Inulin solid dispersion technology to improve the absorption of the BCS Class IV drug TMC240.
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.
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
Marinella R
MR
Visser
Lieven
L
Baert
Gerben van 't
Gv
Klooster
Laurent
L
Schueller
Marian
M
Geldof
Iris
I
Vanwelkenhuysen
Herman
H
de Kock
Sandra
S
De Meyer
Henderik W
HW
Frijlink
Jan
J
Rosier
Wouter L J
WL
Hinrichs
D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D004337:Drug Carriers / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004339:Drug Compounding / Q000379:methods*; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects; D007444:Inulin / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D019438:Ritonavir / Q000494:pharmacology; D012995:Solubility; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics*; D013535:Suspensions / Q000737:chemistry / Q000493:pharmacokinetics; D013607:Tablets / Q000737:chemistry / Q000493:pharmacokinetics
D052160:Benzothiazoles; D004337:Drug Carriers; D017320:HIV Protease Inhibitors; D013450:Sulfones; D013535:Suspensions; C549546:TMC 240; D013607:Tablets; D011092:Polyethylene Glycols; D007444:Inulin; D019438:Ritonavir