Ghiciuc Cristina Mihaela, Shleghm Maytham Razaq, Vasile Cornelia, Tantaru Gladiola, Creteanu Andreea, Ochiuz Lacramioara
Department of Pharmacology, Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania.
Department of "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.
Front Pharmacol. 2021 Mar 4;12:640705. doi: 10.3389/fphar.2021.640705. eCollection 2021.
Amiodarone low solubility and high permeability is the limiting step for its bioavailability, therefore new formulations are needed to improve the solubility of amiodarone either to increase its oral bioavailability or to reduce its toxic effects. Complexation of amiodarone with cyclodextrin results in improved dissolution rate, solubility, and allows for a more controlled drug release. We characterized the acute toxicity of a new amiodarone 2-hydroxypropyl-β-cyclodextrin complex (AMD/HP-β-CD) as powdered form and as a matrix based on Kollidon® and chitosan, administered intraperitoneally in laboratory animals. There were developed two formulations of matrix: one containing only pure AMD as a control sample (Fc) and one containing the inclusion complex with the optimal solubility (F). AMD was equitoxic with HP-β-CD after intraperitoneal administration (289.4 mg/kg for AMD and 298.3 mg/kg for AMD/HP-β-CD), with corresponding histopathological changes. The matrix based formulations presented higher LD50 values for acute toxicity, of 347.5 mg/kg for Fc and 455.6 mg/kg for F10, conducting to the idea of a safer administration because KOL and CHT matrix modified the solubility and controlled the AMD release. The LD50 is 1.5 higher for AMD/HP-β-CD included in a KOL and CHT based matrix compared to the pure AMD, administered intraperitoneally.
胺碘酮的低溶解度和高渗透性是其生物利用度的限制步骤，因此需要新的制剂来提高胺碘酮的溶解度，以增加其口服生物利用度或降低其毒性作用。胺碘酮与环糊精络合可提高溶解速率、溶解度，并实现更可控的药物释放。我们对一种新型胺碘酮2-羟丙基-β-环糊精络合物（AMD/HP-β-CD）以粉末形式以及基于聚乙烯吡咯烷酮和壳聚糖的基质形式腹腔注射给实验动物后的急性毒性进行了表征。开发了两种基质制剂：一种仅含有纯AMD作为对照样品（Fc），另一种含有具有最佳溶解度的包合物（F）。腹腔注射后，AMD与HP-β-CD的毒性相当（AMD为289.4mg/kg，AMD/HP-β-CD为298.3mg/kg），伴有相应的组织病理学变化。基于基质的制剂急性毒性的LD50值更高，Fc为347.5mg/kg，F10为455.6mg/kg，这表明由于聚乙烯吡咯烷酮和壳聚糖基质改变了溶解度并控制了AMD的释放，从而实现了更安全的给药。与腹腔注射的纯AMD相比，基于聚乙烯吡咯烷酮和壳聚糖基质的AMD/HP-β-CD的LD50高出1.5倍。
