CN115212189A - 一种提高壳寡糖口服生物利用度的纳米微球及其制备方法 - Google Patents
一种提高壳寡糖口服生物利用度的纳米微球及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种提高壳寡糖口服生物利用度的纳米微球及其制备方法,本发明制备的纳米微球粒径在800nm左右,成规则的球型,载药率为15.63%,包封率为30.05%。小鼠口服后药时曲线下面积为(69904.5±412.24)ng·min·mL‑1显著高于单独壳寡糖的药时曲线下面积(45228.5±879.93)ng·min·mL‑1,且在口服7天后,小鼠肠道中M细胞表达量显著上调,且不同程度提高肠相关淋巴组织中巨噬细胞和树突状细胞的丰度。
Description
技术领域
本发明涉及一种提高壳寡糖口服生物利用度的纳米微球及其制备方法,属于医药技术领域。
背景技术
壳寡糖是将壳聚糖经特殊的生物酶技术(也有使用化学降解、微波降解技术的报道)降解得到的一种聚合度在2~20之间寡糖产品,分子量≤3200Da,是功能作用大、生物活性高的低分子量产品。其生理功能广泛,调节动物肠道内微生物的代谢活动,改善肠道微生物区系分布,促进双歧杆茵生长繁殖,从而提高机体免疫力,使肠道内pH下降,抑制肠道有害菌生长;提高动物的回肠微绒毛密度,通过改善肠道组织形态来促进营养物质的吸收;可以直接激活巨噬细胞,增加其杀伤活性,多数学者已经证实壳寡糖的杀伤活性的产生主要是激活T淋巴细胞与巨噬细胞相互作用加强的结果。另外,壳寡糖还具有抗肿瘤、降血糖、降血脂及抗氧化等作用。目前研究调研显示,多数研究学者主要针对壳寡糖的分离、制备及其生理功能研究,然而,关于壳寡糖的吸收利用情况却研究的少之又少。
上世纪发展而来的纳米给药系统是提高药物口服生物利用度的有效策略,而且其肠道吸收机制也较为清楚。在肠黏膜的孤立和集合淋巴小结表面,黏膜向肠腔呈圆顶状隆起,此部位无绒毛和小肠腺,上皮内散在分布一种微褶皱细胞(Microfold cell,M细胞),M细胞的胞质少,表面的微绒毛短小稀疏,基底面的质膜内陷形成脚都的穹窿状凹腔,内含多个淋巴细胞;胞质中有丰富的囊泡,溶酶体非常少,且不含酸性蛋白酶,以囊泡形式将肠腔中的大分子抗原进行转运传递给下方的淋巴细胞,后者进入固有层淋巴小结将抗原信息传递给其他淋巴细胞。
研究报道显示,M细胞可以将粒径小于5μm的大分子在吞噬进淋巴循环系统后进入血液循环系统,对于粒径5μm~10μm的大分子则只能滞留在淋巴循环系统,而不能吞噬粒径大于10μm的大分子。鉴于此,本发明研发了一种粒径小于1μm的纳米微球,并选择海藻酸钠、透明质酸以及壳聚糖作为包埋材料。众所周知,壳寡糖的生物活性功能广泛,而如何提高壳寡糖的生物利用度是目前面临的一个难点和热点,通过给药剂型的改变而不改变壳寡糖本身物理性质,对于增加壳寡糖的口服生物利用度具有重要意义。
发明内容
为解决上述技术问题,本发明提供一种提高壳寡糖口服生物利用度的纳米微球,以海藻酸钠为包埋材料时,粒径在1μm以下,其口服生物利用度最佳,其中壳寡糖的载药率为15.63%,药时曲线下面积为(69904.5±412.24)ng·min·mL-1显著高于单独壳寡糖的药时曲线下面积(45228.5±879.93)ng·min·mL-1,且显著提高小鼠肠道中M细胞的表达水平,改变肠相关淋巴组织中巨噬细胞和树突状细胞亚群丰度。
本发明的第一个目的是提供一种提高壳寡糖口服生物利用度的纳米微球的制备方法,包括如下步骤:
S1、配制浓度为0.5%~2%的海藻酸钠水溶液,浓度为0.5%~2%的壳寡糖水溶液,以及氯化钙水溶液,以三种所述的水溶液作为水相;
