College of Pharmacy, Yeungnam University, 214-1 Dae-Dong, Gyongsan 712-749, South Korea.
Int J Pharm. 2010 Aug 16;395(1-2):161-6. doi: 10.1016/j.ijpharm.2010.05.023. Epub 2010 May 24.
Three solid dispersions containing poorly water-soluble tacrolimus were prepared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and dioctyl sulfosuccinate (DOSS) using a spray-drying technique via the solvent-evaporation method with a methylene chloride/ethanol mixture, the solvent-wetting method with ethanol and the surface-attached method with water, respectively. The solubility and dissolution of the drug in the three solid dispersions were evaluated compared to drug powder. Furthermore, their physicochemical properties were investigated using SEM, DSC and powder X-ray diffraction. The solubility and dissolution of the drug were significantly improved in the order of the tacrolimus-loaded solid dispersion prepared by: solvent-evaporation method>solvent-wetting method>surface-attached method. The solid dispersions prepared by solvent evaporation appeared as an aggregated form with the amorphous form. In particular, the solid dispersion prepared by the solvent-evaporation method improved solubility about 900-fold and dissolution of tacrolimus 15-fold because of its reduced particle size, increased surface area and close contact between the hydrophilic carrier and the drug. In the solvent-wetting method, the drug, which was changed to an amorphous form, was attached onto the surface of undissolved carriers. However, the solid dispersion prepared by the surface-attached method gave an unchanged crystalline form. In this solid dispersion, the carriers were attached to the surface of the undissolved drug, resulting in changing the drug from being hydrophobic to hydrophilic. As the crystal form of drug in this solid dispersion was not converted to the amorphous form unlike other solid dispersions, it gave relatively less solubility and dissolution of the drug than did the others. Thus, in the development of a solid-dispersion system containing poorly water-soluble drugs, the method of preparation plays an important role in the solubility and crystallinity of the drugs.
三种包含难溶性他克莫司的固体分散体分别使用羟丙基-β-环糊精（HP-β-CD）和二辛基磺基琥珀酸钠（DOSS），通过溶剂蒸发法（以二氯甲烷/乙醇混合物为溶剂）、溶剂润湿法（以乙醇为溶剂）和表面附着法（以水为溶剂）制备。通过比较药物粉末，评估了三种固体分散体中药物的溶解度和溶解情况。此外，还使用 SEM、DSC 和粉末 X 射线衍射研究了它们的物理化学性质。药物的溶解度和溶解度按照载药固体分散体制备方法的顺序显著提高：溶剂蒸发法>溶剂润湿法>表面附着法。通过溶剂蒸发法制备的固体分散体呈现出聚集形式，为无定形形式。特别是，通过溶剂蒸发法制备的固体分散体由于粒径减小、比表面积增加以及亲水性载体与药物之间的紧密接触，使他克莫司的溶解度提高了约 900 倍，溶解速度提高了 15 倍。在溶剂润湿法中，药物变为无定形形式附着在未溶解载体的表面上。然而，通过表面附着法制备的固体分散体保持了不变的结晶形式。在这种固体分散体中，载体附着在未溶解药物的表面上，使药物由疏水性变为亲水性。由于该固体分散体中的药物晶型与其他固体分散体不同，没有转化为无定形形式，因此与其他固体分散体相比，药物的溶解度和溶解速度相对较低。因此，在开发包含难溶性药物的固体分散体系时，制备方法对药物的溶解度和结晶度起着重要作用。
