Affordable Access

deepdyve-link
Publisher Website

Formulation and Bioequivalence Testing of Fixed-Dose Combination Orally Disintegrating Tablets for the Treatment of Tuberculosis in the Paediatric Population.

Authors
  • Dennison, Thomas J1
  • Smith, Julian C2
  • Badhan, Raj K S1
  • Mohammed, Afzal R3
  • 1 Aston School of Pharmacy, Aston University, Birmingham, UK.
  • 2 Faculty of Computing, Engineering and Science, University of South Wales, UK.
  • 3 Aston School of Pharmacy, Aston University, Birmingham, UK. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Oct 01, 2020
Volume
109
Issue
10
Pages
3105–3113
Identifiers
DOI: 10.1016/j.xphs.2020.07.016
PMID: 32710905
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Tuberculosis (TB) is believed to affect around 10 million people worldwide. Treatment for TB includes isoniazid and rifampicin, with fixed-dose combination (FDC) recommended for improved patient compliance. Similarly, orally disintegrating tablets (ODTs) are an increasingly popular dosage form that aid compliance since they do not require swallowing. In this study ODTs of isoniazid and rifampicin, either as discrete or FDC doses, were formulated and bioequivalence between single and combination doses compared using in vitro and in silico approaches. Dissolution profiles were compared using FDA advised difference (f1) and similarity (f2) testing in biorelevant media. Rifampicin release from FDCs decreased by approximately 15% in fed-state media (failed f1 and f2), which was attributed to enhanced rifampicin degradation in the presence of isoniazid at lower pH. Apparent permeability (Papp) values derived from Caco-2 transport studies were included alongside dissolution results into a physiologically based pharmacokinetic (PBPK) model, to simulate in vivo bioavailability in healthy subjects. Models showed no difference in bioavailability between formulations or dosing (fasted or fed) state, despite the failures in dissolution-based bioequivalence testing, highlighting shortcomings in f1 and f2 assessment and the strength of PBPK models. Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times