CN111689972A - 一种替莫唑胺与橙皮素的共晶及其制备方法 - Google Patents
一种替莫唑胺与橙皮素的共晶及其制备方法 Download PDFInfo
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- CN111689972A CN111689972A CN202010708666.8A CN202010708666A CN111689972A CN 111689972 A CN111689972 A CN 111689972A CN 202010708666 A CN202010708666 A CN 202010708666A CN 111689972 A CN111689972 A CN 111689972A
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- temozolomide
- hesperetin
- eutectic
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Abstract
本发明公开了一种替莫唑胺与橙皮素的共晶及其制备方法。该共晶中替莫唑胺与橙皮素的摩尔比为1∶1,该共晶X射线粉末衍射图在2theta值为11.9±0.2°、25.3±0.2°、26.8±0.2°、27.1±0.2°处具有特征峰。本发明提供的共晶制备方法工艺简单,结晶过程易于控制,重现性好,适用于工业化生产。这种共晶可以有效的提高替莫唑胺的稳定性和压片性,改善橙皮素的溶解性,减缓替莫唑胺的溶出,为联合替莫唑胺和橙皮素用于癌症的治疗提供了研究基础。
Description
技术领域
本发明涉及医药化学技术领域,特别是涉及一种替莫唑胺与橙皮素的共晶及其制备方法。
背景技术
药物共结晶是指药物分子与其他生理上可接受的酸、碱、盐及非离子化合物分子以氢键、π-π堆积作用、范德华力等非共价键作用而结合在同一晶格中的晶体。在不破坏药物共价键的前提下,共晶的形成可以改变药物的理化性质,包括稳定性、溶解性和压片性等。此外,形成共晶以后,也可以改变一些药物的药代动力学参数,如Cmax(血药峰浓度)、Tmax(达峰时间)、t1/2(消除半衰期)和AUC(血药浓度-时间曲线下面积)等。当两种药物形成共晶时,可以在改善两者理化性质和药动学参数的同时,达到联合用药的目的。
替莫唑胺(temozolomide)是一种含有咪唑四嗪环的烷化剂类抗肿瘤药物,化学名为3,4-二氢-3-甲基-4-氧代咪唑[5,1-d]并1,2,3,5-四嗪-8-甲酰胺,其化学结构式为:
替莫唑胺属于前体药物,本身并没有活性,在生理pH水平下经非酶途径转化为活性化合物MITC(5-(3-甲基三氮烯-1-基)咪唑-4-酰胺),后者进一步水解成AIC(5-氨基-咪唑-4-酰胺)和甲基重氮离子,随后甲基重氮离子通过作用于鸟嘌呤上的O6和N7位点甲基化DNA,使其无法与胸腺嘧啶配对而产生细胞毒性,发挥抗肿瘤活性。该药可通过血脑屏障,故对脑部肿瘤效果较好,对白血病,黑色素瘤,淋巴瘤及实体瘤也有明显的效果。
该药于1999年1月20日获得欧洲药品管理局(EMEA)批准上市,获准适应症为常规治疗后病情仍有发展或复发的多形性胶质母细胞瘤(脑癌);1999年8月11日通过美国食品和药品管理局(FDA)批准上市,获准适应症为多形性胶质母细胞瘤和退形性星形胶质细胞瘤等。临床常用为口服胶囊,口服后吸收迅速,生物利用度高,药代动力学显示其血药浓度于1小时内达峰,之后消除迅速,平均半衰期为1.7~1.8小时,在病灶处难以维持有效的药物浓度。此外,替莫唑胺的稳定性和压片性能都比较差。为了确保替莫唑胺的安全、疗效和可加工性,迫切需要提高其稳定性、延长其口服半衰期、改善其压片性能。
