CN104761484A - 一种稳定的不含溶剂化物的阿普司特晶型ii及其制备方法 - Google Patents
一种稳定的不含溶剂化物的阿普司特晶型ii及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种稳定的不含溶剂化物的阿普司特(式I)晶型II及其制备方法、药物组合物和医药用途,也公开了包含晶型II和晶型B的混晶及其制备方法。通过熔点,X-射线粉末衍射图(XRPD)、红外图谱(IR)、差热分析图谱(DSC)以及热失重图谱(TG)确证。和现有文献报道的晶型A,B,C,D,E,F和G相比,本发明的阿普司特晶型II对温度、光照和湿度更为稳定,有利于长期存放,所用结晶溶剂安全并易于除去,所得晶型II颜色为白色或类白色,并可直接用于制剂加工,所用制备方法操作简单,易于重现,适合工业化生产。
Description
技术领域
本发明涉及阿普司特晶型II,具体地说,涉及一种磷酸二酯酶4(PDE4)的小分子抑制剂阿普司特的晶型II、药物组合物及其制备方法,以及使用该晶型治疗各种疾病或病症的用途。本发明属于药物化学领域。
背景技术
众所周知,结晶溶剂不同或结晶方法差异,如结晶温度,冷却速度的不同,搅拌或静置等,会产生不同的晶型,而不同的晶型具有不同的稳定性和溶解性,有时甚至在体内的生物利用度不一样。因而在药物开发中需要寻找一种获得高纯度的且热力学稳定的晶型非常必要,并且该方法易于重现且适合工业大规模的制备。另外,X-射线粉末衍射图(XRPD)、红外图谱(IR)、差热分析图谱(DSC)以及热失重图谱(TG)是确定晶型的一种有效手段。
阿普司特(Apremilast,化合物I,化学名:(+)-2-[1-(3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-乙酰基氨基异吲哚啉-1,3-二酮)是一种磷酸二酯酶4(PDE4)的小分子抑制剂,特定作用于单磷酸环腺苷酸(cAMP),PDE4抑制可导致细胞内cAMP水平升高,能够减轻关节肿胀并改善关节部位的生理机能。结构式如下:
该药物已于2014年3月在美国获准上市,用于治疗银屑病性关节炎。然而,关于该药物的晶型文献报道主要有中国专利CN102702070A,该专利总共报道了阿普司特的固体形式有形式A,B,C,D,E,F和G,共7种固体形式或晶型,根据其报道的有关XRPD图,DSC图以及TGA图及数据,现总结如下,见表一。
其中晶型C、D、E及G为溶剂化物,不适合药用,晶型A、B及F为非溶剂化物或基本不含溶剂,celgene仅对形式B(即晶型B)和形式F(即晶型F)提出了权利要求。该专利同时报道了各种晶型之间的互变现象和结果,而对于每一个晶型的制备方法并无具体实施例,因而难以重现。
表1、CN102702070A报道的阿普司特晶型的数据
专利CN102702070A报道的阿普司特的A,B,C,D,E,F和G这7种固体形式或晶型中,晶型 B被认为是热力学最稳定的晶型,易于储存,适合用于制剂的加工。然而,Celgene的市售商品Otezla的有效期仅为一年,这对商业化的产品来说是极为不利的。因而需要找到一种热力学更稳定的晶型,有利于原料和制剂的长期储存,同时又不影响体内的生物利用度,甚至体内生物利用度优于现有晶型B。
发明内容
本发明提供了一种新颖的稳定的不含溶剂化物的阿普司特晶型II、组合物及用途,本发明还提供简单的适合工业化的制备阿普司特晶型II的方法。另外,本发明也提供了一种阿普司特混晶的制备方法,即制备含阿普司特晶型II和阿普司特晶型B的混晶的方法。
尤为重要的是,本发明的阿普司特晶型II在热力学稳定性方面均要优于现有报道的阿普司特各种晶型,如阿普司特晶型A,B,C,D,E,F或者G。
并且,在某些方面,本发明的阿普司特晶型II在体内的生物利用度优于现有的阿普司特晶型B。
CN201410335852.6涉及制备阿普司特及其中间体的产业化方法,CN201410420960.3涉及一种稳定的不含溶剂化物阿普司特晶型I及其制备方法,均为本申请技术上相关的专利申请,其专利申请全文将引入本申请。
本发明不含溶剂化物的阿普司特晶型II特征如下:
一种式(I)的不含溶剂化物的阿普司特晶型II,
其X-射线粉末衍射图(XRPD)在2θ±0.2具如下典型特征吸收峰:
# | 2-Theta | d(A) | Height | I% | Area | I% | FWHM |
1 | 10.666 | 8.2876 | 568 | 10.9 | 1090 | 2.4 | 0.077 |
2 | 11.290 | 7.8312 | 3576 | 68.5 | 45434 | 100.0 | 0.234 |
3 | 12.573 | 7.0346 | 833 | 15.9 | 2789 | 6.1 | 0.111 |
4 | 13.203 | 6.7001 | 3140 | 60.1 | 31411 | 69.1 | 0.192 |
5 | 13.541 | 6.5338 | 2509 | 48.0 | 22813 | 50.2 | 0.174 |
