CN109464482A - 用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊及制备方法 - Google Patents
用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊及制备方法 Download PDFInfo
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- CN109464482A CN109464482A CN201811494619.7A CN201811494619A CN109464482A CN 109464482 A CN109464482 A CN 109464482A CN 201811494619 A CN201811494619 A CN 201811494619A CN 109464482 A CN109464482 A CN 109464482A
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- enrofloxacin
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Abstract
用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊及制备方法,肠溶胶囊的囊心由恩诺沙星、艾叶油、肠粘膜保护剂、润湿剂、粘合剂和稀释剂组成,囊心喷有肠溶衣材料喷雾剂。本发明的用于预防和治疗仔猪黄白痢的复方恩诺沙星肠溶胶囊,先制成颗粒,载药量大,便于灌封包装,理化性质稳定,便于保存;该胶囊能够迅速到达靶组织,发挥抗菌性,不仅能延长药物的半衰期,还可以提高其生物利用度,可降低细菌对恩诺沙星的耐药性,增强机体的抵抗力,达到标本兼治的效果。
Description
技术领域
本发明属于兽用药物领域,尤其涉及一种用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊及制备方法。
背景技术
仔猪黄白痢是由产肠毒素性致病大肠杆菌引起的腹泻,主要危害1个月龄以内的仔猪和断奶仔猪,发病率和死亡率高等特点。养猪生产中,尤其是一些饲养管理条件较差的中小型猪场,一旦出现环境卫生改变,天气忽冷忽热,大肠杆菌就容易趁虚而入,还常常和流行性腹泻,伪狂犬等病毒性疾病混合感染,给养猪业造成巨大的经济损失。目前,对本病的防治主要是应用疫苗预防和药物防治。然而由于大肠杆菌菌株血清型众多且每个地方流行血清型不同,应用疫苗对大肠杆菌病常常无法有效预防,目前对该病的防治仍以药物为主,但是由于抗菌药物的大量使用,大肠杆菌又产生了耐药性,甚至出现了多重耐药菌株,导致许多养殖场往往无药可用
恩诺沙星为合成的第三代喹诺酮类动物专用抗菌药。本品为广谱杀菌药,对大肠杆菌、沙门氏菌、变形杆菌、多杀性巴氏杆菌、金葡菌、链球菌等都有杀菌效用。口服吸收好,血药浓度高且稳定,能广泛分布于组织中,其代谢产物为环丙沙星,仍有强大抗菌作用,在动物体内半衰期长,有良好的组织分布性。艾叶作为中草药自古以来就广泛应用于临床,现代医学药理研究表明艾叶是一种广谱抗菌抗病毒药物,对好多病毒和细菌都有杀伤作用,其中艾叶挥发油是杀菌的重要成分尤其对大肠杆菌有很强的抑菌效果。不仅如此,据文献报道,对一些产生耐药性的致病性大肠杆菌菌株,艾叶还能消除致病菌株携带的耐药质粒,提高药物的敏感性。因此,恩诺沙星和艾叶油中西药联合应用,可以消除细菌对恩诺沙星的耐药质粒,大大提高恩诺沙星的抗菌活性,减少抗菌药的使用量。
鉴于恩诺沙星性质稳定,但味苦,适口性较差的特点,目前临床上恩诺沙星大多直接做出注射剂进行注射给药,口服剂型很少,胶囊几乎没有。因此,根据产肠毒素型大肠杆菌作用于肠道的特点结合恩诺沙星自身的物理性质考虑将这一组合药物直接做成缓释颗粒剂,密封在肠溶胶囊,仔猪内服后直接到达肠道,发挥靶向抗菌作用。该药药物性质稳定,临床用药次数减少,靶向性强,在临床上有很大的应用前景。
发明内容
本发明所要解决的技术问题在于克服上诉现有技术之不足,提供一种疗效显著、便于大规模集约化生产的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊及制备方法。
