CN102283856B - 一种兽用复方伊维菌素脂质体药物及其制备方法 - Google Patents
一种兽用复方伊维菌素脂质体药物及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种复方伊维菌素药物及其制备方法,特别是一种采用包封技术研制而成的兽用复方伊维菌素脂质体药物及其制备方法,属于兽用药物技术领域。一种兽用复方伊维菌素脂质体药物,其原料组分如下,均为重量份数:伊维菌素0.5~1.5份,盐酸左旋咪唑1~10份,卵磷脂5~20份,胆固醇1~10份,有机溶剂10~40份,丙二醇10~20份,月桂氮卓酮0.1~1.0份,注射用水30~60份。本发明所述兽用复方伊维菌素脂质体药物具有靶向性、长效性、降低毒性和提高被包封药物的稳定性、对提高畜禽成活率极具潜力;同时,本发明创新性的将伊维菌素与盐酸左旋咪唑复方,既提高了药物疗效又降低了药物毒性。
Description
技术领域
本发明涉及一种复方伊维菌素药物及其制备方法,特别是一种采用包封技术研制而成的兽用复方伊维菌素脂质体药物及其制备方法,属于兽用药物技术领域。
背景技术
伊维菌素属大环内酯类抗生素,是阿维菌素B1的衍生物,为两种组分B1a和B1b在C22和C23之间的双键饱和后的混合物。伊维菌素对体内外寄生虫特别是节肢动物和体内线虫具有良好驱杀作用。其驱虫作用机理在于促进突触前神经元释放Y-氨基古酸(GABA),从而打开GABA介导的氯离子通道,伊维菌素对无脊椎动物神经和肌肉细胞位于GABA介导位点附近的谷氨酸介导的恨离子通道也具有选择性和高亲和力。主要用于马、牛、羊、猪的胃肠道线虫、肺线虫和寄生节肢昆虫,犬的肠道线虫、耳螨、疥螨、心丝虫和微生蚴,以入家禽胃肠线虫和体外寄生虫。马内服伊维菌素对大型圆形线虫(普通圆形线虫、马圆形线虫、无齿圆形线虫)、蛔虫(马副蛔虫)、蛲虫(马类尾线虫)、胃虫(大口德拉西线虫、柔线属线虫)、小肠线虫(艾氏毛圆形虫、韦氏类圆形虫)、肺线虫安氏网尾线虫(等的成虫及第四期幼虫均有高效(95%-100%),对移行或胃驻留期的马胃蝇蛆、引起皮肤操作的盘尾丝虫微丝蚴以及胃线虫第三期幼虫,也很有效。给牛、羊内服或皮下注射伊维菌素,对血矛线虫、奥斯特线虫、古柏线虫、毛圆线虫(包括艾氏毛圆线虫)、圆形线虫、仰口线虫、细颈线虫、毛首线虫、食道口线虫、网尾线虫以及绵羊夏伯特线虫成虫及第四期幼虫驱除率97%-100%;肌内注射伊维菌素,对猪蛔虫、红色猪圆线虫、兰氏类圆线虫、猪毛首线虫、食道口线虫、后圆线虫、有齿冠尾线虫成虫及未成熟虫体驱除率达94%-100%,对肠道内旋毛虫、也极有效,对猪血虱和猪疥螨也有良好控制作用;犬、猫的某些体外寄生虫如耳螨、疥螨等的感染也有效;对家禽线虫和鸡蛔虫和封闭毛细线虫以及寄生在家禽节肢动物如膝螨等均有高效。
