CN108309943B - 一种基于药物颗粒的复方制剂 - Google Patents
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Abstract
本发明属于药物制剂,药物递送等领域,特别涉及药物颗粒所形成的复方制剂的设计和应用。本发明设计的药物递送药物体系,可以在保证载体高安全性低毒性,同时以药物颗粒的形式有效的联合递送两种药物进入体内发挥作用,诸多实例证明该体系在体外具有较高的细胞毒性,优良的体内抗肿瘤增殖效果。
Description
技术领域:
本发明属于药物制剂,药物递送等领域,特别涉及注射用复方纳米晶体系的设计和应用。
背景技术:
天然或者合成的抗肿瘤药物大多属于BCS分类中的IV类药物,渗透性差,溶解度低,毒副作用大等缺点严重影响其发挥治疗作用,对于难溶性药物,采用纳米制剂进行药物递送是现在广泛研究的递药策略,此外,直接递送的药物晶体经静脉注射给药后会在体循环的过程中被溶解掉,加之目前单独递送一种作用机制的药物已经无法满足具备超强环境适应性的疾病的治疗需求,基于目前待解决的问题,本发明设计了一种复方纳米晶体系,采用双亲性蛋白质,多糖或者高分子材料为稳定剂递送两种药物,以药物颗粒的形式将一种药物包裹或者嵌入到药物颗粒表面制成复方制剂,实现联合给药。
蛋白质是一种具有天然双亲性的优良载体,由不同氨基酸单体和多肽链通过α-螺旋,β-折叠,无规卷曲等组成空间结构,通常含空腔或者可以自组装形成载药空腔。此外,一些常见的食物蛋白如酪蛋白,乳球蛋白,白蛋白等来源于食物,具有良好的生物相容性,生物可降解性,体内低免疫原性等特点,用之作为注射剂的载体具有更高的安全性。因此,使用蛋白质作为给药系统的载体,难溶性药物颗粒可被包裹在蛋白质的疏水性内芯,从而实现注射给药。一些人工合成的高分子化合物如PLGA,PEI等和多糖如壳聚糖等也具备自组装,高载药量的特性。
基于以上特点,本发明使用蛋白质,多糖或者高分子材料为稳定剂,通过简单的制备手段实现同时递送两种具有不同药物作用靶点和药理作用的药物,实现药物的联合治疗。
发明内容:
本发明的目的一方面是采用生物相容性好,毒性低的双亲性食物蛋白,多糖或者高分子材料为稳定剂,形成一种基于药物颗粒的复方制剂,同时作用于不同药物靶点,实现多种药理作用,另一方面是设计药物递送药物的体系,从而实现两种不同药物的联合给药的制备方法,且该方法过程简单,制备过程易于控制,制备的复方纳米晶体系性质稳定。
本发明具体技术方案(以超声共沉淀法和β-酪蛋白做稳定剂为例):
1)制备药物蛋白复合物作为纳米晶的载体
将0.5-1.0mg的马立马司他溶于1.0mL蒸馏水,在磁力搅拌条件下,加入到浓度为1.0mg/mL的β-酪蛋白水溶液中使搅拌均匀,冰水浴条件下,使用功率200W探头超声10min,使形成稳定的药物蛋白复合物。
2)以药物蛋白复合物为载体,制备难溶性药物的纳米晶
将3-20mg的紫杉醇原料药溶解在200μL的丙酮中成为有机相,上述药物蛋白复合物为水相,在磁力搅拌条件下,将有机相缓慢加入到水相,冰水浴条件下,使用功率200W探头超声10min,减压蒸发法除去体系中残留的丙酮,使形成难溶性药物的纳米晶。
本发明中所用的原料药或者试剂均市售可得。
本发明采用动态光散射纳米粒径仪(ZetaPlus),扫描电镜等对纳米晶的结构和粒径进行表征。
本发明所用载体安全性高,毒性低。
本发明所制备的复合制剂体内外药效良好。
附图说明:
附图1为实施例1制备的纳米晶的粒径分布图和扫描电镜图片。
附图2为实施例2制备的纳米晶的X粉末射线衍射图片。
附图3为实施例3制备的纳米晶的体外细胞毒性评价
