Research Articles
Effect of Mono‐ and Di‐acylation on the Ocular Disposition of Ganciclovir: Physicochemical Properties, Ocular Bioreversion, and Antiviral Activity of Short Chain Ester Prodrugs

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Abstract

A series of short‐chain carboxylic mono‐ and diesters of ganciclovir were synthesized in our laboratory. Physico‐chemical properties, i.e., solubility (pH 4.2), partition coefficient in 1‐octanol/phosphate buffer (pH 7.4), aqueous stability at various pH values, bioreversion kinetics in various ocular homogenates and effectiveness against various Herpes viruses in vitro were determined. The compounds exhibited a decrease in solubility as the ester length ascended with a corresponding increase in the octanol/buffer partition coefficient values. All of the prodrugs exhibit stability profiles typical of a carboxylic ester with maximum stability at neutral or slight acidic pH (4.0–7.0). Apparent first‐order rate constants associated with prodrug to drug hydrolysis in the ocular homogenates varied depending on the size of the promoiety, lipophilicity of the compound, and the ocular tissue studied. The acetyl and butyryl mono and diesters were screened against various Herpes viruses. The monobutyrate ester of ganciclovir exhibits excellent activity against HSV‐2 and VZV and provides a very high selectivity index against most of the viruses studied. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:660–668, 2002

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INTRODUCTION

Human Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection occurring in HIV‐infected patients. It occurs in about 20–40% of AIDS patients, especially in individuals with blood CD4 cell counts less than 50/μL.1 Focal yellowish‐white granular patches, large areas of retinal hemorrhage with necrosis, diffuse edema are symptoms of advanced CMV retinitis, and if left untreated can lead to blindness. Many agents are available to treat this infection, including intravenous

MATERIALS AND METHODS

GCV was obtained as a gift from Hoffman La Roche (Nutley, NJ). All the prodrugs were synthesized in our laboratory according to published procedures.9 All reagents used were of HPLC grade. New Zealand albino male rabbits weighing between 2–2.5 kg were obtained from Myrtle's Rabbitry, Thompson Station, TN.

Aqueous Stability

The stability of the eight prodrugs was examined within the pH range pH 1.2 to pH 9.0. The effect of pH on the stability of these prodrugs was examined. Figure 1 exhibits the GCVMP stability profile. The observed profile exhibits a typical V‐shape characterization of a carboxylic ester with maximal stability occurring between pH 4.0 and 5.0. All of the prodrugs studied showed similar behavior in the pH range studied with varying rate constants of degradation for specific acid and base catalyzed

CONCLUSIONS

The ideal ocular prodrug should be the one that possesses sufficient lipophilicity to cross the BRB and possess sufficient solution stability for it to be formulated into an appropriate ophthalmic dosage form. The ester prodrugs must exhibit the desired hydrolytic kinetics when delivered into the eye. The prodrug must hydrolyze to generate the therapeutically active parent compound at the target site. From the various studies performed on the prodrugs synthesized so far it can be concluded that

Acknowledgements

This work was supported by grants from the National Eye Institute EY09171 and EY10659. We would like to acknowledge Dr. HongWu Gao for synthesizing the various ester prodrugs in our laboratory, and Dr. Christopher Tseng from the NIAID for conducting all of the in vitro antiviral screening.

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