S2、按照质量体积比,油相:水相=5:1~8:1,在油相中加入海藻酸钠水溶液,高压均质后加入壳寡糖水溶液,再次高压均质后加入氯化钙水溶液,进行搅拌固化;
其中,按照体积比,海藻酸钠水溶液:壳寡糖水溶液:氯化钙水溶液=3~5:1~3:1;
S3、采用有机溶剂洗涤离心后,重悬在水溶液中,冷冻干燥得到所述的纳米微球。
进一步地,所述的油相为包含表面活性剂的石蜡油。
进一步地,所述的表面活性剂在油相中的质量占比为20%~30%。
进一步地,所述的表面活性剂由质量比值为8:1~5:1的Span80与Tween80组成。
进一步地,在S2步骤中,高压均质的时间为2min~8min。
进一步地,氯化钙的添加量为氯化钙在水相中的浓度为0.5%~3%。
进一步地,所述的搅拌固化是在300rpm~700rpm条件下搅拌2h~10h。
进一步地,在S3步骤中,有机溶剂为石油醚和/或异丙醇。
进一步地,在S3步骤中,离心是在6,000~10,000rpm离心8~12min。
本发明的第二个目的是提供所述的制备方法制备得到提高壳寡糖口服生物利用度的纳米微球。
本发明的有益效果是:
本发明制备的纳米微球粒径在800nm左右,成规则的球型,载药率为15.63%,包封率为30.05%。小鼠口服后药时曲线下面积为(69904.5±412.24)ng·min·mL-1显著高于单独壳寡糖的药时曲线下面积(45228.5±879.93)ng·min·mL-1,且在口服7天后,小鼠肠道中M细胞表达量显著上调,且不同程度提高肠相关淋巴组织中巨噬细胞和树突状细胞的丰度。
附图说明:
图1为壳寡糖HPLC分析;
图2为壳寡糖荧光标记MALDI-TOF/TOF分析;(A)壳二糖、壳三糖和壳四糖荧光标记后图谱分析;(B)标记前后游离2-氨基吖啶酮图谱分析;
图3为壳寡糖/海藻酸钠纳米微球扫描电镜图;
图4为原位结扎肠段灌注法探究小肠吸收实验结果;(A)COS在小肠中残留情况;(B)CANs组中COS不同聚合度在小肠中残留情况;(C)COS组中COS不同聚合度在小肠中残留情况。(与0h比较,*:p<0.05,**:p<0.01);
图5为药时曲线情况;
图6组织分布情况;(A)COS组不同组织中荧光强度情况;(B)CANs组不同组织中荧光强度情况;(C)荧光强度峰下面积统计情况;(与COS组比较,*:p<0.05);
图7为肠相关淋巴组织巨噬细胞和树突状细胞变化情况;(A)潘氏结、(B)肠上皮淋巴组织、(C)肠固有层淋巴组织和(D)肠系膜淋巴结中巨噬细胞和树突状细胞变化情况;(与CTL组比较,*:p<0.05,**:p<0.01,***:p<0.001;与CANs组比较,#:p<0.05,##:p<0.01,###:p<0.001);
图8为潘氏结组织中M细胞表达水平情况;(A)流式细胞分析M细胞荧光强度;(B)荧光强度统计分析;(与CTL组比较,**:p<0.01,***:p<0.001;与COS比较,#:p<0.05,###:p<0.001)。
具体实施方式
下面结合具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1:
壳寡糖基本表征
(1)壳寡糖HPLC表征:高效液相色谱仪(UltiMate3000,DIONEX,USA)检测壳寡糖,主要如下:色谱柱:Asahipak NH2P-50 4E(4.6*250mm,5μm);流动相:20%3%o氨水和80%乙腈,流速1mL/min,柱温30℃,蒸发光检测器,氮气流速1mL/min,蒸发室温度90℃。
