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M. Barot, R. Gaudana, S. Samantha, R. Earla, A. K. Mitra; Development and Evaluation of Dexamethasone Prodrugs for the Treatment of Ocular Ailments. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4998.
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© ARVO (1962-2015); The Authors (2016-present)
Drug delivery to posterior segment of the eye has always been considered as a big challenge for the scientists of the field. A noninvasive drug delivery has always been preferred for the treatment of posterior segment diseases. Dexamethasone is a widely used drug for posterior segment ailments. The current delivery method of dexamethasone includes intravitreal injections, implants etc. Therefore the objective of the present work is to develop transporter targeted prodrug therapy of dexamethasone, which can be recognized by peptide transporter present on the retina.
Amino acid and peptide prodrugs of dexamethasone were synthesized and evaluated. Aqueous solubility, partition coefficient (log P), stability in buffers and ocular tissue homogenates (retina, sclera, cornea, aqueous humor, vitreous humor, lens and conjunctiva) of dexamethasone prodrugs were studied. Transport studies of drug and prodrugs were performed across excised sclera and retinal pigment epithelium-choroid-sclera (RCS) tissue preparations (sclera to retina direction) of male NewZeland albino rabbits. A novel LC-MS/MS method was developed for simultaneous analysis of dexamethasone and its prodrugs.
Amino acid and dipeptide prodrug were synthesized and confirmed by NMR and Mass spec. The aqueous solubility of peptide prodrug [(Valine-valine-dexamethasone (7.07 ± 1.86 mg/ml)] was significantly higher than parent drug [(0.14 ± 0.09 mg/ml)]. Stability studies in ocular tissue homogenate revealed rapid bio-reversion of the prodrug into parent drug. The prodrugs have shown pH dependent stability. Peptide prodrugs were highly stable at lower pH compared to higher pH. The cumulative amount of dexamethasone transported across sclera and RCS tissue preparation was found to be comparable for parent dexamethasone and its prodrugs, indicating that prodrug modification of dexamethasone had no negative effect on the permeability.
Owning to their higher aqueous solubility, buffer stability, bio-reversion property and comparable permeability across ocular posterior segment tissues, amino acid and peptide prodrugs of dexamethasone may improve overall ocular bioavailability. Transporter targeted prodrug modification can be a promising strategy for transscleral delivery of dexamethasone in the treatment of posterior segment ocular diseases.
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