CN112843066B - 具良好溶解度的含吡唑并嘧啶衍生物的组合物及其应用 - Google Patents
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Abstract
本发明公开了具有良好溶解度的含有吡唑并嘧啶衍生物的组合物及其应用。其中，所述组合物主要包括吡唑并嘧啶衍生物和表面活性剂。所述组合物的应用涉及其在药物制剂中的应用。本发明提供的组合物中吡唑并嘧啶衍生物的水溶性得到极大的提高，将其用于药物中可有效提高吡唑并嘧啶衍生物的生物利用度。
Description
技术领域
本发明涉及含有吡唑并嘧啶衍生物及其应用，尤其涉及具有良好溶解度的含有吡唑并嘧啶衍生物的组合物及其应用。
背景技术
吡唑并嘧啶衍生物对激酶的具有良好的抑制作用，对治疗肿瘤、自身免疫基本、白血病等有重要意义。如中国专利CN103570723中提供的吡唑并嘧啶衍生物，其通式如式Ⅰ所示。其中，Y为氧或硫；L为取代在母体苯环4位的
R1为-H，R2为-H、-F、-Cl、甲基、甲氧基或-NO2；R3为取代的吡唑基、取代的异噁唑基、取代的喹啉基、取代的吡啶基、
取代基为-H、C1～C4烷基、苯基、-CF3或喹啉；R4为-H、-F、-Cl、-Br、甲基、异丙基、甲氧基、-CF3、-OCF3或吗啡；R5为-H、苯基或环己基；n＝0～3。
上述吡唑并嘧啶衍生物对多种激酶的具有良好的抑制作用，对多种实体瘤以及自身免疫性疾病均具有抑制作用，可以在临床上作为激酶抑制剂、抗自身免疫性疾病药物、抗肿瘤药物、白血病药物等。
但是，在实际应用当中发现吡唑并嘧啶衍生物水中溶解度较低，大概在1mg/L左右，因此作为口服制剂，其生物利用度不高。
发明内容
本发明的目的之一在于提供含有吡唑并嘧啶衍生物的组合物。该组合物主要由吡唑并嘧啶衍生物和表面活性剂组成，使得吡唑并嘧啶衍生物的水溶性得到极大的改善，将其用于药物中可有效提高吡唑并嘧啶衍生物的生物利用度。
本发明的上述目的通过以下技术方案来实现：含有吡唑并嘧啶衍生物的组合物，主要包括吡唑并嘧啶衍生物和表面活性剂。
所述吡唑并嘧啶衍生物和表面活性剂之间的质量比为5～15:2～8。
所述的吡唑并嘧啶衍生物通式如下式Ⅰ所示：
其中，Y为氧或硫；L为取代在母体苯环4位的
R1为-H，R2为-H、-F、-Cl、甲基、甲氧基或-NO2；R3为取代的吡唑基、取代的异噁唑基、取代的喹啉基、取代的吡啶基、
取代基为-H、C1～C4烷基、苯基、-CF3或喹啉；R4为-H、-F、-Cl、-Br、甲基、异丙基、甲氧基、-CF3、-OCF3或吗啡；R5为-H、苯基或环己基；n＝0～3。
作为本发明的一个实施例，所述吡唑并嘧啶衍生物为以下结构式所示。
所述表面活性剂包括非离子型表面活性剂或阴离子表面活性剂。所述非离子型表面活性剂可以是吐温类表面活性剂、泊洛沙姆、聚烃氧40硬脂酸酯、聚氧乙烯蓖麻油35。吐温类表面活性剂包括吐温60、吐温80；泊洛沙姆包括泊洛沙姆188、泊洛沙姆407。所述阴离子表面活性剂为十二烷基硫酸钠。
本发明第二个目的提供上述含有吡唑并嘧啶衍生物的组合物的应用。具体地，提供上述含有吡唑并嘧啶衍生物的组合物在药物制剂中的应用。进一步地提供上述含有吡唑并嘧啶衍生物的组合物在肠溶药物制剂中的应用。
本发明第三个目的提供包含上述含有吡唑并嘧啶衍生物的组合物的口服制剂。
具体地，包含上述含有吡唑并嘧啶衍生物的组合物的口服制剂，包括所述吡唑并嘧啶衍生物的组合物以及药学上可用的辅料。
药学上可用的辅料包括填充剂、崩解剂和润滑剂等中的一种或两种以上的组合。所述填充剂包括微晶纤维素、乳糖和预胶化淀粉的一种或两种以上的组合。所述润滑剂包括硬脂酸镁、氢化蓖麻油等的一种或两种以上的组合。所述崩解剂包括低取代羟丙纤维素、羧甲淀粉钠和交联羧甲基纤维素钠的一种或两种以上的组合。
所述口服制剂包括片剂、胶囊剂、丸剂等。优选地，口服制剂为肠溶制剂，包括肠溶片剂、肠溶胶囊剂、肠溶丸剂等。
作为本发明的一个实施例，所述口服制剂包括如下重量份的组分：吡唑并嘧啶衍生物5～15份、填充剂60～90份、崩解剂1～5份、表面活性剂2～8份、润滑剂0.2～0.7份。
在上述口服制剂的基础上，还包括肠溶型薄膜包衣预混悬剂6～12份，用于将其制成肠溶制剂。
本发明具有以下优点：
1.本发明提供的含有吡唑并嘧啶衍生物的组合物主要由吡唑并嘧啶衍生物和表面活性剂组成，吡唑并嘧啶衍生物的水溶性得到极大的改善，将其用于药物中可有效提高吡唑并嘧啶衍生物的生物利用度。
