Poudel Surendra, Kim Dong Wuk
Vessel-Organ Interaction Research Center (VOICE, MRC), BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea.
Pharmaceutics. 2021 Apr 6;13(4):497. doi: 10.3390/pharmaceutics13040497.
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 (//) 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 (CCSD), 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 and of candesartan, had a 4.45-fold and 7.42-fold improvement, respectively, in CCSD-treated rats compared to those in the CC-treated rats. Thus, these results suggest that CCSD is highly effective for increasing oral absorption. The application of these techniques can be a viable strategy to improve a drug's bioavailability.
坎地沙坦酯（CC）是一种前体药物，也是一种高效的抗高血压药物，它是一种难溶性（生物药剂学分类系统II类）药物，生物利用度有限。在此，我们尝试通过喷雾干燥技术，用亲水性载体（聚乙烯吡咯烷酮K30，PVPK30）和pH调节剂（碳酸钠）制备几种载CC的无定形固体分散体，以提高CC的生物利用度。通过溶解度、体外溶出度和水分含量测试来筛选优化后的制剂。我们确定了CC/PVPK30/SC的优化制剂，其比例为1:0.5:1（//）时，与纯CC相比，溶解度提高了30000倍，溶出度提高了9倍以上。固态表征显示，在pH调节的CC无定形固体分散体（CCSD）中，CC的结晶度转变为无定形状态，且不存在不良相互作用。稳定性研究还表明，优化后的制剂在加速条件下长达4周以及实时稳定性条件下长达12周时，具有良好的药物含量和药物释放稳定性。此外，与CC治疗的大鼠相比，CCSD治疗的大鼠中坎地沙坦的药代动力学参数，如AUC和Cmax分别提高了4.45倍和7.42倍。因此，这些结果表明CCSD对增加口服吸收非常有效。应用这些技术可能是提高药物生物利用度的可行策略。
