CN112915070A - 一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法 - Google Patents
一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法 Download PDFInfo
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Abstract
本发明涉及一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,该方法是由制备基底模板、载带四环素模型药物和载药微囊的合成步骤完成。将具有胃黏膜膜保护作用的铋金属离子和具有抗炎、抗菌作用的单宁通过自组装,构建成可以在胃内低pH环境下释放的空心微囊,微囊表面保留的酚羟基为微囊的功能化提供了靶向、缓释等延伸空间的可能;铋金属离子很容易被PET/CT等检测仪器识别,为药物示踪提供了可能,微囊的空腔可以载带四环素等具有胺基和苄基的抗胃溃疡的药物,作为一种协同治疗,从而为胃溃疡伴有Hp感染患者提供安全而且有效的治疗参考。该微囊制备过程无需其他辅料,节约了辅料。
Description
技术领域
本发明涉及一种用于胃溃疡药物递送的药物载体领域,更具体的,用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,该药物载体同时协同具有治疗胃溃疡的药物活性。
背景技术
胃溃疡(Gastric ulcer)是我国常见的上消化道酸相关性疾病,多于春秋季高发,常由胃酸分泌过多、胃黏膜屏障功能下降等多种因素引起。在侵袭因子增强,屏障作用减弱的情况下,胃粘膜上皮会发生充血水肿,严重者可以发生坏死脱落,当上皮损伤达到或超过粘膜肌层时,则被称作溃疡。胃溃疡可以导致一系列不适症状,严重者甚至可能引起消化道穿孔、出血、梗阻,甚至癌变。
Hp(Helicobacter pylori,幽门螺杆菌)被认为是上消化道炎症的首要危险因素,严重危害着人们身体健康。我国由于饮食习惯等多方面原因,其感染率居高不下。我国普遍存在抗生素过度使用等问题,各类抗生素耐药率在全球处于较高的水平,这也进一步影响了Hp根除率与胃溃疡的愈合。临床实践中广泛使用的胃溃疡治疗药物一般采用联合用药,包括毒蕈碱拮抗剂,抗酸剂,阻断H-2受体拮抗剂,质子泵抑制剂和抗菌剂以及根除幽门螺杆菌的抗生素等,但根除率呈现逐年下降的趋势,且持续使用这些药物会产生许多不良反应,例如毒蕈碱拮抗剂类会产生心律不齐,低镁血症,质子泵抑制剂类会产生超敏反应,男性乳房发育等。而其他一些治疗方案,例如伴随治疗、序贯治疗尚缺乏大规模多中心的研究,也没有证据提示其和铋剂四联方案相比可以达到更好的治疗效果。
因此,这一难题的解决亟需确定一种新的治疗安全、有效的方法。从这个角度来看,天然药用植物正变得越来越重要,因为它们具有抗溃疡作用的多酚成分。在药用植物中,多酚也因其治疗特性而受到广泛欢迎。YoshikazuI wasaki等人证明半纯化的植物酚类物质对乙醇化学诱导所致的胃粘膜损伤有强烈的抑制作用,髓过氧化物酶活性也受到明显抑制,而超氧化物歧化酶活性明显增强。胃肠激素方面,胃泌素、生长抑素和组胺的分泌受到明显抑制,前列腺素E(2)的分泌受到明显刺激。贾淑平等人报道茶多酚能有效抑制变形链球菌、粘性放线菌和血链球菌的生长、产酸等作用。