Flutamide-hydroxypropy-beta-chiyclodextrin complex: formulation, physical characterization, and absorption studies using the Caco-2 in vitro model.

PURPOSE The objective of this research was to formulate flutamide (FLT) in hydroxypropyl-beta-cyclodextrin (HPbetaCyD), and to investigate FLT transcellular permeation from the complex using the Caco-2 monolayer in vitro model. METHODS Classical solubility data were used to derive thermodynamic parameters which, together with Differential Scanning Calorimetry (DSC), (1)H-NMR and (19)F-NMR, were used to characterize and derive stability constants for the FLT-HPbetaCyD complex. The Caco-2 cell line was used to examine the role of HPbetaCyD on the passage of FLT across cell monolayers in vitro. RESULTS The solubility of FLT in water (1.46 mmol/L) increased almost 170 times (to 243.45 mmol/L) in the presence of 50% (w/v) HPbetaCyD. Solubility data for FLT in aqueous HPbetaCyD were used to derive thermodynamic parameters (DeltaG degrees at 298 K = -3.48, DeltaH degrees = 2.85, DeltaS degrees at 298 K = 21.24). The solubility of FLT in HPbetaCyD increased proportionally with an increase in temperature. The FLT-HPbetaCyD complex had an A(L)-type (DSC) isotherm, consistent with a linear increase in FLT solubility and unchanged stoichiometry. The DSC of free FLT and HPbetaCyD showed endothermic peaks at 110 degrees C and 300 degrees C, respectively. FLT-HPbetaCyD did not display a free-FLT endothermic response, but exhibited broadening of the endothermic peak in the HPbetaCyD region. (19)F- and (1)H-NMR chemical shifts of FLT moved upfield as a function of its increased solubility in the presence of HPbetaCyD. The FLT-HPbetaCyD stability constant, K(s) (1:1) was estimated to be 356 M(-1 )and 357 M(-1), from thermodynamic and (19)F NMR data, respectively. The apical-to-basal permeability coefficient (P(eff) = 4.75 x 10(-5) cm.s(-1)) for FLT across Caco-2 cell monolayers at 37; C increased as HPbetaCyD concentrations were reduced, indicative of transepithelial passage via passive diffusion of available free FLT in solution. Studies in the presence and absence of Ca(2+ )ruled out a significant paracellular transport component. CONCLUSIONS FLT-HPbetaCyD is a relatively stable, 1:1 inclusion complex. Formation of this complex substantially increases the water solubility of FLT, but HPbetaCyD, except in high dilution, reduces transcellular passage of FLT in the Caco-2 cell in vitro model.