6 | 13.874 | 6.3775 | 1946 | 37.3 | 17299 | 38.1 | 0.193 |
7 | 14.724 | 6.0114 | 5224 | 100.0 | 42800 | 94.2 | 0.149 |
8 | 16.223 | 5.4592 | 2582 | 49.4 | 21876 | 48.1 | 0.163 |
9 | 17.924 | 4.9448 | 2862 | 54.8 | 24450 | 53.8 | 0.164 |
10 | 18.751 | 4.7285 | 2068 | 39.6 | 15517 | 34.2 | 0.153 |
11 | 20.290 | 4.3731 | 1268 | 24.3 | 7487 | 16.5 | 0.139 |
12 | 20.725 | 4.2822 | 832 | 15.9 | 3836 | 8.4 | 0.143 |
13 | 21.531 | 4.1238 | 1573 | 30.1 | 8335 | 18.3 | 0.132 |
14 | 21.989 | 4.0388 | 1666 | 31.9 | 18358 | 40.4 | 0.277 |
15 | 22.778 | 3.9007 | 1887 | 36.1 | 19298 | 42.5 | 0.244 |
16 | 23.194 | 3.8317 | 1404 | 26.9 | 19738 | 43.4 | 0.375 |
17 | 25.265 | 3.5221 | 1412 | 27.0 | 22193 | 48.8 | 0.382 |
18 | 25.641 | 3.4714 | 1702 | 32.6 | 19926 | 43.9 | 0.268 |
19 | 26.587 | 3.3499 | 1904 | 36.4 | 20529 | 45.2 | 0.244 |
20 | 27.022 | 3.2970 | 3644 | 69.8 | 44458 | 97.9 | 0.234 |
21 | 27.596 | 3.2297 | 962 | 18.4 | 5166 | 11.4 | 0.194 |
22 | 28.226 | 3.1590 | 1147 | 22.0 | 7133 | 15.7 | 0.170 |
23 | 29.112 | 3.0648 | 581 | 11.1 | 973 | 2.1 | 0.103 |
24 | 29.667 | 3.0087 | 463 | 8.9 | 696 | 1.5 | 0.133 |
25 | 30.934 | 2.8884 | 482 | 9.2 | 1767 | 3.9 | 0.207 |
26 | 32.035 | 2.7916 | 486 | 9.3 | 1075 | 2.4 | 0.150 |
27 | 33.023 | 2.7103 | 450 | 8.6 | 1343 | 3.0 | 0.215 |
28 | 33.597 | 2.6653 | 473 | 9.1 | 2192 | 4.8 | 0.261 |
29 | 34.207 | 2.6191 | 509 | 9.7 | 2957 | 6.5 | 0.263 |
30 | 34.915 | 2.5676 | 404 | 7.7 | 1621 | 3.6 | 0.275 |
31 | 36.222 | 2.4779 | 336 | 6.4 | 662 | 1.5 | 0.174 |
32 | 39.625 | 2.2726 | 318 | 6.1 | 343 | 0.8 | 0.087 |
33 | 40.351 | 2.2334 | 311 | 6.0 | 690 | 1.5 | 0.156 |
34 | 41.080 | 2.1954 | 288 | 5.5 | 1946 | 4.3 | 0.583 |
35 | 43.804 | 2.0650 | 372 | 7.1 | 1599 | 3.5 | 0.190 |
其差热分析(DSC)图谱显示在100-180℃之间有一个吸热峰,为150±3℃。
其热失重(TG)图谱显示不含或基本不含结晶水或结晶溶剂。
本发明所述的晶型II的熔点为146-151℃。
另一方面,本发明还提供了制备上述的不含溶剂化物的阿普司特的晶型II的方法,其特征在于所用溶剂是由丙酮和水或者THF和水组成的混合溶剂,优选丙酮和水组成的混合溶剂。
具体地说,上述所述方法,其特征在于包括:
i)将阿普司特或其溶剂化物加热用丙酮或THF溶解,然后冷却至40℃以下,接着
ii)搅拌下缓慢滴加相当于0.5-3倍丙酮或THF量的水,加入或者不加入阿普司特晶型II的晶种,搅拌30~180分钟,然后
iii)继续加入相当于2-6倍丙酮或THF量的水,于10-60℃下搅拌1-24小时,然后
iv)过滤,60℃烘干得到阿普司特晶型II。
其中,作为优选,上述所述的制备方法具体为:
