Dendrimers as nanocarriers in the ocular administration of drugs using iontophoresis

Abstract

Topical administration of drugs for the treatment of eye disease, while very convenient for the patient, rarely provides high bioavailability of the drug administered, especially in the posterior segment of the eye. The development of strategies that enable effective topical application of these drugs could be valuable for the treatment of these diseases and patient comfort. One promising strategy is the development of delivery systems that provide a greater residence time of the drug on the ocular surface, and facilitate its penetration to the posterior segments of the eye. Dendrimers are a special class of polymers that have highly branched and regular structure and can serve as delivery systems for topical drugs. The fourth generation polyamidoamine dendrimer (PAMAM G4) has around 4 nm and different peripheral functional groups. Its unique architecture enables interaction with drugs with different polarities, forming complexes via molecular encapsulation with non-covalent and covalent bonds. Depending on the final characteristics of the dendrimer-drug complexes, they can interact with the ocular surface, increasing the residence time of the drug in the eye. Moreover, the dendrimer penetration in the cornea or even in the vitreous humor could carry the drug to be released direct in the location of the eye that is intended to treat. However, because PAMAM G4-drug complexes usually have more than 30 nm in size, passive dendrimer penetration through ocular membranes is unlikely. Nevertheless, the application of a weak electrical current of low intensity in the formulation, known as iontophoresis, could facilitate both the penetration of the drug and the dendrimer itself. However, the influence of iontophoresis in ocular penetration of dendrimers has never been studied. Therefore, the aim of this proposal is to prepare and characterize dendrimers containing a lipophilic model drug (dexamethasone) and a hydrophilic (ganciclovir), separately, and study, in vitro and in vivo, the passive and iontophoretic ocular absorption of these substances from the dendrimers developed. The ability of dendrimers-drug complexes to extend the residence time of drugs in the eye will be evaluated in vivo. The influence of iontophoresis on the penetration of the formulations containing the delivery systems developed will be evaluated in vitro and in vivo by quantification of drugs and the dendrimer in different segments of the eye. Finally, the mechanisms that influence the iontophoretic release and ocular penetration of lipophilic and hydrophilic drugs, administered alone or encapsulated in dendrimers, will be studied in an attempt to propose efficient formulations for the topical route of administration aimed at treating eye diseases. (AU)