人体通过摄入多酚类物质可加强免疫细胞功能,起到消炎功能。Jie Zang等人筛选多酚抗炎活性成分,并阐明其相关的分子机制。因此,发展了系统药理学来预测成分与相应的靶点和途径之间的关系。阐明了多酚的抗炎作用,而且为该草药的基质成分和作用机理的发现提供了有益的参考。本小组在前期研究中,构建葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎模型,已证实没食子乙酸乙酯部位(富含鞣质)是治疗UC的有效部位,且发现其可能通过调节核转录因子(NF-κB)通路治疗结肠炎。
铋(bismuth,Bi)属ⅤA族金属元素,目前被认定为周期表中原子序数最大的稳定元素。铋化合物作为药物进入人体后容易代谢,经肾24h代谢率为100%。其作为药物开发的一种主要成分,有着广泛的应用前景。根据大量研究显示,金属铋的生物学活性主要体现于以下三个方面:抗肿瘤活性、溃疡修复作用和抗菌活性。铋类药物在根除幽门螺杆菌方面显示出极高的成功率,即使是对抗生素耐药的菌株也是如此,事实上,它们在临床上用于治疗H.pylori感染已有数十年的历史。铋金属作为一种新的配体金属首次被应用,发明人在解决了其水不溶性问题以后,成功的在模板上形成了坚固的纳米级薄膜,膜的形成是通过多酚的吸附开始的,并通过pH依赖的多价配位键控制。在模板去除后获得了中空的金属-酚醛网络胶囊。实验过程中显示出可控的pH依赖性降解和治疗胃溃疡的药效。胶囊在体内降解后,作为递送药物的该载体同样对疾病具有治疗作用。
美国食品和药物管理局(FDA)指出,胃灼热和胃溃疡药物Zantac(雷尼替丁)及其通用等效物应从药房架子上拿走,如果在家中发现,应丢弃。该机构引用了其储存的雷尼替丁分析中的新发现,该发现表明该药物在储存期间可能随时间推移而增加了致癌物N-亚硝基二甲胺(NDMA)的水平。
鉴于治疗胃溃疡一般采用多处方给药、以及雷尼替丁等原料药储存期间可能随时间推移而增加了致癌物含量这一现状,申请人考虑设计一种理想的药物载体,能够满足一次性给药,从而增加患者的依从性。当下,由于无机和有机构件的共同优点,金属-有机配位材料受到广泛关注,因此金属-有机物络合有望成为这一理想药物载体的实现途径。
本发明将具有胃黏膜膜保护作用的铋金属离子和具有抗炎、抗菌作用的单宁通过自组装,构建成可以在胃内低pH环境下释放的空心微囊,因此微囊制备过程无需其他辅料,节约了辅料。微囊表面保留的酚羟基为微囊的功能化提供了靶向、缓释等延伸空间的可能。铋金属离子很容易被PET/CT等检测仪器识别,为药物示踪提供了可能,微囊的空腔可以载带四环素等具有胺基和苄基的抗胃溃疡的药物,作为一种协同治疗,从而为胃溃疡伴有Hp感染患者提供安全而且有效的治疗参考。
参考文献:
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发明内容
本发明目的在于,提供一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,该方法是由制备基底模板、载带四环素模型药物和载药微囊的合成步骤完成。将具有胃黏膜膜保护作用的铋金属离子和具有抗炎、抗菌作用的单宁通过自组装,构建成可以在胃内低pH环境下释放的空心微囊,微囊表面保留的酚羟基为微囊的功能化提供了靶向、缓释等延伸空间的可能。铋金属离子很容易被PET/CT等检测仪器识别,为药物示踪提供了可能,微囊的空腔可以载带四环素等具有胺基和苄基的抗胃溃疡的药物,作为一种协同治疗,从而为胃溃疡伴有Hp感染患者提供安全而且有效的治疗参考。该微囊制备过程无需其他辅料,节约了辅料。
