CN115245487A - 美沙拉嗪与马来酸共晶物及制备方法和其组合物与用途 - Google Patents
美沙拉嗪与马来酸共晶物及制备方法和其组合物与用途 Download PDFInfo
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- CN115245487A CN115245487A CN202110773439.8A CN202110773439A CN115245487A CN 115245487 A CN115245487 A CN 115245487A CN 202110773439 A CN202110773439 A CN 202110773439A CN 115245487 A CN115245487 A CN 115245487A
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- maleic acid
- mesalazine
- mesalamine
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- acid eutectic
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Abstract
本发明公开了美沙拉嗪与马来酸共晶物及制备方法和其组合物与用途,属于医药技术领域。具体而言,本发明公开了美沙拉嗪与马来酸形成的共晶物,该共晶物的分子式为(C7H7NO3)·(C4H4O4);美沙拉嗪与马来酸共晶物的制备方法;美沙拉嗪与马来酸共晶物作为药物有效成分,在制备能够起到治疗慢性结肠炎、溃疡性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症、痛风等疾病及并发症药物中的应用。
Description
技术领域
本发明涉及一种美沙拉嗪与马来酸形成的共晶物;美沙拉嗪与马来酸共晶物的制备方法;美沙拉嗪与马来酸共晶物作为药物有效成分,在制备能够起到治疗慢性结肠炎、溃疡性结肠炎、淋巴细胞性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症、痛风等疾病及并发症药物中的应用;属于医药技术领域。
背景技术
美沙拉嗪(英文名:Mesalazine),化学名为5-氨基水杨酸,结构式如a所示,是一种治疗慢性结肠炎药物,对肠壁的炎症有显著的抑制作用,此外还可以抑制引起炎症的前列腺素的合成和炎性介质白三烯的形成,从而对肠粘膜的炎症起显著抑制作用。对有炎症的肠壁的结缔组织效果更佳,能够用于治疗溃疡性结肠炎、溃疡性直肠炎、克罗恩病和脊柱关节炎[1-3]。现阶段通过对药物功能进行重定位研究发现,其能够在治疗高尿酸血症方面发挥一定治疗作用。美沙拉嗪的共晶物研究已经取得了一些进展,如美沙拉嗪与哌嗪共晶物,美沙拉嗪与4,4′-联吡啶共晶物,美沙拉嗪与4-氨基吡啶共晶物[4]等。
马来酸(英文名:Maleic acid)是药典中常用辅料,结构式如b所示。马来酸的共晶物研究已经取得了一些进展,如马来酸与帕罗西汀共晶物[6],马来酸与甘氨酸共晶物[7],马来酸与培氟沙星共晶物[8]等。
关于美沙拉嗪的多晶型研究:目前发现的美沙拉嗪具有一种晶型状态[9],且为不含水晶型。本专利使用的美沙拉嗪原料药为此晶型。
综上所述,迄今在CCDC数据库中尚未见到美沙拉嗪与马来酸共晶物研究报道,在用途等方面,也未见与本发明相似或冲突研究内容。
发明内容
本发明的研究是通过将美沙拉嗪与马来酸制备成为具有特定非共价作用力的共晶物型固体物质,从而形成有别于美沙拉嗪和马来酸及二者简单联合应用的新物质,进而发现本发明的新共晶物固体物质在制备能够起到治疗慢性结肠炎、溃疡性结肠炎、淋巴细胞性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症、痛风等疾病及并发症药物中的应用。
本发明要解决的技术问题:
