CN1290843C - 4-[2-[4-[1-(2-乙氧基乙基)-1H-苯并咪唑-2-基]-1-哌啶基]乙基]-α,α-二甲基苯乙酸的多晶型物 - Google Patents
4-[2-[4-[1-(2-乙氧基乙基)-1H-苯并咪唑-2-基]-1-哌啶基]乙基]-α,α-二甲基苯乙酸的多晶型物 Download PDFInfo
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
描述了式(I)的4-[2-[4-[1-(2-乙氧基乙基)-1H-苯并咪唑-2-基]-1-哌啶基]乙基]-αα-二甲基-苯乙酸的多晶型物,其制备的方法,含有多晶型物1的药学配方和多晶型物1治疗哺乳动物如人类中的过敏反应和由组胺介导的病理过程的用途。
Description
发明领域
本发明涉及一种新的式(I)的4-[2-[4-[1-(2-乙氧基乙基)-1H-苯并咪唑-2-基]-1-哌啶基]乙基]-α,α-二甲基苯乙酸(此处称作“比拉斯定(bilastine)”)的多晶型物形式。
此处涉及式1的多晶型物,制备它的方法,含有多晶型物1的药学配方和多晶型物1用于治疗哺乳动物,例如人的过敏性反应和由组胺介导的病理过程的方法。
发明背景
美国专利号5,877,187获得比拉斯定的权利,一种具有抗组胺性质但没有镇静或心血管作用的制剂。该专利也涉及制备比拉斯定的方法和使用该制剂治疗哺乳动物过敏性反应的应用,但是并不包括或暗示该化合物多晶型物的存在可能。
为了制备用于哺乳动物,尤其是人的含有比拉斯定的药物制剂,根据国际健康权威规范,比拉斯定必须以最稳定的晶型,特别是有稳定物理性能的形式制造。
发明概述
我们已经发现比拉斯定可以三种不同的结晶多晶型物存在,各自具有不同的物理性质。
本发明涉及一种比拉斯定多晶型物的纯结晶形式,通过X射线结晶分析得到表征,大约的结晶参数如下:
晶系 单斜
空间群 P2(1)/c
晶粒大小 0.56×0.45×0.24毫米
晶胞大小 a=23.38(5)埃 α=90°
b=8.829(17)埃 β=90°
c=12.59(2)埃 γ=90°
体积 2600A3
Z,计算密度 4,1.184mg/m3
比拉斯定的结晶多晶型物还通过它在溴化钾压片中的红外吸收光谱进行表征,用厘米倒数表示,特征吸收谱带如下:
3430(s)*;3057(w)*;2970(s);2929(s);2883(m)*;2857(m);2797(w);1667(m);1614(m);1567(w);1509(s);1481(m);1459(vs)*;1431(m);1378(w);1346(m);1326(m);1288(w);1254(m);1199(w);1157(w);1121(vs);1045(w);1020(w);1010(w);991(w);973(w);945(w);829(w);742(s);723(w);630(w),*其中(w)=低强度,(m)=中等强度,(s)=高强度,(vs)=很高强度。图1所示为比拉斯定的结晶多晶型物1在Perkin ElmerSpectrum One FTIR分光光度计中溴化钾压片中记录的红外光谱。
附图说明
图1所示为多晶型物1在溴化钾中的典型红外吸收光谱。(纵轴:透过率(%);横轴:波数(cm-1))
图2所示为多晶型物2在溴化钾中的典型红外吸收光谱。(纵轴:透过率(%);横轴:波数(cm-1))
图3所示为多晶型物3在溴化钾中的典型红外吸收光谱。(纵轴:透过率(%);横轴:波数(cm-1))
发明详述
我们已经发现比拉斯定可以以三种完全不同的多晶型物存在,称之为多晶型物1,多晶型物2和多晶型物3。
美国专利5,877,187所描述的方法制得了多晶型物2和3的混合物。我们发现可以产生截然不同的比拉斯定的多晶型形式的实验条件和特定溶剂。纯的比拉斯定的结晶多晶型物1根据本发明的方法制备。多晶型物1和2是稳定的。多晶型物3不是很稳定且很难获得纯品。根据本发明的方法,多晶型物2和多晶型物3被转变为多晶型物1。
比拉斯定的多晶型物1的熔点为200.3℃。多晶型物2的熔点为205.2℃。多晶型物3的熔点为197.0℃。
比拉斯定的结晶多晶型形式1还通过它在溴化钾压片中的红外吸收光谱进行表征,用厘米倒数表示,特性吸收谱带如下:
3430(s)*;3057(w)*;2970(s);2929(s);2883(m)*;2857(m);2797(w);1667(m);1614(m);1567(w);1509(s);1481(m);1459(vs)*;1431(m);1378(w);1346(m);1326(m);1288(w);1254(m);1199(w);1157(w);1121(vs);1045(w);1020(w);1010(w);991(w);973(w);945(w);829(w);742(s);723(w);630(w),*其中(w)=低强度,(m)=中等强度,(s)=高强度,(vs)=很高强度。图1所示为比拉斯定的结晶多晶型物1在Perkin ElmerSpectrum One FTIR分光光度计中的溴化钾压片记录的红外光谱。
