Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles.

Pescina Pescina,Santi Santi,Padula Padula,Govoni Govoni,Cantù Cantù,Nicoli Nicoli,Favero Favero,Lucca Lucca

doi:10.3390/pharmaceutics11090476

Pescina Pescina, Santi Santi + Show 6 more

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https://doi.org/10.3390/pharmaceutics11090476

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Abstract

This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.

Highlights

The treatment of ocular diseases is a challenging task, due to the peculiar structure of the eye, characterized by the presence of several anatomical and functional barriers
Recent data have demonstrated the ability of polymeric micelles to increase drug uptake and permeation across different ocular tissues [2,3] such as the cornea [4,5], sclera [6,7], and conjunctival cells [8,9]
Polymeric micelles made by polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer were prepared to increase the solubility of fluorometholone, a corticosteroid used for the treatment of inflammation of the anterior segment of the eye, and to promote its transcorneal diffusion in an ex vivo model [5]

Summary

Introduction

The treatment of ocular diseases is a challenging task, due to the peculiar structure of the eye, characterized by the presence of several anatomical and functional barriers. Colloidal formulations are increasingly investigated to overcome some of the cited limitations and, among them, polymeric micelles have been shown to be able to provide efficient drug delivery These nanocarriers (10–200 nm), simple to prepare and sterilized, are self-assembled aggregates of amphiphilic polymers with a nonoily hydrophobic core and a hydrophilic corona. Recent data have demonstrated the ability of polymeric micelles to increase drug uptake and permeation across different ocular tissues [2,3] such as the cornea [4,5], sclera [6,7], and conjunctival cells [8,9] Due to these advantages, interest in the field has increased over time and brought about, in 2018, the approval by the FDA of a cyclosporine-based micellar product for ophthalmic use. Cyclosporine, a poorly soluble immunosuppressant cyclic peptide, has been the subject of several studies involving micelles [2]; among them, the use of polyoxyl 35 hydrogenated castor oil micelles demonstrated, in a dry-eye syndrome model, the improvement of the functionality and morphology of the conjunctival epithelium [16]

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