本发明要解决的技术问题之一:提供美沙拉嗪与马来酸共晶物存在状态和表征方式。
本发明要解决的技术问题之二:提供美沙拉嗪与马来酸共晶物的制备方法。
本发明要解决的技术问题之三:提供使用美沙拉嗪与马来酸共晶物作为药物活性成分的药物组合物,其每次用药剂量在10~1000mg范围内。所述的药物组合物包括片剂、胶囊、丸剂、针剂、缓释或控释制剂药物。
本发明要解决的技术问题之四:提供美沙拉嗪与马来酸共晶物在治疗疾病过程中由于二者共晶物结合而提高生物体内血药浓度而发挥药物更有效治疗作用。
本发明要解决的技术问题之五:提供了使用美沙拉嗪与马来酸共晶物及其混合晶型固体物质作为药物有效成分的原料,在制备能够起到治疗慢性结肠炎、溃疡性结肠炎、淋巴细胞性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症、痛风等疾病及并发症药物中的应用。
为解决上述技术问题,本发明采用如下技术方案:
1.美沙拉嗪与马来酸共晶物样品形态特征:
1.1本发明涉及的美沙拉嗪与马来酸共晶物,美沙拉嗪与马来酸以非共价键相结合形成共晶物质,二者的摩尔比为1:1。
1.2本发明涉及的美沙拉嗪与马来酸共晶物,不含有结晶溶剂或结晶水成分,当使用粉末X射线衍射分析,采用CuKα辐射实验条件时,表现为衍射峰位置:2-Theta值(°)或d值衍射峰相对强度峰高值(Height%)或峰面积值(Area%)具有如下特征峰值时的固体物质(表1,图1)。美沙拉嗪和马来酸物理混合物的粉末X射线衍射图谱数据见图2、表2。美沙拉嗪与马来酸共晶物以及美沙拉嗪和马来酸物理混合物的粉末X射线衍射图谱在衍射峰数量、衍射峰位置、衍射峰强度、衍射峰拓扑图形等方面均存在明显差异,表明美沙拉嗪与马来酸共晶物以及美沙拉嗪和马来酸物理混合物既不相同也不等同。
表1 美沙拉嗪与马来酸共晶物的粉末X射线衍射峰数据
表2 美沙拉嗪和马来酸物理混合物的粉末X射线衍射峰数据
1.3本发明涉及的美沙拉嗪与马来酸共晶物,使用衰减全反射傅立叶红外光谱法进行分析时,在3067、3043、2860、2726、2610、2234、1932、1678、1641、1624、1569、1519、1482、1449、1403、1373、1357、1330、1298、1265、1219、1147、1112、1036、1012、958、919、906、869、833、799、779、755、749、680、666cm-1处存在红外光谱特征峰,其中红外光谱特征峰的允许偏差为±2cm-1(图3)。
1.4本发明涉及的美沙拉嗪与马来酸共晶物,使用差示扫描量热技术分析时,在30~300℃范围内,升温速率为每分钟10℃时,其DSC图谱中在167℃±3℃处存在1个吸热峰(图4)。美沙拉嗪与马来酸共晶物与美沙拉嗪、马来酸的DSC图谱在吸/放热峰数量、位置等方面均存在明显差异,表明美沙拉嗪与马来酸共晶物与美沙拉嗪及马来酸原料既不相同也不等同(图5)。
2.美沙拉嗪与马来酸共晶物的制备方法特征:
2.1本发明所涉及的美沙拉嗪与马来酸共晶物的制备方法,采用溶剂混悬法,将美沙拉嗪与马来酸按摩尔比1:1混合,加入有机溶剂,室温条件下,搅拌速度为20r/min~400r/min,搅拌1小时~96小时,所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥,获得美沙拉嗪与马来酸共晶物。所述的有机溶剂优选自甲醇、乙醇、乙腈、丙酮、乙酸乙酯、二氧六环、正己烷、环己烷中的任意一种或多种经不同配比组合制成的混合溶剂;保持美沙拉嗪与马来酸总质量与有机溶剂固液比为1mg/ml~500mg/ml范围内。
2.2本发明所涉及的美沙拉嗪与马来酸共晶物的制备方法,控制压力与温度的机械化学方法,将美沙拉嗪与马来酸按摩尔比1:1混合,加入有机溶剂,室温条件下,采用控制压力与温度的机械化学方法制备美沙拉嗪与马来酸共晶物。所述的机械化学方法优选加液球磨法,其中加液球磨法的球料比为1:1~10:1,优选为1:1~5:1;球磨转速20r/min~400r/min;,所获得的混悬液通过自然干燥或真空干燥,获得美沙拉嗪与马来酸共晶物。所述的有机溶剂优选自甲醇、乙醇、乙腈、丙酮、乙酸乙酯、二氧六环、正己烷、环己烷中的任意一种或多种经不同配比组合制成的混合溶剂;加液量为0.01~100ml;研磨时间为0.1~10小时。
