CN115120565A - 大麻二酚纳米晶及其制备方法 - Google Patents
大麻二酚纳米晶及其制备方法 Download PDFInfo
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- CN115120565A CN115120565A CN202110336746.XA CN202110336746A CN115120565A CN 115120565 A CN115120565 A CN 115120565A CN 202110336746 A CN202110336746 A CN 202110336746A CN 115120565 A CN115120565 A CN 115120565A
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- cannabidiol
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Abstract
本发明提供了一种难溶性药物大麻二酚纳米晶制备方法。将大麻二酚溶于有机溶剂中，得到有机相；将稳定剂与水混合均匀，得到水相；将有机相缓慢加入水相中在一定的转速下搅拌，制得大麻二酚纳米混悬液。本发明制得的大麻二酚纳米混悬液及其冻干品能够显著减小药物粒径，增加药物的溶解度。使用5％的海藻糖或2％～5％的白蛋白作为冻干保护剂，可长期稳定保存，使用时将其复溶即可恢复冻干前的状态。本发明的制备工艺简洁、高效、无污染。所制得的纳米晶经过粒径分布测定、扫描电镜、体内外实验等测试，结果表明其生物利用度大幅提高，证明其具有广阔的应用前景。
Description
技术领域
本发明属于药物纳米晶制备领域，具体为大麻二酚纳米晶及其制备方法和应用。
背景技术
大麻二酚(Cannabidiol，CBD)，又称麻繁愫，是从大麻植物中提取的纯天然成分。与四氢大麻酚不同的是，大麻二酚是大麻中的非成瘾性成分。大麻二酚分子式为C21H30O2，几乎不溶于水。2013年美国有线电视新闻网报道了challotte的病例，使大麻制剂治疗难治性癫痫第一次进入大众视野。除此之外，CBD具有抗焦虑、抗精神病、抗抑郁、抗惊厥、抗恶心、抗氧化、抗炎、抗风湿和抗肿瘤等作用。因此大麻二酚新型制剂市场前景十分广阔。
大麻二酚是一种白色至淡黄色树脂或结晶目前主要以油基胶囊或悬浮液制剂给药，其口服生物利用度很低，小于15％，部分原因是大麻二酚在肠道和肝脏较高的首关消除，而导致进入全身血液循环内的药物量较少，且其血浆蛋白结合率较高(>99％)，致使血浆中游离态的有效药物量减少。设计安全有效且使用方便的大麻二酚新制剂具有重要的临床价值。
纳米药物晶体是药物仅借助少量表面活性剂或高分子聚合物的稳定作用，将纳米级别的药物分子悬浮于分散介质中，通过控制晶体的析出过程或者是机械粉碎的方法形成的稳定的亚微米胶体分散体系。国外从20世纪末就已开始进行有关的研究，作为一种新的纳米微粒药物传递系统，其能减小药物的粒径，增大药物的比表面积，很好地改善难溶性药物的溶解度，提高其生物利用度。作为一种制剂中间体，纳米晶可进一步制成口服、注射、透皮等多种给药途径的制剂。根据Noyes Whitney方程：粒径减小，比表面积增加，扩散层厚度变小，从而加快溶出。除此之外，比表面积增大有利于增加药物与肠壁的接触面积，使得接触时间增加，可使药物在靶点充分有效的吸收。
