Pharmacokinetic profiles of probucol were evaluated after oral administration of the various nanosuspensions in rats. Probucol nanoparticles were prepared by co-grinding with various molecular weights of polyvinylpyrrolidone (PVP K12, PVP K17 and PVP K30) and sodium dodecyl sulfate (SDS). The average particle sizes of probucol after dispersing the ternary ground mixtures (GMs), probucol/PVP K12/SDS, probucol/PVP K17/SDS and probucol/PVP K30/SDS into water were 28, 75 and 89 nm respectively. The ternary GM suspensions with PVP K17/SDS and PVP K30/SDS were stable at 25°C. However the particle size of probucol from the ternary GM with PVP K12/SDS gradually increased. Pharmacokinetic profiles of probucol indicated that variation in particle surface condition covered with PVP and SDS in addition to the particle size affected the improvement of in vivo absorption of probucol. The ternary GM with PVP K12/SDS exhibited a superior improvement of probucol absorption compared to the GMs with PVP K17/SDS and PVP K30/SDS. The binary GM with PVP or SDS and physical mixtures with PVP and/or SDS did not show significant differences in the area under the plasma concentration-time curve compared to the unprocessed probucol. In conclusion, preparation of probucol nanoparticles by co-grinding with PVP K12 and SDS could be a promising method for bioavailability enhancement.

Morphology and surface states of colloidal probucol nanoparticles after dispersion of probucol/polyvinylpyrrolidone (PVP)/sodium dodecyl sulphate (SDS) ternary ground mixture into water were investigated by atomic force microscopy (AFM). The observed particles had core-shell structure, i.e. drug nanocrystals were covered with PVP and SDS complex. The AFM phase image and the force curve analyses indicated that probucol nanoparticles with PVP K17 showed layer structure, compared to those with PVPK12. The structural difference was explainable in terms of the molecular states of PVP-SDS complex on the particle surface. These findings support not only the mechanism of drug nanoparticle formation but also the in vivo absorption results with the almost same particle size of ca. 40 nm.Key words atomic force microscopy; colloidal nanoparticle; surface state; grinding; probucol Co-grinding, where a drug is ground together with excipients, is a promising method for an effective reduction of particle size. A certain number of studies revealed that the coground mixture enhanced dissolution, resulting in the improvement of oral absorption and bioavailability.1-3) Wet cogrinding method has been known as an effective method to produce stable nanosuspensions.4-7) Liversidge and Cundy proposed a preparation method for crystalline nanoparticle by wet co-grinding of danazol with polyvinylpyrrolidone (PVP).4) Oral absorption of poorly water-soluble drugs in nanocrystal form was remarkably improved. 4,5) Shi et al. reported the image of drug nanocrystals in the formulation by atomic force microscopy and complementary techniques. 8)They showed the morphology of nanocrystals, though the surface states of the nanocrystals were not well characterized.Compared with the wet co-grinding method, the dry cogrinding process has some advantages for solid pharmaceutical applications due to its simple preparation with free solvents. Our previous studies demonstrated that drug nanoparticle was successfully produced by the dry co-grinding of a poorly water-soluble drug with PVP and sodium dodecyl sulfate (SDS).9-11) When probucol, which is mainly used as a cholesterol-lowering agent, was used as a model drug, solidstate 13 C-NMR studies revealed that the nanoparticle formation and stabilization were attributable to grinding-induced solid-state interactions among components of the drug/ PVP/SDS ternary system.12) The agglomeration of colloidal nanoparticles after dispersing the ground mixture (GM) into water was effectively inhibited in the presence of PVP and SDS. The results of particle size and zeta-potential measurements suggested that the adsorption of both PVP and SDS as the complex on the surface of crystalline particles stabilized the drug nanoparticles.13) Because surface states of the probucol nanoparticles certainly affected the dissolution and the subsequent absorption, the direct observation of the nanoparticles in aqueous environment was an urgent requisite. We have observed the morphology of probucol nanoparticles in water by environm...