Title
Cochleate formulations of Amphotericin b designed for oral administration using a naturally occurring phospholipid
Date Issued
15 June 2021
Access level
open access
Resource Type
journal article
Author(s)
Université Paris-Saclay
Publisher(s)
Elsevier B.V.
Abstract
The purpose of this work was to formulate the poor soluble antifungal and antiparasitic agent Amphotericin B (AmB) in cost-effective lipid-based formulations suitable for oral use in developing countries, overcoming the limitations of poor water solubility, nephrotoxicity and low oral bioavailability. The antifungal agent was formulated, at different molar proportions, in cochleate nanocarriers prepared using an accessible naturally occurring phospholipid rich in phosphatidylserine (Lipoid PSP70). These nanoassemblies were prepared by condensation of negatively charged phospholipid membrane vesicles with divalent cations (Ca2+). Small-angle X-ray scattering studies revealed the Ca2+-triggered condensation of loosely packed multilamellar vesicles into tightly packed bilayers of strongly dehydrated multilamellar organization characterized by narrow Bragg peaks. Transmission electron microscopy and quasi-elastic light scattering studies demonstrated the formation of nanosized particles. AmB drug loading was above 55% in all formulations. Circular dichroism demonstrated the prevalence of monomeric and complexed forms of AmB over toxic aggregates. The stability of AmB in gastric medium was improved by loading in cochleates and its release in gastrointestinal media was retarded. Confocal microscopy studies revealed the in-vitro interactions of Lipoid PSP70-based cochleates with Caco2 intestinal cell monolayers. The results suggest that the low-cost AmB-loaded cochleates may increase the therapeutic range of this drug.
Volume
603
Language
English
OCDE Knowledge area
Farmacología, Farmacia
Subjects
Scopus EID
2-s2.0-85106299192
PubMed ID
Source
International Journal of Pharmaceutics
ISSN of the container
03785173
Sponsor(s)
A. L-C. received a Ph.D. grant from FONDECYT, Peru. A.A. acknowledges the allocation of beam time at Synchrotron SOLEIL (Saint Aubin, France) through the project 20191836 and the scientific and technical support of Dr. T. Bizien at the SWING beamline. The authors would like to thank Audrey Solgadi (Université Paris-Saclay, Inserm, CNRS, Ingénierie et Plateformes au Service de l’Innovation Thérapeutique) for help with the analysis of phospholipids in Lipoid PSP70; Claire Boulogne and Cynthia Gillet (Imagerie-Gif) for help with electron microscopy; Claire Gueutin (Institut Galien Paris-Saclay) for help with the analysis of AmB. Nicolas Huang and Baptiste Robin (Institut Galien Paris-Saclay) for help with morphogranulometry. We thank Jean-Jacques Vachon (Institut Galien Paris-Saclay) for help with X-ray diffraction experiments and also Claudie Bourgaux (Institut Galien Paris-Saclay) for performing additional SAXS experiments. We are grateful to Christina Sizun (Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301) for preliminary studies with circular dichroism and François-Xavier Legrand for useful discussions. We thank Joelle Salameh (Mécanismes cellulaires et moléculaires d’adaptation au stress et cancérogénèse, Faculté de Pharmacie, Université Paris-Saclay) for the gift of FITC-phalloidin.
A. L-C. received a Ph.D. grant from FONDECYT, Peru. A.A. acknowledges the allocation of beam time at Synchrotron SOLEIL (Saint Aubin, France) through the project 20191836 and the scientific and technical support of Dr. T. Bizien at the SWING beamline. The authors would like to thank Audrey Solgadi (Universit? Paris-Saclay, Inserm, CNRS, Ing?nierie et Plateformes au Service de l'Innovation Th?rapeutique) for help with the analysis of phospholipids in Lipoid PSP70; Claire Boulogne and Cynthia Gillet (Imagerie-Gif) for help with electron microscopy; Claire Gueutin (Institut Galien Paris-Saclay) for help with the analysis of AmB. Nicolas Huang and Baptiste Robin (Institut Galien Paris-Saclay) for help with morphogranulometry. We thank Jean-Jacques Vachon (Institut Galien Paris-Saclay) for help with X-ray diffraction experiments and also Claudie Bourgaux (Institut Galien Paris-Saclay) for performing additional SAXS experiments. We are grateful to Christina Sizun (Universit? Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301) for preliminary studies with circular dichroism and Fran?ois-Xavier Legrand for useful discussions. We thank Joelle Salameh (M?canismes cellulaires et mol?culaires d'adaptation au stress et canc?rog?n?se, Facult? de Pharmacie, Universit? Paris-Saclay) for the gift of FITC-phalloidin. This work did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors for running costs.
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