CN108066296B - 一种生物学活性组分结肠靶向组合物及其应用 - Google Patents
一种生物学活性组分结肠靶向组合物及其应用 Download PDFInfo
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- CN108066296B CN108066296B CN201611013848.3A CN201611013848A CN108066296B CN 108066296 B CN108066296 B CN 108066296B CN 201611013848 A CN201611013848 A CN 201611013848A CN 108066296 B CN108066296 B CN 108066296B
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Abstract
本发明属于食品与保健品以及药品技术领域,涉及一种生物学活性组分结肠靶向组合物及其制剂和制备方法。本发明的生物学活性组分结肠靶向组合物包括:羟丙甲纤维素、生物学活性组分和辅料,其中所述羟丙甲纤维素的粘度>1000mPa.s。与现有技术相比,本发明的组合物具有显著改进的结肠靶向效果,大大提高了生物学活性组分的生物利用度和体内活性。
Description
技术领域
本发明属于食品、保健品与药品技术领域,具体涉及一种生物学活性组分结肠靶向组合物、其制剂和它们的制备方法。
背景技术
生物学活性组分是一大类具有生理活性的组分,通过获取适当的生物学活性组分,可对营养的改善、疾病的预防和治疗以及保健起到重要作用。然而,大多数的生物学活性组分经口服时往往存在以下问题:1)上消化道环境(如胃酸、消化酶等)对大部分生物学活性组分的活性具有相当大的破坏力,以至于这些活性组分不能充分发挥相应作用;2)生物学活性组分经口服后大量存在于胃及小肠,无法被人体有利地吸收和利用,从而容易对机体产生相应的危害;3)苛刻的生产加工条件(如温度、湿度、一些溶剂的引入等)对组分活性有破坏作用。
基于上述问题,结肠靶向传递系统通过使用适当的方法,能避免有效物质在胃、十二指肠、空肠和回肠释放,直接运送到患者的结肠部位释放,可提高有效物质在结肠部位的局部浓度,便于充分吸收、充分发挥治疗和保健作用,避免在胃及小肠的释放,降低不良反应,提高易被胃酸破坏或易被胃蛋白酶、胰酶代谢的有效物质的生物利用度,从而大大弥补了上述不足。
结合现代药物制剂技术来设计剂型,结肠靶向给药传递系统主要分为时滞型释药系统、pH依赖型释药系统、酶触发型释药系统、压力依赖型释药系统及前体药物型释药系统。时滞型释药系统利用物质口服依次经过胃、小肠到达结肠需要5~6h的时滞特点而使药物在胃、小肠不释放,而到达结肠后才开始释放;pH依赖型释药系统是利用胃肠道pH条件的不同,通过选择包衣方法,以达到结肠释放目的,包衣制备过程较复杂,需使用溶剂且溶剂需要在一定的温度下挥发干净,该方法很可能导致生物学活性组分的活力显著下降。酶触发型释药系统、压力依赖型释药系统以及前体药物型释药系统目前虽受重视,但三者的非常规性的限制、内在复杂性,甚至是需要专业化的装置和复杂的处理步骤不仅增加了研发过程的复杂性,并且大大降低了产品大规模生产的可能性。
生物学活性组分,特别是有益微生物的活性难以耐受相关制剂制备过程中稍高温度或湿度、溶剂或者其他物质的影响,因此其结肠靶向传递系统的研究和开发受到极大的限制,往往越是复杂的制备工艺对其活性的破坏越大,因而迄今为止尚未见到结肠靶向的益生菌相关产品面市。
