CN108401418A - 口服结肠靶向的递送系统及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种口服结肠靶向的递送系统,包括:菌群敏感层,其包含多糖类物质,并包覆于活性成分外面;pH敏感层,其包含任何在pH≥7条件下溶解的高分子材料组合物,并包覆于所述菌群敏感层外面。本发明还公开了该递送系统的制备方法和应用。本发明口服结肠靶向的递送系统,结合pH敏感及菌群敏感机制,通过采用双层保护有效提高了活性成分在结肠部位的选择性溶解释放,增强了治疗或诊断效果,应用前景广阔。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种新型口服结肠靶向的递送系统及其制备方法和应用,该递送系统可获得理想的结肠选择性靶向,对结肠类疾病的诊断和治疗具有很好的应用价值。
背景技术
目前,结肠类疾病,比如:结肠癌、炎症型肠炎正在威胁着人类的健康。2015年的癌症致死率统计结果显示:世界结直肠癌的发病人数是102万,发病率高居所有致死癌症的第三位。而其中中国患者17.7万,排所有国家第四位。而炎症型肠炎发病率的分布统计显示,在西方国家有较高的发病率,在我们中国发病人口随着环境的变化及生活习惯的改变日趋增涨,并且其发病率正在全球范围内以惊人的速度逐年上升。这将给全人类的健康带来巨大的威胁,因此能设计出相关的方式治疗,将会有巨大的意义。
目前针对结肠部位疾病的治疗主要是单一pH依赖型结肠靶向给药系统、时间依赖型结肠靶向给药系统或菌群/酶触发型结肠靶向给药系统三种给药系统,详述如下:(1)PH依赖的靶向给药系统是一类比较常见的靶向给药系统,它通过利用结肠部位pH值高于小肠的特点,采用一定pH敏感型聚合物作为包衣包裹药物,使包衣在结肠部位的pH条件下溶解并大量释放药物。如:丙烯酸树脂共聚物、邻苯二甲醋酸纤维素等,其中S100为基于甲基丙烯酸和甲基丙烯酸甲酯的阴离子共聚物,在pH≥7时溶解,使药物在胃部得到保护,免受酸性环境破坏,直到到达肠道才释放其有效成分。(2)时间依赖型结肠靶向给药系统指生物材料的溶胀性产生的时间差,在胃肠道进行更长时间的活动后释放药物,以达到肠道靶向的目的。时滞的调控主要通过颗粒大小、涂层的厚度及渗透性到达结肠部位,但此系统受个体差异、食物种类、进食时间、病理状态等因素影响较大。(3)菌群/酶触发型结肠靶向给药系统是利用结肠部位较胃和小肠,菌群浓度急剧上升,这些菌群可以分泌许多特异的还原酶和水解酶,如β-葡萄苷酸酶、β-葡萄苷酶、纤维素酶、硝基还原酶、偶氮还原酶、α-脱羟酶、胆固醇脱氢酶等,而偶氮聚合物和多糖等材料,可被结肠特异的酶所降解,以此设计菌群触发型结肠靶向制剂。如壳聚糖为天然多糖,其中的1,4糖苷键使其在胃和小肠中不能降解和吸收,却可在结肠处所特有细菌产生的酶的作用下降解,靶向性强,并且安全、稳定、无毒及可生物降解,故其是一类良好的结肠靶向给药系统的载体材料。
但是胃肠道环境复杂,pH变化范围广,胃肠道长度不一,存在个体差异,当前报道的口服结肠递送系统存在的缺点是:单一的pH依赖或时间依赖型递送结肠药物由于个体差异不能保证完全到达结肠部位,通常在小肠中下端就提前将药物释放,使药物提前吸收或分解,导致到达结肠部位剂量较少,从而需要给予较高的初始剂量或者重复给药,造成严重的全身副作用。而单一的菌群敏感性机制所用材料多为含偶氮结构化合物及多糖类,含偶氮结构化合物结肠靶向较显著,但偶氮类小分子化合物是一种强致癌物质,而多糖类材料由于吸水性好,极易吸水溶胀,提前将药物释放。
