盐酸维拉帕米微乳凝胶经皮给药系统的研究

发布时间：2018-06-19 16:17

本文选题：盐酸维拉帕米 + 微乳　；参考：《郑州大学》2014年硕士论文

【摘要】：盐酸维拉帕米(Verapamil hydrochloride，VRP)是罂粟碱的衍生物。是钙离子拮抗剂，而且是治疗阵发性室上心动过速的首选药物，临床上主要用于治疗原发性高血压。目前临床上VRP的应用主要是口服制剂和注射制剂，但是口服制剂首过效应明显，而且生物利用度低（20%-35%）；注射剂半衰期短、清除率高、需要重复给药、病人的顺应性差，这些缺点都限制了临床上的大量应用，因此开发一个新的剂型，改善VRP的临床应用成为药剂工作者的一大难题。目的：为了克服口服制剂的首过效应，注射制剂的半衰期短、清除率高的缺点，考虑将VRP制成微乳凝胶制剂，然后经皮肤给药，避免肝脏的首过效应、提高药物的生物利用度、维持稳态血药浓度、改善病人的顺应性。方法：1确定VRP的紫外吸收波长，通过考察所建方法的标准曲线、重复性、稳定性、专属性、回收率，确定用HPLC测定含量的方法。 2采用转相乳化法制备微乳，采用滴水法绘制伪三元相图，研究各组成对微乳形成的影响。同时还进行了单因素考察，确定了空白微乳和VRP微乳的初步处方和制备工艺。并对处方和工艺进行了优化，对制备的微乳的理化性质进行了考察。 3确定制备微乳凝胶剂的方法，选择合适的卡波姆基质浓度。并对其理化性质进行考察。采用离体鼠皮进行体外透皮方法考察，考察制剂的体外经皮渗透性。 4用高效液相建立VRP微乳凝胶在大鼠体内的分析方法，对VRP片剂、微乳凝胶在大鼠体内的药代动力学和生物等效性进行了研究。 5采用Sprague-Dawley大鼠作为模型动物进行了皮肤刺激性实验，测定空白凝胶、微乳凝胶的皮肤刺激性。结果：1VRP在浓度2～256μg/mL的范围内线性关系良好，A=24.298C－14.221，R2=0.9999。在8、32、128μg/mL三个浓度下的精密度和回收率符合方法学要求。 2VRP微乳的最优处方：表面活性剂：吐温80；助表面活性剂：异丙醇（表面活性剂：助表面活性剂=3:2）；油相：IPM；含水量：80%；含药量：7.8%。外观表现为淡蓝色乳光，呈半透明状态。平均粒径为68.55nm，PDI为0.193，电位-7.1mV，在透射电镜下观察到微乳呈圆球形或类球形。 3体外经皮渗透性实验结果表明：VRP微乳凝胶的体外透皮效果好于水溶液凝胶的透皮效果。VRP微乳凝胶剂的增渗比为4.88倍。体外透皮模型拟合结果表明VRP的体外透皮符合一级动力学模型。 4VRP微乳凝胶透皮组和片剂灌胃组，均符合一室模型，权重都为1/C/C。微乳凝胶剂的AUC、Cmax、消除半衰期分别为111.10±16.99μg/mL/h、2.38±0.10μg/mL和31.33±6.14h；市售的VRP片的AUC、Cmax、消除半衰期分别为27.19±1.64μg/mL/h、4.43±0.27μg/mL和3.39±0.35h，VRP微乳的相对生物利用度为174.24%。 5按照皮肤刺激性安全评价标准对12只大鼠进行了皮肤刺激性实验，实验结果表明空白凝胶和微乳凝胶在实验过程中均未出现明显的红肿和红斑。结论：高效液相测定VRP的含量，稳定性，专属性，重复性，精密度和回收率都达到了测定要求，符合方法学的要求。制备的VRP微乳外观良好，粒径也符合微乳要求，稳定性良好；VRP微乳凝胶外观良好，制剂稳定，并且体外渗透效果优于水溶液凝胶。VRP微乳与口服制剂相比，提高了生物利用度、延长了半衰期，并且体内清除率低。皮肤刺激性实验结果显示VRP微乳对皮肤无明显的刺激性。
[Abstract]:Vera Pammy (Verapamil hydrochloride, VRP) is a derivative of papaverine. It is a calcium antagonist, and it is the first drug to treat paroxysmal supraventricular tachycardia. It is mainly used in the treatment of primary hypertension. At present, the main clinical application of VRP is oral and injection, but the first effect of oral preparation is obvious, And the bioavailability is low (20%-35%); the half-life of the injection is short, the clearance rate is high, the patient needs to be repeated, and the patient's compliance is poor. These shortcomings restrict the large number of clinical applications. Therefore, it is a difficult problem to develop a new dosage form and improve the clinical application of VRP.
Objective: in order to overcome the first effect of oral preparation, the half life of the injection is short and the clearance rate is high, VRP microemulsion gel preparation is considered, and then the skin is given to avoid the first over effect of the liver, improve the bioavailability of the drug, maintain the steady state blood drug concentration and improve the patient's compliance.
Methods: 1 to determine the UV absorption wavelength of VRP, by examining the standard curve of the method, repeatability, stability, specificity, recovery rate, and determining the method for the determination of content by HPLC.
2 the microemulsion was prepared by phase transfer emulsification method. The pseudo three element phase diagram was plotted by drip water method, and the influence of each component on the formation of microemulsion was studied. At the same time, a single factor investigation was carried out and the preliminary formulation and preparation process of the blank microemulsion and VRP microemulsion were determined. The prescription and technology were optimized, and the physicochemical properties of the prepared microemulsion were investigated.