现有的益生菌制剂技术能使得益生菌绕过胃而在小肠中释放,但即便是这样,若益生菌在小肠中过多地聚集,也会出现严重的肠道菌群失调等安全性问题(CN200910229403.2)。现有的益生菌制剂技术虽能将益生菌递送到胃肠道的远端区段(包括回肠),但却并非能直接定位递送到结肠,因此益生菌的利用率并不能达到最佳(US2016022592)。现有的益生菌制剂技术还存在所用辅料的安全性问题(ALBERTINI B,VITALI B,PASSERINI N,et al.Development of microparticulate systems forintestinal delivery of Lactobacillus acidophilus and Bifidobacterium lactis[J].European Journal of Pharmaceutical Sciences,2010,40(4):359-366.)。现有的益生菌制剂技术无法避免制备过程中所用溶剂以及制备时升高的温度、湿度等对益生菌活性的影响(KLEMMER K J,KORBER D R,NICHOLAS H,et al.Pea proteinbased capsules forprobiotic and prebiotic delivery[J].International Journal of Food Science andTechnology,2011,46(11):2248-2256.)。现有的益生菌制剂技术为了满足有效口服剂型的条件,往往所需用的辅料体积较大,载活菌数较低。现有的益生菌制剂技术制备工艺复杂,难以工业化生产(CALINESCU C,MATEESCU M A.Carboxymethyl high amylase starch:chitosan self-stabilized matrix for probiotic colon delivery[J].EuropeanJournal of Pharmaceutics and Biopharmaceutics,2008,70(2):582-589.)。
发明内容
本发明的目的是提供一种生物学活性组分的结肠靶向组合物及含有该组合物的制剂,它们能够经过胃和小肠、大部分在到达结肠部位后才释放,从而提高生物学活性组分的生物利用度,更好地发挥其体内活性,从而解决现有技术存在的上述问题。
本发明是通过以下方式实现的:
一方面,本发明提供了一种基于羟丙甲纤维素(HPMC)的生物学活性组分结肠靶向组合物,包括:羟丙甲纤维素、生物学活性组分和辅料,其中,所述羟丙甲纤维素的重量百分含量为10~99%,所述生物学活性组分的重量百分含量为1~60%,辅料的重量百分含量为0~80%;进一步优选地,所述羟丙甲纤维素的重量百分含量为40~90%,所述生物学活性组分的重量百分含量为10~40%,所述辅料的重量百分含量为0~50%;其中,所述羟丙甲纤维素的粘度>1000mPa.s。
优选地,所述羟丙甲纤维素的粘度为15000mPa.s-200000mPa.s。
优选地,所述生物学活性组分为微生物;更优选地,所述微生物为益生菌,所述益生菌包括食品、保健品和药品中允许使用的双歧杆菌、乳杆菌或革兰氏阳性球菌中的一种或多种;优选地,所述双歧杆菌是乳双歧杆菌、婴儿双歧杆菌、两歧双歧杆菌、长双歧杆菌、短双歧杆菌和青春双歧杆菌中的一种或多种;所述乳杆菌是嗜酸乳杆菌、干酪乳杆菌、卷曲乳杆菌、德氏乳杆菌保加利亚亚种(保加利亚乳杆菌)、德氏乳杆菌亚种、发酵乳杆菌、格氏乳杆菌、瑞士乳杆菌、约氏乳杆菌、副干酪乳杆菌、植物乳杆菌、罗伊氏乳杆菌、鼠李糖乳杆菌、唾液乳杆菌中的一种或多种;所述革兰氏阳性球菌是粪链球菌和乳球菌中的一种或多种。
进一步优选地,所述结肠靶向组合物中益生菌的量为0.01亿-1200亿cfu/g。
