Electronic Theses and Dissertations

Date of Award

2011

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Soumyajit Majumdar

Second Advisor

John S. Williamson

Third Advisor

Sathyanarayana N. Murthy

Abstract

The bioflavonoid hesperidin and its aglycone hesperetin are promising candidates for the treatment of diabetic retinopathy and diabetic macular edema because of their pharmacological properties. The objective of this project was to characterize the biopharmaceutic and pharmacokinetic characteristics of hesperidin and hesperetin for ocular delivery, especially with respect to the distribution of these compounds to the posterior segment of the eye. Hesperidin and hesperetin were found to be water insoluble compounds. Although they demonstrated good permeability across the ocular tissues, hesperetin's permeability was found to be higher than that of hesperidin. Hesperidin demonstrated symmetrical transcorneal and transretinal permeation whereas hesperetin exhibited asymmetrical transcorneal and symmetrical transretinal transport. However, none of the influx or efflux transporters, expressed on the cornea, were involved in hesperetin's corneal transport. It was concluded that hesperetin's physicochemical properties, ultrastructure of the cornea and components of the diffusion media play a major role in the passive asymmetric transport. Results from the intravitreal kinetic studies of hesperidin, hesperetin and glucosyl-hesperidin (a water soluble derivative of hesperidin), following intravitreal injection, revealed that all three compounds have relatively short half-lives (< 8h) in the vitreous humor. Hesperetin demonstrated the shortest half-life, consistent with its physiochemical characteristics. All three compounds exhibited linear pharmacokinetics, within the dose range tested. This information will be critical in the design of ocular drug delivery systems for these compounds. The ocular bioavailability studies following systemic administration suggested that vitreal bioavailability is negligible because of rapid conversion of both hesperidin and hesperetin into their hydrophilic metabolite, hesperetin-glucuronide, in the plasma. In contrast, topical instillation produced significant concentrations of hesperidin and hesperetin in the ocular tissues. Hesperetin's diffusion into the ocular tissues, in vivo, was high compared to hesperidin; however, very low levels were observed in the vitreous humor. Inclusion of benzalkonium chloride, as a penetration enhancer/preservative, significantly improved the vitreal levels of hesperetin. In conclusion, topical administration would be ideal for the delivery of hesperetin to the deeper ocular tissues. Development of a controlled release drug delivery system and specialized ophthalmic formulations will reduce the frequency of administration needed to sustain the levels at the target site.

Concentration/Emphasis

Pharmaceutics

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