Part 1. Cyclodextrins: Complexation and mucosal absorption enhancer effects. Part 2. Ocular pigmentation effects on the intravitreal disposition of novel acycloguanosine analogs

Ramesh Krishnamoorthy, Purdue University

Abstract

Part 1. The utility of modified cyclodextrins as solubility and penetration enhancers has been investigated. A simple phase solubility approach has been used to study weak electrolyte/cyclodextrin complexation. An easy mathematical model has been proposed for the estimation and interpretation of association constants of weak acids and bases with cyclodextrins. Substrate ionization has been shown to alter the stability of the complex. The nasal mucotoxicity of a wide variety of modified cyclodextrins was evaluated by simple biochemical tests. The rank order of nasal mucotoxicity was found to be correlated to the hydrophobicity of the torus and nature of chemical modification. These compounds were found to dissociate insulin oligomers without adversely affecting the bioactivity. Part 2. The acquired immunodeficiency syndrome epidemic has increased the occurrence of cytomegalovirus retinitis and endophthalmitis. Treatment of the diseases of the internal ocular structures necessitates an adequate intraocular delivery system. Prodrug derivitization of acycloguanosine antiviral agents, acyclovir and ganciclovir, was attempted to improve residence time in the vitreous. These derivatives had a higher lipophilicity and lower solubility relative to the parent compound. Enzymatic hydrolysis of these compounds was evaluated in the ocular tissue homogenates of albino and pigmented rabbits. Tissue pigmentation had a profound impact on hydrolysis. The rank order of enzymatic activity followed iris-ciliary body $>$ cornea $>$ aqueous humor. The vitreous possessed some esterase activity. Further, binding studies to melanin was performed, and all compounds showed significant binding, with the esters binding far more than the parent drug. The binding of these drugs appear to be through weak electrostatic interactions. A novel ocular microdialysis procedure was developed to sample the vitreous continuously. Intravitreal injection of these compounds elicited pharmacokinetic parameters quite different in the two rabbit species studied. Pigmentation has a distinct impact on this process, as seen by the elimination half lives and apparent volume of distribution values. A transretinal mechanism is implied for the elimination of these agents. Intraocular injection of the esters studied produced levels of acyclovir above minimum inhibitory concentration and these levels were sustained for over 7 hours. The esters show a lot of promise for further investigation.

Degree

Ph.D.

Advisors

Mitra, Purdue University.

Subject Area

Pharmaceuticals|Pharmacology|Surgery

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