柚皮素纳米晶体的制备及药剂学性质研究
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摘要
目的制备柚皮素纳米晶体,并进行药剂学性质研究。方法采用介质研磨-喷雾干燥法制备柚皮素纳米晶体;用马尔文激光粒度测定仪测定柚皮素纳米晶体的平均粒径和多分散指数(PDI);用扫描电镜观察晶体形态;用X-射线粉末衍射法、差示扫描量热法及傅里叶红外光谱法考察晶型和化学结构是否变化;用转篮法测定纳米晶体的溶出度。结果柚皮素纳米晶体平均粒径为(400.7±6.9)nm,PDI为0.23;制备成纳米晶体后,柚皮素晶型及化学结构未发生明显变化;溶解度明显提高(在pH 1.2盐酸溶液和pH 4.5磷酸盐溶液中,P<0.01;在pH 6.8磷酸盐溶液和水中,P<0.05);溶出度明显改善,药物溶出参数T_(50)、T_d(药物溶出50%和63.2%所需时间)显著减小(P<0.01)。结论优选的柚皮素纳米晶体制备工艺稳定可行,制备的纳米晶体粒径小且较为均匀,纳米化后柚皮素仍为结晶态,溶解和溶出得到明显改善,这为柚皮素进一步开发提供了依据。
Objective To prepare and investigate the pharmaceutical characteristics of naringenin(NAR) nanocrystals. Methods NAR nanocrystals were prepared by media milling combined with spray drying method. The mean particle size and polydispersity index(PDI) of NAR nanocrystals were analyzed by Malvern Zetasizer. The morphology of the nanoparticles was observed by scanning electron microscope(SEM). The crystalline state and the chemical structure of NAR before and after nanonization were characterized using X-ray powder diffraction(XRPD), differential scanning calorimetry(DSC), and fourier transform infrared spectrometry(FT-IR). Dissolution rate of NAR before and after nanonization were studied using rotary basket method. Results The mean particle size of NAR nanocrystals was(400.7 ± 6.9) nm, and PDI value was 0.23. After nanonization, the crystalline state and chemical structure of NAR were not obviously altered, and the solubility was significantly increased(in pH 1.2 hydrochloric acid solution and pH 4.5 phosphate solution, P < 0.05; in pH 6.8 phosphate solution and water, P < 0.01). The dissolution was obviously improved, T_(50) and T_d were visibly decreased(P < 0.01). Conclusion The optimized process is stable and feasible for the preparation of NAR nanocrystals. NAR nanocrystals have a tiny and uniform particle size. After nanonization, NAR was still crystalline, the solubility and the dissolution were significantly increased, which can provide the basis for the further development of NAR.
Objective To prepare and investigate the pharmaceutical characteristics of naringenin(NAR) nanocrystals. Methods NAR nanocrystals were prepared by media milling combined with spray drying method. The mean particle size and polydispersity index(PDI) of NAR nanocrystals were analyzed by Malvern Zetasizer. The morphology of the nanoparticles was observed by scanning electron microscope(SEM). The crystalline state and the chemical structure of NAR before and after nanonization were characterized using X-ray powder diffraction(XRPD), differential scanning calorimetry(DSC), and fourier transform infrared spectrometry(FT-IR). Dissolution rate of NAR before and after nanonization were studied using rotary basket method. Results The mean particle size of NAR nanocrystals was(400.7 ± 6.9) nm, and PDI value was 0.23. After nanonization, the crystalline state and chemical structure of NAR were not obviously altered, and the solubility was significantly increased(in pH 1.2 hydrochloric acid solution and pH 4.5 phosphate solution, P < 0.05; in pH 6.8 phosphate solution and water, P < 0.01). The dissolution was obviously improved, T_(50) and T_d were visibly decreased(P < 0.01). Conclusion The optimized process is stable and feasible for the preparation of NAR nanocrystals. NAR nanocrystals have a tiny and uniform particle size. After nanonization, NAR was still crystalline, the solubility and the dissolution were significantly increased, which can provide the basis for the further development of NAR.
引文
[1]王元文.柚皮素脂质体的制备及其特性研究[D].镇江:江苏大学,2016.
[2]Khan A W,Kotta S,Husain A,et al.Enhanced dissolution and bioavailability of grapefruit flavonoid naringenin by solid dispersion utilizing fourth generation carrier[J].Drug Dev Ind Pharm,2014,41(5):772-779.
[3]Jayaraman J,Veerappan M,Namasivayam N.Potential beneficial effect of naringenin on lipid peroxidation and antioxidant status in rats with ethanol-induced hepatotoxicity[J].J Pharm Pharmacol,2009,61(10):1383-1390.
[4]季鹏,赵文明.柚皮素脂质体冻干粉的制备及其药效学评价[J].中国医学科学院学报,2015,37(2):208-214.
[5]杨文青,马晶,余华荣.柚皮素改善阿尔茨海默病模型大鼠的认知能力及其机制研究[J].中草药,2013,44(6):715-720.
[6]霍平,刘万云.柚皮素芳酰腙化合物的微波合成与抑菌活性研究[J].化学试剂,2012,34(4):312-314.
[7]李瑞芳,左学兰,周颖,等.柚皮素对人髓系白血病K562细胞增殖的作用[J].武汉大学学报:医学版,2007,28(3):344-347.
[8]Esmaeili M A,Alilou M.Naringenin attenuates CCl4-induced hepatic inflammation by the activation of an Nrf2-mediated pathway in rats[J].Clin Exp Pharmacol P,2014,41(6):416-422.
