Cargando…

Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a wea...

Descripción completa

Detalles Bibliográficos
Autores principales: Murashov, Mikhail D., Diaz-Espinosa, Jennifer, LaLone, Vernon, Tan, Joel W. Y., Laza, Raluca, Wang, Xueding, Stringer, Kathleen A., Rosania, Gus R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321048/
https://www.ncbi.nlm.nih.gov/pubmed/30453628
http://dx.doi.org/10.3390/pharmaceutics10040238
_version_ 1783385349304614912
author Murashov, Mikhail D.
Diaz-Espinosa, Jennifer
LaLone, Vernon
Tan, Joel W. Y.
Laza, Raluca
Wang, Xueding
Stringer, Kathleen A.
Rosania, Gus R.
author_facet Murashov, Mikhail D.
Diaz-Espinosa, Jennifer
LaLone, Vernon
Tan, Joel W. Y.
Laza, Raluca
Wang, Xueding
Stringer, Kathleen A.
Rosania, Gus R.
author_sort Murashov, Mikhail D.
collection PubMed
description Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy.
format Online
Article
Text
id pubmed-6321048
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-63210482019-01-11 Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration Murashov, Mikhail D. Diaz-Espinosa, Jennifer LaLone, Vernon Tan, Joel W. Y. Laza, Raluca Wang, Xueding Stringer, Kathleen A. Rosania, Gus R. Pharmaceutics Article Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy. MDPI 2018-11-17 /pmc/articles/PMC6321048/ /pubmed/30453628 http://dx.doi.org/10.3390/pharmaceutics10040238 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Murashov, Mikhail D.
Diaz-Espinosa, Jennifer
LaLone, Vernon
Tan, Joel W. Y.
Laza, Raluca
Wang, Xueding
Stringer, Kathleen A.
Rosania, Gus R.
Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration
title Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration
title_full Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration
title_fullStr Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration
title_full_unstemmed Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration
title_short Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration
title_sort synthesis and characterization of a biomimetic formulation of clofazimine hydrochloride microcrystals for parenteral administration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321048/
https://www.ncbi.nlm.nih.gov/pubmed/30453628
http://dx.doi.org/10.3390/pharmaceutics10040238
work_keys_str_mv AT murashovmikhaild synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT diazespinosajennifer synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT lalonevernon synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT tanjoelwy synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT lazaraluca synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT wangxueding synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT stringerkathleena synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration
AT rosaniagusr synthesisandcharacterizationofabiomimeticformulationofclofaziminehydrochloridemicrocrystalsforparenteraladministration