DNJ双层渗透泵片的制备及比格犬体内药动学研究
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摘要
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,Mr6×106) 80 mg,the coating layer cellulose acetate( CA) 15 mg and polyethylene glycol( PEG) 40005 mg. Under these conditions,the dissolution rate of DNJ was the most suitable,and it was not affected by the change of p H 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( tmax)( 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.
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,Mr6×106) 80 mg,the coating layer cellulose acetate( CA) 15 mg and polyethylene glycol( PEG) 40005 mg. Under these conditions,the dissolution rate of DNJ was the most suitable,and it was not affected by the change of p H 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( tmax)( 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.
引文
[1]KIMURA T,NAKAGAWA K,KUBUTA H,et al. Food-grade mulberry powder enriched with 1-deoxynojirimycin suppresses the elevation of postprandial blood glucose in human[J]. Journal of Agricultural and Food Chemistry,2007,55(14):5869-5874.
[2]WENNEKES T,RICHARD J B,BERG V D,et al. Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man[J]. Journal of Organic Chemistry,2007,72(4):1088-1097.
[3]VICHASILP C,NAKAGAWA K,SOOKWONG P,et al. Development of high 1-DNJ content mulberry tea and use of response surface methodology to optimize tea-making conditions for highest DNJ extraction[J]. LWT-Food Science and Technology,2012,45(2):226-232.
[4]章靖芳,苏峰,刘为中,等.渗透泵药物传递系统制备技术研究进展[J].安徽医药,2017,21(4):591-594.
[5]陈伶俐,罗燕娜,朱翠霞,等.口服渗透泵缓控释给药系统的研究概况[J].中国民族民间医药,2017,26(14):61-65.
[6]王健,王浩,侯惠民.药物制剂国家工程研究中心近十年研究进展[J].中国医药工业杂志,2017,48(3):293-306.
[7]章靖芳,苏峰,刘为中,等.渗透泵药物传递系统制备技术研究进展[J].安徽医药,2017,21(4):591-594.
[8]HERRLICH S,SPIETH S,MESSNER S,et al. Osmotic micropumps for drug delivery[J]. Advanced Drug Delivery Reviews,2012,64(14):1617-1627.
[9]KUMARAVELRAJAN R,NARAYAN N,SUBA V,et al. Simultaneous delivery of Nifedipine and Metoprolol tartarate using sandwiched osmotic pump tablet system[J]. International Journal of Pharmaceutics,2010,399(1/2):60-70.
[10]邱阳,吴超,赵宗哲,等. SBA-15增溶非洛地平的双层渗透泵片的制备[J].中国新药杂志,2016(7):823-829.
[11]朱兰琼,刘辉,廖诗琴,等.盐酸地芬尼多双层渗透泵片的制备及体外释放研究[J].中国药房,2017,28(13):1823-1826.
[12]国家药典委员会.中华人民共和国药典2015年版[M].北京:中国医药科技出版社,2015:866.
[13]ZHANG Z H,DONG H Y,PENG B,et al. Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs[J]. International Journal of Pharmaceutics,2011,410(1/2):41-47.
[14]YIN L F,HUANG S H,ZHU C L,et al. In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier[J]. Drug Development and Industrial Pharmacy,2012,38(11):1371-1380.
[15]徐兵勇,潘迎锋,平丽.左乙拉西坦缓释片的制备及其Beagle犬体内药动学研究[J].中国现代应用药学,2017,34(9):1266-1271.
[16]吕小波,张明泽,黄春球,等.血塞通分散片和普通片在比格犬体内的药动学研究[J].中国药学杂志,2018(1):52-57.
[17]ZHANG Z H,WANG C G,SUN G M,et al. Pharmacokinetics of two modified release system of dipyridamole in beagle dogs[J]. Jourmal of Chinese Pharmaceutical Sciences,2008,17(4):297-302.
[18]张琳,林晓冬,刘娜,等.富马酸喹硫平缓释片体外释放及体内外相关性研究[J].食品与药品,2017,19(4):235-240.
[2]WENNEKES T,RICHARD J B,BERG V D,et al. Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man[J]. Journal of Organic Chemistry,2007,72(4):1088-1097.
[3]VICHASILP C,NAKAGAWA K,SOOKWONG P,et al. Development of high 1-DNJ content mulberry tea and use of response surface methodology to optimize tea-making conditions for highest DNJ extraction[J]. LWT-Food Science and Technology,2012,45(2):226-232.
[4]章靖芳,苏峰,刘为中,等.渗透泵药物传递系统制备技术研究进展[J].安徽医药,2017,21(4):591-594.
[5]陈伶俐,罗燕娜,朱翠霞,等.口服渗透泵缓控释给药系统的研究概况[J].中国民族民间医药,2017,26(14):61-65.
[6]王健,王浩,侯惠民.药物制剂国家工程研究中心近十年研究进展[J].中国医药工业杂志,2017,48(3):293-306.
[7]章靖芳,苏峰,刘为中,等.渗透泵药物传递系统制备技术研究进展[J].安徽医药,2017,21(4):591-594.
[8]HERRLICH S,SPIETH S,MESSNER S,et al. Osmotic micropumps for drug delivery[J]. Advanced Drug Delivery Reviews,2012,64(14):1617-1627.
[9]KUMARAVELRAJAN R,NARAYAN N,SUBA V,et al. Simultaneous delivery of Nifedipine and Metoprolol tartarate using sandwiched osmotic pump tablet system[J]. International Journal of Pharmaceutics,2010,399(1/2):60-70.
[10]邱阳,吴超,赵宗哲,等. SBA-15增溶非洛地平的双层渗透泵片的制备[J].中国新药杂志,2016(7):823-829.
[11]朱兰琼,刘辉,廖诗琴,等.盐酸地芬尼多双层渗透泵片的制备及体外释放研究[J].中国药房,2017,28(13):1823-1826.
[12]国家药典委员会.中华人民共和国药典2015年版[M].北京:中国医药科技出版社,2015:866.
[13]ZHANG Z H,DONG H Y,PENG B,et al. Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs[J]. International Journal of Pharmaceutics,2011,410(1/2):41-47.
[14]YIN L F,HUANG S H,ZHU C L,et al. In vitro and in vivo studies on a novel solid dispersion of repaglinide using polyvinylpyrrolidone as the carrier[J]. Drug Development and Industrial Pharmacy,2012,38(11):1371-1380.
[15]徐兵勇,潘迎锋,平丽.左乙拉西坦缓释片的制备及其Beagle犬体内药动学研究[J].中国现代应用药学,2017,34(9):1266-1271.
[16]吕小波,张明泽,黄春球,等.血塞通分散片和普通片在比格犬体内的药动学研究[J].中国药学杂志,2018(1):52-57.
[17]ZHANG Z H,WANG C G,SUN G M,et al. Pharmacokinetics of two modified release system of dipyridamole in beagle dogs[J]. Jourmal of Chinese Pharmaceutical Sciences,2008,17(4):297-302.
[18]张琳,林晓冬,刘娜,等.富马酸喹硫平缓释片体外释放及体内外相关性研究[J].食品与药品,2017,19(4):235-240.