CN107518176A - 一种吸附细菌内毒素并缓解其毒性的复合制剂和应用 - Google Patents
一种吸附细菌内毒素并缓解其毒性的复合制剂和应用 Download PDFInfo
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- CN107518176A CN107518176A CN201710630638.7A CN201710630638A CN107518176A CN 107518176 A CN107518176 A CN 107518176A CN 201710630638 A CN201710630638 A CN 201710630638A CN 107518176 A CN107518176 A CN 107518176A
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Abstract
本发明公开了一种吸附细菌内毒素并缓解其毒性的复合制剂和应用,按质量百分含量计,该复合制剂包含改性凹凸棒石71.43%~98.95%、维生素0.09%~10.34%、氨基酸0.96%~23.69%。本发明的复合制剂按照0.05%~1.00%的质量比添加到动物配合饲料中混合均匀后饲喂,不仅可以通过吸附细菌内毒素以防止其对机体的直接毒性作用,还可抑制肠道病原菌增殖、增强机体免疫力、改善机体抗氧化功能,从而提高机体对细菌内毒素的抵抗力,改善动物生产性能;同时本发明还具有制剂制备简单、可操作性强、原材料丰富等特点。
Description
技术领域
本发明属于养殖领域,具体涉及一种吸附细菌内毒素并缓解其毒性的复合制剂和应用。
背景技术
细菌内毒素(Endotoxins)是革兰氏阴性菌细胞壁外膜的脂多糖(Lipopolysaccharide,LPS),其单体分子量约为10000~20000,具有良好的热稳定性。当细菌处于对数生长期或细菌营养缺乏时,细菌会自行释放LPS。此外,当细菌发生死亡裂解时,LPS亦会被释放到细菌所处的环境中。LPS是引起全身性炎症综合征的主要原因,正常状态下机体通过肠道网状内皮组织系统清除肠道内毒素,当LPS进入动物循环系统后,就可能导致全身性炎症、内毒素血症、休克甚至死亡。由内毒素引起的急性肝损伤会导致急性肝功能衰竭,且病死率高,内毒素引起的肝损伤可能由巨噬细胞介导,肝脏内的巨噬细胞被激活后释放多种免疫效应分子,如ROS和细胞因子等,从而导致肝细胞的氧化性损伤。
LPS由类脂A、核心多糖和O-抗原三部分组成,类脂A结构是磷酸化葡萄胺二糖被不同数量的脂肪酸修饰,这些疏水性的脂肪酸链将LPS固定在细菌细胞壁外膜上,其余部分则游离在细胞表面。核心多糖一般是单糖(己糖、庚糖等)、半乳糖以及3-脱氧-D-甘露醇辛酮酸糖(KDO)等组成的链状化合物,很多细菌LPS的核心多糖还含有非碳水化合物部分,如磷酸盐、氨基酸和乙酰胺取代基等。该链一端与O-抗原链相连,另一端通过一个寡糖成分直接与类脂A相连。一般同一菌种之间的核心多糖变化不大。O-抗原链也叫O-多糖或O-侧链,是多个多糖的聚合物,它是LPS分子最外层部分,不同菌种的O-抗原链各不相同。LPS的特殊结构决定了它的双亲性,既具有亲水能力也具有亲脂性质。
内毒素的去除方法主要有:通过强酸、强碱或强氧化剂的化学分解,以及超滤、双水相萃取、层析等,但这些均不适用于动物机体中;也有采用活性炭、多黏菌素吸附去除细菌内毒素的研究报道,活性炭、多粘菌素对内毒素具有良好的去除效果,但活性炭选择性差,多黏菌素价格昂贵且对人体神经系统和肾脏有较强的毒性作用;硅铝酸盐矿物吸附细菌内毒素的报道主要集中在蒙脱石和沸石,且作用效果不明确或吸附效率低。
发明内容
本发明的目的在于提供一种吸附细菌内毒素并缓解其毒性的复合制剂,以及这种复合制剂的制备方法和应用。
本发明的目的可以通过以下技术方案实现:
一种吸附细菌内毒素并缓解其毒性的复合制剂,按质量百分比计,该复合制剂包含改性凹凸棒石71.43%~98.95%、维生素0.09%~10.34%、氨基酸0.96%~23.69%,本发明配方中,所有组分质量百分含量之和为100%。
