kinds of diseases. Honokiol is one of its main active components, but its solubility in water is very low. Therefore, it has not been listed at present.
Self microemulsifying drug delivery system (Self-microemulsifying drug delivery systems, SMEDDS) consists of four components, surfactant, CO surfactant, oil and drugs, mild mixing, can spontaneously in water droplet formation of small.SMEDDS can increase the water insoluble drugs in the gastrointestinal tract of the dissolution, to the absorption of the drug.
At present, self microemulsifying agents can be combined with solid materials by different ways and means to form solid self emulsifying tablets, pellets and microspheres. Compared with traditional self microemulsifying agents, solid self microemulsion formulations are more convenient, stable and patient compliant.
This subject is to improve the solubility and bioavailability of honokiol and magnolol will use, preparation of self microemulsifying drug delivery system, the formulation was optimized on a preliminary evaluation of its quality, and study its pharmacokinetic characteristics in rats, to further explore the combined with polysaccharide polymer made of solid preparation, to provide a theoretical basis for the clinical application of insoluble drugs. The research contents include the following two parts:
Study on the first part and the self microemulsification system of magnolol
1 the content of a UV spectrophotometric method for the determination of honokiol, the maximum UV detection wavelength of honokiol and magnolol in 294nm, 4 ~ 28 g/ml concentration range, a good linear relationship between absorbance and concentration, the standard curve equation was A=0.0292C-0.0038, r=0.9996. at the same time, precision and recovery rate are satisfied learn the requirements.
The solubility of 2 investigated honokiol in various excipients, screening of honokiol higher solubility materials, preliminary determination of oil phase, surfactant, cosurfactant; and then through the prescription experiment, better emulsifying effect and stability of prescription accessories, then using drip method of drawing the pseudo three component phase diagram, in microemulsion the size of the region as the index to determine the MCT as oil phase, Cremophor RH40 as surfactant, Transcutol P as cosurfactant, ratio of surfactant and co surfactant (Km) was 2, the in vitro release and particle size examination results obtained the best proportion of each component is MCT: Cremophor RH40 Transcutol: P=20.0: 53.3: 26.7.
3 Identification of honokiol self microemulsion after microemulsification and identification of the self emulsifying rate and initial stability of the prepared self emulsifying microemulsion. The results showed that after emulsification, honokiol self microemulsifying agent was O/W microemulsion with short self emulsifying time and good stability.
4 to establish a HPLC method for the determination of magnolol and plasma drug concentration in vivo, honokiol in 0.0355 ~ 9.0909 g/ml concentration range, good linear relationship, the regression equation is: Y=0.3890C+0.0249, r=0.9996, the method has high accuracy, strong specificity and good reproducibility, meet the requirements of blood drug concentration analysis. Rat oral Honokiol and SMEDDS suspension, the bioavailability is 1.25 times of the latter. Therefore, honokiol and magnolol SMEDDS to improve the bioavailability of the effect.
Preparation and characterization of colder calcium pellets in the second part and the self microemulsification system of magnolol
1 by ion gel preparation containing honokiol SMEDDS calcium gellan gum pellets (calcium-gellan beads containing honokiol self-microemulsifying drugdelivery system, GB-HSMEDDS), with gellan gum concentration, calcium chloride concentration, crosslinking time, self microemulsion and gellan gum solution quality ratio (g/g) as a variable, the single factor experiment GB-HSMEDDS, the entrapment efficiency as indexes, when the gellan gum concentration was 1.25%, the concentration of CaCl2 was 8%, and the junction of magnolol SMEDDS gellan gum solution quality ratio is 0.15, crosslinking time of preparation conditions for 15min system, GB-HSMEDDS encapsulation efficiency and good morphology.
On the 2 and release properties of the optimized GB-HSMEDDS in pH1.2HCl solution and pH6.8PBS of the swelling were studied. The results showed that GB-HSMEDDS in pH6.8PBS in the degree of swelling was significantly higher than that in pH1.2HCl solution (P < 0.01), the cumulative drug release in HCl solution 2h of more than 50%, while in PBS 20%.

【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

【参考文献】