拉西地平自微乳的制备和体内外质量评价
发布时间：2019-01-27 18:47
【摘要】：目的拉西地片是一种新型的二氢吡啶类钙拮抗剂,临床研究显示:拉西地平具有高度的血管选择性,扩血管效应缓和持久,降压平稳,能显著降低血压及延缓颈动脉粥样硬化的作用,且不良反应较少。但拉西地平存在水溶性差,首过效应明显,生物利用度低等问题。本实验就将拉西地平制备成自微乳,优化拉西地平自乳化处方,有效提高拉西地平的生物利用度,提高拉西地平的临床疗效,具有较大的发展前景和应用价值。方法通过考察拉西地平在不同乳化介质中的溶解度,选择溶解度相对较大的油相、乳化剂和助乳化剂。通过绘制三元相图,确定成乳区域,筛选配伍处方。以油相、乳化剂和助乳化剂的百分含量为考察因素,以Zeta电位、微乳粒径为评价指标,利用星点设计-效应面法进行处方优化。通过对微乳的外观、乳化速度、粒径分布、Zeta电位等指标,综合考虑确定自微乳的最优处方,并对其稳定性进行考察。建立拉西地平血药浓度的HPLC测定方法,以制备拉西地平自微乳胶囊(规格:含量4 mg)为受试制剂,市售拉西地平片(规格:含量4 mg)为参比制剂,采用6只健康实验犬进行两制剂双周期单剂量口服给药的实验方法,测定不同时间点的血药浓度,绘制血药浓度时间曲线,计算相关药物动力学参数。结果根据药物在各辅料溶解度的考察、三元相图的绘制和星点设计-效应面法对处方优化,确定拉西地平自微乳最佳的处方组成为:Labrafil M 1944cs、EL和PEG400,各自所占的质量分数分别为:29.15%、51.16%和19.69%。并测得拉西地平自微乳的平均粒径为(25.86±1.32)nm,Zeta电位为(-24.78±1.45)m V,拉西地平自微乳外观澄清透明,显微淡蓝色,透射电镜下观察微乳形态呈均匀球型。拉西地平自微乳制剂稳定性好,溶出度明显高于拉西地平片剂。通过动物体内药物动力学实验可得,受试制剂与参比制剂的药物动力学参数分别为:Cmax(861.12±42.36)ng·m L-1,(429.45±22.16)ng·m L-1;Tmax(0.561±0.09)h,(1.377±0.12)h;AUC0~t(1752.95±38.32)ng·h·m L-1,(977.42±28.26)ng·h·m L-1;AUC0~∞(1864.13±35.47)ng·h·m L-1,(1012.73±26.43)ng·h·m L-1,相对生物利用度为(180.51±1.03)%。结论拉西地平自微乳制剂的制备工艺相对比较简单,优化后的处方溶液外观澄清显微淡蓝色,电镜下乳滴形态均匀呈圆形,微乳粒径较小,分布集中。拉西地平自微乳具有良好的稳定性,且体外溶出度明显提高。药物动力学实验结果表明,拉西地平自微乳制剂与拉西地平片相比,药动学参数Tmax、Cmax、AUC0~t存在显著差异。本实验制备的拉西地平自微乳化制剂的Tmax明显提前,Cmax显著增大,相对生物利用度是拉西地平片的180.51%。根据药动学实验结果,初步证实拉西地平自微乳制剂,在体内释药速度加快,血药浓度显著提高,有效提高了拉西地平的生物利用度,达到了实验的预期目的,为拉西地平的临床应用提供有效参考。
[Abstract]:Objective Lasidipine is a new type of dihydropyridine calcium antagonist. Clinical studies have shown that lacidipine has high vascular selectivity, mild and lasting vasodilatation, and stable hypotension. Can significantly reduce blood pressure and delay carotid atherosclerosis, and less adverse reactions. However, lacidipine has some problems such as poor water solubility, obvious first pass effect and low bioavailability. In this experiment, lacidipine was prepared into self-microemulsion, the formulation of self-emulsification of lacidipine was optimized, the bioavailability of lacidipine was improved effectively, and the clinical efficacy of lacidipine was improved. It has a great development prospect and application value. Methods by investigating the solubility of lacidipine in different emulsified media, the oil phase, emulsifier and co-emulsifier with relatively high solubility were selected. By drawing ternary phase diagram, to determine the region of milk formation, and to screen the prescription of compatibility. With the oil phase, emulsifier and coemulsifier content as the investigation factors, the Zeta potential and the particle size of the microemulsion as the evaluation index, the formulation was optimized by the star design-effect surface method. Based on the appearance, emulsifying speed, particle size distribution and Zeta potential of microemulsion, the optimum formulation of self-microemulsion was determined and its stability was investigated. A HPLC method for the determination of the plasma concentration of lacidipine was established. The self-emulsion capsule of lacidipine (standard: 4 mg) was prepared as the test preparation, and the marketable lacidipine tablet (4 mg) was used as the reference preparation. Six healthy dogs were administered orally with two preparations and one dose. The blood concentration at different time points was measured, the time curve of blood concentration was plotted, and the related pharmacokinetic parameters were calculated. Results according to the investigation of the solubility of the drug in each excipient, the drawing of ternary phase diagram and the optimization of formulation by star design-effect surface method, the optimum formulation composition of lacidipine self-microemulsion was determined to be: Labrafil M 1944csEL and PEG400,. The respective mass fractions were 29.15% and 19.69%, respectively. The mean particle size of the