CN114929659A - 蝶芪的共晶和包含它们的组合物 - Google Patents
蝶芪的共晶和包含它们的组合物 Download PDFInfo
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- CN114929659A CN114929659A CN202080092038.XA CN202080092038A CN114929659A CN 114929659 A CN114929659 A CN 114929659A CN 202080092038 A CN202080092038 A CN 202080092038A CN 114929659 A CN114929659 A CN 114929659A
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Abstract
本公开涉及蝶芪与能够形成氢键相互作用的共形成体的共晶、用于其制备的方法以及它作为药剂或膳食补充剂的用途。本公开还涉及包含该共晶的组合物。
Description
本申请要求于2019年12月20日提交的欧洲专利申请EP19383178.1和于2020年3月9日提交的EP20382170.7的权益。
技术领域
本公开涉及蝶芪的共晶、用于其制备的方法以及它们作为药剂或膳食补充剂的用途。它还涉及包含它们的组合物。
背景技术
蝶芪(反式-3,5-二甲氧基-4-羟基芪)是天然的饮食化合物以及蓝莓的主要抗氧化成分。与其他芪化合物相比它增加了生物利用率,这可能会提高它的饮食效益并且可能有助于有价值的临床作用。
蝶芪的结构对应于式(I):
多项研究已经证明了蝶芪的抗氧化活性以及它在预防和治疗包括神经性、心血管、代谢和血液学疾病在内的各种医疗状况方面的临床潜力。特别地,蝶芪的抗氧化活性与抗癌作用、神经性疾病的调节、抗炎症、血管疾病的衰减、糖尿病和其他年龄相关疾病的改善有关。
蝶芪以熔点为89-92℃的结晶固体提供。它极少溶于水。
令人满意的生物利用率的基本要求是活性成分能够在消化道中充分溶解。蝶芪的低水溶性造成了一些关于它的生物利用率的问题。
众所周知,活性成分的不同固体形式可以具有不同的特性,并提供某些优势,例如关于溶解度或生物利用率。从而,新固体形式的发现允许改进活性成分的药物动力学性质并且因此改进含有活性成分的药物制剂的特性,因为有些形式更适合制剂的一种类型,并且其他形式更适合其他不同的制剂。
特别地,近年来共晶形成已成为改进活性成分的药物动力学数据的可行策略。通过将活性成分或活性成分的盐与共形成体(coformer)(共晶的第二成分)共结晶,形成了与活性成分或其盐的现有固体形式相比具有独特性质的活性成分的新固态形式。此类不同的性质可以为改进制剂提供基础,例如通过促进更好的加工或处理特性、向有利的方向改变溶出曲线或者提高稳定性和贮存期限。然而,共晶形成是不可预测的,并且事实上也不总是可能的。此外,在化合物形成之前没有办法预测其具体的共晶的性质。寻找合适的共形成体和适当的条件来获得特定的共晶可能花费大量的时间、精力和资源。
从本领域已知的技术来看,仍然需要找到蝶芪的新的更易溶的固体形式,以改进含有它们的药物制剂的药物性质,特别是就生物利用率而言。
发明内容
本发明人发现蝶芪可以与如下文限定的能够形成氢键相互作用的共形成体形成共晶。上述蝶芪共晶的提供为克服与蝶芪的水溶性相关的问题提供了新的工具,因为已经发现这些共晶在水介质中具有更好的水溶性和更高的溶出度,这使它们更加生物可利用。这个特性使共晶更适合于制备含有蝶芪的药物或膳食组合物。
共晶形成不能被预测,特别是与能够形成氢键相互作用的共形成体的共晶形成。
相应地,蝶芪的改进晶体形式的提供被认为是对该领域的贡献,所述蝶芪的改进晶体形式是与如下文限定的能够形成氢键相互作用的共形成体的共晶。
因此,本公开的第一方面涉及提供蝶芪与能够形成氢键相互作用的共形成体的共晶。本公开的第二方面涉及一种组合物,其包含有效量的如上文和下文限定的蝶芪与能够形成氢键相互作用的共形成体的共晶和一种或多种合适的可接受的赋形剂或载体。
最后,本公开的第三方面涉及用作药剂的如上文和下文限定的蝶芪与能够形成氢键相互作用的共形成体的共晶。
附图说明
图1显示蝶芪与吡啶甲酸(1:1)的共晶的X-射线粉末衍射图(XRPD)。
图2显示蝶芪与吡啶甲酸(2:1)的共晶的X-射线粉末衍射图(XRPD)。
图3显示蝶芪与1,4-二甲基哌嗪(2:1)的共晶的XRPD。
图4显示蝶芪与2,3,5-三甲基吡嗪(2:1)的共晶的XRPD。
图5显示蝶芪:茶碱:二氯甲烷(1:1:1)的共晶的XRPD。
图6显示蝶芪与1,4,8,11-四氮杂环十六烷(2:1)的共晶的XRPD。
图7显示蝶芪与乙二胺(2:1)的无水共晶的XRPD。
图8显示蝶芪与乙二胺(2:1:2)的水合物共晶的XRPD。
图9显示蝶芪与1,4-二氮杂二环[2.2.2]辛烷(DABCO)(2:1)的共晶的XRPD。
图10显示蝶芪与吲哚的共晶的XRPD。
图11显示蝶芪与赖氨酸的共晶的XRPD。
图12显示蝶芪与乳清酸的共晶的XRPD。
图13显示蝶芪与1,10-菲咯啉的共晶的XRPD。
图14显示蝶芪与尿素的共晶的XRPD。
图15显示蝶芪的形式VI的XRPD。
图16显示蝶芪共晶与蝶芪形式I和蝶芪形式VI相比的溶出曲线,其中:
○蝶芪形式I
◆蝶芪:吡啶甲酸共晶体(1:1)
●蝶芪:乙二胺水合物共晶
◇蝶芪形式VI
▲蝶芪:乙二胺共晶
■蝶芪:咖啡因共晶
图17显示蝶芪:吡啶甲酸共晶2:1的溶出曲线,与蝶芪形式I与蝶芪形式VI相比,其中:
●蝶芪:吡啶甲酸共晶2:1
■蝶芪形式I
▲蝶芪形式VI
图18显示在大鼠中单次口服施用之后蝶芪的血浆浓度-时间曲线(20mg/kg蝶芪,游离碱)。
图19显示在大鼠中单次口服施用蝶芪与吡啶甲酸的共晶之后蝶芪的血浆浓度-时间曲线(20mg/kg P56-VIII,13.5mg蝶芪)。
图20显示在雄性SD大鼠中单次口服施用蝶芪游离碱(20mg/kg P56)和蝶芪与吡啶甲酸的共晶(20mg/kg P56-VIII,13.5mg/kg蝶芪)之后蝶芪的血浆浓度-时间曲线的比较。算术平均值±SD。
具体实施方式
除另有说明外,在本申请中本文所使用的所有术语应按它们在本领域中已知的通常含义理解。对于在本申请中使用的某些术语的其他更具体的定义如下所述,并且除非另有明确陈述的定义提供了更广泛的定义,否则拟在本说明书和权利要求书中统一适用。
就本公开的目的而言,给定的范围,诸如温度、时间等等,应视被认为是近似,除非特别地声明。
就本公开的目的而言,本文中术语“共晶”指的是具有在室温(20-25℃)下构成晶胞并且通过分子间相互作用而相互作用的至少两种不同成分的晶体状实体。从而,在共晶中,一种成分与一种或多种中性成分一起结晶。
共晶可以包括晶格中的一种或多种溶剂分子。从而,术语“共晶水合物”或“水合物共晶”具有相同的意义并且可互换使用。它们指的是在晶格中包括水作为溶剂的共晶。同样地,包括其他溶剂诸如如二氯甲烷的共晶也可以形成。
表达“通过...能获得的共晶”在本文用于通过获得它的方法来定义本公开的每个具体的共晶,并且指的是通过本文所公开的任何相应方法获得的产物。就本公开的目的而言,表达“能获得的”、“获得”和等效表达可互换使用,并且在任何情况下,表达“能获得的”包含表达“获得”。
术语“能够形成氢键相互作用的共形成体”指的是具有氢原子与电负性原子(诸如氮、氧或硫)结合的化合物,或者具有碱性原子(诸如氮或氧)并具有建立强分子间氢键能力的化合物。能够形成氢键相互作用的共形成体的实例包括磷酸、羧酸、醇、咪唑、硫代酰胺、亚磺酰胺、吡咯、尿素、酰胺、氨磺酰、氨基甲酸酯、胺、酮和亚砜。
当指定本公开的共晶的成分的比例时,它指的是形成共晶的成分的摩尔比。术语“摩尔比”已经被用来表示共晶的每个成分的摩尔为单位的化学计量的量。摩尔比可通过1HNMR(质子核磁共振)、热解重量分析法(TGA)或单晶X-射线衍射法(SCXRD)测定。当根据TGA或1H NMR给出摩尔比的值时,认为这些值是由于测量误差造成的“近似”值。应该理解的是,当提到摩尔比时,它对应于是摩尔比±0.2%。结果的可变性是由于TGA或1H NMR设备的固有灵敏度。
术语“室温”指的是没有加热或冷却的环境的温度,并且通常为20℃至25℃。
术语“过夜”指的是从10h至20h的时间间隔。