橙皮素(hesperetin)的化学名为4-甲氧基-3,5’,7’-三羟基黄酮,其化学结构式为:
橙皮素是一种在柑橘类水果中发现的二氢黄酮类化合物,其结构中含有酮羰基、醚键及多个酚羟基,具有较为广泛的药理作用。如抗菌、抗炎、抗氧化、降糖、增强免疫等。近年来,有文献报道橙皮素及其衍生物还具有抗阿尔茨海默病,抗帕金森病,抗肺、肾、肝纤维化等作用。此外,橙皮素具有广谱的抗肿瘤活性,对包括脑胶质瘤、肺癌、卵巢癌、肝癌、乳腺癌等多种肿瘤具有显著的抑制效果以及可以逆转肿瘤的耐药性。且橙皮素不会在任何器官中积累,使用安全、无明显副作用。
橙皮素化合物为淡黄色针状晶体,可溶于甲醇、乙醇、丙酮、乙腈、乙酸乙酯等有机溶剂。橙皮素几乎不溶于水,亲水性很差,所以它的口服吸收差,生物利用度低,大大限制了它的临床应用。国内外目前还没有橙皮素制剂上市。
迄今为止,专利WO 2011/036676报道了替莫唑胺和草酸、琥珀酸、水杨酸、邻氨基苯甲酸、D,L-苹果酸、D,L-酒石酸的共晶,专利CN108623601B公开了替莫唑胺与黄芩素的共晶,在以上两篇专利中,共晶中替莫唑胺的稳定性相比替莫唑胺原料药得到显著改善,且共晶中的替莫唑胺在生理条件下的半衰期也明显延长。另有文献报道了替莫唑胺与烟酰胺、异烟碱、糖精、咖啡因、吡嗪酰胺、对羟基苯甲酰胺的共晶(Sanphui P,Babu N J,Nangia A,Crystal Growth&Design,2013,13(5),2208-2219)。橙皮素与茶碱,腺嘌呤,没食子酸和可可碱的共晶,在pH 7.4的溶出介质中测得的共晶的溶解度提高了2至4倍(Chadha K,KaranM,Chadha R,Bhalla Y,Vasisht K,Journal of Pharmaceutical Sciences,2017,106(8),2026-2036)。橙皮素与吡啶甲酸,烟酰胺,咖啡因的共晶在水性缓冲液中的溶解比橙皮素高4-5倍,相对生物利用度均有所提高(橙皮素-吡啶甲酸:1.36,橙皮素-烟酰胺:1.57,橙皮素-咖啡因:1.60)(Chadha K,Karan M,Bhalla Y,Chadha R,Khullar S,Mandal S,VasishtK,Crystal Growth&Design,2017,17(5),2386-2405)。目前,尚未见将替莫唑胺和橙皮素两种药物活性成分制成共晶的相关报道。我们通过研究发现了一种替莫唑胺和橙皮素的共晶,一方面可以改善这两种药物的稳定性、溶解性和压片性;另一方面可以联合替莫唑胺和橙皮素用于癌症,特别是神经胶质细胞瘤的治疗。
发明内容
本发明的目的之一在于提供一种替莫唑胺与橙皮素共晶;本发明的目的之二在于提供这种替莫唑胺与橙皮素共晶的制备方法;本发明的目的之三在于提供这种替莫唑胺与橙皮素共晶的应用。
本发明人经过大量的试验研究,尝试将替莫唑胺与橙皮素、大豆素、姜黄素、葛根素等进行共晶筛选实验,最终成功发现了替莫唑胺与橙皮素的共晶,可以有效提高替莫唑胺的稳定性和压片性,改善橙皮素的溶解性,减缓替莫唑胺的溶出,为联合替莫唑胺和橙皮素用于癌症的治疗提供了研究基础。
本发明所采取的技术方案是:
本发明提供了一种替莫唑胺与橙皮素共晶。
一种替莫唑胺与橙皮素共晶,该共晶的结构式如式(I)所示:
这种共晶中,替莫唑胺与橙皮素的摩尔比为1∶1;这种共晶以Cu Kα射线测得的X射线粉末衍射图谱在衍射角度2theta为11.9±0.2°、25.3±0.2°、26.8±0.2°、27.1±0.2°处具有特征峰。
