【摘要】：目的拉西地片是一種新型的二氫吡啶類鈣拮抗劑,臨床研究顯示:拉西地平具有高度的血管選擇性,擴(kuò)血管效應(yīng)緩和持久,降壓平穩(wěn),能顯著降低血壓及延緩頸動(dòng)脈粥樣硬化的作用,且不良反應(yīng)較少。但拉西地平存在水溶性差,首過(guò)效應(yīng)明顯,生物利用度低等問題。本實(shí)驗(yàn)就將拉西地平制備成自微乳,優(yōu)化拉西地平自乳化處方,有效提高拉西地平的生物利用度,提高拉西地平的臨床療效,具有較大的發(fā)展前景和應(yīng)用價(jià)值。方法通過(guò)考察拉西地平在不同乳化介質(zhì)中的溶解度,選擇溶解度相對(duì)較大的油相、乳化劑和助乳化劑。通過(guò)繪制三元相圖,確定成乳區(qū)域,篩選配伍處方。以油相、乳化劑和助乳化劑的百分含量為考察因素,以Zeta電位、微乳粒徑為評(píng)價(jià)指標(biāo),利用星點(diǎn)設(shè)計(jì)-效應(yīng)面法進(jìn)行處方優(yōu)化。通過(guò)對(duì)微乳的外觀、乳化速度、粒徑分布、Zeta電位等指標(biāo),綜合考慮確定自微乳的最優(yōu)處方,并對(duì)其穩(wěn)定性進(jìn)行考察。建立拉西地平血藥濃度的HPLC測(cè)定方法,以制備拉西地平自微乳膠囊(規(guī)格:含量4 mg)為受試制劑,市售拉西地平片(規(guī)格:含量4 mg)為參比制劑,采用6只健康實(shí)驗(yàn)犬進(jìn)行兩制劑雙周期單劑量口服給藥的實(shí)驗(yàn)方法,測(cè)定不同時(shí)間點(diǎn)的血藥濃度,繪制血藥濃度時(shí)間曲線,計(jì)算相關(guān)藥物動(dòng)力學(xué)參數(shù)。結(jié)果根據(jù)藥物在各輔料溶解度的考察、三元相圖的繪制和星點(diǎn)設(shè)計(jì)-效應(yīng)面法對(duì)處方優(yōu)化,確定拉西地平自微乳最佳的處方組成為:Labrafil M 1944cs、EL和PEG400,各自所占的質(zhì)量分?jǐn)?shù)分別為:29.15%、51.16%和19.69%。并測(cè)得拉西地平自微乳的平均粒徑為(25.86±1.32)nm,Zeta電位為(-24.78±1.45)m V,拉西地平自微乳外觀澄清透明,顯微淡藍(lán)色,透射電鏡下觀察微乳形態(tài)呈均勻球型。拉西地平自微乳制劑穩(wěn)定性好,溶出度明顯高于拉西地平片劑。通過(guò)動(dòng)物體內(nèi)藥物動(dòng)力學(xué)實(shí)驗(yàn)可得,受試制劑與參比制劑的藥物動(dòng)力學(xué)參數(shù)分別為: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,相對(duì)生物利用度為(180.51±1.03)%。結(jié)論拉西地平自微乳制劑的制備工藝相對(duì)比較簡(jiǎn)單,優(yōu)化后的處方溶液外觀澄清顯微淡藍(lán)色,電鏡下乳滴形態(tài)均勻呈圓形,微乳粒徑較小,分布集中。拉西地平自微乳具有良好的穩(wěn)定性,且體外溶出度明顯提高。藥物動(dòng)力學(xué)實(shí)驗(yàn)結(jié)果表明,拉西地平自微乳制劑與拉西地平片相比,藥動(dòng)學(xué)參數(shù)Tmax、Cmax、AUC0~t存在顯著差異。本實(shí)驗(yàn)制備的拉西地平自微乳化制劑的Tmax明顯提前,Cmax顯著增大,相對(duì)生物利用度是拉西地平片的180.51%。根據(jù)藥動(dòng)學(xué)實(shí)驗(yàn)結(jié)果,初步證實(shí)拉西地平自微乳制劑,在體內(nèi)釋藥速度加快,血藥濃度顯著提高,有效提高了拉西地平的生物利用度,達(dá)到了實(shí)驗(yàn)的預(yù)期目的,為拉西地平的臨床應(yīng)用提供有效參考。
[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 鹵1.32) nm,Zeta potential (-24.78 鹵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 鹵42.36) ng m L -1 and (429.45 鹵22.16) ng m L -1), respectively. Tmax (0.561 鹵0.09) h, (1.377 鹵0.12) AUC 0t (1752.95 鹵38.32) ng h m L-1, 977.42 鹵28.26) ng h m L-1); AUC0~ 鈭，

本文編號(hào)：2416576