微环境pH对泊沙康唑固体分散体溶出度的影响

The Effect of Microenvironment pH on Dissolution of Solid Dispersion of Posaconazole

目的 研究并评价微环境pH对无定形固体分散体溶出行为的影响。方法 以泊沙康唑(posaconazole, POS)为模型药物并测定其在不同pH值的饱和溶解度,以醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)和聚乙烯吡咯烷酮(PVP K30)为载体材料,枸橼酸和磷酸二氢钾分别为酸化剂和碱化剂,通过热熔挤出法(hot melt extrusion, HME)制备POS无定形固体分散体(SD),使用X射线粉末衍射法(PXRD)进行表征。随后以乳糖和微晶纤维素为填充剂、硬脂酸镁为润滑剂进行粉末直压制备得到片剂,并考察各组片剂的溶出情况以及片剂溶出过程中的微环境pH。结果 POS在不同pH环境中的饱和溶解度相差很大,在pH 1.2的盐酸溶液中,其饱和溶解度达到700μg·mL^(-1),而在pH 6.8的磷酸缓冲盐中,其饱和溶解度仅有0.32μg·mL^(-1)。利用HME所制备的固体分散体中POS以无定形的形式存在,粉末直压所制备的片剂的硬度在65N左右。在体外溶出实验中,HPMCAS组和PVP K30与枸橼酸的复合载体组的溶出度较高,都达到90%左右,而PVP K30组和HPMCAS与磷酸二氢钾的复合载体组的溶出度相对较低,分别约为40%和60%,利用甲基橙显色剂显示HPMCAS组和PVP K30与枸橼酸的复合载体组在溶出过程中,甲基橙显示红色,提示其微环境pH小于3.1。而在PVP K30组和HPMCAS与磷酸二氢钾的复合载体组在溶出过程中,甲基橙显示黄色,提示其pH微环境大于4.4。结论 pH微环境是影响POS溶出的重要因素,通过调控药物周围pH可以改变药物的溶行为。

OBJECTIVE To study and evaluate the effect of microenvironment pH on the dissolution behavior of amorphous solid dispersions. METHODS Using posaconazole(POS) as a model drug and measuring its saturated solubility at different pH values. Hydroxypropyl methylcellulose acetate succinate(HPMCAS) and polyvinylpyrrolidone(PVP K30) work as carrier materials. Citric acid and potassium dihydrogen phosphate are acidifiers and alkalizers, respectively. POS amorphous solid dispersions(SD) were prepared by hot melt extrusion(HME) and characterized by X-ray powder diffraction(PXRD). Subsequently, lactose and microcrystalline cellulose were used as fillers and magnesium stearate was used as a lubricant to prepare tablets by direct powder compression. The dissolution of each group of tablets and the microenvironment pH during the dissolution of the tablets were investigated.RESULTS The saturated solubility of POS in different pH environments varies greatly. In the hydrochloric acid solution of pH 1.2, its saturated solubility reaches 700μg/mL^(-1), while in the phosphate buffer salt of pH 7.0, its saturated solubility is only 0.32 μg/mL^(-1). The POS in the solid dispersion prepared by HME exists in an amorphous form, and the hardness of the tablet prepared by direct compression is about 65 N. In vitro dissolution experiment showed that dissolution rates of the HPMCAS group and the composite carrier group of PVP K30 and citric acid were higher, reaching about 90%, while the dissolution rates of the PVP K30 group and the composite carrier group of HPMCAS and potassium dihydrogen phosphate were relatively lower, about 40% and 60% respectively. The methyl orange developer showed red in HPMCAS group and the composite carrier group of PVP K30 and citric acid during the dissolution process, indicating that the pH microenvironment was less than 3.1.While the methyl orange developer showed yellow in the PVP K30 group and the composite carrier group of HPMCAS and potassium dihydrogen phosphate during the dissolution process, indicating that its pH microenvironment was greater than 4.4.CONCLUSION The pH microenvironment is an important factor affecting the dissolution of POS, and the dissolution behavior can be changed by adjusting the pH microenvironment of drug.