self-microemulsion was (25.86 卤1.32) nm,Zeta potential (-24.78 卤1.45) m V,). The appearance of the self-microemulsion was clear and transparent, and the microemulsion was light blue. The morphology of the microemulsion was spherical under transmission electron microscope. The stability of lacidipine self-emulsion was better than that of lacidipine tablets. The pharmacokinetic parameters of the test preparation and the reference preparation were: Cmax (861.12 卤42.36) ng m L -1 and (429.45 卤22.16) ng m L -1), respectively. Tmax (0.561 卤0.09) h, (1.377 卤0.12) AUC 0t (1752.95 卤38.32) ng h m L-1, 977.42 卤28.26) ng h m L-1); AUC0~ 鈭，
本文编号：2416576
[Abstract]:Objective Lasidipine is a new type of dihydropyridine calcium antagonist. Clinical studies have shown that lacidipine has high vascular selectivity, mild and lasting vasodilatation, and stable hypotension. Can significantly reduce blood pressure and delay carotid atherosclerosis, and less adverse reactions. However, lacidipine has some problems such as poor water solubility, obvious first pass effect and low bioavailability. In this experiment, lacidipine was prepared into self-microemulsion, the formulation of self-emulsification of lacidipine was optimized, the bioavailability of lacidipine was improved effectively, and the clinical efficacy of lacidipine was improved. It has a great development prospect and application value. Methods by investigating the solubility of lacidipine in different emulsified media, the oil phase, emulsifier and co-emulsifier with relatively high solubility were selected. By drawing ternary phase diagram, to determine the region of milk formation, and to screen the prescription of compatibility. With the oil phase, emulsifier and coemulsifier content as the investigation factors, the Zeta potential and the particle size of the microemulsion as the evaluation index, the formulation was optimized by the star design-effect surface method. Based on the appearance, emulsifying speed, particle size distribution and Zeta potential of microemulsion, the optimum formulation of self-microemulsion was determined and its stability was investigated. A HPLC method for the determination of the plasma concentration of lacidipine was established. The self-emulsion capsule of lacidipine (standard: 4 mg) was prepared as the test preparation, and the marketable lacidipine tablet (4 mg) was used as the reference preparation. Six healthy dogs were administered orally with two preparations and one dose. The blood concentration at different time points was measured, the time curve of blood concentration was plotted, and the related pharmacokinetic parameters were calculated. Results according to the investigation of the solubility of the drug in each excipient, the drawing of ternary phase diagram and the optimization of formulation by star design-effect surface method, the optimum formulation composition of lacidipine self-microemulsion was determined to be: Labrafil M 1944csEL and PEG400,. The respective mass fractions were 29.15% and 19.69%, respectively. The mean particle size of the self-microemulsion was (25.86 卤1.32) nm,Zeta potential (-24.78 卤1.45) m V,). The appearance of the self-microemulsion was clear and transparent, and the microemulsion was light blue. The morphology of the microemulsion was spherical under transmission electron microscope. The stability of lacidipine self-emulsion was better than that of lacidipine tablets. The pharmacokinetic parameters of the test preparation and the reference preparation were: Cmax (861.12 卤42.36) ng m L -1 and (429.45 卤22.16) ng m L -1), respectively. Tmax (0.561 卤0.09) h, (1.377 卤0.12) AUC 0t (1752.95 卤38.32) ng h m L-1, 977.42 卤28.26) ng h m L-1); AUC0~ 鈭，
本文编号：2416576
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