多孔淀粉负载青蒿素微球的溶出、生物利用度和组织分布研究
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摘要
探讨多孔淀粉负载青蒿素微球(ART-PS)在体外溶出实验中,相比于青蒿素原药的溶出效果以及在大鼠体内的生物利用度和组织分布规律。在体外溶出实验中,分别在水、人工胃液和人工肠液三种溶出介质中,与青蒿素原药的溶出效果进行比较分析。在体内生物利用度实验中,通过对18只大鼠分别灌胃青蒿素原药与多孔淀粉负载青蒿素微球后,检测不同时间点的血药浓度,考察药物在大鼠体内的吸收和代谢差异。在组织分布规律的研究中,对98只大鼠分别灌胃多孔淀粉负载青蒿素微球和青蒿素原药,在不同时间点检测大鼠心、肝、脾、肺、肾、脑,共6个组织器官中的药物浓度。多孔淀粉负载青蒿素微球的体外溶出率在水、人工胃液、人工肠液中分别是青蒿素原药的4. 04、3. 59和3. 82倍。多孔淀粉负载青蒿素微球在大鼠体内的血药浓度明显高于青蒿素原药,生物利用度提高为青蒿素原药的2. 90倍。在组织分布的结果中,多孔淀粉负载青蒿素微球和青蒿素原药都主要分布在心脏和肝脏中,其中多孔淀粉负载青蒿素微球在不同时间各个组织中的相应含量都比原药高。多孔淀粉负载青蒿素微球相比于青蒿素原药,在体外的溶出效果更好,在体内的吸收释放效果更佳,在各组织器官中的药物含量明显高于原药,为解决青蒿素因难溶于水而在实际应用中受限提供了重要的理论依据。
To investigate the dissolution effect of artemisinin microspheres( ART-PS) loaded with porous starch in vitro compared with artemisinin,bioavailability and tissue distribution in rats,in the in vitro dissolution experiment,the dissolution effect of artemisinin was compared with that of artemisinin in water,artificial gastric juice and artificial intestinal fluid. In the in vivo bioavailability experiment,18 rats were given artemisinin raw drug and porous starch loaded artemisinin microspheres respectively,and the blood drug concentrations at different time points were detected to investigate the differences in drug absorption and metabolism in rats. In the tissue distribution,the drug contents in heart,liver,spleen,lung,kidney and brain of 98 rats were detected at different points in time by gavage of porous starch loaded artemisinin microspheres and artemisinin active drugs. The dissolution rates of artemisinin microspheres loaded with porous starch in vitro were 4. 04,3. 59 and 3. 82 times higher than those of artemisinin in water,artificial gastric juice and artificial intestinal fluid,respectively. The blood content of artemisinin microspheres loaded with porous starch in rats was significantly higher than that of artemisinin,and the bioavailability was 2. 90 times higher than that of artemisinin. In the results of tissue distribution,artemisinin microspheres loaded with porous starch and artemisinin active drugs were mainly distributed in the heart and liver,and the corresponding content of artemisinin active starch active microspheres in different tissues at different times was higher than that of active drugs. Compared with artemisinin,artemisinin microspheres loaded with porous starch have better dissolution effect in vitro and better absorption and release effect in vivo. The drug content in various tissues and organs is significantly higher than that of the original drug,providing an important theoretical basis for solving the limitation of artemisinin in practical application due to its insoluble in water.
To investigate the dissolution effect of artemisinin microspheres( ART-PS) loaded with porous starch in vitro compared with artemisinin,bioavailability and tissue distribution in rats,in the in vitro dissolution experiment,the dissolution effect of artemisinin was compared with that of artemisinin in water,artificial gastric juice and artificial intestinal fluid. In the in vivo bioavailability experiment,18 rats were given artemisinin raw drug and porous starch loaded artemisinin microspheres respectively,and the blood drug concentrations at different time points were detected to investigate the differences in drug absorption and metabolism in rats. In the tissue distribution,the drug contents in heart,liver,spleen,lung,kidney and brain of 98 rats were detected at different points in time by gavage of porous starch loaded artemisinin microspheres and artemisinin active drugs. The dissolution rates of artemisinin microspheres loaded with porous starch in vitro were 4. 04,3. 59 and 3. 82 times higher than those of artemisinin in water,artificial gastric juice and artificial intestinal fluid,respectively. The blood content of artemisinin microspheres loaded with porous starch in rats was significantly higher than that of artemisinin,and the bioavailability was 2. 90 times higher than that of artemisinin. In the results of tissue distribution,artemisinin microspheres loaded with porous starch and artemisinin active drugs were mainly distributed in the heart and liver,and the corresponding content of artemisinin active starch active microspheres in different tissues at different times was higher than that of active drugs. Compared with artemisinin,artemisinin microspheres loaded with porous starch have better dissolution effect in vitro and better absorption and release effect in vivo. The drug content in various tissues and organs is significantly higher than that of the original drug,providing an important theoretical basis for solving the limitation of artemisinin in practical application due to its insoluble in water.
引文
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17 . Gao F,Li D,Bi C H,et al. The adsorption and release characteristics of CPFX in porous starch produced through different drying methods[J]. Drying Technology,2013,31(13-14):1592-1599.