优选的,这种替莫唑胺与橙皮素共晶以Cu Kα射线测得的X射线粉末衍射图谱还在衍射角度2theta为14.0±0.2°、14.4±0.2°、17.0±0.2°、25.6±0.2°、26.2±0.2°中的一处或多处具有特征峰。
优选的,这种替莫唑胺与橙皮素共晶为正交晶系,空间群为Pca21,晶胞参数 α=90°,β=90°,γ=90°;在一些优选的具体实施方式中,这种替莫唑胺与橙皮素共晶的晶胞参数为α=90°,β=90°,γ=90°。
本发明提供了这种替莫唑胺与橙皮素共晶的制备方法。
一种替莫唑胺与橙皮素共晶的制备方法,包括如下步骤:将替莫唑胺与橙皮素按照摩尔比1∶1投料,加入适量溶剂,然后通过搅拌或研磨得到共晶。
优选的,这种共晶的制备方法中,溶剂为水、醇类溶剂、酯类溶剂、酮类溶剂、腈类溶剂中的至少一种。其中,醇类溶剂包括但不限于甲醇、乙醇、异丙醇;酯类溶剂包括但不限于乙酸甲酯、乙酸乙酯、乙酸异丙酯;所述的酮类溶剂包括但不限于丙酮;腈类溶剂包括但不限于乙腈;进一步优选的,溶剂选自水、甲醇、乙醇、乙酸乙酯、丙酮、乙腈中的一种或多种。
优选的,这种共晶的制备方法中,搅拌时替莫唑胺与橙皮素的总质量与溶剂的用量比为1g∶(4~40)mL;研磨时替莫唑胺与橙皮素的总质量与溶剂的用量比为1g∶(100~200)μL。
在本发明一些优选的实施方式中,这种共晶的制备方法具体是:将替莫唑胺与橙皮素按照摩尔比1∶1投料,加入溶剂后搅拌,过滤,将所得的固体产物干燥,得到共晶。
在本发明另一些优选的实施方式中,这种共晶的制备方法具体是:将替莫唑胺与橙皮素按照摩尔比1∶1投料,加入溶剂后研磨,得到共晶。
优选的,这种共晶的制备方法中,搅拌时替莫唑胺与橙皮素的总质量与溶剂的用量比为1g∶(4~40)mL。
优选的,这种共晶的制备方法中,研磨时替莫唑胺与橙皮素的总质量与溶剂的用量比为1g∶(100~200)μL。
本发明提供了一种药物组合物,这种药物组合物,包括这种替莫唑胺与橙皮素共晶和药学上可接受的赋形剂。
本发明中,药学上可接受的赋形剂是指与给药剂型或药物组合物一致性相关的药学上可接受的材料、混合物或溶媒。合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外,可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。
优选的,药学上可接受的赋形剂包括以下类型的赋形剂:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、塑化剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。
本发明还提供了这种替莫唑胺与橙皮素共晶在制备预防和/或治疗癌症的药物中的应用。
本发明的有益效果是:
本发明首次将替莫唑胺转化为一种全新的替莫唑胺与橙皮素共晶,可以有效的提高替莫唑胺的稳定性和压片性,改善橙皮素的溶解性,为减缓替莫唑胺的溶出,为联合替莫唑胺和橙皮素用于癌症的治疗提供了研究基础。
本发明公开的替莫唑胺与橙皮素共晶的制备方法工艺简单,结晶过程易于控制,重现性好,适用于工业化生产。
本发明这种替莫唑胺与橙皮素共晶在制备预防和/或治疗癌症的药物中具有广阔的应用前景。
附图说明
图1是实施例1制得的替莫唑胺与橙皮素共晶的X射线粉末衍射图;
图2是实施例1制得的替莫唑胺与橙皮素共晶的差示扫描量热分析图;
图3是实施例1制得的替莫唑胺与橙皮素共晶的热失重分析图;
图4是实施例1制得的替莫唑胺与橙皮素共晶的傅里叶变换红外谱图;
图5是实施例1制得的替莫唑胺与橙皮素共晶的核磁共振氢谱图;