发明内容
本发明要解决的技术问题是提供一种口服结肠靶向的递送系统,该递送系统结合pH敏感及菌群敏感机制,通过采用双层保护有效增强了结肠部位的选择性溶解释放,增强了治疗或诊断成像效果,同时降低了毒副作用。
此外,还需要提供一种上述口服结肠靶向的递送系统的制备方法及应用。
为了解决上述技术问题,本发明通过如下技术方案实现:
在本发明的一个方面,提供了一种口服结肠靶向的递送系统,包括:
菌群敏感层,其包含多糖类物质,并包覆于活性成分外面;
pH敏感层,其包含任何在pH≥7条件下溶解的高分子材料组合物,并包覆于所述菌群敏感层外面。
所述多糖类物质包括β-环糊精衍生物、和/或植物提取物及其衍生物。
所述pH敏感层的高分子材料组合物包含以下重量百分比的组分:甲基丙烯酸和甲基丙烯酸甲酯共聚物10%~43%、增塑剂5%~36%、滑石粉5%~22%。
在本发明中,术语“包覆”包括用于固体载体的包衣及封套了流体和/或固体的胶囊或微型胶囊。
在本发明中,术语“活性成分”是指对疾病的诊断和/或治疗有用的任何化合物或生物材料。
本发明的递送系统,外层是pH敏感层材料,由于其只在pH≥7时溶解,可抵制胃及小肠中上端的酸性环境;中层的菌群敏感材料,其只能被结肠部位特有的菌群触发而溶解,能有效增强该递送系统对结肠部位的选择性递送能力;内层为活性成分,包括药物或诊断试剂,其中药物包括抗体药物、蛋白药物、基因药物、纳米药物、小分子药物等;诊断试剂包括造影剂、影像探针等用于炎性肠病或结肠癌诊断的影像试剂。
优选的,所述药物为靶向纳米粒剂型。
采用靶向纳米粒的药物,通过纳米粒表面修饰的靶向分子与细胞表面特异性受体结合,在细胞摄取作用下进入胞内,实现安全有效的靶向性药物治疗。
更优选的,所述靶向纳米粒为CD-98抗体修饰的PLGA-PEG纳米粒。
本发明CD-98抗体修饰的靶向纳米粒,可以特异性识别和富集在结肠炎性部位,并长效停留、缓慢释放药物,延长了药物作用时间,提高了药物的治疗效果,从而有效克服了弥散型结肠炎治疗时,由于小分子药物到达结肠部位后很快随食糜或粪便蠕动带出体外,致使药物不能在炎症部位停留起不到治疗效果的技术问题。
本发明的菌群敏感层材料β-环糊精衍生物,优选为环氧氯丙烷交联的β-环糊精聚合物。该菌群敏感层材料也可选用天然植物提取物,如芹菜提取物、魔芋胶、或果胶等,也可选用这些天然植物提取物的衍生物。本发明的菌群敏感层材料还可选用β-环糊精衍生物和植物提取物及其衍生物的混合物。
本发明pH敏感层材料中的甲基丙烯酸和甲基丙烯酸甲酯共聚物,优选甲基丙烯酸和甲基丙烯酸甲酯的比例为1:2。
本发明pH敏感层材料中的增塑剂可以选自甲基或乙基酯类、有机酸脂肪酯类或无机酸酯类(如乳酸、柠檬酸、琥珀酸、己二酸、癸二酸、邻苯二甲酸、戊二酸或磷酸),或选自一元醇、二元醇、三元醇或多元醇的乙酸酯类或脂肪酯类。具体可选自甘油二乙酸酯(二乙酸甘油酯)、甘油三乙酸酯(三乙酸甘油酯)、或柠檬酸三乙酯,以及这些产品的任何混合物。增塑剂优选为柠檬酸三乙酯。
