Visser MR, Baert L, van 't Klooster G, Schueller L, Geldof M, Vanwelkenhuysen I, De Kock H, De Meyer S, Frijlink HW, Rosier J, Hinrichs WL
Inulin solid dispersion technology to improve the absorption of the BCS Class IV drug TMC240. [JOURNAL ARTICLE]
Eur J Pharm Biopharm 2009 Oct 24.
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 30 min, while the physical mixture tablet of the same composition released only 6% after 2 h. In a subsequent single-dose study in dogs (200 mg of TMC240), plasma concentrations of TMC240 remained below the lower limit of quantification (<1.00 ng/mL) in all animals (n=3 per tested formulation), except in one dog receiving the inulin solid dispersion tablet (C(max)=1.8 ng/mL, AUC(0-7h)=3.0 ng.h/mL). In the latter treatment group, ritonavir co-administration (10 mg/kg b.i.d.) increased TMC240 exposure more than 30-fold (mean AUC(0-7h)=108 ng.h/mL; F(rel)=3588%). Exposure was also 16-fold higher than after TMC240 administration as PEG400 suspension in presence of ritonavir (AUC(0-7h)=6.7 ng.h/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 presence of a surfactant and in vivo upon oral administration.
More from this journal |
