CN117017999A - 一种夫西地酸磷脂复合物及其制备方法和用途 - Google Patents
一种夫西地酸磷脂复合物及其制备方法和用途 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
本发明公开了一种夫西地酸磷脂复合物及其制备方法和用途。该夫西地酸磷脂复合物,包括摩尔比为1:0.1~1:5的夫西地酸和磷脂。本发明通过夫西地酸和磷脂在一定条件下制备得到了一种分子型复合物,由于复合物中药物自身化学结构并未发生改变,药物仍具有原来的药理活性。当复合物在作用于革兰阴性菌时,复合物中的磷脂能保护夫西地酸不被细菌细胞外膜结合,从而能帮助夫西地酸进入胞浆发挥抗菌作用。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种夫西地酸磷脂复合物及其制备方法和用途。
背景技术
从1929年fleming发现青霉素开始,各种抗生素的发明对人类健康产生了巨大影响,但随着抗生素的广泛运用,细菌耐药性的产生给人类带来了严重威胁。2017年WHO公布了耐药病原菌名录,而其中大部分为革兰氏阴性菌。
夫西地酸(fusidic acid)又名褐霉菌酸,由Godtfredsen等于1962年从是绯红梭链孢菌培养液中分离发现的一种易溶于脂类的类固醇样物质,结构上与头孢菌素类P1和烟曲霉酸类似。其通过结合延长因子G,阻止其从核糖体的释放而抑制细菌蛋白质的合成而表现出抗菌性,但主要对革兰氏阳性菌起作用,因而从上世纪60年代开始,广泛应用于皮肤以及骨关节等革兰氏阳性菌感染的治疗。然而,夫西地酸对革兰氏阴性菌几乎没有作用,主要原因是革兰氏阴性菌的外膜具有保护和屏障作用。同时,目前尚未见有关通过制备夫西地酸磷脂复合物以增强夫西地酸对革兰氏阴性菌的抗菌性的报道。
发明内容
针对现有技术中的上述不足,本发明提供一种夫西地酸磷脂复合物及其制备方法和用途,本申请制备得到的夫西地酸磷脂复合物可有效的抑制革兰氏阴性菌,同时增强夫西地酸对革兰氏阴性菌的抗菌性。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:
一种夫西地酸磷脂复合物,包括夫西地酸和磷脂。
进一步地,夫西地酸和磷脂的摩尔比为1:0.1~1:5。
进一步地,夫西地酸和磷脂的摩尔比为1:0.5~1:3。
进一步地,夫西地酸和磷脂的摩尔比为1:1。
进一步地,夫西地酸和磷脂的摩尔比为1:0.5。
进一步地,磷脂为天然类磷脂成分或通过合成方式获得的磷脂。
进一步地,磷脂为大豆卵磷脂、蛋黄卵磷脂、DSPE、DPPE、DSPC、DPPC、DSPG、DPPA、DOTAP、DEPC、DPPG或DSPE-MPEG2000。
上述夫西地酸磷脂复合物的制备方法,具体如下:
将夫西地酸和磷脂溶于有机溶剂中,然后于20-60℃下搅拌,再减压除去有机溶剂,即可得到夫西地酸磷脂复合物。
进一步地,有机溶剂为乙酸乙酯、丙酮、氯仿、二氯甲烷、四氢呋喃、正己烷、乙醇和甲醇中的至少一种。
进一步地,温度为55℃。
上述夫西地酸磷脂复合物在制备可抑制革兰氏阴性菌的抗菌剂中的用途。
进一步地,革兰氏阴性菌为大肠杆菌、铜绿假单胞菌或变形杆菌。
本发明的有益效果:
磷脂作为生物膜的主要成分,对生物的生命活动起到重要作用。结构上,磷脂分子由极性头端和疏水性尾部组成,由于其磷原子上游离羟基氧原子有极强得电子倾向而极性头端氮原子有极强失电子倾向,因而在非质子体系能和具有特定结构的物质按一定比例形成复合物——磷脂复合物,显著改善药物的物理特性但其药物结构并不改变,在一定条件下能游离出发挥作用。