2.3本发明的含有美沙拉嗪与马来酸共晶物的混合固体物质,是将上述方法制备获得的美沙拉嗪与马来酸共晶物,与其他化学物质按照任意非零比例和常规的方法进行混合。
3.含有美沙拉嗪与马来酸共晶物成分、给药剂量特征和药物制剂组合物特征:
3.1本发明涉及的药物组合物,含有有效剂量的美沙拉嗪与马来酸共晶物和药学上可接受的载体。
3.2本发明涉及的药物组合物,美沙拉嗪与马来酸共晶物的每日用药剂量在10mg~1000mg范围内。
3.3本发明涉及的药物组合物,所述药物组合物的剂型是片剂、胶囊、丸剂、针剂、缓释制剂或控释制剂。
3.4本发明涉及的美沙拉嗪与马来酸共晶物在制备能够起到治疗慢性结肠炎、溃疡性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症等疾病及并发症药物中的应用。
本发明涉及以本发明美沙拉嗪与马来酸共晶物为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明美沙拉嗪与马来酸共晶物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明美沙拉嗪与马来酸共晶物成分通常为10~90%重量范围内。
本发明美沙拉嗪与马来酸共晶物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
本发明的给药剂型优选是固体剂型。固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等。
本发明美沙拉嗪与马来酸共晶物、本发明美沙拉嗪与马来酸共晶物的混合固体物质可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明美沙拉嗪与马来酸共晶物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明美沙拉嗪-马来酸共晶物与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明美沙拉嗪与马来酸共晶物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明美沙拉嗪与马来酸共晶物成分片剂的各种稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明美沙拉嗪与马来酸共晶物的胶囊剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
4.含有美沙拉嗪与马来酸共晶物的用途:
本发明发现了美沙拉嗪与马来酸共晶物在制备和/或治疗慢性结肠炎、溃疡性结肠炎、淋巴细胞性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症、痛风等疾病及并发症药物中的应用。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明美沙拉嗪与马来酸共晶物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明美沙拉嗪与马来酸共晶物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明美沙拉嗪与马来酸共晶物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明的技术方案具有如下有益技术效果:
本发明的美沙拉嗪与马来酸共晶物在安全性、稳定性和生物活性等方面和现有技术中的美沙拉嗪相比具有显著优势。
本发明的美沙拉嗪与马来酸共晶物不含任何结晶溶剂,具有良好的安全性成药优势。