如本文中使用的,不定冠词“一个”和“一种”与“至少一个”或“一个或多个”同义。除非另有说明,本文中使用的定冠词,诸如“该”,也包括名词的复数形式。
如上所述,本公开的第一方面是提供蝶芪与能够形成氢键相互作用的共形成体的共晶。同样如上所述,本公开的共晶可以是晶体形式,作为游离溶剂化化合物或作为溶剂合物(例如,水合物或二氯甲烷溶剂合物),并且意欲使这两种形式都在本公开的范围内。溶剂化的方法在本领域内是众所周知的。
特别地,共形成体选自吡啶甲酸、1,4-二甲基哌嗪、2,3,5-三甲基吡嗪、茶碱、乙二胺、1,4-二氮杂二环[2.2.2]辛烷(DABCO)、1,4,8,11-四氮杂环十六烷、2,4-二羟基苯甲酸(2,4-DHBA)、吲哚、赖氨酸、乳清酸、菲咯啉和尿素。
在实施方式中,该共形成体是羧酸,特别地选自吡啶甲酸、2,4-二羟基苯甲酸、乳清酸、吲哚和赖氨酸的羧酸。
在实施方式中,该共形成体是吡啶甲酸。在具体的实施方式中,蝶芪与吡啶甲酸的共晶的特征在于包含在大约5.6和14.0±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与吡啶甲酸的共晶的特征在于包含在13.5、21.8和24.4±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与吡啶甲酸的摩尔比为1:1。
更具体而言,本公开的蝶芪与吡啶甲酸[1:1]的共晶的特征在于在X-射线粉末衍射图中展示在表1中显示的峰的模式以度为单位的2θ单位2θ(°)表示。
表1:选择的峰的列表(只显示相对强度大于或等于1%的峰):
位置[°2θ] | 相对强度[%] |
5.6169 | 33.15 |
11.2739 | 12.33 |
12.346 | 31.99 |
13.4496 | 35.69 |
13.9625 | 89.18 |
15.3097 | 13.08 |
15.99 | 10.56 |
16.9149 | 17.72 |
18.6129 | 17.71 |
18.809 | 16.7 |
19.5284 | 22.76 |
19.9678 | 8.47 |
21.0446 | 21.91 |
21.6278 | 7.78 |
21.8238 | 63.62 |
22.071 | 44.8 |
23.5635 | 7.54 |
23.932 | 6.82 |
24.3877 | 100 |
24.6273 | 10.26 |
24.858 | 12.15 |
25.4181 | 25.59 |
26.2045 | 12.31 |
27.0818 | 9.5 |
29.353 | 24.27 |
29.603 | 21.9 |
30.8981 | 8.78 |
本公开的蝶芪与吡啶甲酸[1:1]的共晶的进一步特征可在于图1所示的X-射线衍射图。
在另一个具体的实施方式中,蝶芪与吡啶甲酸的共晶的特征在于具有包含在大约18.3和26.0±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与吡啶甲酸的共晶的特征在于具有包含在3.2、16.8和23.6±0.3°2θ(Cu-Kα辐射, )的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与吡啶甲酸的摩尔比为2:1。
更具体而言,本公开的蝶芪与吡啶甲酸[2:1]的共晶的特征在于在X-射线粉末衍射图中展示在表2中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表2
位置[°2θ] | 相对强度[%] |
3.2296 | 87.84 |
6.4402 | 21.29 |
9.5395 | 22.26 |
9.8263 | 12.62 |
10.5625 | 9.23 |
15.8652 | 11.37 |
16.8271 | 38.15 |
17.1356 | 20.43 |
17.4453 | 28.77 |
18.3181 | 67.28 |
18.6681 | 12.78 |
19.1243 | 23.32 |
19.4168 | 16.33 |
19.6903 | 17.62 |
20.2394 | 6.17 |
22.2772 | 14.18 |
23.5945 | 53.51 |
23.8152 | 14.6 |
24.0743 | 51.67 |
25.6849 | 17.99 |
26.0389 | 100 |
26.829 | 12.3 |
27.8083 | 7.22 |
28.2253 | 10.49 |
28.7149 | 7.38 |
29.0089 | 17.16 |
本公开的蝶芪与吡啶甲酸[2:1]的共晶的进一步的特征可在于图2所示的X-射线衍射图。
在另一个实施方式中,共形成体是1,4-二甲基哌嗪,并且蝶芪与1,4-二甲基哌嗪的共晶的特征在于包含在大约17.3和21.2±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与1,4-二甲基哌嗪的共晶的特征在于具有包含在6.9、13.7和15.8±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与1,4-二甲基哌嗪的摩尔比为2:1。
更具体而言,本公开的蝶芪与1,4-二甲基哌嗪的共晶的特征在于在X-射线粉末衍射图中展示在表2中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表3:选择的峰的列表(只显示相对强度大于或等于1%的峰):
位置[°2θ] | 相对强度[%] |
6.8894 | 26.57 |
10.5211 | 21.64 |
13.7014 | 71.72 |
15.751 | 48.36 |
15.9548 | 24.75 |
16.4869 | 5.82 |
16.6605 | 30.99 |
16.9633 | 6.88 |
17.3097 | 82.43 |
17.7078 | 16.93 |
18.3773 | 20.85 |
18.5668 | 16.6 |
19.0475 | 39.34 |
20.6378 | 7.91 |
21.2175 | 100 |
21.371 | 31.19 |
21.7758 | 13.97 |
21.9854 | 11.06 |
22.2378 | 21.28 |
25.7444 | 7.52 |
26.0175 | 9.4 |
26.4516 | 13.36 |
28.1315 | 30.2 |
28.4889 | 5.32 |
29.3592 | 9.47 |
31.9421 | 6.8 |
33.3093 | 5.17 |
通过单晶X-射线衍射法得到的上述限定的蝶芪与1,4-二甲基哌嗪的共晶的结构的数据对应于共晶并且如下所示:
本公开的蝶芪与1,4-二甲基哌嗪的共晶的进一步特征可在于图3所示的X-射线衍射图。
在另一个实施方式中,共形成体是2,3,5-三甲基吡嗪,并且蝶芪与2,3,5-三甲基吡嗪的共晶的特征在于具有包含在大约13.4和25.9±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与2,3,5-三甲基吡嗪的共晶的特征在于具有包含在11.4、22.7和26.9±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与2,3,5-三甲基吡嗪的摩尔比为2:1。
更具体而言,蝶芪与2,3,5-三甲基吡嗪的共晶的特征在于在X-射线粉末衍射图中展示在表4中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表4:选择的峰的列表(只显示相对强度大于或等于1%的峰):
位置[°2θ] | 相对强度[%] |
10.7026 | 18.75 |
11.3585 | 61.1 |
11.7648 | 27.96 |
12.8156 | 28.31 |
13.4444 | 78.59 |
13.5684 | 41.14 |
14.2798 | 37.2 |
14.9221 | 24.32 |
15.1696 | 17.84 |
15.7685 | 32.26 |
