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Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B

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Abstract

Purpose

Fungizone® (AmB-SD), amphotericin B solubilized by sodium deoxycholate, contains a highly aggregated form of the antifungal agent that causes dose-limiting renal toxicity. With the aim of reducing the formulation’s toxicity by co-delivering monomeric amphotericin B (AmB) and sodium supplementation, we deaggregated AmB-SD with FDA-approved excipient PEG-DSPE in 0.9% NaCl-USP. Herein, we describe a reformulated AmB-SD with PEG-DSPE micelles that results in a less toxic drug with maintained antifungal activity.

Methods

We compared the aggregation state and particle size of AmB-SD alone or combined with PEG-DSPE micelles. In vitro hemolytic activity and in vivo renal toxicity were measured to determine the toxicity of different formulations. In vitro antifungal assays were performed to determine differences in efficacy among formulations.

Results

PEG-DSPE micelles in saline deaggregated AmB-SD. Deaggregated AmB-SD exhibited significantly reduced in vitro and in vivo toxicity. In vitro antifungal studies showed no difference in minimum inhibitory and fungicidal concentrations of AmB-SD combined with PEG-DSPE relative to the drug alone.

Conclusions

Reformulation of AmB-SD with PEG-DSPE micelles in saline facilitates co-delivery of monomeric AmB and sodium supplementation, potentially reducing the dose-limiting nephrotoxicity of AmB-SD. Ease of preparation and commercially available components lead us to acknowledge its potential for clinical use.

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Abbreviations

AmB:

Amphotericin B

AmB-SD:

Fungizone

BUN:

Blood urea nitrogen

CAC:

Critical aggregation concentration

MFC:

Minimum fungicidal concentration

MIC:

Minimum inhibitory concentration

SD:

Sodium deoxycholate

SDA:

Sabouraud dextrose agar

TL:

Total lysis

YPD:

Yeast peptone dextrose

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the NIH (R01 AI-43346). Special thanks to Dr. Tim Bugni for kindly providing C. albicans strain K1.

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Authors and Affiliations

  1. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin, 53705-2222, USA

    Celeste Alvarez, Dae Hwan Shin & Glen S. Kwon

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  1. Celeste Alvarez
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  2. Dae Hwan Shin
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  3. Glen S. Kwon
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Correspondence to Glen S. Kwon.

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Alvarez, C., Shin, D.H. & Kwon, G.S. Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B. Pharm Res 33, 2098–2106 (2016). https://doi.org/10.1007/s11095-016-1948-7

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  • DOI: https://doi.org/10.1007/s11095-016-1948-7

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