CN116410165A - 一种淫羊藿素与尿素共晶 - Google Patents
一种淫羊藿素与尿素共晶 Download PDFInfo
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
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Abstract
Description
技术领域
本发明涉及晶型药物分子技术领域,特别涉及淫羊藿素有机药物共晶技术领域,具体涉及一种淫羊藿苷元与尿素的药物共晶及其制备方法和应用。
背景技术
淫羊藿素又名淫羊藿苷元,分子式C21H20O6,相对分子质量为368.126,结构如下所示:
淫羊藿素是淫羊藿中主要药效单体成分,属于黄酮类化合物。黄酮类化合物的基本母核为苯并吡喃酮(C6-C3-C6)的一类多酚化合物,以游离或与糖结合成苷的形式广泛存在于多种植物中,具有抗氧化、抗肿瘤、抗病毒、神经保护、清除自由基、抗炎、心血管保护、α-糖苷酶抑制等多种药理活性。如在《中国实验方剂学》2012年第18卷14期中公开了“淫羊藿素对雌激素依赖性乳腺癌MCF-7细胞作用的影响”,并且通过研究揭示了淫羊藿素与雌二醇联合作用具有抑制E2诱导的人乳腺癌MCF-7细胞的增殖作用。在《中国比较医学杂志》2011年第6期公开了“淫羊藿素体外抗淋巴瘤细胞增殖效应”的文章,并且该文章揭示了淫羊藿素对肿瘤细胞增殖的作用。虽然淫羊藿素具有较好的临床应用前景,但是其较差的水溶性极大的限制了其临床应用。淫羊藿素在水中微溶,较差的水溶性导致其口服吸收差,具有较低的生物利用度。据统计,在药物研发过程中有40%以上的候选药物因水溶性较差、渗透性差、生物利用度低,使得一些具有潜在临床价值的候选药物不能进入临床研究。
近些年研究发现,药物晶型不同,其理化性质(密度、硬度、溶解度、稳定性、光学性及电学性等)、溶出速率、生物效应等均能发生变化,因此研究药物晶型在医药学上具重要价值。
目前报道的淫羊藿黄酮类化合物包括淫羊藿苷、淫羊藿素、脱水淫羊藿素等,均存在水溶性差,生物利用度低的问题。针对IV类低溶解性低通透性的淫羊藿苷,文献《淫羊藿苷多晶型及血根碱甲醇化物结晶诱导不对称转化研究》(南昌大学,贾丽娜)研究制备了系列淫羊藿苷水合物及无水晶型;专利CN104844668A公开制备了一种淫羊藿苷无水α晶型,专利CN104829667A和CN104804053A进一步通过晶型研究制备了溶出速率稍有改善的淫羊藿苷水合物晶型H1和H2。文献《淫羊藿炮制过程中物质基础的转化历史》研究报道了脱水淫羊藿素的A、B、C三种晶型及淫羊藿素晶型D。专利CN103936705A公开了4中淫羊藿素溶剂合物及1种无水晶型B,并且报道其溶剂合物晶型均不稳定,容易发生转晶,转变为无水晶型B。专利CN104230870A、CN104945364A公开了2种淫羊藿素水合物晶型,并研究淫羊藿素水合物晶型和无水晶型B的光照稳定性,报道了无水晶型B光照不稳定,水合物晶型在光照稳定性上取得了一定程度的改善。专利CN112294765A公开了一种淫羊藿素无定型,其相较于淫羊藿素晶型,无定型淫羊藿素溶解度及生物利用度取得了改善,但无定型普遍具有稳定性差的特点,不利于其在药物中的实际应用。
分析目前报道的淫羊藿素晶型,药用效果改善并不理想,如无水晶型B,其在物理稳定性上有一定的改善,但在化学稳定性特别是光照稳定性及生物利用度方面效果较差;无定型淫羊藿素在溶解度和生物利用度方面取得了一定的改善,但无定型稳定性较差。鉴于上述问题,进一步研究开发适于药用的淫羊藿素优势晶型,仍是目前需要解决的问题。
发明内容