上述的改性凹凸棒石包括固相载锌凹凸棒石、液相载锌凹凸棒石和壳聚糖改性凹凸棒石,具体可以是其中的一种,也可以是任意几种的混合材料。
上述改性凹凸棒石的改性用凹凸棒石原料为从天然矿石中采选得到的原土,也可以是经过提纯或超微粉碎后的产品。
上述凹凸棒石原料的纯度不低于60%。
上述的维生素包括维生素A、维生素C和维生素E,具体可以是其中的一种,也可以是任意几种的混合材料。优选为包括维生素A、维生素C和维生素E。
上述的维生素E可以是天然生育酚或合成生育酚,也可以是天然生育酚和合成生育酚的混合材料。
上述的氨基酸包括精氨酸、赖氨酸、谷氨酰胺、丝氨酸和各自的衍生物,具体可以是其中的一种,也可以是任意几种的混合材料。优选为精氨酸、谷氨酰胺和丝氨酸中的至少一种与赖氨酸的混合物。
上述的吸附细菌内毒素并缓解其毒性的复合制剂,采用以下步骤制备:按照上述质量百分比称取改性凹凸棒石、维生素和氨基酸,充分混合即得到所述的复合制剂。
上述的复合制剂在动物饲料中的应用,取上述的复合制剂按照0.05%~1.00%的质量比添加到动物配合饲料中,混合均匀即可。
上述的固相载锌凹凸棒石采用以下步骤制备:
a1.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围为250~300℃;
b1.将活化后的凹凸棒石冷却后与ZnCl2按照质量比1:0.13~0.50均匀混合得到混合物;
c1.将所述的混合物进行高温煅烧负载,所述高温煅烧的温度范围为200~300℃;
d1.用去离子水洗涤煅烧后的样品,以去除未负载锌,洗涤后的样品经烘干粉碎后,即得固相载锌凹凸棒石;
上述的液相载锌凹凸棒石采用以下步骤制备:
a2.称取ZnCl2配制成离子溶液,所述离子溶液的浓度范围为0.10~3.00mol/L;
b2.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围250~300℃;
c2.按照凹凸棒石与ZnCl2的质量摩尔比g:mmol为1:1~30向ZnCl2溶液中加入凹凸棒石,得到凹凸棒石和ZnCl2的混合悬浊液;
d2.将所述的混合悬浊液升温至20~80℃,并搅拌6~48h后进行固液分离,所得沉淀用去离子水洗涤;
e2.将洗涤后的沉淀置于烘箱中烘干后粉碎,即得液相载锌凹凸棒石;
上述的壳聚糖改性凹凸棒石采用以下步骤制备:
a3.按照壳聚糖和0.17mol/L的醋酸溶液质量体积比g:mL为1:5~20制成壳聚糖醋酸溶液;
b3.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围250~300℃;
c3.按照凹凸棒石与壳聚糖的质量摩尔比g:mmol为1:0.5~1.5向壳聚糖溶液中加入凹凸棒石,得到凹凸棒石和壳聚糖的混合悬浊液;
d3.将所述的混合悬浊液升温至20~80℃,并搅拌6~48h后进行固液分离,所得沉淀用蒸馏水洗涤3-4次使洗涤液pH值在6.8-7.2之间;
e3.将洗涤后的沉淀置于烘箱中烘干后粉碎,即得壳聚糖改性凹凸棒石。
凹凸棒石(attapulgite)又称坡缕石(palygorskite),是一种含水富镁铝硅酸盐粘土矿物,在矿物学上隶属于海泡石族。丰富的内部空隙层链状以及表面凹凸相间结构使其具有巨大的比表面积和良好的吸附及承载性能。同时凹凸棒石作为一种天然矿物粘土,其表面聚合物层的酯基和表面羟基群,使其具有亲水和疏水性。为充分发挥凹土的功能优势,基于LPS的结构性质,通过金属、多糖对其进行改性处理,进而提高凹凸棒石对LPS的吸附有效性和选择性。
维生素A是一种脂溶性维生素,在维持视力正常、促进生长和提高机体免疫力等方面具有重要作用。维生素C又称L-抗坏血酸,是一种水溶性维生素,参与体内多种代谢过程,是机体生命过程中必需的营养素,同时它也是一种抗氧化剂,可以清除机体中的自由基。维生素E是一种脂溶性维生素,主要作用是作为生物抗氧化剂,可阻止自由基反应的进行,从保护细胞膜磷脂和血浆脂蛋白中的多不饱和脂肪酸免受氧自由基的攻击;同时它也是哺乳动物维持生育必不可少的营养素,具有调节免疫系统的作用。