本发明是以如下技术方案实现的:用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,所述肠溶胶囊的囊心由恩诺沙星、艾叶油、肠粘膜保护剂、润湿剂、粘合剂和稀释剂组成,所述囊心喷有肠溶衣材料喷雾剂。
其进一步是:各组分重量百分比含量为:恩诺沙星2~10%W/W、艾叶油5~10%W/W、肠粘膜保护剂10~20% W/W、润湿剂5~10%W /W、粘合剂2~20% W/W、稀释剂加至100% W/W(不包括肠溶衣材料的含量)、肠溶衣材料1-20%W/W。
所述艾叶油为艾叶提取物、艾叶水提物或艾叶醇提物。
所述肠粘膜保护剂选自山药多糖、黄芪多糖、党参多糖、蒲公英多糖、桑叶多糖、葫芦巴多糖、长根菇多糖中的一种或两种以上组合。
所述润湿剂选自水或乙醇,所述乙醇的浓度为5%-90%。
所述粘合剂选自羧甲基纤维素钠、乙基纤维素、微晶纤维素、聚乙烯吡咯烷酮、聚乙二醇、海藻酸钠中的一种或两种以上组合,所述聚乙二醇的分子量为PEG400-PEG6000。
所述稀释剂选自甘露醇、木糖醇、乳糖、淀粉、微晶纤维素、羧甲基淀粉钠、滑石粉、硬脂酸等中的一种或两种以上组合。
所述肠溶衣材料选自羟丙基纤维素钛酸酯、醋酸纤维素钛酸酯、乙基纤维素、聚乙烯醇、聚乙二醇中的一种或几种复合物。
一种如权利要求1所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊的制备方法,包括以下步骤:
a)将恩诺沙星粉碎过100目筛,将其余辅料粉碎过80目筛;
b)准确称取处方量原辅料,混合均匀;
c)加适量润湿剂进行调和至手握不散开为宜;
d)在制粒机上进行制粒,18目筛整粒,备用;
e)将肠溶衣材料加适量水调成肠溶衣液;
f)将之前制备好的颗粒置于包衣锅内,以喷雾法将肠溶衣液均匀喷洒在颗粒表面,并在40-50度的温度范围内进行干燥,将所制颗粒分装入空胶囊壳即可。
本发明具有以下优点:本发明的用于预防和治疗仔猪黄白痢的复方恩诺沙星肠溶胶囊,先制成颗粒,载药量大,便于灌封包装,理化性质稳定,便于保存。口服给药后胶囊掩盖了恩诺沙星的苦味,能够迅速到达靶组织,艾叶油经吸收后迅速达到有效血药浓度,发挥抗菌,消除耐药质粒的作用,而恩诺沙星则以微粒状态在肠道内缓慢持续的释放保证药物在体液内长期处于有效血药浓度以上,不仅延长了药物的半衰期,提高了其生物利用度,还减少了细菌对恩诺沙星的耐药性,同时配合增强了机体的抵抗力,达到标本兼治的效果。
具体实施方式
实施例1:
复方恩诺沙星肠溶胶囊的组方:
组方 | 用量 |
恩诺沙星 | 2kg |
艾叶油 | 5kg |
黄芪多糖 | 10kg |
50%乙醇 | 5kg |
羧甲基纤维素钠 | 5kg |
微晶纤维素 | 73 kg(加至100kg) |
羟丙基纤维素钛酸酯 | 1kg |
复方恩诺沙星肠溶胶囊的制备方法:
(1)将恩诺沙星粉碎过100目筛,将其余辅料粉碎过80目筛。
(2)准确称取处方量原辅料,混合均匀。
(3)加适量50%乙醇进行调和至手握不散开为宜
(4)在制粒机上进行制粒,18目筛整粒,备用。
(5)将羟丙基纤维素钛酸酯加适量水调成肠溶衣液
(6)将之前制备好的颗粒置于包衣锅内,以喷雾法将肠溶衣液均匀喷洒在颗粒表面。40-50度干燥。
(7)将所制颗粒分装入空胶囊壳即可。
实施例2:
复方恩诺沙星肠溶胶囊的组方:
组方 | 用量 |
恩诺沙星 | 4kg |
艾叶油 | 10kg |
蒲公英多糖-黄芪多糖(1:2) | 10kg |
60%乙醇 | 5kg |
微晶纤维素 | 10kg |
乳糖 | 61 kg(加至100kg) |
羟丙基纤维素钛酸酯-醋酸纤维素钛酸酯(1:5) | 2kg |
复方恩诺沙星肠溶胶囊的制备方法:
(1)将恩诺沙星粉碎过100目筛,将其余辅料粉碎过80目筛。
(2)准确称取处方量原辅料,混合均匀。
(3)加适量60%乙醇进行调和至手握不散开为宜
(4)在制粒机上进行制粒,18目筛整粒,备用。
(5)将羟丙基纤维素钛酸酯-醋酸纤维素钛酸酯(1:5)加适量水调成肠溶衣液