针对现有技术的问题,本发明提供了一种淫羊藿素尿素共晶,该共晶具有确切的晶体学主要参数及原子空间位置;本发明另一方面提供了该共晶的制备方法。
本发明具体技术方案如下:
第一方面,本发明提供了一种淫羊藿素-尿素共晶,所述共晶中,淫羊藿素与尿素的摩尔比为1:1,一分子淫羊藿素、一分子尿素构成晶型的基本单元,具体结构如式I:
优选地,所述淫羊藿素-尿素共晶,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在6.08±0.2°,22.23±0.2°,22.31±0.2°,29.28±0.2°,29.34±0.2°,35.41±0.2°有特征峰。
优选地,所述淫羊藿素-尿素共晶,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在6.08±0.2°,11.44±0.2°,13.13±0.2°,22.23±0.2°,22.31±0.2°,24.57±0.2°,29.28±0.2°,29.34±0.2°,31.59±0.2°,35.41±0.2°,35.57±0.2°有特征峰。
优选地,所述淫羊藿素-尿素共晶,使用Cu-Kα辐射,其特征峰符合如图1所示的X射线粉末衍射图谱。
第二方面,本发明提供了一种淫羊藿素-尿素共晶的制备方法,包括以下步骤:
将淫羊藿素与尿素置于有机溶剂中,加热搅拌,降温析晶,过滤,洗涤,干燥,得淫羊藿素-尿素共晶。
优选地,所述淫羊藿素与尿素的投料摩尔比为1:1~1.5,优选1:1.2。
优选地,所述有机溶剂为乙腈、丙酮、四氢呋喃、甲醇、乙醇、异丙醇中的一种或组合;进一步优选为乙腈、丙酮中的一种或组合;若所述有机溶剂为两种混合溶剂时,其中所述极性较小溶剂与极性较大溶剂的体积比优选为1:1~1.5。
优选地,所述淫羊藿素与有机溶剂的质量体积比为5~7:1,其中质量以mg计,体积以mL计。
优选地,所述加热温度为45~75℃;所述加热搅拌时间为2~6小时。
优选地,所述降温析晶温度为0~15℃;优选为5~10℃。
优选地,所述洗涤溶剂为乙醇、丙酮、乙腈中的一种或两种。
第三方面,本发明提供一种药物组合物,该组合物含本发明所述的淫羊藿素-尿素共晶和其它药学上接受的组分。
优选地,所述的其它药学上接受的组分包括可联合使用的其它活性成分、赋形剂、填充剂等。
优选地,本发明的药物组合物可使用如下方法制备:使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成可用剂型。
优选地,所述的药物组合物为喷雾剂、片剂、胶囊剂、粉针剂、液体注射剂等。
第四方面,本发明提供一种淫羊藿素-尿素共晶作为活性成分制备治疗抗肿瘤药物中的应用及作为活性成分制备α-葡萄糖苷酶抑制剂药物的应用。
本发明的有益效果:
本发明制备的淫羊藿素-尿素共晶在稳定性、生物利用度等方面均取得了较大的改善。该淫羊藿素-尿素共晶制备方法简单,适于工业化生产;所得共晶体晶型规则,粒径尺寸均匀,具有明确的晶体学主要参数及确切的原子空间位置,适于大规模推广应用。
附图说明
图1:淫羊藿素-尿素共晶X射线粉末衍射图谱。
图2:淫羊藿素-尿素共晶ORTEP图。
图3:淫羊藿素-尿素共晶堆积图。
图4:淫羊藿素-尿素共晶的DSC-TGA图。
具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
实验所用物料:淫羊藿素可购买,也可参照现有技术公开的方法制备。对比试验所需的淫羊藿素晶型可参照现有技术制备;本其他实验所用物料未标明来源和规格的均为市售分析纯或化学纯。
实施例1