目前,临床使用中,伊维菌素对体内外寄生虫特别是节肢动物和体内线虫具有良好驱杀作用,并广泛应用于马、牛、羊、猪的胃肠道线虫、肺线虫和寄生节肢昆虫,犬的肠道线虫、耳螨、疥螨、心丝虫和微丝螨,以及家禽胃肠线虫和体外寄生虫。伊维菌素除了具有驱虫活性外,还能明显提高免疫反应,它可恢复外周T淋巴细胞的细胞介导免疫功能,兴奋单核细胞的吞噬作用,对免疫功能受损的动物作用更明显。在兽医临床上用作牛、羊、猪、犬、猫、禽的胃肠道线虫、肺线虫、犬心丝虫、猪肾虫感染的治疗,其次也用于免疫功能低下动物的辅助治疗和提高疫苗的免疫效果;内服可从胃肠道吸收,皮肤给药也右从皮肤吸收,但生物利用度不稳定,左旋咪唑吸收后可全身分布,猪的表观分布容积为2.5L/kg。大部分在肝和肾中被代谢,代谢物主要在尿中排泄,不到6%以原形排泄,少量在粪便中排泄。血浆半衰期分别为:牛4-6小时,羊3-4小时,犬1.8-4小时,猪3.5-6.8小时。
盐酸左旋咪唑是一种广谱抗线虫药,对马、牛、绵羊、猪、犬、鸡的大多数线虫具有活性。其驱虫作用机理是兴奋敏感蠕虫的副交感和交感神经节,总的表现为烟碱样作用;高浓度时,左旋咪唑通过阻断延胡索酸还原和琥珀酸氧化作用,干扰线虫的糖代谢,最终对里蠕虫起麻痹作用,使活虫体排出;
脂质体是将药物包封于磷脂质双分子,通过渗透或被巨噬细胞吞噬后,载体被酶类分解而释放药物,从而发挥作用。其最大特点是在血液中稳定,可与细胞相互作用而将药物输入到细胞内,增加包封药物透过细胞膜的能力。同时,脂质体靶向性强,大量的技术研究和临床应用表明,脂质体可以将携带的药物运载到指定的病性区/靶区。并可以达到缓慢释药及延长药物半衰期的作用。而脂质体主要集中在肝脾和骨髓等网状内皮细胞较丰富的器官中,而在心肾及其它正常器官中则会有较小含量,使其免受毒性较大药物的损害;实验证明,脂质体可以显著地降低药物毒性。
将伊维菌素与盐酸左旋咪唑复方后做成脂质体并应用于畜禽疾病治疗,还未见报道。主要是因为伊维菌素与盐酸左旋咪唑作用机理不同,本领域技术人员无法预料到二者复配后的效果。
发明内容
本发明针对现有技术的不足,提供一种复方伊维菌素脂质体药物及其制备方法。
一种兽用复方伊维菌素脂质体药物,其原料组分如下,均为重量份数:
伊维菌素0.5~1.5份,盐酸左旋咪唑1~10份,卵磷脂5~15份,胆固醇1~10份,有机溶剂10~30份,丙二醇1~10份,月桂氮卓酮0.1~1.0份,注射用水20~80份。
优选的,原料组分如下,均为重量份数:
伊维菌素1份,盐酸左旋咪唑5份,卵磷脂5份,胆固醇1份,有机溶剂20份,丙二醇10份,月桂氮卓酮0.1份,注射用水58份。
所述的有机溶剂选自甘油甲缩醛、乙酸乙酯或乙醇中的一种、两种或两种以上以任意比混合的混合物。
上述兽用复方伊维菌素脂质体药物的制备方法,步骤如下:
(1)将卵磷脂、胆固醇溶解于有机溶剂中,加入伊维菌素,得到混悬液;
(2)将步骤(1)制得的混悬液,在35~50℃,压力0.02~0.06Mpa,转速≥70r/min条件下减压蒸发10~20min,当容器壁形成一层脂质体薄膜,停止蒸发,通氮气10~20min;
(3)将步骤(2)制得的脂质体薄膜用磷酸缓冲液在转速≥90r/min、35~50℃条件下搅拌1h进行洗膜,然后静置1h,制得多室脂质体混悬液;
(4)将盐酸左旋咪唑溶解于注射用水中,然后加入到步骤(3)制得的多室脂质体混悬液中,再加入经丙二醇溶解的月桂氮卓酮,转速≥70r/min,搅拌30min,研磨获得小单室脂质体,即得复方伊维菌素脂质体。
所述步骤(3)中的磷酸缓冲液为浓度0.01mol/L,pH=7的NaH2PO4和Na2HPO4缓冲液。
