田蓟苷纳米混悬剂冻干粉缓释片制备工艺研究
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摘要
目的制备田蓟苷纳米混悬剂冻干粉缓释片,并研究影响缓释片药物释放的因素及缓释片的释药机制。方法采用高压均质法制备田蓟苷纳米混悬剂,乳糖-甘露醇(3∶1)作为冻干保护剂制备冻干粉末。以HPMC作为骨架材料进一步制备成田蓟苷纳米混悬剂冻干粉缓释片,单因素考察骨架材料HPMC K4M和HPMC K15M比例及其用量、PEG 4000用量和硬脂酸镁用量对缓释片体外释药的影响,正交试验得出最佳处方。结果田蓟苷纳米混悬剂平均粒径及Zeta电位分别为(164.41±9.72)nm和(-37.21±2.38)mV;冻干粉复溶后平均粒径及Zeta电位分别为(211.83±11.26)nm和(-31.66±2.92)mV。正交试验优化后的最佳处方为骨架材料HPMCK4M和HPMCK15M用量比为2∶1,用量为40mg,释放速率调节剂PEG 4000用量为20 mg,硬脂酸镁用量为片质量的0.5%。田蓟苷纳米混悬剂冻干粉缓释片体外释药行为符合Higuchi释药模型:M_t/M_∞=0.286 8 t~(1/2)-0.073 8,r~2=0.981 4,在12 h内的累积释放度达到92.36%,释药机制为扩散与骨架溶蚀并存。结论田蓟苷纳米混悬剂冻干粉缓释片制备工艺重复性良好,可有效控制田蓟苷纳米粒在体外缓慢释放。
Objective To prepare sustained-release tablets of tilianin nanosuspension lyophilized powder. The factors that might influence drug release and release mechanism were studied in present study. Methods High pressure homogenization method was used to prepare tilianin nanosuspension. Lactose and mannitol(3∶1) were employed as freeze-drying protective agent to prepare lyophilized powder. HPMC was used as framework material to prepare sustained-release tablets of tilianin nanosuspension lyophilized powder. Based on single factor test, the effects of proportion and amounts of HPMC K4M and HPMC K15, amounts of PEG 4000 and magnesium stearate on in vitro drug release of sustained-release tablets were investigated. Orthogonal test was designed to gain the optimum prescription. Results The particle size and zeta potential of tilianin nanosuspension were(164.41 ±9.72) nm and(-37.21 ± 2.38) mV, respectively. The particle size and zeta potential of re-dispersed freeze-drying products were(211.83 ± 11.26) nm and(-31.66 ± 2.92) mV, respectively. The optimum prescription was as follow: the proportion and amounts of HPMC K4M and HPMC K15 were 2∶1 and 40 mg, amounts of PEG 4000 was 20 mg, and amounts of magnesium stearate were 0.5%. Sustained release tablets of tilianin nanosuspension were well accorded with Higuchi kinetics model. The equation was M_t/M_∞=0.286 8 t~(1/2)-0.073 8, r~2 = 0.981 4. And the cumulative release could achieve 92.36% in 12 h. The drug release from the tablets was controlled by diffusion and degradation of the matrix. Conclusion The preparation technology of sustained release tablets of tilianin nanosuspension lyophilized powder has good reproducibility. This sustained release tablets could control the release of tilianin nanosuspension in a slow characteristic.
