CN116270433A - 一种莫匹罗星软膏、制备方法及用途 - Google Patents
一种莫匹罗星软膏、制备方法及用途 Download PDFInfo
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- CN116270433A CN116270433A CN202310242130.5A CN202310242130A CN116270433A CN 116270433 A CN116270433 A CN 116270433A CN 202310242130 A CN202310242130 A CN 202310242130A CN 116270433 A CN116270433 A CN 116270433A
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- mupirocin
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Abstract
本发明属于药物制剂技术领域,具体涉及一种莫匹罗星软膏、制备方法及用途。本发明利用制备的莫匹罗星醇质体与药学上可接受的辅料制备成莫匹罗星软膏,符合软膏的各项规定,且有效解决了莫匹罗星稳定性较低,在高温、酸性、碱性条件下容易发生降解产生杂质的问题,加速试验中本发明莫匹罗星软膏有关物质含量低且含量变化较小,制剂稳定高。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种莫匹罗星软膏、制备方法及用途。
背景技术
皮肤的创口感染在处理方面,需要阻止病原体细菌的侵入,可以通过涂抹药物的方法来防止伤口的感染进一步加重。
莫匹罗星属于局部外用抗生素,涂于皮肤后,能渗透达角质层下,与人血清蛋白的结合率为95%,适用于多种细菌尤其是革兰阳性球菌引起的皮肤感染,如脓疱病、疖病,毛囊炎及湿疹、皮炎、各型溃疡和创伤等基础上的继发性细菌感染。
莫匹罗星稳定性较低,在高温、酸性、碱性条件下会发生降解,是由于莫匹罗星分子结构中含有的环氧键极易开环,易与邻近的羟基结合成环生成杂质。
中国专利201110167488.3公开了一种莫匹罗星软膏及其制备方法,采用0.5-5%的莫匹罗星、60-89%的PEG400、10-36%的PEG4000以及0.04-0.4%的有机酸制成制剂,有机酸作为稳定剂,但是效果不尽如人意,在40℃的条件下贮存10天,测得杂质总含量高达4.77%.
随着药品研发的不断进展,通过改变剂型等药剂学方法促进药物经皮吸收也成了不可或缺的一部分,尤其是借助微米或纳米载体,包括微乳、脂质体等,来改善药物经皮肤渗透吸收的能力。
中国专利201580019117.7公开了一种脂质体莫匹罗星,脂质体内区室封装莫匹罗星、至少一种环糊精化合物和pH依赖性的可电离阴离子,利用脂质体技术包载莫匹罗星,开创莫匹罗星制剂领域新思路。
发明内容
克服现有技术的不足,本发明提供了一种稳定性高的莫匹罗星软膏,解决了莫匹罗星稳定性较低,在高温、酸性、碱性条件下容易发生降解产生杂质的问题。
具体而言,本发明的技术方案如下:
本发明提供了一种莫匹罗星软膏,所述莫匹罗星软膏包含莫匹罗星醇质体、水溶性基质。
其中,所述莫匹罗星醇质体的制备方法为:
将磷脂、胆固醇溶于木犀草素醇提液中,作为醇相;将莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
木犀草素是一种天然黄酮类化合物,存在于多种植物中,在自然界中分布广泛,可从多种天然药材、蔬菜果实中分离得到。在多个实施例中,所述木犀草素醇提液提取于全叶青兰、菊花、荆芥、白毛夏枯草、金银花、紫苏、洋蓟、黄芩、裸花紫珠中的至少一种。
在一个较优的实施例中,所述木犀草素醇提液提取于金银花。是由于金银花木犀草素的含量较高,提取效率较高;不同品种的金银花中木犀草素的含量存在差异,最低含量为128.66微克/克,最高含量为240.39克/微克。
在多个实施例中,所述磷脂为蛋黄卵磷脂或/和大豆卵磷脂,在一个较优的实施例中,所述磷脂为大豆卵磷脂。
大豆磷脂的一般组成是:磷脂酰胆碱PC(卵磷脂)25-32%、磷脂酰乙醇胺PE(脑磷脂)15-22%、磷脂酰肌醇PI(肌醇磷脂)15%左右、磷脂酰甘油PG(神经鞘磷脂)16%左右、磷脂酸PA4%左右、其他磷脂8%左右。
在多个实施例中,磷脂、胆固醇、木犀草素醇提液、莫匹罗星的重量比为1-4:0.5-2:5-50:1-3;在一个较优的实施例中,所述磷脂、胆固醇、木犀草素醇提液、莫匹罗星的重量比为2:1:20:2。