将阿普司特或其溶剂化物加热溶解于2-10倍丙酮(ml/g)中,优选3-5倍丙酮,接着冷却至35℃以下,搅拌下缓慢滴加相当于丙酮量的0.5-3倍量的水,加或者不加晶型II的晶种,然后保温搅拌1-3小时后再加入相当于2-6倍丙酮量的水,加毕,于10-60℃下搅拌1-24小时,过滤,用水洗涤,60℃烘干得到白色固体,即阿普司特晶型II。加水之后搅拌的时间的不同得到的晶型II的粉末X衍射图谱略有不同,但其2θ位于0-20之间主要特征峰无区别,见图2和图5,其差热分析和热失重图谱基本无区别。
本发明人惊奇的发现,用丙酮/水或THF/水结晶析晶时的温度以及初始加入水的量对生成晶型类型有重要影响,温度小于40℃有利于得到晶型II。更为有利的是,在析晶过程中加入晶型II的晶种更有利于快速生成晶型II。初始加水后,搅拌1-3小时以使晶型II充分析出,然后再加入相当于丙酮或THF量的2-6倍量的水,于10-60℃下保温搅拌1-24小时以使晶型II粉末更细腻,然后冷却,过滤,烘干得到晶型II。
另一方面,本发明也提供了第二种制备晶型II的方法,即将粒径适当的阿普司特其他晶型,如晶型A,B,C,D,E,F,G或晶型I混悬于丙酮和水或者THF和水的混合溶剂中,优选混悬于丙酮和水的混合溶剂中,接着于30℃-回流温度下搅拌1-48小时,然后冷却,过滤,烘干得到晶型II。丙酮和水的比例优选1:1—1:4。
另外,用丙酮/水结晶也可以得到一种阿普司特混晶,即阿普司特晶型B与晶型II的混晶, 通过控制丙酮和水的比例、水的滴加速度或加入时间可以使混晶中晶型B与晶型II的比例可以是任意的,也就是说混晶中晶型II所占比例在0-100%之间。所述混晶的X粉末衍射图谱会因两者的比例不一样而差别较大,且其DSC图谱也会在150±3℃及157±3℃显示两个吸收峰,这两个吸收峰的强度会因为两者比例不同而强度各不相同。总之,通过X粉末衍射图谱是否含有晶型II的特征吸收峰即可判断混晶中是否含有晶型II,并通过DSC图谱在150±3℃是否有吸收峰来进一步确认是否含有晶型II。
显然,阿普司特混晶的制备也可通过将粒径适当的阿普司特其他晶型,如晶型A,B,C,D,E,F或G混悬于丙酮和水或者THF和水的混合溶剂中,然后于30℃-回流温度下搅拌不同时间得到。同样地,通过控制搅拌时间,温度也可以得到各种比例的混晶。
本发明所指的阿普司特混晶指含有两种或两种以上的晶型,其中至少一种为阿普司特晶型II,另外一种选自文献报道的其它晶型,如阿普司特晶型A,B,C,D,E,F或G。
进一步地,本发明所述的阿普司特混晶优选是由阿普司特晶型II与阿普司特晶型B组成的混晶,且两者的比例可以是任意的。
有利的是,通过用丙酮/水结晶可以得到白色或类白色的阿普司特晶型II产物,并获得高纯度,达99.8%以上,单杂小于0.1%的阿普司特成品,且产物的光学异构体基本不会发生变化。而用丙酮或丙酮/乙醇结晶的得到的阿普司特晶型B颜色略呈黄色,但最为不利的是每结晶一次产物的R-异构体均会相应增加。如中国专利CN102702070报道由光学纯度为99.2%中间体制备得到的产物的的光学纯度仅为98%,且所得产物烘干过程中易结块,在乙醇用量大的时候易生成颗粒较大的晶体,颗粒大也不易粉碎,难以直接用于制剂的加工。
更为有利的是本发明所得阿普司特晶型II通常呈粉末状,某些情况下粒径D90低于15um。所得产物无需粉碎即可用于制剂加工。
具体地,由本发明制备的阿普司特晶型II经X-射线粉末衍射图谱(XRPD)、红外光谱(IR)(KBr压片)、差热分析图谱(DSC)以及热失重图谱(TGA)确证。热失重图谱(TGA)表明得到的是不含或基本不含溶剂化物的晶型II,其X衍射图谱数据与中国专利CN102702070报道的晶型A,B,C,D,E,F和G完全不同,为一种新型的晶型,测试结果如下:
X-射线粉末衍射图显示晶型II在反射角2θ±0.2有如下显著特征吸收峰。
# | 2-Theta | d(A) | Height | I% | Area | I% | FWHM |
1 | 10.666 | 8.2876 | 568 | 10.9 | 1090 | 2.4 | 0.077 |
2 | 11.290 | 7.8312 | 3576 | 68.5 | 45434 | 100.0 | 0.234 |
3 | 12.573 | 7.0346 | 833 | 15.9 | 2789 | 6.1 | 0.111 |
4 | 13.203 | 6.7001 | 3140 | 60.1 | 31411 | 69.1 | 0.192 |
5 | 13.541 | 6.5338 | 2509 | 48.0 | 22813 | 50.2 | 0.174 |
6 | 13.874 | 6.3775 | 1946 | 37.3 | 17299 | 38.1 | 0.193 |
7 | 14.724 | 6.0114 | 5224 | 100.0 | 42800 | 94.2 | 0.149 |
8 | 16.223 | 5.4592 | 2582 | 49.4 | 21876 | 48.1 | 0.163 |
9 | 17.924 | 4.9448 | 2862 | 54.8 | 24450 | 53.8 | 0.164 |
10 | 18.751 | 4.7285 | 2068 | 39.6 | 15517 | 34.2 | 0.153 |