图6是替莫唑胺与橙皮素共晶的单晶不对称单元示意图;
图7是替莫唑胺与橙皮素共晶的晶胞结构示意图;
图8是替莫唑胺、替莫唑胺与橙皮素共晶于40℃/75%RH条件下放置3个月的含量变化图;
图9是替莫唑胺、共晶中的替莫唑胺在pH1.2和pH6.8溶出介质中的粉末溶出曲线图;
图10是橙皮素、共晶中的橙皮素在pH1.2和pH6.8溶出介质中的粉末溶出曲线图;
图11是替莫唑胺粉末在400MPa压力下压制后的图片;
图12是替莫唑胺与橙皮素共晶粉末在400MPa压力下压制后的图片;
图13是替莫唑胺、替莫唑胺与橙皮素共晶粉末可压性曲线图。
具体实施方式
以下通过具体的实施例对本发明的内容作进一步详细的说明。实施例中所用的原料如无特殊说明,均可从常规商业途径得到。
实施例1
称取1.94g替莫唑胺与3.02g橙皮素,加入50mL80%乙醇中得混悬液,将该混悬液置于室温搅拌1h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品,产率为94%。
实施例2
称取19.4mg替莫唑胺与30.2mg橙皮素,加入1mL丙酮中得混悬液,将该混悬液置于室温下搅拌12h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例3
称取19.4mg替莫唑胺与30.2mg橙皮素,加入球磨罐中,然后加入20μL乙醇,在20Hz频率下研磨30min,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例4
称取19.4mg替莫唑胺与30.2mg橙皮素,加入0.5mL乙醇与0.5mL超纯水的混合溶剂中得混悬液,将该混悬液置于室温下搅拌12h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例5
称取19.4mg替莫唑胺与30.2mg橙皮素,加入1mL甲醇中得混悬液,将该混悬液置于室温下搅拌12h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例6
称取19.4mg替莫唑胺与30.2mg橙皮素,加入1mL乙酸乙酯得混悬液,将该混悬液置于室温搅拌12h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例7
称取19.4mg替莫唑胺与30.2mg橙皮素,加入1mL蒸馏水中得混悬液,将该混悬液置于室温搅拌12h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例8
称取19.4mg替莫唑胺与30.2mg橙皮素,加入1mL乙腈中得混悬液,将该混悬液置于室温下搅拌16h后,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例9
称取19.4mg替莫唑胺与30.2mg橙皮素,加入0.5mL乙腈与0.5mL超纯水的混合溶剂得混悬液,将该混悬液置于室温搅拌12h,过滤,所得淡黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
实施例10
称取19.4mg替莫唑胺与30.2mg橙皮素,加入0.5mL丙酮与0.5mL超纯水的混合溶剂中得混悬液,将该混悬液置于室温搅拌12h,过滤,所得黄色固体在40℃干燥,获得替莫唑胺与橙皮素共晶的固体样品。
表征分析
本发明提供的一种替莫唑胺与橙皮素共晶,通过X射线粉末衍射、差示扫描量热分析、热失重分析、傅里叶变换红外光谱、核磁共振氢谱等方法表征。