本发明口服结肠靶向的递送系统可以制成任意剂型,包括胶囊、微囊、片剂、丸剂、或颗粒剂。
所述胶囊剂型的口服结肠靶向递送系统的制备方法,包括以下步骤:
将多糖类物质溶解在有机溶剂中,吸取适量该溶液加到胶囊壳内,在45~65℃的温度下干燥5~15小时,然后冷却至室温,得菌群敏感层;
将pH≥7条件下溶解的高分子材料组合物混合制成pH敏感层的包衣液,喷涂在所述含菌群敏感层胶囊壳的外面,干燥后即得pH和菌群双敏感的口服结肠靶向的递送系统。
在本发明的另一方面,还提供了上述口服结肠靶向的递送系统在制备治疗结肠疾病的药物中的应用。
在本发明的另一方面,还提供了上述口服结肠靶向的递送系统在制备诊断结肠疾病的试剂中的应用。
在本发明的另一方面,还提供了上述口服结肠靶向的递送系统在制备诊断和治疗结肠疾病的药物中的应用。
在本发明的另一方面,还提供了上述口服结肠靶向的递送系统在制备口服结肠吸收的药物中的应用。
所述结肠疾病包括结肠癌、炎症型结肠炎、阿米巴肠病、或肠结核。
本发明的口服结肠靶向的递送系统,结合pH敏感及菌群敏感机制,通过采用双层保护有效增强了结肠部位的选择性溶解释放,使内层的药物达到结肠部位才释放出,减少了给药次数,降低了毒副作用,实现了更好的治疗效果,具有广阔的应用前景。
附图说明
下面结合附图和具体实施方式对本发明作进一步详细的说明。
图1是本发明实施例1的体外模拟胃液、小肠液及结肠液中的胶囊释放曲线图;
图2是本发明实施例1的菌群敏感层在有菌和无菌模拟结肠液中的释放曲线图;
图3是本发明口服结肠靶向的递送系统的结构示意图;
图4是本发明实施例2的靶向纳米粒表征及其体外药物释放曲线图;
图5是本发明实施例3的纳米粒靶向性实验结果图;
图6是本发明实施例4的pH和菌群双敏感胶囊在体内的分布情况图;
图7是本发明实施例4的胶囊在体内分布的柱状比较图;
图8是本发明实施例5的纳米粒在结肠部位累积18h、24h、30h时结肠部位荧光统计数据柱状图;
图9是本发明实施例6的普通胶囊、包封游离药物的pH敏感胶囊及包封NP-CD98PH和菌群双敏感胶囊对DSS诱导的大鼠疾病模型的治疗结果图。
具体实施方式
为了克服目前单一pH机制递送结肠药物,常导致到达结肠部位剂量太少,而单一的菌群触发型结肠靶向给药由于使菌群敏感层材料高亲水性容易在经过胃和小肠的长时间作用后出现溶胀、不利于在结肠部位正常起效的技术问题,本发明研制出了一种口服结肠靶向的递送系统,包括:菌群敏感层,其包含多糖类物质,并包覆于活性成分外面;pH敏感层,其包含任何在pH≥7条件下溶解的高分子材料组合物,并包覆于所述菌群敏感层外面。其中,活性成分包括药物或诊断影像试剂。
所述多糖类物质包括β-环糊精衍生物、和/或植物提取物及其衍生物。
所述pH敏感层的高分子材料组合物包含以下重量百分比的组分:甲基丙烯酸和甲基丙烯酸甲酯共聚物10%~43%、增塑剂5%~36%、滑石粉5%~22%。