11 | 20.290 | 4.3731 | 1268 | 24.3 | 7487 | 16.5 | 0.139 |
12 | 20.725 | 4.2822 | 832 | 15.9 | 3836 | 8.4 | 0.143 |
13 | 21.531 | 4.1238 | 1573 | 30.1 | 8335 | 18.3 | 0.132 |
14 | 21.989 | 4.0388 | 1666 | 31.9 | 18358 | 40.4 | 0.277 |
15 | 22.778 | 3.9007 | 1887 | 36.1 | 19298 | 42.5 | 0.244 |
16 | 23.194 | 3.8317 | 1404 | 26.9 | 19738 | 43.4 | 0.375 |
17 | 25.265 | 3.5221 | 1412 | 27.0 | 22193 | 48.8 | 0.382 |
18 | 25.641 | 3.4714 | 1702 | 32.6 | 19926 | 43.9 | 0.268 |
19 | 26.587 | 3.3499 | 1904 | 36.4 | 20529 | 45.2 | 0.244 |
20 | 27.022 | 3.2970 | 3644 | 69.8 | 44458 | 97.9 | 0.234 |
21 | 27.596 | 3.2297 | 962 | 18.4 | 5166 | 11.4 | 0.194 |
22 | 28.226 | 3.1590 | 1147 | 22.0 | 7133 | 15.7 | 0.170 |
23 | 29.112 | 3.0648 | 581 | 11.1 | 973 | 2.1 | 0.103 |
24 | 29.667 | 3.0087 | 463 | 8.9 | 696 | 1.5 | 0.133 |
25 | 30.934 | 2.8884 | 482 | 9.2 | 1767 | 3.9 | 0.207 |
26 | 32.035 | 2.7916 | 486 | 9.3 | 1075 | 2.4 | 0.150 |
27 | 33.023 | 2.7103 | 450 | 8.6 | 1343 | 3.0 | 0.215 |
28 | 33.597 | 2.6653 | 473 | 9.1 | 2192 | 4.8 | 0.261 |
29 | 34.207 | 2.6191 | 509 | 9.7 | 2957 | 6.5 | 0.263 |
30 | 34.915 | 2.5676 | 404 | 7.7 | 1621 | 3.6 | 0.275 |
31 | 36.222 | 2.4779 | 336 | 6.4 | 662 | 1.5 | 0.174 |
32 | 39.625 | 2.2726 | 318 | 6.1 | 343 | 0.8 | 0.087 |
33 | 40.351 | 2.2334 | 311 | 6.0 | 690 | 1.5 | 0.156 |
34 | 41.080 | 2.1954 | 288 | 5.5 | 1946 | 4.3 | 0.583 |
35 | 43.804 | 2.0650 | 372 | 7.1 | 1599 | 3.5 | 0.190 |
阿普司特晶型II的X-射线粉末衍射图在反射角2θ±0.2具以下主要特征吸收峰为11.2,13.2,13.5,13.8,14.7,16.2,17.9,18.7,20.2,20.7,27.0。
尤为重要的是,阿普司特晶型II的X-射线粉末衍射图在反射角2θ±0.2处同时具以下五个特征吸收峰:11.2,13.2,13.5,13.8,14.7。
最后,阿普司特晶型II的X-射线粉末衍射图在反射角2θ±0.2处同时具以下两个特征吸收峰:11.2,14.7。
另一方面,利用丙酮和水所得晶型II在反射角2θ±0.2位于20-30范围的特征吸收峰会因测量误差会产生一定差异,但通过所得产物反射角2θ±0.2处是否有上述主要特征吸收峰即可判断产物是否含有部分或全部晶型II,尤为重要的是晶型II在2θ±0.2位于10-20范围的特征吸收峰基本一致,参见附图2,附图5,附图6,附图8,附图12,附图14,附图16和附图17。其DSC图谱均无太大的差异,在100-180℃显示单一吸收峰,位于150±3℃。
与空白辅料相比,以阿普司特晶型II作活性组分的制剂也会出现上述主要特征吸收峰,如11.2,13.2,13.5,13.8,14.7等,或者11.2,14.7。
阿普司特晶型II的差热分析(DSC)图谱在100-180℃显示单峰,为150±3℃;晶型II的热失重(TG)图谱显示不含或基本不含结晶溶剂或水,250℃左右开始失重并分解,见附图3;晶型II的熔点为146-151℃。
红外(IR)光谱显示晶型II具如下显著特征吸收峰。
3002,2932,1763,1697,1621,1519,1480,1428,1394,1367,1340,1297,1269,1234,1163,1139,1095,1044,1028,971,908,859,826,774,750
