Bioavailability Enhancement of Olmesartan Medoxomil Using Hot-Melt Extrusion: In-Silico , In-Vitro , and In-Vivo Evaluat
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Research Article Bioavailability Enhancement of Olmesartan Medoxomil Using Hot-Melt Extrusion: In-Silico, In-Vitro, and In-Vivo Evaluation Pankaj Jadhav,1 Vinod Gokarna,2 Vineeta Deshpande,3 and Pradeep Vavia1,4
Received 21 April 2020; accepted 5 August 2020 Abstract. Olmesartan medoxomil (OLM) an antihypertensive molecule with poor solubility and poor bioavailability (26% when taken orally) was selected as a model drug. Herein, rationale development of amorphous solid dispersion with hot-melt extrusion of poorly bioavailable OLM was carried out with the aid of quality by design (QbD), in-silico, in-vitro, and in-vivo evaluations. Polymer selection commenced with the selection of thermoplastic water-soluble polymers with the compatible processing temperature window as per the thermal behavior of OLM. Molecular dynamics (MD) simulations as well assisted in the selection of a carrier. Promising dissolution enhancement was observed with the help of Kollidon VA-64 (VA-64) as a carrier. Optimization of the formulation was executed using the QbD approach with design of experiment as a statistical optimization tool. Interactions between VA-64 and OLM on the atomic level were studied with the help of atomistic MD simulations. Characterization of the optimized extrudates were carried out with scanning electron microscopy, atomic force microscopy, differential scanning calorimetry, thermogravimetric analysis, Fourier transforms infrared spectroscopy, powder X-ray diffraction, in-vitro dissolution study, and in-vivo pharmacokinetic studies. Molecular-level mixing of OLM with VA-64 resulted into glass solution formation which rapidly dissolves (28 times in-vitro dissolution enhancement) in GI tract fluids and instantly gets absorbed into blood circulation. In-vivo pharmacokinetic studies performed in Sprague-Dawley rats reflected superior bioavailability (201.60%) with a significant increase in the Cmax with short Tmax through amorphization of OLM. The in-silico results were in agreement with the observed results of in-vitro dissolution studies and in-vivo pharmacokinetic study. KEY WORDS: Olmesartan medoxomil; hot-melt extrusion; amorphization; molecular dynamics (MD) simulations.
INTRODUCTION Nowadays during drug development with the advancement of high throughput screening, drug molecules are discovered with undesirable properties such as high molecular Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12249-020-01780-3) contains supplementary material, which is available to authorized users. 1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University under Section 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, TEQIP Phase II Funded, Matunga (E), Mumbai, 400019, India. 2 Don Bosco Institute of Technology, Kurla (W), Mumbai, 400070, India. 3 Department of Physics, Institute of Chemical Technology, University under Section 3 of UGC Act – 1956, Elite Status and Center of Excellence – Govt. of Maharashtra, T
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