Research Articles
Amphotericin B in Oil–Water Lecithin-Based Microemulsions: Formulation and Toxicity Evaluation

https://doi.org/10.1002/jps.10065Get rights and content

Abstract

A novel lecithin-based microemulsion containing AmB was developed to reduce the toxic effects of the drug, comparing it with the commercial formulation Fungizone®. Phase diagrams containing the microemulsion region were constructed for pseudoternary systems composed of isopropil myristate (IPM)/Brij® 96V/lecithin/water. The incorporation of AmB to the microemulsions was done following the Phase Inversion Temperature (PIT) method or by diluting the drug in the aqueous phase of the disperse system before forming the microemulsion. The percentage of drug entrapped in the microemulsion was analyzed by an HPLC method obtaining recoveries > 98%. Mean droplet size of the microemulsions chosen for the acute toxicity evaluation was of 45 nm, and the rheological studies showed that those microemulsions mentioned followed a Newtonian behavior. Different studies are described in this work to prove the stability of these new dosage forms. Acute toxicity results, determined by a graphic method, the probit binary model and the Reed and Muench method showed that lethal dose 50 (LD50) for AmB microemulsions was of 2.9 mgkg−1 compared to 1.4 mgkg−1 for the commercial deoxycholate suspension, Fungizone®. The overall results indicate that treatment with AmB microemulsions was less toxic than Fungizone®, suggesting a potential therapeutic application. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1178–1185, 2002

Section snippets

INTRODUCTION

Amphotericin B (AmB) is a macrocyclic, polyene antibiotic with a potent fungistatic and fungicidal activity against a broad range of pathogenic and opportunistic fungal species, and since its introduction in 1956 it has remained the most effective systemic therapy for serious fungal infections such as candidiasis, histoplasmosis, and aspergillosis.1,2 The incidence of these infections has increased in recent years due to frequent use of indwelling intravascular cathethers, immunossuppressive

Materials and Chemicals

All chemicals were used as received. Sodium hydroxide was obtained from Panreac (Barcelona, Spain). Isopropyl myristate (IPM) was obtained from Merck Schuchardt (Madrid, Spain). Polyoxyethylene-10-oleyl ether (Brij® 96V) was obtained from Fluka Chemika (Madrid, Spain). L-α-phosphatidyl-choline (L-α-Lecithin) was obtained from Sigma. Amphotericin B and Fungizone® (AmB) were a gift from Squibb Pharmaceutical Industry (Barcelona, Spain). Triple-distilled water, obtained from a Milli-Q Plus system

RESULTS AND DISCUSSION

Microemulsion components were IPM, water, lecithin and Brij® 96V. Lecithin, a nontoxic, naturally occurring biological surfactant, is a major component of membrane lipids. When administered in optimum amounts, it does not have the toxicity and sensitivity problems associated with most other surfactants. Hence, it is the ideal surfactant choice for preparing pharmaceutically acceptable microemulsions, especially via the parenteral route.21 Lecithin could not be used as surfactant alone because

CONCLUSIONS

The results presented in this article demonstrate that AmB microemulsions present optimal characteristics to be administered by the parenteral route. Their mean particle size, pH, and viscosity make them highly attractive carrier systems for the controlled delivery of AmB. It has also been demonstrated that AmB microemulsions were less toxic than was Fungizone®, suggesting its potential therapeutic application.

Acknowledgements

This work was supported by a grant from the Science and Education Ministry and by a grant No. 99/0853 from the National Fonds for Health Investigation (FIS). We also would like to acknowledge David Castro for valuable comments and critical reading of the manuscript.

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