本发明所述的一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,按下列步骤进行:
制备基底模板:
a、将2.4mL Na2CO3和200mL聚苯乙烯磺酸钠1mg/mL混合到200mL烧杯中,然后在猛烈搅拌下快速加入4.8mLCaCl2溶液,30s后,将生成的碳酸钙沉淀用去离子水水洗3次,以除去未反应的物质,并将其重新悬浮在24mL的去离子水中,得到了平均直径为3.5μm的多孔球形碳酸钙颗粒,其中Na2CO3、聚苯乙烯磺酸钠与CaCl2的质量比为31.8:25:88.2;
载带盐酸四环素模型药物:
b、将4ml体积比为1:1的盐酸四环素溶液10mg/mL与CaCO3悬浮液2mg/ml混合30min,然后用大量去离子水冲洗以去除过量的四环素,得到CaCO3颗粒;
载药微囊的合成:
c、将步骤b合成的载药CaCO3颗粒悬浮在去离子水中,按摩尔比24:103将单宁酸和五水硝酸铋添加到CaCO3颗粒的悬浮液中,剧烈搅拌2分钟,再加入3-(N-吗啡啉)丙磺酸缓冲液或加入tris缓冲液,pH8.0,继续剧烈搅拌,接着再进行磁力搅拌2min后,离心弃上清,除去过量的单宁酸和铋离子,离心2200rpm,3分钟,水洗3次,继续离心,再将颗粒用等体积的乙二胺四乙酸二钠200mM,pH8.0洗涤以溶解CaCO3模板,然后用去离子水水洗涤并离心3300rpm,5分钟,即得到自组装载药微囊。
本发明所述的一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,通过该方法获得的自组装载药微囊进行系列表征:
紫外-可见吸收分光光度法和紫外-可见漫反射光谱表征:在200-800nm范围内对微囊进行紫外光谱以及漫反射光谱扫描;
Zeta电位表征:将微囊均匀的分散在去离子水水中,置于比色皿中,通过马尔文粒度仪测定其Zeta电位;
电镜分析和表征:扫描电镜(SEM),取微囊分散到去离子水水中,滴加1滴溶液于5mm×5mm硅片上,待干燥后SEM扫描观察其形貌和粒径;透射电镜(TEM),取微囊分散到去离子水水中,滴至铜网上,待干燥后,用场发射透射电镜观察微囊的形貌和粒径尺寸;原子力显微镜(AFM),取微囊分散到去离子水水中,滴加适量溶液于硅片上,待干燥后采用原子力显微镜(AFM)扫描观察微囊的形貌及囊壁厚度;X射线能谱(Mapping),直接对微囊进行元素分布和半定量分析;
微囊载药量测量:稀释的载药微囊溶液的荧光光谱首先在(Perkin-Elmer-FL8500)荧光分光光度计进行测量,并使用标准曲线计算封装的四环素浓度,该标准曲线通过测量已知浓度不同的四环素溶液进行校准。计算胶囊的数量,使100μL载药微囊流过流式细胞仪(BD FACSCALIBUR),进行计数分析。每个胶囊的载药量用pg表示。用于测量载药微囊的四环素标准品,在激发下测量荧光激发波长为383nm,发射波长为441nm。计算公式为:
载药量%=(微囊内的药量/载药微囊总重量)x100%
单个微囊载药量(g)=1ml微囊内的药量/1ml微囊计数个数;
流式细胞仪:借助流式细胞仪对微囊的pH响应性分解动力学进行表征;
电感耦合等离子体发射光谱仪(ICP-OES):对微囊中所含金属元素进行定量分析;