纳米结晶技术的应用仍受到设备能耗高、易磨损等因素的制约,药物本身的性质如脆碎性和热敏感性也限制了纳米结晶技术的应用，很难做到产业化开发。因此，开发出一种低成本、便于产业化生产的药物纳米晶的制备工艺具有重要意义。
发明内容
本发明的目的在于提供一种大麻二酚纳米晶组合物，组合物含有大麻二酚纳米晶94～97.9％，0.1％～1％的吐温80，2％～5％甘露醇、海藻糖或白蛋白；所述组合物分散性良好，粒径大小均匀，残留溶剂少，可显著提高大麻二酚的溶出度与生物利用度。本发明同时提供所述纳米晶的制备方法，方法具有制备工艺简单、快速、环保、成本低等优势。
本发明制备的大麻二酚纳米晶的粒径为100～500nm，优选粒径范围在130～250nm，更优选150～200nm。
本发明所涉及制备方法为：
(1)配制含0.1％～1％稳定剂的水溶液，制得水相；
(2)将大麻二酚溶于有机溶剂，制得有机相；
(3)将有机相与水相混合并持续搅拌，得到大麻二酚纳米混悬液；
(4)用旋转蒸发仪将大麻二酚纳米混悬液中的有机溶剂去除。
(5)将去除有机溶剂的纳米混悬液加入冻干保护剂真空冷冻干燥得到大麻二酚纳米晶体冻干粉。
本处方工艺中所涉及的稳定剂为羟丙甲纤维素、泊洛沙姆188、卵磷脂、吐温80、聚乙烯醇、十二烷基硫酸钠中的一种，优选吐温80。
本处方工艺中所涉及的水相为水、生理盐水、磷酸盐缓冲液中的一种，优选为水。
本处方工艺中所涉及的混合方法为含药有机相缓慢加入水相，在转速为100～800rpm条件下搅拌5～20min。
本处方工艺中所涉及的旋蒸温度为35～40℃。
本处方工艺中所涉及的冻干保护剂为甘露醇、海藻糖、人血白蛋白、牛血白蛋白、麦芽糖，优选人血白蛋白和牛血白蛋白，更优选人血白蛋白。
本处方工艺中所涉及的人血白蛋白作为冻干保护剂的浓度为1％～20％，优选1％～10％，更优选2％～5％。
本处方工艺中所涉及吐温80的浓度为0.1％～1％，制得的大麻二酚纳米晶粒径为粒径为100～500nm，优选粒径范围在130～250nm，更优选150～200nm；所制得的纳米晶中大麻二酚浓度为5～20mg/ml。
本发明还提供了大麻二酚纳米晶的剂型，可以是片剂、胶囊剂、粉针剂等多种形式的制剂，优选注射剂，可以在肌肉注射，所述的注射剂为混悬液或冻干粉针。
本发明中肌肉注射剂型的使用在药效学实验中得到体现。
本发明的有益效果是：
本发明的制备工艺操作简洁、高效、无污染，并且条件温和，所得产品具有分散性好，粒径大小均匀，残留溶剂少等优势。
本发明方法制备得到的大麻二酚纳米晶混悬液及其冻干制剂能够显著减小药物的粒径，增加药物溶出度和生物利用度。制备得到的纳米晶混悬液在室温避光条件下可以稳定保存。
本发明制备的大麻二酚冻干制剂，在水中可迅速复溶再分散成纳米混悬液，并且粒径与之前无变化。
本发明制备的大麻二酚冻干品，加入优选冻干保护剂的冻干制剂，复溶后大麻二酚纳米粒呈球形，肌肉刺激性小。
本发明制备的大麻二酚冻干制剂可以进一步制备成片剂、胶囊剂、粉针剂等多种形式的制剂。
本发明注射给药后，纳米晶可以较传统注射剂获得更好的药物浓度、更长的血浆半衰期和更高的血药浓度-时间曲线下面积(AUC)。
本发明冻干制剂通过复溶，显示出良好的复溶性，复溶后用于药效学实验，针对大鼠坐骨神经分支选择损伤模型，作为受试药物，显示出与上市药物普瑞巴林相近的镇痛效果。
附图说明
图1为大麻二酚纳米晶体混悬液粒径图；
图2为大麻二酚纳米晶体冻干粉末加水复溶后粒径图；
图3为大麻二酚纳米晶体透射电镜图；
图4为大麻二酚纳米晶体扫描电镜图；
图5为X射线粉末衍射图；
图6为差示扫描量热图；