精氨酸的等电点为10.76,是机体鸟氨酸循环的中间代谢产物,可促进尿素的生成和排泄。赖氨酸是机体的一种必需氨基酸,等电点为9.74,能够促进机体发育,增强机体免疫功能,并具有提高中枢神经组织功能的作用。丝氨酸是一种非必需氨基酸,等电点为5.68,远小于精氨酸和赖氨酸,但其特殊的分子结构显著降低了它的空间位阻,在脂肪和脂肪酸的新陈代谢、肌肉的生长及维持机体的免疫功能中均发挥着重要作用。谷氨酰胺是一种谷氨酸的酰胺,等电点为5.65,是动物机体中含量最丰富的游离氨基酸,是肠道细胞和免疫细胞的主要能量物质,有利于维持肠道细胞骨架的完整性,提高丝状肌动蛋白与球状肌动蛋白的比率,降低小肠绒毛的渗透性。
本发明所涉及的材料除特别说明外,均可通过市场购买获得。
本发明有如下优点:
(1)本发明提供了一种吸附细菌内毒素并缓解其毒性的复合制剂材料且可直接应用于动物饲料中。
(2)本发明采用多种饲料添加剂进行复配,发挥其协同作用,不仅可以吸附内毒素防止其直接的毒性作用,同时还可抑制肠道病原菌增殖、增强机体免疫力、改善机体抗氧化功能,从而增强机体对细菌内毒素的抵抗力,提高动物生产性能。
(3)本发明制剂制备简单,原材料丰富,可操作性强。
具体实施方式
下面结合实例对本发明作进一步说明,但本发明不受其限制。
实施例1制备固相载锌凹凸棒石和壳聚糖改性凹凸棒石
(1)制备固相载锌凹凸棒石:
a1.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度为280℃;
b1.将活化后的凹凸棒石冷却后与ZnCl2按照质量比1:0.40均匀混合得到混合物;
c1.将所述的混合物进行高温煅烧负载,所述高温煅烧的温度为250℃;
d1.用去离子水洗涤煅烧后的样品,以去除未负载锌,洗涤后的样品经烘干粉碎后,即得固相载锌凹凸棒石。
(2)制备液相载锌凹凸棒石:
a2.称取ZnCl2配制成离子溶液,所述离子溶液的浓度范围为1.00mol/L;
b2.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围280℃;
c2.按照凹凸棒石与ZnCl2的质量摩尔比为g:mmol为1:10向ZnCl2溶液中加入凹凸棒石,得到凹凸棒石和ZnCl2的混合悬浊液;
d2.将所述的混合悬浊液升温至60℃,并搅拌30h后进行固液分离,所得沉淀用去离子水洗涤;
e2.将洗涤后的沉淀置于烘箱中烘干后粉碎,即得液相载锌凹凸棒石;
(3)制备壳聚糖改性凹凸棒石:
a3.按照壳聚糖和0.17mol/L的醋酸溶液质量体积比g:mL为1:15制成壳聚糖醋酸溶液;
b3.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围280℃;
c3.按照凹凸棒石与壳聚糖的质量摩尔比为g:mmol为1:1向壳聚糖溶液中加入凹凸棒石,得到凹凸棒石和壳聚糖的混合悬浊液;
d3.将所述的混合悬浊液升温至60℃,并搅拌30h后进行固液分离,所得沉淀用蒸馏水洗涤3-4次使洗涤液pH值在6.8-7.2之间;
e3.将洗涤后的沉淀置于烘箱中烘干后粉碎,即得壳聚糖改性凹凸棒石。
凹凸棒石原料为从天然矿石中采选得到的原土,纯度不低于60%。
实施例2制备畜禽用吸附细菌内毒素并缓解其毒性的复合制剂
按照质量百分比计,分别称取实施例1制备的固相载锌凹凸棒石78.13%,维生素A1.75%,维生素C 4.41%,合成维生素E 3.84%,赖氨酸4.06%,精氨酸7.81%,充分混合即得到所述的复合制剂。
实施例3制备水产用吸附细菌内毒素并缓解其毒性的复合制剂
按照质量百分比计,分别称取实施例1制备的固相载锌凹凸棒石83.95%,维生素A1.23%,维生素C 6.30%,合成维生素E 2.47%,赖氨酸4.94%,谷氨酰胺1.11%,充分混合即得到所述的复合制剂。
实施例4制备畜禽用吸附细菌内毒素并缓解其毒性的复合制剂
按照质量百分比计,分别称取实施例1制备的壳聚糖改性凹凸棒石95.15%,维生素A 0.95%,维生素C 0.95%,合成维生素E 0.57%,赖氨酸0.95%,精氨酸1.43%,充分混合即得到所述的复合制剂。