微囊负载抗生素类药物的载药量的测量:见表1和表2;
表1
表2
有益效果:
本发明所述的一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,该方法将具有胃黏膜膜保护作用的铋金属离子和具有抗炎、抗菌作用的单宁通过自组装,构建成可以在胃内低pH环境下释放的空心微囊,因此微囊制备过程无需其他辅料,节约了辅料。微囊表面保留的酚羟基为微囊的功能化提供了靶向、缓释等延伸空间的可能。铋金属离子很容易被PET/CT等检测仪器识别,为药物示踪提供了可能,微囊的空腔可以载带四环素等具有胺基和苄基的抗胃溃疡的药物,作为一种协同治疗,从而为胃溃疡伴有Hp感染患者提供安全而且有效的治疗参考。
附图说明
图1为本发明微囊自组装过程的透射电子显微镜表征图,其中a和e为碳酸钙模板,b和f为加入单宁酸后的第一步组装,c和g为加入铋配体后的第二步组装,d和h为去除碳酸钙模板后的空心微囊;通过乙二胺四乙酸二钠(200mM,pH8.0),刻蚀模板后,在透射电子显微镜下观察到单分散、尺寸分布与模板尺寸相似、并且空心的球形微囊,因此判断在一定的配比下能够使其在模板表面自组装,形成厚度均匀的金属酚醛网络,标尺在a-d,g中为2μm,在h的内嵌中为500nm,在e、f和h中为5μm;
图2为本发明微囊自组装过程的原子力显微镜表征图,其中风干后,微囊塌陷并出现褶皱和折痕,这是中空聚合物胶囊的典型特征,这由透射电子显微镜(TEM),扫描电子显微镜(SEM)和原子力显微镜(AFM)证实;
图3为本发明微囊自组装过程的扫描电子显微镜表征图,其中a为碳酸钙颗粒的扫描电子显微镜表征,在插图中可以清楚地观察到颗粒的多孔结构;b为微囊的扫描电子显微镜图像,图像中的比例尺表示2μm,内嵌图中为200nm;
图4为本发明微囊的相应能量色散X射线元素图谱的结构mapping表征图,通过微囊的能量色散X射线(EDX)光谱确认了微囊中Bi的存在,EDX映射分析显示,Bi分布模式与氧和碳元素模式以及高角度环形暗场(HAADF)图像紧密匹配,表明Bi与多酚缔合且均匀分布在Bi与多酚络合形成的薄膜中;
图5为本发明微囊的能量色散X射线荧光光谱图,其中a为微囊样品的荧光光谱图;b为为承载样品的Formvar碳涂层透射电子显微镜网格的荧光光谱图,在2.435keV、10.835keV和13.015keV的强信号表明微囊中铋的存在;
图6为本发明微囊的紫外-可见漫反射谱图,微囊的UV-Vis吸收光谱显示,在520nm处存在配体到金属的电荷转移(LMCT)带,这在模板和多酚的单独光谱中是没有的,确认了TA和金属之间的配位;
图7为本发明微囊中金属元素通过电感耦合等离子体发射光谱仪(ICP-OES)进行定量分析图,其中a为单个微囊中铋元素的元素百分含量;b为微囊中铋元素的重量质量分数;随着加入金属配体浓度的增加,微囊中的金属含量递增,在配体浓度达75mg·mL-1时到达峰值,为19.24%;
图8为本发明自组装前后的紫外-可见吸收光谱图,其中a为不同pH值下球形微囊分散体的紫外-可见吸收光谱,b为多酚吸附模板后的紫外-可见吸收光谱;微囊在pH8.5的UV-Vis吸收光谱显示,在520nm处出现新的吸收带,表明微囊的去质子化形式之间的共轭,这是三价铋离子与酚羟基螯合物的特征存在配体到金属的电荷转移(LMCT)带,这在模板和多酚的单独光谱中是没有的,该LMCT带在pH1.0时消失,表明MPN在该pH下拆卸;