优选的,所述药物为靶向纳米粒剂型。在本发明下述一个优选实施例中,所述靶向纳米粒为CD-98抗体修饰的PLGA-PEG纳米粒。该CD-98抗体修饰的靶向纳米粒,可以特异性识别和富集在结肠炎性部位,并长效停留、缓慢释放药物,延长了药物作用时间,提高了药物的治疗效果。这对于目前的弥散型结肠炎治疗具有重要意义,因为现有的普通剂型小分子药物到达结肠部位后很快随食糜或粪便蠕动带出体外,致使药物不能在炎症部位停留起到应有的治疗效果,而本发明pH及菌群双敏感的递送系统再结合靶向纳米粒,能实现结肠发病部位长效停留、缓慢释放药物、充分发挥药效,这是因为pH及菌群双敏感的递送系统能确保将靶向纳米粒完整递送到结肠发病部位,而该靶向纳米粒在结肠发病部位可特异性识别细胞,并由细胞内吞作用进入细胞里面,不会随食糜或粪便蠕动很快被排出体外。
下面通过具体实施例阐述本发明。
实施例1制备口服结肠靶向的递送系统
1.pH敏感层制备
20%±10%的尤特奇S100(德国罗姆公司),15%±10%柠檬酸三乙酯(美国西格玛奥德里奇)被用作增塑剂以及5%±10%的滑石粉(美国西格玛奥德里奇)作为防黏剂,三组份加入到乙醇中组成pH敏感层的包衣液,搅拌(宁波Scientz生物技术有限公司,中国)混合均匀。通过BY-300A型小型包衣锅(上海黄海药检仪器有限公司),在45±10℃下均匀喷涂在胶囊上,干燥后即为胶囊外层的pH敏感层膜,其只在pH≥7时溶解,可使胶囊抵制胃及小肠中上端的酸性环境。
2.菌群敏感层制备
1.8±1g环氧氯丙烷交联的β-环糊精聚合物(β-CDP)(滨州智源生物技术,中国)或植物纤维提取物溶解在8±5毫升二甲基亚砜DMSO(国药控股,中国)中。吸取8±5ul该溶液添加到3D打印制作的模具明胶胶囊壳内,然后在55±10℃的温度下干燥10±5h。在冷却到室温后,即得到对结肠菌群敏感的胶囊中间层,其只能被结肠部位特有的菌群触发而溶解,可有效增强对结肠部位的选择性。在将该结肠菌群敏感的胶囊壳上下卡紧后,再按上述1的方法对胶囊外层进行pH敏感层的包衣,得结肠靶向的酸碱和菌群双敏感的口服给药胶囊。
利用模拟胃肠液对双敏感胶囊的溶解释放情况进行体外考察,结果如图1所示,由图1中可以看出,普通的胶囊加染料在pH=1.2环境下就完全溶解释放,单独的pH敏感层经受住了酸性条件后在pH=6.8的模拟小肠液里有部分释放,而双敏感层胶囊完全经受住模拟胃液和小肠液达到结肠液后才进行释放。随后,对菌群敏感的特异性进行了考察,胶囊在有菌和无菌的模拟结肠液中的释放结果如图2所示,在有菌条件下进行了快速的释放,而在无菌的条件则表现不完全的释放,因此证明了菌群敏感层的特异性。
3.靶向纳米粒制备
CD-98抗体修饰的PLGA-PEG纳米粒由双乳液法制备。药物或影像试剂溶解在水相中,把20±10mg PLGA-PEG溶解在二氯甲烷(DCM)(百灵威,中国)中,超声使成乳液后加入到含有1.5±1%吐温-80的水相中进行第二次超声乳化。搅拌挥发2.5±1h后用超速离心管进行超滤,二蒸水洗三次,得纳米粒,冻干备用。
加入NHS及EDC活化PEG末端-COOH,加入CD-98抗体孵育得修饰CD-98抗体的纳米粒,冻干备用。
4.口服结肠靶向的递送系统制备
将环氧氯丙烷交联的β-环糊精聚合物或植物纤维提取物溶解在二甲基亚砜中。吸取适量该溶液加到3D打印制作的模具明胶胶囊壳内,然后高温干燥。在冷却到室温后,即得到对结肠菌群敏感的胶囊中间层。
在将结肠菌群敏感的胶囊壳上下卡紧后,将尤特奇S100、柠檬酸三乙酯以及滑石粉混合组成pH敏感层的包衣液,搅拌混合均匀。利用包衣锅将包衣液均匀喷涂在胶囊外,干燥后得外层为pH敏感层、中层为菌群敏感层的双敏感口服胶囊。