优选地,所述辅料包括有利于生物学活性组分生存稳定性的营养物质,该营养物质可以为益生元(如低聚果糖、低聚半乳糖、低聚木糖、低聚乳果糖、大豆低聚糖、果胶、菊粉和蔓越莓粉等)、维生素和/或糖醇。
优选地,所述辅料还包括果胶、海藻酸钠、壳聚糖等对生物学活性组分的结肠靶向递送有益的药用辅料或食品添加剂。
优选地,所述辅料还包括其他粘合剂(阿拉伯胶、瓜尔胶、藻酸、羟甲基纤维素、糊精、卡波姆、麦芽糖、明胶、葡萄糖、乙基纤维素、甲基纤维素、聚环氧乙烷或聚维酮)、填充剂(淀粉、可压性淀粉、变性淀粉、山梨醇、甘露醇、微晶纤维素、糖粉、糊精、无机盐、无水乳糖、乳酸钙)、润滑剂(硬脂酸镁、硬脂酸、矿物油、聚乙二醇、滑石粉、二氧化硅)、崩解剂(羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲纤维素钠、交联聚维酮、干淀粉)等可优化制剂本身性质的其它辅料。
第二方面,本发明提供了一种生物学活性组分结肠靶向制剂,它包含本发明的生物学活性组分结肠靶向组合物。
优选地,所述制剂的剂型为片剂;更优选地,为便于吞服,所述片剂单片质量≤500mg,直径≤10mm。这种剂型可以进一步帮助生物学活性组分在具有大量菌群的结肠中释放,而在胃、小肠和回肠仅部分或少量释放。
第三方面,提供了本发明的生物学活性组分结肠靶向组合物在制备生物学活性组分结肠靶向制剂中的应用。
第四方面,提供了本发明的生物学活性组分结肠靶向制剂的制备方法,包括:
(1)在操作温度<28℃、湿度<40%下,将羟丙甲纤维素、生物学活性组分和辅料混合;
(2)将混合物直接干压成片剂,或干法制粒后压成片剂。
本发明首次将羟丙甲纤维素与生物学活性组分结合,利用羟丙甲纤维素缓释特性和粘合作用即可经粉末直接干压或干法制粒后压片,从而制得生物学活性组分结肠靶向片剂,避免了湿法制粒和现有结肠靶向相关文献中常见的包衣方法所用的溶剂及温度对生物学活性组分活性的不利影响,且制备工艺简单,易于产业化。所制备的生物学活性组分结肠靶向片剂与市售生物学活性组分片剂相比,由于羟丙甲纤维素的多重作用,可使生物学活性组分经过胃和小肠、到达结肠部位后才释放,耐受胃和小肠环境而不被代谢分解,减小其对小肠可能产生的危害因素,提高生物学活性组分的生物利用度,从而更好地发挥体内活性。特别地就益生菌制剂而言,还可大大减少其他辅料的使用,从而显著提高每片片剂的载菌量,使得日服用量由市售常见的9片以上降至1-2片,并且片形可以更小,更便于吞服。
与现有技术相比,本发明的组合物具有显著改进的结肠靶向效果;此外,可采用食品级辅料,具有极高的安全性;能够便于工业化生产,工艺简单。因此,本发明对于食品、保健品和药品行业均具有重大的开发意义。
附图说明
图1:实施例1-7的片剂在依次经过人工胃液2h、人工肠液3h、人工结肠液18h后的溶出曲线图。
图2:不同粘度的羟丙甲纤维素制备的片剂在依次经过人工胃液2h、人工肠液3h、人工结肠液18h后的溶出曲线图。
具体实施方式
以下通过具体实施例对本发明技术方案及其效果做进一步说明。应当理解,本发明实施例仅用于示例说明本发明的具体实施方法,并不用于限制本发明的保护范围。应用本发明的构思对本发明进行的简单改进都在本发明要求保护的范围内。
如无特别说明,以下实施例中使用的试剂和仪器均是常规试剂和仪器,可以从普通商购途径获得;所使用的操作方法是本领域的常规方法,本领域技术人员结合自己的认知水平和实验能力,能够实现本文所述的实验过程并获得相应的结果。
本发明中所用的益生菌菌粉包括:乳双歧杆菌BLa80、长双歧杆菌BL21、嗜酸乳杆菌LA85和两歧双歧杆菌BBi32,它们来源于江苏紫石微康生物科技有限公司;鼠李糖乳杆菌R11、长双歧杆菌R175和乳双歧杆菌lafti B84,它们来源于法国LALLEMAND公司。所用的羟丙甲纤维素K4M、K15M、K100M来源于安徽山河辅料有限公司,所用羟丙甲纤维素K100LV和K200M来源于美国陶氏化学。