图9为本发明微囊自组装前后的ζ-电位,基底模板具有大约-20±6mV的ζ-电位(见左图),由于TA中的Galloyl基团的酸性性质,基底上金属-多酚膜的形成使得表面的Zeta电位从-20±6mV转移到了-30±4mV,刻蚀模板后,获得了具有–31±5mV的zeta电位的高度均一的微囊,其误差与模板刻蚀前的值相同;总之,综合以上这些数据表明,通过在水/油界面的自组装成功地形成了金属酚醛网络;
图10为本发明微囊的pH响应性分解动力学图,在pH2.2下,所有的胶囊均在8小时内分解。在pH3.2下,接近50%的微囊在1小时内即可拆卸;在pH4.2下,2小时内降解超过50%的微囊,降解速率较快;在5.2pH下,孵育8小时能够降解约60%的微囊;相反,分别在pH6.2和pH7.4下孵育2天后,仍然有约60%的胶囊保持完整,微囊的分解动力学符合药物递送的理想情况,因为这些胶囊在血流pH值(7.4)时相对稳定,并在胃内pH值(2.2-3.2)下逐渐分解;
图11为本发明微囊通过层层自组装载药前后的可视化表征图,将四环素为代表的抗生素类药物包囊到微囊中用于药物定向递送,对微囊载药前后进行可视化表征,其中a为最初,通过共沉淀法将四环素预装到CaCO3模板中,倒置荧光显微镜证实了成功制备CaCO3模板;b为与没有添加剂制备的CaCO3颗粒相比,与四环素共沉淀的CaCO3颗粒显示出更光滑的表面;
C为通过随后添加GA多酚和Bi(NO3)3·5H2O溶液,将MPN膜沉积在载有药物的CaCO3模板上,除去模板后,装有四环素的胶囊分别从3.4±0.2膨胀到3.9±0.2μm和从4.5±0.3膨胀到4.9±0.3μm,药物的成功封装四环素通过荧光显微镜证实,该荧光显示胶囊内荧光均匀分布,但颜色相较于b中较浅,原因是经过多次离心、水洗等工序囊中药物有泄露;d为对照制备了一组没有包裹药物的微囊,发现其本身并没有荧光,因此可以确定c中黄色荧光来源于包裹于微囊内部的药物;
图12为本发明微囊载药后,进行透射电子显微镜形貌观察图,除了最外层圆形的囊壁,在囊芯又出现了一个小圆,这是在载药前所没有的形貌。结合前面的载药荧光显微镜的结果;和后期的载药量计算、体外药物释放的结果分析,囊芯的小圆正是装载的四环素模型药物,该实验也再一次证明了四环素药物在微囊内部的成功封装;
图13为本发明载药微囊在模拟体液、胃液的pH条件下的时间依赖性体外释放曲线图,鉴于pH 7.4和2.2之间微囊降解速率的主要差异,研究了在这些pH条件下载药微囊中四环素的释放,如图所示,载药囊在pH值2.2时表现出快速释放,在pH值6.2时呈现中等释放率,在最初2小时内,pH2.2和6.2两种pH条件下的载药微囊的四环素释放率分别为40%和10%;11小时后,2.2pH条件下的四环素释放率达到100%,而6.2pH条件下,仍有近70%的四环素保留在微囊中,这表明载药微囊的四环素释放是pH依赖性的。因此,在模拟的胃液内pH下,载药微囊的降解在四环素的释放中起主要作用,所有数据均为平均值±标准差(n=3);
图14为本发明微囊体外抗幽门螺杆菌的研究图,其中a为牛津杯法考察各组样品对H.p生长的抑制效果,其中1、2号为制备微囊必需的单一多酚/金属配体,3号为微囊,4号为阳性对照四环素,5号为阳性对照枸橼酸铋钾,6号是pH为2.2的缓冲液;图b为微囊的最低抑菌浓度(MIC)测定,设置空白与阳性对照;
