Advances in the use of prodrugs for drug delivery to the eye

ABSTRACT

Introduction: Ocular drug delivery is presented with many challenges, taking into account the distinctive structure of the eye. The prodrug approach has been, and is being, employed to overcome such barriers for some drug molecules, utilizing a chemical modification approach rather than a formulation-based approach. A prodrug strategy involves modification of the active moiety into various derivatives in a fashion that imparts some advantage, such as membrane permeability, site specificity, transporter targeting and improved aqueous solubility, over the parent compound.

Areas covered: The following review is a comprehensive summary of various novel methodologies and strategies reported over the past few years in the area of ocular drug delivery. Some of the strategies discussed involve polymer and lipid conjugation with the drug moiety to impart hydrophilicity or lipophilicity, or to target nutrient transporters by conjugation with transporter-specific moieties and retrometabolic drug design.

Expert opinion: The application of prodrug strategies provides an option for enhancing drug penetration into the ocular tissues, and overall ocular bioavailability, with minimum disruption of the ocular diffusion barriers. Although success of the prodrug strategy is contingent on various factors, such as the chemical structure of the parent molecule, aqueous solubility and solution stability, capacity of targeted transporters and bioreversion characteristics, this approach has been successfully utilized, commercially and therapeutically, in several cases.

KEYWORDS:

• Lipid prodrug
• polymer-conjugated prodrug
• retrometabolic drug design
• transporter targeted drug delivery

Article highlights

• This article is a comprehensive review of the prodrug approach, which involves chemical modification of the active drug moiety, in the field of ocular drug delivery.

• Various examples of transporter targeted prodrug systems, involving modification of drug molecules for increased transporter affinity, have been reviewed. A wide array of studies utilizing prodrug derivatization to overcome the efflux of drug molecules, as well as novel lipid-drug linkages, some targeting transporters, have also been discussed.

• Retrometabolic drug design, i.e. development of soft drug and chemical delivery systems, is another aspect covered in this review.

• The concept of pro-prodrugs, in which the double prodrugs undergo chemical as well as enzymatic hydrolysis, to improve the stability of the active moiety, have also been discussed.

• The review also visits polymeric prodrug systems, such as drug-PEG conjugations, which undergo enzymatic hydrolysis in-vivo, releasing the drug. We also explore supramolecular nanofibers, of low molecular weight gelators, self-assembling to form gels.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This project was supported by U.S. Department of Health and Human Services (National Institutes of Health grant 1R01EY025365-01).