载雷帕霉素pH敏感性口服纳米骨架给药系统的研究
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摘要
目的:雷帕霉素(Rapamycin,RAPA),又称西罗莫司(Sirolimus),属大环内酯类抗生素。RAPA不仅是一种疗效好,低毒,无肾毒性的新型免疫抑制剂,还有抗肿瘤作用。文献资料表明该药物易溶于甲醇、乙醇等有机溶剂,难溶于水,口服吸收效果差。目前已上市的雷帕霉素制剂主要是口服微乳制剂,服用前需要加水乳化成乳剂,其中含有大量表面活性剂及助表面活性剂,长期频繁口服给药,可能会造成胃肠道粘膜损伤。本课题设计采用纳米骨架材料SiO2为药物载体,利用pH敏感性丙烯酸树脂材料包衣制备成pH敏感性骨架释药系统。
方法:采用单因素分析和正交实验设计进行处方工艺优化,确定最优处方和制备工艺,并在实验室条件下放大制备一批样品。采用体外药物释放实验、电子扫描显微镜、X-射线衍射、红外光谱等方法进行了体外质量表征,并采用大鼠口服灌胃给药方式开展体内药物动力学研究。
结果:研究结果表明,纳米骨架载药系统具有较好的pH敏感性,在模拟人工胃酸环境中,几乎不释放药物,而在模拟人工肠液中迅速释放药物;体外质量表征结果表明,药物与纳米骨架材料之间未发生明显的化学反应,且药物能被纳米骨架材料高度分散并包裹在空隙内部。药物动力学实验结果表明,与上市自微乳制剂Rapamune相比,pH敏感性纳米骨架载药系统可明显增加药物口服吸收生物利用度,相对生物利用度为:266.05%。
结论:上述研究结果显示,pH敏感性纳米骨架载药系统具有良好的pH敏感性,且对增加难溶性药物体内口服吸收具有较好的应用价值,制备工艺较简单,易于工业化生产。
Objective: Rapamycin, also know as Sirolimus, is belong to macrolides antibiotics. Rapamycin as an immunosuppressant drug and anti-cancer agent has good therapeutic effect and low renal toxicity. According to literatures, RAPA, well soluble in various organic solvents such as methanol and ethanol but poorly soluble in water, has poor oral absorption, and incomplete bioavailability. At present, the marketed formulation of RAPA is emulsion, which contains considerable quantities of surfactants and co-surfactants, which may cause mucosa damage of the gastrointestinal tract for frequent long-term use. This study was to prepare pH sensitive nanoparticles drug delivery system which consisting of the nanosized and micronsized silicon dioxides as carrier materials with coated by the Eudragit? polymer.
Methods: Mono-factor analysis and Orthogonal experimental design were used to screen the optimum formulation and technology. In the condition of laboratory, the final optimum solid preparation was prepared and investigated, including in vitro release, scanning electron microscope(SEM), X-ray diffraction and FT-IR spectrum. The pharmacokinetics study of the final solid preparation of RAPA was performed after administered orally in normal SD rats.
Result: The results of in vitro release experiments showed that the nanoparticulate drug delivery system has perfect pH dependant sensitivity, a little drug was released in mimic gastric fluid, but a large drug was released quickly in mimic intestinal fluid. It was shown from X-ray diffraction and FT-IR spectrum that there is no chemical reaction between drug and carriers. It suggested that drug molecule was evenly dispersed in the polymeric matrix of the solid preparation. The pharmacokinetics study reveals that the relative bioavailability and the oral absorption ability markedly increased to 266.05 %, respectively when compared with the RAPA microemulsion.
Conclusion: In conclusions, the nanoparticulate solid preparation might be a potential carrier for improving the oral bioavailability of water insoluble drugs, with simple preparation technology and easy industrial production.
