头痛宁鼻腔喷雾剂在大鼠体内的药动学及脑靶向研究
|
摘要
目的:研究头痛宁鼻腔喷雾剂经鼻给药后在大鼠体内的药动学及脑靶向情况。方法:84只SD大鼠分为鼻腔给药组和静脉给药组,每组42只,给药剂量均为1.2 mL/kg。分别于给药后5、10、15、30、60、90、120 min于腹主动脉取血5 mL,并取脑组织(每个时间点6只)。采用高效液相色谱-串联质谱法测定各组大鼠血浆和脑组织中升麻素苷、5-O-甲基维斯阿米醇苷的浓度,采用DAS 2.0软件计算药动学参数及脑靶向性指数。结果:鼻腔给药组大鼠血浆中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.202 4±0.015 8)、(0.373 8±0.085 7)μg/mL,t_(max)均为(10.000 0±0.000 0)min,AUC_(0-∞)分别为(16.542 9±2.110 3)、(27.452 7±5.572 1)μg·h/mL;脑组织中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.180 2±0.038 4)、(0.320 4±0.027 7)μg/g,t_(max)均为(10.000 0±0.000 0)min,AUC_(0-∞)分别为(17.105 3±2.432 9)、(24.541 6±3.753 4)μg·h/g。静脉给药组大鼠血浆中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.300 2±0.016 1)、(0.526 7±0.044 1)μg/mL,t_(max)均为(10.000 0±0.000 0)min,AUC_(0-∞)分别为(28.010 5±4.112 8)、(60.294 1±11.290 2)μg·h/mL;脑组织中升麻素苷、5-O-甲基维斯阿米醇苷的c_(max)分别为(0.149 8±0.031 5)、(0.199 8±0.040 1)μg/g,t_(max)均为(15.000 0±0.000 0)min,AUC_(0-∞)分别为(22.643 4±2.883 1)、(36.721 8±14.885 6)μg·h/g。升麻素苷、5-O-甲基维斯阿米醇苷脑靶向性指数分别为2.387 0、2.176 1。结论:头痛宁鼻腔喷雾剂鼻腔给药后一部分药物可经鼻腔吸收直接转运至脑,制成鼻腔喷雾剂科学合理。
OBJECTIVE:To study the pharmacokinetics and brain targeting of Toutongning nasal spray in rats in vivo. METHODS:84 SD rats were divided into nasal administration group and vein administration group,42 in each group,with dose of 1.2 mL/kg. 5 mL sample blood was taken in abdominal aorta after 5,10,15,30,60,90,120 min of administration,and brain tissue was taken(6 rats in each time point). HPLC-MS was adopted to determine the concentration of prim-o-glucosylcimifugin and 5-Omethylvisammioside in plasma and brain tissue of rats in each group,and DAS 2.0 software was used to calculate the pharmacokinetic parameters and brain targeting indexes. RESULTS:The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in nasal administration group were(0.202 4 ± 0.015 8),(0.373 8 ± 0.085 7)μg/mL;t_(max) were(10.000 0 ± 0.000 0)min;and AUC_(0-∞) were(16.542 9±2.110 3),(27.452 7±5.572 1)μg·h/mL,respectively. The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.180 2 ± 0.038 4),(0.320 4 ± 0.027 7)μg/g;t_(max) were(10.000 0 ±0.000 0)min;and AUC_(0-∞) were(17.105 3±2.432 9),(24.541 6±3.753 4)μg·h/g,respectively. The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in vein administration group were(0.300 2±0.016 1),(0.526 7±0.044 1)μg/mL;t_(max) were(10.000 0±0.000 0)min;and AUC_(0-∞) were(28.010 5±4.112 8),(60.294 1±11.290 2)μg·h/mL,respectively. The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.149 8±0.031 5),(0.199 8±0.040 1)μg/g;t_(max) were(15.000 0±0.000 0)min;and AUC_(0-∞) were(22.643 4±2.883 1),(36.721 8±14.885 6)μg·h/g,respectively. The brain targeting indexes of prim-o-glucosylcimifugin and 5-O-methylvisammioside were 2.387 0 and 2.176 1,respectively. CONCLUSIONS:After nasal administration of Toutongning nasal spray,parts of drugs can directly transport to the brian by nasal absorption. It is scientific and reasonable to make nasal spray.
