泊沙康唑肠溶片的制备及Beagle犬体内药动学初探

Preparation of enteric tablets of posaconazole and preliminary study on pharmacokinetics of Beagle dogs in vivo

目的:制备泊沙康唑肠溶片,并考察其在Beagle犬体内的初步药动学。方法:采用热熔挤出技术制备泊沙康唑分散体并压成片,利用差示扫描量热法和X线衍射技术对其表征,并考察其体外溶出曲线和Beagle体内药时曲线。结果:差示扫描量热法和X线衍射结果表明分散体中的泊沙康唑呈无定型态;泊沙康唑肠溶片体外溶出可达100%,约为泊沙康唑普通片的4倍;泊沙康唑肠溶片在空腹Beagle犬体内呈二室吸收动力学模型,权重系数为1/cc,AUC_(0-∞)为(2 554±224)μg·L^(-1)·h,约为泊沙康唑普通片的5倍;在饱腹Beagle犬体内呈一室吸收动力学模型,权重系数为1/cc,AUC_(0-∞)为(2 719±411)μg·L^(-1)·h,约为泊沙康唑普通片的3倍。结论:热熔挤出技术制得的泊沙康唑肠溶片有助于提高其体外的溶出度和体内的生物利用度;泊沙康唑具有食物依赖效应,制成肠溶片后食物效应降低,在餐后服用药效较佳。

OBJECTIVE To prepare enteric tablets of posaconazole and investigate its pharmacokinetics in Beagle dogs.METHODS Hot-melt extrusion（HME）technology was used to prepare the dispersion of posaconazole and then compress into tablets.Differential scanning calorimetry（DSC）and X-ray diffraction（XRD）were used to characterize the phase of posaconazole,in vitro dissolution curves and the in vivo drug time curves of Beagle dogs were investigated.RESULTS The results of DSC and XRD showed that posaconazole in solid dispersion was amorphous form.The dissolution rate of the enteric tablets of posaconazole was up to 100%,which was about 4 times of that of the normal tablets of posaconazole.A two compartment absorption kinetic model was established in fasting Beagle dogs,and the weight coefficient was 1/cc,AUC0-∞was（2 554±224）μg·L-1·h,which was about 5 times of that of the normal tablets of posaconazole.A one compartment absorption kinetic model was established in fed Beagle dogs,and the weight coefficient was 1/cc,AUC0-∞was（2 719±411）μg·L-1·h,which was about3 times of that of the normal tablets.CONCLUSION The enteric tablets of posaconazole prepared by HME technology can improve the dissolution and bioavailability.The food effect is reduced after enteric tablets of posaconazole are taken,and it is better to take the tablets after meals.