CN114983949B - 汉防己甲素固体脂质纳米粒的制备方法及其应用 - Google Patents
汉防己甲素固体脂质纳米粒的制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及一种汉防己甲素固体脂质纳米粒的制备方法及其应用。所述的汉防己固体脂质纳米粒由汉防己甲素、大豆卵磷脂、大豆油、水组成。在制备过程中,首先利用溶剂法形成汉防己甲素磷脂复合物,接着采用薄膜分散、超声冻干法制备汉防己甲素固体脂质纳米粒。本发明所涉及的汉防己甲素固体脂质纳米粒制备方法简便,且包封率及载药量高。制备得到的汉防己甲素固体脂质纳米粒为冻干粉末状,能有效提高制剂的稳定性及运输便捷性。本发明所制备的汉防己甲素固体脂质纳米粒可通过口服给药、注射给药、吸入给药等,用于组织纤维化、尘肺疾病的治疗。
Description
技术领域
本发明涉及药物制剂技术领域,具体是指一种汉防己甲素固体脂质纳米粒的制备方法及其应用。
背景技术
汉防己甲素又名粉防己碱,是从防己科植物粉防己块根中提取的一种双苄基异喹啉类生物碱,属于双苄基异喹啉类化合物,为新型钙拮抗剂,是粉防己的主要Chemicalbook有效成分;具有消炎、镇痛、降压、抗矽肺、降低血糖、抗自由基损伤、抗肝纤维化和等抗肿瘤多种药理作用;临床用于单纯性硅肺和煤硅肺。也用于早期轻度高血压、风湿痛、关节痛、神经痛等。同时还用于肝癌、肺癌、结肠癌、膀胱癌以及白血病的治疗。但是汉防己甲素不溶于水,其普通制剂生物利用度不高,也无组织靶向作用,影响了该药的治疗效果;而且汉防己甲素安全范围较小,毒副作用较大,使该药在临床的使用范围受到一定的限制。
固体脂质纳米粒是一种以天然或合成的固体脂质为载体制成的给药体系,所含有的固体脂质成分是机体可利用、可生物降解的,与聚合纳米粒相比,它的毒性更低。与脂质体相比,由于药物被包封在固体脂粒的骨架中,不存在药物在贮存过程中的泄漏问题。SLN还具有缓释、控释和靶向作用。
超声法是最早用于制备固体脂质纳米粒的技术,特别适用于实验室制备少量样品,采用的乙醇来分散汉防己甲素,分散效果差,不利于包封率及载药量,这种分散得到的产品只能为注射给药,制剂的稳定性及运输不便。
发明内容
为解决上述技术问题,本发明提供了一种汉防己甲素固体脂质纳米粒,含有如下重量份数的组分:汉防己甲素1-100份、磷脂1-500份、大豆油1-600份和水30-3000份。
进一步地,所述汉防己甲素与磷脂和大豆油的质量比1:(1-5):(3-6)。
更进一步地,所述汉防己甲素与磷脂和大豆油的质量比为1:(2-4):(3-5)。
更进一步地,所述磷脂为大豆卵磷脂、大豆磷脂或蛋黄磷脂。
更进一步地,所述磷脂是大豆卵磷脂。
更进一步地,所述固体脂质纳米粒质量份组成为:汉防己甲素1份,大豆卵磷脂2份,大豆油3份和水200份。
本发明还提供了一种汉防己甲素固体脂质纳米粒粉末,所述固体脂质纳米粒粉末含有汉防己甲素、磷脂、大豆油、冻干保护剂,所述冻干保护剂为海藻糖、甘露醇或葡萄糖,所述汉防己甲素、磷脂、大豆油以及冻干保护剂的质量比为1:(1-5):(3-6):(2-14)。
进一步地,所述固体脂质纳米粒粉末是上述的汉防己甲素固体脂质纳米粒溶液冻干制备而成。
