Chaudhari Pinal, Ghate Vivek M, Kodoth Arun K, Birangal Sumit, Lewis Shaila A
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.
University Institute of Pharma Sciences, Chandigarh University, Gharuan, India.
Pharm Dev Technol. 2025 Jan;30(1):114-125. doi: 10.1080/10837450.2024.2448625. Epub 2025 Jan 19.
Supersaturated formulations have been widely explored for improving the oral bioavailability of drugs by using mesoporous silica (MS) to generate supersaturation molecular adsorption; however, this is followed by precipitation. Several precipitation inhibitors (PI) have been explored to prevent precipitation and maintain the drug in solution for a longer period. However, the combined approach of MS and PIs, the impact of MS and Silica, and the loading of high-molecular-weight neutral molecules such as Cyclosporine A (CsA) have not yet been explored. The present study aimed to explore the impact of MS and a hydroxypropyl methylcellulose (HPMC) matrix on the supersaturation and bioavailability of the neutral drug CsA.
A CsA-loaded mesoporous silica/HPMC ternary matrix and CsA-HPMC and CsA-MS controls were prepared, and physicochemical characterization was carried out. The ternary matrix and controls were investigated for the Non-sink Mini FaSSIF dissolution and biorelevant transfer studies. Furthermore, drug release modeling was performed using DDSolver, and pharmacokinetic studies were performed to assess the impact on oral bioavailability compared with the marketed formulation.
The study suggested that the co-loaded CsA, HPMC, and MS demonstrated higher supersaturation than CsA-loaded silica and CsA-HPMC controls. A significant improvement in FaSSIF single medium (2-fold) and biorelevant transfer (3.37-fold) increase in the dissolution profile was observed for the co-loaded CsA-MS-HPMC samples. The dissolution profile was corroborated by pharmacokinetic studies, which showed a 1.19-fold higher oral bioavailability of CsA-MS-HPMC compared to that of CsA-MS and CsA-HPMC.
The pharmacokinetics indicated that CsA-MS-HPMC co-loaded samples demonstrated supersaturation and improved bioavailability compared with the physical mixture.
通过使用介孔二氧化硅（MS）产生过饱和分子吸附来提高药物的口服生物利用度，已对过饱和制剂进行了广泛研究；然而，随后会发生沉淀。人们已经探索了几种沉淀抑制剂（PI）来防止沉淀并使药物在溶液中保持更长时间。然而，MS和PI的联合方法、MS和二氧化硅的影响以及环孢素A（CsA）等高分子量中性分子的负载情况尚未得到研究。本研究旨在探讨MS和羟丙基甲基纤维素（HPMC）基质对中性药物CsA过饱和度和生物利用度的影响。
制备了负载CsA的介孔二氧化硅/HPMC三元基质以及CsA-HPMC和CsA-MS对照，并进行了理化表征。对三元基质和对照进行非漏槽Mini FaSSIF溶出和生物相关转运研究。此外，使用DDSolver进行药物释放建模，并进行药代动力学研究以评估与市售制剂相比对口服生物利用度的影响。
研究表明,共负载CsA、HPMC和MS的制剂比负载CsA 的二氧化硅和CsA-HPMC对照表现出更高的过饱和度。对于共负载CsA-MS-HPMC样品，在FaSSIF单一介质（2倍）和生物相关转运（3.37倍）的溶出曲线中观察到显著改善。药代动力学研究证实了溶出曲线,结果显示CsA-MS-HPMC的口服生物利用度比CsA-MS和CsA-HPMC高1.19倍。
药代动力学表明，与物理混合物相比，共负载CsA-MS-HPMC样品表现出过饱和并提高了生物利用度。
