摘要
姜黄素是用途广泛的天然活性物质，具有多种生物活性。姜黄素的水溶性极低而脂溶性良好，是典型的II型药物。药物的口服吸收极差，体内代谢迅速，导致其口服生物利用度极低，限制了其临床应用。本论文采用水不溶性材料作为载体控制药物的释放速率，并利用固体高度分散技术降低药物的结晶度以改善其溶解度/溶出度，最终改善姜黄素的口服生物利用度。
建立了姜黄素HPLC体外/内含量测定方法。硅胶柱层析纯化市售姜黄，得到纯度为99.04%的姜黄素产品。理化性质研究表明药物的水溶性极低，脂溶性良好；药物对光照和pH敏感，粉末光照10天含量降低30.57%，溶液光照6h含量降至原来的20%；在20oC-40oC时，溶液在pH2-6内保持稳定。
以醋酸纤维素为载体，丙酮为溶剂，溶剂法制备处方。药物能够被完全包裹于醋酸纤维素所形成的光滑致密的薄膜中并且能够均匀分散，颗粒具有良好的流动性。药物与载体之间形成了分子间氢键。药材比为1:10(w/w)，10%(w/w)甘露醇为致孔剂的处方12h内药物累积释放量为94.92%，为一级释放模型，药物为无定形态；药材比为1:1(w/w)，10%PEG6000(w/w)为致孔剂的处方12h内药物累积释放量为82.52%，为零级释放模型，药物为微晶态。两个处方均显著改善了药物的可润湿性、溶解度和溶出度。
以壳聚糖为载体，三聚磷酸钠为交联剂，离子凝胶化法制备处方。处方的粒径随着制备体系中pH的升高而增大，同时表面则变得更为粗糙。药材比1:1(w/w)，交联剂的浓度为0.3%(w/v)的处方的载药量为33.50±1.15%，包封率为85.20±0.92%，收率为71.33±2.15%，平均粒径为58.50μm，粒径分布为33.71-87.90μm。处方显著改善了药物的可润湿性、溶解度和溶出度。
对给药系统的稳定性考察结果表明，药物的稳定性特别是光照稳定性得到了显著的改善；处方在6个月内能够保持外观、粒径、流动性（休止角）、含量和溶出度的稳定性。
处方的载药量与其他给药系统相比得到了显著的提高。体内药代动力学研究结果表明，药物的C_(max)显著增加，t_(max)显著延长，K_(el)和K_a则显著降低，AUC显著增加。处方具有良好的体内外相关性。处方在体内具有明确的缓释药物的能力，能够显著的改善药物的口服生物利用度，降低给药剂量和给药频率，是用于改善姜黄素口服吸收的最有应用前景的给药系统之一。
Curcumin, one of the most widely used natural active constituents with greatvariety of beneficial biological and pharmacological activities, is a typical Class IIdrug with a very short biologic half-life, and was used as the model drug. The aim ofthis paper was to develop sustained-release solid dispersion systems by employingwater-insoluble carrier for release control, solubility/dissolution enhancement andoral bioavailability improvement of curcumin.
High-performance liquid chromatography was established in quantitativedetermination of the drug in vitro/vivo. Curcumin was determined to be insoluble inwater with high liposolubility and sensitive with light and pH. The purity of theconventional products of curcumin was improved to be99.04%through columnchromatography.
Solid dispersions were prepared with cellulose acetate by the solvent evaporationtechnique. Two formulations were chosen for the following studies: Curcumin:cellulose acetate=1:10(w/w,10%mannitol); Curcumin: cellulose acetate=1:1(w/w,10%PEG6000). Solid state characterization techniques revealed thecrystallinity decrease nature of curcumin in solid dispersions. Solubility/dissolutionand wettability of curcumin were enhanced in the formulations in comparison withpure drug. Sustained-release profiles or controlled-release profoles of curcumin fromthe solid dispersions were ideally achieved in vitro up to12h.
Microparticles wre prepared with chitosan and sodium tripolyphosphate byionotropic gelation method. The optimal formulation was as follow:curcumin/chitosan=1:1(w/w,0.3%sodium tripolyphosphate). The microparticlespossessed an average diameter of58.50μm, drug loading of33.50%, encapsulationefficiency of85.20%, and yield of71.33%. Solubility/dissolution and wettability ofcurcumin were enhanced in the formulations in comparison with pure drug.Sustained-release profiles of curcumin from the solid dispersions were ideallycontrolled in vitro up to12h.
The sustained-release solid dispersion systems improved the drug stabilityespecially the light stability significantly. The appearance, particle size, flowability,content and dissolution of the formulations changed slightly in6months.
The prepared drug delivery system achieved higher drug loading efficiency than the other ones. The formulations provided improved pharmacokinetic parameter inrats as compared with pure drug with good in vivo-in vitro correlations. The resultsobtained from this paper suggests that the developed sustained-release soliddispersion systems successfully enhanced solubility and sustained release of thepoorly water-soluble drug curcumin, and eventually, improved its oral bioavailabilityeffectively.
引文
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