自组装法构建的疏水药物新型口服递送系统及其体内外评价  

In vitro and in vivo evaluation of a novel self-assembled oral delivery system for hydrophobic drugs

作　　者：赵阳 刘仁凤 窦寅[1] 郭嘉伟[1] 张建祥[1] ZHAO Yang;LIU Renfeng;DOU Yin;GUO Jiawei;ZHANG Jianxiang(Department of Pharmaceutics,Faculty of Pharmacy and laboratory Medicine,Army Medical University(Third Military Medical University),Chongqing,400038,China)

机构地区：[1]陆军军医大学(第三军医大学)药学与检验医学系药剂学教研室,重庆400038

出　　处：《第三军医大学学报》2020年第10期1053-1062,F0003,共11页Journal of Third Military Medical University

基　　金：国家自然科学基金(81971727);陆军军医大学杰青人才库项目(2017年度)。

摘　　要：目的新设计并合成一种亲水性天冬氨酸多肽衍生物聚(异丙基)天冬酰胺(PIPAA),考察PIPAA能否有效负载含羧基疏水药物形成pH响应性微球,增加其在肠道pH条件下的溶出,并提高其口服生物利用度。方法以浓磷酸催化D,L-天冬氨酸在高温条件下聚合成聚琥珀酰亚胺(PSI),并用异丙胺氨解PSI得到PIPAA;PSI和PIPAA结构经红外(FT-IR)和核磁(1H NMR)进行谱学表征。采用透析法制备负载吲哚美辛(IND)的IND/PIPAA微球,并对其形态、粒径、载药量和包封率进行表征;利用FT-IR、1H NMR、差示扫描量热法(DSC)和X射线衍射法(XRD)分析IND与PIPAA分子间的相互作用及IND分子在微球中的存在形式;体外评价了微球的pH响应性释药行为;灌胃给予大鼠载药微球后,高效液相色谱(HPLC)法测定不同时间点血样中的IND含量;利用角叉菜胶诱导的大鼠足跖肿胀模型评价IND/PIPAA微球的抗炎效果。结果FT-IR和1H NMR图谱证明PSI和PIPAA的成功合成。IND和PIPAA可以通过静电力、氢键和疏水作用自组装形成形态规整、粒径均一的载药微球,其中IND载药量和载药效率高,且IND以无定型形式存在于微球中。该微球在体外表现出良好的pH响应性释药行为。大鼠体内药动学研究表明IND/PIPAA微球组的药时曲线下面积(AUC)为IND组的2.4倍。在急性足跖肿胀模型中,与生理盐水和IND相比,IND/PIPAA微球可以显著减轻足跖部位的炎症程度(P=0.046,P=0.002)。结论含羧基小分子疏水药物IND与亲水性天冬氨酸多肽衍生物PIPAA可以通过多重非共价键作用自组装形成形态规整、粒径均一的IND/PIPAA微球,该递送系统可有效增加IND在肠道环境的溶出速率,并提高其口服生物利用度和疗效。Objective To design and synthesize a new hydrophilic aspartic acid peptide derivative,poly(isopropyl-D,L-aspartamide)(PIPAA),and investigate its efficiency to self-assemble with carboxycontaining therapeutics into pH-sensitive microspheres to enhance the dissolution and oral bioavailability of hydrophobic drugs.Methods With phosphoric acid as the catalyst,D,L-aspartic acid was polymerized into polysuccinimide(PSI)at 180℃followed by ring-opening reaction with isopropylamine to form PIPAA.The successful synthesis of PSI and PIPAA was characterized by Fourier transform infrared spectroscopy(FT-IR)and 1H NMR spectroscopy.The morphology,size,drug loading content and loading efficiency of IND/PIPAA microspheres were characterized.FT-IR and 1H NMR spectroscopy were used to determine non-covalent forces between IND and PIPAA in IND/PIPAA microspheres,and the existence form of IND in IND/PIPAA microspheres was examined by differential scanning calorimetry(DSC)and Xray diffraction(XRD)measurement.We carried out in vitro tests to investigate pH-responsive release profiles of IND/PIPAA microspheres.We also examined plasma concentrations of IND using high-performance liquid chromatogrpahy(HPLC)in rats after oral administration of IND/PIPAA microspheres,and evaluated the anti-inflammatory efficacy of IND/PIPAA microspheres in rats with carrageen-induced paw edema.Results FT-IR and 1H NMR spectra demonstrated successful synthsis of PSI and PIPAA.Morphological observation and size determination revealed a spherical shape and uniform particle size of the IND/PIPAA microspheres,which were self-assembled through electrostatic force,hydrogen bonding,and hydrophobic interactions between IND and PIPAA as confimred by FT-IR and 1H NMR spectra.DSC and XRD measurements indicated that IND molecules entrapped in the microspheres were essentially amorphous.While drug release was almost completely suppressed at a gastric pH level,rapid IND release from the microspheres in vitro was observed at pH 7.4.After oral administration in rats,IND/P

关 键 词：聚(异丙基)天冬酰胺 自组装 肠道靶向 难溶性药物 PH响应性 

分 类 号：R914.2[医药卫生—药物化学] R944.9[医药卫生—药学]