(2)壳寡糖荧光标记。1mg壳寡糖与20μL 0.1M 2氨基吖啶酮混匀溶解,室温静置20min,加入新配置的1M硼氢氰化钠溶液,涡旋混匀,45℃,反应5h。冰上放置10min,终止反应。40μL四氢呋喃洗涤纯化,12,000rpm,15min,取上清进行MALDI-TOF/TOF基质辅助激光解析电离串联飞行时间质谱仪(ultrafleXtreme,Bruker Daltonics Inc.,USA)验证检测。
(3)结果表明:本发明作用的壳寡糖主要由壳二糖(Chitobiose)、壳三糖(chitotriose)和壳四糖(Chitotetraose)组成,且由标曲计算得出壳二糖、壳三糖和壳四糖占比分别为28.4%、50.07%和21.52%(图1)。
为了证明壳寡糖成功标记上2-氨基吖啶酮(2-AMAC)荧光标签,基质辅助激光解析电离串联飞行时间质谱(MALDI-TOF/TOF)分析发现,壳二糖、壳三糖和壳四糖成功标记上标签后的理论分子量均能找到(图2A)。而且,2-氨基吖啶酮分子量为210.23,在反应混合物中未被检出(图2B),这说明反应混合物中不存在游离的荧光标签。
实施例2:
壳寡糖纳米微球制备工艺
壳寡糖/海藻酸钠纳米微球制备工艺
(1)称取海藻酸钠溶解于超纯水中过夜搅拌溶解成浓度1%。并配制1%壳寡糖水溶液和5%氯化钙水溶液。
(2)称取24g石蜡油,包含25%表面活性剂,表面活性剂为Span80和Tween80,比值为6:1(m/m),并搅拌混匀。
(3)油相:水相=6:1(m/v),反应时,向盛有28g油相的烧杯中滴加海藻酸钠水溶液2.67mL,16,000rpm高压均质机均质3min后,滴加壳寡糖水溶液1.33mL,并立马再次均质2min,最后滴加氯化钙水溶液至其浓度为1%进行交联固定。
(4)于磁力搅拌器上400rpm缓慢搅拌3h~4h。分别用石油醚和异丙醇离心洗涤(8,000rpm,10min,4℃),并最后重悬在水溶液中,低温真空冻干即可。
壳寡糖/透明质酸纳米微球制备工艺
(1)称取透明质酸溶解于超纯水中过夜搅拌溶解成浓度1%。并配制1%壳寡糖水溶液和5%氯化钙水溶液。
(2)称取24g石蜡油,包含25%表面活性剂,表面活性剂为Span80和Tween80,比值为6:1(m/m),并搅拌混匀。
(3)油相:水相=6:1(m/v),反应时,向盛有28g油相的烧杯中滴加透明质酸水溶液2.67mL,16,000rpm高压均质机均质3min后,滴加壳寡糖水溶液1.33mL,并立马再次均质2min。
(4)于磁力搅拌器上400rpm缓慢搅拌3h~4h。分别用石油醚和异丙醇离心洗涤(8,000rpm,10min,4℃),并最后重悬在水溶液中,低温真空冻干即可。
壳寡糖/壳聚糖纳米微球制备工艺
(1)称取壳聚糖溶解在1%醋酸溶液中均过夜搅拌溶解成浓度1%。并配制1%壳寡糖水溶液和5%氯化钙水溶液。
(2)称取24g石蜡油,包含25%表面活性剂,表面活性剂为Span80和Tween80,比值为6:1(m/m),并搅拌混匀。
(3)油相:水相=6:1(m/v),反应时,向盛有28g油相的烧杯中滴加壳聚糖溶液2.67mL,16,000rpm高压均质机均质3min后,滴加壳寡糖水溶液1.33mL,并立马再次均质2min。
(4)于磁力搅拌器上400rpm缓慢搅拌3h~4h。分别用石油醚和异丙醇离心洗涤(8,000rpm,10min,4℃),并最后重悬在水溶液中,低温真空冻干即可。
实施例3:
壳寡糖纳米微球表征
(1)载药率=(纳米微球中含有的壳寡糖质量/纳米微球总质量)×100%;包封率=(纳米微球中含有的壳寡糖质量/反应时投放的总壳寡糖质量)×100%,经HPLC检测得到,对不同包埋材料制备的壳寡糖纳米微球的粒径、Zeta电位、载药率和包封率进行表征。结果显示,海藻酸钠作为包埋材料表现最佳。本发明的壳寡糖/海藻酸钠纳米微球载药率为15.63%,包封率为30.05%。流体力学粒径和Zeta电位检测,壳寡糖/海藻酸钠纳米微球Z-average数值在800nm左右,Zeta电位为-42.64左右,且为了后续研究,同时制备了空载微球(海藻酸钠纳米微球)其Z-average数值和Zeta电位与壳寡糖/海藻酸钠纳米微球基本一致(表1)(表2)。