3 to determine the preparation method of microemulsion gel, select the appropriate carbomer matrix concentration and investigate its physicochemical properties. The transdermal method of vitro rat skin was used to investigate the transdermal permeability of the preparation in vitro.
4 the analytical methods of VRP microemulsion gel in rats were established by high performance liquid phase. The pharmacokinetics and bioequivalence of VRP tablets and microemulsion gel in rats were studied.
5 Sprague-Dawley rats were used as model animals for skin irritation test to determine the skin irritation of blank gel and microemulsion gel.
Results: the linear relationship of 1VRP in the range of 2~256 micron g/mL is good, a = 22. 29, 8 c - 1. 2. 2. The precision and recovery of R2=0.9999. at the three concentrations of 8,32128 mu g/mL conforms to the methodological requirements.
2VRP microemulsion optimum prescription: surface active agent: Twain 80; surfactants: isopropanol (surface active agent: surfactant =3:2); oil phase: IPM; water content: 80%; 7.8%. appearance is light blue milk light, translucent state. The average particle size is 68.55nm, PDI is 0.193, potential -7.1mV, under transmission electron microscope The microemulsion was observed to be spherical or spherical.
3 the results of in vitro percutaneous permeability test showed that the transdermal effect of VRP microemulsion gel in vitro was better than that of aqueous solution gel. The infiltration ratio of.VRP microemulsion gel was 4.88 times. In vitro transdermal model fitting results showed that the transdermal penetration of VRP in vitro conformed to the first order kinetic model.
4VRP microemulsion gel transdermal group and tablet gavage group were all in line with one compartment model. The weight of the 1/C/C. microemulsion gel was AUC, Cmax, and the half-life was 111.10 + 16.99 mu g/mL/h, 2.38 + 0.10 mu g/mL and 31.33 + 6.14h respectively. The AUC and Cmax of the VRP tablets sold in the market were 27.19 + 1.64 mu g/mL/h, 4.43 + 0.27 micron g/mL and 3.39 + microsatellite. The relative bioavailability of milk is 174.24%.
5 the skin irritation test was carried out in 12 rats according to the skin irritation safety assessment standard. The experimental results showed that there was no obvious redness and erythema in the blank gel and microemulsion gel during the experiment.
Conclusion: the content, stability, specificity, reproducibility, precision and recovery of VRP have reached the requirements of determination and meet the requirements of the methodology. The prepared VRP microemulsion has good appearance, the particle size fits microemulsion and the stability is good, and the VRP microemulsion gel has a good appearance, the preparation is stable, and the in vitro osmosis effect is superior to aqueous solution. The gel.VRP microemulsion increased the bioavailability, prolonged the half-life and lower clearance rate in the body compared with the oral preparation. The results of skin irritation test showed that the VRP microemulsion had no obvious irritation to the skin.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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