图7为体外溶出曲线图；
图8为血药浓度-时间曲线图；
图9为药效学实验中连续给药14天的镇痛效果比较。
具体实施方式
为使本发明更好地被理解，下面结合具体实例对本发明的实施方法进行详细叙述。但是本发明所要求的保护范围完全不限制于此。如实施方法中未标注具体条件，则按常规条件以及制造商建议的条件进行；如所用仪器或试剂未标注生产厂家，则视为均可以通过市场购买获得的常规产品。
实施例1：大麻二酚纳米混悬液的制备
采用反溶剂法制备大麻二酚纳米混悬液。称取0.025～0.1g大麻二酚，溶于1～4ml乙醇中，得到大麻二酚乙醇溶液，作为有机相；取25～100μL的吐温80溶于5～20μL的水中，作为水相。即药物与辅料之比为1:1，良溶剂与不良溶剂(乙醇与纯水)的比为1:5。然后在室温下，将有机相于水相液面下缓慢滴加，经磁力搅拌器搅拌，转速为100～800rpm，搅拌时间为5～20min，制得的纳米晶混悬液。使用马尔文粒径仪测定其粒度，根据图1显示，平均粒径为：130.7±2.57nm，多分散性系数(PDI)为：0.212±0.02。
实施例2：大麻二酚纳米晶体混悬液形态测定
将实例1中制备的大麻二酚纳米晶体混悬液稀释至0.1mg/ml，吸取5μl滴到230目的铜网上，空气中自然晾干，用2％磷钨酸染色2min，透射电镜下观察粒子的形态(图3)，为圆整球形。
实施例3：大麻二酚纳米晶体混悬液冻干制剂的制备
实例1制备的大麻二酚纳米晶体混悬液，加入0.5ml 2％～5％的冻干保护剂后进行冻干，在-20℃预冻，在0.466mbar-20℃下冷冻干燥，并最终稳定在15℃解析干燥。冻干后加入0.5ml纯水复溶，使用马尔文粒径仪测定其粒度，不同冻干保护剂复溶后粒径如表1，白蛋白复溶后如图2显示，平均粒径为：129.8±1.66nm，多分散性系数(PDI)为：0.179±0.02。
表1：不同冻干保护剂复溶后粒径及PDI
实施例4：扫描电镜测定
将不同冻干保护剂的固化物样品固定在铜台的导电胶上，减压下喷涂胶体金10min，扫描电镜观察固化物表面药物粒子聚集情况，操作电压为15kV。典型的形态分布测定图像见图4，从左向右依次为：白蛋白、甘露醇、乳糖、海藻糖、麦芽糖，以白蛋白作为冻干保护剂为球形，且粒径在100nm左右，以甘露醇、乳糖、麦芽糖作为冻干保护剂均不是球形，肌肉注射刺激性严重，且不易复溶或粒径增大，以海藻糖作为冻干保护剂虽为球形，但粒径增大至微米级别，故以白蛋白为最佳保护剂。
实施例5：X-粉末射线衍射
实例3制备的样品以及大麻二酚原料药、空白辅料及物理混合物采用Cu靶，实验电压和电流为40kV和40mA，步宽0.02，以4°/min扫描速度测试样品的角度范围为5-80°的X粉末射线衍射图谱见图5，结果可知大麻二酚纳米冻干制剂中药物以无定形的形式存在。
实施例6：差示扫描量热法
实例3制备的样品、大麻二酚原料药、空白辅料及物理混合物各称取3～5mg于DSC坩埚中，压盖密封，盖上留一针孔。在N2保护下，以10℃/min，30～220℃之间进行测试，图谱见图6结果表明大麻二酚原料药显示出明显的晶体熔化特征：69.2℃，出现最强吸收峰；而冻干品则未出现晶体熔化特征峰，进一步说明大麻二酚冻干品以无定形存在。
实施例7：大麻二酚纳米晶体外溶出度的测定