附图4位实施例4制备的纳米晶和体外抗侵袭评价
附图5为实施例5的药效学实验的肿瘤体积变化率曲线。
附图6为实施例5的药效学实验的抗肿瘤转移的肺部结节图片。
具体实施方式:
实施例1:
处方:
制备方法:
将1.0 mg的马立马司他溶于1.0ml蒸馏水,在磁力搅拌条件下,加入到浓度为1.0mg/mL的10mLβ-酪蛋白水溶液中使搅拌均匀,冰水浴条件下,使用功率200W探头超声10min,使形成稳定的药物蛋白复合物。将3-20mg的紫杉醇原料药溶解在200μL的丙酮中成为有机相,上述药物蛋白复合物为水相,在磁力搅拌条件下,将有机相缓慢加入到水相,冰水浴条件下,使用功率200W探头超声10min,减压蒸发法除去体系中残留的丙酮,使形成难溶性药物的纳米晶。
利用动态光散射纳米粒径仪对实施例1所制备得到的纳米晶的粒径和多分散系数进行测定;利用扫描电镜对其进行形态学表征。实施例1中所制备得到的纳米晶的粒径为150nm,多分散系数为0.20。附图1为粒径分布图和扫描电镜图片。
实施例2:
处方:
制备方法:
将1.0mg的马立马司他溶于1.0mL蒸馏水,在磁力搅拌条件下,加入到浓度为1.0mg/mL的10mlβ-酪蛋白水溶液中使搅拌均匀,冰水浴条件下,使用功率200W探头超声10min,使形成稳定的药物蛋白复合物。将20mg的紫杉醇原料药溶解在200μL的丙酮中成为有机相,上述药物蛋白复合物为水相,在磁力搅拌条件下,将有机相缓慢加入到水相,冰水浴条件下,使用功率200W探头超声10min,减压蒸发法除去体系中残留的丙酮,使形成难溶性药物的纳米晶。100000g超速离心20min取沉淀,60℃烘干,待用。
用X射线衍射仪进行X粉末射线衍射检测。结果表明自制的纳米晶中的药物以药物晶体的形式存在,附图2为检测结果。
实施例3
根据实施例1所述的处方和方法制备纳米晶,与4T1细胞共孵育进行体外细胞评价,具体操作方法如下:将4T1细胞以8000个/孔接种于96孔板中,孵育24小时后,将不同浓度的纳米晶,蛋白药物复合物,游离药物,空白载体加入到96孔板中,孵育24小时后,取20μL四甲基偶氮唑蓝(5mg/mL)加入各孔内,继续孵育4小时,弃去孔内液体,加入二甲亚砜200μL,振摇,使结晶充分溶解,在490nm波长下用酶标仪测定各样品的吸光度值,同时测定空白组吸光度值,并计算细胞存活率。
结果表明,同一浓度下,纳米晶的细胞毒性显著高于游离药物,且作为载体的β-酪蛋白和药物蛋白复合物在实验浓度下存活率均高于80%,表明此纳米晶体系载体安全性高,且可以保留所递送抗肿瘤药物的细胞毒性。
实施例4
根据实施例1所述的处方和方法制备纳米晶,与4T1细胞共孵育进行体外抗肿瘤侵袭评价,具体操作方法如下:将与不同浓度的纳米晶,蛋白药物复合物,游离药物,空白载体共孵育后的4T1细胞以10000个/孔接种于Transwell小室的上室中,下室加入血清浓度20%为诱导剂,观察药物作用后,肿瘤细胞的体外侵袭情况。
结果表明,本发明制备的复方纳米晶在体外具有良好的抗肿瘤转移效果。
实施例5
药效学评价,以Balb/c荷瘤小鼠为模型,考察本发明纳米晶体系的体内抗肿瘤活性。
处方:
根据实施例1所述的方法制备纳米晶,待用。
收集对数生长期4T1细胞,以空白RPMI 1640培养基调整细胞浓度为1×107个/mL,在Balb/c小鼠左侧腋下进行无菌皮下接种,接种浓度为1×106个细胞/只。待肿瘤体积生长至100-200mm3时,将小鼠随机分成5组,每组10只,分别静脉注射生理盐水,自制纳米晶,蛋白药物复合物,马立马司他游离药物,紫杉醇游离药物,每两天给药一次,连续给药7次,给药剂量为紫杉醇5mg/kg,马立马司他5mg/kg。测量每次给药前的肿瘤体积,并在给药周期结束后处死所有小鼠解剖取肺部组织,Bouin氏固定液染色观察肺部结节转移情况。