实施例1
处方:羟丙甲纤维素(HPMC K15M,粘度15000mPa.s)85wt%,乳双歧杆菌BLa80菌粉(活菌数1.0*1011cfu/g)15wt%。
制备方法:
(1)将各物料按处方量混合均匀、过100目筛子,再使之均匀混合;
(2)将粉末混合物用GL2-25型干法制粒机(张家港开创机械制造公司)进行制粒后,压片,单片重150mg,片直径8mm,所含乳双歧杆菌活菌数为1.5*1010cfu/g。
实施例2
处方:羟丙甲纤维素(HPMC K200M,粘度200000mPa.s)65wt%,鼠李糖乳杆菌R11菌粉(活菌数1.5*1011cfu/g)30wt%,硬脂酸镁5wt%。
制备方法:
(1)将各物料按处方量混合均匀;
(2)将该混合物粉末直接干压成片剂,片重450mg,片直径10mm,所含鼠李糖乳杆菌活菌数为4.5*1010cfu/g。
实施例3
处方:羟丙甲纤维素(HPMC K100M,粘度100000mPa.s)65wt%,嗜酸乳杆菌LA85菌粉(活菌数1.0*1011cfu/g)30wt%,硬脂酸镁5wt%。
制备方法:
(1)将各物料按处方量混合均匀;
(2)将该混合物粉末直接干压成片剂,片重300mg,片直径10mm,所含嗜酸乳杆菌活菌数为3.0*1010cfu/g。
实施例4
处方:羟丙甲纤维素(HPMC K200M,粘度200000mPa.s)45wt%,乳双歧杆菌BLa80菌粉(活菌数1.0*1011cfu/g)25wt%,长双歧杆菌BL21菌粉(活菌数1.5*1011cfu/g)25wt%,硬脂酸镁5wt%。
制备方法:
(1)将各物料按处方量混合均匀;
(2)将该混合物粉末直接干压成片剂,片重300mg,片直径10mm,所含乳双歧杆菌活菌数为2.5*1010cfu/g,长双歧杆菌活菌数为3.75*1010cfu/g。
实施例5
处方:羟丙甲纤维素(HPMC K4M,粘度4000mPa.s)70wt%,无水乳糖20wt%,麦芽糖醇5wt%,两歧双歧杆菌BBi32菌粉(活菌数1.5*1011cfu/g)3wt%,二氧化硅1wt%,硬脂酸镁1wt%。
制备方法:
(1)将各物料按处方量混合均匀;
(2)将该混合物粉末直接干压成片剂,片重300mg,片直径10mm,所含两歧杆菌活菌数为4.5*109cfu/g。
实施例6
处方:羟丙甲纤维素(HPMC K100M,粘度100000mPa.s)13wt%,长双歧杆菌R175菌粉(活菌数5*1010cfu/g)30wt%,异麦芽酮糖醇25wt%,菊粉15wt%,乳酸钙10wt%,果胶5wt%,硬脂酸镁2wt%。
制备方法:
(1)将各物料按处方量混合均匀;
(2)将该混合物粉末直接干压成片剂,片重300mg,片直径10mm,所含长双歧杆菌活菌数为1.5*1010cfu/g。
实施例7
处方:羟丙甲纤维素(HPMC K100M,粘度100000mPa.s)45wt%,低聚果糖20wt%,嗜乳酸杆菌R418菌粉(活菌数1.5*1011cfu/g)15wt%,乳双歧杆菌lafti B84菌粉(活菌数1*1011cfu/g)10wt%,蔓越莓粉5wt%,山梨糖醇5wt%。
制备方法:
(1)将各物料按处方量混合均匀;
(2)混合物粉末用干法制粒机制粒后,压片,片重450mg,片直径10mm,所含嗜乳酸杆菌活菌数为2.25*1010cfu/g,所含乳双歧杆菌活菌数为1.0*1010cfu/g。
实验例一:本发明实施例的溶出试验