表1不同包埋材料粒径和Zeta电位情况
表2不同包埋材料制备的壳寡糖纳米微球载药率和包封率
(2)根据上述结果对壳寡糖/海藻酸钠纳米微球进行扫描电镜分析,由图3可知制备的壳寡糖/海藻酸钠纳米微球成规则的球型,表面略显粗糙,粒径在600nm~1000nm之间。
实施例4:
原位结扎肠段灌注法探究小肠吸收实验
(1)动物禁食24h后,腹腔注射注入麻醉剂,麻醉后将其仰卧绑定于固定板上,剪去腹部体毛打开腹腔,找出小肠段(避免损伤肠系膜血管);结扎空肠前段,以空肠前段1/3处相对位置开始结扎,固定结扎约5cm)。先将下游一端的结扎点系紧,用注射器从上游结扎点开始插入(注意:不要弄伤结扎肠段内壁)注入0.5mL壳寡糖(COS)水溶液(30mg/mL),壳寡糖/海藻酸钠纳米微球(CANs)(190mg/mL),同样注入0.5mL。以上操作完成后,将小肠重新放回腹腔,并覆盖温纱布以保证肠腔打开前的温度。在整个试验过程中,实验动物应一直处于麻醉状态。灌注时间分别为0h、0.5h、1h、2h、4h,每个时间点平行3只小鼠。实验结束后,取出肠段,将每个小段分别剪下,用注射器小心抽出各段中的剩余灌注液,注入离心管中保存HPLC待测。
(2)通过原位结扎肠段灌注法探究COS和CANs在小肠不同时间中剩余率,COS在小肠4h时的残留率约为75%,且不同聚合度COS观察显示,壳四糖几乎残留率为100%,吸收最大的主要为壳二糖。CANs在小肠4h时残留率约为55%,且不同聚合度的COS几乎同等程度被吸收。这说明和COS组比较,CANS明显促进了COS的吸收(图4)。
实施例5:
小鼠口服后生物利用度和组织分布情况分析
(1)动物分组:选用3~4周龄C57BL/6J雄性小鼠,分为3组,每组18只,分别为对照组、壳寡糖组(COS)和纳米微球组(CANs)。COS组给予50mg/kg标记上荧光的壳寡糖,CANs组给予同等剂量COS,对照组给予同等体积的溶剂。并于25min、45min、90min、180min、360min和720min随机取三只小鼠,进行眼眶取血和组织分离,避光保存检测荧光值。
比较在单独壳寡糖(COS)和壳寡糖/海藻酸钠纳米微球(CANs)的相对生物利用度(主要指标:药时曲线下面积(AUC)代表药物的生物利用度,即药物在机体中被吸收利用的程度,AUC大则生物利用度高,反之则低)。
(2)结果表明:以壳寡糖浓度为横坐标,以荧光值为纵坐标(EX/EM=450nm/530nm)测得的标准曲线,并以此统计得到药时曲线(图5),计算得到CANs组的AUC为(69904.5±412.24)ng·min·mL-1显著高于单独COS的AUC(45228.5±879.93)ng·min·mL-1,且发现CANs口服后具有缓释效果。另外,对不同组织进行荧光强度检测,结果显示,单独COS主要分布在肝脏和肾脏中,且分别在25-45min和45-90min到达最高峰(图6A)。虽然,CANs同样也主要分布在肝脏和肾脏中,但是其分别在90min和90-360min到达最高峰,这同样验证了相较于COS,CANs口服后到达各个组织具有缓释效果(图6B)。另外在对其峰下面积进行积分后发现,在肝脏、肾脏和肠系膜淋巴结中,CANs组的荧光强度明显高于COS组(图6C)。这说明CANs促进了COS在肝脏、肾脏和肠系膜淋巴结中的积累。
实施例6:
小鼠肠相关淋巴组织M细胞和淋巴亚群变化情况
