A facile loading method for Amphotericin B contact lenses for infectious keratitis

Introduction: Infectious keratitis leads to corneal opacification and ulcers, vision impairment, and blindness affecting 36 million worldwide and contact lens wear remains a leading predisposing factor. Fungal keratitis remains difficult to treat to due to the absence of clinically available ocular antifungal formulations thus relying on extemporaneously prepared ocular drops requiring hourly administration over prolonged time. Broad spectrum antifungals, such as Amphotericin B, although highly efficacious, are unable to reach in adequate concentration due to poor solubility and low bioavailability. Diluted formulations of AmB lyophilized injectable formulations in artificial tears are used (0.15%) but require weekly extemporaneous preparation as they are only stable for 7 days in the refrigerator.
Contact lenses can help deliver ocular drugs as they can simultaneously decrease tear flow and provide sustained drug release. When a contact lens is placed in the eye, the tear film (7µL) is divided in the pre-lens tear film (1-2 µm) in contact with air and the post-lens tear film (~ 5 µm) in contact with the cornea1. Drugs diffuse from the contact lens to the post-lens tear film, as blinking and contact with air can dry the external surface of the lens hindering drug diffusion. Ocular bioavailability of up to 50% can be obtained using drug-loaded lenses2.
Here, we aim to develop a facile method for the preparation of Amphotericin B contact lenses that can be readily manufactured industrially or extemporaneously in hospital pharmacies for daily use using commercially available lenses.

Methods: An AmB solution (4 mg/mL in DMSO, 0.8 mL) was used for soaking Nelficon A lenses (Dailies™ AquaComfort™ PLUS, Alcon) and Omalficon A (Proclear®, CooperVision) over various soaking times to identify optimal time for a high molecular weight agent such as AmB. Uniformity of content was assessed and the aggregation state of the AmB loaded in the lens was assesed. Lenses were also soaked in a vitamin E (2.3 mg/mL) ethanolic solution post loading to create a diffusional barrier that would control the release of AmB over time. The release of AmB in artificial tear fluid was assessed using a validated HPLC method3.

Results: Successful uniform loading of AmB in lenses (74±6 μg/mL) using soaking over 2 hours has been achieved for the first time using AmB-DMSO solutions (monomeric state) and was maintained after exposure to an ethanolic Vitamin E solution (Fig1). Release was controlled over the first 24 hours (Fig 1).

Conclusions/Implications: A facile method for loading of AmB that when combined with Vitamin E can result in control release of AmB profile is developed. Further permeability studies using procine cornea are under way.