实例3制备的样品、大麻二酚原料药及物理混合物各取适量，置于100ml含2％SDS磷酸盐缓冲液(pH7.4)。具体方法为：配制新鲜的2％SDS磷酸盐缓冲液(pH7.4)，取适量制剂于100mL释放介质中。调控仪器参数：37℃，100rpm。分别于5min，15min，30min，45min，60min，90min，120min，180min，240min取样，14000rpm，离心10min，结果见图7。在体外累积溶出研究中，CBD-NS在15min内累积释放量为91.57％，与原料药粉末(累积释放量释放42.91％)相比，释放速度相对较快。
实施例8：实施例3药代动力学研究
实验动物：健康的SD大鼠18只，雄性，体重180～220g。
实验分组：分为大麻二酚油溶液(口服)、大麻二酚纳米晶体混悬液(肌肉注射)和大麻二酚真溶液(静脉注射)组，每组6只。给药前隔夜禁食不禁水，给药后持续禁食。
给药方案：口服给药剂量为15mg/kg，浓度为15mg/ml，给药体积为1ml/kg。肌肉给药剂量为5mg/kg，浓度为5mg/ml，给药体积为1ml/kg。静脉给药剂量为4mg/kg，浓度为4mg/ml，给药体积为1ml/kg。
样品采集：大麻二酚油溶液口服组于给药前和给药后15min、30min、45min、1h、1.5h、2h、4h、6h、8h、12h、24h、48h、72h；大麻二酚真溶液静脉注射组于给药前和给药后5min、15min、30min、45min、1h、2h、4h、8h、12h、24h、48h、72h；大麻二酚纳米晶体混悬液肌肉注射组于给药前和给药后10min、15min、30min、45min、1h、2h、4h、6h、8h、12h、24h、48h、72h分别于眼眶采血约0.5mL，EDTA抗凝，3000rpm离心10min，收集血浆，-20℃保存待测。取50μL的血浆，加入5μL的内标大麻酚(CBG；2μg/mL)，加入乙腈(150μL)，涡旋2min，10000rpm，离心10min，进样体积为5μL供UPLC-MS/MS分析。
结果：药-时曲线见图8。平均血药浓度数据用Phoenix WinNonlin拟合，计算药代动力学参数，药代动力学参数如下表：
表2：CBD药代动力学参数
结果表明，大麻二酚口服油溶液的生物利用度为22.56％，大麻二酚纳米晶混悬液肌肉注射生物利用度为285.08％。与大麻二酚油溶液相比，大麻二酚纳米晶体混悬液肌肉注射组的最大血药浓度均显著增加，达峰时间缩短，药时曲线下面积显著增加，生物利用度显著提高。而文献中提出CBD原料药口服的绝对生物利用度仅为6％(Perucca E,BialerM.Critical Aspects Affecting Cannabidiol Oral Bioavailability and MetabolicElimination,and Related Clinical Implications[J].CNS Drugs,2020,34(23).)，进一步说明CBD制备成纳米晶的优势所在。
实施例9：药效学实验
实验目的：对SD大鼠建立坐骨神经分支选择损伤(SNI)模型，使大鼠产生慢性神经性疼痛临床病症，欲探索肌肉注射大麻二酚纳米晶治疗神经病理性疼痛的药效。
实验动物：Sprague Dawley(SD)大鼠SPF级，雄性，180-220g。
模型制备：动物术前禁食8-10h，做好标记。实验开始前，手术器械消毒处理，结扎线浸泡于生理盐水或消毒酒精中，室温维持24～26℃。用10％水合氯醛按大鼠体重30～40mg/100g将大鼠深麻后，将一侧(左侧)后肢外侧备皮，沿股骨剪开皮肤，用眼科镊顺肌肉纹理扒开找到坐骨神经分支，结扎并剪断胫神经和腓总神经，保留最的细腓肠神经。神经结扎后用医用真丝编织线进行缝合，缝合处擦拭碘酒，手术部位注射广谱抗生素青霉素钾。将大鼠分笼放置，室温待其自然清醒。
