根皮素和缬沙坦共非晶的制备与评价  

Preparation and evaluation of phloretin and valsartan co-amorphous

作　　者：郭宇斐 陈婷 黄花 钟雪萍 刘耀 胡春晖 严海英 GUO Yufei;CHEN Ting;HUANG Hua;ZHONG Xueping;LIU Yao;HU Chunhui;YAN Haiying(Department of Pharmacy,Qinghai University,Xining 810001,China;Social Insurance Department,China Railway Qinghai Tibet Group Co.,Ltd.,Xining 810001,China;State Key Laboratory of Plateau Ecology and Agriculture,Xining 810016,China)

机构地区：[1]青海大学药学系,青海西宁810001 [2]中国铁路青藏集团有限公司社会保险部,青海西宁810001 [3]三江源生态与高原农牧业国家重点实验室,青海西宁810016

出　　处：《药物评价研究》2024年第11期2627-2636,共10页Drug Evaluation Research

基　　金：2024年中央引导地方科技发展资金计划项目(2024ZY002);青海省基础研究计划项目(2022-ZJ-748)。

摘　　要：目的根皮素(PT)为难溶性药物,且口服相对生物利用度低,通过与缬沙坦(VST)制备成共非晶(CA)提高其溶出速率,从而提高其口服相对生物利用度。方法以VST为药物载体,PT为模型药物,采用喷雾干燥法制备CA。傅里叶红外图谱(FT-IR)观察样品的官能团结构及分子间相互作用力;差示扫描量热法(DSC)测定玻璃化转变温度(T_(g))进一步验证PT和VST分子间的相互作用力;粉末X-射线衍射(PXRD)观察晶体学特性;扫描电子显微镜(SEM)观察样品的微观结构。考察药物在模拟胃液、模拟肠液中的本征溶出,计算溶出速率(IDR);考察CA在高温、不同湿度下的稳定性;考察CA、PT(200 mg·kg^(−1))在大鼠体内药动学。结果FT-IR和DSC表明CA中PT与VST有较强的分子之间相互作用力,PXRD和SEM证明CA为无定形态,表明PT与VST共喷雾形成了共非晶;CA本征溶出结果表明相较于PT,CA溶出速率有明显提升(P<0.05);CA大鼠体内口服相对生物利用度相较原料药提高4.12倍,C_(max)提高7.44倍。CA在高温条件(50±2)℃表现出良好的稳定性,但湿稳定性较差。结论PT与VST成功制备成CA,明显的改善了PT的溶出及口服相对生物利用度,并且有较好的热稳定性。Objective Phloretin(PT)is an insoluble drug with low oral bioavailability.It is proposed to improve its dissolution rate by preparing co-amorphous(CA)with valsartan(VST),so as to improve its oral bioavailability.Methods CA was prepared by spray drying method with VST as drug carrier and PT as model drug.Fourier infrared spectroscopy(FT-IR)was used to observe the structure of functional groups and the intermolecular forces of the samples.The glass transition temperature(T_(g))was determined by differential scanning calorimetry(DSC)to further verify the interaction between PT and VST molecules.The crystallographic properties of powder were observed by X-ray diffraction(PXRD).The microstructure of the sample was observed by scanning electron microscopy(SEM).Investigate the intrinsic dissolution of drugs in simulated gastric and intestinal fluids,and calculate the dissolution rate(IDR);Assess the stability of CA under high temperature and different humidity conditions;Investigating the pharmacokinetics of CA and PT(200 mg·kg^(−1))in rats.Results FT-IR and DSC show that there is a strong interaction force between PT and VST in CA,and PXRD and SEM show that CA is amorphous,indicating that PT and VST are co-sprayed to form eutectic amorphous.The dissolution rate of CA is significantly higher than that of PT(P<0.05).The oral bioavailability in vivo was 4.12 times higher than that of the bulk drug,and the C_(max) was 7.44 times higher.CA showed good stability at high temperature(50±2)℃,but poor wet stability.Conclusion The CA prepared by PT and VST can obviously improve the dissolution rate and oral bioavailability of PT,and has good thermal stability.

关 键 词：根皮素 缬沙坦 共非晶 本征溶出 相对生物利用度 稳定性 

分 类 号：R943[医药卫生—药剂学]