介孔二氧化硅吲哚美辛固体分散体复合物的制备及质量评价
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摘要
以吲哚美辛(IMC)为模型药物,选用聚乙烯吡咯烷酮k30(PVPk30)与介孔二氧化硅(SiO_2)Syloid SP53D作为共同载体材料,制备介孔二氧化硅固体分散体复合物,以提高固体分散体中主药的载药量和溶出度.采用溶剂蒸发法制备IMC-PVPk30固体分散体(简称IMC-PVPk30),浸没-溶剂蒸发法制备IMC-SiO_2固体分散体(简称IMC-SiO_2)和IMC-PVPk30-SiO_2固体分散体复合物(简称IMC-PVPk30-SiO_2);利用差示扫描量热法(DSC)、扫描电镜(SEM)等方法对其表征;采用紫外-可见分光光度法测定固体分散体及其复合物的载药量与溶出度. DSC显示,制备的两种固体分散体及其复合物中, IMC的熔点峰均消失,表明固体分散体制备成功; SEM显示, IMC-PVPk30结构呈不规则的块状,而IMC-SiO_2和IMC-PVPk30-SiO_2的粒径大小均匀,且IMC,PVPk30与介孔二氧化硅复合在一起;在不同pH的溶出介质中, IMC-SiO_2和IMC-PVPk30-SiO_2的溶出率均高于IMC-PVPk30,且IMC-PVPk30-SiO_2的溶出率最高.得出介孔二氧化硅吲哚美辛固体分散体复合物(IMC-PVPk30-SiO_2)具有较高的载药率和溶出率,为改善固体分散体的稳定性和进一步提高难溶性药物溶出度提出了新的思路和方法.
Objective: To improve the drug loading efficiency, dissolution rate and stability of the main drug in the solid dispersion of mesoporous silica, polyvinylpyrrolidone k30(PVPk30) and mesoporous SiO_2 Syloid SP53 D were applied as solid dispersion carriers for indomethacin(IMC) to prepare the drug-loaded mesoporous SiO_2 solid dispersions(IMC-PVPk30-SiO_2). Methods: IMC-PVPk30 solid dispersion was prepared with the solvent evaporation method; IMC-SiO_2 solid dispersion and IMC-PVPk30-SiO_2 solid dispersion composite were prepared with the immersion-solvent evaporation method. Then samples were characterized by differential scanning calorimetry(DSC) and scanning electron microscopy(SEM). The drug loading efficiency and dissolution rate of the solid dispersion and its complex were determined by ultraviolet-visible spectrophotometry. Results: The results of DSC showed that the melting peak of IMC disappeared practically between IMC-PVPk30, IMC-SiO_2 and IMC-PVPk30-SiO_2, suggesting that IMC existed in the amorphous state in these samples and the solid dispersions were prepared successfully. SEM showed that the IMC-PVPk30 structure was irregularly blocked, and the IMC-SiO_2 and IMC-PVPk30-SiO_2 had a nearly identical particle size. Compared with the mesoporous SiO_2 materials, the particle size increased slightly, which indicated that IMC may be distributed on both the outer surface and the inner channel of SiO_2. The dissolution determination experiment showed that the dissolution rates of IMC-SiO_2 and IMC-PVPk30-SiO_2 were higher than those of IMC-PVPk30 within 2 hours. Conclusion: The IMC silica solid dispersion composite(IMC-PVPk30-SiO_2) has a high drug loading efficiency and dissolution rate, and it is expected to be a novel drug delivery system for poorly soluble drugs with better bioavailability.
Objective: To improve the drug loading efficiency, dissolution rate and stability of the main drug in the solid dispersion of mesoporous silica, polyvinylpyrrolidone k30(PVPk30) and mesoporous SiO_2 Syloid SP53 D were applied as solid dispersion carriers for indomethacin(IMC) to prepare the drug-loaded mesoporous SiO_2 solid dispersions(IMC-PVPk30-SiO_2). Methods: IMC-PVPk30 solid dispersion was prepared with the solvent evaporation method; IMC-SiO_2 solid dispersion and IMC-PVPk30-SiO_2 solid dispersion composite were prepared with the immersion-solvent evaporation method. Then samples were characterized by differential scanning calorimetry(DSC) and scanning electron microscopy(SEM). The drug loading efficiency and dissolution rate of the solid dispersion and its complex were determined by ultraviolet-visible spectrophotometry. Results: The results of DSC showed that the melting peak of IMC disappeared practically between IMC-PVPk30, IMC-SiO_2 and IMC-PVPk30-SiO_2, suggesting that IMC existed in the amorphous state in these samples and the solid dispersions were prepared successfully. SEM showed that the IMC-PVPk30 structure was irregularly blocked, and the IMC-SiO_2 and IMC-PVPk30-SiO_2 had a nearly identical particle size. Compared with the mesoporous SiO_2 materials, the particle size increased slightly, which indicated that IMC may be distributed on both the outer surface and the inner channel of SiO_2. The dissolution determination experiment showed that the dissolution rates of IMC-SiO_2 and IMC-PVPk30-SiO_2 were higher than those of IMC-PVPk30 within 2 hours. Conclusion: The IMC silica solid dispersion composite(IMC-PVPk30-SiO_2) has a high drug loading efficiency and dissolution rate, and it is expected to be a novel drug delivery system for poorly soluble drugs with better bioavailability.