方法:采用单因素分析和正交实验设计进行处方工艺优化,确定最优处方和制备工艺,并在实验室条件下放大制备一批样品。采用体外药物释放实验、电子扫描显微镜、X-射线衍射、红外光谱等方法进行了体外质量表征,并采用大鼠口服灌胃给药方式开展体内药物动力学研究。
结果:研究结果表明,纳米骨架载药系统具有较好的pH敏感性,在模拟人工胃酸环境中,几乎不释放药物,而在模拟人工肠液中迅速释放药物;体外质量表征结果表明,药物与纳米骨架材料之间未发生明显的化学反应,且药物能被纳米骨架材料高度分散并包裹在空隙内部。药物动力学实验结果表明,与上市自微乳制剂Rapamune相比,pH敏感性纳米骨架载药系统可明显增加药物口服吸收生物利用度,相对生物利用度为:266.05%。
结论:上述研究结果显示,pH敏感性纳米骨架载药系统具有良好的pH敏感性,且对增加难溶性药物体内口服吸收具有较好的应用价值,制备工艺较简单,易于工业化生产。
Objective: Rapamycin, also know as Sirolimus, is belong to macrolides antibiotics. Rapamycin as an immunosuppressant drug and anti-cancer agent has good therapeutic effect and low renal toxicity. According to literatures, RAPA, well soluble in various organic solvents such as methanol and ethanol but poorly soluble in water, has poor oral absorption, and incomplete bioavailability. At present, the marketed formulation of RAPA is emulsion, which contains considerable quantities of surfactants and co-surfactants, which may cause mucosa damage of the gastrointestinal tract for frequent long-term use. This study was to prepare pH sensitive nanoparticles drug delivery system which consisting of the nanosized and micronsized silicon dioxides as carrier materials with coated by the Eudragit? polymer.
Methods: Mono-factor analysis and Orthogonal experimental design were used to screen the optimum formulation and technology. In the condition of laboratory, the final optimum solid preparation was prepared and investigated, including in vitro release, scanning electron microscope(SEM), X-ray diffraction and FT-IR spectrum. The pharmacokinetics study of the final solid preparation of RAPA was performed after administered orally in normal SD rats.
Result: The results of in vitro release experiments showed that the nanoparticulate drug delivery system has perfect pH dependant sensitivity, a little drug was released in mimic gastric fluid, but a large drug was released quickly in mimic intestinal fluid. It was shown from X-ray diffraction and FT-IR spectrum that there is no chemical reaction between drug and carriers. It suggested that drug molecule was evenly dispersed in the polymeric matrix of the solid preparation. The pharmacokinetics study reveals that the relative bioavailability and the oral absorption ability markedly increased to 266.05 %, respectively when compared with the RAPA microemulsion.
Conclusion: In conclusions, the nanoparticulate solid preparation might be a potential carrier for improving the oral bioavailability of water insoluble drugs, with simple preparation technology and easy industrial production.
引文
1 Rapamune说明书,惠氏
2 Heike Friedrich, Bernd Fussnegger, Karl Kolter, et al. Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 62: 171– 177
3 Bhaskar Chauhan, Shyam Shimpi, Anant Paradkar. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. European Journal of Pharmaceutical Sciences, 2005, 26 : 219–230
4 Hirofumi Takeuchi, Shinsuke Nagira, Hiromitsu Yamamoto, et al. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. International Journal of Pharmaceutics, 2005, 293: 155–164
5 Yano K, Takamatsu N , Yamazaki S, et al. Crystal forms, improvement of dissolution and absorption of poorly water-soluble (R)-1-[ 2, 3-dihydro-1-( 2′-methylphenacyl ) -2-oxo-5-phenyl-1H-1, 4-benzodiazep in-3-yl ] -3- (3-methylphenyl) urea (YM 022). Yakugaku Zasshi, 1996, 116 (8) : 639-646
6黎曙霞,任斌,王长希等.固相萃取- HPL C法测定西罗莫司的血药浓度及其临床应用研究.中国药房,2008 ,19(20): 1540-1542
7 Christian Vidal, Gabriele I. Kirchner, and Karl-Friedrich Sewing. Structural Elucidation by Electrospray Mass Spectrometry: An Approach to the In Vitro Metabolism of the Macrolide Immunosuppressant SDZ RAD. J Am Soc Mass Spectrom, 1998, 9: 1267–1274
8 Paul J. Taylor, Anthony G. Johnson. Quantitative analysis of sirolimus (Rapamycin) in blood by highperformance liquid chromatography - electrospray tandem mass spectrometry. Journal of Chromatography B, 1998,718: 251–257
9 Wolfgang Buchberger, Matthias Ferdig, Rudolf Sommer, et al. Trace analysis of rapamycin in human blood by micellar electrokinetic chromatography. Anal Bioanal Chem, 2004, 380: 68–71