所述步骤(4)中将盐酸左旋咪唑溶解于注射用水中的过程中同时加入注射用水重量0.04%的抗氧化剂EDTA。
上述兽用复方伊维菌素脂质体药物在防治畜禽体内外寄生虫中的应用。
有益效果
1、本发明所述兽用复方伊维菌素脂质体药物具有靶向性、长效性、降低毒性和提高被包封药物的稳定性、对提高畜禽成活率极具潜力。
2、本发明创新性的将伊维菌素与盐酸左旋咪唑复方,既提高了药物疗效又降低了药物毒性。
3、本发明将复方伊维菌素包封于脂质体内,填补了兽药领域伊维菌素脂质体的空白,作为靶向给药载体,脂质体是兽医临床上最先进的药物传输技术,市场前景十分广阔。
具体实施方式
实施例1
一种兽用复方伊维菌素脂质体药物,其原料组分如下:
伊维菌素1份,盐酸左旋咪唑5份,卵磷脂5份,胆固醇1份,乙酸乙酯20份,丙二醇10份,月桂氮卓酮0.1份,注射用水58份。
上述兽用复方伊维菌素脂质体药物的制备方法,步骤如下:
(1)将卵磷脂、胆固醇溶解于有机溶剂中,加入伊维菌素,得到混悬液;
(2)将步骤(1)制得的混悬液,在35~50℃,压力0.02~0.06Mpa,转速≥70r/min条件下减压蒸发10-20min,容器壁有一层膜形成,停止蒸发,通氮气10~20min。
(3)将步骤(2)制得的脂质体薄膜用磷酸缓冲液在转速≥90r/min、35~50℃条件下搅拌1h进行洗膜,然后静置1h,制得多室脂质体混悬液;
(4)将0.02份抗氧化剂EDTA和盐酸左旋咪唑溶解于注射用水中,然后加入到步骤(3)制得的多室脂质体混悬液中,再加入经丙二醇溶解的月桂氮卓酮,转速≥70r/min,搅拌30min,研磨获得小单室脂质体,即得兽用复方伊维菌素脂质体。
所述步骤(3)中的磷酸缓冲液为浓度0.01mol/L,pH=7的NaH2PO4和Na2HPO4缓冲液。
实验例
邹平县长山镇李某饲养绵羊116头,突然发病,表现为消化失调、食欲不振和腹泻,早期出现咳嗽,口腔内有特殊的臭味,排多量黏液或血便,患畜虚弱消瘦,精神迟顿,后肢无力,站立不稳,经病理剖检,发现死亡牛的小肠内有虫体,在血管、肺脏内有移行期幼虫,综合诊断为牛消化道线虫病。用本发明脂质体治疗,注射液规格10ml/支,用量0.1ml/kg,注射一次后,症状明显减轻,继续治疗,三天后,基本康复,治愈率达96.55%。结果见表1。
安全性试验结果:注射后病猪无异常死亡。观察30天,给药后的患畜长势良好,无任何疾病发生,对照组死亡2只。安全试验证明,本发明未显出毒副作用。
表1
病羊368只,随机分成四组,每组92只,分别用本发明注射液、伊维菌素注射液、盐酸左旋咪唑注射液治疗,连续3天,皮下注射,注射液规格10ml/支,用量0.1ml/kg。本发明治愈率97.83%,伊维菌素注射液88.21%,盐酸左旋咪唑注射液66.97%,对照组治愈率为35%。本发明注射液治愈率明显高于单方伊维菌素注射液和盐酸左旋咪唑注射液。结果见表2。
表2
实施例2
如实施例1所述的复方伊维菌素脂质体药物,不同之处在于,原料组分如下:
伊维菌素1.5份,盐酸左旋咪唑7.5份,卵磷脂10份,胆固醇2份,甘油甲缩醛30份,丙二醇10份,月桂氮卓酮0.25份,注射用水38份。