根据高效液相色谱法质控,所述木犀草素醇提液中木犀草素的含量为50-1000μg/g;在一个较优的实施例中,所述木犀草素醇提液中木犀草素的含量为200μg/g。
在多个实施例中,所述莫匹罗星软膏中水溶性基质选自PEG类、聚氧乙烯硬脂酸酯、聚山梨酯中的至少一种,优选的,所述水溶性基质为PEG类。
在多个实施例中,所述PEG类水溶性基质为PEG-200、PEG-400、PEG-600、PEG-800、PEG-1450、PEG-3350中的至少一种。
在一个较优的实施例中,所述PEG类水溶性基质为PEG-400、PEG-3350。
本发明的第二个目的在于提供上述莫匹罗星软膏在抗感染药物中的用途。
具体的,所述抗感染药物为抗革兰阳性球菌引起的皮肤感染的药物,例如:脓疱病、疖肿、毛囊炎等原发性皮肤感染及湿疹合并感染、溃疡合并感染、创伤合并感染等继发性皮肤感染。
与现有技术相比,本发明的有益效果在于:
本发明通过醇质体技术,将莫匹罗星包封于脂质载体中,并优选脂质体载体材料,尤其是木犀草素的加入,显著提高了莫匹罗星醇质体的载药量和包封率。
本发明利用制备的莫匹罗星醇质体与药学上可接受的辅料制备成莫匹罗星软膏,酸碱度适宜,符合软膏的各项规定,且有效解决了莫匹罗星稳定性较低,在高温、酸性、碱性条件下容易发生降解产生杂质的问题,检测显示加速试验中本发明莫匹罗星软膏有关物质含量低且含量变化较小,稳定高。
附图说明
图1:莫匹罗星软膏有关物质含量检测梯度洗脱参数
图2-3:莫匹罗星软膏有关物质总含量变化曲线
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
一、木犀草素醇提液
(1)取全叶青兰、菊花、荆芥、白毛夏枯草、金银花、紫苏、洋蓟、黄芩、裸花紫珠中的至少一种置60℃烘箱干燥12h;
(2)将干燥的上述中药物料粉碎至20~40目,按物料重量的6~10倍加入浓度75~85%乙醇,60~80℃回流提取1~3h,获得提取液A;
(3)滤渣按物料重量的8~10倍加入浓度75%的乙醇提取0.5~1.5h,获得提取液B;
(4)合并滤液AB,减压旋蒸,浓缩滤液;
(5)浓缩液用大孔树脂吸附,用浓度75%的乙醇洗脱,重复1~3次,得到木犀草素醇提液。
二、莫匹罗星软膏
实施例1莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g大豆卵磷脂、10g胆固醇溶于200g 200μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
实施例2莫匹罗星软膏
莫匹罗星醇质体的制备:
将10g大豆卵磷脂、5g胆固醇溶于50g 50μg/ml木犀草素醇提液中,作为醇相;将1g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于55℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
实施例3莫匹罗星软膏
莫匹罗星醇质体的制备:
将40g大豆卵磷脂、20g胆固醇溶于500g 1000μg/ml木犀草素醇提液中,作为醇相;将3g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于75℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
实施例4莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g蛋黄卵磷脂、10g胆固醇溶于100g 500μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-200、PEG-1450于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
实施例5莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g大豆卵磷脂、10g胆固醇溶于300g 200μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-60、PEG-3350于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