Objective To prepare sustained-release tablets of tilianin nanosuspension lyophilized powder. The factors that might influence drug release and release mechanism were studied in present study. Methods High pressure homogenization method was used to prepare tilianin nanosuspension. Lactose and mannitol(3∶1) were employed as freeze-drying protective agent to prepare lyophilized powder. HPMC was used as framework material to prepare sustained-release tablets of tilianin nanosuspension lyophilized powder. Based on single factor test, the effects of proportion and amounts of HPMC K4M and HPMC K15, amounts of PEG 4000 and magnesium stearate on in vitro drug release of sustained-release tablets were investigated. Orthogonal test was designed to gain the optimum prescription. Results The particle size and zeta potential of tilianin nanosuspension were(164.41 ±9.72) nm and(-37.21 ± 2.38) mV, respectively. The particle size and zeta potential of re-dispersed freeze-drying products were(211.83 ± 11.26) nm and(-31.66 ± 2.92) mV, respectively. The optimum prescription was as follow: the proportion and amounts of HPMC K4M and HPMC K15 were 2∶1 and 40 mg, amounts of PEG 4000 was 20 mg, and amounts of magnesium stearate were 0.5%. Sustained release tablets of tilianin nanosuspension were well accorded with Higuchi kinetics model. The equation was M_t/M_∞=0.286 8 t~(1/2)-0.073 8, r~2 = 0.981 4. And the cumulative release could achieve 92.36% in 12 h. The drug release from the tablets was controlled by diffusion and degradation of the matrix. Conclusion The preparation technology of sustained release tablets of tilianin nanosuspension lyophilized powder has good reproducibility. This sustained release tablets could control the release of tilianin nanosuspension in a slow characteristic.
引文
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[10]苏文晶,肖瑶,张明珠,等.番荔素纳米混悬剂的制备及其抗肿瘤作用研究[J].药物评价研究,2016,39(6):966-972.
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[12]张小飞,果秋婷.姜黄素纳米混悬剂的制备及大鼠体内药动学研究[J].中药材,2015,38(1):163-166.
[13]石淼,张洪,吕舰,等.氯雷他定纳米混悬剂的制备与稳定性考察[J].医药导报,2018,37(11):1381-1385.
[14]蒋爱,李国源,王鑫,等.星点设计-效应面法优化紫杉醇-白桦脂酸混合纳米混悬剂[J].中草药,2019,50(4):852-859.
[15]袁勇,邢建国,王新春,等.香青兰黄酮类化合物的大鼠在体肠吸收[J].中国医院药学杂志,2011,31(20):1667-1670.
[16]Mandal B,Moulik S P,Ghosh S.Physicochemistry of interaction of polyvinylpyrrolidone(PVP)with sodium dodecyl sulfate(SDS)in salt solution[J].J Surf Interfaces Mater,2013,1(1):77-86.
[17]邓向涛,阮晓东,郝海军.马钱子碱固体脂质纳米粒凝胶骨架缓释片的研制[J].中草药,2018,49(22):5298-5304.
[18]邓向涛,郝海军,韩茹,等.黄芩素包合物单层渗透泵片制备工艺研究[J].第二军医大学学报,2015,36(5):513-517.
[19]郭留城,杜利月,郝海军,等.青藤碱固体脂质纳米粒凝胶骨架缓释片的制备及处方优化[J].中国医院药学杂志,2018,38(18):1893-1897.
[20]曹伶俐,刘刚,胡彬,等.槲皮素固体脂质纳米粒凝胶骨架缓释片制备工艺研究[J].中药材,2016,39(6):1369-1371.
[21]吴先闯,郝海军,宋晓勇,等.白藜芦醇固体脂质纳米粒缓释凝胶骨架片的研制[J].中草药,2016,47(8):1303-1308.
[22]徐凯,魏永鸽.高乌甲素磷脂复合物纳米粒的制备、表征及药动学研究[J].天然产物研究与开发,2018,30(5):870-874.
[23]贾欣,张超锋,张青青,等.2-甲氧基雌二醇纳米混悬剂的安全性实验[J].医药导报,2016,35(9):934-937.
[24]王金凤,王芳,杨翠燕,等.鸢尾苷元胃内漂浮缓释片兔体内药动学及其体内外相关性研究[J].中草药,2017,48(2):266-271.
[2]曾诚,郑瑞芳,都研文,等.TAT和PEG双修饰田蓟苷复合磷脂脂质体的工艺优化及体外评价[J].中草药,2018,49(21):5061-5069.
[3]Kerem Y,Eastvold J S,Faragoi D,et al.The role of prehospital electrocardiograms in the recognition of ST-segment elevation myocardial infarctionsand reperfusion times[J].J Emerg Med,2014,46(2):202-207.