15.9571 | 39.6 |
17.2914 | 19.76 |
18.7415 | 21.64 |
18.9979 | 17.25 |
19.2373 | 32.04 |
19.4689 | 8.92 |
20.0074 | 11.06 |
20.7256 | 10.55 |
22.5371 | 7.56 |
22.7423 | 39.05 |
22.9157 | 12.55 |
24.1122 | 24.45 |
24.6101 | 57.17 |
24.9353 | 13.75 |
25.8607 | 100 |
26.2228 | 39.92 |
26.8841 | 44.7 |
27.6633 | 9.79 |
29.5435 | 10.23 |
通过单晶X-射线衍射法得到的上述限定的蝶芪与2,3,5-三甲基吡嗪的共晶的结构的数据对应于共晶并且如下所示:
本公开的蝶芪与2,3,5-三甲基吡嗪的共晶的进一步特征可在于图4所示的X-射线衍射图。在另一个实施方式中,共形成体是茶碱并且蝶芪与茶碱的共晶的特征在于具有包含在大约8.5和11.7±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与茶碱的共晶的特征在于具有包含在13.7、15.0和16.7±0.3°2θ(Cu-Kα辐射, )的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与茶碱的摩尔比为1:1。更具体而言,本公开的蝶芪与茶碱的共晶的特征在于在X-射线粉末衍射图中展示在表5中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表5:选择的峰的列表(只显示相对强度大于或等于1%的峰):
在另一个实施方式中,共形成体是茶碱,并且蝶芪与茶碱的共晶是二氯甲烷溶剂合物的形式,并且特征在于具有包含在大约13.4和26.0±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地。本公开的蝶芪与茶碱的二氯甲烷溶剂合物共晶的特征在于具有包含在10.8、14.4和23.5±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪:茶碱:二氯甲烷的摩尔比为1:1:1。
更具体而言,本公开的蝶芪:茶碱:二氯甲烷溶剂合物共晶的特征在于在X-射线粉末衍射图中展示在表6中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表6:选择的峰的列表(只显示相对强度大于或等于1%的峰):
通过单晶X-射线衍射法得到的上述限定的蝶芪:茶碱:二氯甲烷溶剂合物共晶的结构的数据对应于共晶并且如下所示:
本公开的蝶芪:茶碱:二氯甲烷溶剂合物共晶的进一步特征可在于图5所示的X-射线衍射图。在另一个实施方式中,共形成体是1,4,8,11-四氮杂环十六烷,并且蝶芪与1,4,8,11-四氮杂环十六烷的共晶的特征在于具有包含在大约10.8和23.6±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与1,4,8,11-四氮杂环十六烷的共晶的特征在于具有包含在16.2、18.0和20.6±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与1,4,8,11-四氮杂环十六烷的摩尔比为2:1。
更具体而言,本公开的蝶芪与1,4,8,11-四氮杂环十六烷的共晶的特征在于在X-射线粉末衍射图中展示在表7中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表7:选择的峰的列表(只显示相对强度大于或等于1%的峰):
通过单晶X-射线衍射法得到的上述限定的蝶芪与1,4,8,11-四氮杂环十六烷的共晶的结构的数据对应于共晶并且如下所示:
本公开的蝶芪与1,4,8,11-四氮杂环十六烷的共晶的进一步特征可在于图6所示的X-射线衍射图。
在另一个实施方式中,共形成体是乙二胺,并且蝶芪与乙二胺的共晶是无水共晶,特征在于具有包含在大约14.3和19.3±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与乙二胺的共晶的特征在于具有包含在6.7、13.4和22.0±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与乙二胺的摩尔比为2:1。
更具体而言,本公开的蝶芪与乙二胺的无水共晶的特征在于在X-射线粉末衍射图中展示在表8中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表8:选择的峰的列表(只显示相对强度大于或等于1%的峰):
位置[°2θ] | 相对强度[%] |
6.6926 | 28.17 |
7.7966 | 4.85 |
11.1893 | 15.31 |
13.4421 | 28.42 |
14.2703 | 100 |
17.3612 | 4.75 |
18.1561 | 18.6 |
18.3322 | 14.19 |
18.8099 | 15.7 |
19.3235 | 54.2 |
20.314 | 7.61 |
20.6456 | 9.02 |
21.7635 | 3.78 |
22.023 | 38.13 |
22.5143 | 5.52 |
23.0457 | 10.35 |
23.236 | 11.7 |
23.3786 | 9.98 |
23.997 | 4.47 |
24.1765 | 8.76 |
25.0016 | 18.12 |
25.4203 | 4.2 |
25.7345 | 6.3 |
26.2684 | 5.49 |
26.5054 | 13.19 |
26.634 | 10.26 |
27.0518 | 1.15 |
28.367 | 4.63 |
28.7839 | 10.26 |
通过单晶X-射线衍射法得到的上述限定的蝶芪与乙二胺的共晶的结构的数据对应于共晶并且如下所示:
本公开的蝶芪与乙二胺的共晶的进一步特征可以在于图7所示的X-射线衍射图。
在另一个实施方式中,共形成体是乙二胺,并且蝶芪与乙二胺的共晶是水合物共晶,特征在于具有包含在大约14.3和19.3±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与乙二胺的水合物共晶的特征在于具有包含在17.5、21.5、23.6和29.3±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与乙二胺的共晶是水合物并且蝶芪、乙二胺和水的摩尔比为2:1:2。
更具体而言,本公开的蝶芪与乙二胺的水合物共晶的特征在于在X-射线粉末衍射图中展示在表9中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表9:选择的峰的列表(只显示相对强度大于或等于1%的峰):
本公开的蝶芪与乙二胺的水合物共晶的进一步特征可在于图8所示的X-射线衍射图。
在另一个实施方式中,共形成体是1,4-二氮杂二环[2.2.2]辛烷(DABCO),并且蝶芪与DABCO的共晶的特征在于具有包含在大约17.9和21.7±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。在实施方式中,本公开的蝶芪与DABCO的共晶的特征在于具有包含在10.6、16.0和19.0±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。更特别地,蝶芪与DABCO的摩尔比为2:1。
更具体而言,本公开的蝶芪与DABCO的共晶的特征在于在X-射线粉末衍射图中展示在表10中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表10:选择的峰的列表(只显示相对强度大于或等于1%的峰):
通过单晶X-射线衍射法得到的上述限定的蝶芪与DABCO的共晶的结构的数据对应于共晶并且如下所示:
本公开的蝶芪与DABCO的共晶的进一步特征在于图9所示的X-射线衍射图。