(1)选用3~4周龄C57BL/6J雄性小鼠,每组8只,分4组,分别为对照组(CTL)、壳寡糖组(COS)、空微球组(ANs)和壳寡糖/海藻酸钠纳米微球组(CANs)。对照组灌胃等体积溶剂,COS组灌胃COS水溶液(500mg/kg/day),ANs组灌胃海藻酸钠空微球水溶液(500mg/kg/day),CANs组灌胃壳寡糖/海藻酸钠纳米微球(500mg/kg/day),均灌胃7天。
(2)检测指标:分别分离各组小鼠小肠的潘氏结(PP)淋巴细胞、肠上皮淋巴细胞(IEL)、肠固有层(LPL)淋巴细胞及肠系膜(MLN)淋巴细胞,通过细胞流式技术检测上述肠相关淋巴组织中巨噬细胞和树突状淋巴细胞的变化情况及小肠潘氏结中M细胞表达情况。UEA-1-FITC标记M细胞;F4/80-PE和CD11b-APC标记巨噬细胞CD11c-APC和CD86-PE标记树突状细胞。
(3)结果表明,在给予COS、ANs和CANs口服7天后,与COS和ANs组比较,给予CANs处理后PP、IEL、LPL和MLN组织中巨噬细胞和树突状细胞均出现不同程度的提高(图7)。且与COS组比较,ANs也在一定程度上上调了巨噬细胞和树突状细胞的丰度。且对PP组织中M细胞进行荧光检测发现(图8),ANs组和CANs组小鼠PP组织中M细胞荧光值均显著提高。这说明纳米微球可能通过PP组织中的M细胞吞噬作用进入PP组织中,并再次激活了肠相关淋巴组织中巨噬细胞和树突状细胞而引起一定的免疫反应。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例,本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换,均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (10)
1.一种提高壳寡糖口服生物利用度的纳米微球的制备方法,其特征在于,包括如下步骤:
S1、配制浓度为0.5%~2%的海藻酸钠水溶液,浓度为0.5%~2%的壳寡糖水溶液,以及氯化钙水溶液,以三种所述的水溶液作为水相;
S2、按照质量体积比,油相:水相=5:1~8:1,在油相中加入海藻酸钠水溶液,高压均质后加入壳寡糖水溶液,再次高压均质后加入氯化钙水溶液,进行搅拌固化;
其中,按照体积比,海藻酸钠水溶液:壳寡糖水溶液:氯化钙水溶液=3~5:1~3:1;
S3、采用有机溶剂洗涤离心后,重悬在水溶液中,冷冻干燥得到所述的纳米微球。
2.根据权利要求1所述的制备方法,其特征在于,所述的油相为包含表面活性剂的石蜡油。
3.根据权利要求2所述的制备方法,其特征在于,所述的表面活性剂在油相中的质量占比为20%~30%。
4.根据权利要求3所述的制备方法,其特征在于,所述的表面活性剂由质量比值为8:1~5:1的Span80与Tween80组成。
5.根据权利要求1所述的制备方法,其特征在于,在S2步骤中,高压均质的时间为2min~8min。
6.根据权利要求1所述的制备方法,其特征在于,氯化钙的添加量为氯化钙在水相中的浓度为0.5%~3%。
7.根据权利要求1所述的制备方法,其特征在于,所述的搅拌固化是在300rpm~700rpm条件下搅拌2h~10h。
8.根据权利要求1所述的制备方法,其特征在于,在S3步骤中,有机溶剂为石油醚和/或异丙醇。
9.根据权利要求1所述的制备方法,其特征在于,在S3步骤中,离心是在6,000~10,000rpm离心8~12min。
10.一种权利要求1~9任一项所述的制备方法制备得到提高壳寡糖口服生物利用度的纳米微球。
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