In situ Gelling Amphotericin B Nanofibers: A New Option for the Treatment of Keratomycosis

Abstract

The purpose of our research was the development of Amphotericin B-loaded in situ gelling nanofibers for the treatment of keratomycosis. Different formulation strategies were applied to increase the drug load of the sparingly water-soluble Amphotericin B in electrospun Gellan Gum/Pullulan fibers. These include bile salt addition, encapsulation in poly(lactic-co-glycolic acid) (PLGA) nanoparticles and formation of a polymeric Amphotericin B polyelectrolyte complex. The Amphotericin B polyelectrolyte complex (AmpB-Eu L) performed best and was very effective against the fungal strain Issatchenkia orientalis in vitro. The complex was characterized in detail by attenuated total reflection infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. A heat induced stress test was carried out to ensure the stability of the polyelectrolyte complex. To gain information about the cellular tolerance of the developed polyelectrolyte complex a new, innovative multilayered-stratified human cornea cell model was used for determination of the cellular toxicity in vitro. For a safe therapy, the applied ophthalmic drug delivery system has to be sterile. Sterilization by electron irradiation caused not degradation of pure Amphotericin B and also for the bile salt complex. Furthermore, the developed Amphotericin B polyelectrolyte complex was not degraded by the irradiation process. In conclusion, a new polyelectrolyte Amphotericin B complex has been found which retains the antifungal activity of the drug with sufficient stability against irradiation-sterilization induced drug degradation. Furthermore, in comparison with the conventional used eye drop formulation, the new AmpB-complex loaded nanofibers were less toxic to cornea cells in vitro. Electrospinning of the Amphotericin B polyelectrolyte complex with Gellan Gum/ Pullulan leads to the formation of nanofibers with in situ gelling properties, which is a new and promising option for the treatment of keratomycosis.

Considerations for Polymers Used in Ocular Drug Delivery

“…Co-polymerization of pullulan with other biopolymers or synthetic polymers has shown promise for extending biodegradation rate compared to the polysaccharide alone. Examples include pullulan-gellan gum electrospun nanofibers for an in situ forming gel for extended topical therapeutic bioavailability (115). The gelation properties of pullulan in water make it popular for use in thin films and hydrogel inserts.…”

Advancement of Nanofibrous Mats and Common Useful Drug Delivery Applications

“…The theoretical analogy concerning the fabrication of the electrospun scaffold had promising prospects. In this case, the authors intend to fabricate a platform that would hold the treatment of topical ocular diseases and the electric spun nanofibers scaffold composed of Gellan gum/pullulan polymers [ 102 ]. The aim of using such materials is to manipulate the material into specific shapes that would cover as much surface area of the eye to increase the effectiveness of the treatment.…”

In Situ Gelling Electrospun Ocular Films Sustain the Intraocular Pressure-Lowering Effect of Timolol Maleate: In Vitro, Ex Vivo, and Pharmacodynamic Assessment

“…To increase corneal residence time and sustain drug release, other types of formulations (e.g., suspensions, ointments, and drops with increased viscosity) have been employed. However, suspensions are limited by reflexive lacrimation when a certain particle size is exceeded (10 μm), viscous formulations may cause blurred vision, and lipophilic ointments hinder oxygen permeability …”

“…Even though the use of solid dosage forms for ophthalmic application is still limited, they exhibit significant advantages compared to conventional eye drops. These mainly relate to the absence of water, which decreases hydrolysis and improves storage stability, and the prolonged ocular residence, resulting in better bioavailability. , Solid formulations are also characterized by better dosing accuracy, less systemic side effects, more convenient dosing frequency, and better patient compliance . At the same time, an ideal solid formulation should quickly convert to a clear film upon contact with the corneal surface to not interfere with the patient’s vision …”

“…Several attempts have been made for the ocular delivery of antiglaucoma drugs using contact lenses, nanoliposomes, and self-assembling peptides, also employing electrospinning to fabricate draining implants, , coat soft contact lenses, or control the delivery of therapeutic agents. , Other groups have produced electrospun nanofibers to improve the ocular delivery of anti-inflammatory ,,, and antimicrobial agents ,, for the treatment of common infections and medical conditions of the eye.…”