更进一步地,所述固体脂质纳米粒溶液内加冻干保护剂后冻干,所述冻干保护剂为:海藻糖、甘露醇或葡萄糖,所述冻干保护剂在固体脂质纳米粒溶液中的浓度为1%-7%。
更进一步地,所述固体脂质纳米粒溶液内加冻干保护剂后冻干,所述冻干保护剂为:葡萄糖,所述冻干保护剂在所制备的固体脂质纳米粒溶液中的浓度为3%。
本发明还提供了一种汉防己固体脂质纳米粒制备方法,包括如下步骤:1)将汉防己甲素与磷脂分散于溶剂中,搅拌分散均匀,除去溶剂,得到汉防己甲素磷脂复合物;2)将汉防己甲素磷脂复合物与大豆油溶于溶剂中,搅拌分散均匀,形成混合物,除去溶剂,形成薄膜;3)向薄膜里加入水,剧烈震荡,形成初乳;4)将得到的初乳进行超声,即得汉防己固体脂质纳米粒溶液。
进一步地,上述的步骤1)和步骤2)中溶剂为丙酮。
更进一步地,所述步骤1)中搅拌的温度为50-70℃,搅拌的时间为0.5-3h;步骤2)中所述搅拌的温度为50-70℃,搅拌的时间为10-50min;步骤4)中所述超声功率为200-300W,超声时间为5-30min。
本发明还提供了一种汉防己甲素固体脂质纳米粒在制备治疗肺纤维化、尘肺、肺癌、肝纤维化、肾脏纤维化、风湿痛、关节痛疾病的药物中的用途。
进一步地,所述药物是喷雾剂、粉雾剂、粉针剂或注射剂。
更进一步地,所述药物可用于肺部吸入给药。
本发明还提供了一种汉防己甲素固体脂质纳米粒冻干粉末在制备治疗肺纤维化、尘肺、肺癌、肝纤维化、肾脏纤维化、风湿痛、关节痛疾病的药物中的用途。
本发明还提供了一种药物,它是由上述冻干粉末为活性成分加上药学上可接受的辅料制备而成的制剂。
进一步地,所述药物是喷雾剂、粉雾剂、粉针剂或注射剂。
更进一步地,所述药物为喷雾剂、粉雾剂时,可用于肺部吸入给药。
药学上可接受的辅料是保证药物制剂生产和发展的物质基础,在制剂剂型和生产中起着关键的作用,能提高药物的疗效、降低不良反应。药学上可接受的辅料包括表面活性剂、助悬剂、乳化剂、稀释剂、黏合剂、崩解剂、润滑剂等,如吐温、司盘、聚乳酸(PLA)、聚乳酸-聚乙醇酸共聚物(PLGA)、羧甲基淀粉钠(CMS-Na)、交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC-Na)等。
本发明具有如下优点:
1、本发明所涉及的固体脂质纳米粒的制备方法简单易得,选用的材料均为药用辅料,更易于临床转化。
2、制备过程中选择丙酮作为分散剂,分散效果比乙醇更好,更有利于包封率及载药量的提高。
3、本方法所制备的固体脂质纳米粒冻干后为粉末状,能有效提高制剂的稳定性及运输便捷性,应用更加便捷。
4、本方法所制备的汉防己甲素固体脂质纳米粒粉末可制备为粉雾剂肺部吸入给药,或者用注射用水溶解后作为吸入喷雾剂使用,扩充了制剂的应用途径。
附图说明
图1是本发明实施例1所制备的汉防己甲素固体脂质纳米粒的透射电镜图。
图2是本发明实施例2所制备的汉防己甲素固体脂质纳米粒的透射电镜图。
图3是本发明实施例6所制备的汉防己甲素固体脂质纳米粒冻干粉末的扫描电镜图。
图4是加入不同浓度的甘露醇冻干后汉防己甲素固体脂质纳米粒的粒径变化图。
图5是加入不同浓度的海藻糖冻干后汉防己甲素固体脂质纳米粒的粒径变化图。
