Effect of Hydroxypropyl Beta Cyclodextrin Complexation on Aqueous Solubility, Stability, and Corneal

The
purpose of the study was to investigate the effect of hydroxypropyl
beta cyclodextrin (HPβCD) on aqueous solubility, stability, and in
vitro corneal permeation of acyl ester prodrugs of ganciclovir (GCV).
Aqueous solubility and stability of acyl ester prodrugs of Ganciclovir
(GCV) were evaluated in pH 7.4 isotonic phosphate buffer solution
(IPBS) in the presence and absence of HPβCD. Butyryl
cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was
studied using various percentage w/v HPβCD. In vitro corneal permeation
of GCV and its prodrugs (with and without 5% HPβCD) across isolated
rabbit cornea was studied using side-by-side diffusion cells.
HPβCD-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 HPβCD. The stabilizing effect of HPβCD was
found to depend on the degree of complexation and the degradation rate
of prodrug within the complex. Five percent w/v HPβCD was found to
enhance the corneal permeation of only the most lipophilic prodrug GCV
dibutyrate (2.5-fold compared with 0% HPβCD). All other prodrugs showed
little or no difference in transport in the presence of 5% w/v HPβCD.
Agitation in the donor chamber largely influenced the transport
kinetics of GCV dibutyrate across cornea. Results indicate the presence
of an unstirred aqueous diffusion layer at the corneal surface that
restricts the transport of the highly lipophilic GCV dibutyrate
prodrug. HPβCD improves corneal permeation by solubilizing the
hydrophobic prodrug and delivering it across the mucin layer at the
corneal surface

View Full Article