在另一个实施方式中,共形成体是2,4-二羟基苯甲酸,并且蝶芪与2,4-二羟基苯甲酸的共晶的特征在于具有包含在大约11.3和27.9±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,蝶芪与2,4-二羟基苯甲酸的共晶的特征在于具有包含在13.2、13.3和15.8±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。
更具体而言,本公开的蝶芪与2,4-二羟基苯甲酸的共晶的特征在于在X-射线粉末衍射图中展示在表11中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表11
在另一个实施方式中,共形成体是吲哚,并且蝶芪与吲哚的共晶的特征在于具有包含在大约10.8和18.0±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,蝶芪与吲哚的共晶的特征在于具有包含在16.3、20.6和23.7±0.3°2θ(Cu-Kα辐射, )的进一步特征峰的X-射线粉末衍射图。
更具体而言,本公开的蝶芪与吲哚的共晶的特征在于在X-射线粉末衍射图中展示在表12中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表12
位置[°2θ] | 相对强度[%] |
10.8127 | 100 |
13.3149 | 4.6 |
16.2541 | 31.2 |
17.634 | 14.73 |
18.0393 | 79.59 |
18.7211 | 12.17 |
20.6195 | 48.43 |
21.2805 | 21.97 |
21.6648 | 20.36 |
23.2261 | 37.01 |
23.652 | 85.61 |
23.9805 | 14.12 |
24.5374 | 29.78 |
24.8509 | 6.15 |
25.27 | 4.89 |
25.9634 | 32.14 |
26.6578 | 25.61 |
26.9455 | 7.28 |
27.1738 | 7.76 |
27.3954 | 6.82 |
27.6082 | 9.54 |
28.09 | 4.43 |
29.5453 | 7.3 |
31.5065 | 4.47 |
32.0389 | 5.98 |
33.414 | 4.48 |
本公开的蝶芪与吲哚的共晶的进一步特征在于图10所示的X-射线衍射图。
在另一个实施方式中,共形成体是赖氨酸,并且蝶芪与赖氨酸的共晶的特征在于具有包含在大约15.5和20.0±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪与赖氨酸的共晶的特征在于具有包含在3.5、23.6和25.7±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。
更具体而言,本公开的蝶芪与赖氨酸的共晶的特征在于在X-射线粉末衍射图中展示在表13中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表13
位置[°2θ] | 相对强度[%] |
3.5372 | 58.59 |
7.0925 | 12.94 |
8.263 | 26.72 |
9.3437 | 29.01 |
9.8408 | 16.14 |
10.6194 | 14.64 |
10.9997 | 20.94 |
14.0827 | 15.2 |
15.4576 | 83.06 |
17.732 | 33.82 |
17.9985 | 22.34 |
18.2017 | 17.84 |
18.4432 | 36 |
18.7727 | 36.37 |
18.9555 | 20.78 |
20.0115 | 100 |
20.2595 | 54.06 |
21.0027 | 15.9 |
21.1783 | 27.87 |
21.3545 | 32.72 |
21.6824 | 17.66 |
21.8514 | 19.04 |
22.6687 | 30.38 |
23.5542 | 79.26 |
23.7813 | 22.16 |
24.5422 | 29 |
24.7264 | 25.04 |
24.9756 | 34.11 |
25.2936 | 16.76 |
25.6522 | 56.34 |
25.9003 | 32.12 |
26.2167 | 38.92 |
26.8416 | 17.9 |
27.1881 | 17.92 |
本公开的蝶芪与赖氨酸的共晶的进一步特征在于图11所示的X-射线衍射图。
在另一个实施方式中,共形成体是乳清酸,并且蝶芪与乳清酸的共晶的特征在于具有包含在大约19.3和25.5±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本发明的蝶芪与乳清酸的共晶的特征在于具有包含在10.7、16.1和20.1±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。
更具体而言,本公开的蝶芪与乳清酸的共晶的特征在于在X-射线粉末衍射图中展示在表14中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表14
位置[°2θ] | 相对强度[%] |
3.6034 | 4.21 |
9.6181 | 13.7 |
10.7456 | 13.13 |
12.7087 | 4.66 |
13.1924 | 4.45 |
15.7259 | 4.68 |
16.0899 | 35.29 |
16.7439 | 12.99 |
16.9612 | 23.52 |
17.5256 | 6.42 |
18.2323 | 4.08 |
18.4244 | 18.03 |
19.1095 | 20.12 |
19.3097 | 73.08 |
19.9028 | 12.88 |
20.101 | 31.23 |
20.6062 | 4.72 |
21.1852 | 8.59 |
22.3908 | 11.47 |
25.5314 | 100 |
25.7893 | 13.51 |
27.9472 | 4.56 |
28.2071 | 4.64 |
29.4033 | 2.95 |
31.2678 | 3.36 |
本公开的蝶芪与乳清酸的共晶的进一步特征在于图12所示的X-射线衍射图。
在另一个实施方式中,共形成体是1,10-菲咯啉,并且蝶芪与1,10-菲咯啉的共晶的特征在于具有包含在大约13.7和22.5±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本发明的蝶芪与1,10-菲咯啉的共晶的特征在于具有包含在7.2、19.0和21.4±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。
更具体而言,本公开的蝶芪与1,10-菲咯啉的共晶的特征在于在X-射线粉末衍射图中展示在表15中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表15
本公开的蝶芪与1,10-菲咯啉的共晶的进一步特征在于图13所示的X-射线衍射图。
在另一个实施方式中,共形成体是尿素,并且蝶芪与尿素的共晶的特征在于具有包含在大约14.6和21.5±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本发明的蝶芪与尿素的共晶的特征在于具有包含在15.7、20.1和23.3±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。
更具体而言,本公开的蝶芪与尿素的共晶的特征在于在X-射线粉末衍射图中展示在表16中显示的峰的模式,以度为单位的2θ单位2θ(°)表示(只显示相对强度大于或等于1%的峰)。
表16
位置[°2θ] | 相对强度[%] |
9.1326 | 16.9 |
14.4456 | 24.51 |
14.6247 | 62.75 |
15.6623 | 44.48 |
15.8453 | 11.53 |
