目的采用快速膜乳化-溶劑揮發(fā)法制備不含載體輔料的阿立哌唑微粒，并對其體外釋藥行為進(jìn)行評價。方法采用快速膜乳化-溶劑揮發(fā)法制備阿立哌唑微粒，將主藥于室溫條件下超聲溶解于有機(jī)溶劑中作為油相。將聚乙烯醇（PVA）于磁力攪拌且加熱的條件下溶解于去離子水中，并趁熱用0.45 μm的微孔濾膜真空抽濾，得續(xù)濾液，作為水相。油相與水相經(jīng)磁力攪拌混合均勻后得初乳液，將初乳液倒入快速不銹鋼膜乳化裝置，氮?dú)饧訅?，過膜，收集乳液。將乳液與固化液混合后固化至無有機(jī)溶劑氣味，離心洗滌，冷凍干燥即得到阿立哌唑微粒凍干粉。以微粒粒徑、跨距及表觀形態(tài)為指標(biāo)，采用單因素考察法對有機(jī)溶劑、水相PVA濃度、阿立哌唑質(zhì)量濃度、油水相體積比、固化液pH值、過膜次數(shù)、固化方式進(jìn)行考察，并初步確定最優(yōu)制備條件；采用直接釋藥法測定并比較阿立哌唑原料藥與微粒在不同時間點(diǎn)的累積釋放率，并對其釋放行為進(jìn)行數(shù)學(xué)模型擬合。結(jié)果經(jīng)過單因素考察，確定阿立哌唑微粒的制備工藝條件為：有機(jī)溶劑二氯甲烷，水相PVA濃度3%，藥物質(zhì)量濃度7 mg/mL，油水相體積比1：1，固化液3% PVA溶液（pH 8.5），四級串聯(lián)不銹鋼膜乳化器過膜1次，機(jī)械攪拌固化。阿立哌唑微粒平均D₁₀、D₅₀、D₉₀及跨距分別為2.03、4.38、8.09 μm、1.39；掃描電鏡下呈現(xiàn)較為均勻的薄片狀；差示掃描量熱法顯示其結(jié)晶程度降低；平均藥物質(zhì)量分?jǐn)?shù)為99.27%。阿立哌唑微粒在48 h時累積釋放率可達(dá)100.17%，體外釋放符合Logistic方程，而原料藥在48 h時僅釋放47.17%，釋放符合一級方程。結(jié)論快速膜乳化法可用于提高難溶性藥物的溶出速度，具有廣闊的應(yīng)用前景。

Objective To prepare aripiprazole microparticles without carrier excipients by rapid membrane emulsification-solvent evaporation method and evaluate their drug release behavior in vitro. Methods Aripiprazole microparticles were prepared by rapid membrane emulsification and solvent evaporation method. The main drug was dissolved in good solvent as oil phase by ultrasound at room temperature. The polyvinyl alcohol (PVA) was dissolved in deionized water under the condition of magnetic stirring and heating, and the filtrate was obtained by vacuum pumping with a 0.45 μm microporous filter membrane as the aqueous phase. After the oil phase and water phase were mixed uniformly by magnetic stirring, the primary emulsion was obtained. The primary emulsion was poured into the rapid stainless steel membrane emulsifying device. The nitrogen was pressurized, the film is passed, and the emulsion was collected. The emulsion was mixed with the curing solution and cured until there was no odor of organic solvent. Then the emulsion was centrifugally washed and freeze-dried to obtain the freeze-dried powder of aripiprazole microparticles. Taking the particle size, span and apparent morphology as indexes, the the organic solvent, aqueous PVA concentration, aripiprazole mass concentration, volume ratio of oil to water, pH value of curing solution, times of membrane crossing and curing method were investigated by single factor method, and the optimal preparation conditions were preliminarily determined; The cumulative release rates of aripiprazole and its microparticles at different time points were measured and compared by direct release method, and the release behavior was fitted by mathematical model. Results After single factor investigation, the preparation conditions of aripiprazole microparticles were determined as follows: organic solvent methylene chloride, aqueous phase PVA concentration of 3%, drug mass concentration of 7 mg/mL, oil-water phase volume ratio of 1∶1, curing liquid of 3%PVA solution (pH 8.5), fourstage series stainless steel membrane emulsifier through the membrane once, mechanical stirring curing. The average D₁₀, D₅₀, D₉₀ and Span of aripiprazole microparticles were 2.03, 4.38, 8.09 μm and 1.39, respectively. Under scanning electron microscope, aripiprazole microparticles showed a relatively uniform sheet shape. The differential scanning calorimetry showed that the crystallinity of aripiprazole microparticles decreased. The average drug content was 99.27%. The cumulative release rate of aripiprazole microparticles was 100.17% at 48 h. The in vitro release of aripiprazole microparticles conformed to the logstic equation, while the release of API was only 47.17% at 48 h, and the release followed the first-order equation. Conclusion Rapid membrane emulsification can be used to improve the dissolution rate of insoluble drugs and has a broad application prospect.

R943

國家科技重大專項項目（2011ZX09201-201）；北京市科技計劃專項研發(fā)項目（Z16010101390）