Improved oral absorption of enteric coprecipitates of a poorly soluble drug.
An anticancer agent, N-[[[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]amino]carbonyl]-2 - nitrobenzamide (HO-221, 1), shows poor oral absorption and is only slightly soluble in water (0.055 microgram/mL at 37 degrees C). The coprecipitates with polyvinylpyrrolidone or a vinylpyrrolidone and vinylacetate copolymer (copolyvidone) showed a marked increase of the dissolution rate and attainment of temporary supersaturation of 1. The oral bioavailability of these preparations in dogs at a dose of 1 of 5 mg/kg was approximately 60%, which was 3.5 times greater than that of a micronized preparation. Further, the enteric coprecipitate with hydroxypropyl methylcellulose phthalate 200731, which showed a dissolution profile similar to that of the copolyvidone preparation at pH 6.5 but no dissolution at pH 1.2, revealed the almost complete oral absorption. Because intraduodenal administration of the copolyvidone coprecipitate showed a higher absorption than that of per oral administration, it was suggested that the partial precipitation of crystallites in the nonenteric coprecipitates occurred before reaching the absorption site, the small intestine.
Kondo
N
N
Research Division, Green Cross Corp., Osaka, Japan.
Iwao
T
T
Hirai
K
K
Fukuda
M
M
Yamanouchi
K
K
Yokoyama
K
K
Miyaji
M
M
Ishihara
Y
Y
Kon
K
K
Ogawa
Y
Y
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D001549:Benzamides; D009578:Nitrobenzenes; D011208:Powders; C066688:N-(4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl)-N'-(2-nitrobenzoyl)urea