本发明制备了夫西地酸磷脂复合物,其为夫西地酸和磷脂在一定条件下形成的复合物是一种分子型复合物。由于复合物中药物自身化学结构并未发生改变,药物仍具有原来的药理活性。当复合物在作用于革兰阴性菌时,复合物中的磷脂能保护夫西地酸不被细菌细胞外膜结合,从而能帮助夫西地酸进入胞浆发挥抗菌作用。
附图说明
图1为夫西地酸(FA)及夫西地酸磷脂复合物(FA-PC,1:0.5和1:1)在水中的溶解度;
图2为夫西地酸(FA)、夫西地酸磷脂复合物(FA-PC,1:1)、磷脂(PC)对革兰阴性菌大肠杆菌的抗菌效果;
图3为夫西地酸(FA)、夫西地酸磷脂复合物(FA-PC,1:1)、磷脂(PC)对革兰阴性菌铜绿假单胞菌的抗菌效果。
具体实施方式
下面对本发明的具体实施方式进行描述,以便于本技术领域的技术人员理解本发明,但应该清楚,本发明不限于具体实施方式的范围,对本技术领域的普通技术人员来讲,只要各种变化在所附的权利要求限定和确定的本发明的精神和范围内,这些变化是显而易见的,一切利用本发明构思的发明创造均在保护之列。
实施例1
一种夫西地酸磷脂复合物,其制备方法如下:
取13.4mg夫西地酸和20.3mg大豆卵磷脂,一同溶于5mL的无水乙醇中,55℃磁力搅拌2h得透明澄清液,然后于55℃减压30min除去无水乙醇,得夫西地酸和大豆卵磷脂摩尔比为1:1的夫西地酸磷脂复合物。
实施例2
一种夫西地酸磷脂复合物,其制备方法如下:
取13.4mg夫西地酸和10.2mg大豆卵磷脂,一同溶于5mL的无水乙醇中,50℃磁力搅拌2h得透明澄清液,然后于50℃减压30min除去无水乙醇,得夫西地酸和大豆卵磷脂摩尔比为1:0.5的夫西地酸磷脂复合物。
实施例3
一种夫西地酸磷脂复合物,其制备方法如下:
取13.4mg夫西地酸和20.3mg蛋黄卵磷脂,一同溶于5mL的无水乙醇中,60℃磁力搅拌2h得透明澄清液,然后于50℃减压30min除去无水乙醇,得夫西地酸和蛋黄卵磷脂摩尔夫为1:1的夫西地酸磷脂复合物。
实施例4
一种夫西地酸磷脂复合物,其制备方法如下:
取13.4mg夫西地酸和20.3mg DSPC,一同溶于5mL的无水乙醇中,60℃磁力搅拌2h得透明澄清液,然后于50℃减压30min除去无水乙醇,得夫西地酸和DSPC摩尔夫为1:1的夫西地酸磷脂复合物。
实施例5
一种夫西地酸磷脂复合物,其制备方法如下:
取13.4mg夫西地酸和20.3mg DSPG,一同溶于5mL的无水乙醇中,60℃磁力搅拌2h得透明澄清液,然后于50℃减压30min除去无水乙醇,得夫西地酸和DSPG摩尔夫为1:1的夫西地酸磷脂复合物。
实施例6
一种夫西地酸磷脂复合物,其制备方法如下:
取13.4mg夫西地酸和20.3mg DPPG,一同溶于5mL的无水乙醇中,60℃磁力搅拌2h得透明澄清液,然后于50℃减压30min除去无水乙醇,得夫西地酸和DPPG摩尔夫为1:1的夫西地酸磷脂复合物。
实验例
1、检测实施例1和实施例2制备得到的夫西地酸磷脂复合物的溶解性,结果见图1。
由图1可见,与磷脂形成复合物可显著增加夫西地酸在水中的溶解度,且溶解度随磷脂含量增加而增加。
2、取大肠杆菌(E.Coli)菌株,在20℃、1800rcf条件下离心15min,弃上清液,沉淀用1ml LB培养基溶液重悬,并稀释到菌液浓度为5×105cfu/ml。取200μL菌液,分别加入夫西地酸(FA)水溶液、夫西地酸磷脂复合物(FA-PC,1:1)水溶液、磷脂(PC)水溶液,于37℃培养12h,然后吸取100μL样品梯度稀释至适当浓度后,均匀涂布在LB琼脂固体培养基平板上,于37℃条件下培养24h,然后计数平板上的菌落形成数量(CFU),进而定量分析抗菌效果,见图2。
由图2可知,夫西地酸(FA)及磷脂(PC)在各个浓度均无抗菌性,而通过本发明方法制备的夫西地酸磷脂复合物(FA-PC),在5μg/ml时开始具备微弱的抗菌性(抑菌率55%),10μg/ml时抑菌率达到97%,20μg/ml时达到99.97%。
