CN107412170B - 一种头孢洛宁纳米混悬剂冻干粉及其制备方法 - Google Patents
一种头孢洛宁纳米混悬剂冻干粉及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种头孢洛宁纳米混悬剂冻干粉及其制备方法,由按重量份计的如下组分制备而成:头孢洛宁原料药1‑5份,表面活性剂0.1‑0.5份,助悬剂0.1‑0.5份,冻干保护剂1‑10份。本发明所制备的头孢洛宁纳米混悬剂冻干粉稳定性好,粒度分布均匀,重分散性好,可以提高头孢洛宁的溶解度、生物利用度。并且配方中不使用有机溶剂,辅料使用少,毒副作用小,制备工艺简单,便于推广应用。本发明所述头孢洛宁纳米混悬剂冻干粉对金黄色葡萄球菌,链球菌和大肠杆菌临床分离株均具有良好的抑制活性。
Description
技术领域
本发明涉及头孢洛宁的制剂,具体涉及一种头孢洛宁纳米混悬剂冻干粉及其制备方法。
背景技术
头孢洛宁分子式为C20H18N4O5S2,分子量为458.5。头孢洛宁(cefalonium)属于第一代半合成头孢菌素类广谱抗生素,是防治干乳期奶牛乳腺炎的特效药物,具有抗菌谱广、杀菌力强、过敏反应少、毒性低等优点。其作用机理是通过结合单个或多个位于敏感菌细胞壁上的青霉素结合蛋白使其活性丧失,从而阻碍菌体细胞壁的合成,改变细胞壁渗透性,使得菌体内细胞渗透压升高,细胞膜破裂后菌体裂解死亡。
由于头孢洛宁既难溶于水又难溶于油,且易分解,大大限制了在兽医临床上的应用。目前,头孢洛宁的制剂主要包括眼膏剂和乳房灌注剂(油性混悬剂),油性混悬剂的缺点是有机溶剂含量高,毒性较大,生产成本高,不利于推广应用。
发明内容
针对现有技术中存在问题,本发明的目的在于提供一种头孢洛宁纳米混悬剂冻干粉及其制备方法。本发明所制备的头孢洛宁纳米混悬剂冻干粉稳定性好,粒度分布均匀,重分散性好,可以提高头孢洛宁的溶解度、生物利用度。并且配方中不使用有机溶剂,辅料使用少,毒副作用小,制备工艺简单,便于推广应用。
实现本发明的第一个目的可以通过采取如下技术方案达到:
一种头孢洛宁纳米混悬剂冻干粉,其特征在于,由按重量份计的如下组分制备而成:头孢洛宁原料药1-5份,表面活性剂0.1-0.5份,助悬剂0.1-0.5份,冻干保护剂1-10份。
作为优选,所述头孢洛宁纳米混悬剂冻干粉的平均粒径小于800nm。
作为优选,所述表面活性剂为泊洛沙姆188,泊洛沙姆403,吐温80,聚维酮30,聚维酮25,聚维酮90,聚氧乙烯氢化蓖麻油(EL-40),聚乙烯醇1788,大豆卵磷脂,VE-TPGS,十二烷基磺酸钠,多库酯钠中的任意一种或两种以上;
作为优选,所述表面活性剂选自:
聚维酮30与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10);
或者是,β-环糊精与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10);
或者是,β-环糊精与聚氧乙烯氢化蓖麻油(EL-40)的混合物,它们的质量比为1:(0.1~10);
或者是,泊洛沙姆188与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10);
或者是,聚乙烯醇1788与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10)。
作为优选,所述助悬剂为阿拉伯树胶粉、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、西黄耆胶、黄原胶中的一种。
作为优选,所述冻干保护剂为乳糖、蔗糖、葡萄糖、甘露醇、山梨醇中的一种。
作为优选,一种头孢洛宁纳米混悬剂冻干粉,由按重量份计的如下组分制备而成:头孢洛宁原料药3份,表面活性剂0.3份,助悬剂0.1份,冻干保护剂5份。
实现本发明的第二个目的可以通过采取如下技术方案达到:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,其特征在于,包括如下步骤:
1)将配方量的助悬剂溶解或分散于去离子水中,得分散介质A;助悬剂与去离子水的质量比为(0.1-0.5):100;
2)将配方量的表面活性剂溶解或分散于分散介质A中,超声处理3-5min,得分散介质B;
3)将配方量的头孢洛宁原料药加入分散介质B中,在10000-15000rpm下高速剪切处理3-5min,得头孢洛宁粗混悬液C;
4)采用高压均质法将头孢洛宁粗混悬液C制备得到头孢洛宁纳米混悬液D;
5)向头孢洛宁纳米混悬液D中加入配方量的冻干保护剂,搅拌均匀后,冷冻干燥处理,即得头孢洛宁纳米混悬剂冻干粉。
作为优选,步骤4)中,高压均质法的控制过程具体如下:控制压力在200~1000bar,循环次数5~20次。