本发明涉及的美沙拉嗪与马来酸共晶物,在高温(60℃)、高湿(25℃),相对湿度(90%±5%)、光照(4500lx±500lx)条件下均可以稳定存在,具有良好的稳定性成药优势(图7)。
附图说明
图1美沙拉嗪与马来酸共晶物的粉末X射线衍射图谱
图2美沙拉嗪与马来酸物理混合物的粉末X射线衍射图谱
图3美沙拉嗪与马来酸共晶物的红外吸收光谱图
图4美沙拉嗪与马来酸共晶物的差示扫描量热图谱
图5美沙拉嗪与马来酸共晶物及原料的差示扫描量热图谱
图6美沙拉嗪与马来酸共晶物的稳定性图谱
图7美沙拉嗪与马来酸共晶物的SD大鼠体内药时曲线
具体实施方式
为更好说明本发明的技术方案,特给出以下实验例,但本发明并不仅限于此。
实验例1
美沙拉嗪与马来酸共晶物制备方法1
取美沙拉嗪与马来酸适量,二者摩尔比为1:1,室温下采用溶剂混悬法将样品加入适宜容器中,加入适量有机溶剂,于室温条件下搅拌适当时间,将所得的混悬液溶剂蒸发干燥、过滤自然干燥或过滤真空干燥,条件参数参见表4。对其进行粉末X射线衍射分析,其衍射图谱与图1一致,表明所得样品为美沙拉嗪与马来酸共晶物。
表4 美沙拉嗪与马来酸共晶物制备方法1具体实例
美沙拉嗪与马来酸共晶物制备方法2
取美沙拉嗪与马来酸适量,二者摩尔比为1:1,室温下采用机械研磨法将样品加入适宜容器中,加入适量有机溶剂,加入适量有机溶剂,选择适当球料比,设定适当转速,研磨适当时间。对其进行粉末X射线衍射分析,其衍射图谱与图1一致,表明所得样品为美沙拉嗪与马来酸共晶物,条件参数参见表5。
表5 美沙拉嗪与马来酸共晶物制备方法2具体实例
美沙拉嗪与马来酸共晶物的制备方法3:
取美沙拉嗪与马来酸适量按照摩尔比为1:1放入研钵中,加入适量有机溶剂,人工研磨适当时间。对其进行粉末X射线衍射分析,其衍射图谱与图1一致,表明所得样品为美沙拉嗪与马来酸共晶物。
表6 美沙拉嗪与马来酸共晶物制备方法3具体实例
实验例2
美沙拉嗪与马来酸共晶物的稳定性优势
高温试验:将取美沙拉嗪与马来酸共晶物样品置开口洁净表面皿中,在60℃温度下放置10天,并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析,结果表明美沙拉嗪与马来酸共晶物在高温影响因素试验下稳定。
高湿试验:将美沙拉嗪与马来酸共晶物样品置开口洁净表面皿中,在25℃于相对湿度90%±5%条件下放置10天,并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析,结果表明美沙拉嗪与马来酸共晶物在高湿条件下稳定。
光照试验:将美沙拉嗪与马来酸共晶物样品置开口洁净表面皿中,放在装有日光灯的光照箱,于照度为4500lx±500lx的条件放置10天,并于第0天、第5天和第10天取样。将上述取样点所得样品进行粉末X射线衍射分析,结果表明美沙拉嗪与马来酸共晶物在高湿条件下稳定。(图6)
实验例3
组合药物制剂的制备方法1(片剂):
一种组合药物片剂的制备方法,其特征是使用美沙拉嗪与马来酸共晶物纯品作为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分,按照一定比例配比制成每片含药量在10~500mg的片剂样品,表7给出片剂配方比例:
表7 美沙拉嗪与马来酸共晶物组合药物片剂的制备配方
将美沙拉嗪与马来酸共晶物纯品原料药制备成片剂制剂的方法是:将几种赋形剂与原料药混合均匀,直接压片;或辅料混合干法制粒再与原料药混合均匀后压片,即得。
组合药物制剂的制备方法2(片剂):
一种组合药物片剂的制备方法,其特征是使用美沙拉嗪与马来酸共晶物纯品为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分,按照一定比例配比制成每片含药量在10~500mg的片剂样品,表8给出片剂配方比例:
表8 美沙拉嗪与马来酸共晶物组合药物片剂的制备配方
将美沙拉嗪与马来酸共晶物纯品原料药制备成片剂制剂的方法是:将几种赋形剂与原料药混合均匀,加入1%羟甲基纤维素钠溶液适量,制成软料,过筛制粒,湿粒烘干,过筛整粒,加入硬脂酸镁和滑石粉混合均匀,压片,即得。
