黄豆苷元纳米混悬剂胶囊的制备、表征及其体内外吸收特性考察
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摘要
目的:制备黄豆苷元纳米混悬剂胶囊,以市售黄豆苷元胶囊为参考,考察两者对小肠吸收与口服生物利用度的影响。方法:采用沉淀法联用高压均质技术制备黄豆苷元纳米混悬剂,通过正交试验优化其处方,利用X射线粉末衍射分析(XRPD),傅里叶红外光谱(FT-IR),透射电子显微镜(TEM)以及粒径,多分散指数和Zeta电位等指标对黄豆苷元纳米混悬剂进行表征。采用外翻肠囊法研究自制制剂与市售黄豆苷元胶囊的体外肠吸收情况,考察了黄豆苷元纳米混悬剂在体内胃肠道的分布,并通过HPLC测定大鼠体内黄豆苷元的血药浓度,以考察口服给药后的生物利用度。结果:以市售黄豆苷元胶囊内容物为参比制剂,自制黄豆苷元纳米混悬剂胶囊的小肠吸收促进率2. 49(P <0. 01),胃肠道生物分布评价证实了纳米混悬液的生物黏附性,相对生物利用度294%。结论:沉淀法联用高压均质技术制备的黄豆苷元纳米混悬剂冻干后可用于胶囊剂等剂型的生产,有益于增加药物的小肠吸收并改善口服以后的体内生物利用度。
Objective: To prepare daidzein nanosuspension capsules, and to investigate intestinal absorption and oral bioavailability by comparing with commercial daidzein capsules. Method: Daidzein nanosuspensions were prepared by precipitation method combined with high pressure homogenization,orthogonal design method was utilized to optimize its formulation. Daidzein nanosuspensions was characterized by X-ray powder diffraction( XRPD),Fourier transform infrared spectroscopy( FT-IR),transmission electron microscope( TEM),and indexes including mean particle size,polydispersity index( PDI),and Zeta potential. Intestinal absorption study was carried out to compare the accumulative permeated amount of daidzein from daidzein nanosuspensions and commercial daidzein capsules. Biodistribution of daidzein in gastrointestinal tract was investigated,and oral bioavailability was examined through pharmacokinetic study by HPLC. Result: The in vitro small intestinal absorption enhancement ratio of daidzein nanosuspension capsules was approximately 2. 49-fold higher than that of commercial capsules( P < 0. 01). Biodistribution evaluation in gastrointestinal tract verified the bioadhesion of the nanosuspensions. Pharmacokinetic study calculated by DAS 2. 0 revealed that the relative bioavailability of daidzein nanosuspension capsules was 294%. Conclusion: Daidzein nanosuspensions prepared by combined method can be applied to the production of capsules,which is beneficial to increase the absorption of drug in small intestine and improve its bioavailability after oral administration.
Objective: To prepare daidzein nanosuspension capsules, and to investigate intestinal absorption and oral bioavailability by comparing with commercial daidzein capsules. Method: Daidzein nanosuspensions were prepared by precipitation method combined with high pressure homogenization,orthogonal design method was utilized to optimize its formulation. Daidzein nanosuspensions was characterized by X-ray powder diffraction( XRPD),Fourier transform infrared spectroscopy( FT-IR),transmission electron microscope( TEM),and indexes including mean particle size,polydispersity index( PDI),and Zeta potential. Intestinal absorption study was carried out to compare the accumulative permeated amount of daidzein from daidzein nanosuspensions and commercial daidzein capsules. Biodistribution of daidzein in gastrointestinal tract was investigated,and oral bioavailability was examined through pharmacokinetic study by HPLC. Result: The in vitro small intestinal absorption enhancement ratio of daidzein nanosuspension capsules was approximately 2. 49-fold higher than that of commercial capsules( P < 0. 01). Biodistribution evaluation in gastrointestinal tract verified the bioadhesion of the nanosuspensions. Pharmacokinetic study calculated by DAS 2. 0 revealed that the relative bioavailability of daidzein nanosuspension capsules was 294%. Conclusion: Daidzein nanosuspensions prepared by combined method can be applied to the production of capsules,which is beneficial to increase the absorption of drug in small intestine and improve its bioavailability after oral administration.