对实施例1制得的替莫唑胺与橙皮素共晶的固体样品进行X射线粉末衍射分析,其采用德国布鲁克仪器有限公司Bruker D2 PHASER型的衍射仪,Cu Kα射线,电压为30千伏,电流为10毫安,步长0.01°,扫描速度10°/min,扫描范围5.0~40.0°,测试温度为室温。其分析结果见附图1的X射线粉末衍射图,X射线粉末衍射数据如表1所示。
表1实施例1的替莫唑胺与橙皮素共晶的X射线粉末衍射数据
基于与实施例1相同的X射线粉末衍射测试方法,实施例2制得的替莫唑胺与橙皮素共晶的固体样品的X射线粉末衍射数据如表2所示。
表2实施例2的替莫唑胺与橙皮素共晶的X射线粉末衍射数据
基于与实施例1相同的X射线粉末衍射测试方法,实施例3制得的替莫唑胺与橙皮素共晶的固体样品的X射线粉末衍射数据如表3所示。
表3实施例3的替莫唑胺与橙皮素共晶的X射线粉末衍射数据
本领域技术人员公知,结晶物质可以用X射线衍射技术表征,但是X射线衍射图通常会随着仪器的测试条件而有所改变。特别需要指出的是,X射线衍射图的相对强度可能随着实验条件的变化而变化,所以X射线衍射峰的相对强度顺序不能作为结晶物质表征的唯一或决定性因素。另外,峰角度通常允许有±0.2°的误差,由于样品高度、测试温度等实验因素的影响,会造成峰角度的整体偏移,通常允许一定的偏移。因而,本领域技术人员可以理解的是,本发明所述的替莫唑胺与橙皮素共晶的X射线衍射图不必和本实施例中的X射线衍射图完全一致,任何具有和这个图谱中的特征峰相同或相似的情况均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知物质的图谱相比较,以证实未知物质是或不是本发明所述的替莫唑胺与橙皮素共晶。
对实施例1制得的替莫唑胺与橙皮素共晶的固体样品进行差示扫描量热分析,其采用德国耐驰科学仪器有限公司DSC 214型差示量热仪检测,气氛为氮气,升温速率为10℃/min。其分析结果见附图2的差示扫描量热分析图。如图2所示,替莫唑胺与橙皮素共晶在热分解之前未发现明显的吸热或放热现象。
对实施例1制得的替莫唑胺与橙皮素共晶的固体样品进行热失重分析,其采用德国耐驰科学仪器有限公司TG209 F3型热重分析仪,气氛为氮气,升温速率为10℃/min。其分析结果见附图3的热失重分析图。如图3所示,替莫唑胺与橙皮素共晶被加热至200℃附近开始分解,并且在此温度之前无重量损失。
对实施例1制得的替莫唑胺与橙皮素共晶样品进行红外光谱分析,其采用Bruker公司Vertex 70傅里叶变换红外光谱仪检测,检测范围为4000~500cm-1,其分析结果见附图4的傅里叶变换红外谱图。从图4中可以看出,其红外光谱特征峰位置为(cm-1):3464、3301、3130、1743、1699、1635、1591、1512、1485、1460、1357、1299、1269、1201、1163、1078、1047、1020、947、883、840、796、765、734、703、611、563、513。
对实施例1制得的替莫唑胺与橙皮素共晶样品进行核磁共振氢谱分析,采用德国Bruker公司Avance III 400 M核磁共振波谱仪检测,其分析结果见附图5的核磁共振氢谱谱图。从图5中可以看出,替莫唑胺的峰为:1H NMR(400MHz,DMSO)δ8.83(s,1H),7.81(s,1H),7.69(s,1H),3.87(s,3H);橙皮素的峰为:1H NMR(400MHz,DMSO)δ12.14(s,1H),10.80(s,1H),9.11(s,1H),6.91(dd,J=25.3,8.4Hz,3H),5.89(dd,J=5.6,2.1Hz,2H),5.44(dd,J=12.3,3.0Hz,1H),3.78(s,3H),3.21(dd,J=17.1,12.4Hz,1H),2.71(dd,J=17.1,3.1Hz,1H)。根据各个峰的积分结果可知,共晶中替莫唑胺与橙皮素的化学计量比为1∶1。