16.4798 | 28.51 |
17.5585 | 43.85 |
17.8678 | 15.69 |
18.2891 | 11.94 |
18.714 | 11.63 |
20.081 | 70.24 |
21.1043 | 32.85 |
21.4926 | 100 |
23.2553 | 60.86 |
25.0127 | 10.52 |
25.2546 | 13.54 |
25.8663 | 43.67 |
26.2836 | 8.76 |
28.6094 | 9.42 |
28.8096 | 25.83 |
29.1012 | 14.81 |
29.3163 | 9.05 |
29.7263 | 6.85 |
31.4451 | 6.47 |
32.0163 | 7.5 |
本公开的蝶芪与尿素的共晶的进一步特征在于图14所示的X-射线衍射图。
本文还公开了蝶芪的形式VI,其特征在于具有包含在大约11.8和19.5±0.3°2θ(Cu-Kα辐射,)的特征峰的X-射线粉末衍射图。特别地,本公开的蝶芪的形式VI的特征在于具有包含在15.3、23.4和25.8±0.3°2θ(Cu-Kα辐射,)的进一步特征峰的X-射线粉末衍射图。
更具体而言,蝶芪的形式VI的特征在于在X-射线粉末衍射图中展示在表17中显示的峰的模式,以度为单位的2θ单位2θ(°)表示。
表17:选择的峰的列表(只显示相对强度大于或等于1%的峰):
位置[°2θ] | 相对强度[%] |
4.2415 | 5.57 |
8.5502 | 10.81 |
10.5774 | 13.07 |
11.7962 | 61.38 |
12.679 | 5.74 |
14.4366 | 5.91 |
15.2677 | 49.74 |
15.7733 | 14.73 |
17.1543 | 26.63 |
17.544 | 12.49 |
17.766 | 11.37 |
19.1093 | 20.45 |
19.2979 | 47.49 |
19.4603 | 100 |
20.2995 | 17.98 |
20.4558 | 23.57 |
21.2784 | 31.03 |
22.4938 | 9.61 |
23.3938 | 41.8 |
23.692 | 29.25 |
24.4406 | 9.04 |
25.546 | 46.13 |
25.7874 | 50.63 |
26.4831 | 22.59 |
27.2929 | 10.96 |
27.5235 | 6.7 |
27.7108 | 7.42 |
27.8379 | 7.24 |
29.4516 | 17.27 |
31.4595 | 7.66 |
通过单晶X-射线衍射法得到的上述限定的蝶芪的形式VI的结构的数据对应于蝶芪的多晶型物并且如下所示:
本公开的蝶芪的形式VI的进一步特征在于图15所示的X-射线衍射图。
提供用于制备如上面限定的蝶芪与共形成体的共晶的方法也是本公开的一部分。
在实例中,该方法包含以下步骤:
a)在甲苯作为溶剂存在的情况下混合蝶芪和吡啶甲酸;
b)在室温下搅拌步骤a)的混合物,直到共晶形成;和
c)分离如此获得的共晶。
在另一个实例中,该方法包含以下步骤:
a)将蝶芪和共形成体混合;
b)在室温下搅拌步骤a)的混合物,直到共晶形成;和
c)分离如此获得的共晶。
在特定的实例中,共形成体选自1,4-二甲基哌嗪、2,3,5-三甲基吡嗪和乙二胺。
在另一个实例中,该方法包含以下步骤:
a)将蝶芪和二氯甲烷混合,然后加入茶碱以形成悬浮液;
b)在室温下搅拌步骤a)的混合物,直到共晶形成;
c)分离如此获得的共晶;和
d)任选地,通过加热使共晶去溶剂化。
在另一个实例中,该方法包含以下步骤:
a)将蝶芪和1,4,8,11-四氮杂环十六烷混合,然后加入茶碱以形成悬浮液;
b)在室温下搅拌步骤a)的混合物,直到共晶形成;
c)分离如此获得的共晶。
在另一个实例中,该方法包含以下步骤:
a)将1,4-二氮杂二环[2.2.2]辛烷(DABCO)溶解于二甲苯中然后加入蝶芪;
b)在室温下搅拌步骤a)的混合物,直到共晶形成;
c)分离如此获得的共晶。
蝶芪与2,4-DHBA、吲哚、赖氨酸、乳清酸、菲咯啉和尿素的共晶按照下列解释获得。
如本公开上文限定的蝶芪与共形成体的共晶也可以通过其制备方法限定。相应地,本公开的这一方面可以归结为通过前面的方法可获得的如上文限定的蝶芪与共形成体的共晶,任选地包括上面公开的方法的任何优选的或具体的实施方式以及一些方法特性的可能组合。
本公开的第二方面涉及一种组合物,其包含有效量的如上文限定的蝶芪与共形成体的共晶和一种或多种合适的可接受的赋形剂或载体。本文还公开了一种组合物,其包含有效量的如上文限定的蝶芪的晶形VI和一种或多种合适的可接受的赋形剂或载体,诸如药物组合物、膳食补充剂、化妆品组合物、功能性食品或饮料、预混料、宠物食品或医疗食品组合物。术语“有效量”指的是在其应用之后提供治疗效果的共晶的量。
在实施方式中,本公开的第二方面的组合物是药物组合物,其包含药学有效量的如上文限定的蝶芪与共形成体的共晶和一种或多种合适的可接受的赋形剂或载体。术语“药物组合物”指的是本文公开的蝶芪的共晶与其他化学成分诸如稀释剂或载体的混合物。该药物组合物促进将该共晶施用至有机体。特别地,该药物组合物可配制用于吸入、肌肉内、皮下、口服或局部施用。
在实施方式中,本公开的第二方面的组合物是膳食补充剂,其包含有效量的如上文限定的蝶芪与共形成体的共晶和一种或多种合适的口服可接受的赋形剂或载体。术语“膳食补充剂”指的是含有旨在补充膳食的成分的口服产品。膳食补充剂可以是片剂、胶囊、软胶囊、凝胶帽(gelcaps)、液体、粉末、棒状、饮料、奶昔(shakes)和其他食物产品形式。作为实例,膳食补充剂可能是为了提高运动体能。
术语“可接受的赋形剂或载体”指的是可接受的材料、组合物或媒介物,诸如液体或固体填料、稀释剂、粘合剂、润滑剂、崩解剂、溶剂或包封材料。每个成分必须在与组合物的其他组分兼容的意义上是可接受的。它还必须适合于与人类和动物的组织或器官接触使用,而没有与合理的利益/风险比相称的过度毒性、刺激性、过敏反应、免疫原性或其他问题或并发症。在药物组合物中,该可接受的赋形剂或载体是药学上可接受的赋形剂或载体。
在具体的实施方式中,如上文限定的药物组合物进一步包含一种或多种活性成分,所述活性成分选自抗炎剂、化学治疗剂、免疫调节剂、癌症激素治疗剂、靶向癌症治疗剂、抗糖尿病药、降脂药、抗关节炎药、痴呆症治疗剂、抗动脉粥样硬化药、抗肥胖药、抗骨质疏松药以及老年相关疾病药剂。在具体的实施方式中,如上文限定的膳食补充剂进一步包含一种或多种活性成分,所述活性成分选自L-肉碱、木糖醇、维生素、类胡萝卜素、Ω-3脂肪酸、类黄酮、辅酶Q10、抑制5-LOX的天然产物、哈巴俄苷(玄参或南非钩麻)、铜、锌和锰。所提及的活性成分可以是任何固体形式,包括可能的药学上可接受的其盐、溶剂合物、多晶型物和共晶。
抗炎剂的实例包括非甾体抗炎药(NSAID),诸如水杨酸盐,包括乙酰水杨酸、二氟尼柳、水杨酸及其盐、水杨酰水杨酸;丙酸衍生物,包括布洛芬、右布洛芬、萘普生、非诺洛芬、酮洛芬、右酮洛芬、氟比洛芬、奥沙普嗪、洛索洛芬;醋酸衍生物,包括消炎痛、托美汀、舒林酸、依托度酸、酮咯酸、双氯芬酸、醋氯芬酸、萘丁美酮;烯醇酸(昔康)衍生物,包括吡罗昔康、美洛昔康、替诺昔康、屈恶昔康、氯诺昔康(lornopxicam)、伊索昔康、苯基保泰松;邻氨基苯甲酸衍生物(芬那酯),包括甲芬那酸、甲氯芬那酸、氟芬那酸、托芬那酸;选择性COX-2抑制剂(考昔),包括塞来昔布、罗非考昔、伐地考昔、帕瑞昔布、罗美昔布、依托考昔、非罗考昔;磺胺药(sulfoanilides),包括尼美舒利、氯尼辛、利克飞龙;抗炎剂也包括抗白三烯药物,诸如甲氯芬那酸钠、齐留通;免疫选择性抗炎衍生物(ImSAID),诸如下颌下腺肽-T(SGP-T)、三肽苯丙氨酸-谷氨酰胺-甘氨酸(FEC)及其D-同分异构形式(feG)。