图6是加入不同浓度的葡萄糖冻干后汉防己甲素固体脂质纳米粒的粒径变化图。
具体实施方式
下面通过结合具体实施方式,对本发明内容作进一步的详细描述。但本发明的范围并不因此局限于下述实施例。实施例中所采用的试剂和仪器及实验条件可以根据实际情况做进一步调整,未注明实施条件为常规实验条件,未注明生产厂商的试剂和仪器,均为可以通过市售购买的常规产品。
实施例1:
1)、称取0.1g的汉防己甲素和0.2g的大豆卵磷脂分散于5ml的丙酮中,55℃搅拌1h后,除去丙酮,即得汉防己甲素磷脂复合物;
2)、取1)步骤中的汉防己甲素磷脂复合物,加入0.3g的大豆油,并加入5ml的丙酮溶解,在50℃的温度下继续搅拌20min,形成混合物;减压旋蒸除去丙酮,直至形成一层脂质薄膜;
3)、向步骤2)中所形成的脂质薄膜里加入20ml预热到55℃的水,剧烈震荡搅拌30min,形成乳白色混悬液,形成初乳;
4)、将3)步骤中得到的初乳进行超声,超声功率为200W,超声时间为10min,即得汉防己甲素固体脂质纳米粒溶液。
实施例2:
1)、称取0.1g的汉防己甲素和0.3g的大豆卵磷脂分散于5ml的丙酮中,55℃搅拌1h后,除去丙酮,即得汉防己甲素磷脂复合物;
2)、取1)步骤中的汉防己甲素磷脂复合物,加入0.4g的大豆油,并加入5ml的丙酮溶解,在50℃的温度下继续搅拌20min,形成混合物;减压旋蒸除去丙酮,直至形成一层脂质薄膜;
3)、向步骤2)中所形成的脂质薄膜里加入20ml预热到55℃的水,剧烈震荡搅拌30min,形成乳白色混悬液,形成初乳;
4)、将3)步骤中得到的初乳进行超声,超声功率为200W,超声时间为10min,即得汉防己甲素固体脂质纳米粒溶液。
实施例3:
1)、称取0.1g的汉防己甲素和0.4g的大豆卵磷脂分散于5ml的丙酮中,55℃搅拌1h后,除去丙酮,即得汉防己甲素磷脂复合物;
2)、取1)步骤中的汉防己甲素磷脂复合物,加入0.5g的大豆油,并加入5ml的丙酮溶解,在50℃的温度下继续搅拌20min,形成混合物;减压旋蒸除去丙酮,直至形成一层脂质薄膜;
3)、向步骤2)中所形成的脂质薄膜里加入20ml预热到55℃的水,剧烈震荡搅拌30min,形成乳白色混悬液,形成初乳;
4)、将3)步骤中得到的初乳进行超声,超声功率为200W,超声时间为10min,即得汉防己甲素固体脂质纳米粒溶液。
实施例4:
1)、称取0.1g的汉防己甲素和0.2g的大豆卵磷脂分散于5ml的丙酮中,55℃搅拌1h后,除去丙酮,即得汉防己甲素磷脂复合物;
2)、取1)步骤中的汉防己甲素磷脂复合物,加入0.3g的大豆油,并加入5ml的丙酮溶解,在50℃的温度下继续搅拌20min,形成混合物;减压旋蒸除去丙酮,直至形成一层脂质薄膜;
3)、向步骤2)中所形成的脂质薄膜里加入20ml预热到55℃的水,剧烈震荡搅拌30min,形成乳白色混悬液,形成初乳;
4)、将3)步骤中得到的初乳进行超声,超声功率为250W,超声时间为10min,即得汉防己甲素固体脂质纳米粒溶液。
实施例5
1)、汉防己甲素磷脂复合物的制备:称取0.1g的汉防己甲素和0.2g的大豆卵磷脂分散于5ml的丙酮中,55℃搅拌1h后,除去丙酮,即得汉防己甲素磷脂复合物;