实施例6莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g大豆卵磷脂、10g胆固醇溶于600g 200μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-800、PEG-1450于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
对比实施例1莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g大豆卵磷脂、10g胆固醇溶于200g乙醇中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
对比实施例2莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g磷脂酰胆碱、10g胆固醇溶于200g 200μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
对比实施例3莫匹罗星软膏
莫匹罗星醇质体的制备:
将5g大豆卵磷脂、2g胆固醇溶于20g 200μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
对比实施例4莫匹罗星软膏
莫匹罗星醇质体的制备:
将20g大豆卵磷脂、10g胆固醇溶于100g 50μg/ml木犀草素醇提液中,作为醇相;将2g莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
莫匹罗星软膏的制备:
将PEG-400、PEG-3350于65℃水浴加热融化,加入莫匹罗星醇质体,混合,搅拌,冷凝,即得莫匹罗星软膏。
对比实施例5莫匹罗星软膏(国药准字H10930064)
三、莫匹罗星醇质体质量评价
1.莫匹罗星醇质体粒径
醇质体的粒径大小和粒径均匀程度会影响醇质体的稳定性,直接影响醇质体在肌体组织的行为和处置,表1为莫匹罗星醇质体粒径大小及均匀程度的统计。
表1莫匹罗星醇质体粒径大小及均匀程度
根据表1中莫匹罗星醇质体粒径大小的统计,得知本发明制备的莫匹罗星醇质体平均粒径约为105~120nm之间,且较分布为均匀。
2.莫匹罗星醇质体载药量和包封率
载药量=包合物中所含药物的量/载药包合物的总量×100%。
包封率=(投入总药量-未包入包合物内的游离药物量)/投入总药量×100%。
表2莫匹罗星醇质体的载药量和包封率
载药量(%) | 包封率(%) | |
实施例1莫匹罗星醇质体 | 23.67 | 89.92 |
实施例2莫匹罗星醇质体 | 24.51 | 86.37 |
实施例3莫匹罗星醇质体 | 22.23 | 90.55 |
实施例4莫匹罗星醇质体 | 24.01 | 89.02 |
实施例5莫匹罗星醇质体 | 23.16 | 88.67 |
实施例6莫匹罗星醇质体 | 22.89 | 88.21 |
对比实施例1莫匹罗星醇质体 | 12.46 | 72.50 |
对比实施例2莫匹罗星醇质体 | 15.90 | 78.34 |
对比实施例3莫匹罗星醇质体 | 18.63 | 80.11 |
对比实施例4莫匹罗星醇质体 | 16.05 | 75.09 |
对本发明实施例1-6莫匹罗星醇质体和对比实施例1-4莫匹罗星醇质体进行载药量和包封率的测定,显示利用本发明技术方案制备的莫匹罗星醇质体载药量高包封率高,能够有效提高传递药物的效率。
四、莫匹罗星软膏质量评价
1.酸碱度测定
莫匹罗星酸性在条件下极易降解,且软膏剂直接涂布于皮肤或黏膜表面,人体皮肤的正常pH在5.0~7.0之间,超出此范围可能会对皮肤造成不同程度的刺激、损伤,引起不适。对实施例1-6莫匹罗星软膏、对比实施例1-5莫匹罗星软膏的pH进行检测。
表3实施例与对比实施例莫匹罗星软膏的pH
pH | pH | ||
实施例1莫匹罗星软膏 | 6.9 | 对比实施例1莫匹罗星软膏 | 6.0 |
实施例2莫匹罗星软膏 | 6.7 | 对比实施例2莫匹罗星软膏 | 6.2 |
实施例3莫匹罗星软膏 | 6.8 | 对比实施例3莫匹罗星软膏 | 6.5 |
实施例4莫匹罗星软膏 | 6.8 | 对比实施例4莫匹罗星软膏 | 6.4 |
实施例5莫匹罗星软膏 | 6.7 | 对比实施例5莫匹罗星软膏 | 6.8 |
实施例6莫匹罗星软膏 | 6.7 |
表3结果表明,实施例1-6莫匹罗星软膏的pH值均在6.7~6.9之间,与市售莫匹罗星软膏的pH值基本一致,本发明莫匹罗星软膏对皮肤的酸碱刺激作用较小。