化学治疗剂的实例包括烷基化剂,诸如氮芥、环磷酰胺、美法仑、苯丁酸氮芥、异环磷酰胺、白消安、N-亚硝基-N-甲基脲、卡莫司汀、洛莫司汀、司莫司汀、福莫司汀、链脲佐菌素、达卡巴嗪、米托唑胺、替莫唑胺、噻替哌、丝裂霉素、亚丝醌、顺铂、卡铂、奥沙利铂、甲基苄肼、六甲三聚氰胺;抗代谢物,诸如甲氨蝶呤、培美曲塞、氟尿嘧啶、卡培他滨、阿糖胞苷、吉西他滨、地西他滨、氮杂胞苷、氟达拉滨、奈拉滨、克拉屈滨、氯法拉滨、喷司他丁、硫鸟嘌呤、巯嘌呤;抗微管药,诸如长春新碱、长春花碱、长春瑞滨、长春地辛、长春氟宁、紫杉醇、多西他赛、鬼臼素、依托泊苷、替尼泊苷;拓扑异构酶抑制剂,诸如伊立替康、拓扑替康、依托泊苷、阿霉素、米托蒽醌、替尼泊苷、新生霉素、美巴龙、阿柔比星;细胞毒性抗生素,诸如丝裂霉素C、放线菌素、多柔吡星、道诺红菌素、表柔吡星、阿柔比星、米托蒽醌、博莱霉素;以及诸如先前描述的janus激酶抑制剂。
免疫调节剂的实例包括易普利姆玛、纳武单抗、派姆单抗、阿特珠单抗、阿维单抗、度伐利尤单抗、西米普利单抗、利妥昔单抗、安柯瑞、talimogene、laherparecvec、tisagenlecleucel、axicabtagene、ciloleucel、干扰素α2a、干扰素α2b、人类白细胞干扰素-α、干扰素β1a、干扰素β1b、干扰素聚乙二醇化版本、白介素-2、白介素-7、白介素-12、趋化因子配体-3、趋化因子配体-26、趋化因子配体-7、卡介苗、沙利度胺、来那度胺、泊马度胺、阿普斯特、磷酸胞嘧啶-鸟嘌呤核苷、寡脱氧核苷酸、葡聚糖和西普鲁塞-T疫苗(sipuleucel-T vaccine)。
癌症激素治疗剂的实例包括三苯氧胺、阿那曲唑、来曲唑、依西美坦、雷洛昔芬和氟维司群。
靶向癌症治疗剂的实例包括伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、拉帕替尼、尼洛替尼、硼替佐米、三苯氧胺、托法替尼、克唑替尼、奥巴克拉(obatoclax)、navitoclax、棉子酚、iniparib、奥拉帕利、哌立福辛、阿帕替尼、维莫非尼、达拉非尼、曲美替尼、盐霉素、vintafolide、替西罗莫司(temsitolimus)、依维莫司、维莫非尼、曲美替尼、达拉菲尼、派姆单抗、利妥昔单抗、曲妥珠单抗、阿仑单抗、西妥昔单抗、帕尼单抗、贝伐单抗和易普利姆玛。
抗糖尿病药的实例包括双胍类(即二甲双胍、丁双胍、苯乙双胍),磺酰脲类(即乙酰苯磺酰环己脲、氨磺丁脲、氯磺丙脲、格列波脲、格列齐特、格列美脲、格列吡嗪、格列喹酮、格列派特、格列苯脲、格列噻唑、格列丁唑、格列己脲、格列嘧啶、格列平脲、苯磺丁脲、妥拉磺脲、甲苯磺丁脲、格列环脲),噻唑烷二酮类(即吡格列酮、罗格列酮、曲格列酮),β-肾上腺素能阻滞剂以及其他抗糖尿病药,诸如阿卡波糖、丙酮二酸钙、米格列醇、那格列奈、瑞格列奈和伏格列波糖。
降脂剂的实例包括他汀类,诸如阿托伐他汀、氟伐他汀、洛伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀和辛伐他汀;胆汁酸结合树脂,诸如消胆胺、考来维仑、考来替泊;胆固醇吸收抑制剂,诸如依折麦布;PCSK9抑制剂,诸如阿莫罗布单抗、依洛尤单抗;贝特类,诸如非诺贝特、吉非罗齐;和烟酸。
抗关节炎药的实例包括:止痛药,包括对乙酰氨基酚、曲马多、氧可酮、氢可酮;如先前所描述的非甾体抗炎药(NSAID);含有薄荷醇或辣椒素的抗刺激药膏和软膏;疾病调节抗风湿药物(DMARD),诸如氨甲叶酸和羟化氯喹;生物反应调节剂,诸如包括依那西普、英利昔单抗的肿瘤坏死因子(TNF)抑制剂;白介素-1(IL-1)、白介素-6(IL-6)、Janus激酶、B细胞和T细胞。
痴呆症治疗剂的实例包括抗阿尔茨海默病药,诸如胆碱酯酶抑制剂,诸如多奈哌齐、加兰他敏、卡巴拉汀、他克林、毒扁豆碱、新斯的明、吡啶斯的明、酶抑宁、地美溴铵(demacarium)、咖啡因、迷迭香酸、α-蒎烯、腾喜龙、石杉碱甲A、拉多替吉、恩其明、山莴苣苦素、阿考替胺;以及NMDA受体拮抗剂,诸如美金刚;以及抗帕金森药的实例包括卡比多巴-左旋多巴;多巴胺激动剂,诸如普拉克索、罗匹尼洛、罗替戈汀、阿朴吗啡、麦角腈、培高利特、溴麦角环肽、麦角乙脲、阿立哌唑、苯环己哌啶、喹吡罗、salvinorin A、卡麦角林、西拉多巴、二氢西汀(dihydrexidine)、迪那普索林(dinapsoline)、doxanthrine、表隐亭、吡贝地尔、普拉克索、丙基去甲阿朴吗啡、喹高利特、罗克吲哚、苏马尼洛(sumanirole)、非诺多泮;MAO B抑制剂,诸如异卡波肼、烟肼酰胺、苯乙肼、肼卡巴嗪、反苯环丙胺、二苯美伦、吗氯贝胺、吡吲哚、托洛沙酮、雷沙吉兰、司来吉兰、沙芬酰胺、linezolidbenmoxin、异丙氯肼、异丙烟肼、menabazine、octamonix、苯异丙肼、苯氧丙肼、pivalylbenzhydrazine、沙夫肼、卡罗沙酮、米那卜林、溴法罗明、依普贝胺、亚甲蓝、美曲吲哚、姜黄素、骆驼蓬灵、哈尔明碱、阿米夫胺、贝氟沙通、西莫沙酮、乙磺普隆、sercloremide、四吲哚(tetrindole)、CX157;儿茶酚氧位甲基转移酶(COMT)抑制剂,诸如恩他卡朋、托卡朋、硝苄卡朋(nebicapone)、硝替卡朋、奥匹卡朋;抗胆碱能类,诸如苯托品、苯海索、氯氮平、喹硫平、阿托品、比哌立登、扑尔敏和某些SSRI(诸如西酞普兰)。
抗动脉粥样硬化药的实例包括如先前所描述的降脂药;抗血小板药,诸如不可逆的环氧合酶抑制剂,包括阿司匹林和三氟柳,腺苷二磷酸(ADP)受体抑制剂,包括坎格雷洛、氯吡格雷、普拉格雷、替格瑞洛、噻氯匹定,磷酸二酯酶抑制剂,包括西洛他唑,蛋白酶激活受体-1(PAR-1)拮抗剂,包括沃拉帕沙,糖蛋白IIB/IIIA抑制剂,包括阿昔单抗、依替巴肽、替罗非班,腺苷再摄取抑制剂,包括双嘧达莫,血栓素抑制剂;非选择性β阻滞剂,包括普萘洛尔、布新洛尔、卡替洛尔、卡维地洛尔、拉贝洛尔、纳多洛尔、氧烯洛尔、喷布洛尔、吲哚洛尔、索他洛尔、噻吗洛尔;β-1选择性β阻滞剂,诸如醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、塞利洛尔、美托洛尔、奈比洛尔、艾司洛尔;β-2选择性β阻滞剂,诸如布他沙明,ICI-118,551;β-3选择性β阻滞剂,诸如SR 59230A;血管紧张素转化酶(ACE)抑制剂,诸如依那普利、雷米普利、喹那普利、培哚普利、赖诺普利、贝那普利、咪达普利、群多普利、西拉普利、福辛普利、抗高血压肽、阿法拉新;钙通道阻滞剂诸如;利尿剂,诸如髓袢利尿剂,包括布美他尼、呋喃苯胺酸、利尿酸、托拉塞米(toresamide),噻嗪类,包括苄氟噻嗪、氢氯噻嗪,精氨酸加压素受体2拮抗剂,包括两性霉素B、锂,选择性加压素V2拮抗剂,包括托伐普坦、考尼伐坦,Na-H交换器拮抗剂,包括多巴胺,碳酸酐酶抑制剂,包括乙酰唑胺和多佐胺,保钾利尿剂,包括氨氯吡咪、安体舒通、依普利酮、氨苯蝶啶、坎利酸钾,黄嘌呤,包括咖啡因、茶碱、可可碱以及其他利尿剂,包括葡萄糖、甘露醇、氯化钙和氯化铵。
抗肥胖药的实例包括奥利司他、西替司他、氯卡色林、西布曲明、利莫那班、二甲双胍、艾塞那肽、利拉鲁肽、马鲁肽、糊精、普兰林肽、芬特明/托吡酯、安非他酮/纳曲酮、特索芬辛、右芬氟拉明、芬氟拉明/芬特明。
抗骨质疏松药的实例包括双膦酸盐,诸如阿仑膦酸盐、利塞膦酸盐、伊班膦酸盐、依替膦酸盐、唑来膦酸盐或唑来膦酸;特立帕肽,阿巴洛肽和甲状旁腺激素,雷洛昔芬,降血钙素,狄诺塞麦,雷奈酸锶,以及激素替代疗法,诸如用雌激素。
在具体的实施方式中,如上文限定的化妆品组合物、膳食补充剂、功能性食品或饮料、预混料、动物饲料、宠物食品或医疗食品组合物进一步包含一种或多种营养成分,诸如维生素、类胡萝卜素、Ω-3脂肪酸、类黄酮或类似物。
维生素的实例包括但不限于维生素A(醋酸酯或棕榈酸酯,β-胡萝卜素)、维生素B1(硫胺素(抗神经炎素))(盐酸盐或一硝酸盐)、B2(核黄素)、维生素B6(盐酸吡哆醇)、维生素B12(钴胺素)、维生素B12(氰钴胺)、维生素B12(甲钴胺)、维生素C(抗坏血酸)、烟酸、维生素D2(麦角钙化醇)、维生素D3(胆钙化醇)、维生素E(α生育酚乙酸酯、α生育酚琥珀酸酯、α生育酚、γ-生育酚)、维生素K(叶绿醌、甲萘醌等),和烟酰胺核糖。
类胡萝卜素的实例包括但不限于叶黄素、番茄红素、α-胡萝卜素、β-胡萝卜素、γ-胡萝卜素、β-隐黄质、辣椒黄素、角黄素、玉米黄素和虾青素。
Ω-3脂肪酸的实例包括但不限于α-亚麻酸(ALA)、二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。
