PDF(Sci-hub)
Abstract：
Candesartan cilexetil (CC), a prodrug and highly effective antihypertensive agent, is a poorly soluble (BCS Class II) drug with limited bioavailability. Here, we attempted to improve CC\'s bioavailability by formulating several CC-loaded amorphous solid dispersions with a hydrophilic carrier (PVPK30) and pH modifier (sodium carbonate) using the spray drying technique. Solubility, in vitro dissolution, and moisture content tests were used for screening the optimized formulation. We identified an optimized formulation of CC/PVPK30/SC, which at the ratio of 1:0.5:1 (w/w/w) exhibited a 30,000-fold increase in solubility and a more than 9-fold enhancement in dissolution compared to pure CC. Solid-state characterization revealed that in pH-modulated CC amorphous solid dispersion (CCSDpM), CC\'s crystallinity was altered to an amorphous state with the absence of undesirable interactions. Stability studies also showed that the optimized formulation was stable with good drug content and drug release under accelerated conditions of up to 4 weeks and real-time stability conditions of up to 12 weeks. Furthermore, pharmacokinetic parameters, such as AUC and Cmax of candesartan, had a 4.45-fold and 7.42-fold improvement, respectively, in CCSDpM-treated rats compared to those in the CC-treated rats. Thus, these results suggest that CCSDpM is highly effective for increasing oral absorption. The application of these techniques can be a viable strategy to improve a drug\'s bioavailability.
摘要：
坎地沙坦酯（CC），一种前药和高效的抗高血压药，是一种溶解性差的（BCSII类）药物，生物利用度有限。这里,我们试图通过使用喷雾干燥技术，用亲水性载体（PVPK30）和pH调节剂（碳酸钠）配制几种负载CC的无定形固体分散体，以提高CC的生物利用度。溶解度,体外溶出度,和水分含量测试用于筛选优化的配方。我们确定了CC/PVPK30/SC的优化配方，与纯CC相比,在1:0.5:1(w/w/w)的比率下表现出30,000倍的溶解度增加和超过9倍的溶出增加。固态表征表明，在pH调节的CC无定形固体分散体(CCSDpM)中，CC的结晶度改变为无定形状态，没有不希望的相互作用。稳定性研究还表明,优化的制剂在长达4周的加速条件和长达12周的实时稳定性条件下是稳定的,具有良好的药物含量和药物释放。此外，药代动力学参数，例如坎地沙坦的AUC和Cmax，分别提高了4.45倍和7.42倍，分别,与CC处理的大鼠相比，CCSDpM处理的大鼠。因此，这些结果表明,CCSDpM对增加口服吸收非常有效.这些技术的应用可以成为提高药物生物利用度的可行策略。
