载甲氨蝶呤-亚叶酸钙温敏水凝胶的制备及体外释药研究
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摘要
为了实现疏水性药物和亲水性药物共同包载,采用自由基聚合法和物理交联法制备了羟丙基甲基纤维素(HPMC)/聚异丙基丙烯酰胺(PNIPAm)水凝胶。甲氨蝶呤(MTX)和亚叶酸钙(CaF)被选为模型药物。用相转变分析、差示扫描量热法(DSC)、傅里叶红外光谱(FT-IR)、扫描电子显微镜(SEM)和紫外-可见分光光度计(UV)等考察了水凝胶的理化性能及其体外释药行为。结果表明,该水凝胶最低临界溶解温度(LCST)为32.6℃,呈相互连接3D多孔结构,孔径30～80μm。加入HPMC有利于包载以及药物的减缓释放;体外释放发现,CaF的释放速率略高于MTX,在MTX释放时,其周围环境中已存在部分CaF,预示该水凝胶可能有较好的预防MTX过量或大剂量应用后引起的严重不良反应的效果。
In order to achieve the entrapment of hydrophobic drugs and hydrophilic drugs,hydroxypropyl methylcellulose(HPMC)/polyisopropyl acrylamide(PNIPAm)hydrogels were prepared by free radical polymerization and physical cross-linking.Methotrexate(MTX)and calcium folinate(CaF)were selected as model drugs.The physicochemical properties of the hydrogels and their release behaviors in vitro were investigated by using phase transition analysis,differential scanning calorimetry(DSC),Fourier transform infrared spectroscopy(FT-IR),scanning electron microscopy(SEM)and UV-visible spectrophotometry(UV).The results showed that the lower critical solution temperature(LCST)of the hydrogel was 32.6℃.The hydrogel was connected to a 3 Dporous structure with a pore size of 30 to 80μm.The addition of HPMC helps to entrap the hydrophobic drug.The addition of HPMC facilitates the entrapment of hydrophobic drugs and the sustained release of the drug.In vitro release showed that the release rate of CaF was slightly higher than that of MTX.When MTX was released,part of CaF was already present in its surrounding environment,indicating that the hydrogel may have better effects of preventing serious adverse reactions caused by excessive MTX or high-dose application.
In order to achieve the entrapment of hydrophobic drugs and hydrophilic drugs,hydroxypropyl methylcellulose(HPMC)/polyisopropyl acrylamide(PNIPAm)hydrogels were prepared by free radical polymerization and physical cross-linking.Methotrexate(MTX)and calcium folinate(CaF)were selected as model drugs.The physicochemical properties of the hydrogels and their release behaviors in vitro were investigated by using phase transition analysis,differential scanning calorimetry(DSC),Fourier transform infrared spectroscopy(FT-IR),scanning electron microscopy(SEM)and UV-visible spectrophotometry(UV).The results showed that the lower critical solution temperature(LCST)of the hydrogel was 32.6℃.The hydrogel was connected to a 3 Dporous structure with a pore size of 30 to 80μm.The addition of HPMC helps to entrap the hydrophobic drug.The addition of HPMC facilitates the entrapment of hydrophobic drugs and the sustained release of the drug.In vitro release showed that the release rate of CaF was slightly higher than that of MTX.When MTX was released,part of CaF was already present in its surrounding environment,indicating that the hydrogel may have better effects of preventing serious adverse reactions caused by excessive MTX or high-dose application.
引文
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[3] Guevara-Pantoja F J,Gómez-Galván F,Cipriano I E,et al.Microrheology and electrical conductivity of a dilute PNIPAm suspension[J].Rheologica Acta,2014,53(2):159-164.
[4] Samah N H A,Heard C M.Enhanced in vitro transdermal delivery of caffeine using a temperature-and Ph-sensitive nanogel,poly(NIPAm-co-AAc)[J].International Journal of Pharmaceutics,2013,453(2):630-640.
[5] Gu Jingxia,Xia Fan,Wu Yan,et al.Programmable delivery of hydrophilic drug using dually responsive hydrogel cages[J].Journal of Controlled Release,2007,117(3):396-402.
[6] Guan Ying,Zhang Yongjun.PNIPAm microgels for biomedical applications:from dispersed particles to 3Dassemblies[J].Soft Matter,2011,7(14):6375-6384.
[7] Guo Qingli,Nie Lei,Li Lian,et al.Estimation of the critical quality attributes for hydroxypropyl methylcellulose with near-infrared spectroscopy and chemometrics[J].Spectrochimica Acta Part A:Molecular and Biomolecular Spectroscopy,2017,177:158-163.
[8] Guiastrennec B,S9derlind,Richardson S,et al.In vitro and in vivo modeling of hydroxypropyl methylcellulose(HPMC)matrix tablet erosion under fasting and postprandial status[J].Pharmaceutical Research,2017,34(4):847-859.
[9] Lai Enping,Wang Yuxia,Wei Yi,et al.Effects of crosslink density on structures and properties of dual-sensitive semi-interpenetrating polymer networks hydrogel microspheres[J].Macromolecular Chemistry and Physics,2017,218(9):1600596(1-10).
[10] Rwei S P,Tuan H N A,Chiang W Y,et al.Synthesis and characterization of Ph and thermo dual-responsive hydrogels with a semi-ipn structure based on N-isopropylacrylamide and itaconamic acid[J].Materials,2018,11(5):196(1-21).
[11] Luo Yanling,Zhang Xueyin,Fu Jingyu,et al.Novel temperature and pH dual-sensitive PNIPAm/CMCS/MWCNT semi-IPN nanohybrid hydrogels:synthesis,characterization,and dox drug release[J].International Journal of Polymeric Materials and Polymeric Biomaterials,2017,66(8):398-409.
[12] Qin Yingzhou,Chen Han,Zhang Yang,et al.Antitumor activity of methotrexate long-circulating liposome on human osteosarcoma cells in vitro[J].Journal of Clinical Rehabilitative Tissue Engineering Research,2016,20(30):4489-449(5(in Chinese).秦迎州,陈汉,张洋,等.甲氨喋呤长循环脂质体对人骨肉瘤细胞的体外抗瘤活性[J].中国组织工程研究,2016,20(30):4489-4495.
[13] Ray S,Saha S,Sa B,et al.In vivo pharmacological evaluation and efficacy study of methotrexate-encapsulated polymer-coated layered double hydroxide nanoparticles for possible application in the treatment of osteosarcoma[J].Drug Delivery and Translational Research,2017,7(2):259-275.
[14] Zhang Wei,ZhangQing,Zheng Tingting,et al.Delayed high-dose methotrexate excretion and influencing factors in osteosarcoma patients[J].Chinese Medical Journal,2016,129(21):2530-2534.
[15] Li Junjie,Guo Shuangzhuang,Wang Min,et al.Poly(lactic acid)/poly(ethylene glycol)block copolymer based shell or core cross-linked micelles for controlled release of hydrophobic drug[J].Rsc Advances,2015,5(25):19484-19492.