Candesartan Cilexetil Formulations in Mesoporous Silica: Preparation, Enhanced Dissolution In Vitro, and Oral Bioavailability In Vivo

• Published in: Journal of pharmaceutical sciences 2024-10, Vol.113 (10), p.3045-3053
• Main Authors: Guan, Huijian, Wang, Miao, Yu, Shaowen, Wang, Caimei, Chen, Qi, Chen, Ying, Zhang, Weiguang, Fan, Jun
• Format: Article
• Language: English
• Subjects: Administration, Oral; Amino modification; Animals; Antihypertensive Agents - administration & dosage; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacokinetics; Benzimidazoles - administration & dosage; Benzimidazoles - chemistry; Benzimidazoles - pharmacokinetics; Bioavailability; Biological Availability; Biphenyl Compounds - administration & dosage; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacokinetics; Candesartan cilexetil; Chemistry, Pharmaceutical - methods; Drug Carriers - chemistry; Drug release; Male; Mesoporous silica; Porosity; Rats; Rats, Sprague-Dawley; Silicon Dioxide - chemistry; Solubility; Tetrazoles - administration & dosage; Tetrazoles - chemistry; Tetrazoles - pharmacokinetics; X-Ray Diffraction - methods
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2024.07.007

•Four candesartan cilexetil-loaded mesoporous silica dispersions were prepared through solvent immersion.•Dissolution in vitro of four formulations were evaluated using flow-through cell dissolution method.•Pore size and surface area of carriers played key roles in drug loading and release.•CC-XDP 3150 exhibited a 1.88-fold larger release of CC as compared to crystalline drug.•The relative bioavailability of CC-XDP3150 in rats was enhanced 326 % in comparison with CC. 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. [Display omitted]