10 C. Paul Wang, Joann Scatina, Samuel F. Sisenwine. A High Performance Liquid Chromatographic Method for the Determination of Rapamycin (Sirolimus) in Rat Serum, Plasma, and Blood and in Monkey Serum. Journal of Liquid Chromatography and Related Technologies, 1995, 18(9): 1801 -1808
11陈宏林、尤庆生、孟小勇.HPLC法测定组织中雷帕霉素的含量.实用医药杂志,2008 ,25 (7) :813-814
12任斌、黎曙霞、邓斌等.高效液相色谱法测定西罗莫司血药浓度.中国药学杂志,2004,39(1):52-53
13沈佳楠.抗肿瘤药物TM208制剂的体内外研究.北京大学医学部.2008年本科毕业论文
1程元荣、林文良、黄捷等.新型强效免疫抑制剂西罗莫司F904的研究.中国抗生素杂志,2002,27(12):709-712
2 MeMallon L , P.Choi KM , Lin TA , et al. The rpamayein-binding domain governs substate selectivity by mammalian targer of rapamycin. Mol Cell Biol, 2002,22(21):7428-7438
3 Fingar DC,Salama S,Tsou C,et al. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP/eFI4E. Genes Dev, 2002,16(12):1472-1487
4 Abraham RT. Mammalian target of rapamycin: immunosuppressive druds uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol,1998,10(3):330-336
5 S.M. Stepkowski. Preclinical Results of Sirolimus Treatment in Transplant Models. Transplantation Proceedings, 2003,35: 219S–226S
6 Aagaard KM, Jelinek DF. Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin. Cell Immunol, 1994,156:493-507
7季曙明.雷帕霉素免疫抑制作用机制的研究进展.肾脏病与透析肾移植杂志,2001;10(5):483-486
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2 Heike Friedrich, Bernd Fussnegger, Karl Kolter, et al. Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 62: 171– 177
3 Bhaskar Chauhan, Shyam Shimpi, Anant Paradkar. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. European Journal of Pharmaceutical Sciences, 2005, 26 : 219–230
4 Hirofumi Takeuchi, Shinsuke Nagira, Hiromitsu Yamamoto, et al. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. International Journal of Pharmaceutics, 2005, 293: 155–164
5 Yano K, Takamatsu N , Yamazaki S, et al. Crystal forms, improvement of dissolution and absorption of poorly water-soluble (R)-1-[ 2, 3-dihydro-1-( 2′-methylphenacyl ) -2-oxo-5-phenyl-1H-1, 4-benzodiazep in-3-yl ] -3- (3-methylphenyl) urea (YM 022). Yakugaku Zasshi, 1996, 116 (8) : 639-646
6黎曙霞,任斌,王长希等.固相萃取- HPL C法测定西罗莫司的血药浓度及其临床应用研究.中国药房,2008 ,19(20): 1540-1542
7 Christian Vidal, Gabriele I. Kirchner, and Karl-Friedrich Sewing. Structural Elucidation by Electrospray Mass Spectrometry: An Approach to the In Vitro Metabolism of the Macrolide Immunosuppressant SDZ RAD. J Am Soc Mass Spectrom, 1998, 9: 1267–1274
8 Paul J. Taylor, Anthony G. Johnson. Quantitative analysis of sirolimus (Rapamycin) in blood by highperformance liquid chromatography - electrospray tandem mass spectrometry. Journal of Chromatography B, 1998,718: 251–257
9 Wolfgang Buchberger, Matthias Ferdig, Rudolf Sommer, et al. Trace analysis of rapamycin in human blood by micellar electrokinetic chromatography. Anal Bioanal Chem, 2004, 380: 68–71
10 C. Paul Wang, Joann Scatina, Samuel F. Sisenwine. A High Performance Liquid Chromatographic Method for the Determination of Rapamycin (Sirolimus) in Rat Serum, Plasma, and Blood and in Monkey Serum. Journal of Liquid Chromatography and Related Technologies, 1995, 18(9): 1801 -1808
11陈宏林、尤庆生、孟小勇.HPLC法测定组织中雷帕霉素的含量.实用医药杂志,2008 ,25 (7) :813-814
12任斌、黎曙霞、邓斌等.高效液相色谱法测定西罗莫司血药浓度.中国药学杂志,2004,39(1):52-53
13沈佳楠.抗肿瘤药物TM208制剂的体内外研究.北京大学医学部.2008年本科毕业论文
1程元荣、林文良、黄捷等.新型强效免疫抑制剂西罗莫司F904的研究.中国抗生素杂志,2002,27(12):709-712
2 MeMallon L , P.Choi KM , Lin TA , et al. The rpamayein-binding domain governs substate selectivity by mammalian targer of rapamycin. Mol Cell Biol, 2002,22(21):7428-7438
3 Fingar DC,Salama S,Tsou C,et al. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP/eFI4E. Genes Dev, 2002,16(12):1472-1487
4 Abraham RT. Mammalian target of rapamycin: immunosuppressive druds uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol,1998,10(3):330-336
5 S.M. Stepkowski. Preclinical Results of Sirolimus Treatment in Transplant Models. Transplantation Proceedings, 2003,35: 219S–226S
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