将约3.7g淫羊藿素、0.72g尿素置于700ml乙腈中,加热至75℃搅拌反应4小时后,缓慢降温至5~10℃,控温析晶,析晶完毕,过滤,滤饼用乙醇洗涤,干燥,得淫羊藿素-尿素共晶,收率95.6%,纯度99.95%。
实施例2
将约3.7g淫羊藿素、0.6g尿素置于550ml丙酮中,加热至50℃搅拌反应3小时后,缓慢降温至0~5℃,控温析晶,析晶完毕,过滤,滤饼用丙酮洗涤,干燥,得淫羊藿素-尿素共晶,收率93.4%,纯度99.92%。
实施例3
将约3.7g淫羊藿素、0.9g尿素置于750ml丙酮/乙腈(V丙酮:V乙腈=1:1)的混合溶剂中,加热至55℃搅拌反应6小时后,缓慢降温至5~10℃,控温析晶,析晶完毕,过滤,滤饼用乙腈洗涤,干燥,得淫羊藿素-尿素共晶,收率94.3%,纯度99.90%。
实施例4
将约3.7g淫羊藿素、0.75g尿素置于600ml乙醇中,加热至70℃搅拌反应5小时后,缓慢降温至10~15℃,控温析晶,析晶完毕,过滤,滤饼用乙醇洗涤,干燥,得淫羊藿素-尿素共晶,收率94.8%,纯度99.93%。
实施例5
将约3.7g淫羊藿素、0.82g尿素置于650ml四氢呋喃/乙醇(V四氢呋喃:V乙醇=1:1.5)的混合溶剂中,加热至60℃搅拌反应4小时后,缓慢降温至5~10℃,控温析晶,析晶完毕,过滤,滤饼用乙醇洗涤,干燥,得淫羊藿素-尿素共晶,收率93.8%,纯度99.87%。
实施例6
将约3.7g淫羊藿素、0.65g尿素置于650ml甲醇中,加热至55℃搅拌反应6小时后,缓慢降温至0~5℃,控温析晶,析晶完毕,过滤,滤饼用乙醇洗涤,干燥,得淫羊藿素-尿素共晶,收率94.2%,纯度99.91%。
淫羊藿素-尿素共晶体表征
本发明中所涉及的X-射线粉末衍射测试仪器及测试条件:X-射线粉末衍射仪:PANalytical EMPYREA;Cu-Kα;样品台:平板;入射光路:BBHD;衍射光路:PLXCEL;电压45kv,电流40mA;发散狭缝:1/4;防散射狭缝:1;索拉狭缝:0.04rad;步长:0.5s;扫描范围:3~50°。其对应的X射线分泌衍射图(Cu-Kα)中特征峰详见附图1及表1。
表1淫羊藿素-尿素共晶PXRD峰
本发明提供的淫羊藿素-尿素共晶进行X-射线单晶衍射测试分析。本发明所涉及的X-射线单晶衍射仪器及测试条件为:理学XtaLAB Synergy X-射线单晶衍射仪,测试温度293(2)K,用CuKa辐射,以ω扫描方式收集数据并进、行Lp校正。用直接法解析结构,差值傅里叶法找出全部非氢原子,所有碳及氮上的氢原子采用理论加氢得到,采用最小二乘法对结构进行精修。
测试及解析本发明制备的淫羊藿素-尿素共晶所得晶体学参数是:monoclinic晶系,空间群为P21/c;晶胞参数为:α=90°,β=110.872(6)°,γ=90°,晶胞体积/>本发明的淫羊藿素-尿素共晶的ORTEP图2表明,一分子的淫羊藿素与一分子尿素结合形成共晶体。本发明的淫羊藿素-尿素共晶的堆积图,如附图3所示。
表2淫羊藿素-尿素共晶的主要晶体学数据
本发明中TGA/DSC热分析测试仪及测试条件:TGA/DSC热分析仪:METTLER TOLEDOTGA/DSC3+;动态温度段:30~300℃;加热速率:10℃/min;程序段气体N2;气体流量:50mL/min;坩埚:铝坩埚40μl。其差示扫描量热曲线及热重分析(DSC/TGA)图如图4所示。
实施例1~6的样品都符合X-射线粉末衍射图谱、晶体学参数、差示扫描量热曲线及热重分析(DSC/TGA)图。
对比实施例1
取6.5g淫羊藿素加入200ml丙酮溶解,过滤、滤液加入100ml蒸馏水,75℃回流溶解,20℃放置析晶24小时,过滤,80℃下连续干燥,直至重量不在变化,得淫羊藿素晶型B,收率90.3%,纯度99.86%。