组合药物制剂的制备方法3(胶囊):
一种组合药物胶囊的制备方法,其特征是使用美沙拉嗪与马来酸共晶物纯品作为组合药物的原料药、使用几种赋形剂作为制备组合药物胶囊的辅料成分,按照一定比例配比制成每片含药量在10~500mg的胶囊样品,表9给出胶囊配方比例:
表9 美沙拉嗪与马来酸共晶物组合药物胶囊制剂的原料药和辅料配方
将美沙拉嗪与马来酸共晶物原料药制备成片剂制剂的方法是:将几种赋形剂与原料药混合均匀,加入1%羟甲基纤维素钠溶液适量,制成湿粒烘干过筛整粒,加入硬脂酸镁混合均匀,插入胶囊制得;或不使用制粒步骤,而直接将美沙拉嗪与马来酸共晶物原料药与几种赋形剂辅料混合均匀,过筛后,直接装入胶囊制得。
实验例4
美沙拉嗪与马来酸共晶物组合药物的给药剂量1(片剂):
使用美沙拉嗪与马来酸共晶物样品作为药物活性成分制备开发的药物组合物,其特征是使用美沙拉嗪与马来酸共晶物作为药物的活性成分,每日给药剂量为300mg,可分别制备成每日3次/每次1片100mg普通片剂,或每日1次/每次1片300mg的片剂类。
美沙拉嗪与马来酸共晶物组合药物的给药剂量2(胶囊):
使用美沙拉嗪与马来酸共晶物样品作为药物活性成分制备开发的药物组合物,其特征是使用美沙拉嗪与马来酸共晶物作为药物的活性成分,每日给药剂量为300mg,可分别制备成每日2次/每次1粒150mg胶囊,或每日1次/每次1粒300mg胶囊。
需要说明的问题:本发明涉及的美沙拉嗪与马来酸共晶物药物组合物在有效成分的给药剂量上存在有许多因素影响,例如:用于预防和治疗的用途不同而造成每日用药剂量的不同;患病性质与患病严重程度不同而造成每日用药剂量的不同;患者性别、年龄、体表面积的不同,给药途径、给药次数、治疗目的不同而造成每日用药剂量的不同;此外,晶型样品间存在的吸收和血药浓度不同等,亦造成本发明在使用美沙拉嗪与马来酸共晶物成分的每日合适剂量范围为0.003~300mg/kg体重,优选为0.03~30mg/kg体重。使用时应根据实际的预防与治疗不同情况需求制定不同的美沙拉嗪与马来酸共晶物有效成分总剂量方案,并可分为多次或一次给药方式完成。
实验例5
美沙拉嗪与马来酸共晶物在大鼠体内吸收特征和血药浓度特征:
本发明所涉及的的美沙拉嗪与马来酸共晶物的动物体内代谢特点,包括如下过程:
将12只SD大鼠,随机分为4组,每组3只。于给药前12h禁食不禁水。称取大鼠体重,按150mg·kg-1的美沙拉嗪给药剂量计算,将美沙拉嗪与马来酸共晶、美沙拉嗪样品装入固体给药器内,通过口腔将药粉直接置入大鼠胃中。分别于给药后5分钟、15分钟、30分钟、45分钟、1小时、1.5小时、2小时、4小时、6小时、8小时、12小时眼球后静脉丛采血置肝素化管中,4℃、4000rpm离心10min,冻存于-40℃冰箱内待测。精密吸取经肝素抗凝后血浆100μL,置于1.5mL离心管中,加入内标对氨基苯甲酸工作液(5μg/ml),10%三氟乙酸,充分震荡3min,离心(13400rpm,10min),再加入10μL丙酸酐,充分震荡15min,离心(13400rpm,10min),加入1mL萃取剂(乙酸乙酯),充分震荡3min,离心(13400rpm,10min),取上层溶液1mL于离心管中,常温以氮气吹干。加入100μL的流动相(甲醇:水=30:70,v/v)复溶,震荡3min,离心(13400rpm,10min),取上层溶液100μL于内衬管中,进样10μL。以药物与内标峰面积之比进行定量分析。
色谱、质谱条件:色谱柱:Agilent ZEclipse XDB-C18(4.6×150mm,5μm,USA);流动相为乙腈:水:甲醇(20:50:30,v/v/v);流速0.3mL/min;进样量:10μL;运行时间:20min;质谱信号:ESI源(负离子检测模式),用于定量分析的离子m/z=192(对氨基苯甲酸衍生物),m/z=208(美沙拉嗪衍生物)不同样品在大鼠体内的美沙拉嗪,美沙拉嗪-马来酸共晶的药代动力学数据见表10所示,血药浓度-时间曲线见图7所示。美沙拉嗪与马来酸共晶物在大鼠体内具有达峰速度快,血药浓度高的优势生物学特征。
