TM-4000磺丁基醚-β-环糊精包合物的制备及增溶效果研究
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摘要
目的制备TM-4000磺丁基醚-β-环糊精包合物并考察其增溶效果。方法初步考察磺丁基醚-β-环糊精对TM-4000的增溶效果,并测定不同温度下包合反应的表观稳定常数。通过工艺筛选,确定合理的制备方法和最佳的工艺参数,制备TM-4000的磺丁基醚-β-环糊精包合物,并对其进行表征和溶出度测定。结果在pH为2.0的盐酸溶液中,磺丁基醚-β-环糊精对TM-4000的增溶效果较好,采用饱和溶液法,水浴温度为50℃,转速为60 r·min~(-1),反应时间为6 h,TM-4000和磺丁基醚-β-环糊精的重量比为1∶5时,能够制备出稳定性较好的包合物。TM-4000的磺丁基醚-β-环糊精包合物在pH2.0介质中1h内的累积溶出量可以达到80%。结论以简便可行的方法制备的TM-4000磺丁基醚-β-环糊精包合物能够显著提高TM-4000的溶出水平。
OBJECTIVE To prepare TM-4000 sulfobutyl ether-β-cyclodextrin inclusion complex and investigate the solubilization effect. METHODS The solubilization effect of sulfobutyl ether-β-cyclodextrin on TM-4000 was preliminary investigated, and the apparent stability constant of the inclusion reaction at different temperatures was determined. The sulfobutyl ether-β-cyclodextrin inclusion complex of TM-4000 was prepared through process screening. A reasonable preparation method and optimal reaction parameters were determined. The sulfobutyl ether-β-cyclodextrin inclusion complex of TM-4000 was prepared, characterized and tested for dissolution. RESULTS In pH 2.0 hydrochloric acid solution, sulfobutyl ether-β-cyclodextrin solubilization effect of TM-4000 was the best. Inclusion compound with a better stability could be prepared through saturated solution method at 50 ℃ with 60 r·min~(-1) stirring in 6 h. The weight ratio of TM-4000 to sulfobutyl ether-β-cyclodextrin was 1∶5. The accumulative dissolution of TM-4000-sulfobutyl ether-β-cyclodextrin inclusion complex within 1 h in pH 2.0 medium could reach 80%. CONCLUSION The TM-4000 sulfobutyl ether-β-cyclodextrin inclusion complex prepared in a simple and feasible way can significantly increase the dissolution level of TM-4000.
OBJECTIVE To prepare TM-4000 sulfobutyl ether-β-cyclodextrin inclusion complex and investigate the solubilization effect. METHODS The solubilization effect of sulfobutyl ether-β-cyclodextrin on TM-4000 was preliminary investigated, and the apparent stability constant of the inclusion reaction at different temperatures was determined. The sulfobutyl ether-β-cyclodextrin inclusion complex of TM-4000 was prepared through process screening. A reasonable preparation method and optimal reaction parameters were determined. The sulfobutyl ether-β-cyclodextrin inclusion complex of TM-4000 was prepared, characterized and tested for dissolution. RESULTS In pH 2.0 hydrochloric acid solution, sulfobutyl ether-β-cyclodextrin solubilization effect of TM-4000 was the best. Inclusion compound with a better stability could be prepared through saturated solution method at 50 ℃ with 60 r·min~(-1) stirring in 6 h. The weight ratio of TM-4000 to sulfobutyl ether-β-cyclodextrin was 1∶5. The accumulative dissolution of TM-4000-sulfobutyl ether-β-cyclodextrin inclusion complex within 1 h in pH 2.0 medium could reach 80%. CONCLUSION The TM-4000 sulfobutyl ether-β-cyclodextrin inclusion complex prepared in a simple and feasible way can significantly increase the dissolution level of TM-4000.
引文
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[2]DEL VALLE E M.Cyclodextrins and their uses:a review[J].Proc Biochem,2004,39(9):1033-1046.
[3]XU W l,ZHAN Y f,YANG L.Study on the preparation of NL-101-hydroxypropylbetadex Inclusion Complex and its characteristic[J].Chin J Mod Appl Pharm(中国现代应用药学),2017,34(11):1568-1571.
[4]王彦竹,宋丽明,张赫然等.β-环糊精及其衍生物在药学中的应用进展[J].中国药房,2014,25(33):3149-3152.
[5]MOHTAR N,TAYLOR K M,SHEIKH K,et al.Design and development of dry powder sulfobutylether-β-cyclodextrin complex for pulmonary delivery of fisetin[J].Eur J Pharm Biopharm,2017(113):1-10.
[6]SEMCHEDDINE F,GUISSI N,LIU X Y,et al.Effects of the preparation method on the formation of true nimodipine SBE-β-CD/HP-β-CD inclusion complexes and their dissolution rates enhancement[J].AAPS Pharm Sci Tech,2015,16(3):704-715.
[7]LOCKWOOD S F,O'MALLEY S,MOSHER G L.Improved aqueous solubility of crystalline astaxanthin(3,3′-dihydroxy-β,β-carotene-4,4′-dione)by Captisol?(sulfobutyl etherβ-cyclodextrin)[J].J Pharm Sci,2003,92(4):922-926.
[8]HIGUCHI T K,CONNORS A.Phase-solubility techniques[J].Adv Anal Chem Instr,1965(4):117-212.
[9]MARQUES H M C,HADGRAFT J,KELLAWAY I W.Studies of cyclodextrin inclusion complexes.I.The salbutamol-cyclodextrin complex as studied by phase solubility and DSC[J].Int J Pharm,1990,63(3):259-266.
[10]JAIN A C,ADEYEYE M C.Hygroscopicity,phase solubility and dissolution of various substituted sulfobutyletherβ-cyclodextrins(SBE)and danazol-SBE inclusion complexes[J].Int J Pharm,2001,212(2):177-186.