Synthesis and in vitro/in vivo assessment of sustained-release oral oseltamivir phosphate suspension  

口服磷酸奥司他韦缓释混悬液的制备及其体内外评价

作　　者：Yuanrong Xin Yutian Dou Xiaolin Chen Yingshu Feng Xuesheng Liu Caleb Kesse Firempong Dan Yang Hongfei Liu Haibing He 辛渊蓉;窦玉甜;陈晓琳;冯颖淑;刘学盛;Caleb Kesse Firempong;杨丹;刘宏飞;何海冰(江苏大学药学院,江苏镇江212013;江苏苏南药业工业有限公司,江苏镇江212400;镇江医学院医学化学研究所,镇江市功能化学重点实验室,江苏镇江212028;沈阳药科大学药学院,辽宁沈阳110016;江苏海之宏生物医药有限公司,江苏南通226001;扬子江药业集团南京海陵药业有限公司,江苏南京210046)

机构地区：[1]College of Pharmacy,Jiangsu University,Zhenjiang 212013,Jiangsu,China [2]Jiangsu Sunan Pharmaceutical Industrial Co.,LTD.,Zhenjiang 212400,Jiangsu,China [3]Zhenjiang Key Laboratory of Functional Chemistry,Institute of Medicine&Chemical Engineering,Zhenjiang College,Zhenjiang 212028,Jiangsu,China [4]Department of Pharmaceutics,Shen yang Pharmaceutical University,Shen yang 110016,Liaoning,China [5]Jiangsu Haizhihong Biomedical Co.,Ltd,Nantong 226001,Jiangsu,China [6]Yangtze River Pharmaceutical Group Nanjing Hailing Pharmaceutical Company,Nanjing 210046,Jiangsu,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2025年第3期269-283,共15页中国药学(英文版)

基　　金：2023 Nantong Jianghai Talents Project;2023 Nantong Social Livelihood Science and Technology Plan;2021 Jurong Social Development Science&Technology Program(Grant No.ZA42109);2022 New Drugs and Platform Enhancement Project of the Yangtze Delta Drug Advanced Research Institute;China Postdoctoral Science Foundation(Grant No.2020M681532);Jiangsu Planned Projects for Postdoctoral Research Funds(Grant No.2020Z209);Natural Science Research Projects of Universities in Jiangsu Province(Grant No.20KJD350001)。

摘　　要：Oseltamivir phosphate(OP),renowned as one of the most effective drugs for influenza treatment,encounters several challenges,including poor stability,difficulty in swallowing,and a bitter taste,thereby limiting its compliance,particularly among children.Consequently,this study aimed to devise a novel sustained-release suspension of OP employing an ion exchange resin as a carrier to address these challenges.The OP-drug resin complex(OP-DRC)was synthesized utilizing ion exchange technology,while OP-coated microcapsules(OP-CM)were fabricated via the emulsion-evaporation method.The optimization of the formulation process for the OP sustained-release suspension was achieved through a combination of single-factor experimentation and orthogonal experimental design.Furthermore,the drug release kinetics and pharmacokinetic properties of the sustained-release suspension were thoroughly evaluated both in vitro and in vivo.Scanning electron microscopy(SEM),X-ray diffraction(XRD),and attenuated total reflectance Fourier-transform infrared spectroscopy(ATR-FTIR)analyses confirmed the formation of drug-resin complexes via ionic bonding.The in vitro cumulative release rates were found to be 16%(1 h),53%(6 h),and 84%(24 h),respectively.Notably,the self-made sustained-release suspension exhibited an extended half-life(21.518 h),delayed time to peak concentration(T_(max))(6 h),and reduced maximum plasma concentration(C_(max))(0.397μg/mL)in comparison to commercial granules(half-life=8.466 h;T_(max)=2 h;C_(max)=0.631μg/mL).Additionally,the area under the curve(AUC)indicated that the bioavailability of the self-made OP suspension surpassed that of the commercial OP granules by 101%.These findings underscored the successful development of an oral OP sustained-release suspension characterized by stability,tastelessness,ease of swallowing,convenient administration,and sustained-release properties,thereby potentially enhancing drug compliance among children.磷酸奥司他韦(OP)是治疗流感最有效的药物之一,面临着稳定性差、吞咽困难和苦味等挑战,制约着儿童用药的依从性。因此,本研究使用离子交换树脂作为载体来补救这种情况,旨在开发一种新型的OP缓释混悬液。我们通过离子交换技术制备OP-药物树脂复合物(OP-DRC),之后采用乳化蒸发法制备OP-包衣微囊(OP-CM)。利用单因素法结合正交试验设计确定OP缓释混悬剂的最佳配方,研究缓释混悬液的体外/体内释放行为和药代动力学活性。SEM、XRD和ATR-FTIR结果表明,药物-树脂复合物是通过离子键形成的。缓释混悬液的体外累积释放率分别为16%(1 h)、53%(6 h)和84%(24 h)。自制缓释混悬液与市售颗粒剂(t1/2=8.466 h;T_(max)=2 h;C_(max)=0.631μg/mL)相比,t1/2(21.518 h)增加,T_(max)(6 h)延迟,C_(max)(0.397μg/mL)降低。AUC显示,自制OP混悬剂的相对生物利用度为101%,高于市售OP颗粒剂。因此,成功研制的口服磷酸奥司他韦缓释混悬液具有稳定、无味、易吞咽、灵活方便、缓释等特点,可提高儿童的用药依从性。

关 键 词：Oseltamivir phosphate SUSTAINED-RELEASE Ion exchange resin SUSPENSION 

分 类 号：R944[医药卫生—药剂学]