替莫唑胺与橙皮素共晶的单晶研究
取4mL混合溶剂(乙腈∶水=3∶1),加入实施例1制得的莫唑胺与橙皮素共晶样品至过饱和,过滤,将滤液放置于室温下,缓慢挥发2天即得淡黄色透明的片状晶体。
X射线单晶衍射仪型号:XtaLAB min system;
测试温度:293K;
用于结构解析的计算机程序:Olex2;
实验通式:C22H17N6O8;
分子量:493.41;
晶系:正交晶系;
空间群:Pca21;
晶胞参数:
α=90°;
β=90°;
γ=90°;
Z(单位晶胞中所含实验通式的个数):4;
计算密度:1.471g/cm3。
结构描述:单晶衍射及结构解析表明,晶体的不对称结构单元中包含有一个替莫唑胺分子和一个橙皮素分子。晶体的单位晶胞中包含四个替莫唑胺分子,四个橙皮素分子,其不对称结构单元示意图如附图6所示,单位晶胞示意图如附图7所示。
稳定性研究
将替莫唑胺、替莫唑胺与橙皮素共晶的稳定性进行对比研究。
受试样品来源:替莫唑胺与橙皮素共晶由本发明实施例1提供的方法制备;替莫唑胺原料药购买于上海升德医药科技有限公司,纯度98%。
加速稳定性试验:分别取一定量的替莫唑胺、替莫唑胺与橙皮素共晶的粉末样品于10mL小烧杯中,将其敞口放置于40℃/75%RH的恒温恒湿条件下。分别于0,1,2,3个月的月末取样通过高效液相色谱检测替莫唑胺的含量。
实验结果见附图8。替莫唑胺原料药的药物含量随时间呈急剧下降趋势,1个月末,2个月末和3个月末药物含量分别降至97.46%±2.45%,65.43±0.76%和31.64±0.64%;相比之下,共晶中替莫唑胺的含量没有下降,至3个月末仍有103.30±4.70%。由此可见替莫唑胺与橙皮素共晶的稳定性优于替莫唑胺。
溶解性评价
将替莫唑胺、橙皮素、替莫唑胺与橙皮素共晶的粉末溶出数据进行对比研究。
受试样品来源:替莫唑胺与橙皮素共晶由本发明实施例1提供的方法制备;替莫唑胺和橙皮素原料药购买于上海升德医药科技有限公司,纯度均为98%。
粉末溶出实验方法:将替莫唑胺、橙皮素、替莫唑胺与橙皮素共晶的粉末样品研磨后分别过100和200目筛,控制粒径在75~150μm,对于pH1.2的盐酸溶液,分别称量500mg替莫唑胺,778mg橙皮素、1278mg的替莫唑胺与橙皮素共晶;对于pH6.8的磷酸盐缓冲溶液,分别称量600mg替莫唑胺,934mg橙皮素、1534mg的替莫唑胺与橙皮素共晶,加入溶出介质中进行搅拌,每隔一段时间取0.2mL溶液,经0.45μm微孔滤膜过滤,并稀释到适当倍数,用高效液相色谱监测各个时间点的药物浓度,最终得到各样品的粉末溶出曲线。
粉末溶出条件:
溶出介质:pH1.2的盐酸溶液和pH6.8的磷酸盐缓冲溶液
溶出介质体积:45mL
搅拌速度:150转/分钟
溶出温度:37±0.5℃;
取样时间:0.16,0.5,1,2,3,5,10,20,30,60,120,240分钟;
液相条件:
仪器:SHIMADZU LC-2030C 3D;
色谱柱:Inertsil ODS C18柱(4.6mm×150mm,5μm);
紫外检测波长:替莫唑胺329nm,橙皮素288nm;
流动相:甲醇/pH2.8醋酸水溶液梯度洗脱(0-7min:10%甲醇;8-16min:60%甲醇;17.5-20min:10%甲醇)
柱温:35℃;
流速:1mL/min;
进样量:20μL。
