Title:Use of In silico Methodologies to Predict the Bioavailability of Oral
Suspensions: A Regulatory Approach
Volume: 29
Issue: 38
Author(s): Thiago da Silva Honório, Alice Simon, Raiane Monteiro Clacino Machado, Carlos Rangel Rodrigues, Flávia Almada do Carmo, Lucio Mendes Cabral*Valeria Pereira de Sousa
Affiliation:
- Laboratory of Cell Culture (LabCel), Department of Drugs and Pharmaceutics, Faculty
of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratory of Pharmaceutical Industrial Technology
(LabTIF), Department of Drugs and Pharmaceutics, Faculty of Pharmacy, Universidade Federal do Rio de Janeiro, Rio de
Janeiro, Brazil
Keywords:
Oral suspensions, dissolution test, in vitro-in vivo correlation (IVIVC), in silico pharmacokinetics, GastroPlusTM, regulatory actions.
Abstract:
Background: Oral suspensions are heterogeneous disperse systems, and the particle size distribution,
crystalline form of the dispersed solid, and composition of the formulation can be listed as parameters
that control the drug dissolution rate and its bioavailability.
Objective: The aim of this work was to develop a discriminative dissolution test, which, in association with in
silico methodologies, can make it possible to safely anticipate bioavailability problems.
Methods: Nimesulide and ibuprofen (BCS class II) and cephalexin (BCS class I) oral suspensions were
studied. Previously, solid-state structure and particle size in active pharmaceutical ingredients were characterized
and the impact of differences on solubility was evaluated for the choice of discriminative medium. Afterwards,
particle size distribution (0.1 to 360 μm), dissolution profile, and
in vitro permeability in Caco-2 cell of
commercial suspensions, were determined. These parameters were used as input for the establishment of the
in
vitro-in vivo correlation (IVIVC) for the suspensions using the GastroPlus™ with Wagner-Nelson and Loo-
Riegelmann deconvolution approach.
Results: The predicted/observed pharmacokinetic model showed good correlation coefficients (r) of 0.960,
0.950, and 0.901, respectively. The IVIVC was established for one nimesulide and two ibuprofen suspensions
with r between 0.956 and 0.932, and the percent prediction error (%PE) did not exceed 15%.
Conclusion: In this work, we have performed a complete study combining
in vitro/in silico approaches with
the aim of anticipating the safety and efficacy of oral pharmaceutical suspensions in order to provide a regulatory
tool for this category of products in a faster and more economical way.