18 .唐宜轩,韩丽,张定堃,等.多孔淀粉的制备及其在医药应用中的研究进展[J].中成药,2015,37(6):1321-1324.Tang Y X,Han L,Zhang D K,et al. Preparation of porous starch and its application in medicine[J]. Chinese Traditional Patent Medicine,2015,37(6):1321-1324.
19 . Wu C,Wang Z Y,Zhi Z Z,et al. Development of biodegradable porous starch foam for improving oral delivery of poorly water soluble drugs[J]. International Journal of Pharmaceutics,2011,403(1-2):162-169.
20 . Zhang Z W,Huang J,Jiang S J,et al. Porous starch based self-assembled nano-delivery system improves the oral absorption of lipophilic drug[J]. International Journal of Pharmaceutics,2013,444(1-2):162-168.
21 . Isacchi B,Bergonzi M C,Grazioso M,et al. Artemisinin and artemisinin plus curcumin liposomal formulations:Enhanced antimalarial efficacy against Plasmodium bergheiinfected mice[J]. European Journal of Pharmaceutics and Biopharmaceutics,2012,80(3):528-534.
2 . Tu Y Y. The discovery of artemisinin(Qinghaosu)and gifts from Chinese medicine[J]. Nature Medicine,2011,17(10):1217-1220.
3 . Klayman D L. Qinghaosu(artemisinin):an antimalarial drug from China[J]. Science,1985,228(4703):1049-1055.
4 . Rosenthal P J,Meshnick S R. Hemoglobin catabolism and iron utilization by malaria parasites[J]. Molecular and Biochemical Parasitology,1996,83(2):131-139.
5 . Li Y. Qinghaosu(artemisinin):chemistry and pharmacology[J]. Acta Pharmacologica Sinica,2012,33(9):1141-1146.
6 . Meshnick S R. Artemisinin antimalarials:mechanisms of action and resistance[J]. Medecine Tropicale,1997,58(S1):13-17.
7 . Morris C A,Duparc S,Borghini-Fuhrer I,et al. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous,intramuscular,oral or rectal administration[J]. Malaria Journal,2011,10:263.
8 . Lu J J,Meng L H,Shankavaram U T,et al. Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cells[J].Biochemical Pharmacology,2010,80(1):22-30.
9 . Wong J W,Yuen K H. Improved oral bioavailability of artemisinin through inclusion complexation withβandγ-cyclodextrins[J]. International Journal of Pharmaceutics,2001,227(1-2):177-185.
10 . Van Nijlen T,Brennan K,Van Den Mooter G,et al. Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions[J]. International journal of Pharmaceutics,2003,254(2):173-181.
11 . Shahzad Y,Sohail S,Arshad M S,et al. Development of solid dispersions of artemisinin for transdermal delivery[J]. International Journal of Pharmaceutics,2013,457(1):197-205.
12 . Isacchi B,Arrigucci S,La Marca G,et al. Conventional and long-circulating liposomes of artemisinin:preparation,characterization,and pharmacokinetic profile in mice[J]. Journal of Liposome Research,2011,21(3):237-244.
13 . Meer T A,Moravkar K,Pawar J,et al. Crosslinked porous starch particles-a promising Carrier[J]. Polimery Medycynie,2015,45(1):11-19.
14 . Glenn G M,Klamczynski A P,Woods D F,et al. Encapsulation of plant oils in porous starch microspheres[J]. Journal of Agricultural and Food Chemistry,2010,58(7):4180-4184.
15 . Jiang T Y,Wu C,Gao Y K,et al. Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug[J]. Drug development and Industrial Pharmacy,2014,40(2):252-259.
16 . Ali M T,Fule R,Sav A,et al. Porous starch:a novel carrier for solubility enhancement of carbamazepine[J]. AAPS Pharm Sci Tech,2013,14(3):919-926.
17 . Gao F,Li D,Bi C H,et al. The adsorption and release characteristics of CPFX in porous starch produced through different drying methods[J]. Drying Technology,2013,31(13-14):1592-1599.
18 .唐宜轩,韩丽,张定堃,等.多孔淀粉的制备及其在医药应用中的研究进展[J].中成药,2015,37(6):1321-1324.Tang Y X,Han L,Zhang D K,et al. Preparation of porous starch and its application in medicine[J]. Chinese Traditional Patent Medicine,2015,37(6):1321-1324.
19 . Wu C,Wang Z Y,Zhi Z Z,et al. Development of biodegradable porous starch foam for improving oral delivery of poorly water soluble drugs[J]. International Journal of Pharmaceutics,2011,403(1-2):162-169.
20 . Zhang Z W,Huang J,Jiang S J,et al. Porous starch based self-assembled nano-delivery system improves the oral absorption of lipophilic drug[J]. International Journal of Pharmaceutics,2013,444(1-2):162-168.
21 . Isacchi B,Bergonzi M C,Grazioso M,et al. Artemisinin and artemisinin plus curcumin liposomal formulations:Enhanced antimalarial efficacy against Plasmodium bergheiinfected mice[J]. European Journal of Pharmaceutics and Biopharmaceutics,2012,80(3):528-534.