实验结果见附图9和图10。本发明提供的共晶中的替莫唑胺相比替莫唑胺原料药具有较慢的溶出速率,而共晶中的橙皮素相比橙皮素原料药具有较快的溶出速率。如附图9所示,在pH1.2的溶出介质中,共晶中的替莫唑胺4小时内的最大溶出浓度为0.48±0.01mg/mL,降低至替莫唑胺原料药的1/15;在pH6.8的溶出介质中,共晶中的替莫唑胺4小时内的最大溶出浓度为0.19±0.02mg/mL,降低至替莫唑胺原料药的1/30,这可能是由于替莫唑胺在较高pH环境下逐渐发生水解转变为AIC,导致药物浓度较低。如附图10所示,在pH1.2的溶出介质中,共晶中的橙皮素在1分钟内迅速溶解,最大溶出浓度达到31.68±2.44μg/mL,为橙皮素原料药的17.5倍;在pH6.8的溶出介质中,共晶中的橙皮素在10分钟内迅速溶解,最大溶出浓度达到20.67±3.13μg/mL,为橙皮素原料药的25.8倍。
压片性能评价
替莫唑胺、替莫唑胺与橙皮素共晶的粉末样品的压片性实验对比研究
受试样品来源:替莫唑胺与橙皮素共晶由本发明实施例1提供的方法制备;替莫唑胺原料药购买于上海升德医药科技有限公司,纯度为98%。
将替莫唑胺、替莫唑胺与橙皮素共晶的粉末样品研磨后分别过100和200目筛,控制粒径在75~150μm,放置1周后采用Specac GS01190型压片机和压片模具,调节100至400MPa的压力施压,压制成直径5mm的药片。在100至400MPa范围内替莫唑胺粉末均无法压制成片,说明压片性能很差。与之相比,替莫唑胺与橙皮素共晶粉末在100至400MPa范围内均可以压制成完整的药片,说明其压片性能显著改善。替莫唑胺、替莫唑胺与橙皮素共晶的粉末在400MPa压力下压制后所得的图片见附图11和图12。如图11所示,替莫唑胺粉末无法压制成片。如图12所示,替莫唑胺与橙皮素共晶粉末可以压制成片。
压制成药片的替莫唑胺与橙皮素共晶放置24小时后,所有这些药片均保持完整,没有出现裂开、分层迹象。测量药片的直径、厚度和重量,采用天大天发YD-20KZ型智能片剂硬度仪测量药片的硬度。实验结果见附图13的可压片性曲线。如图13所示,替莫唑胺粉末由于无法压制成片,硬度为0;相比之下,替莫唑胺与橙皮素共晶药片的硬度远高于替莫唑胺。可见,共晶的形成显著改善了替莫唑胺的压片性能。
本发明提供的这种替莫唑胺与橙皮素共晶可应用于制备预防和/或治疗癌症的药物,具有广阔的应用前景。
上述实施例为本发明效果较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
2.根据权利要求1所述的共晶,其特征在于:所述共晶的X射线粉末衍射图谱还在2theta值为14.0±0.2°、14.4±0.2°、17.0±0.2°、25.6±0.2°、26.2±0.2°中的一处或多处具有特征峰。
4.一种权利要求1~3中任一项所述共晶的制备方法,其特征在于:包括如下步骤,将替莫唑胺与橙皮素按照摩尔比1∶1投料,加入适量溶剂,然后通过搅拌或研磨得到共晶。
5.根据权利要求4所述的制备方法,其特征在于:所述溶剂为水、醇类、酯类、酮类、烷基腈类中的至少一种。
6.根据权利要求4所述的制备方法,其特征在于:所述搅拌时,替莫唑胺与橙皮素的总质量与溶剂的用量比为1g∶(4~40)mL。
7.根据权利要求4所述的制备方法,其特征在于:所述研磨时,替莫唑胺与橙皮素的总质量与溶剂的用量比为1g∶(100~200)μL。
8.一种药物组合物,其特征在于:包括权利要求1~3任一项所述的共晶和药学上可接受的赋形剂。
9.权利要求1~3任一项所述共晶在治疗癌症的药物中的应用。
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