制备步骤如实施例1所述,不同之处在于,所得复方伊维菌素脂质体药物与葡萄糖混合,搅拌均匀,即得复方伊维菌素脂质体粉散剂。
实施例3
如实施例1所述的复方伊维菌素脂质体药物,不同之处在于,原料组分如下:
伊维菌素0.5份,盐酸左旋咪唑5.5份,卵磷脂15份,胆固醇5份,甘油甲缩醛30份,丙二醇10份,月桂氮卓酮0.25份,注射用水33份。
制备步骤如实施例1所述,不同之处在于,将制得的得复方伊维菌素脂质体药物溶于纯净水中,即得复方利福昔明脂质体口服液。
Claims (2)
1.一种兽用复方伊维菌素脂质体药物,其包括下述重量份数的原料组分:
伊维菌素0.5~1.5份,盐酸左旋咪唑1~10份,卵磷脂5~15份,胆固醇1~10份,有机溶剂10~30份,丙二醇1~10份,月桂氮卓酮0.1~1.0份,注射用水20~80份;
所述有机溶剂选自甘油甲缩醛、乙酸乙酯或乙醇中的一种、两种或两种以上以任意比混合的混合物;
上述原料按照如下方法制备:
(1)将卵磷脂、胆固醇溶解于有机溶剂中,加入伊维菌素,得到混悬液;
(2)将步骤(1)制得的混悬液,在35~50℃,压力0.02~0.06Mpa,转速≥70r/min条件下减压蒸发10~20min,当容器壁形成一层脂质体薄膜,停止蒸发,通氮气10~20min;
(3)将步骤(2)制得的脂质体薄膜用磷酸缓冲液在转速≥90r/min、35~50℃条件下搅拌1h进行洗膜,然后静置1h,制得多室脂质体混悬液;
(4)将盐酸左旋咪唑溶解于注射用水中,然后加入到步骤(3)制得的多室脂质体混悬液中,再加入经丙二醇溶解的月桂氮卓酮,转速≥70r/min,搅拌30min,研磨获得小单室脂质体,即得复方伊维菌素脂质体。
2.如权利要求1所述的脂质体药物,其特征在于,原料组分如下,均为重量份数:
伊维菌素1份,盐酸左旋咪唑5份,卵磷脂5份,胆固醇1份,有机溶剂10份,丙二醇10份,月桂氮卓酮 0.1份,注射用水45份。
3、如权利要求1或2所述兽用复方伊维菌素脂质体药物的制备方法,其特征在于,步骤如下:
(1)将卵磷脂、胆固醇溶解于有机溶剂中,加入伊维菌素,得到混悬液;
(2)将步骤(1)制得的混悬液,在35~50℃,压力0.02~0.06Mpa,转速≥70r/min条件下减压蒸发10~20min,当容器壁形成一层脂质体薄膜,停止蒸发,通氮气10~20min;
(3)将步骤(2)制得的脂质体薄膜用磷酸缓冲液在转速≥90r/min、35~50℃条件下搅拌1h进行洗膜,然后静置1h,制得多室脂质体混悬液;
(4)将盐酸左旋咪唑溶解于注射用水中,然后加入到步骤(3)制得的多室脂质体混悬液中,再加入经丙二醇溶解的月桂氮卓酮,转速≥70r/min,搅拌30min,研磨获得小单室脂质体,即得复方伊维菌素脂质体。
4、如权利要求3所述的制备方法,其特征在于,所述步骤(3)中的磷酸缓冲液为浓度0.01mol/L,pH=7的NaH2PO4和Na2HPO4缓冲液。
5、如权利要求3所述的制备方法,其特征在于,所述步骤(4)中将盐酸左旋咪唑溶解于注射用水中的过程中同时加入注射用水重量0.04%的抗氧化剂EDTA。
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