作为优选,本发明采用高压均质法制备纳米混悬液,主要通过调节压力和次数来控制药物的粒径。步骤4)中,高压均质法的控制过程具体如下:在200-500bar下循环5-10次,在800-1000bar下循环10-20次,制备的头孢洛宁纳米混悬剂冻干粉粒径小于800nm。
本发明的有益效果在于:
纳米混悬剂是通过表面活性剂或高分子聚合物的稳定作用,将药物分散于液体中,通过粉碎或者控制析晶技术形成的一种较稳定的分散体系。与传统意义上的基质骨架型纳米体系不同,纳米混悬剂无需载体材料,不论是难溶于水的药物还是既难溶于水又难溶于油的药物,均可以通过纳米技术而制备得到相应的纳米混悬剂。同时,药物颗粒达到纳米级别后,可使其具备不同于普通制剂的理化性质,其在各种给药途径中都体现出独特的优势,如处方简单、制备快速、有利于降低活性化合物的筛选成本、降低毒副作用和给药剂量等。对于稳定性较差的药物,可将纳米混悬剂制成冻干粉末保存。此外,还可对纳米混悬剂的药物粒子进行表面修饰以满足不同需要。
本发明将头孢洛宁原料药分散于含有表面活性剂和助悬剂的均匀分散介质中,然后进行高压均质制得头孢洛宁纳米混悬剂,最后加入适量冻干保护剂进行冷冻干燥得到头孢洛宁纳米混悬剂冻干粉。
本发明所述头孢洛宁纳米混悬剂冻干粉,可以提高头孢洛宁的溶解度、生物利用度;纳米混悬冻干粉中的表面活性剂和高分子聚合物对药物颗粒的保护作用,及纳米尺寸的头孢洛宁晶体提高了制剂的化学稳定性。本发明所制备的头孢洛宁纳米混悬剂冻干粉稳定性好,粒度分布均匀,重分散性好,并且配方中不使用有机溶剂,辅料使用少,毒副作用小,制备工艺简单,便于推广应用。本发明所述头孢洛宁纳米混悬剂冻干粉对金黄色葡萄球菌,链球菌和大肠杆菌临床分离株均具有良好的抑制活性。
附图说明
图1为实施例1头孢洛宁纳米混悬剂冻干粉的复溶后粒径分布图。
图2为实施例1头孢洛宁纳米混悬剂冻干粉的透射电镜(TEM)图。
具体实施方式
以下将对本发明的一种头孢洛宁纳米混悬剂冻干粉的制备方法进行详细描述,但不应就此理解为本发明主题的范围仅限于以下实施例。本发明各原料都可以从化工或医药市场购得。
实施例1:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量羟丙基甲基纤维素(HPMC)0.1g,加入100g去离子水中,充分溶解后加入0.3g大豆卵磷脂,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,得头孢洛宁纳米混悬剂冻干粉。
参照图1和图2,所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern Nano ZS测得平均粒径为623.2nm,多分散系数为0.262。
实施例2:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量阿拉伯树胶粉0.5g,加入100g去离子水中,充分溶解后加入0.3g大豆卵磷脂,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为705.2nm,多分散系数为0.292。
实施例3:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量羟丙基甲基纤维素(HPMC)0.1g,加入100g去离子水中,充分溶解后加入0.3g甘氨酸,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为788.6nm,多分散系数为0.351。
实施例4:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量聚维酮K30 0.1g,加入100g去离子水中,充分溶解后加入0.3g大豆卵磷脂,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为734.7nm,多分散系数为0.322。
实施例5:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量泊洛沙姆188 0.1g,加入100g去离子水中,充分溶解后加入0.3g大豆卵磷脂,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,制得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为744.7nm,多分散系数为0.329。
实施例6:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量β-环糊精0.75g,加入100g去离子水中,充分溶解后加入0.3g聚氧乙烯氢化蓖麻油,高速剪切5分钟使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,制得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为687.9nm,多分散系数为0.289。