类黄酮的实例包括但不限于山酚、杨梅素、槲皮素、芦丁、儿茶素、表儿茶素、ECG、没食子酰儿茶素、EGC、EGCG、花青素、咖啡酸、茶黄素、茶黄素没食子酸盐、木犀草素、大豆苷元、染料木素和黄豆黄素。
抑制5-LOX的天然产物的实例包括但不限于黄芩素、咖啡酸、姜黄素、贯叶金丝桃素和圣约翰草。
本公开的组合物可以根据在本领域状况中众所周知的方法制备。合适的赋形剂和/或载体及它们的量可以由本领域普通技术人员根据正在制备制剂的类型轻而易举地决定。
上述所公开的用于如上文限定的蝶芪的共晶的所有实施方式也适用于本公开的组合物。
本公开的第三方面涉及用作药剂的如上文限定的蝶芪与共形成体的共晶。本文还公开了用作药剂的如上文限定的蝶芪的晶形VI。
特别地,如上文限定的蝶芪与共形成体的共晶或蝶芪的晶形VI用于预防和/或治疗神经性、心血管、代谢、血液学疾病,癌症、动脉粥样硬化、糖尿病、炎症、血脂异常、骨质疏松症和其他之前没有提及的老年相关疾病。
这方面也可以表述为如上文限定的蝶芪与共形成体的共晶用于制备药剂的用途,所述药剂用于预防和/或治疗神经性、心血管、代谢、和血液学疾病,癌症、动脉粥样硬化、糖尿病、炎症、血脂异常、骨质疏松症和其他之前没有提及的老年相关疾病。它还涉及预防和/或治疗哺乳动物的方法,所述哺乳动物遭受或易遭受神经性、心血管、代谢或血液学疾病,癌症、动脉粥样硬化、糖尿病、炎症、血脂异常、骨质疏松症和其他以前未提及的与年龄相关的疾病,其中该方法包括给所述哺乳动物施用有效量的如上文限定的蝶芪与共形成体的共晶或蝶芪的晶形VI和一种或多种可接受的赋形剂或载体。
在整个说明书和权利要求中,“包含(comprise)”一词及该词的变体并非意欲排除其他技术特点、添加剂、成分或步骤。此外,“包含(comprise)”一词包括“由……组成(consisting of)”的情况。在审查说明书后,本公开的其他目的、优点和特征对本领域的普通技术人员而言将变得显而易见,或者可以通过本公开的实践了解本公开的其他目的、优点和特征。下列实施例和附图是通过说明的方式提供的,并且它们并非意欲是对本公开的限制。此外,本公开覆盖本文所描述的具体的和优选的实施方式的所有可能的组合。
实施例
一般考虑
蝶芪、吡啶甲酸、1,4-二甲基哌嗪、2,3,5-三甲基吡嗪、茶碱、1,4,8,11-四氮杂环十六烷、乙二胺、1,4-二氮杂二环[2.2.2]辛烷(DABCO)是商业上可获得的。
粉末X-射线衍射(PXRD)分析是通过将粉末样品夹在3.6微米厚度的聚酯薄膜之间,在240毫米半径的PANalytical X’Pert PRO MPDθ/θ粉末衍射仪中、在用聚焦镜和平面样品传输几何形状会聚光束的配置中、在以下实验条件中进行分析执行的,所述实验条件为:Cu Kα辐射工作功率:45kV和40mA;限定了0.4毫米的光束高度的入射光束狭缝;入射和衍射光束0.02弧度的索勒狭缝;PIXcel探测器:活动长度=3.347°;2θ/θ用每步0.026°2θ的步长和76秒的测量时间从2至40°2θ扫描。
实施例1.-蝶芪:吡啶甲酸(1:1)的共晶的制备
将蝶芪(200mg,0.780mmol)和吡啶甲酸(24mg,0.195mmol)在甲苯(0.8mL)中在室温下过夜混合和搅拌。得到的悬浮液在真空下过滤和干燥。
实施例2.-蝶芪:吡啶甲酸(2:1)的共晶的制备
在60℃下制备蝶芪(5000mg)在甲苯(23.6mL)中的饱和溶液。然后该溶液在25℃下冷却并且加入吡啶甲酸(1635mg)。该悬浮液在25℃下搅拌2h然后在真空下过滤和干燥。
实施例3.-蝶芪:1,4-二甲基哌嗪(2:1)的共晶的制备
将蝶芪(97.6mg,0.381mmol)和1,4-二甲基哌嗪(0.3mL)在室温下过夜混合和搅拌。得到的悬浮液在真空下过滤和干燥。
实施例4.-蝶芪:2,3,5-三甲基吡嗪(2:1)的共晶的制备
将蝶芪(61.3mg,0.239mmol)和2,3,5-三甲基吡嗪(0.05mL)在室温下过夜混合和搅拌。得到的悬浮液在真空下过滤和干燥。
实施例5.-蝶芪:茶碱(1:1)的共晶的制备
将蝶芪(113mg,0.441mmol)在室温下溶于二氯甲烷(0.2mL)中。然后,加入茶碱(20mg,0.111mmol),将得到的悬浮液搅拌过夜并且在真空下过滤和干燥。然后,该固体被放进圆底烧瓶中并且在真空下的硅油浴中加热至80℃,持续1h,直到完全去溶剂化。
实施例6.-蝶芪:茶碱:二氯甲烷(1:1:1)的共晶溶剂合物的制备
将蝶芪(113mg,0.441mmol)在室温下溶于二氯甲烷(0.2mL)中。然后,加入茶碱(20mg,0.111mmol),将得到的悬浮液搅拌过夜并且在真空下过滤和干燥。
实施例7.-蝶芪:1,4,8,11-四氮杂环十六烷共晶(2:1)的共晶的制备
在室温下将蝶芪(50mg,0.195mmol)和1,4,8,11-四氮杂环十六烷(20mg,0.0998mmol)混合并且溶于氯仿(0.3mL)中。然后,将溶液在室温下密闭保存。35天之后,将得到的晶体在真空下过滤和干燥。
实施例8.-蝶芪:乙二胺共晶(2:1)的制备
在50℃下将蝶芪(50mg,0.195mmol)溶于乙二胺(0.05mL)中。然后,混合物在室温下缓慢冷却并且在室温下密闭保存。5天之后,混合物结晶并且在将它在真空下过滤和干燥。
实施例9.-蝶芪:乙二胺:H2O共晶水合物(2:1:2)的制备
将蝶芪(162mg,0.632mmol)和乙二胺(2mL)在室温下过夜混合和搅拌。得到的悬浮液在真空下过滤和干燥。
实施例10.-蝶芪:DABCO共晶(2:1)的制备
在50℃将DABCO(100.0mg,0.892mmol)溶于二甲苯(1.5mL)中。然后该溶液在室温下缓慢冷却,加入蝶芪(197.1mg,0.769mmol)并且过夜搅拌该混合物。得到的悬浮液在真空下过滤和干燥。
实施例11.-蝶芪:2,4-二羟基苯甲酸共晶的制备
在25℃下制备蝶芪(100mg)在IPA(0.25mL)中的饱和溶液。然后加入2,4-二羟基苯甲酸(131.7mg)并且在25℃下过夜搅拌。得到的悬浮液在真空下过滤和干燥。
实施例12.-蝶芪:吲哚共晶的制备
在25℃下将蝶芪(20mg,0.0780mmol)和吲哚(9.2mg,0.078mmol)在苄醇中研磨15分钟。
实施例13.-蝶芪:赖氨酸共晶的制备
在25℃下制备蝶芪(50mg)在ACN(0.1mL)中的饱和溶液。然后加入赖氨酸(34.9mg)并且在25℃下过夜搅拌。得到的悬浮液在真空下过滤和干燥。
实施例14.-蝶芪:乳清酸共晶的制备
在25℃下将蝶芪(20mg,0.0780mmol)和乳清酸(12.2mg,0.078mmol)在DMSO中研磨15分钟。
实施例15.-蝶芪:1,10-菲咯啉共晶[1:1]的制备
在25℃下制备蝶芪(100mg)在MEK(0.2mL)中的饱和溶液。然后加入1,10-菲咯啉(70.3mg)并且该悬浮液在25℃下过夜搅拌。得到的悬浮液在真空下过滤和干燥。
实施例16.-蝶芪:尿素共晶的制备
在25℃下将蝶芪(20mg,0.0780mmol)和尿素(4.7mg,0.078mmol)在苄醇中研磨15分钟。
实施例17.-蝶芪的形式VI的制备
在室温下以30Hz的振动频率研磨蝶芪(20mg,0.0780mmol)和丙酮(1滴)15分钟,形成形式VI。
实施例18.-蝶芪相较于共晶的溶出率
1.FaSSIFv2介质中摩尔消光系数(MEC)的测定
蝶芪的和每一个共形成体的摩尔消光系数是通过使用GlpKaTM滴定仪(英国Sirius Analytical Instruments)的UV-metric滴定法确定的。简要而言,在DMSO中制备样品的10mM储备溶液。将50μL的样品储备溶液和0.25mL的15mM磷酸钾缓冲液加入到10mL的0.15M KCl溶液中,所述溶液又含有17.9mg的FaSSIF v2粉末。在开始滴定之前用0.5M的HCl调整样品溶液的pH为2,然后使用0.5M的KOH直至pH为12完成滴定。通过光纤浸渍探针在每次滴定液添加时记录溶液的紫外吸收光谱(在250至450nm之间)。收集的数据通过RefinamentPro软件进行精炼,并且通过目标因子分析得到pKa值和摩尔消光系数。
2.溶出率实验
-片剂生产:使用手动液压压片机(英国Applied Measurements Ltd)制备3mm直径的片剂。施加的压力为100Kg,持续2分钟。从10到15mg的每个固体形式,称重蝶芪或共晶。总暴露表面积为0.5cm2。
