Delivery of antitumor compounds to the rat colon: In vitro and in vivo evaluation

Using a rat model we have demonstrated that an enteric-coated hydroxypropyl-methylcellulose (HPMC) granular formulation was capable of targeting or persisting in the colonic region. The formulation was optimized by measuring the in vitro release of 5-fluorouracil (5-FU) of granules prepared with different molecular weights of HPMC ('Methocel') coated with different hydrophobicities of acrylic acid copolymers ('Eudragits'), a 'Methocel' K100M granule coated with 'Eudragit'-S being selected. X-ray examination of lightly anaesthetized rats demonstrated that orally administered enteric-coated granules containing 50% w/w barium sulfate persisted in the colon for longer than similar barium sulfate suspensions. Granules of HPMC, coated and uncoated, containing 5-FU were administered by oral gavage and the tissue levels of drug were determined by high performance liquid chromatography. At 6 h, drug from the uncoated formulation could be found in all tissues examined. On the other hand, at 8 h, drug from the coated granules could only be found in significant quantities in colon contents and colon tissue homogenates with increasing amounts being measured at 12 and 24 h. These data suggest that, at least in the rat model, formulations can be designed that would persist in the colon and rectal regions, releasing drug to and not through the tissues. This concept might be valuable in the post-surgical treatment of colonic cancer, reducing the required dose of drug and therefore side effects. This should improve patient compliance and thus, the treatment outcome. Copyright (C) 1996 Elsevier Science B.V.