实验结果表明,纳米晶体系表现出良好的抑瘤效果,相对肿瘤体积增长倍数最低,且肺部转移结节最少,附图4和附图5分别为肿瘤体积增长率曲线和肺部结节转移图。
实施例6
处方:
将1.0mg的马立马司他溶于1.0ml蒸馏水,在磁力搅拌条件下,加入到浓度为1.0mg/mL的10mL人β-乳球蛋白水溶液中使搅拌均匀,冰水浴条件下,使用功率200W探头超声10min,使形成稳定的药物蛋白复合物。将3-20mg的黄芩素原料药溶解在200μL的丙酮中成为有机相,上述药物蛋白复合物为水相,在磁力搅拌条件下,将有机相缓慢加入到水相,冰水浴条件下,使用功率200W探头超声10min,减压蒸发法除去体系中残留的丙酮,使形成难溶性药物的纳米晶。
实施例7:
处方:
90℃加热30min使人β-乳球蛋白变性,冷却后调节pH至7.0待用为水相,用1mL丙酮同时溶解6mg紫杉醇和1mg双硫仑为有机相,冰水浴磁力搅拌条件下,缓慢将水相加入到有机相中,600W探头超声15min,减压蒸发法除去体系中残留的丙酮,形成双硫仑嵌入到紫杉醇颗粒内部的纳米晶体系。
Claims (5)
1.一种由药物颗粒形成的复方纳米晶体系,其特征在于:所述复方纳米晶体系由一种药物颗粒和另一包裹在所述颗粒表面的药物-载体复合物构成;
所述复方纳米晶体系中的两种药物能够作用于不同的药物靶点,以实现复方中不同药理作用的药物功能,从而实现药物的联合治疗;
其中,所述药物颗粒为难溶性药物颗粒,所述复方纳米晶体系中包裹在药物颗粒表面的另一种药物为马立马司他;
所述复方纳米晶体系的制备工艺为超声共沉淀,操作步骤如下:
1)将复方中的马立马司他用蒸馏水溶解,缓慢加入到磁力搅拌的载体水溶液中,冰浴,探头超声使形成载体-药物复合物,成为整个体系的水相;
2)将难溶性药物溶于有机物中为有机相,磁力搅拌下,将有机相缓慢加入到水相,冰浴,探头超声使形成共载两种不同药理作用药物的复方纳米晶体系;
所述难溶性药物为紫杉醇;所述有机物为丙酮;所述载体为β-酪蛋白。
2.根据权利要求1所述的复方纳米晶体系,其特征在于:所述复方纳米晶体系呈球状,杆状或者其他不规则形状。
3.根据权利要求1所述的复方纳米晶体系,其特征在于:所述复方纳米晶体系具有以下特性:
1)可以同时递送两种药物,载药量分别为5%~10%和50%~100%
2)体系的粒径为10nm-250nm,多分散系数小于0.3。
4.根据权利要求1所述的复方纳米晶体系,其特征在于:所述复方纳米晶体系的制备方法简便,且所述复方纳米晶体系的制备工艺为探头超声,高压均质,高速剪切。
5.如权利要求1~权利要求4任一项所述的复方纳米晶体系在制备注射用抗肿瘤药物中的应用。
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CN105748442A (zh) * | 2016-04-07 | 2016-07-13 | 天津中医药大学 | 一种红景天苷及他莫昔芬的双载药抗乳腺癌纳米制剂的制备方法 |
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CN103432073A (zh) * | 2013-09-11 | 2013-12-11 | 中国药科大学 | 一种肿瘤靶向纳米制剂及其制备方法 |
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