由于益生菌对温度和水均敏感,溶出试验需要取不同时间点的溶出液,因此以考察结肠释药性的模型药物5-氨基水杨酸代替益生菌进行试验。按照中国药典(2015年版四部0931溶出度与释放度测定法第一法转篮法,50r/min,37℃,将利用上述实施例中的方法和处方制备的片剂(以5-氨基水杨酸代替相应量的益生菌)放入转篮中,依次进行人工胃液(pH1.2)2h、人工肠液(pH6.8)3h、人工结肠液(pH7.8)18h后的溶出测定。各实施例中片剂的溶出结果见图1,结肠释放百分率见表1。
表1:实施例中片剂结肠释放百分率(%)
实施例 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
片剂的结肠释放百分率(%) | 61 | 81 | 76 | 55 | 45 | 58 | 74 |
由图1和表1结果可知:实施例1-7的片剂的结肠释放百分率均可达45%以上,具有显著的结肠靶向效果。
实验例二:不同粘度羟丙甲纤维素片剂的溶出试验
以五种不同粘度的羟丙甲纤维素:HPMC K100LV(粘度:100mPa.s)、K4M、K15M、K100M和K200M,用量均为90wt%,和用量为10wt%的5-氨基水杨酸按本文所述的方法制备片剂和检测溶出结果,结果见图2。图中溶出结果显示:低粘度HPMC(K100LV)制备的片剂经人工胃液和人工肠液后释放即近100%,无法达到结肠释放;而较高粘度HPMC(K4M、K15M、K100M和K200M)制备的片剂在相同条件下可至少保持60%以上在结肠释放,且在人工结肠液中近线性释放,具有显著的结肠靶向效果。
实验例三:活菌数检测实验
以市售思连康片剂(双歧杆菌四联活菌片,500mg/片,其中婴儿双歧杆菌、嗜酸乳杆菌和粪肠球菌分别不低于0.5*106cfu/g,蜡样芽孢杆菌不低于0.5*105cfu/g,辅料为淀粉和奶粉类物质)与上述实施例制得的片剂溶出后进行活菌数检测。
(一)实验方法
(1)培养基配制
取MRS琼脂粉39.7g,加入600ml蒸馏水中,加热溶解。2.9mm玻璃培养皿用自来水洗净后,再用蒸馏水冲洗三遍,晾干。
(2)灭菌
培养基和培养皿置于灭菌锅中,121℃,103.4kPa灭菌30min。
(3)培养基置于52℃水浴锅中备用,培养皿室温放置冷却备用。
(4)溶出条件
按照中国药典(2015年版四部0931溶出度与释放度测定法第一法转篮法,50r/min,37℃),将市售思连康片剂进行人工胃液(pH1.2)2h后取出,将实施例1-7的片剂放入转篮中,依次进行人工胃液(pH1.2)2h、人工肠液(pH6.8)3h后取出。
(二)培养
取上述未经与经过溶出处理的思连康片剂与实施例1-7的片剂样品,分别置于玻璃研钵中研碎,然后用50ml生理盐水稀释,混匀后取1ml混合液10倍倍比稀释,稀释后取各个稀释度0.1ml涂布于MRS培养基上。将涂布后的平板至于厌氧袋中放在37℃恒温培养箱中培养48h后将平板取出进行菌落计数。
(三)结果
市售思连康片剂经人工胃液(pH 1.2、37℃)2h处理后,在10-4倍稀释仍无菌落数;而实施例1-7的片剂经人工胃液(pH 1.2、37℃)2h、人工肠液(pH 6.8、37℃)3h处理后,活菌数仍较多,与市售思连康片剂相比有显著性差异,具体活菌数检测结果见表2。该比较结果说明,本发明的益生菌片剂使得益生菌可以成功地耐受胃和小肠环境,从而保持其一定的活菌数递送到结肠部位释放,并且本发明对不同厂家来源的不同菌种均可保护其被递送到结肠部位释放。
表2:市售思连康和实施例1-7片剂溶出后活菌数检测结果
Claims (11)
