Do Ophthalmic Solutions of Amphotericin B Solubilised in 2-Hydroxypropyl-γ-Cyclodextrins Possess an Extended Physicochemical Stability?

Mouloud Yessaad,Philip Chennell,Yassine Bouattour,Florence Abd El Kader,Mireille Jouannet,Mathieu Wasiak,Valérie Sautou

doi:10.3390/pharmaceutics12090786

Abstract

Fungal keratitis is a sight-threatening disease for which amphotericin B eye drops is one of the front-line treatments. Unfortunately, there are currently no commercial forms available, and there is little data concerning the long-term stability of compounded formulations based on intravenous dosages forms. New formulations of amphotericin B ophthalmic solutions solubilised with γ-cyclodextrins have shown promising in-vitro results, but stability data is also lacking. The objective of this study was therefore to investigate the stability of a formulation of ready-to-use amphotericin B solubilised in 2-hydroxypropyl-γ-cyclodextrins (AB-HP-γ-CD), for 350 days. An amphotericin B deoxycholate (ABDC) formulation was used as a comparator. Analyses used were the following: visual inspection, turbidity, osmolality and pH measurements, amphotericin B quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. AB-HP-γ-CD formulation showed signs of chemical instability (loss of amphotericin B) after 28 and 56 days at 25 °C and 5 °C. Adding an antioxidant (ascorbic acid) to the formulation did not improve stability. ABDC formulation showed signs of physical instability (increased turbidy and amphotericin B precipitation) after 28 days and 168 days at 25 °C and 5 °C. As such, AB-HP-γ-CD formulation does not provide long-term stability for ophthalmic amphotericin B solutions.

Highlights

Fungal keratitis is a purulent, ulcerative infection of the cornea that can cause corneal opacification and irreversible blindness if left untreated [1,2]
The objective of this study was to investigate the stability of a formulation of ready-to-use amphotericin B solubilised in 2-hydroxypropyl-γ-cyclodextrins (AB-HP-γ-CD) in Pharmaceutics 2020, 12, 786 low-density polyethylene eyedroppers, for 350 days at 5 ◦ C and 25 ◦ C
In this we show that amphotericin is not as conventional conventional amphotericin B deoxycholate, as amphotericin B loss reached nearly 10 and 20% after amphotericin B deoxycholate, as amphotericin B loss reached nearly 10 and 20% after respectively 56 and 168 days of storage at 5 ◦ C, whereas for convention ABDC formulation, the loss was of only of

Summary

Introduction

Fungal (or mycotic) keratitis is a purulent, ulcerative infection of the cornea that can cause corneal opacification and irreversible blindness if left untreated [1,2]. For the treatment of such infections, clinicians have the choice between drugs from two main typical classes of antifungal agents that are azoles (voriconazole, fluconazole, ketoconazole, posaconazole, itraconazole) and polyenes (natamycin and amphotericin B) [12]. Of these drugs, amphotericin B is broad-spectrum agent and is active against most of fungi, especially Candida spp [13], and possesses very low Pharmaceutics 2020, 12, 786; doi:10.3390/pharmaceutics12090786 www.mdpi.com/journal/pharmaceutics

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