引文
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[23] ZHANG J Y,SHEN Z G,ZHONG J,et al. Preparation of amorphous cefuroxime axetil nanoparticles by controlled nanoprecipitation method without surfactants[J]. Int J Pharm,2006,323(1/2):153-160.
[2]姜铁夫,康万军,杜妙,等.葛根黄豆苷元衍生物的合成及理化性质研究[J].解放军药学学报,2006,22(3):228-230.
[3]王廉卿,戎欣玉,刘魁,等.纳米药物晶体的制备技术及其应用[J].河北科技大学学报,2014,35(4):339-348.
[4] M9schwitzer J P. Drug nanocrystals in the commercial pharmaceutical development process[J]. Int J Pharm,2013,453(1):142-156.
[5]国家药典委员会.中华人民共和国药典.四部[M].北京:中国医药科技出版社,2015:59-61.
[6] Kayser O,Olbrich C,Yardley V,et al. Formulation of amphotericin B as nanosuspension for oral administration[J]. Int J Pharm,2003,254(1):73-75.
[7] Jacobs C,Müller R H. Production and characterization of a budesonide nanosuspension for pulmonary administration[J]. Pharm Res,2002,19(2):189-194.
[8] GAO Y, LI Z, SUN M, et al. Preparation,characterization, pharmacokinetics, and tissue distribution of curcumin nanosuspension with TPGS as stabilizer[J]. Drug Dev Ind Pharm,2010,36(10):1225-1234.
[9] Verma S,Huey B D,Burgess D J. Scanning probe microscopy method for nanosuspension stabilizer selection[J]. Langmuir,2009,25(21):12481-12487.
[10]吴超群,李小芳,牟倩倩,等.甘草总黄酮纳米混悬剂冻干粉的表征及稳定性考察[J].中国实验方剂学杂志,2018,24(2):29-33.
[11]许海舰,刘一鑫,刘喜纲,等.黄芩苷镁盐和黄芩苷的肠吸收动力学和药代动力学比较[J].中国实验方剂学杂志,2018,24(4):78-83.
[12] Hecq J,Deleers M,Fanara D,et al. Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3,a highly dosed poorly water-soluble weak base[J]. Eur J Pharm Biopharm,2006,64(3):360-368.
[13] MOU D,CHEN H,WAN J,et al. Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with p H-dependent solubility[J].Int J Pharm,2011,413(1/2):237-244.
[14] Lenhardt T,Vergnault G,Grenier P,et al. Evaluation of nanosuspensions for absorption enhancement of poorly soluble drugs:in vitro transport studies across intestinal epithelial monolayers[J]. AAPS J,2008,10(3):435-438.
[15] GAO Y,WANG C,SUN M,et al. In vivo evaluation of curcumin loaded nanosuspensions by oral administration[J]. J Biomed Nanotechnol,2012,8(4):659-668.
[16] Kawabata Y,Wada K,Nakatani M,et al. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system:basic approaches and practical applications[J]. Int J Pharm,2011,420(1):1-10.
[17] Mane V,Muro S. Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice[J]. Int J Nanomed,2012,7:4223-4237.
[18] Blanchfield J T,Gallagher O P,Cros C,et al. Oral absorption and in vivo biodistribution of alpha-conotoxin MII and a lipidic analogue[J]. Biochem Biophys Res Commun,2007,361(1):97-102.
[19] Bhavsar M D,Amiji M M. Gastrointestinal distribution and in vivo gene transfection studies with nanoparticlesin-microsphere oral system(Ni MOS)[J]. J Control Release,2007,119(3):339-348.
[20] Kimura T,Higaki K. Gastrointestinal transit and drug absorption[J]. Biol Pharm Bull,2002,25(2):149-164.
[21] Shingaki T,Takashima T,Wada Y,et al. Imaging of gastrointestinal absorption and biodistribution of an orally administered probe using positron emission tomography in humans[J]. Clin Pharmacol Ther,2012,91(4):653-659.
[22] Ponchel G,Montisci M J,Dembri A,et al. Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract[J]. Eur J Pharm Biopharm,1997,44(1):25-31.
[23] ZHANG J Y,SHEN Z G,ZHONG J,et al. Preparation of amorphous cefuroxime axetil nanoparticles by controlled nanoprecipitation method without surfactants[J]. Int J Pharm,2006,323(1/2):153-160.
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