2.有关物质含量
采用pH6.3的磷酸盐缓冲液制备样品溶液;色谱方法:Agilent Zorbax C8(250mm×4.6mm,5μm)色谱柱;流动相:pH5.7的乙酸铵溶液-四氢呋喃;柱温:30℃;流速:0.8mL/min;检测波长240nm;进样量:20μL。梯度洗脱参数见图1。
加速试验,将实施例1-6莫匹罗星软膏、对比实施例1-5莫匹罗星软膏作为供试品,于温度40±2℃,相对湿度75%±5%条件下放置6个月,在试验期间的第1个月、2个月、3个月、6个月末分别取样,检测有关物质含量,绘制有关物质总含量变化曲线。
图2-3为莫匹罗星软膏有关物质总含量变化曲线,可以看出本发明提供的莫匹罗星软膏在加速试验中有关物质含量低且变化较小,稳定性高。
Claims (10)
1.一种莫匹罗星软膏,其特征在于,所述莫匹罗星软膏包含莫匹罗星醇质体、水溶性基质。
2.根据权利要求1所述的莫匹罗星软膏,其特征在于,所述莫匹罗星醇质体的制备方法为:
将磷脂、胆固醇溶于木犀草素醇提液中,作为醇相;将莫匹罗星溶于水中,作为水相,将醇相缓慢滴加于水相中,水合,旋转蒸发浓缩,超声,滤膜滤过,得莫匹罗星醇质体。
3.根据权利要求2所述的莫匹罗星软膏,其特征在于,所述木犀草素醇提液提取于全叶青兰、菊花、荆芥、白毛夏枯草、金银花、紫苏、洋蓟、黄芩、裸花紫珠中的至少一种,优选的,所述木犀草素醇提液提取于金银花。
4.根据权利要求2所述的莫匹罗星软膏,其特征在于,所述磷脂为蛋黄卵磷脂或/和大豆卵磷脂,优选的,所述磷脂为大豆卵磷脂。
5.根据权利要求2所述的莫匹罗星软膏,其特征在于,所述磷脂、胆固醇、木犀草素醇提液、莫匹罗星的重量比为1-4:0.5-2:5-50:1-3;优选的,所述磷脂、胆固醇、莫匹罗星的重量比为2:1:20:2。
6.根据权利要求2所述的莫匹罗星软膏,其特征在于,所述木犀草素醇提液中木犀草素的含量为50-1000μg/g;优选的,所述木犀草素醇提液中木犀草素的含量为200μg/g。
7.根据权利要求1所述的莫匹罗星软膏,其特征在于,所述水溶性基质选自PEG类、聚氧乙烯硬脂酸酯、聚山梨酯中的至少一种,优选的,所述水溶性基质为PEG类。
8.根据权利要求7所述的莫匹罗星软膏其特征在于,所述PEG类为PEG-200、PEG-400、PEG-600、PEG-800、PEG-1450、PEG-3350中的至少一种。
9.根据权利要求8所述的莫匹罗星软膏其特征在于,所述PEG类为PEG-400、PEG-3350。
10.权利要求1-9任意一项所述莫匹罗星软膏在抗感染药物中的用途。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
CN106659795A (zh) * | 2014-04-10 | 2017-05-10 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | 脂质体莫匹罗星 |
CN110787128A (zh) * | 2019-12-17 | 2020-02-14 | 福元药业有限公司 | 一种莫匹罗星软膏及其制备方法 |
CN113520994A (zh) * | 2021-08-12 | 2021-10-22 | 福元药业有限公司 | 一种莫匹罗星软膏制剂 |
CN114053210A (zh) * | 2021-10-26 | 2022-02-18 | 海南全星制药有限公司 | 一种莫匹罗星软膏及其制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
CN106659795A (zh) * | 2014-04-10 | 2017-05-10 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | 脂质体莫匹罗星 |
CN110787128A (zh) * | 2019-12-17 | 2020-02-14 | 福元药业有限公司 | 一种莫匹罗星软膏及其制备方法 |
CN113520994A (zh) * | 2021-08-12 | 2021-10-22 | 福元药业有限公司 | 一种莫匹罗星软膏制剂 |
CN114053210A (zh) * | 2021-10-26 | 2022-02-18 | 海南全星制药有限公司 | 一种莫匹罗星软膏及其制备方法 |
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