实施例7:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量微晶纤维素0.1g,加入100g去离子水中,充分溶解后加入0.3g泊洛沙姆403,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,制得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为802.3nm,多分散系数为0.371。
实施例8:
一种头孢洛宁纳米混悬剂冻干粉的制备方法,包括如下步骤:
1)精密称量聚乙烯醇1788 0.1g,加入100g去离子水中,充分溶解后加入0.3g大豆卵磷脂,超声5min使其混合均匀,然后加入头孢洛宁原料药3g,12000rpm高速剪切10min,制得粗混悬液。然后将粗混悬液在高压均质机中200bar循环3次,500bar循环10次,1000bar循环15次,得头孢洛宁纳米混悬剂。
2)量取5ml所制得的头孢洛宁纳米混悬剂置于15ml西林瓶中,加入0.25g甘露醇,搅拌均匀后置于置于-80℃超低温冰箱中预冻24h,取出后迅速转移至冷冻干燥机中,-70℃、0.3mbar条件下冷冻干燥36-48h,制得头孢洛宁纳米混悬剂冻干粉。
所制得的头孢洛宁纳米混悬剂冻干粉加入等量去离子水复溶后,用malvern NanoZS测得平均粒径为817.4nm,多分散系数为0.377。
测试实施例9:
取实施例1所制得的头孢洛宁纳米混悬剂冻干粉与市售头孢洛宁原料药,采用琼脂稀释法测定对金黄色葡萄球菌,链球菌和大肠杆菌临床分离株的体外抑菌活性,测得MIC50,MIC90结果如表1所示
表1
结果表明头孢洛宁纳米混悬剂冻干粉对3种病原菌的抑菌效果较原料药更好,在临床应用时可以降低临床用药量,提高疗效。
对于本领域的技术人员来说,可根据以上描述的技术方案以及构思,做出其它各种相应的改变以及变形,而所有的这些改变以及变形都应该属于本发明权利要求的保护范围之内。
Claims (7)
1.一种头孢洛宁纳米混悬剂冻干粉,其特征在于,由按重量份计的如下组分制备而成:头孢洛宁原料药3份,表面活性剂0.3份,助悬剂0.1份,冻干保护剂5份;
所述表面活性剂为泊洛沙姆403,聚维酮30,聚维酮25,聚维酮90,聚氧乙烯氢化蓖麻油,聚乙烯醇1788,大豆卵磷脂,VE-TPGS,十二烷基磺酸钠,多库酯钠中的任意一种或两种以上;
所述头孢洛宁纳米混悬剂冻干粉是通过以下方法制备的:
1)将配方量的助悬剂溶解或分散于去离子水中,得分散介质A;助悬剂与去离子水的质量比为(0.1-0.5):100;
2)将配方量的表面活性剂溶解或分散于分散介质A中,超声处理3-5min,得分散介质B;
3)将配方量的头孢洛宁原料药加入分散介质B中,在10000-15000rpm下高速剪切处理3-5min,得头孢洛宁粗混悬液C;
4)采用高压均质法将头孢洛宁粗混悬液C制备得到头孢洛宁纳米混悬液D;
5)向头孢洛宁纳米混悬液D中加入配方量的冻干保护剂,搅拌均匀后,冷冻干燥处理,即得头孢洛宁纳米混悬剂冻干粉。
2.根据权利要求1所述的头孢洛宁纳米混悬剂冻干粉,其特征在于,所述头孢洛宁纳米混悬剂冻干粉的平均粒径小于800nm。
3.根据权利要求1所述的头孢洛宁纳米混悬剂冻干粉,其特征在于,所述表面活性剂选自:
聚维酮30与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10);
或者是,β-环糊精与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10);
或者是,β-环糊精与聚氧乙烯氢化蓖麻油的混合物,它们的质量比为1:(0.1~10);
或者是,聚乙烯醇1788与大豆卵磷脂的混合物,它们的质量比为1:(0.1~10)。
4.根据权利要求1所述的头孢洛宁纳米混悬剂冻干粉,其特征在于,所述助悬剂为阿拉伯树胶粉、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、西黄耆胶、黄原胶中的一种。
5.根据权利要求1所述的头孢洛宁纳米混悬剂冻干粉,其特征在于,所述冻干保护剂为乳糖、蔗糖、葡萄糖、甘露醇、山梨醇中的一种。
6.根据权利要求1所述的头孢洛宁纳米混悬剂冻干粉,其特征在于,步骤4)中,高压均质法的控制过程具体如下:控制压力在200~1000bar,循环次数5~20次。
7.根据权利要求1所述的头孢洛宁纳米混悬剂冻干粉,其特征在于,步骤4)中,高压均质法的控制过程具体如下:在200-500bar下循环5-10次,在800-1000bar下循环10-20次,制备的头孢洛宁纳米混悬剂冻干粉粒径小于800nm。
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