下面对晶型I、晶型II和晶型B进行了一系列的比较研究,具体如下:
1、晶型I、晶型II和晶型B特征比较:
阿普司特的晶型I、晶型II和晶型B具体比较见表2。
表2、阿普司特的晶型I、晶型II和晶型B差别比较
2、晶型I、晶型II和晶型B的影响因素试验:
另外,同一批原料分别用丙酮/乙醇结晶得晶型B、丙酮/水结晶得晶型I以及晶型II,比较产物外观颜色,并对三种晶型进行影响因素研究。结果表明,阿普司特晶型I、晶型II、晶型B在高湿、高温条件下均稳定,光照实验表明两者稳定性差不多,具体比较见下表3。
表3、晶型I、晶型II和晶型B的稳定性实验研究结果
3、晶型II和晶型B热力学稳定性研究
通过将阿普司特的晶型II和晶型B悬浮于水中,分别于60和100℃下搅拌24-48小时,然后冷却过滤,烘干测试其X粉末衍射图谱、DSC图、熔点及有关物质等,结果见表4。
表4、阿普司特的晶型II和晶型B热力学稳定性研究
上述实验结果说明阿普司特的晶型B的热力学稳定性不如阿普司特的晶型II,加热后的晶 型B的X衍射图谱和DSC图会显示晶型II的独有特征吸收峰,而晶型II基本无变化。更为有利的是,同样微粉化,晶型II的静电效应弱或几乎没有,而晶型B明显产生更大的静电效应。另外,将晶型B于100℃悬浮于水中搅拌24小时,过滤,烘干后晶型B的静电效应更是极为严重,而晶型II几乎没有静电效应,而静电效应越大对制剂的加工越为不利。100℃搅拌48小时,两者光学异构体基本无明显变化,有关物质N-去乙酰物均有所增加,晶型B的增加幅度略大于晶型II,分别增加0.059%和0.046%,两者差异不太明显。
4、晶型A,B,C,D,E,F,G和晶型II转化研究
另外,通过将粉碎的晶型A,B,C,D,E,F和/或G悬浮于丙酮/水中,于50-80℃搅拌1-48小时,可以得到纯的晶型II。这再次说明晶型II的热力学稳定性优于晶型B。
先前CN102702070A文献报道的晶型A,B,C,D,E,F和G中,晶型B是热力学最为稳定的晶型。我们现有实验表明晶型II比晶型B更为稳定,这更有利于长期储存,更适合作为药用晶型用于制剂的加工。
5、晶型B与晶型II溶解性试验
比较了晶型II与晶型B在丙酮,丁酮,乙醇,甲醇,乙酸乙酯,乙腈,二氯甲烷,四氢呋喃,石油醚,正己烷,水等常见溶剂中的溶解性,实验表明晶型II与晶型B基本无区别。
6、晶型B与晶型II动物体内的药代动力学研究
1)大鼠试验
在SD大鼠体内比较研究粒径基本接近的阿普司特晶型B与晶型II的药代动力学,结果表明本发明的阿普司特晶型II与阿普司特晶型B均显示出较大的雌雄差异,两者的Tmax,Cmax,T1/2基本一致。在雌性大鼠体内,晶型II的暴露量约为晶型B的1.5倍,因此晶型II显示更强的活性。
7、药物组合物
作为本发明内容,本发明还提供一种药物组合物,其包含上述所述的不含溶剂化物的阿普司特的晶型II作为药物活性成分和药学上可接受的载体,其中所述的药物活性成分中阿普司特晶型II的含量为1-100%。
显然,与晶型B的适应症等用途一样,按照本发明制备的不含溶剂化物的阿普司特晶型II同样可用于制备治疗可通过抑制TNF-α产生来改善的疾病或病症的药物中的用途,其中所述的疾病或病症选自银屑病,银屑病关节炎,强直性脊柱炎、类风湿性关节炎、特应性皮炎、白塞病口腔溃疡、慢性皮肤肉样瘤,巨细胞动脉炎、帕金森病、结节性痒疹,扁平苔藓、复 杂性口腔病、狼疮、肝炎、葡萄膜炎、干燥综合征、抑郁、间质性膀胱炎、外阴痛、***炎、骨关节炎、弥漫性大B细胞瘤、多肌炎、皮肌炎、包涵体肌炎、侵蚀性骨关节炎、子宫内膜异位、神经病根、和坏疽性脓皮病或慢性阻塞性肺病。
另一方面,按照本发明制备的不含溶剂化物的阿普司特的晶型II也同样可用于制备治疗可通过抑制PDE4来改善的疾病或病症的药物中的用途,其中所述的疾病或病症选自:HIV、肝炎、成人呼吸窘迫综合征、骨吸收疾病、慢性阻塞性肺病、慢性肺部炎性疾病、皮炎、炎症性皮肤疾病、特应性皮炎、囊性纤维化、感染性休克、败血症、内毒性休克、血流动力学休克、败血症综合征、缺血后再灌注损伤、脑膜炎、银屑病,纤维化疾病、银屑病关节炎,恶病质、移植排斥、移植物抗宿主病、自体免疫性疾病、类风湿性脊椎炎、关节炎病症、强直性脊柱炎、类风湿性关节炎、骨关节炎、骨质疏松症、节段性肠炎、溃疡性结肠炎、炎性肠病、多发性硬化、全身性红斑狼疮、麻风病中的麻风结节性红斑、辐射损伤和高氧肺泡损伤。
再者,按照本发明制备的不含溶剂化物的阿普司特的晶型II还可用于制备治疗癌症的药物中的用途,其中所述的癌症选自多发性骨髓瘤、恶性黑色素瘤、恶性胶质瘤、白血病和实体瘤。
显然,不含溶剂化物的阿普司特晶型II可作为用于上述疾病或症状的治疗的活性成分,合适的药物剂型包括片剂,胶囊,分散片,口崩片等,辅料选自但不限于乳糖,甘露醇,交联聚维酮,微粉硅胶,硬脂酸镁,微晶纤维素,羧甲基纤维素钠,羟丙基纤维素,交联羧甲基纤维素钠等。优选乳糖,微晶纤维素,交联羧甲基纤维素钠,微粉硅胶,硬脂酸镁等辅料。
本发明所提到的阿普司特可参考现有文献如US6020358及US6962940报道的方法轻易制备。
