CN106727567A - 一种阿莫西林恩诺沙星油混悬剂及其制备方法 - Google Patents
一种阿莫西林恩诺沙星油混悬剂及其制备方法 Download PDFInfo
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- CN106727567A CN106727567A CN201611054744.7A CN201611054744A CN106727567A CN 106727567 A CN106727567 A CN 106727567A CN 201611054744 A CN201611054744 A CN 201611054744A CN 106727567 A CN106727567 A CN 106727567A
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- Prior art keywords
- enrofloxacin
- oil
- amoxicillin
- agent
- oil suspension
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Abstract
本发明公开了一种油混悬剂,所述混悬剂每100mL含有如下原辅料:阿莫西林10g、恩诺沙星或其盐10g、表面活性剂0.9~1.0g、胶体保护剂5.0~5.1g、助悬剂4.0~7.0g、抗氧化剂0.075~0.1g,余量为油相。在采用特定辅料种类及用量配比的条件下,本发明制备得到的混悬剂物理稳定性、通针性及重分散性良好,且在60℃环境中贮存10天未见质量下降的情况,表明其质量稳定。
Description
技术领域
本发明涉及一种阿莫西林恩诺沙星油混悬剂及其制备方法,属于医药领域。
背景技术
阿莫西林,又名安莫西林或安默西林,为白色粉末,半衰期约为61.3分钟,在酸性条件下稳定,胃肠道吸收率达90%。阿莫西林杀菌作用强,穿透细胞膜的能力也强,是目前应用较为广泛的口服半合成青霉素之一。恩诺沙星又名乙基环丙沙星、恩氟沙星,属于氟喹诺酮类人工合成抑菌剂。恩诺沙星为广谱杀菌药,对支原体有特效,对大肠杆菌、克雷白杆菌、沙门氏菌、变形杆菌、绿脓杆菌、嗜血杆菌、多杀性巴氏杆菌、溶血性巴氏杆菌、金葡菌、链球菌等都有杀菌效用。
青霉素类抗生素与喹诺酮类药物具有协同抗菌作用,在兽医临床上常常联合使用,可扩大抗菌谱、增强治疗效果。然而,由于阿莫西林与恩诺沙星的理化性质差异较大,将二者制备成复方制剂较为困难,目前鲜有制备阿莫西林恩诺沙星复方制剂的相关报道,更未见复方油混悬剂的报道。
油混悬剂系将难溶性药物分散于油相中形成的非均相液体制剂,常用于在水中不稳定的药品,其最大优势在于使药物作用时间延长,减少用药次数,可降低给药的劳动强度和减少对机体的应激。然而,油混悬剂尤其是注射用油混悬剂的制备较为困难,要得到物理稳定性、通针性和重分散性较好的产品,确定适宜的辅料种类及用量非常关键,而且,油混悬剂对贮存环境要求较高,提高其贮存稳定性也是制备过程中需要考虑的因素。因此,如何提供一种质量较好的阿莫西林恩诺沙星油混悬剂,成为了一个亟待解决的问题。
发明内容
本发明的目的在于提供一种阿莫西林恩诺沙星油混悬剂及其制备方法。
本发明提供了一种油混悬剂,所述混悬剂每100mL含有如下原辅料:阿莫西林10g、恩诺沙星或其盐10g、表面活性剂0.9~1.0g、胶体保护剂5.0~5.1g、助悬剂4.0~7.0g、抗氧化剂0.075~0.1g,余量为油相。
进一步地,所述的表面活性剂为司班-80、吐温-80、大豆磷脂中一种或两种以上的混合物。
进一步地,所述的表面活性剂由下述组分组成:吐温-80 0.3g、司班-80 0.3g、大豆磷脂0.3g。