图15为本发明动物实验病理结果图,其中A.实验时间轴,B.给药期间小鼠体重百分数变化,C.给药期间小鼠疾病活动指数,D.造模后与给药后小鼠粪便,E.小鼠胃组织,a)正常组,b)模型组,c)阳性药组,d)微囊给药组,e)载药微囊给药组;F.病理切片,a)正常组,b)模型组,c)阳性药组,d)微囊给药组,e)载药微囊给药组,与模型组比较,*P<0.05。
具体实施方式
本发明结合附图进一步说明。
实施例1
制备基底模板:
a、将2.4mL Na2CO3和200mL聚苯乙烯磺酸钠1mg/mL混合到200mL烧杯中,然后在猛烈搅拌下快速加入4.8mLCaCl2溶液,30s后,将生成的碳酸钙沉淀用去离子水水洗3次,以除去未反应的物质,并将其重新悬浮在24mL的去离子水中,得到了平均直径为3.5μm的多孔球形碳酸钙颗粒,其中Na2CO3、聚苯乙烯磺酸钠与CaCl2的质量比为31.8:25:88.2;
载带盐酸四环素模型药物:
b、将4ml体积比为1:1的盐酸四环素溶液10mg/mL与CaCO3悬浮液2mg/ml混合30min,然后用大量去离子水冲洗以去除过量的四环素,得到CaCO3颗粒;
载药微囊的合成:
c、将步骤b合成的载药CaCO3颗粒悬浮在去离子水中,按摩尔比24:103将单宁酸和五水硝酸铋添加到CaCO3颗粒的悬浮液中,剧烈搅拌2分钟,再加入3-(N-吗啡啉)丙磺酸缓冲液或加入tris缓冲液,pH8.0,继续剧烈搅拌,接着再进行磁力搅拌2min后,离心弃上清,除去过量的单宁酸和铋离子,离心2200rpm,3分钟,水洗3次,继续离心,再将颗粒用等体积的乙二胺四乙酸二钠200mM,pH8.0洗涤以溶解CaCO3模板,然后用去离子水水洗涤并离心3300rpm,5分钟,即得到自组装载药微囊。
实施例2
制备的微囊药物载体对胃溃疡及抗Hp的药效实验:
微囊的体内药效实验:
实验方法:胃溃疡动物模型的建立及分组给药:健康小鼠30只,雌雄对半,适应性饲养1周,结合其体重,进行随机分组,将其分为空白组、模型组、阳性药组,微囊给药组、载药四环素微囊给药组。除空白组外,其余各组根据Djahanguiri和Pereira等的方法进行造模实验,并稍作修改,进行造模实验前的24小时内,禁食不禁水,24小时后除空白组外其余各组均以吲哚美辛50mg/kg灌胃造模,造模后7小时内自由饮食,各组放在同一条件下进行饲养,7小时后,空白组与模型组注射等体积的生离盐水,阳性药组灌胃枸橼酸铋钾100mg/kg,微囊给药组灌胃给予微囊100mg/kg,载药四环素微囊给药组灌胃给予微囊116mg/kg,每天1次,连续7天,给药结束后处死小鼠进行解剖,取出胃组织进行各项指标的检测;
疾病活动指数(Disease activity index)值为体重下降百分比、大便的性状和大便隐血情况三者的评分的平均值,每项的评价标准如表3所示;DAI得分越高,表明胃溃疡症状越严重;
表3疾病活动指数评分标准
各项病理指标的检测:
对部分生化指标诶超氧化物歧化酶(SOD)、丙二醛(MDA)、过氧化氢酶(CAT)等进行测定。检查病理切片,将胃组织置于福尔马林中固定后,按照常规方法包埋,切成厚度约4-5μm的切片,固定在粘附性载玻片上。采用苏木素-伊红(H&E)染色,首先将玻片置于二甲苯中脱蜡5min;其次置于不同浓度的乙醇中各5min,水洗2min;再用苏木素蓝化2min,自来水冲洗;然后置于酸酒精中数秒,自来水冲洗;再用伊红染液染2min,自来水冲洗2遍;最后脱水,透明,中性树胶封片,显微镜下进行组织学观察分析。根据炎性细胞的浸润、隐窝形态、上皮细胞退化程度以及杯状细胞丢失、黏膜肌层可见组织水肿和充血情况进行炎症评分。
