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Dissolution/Permeation of Albendazole in the Presence of Cyclodextrin and Bile Salts: A Mechanistic In Vitro Study into Factors Governing Oral Bioavailability.

Authors
  • Eriksen, Jonas Borregaard1
  • Christensen, Stine Bredow1
  • Bauer-Brandl, Annette1
  • Brandl, Martin2
  • 1 Department of Physics Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark. , (Denmark)
  • 2 Department of Physics Chemistry and Pharmacy, University of Southern Denmark, Odense M, Denmark. Electronic address: [email protected] , (Denmark)
Type
Published Article
Journal
Journal of Pharmaceutical Sciences
Publisher
Elsevier
Publication Date
Jun 01, 2022
Volume
111
Issue
6
Pages
1667–1673
Identifiers
DOI: 10.1016/j.xphs.2021.11.010
PMID: 34808218
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

We aimed to understand the impact of the interplay between bile salts and cyclodextrins on the dissolution-permeation of poorly soluble drug compounds with a moderate-strong binding constant to cyclodextrin. Phase diagrams were prepared on the chosen model compound albendazole in phosphate buffer, fasted state simulated intestinal fluid (FaSSIF), and a modified fed state simulated intestinal fluid (FeSSIFmod) with (2-hydroxypropyl)-beta-cyclodextrin (HP-β-CD) concentrations of up to 10 % (m/m). Then we investigated the dissolution/permeation interplay of albendazole dissolved/suspended in the different media through a biomimetic barrier on a 96-well in vitro model. The apparent solubility of albendazole was enhanced by HP-β-CD and FaSSIF/FeSSIFmod separately. However, when albendazole was dissolved in HP-β-CD and biomimetic media together, the solubility was significantly lower than the predicted additive solubility from the solubilizing effects. It is postulated that this is due to the sodium taurocholate from the biomimetic media displacing albendazole from the hydrophobic cavity of HP-β-CD. In the permeation experiments, the highest permeation was observed at cyclodextrin concentrations able to solubilize close to the total dose of albendazole without a major surplus of solubilization capacity. Furthermore, an over-proportional permeation enhancement was observed when both, cyclodextrin and biomimetic media were present. These results indicate that the interplay between bile salts and cyclodextrins can enhance the free (molecularly dissolved) fraction of drug in solution to a greater extent than could be obtained with one of the solubilizing components alone. In conclusion, at carefully selected cyclodextrin-concentrations in combination with biomimetic media, obviously, a transient supersaturation is induced, which is made responsible for the observed major permeation enhancement. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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