OBJECTIVE:To study the pharmacokinetics and brain targeting of Toutongning nasal spray in rats in vivo. METHODS:84 SD rats were divided into nasal administration group and vein administration group,42 in each group,with dose of 1.2 mL/kg. 5 mL sample blood was taken in abdominal aorta after 5,10,15,30,60,90,120 min of administration,and brain tissue was taken(6 rats in each time point). HPLC-MS was adopted to determine the concentration of prim-o-glucosylcimifugin and 5-Omethylvisammioside in plasma and brain tissue of rats in each group,and DAS 2.0 software was used to calculate the pharmacokinetic parameters and brain targeting indexes. RESULTS:The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in nasal administration group were(0.202 4 ± 0.015 8),(0.373 8 ± 0.085 7)μg/mL;t_(max) were(10.000 0 ± 0.000 0)min;and AUC_(0-∞) were(16.542 9±2.110 3),(27.452 7±5.572 1)μg·h/mL,respectively. The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.180 2 ± 0.038 4),(0.320 4 ± 0.027 7)μg/g;t_(max) were(10.000 0 ±0.000 0)min;and AUC_(0-∞) were(17.105 3±2.432 9),(24.541 6±3.753 4)μg·h/g,respectively. The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in plasma of rats in vein administration group were(0.300 2±0.016 1),(0.526 7±0.044 1)μg/mL;t_(max) were(10.000 0±0.000 0)min;and AUC_(0-∞) were(28.010 5±4.112 8),(60.294 1±11.290 2)μg·h/mL,respectively. The c_(max) of prim-o-glucosylcimifugin and 5-O-methylvisammioside in brain tissue of rats were(0.149 8±0.031 5),(0.199 8±0.040 1)μg/g;t_(max) were(15.000 0±0.000 0)min;and AUC_(0-∞) were(22.643 4±2.883 1),(36.721 8±14.885 6)μg·h/g,respectively. The brain targeting indexes of prim-o-glucosylcimifugin and 5-O-methylvisammioside were 2.387 0 and 2.176 1,respectively. CONCLUSIONS:After nasal administration of Toutongning nasal spray,parts of drugs can directly transport to the brian by nasal absorption. It is scientific and reasonable to make nasal spray.
引文
[1]黄金华,陈伟.头痛宁治疗偏头痛的系统评价[J].中医药临床杂志,2015,27(5):642-645.
[2]王建平.头痛宁鼻腔喷雾剂的质量标准研究[J].中国中医药现代远程教育,2010,8(23):203-204.
[3]赵焱玲.头痛宁鼻腔喷雾剂的药学研究[D].南京:南京中医药大学,2007.
[4]吕莹,张栋,张超,等.鼻腔给药研究进展[J].天津中医药,2014,31(12):766-768.
[5]蒋新国.脑靶向递药系统的研究进展[J].复旦学报(医学版),2012,39(5):441-448.
[6]董宇,狄留庆,赵晓莉,等.经鼻给药脑部递药系统设计的药剂学研究进展[J].中国药房,2010,21(3):271-273.
[7]邓春丽,罗洁琦,沙先谊,等.三七总皂苷鼻用凝胶喷雾剂的药动学与药效学研究[J].中国临床药学杂志,2014,23(5):276-282.
[8]赵琰玲.头痛宁鼻腔喷雾剂的药学研究[D].南京:南京中医药大学,2007.
[9]周荣,金铭,沈淼山,等.聚山梨醇-80的神经毒素纳米粒经大鼠鼻腔给药后体内分布研究[J].中草药,2015,46(17):2599-2562.
[10]Wang XM,He HB,Leng W,et al.Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method[J].Int J Pharm,2006,317(1):40-46.
