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A.K. Mitra, G.S. Tirucherai; Effect of Hydroxypropyl ß -Cyclodextrin Complexation on Solubility, Stability and Corneal Permeation of Ganciclovir and Acyl Ester Prodrugs . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3463.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine the effect of hydroxypropyl beta cyclodextrin (HPßCD) complexation on corneal permeation of ganciclovir (GCV) and its prodrugs and to develop a novel animal model for the determination of anterior chamber pharmacokinetics. Methods: Hydroxy propyl beta cyclodextrin was employed to enhance the solubility, stability and corneal permeation of various prodrugs of GCV. Aqueous solubility and stability of GCV prodrugs was evaluated in pH 7.4 isotonic phosphate buffer solution in the presence and absence of HPßCD. In vitro corneal permeation of GCV prodrugs (with and without 5% HPß CD) was studied at 34°C using freshly excised rabbit cornea. A novel animal model combining topical infusion and aqueous humor microdialysis was developed for the determination of anterior chamber pharmacokinetics of GCV and marker compounds- 14C mannitol and 14C diazepam. Results: HPßCD-prodrug complexation was of the AL type with values for complexation constants ranging between 12 and 108 M-1. Considerable improvement in chemical and enzymatic stability of the GCV prodrugs was observed in the presence of HPßCD. The stabilizing effect of HPßCD was found to depend on the degree of complexation and the degradation rate of prodrug within the complex. 5% w/v HPßCD was found to enhance the corneal permeation of only the most lipophilic prodrug- GCV di butyrate (2.5 fold). All other prodrugs showed little or no difference in transport in the presence of 5% w/v HPßCD. Agitation in the donor chamber greatly influenced the transport kinetics of GCV di butyrate across the cornea. Results from the animal model studies indicated that the corneal absorption rate constant of 14C diazepam was at least 3 fold greater than either 14C mannitol or GCV. Conclusions: HPßCD improves corneal permeation of GCV dibutyrate by solubilizing the hydrophobic prodrug and delivering it across the mucin layer at the corneal surface. The "topical well infusion" model allows an accurate determination of the transcorneal absorption rate constant.
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