表10 美沙拉嗪,美沙拉嗪-马来酸共晶固体灌胃给药后主要药代动力学参数
****:相比美沙拉嗪,P<0.0001
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Claims (14)
1.一种美沙拉嗪与马来酸共晶物,其特征在于,美沙拉嗪与马来酸按照1:1摩尔比以非共价键形成共晶物。
3.根据权利要求1所述的美沙拉嗪与马来酸共晶物,其特征在于,使用衰减全反射傅立叶红外光谱法进行分析时,在3067、3043、2860、2726、2610、2234、1932、1678、1641、1624、1569、1519、1482、1449、1403、1373、1357、1330、1298、1265、1219、1147、1112、1036、1012、958、919、906、869、833、799、779、755、749、680、666cm-1处存在红外光谱特征峰,其中红外光谱特征峰的允许偏差为±2cm-1。
4.根据权利要求1所述的美沙拉嗪与马来酸共晶物,其特征在于,使用差示扫描量热技术分析时,表现为在30~300℃范围内,升温速率为每分钟10℃时,其DSC图谱中在167℃±3℃处存在1个吸热峰。
5.一种如权利要求1-4任一所述的美沙拉嗪与马来酸共晶物的制备方法,其特征在于,美沙拉嗪与马来酸按照1:1的摩尔比例投料,采用溶剂混悬的化学方法制备获得美沙拉嗪与马来酸共晶物。
6.根据权利要求5的制备方法,所述的溶剂混悬法,其中溶剂的选择为甲醇、乙醇、乙酸乙酯、丙酮、乙腈、二氧六环、正己烷、环己烷,其中1种或2种按一定比例混合;搅拌速度为20r/min~400r/min;搅拌时间为1小时~96小时,所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥制备获得美沙拉嗪与马来酸共晶物。
7.权利要求1-4中任一项所述的美沙拉嗪与马来酸共晶物的制备方法,其特征在于,按照美沙拉嗪与马来酸按1:1的摩尔比例投料,采用控制压力与温度的机械化学方法制备美沙拉嗪与马来酸共晶物。
8.根据权利要求7所述的制备方法,所述的机械化学方法优选加液球磨法,其中加液球磨法的球料比为1:1~10:1,优选为1:1~5:1;球磨转速20r/min~400r/min;加液的有机溶剂种类为任意一种或多种经不同配比组合制成的混合溶剂;所述的有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、戊醇、异戊醇、正己醇、乙二醇、乙腈、丙酮、乙酸乙酯、二氧六环、四氢呋喃、正己烷、环己烷;加液量为0.01~100ml;研磨时间为0.1~10小时。
9.一种含有美沙拉嗪与马来酸共晶物的混合固体物质,其特征在于,含有权利要求1-4任一项所述的美沙拉嗪与马来酸共晶物的量为1~99.9%,优选为10~99.9%,再优选为50~99.9%,最优选为85~99.9%。
10.一种药物组合物,其特征在于,含有有效剂量的权利要求1-4中任一项的美沙拉嗪与马来酸共晶物和药学上可接受的载体。
11.一种药物组合物,其特征在于,含有有效剂量的权利要求8中所述的美沙拉嗪与马来酸共晶物的混合固体物质和药学上可接受的载体。
12.根据权利要求10或11的药物组合物,其特征在于,美沙拉嗪与马来酸共晶物的每日用药剂量在10mg~1000mg范围内。
13.根据权利要求10或11的药物组合物,其特征在于,所述药物组合物的剂型是片剂、胶囊、丸剂、粉针剂、缓释制剂或控释制剂。
14.权利要求1-4中任一项所述的美沙拉嗪与马来酸共晶物或权利要求9所述的含有美沙拉嗪与马来酸共晶物的混合固体物质或权利要求10或11所述的药物组合物在制备预防或治疗治疗慢性结肠炎、溃疡性结肠炎、淋巴细胞性结肠炎、溃疡性直肠炎和克罗恩病、脊柱关节炎、高尿酸血症、痛风等疾病及并发症。
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