Optimized transdermal delivery of ketoprofen using pH and hydroxypropyl-β-cyclodextrin as co-enhancers

The role of pH and pK(a) of ionizable drugs in transdermal delivery has been well documented by the pH partition hypothesis. Similarly the role of pH in complexation has also been addressed by many studies. Reports contrary to the well believed theory that both molecular encapsulation by hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and transdermal delivery are considered a phenomenon of unionized drug species prompted investigation into the combined effect of pH and HP-beta-CD on transdermal delivery of ketoprofen. In order to optimize the delivery of ketoprofen, solubility studies and permeation studies were conducted in vitro at pH 3.0, 4.5 and 6.0 at various concentrations of cyclodextrin. The stability constants for unionized and ionized drugs were calculated. The solubility of the ionized complex of the drug was 2.5 fold greater than the unionized complex. The flux increased linearly with increasing HP-beta-Cl) concentration at all the pH values. However, the increase was significant at pH 6.0 where the drug is predominantly in the ionized state. The flux of the ionized drug at 10% w/v HP-beta-CD concentration was enhanced to an order of approximately eight times compared to the intrinsic permeability of the unionized drug. The study shows that at higher pH, HP-beta-CD can be utilized to achieve greater transdermal flux of ketoprofen. (C) 2002 Published by Elsevier Science B.V.