Boyd Ben J, Porter Christopher J H, Charman William N
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, 3052, Australia.
J Pharm Sci. 2003 Jun;92(6):1262-71. doi: 10.1002/jps.10390.
The thermodynamic activity of solubilized drug is an important determinant of the extent of absorption of lipophilic drugs from the gastrointestinal tract. In this study, the polymer partitioning method was evaluated for its use in the determination of the thermodynamic activity of lipophilic drugs when solubilized in colloidal digestion products, using drug in dilute solution as a reference ideal solution. The lipophilic drugs griseofulvin, diazepam, and danazol partitioned into a polymeric receiver phase from non-micellar solution as a function of drug lipophilicity. The concentration of drug that partitioned into the polymer was linearly proportional to the concentration of free drug in solution, and this allowed the measured partition coefficient to be utilized as an indicator of the drug activity coefficient. The addition of a solubilizing species such as bile salt micelles caused a reduction in drug activity of a similar magnitude to that predicted from micelle equilibrium solubility data in the identical micellar solutions. The addition of micelle swelling lipids such as lecithin and fatty acids resulted in further reductions in activity coefficient. The ability to measure drug activity in model digestive systems has potential for application in the rational development of improved lipid-based formulations of poorly water-soluble drugs for oral administration.
溶解药物的热力学活性是亲脂性药物从胃肠道吸收程度的重要决定因素。在本研究中，以稀溶液中的药物作为参考理想溶液，评估了聚合物分配法在测定亲脂性药物溶解于胶体消化产物时的热力学活性方面的应用。亲脂性药物灰黄霉素、地西泮和达那唑从非胶束溶液分配到聚合物接受相中，这是药物亲脂性的函数。分配到聚合物中的药物浓度与溶液中游离药物的浓度呈线性比例关系，这使得测得的分配系数能够用作药物活度系数的指标。添加增溶物质如胆盐胶束会导致药物活性降低，其幅度与相同胶束溶液中胶束平衡溶解度数据预测的幅度相似。添加胶束膨胀脂质如卵磷脂和脂肪酸会导致活度系数进一步降低。在模型消化系统中测量药物活性的能力在合理开发用于口服给药的水溶性差的药物的改进脂质制剂方面具有应用潜力。