对比实施例2
取约1g淫羊藿素,向其加入氯仿/甲醇(V氯仿:V甲醇=1:1)的混合溶剂至完全溶解后、放置于温度30℃、相对湿度90%的环境下挥发析晶,析晶完毕,过滤,得晶型D,收率82.4%,纯度99.83%。
对比实施例3
取10g淫羊藿素、700mL丙酮置于5.0L烧瓶中,温水浴中搅拌溶解后,在搅拌下快速加入4L纯化水,继续搅拌10min,析晶,待溶液降至室温后过滤,滤饼置于25℃鼓风干燥箱中干燥48小时,得淫羊藿素一水合物,收率92.8%,纯度99.88%。
对比实施例4
取10g淫羊藿素、700mL丙酮置于1L烧杯中,温水浴中搅拌溶解后,将淫羊藿素的丙酮溶液快速加入到装有4L常温的纯化水的烧瓶中,剧烈搅拌10min,析晶,待溶液降至室温后过滤,滤饼置于25℃鼓风干燥箱中干燥48小时,得淫羊藿素半水合物,收率90%,纯度99.85%。
对比实施例5
取淫羊藿素2.4g置于120ml氢氧化钠水溶液(0.2mol/L)中,搅拌溶解,得淫羊藿素碱溶液;取3.84g聚合物Soluplus置于480ml盐酸水溶液(0.05mol/L)中,搅拌溶解,得聚合物Soluplus盐酸水溶液;利用蠕动泵将淫羊藿素碱溶液加入盐酸水溶液中,控制1000r/min的速度搅拌20min,过滤,收集沉淀后,置于-40℃下预冻,冻干24小时,得淫羊藿素无定型颗粒,收率73.2%,纯度99.80%。
验证实施例:
本发明在稳定性、生物利用度等方面对上述制备的淫羊藿素晶型进行了考察,具体实施内容如下:
稳定性试验
1.光照试验:参照《中国药典2020版四部-9001原料药与制剂稳定性试验指导原则》,分别取实施例1及对比实施例1-5的淫羊藿素晶型适量,分散放置于开口容器中(厚度不超过3mm),置于光照箱内,在照度为4500lx±500lx的条件下测试,分别于第0天、5天、10天、30天取样检测纯度。
2.高温试验:参照《中国药典2020版四部-9001原料药与制剂稳定性试验指导原则》,分别取实施例1及对比实施例1-5的淫羊藿素晶型适量,置于60℃密闭恒温箱中,分别于第0天、5天、10天、30天取样检测纯度。
表3淫羊藿素晶型光稳定性试验结果
光照和高温稳定性试验结果表明,淫羊藿素无定型稳定性较差,经过光照和高温考察后,显著降解。淫羊藿素晶型B和晶型D光稳定性较差,经光照稳定考察后,显著降解。本发明制备的淫羊藿素-尿素共晶在光照和高温条件下均稳定性良好。考察发现实施例1~6具有类似的稳定性试验结果。
相对湿度(RH)及高温稳定性比较
分别取实施例1和对比例1~5制备得到的淫羊藿素晶型,分别在40℃、75%RH条件下及80℃条件下,储存1周后,进行PXRD检测,测试各晶型相对湿度及高温稳定性,结果见表4。
表4淫羊藿素晶型相对湿度稳定性结果
注释:√表示该储存条件下稳定,PXRD图谱不变;╳表示该储存条件下不稳定。
相对湿度(RH)稳定性比较结果显示,本发明制备的淫羊藿素-尿素共晶在高湿和高温环境下,稳定性良好,晶型不发生转变。
比格犬药代动力学试验
取健康雄性比格犬(体重在6~8kg,年龄1~2岁),安置在相同环境下,允许自由进食和水。在给药前禁食24小时,分别口服给予实施例1淫羊藿素-尿素共晶、对比实施例1~5的淫羊藿素晶型及对照品(山东新时代药业有限公司产品淫羊藿素纳米晶),给药剂量为10mg/kg(以淫羊藿素计);分别于给药前及给药后的10min,30min,1h,1.5h,2h,2.5h,3h,3.5h,4h,4.5h,5h,6h,8h,10h,12h,24h从外周静脉采集血液样品,采血后离心10min(3000r/min),分离出血浆,于-20℃冷冻保存待测。
