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Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir.
AAPS PharmSciTech 2003; 4(3):E45AP

Abstract

The purpose of the study was to investigate the effect of hydroxypropyl beta cyclodextrin (HPbetaCD) 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 HPbetaCD. Butyryl cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was studied using various percentage w/v HPbetaCD. In vitro corneal permeation of GCV and its prodrugs (with and without 5% HPbetaCD) across isolated rabbit cornea was studied using side-by-side diffusion cells. HPbetaCD-prodrug complexation was of the A(L) 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 HPbetaCD. The stabilizing effect of HPbetaCD was found to depend on the degree of complexation and the degradation rate of prodrug within the complex. Five percent w/v HPbetaCD was found to enhance the corneal permeation of only the most lipophilic prodrug GCV dibutyrate (2.5-fold compared with 0% HPbetaCD). All other prodrugs showed little or no difference in transport in the presence of 5% w/v HPbetaCD. 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. HPbetaCD improves corneal permeation by solubilizing the hydrophobic prodrug and delivering it across the mucin layer at the corneal surface.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14621977

Citation

Tirucherai, Giridhar S., and Ashim K. Mitra. "Effect of Hydroxypropyl Beta Cyclodextrin Complexation On Aqueous Solubility, Stability, and Corneal Permeation of Acyl Ester Prodrugs of Ganciclovir." AAPS PharmSciTech, vol. 4, no. 3, 2003, pp. E45.
Tirucherai GS, Mitra AK. Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir. AAPS PharmSciTech. 2003;4(3):E45.
Tirucherai, G. S., & Mitra, A. K. (2003). Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir. AAPS PharmSciTech, 4(3), pp. E45.
Tirucherai GS, Mitra AK. Effect of Hydroxypropyl Beta Cyclodextrin Complexation On Aqueous Solubility, Stability, and Corneal Permeation of Acyl Ester Prodrugs of Ganciclovir. AAPS PharmSciTech. 2003;4(3):E45. PubMed PMID: 14621977.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir. AU - Tirucherai,Giridhar S, AU - Mitra,Ashim K, PY - 2003/11/19/pubmed PY - 2004/2/12/medline PY - 2003/11/19/entrez SP - E45 EP - E45 JF - AAPS PharmSciTech JO - AAPS PharmSciTech VL - 4 IS - 3 N2 - The purpose of the study was to investigate the effect of hydroxypropyl beta cyclodextrin (HPbetaCD) 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 HPbetaCD. Butyryl cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was studied using various percentage w/v HPbetaCD. In vitro corneal permeation of GCV and its prodrugs (with and without 5% HPbetaCD) across isolated rabbit cornea was studied using side-by-side diffusion cells. HPbetaCD-prodrug complexation was of the A(L) 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 HPbetaCD. The stabilizing effect of HPbetaCD was found to depend on the degree of complexation and the degradation rate of prodrug within the complex. Five percent w/v HPbetaCD was found to enhance the corneal permeation of only the most lipophilic prodrug GCV dibutyrate (2.5-fold compared with 0% HPbetaCD). All other prodrugs showed little or no difference in transport in the presence of 5% w/v HPbetaCD. 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. HPbetaCD improves corneal permeation by solubilizing the hydrophobic prodrug and delivering it across the mucin layer at the corneal surface. SN - 1530-9932 UR - https://www.unboundmedicine.com/medline/citation/14621977/Effect_of_hydroxypropyl_beta_cyclodextrin_complexation_on_aqueous_solubility_stability_and_corneal_permeation_of_acyl_ester_prodrugs_of_ganciclovir_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/14621977/ DB - PRIME DP - Unbound Medicine ER -