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Aug 29, 2020

Impact of differential particle size of fenofibrate nanosuspensions on biopharmaceutical performance using physiologically based absorption modeling in rats

Abstract

Particle size and its distribution governs oral biopharmaceutical performance of poorly water-soluble active pharmaceutical ingredients (APIs). Fenofibrate, a poorly water-soluble API, is marketed as both micronized and nanosized formulations having differential biopharmaceutical performance. The present study investigated the impact of differential particle size of fenofibrate (FNT) nanosuspensions on biopharmaceutical performance using physiologically based absorption modeling (PBAM). Nanosuspensions with particle size (D90) of 200–300 nm, 500–600 nm, and 800–1000 nm, coded as B1, B2, and B3, respectively, were generated using media milling. Micronized fenofibrate and Tricor® (nano-sized marketed formulation) were used as controls for the study. Formulations were evaluated for apparent solubility, dissolution, permeability and cellular uptake, while oral bioavailability studies were conducted in Sprague-Dawley rats. PBAM was developed using physicochemical properties and disposition kinetics along fasted-state rat physiology. The model was optimized and used for the prediction of in vivo biopharmaceutical performance of nanosized formulations. The model predicted faster absorption for B1 and Tricor®, which was inconsistent with the observed plasma concentration-time profiles of orally administered formulations in rats. In vitro cellular uptake studies revealed that inconsistency could be due to extended period of absorption with B1 and Tricor®. The latter can be ascribed to (i) mucoadhesion of nanocrystals leading to extended release of FNT and (ii) higher flux and ingress of FNT into enterocyte due to higher apparent solubility of FNT nanocrystals. Once inside enterocytes, FNT rapidly converts to fenofibric acid. It ionizes at cellular pH and gets trapped inside due to poorer permeability of ionized species, which is subsequently absorbed slowly. This phenomenon was incorporated to the model by extending small intestinal transit time and it revealed that the apparent solubilization triggered flux can lead to extension in small intestinal transit time for B1 and Tricor®. The findings from the current study can be useful in the development of bioequivalent nanosuspensions of fenofibrate and PBAM of nanosuspensions for poorly water-soluble APIs.

By Divisha Jain, Poonam Singh Thakur, Samarth D.Thakore, Sanjaya K.Samal, Arvind K.Bansal

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