Pharmacokinetics of Pullulan-Dexamethasone Conjugates in Retinal Drug Delivery.

Eva Kicková,Elisa Toropainen,Merve Sen,Veli-Pekka Ranta,Stefano Salmaso,Sylvia Bolz,Marius Ueffing,Jooseppi Puranen,Amir Sadeghi,Shirin Tavakoli,Arto Urtti,Marika Ruponen,Blanca Arango-Gonzalez,Paolo Caliceti

doi:10.3390/pharmaceutics14010012

Abstract

The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan–dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan–dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan–dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan–dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.

Highlights

We investigated dexamethasone conjugates of pullulan that were obtained with recently published synthetic procedures [26]
Pullulan is a water-soluble pullulan with dexamethaPullulan water-solublepolysaccharide polysaccharidebut butconjugation conjugationofof pullulan with dexamesone (DEX)
Delivery of intravitreally administered drugs may be improved with innovative drug delivery systems enabling more patient compliant administration, prolonged drug retention in the eye, controlled release and delivery to the retinal target cells

Summary

Introduction

Intravitreal injection is the most important mode of drug administration in the treatment of retinal diseases. Anti-neovascular inhibitors of vascular endothelial growth factor (VEGF) (antibodies, Fab-fragments, soluble receptors and aptamers) are widely used in clinics [4–8]. Intravitreal injections are safe, but frequent injections may result in reduced patient compliance and some rare, but serious, adverse effects (e.g., infection and retinal detachment) [5,9]. Implants with prolonged ocular residence and controlled release have been developed to prolong injection intervals of dexamethasone (e.g., Ozurdex) [1,3,9]. Delivery systems for trafficking therapeutics to the retinal cells

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Discussion

Conclusion