进一步地,所述胶体保护剂由下述组分组成:硅酸铝镁2.5g、硬脂酸镁2.5g。
进一步地,所述的助悬剂为泊洛沙姆188、聚乙二醇6000、羧甲基纤维素钠、聚乙烯吡咯烷酮K30中一种或两种以上的混合物。
进一步地,所述的助悬剂由下述组分组成:聚乙二醇6000 5.0g、聚乙烯吡咯烷酮K30 2.0g。
进一步地,所述的抗氧化剂为维生素C棕榈酯0.01~0.02g、叔丁基对羟基茴香醚0.005~0.02g、没食子酸丙酯0.05~0.1g或维生素E 0.05~0.075g。
进一步地,所述的油相为体积百分比为90%:10%的大豆油:肉豆蔻酸异丙酯。
进一步地,所述混悬剂每100mL含有如下原辅料:阿莫西林10g、恩诺沙星或其盐10g、吐温-80 0.3g、司班-80 0.3g、大豆磷脂0.3g、硅酸铝镁2.5g、硬脂酸镁2.5g、聚乙二醇6000 5.0g、聚乙烯吡咯烷酮K30 2.0g、抗氧化剂,余量为体积百分比为90%:10%的大豆油:肉豆蔻酸异丙酯;
其中,所述的抗氧化剂为维生素C棕榈酯0.01~0.02g、叔丁基对羟基茴香醚0.005~0.02g、没食子酸丙酯0.05~0.1g或维生素E0.05~0.075g。
进一步地,所述的恩诺沙星盐为盐酸恩诺沙星或乳酸恩诺沙星。
本发明提供了一种所述油混悬剂的制备方法,包括如下步骤:
将油相加热至60℃~70℃,加入抗氧化剂、胶体保护剂、表面活性剂,冷却至15~25℃,加入助悬剂,最后加入阿莫西林、恩诺沙星,搅拌均匀,均质,即得;或,
将油相加热至60℃~70℃,加入抗氧化剂、胶体保护剂、聚乙二醇6000,熔化,加入表面活性剂,冷却至15~25℃,加入聚乙烯吡咯烷酮K30,最后加入阿莫西林、恩诺沙星,搅拌均匀,均质,即得。
本发明提供了一种阿莫西林恩诺沙星油混悬剂。在采用特定辅料种类及用量配比的条件下,本发明制备得到的混悬剂物理稳定性、通针性及重分散性良好,且在60℃环境中贮存10天未见质量下降的情况,表明其质量稳定。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1本发明阿莫西林恩诺沙星油混悬剂的制备
取大豆油60ml与肉豆蔻酸异丙酯10ml的混合物,加热(60℃-70℃)混合均匀后,加入维生素C棕榈酯(0.01%-0.02%w/v)、胶体保护剂(硅酸铝镁:硬脂酸镁1:1的混合物5.0g)溶解,加入表面活性剂(大豆磷脂0.3g、吐温-80 0.3g和司班-80 0.3g)溶解,再加入助悬剂聚乙二醇6000 5.0g熔化后搅拌均匀,冷却至室温(15~25℃)后加入助悬剂聚乙烯吡咯烷酮K302.0g,搅拌均匀,最后加入阿莫西林10g和恩诺沙星10g,搅拌均匀后用大豆油定容至100ml,均质,即得本发明阿莫西林恩诺沙星油混悬液。
实施例2本发明阿莫西林恩诺沙星油混悬剂的制备
取大豆油60ml与肉豆蔻酸异丙酯10ml的混合物,保持加热60℃-70℃,将油相混合均匀,加入胶体保护剂(硅酸铝镁硬脂酸镁1:1混合物5.0g)、表面活性剂(大豆磷脂0.3g、吐温-80 0.3g和司班-80 0.3g);将上述混合物冷却至室温(15~25℃),加入助悬剂(聚乙二醇6000 5.0g和聚乙烯吡咯烷酮K30 2.0g),搅拌均匀,最后加入阿莫西林10g和恩诺沙星10g,搅拌均匀后用大豆油定容至100ml,均质,即得本发明阿莫西林恩诺沙星油混悬液。
以下通过实验例证明本发明的有益效果。
1材料
阿莫西林,华北制药集团;恩诺沙星、盐酸恩诺沙星、乳酸恩诺沙星,上虞京新药业有限公司;苯甲酸苄酯,上海皓月日化有限公司;聚乙二醇-6000,阿拉丁试剂有限公司;泊洛沙姆-188,北京凤礼国际贸易有限公司;硬脂酸铝,硬脂酸镁,吐温-80,司班-80、甲醇、磷酸二氢钠等化学试剂,西陇化工有限公司;甲醇,赛默飞世尔(中国)有限公司,均质机,上海恒川机械设备有限公司。
