Polymeric Micelles for the Enhanced Deposition of Hydrophobic Drugs into Ocular Tissues, without Plasma Exposure.

Ijeoma F Uchegbu,Andreas G Schätzlein,Jan Breznikar,Alessandra Zaffalon,Uche Odunze

doi:10.3390/pharmaceutics13050744

Abstract

Commercial topical ocular formulations for hydrophobic actives rely on the use of suspensions or oil in water emulsions and neither of these formulation modalities adequately promote drug penetration into ocular tissues. Using the ocular relevant hydrophobic drug, cyclosporine A (CsA), a non-irritant ocular penetration enhancer is showcased, which may be used for the formulation of hydrophobic actives. The activity of this penetration enhancer is demonstrated in a healthy rabbit model. The Molecular Envelope Technology (MET) polymer (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan), a self-assembling, micelle-forming polymer, was used to formulate CsA into sterile filtered nanoparticulate eye drop formulations and the stability of the formulation tested. Healthy rabbits were dosed with a single dose of a MET–CsA (NM133) 0.05% formulation and ocular tissues analyzed. Optically clear NM133 formulations were prepared containing between 0.01–0.1% w/v CsA and 0.375–0.75% w/v MET polymer. NM133 0.01%, NM133 0.02% and NM133 0.05% were stable for 28 days when stored at refrigeration temperature (5–6 °C) and room temperature (16–23 °C), but there was evidence of evaporation of the formulation at 40 °C. There was no change in drug content when NM133 0.05% was stored for 387 days at 4 °C. On topical dosing to rabbits, corneal, conjunctival and scleral AUC0–24 levels were 25,780 ng.h g−1, 12,046 ng.h g−1 and 5879 ng.h g−1, respectively, with NM133 0.05%. Meanwhile, a similar dose of Restasis 0.05% yielded lower values of 4726 ng.h/g, 4813 ng.h/g and 1729 ng.h/g for the drug corneal, conjunctival and scleral levels, respectively. NM133 thus delivered up to five times more CsA to the ocular surface tissues when compared to Restasis. The MET polymer was non-irritant up to a concentration of 4% w/v. The MET polymer is a non-irritant ocular penetration enhancer that may be used to deliver hydrophobic drugs in optically clear topical ocular formulations.

Highlights

The topical ocular delivery of drugs is usually accomplished using eye drop formulations; these formulations have a short ocular residence time, draining through the nasolacrimal duct within 1–3 min [1]
Molecular Envelope Technology (MET)–cyclosporine A (CsA) (NM133) formulations were prepared at various strengths and characterized (Table 1)
Polymer [4,21], in which CsA was encapsulated within MET polymer micelles (Table 2, Figure 1a,b)

Summary

Introduction

The topical ocular delivery of drugs is usually accomplished using eye drop formulations; these formulations have a short ocular residence time, draining through the nasolacrimal duct within 1–3 min [1]. There is a requirement for transparent ocular formulations for hydrophobic drugs [4], that enhance drug transport into the ocular tissues and, importantly, are non-irritant. Such a formulation is presented using the hydrophobic cyclosporine A (CsA, water solubility = 4–134 μg/mL, with a lower solubility at 37 ◦ C–4 μg/mL and a higher solubility at 10 ◦ C–134 μg/mL) [5] as the model drug

Results

Discussion

Conclusion