2)、取1)步骤中的汉防己甲素磷脂复合物复合物,加入0.3g的大豆油,并加入5ml的丙酮溶解,在50℃的温度下继续搅拌20min,形成混合物;减压旋蒸除去丙酮,直至形成一层脂质薄膜;
3)、向步骤2)中所形成的脂质薄膜里加入20ml预热到55℃的蒸馏水,剧烈震荡搅拌30min,形成乳白色混悬液,形成初乳;
4)、将3)步骤中得到的初乳进行超声,超声功率为300W,超声时间为10min,即得汉防己甲素固体脂质纳米粒溶液。
实施例6
取实施例1-5所述的汉防己甲素固体脂质纳米粒溶液,加入3%葡萄糖(w/v)作为冻干保护剂,采用冷冻干燥法进行冻干,即得汉防己甲素固体脂质纳米粒冻干粉末
实施例7
取实施例6中所得的汉防己甲素固体脂质纳米粒粉末,封装于特定的胶囊中,然后将其装入特制的吸入器中,即可制得汉防己甲素固体脂质纳米粒粉雾剂。
实施例8
取实施例6中所制得的汉防己甲素固体脂质纳米粒粉末,加入一定量的注射用水复溶,将得到的纳米溶液罐装于适当容器中,装上手动泵,即可得到汉防己甲素固体脂质纳米粒喷雾剂。
以下通过实验例证明本发明的益处。
实验例1
汉防己甲素固体脂质纳米粒粒径的测定
采用动态光散射法对实施例1-5所制备的汉防己甲素固体脂质纳米粒的粒径及其分布进行测量,测量仪器为Zetasizer Nano ZS90激光粒度分析仪(Malvern公司,英国)。实验结果如表1所示。
表1汉防己甲素固体脂质纳的粒径及其分布情况
实验例2
汉防己甲素固体脂质纳米粒形态观察利用透射电镜对汉防己甲素固体脂质纳米粒的形态进行观察。取实施例1和实施例2新制备的汉防己固体脂质纳米粒溶液,滴加至覆盖有碳膜的铜网上,吸取边缘多余的液体后用磷钨酸钠染液进行染色,染色2-3分钟后,用滤纸吸除染液,干燥后电镜进行观察。实验结果附图1-2所示。本发明所制备的汉防己甲素固体脂质纳米粒为实心的均匀圆球状,大小均一、形状圆整,且投入的脂质的量不会对形态造成明显区别。放大的图片可以看出汉防己甲素完全被脂质所包裹,具有明显的“核壳”结构。
实验例3
汉防己甲素固体脂质纳米粒冻干粉末形态观察利用扫描电镜对汉防己甲素固体脂质纳米粒冻干粉针的形态进行观察。取实施例6所制备的汉防己甲素固体脂质纳米粒冻干粉末,将其喷金后放入扫描电镜仪器中观察。实验结果如附图3所示。从扫描电镜中可观察到球状颗粒,也可见块状团聚体。所形成的团聚体多数大小在2-10μm,可以满足其作为干粉吸入剂的要求。样品中出现的的团聚体,考虑可能是因为在利用扫描电镜观察时,其喷金以及电子束扫描样品的过程中,会使温度大大升高,引起脂质的融化而加剧了团聚现象。
实验例4
包封率及载药量的测定
包封率是纳米粒质量控制的一个重要指标,用来表示药物被纳米粒包封的程度。纳米粒包封率的测量,通常是先将含药的纳米粒与游离药物分开,然后通过一定的测量方式,测出药物含量,计算出纳米粒的包封率。我们采用HPLC法测量汉防己甲素的含量,用葡聚糖凝胶柱层析法分离纳米粒和游离药物。
分别取实施例1-3中新制备的纳米粒溶液0.1ml,过G50葡聚糖凝胶柱分离纳米粒和游药药物,分离出的纳米粒溶液用三倍甲醇破乳,超速离心,0.22μm滤膜过后,采用高效液相色谱法测定纳米粒中包载的药物含量(We)。另取未过柱的样品0.1ml,直接用三倍甲醇破乳,0.22μm滤膜过后,同法测定。体系中药物总含量Wt,纳米粒总质量Wd等于药物总含量与辅料总质量之和。