(6)将之前制备好的颗粒置于包衣锅内,以喷雾法将肠溶衣液均匀喷洒在颗粒表面。40-50度干燥。
(7)将所制颗粒分装入空胶囊壳即可。
实施例3:
复方恩诺沙星肠溶胶囊的组方:
组方 | 用量 |
恩诺沙星 | 5kg |
艾叶水提取物 | 15kg |
山药多糖 | 15kg |
75%乙醇 | 10kg |
聚乙烯吡咯烷酮 | 6kg |
淀粉 | 49 kg(加至100kg) |
羟丙基纤维素钛酸酯-乙基纤维素(4:6) | 5kg |
复方恩诺沙星肠溶胶囊的制备方法:
(1)将恩诺沙星粉碎过100目筛,将其余辅料粉碎过80目筛。
(2)准确称取处方量原辅料,混合均匀。
(3)加适量75%乙醇进行调和至手握不散开为宜
(4)在制粒机上进行制粒,18目筛整粒,备用。
(5)将羟丙基纤维素钛酸酯-乙基纤维素(4:6)加适量水调成肠溶衣液
(6)将之前制备好的颗粒置于包衣锅内,以喷雾法将肠溶衣液均匀喷洒在颗粒表面。40-50度干燥。
(7)将所制颗粒分装入空胶囊壳即可。
实施例4:
复方恩诺沙星肠溶胶囊的组方:
组方 | 用量 |
恩诺沙星 | 10kg |
艾叶醇提取物 | 10kg |
山药多糖-桑叶多糖 | 20kg |
70%乙醇 | 10kg |
聚乙二醇4000 | 7kg |
木糖醇-甘露醇 | 43 kg(加至100kg) |
醋酸纤维素钛酸酯-乙基纤维素(3:7) | 10kg |
复方恩诺沙星肠溶胶囊的制备方法:
(1)将恩诺沙星粉碎过100目筛,将其余辅料粉碎过80目筛。
(2)准确称取处方量原辅料,混合均匀。
(3)加适量70%乙醇进行调和至手握不散开为宜
(4)在制粒机上进行制粒,18目筛整粒,备用。
(5)将醋酸纤维素钛酸酯-乙基纤维素(3:7)加适量水调成肠溶衣液
(6)将之前制备好的颗粒置于包衣锅内,以喷雾法将肠溶衣液均匀喷洒在颗粒表面。40-50度干燥。
(7)将所制颗粒分装入空胶囊壳即可。
实施例5:本发明药物的体外抑菌试验
1 试验材料
试验菌种:大肠杆菌标准株(ATCC25922)、临床分离大肠杆菌耐药菌株,产ECCT大肠杆菌菌株。试验药物:本发明实施例一所配制的复方恩诺沙星肠溶胶囊(5%),单方恩诺沙星肠溶胶囊(5%),盐酸恩诺沙星可溶性粉(5%)。
2 试验方法
通过测定不同剂型恩诺沙星以及单方恩诺沙星和复方恩诺沙星对致病性大肠杆菌、耐药性大肠杆菌、产ECCT大肠杆菌的最低抑菌浓度(MIC)来评价复方恩诺沙星肠溶胶囊的体外抗菌活性。 试验分为复方恩诺沙星肠溶胶囊组,单方恩诺沙星肠溶胶囊组和盐酸恩诺沙星可溶性粉组。以恩诺沙星计,首先用生理盐水将3组药物浓度稀释至1 000μg/mL,将各细菌菌液用肉汤培养液稀释成10 5CFU/mL浓度。根据所试药物排列有棉塞的无菌试管,每种药物一列,每列为13管。每管加营养肉汤1 mL,第1管加药液1 mL,依次作倍比稀释至第11管,第12管作为细菌对照,第13管作药液对照,第1-12管起每管0.1 mL的10 5CFU/mL浓度菌液,37℃培养24h,观察每组试管,未见检测菌生长的试管药液浓度为该药的最低抑菌浓度(MIC)。每个试验重复3次,结果取平均值。
3 试验结果
复方阿莫西林混悬注射剂的体外抑菌活性评价
试验药物组 | 大肠杆菌标准株(ug/mL) | 大肠杆菌耐药菌株(ug/mL) | 产ECCT大肠杆菌(ug/mL) |
复方恩诺沙星肠溶胶囊组 | 37 | 75 | 125 |
单方恩诺沙星肠溶胶囊组 | 37 | 250 | 250 |
恩诺沙星可溶性粉组 | 37 | 250 | 500 |
结论:由实验结果可以看出,对于大肠杆菌添加了艾叶油的复方恩诺沙星肠溶胶囊其最小抑菌浓度降低了5-10.5倍,抗菌活性大大提高,这也从另一方面印证了文献报道的艾叶油与抗菌素连用,可有效消除耐药细菌的耐药质粒,从而具有协同增效作用。
实施例6 :临床疗效对比试验
1 试验材料
试验动物选择大型养猪场三元杂交患白痢的哺乳小仔猪。临床症状表现为患病仔猪排粪次数增加,粪便腥臭,颜色呈淡灰白色或微黄白色,稀糊状,水样或呈牙膏状等。经临床兽医诊断为仔猪白痢。试验药物选择本发明实施例一所配制的复方恩诺沙星肠溶胶囊(5%),以及按实施例一方法配制的单方恩诺沙星肠溶胶囊(5%)和市售恩诺沙星可溶性粉(5%)三种药物分别进行治疗。