实验结果:如图15A为动物实验时间轴,图15B为给药期间小鼠体重变化的百分数,通过观察表明:空白组小鼠体重随实验周期的变长而增加;与空白组相比,造模后小鼠体重变化的百分数比在1-4天内呈现下降的趋势,在5-7天内小鼠体重变化的百分数呈上升趋势,具有显著性差异(P<0.05);通过观察,除空白组外,造模1-4天后,其余各组小鼠普遍出现了食量减少,体重下降,精神萎靡,身体蜷曲,活动范围缩小,皮毛变得无光泽且凌乱等现象;上述症状在第1-4天时最明显,第5-7天后以上述症状逐渐缓解,饮食和活动量增加,症状减轻;在整个实验期间,空白组的小鼠饮食状况良好,精神活跃,粪便呈健康色且有型,大便无隐血现象;如图15C为给药期间小鼠疾病活动指数(Disease activity index)的变化;在1-4天内,小鼠的DAI评分呈现上升的趋势,5-7天内呈下降并趋向平稳;与模型组比较,阳性药组与微囊、载药微囊给药组的疾病活动指数具有显著性差异(P<0.05),这与体重在1-4天内呈现下降的趋势,在5-7天内小鼠体重变化的百分数呈上升趋势相对应;
图15D为造模后与给药后小鼠的粪便。实验发现,症状轻的小鼠的大便稀软,呈浅黄色。症状重的小鼠大便带血,甚至呈现黑色;
图15E为实验动物胃组织的解剖形态学。Indomethacin诱导引起胃黏膜病变,使小鼠胃粘膜大小和形状变得不规则。如预期结果一样,通过观察发现空白组小鼠的胃组织粘膜未见病变,胃组织结构完整,胃粘膜光滑且呈现粉色,皱襞光滑干净,胃壁弹性良好,表面无出血点、血色及充血状态,无溃疡及水肿现象如图15Ea所示;模型组胃溃疡比较严重如图15Eb所示,肉眼可见的胃粘膜水肿,腺体充血,线状出血,深红色和黑色条带,伴有胃壁拉长,可确定造模成功;而微囊、载药微囊给药组显著减少了indomethacin诱导的胃溃疡,如图15Ec、15Ed、15Ee所示,可见胃腔清洁,溃疡基底及周围无充血水肿状态,肉眼观看溃疡面积、出血、糜烂及水肿等症状轻于仅造模组;
如图15D所示,即使小鼠个体存在差异性,indomethacin也可以引起小鼠胃组织不同程度的胃粘膜损伤,使胃组织出现水肿,出血,糜烂。关于诱导胃溃疡模型的实验,总体来说算是成功的;但也存在着一些问题,因疫情影响,导致实验时间缩短,预实验做的不够,关于indomethacin的用量及其用法,掌握的不够准确。如用的剂量过大,使个别小鼠胃溃疡太严重,如造成胃穿孔,胃壁变薄,甚至胃组织糜烂,而不能进食,最后死亡;
图15F为小鼠胃组织的病理切片,显示indomethacin引起的胃粘膜损伤和微囊的预防或治疗胃溃疡的生物活性;图15F-a为空白组:表面上皮结构完整,固有层腺体排列整齐且较为紧密,粘膜层结构中未见炎性细胞浸润。与空白组小鼠的表面上皮细胞未受到破坏相比,在通过HE染色后,除正常组外,其余各组发现胃黏膜受到了不同程度破坏,单纯柱状上皮的紊乱并伴有广泛的水肿、充血,固有层腺体变性坏死且紊乱,有炎症细胞浸润,从而形成溃疡,如图15F-b、图15F-c、图15F-d、图15F-e所示,特别是模型组(图15F-b),黏膜上皮细胞受到严重的破坏,结构不完整;经过微囊(图15F-d)、载药微囊(图15F-e)处理后,没有出现胃粘膜水肿及充血的状态,固有层腺体排列也相对模型组较整齐,这表明微囊、载药微囊对胃粘膜的修复作用相对增强,对非甾体类抗炎药诱导的胃溃疡具有一定的治疗作用;单独比较微囊组与载药微囊组的病理切片发现,后者对于粘膜修复的程度强于前者,这得益于微囊内部负载的四环素对于幽门螺杆菌的清除,溃疡能够更快的修复;
