Electronic Theses and Dissertations

Date of Award

1-1-2011

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

Soumyajit Majumdar

Second Advisor

John S. Williamson

Third Advisor

Walter G. Chambliss

Relational Format

dissertation/thesis

Abstract

The eye is protected from the external environment by various physiological and anatomical barriers. These barriers through there protective actions drastically diminish the ocular bioavailability of drugs. The corneal epithelium acts as a major barrier towards the permeation of hydrophilic agents, whereas poor aqueous solubility presents a formulation challenge for lipophilic compounds. Additionally, P-glycoprotein (P-gp) expressed on the retinal pigmented epithelium (RPE P-gp) limits the penetration of substrates, in therapeutically relevant concentrations, into the back-of-the-eye.

In the present research, use of penetration enhancers (chitosan, benzalkonium chloride (BAK) and ethylenediaminetetraacetic acid (EDTA)) and formulation approaches (cyclodextrins and solid lipid nanoparticles (SLNs)) were evaluated in terms of their ability to improve the ocular bioavailability of hydrophilic and lipophilic compounds, respectively. A novel approach, localized modulation of RPE P-gp using topically co-administered P-gp inhibitors, was investigated to improve the back-of-the eye delivery of P-gp substrates.

In vitro transcorneal permeation results demonstrated that chitosan brought about a dose dependent increase in the permeability of acyclovir, a model hydrophilic compound. Combination of chitosan, BAK and EDTA resulted in a synergistic effect on the permeation of acyclovir. Dramatic increase in aqueous solubility, stability and in vitro transcorneal permeability of delta-8-tetrahydrocannabinol, a model lipophilic agent, was observed in the presence of 2-Hydroxypropyl-β-cyclodextrin (HPβCD), randomly methylated-β-cyclodextrin and sulfobutylether-β-cyclodextrin. The indomethacin loaded SLN (IN-SLNs) formulation was physically stable following sterilization and on storage. The IN-SLNs formulation increase stability and in vitro corneal permeability of indomethacin in comparison to the solution formulations (cosolvent and HPβCD based) tested.

Furthermore, for the first time, studies in anesthetized male New Zealand rabbits demonstrate that topically applied P-gp inhibitors can diffuse to the RPE and alter the elimination kinetics of a systemically or intravitreally administered P-gp substrate, probably through inhibition of the basolateral RPE P-gp. The degree of inhibition was found to be dependent on the physicochemical characteristics of the inhibitor and its affinity for P-gp and the concentration of the therapeutic agent in the plasma or in the vitreous humor. Formulation factors such as inclusion of permeation enhancers may play a major role in yielding effective levels of the inhibitor at the RPE.

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