将上述3制得的载药靶向纳米粒加入双敏感口服胶囊中,制得本发明口服结肠靶向的递送系统,其结构如图3所示,外层为pH敏感层,该层只在pH≥8时溶解,可抵制胃及小肠中上端的酸性环境;中层为菌群敏感层,其只能被结肠部位特有的菌群触发而溶解,能有效增强该递药系统对结肠部位的选择性递送能力;内层的活性成分为载药靶向纳米粒,其可以特异性识别并富集在炎性部位,长效停留、缓慢释放药物,减少给药次数,增强结肠病变部位的治疗效果。
实施例2靶向纳米粒的表征及体外药物释放
1.靶向纳米粒粒径及表面zeta电位测定
采用动态光散射法测定纳米粒及靶向纳米粒的粒径和zeta电位,包取溶液样品1mL,加入样品池中,确定容器内无气泡产生,利用英国马尔文公司纳米粒径测定仪(DLC)测定样品的粒径和zeta电位,每个样品重复测量三次,得到粒径及电位。并使用电镜(TEM)对其观察。
动态光散射的结果表明(见表1),纳米颗粒尺寸约为143.1nm,其ζ电势约-27.9mv。正如图4所示,对NP-CD98的分析显示通过TEM评价平均粒径为图4A中约200nm的,而由DLC评价是在图4B约为224.9nm。因为TEM技术需要真空下干燥颗粒,这会导致颗粒收缩。图4C示出了纳米粒子的ζ电位为-16.8±0.452mV。大小增加80nm左右,ζ电势也产生了较大的变化,这都表明NP和CD98抗体结合成功。
表1纳米粒及靶向纳米粒的尺寸及电荷分布
2.药物释放
靶向纳米粒的体外释放在磷酸盐缓冲液(PBS,pH6.8)中进行。0.02毫克/毫升浓度纳米颗粒悬浮在微量透析器中(赛默飞,美国),然后在摇床中以100rpm速度37℃孵育。在每个指定的时间点(0,1,2,3,4,...0.12,24和48小时),从三个管中分别取出100ul并加入100ul的PBS(pH=7.4,0.01M)(Gibio,USA)补足体积,平衡系统。用NanoDrop 2000UV-Vis紫外可见分光光度计测量PBS中的5-ASA药物含量,并拟合成曲线。
结果如图4D显示,通过使用pH 7.4的PBS作为释放介质,以提供一个良好的漏槽条件,NP-CD98呈现一个缓慢的释放曲线,48h孵育后才有80%以上的释放。这样可以使药物在IBD的炎症部位实现持续释放。
实施例3纳米粒靶向性实验
1.细胞摄取
RAW 264.7巨噬细胞在培养皿中培养过夜。将培养基更换为含有NP和NP-CD98无血清培养基。孵育3小时后,将RAW264.7巨噬细胞用PBS(pH值=7.4)彻底漂洗干净,来清除过量的纳米颗粒,然后用4%多聚甲醛固定20分钟后。6-二脒基-2-苯基二盐酸盐(DAPI)稀释10,000倍后染色细胞核5分钟,在激光共聚焦下观察纳米粒子的细胞摄取。
2.纳米粒子的定量细胞摄取
RAW 264.7巨噬细胞在6孔板中接种。与NP和NP-CD98孵育2小时后,为了除去游离的纳米粒,用PBS洗涤3次,分散细胞,离心(1000转,10分钟),并再分散达1×106个细胞/1毫升浓度。细胞的荧光摄取量用Accuri C6流式细胞仪(Becton Dickinson公司,加利福尼亚州)测量。
结果如图5所示,从图5A可以看出,带红色荧光的纳米粒是可以被内吞。图5B黑色线代表纳米粒,红色线代表靶向纳米粒,可以观察到红色线比黑色线明显的右移,说明靶向纳米粒产生的荧光信号明显比纳米粒高,即靶向纳米粒的靶向性明显。图5中,A.纳米粒内吞激光共聚焦图;B.NP及NP-CD98内吞流式图。
