ABSTRACT
TMC240 is a very poorly soluble and poorly permeating HIV protease inhibitor. In order to enhance its oral bioavailability, a fast dissolving inulin-based solid dispersion tablet was developed. During the dissolution test in water (0.5% or 1.0% SLS), this tablet released at least 80% of TMC240 within 30min, while a tablet with the same composition, but manufactured as physical mixture, released only 6% after 2h. In a subsequent single-dose study in dogs (200mg of TMC240), plasma concentrations of TMC240 remained below the lower limit of quantification (<1.00ng/mL) in all animals (n=3 per tested formulation), except in one dog receiving the inulin solid dispersion tablet (C(max)=1.8ng/mL, AUC(0-7 h)=3.0ngh/mL). In the latter treatment group, ritonavir co-administration (10mg/kg b.i.d.) increased TMC240 exposure more than 30-fold (mean AUC(0-7 h)=108ngh/mL; F(rel)=3588%). Exposure was also 16-fold higher than after TMC240 administration as PEG400 suspension in the presence of ritonavir (AUC(0-7 h)=6.7ngh/mL). The current data demonstrate that a solid dispersion of TMC240 in an inulin matrix allows considerable improvement in the release of poorly water-soluble TMC240, both in vitro in the presence of a surfactant and in vivo upon oral administration.