微囊的体外抗Hp药效实验:
实验1:抑菌圈实验:
实验方法:取哥伦比亚血琼脂培养基,用灭菌打孔器(直径7mm)打孔,按照样品顺序吸取样品加入孔中(100μL/孔);然后将加入样品的培养基放于密封培养罐,并放入微需氧产气袋,立即密封培养罐。将培养罐放于恒温培养箱中温度37℃培养72h,培养完成后取出培养基,用游标卡尺测量抑菌圈大小,并拍照记录;
实验结果:1μg/ml的四环素阳性组平均抑菌圈直径最大(如图14表),为(15.7±1.6)mm,其次为微囊组,为(12.5±0.9)mm;其余由大到小依次为五水硝酸铋0.37mg/ml组,为(7.1±1.1)mm;多酚0.64mg/ml组,为(5.2±0.4)mm;pH2.2的缓冲液,为(8.2±0.4)mm等。实验证明,各组均显示有不同程度的抑菌活性,除阳性对照组外,微囊组对幽门螺杆菌的抑菌活性最高;
实验2:最小抑菌浓度测定:
实验方法:采用二倍倍比稀释法,在90mm培养皿内配制含不同浓度测试样品的哥伦比亚血琼脂培养基,使培养基中枸橼酸铋钾的浓度分别为100μg/mL-3.125μg/mL,微囊材料的浓度分别为400μg/mL-3.125μg/mL;取上述稀释的菌液1μL接种于含测试样品的培养基表面,并同时接种一个不含测试样品的培养基作为对照;接种完成后,将培养基置于培养罐放于恒温培养箱中37℃培养72h,培养完成后取出培养基,以不长菌落的培养基上的测试样品浓度为其最低抑菌浓度值(MIC);
实验结果:四环素阳性对照组和微囊组的MIC值分别为50和800ug/ml(如图14表),综上实验,微囊组相较于多酚组、五水硝酸铋组,具有最高的抑菌活性。
Claims (1)
1.一种用于治疗胃溃疡的pH响应性的自组装载药微囊的制备方法,其特征在于按下列步骤进行:
制备基底模板:
a、将2.4mL Na2CO3和200mL 聚苯乙烯磺酸钠1mg/mL混合到200mL烧杯中,然后在猛烈搅拌下快速加入4.8mLCaCl2溶液,30s后,将生成的碳酸钙沉淀用去离子水水洗3次,以除去未反应的物质,并将其重新悬浮在24mL的去离子水中,得到了平均直径为3.5μm的多孔球形碳酸钙颗粒,其中Na2CO3、聚苯乙烯磺酸钠与CaCl2的质量比为31.8:25:88.2;
载带盐酸四环素模型药物:
b、将4ml体积比为1:1的盐酸四环素溶液10mg/mL与CaCO3悬浮液2mg/ml混合30min,然后用大量去离子水冲洗以去除过量的四环素,得到CaCO3颗粒;
载药微囊的合成:
c、将步骤b合成的载药CaCO3颗粒悬浮在去离子水中,按摩尔比24:103将单宁酸和五水硝酸铋添加到CaCO3颗粒的悬浮液中,剧烈搅拌2分钟,再加入3-(N-吗啡啉)丙磺酸缓冲液或加入tris缓冲液将pH升高至8.0,继续剧烈搅拌2min后,为除去过量的单宁酸和铋离子,离心2200rpm,3分钟,水洗3次,再将颗粒用等体积的乙二胺四乙酸二钠200mM,pH8.0洗涤以溶解CaCO3模板,然后用去离子水洗涤并离心3300rpm,5分钟,即得到自组装载药微囊。
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