对比试验1
为了验证一种吸附细菌内毒素并缓解其毒性的复合制剂的应用效果,采用实施例2配制的制剂产品进行体外吸附对比试验,同时设置凹凸棒石原土对照。试验分对照组、凹凸棒石组、实施例2配制制剂组和实施例4配制制剂组,每组设三个重复,凹凸棒石组、实施例2配制制剂组和实施例4配制制剂组试管中分别添加5mg相应产品;脂多糖(LPS)购于Sigma公司,血清型为E.Coli O55:B5,对原液进行稀释后,5mL稀释液分别加入到不同试管中,37℃,300r/min摇床振摇2h,然后把样品在500×g速度下离心15min,分别测定上清液中LPS的含量,结果如表1所示:凹凸棒石组、实施例2配制制剂组和实施例4配制制剂组LPS去除率分别为46.34%、83.00%和78.16%。说明凹凸棒石原土对细菌内毒素的吸附效果较差,而本发明实施例2配制制剂和实施例4配制制剂对细菌内毒素具有良好的吸附效果。
表1实施例2和实施例4配制制剂对LPS吸附去除效果研究
对比试验2
为了验证一种吸附细菌内毒素并缓解其毒性的复合制剂的应用效果,采用实施例2配制的制剂产品进行饲养试验。选用1日龄AA肉鸡180只分成2组,每组6个重复,每个重复15只,其中对照组饲喂基础日粮,试验组在基础日粮中额外添加0.06%的实施例2配制的制剂产品,肉鸡试验周期为21天。于1天和21天对每重复肉鸡进行空腹称重,并统计采食量,计算平均日增重、平均日采食量及料重比,试验结果如表2所示:与对照组相比,试验组料重比显著降低了4.86%。于试验第21天每重复随机挑选1只肉鸡采集血液样品两份分别装于无热源抗凝管和干净离心管中,4℃3000r/min分别离心无热源抗凝管和干净离心管5分钟和15分钟,分离血浆和血清用于测定血浆内毒素含量和血清溶菌酶活性;肉鸡死亡解剖后,分离十二指肠、空肠、回肠和盲肠,使用洁净的载破片刮取十二指肠、空肠和回肠黏膜,收集于冻存管,液氮速冻后置于-80℃用于免疫球蛋白和抗氧化功能的测定;无菌条件下,称取盲肠内容物经稀释涂板培养,计算盲肠细菌数量。试验结果如表3所示:与对照组相比,试验组血浆内毒素含量显著降低了78.75%,血清溶菌酶活性提高了24.44%;由表4可知,与对照组相比,试验组降低了盲肠大肠杆菌和沙门氏菌数量;由表5可知,试验组十二指肠黏膜SigA和IgM分别比对照组提高了18.29%和29.36%;由表6可知,试验组空场黏膜和回肠黏膜T-SOD含量比对照组提高了5.08%和14.66%。说明本发明实施例2配制的制剂能够吸附缓解进入肉鸡机体内毒素的含量、抑制有害病原菌增殖、增强机体免疫力、改善机体抗氧化能力,进而保护肉鸡生长。
表2实施例2配制制剂对肉鸡1-21d生产性能的影响
表3实施例2配制制剂对肉鸡21d血浆内毒素含量和血清溶菌酶活性的影响
表4实施例2配制制剂对肉鸡21d盲肠菌群的影响(lg CFU/g)
表5实施例2配制制剂对肉鸡21d肠道黏膜免疫球蛋白的影响(μg/mgprot)
表6实施例2配制制剂对肉鸡21d肠道黏膜抗氧化功能的影响
本发明通过在普通饲料中加入改性凹凸棒石材料、维生素和氨基酸制备的复合制剂,能够有效吸附动物机体内毒素、抑制肠道病原菌增殖、增强机体免疫力、改善机体抗氧化性能,提高动物生产性能。
以上实施例和对比试验仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡依据本发明所提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明保护范围之内,本发明未涉及的技术均可通过现有技术加以实现。
Claims (10)
1.一种吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:按质量百分比计,该复合制剂包含改性凹凸棒石71.43%~98.95%、维生素0.09%~10.34%、氨基酸0.96%~23.69%。