附图说明
本申请中包括的附图是构成说明书的一部分,附图与说明书和权利要求项一起用于说明本发明的实质内容,用于更好地理解本发明。
图1:阿普司特晶型B的X-射线粉末衍射图(XRPD)
图2:阿普司特晶型II的X-射线粉末衍射图(XRPD),加水后搅拌4h
图3:阿普司特晶型II的热失重(TG)图谱和差热分析(DSC)图谱,加水后搅拌23h
图4:阿普司特晶型II的红外图谱(IR),加水后搅拌23h
图5:阿普司特晶型II的X-射线粉末衍射图(XRPD),加水后搅拌23h
图6:阿普司特晶型II的X-射线粉末衍射图(XRPD),60℃搅拌48h
图7:阿普司特晶型B的X-射线粉末衍射图(XRPD),60℃搅拌48h
图8:阿普司特晶型II的X-射线粉末衍射图(XRPD),100℃搅拌24h
图9:阿普司特晶型B的X-射线粉末衍射图(XRPD),100℃搅拌24h
图10:阿普司特晶型II的DSC图,100℃搅拌24h
图11:阿普司特晶型B的DSC图,100℃搅拌24h
图12:阿普司特晶型B悬浮于丙酮/水,70℃搅拌36h,所得产物的X-射线粉末衍射图(XRPD)
图13:阿普司特晶型B悬浮于丙酮/水,70℃搅拌36h,所得产物的差热分析(DSC)图谱
图14:阿普司特晶型D悬浮于丙酮/水,70℃搅拌10h,所得产物的X-射线粉末衍射图(XRPD)
图15:阿普司特晶型B悬浮于丙酮/水,70℃搅拌36h,所得产物的差热分析(DSC)图谱
图16:阿普司特晶型II的X-射线粉末衍射图(XRPD)
图17:阿普司特晶型II的X-射线粉末衍射图(XRPD)
图18:阿普司特混晶(即晶型II和晶型B)的X-射线粉末衍射图(XRPD),两者比例大致1:1
图19:大鼠灌胃10mg/kg APST-B混悬溶液后血浆浓度-时间曲线
图20:大鼠灌胃10mg/kg APST-II混悬溶液后血浆浓度-时间曲线
图21:雄性大鼠分别灌胃10mg/kg APST-B和APST-II混悬溶液后血浆浓度-时间曲线
图22:雌性大鼠分别灌胃10mg/kg APST-B和APST-II混悬溶液后血浆浓度-时间曲线
测试仪器及测试方法:
X射线粉末衍射(XRPD):
仪器型号:Bruker D8 ADVANCE粉末X射线衍射仪
实验条件:光源:CuKα40kV 40mA;发散狭缝:1mm;索拉狭缝:0.4mm;扫描方式:连续扫描;扫描范围:3°~45°;采样间隔:0.02°;扫描速度:8°/min。
红外:
仪器型号:NICOLET 670-FTIR实验条件:KBr压片
DSC parmeters:
仪器型号:NETZSCH DSC 204F 1
坩埚类型:铝坩埚(针刺穿孔)
吹扫气:高纯氮,20mL/min
保护气:高纯氮,60mL/min
升温速度:10℃/min
TG parmeters
仪器型号:NETZSCH TG 209 F1
坩埚类型:氧化铝坩埚
吹扫气:高纯氮,20mL/min
保护气:高纯氮,10mL/min
升温速度:10℃/min
熔点:RD-1熔点测试仪,天津旭阳仪器设备有限公司。
粒径测试:Mastersizer 2000粒径测试仪,马尔文仪器有限公司
具体实施方式
下面结合实施例对本发明作进一步阐述,但这些实施例不对本发明构成任何限制,任何温度,溶剂比例的调整都在本发明保护范围内。
实施例1:阿普司特晶型II
将阿普司特(10.0g),丙酮35ml加入三口烧瓶,加热溶解,然后冷却至35℃以下,缓慢滴加0.5-3.0倍量纯化水,加入少量晶型II作为晶种,搅拌1小时至产物析出后,继续加5倍量纯化水(175ml),于15-20℃继续搅拌过夜,共约24小时,过滤,水洗,60℃烘干,得到阿普司特晶型II约9.32克,mp:147.2-149.8℃。
实施例2:阿普司特晶型II
将阿普司特(400.0g),丙酮1200ml加入三口烧瓶,加热溶解,缓慢滴加0.5-2.0倍量纯化水,加入少量晶型II作为晶种,搅拌1小时至产物析出后,继续加2倍量纯化水(2.4L),于10-60℃继续搅拌过夜,共约18小时,过滤,水洗,60℃烘干,得到阿普司特晶型II约392.3克,mp:147.2-150.2℃。
实施例3:阿普司特晶型B
将阿普司特(10.0g),加入丙酮(30ml)加入三口烧瓶中,加热溶解,然后冷却至30℃下缓慢加入10ml纯化水,冷却下搅拌至产物析出,搅拌2小时,继续缓慢滴加水(100ml),继续保温搅拌过夜,约24小时,过滤,水洗,60℃烘干,得到阿普司特晶型B约9.45克,mp:156.2-157.8℃。
实施例4:
主药过200目筛,填充剂、崩解剂过80目筛,称取处方量的填充剂、崩解剂混合均匀,然后将处方量的主药与其按照等量递加法混合均匀,加入处方量的助流剂和润滑剂,混合均匀后,压片即得。
实施例5:
主药过200目筛,填充剂、崩解剂过80目筛,称取处方量的填充剂、崩解剂混合均匀,然后将处方量的主药与其按照等量递加法混合均匀,加入处方量的助流剂和润滑剂,混合均匀后,压片即得。
实施例6:晶型II与晶型B的热稳定性研究