2方法与结果
2.1混悬剂的考察方法
参考《中国兽药典》对混悬液的要求,拟用以下方法检查制备的阿莫西林恩诺沙星混悬液。
2.1.1沉降体积比
用具塞量筒量取供试品50ml,密塞,用力振摇1min,记下混悬物的开始高度H0,静置3小时,记下混悬物的最终高度H,按下式计算:
沉降体积比=H/H0,沉降体积比不小于0.90。
2.1.2通针性
取供试品,振摇后用用12号针头吸取,1分钟内吸取体积不少于2ml。2.1.3分散性
参考乳剂的离心标准,将供试品以4000r/min的转速离心15min后振摇,应易分散。
2.2混悬液的制备
取溶剂适量,按拟定的比例加入表面活性剂、抗氧化剂、增稠剂溶解,冷却后加入阿莫西林恩诺沙星搅拌均匀,用均质机均质即得。
实验例1油相种类对阿莫西林恩诺沙星混悬剂质量的影响
分别以大豆油、菜籽油、花生油、玉米油、白油、油酸乙酯、苯甲酸苄酯、肉豆蔻酸异丙酯作为油相,并配合表面活性剂司盘-80(5%w/v)、抗氧化剂对羟基叔丁基茴香醚(BHA)(0.02%w/v),增稠剂硬脂酸铝(1%w/v)及主药阿莫西林(10%w/v)、恩诺沙星(10%w/v)制备不同的混悬剂,并考察其沉降体积比、通针性、离心后的分散情况,结果见表1。
表1采用不同种类油相制备混悬剂的质量评价结果
由表1可以得出,以单一植物、矿物油或酯类为油相制备的阿莫西林恩诺沙星混悬液离心后均不能分散,重分散性较差,表明仅使用单一种类的油相难以将阿莫西林、恩诺沙星制备成质量较好的混悬剂。
实验例2复合油相种类及比例对阿莫西林恩诺沙星混悬剂质量的影响
根据表2所示的比例制备复合油相,并配合表面活性剂司盘-80(5%w/v)、抗氧化剂对羟基叔丁基茴香醚(BHA)(0.02%w/v),增稠剂硬脂酸铝(1%w/v)及主药阿莫西林(10%w/v)、恩诺沙星(10%w/v)制备不同的混悬剂,考察其沉降体积比、通针性、离心后的分散情况,结果见表2。
表2根据不同复合油相制备混悬剂的质量评价结果
由表2的试验结果可以看出,仅有在采用本发明大豆油90%-肉豆蔻酸异丙酯10%复合油相制备阿莫西林恩诺沙星混悬剂时,所得产品在沉降体积比、通针性、重分散性等方面均能符合药典规定。若改变复合油相中油相的种类,或者即使只是调整其用量,都会导致制剂质量的下降。
实验例3表面活性剂种类和用量对混悬剂质量的影响
分别根据表3所示的表面活性剂种类和用量,并配合油相(大豆油90%-肉豆蔻酸异丙酯10%)、抗氧化剂对羟基叔丁基茴香醚(BHA)(0.02%w/v),增稠剂硬脂酸铝(1%w/v)及主药阿莫西林(10%w/v)、恩诺沙星(10%w/v)制备不同的混悬剂,并考察其沉降体积比、通针性、离心后的分散情况,结果见表3。
表3根据不同表面活性剂种类和用量制备混悬剂的质量评价结果
由表3的实验结果可以得出,各组制备的混悬剂质量均符合要求,表明司班-80、吐温-80、大豆磷脂均适宜作为表面活性剂在本发明混悬剂中使用。其中,0.3%吐温-80+0.3%司班-80+0.3%大豆磷脂组表面活性剂的用量较其它组少,从安全性方面考虑更优。
实验例4胶体保护剂种类对阿莫西林恩诺沙星混悬剂质量的影响
分别采用表4所示的胶体保护剂,并配合油相(大豆油90%-肉豆蔻酸异丙酯10%)、表面活性剂(0.3%吐温-80+0.3%司班-80+0.3%大豆磷脂)、抗氧化剂对羟基叔丁基茴香醚(BHA)(0.02%w/v)制备阿莫西林(10%w/v)恩诺沙星(10%w/v)混悬液,并考察其沉降体积比、通针性、离心后的分散情况,结果见表4。
表4采用不同胶体保护剂制备混悬剂的质量评价结果
由表4的结果可以得出,以硬脂酸铝、硬脂酸镁、硅酸铝镁作为胶体保护剂制备的混悬剂质量均符合要求,表明上述三种胶体保护剂均适宜在本发明混悬剂中作用。其中,硅酸铝镁2.5%+硬脂酸镁2.5%组混悬剂通针性明显优于其它组,表明由硅酸铝镁2.5%、硬脂酸镁2.5%组成的复合胶体保护剂为最佳。
