Drug solubilization in dog intestinal fluids with and without administration of lipid-based formulations.

Autor: Parrow A; Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden., Kabedev A; Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden., Larsson P; Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden; The Swedish Drug Delivery Center, Department of Pharmacy, Uppsala University, Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden., Johansson P; AstraZeneca R&D, SE-431 50, Gothenburg, Sweden., Abrahamsson B; AstraZeneca R&D, SE-431 50, Gothenburg, Sweden., Bergström CAS; Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden; The Swedish Drug Delivery Center, Department of Pharmacy, Uppsala University, Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden. Electronic address: christel.bergstrom@farmaci.uu.se.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2024 Jul; Vol. 371, pp. 555-569. Date of Electronic Publication: 2024 Jun 13.
DOI: 10.1016/j.jconrel.2024.06.008
Abstrakt: The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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