School of Chemistry, South China Normal University, Key Laboratory of Process Control and Quality Evaluation of Chiral Drugs, Guangdong Provincial Drug Administration, Guangzhou Key Laboratory of Biomedical Analytical Chemistry, Guangzhou 510006, China.
Department of Pharmaceutical Excipients, Guangdong Institute for Drug Control, Key Laboratory of Quality Control and Evaluation of Pharmaceutical Excipients, State Drug Administration, Guangzhou 510663, China.
J Pharm Sci. 2024 Oct;113(10):3045-3053. doi: 10.1016/j.xphs.2024.07.007. Epub 2024 Aug 2.
Candesartan cilexetil (CC) is one of well-tolerated antihypertensive drugs, while its poor solubility and low bioavailability limit its use. Herein, two mesoporous silica (Syloid XDP 3150 and Syloid AL-1 FP) and the corresponding amino-modified products (N-XDP 3150 and N-AL-1 FP) have been selected as the carriers of Candesartan cilexetil to prepare solid dispersion through solvent immersion, and characterized through using powder X-ray diffraction analysis, infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance spectroscopy, etc. The state of CC changed from crystalline to amorphous after loading onto the silica carriers, in which no interactions between CC and silica existed. Then, the dissolution behaviors in vitro were studied through using flow-through cell dissolution method. CC-XDP 3150 sample exhibited the most extensive dissolution, and the cumulative release of CC from it was 1.88-fold larger than that of CC. Moreover, the pharmacokinetic results in rats revealed that the relative bioavailability of CC-XDP 3150 and CC-N-XDP 3150 solid dispersions were estimated to be 326 % % and 238 % % in comparison with CC, respectively. Clearly, pore size, pore volume, and surface properties of silica carrier have remarkable effect on loading, dissolution and bioavailability of CC. In brief, this work will provide valuable information in construction of mesoporous silica-based delivery system toward poorly water-soluble drugs.
坎地沙坦西酯（CC）是一种耐受性良好的降压药，但其溶解度差和生物利用度低限制了其应用。本文选择两种介孔硅（Syloid XDP 3150 和 Syloid AL-1 FP）及其相应的氨基改性产物（N-XDP 3150 和 N-AL-1 FP）作为坎地沙坦西酯的载体，通过溶剂浸渍法制备固体分散体，并通过粉末 X 射线衍射分析、红外光谱、差示扫描量热法、扫描电子显微镜和固态核磁共振波谱等进行了表征。CC 在负载到硅载体后，其状态从结晶态转变为无定形态，其中 CC 与硅之间不存在相互作用。然后，通过流通池溶出法研究了体外的溶解行为。CC-XDP 3150 样品表现出最广泛的溶解，其 CC 的累积释放量是 CC 的 1.88 倍。此外，大鼠的药代动力学结果表明，CC-XDP 3150 和 CC-N-XDP 3150 固体分散体的相对生物利用度分别估计为 CC 的 326%和 238%。显然，硅载体的孔径、孔体积和表面性质对 CC 的负载、溶解和生物利用度有显著影响。总之，这项工作将为构建基于介孔硅的难溶性药物传递系统提供有价值的信息。
