Fenofibrate solid dispersion pellets prepared by fluid-bed coating:physical characterization,improved dissolution and oral bioavailability in beagle dogs

流化床法制备的非诺贝特固体分散体小丸:物理表征、改善溶出和犬口服生物利用度(英文)

Solid dispersion of fenofibrate （FNB）, a poorly water-soluble drug, was prepared by a fluid-bed coating technique with PEG 6000 as the carrier. The physical state was characterized by DSC and X-ray powder diffractometry, which indicated the existence of fenofibrate in crystalline form in the solid dispersion. In vitro dissolution was studied in water containing 1% sodium lauryl sulfate, FASSIF and FESSIF. Significant enhancement in dissolution was achieved at PEG/FNB ratio of 4/1 with near complete dissolution within 30 min. Moderate improvement in dissolution rate was observed at smaller PEG/FNB ratios. Oral bioavailability was studied in beagle dogs after oral administration of fenofibrate solid dispersion pellets by monitoring fenofibric acid in plasma. The oral bioavailability of PEG/FNB 3/1 and 4/1 solid dispersion pellets was improved by 3.4 and 4.4-fold as compared to Lipanthyl, a commercial micronized fenotibrate formulation. There was a strong dependence of oral bioavailability on the in vitro dissolution rate. Good correlation was observed between the in vivo absorption fraction and the in vitro dissolution rate in each of the dissolution media, water containing 1% sodium lauryl sulfate, FASSIF and FESSIF. It could be concluded that PEG/FNB solid dispersion pellets were able to improve the dissolution and oral bioavailability of fenofibrate.

采用流化床包衣法制备难溶性药物非诺贝特(FNB)-PEG6000的固体分散体。差示扫描量热法和X-射线粉末衍射法对固体分散体中非诺贝特的物相进行鉴别,结果表明非诺贝特在固体分散体中以微晶形式存在。在含1%十二硫酸钠的水、FASSIF和FESSIF中对其溶出行为进行了考察,结果表明在PEG/FNB的比例为4/1以上,非诺贝特的体外溶出显著提高,30分钟溶出接近完全。然而,在较小PEG/FNB比例时,溶出并未显著提高。经测定血浆中非诺贝酸的含量,对非诺贝特固体分散体小丸的口服生物利用度进行了研究。PEG/FNB比例为3/1和4/1的固体分散体小丸其口服生物利用度相对于微粉化的非诺贝特lipanthyl提高了近3.4和4.4倍,口服生物利用度显著依赖于体外溶出速率。体内外相关性研究表明非诺贝特吸收分数与含1%十二硫酸钠的水、FASSIF和FESSIF中的溶出速率有很好的相关性。非诺贝特-PEG6000固体分散体小丸可用于提高其溶出速率和生物利用度,并具有良好体内外相关性。