[11]Frenk H,Martin J,Vitouchanskaia C,et al.Effects of contingent and noncontingent nicotine on lever pressing for liquids and consumption in water-deprived rats[J].Eur J Pharm,2017,794(5):224-233.
[12]王慧敏,魏国光,高明月,等.酒石酸卡巴拉汀鼻腔吸收及脑靶向性评价[J].药学学报,2016,51(10):1616-1621.
[13]张龙开,许日鑫,蒋梅,等.β-细辛醚微乳鼻腔给药脑内靶向性评价[J].中草药,2014,45(1):86-89.
[14]史亚军.黄芩有效部位鼻用脑靶向制剂研究[D].成都:成都中医药大学,2012.
[15]董宇.血压平喷雾剂中主要活性成分的鼻黏膜吸收特性研究[D].南京:南京中医药大学,2010.
[16]刘建春,杨婉芳,季新燕,等.中药鼻腔给药的脑靶向性探讨[J].中医杂志,2014,55(15):1284-1287.
[17]李玲,马海忠,廖明琪,等.鼻腔给药系统类型及临床应用进展[J].中国药房,2013,24(17):1615-1617.
[18]李楠,叶英杰,杨明,等.黄芩苷磷脂复合物单侧鼻腔给药脑靶向性研究[J].中国药学杂志,2012,47(4):283-286.
[2]王建平.头痛宁鼻腔喷雾剂的质量标准研究[J].中国中医药现代远程教育,2010,8(23):203-204.
[3]赵焱玲.头痛宁鼻腔喷雾剂的药学研究[D].南京:南京中医药大学,2007.
[4]吕莹,张栋,张超,等.鼻腔给药研究进展[J].天津中医药,2014,31(12):766-768.
[5]蒋新国.脑靶向递药系统的研究进展[J].复旦学报(医学版),2012,39(5):441-448.
[6]董宇,狄留庆,赵晓莉,等.经鼻给药脑部递药系统设计的药剂学研究进展[J].中国药房,2010,21(3):271-273.
[7]邓春丽,罗洁琦,沙先谊,等.三七总皂苷鼻用凝胶喷雾剂的药动学与药效学研究[J].中国临床药学杂志,2014,23(5):276-282.
[8]赵琰玲.头痛宁鼻腔喷雾剂的药学研究[D].南京:南京中医药大学,2007.
[9]周荣,金铭,沈淼山,等.聚山梨醇-80的神经毒素纳米粒经大鼠鼻腔给药后体内分布研究[J].中草药,2015,46(17):2599-2562.
[10]Wang XM,He HB,Leng W,et al.Evaluation of brain-targeting for the nasal delivery of estradiol by the microdialysis method[J].Int J Pharm,2006,317(1):40-46.
[11]Frenk H,Martin J,Vitouchanskaia C,et al.Effects of contingent and noncontingent nicotine on lever pressing for liquids and consumption in water-deprived rats[J].Eur J Pharm,2017,794(5):224-233.
[12]王慧敏,魏国光,高明月,等.酒石酸卡巴拉汀鼻腔吸收及脑靶向性评价[J].药学学报,2016,51(10):1616-1621.
[13]张龙开,许日鑫,蒋梅,等.β-细辛醚微乳鼻腔给药脑内靶向性评价[J].中草药,2014,45(1):86-89.
[14]史亚军.黄芩有效部位鼻用脑靶向制剂研究[D].成都:成都中医药大学,2012.
[15]董宇.血压平喷雾剂中主要活性成分的鼻黏膜吸收特性研究[D].南京:南京中医药大学,2010.
[16]刘建春,杨婉芳,季新燕,等.中药鼻腔给药的脑靶向性探讨[J].中医杂志,2014,55(15):1284-1287.
[17]李玲,马海忠,廖明琪,等.鼻腔给药系统类型及临床应用进展[J].中国药房,2013,24(17):1615-1617.
[18]李楠,叶英杰,杨明,等.黄芩苷磷脂复合物单侧鼻腔给药脑靶向性研究[J].中国药学杂志,2012,47(4):283-286.