2 试验方法
以窝为单位,随机分为4组,每组30头,第一组不给予任何药物治疗,对患猪临床症状观察记录作为对照组;第二组给予恩诺沙星可溶性粉,以恩诺沙星计,内服,一次量,每kg体重10mg,每天2次,连用3天;第三组给予单方恩诺沙星肠溶胶囊,口服,以恩诺沙星计,一次量,每kg体重5mg, 每天一次,连用3天。第四组给予复方恩诺沙星肠溶胶囊,口服,以恩诺沙星计,一次量,每kg体重5mg,每天一次,连用3天。用药后每天观察疗效情况。治疗后患猪精神,食欲恢复正常,粪便呈条状或颗粒状,肛门干燥、收缩、无红肿,7天内无复发为痊愈;治疗后粪便变稠,排便次数减少,肛门红肿尚未完全消失,精神、食欲改善为有效;治疗后患猪精神,食欲,粪便无明显改善,甚至死亡为无效。根据治愈,有效,无效的头数占各组头数的比例计算治愈率,有效率和无效率。
3 试验结果
复方恩诺沙星肠溶胶囊对仔猪白痢的疗效试验结果
结论:由实验结果可知,本发明药物复方恩诺沙星肠溶胶囊较一般的粉剂和单方恩诺沙星肠溶胶囊具有明显的预防和治疗效果,尤其对有大肠杆菌等引起的仔猪黄白痢,水肿病具有较好的临床治疗效果。
Claims (9)
1.用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述肠溶胶囊的囊心由恩诺沙星、艾叶油、肠粘膜保护剂、润湿剂、粘合剂和稀释剂组成,所述囊心喷有肠溶衣材料喷雾剂。
2.根据权利要求1所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:各组分重量百分比含量为:恩诺沙星2~10%W/W、艾叶油5~10%W/W、肠粘膜保护剂10~20%W/W、润湿剂5~10%W /W、粘合剂2~20% W/W、稀释剂加至100% W/W、肠溶衣材料1-20%W/W。
3.根据权利要求1或2所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述艾叶油为艾叶提取物、艾叶水提物或艾叶醇提物。
4.根据权利要求1或2所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述肠粘膜保护剂选自山药多糖、黄芪多糖、党参多糖、蒲公英多糖、桑叶多糖、葫芦巴多糖、长根菇多糖中的一种或两种以上组合。
5.根据权利要求1或2所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述润湿剂选自水或乙醇,所述乙醇的浓度为5%-90%。
6.根据权利要求1或2所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述粘合剂选自羧甲基纤维素钠、乙基纤维素、微晶纤维素、聚乙烯吡咯烷酮、聚乙二醇、海藻酸钠中的一种或两种以上组合,所述聚乙二醇的分子量为PEG400-PEG6000。
7.根据权利要求1或2所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述稀释剂选自甘露醇、木糖醇、乳糖、淀粉、微晶纤维素、羧甲基淀粉钠、滑石粉、硬脂酸等中的一种或两种以上组合。
8.根据权利要求1或2所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊,其特征在于:所述肠溶衣材料选自羟丙基纤维素钛酸酯、醋酸纤维素钛酸酯、乙基纤维素、聚乙烯醇、聚乙二醇中的一种或几种复合物。
9.一种如权利要求1所述的用于防治仔猪黄白痢的复方恩诺沙星肠溶胶囊的制备方法,其特征在于:包括以下步骤:
a)将恩诺沙星粉碎过100目筛,将其余辅料粉碎过80目筛;
b)准确称取处方量原辅料,混合均匀;
c)加适量润湿剂进行调和至手握不散开为宜;
d)在制粒机上进行制粒,18目筛整粒,备用;
e)将肠溶衣材料加适量水调成肠溶衣液;
f)将之前制备好的颗粒置于包衣锅内,以喷雾法将肠溶衣液均匀喷洒在颗粒表面,并在40-50度的温度范围内进行干燥,将所制颗粒分装入空胶囊壳即可。
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