[9]Lin Y,Vermeer M A,Bos W.Molecular structures of citrus flavonoids determine their effects on lipid metabolism in Hep G2 cells by primarily suppressing Apo B secretion[J].J Agr Food Chem,2011,59(9):4496-4503.
[10]杨宏亮,田珩,李沛波,等.柚皮苷及柚皮素的生物活性研究[J].中药材,2007,30(6):752-754.
[11]姚艳胜,季鹏,刘畅,等.柚皮素固体脂质纳米粒冻干粉的制备及其大鼠肺部给药药动学研究[J].中草药,2016,47(4):591-598.
[12]马燕,林宝琴,李卫中,等.柚皮素大鼠在体肠吸收动力学的研究[J].中成药,2012,34(8):1487-1491.
[13]李静静,贾运涛,田睿,等.柚皮素纳米结构脂质载体的处方优化和初步评价[J].中草药,2015,46(2):211-215.
[14]Kanaze F I,Bounartzi M I,Georgarakis M,et al.Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects[J].Eur J Clin Nutr,2007,61(4):472-477.
[15]王章姐,胡容峰,王国凯,等.Box-Behnken设计-效应面法优化柚皮素自微乳给药系统[J].中草药,2014,45(17):2461-2466.
[16]朱勋,靳新位,刁美艳.纳米科技与纳米经济[J].河北工业科技,2013,20(5):6-9.
[17]武娜,张利红,程玲,等.金丝桃苷固体纳米晶体的制备及其体外释放研究[J].中草药,2015,46(12):1759-1763.
[18]马静,王晓青,李翔,等.药物纳米晶体混悬液的给药途径的研究进展[J].中国药学杂志,2012,47(24):1965-1970.
[19]周小圆,林华庆,雷伟.难溶性药物纳米晶体的研究进展[J].中南药学,2013,11(5):353-358.
[20]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.
[21]何小龙,宋红萍.柚皮素纳米晶体的制备及体外性质研究[J].中国医院药学杂志,2016,36(4):289-293.
[2]Khan A W,Kotta S,Husain A,et al.Enhanced dissolution and bioavailability of grapefruit flavonoid naringenin by solid dispersion utilizing fourth generation carrier[J].Drug Dev Ind Pharm,2014,41(5):772-779.
[3]Jayaraman J,Veerappan M,Namasivayam N.Potential beneficial effect of naringenin on lipid peroxidation and antioxidant status in rats with ethanol-induced hepatotoxicity[J].J Pharm Pharmacol,2009,61(10):1383-1390.
[4]季鹏,赵文明.柚皮素脂质体冻干粉的制备及其药效学评价[J].中国医学科学院学报,2015,37(2):208-214.
[5]杨文青,马晶,余华荣.柚皮素改善阿尔茨海默病模型大鼠的认知能力及其机制研究[J].中草药,2013,44(6):715-720.
[6]霍平,刘万云.柚皮素芳酰腙化合物的微波合成与抑菌活性研究[J].化学试剂,2012,34(4):312-314.
[7]李瑞芳,左学兰,周颖,等.柚皮素对人髓系白血病K562细胞增殖的作用[J].武汉大学学报:医学版,2007,28(3):344-347.
[8]Esmaeili M A,Alilou M.Naringenin attenuates CCl4-induced hepatic inflammation by the activation of an Nrf2-mediated pathway in rats[J].Clin Exp Pharmacol P,2014,41(6):416-422.
[9]Lin Y,Vermeer M A,Bos W.Molecular structures of citrus flavonoids determine their effects on lipid metabolism in Hep G2 cells by primarily suppressing Apo B secretion[J].J Agr Food Chem,2011,59(9):4496-4503.
[10]杨宏亮,田珩,李沛波,等.柚皮苷及柚皮素的生物活性研究[J].中药材,2007,30(6):752-754.
[11]姚艳胜,季鹏,刘畅,等.柚皮素固体脂质纳米粒冻干粉的制备及其大鼠肺部给药药动学研究[J].中草药,2016,47(4):591-598.
[12]马燕,林宝琴,李卫中,等.柚皮素大鼠在体肠吸收动力学的研究[J].中成药,2012,34(8):1487-1491.
[13]李静静,贾运涛,田睿,等.柚皮素纳米结构脂质载体的处方优化和初步评价[J].中草药,2015,46(2):211-215.
[14]Kanaze F I,Bounartzi M I,Georgarakis M,et al.Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects[J].Eur J Clin Nutr,2007,61(4):472-477.
[15]王章姐,胡容峰,王国凯,等.Box-Behnken设计-效应面法优化柚皮素自微乳给药系统[J].中草药,2014,45(17):2461-2466.
[16]朱勋,靳新位,刁美艳.纳米科技与纳米经济[J].河北工业科技,2013,20(5):6-9.
[17]武娜,张利红,程玲,等.金丝桃苷固体纳米晶体的制备及其体外释放研究[J].中草药,2015,46(12):1759-1763.
[18]马静,王晓青,李翔,等.药物纳米晶体混悬液的给药途径的研究进展[J].中国药学杂志,2012,47(24):1965-1970.
[19]周小圆,林华庆,雷伟.难溶性药物纳米晶体的研究进展[J].中南药学,2013,11(5):353-358.
[20]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.
[21]何小龙,宋红萍.柚皮素纳米晶体的制备及体外性质研究[J].中国医院药学杂志,2016,36(4):289-293.
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