[4]Wang Y,Ren Q,Zhang X,et al.Neuroprotective mechanisms of calycosin against focal cerebral ischemia and reperfusion injury in rats[J].Cell Physiol Biochem,2018,45(2):537-546.
[5]曾诚,马丽月,于宁,等.香青兰提取物基本理化性质研究[J].中草药,2016,47(21):3817-3823.
[6]曾诚,杨晓艺,帕依曼·亥米提,等.田蓟苷在不同介质中的平衡溶解度及油水分配系数[J].中国医院药学杂志,2017,37(1):84-87.
[7]谭梅娥,姜雯,曾诚,等.田蓟苷固体脂质纳米粒的优化及其在Caco-2细胞模型中的吸收和转运研究[J].中草药,2017,48(10):2051-2060.
[8]袁勇,王新春,陈卫军,等.田蓟苷微乳在大鼠体内的药动学及生物利用度[J].中国医院药学杂志,2015,35(20):1815-1819.
[9]罗开沛,李小芳,罗佳,等.纳米混悬技术在中药制剂中的应用及发展趋势[J].中草药,2016,47(6):865-871.
[10]苏文晶,肖瑶,张明珠,等.番荔素纳米混悬剂的制备及其抗肿瘤作用研究[J].药物评价研究,2016,39(6):966-972.
[11]李怡静,敖惠,李好文,等.西瑞香素纳米混悬剂的制备及其体外抗肿瘤作用研究[J].现代药物与临床,2018,33(2):231-237.
[12]张小飞,果秋婷.姜黄素纳米混悬剂的制备及大鼠体内药动学研究[J].中药材,2015,38(1):163-166.
[13]石淼,张洪,吕舰,等.氯雷他定纳米混悬剂的制备与稳定性考察[J].医药导报,2018,37(11):1381-1385.
[14]蒋爱,李国源,王鑫,等.星点设计-效应面法优化紫杉醇-白桦脂酸混合纳米混悬剂[J].中草药,2019,50(4):852-859.
[15]袁勇,邢建国,王新春,等.香青兰黄酮类化合物的大鼠在体肠吸收[J].中国医院药学杂志,2011,31(20):1667-1670.
[16]Mandal B,Moulik S P,Ghosh S.Physicochemistry of interaction of polyvinylpyrrolidone(PVP)with sodium dodecyl sulfate(SDS)in salt solution[J].J Surf Interfaces Mater,2013,1(1):77-86.
[17]邓向涛,阮晓东,郝海军.马钱子碱固体脂质纳米粒凝胶骨架缓释片的研制[J].中草药,2018,49(22):5298-5304.
[18]邓向涛,郝海军,韩茹,等.黄芩素包合物单层渗透泵片制备工艺研究[J].第二军医大学学报,2015,36(5):513-517.
[19]郭留城,杜利月,郝海军,等.青藤碱固体脂质纳米粒凝胶骨架缓释片的制备及处方优化[J].中国医院药学杂志,2018,38(18):1893-1897.
[20]曹伶俐,刘刚,胡彬,等.槲皮素固体脂质纳米粒凝胶骨架缓释片制备工艺研究[J].中药材,2016,39(6):1369-1371.
[21]吴先闯,郝海军,宋晓勇,等.白藜芦醇固体脂质纳米粒缓释凝胶骨架片的研制[J].中草药,2016,47(8):1303-1308.
[22]徐凯,魏永鸽.高乌甲素磷脂复合物纳米粒的制备、表征及药动学研究[J].天然产物研究与开发,2018,30(5):870-874.
[23]贾欣,张超锋,张青青,等.2-甲氧基雌二醇纳米混悬剂的安全性实验[J].医药导报,2016,35(9):934-937.
[24]王金凤,王芳,杨翠燕,等.鸢尾苷元胃内漂浮缓释片兔体内药动学及其体内外相关性研究[J].中草药,2017,48(2):266-271.