1.一种生物学活性组分结肠靶向组合物,包括:羟丙甲纤维素、生物学活性组分和辅料,其中,所述羟丙甲纤维素的重量百分含量为10~99%,所述生物学活性组分的重量百分含量为1~60%,辅料的重量百分含量为0~80%;其中,所述羟丙甲纤维素的粘度>1000mPa.s,所述生物学活性组分为益生菌,所述组合物经粉末直接干压或干法制粒后压片。
2.根据权利要求1所述的组合物,其中,所述羟丙甲纤维素的重量百分含量为40~90%,所述生物学活性组分的重量百分含量为10~40%,所述辅料的重量百分含量为0~50%。
3.根据权利要求1或2所述的组合物,其中,所述羟丙甲纤维素的粘度为15000mPa.s~200000mPa.s。
4.根据权利要求3所述的组合物,其中,所述益生菌包括双歧杆菌、乳杆菌或革兰氏阳性球菌中的一种或多种。
5.根据权利要求4所述的组合物,其中,所述双歧杆菌是乳双歧杆菌、婴儿双歧杆菌、两歧双歧杆菌、长双歧杆菌、短双歧杆菌和青春双歧杆菌中的一种或多种;所述乳杆菌是嗜酸乳杆菌、干酪乳杆菌、卷曲乳杆菌、德氏乳杆菌保加利亚亚种、德氏乳杆菌亚种、发酵乳杆菌、格氏乳杆菌、瑞士乳杆菌、约氏乳杆菌、副干酪乳杆菌、植物乳杆菌、罗伊氏乳杆菌、鼠李糖乳杆菌、唾液乳杆菌中的一种或多种;所述革兰氏阳性球菌是粪链球菌和乳球菌中的一种或多种。
6.根据权利要求4所述的组合物,其中,所述组合物中益生菌的量为0.01亿-1200亿cfu/g。
7.根据权利要求6所述的组合物,其中,所述辅料包括有利于生物学活性组分生存稳定性的营养物质、对生物学活性组分的结肠靶向递送有益的药用辅料或食品添加剂、和/或优化制剂本身性质的其它辅料,所述优化制剂本身性质的其它辅料包括粘合剂、填充剂、润滑剂、崩解剂。
8.一种生物学活性组分结肠靶向制剂,包含权利要求1-7任一项所述的组合物。
9.根据权利要求8所述的生物学活性组分结肠靶向制剂,其中,所述制剂的剂型为片剂,所述片剂的单片质量≤500mg,直径≤10mm。
10.权利要求1-7任一项的组合物在制备生物学活性组分结肠靶向制剂中的应用。
11.一种制备权利要求9所述的生物学活性组分结肠靶向制剂的方法,包括:
(1)在操作温度为<28℃、湿度<40%下,将羟丙甲纤维素、生物学活性组分和辅料混合;
(2)将混合物直接干压成片剂,或干法制粒后压成片剂。
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CN101843337A (zh) * | 2010-06-07 | 2010-09-29 | 陕西科技大学 | 一种益生菌片的制备方法 |
CN103327990A (zh) * | 2010-12-28 | 2013-09-25 | 日清药业股份有限公司 | 双歧杆菌大肠递送胶囊及其制造方法 |
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RU2744452C2 (ru) | 2021-03-09 |
JP2020500927A (ja) | 2020-01-16 |
US11337926B2 (en) | 2022-05-24 |
CN108066296A (zh) | 2018-05-25 |
RU2019116519A3 (zh) | 2020-12-11 |
EP3539538A1 (en) | 2019-09-18 |
JP6989154B2 (ja) | 2022-01-05 |
EP3539538A4 (en) | 2020-06-03 |
US20190274960A1 (en) | 2019-09-12 |
WO2018086550A1 (zh) | 2018-05-17 |
RU2019116519A (ru) | 2020-12-11 |
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