实验例5助悬剂种类及用量对阿莫西林恩诺沙星混悬剂质量的影响
分别单独将泊洛沙姆188、聚乙二醇4000、聚乙二醇6000、羧甲基纤维素钠、聚乙烯吡咯烷酮K30在大豆油中分散,结果表明只有泊洛沙姆188、聚乙二醇6000、羧甲基纤维素钠、聚乙烯吡咯烷酮K30四种助悬剂在大豆油中分散性较好,说明上述四种物质适宜作为助悬剂使用。
分别采用表5所示的助悬剂,并用油相(大豆油90%-肉豆蔻酸异丙酯10%)、表面活性剂(0.3%吐温-80+0.3%司班-80+0.3%大豆磷脂)、胶体保护剂(硅酸铝镁硬脂酸镁1:1混合物5.0%)和抗氧化剂对羟基叔丁基茴香醚(BHA)(0.02%w/v)制备阿莫西林(10%w/v)恩诺沙星(10%w/v)混悬液,并考察其沉降体积比、通针性、离心后的分散情况,结果见表5。
表5采用不同助悬剂制备混悬剂的质量评价结果
由表5的试验结果可得,聚乙二醇6000、泊洛沙姆188、聚乙烯吡咯烷酮和羧甲基纤维素钠对阿莫西林恩诺沙星混悬液均有较好的助悬作用,制备得到的产品符合药典要求。其中,聚乙二醇6000 5.0%+聚乙烯吡咯烷酮K302.0%组通针性更佳。
实验例6抗氧化剂种类及用量对阿莫西林恩诺沙星混悬剂质量的影响
分别以维生素C棕榈酯(0.01%-0.02%w/v)、叔丁基对羟基茴香醚(0.005%-0.02%w/v)、没食子酸丙酯(0.05%-0.1%w/v)、维生素E(0.05%-0.075%w/v)为抗氧化剂,并用油相(大豆油90%-肉豆蔻酸异丙酯10%)、表面活性剂(0.3%吐温-80+0.3%司班-80+0.3%大豆磷脂)、胶体保护剂(硅酸铝镁硬脂酸镁1:1混合物5.0%)和助悬剂(聚乙二醇6000 5.0%+聚乙烯吡咯烷酮K30 2.0%)制备阿莫西林(10%w/v)恩诺沙星(10%w/v)混悬液,并用空白对照,于80℃水浴中放置12小时,观察其外观。
观察结果:加入抗氧化剂的混悬液均符合质量标准规定,空白对照则颜色变黄。
以上结果表明,上述四种物质均适宜作为抗氧化剂在本发明混悬剂中使用。
实验例7制备工艺对阿莫西林恩诺沙星混悬剂质量的影响
本次试验比较了将聚乙二醇6000加热熔化,或直接于室温下加入油相的助悬效果。具体实验方法如下:
制备工艺A:取大豆油60ml与肉豆蔻酸异丙酯10ml的混合物,加热(60℃-70℃)混合均匀后,加入胶体保护剂(硅酸铝镁:硬脂酸镁1:1的混合物5.0g)溶解,加入表面活性剂(大豆磷脂0.3g、吐温-80 0.3g和司班-80 0.3g)溶解,再加入助悬剂聚乙二醇6000 5.0g熔化后搅拌均匀,冷却至室温(15~25℃)后加入助悬剂聚乙烯吡咯烷酮K30 2.0g,搅拌均匀,最后加入阿莫西林10g和恩诺沙星10g,搅拌均匀后用大豆油定容至100ml,均质,即得阿莫西林恩诺沙星油混悬液A。
制备工艺B:取大豆油60ml与肉豆蔻酸异丙酯10ml的混合物,保持加热60℃-70℃,将油相混合均匀,加入胶体保护剂(硅酸铝镁硬脂酸镁1:1混合物5.0g)、表面活性剂(大豆磷脂0.3g、吐温-80 0.3g和司班-80 0.3g);将上述混合物冷却至室温(15~25℃),加入助悬剂(聚乙二醇6000 5.0g和聚乙烯吡咯烷酮K30 2.0g),搅拌均匀,最后加入阿莫西林10g和恩诺沙星10g,搅拌均匀后用大豆油定容至100ml,均质,即得阿莫西林恩诺沙星油混悬液B。
分别考察混悬液A、B的沉降体积比、通针性、离心后的分散情况,结果见表6。
表6采用不同工艺制备混悬剂的质量评价结果
制剂工艺 | 沉降体积比 | 通针性(ml) | 离心后再分散 |
A | 1.00 | 4.6 | 易分散 |
B | 1.00 | 3.8 | 易分散 |