比拉斯定的结晶多晶型形式2也通过它在溴化钾压片上红外吸收光谱进行表征,用厘米倒数表示,特征吸收谱带如下:
3429(s)*;3053(w)*;2970(s)*;2932(s);2868(s);2804(w);1699(m);1614(m)*;1567(m);1508(s);1461(vs)*;1381(m);1351(s);1331(m);1255(m);1201(w);1156(m);1121(vs);1048(w);995(w);823(w);767(w);744(s);724(d);630(w),*其中(w)=低强度,(m)=中等强度,(s)=高强度,(vs)=很高强度。图2示为比拉斯定的结晶多晶型物2在Perkin ElmerSpectrum One FTIR分光光度计中溴化钾压片记录的红外光谱。
比拉斯定的结晶多晶型形式3通过它在溴化钾压片上红外吸收光谱进行表征,用厘米倒数表示,特征吸收谱带如下:
3430(s)*;3053(w)*;2970(s);2932(s);2868(s);2804(w);1921(w);1708(m)*;1614(m);1568(m);1508(s);1461(vs)*;1380(m);1351(m);1330(m);1271(m);1255(m);1201(w);1156(m);1121(vs);1048(w);995(w);823(m);767(w);744(s);724(w);630(w),*其中(w)=低强度,(m)=中等强度,(s)=高强度,(vs)=很高强度.图3示为比拉斯定的结晶多晶型物3在Perkin Elmer Spectrum One FTIR分光光度计中的溴化钾压片记录的红外光谱。
我们已经发现,根据美国专利5,877,187得到的多晶型物2和3的混合物,在选定的实验条件下,令人惊奇的被转变为多晶型物1。我们也已经发现比拉斯定的多晶型物1很稳定,不会转变为多晶型物2和3的任一种。类似地,在相同实验条件,比拉斯定的纯的多晶型形式2令人惊奇的变成纯的多晶型形式1。最不稳定的多晶型形式3,在相同条件下经历相同的转变。
比拉斯定的多晶型物1在室温下是一种很稳定多晶型物,所以,作为药物制剂的活性成分非常有用。在高于室温的温度存储时,多晶型物1也是稳定的。
比拉斯定的多晶型的晶形1通过下述的单晶的X射线结晶分析的数据,得到下述大约的晶格参数值:
晶系 单斜
空间群 P2(1)/c
晶粒大小 0.56×0.45×0.24mm
晶胞大小 a 23.38(5)埃 α=90°
b=8.829(17)埃 β=90°
c=12.59(2)埃 γ=90°
体积 2600A3
Z,计算密度 4,1.184mg/m3
在用于药物制剂的比拉斯定的多晶型物1的开发期间,精心按照正确的加工工序进行,我们发现比拉斯定的结晶(按照美国专利5,877,187的描述制备)的短链醇类(优选异丙醇、正丁醇和其混合物)溶液会以高产率得到比拉斯定的纯多晶型形式。丙酮、二甲基亚砜、二甲基甲酰胺、乙腈和四氢呋喃或其混合物的结晶也导致多晶型物1的产生,虽然产量较低。所以,溶剂优选使用前者。
比拉斯定的多晶型物1的在溴化钾中的红外光谱以下面的峰表征,没有多晶型物2和3:
波数(厘米-1)
3057
2929
2883
2857
2797
1667
1481
1431
1346
1326
1288
973
945
829
图1所示为比拉斯定的多晶型物1在溴化钾中的完整红外光谱,用Perkin Elmer Spectrum One FTIR分光光度计记录。
药物制剂
本发明的药物制剂可以含有作为抗过敏或抗组胺剂有效成分的有效量的比拉斯定的多晶型物1,多种药学可接受的赋形剂(其可以是固体或液体)。固体药物制剂包括粉剂,片剂,可分散的颗粒,胶囊、贴剂和栓剂。固体赋形剂可以是用作稀释剂、加香剂、胶合剂或崩解剂、封装物质之一。粉剂和片剂优选地含有从大约5到大约20%的活性成分。适当的固体赋形剂是碳酸镁,硬脂酸镁,滑石,糖,乳糖,果胶,糊精,淀粉,明胶,黄芪胶,甲基纤维素,羧甲基纤维素钠,低熔点的蜡,可可脂和类似的产品。术语“制剂”包括含有活性成分和用于封装成胶囊的赋型剂的配方,其中活性成分(带有或不带有其他赋型剂)通过封装物质被赋型剂包裹。片剂、粉剂、贴剂和胶囊能以适当的形式口服。活性成分还可以掺入含有适当的甜味剂、调味品和色素的咀嚼胶中。
为了制备栓剂,将低熔点化合物,例如脂肪酸甘油酯或可可脂的混合物融化,然后充分混合活性成分,搅拌均一的分散在混合物中。均一熔化的混合物放入适当的模子中,然后冷却直到固化。