-介质:FaSSIF v2(pH 6.5),以相应量的磷酸(28.4mM)代替马来酸。
-溶解试验是用安装在GlpKaTM滴定仪(英国Sirius Analytical Instruments)中的小规模溶解分析执行的。
-溶解时间和温度:120分钟25℃。
-步骤:15ml的FaSSIF v2被添加到包含片剂的样品小瓶中。之后立即开始光谱采集。通过具有分岔光纤浸探头(Hellma Analytics)的Sirius D-PAS光谱仪每30秒记录在250到450nm之间的光谱。以恒定的速度搅拌介质。
3.紫外-可见光定量
通过使用先前确定的纯蝶芪的摩尔消光系数,应用比尔-朗伯定律,从光谱数据中确定在每个时间点在溶液中蝶芪的浓度。信号是饱和的(A>1.5)或者呈现介质干扰的光谱区域被丢弃。然后,将浓度数据转换为绝对样品数量并且用于生成显示样品数量与时间的关系图。
4.溶出率的测定
溶出率是通过一阶Noyes-Whitney指数方程对该数据的拟合获得的:
[X]t=S(1-e-kd(t-t0))
在这个方程式中,[X]t为在实验时间(min)时溶液中化合物的以克为单位的重量;S为蝶芪的外推溶解度(g);kd为溶解的速率常数(min-1);并且kd是溶出速率常数(min-1)和t0(min)是允许时间偏移量的项。结果是使用S、kd和t0在其中变化的细化过程计算的,以最小化模拟浓度和实测浓度之间的均方根偏差。溶出率(g min-1)由乘积kdS给出(T.Gravestock et al.,2011)。结果在表18中显示。
表18
在表18中列出的固体形式的溶出率曲线之间的对比在图16和图17中显示。
实施例19.-蝶芪相较于蝶芪与吡啶甲酸的共晶的药物动力学
生命期(In-life phase)
动物:雄性Sprague-Dawley大鼠(重量:417.9-458.6 g)
施用:口服(单次剂量)
剂量:20 mg/kg P56(蝶芪,游离碱)
20 mg/kg P56-VIII(蝶芪与吡啶甲酸的共晶;
13.5 mg/kg为蝶芪游离碱)
制剂:悬浮液(0.5%羧甲基纤维素,CMC)
施用体积:10 ml/kg
喂食/禁食状态:禁食(至少在给药前8 h)
取样:六个血液样品/动物(施用后的1、2、4、6、8和24 h)
血浆样品:以K3-EDTA为抗凝剂的血浆样品。
样品立即在-80℃冷冻,直到它们的分析
药物动力学分析是使用Kinetica v5软件通过非房室模型(non-compartmental)药代动力学分析执行的。描述性统计是使用Microsoft Excel电子表格2007(微软公司,美国雷德蒙德)执行的。血浆生物分析是由LC-MS/MS做出的。
低于定量的下限(BLQ)的浓度值设为零,然而缺失的浓度值不被考虑用于统计和药物动力学评估。使用标称取样时间、标称剂量和浓度水平的所有计算以游离碱表示。下面展示的数字数据是计算机生成的。在某些情况下,由于四舍五入的原因,重新计算下文所展示的来自个别数据的派生值可能产生微小的变化。
血浆浓度-时间曲线从0至t下的面积(AUC0-t)是通过使用梯形法则确定的。对于静脉注射的研究,从时间0至第一个数据点的外推AUC不超过20%。终端半衰期是根据下列规则确定的:(a)时间间隔等于至少1.5xt1/2,(b)回归分析(在对数变换比例上的直线)包含来自在终端阶段至少3个不同时间点的数据和尽可能多的数据点(总是包括最后一个可量化浓度但不包括Cmax),和(c)决定系数(r2)为≥0.85。如果这三个条件中至少有一个没有满足,则终端半衰期和依赖于t1/2的参数被列出但标记为不可靠计算。如果外推AUC的百分比超过20%,则个别的AUCinf结果被列出但标记为不可靠计算。标记参数不包括在描述性统计和统计测试过程中。
在单次口服施用后在大鼠血浆中P56的药物动力学在下列表19和20中显示(图18):
表19:在单次口服施用后在大鼠中蝶芪的血浆水平(20mg/kg P56)。
*算数平均数
BLQ值(<5ng/ml)
表20:在单次口服施用后在大鼠中蝶芪的血浆药物动力学参数(20mg/kg P56)
NC:不可量化的
*中位数(最小值-最大值)
Cmax:最大观察浓度
Tmax:Cmax的发生时刻
t1/2:终端消除半衰期或表观终端消除半衰期
AUCinf:曲线从0至∞下的面积
AUC0-t:曲线从0至最后的可量化浓度的时间下的面积。
在单次口服施用后在大鼠血浆中P56-VIII的药物动力学在表21和22中显示(图19)。
表21:在单次口服施用后在大鼠中蝶芪的血浆水平(20mg/kg P56-VIII)。
*算数平均数
BLQ值(<5ng/ml)
表22:在单次口服施用后在大鼠中蝶芪的血浆药物动力学参数((20mg/kg P56-VIII,13.5mg为蝶芪)
*中位数(最小值-最大值)
相对f计算为frel=(AUCinf P56-VIII/Dose)/(AUCinf FI/Dose),Dose以蝶芪(游离碱)表示。
在P56(20mg/kg蝶芪)和P56-VIII(13.5mg/kg蝶芪)的单次口服施用之后在大鼠中蝶芪的血浆浓度-时间曲线的对比在图20中显示。
在20mg/kg P56(蝶芪,游离碱)对雄性SD大鼠的单次口服施用后,在给药之后2h达到血浆Cmax。平均Cmax值为124.8ng/ml,并且直到给药后8h在5只动物中有4只在接近定量限的浓度水平(5ng/ml)下检测到血浆水平。蝶芪的终端半衰期估计为3.7h,然而Cmax和AUCinf的变异性分别为31.5%和41.2%。
在单次口服施用20mg/kg的蝶芪-吡啶甲酸共晶(13.5mg/kg为蝶芪)后,与P56制剂相比观察到口服吸收的变异性更高,给药后的tmax值范围从1至6h。终端半衰期为3.3h,其与发现于P56制剂的半衰期相当。与先前的制剂相比,在Cmax和AUCinf值上有重要的增长,其分别占大约6倍和大约10倍。这些结果证实,吡啶甲酸的全身性生物利用率由于蝶芪作为吡啶甲酸共晶而显著提高,具有9.9的相对生物利用率(frel)。但是,对于该共晶制剂,观察到蝶芪Cmax和AUCinf值的变异性增加了大约20%。
在本研究获得的结果与口服施用之后的在文献中发现的结果相差无几。然而,值得注意的是,当口服用药增加到25mg/kg以上时观察到蝶芪的降低的全身性清除率,并且在喂养状态下发现增加的口服生物利用率。
文献列表
T.gravstock等人,"The“GI dissolution”method:a low volume,in vitroapparatus for assessing the dissolution/precipitation behaviour of an activepharmaceutical ingredient under biorelevant conditions Anal.Methods,2011,vol.3,pp.560-567
Claims (25)
1.一种蝶芪与能够形成氢键相互作用的共形成体的共晶。
2.根据权利要求1所述的共晶,其中所述共形成体是羧酸。
3.根据权利要求2所述的共晶,其中所述羧酸选自吡啶甲酸、2,4-二羟基苯甲酸、乳清酸、吲哚和赖氨酸。
4.根据权利要求3所述的共晶,其中所述羧酸是吡啶甲酸。
21.一种组合物,其包含有效量的如权利要求1至20中任一项限定的蝶芪的共晶和一种或多种合适的可接受的赋形剂或载体。
22.根据权利要求21所述的组合物,其是药物组合物、膳食补充剂、化妆品组合物、功能性食品或饮料、预混料、宠物食品或医疗食品组合物。
23.根据权利要求22所述的组合物,其是进一步包含一种或多种活性成分的药物组合物,所述活性成分选自抗炎剂、化学治疗剂、免疫调节剂、癌症激素治疗剂、靶向癌症治疗剂、抗糖尿病药、降脂药、抗关节炎药、痴呆症治疗剂、抗动脉粥样硬化药、抗肥胖药、抗骨质疏松药和老年相关疾病药剂。
24.根据权利要求22所述的组合物,其是进一步包含一种或多种活性成分的膳食补充剂,所述活性成分选自L-肉碱、木糖醇、维生素、类胡萝卜素、Ω-3脂肪酸、类黄酮、辅酶Q10、抑制5-LOX的天然产物、哈巴俄苷(玄参或南非钩麻)、铜、锌和锰。
25.根据权利要求1至20中任一项限定的蝶芪的共晶,其用作为药剂。
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