实验结果:聚乙二醇6000经加热熔化,或者直接加入油相中,均能制备得到质量符合兽药典规定的混悬剂;其中,经熔化的混悬液通针性更佳。
实验例8本发明阿莫西林恩诺沙星混悬剂的稳定性试验
将实施例1制备的本发明阿莫西林恩诺沙星油混悬液置于60℃环境中放置10天,于第10天参照阿莫西林、恩诺沙星注射液的质量标准检测含量(农业部新兽药评审中心.兽药质量标准汇编[S].中国农业出版色,2013),结果见表7。
表7本发明混悬剂的稳定性性试验
实验结果表明,本发明混悬剂在60℃放置10天后,其含量、通针性、沉降体积比及分散性变化并不显著,说明本品稳定性良好。
实验例9本发明制剂处方及制备工艺的耐用性试验
根据实施例1制备工艺,分别用不同的恩诺沙星盐为原料药制备阿莫西林恩诺沙星油混悬液,并考察其沉降体积比、通针性、离心后的分散情况,结果见表8。
表8耐用性试验结果
实验结果:采用本发明制备工艺得到的盐酸恩诺沙星或乳酸恩诺沙星油混悬液质量均符合药典规定,表明该方法可通用于恩诺沙星的各种盐类。
Claims (11)
1.一种油混悬剂,其特征是:所述混悬剂每100mL含有如下原辅料:阿莫西林10g、恩诺沙星或其盐10g、表面活性剂0.9~1.0g、胶体保护剂5.0~5.1g、助悬剂4.0~7.0g、抗氧化剂0.075~0.1g,余量为油相。
2.如权利要求1所述的油混悬剂,其特征是:所述的表面活性剂为司班-80、吐温-80、大豆磷脂中一种或两种以上的混合物。
3.如权利要求2所述的油混悬剂,其特征是:所述的表面活性剂由下述组分组成:吐温-80 0.3g、司班-80 0.3g、大豆磷脂0.3g。
4.如权利要求1所述的油混悬剂,其特征是:所述胶体保护剂由下述组分组成:硅酸铝镁2.5g、硬脂酸镁2.5g。
5.如权利要求1所述的油混悬剂,其特征是:所述的助悬剂为泊洛沙姆188、聚乙二醇6000、羧甲基纤维素钠、聚乙烯吡咯烷酮K30中一种或两种以上的混合物。
6.如权利要求5所述的油混悬剂,其特征是:所述的助悬剂由下述组分组成:聚乙二醇6000 5.0g、聚乙烯吡咯烷酮K30 2.0g。
7.如权利要求1所述的油混悬剂,其特征是:所述的抗氧化剂为维生素C棕榈酯0.01~0.02g、叔丁基对羟基茴香醚0.005~0.02g、没食子酸丙酯0.05~0.1g或维生素E 0.05~0.075g。
8.如权利要求1所述的油混悬剂,其特征是:所述的油相为体积百分比为90%:10%的大豆油:肉豆蔻酸异丙酯。
9.如权利要求1~8任意一项所述的油混悬剂,其特征是:所述混悬剂每100mL含有如下原辅料:阿莫西林10g、恩诺沙星或其盐10g、吐温-800.3g、司班-80 0.3g、大豆磷脂0.3g、硅酸铝镁2.5g、硬脂酸镁2.5g、聚乙二醇6000 5.0g、聚乙烯吡咯烷酮K30 2.0g、抗氧化剂,余量为体积百分比为90%:10%的大豆油:肉豆蔻酸异丙酯;
其中,所述的抗氧化剂为维生素C棕榈酯0.01~0.02g、叔丁基对羟基茴香醚0.005~0.02g、没食子酸丙酯0.05~0.1g或维生素E 0.05~0.075g。
10.如权利要求1~9任意一项所述的油混悬剂,其特征是:所述的恩诺沙星盐为盐酸恩诺沙星或乳酸恩诺沙星。
11.一种权利要求1~11任意一项所述油混悬剂的制备方法,其特征是:包括如下步骤:
将油相加热至60℃~70℃,加入抗氧化剂、胶体保护剂、表面活性剂,冷却至15~25℃,加入助悬剂,最后加入阿莫西林、恩诺沙星,搅拌均匀,均质,即得;或,
将油相加热至60℃~70℃,加入抗氧化剂、胶体保护剂、聚乙二醇6000,熔化,加入表面活性剂,冷却至15~25℃,加入聚乙烯吡咯烷酮K30,最后加入阿莫西林、恩诺沙星,搅拌均匀,均质,即得。
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