本文選題：鹽酸維拉帕米 + 微乳��； 參考：《鄭州大學(xué)》2014年碩士論文

【摘要】：鹽酸維拉帕米(Verapamil hydrochloride，VRP)是罌粟堿的衍生物。是鈣離子拮抗劑，而且是治療陣發(fā)性室上心動(dòng)過(guò)速的首選藥物，臨床上主要用于治療原發(fā)性高血壓。目前臨床上VRP的應(yīng)用主要是口服制劑和注射制劑，但是口服制劑首過(guò)效應(yīng)明顯，而且生物利用度低（20%-35%）；注射劑半衰期短、清除率高、需要重復(fù)給藥、病人的順應(yīng)性差，這些缺點(diǎn)都限制了臨床上的大量應(yīng)用，因此開(kāi)發(fā)一個(gè)新的劑型，改善VRP的臨床應(yīng)用成為藥劑工作者的一大難題。 目的：為了克服口服制劑的首過(guò)效應(yīng)，注射制劑的半衰期短、清除率高的缺點(diǎn)，考慮將VRP制成微乳凝膠制劑，然后經(jīng)皮膚給藥，避免肝臟的首過(guò)效應(yīng)、提高藥物的生物利用度、維持穩(wěn)態(tài)血藥濃度、改善病人的順應(yīng)性。 方法：1確定VRP的紫外吸收波長(zhǎng)，通過(guò)考察所建方法的標(biāo)準(zhǔn)曲線(xiàn)、重復(fù)性、穩(wěn)定性、專(zhuān)屬性、回收率，確定用HPLC測(cè)定含量的方法。 2采用轉(zhuǎn)相乳化法制備微乳，采用滴水法繪制偽三元相圖，研究各組成對(duì)微乳形成的影響。同時(shí)還進(jìn)行了單因素考察，確定了空白微乳和VRP微乳的初步處方和制備工藝。并對(duì)處方和工藝進(jìn)行了優(yōu)化，對(duì)制備的微乳的理化性質(zhì)進(jìn)行了考察。 3確定制備微乳凝膠劑的方法，選擇合適的卡波姆基質(zhì)濃度。并對(duì)其理化性質(zhì)進(jìn)行考察。采用離體鼠皮進(jìn)行體外透皮方法考察，考察制劑的體外經(jīng)皮滲透性。 4用高效液相建立VRP微乳凝膠在大鼠體內(nèi)的分析方法，對(duì)VRP片劑、微乳凝膠在大鼠體內(nèi)的藥代動(dòng)力學(xué)和生物等效性進(jìn)行了研究。 5采用Sprague-Dawley大鼠作為模型動(dòng)物進(jìn)行了皮膚刺激性實(shí)驗(yàn)，測(cè)定空白凝膠、微乳凝膠的皮膚刺激性。 結(jié)果：1VRP在濃度2～256μg/mL的范圍內(nèi)線(xiàn)性關(guān)系良好，A=24.298C－14.221，R2=0.9999。在8、32、128μg/mL三個(gè)濃度下的精密度和回收率符合方法學(xué)要求。 2VRP微乳的最優(yōu)處方：表面活性劑：吐溫80；助表面活性劑：異丙醇（表面活性劑：助表面活性劑=3:2）；油相：IPM；含水量：80%；含藥量：7.8%。外觀表現(xiàn)為淡藍(lán)色乳光，呈半透明狀態(tài)。平均粒徑為68.55nm，PDI為0.193，電位-7.1mV，在透射電鏡下觀察到微乳呈圓球形或類(lèi)球形。 3體外經(jīng)皮滲透性實(shí)驗(yàn)結(jié)果表明：VRP微乳凝膠的體外透皮效果好于水溶液凝膠的透皮效果。VRP微乳凝膠劑的增滲比為4.88倍。體外透皮模型擬合結(jié)果表明VRP的體外透皮符合一級(jí)動(dòng)力學(xué)模型。 4VRP微乳凝膠透皮組和片劑灌胃組，均符合一室模型，權(quán)重都為1/C/C。微乳凝膠劑的AUC、Cmax、消除半衰期分別為111.10±16.99μg/mL/h、2.38±0.10μg/mL和31.33±6.14h；市售的VRP片的AUC、Cmax、消除半衰期分別為27.19±1.64μg/mL/h、4.43±0.27μg/mL和3.39±0.35h，VRP微乳的相對(duì)生物利用度為174.24%。 5按照皮膚刺激性安全評(píng)價(jià)標(biāo)準(zhǔn)對(duì)12只大鼠進(jìn)行了皮膚刺激性實(shí)驗(yàn)，實(shí)驗(yàn)結(jié)果表明空白凝膠和微乳凝膠在實(shí)驗(yàn)過(guò)程中均未出現(xiàn)明顯的紅腫和紅斑。 結(jié)論：高效液相測(cè)定VRP的含量，穩(wěn)定性，專(zhuān)屬性，重復(fù)性，精密度和回收率都達(dá)到了測(cè)定要求，符合方法學(xué)的要求。制備的VRP微乳外觀良好，粒徑也符合微乳要求，穩(wěn)定性良好；VRP微乳凝膠外觀良好，制劑穩(wěn)定，并且體外滲透效果優(yōu)于水溶液凝膠。VRP微乳與口服制劑相比，提高了生物利用度、延長(zhǎng)了半衰期，并且體內(nèi)清除率低。皮膚刺激性實(shí)驗(yàn)結(jié)果顯示VRP微乳對(duì)皮膚無(wú)明顯的刺激性。
[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.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R943

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