吸取50μL血浆样品,加入150μL 0.05mol/L磷酸二氢铵水溶液,涡旋1min,取30μL加入125μL 200Uβ-葡萄糖醛酸酶混匀后,37℃孵育1小时,加入50μL内标汉黄芩素甲醇溶液,1.2mL提取甲基叔丁基醚-正己烷(2∶1),涡旋2min,4℃、12000r/min离心5min,取上层有机相960μL于玻璃试管中,40℃水浴氮气吹干,加入100μL 70%甲醇水溶液,涡旋复溶,复溶后样品4℃、12000r/min离心10min后,取上清液50μL进行LC-MS/MS定量分析。
表5比格犬口服给药后的药代动力学参数(n=3)
小鼠糖耐量试验
取80只小鼠,随机分成8组,每组10只。分别取实施例1、对比例1~5的淫羊藿素晶型按照50mg/kg的剂量灌胃。设置阴性对照组、阳性对照组,阴性对照组灌生理盐水,阳性对照组为拜糖平50mg/kg的剂量灌胃。连续给药7天,末次给药前禁食8小时,给药1小时后淀粉5g/kg灌胃,给淀粉后分别在0小时、0.5小时、1小时、2小时、3小时,于眼眶静脉窦采血,用葡萄糖氧化酶试纸测定的血糖值,单位mmol/L,结果见表6:
表6淫羊藿素晶型的小鼠糖耐量实验结果
此外,体外细胞测试发现本发明淫羊藿素-尿素共晶对一系列肿瘤细胞具有抑制作用,如对肝癌Huh-7细胞抑制(IC50=3.2μM)、乳腺癌细MCF-7细胞抑制(IC50=2.3μM)、急性髓性白血病MV-4-11细胞(IC50=4.8μM)均表现良好抑制作用。
本发明制备的淫羊藿素-尿素共晶在稳定性、生物利用度等方面取得了有益效果,综合性能相较于现有技术报道的淫羊藿素晶型取得了较为显著的进步。
Claims (10)
1.一种淫羊藿素共晶,其特征在于,所述共晶由活性药物成分淫羊藿素与共晶配体尿素构成。
3.如权利要求1所述的淫羊藿素-尿素共晶,其特征在于,所述共晶使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在6.08±0.2°,22.23±0.2°,22.31±0.2°,29.28±0.2°,29.34±0.2°,35.41±0.2°有特征峰。
4.如权利要求1所述的淫羊藿素-尿素共晶,其特征在于,所述共晶使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在6.08±0.2°,11.44±0.2°,13.13±0.2°,22.23±0.2°,22.31±0.2°,24.57±0.2°,29.28±0.2°,29.34±0.2°,31.59±0.2°,35.41±0.2°,35.57±0.2°有特征峰。
5.如权利要求1所述的淫羊藿素-尿素共晶,其特征在于,所述共晶具有如图1所示的X-射线粉末衍射图谱。
6.一种制备权利要求1-5任一项所述的淫羊藿素-尿素共晶的方法,其特征在于,所述方法包括以下步骤:将淫羊藿素与尿素置于有机溶剂中,加热搅拌,降温析晶,过滤,洗涤,干燥,得淫羊藿素-尿素共晶。
7.根据权利要求6所述的淫羊藿素-尿素共晶的制备方法,其特征在于,所述淫羊藿素与尿素的投料摩尔比为1:1~1.5;所述淫羊藿素与有机溶剂的质量体积比为5~7:1,其中质量以mg计,体积以mL计。
8.根据权利要求6所述的淫羊藿素-尿素共晶的制备方法,其特征在于,有机溶剂为乙腈、丙酮、四氢呋喃、甲醇、乙醇、异丙醇中的一种或组合。
9.权利要求1-5任一项所述的淫羊藿素-尿素共晶作为活性成分制备α-葡萄糖苷酶抑制剂药物的应用。
10.权利要求1-5任一项所述的淫羊藿素-尿素共晶在制备用于抗细胞异常增殖有关疾病的药物中的用途。
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