發(fā)布時(shí)間：2018-08-29 10:59

【摘要】：目的:多西他賽是一種多西紫杉烷類(lèi)抗癌藥物,屬于難溶性藥物,目前上市劑型僅有注射劑,經(jīng)過(guò)處方調(diào)研,上市產(chǎn)品均通過(guò)吐溫80、乙醇等增溶劑的聯(lián)合使用達(dá)到增溶效果,本文采用脂肪乳作為載體,提高多西他賽的溶解性,并對(duì)其進(jìn)行凍干工藝研究,以期制成更加安全、有效的給藥系統(tǒng)。方法:通過(guò)文獻(xiàn)調(diào)研及處方前研究確定多西他賽相關(guān)理化性質(zhì),為后續(xù)處方工藝研究及儲(chǔ)存條件提供依據(jù)。通過(guò)單因素考察,星點(diǎn)設(shè)計(jì)效應(yīng)面法優(yōu)化,篩選最優(yōu)處方工藝,并進(jìn)行滅菌可行性研究。通過(guò)對(duì)預(yù)凍溫度,一次干燥、二次干燥工藝考察,預(yù)凍過(guò)程中退火技術(shù)的應(yīng)用,確定凍干工藝,制備凍干乳。結(jié)果:1、通過(guò)處方前研究,建立了多西他賽體外分析方法,經(jīng)方法學(xué)初步驗(yàn)證,符合檢測(cè)要求。強(qiáng)降解實(shí)驗(yàn)結(jié)果表明:多西他賽在幾種條件下穩(wěn)定性順序?yàn)?光照氧化高溫強(qiáng)酸強(qiáng)堿。溶解度實(shí)驗(yàn)表示:多西他賽在含有soybean oil/MCT 1:4油相中溶解度為2.31 mg/g。2、本文通過(guò)處方工藝篩選及優(yōu)化,多西他賽最優(yōu)處方工藝為:按質(zhì)量百分比,水相組成為0.35%泊洛沙姆188加注射用水至全量;油相組成為多西他賽1%、大豆磷脂1.0%、soybean oil 2.0%和MCT 8.0%;初乳制備時(shí)水相油相溫度均為60℃;均質(zhì)前調(diào)pH值5.0左右;初乳制備高剪切速度8.0×103 r/min,高剪切時(shí)間為10 min,均質(zhì)壓力為10000 psi,均質(zhì)次數(shù)為3次。進(jìn)行滅菌工藝可行性研究考察,最終采用高壓均質(zhì)技術(shù)與冷凍干燥技術(shù)結(jié)合,采用10%蔗糖作為凍干保護(hù)劑,進(jìn)行預(yù)凍溫度、時(shí)間、一次干燥、二次干燥溫度時(shí)間考察,并采用退火工藝,制備凍干乳劑,復(fù)溶后粒徑變化較小,均在180 nm范圍內(nèi),其不會(huì)引起血管栓塞。結(jié)論:采用脂肪乳劑作為載體,可以在一定程度上提高多西他賽溶解性,并避免有機(jī)溶劑的加入,減少對(duì)人體的刺激性;為難溶性藥物的開(kāi)發(fā)提供新的方向與可能,但仍需后續(xù)進(jìn)行更全面考察。
[Abstract]:Objective: docetaxel is a kind of docetaxel anticancer drug, which belongs to insoluble drug. At present, only the injection is available on the market. After prescription investigation, all the products on the market are solubilized by the combined use of Tween 80, ethanol and other solvents. In this paper, fat milk was used as carrier to improve the solubility of docetaxel, and the freeze-drying process was studied in order to make a more safe and effective drug delivery system. Methods: the physicochemical properties of docetaxel were determined by literature investigation and pre-prescription study, which provided the basis for further study of prescription technology and storage conditions. Through single factor investigation, the star design effect surface method was optimized, the optimum prescription technology was screened, and the feasibility of sterilization was studied. Through the investigation of pre-freezing temperature, primary drying, secondary drying process and the application of annealing technology in the pre-freezing process, the freeze-drying process was determined and the freeze-dried milk was prepared. Results: by pre-prescription study, a method of in vitro analysis of docetaxel was established. The results of strong degradation experiment showed that the stability of docetaxel under several conditions was as follows: oxidation of high temperature and strong acid and strong base by light. Solubility experiment shows that the solubility of docetaxel in the oil phase containing soybean oil/MCT 1:4 is 2.31 mg/g.2,. The optimum formulation process of docetaxel is as follows: percent by mass. The composition of water phase is 0.35% Poloxamer 188 plus injection water, the oil phase is docetaxel 1, soybean phospholipids 1.0% soybean bean oil 2.0% and MCT 8.0%, the oil phase temperature of water phase is 60 鈩，

本文編號(hào)：2210999