引文
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[3] 雷曙光,罗永煌,陈君.吲哚美辛研究概况及其在动物上的应用 [J].中国动物保健,2011,13(1):14-17.
[4] 刘红,李国珍,葛泉丽.非甾体抗炎药的作用机制及进展 [J].实用医技杂志,2003,10(4):401-402.
[5] DIMIZA F,PAPADOPOULOS A N,TANGOULIS V,et al.Biological Evaluation of Non-Steroidal Anti-Inflammatory Drugs-Cobalt(Ii) Complexes [J].Dalton Transactions,2010,39(19):4517.
[6] YALKOWSKY S H,DANNENFELSER R M.Database of Aqueous Solubility [M].Version 5 ed.Tucson:University of Arizona Tucson,1992.
[7] BERGE S M,BIGHLEY L D,MONKHOUSE D C.Pharmaceutical Salts [J].Journal of Pharmaceutical Sciences,1977,66(1):1-19.
[8] RAUTIO J,KUMPULAINEN H,HEIMBACH T,et al.Prodrugs:Design and Clinical Applications [J].Nature Reviews Drug Discovery,2008,7(3):255-270.
[9] LOFTSSON T,DUCHENE D.Cyclodextrins and Their Pharmaceutical Applications [J].International Journal of Pharmaceutics,2007,329(1-2):1-11.
[10] LAVASANIFAR A,SAMUEL J,KWON G S.Poly(Ethylene Oxide)-Block-Poly(L-Amino Acid) Micelles for Drug Delivery [J].Advanced Drug Delivery Reviews,2002,54(2):169-190.
[11] LI G L,LIU J Y,PANG Y,et al.Polymeric Micelles with Water-Insoluble Drug as Hydrophobic Moiety for Drug Delivery [J].Biomacromolecules,2011,12(6):2016-2026.
[12] MUELLER E A,KOVARIK J M,VAN BREE J B,et al.Improved Dose Linearity of Cyclosporine Pharmacokinetics from a Microemulsion Formulation [J].Pharmaceutical Research,1994,11(2):301-304.
[13] CANNON J,SHI Y,GUPTA P.Emulsions,Microemulsions,and Lipid-Based Drug Delivery Systems for Drug Solubilization and Delivery-Part I [M] //Water-Insoluble Drug Formulation.Second Edition.London:CRC Press,2008:195-226.
[14] QIN L H,NIU Y W,WANG Y M,et al.Combination of Phospholipid Complex and Submicron Emulsion Techniques for Improving Oral Bioavailability and Therapeutic Efficacy of Water-Insoluble Drug [J].Molecular Pharmaceutics,2018,15(3):1238-1247.
[15] FATOUROS D G,DEEN G R,ARLETH L,et al.Structural Development of Self Nano Emulsifying Drug Delivery Systems (SNEDDS) during in Vitro Lipid Digestion Monitored by Small-Angle X-Ray Scattering [J].Pharmaceutical Research,2007,24(10):1844-1853.
[16] RABINOW B E.Nanosuspensions in Drug Delivery [J].Nature Reviews Drug Discovery,2004,3(9):785-796.
[17] POTTA S G,MINEMI S,NUKALA R K,et al.Development of Solid Lipid Nanoparticles for Enhanced Solubility of Poorly Soluble Drugs [J].Journal of Biomedical Nanotechnology,2010,6(6):634-640.
[18] CHIOU W L,RIEGELMAN S.Pharmaceutical Applications of Solid Dispersion Systems [J].Journal of Pharmaceutical Sciences,1971,60(9):1281-1302.
[19] BROUGH C,WILLIAMS R O III.Amorphous Solid Dispersions and Nano-Crystal Technologies for Poorly Water-Soluble Drug Delivery [J].International Journal of Pharmaceutics,2013,453(1):157-166.
[20] KHODER M,ABDELKADER H,ELSHAER A,et al.The Use of Albumin Solid Dispersion to Enhance the Solubility of Unionizable Drugs [J].Pharmaceutical Development and Technology,2018,23(7):732-738.
[21] WANG Y Z,SUN L Z,JIANG T Y,et al.The Investigation of MCM-48-Type and MCM-41-Type Mesoporous Silica as Oral Solid Dispersion Carriers for Water Insoluble Cilostazol [J].Drug Development and Industrial Pharmacy,2014,40(6):819-828.
[22] 李永亮,杨世颖,胡堃,等.吲哚美辛溶剂合物多晶型现象与表征方法 [J].医药导报,2015,34(6):785-790.