3、取铜绿假单胞菌(P.aeruginosa)菌株,在20℃、1800rcf条件下离心15min,弃上清液,沉淀用1ml LB培养基溶液重悬,并稀释到菌液浓度为5×105cfu/ml。取200μL菌液,分别加入夫西地酸(FA)水溶液、夫西地酸磷脂复合物(FA-PC,1:1)水溶液、磷脂(PC)水溶液,于37℃培养12h,然后吸取100μL样品梯度稀释至适当浓度后,均匀涂布在LB琼脂固体培养基平板上,于37℃条件下培养24h,然后计数平板上的菌落形成数量(CFU),进而定量分析抗菌效果,见图3。
由图3可知,夫西地酸(FA)及磷脂(PC)在各个浓度均无抗菌性,而通过本发明方法制备的夫西地酸磷脂复合物(FA-PC),在10μg/ml时开始具备微弱的抗菌性(抑菌率>60%),20μg/ml时具有显著的抗菌性(抑菌率>90%)。
综上可知,本发明所记载的夫西地酸磷脂复合物制备方法简单,能显著提高夫西地酸的溶解度以及对革兰阴性菌的抗菌效果,可有效拓宽夫西地酸的抗菌谱和应用范围。
Claims (10)
1.一种夫西地酸磷脂复合物,其特征在于,包括夫西地酸和磷脂。
2.根据权利要求1所述的夫西地酸磷脂复合物,其特征在于,所述夫西地酸和磷脂的摩尔比为1:0.1~1:5。
3.根据权利要求2所述的夫西地酸磷脂复合物,其特征在于,所述夫西地酸和磷脂的摩尔比为1:0.5~1:3。
4.根据权利要求3所述的夫西地酸磷脂复合物,其特征在于,所述夫西地酸和磷脂的摩尔比为1:1。
5.根据权利要求1~4任一项所述的夫西地酸磷脂复合物,其特征在于,所述磷脂为天然类磷脂成分或通过合成方式获得的磷脂。
6.根据权利要求5所述的夫西地酸磷脂复合物,其特征在于,所述磷脂为大豆卵磷脂、蛋黄卵磷脂、DSPE、DPPE、DSPC、DPPC、DSPG、DPPA、DOTAP、DEPC、DPPG或DSPE-MPEG2000。
7.权利要求1~4任一项所述的夫西地酸磷脂复合物的制备方法,其特征在于,包括以下步骤:
将夫西地酸和磷脂溶于有机溶剂中,然后于20-60℃下搅拌,再减压除去有机溶剂,即可得到夫西地酸磷脂复合物。
8.根据权利要求7所述的制备方法,其特征在于,所述有机溶剂为乙酸乙酯、丙酮、氯仿、二氯甲烷、四氢呋喃、正己烷、乙醇和甲醇中的至少一种。
9.权利要求1~5任一项所述的夫西地酸磷脂复合物,或权利要求7或8任一项所述方法制备得到的夫西地酸磷脂复合物在制备可抑制革兰氏阴性菌的抗菌剂中的用途。
10.根据权利要求9所述的用途,其特征在于,所述革兰氏阴性菌为大肠杆菌、铜绿假单胞菌或变形杆菌。
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US5662929A (en) * | 1994-12-23 | 1997-09-02 | Universite De Montreal | Therapeutic liposomal formulation |
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US5662929A (en) * | 1994-12-23 | 1997-09-02 | Universite De Montreal | Therapeutic liposomal formulation |
CN101254184A (zh) * | 2007-12-29 | 2008-09-03 | 四川大学 | 丹参酚酸b磷脂复合物及其制备方法 |
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