实验分组：对照组、模型组、阳性药普瑞巴林组、口服CBD纳米晶组、肌肉注射CBD纳米晶高剂量组、肌肉注射CBD纳米晶低剂量组和假手术组，假手术组作为阴性对照组，实验过程中保证每组n≥6。
给药方案：
数据采集：造模成功后，于给药前、给药后2h进行机械性痛敏测试测定药效。于连续给药第2、4、8、14天测定机械痛敏状况。用冯·弗雷(Von Frey)纤毛机械刺激针，进行上下法触觉测试实验，通过公式PWT＝(10[Xf+kδ])/10,000计算，得到机械痛阈值表示药效，值越大代表药效越好。
结果：连续给药14天镇痛效果见图9，结果显示，给大鼠以20mg/kg/d剂量肌注CBD纳米晶，药效优于灌胃给药；20mg/kg/d剂量肌注与阳性药普瑞巴林相比，前期药效相近，后期药效更优；药效学实验进一步说明CBD纳米晶的研究和开发很有价值。
Claims (10)
1.一种大麻二酚纳米晶体的制备方法，其特征在于采用如下步骤制备：
(1)配制含0.1％～1％稳定剂的水溶液，制得水相；
(2)将大麻二酚溶于有机溶剂，制得有机相；
(3)将有机相与水相混合并持续搅拌，得到大麻二酚纳米混悬液；
(4)用旋转蒸发仪将大麻二酚纳米混悬液中的有机溶剂去除。
(5)将去除有机溶剂的纳米混悬液加入冻干保护剂真空冷冻干燥得到大麻二酚纳米晶体冻干粉。
2.根据权利要求1所述的大麻二酚纳米晶的制备方法，其特征在于：处方工艺中所涉及的稳定剂为羟丙甲纤维素、泊洛沙姆188、卵磷脂、吐温80、聚乙烯醇、十二烷基硫酸钠中的一种，优选吐温80。
3.根据权利要求1所述的大麻二酚纳米晶的制备方法，其特征在于：处方工艺中所涉及的水相为水、生理盐水、磷酸盐缓冲液中的一种，优选为水。
4.根据权利要求1所述的大麻二酚纳米晶的制备方法，其特征在于：处方工艺中所涉及的混合方法为含药有机相缓慢加入水相，在转速为100～800rpm条件下搅拌5～20min。
5.根据权利要求1所述的大麻二酚纳米晶的制备方法，其特征在于：处方工艺中所涉及的旋蒸温度为35～40℃。
6.根据权利要求1所述的大麻二酚纳米晶的制备方法，其特征在于：处方工艺中所涉及的冻干保护剂为甘露醇、海藻糖、人血白蛋白、牛血白蛋白、麦芽糖，优选人血白蛋白和牛血白蛋白，更优选人血白蛋白。
7.根据权利要求6所述的大麻二酚纳米晶的制备方法，其特征为：处方工艺中所涉及的冻干保护剂浓度为1％～20％，优选1％～10％，更优选2％～5％。
8.根据权利要求2所述的大麻二酚纳米晶的制备方法，其特征在于：吐温80的浓度为0.1％～1％。
9.根据权利要求1-6所述的大麻二酚纳米晶的制备方法，其特征在于：制得的大麻二酚纳米晶粒径为粒径为100～500nm，优选粒径范围在130～250nm，更优选150～200nm，优选所制得的纳米晶中大麻二酚含量为5～20mg/ml。
10.根据权利要求1-6任意一项所述的制备方法获得的大麻二酚纳米晶，其特征在于所述的大麻二酚纳米晶采用肌肉注射剂型，剂型为混悬液或冻干粉针。
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| CN116617161B (zh) * | 2023-07-26 | 2023-10-24 | 中国科学院理化技术研究所 | 一种包含大麻二酚混悬液的可溶性微针及其制备方法 |
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