分别将阿普司特的晶型II和晶型B悬浮于水,于60℃下搅拌48h,或100℃下搅拌24h,每隔一段时间取样过滤,烘干测试熔点变化情况,并在24h,48h取样过滤干燥测试X粉末衍射图谱,DSC图,熔点,静电效应及有关物质变化情况。
实施例7:阿普司特晶型B的转化研究
将阿普司特晶型B(5.0g)悬浮于丙酮/水中,加热至50-80℃,保温搅拌36小时,然后搅拌下冷却,过滤,60℃烘干,得到阿普司特晶型II约4.88克,mp:148.3-150.3℃。
X衍射图普和DSC图谱显示完全转化为晶型II。
实施例8:阿普司特晶型D的转化研究
将阿普司特晶型D(5.0g)悬浮于丙酮/水中,加热至50-80℃,保温搅拌8小时,然后搅拌下冷却,过滤,60℃烘干,得到阿普司特晶型II约4.90克,mp:148.3-150.5℃。
X衍射图普和DSC图谱显示完全转化为晶型II。
实施例9:SD大鼠体内阿普司特晶型B与晶型II的药代动力学比较研究
1、晶型的粒径控制
通过微粉化控制两种晶型的粒径如下:
D0.1 | D0.5 | D0.9 | |
阿普司特晶型B(APST-B) | 1.052um | 6.792um | 55.073um |
阿普司特晶型II(APST-II) | 1.395um | 8.722um | 58.942um |
2、方法:
SD大鼠12只,雌雄各半,体重200-220g,随机分为2组,每组6只且雌雄各半,编为A和B组。
参照FDA文献中给药途径和剂量,选择灌胃给药考察两种晶型在大鼠体内药代行为,两种晶型给药剂量均为10mg/kg(溶剂为1%羧甲基纤维素)。试验前禁食12h,给药后4h后提供食物,整个实验过程不禁水。
给药后10,30min,1,2,4,6,8,10,12和24h经眼底静脉丛取血约0.3ml,采集好的血液放置于冰上,经8000rpm离心5min后,分离血浆,放入–20℃冰箱中冷冻暂存。
采用LC-MS/MS法测定血浆中APST的浓度,测定血浆中APST的线性范围为2~1000ng/ml,线性良好。
3、实验结果
大鼠分别灌胃给予10mg/kg APST-B和APST-II混悬溶液后,每组动物的血浆浓度-时间曲线如错误!未找到引用源。9至22所示。
4、结果分析:
大鼠分别灌胃给予10mg/kg APST-B和APST-II混悬溶液后,大鼠体内APST的主要药动学参数:达峰时间Tmax分别为1-6h(中位数为2.5h)和1-6h(中位数为3h),达峰浓度Cmax分别为523.05±417.46和506.90±451.89ng/ml,血浆浓度-时间曲线下面积AUC0-t分别 为3766.48±3617.82和5533.11±5613.02ng·h/ml,10mg/kg APST-B的大鼠体内暴露量约为APST-II的68.07%,两组差距较大,由于暴露量雌雄差异很大,两组的标准偏差较大导致两组之间的暴露量差异无统计学意义。因此进一步对雄性与雌雄大鼠的体内药动学进行比较分析。
大鼠灌胃给予10mg/kg APST-B和APST-II混悬溶液后,雄性大鼠体内APST的主要药动学参数:达峰时间Tmax分别为1h(中位数为1h)和1-2h(中位数为1h),达峰浓度Cmax分别为142.4±13.96和107.63±16.05ng/ml,血浆浓度-时间曲线下面积AUC0-t分别为530.44±70.05和445.59±81.25ng·h/ml,10mg/kg APST-B在雄性大鼠体内Cmax和AUC0-t分别为APST-II的132.3%和119.0%,结果显示在雄性大鼠体内APST-B的吸收程度高于APST-II,但该差异无统计学意义。
大鼠灌胃给予10mg/kg APST-B和APST-II混悬溶液后,雌性大鼠体内APST的主要药动学参数:达峰时间Tmax分别为2-6h(中位数为4h)和4-6h(中位数为6h),达峰浓度Cmax分别为903.7±28.47和906.17±178.89ng/ml,血浆浓度-时间曲线下面积AUC0-t分别为7002.52±1140.54和10620.62±1053.56ng·h/ml,10mg/kg APST-B在雌性大鼠体内AUC0-t为APST-II的65.9%,结果显示在雌性大鼠体内APST-B的吸收程度低于APST-II,且该差异有统计学意义(P<0.05)。
Claims (12)
1.一种式(I)所示阿普司特的晶型II,
其特征在于:
i)其差热分析(DSC)显示在100-180℃之间只有一个吸热峰,为150±3℃;
ii)热失重(TG)显示不含结晶溶剂;
iii)熔点为146-151℃。
2.根据权利要求1所述的阿普司特晶型II,其特征在于其X-射线粉末衍射图(XRPD)在2θ±0.2同时具以下两个特征吸收峰:11.2,14.7;优选其X-射线粉末衍射图(XRPD)在2θ±0.2同时具以下五个特征吸收峰:11.2,13.2,13.5,13.8,14.7;更优选其X-射线粉末衍射图(XRPD)在2θ±0.2同时具以下特征吸收峰:11.2,13.2,13.5,13.8,14.7,16.2,17.9,18.7,20.2,20.7,27.0。
3.根据权利要求1-2所述的阿普司特晶型II,其特征在于其X-射线粉末衍射图(XRPD)在2θ±0.2具如下特征吸收峰:
4.根据权利要求1所述的阿普司特晶型II,其特征在于其具有如附图2,附图5,附图6,附图8,附图12,附图14,附图16或附图17所示的X-射线粉末衍射图(XRPD)。
5.一种制备权利要求1-4所述的阿普司特晶型II的方法,其特征在于所用溶剂是由丙酮和水或者THF和水组成的混合溶剂,优选丙酮和水组成的混合溶剂。
6.根据权利要求5所述的方法,其特征在于:
i)将阿普司特或其溶剂化物加热用丙酮或THF溶解,然后冷却至40℃以下,接着
ii)搅拌下缓慢滴加相当于0.5-3倍丙酮或THF量的水,加入或者不加入晶型II的晶种,继续搅拌30~180分钟,然后
iii)继续加入相当于2-6倍丙酮或THF量的水,于10-60℃下搅拌1-24小时,然后
iv)过滤,烘干得到阿普司特晶型II。
7.根据权利要求5所述的方法,其特征在于将阿普司特其他晶型混悬于丙酮/水或者THF/水的混合溶剂中,加热搅拌1-72小时,然后冷却过滤,烘干得到阿普司特晶型II。
8.一种药物组合物,其含有权利要求1-4所述的阿普司特晶型II作为药物活性成分和药学上可接受的载体。
9.根据权利要求8所述的药物组合物,其特征在于所述的药物活性成分中阿普司特晶型II的含量为1-100%。
10.权利要求1-4所述的阿普司特晶型II在制备用于治疗可通过抑制TNF-α产生来改善的疾病或病症的药物中的用途,其中所述的疾病或病症选自银屑病,银屑病关节炎,强直性脊柱炎、类风湿性关节炎、特应性皮炎、白塞病患者口腔溃疡、慢性皮肤肉样瘤,巨细胞动脉炎、帕金森病、结节性痒疹,扁平苔藓、复杂性口腔病、狼疮、肝炎、葡萄膜炎、干燥综合征、抑郁、间质性膀胱炎、外阴痛、***炎、骨关节炎、弥漫性大B细胞瘤、多肌炎、皮肌炎、包涵体肌炎、侵蚀性骨关节炎、子宫内膜异位、神经病根、和坏疽性脓皮病或慢性阻塞性肺病。
11.权利要求1-4所述的阿普司特晶型II在制备用于治疗可通过抑制PDE4来改善的疾病或病症的药物中的用途,其中所述的疾病或病症选自:HIV、肝炎、成人呼吸窘迫综合征、骨吸收疾病、慢性阻塞性肺病、慢性肺部炎性疾病、皮炎、炎症性皮肤疾病、特应性皮炎、囊性纤维化、感染性休克、败血症、内毒性休克、血流动力学休克、败血症综合征、缺血后再灌注损伤、脑膜炎、银屑病,纤维化疾病、银屑病关节炎,恶病质、移植排斥、移植物抗宿主病、自体免疫性疾病、类风湿性脊椎炎、关节炎病症、强直性脊柱炎、类风湿性关节炎、骨关节炎、骨质疏松症、节段性肠炎、溃疡性结肠炎、炎性肠病、多发性硬化、全身性红斑狼疮、麻风病中的麻风结节性红斑、辐射损伤和高氧肺泡损伤。
12.权利要求1-4所述的阿普司特晶型II在制备用于治疗癌症的药物中的用途,其中所述的癌症选自多发性骨髓瘤、恶性黑色素瘤、恶性胶质瘤、白血病和实体瘤。
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CN106008315A (zh) * | 2016-06-16 | 2016-10-12 | 珠海联邦制药股份有限公司 | 一种阿普斯特晶型s及其制备方法 |
CN108440381A (zh) * | 2018-03-15 | 2018-08-24 | 威海迪素制药有限公司 | 一种阿普斯特新晶型h及其制备方法 |
WO2021000934A1 (zh) * | 2019-07-04 | 2021-01-07 | 南京明德新药研发有限公司 | 一种苯并咪唑-2-酮类化合物的晶型、溶剂化物、溶剂化物的晶型及它们的制备方法 |
CN114072382A (zh) * | 2019-07-04 | 2022-02-18 | 南京明德新药研发有限公司 | 一种苯并咪唑-2-酮类化合物的晶型、溶剂化物、溶剂化物的晶型及它们的制备方法 |
CN114072382B (zh) * | 2019-07-04 | 2023-05-26 | 南京明德新药研发有限公司 | 一种苯并咪唑-2-酮类化合物的晶型、溶剂化物、溶剂化物的晶型及它们的制备方法 |
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EP3269711B1 (en) | 2020-06-24 |
US9850205B2 (en) | 2017-12-26 |
JP2018501317A (ja) | 2018-01-18 |
CN104761484B (zh) | 2018-03-27 |
US20170298018A1 (en) | 2017-10-19 |
AU2015385707B2 (en) | 2018-05-31 |
WO2016141503A1 (zh) | 2016-09-15 |
JP6457658B2 (ja) | 2019-01-23 |
AU2015385707A1 (en) | 2017-08-24 |
RU2673889C1 (ru) | 2018-12-03 |
EP3269711A1 (en) | 2018-01-17 |
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