DNJ双层渗透泵片的制备及比格犬体内药动学研究

Preparation of DNJ Bi-layer Osmotic Pump Tablets and Its Pharmacokinetics Study in Beagle Dogs

制备了1-脱氧野尻霉素(DNJ)双层渗透泵片,以释放度为评价指标优化了处方,考察了DNJ双层渗透泵片的体外释药性,并对比研究了DNJ双层渗透泵片和速释片在比格犬体内的药动学。DNJ双层渗透泵片的最优处方为含药层羟丙基甲基纤维素(HPMC) E50用量为10 mg、助推层聚氧乙烯(PEO,Mr6×10~6)用量为80mg、包衣层醋酸纤维素(CA)用量为15mg及聚乙二醇(PEG) 4000用量为5mg,在此条件下DNJ溶出速度最为适宜,并且不受p H值的变化影响,药物12 h溶出完全,且恒速缓慢释放。对比DNJ双层渗透泵片和速释片在比格犬体内的双制剂双周期交叉试验,结果表明:双层渗透泵片释放的达峰时间(t_(max))为(9.3±3.8) h比速释片(4.4±2.2) h显著延迟,达到了缓控释的目的,渗透泵片的相对生物利用度为(96.1±9.8)%,90%置信区间为84.8%～103.7%,渗透泵片与速释片吸收程度生物等效。

The 1-deoxynojirimycin(DNJ)bi-layer osmotic pump tablets were prepared,and the prescription was optimized by dissolution.The in vitro release of DNJ bi-layer osmotic pump tablets was investigated.And the pharmacokinetics of bi-layer osmotic pump tablets and immediate release tablets were studied in Beagle dogs.The optimal prescription for DNJ bi-layer osmotic pump tablets was the dosage of containing drug layer hydroxypropylmethyl cellulose(HPMC)E50 10 mg,the boost layer polyoxyethylene(PEO,Mr 6×10^6)80 mg,the coating layer cellulose acetate(CA)15 mg and polyethylene glycol(PEG)4000 5 mg.Under these conditions,the dissolution rate of DNJ was the most suitable,and it was not affected by the change of pH value.The drug was completely dissolved in 12 h and slowly released at a constant rate.Comparing the bi-dose two-cycle crossover test of DNJ bi-layer osmotic pump tablets and immediate release tablets in Beagle dogs,the results showed that the time to peak(t max)(9.3±3.8)h of the release of bi-layer osmotic pump tablets was longer than that of the immediate release tablets(4.4±2.2)h,achieving the purpose of controlled release.The relative bioavailability of osmotic pump tablets was(96.1±9.8)%,and the 90%confidence interval was 84.8%103.7%.And the absorption degrees of osmotic pump tablets and immediate release tablets were organisms equivalent.