根据下列公式计算纳米粒的包封率及载药量:
包封率(%)=包封在纳米粒中的药物We/纳米粒溶液的药物总含量Wt*100%
载药量(%)=包封在纳米粒中的药物Wt/纳米粒总质量Wd*100%
实验结果如表2所示:
表2实施例1-3制剂包封率及载药量汇总
实施例1 | 实施例2 | 实施例3 | |
包封率(%) | 88.4 | 95.52 | 95.81 |
载药量(%) | 13.6 | 12.7 | 11.2 |
实验例5
冻干保护剂的筛选
取实施例1所制备的汉防己甲素固体脂质纳米粒溶液,向其中加入一定量的冻干保护剂,进行冻干。实验过程中,筛选了常用的甘露醇、海藻糖与葡萄糖三种冻干保护剂,并对加入的浓度进行了探索,分别设置了1%、3%、5%、7%等浓度。以粒径和PDI为指标进行了考察,结果如下表。
表3加入不同浓度的不同冻干保护剂在冻干前后的粒径变化
甘露醇、海藻糖与葡萄糖三种不同的反应之后的粒径变化如图4-6所示。
如图4-6所示,可以直观地看到选用3%、5%、7%的葡萄糖作为冻干保护剂时,纳米粒的粒径变化最小,并且用3%葡萄糖冻干后的纳米粒PDI为最小。故以3%的葡萄糖作为冻干保护剂为最佳。
实验例6
尘肺病(pneumoconiosis)是在职业活动中,长期吸入生产性粉尘引起的以肺组织慢性纤维化为主要特征的一种全身性疾病。采用二氧化硅粉尘建立大鼠矽肺模型考察汉防己甲素脂质纳米粒对尘肺的治疗效果。
实验方案:取体重约200g的雄性SD大鼠50只,适应性喂养一周后随机分为5组,分别为正常组,假手术组,模型组、汉防己甲素注射液组、汉防己甲素固体脂质纳米粒注射给药组、汉防己甲素固体脂质纳米粒雾化吸入给药组。将二氧化硅粉末以生理盐水为溶剂,配制成25mg/ml的混悬液。除正常组外,其余动物采用水合氯醛麻醉,模型组、各给药组老鼠向其气管中注入1ml二氧化硅混悬液,假手术组向气管中注入1ml生理盐水。在造模后第二天开始给药,汉防己甲素的剂量为30mg/kg,连续给药28天。分别于造模第1、7、14、21及28天观察动物的情况,并记录其体重变化。在造模第14、28天每组取5只大鼠,麻醉后使用RC系统测定大鼠肺功能;处死大鼠,分离肺组织,全肺称重。
肺系数计算公式:肺系数=肺湿重/体重*100%
实验结果
临床表现:正常组和假手术组大鼠精神状态良好,未见异常。模型组大鼠呼吸深缓,食欲减退。给药组老鼠偶尔出现拱背,呼吸深缓的情况,但整体状态优于模型组。其中,各给药组老鼠状态:汉防己甲素固体脂质纳米粒雾化给药组>汉防己甲素固体脂质纳米粒注射给药组>汉防己甲素注射液组。
体重:各组大鼠体重随着饲养时间的增长而呈现缓慢上升的趋势。各组间体重变化趋势略有不同,模型组老鼠的体重在第7天时显著低于假手术组。各给药组老鼠体重与模型组体重差不多。
表4各组大鼠体重变化比较(n=5)
注:与假手术组相比,*p<0.05。
肺系数变化:与正常组以及假手术组大鼠相比,模型组大鼠的肺系数显著升高,肺组织水肿严重。与模型组相比,14天时,各给药组大鼠肺系数明显降低,其中固体脂质纳米粒注射组系数较注射液组更低,固体脂质纳米粒注射给药组和雾化给药组之间无差异。28天时,雾化组大鼠肺系数进一步降低。各组的肺系数如表5所示:
表5各组大鼠肺系数的比较(n=5)
注:与假手术组相比,*p<0.05;与模型组相比,#p<0.05。
肺功能的变化:在14天时,与正常组相比,模型组大鼠的各项肺功能指标都出现了明显的下降,主要表现为呼吸频率加快,气道阻力升高,潮气量及动态肺顺应性降低。与模型组相比,各给药组的肺功能均有所改善,其中汉防己甲素固体脂质纳米粒注射组与雾化给药组缓解情况优于汉防己甲素注射液组。汉防己甲素固体脂质纳米粒两组间无显著性差异。
表614天各组大鼠肺功能比较(n=5)
注:与假手术组相比,*p<0.05。
以上对本发明及其实施方式进行了描述,这种描述没有限制性,附图中所示的也只是本发明的实施方式之一,实际的结构并不局限于此。总而言之如果本领域的普通技术人员受其启示,在不脱离本发明创造宗旨的情况下,不经创造性的设计出与该技术方案相似的结构方式及实施例,均应属于本发明的保护范围。
Claims (7)
1.一种汉防己甲素固体脂质纳米粒粉末,其特征在于,所述固体脂质纳米粒粉末由汉防己甲素、磷脂、大豆油、冻干保护剂组成,所述汉防己甲素、磷脂、大豆油的质量比为1:(2-4):(3-5);所述汉防己甲素固体脂质纳米粒粉末是汉防己甲素固体脂质纳米粒溶液加冻干保护剂冻干制备而成;所述冻干保护剂为葡萄糖,所述冻干保护剂在所述的汉防己甲素固体脂质纳米粒溶液中的浓度为3%;所述汉防己甲素固体脂质纳米粒溶液由如下重量份数的组分组成:汉防己甲素1-100份、磷脂1-500份、大豆油1-600份和水30-3000份。
2.根据权利要求1所述的汉防己甲素固体脂质纳米粒粉末,其特征在于,所述汉防己甲素固体脂质纳米粒溶液由如下重量份数的组分组成:汉防己甲素1份,磷脂2份,大豆油3份和水200份。
3.根据权利要求1或2所述的汉防己甲素固体脂质纳米粒粉末,其特征在于,所述汉防己甲素固体脂质纳米粒溶液的制备包括如下步骤:1)将汉防己甲素与磷脂分散于溶剂中,搅拌分散均匀,除去溶剂,得到汉防己甲素磷脂复合物;2)将汉防己甲素磷脂复合物与大豆油溶于溶剂中,搅拌分散均匀,形成混合物,除去溶剂,形成薄膜;3)向薄膜里加入水,剧烈震荡,形成初乳;4)将得到的初乳进行超声,即得汉防己甲素固体脂质纳米粒溶液。
4.根据权利要求3所述的汉防己甲素固体脂质纳米粒粉末,其特征在于,所述步骤1)中搅拌的温度为50-70℃,搅拌的时间为0.5-3h;步骤2)中所述搅拌的温度为50-70℃,搅拌的时间为10-50min;步骤4)中所述超声功率为200-300W,超声时间为5-30min;所述的步骤1)和步骤2)中溶剂为丙酮。
5.根据权利要求1、2或4所述的汉防己甲素固体脂质纳米粒粉末在制备治疗肺纤维化、肺癌、肝纤维化、肾脏纤维化、风湿痛、关节痛疾病的药物中的用途。
6.根据权利要求5所述的用途,其特征在于,所述药物是喷雾剂、粉雾剂或注射剂,所述药物可用于肺部吸入给药。
7.一种药物,其特征在于,它是以权利要求1~4任一项所述汉防己甲素固体脂质纳米粒粉末为活性成分加上药学上可接受的辅料制备而成的制剂。
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