Improved ocular delivery of idoxuridine using the prodrug approach
Abstract
Problems associated with the use of Idoxuridine (IDU) for the treatment of herpes simplex keratitis can be attributed largely to the polar nature of IDU resulting in its poor permeability across the lipoidal epithelial layer of the corneal membrane. Five aliphatic 5$\sp\prime$-esters of IDU were synthesized and evaluated as prodrugs for potential in reducing the total topical dose. The esters showed a 43-250 fold increase in lipophilicity and a 1-6-14 fold decrease in aqueous solubility, relative to IDU. A parabolic relationship exists between in vitro corneal membrane permeability and carbon chain length of prodrugs. For a given prodrug, enzymatic hydrolysis proceeded most readily in iris-ciliary body followed by cornea and aqueous humor. An increase in carbon chain length made the prodrugs more enzymatically labile, but more resistant to chemical hydrolysis at pH 7.4 and 34$\sp\circ$C. At a concentration of 50$\mu$M, all esters appeared to be less cytotoxic towards uninfected vero cells than IDU. 5$\sp\prime$-butyryl and 5$\sp\prime$-isobutyryl esters of IDU showed an approximately four-fold increase in aqueous humor IDU concentration at 25 minutes post-instillation of 5mM solutions, relative to IDU.
Degree
Ph.D.
Advisors
Mitra, Purdue University.
Subject Area
Pharmaceuticals
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.