The reformulation of Amphotericin B for oral administration to treat systemic fungal infections and visceral leishmaniasis

Abstract

Amphotericin B (AmB) is a parenterally administered broad-spectrum antifungal and leishmanicidal drug that has been on the market for over sixty years. Unfortunately, significant infusion-related side effects and renal toxicity often accompany treatment, limiting its clinical applications. Lipid-based formulations have somewhat ameliorated the associated toxicity, but the increased cost of formulations restricts widespread use. AmB is amphipathic and exhibits low solubility and permeability, resulting in negligible absorption when administered orally. Advances in drug delivery systems have overcome some of the solubility issues that prevent oral bioavailability and new formulations are currently in development. The existence of an effective, safe and inexpensive oral formulation of amphotericin B would have significant applications for the treatment of disseminated fungal infections and would dramatically expand access to treatment of visceral leishmaniasis by introducing a readily available highly tolerated oral formulation of a drug with known efficacy.

Development of Amphotericin B-Loaded Cubosomes Through the SolEmuls Technology for Enhancing the Oral Bioavailability

“…Thus, oral lipid-based formulations could best facilitate AmB uptake across gastrointestinal tract and best protect the acid labile AmB from destruction in the stomach. As a result, these two oral AmB lipid-based formulations led to a positive therapeutic effect equivalent to intravenous therapy as reported (5). Cubosomal formulations are considered as another lipid-based delivery vehicle that has the potential possibility for delivery of AmB, because of their multilayer structures consisting of continuous lipid bilayers which are similar to those of cochleates.…”

“…AmB solution, nanosuspension, PLGA nanoparticles, and lipid nanospheres (5,6,16). However, most of the studies were still in a potential possibility for developing the oral formulation.…”

“…As most of the attempts failed, the pervasive attitude toward the impossibility of developing a practicable oral AmB formulation emerged. More encouragingly, the oral AmB cochleate formulation was under development by Biodelivery Sciences, Inc. (BDSI), releasing the favorable outcome of phase I trial in February 2009 (5). Another oral lipid-based AmB formulation was also in development by iCo Therapeutics Inc (Canada), resulting in a 50-fold increase in AmB solubility over its conventional lipid formulation (5).…”

“…More encouragingly, the oral AmB cochleate formulation was under development by Biodelivery Sciences, Inc. (BDSI), releasing the favorable outcome of phase I trial in February 2009 (5). Another oral lipid-based AmB formulation was also in development by iCo Therapeutics Inc (Canada), resulting in a 50-fold increase in AmB solubility over its conventional lipid formulation (5). Compared with the other drug-delivery systems, the nature of the lipid formulation is similar to the structure of cell membrane.…”

“…As most of the attempts failed, the oral cochleate formulation of AmB developed by Biodelivery Sciences, Inc (USA) stands out to effectively facilitate the oral absorption and provide protection of AmB from gastric acid degradation or prevent P-gp efflux. More encouragingly, a favorable outcome of AmB phase I trial was released in February 2009 and the company emphasized that further plans of AmB clinical trials would be underway (5). Another oral lipid-based AmB formulation is currently in development by iCo Therapeutics Inc (Canada), which uses proprietary mixture comprised of AmB, DSPE-PEG, monoglycerides, and diglycerides (Peceol®), resulting in a 50-fold increase in AmB solubility over its conventional lipid formulation.…”