2.根据权利要求1所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:所述的改性凹凸棒石为固相载锌凹凸棒石、液相载锌凹凸棒石和壳聚糖改性凹凸棒石中的至少一种。
3.根据权利要求2所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:
所述的固相载锌凹凸棒石采用以下步骤制备:
a1.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围为250~300℃;
b1.将活化后的凹凸棒石冷却后与ZnCl2按照质量比1:0.13~0.50均匀混合得到混合物;
c1.将所述的混合物进行高温煅烧负载,所述高温煅烧的温度范围为200~300℃;
d1.用去离子水洗涤煅烧后的样品,以去除未负载锌,洗涤后的样品经烘干粉碎后,即得固相载锌凹凸棒石;
所述的液相载锌凹凸棒石采用以下步骤制备:
a2.称取ZnCl2配制成离子溶液,所述离子溶液的浓度为0.10~3.00mol/L;
b2.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围250~300℃;
c2.按照凹凸棒石与ZnCl2的质量摩尔比g:mmol为1:1~30向ZnCl2溶液中加入凹凸棒石,得到凹凸棒石和ZnCl2的混合悬浊液;
d2.将所述的混合悬浊液升温至20~80℃,并搅拌6~48h后进行固液分离,所得沉淀用去离子水洗涤;
e2.将洗涤后的沉淀置于烘箱中烘干后粉碎,即得液相载锌凹凸棒石;
所述的壳聚糖改性凹凸棒石采用以下步骤制备:
a3.按照壳聚糖和0.17mol/L的醋酸溶液质量体积比g:mL为1:5~20制成壳聚糖醋酸溶液;
b3.反应前将凹凸棒石原料在马弗炉中进行高温活化处理,所述活化处理的温度范围250~300℃;
c3.按照凹凸棒石与壳聚糖的质量摩尔比g:mmol为1:0.5~1.5向壳聚糖溶液中加入凹凸棒石,得到凹凸棒石和壳聚糖的混合悬浊液;
d3.将所述的混合悬浊液升温至20~80℃,并搅拌6~48h后进行固液分离,所得沉淀用蒸馏水洗涤3-4次使洗涤液pH值在6.8-7.2之间;
e3.将洗涤后的沉淀置于烘箱中烘干后粉碎,即得壳聚糖改性凹凸棒石。
4.根据权利要求2或3所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:所述改性凹凸棒石的改性用凹凸棒石原料为从天然矿石中采选得到的原土,或经过提纯或超微粉碎后的产品。
5.根据权利要求3或4所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:所述凹凸棒石原料的纯度不低于60%。
6.根据权利要求1所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:所述的维生素为维生素A、维生素C和维生素E中的至少一种;优选为包括维生素A、维生素C和维生素E。
7.根据权利要求6所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:所述的维生素E可以是天然生育酚或合成生育酚,也可以是天然生育酚和合成生育酚的混合材料。
8.根据权利要求1所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:所述的氨基酸包括精氨酸、赖氨酸、谷氨酰胺、丝氨酸和各自的衍生物,具体可以是其中的一种,也可以是任意几种的混合材料;优选为精氨酸、谷氨酰胺和丝氨酸中的至少一种与赖氨酸的混合物。
9.根据权利要求1所述的吸附细菌内毒素并缓解其毒性的复合制剂,其特征在于:采用以下步骤制备:按照上述质量百分比称取改性凹凸棒石、维生素和氨基酸,充分混合即得到所述的复合制剂。
10.权利要求1~9中任一所述的复合制剂在动物饲料中的应用,其特征在于:取权利要求1~9中任一所述的复合制剂按照0.05%~1.00%的质量比添加到动物配合饲料中,混合均匀即可。
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