实施例4胶囊在胃肠道的分布
1.体内成像
用罗丹明B(30毫克/毫升)放入pH和菌群双敏感(pH+bacteria)胶囊中制备荧光胶囊,然后给大鼠灌胃,把大鼠分为三组。3小时,6小时,12小时后处死,取整个胃肠道,包括胃、小肠(SI-1,SI-2,SI-3)、结肠部分,由Kodak IS ex vivo FX成像系统对成像进行观察和分析。EM=600nm处,Ex=535nm。
结果如图6所示,从图6可以看出,口服灌胃3小时后,胃部出现了胶囊形状的荧光,6小时后,在小肠中部出现,12小时后,完整的胶囊出现在小肠末端靠近盲肠的部位,说明本发明pH和菌群双敏感胶囊在经历胃肠道的时候,保持了完整性。
2.生物分布情况
将普通胶囊、pH敏感胶囊、含TEXAS RED pH+bacteria胶囊这三种分别对大鼠灌胃,18小时后处死。取整个胃肠道并分为四个部分,包括胃、SI-1、SI-2、SI-3、结肠。然后由冰冻切片机进行切片,在激光共聚焦扫描显微镜下观察荧光的具体分布情况。组织样品在PBS中匀浆,随后用乙醇/DMSO混合物萃取(1:1体积/体积)。用荧光板读数器对样品中的荧光含量进行分析。
结果如图7所示,普通胶囊在五段均出现明显红色荧光,说明其并未起到任何保护作用。而单独pH敏感层只在小肠下端及结肠部位出现荧光,本发明pH和菌群双层敏感的胶囊则只在结肠部位出现明显荧光,这与统计数据一致,充分说明了在体内,本发明的双层敏感胶囊具有很好的结肠靶向效果。
实施例5纳米粒在结肠部位的停留时间考察
将游离染料、NP和NP-CD98分别放置在pH+bacteria胶囊中灌胃给大鼠,并在18H,24H,30H后处死取结肠部位。用DAPI染色细胞核。Texas Red在组织更多的细节可以通过激光共聚焦观察。组织样品在PBS中匀浆,随后用乙醇/DMSO混合物萃取(1:1体积/体积)。用荧光板读数器对样品中的荧光含量进行分析。
结果如图8所示,游离染料组,18到30小时过程中,荧光强度明显下降,说明停留时间较短。靶向纳米组明显比纳米组荧光强度高且变化小,表明靶向纳米粒更多的进入到了结肠组织内且进行持续释放,延长了时间。
实施例6体内药效实验
1.灌胃包封游离药物的普通胶囊、包封游离药物的pH敏感胶囊及包封载药NP-CD98的PH+bacteria敏感的胶囊
利用DSS诱导的急性肠炎模型考察体内的药效。大鼠(约150g)分成5组,每组10只。除了第一组是阴性对照组,其他组分别提供自由饮用硫酸钠葡聚糖(DSS)(6.5%)10天,第二组作为阳性对照,其他组则每隔一天分别灌胃普通胶囊包裹的游离药物、具有pH层保护的游离药物、pH+bacteria双敏感层保护携带NP-CD98包裹药物的胶囊,每天称量大鼠体重和计算死亡老鼠数量。10天后,杀死所有大鼠,取出结肠和脾脏。量取结肠部位的长度并对脾脏进行称重。
2.MPO活性
中性粒细胞浸润情况通过测量MPO活性定量。用Sigma公司的髓过氧化物酶试剂盒进行测量。MPO活性表示为每毫克蛋白单元,一个单位定义为在25℃降解为每分钟的过氧化氢的1毫摩尔的量。
3.结果