液体药剂包括悬浮液,溶液和乳剂。对应于水性悬浮液的例子可以通过将细分的活性成分与悬浮剂混和于水中制得。水性溶液可以通过将活性成分放入水中,并加入适当的着色剂、芳香剂、稳定剂、甜味剂、增溶剂和稠化剂制得。
同时,外用制剂也可以用于鼻、眼和真皮给药。适当的经鼻给药的配方可对应于溶液或悬浮液。眼科制剂可以是溶液、悬浮液或软膏。真皮制剂可以是溶液、悬浮液、软膏和霜剂。软膏通常包含亲脂的赋形剂,如矿物油或凡士林。用于眼科的溶液可以包含氯化钠、调节pH的酸和/或碱、纯水和防腐剂。
相似的,意欲用于透皮给药的组合物含有治疗有效量的活性成分,其被掺入相应于液体、凝胶、固体基质或对压力敏感的粘性贴剂的赋型剂中,经透皮给药体系释放。
比拉斯定多晶型物1的局部给药之抗过敏或抗组胺有效量介于药物化合物总重量的0.1和5%之间。优选量范围为基于药物化合物总重量的0.1到2%。
比拉斯定的口服给药之抗过敏或抗组胺有效量为单次或分次剂量从1到50mg/天,优选约2到20mg/天。
比拉斯定的多晶型物1具有抗组胺特性,这已在药理学模型中证实,如防止豚鼠中组胺-诱发的致死,和对抗老鼠中组胺诱发的皮肤毛细管渗透。
下面的例子显示但不限制本发明的范围。
实施例1
比拉斯定多晶型物1的制备
将比拉斯定(美国专利5,877,187)溶于异丙醇中,在氮气氛中边搅拌边加热回流大约15-20分钟。经6小时将溶液冷却到50℃并停止搅拌。将溶液冷却到室温再次搅拌3小时,过滤并用冷异丙醇洗涤。在35-40℃于真空橱中干燥固体残留物直至恒重。
实施例2
比拉斯定多晶型物1的制备
加热比拉斯定(美国专利5,877,187)的正丁醇悬浮液,在氮气氛中边搅拌边回流3小时。边搅拌边冷却溶液,过滤掉固体残留物,在35-40℃于真空橱中干燥固体残留物直至恒重。
实施例3
比拉斯定多晶型物1的制备
用热丙酮处理比拉斯定多晶型物2和3的混合物数小时。混合物冷却到室温,过滤掉固体残余物,干燥至恒重。
实施例4
比拉斯定多晶型物1的制备
将比拉斯定多晶型物3溶于异丙醇中,并在氮气氛下加热回流搅拌约15到20分钟。使溶液达到室温匀速搅拌,过滤并用冷异丙醇洗涤。在真空橱中于35-40℃干燥固体直至恒重。
实施例5
比拉斯定多晶型物1的制备
将比拉斯定的多晶型物2溶于正丁醇中,并加热回流搅拌大约3小时。边搅拌使溶液达到室温,过滤并沥干。在35-40℃于真空橱中干燥固体残留物直至恒重。
Claims (5)
1.X-射线结晶分析表征的比拉斯定的多晶型物1,具有下述的晶体参数:
晶系 单斜
空间群 P2(1)/c
晶粒大小 0.56×0.45×0.24毫米
晶胞大小 a=23.38(5)埃 α=90°
b=8.829(17)埃 β=90°
c=12.59(2)埃 γ=90°
体积 2600A3
Z,计算密度 4,1.184mg/m3,
它在溴化钾中的红外光谱具有如下峰:
波数(cm-1)
3057
2929
2883
2857
2797
1666
1481
1431
1346
1326
1288
973
945
829。
2.制备权利要求1的比拉斯定的多晶型物1的方法,其包括加热溶于选自短链醇、丙酮及其混合物的溶剂之比拉斯定的多晶型物2或3或其混合物,其中多晶型物2具有205.2℃的熔点,多晶型物3具有197.0℃的熔点。
3.根据权利要求2制备比拉斯定的多晶型物1的方法,其中溶剂选自异丙醇和正丁醇、丙酮及其混合物。
4.一种药物制剂,其含有有效量的根据权利要求1的比拉斯定的多晶型物1和药学上可接受的赋形剂。
5.权利要求1的比拉斯定的多晶型物1用于制备治疗过敏反应和由组胺介导的病理过程的药品的用途。
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CN103214454A (zh) * | 2013-03-30 | 2013-07-24 | 北京万全德众医药生物技术有限公司 | 一种比拉斯汀晶型及制备方法 |
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CN103356616A (zh) * | 2013-06-29 | 2013-10-23 | 北京万全德众医药生物技术有限公司 | 一种含有比拉斯汀的药物组合物及其制备方法 |
CN104447682A (zh) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | 比拉斯汀化合物 |
CN104398481A (zh) * | 2014-10-29 | 2015-03-11 | 万全万特制药江苏有限公司 | 比拉斯汀口崩片及其制备方法 |
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