如图9所示(图9中,A.结肠图,B.大鼠的体重变化情况,C.MPO值,D.结肠长度,E.脾脏重量),DSS处理的大鼠体重在第4天开始有差别,在第10天差别最大。三组中,包封NP-CD98PH+bacteria敏感的胶囊体重减少的最少(图9B所示)。从结肠的长度的减少情况(图9D所示)及脾脏的增重(图9E所示)均是表现出更好的疗效。图9C结果显示了MPO活性和结肠长度及脾脏重量的结果一致。这些结果反映包封NP-CD98PH+bacteria敏感的胶囊组达到了最好的效果,明显的降低了结肠的炎性。
以上所述实施例仅表达了本发明的实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (16)
1.一种口服结肠靶向的递送系统,包括:
菌群敏感层,其包含多糖类物质,并包覆于活性成分外面;
pH敏感层,其包含任何在pH≥7条件下溶解的高分子材料组合物,并包覆于所述菌群敏感层外面。
2.根据权利要求1所述的口服结肠靶向的递送系统,其特征在于,所述多糖类物质包括β-环糊精衍生物、和/或植物提取物及其衍生物。
3.根据权利要求1所述的口服结肠靶向的递送系统,其特征在于,所述pH敏感层的高分子材料组合物包含以下重量百分比的组分:甲基丙烯酸和甲基丙烯酸甲酯共聚物10%~43%、增塑剂5%~36%、滑石粉5%~22%。
4.根据权利要求1所述的口服结肠靶向的递送系统,其特征在于,所述递送系统的剂型包括胶囊、微囊、片剂、丸剂、或颗粒剂。
5.根据权利要求1所述的口服结肠靶向的递送系统,其特征在于,所述活性成分包括药物和/或诊断试剂。
6.根据权利要求5所述的口服结肠靶向的递送系统,其特征在于,所述药物包括蛋白药物、抗体药物、基因药物、化学药物、或纳米药物。
7.根据权利要求5所述的口服结肠靶向的递送系统,其特征在于,所述诊断试剂包括影像试剂。
8.根据权利要求5所述的口服结肠靶向的递送系统,其特征在于,所述药物为靶向纳米粒剂型。
9.根据权利要求8所述的口服结肠靶向的递送系统,其特征在于,所述靶向纳米粒为CD-98抗体修饰的PLGA-PEG纳米粒。
10.根据权利要求2所述的口服结肠靶向的递送系统,其特征在于,所述植物提取物包括芹菜提取物、魔芋胶、或果胶。
11.根据权利要求2所述的口服结肠靶向的递送系统,其特征在于,所述β-环糊精衍生物为环氧氯丙烷交联的β-环糊精聚合物。
12.根据权利要求4所述的口服结肠靶向的递送系统,其特征在于,所述胶囊剂型的递送系统的制备方法包括以下步骤:
将多糖类物质溶解在有机溶剂中,吸取适量该溶液加到胶囊壳内,在45~65℃的温度下干燥5~15小时,然后冷却至室温,得菌群敏感层;
将pH≥7条件下溶解的高分子材料组合物混合制成pH敏感层的包衣液,喷涂在所述含菌群敏感层胶囊壳的外面,干燥后即得pH和菌群双敏感的口服结肠靶向的递送系统。
13.权利要求1所述口服结肠靶向的递送系统在制备治疗结肠疾病的药物中的应用。
14.权利要求1所述口服结肠靶向的递送系统在制备诊断结肠疾病的试剂中的应用。
15.权利要求1所述口服结肠靶向的递送系统在制备诊断和治疗结肠疾病的药物中的应用。
16.权利要求1所述口服结肠靶向的递送系统在制备口服结肠吸收的药物中的应用。
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