2.非离子型表面活性剂和阴离子表面活性剂均可提高吡唑并嘧啶衍生物的水溶解度。其中，阴离子表面活性剂中的十二烷基硫酸钠与吡唑并嘧啶衍生物组合，能够极大提高吡唑并嘧啶衍生物的溶解度。
3.本发明提供的吡唑并嘧啶衍生物口服制剂，含有所述组合物，吡唑并嘧啶衍生物溶出度好，生物利用度高。
4.利用本发明提供的含有吡唑并嘧啶衍生物的组合物制备肠溶制剂，进一步解决吡唑并嘧啶衍生物在酸中易降解的问题，使得吡唑并嘧啶衍生物能够通过口服途径进行给药，从而达到理想的生物利用度。
具体实施方式
以式Ⅱ所示的吡唑并嘧啶衍生物为例，将其分别与表1中的表面活性剂混合考察所得组合物的溶解度。
将表1中的表面活性剂分别配成0.5％浓度水溶液，加入过量吡唑并嘧啶衍生物混悬，37℃振摇平衡24h，测试吡唑并嘧啶衍生物的溶解度，结果如表1所示。
表1：含有吡唑并嘧啶衍生物的组合物中的吡唑并嘧啶衍生物的溶解度
| 表面活性剂 | 溶解度(mg/L) | |
| 实施例1 | 吐温60 | 12 |
| 实施例2 | 吐温80 | 15 |
| 实施例3 | 泊洛沙姆188 | 51 |
| 实施例4 | 泊洛沙姆407 | 43 |
| 实施例5 | 十二烷基硫酸钠 | 448 |
| 实施例6 | 聚烃氧40硬脂酸酯 | 36 |
| 实施例7 | 聚氧乙烯蓖麻油35 | 47 |
实施例8～13吡唑并嘧啶衍生物口服制剂
表2：
制备方法：先将吡唑并嘧啶衍生物、乳糖、低取代羟丙纤维素、十二烷基硫酸钠混匀，然后加入硬脂酸镁混合，压制成片芯。肠溶型薄膜包衣预混悬剂配成包衣液喷涂于片芯上，干燥即得肠溶片剂。
实施例8～13所得吡唑并嘧啶衍生物口服制剂的释放量考察
测试方法：按中国药典四部通则0931，浆法，转速50转/分，溶出介质分别为：0.1M盐酸(模拟胃液)和磷酸盐缓冲液(模拟肠液)。
表3：吡唑并嘧啶衍生物肠溶片在0.1M盐酸中释放度
可以看出，实施例8～13所制得的吡唑并嘧啶衍生物口服制剂在0.1M盐酸中基本无释放，2h最高仅0.2％，具有较好的耐酸性，说明制得的吡唑并嘧啶衍生物口服制剂耐酸性较好。
表4：吡唑并嘧啶衍生物口服制剂在磷酸盐缓冲液中释放度：
| 15min | 30min | 45min | 60min | |
| 实施例8 | 39％ | 75％ | 84％ | 92％ |
| 实施例9 | 33％ | 65％ | 73％ | 81％ |
| 实施例10 | 42％ | 71％ | 79％ | 86％ |
| 实施例11 | 41％ | 67％ | 75％ | 83％ |
| 实施例12 | 39％ | 72％ | 70％ | 80％ |
| 实施例13 | 36％ | 76％ | 85％ | 89％ |
从表2可以看出，实施例8～13所制得的吡唑并嘧啶衍生物口服制剂在磷酸盐缓冲液中60min释放量可达80％，溶出迅速。
实施例8～13所得吡唑并嘧啶衍生物口服制剂的小鼠体内药效学研究1.AML异种移植皮下瘤模型的建立与给药
收集处于对数生长期的MV4-11细胞，用不添加血清和抗生素的IMDM培养基重悬细胞，洗涤三次，并计数。以每只小鼠1×107cells/100μL的细胞量注射于NOD-SCID小鼠右侧背部皮下。待肿瘤长至400-500mm3时，将小鼠随机分成8组：模型对照组、实施例8组、实施例9组、实施例10组、实施例11组、实施例12组、实施例13组和奎扎替尼组，每组10只小鼠。分组后于每天相同时间进行口服给药，除模型对照组灌胃给予生理盐水外，其余各组均按6mg/kg剂量灌胃给予相应的药剂，首次给药当天记为0天，连续给药12天，1次/天。每三天用游标卡尺测量肿瘤的长径和短径，并用天平称取小鼠体重，同时观察小鼠毛发色泽、进食情况、精神状态等，以计算药物的抑瘤情况。
肿瘤体积和抑瘤率分别按下述公式进行计算：
肿瘤体积＝0.5×a×b2
其中，a、b分别代表肿瘤长径、短径。
抑瘤率＝[1-(Xn-X0)/(Cn-C0)]×100％
其中，X0、Xn分别为治疗组给药前和给药n天后的平均肿瘤体积，C0、Cn分别为对照组给药前和给药n天后的平均肿瘤体积。
2.结果
如表5所示，模型对照组小鼠给药结束后，平均肿瘤体积由459.33mm3增长1682.44mm3。给药结束后，各给药干预组与模型对照组相比，肿瘤体积均得到了极显著抑制(p<0.01)，阳性药组小鼠肿瘤体积缩小至52.11mm3，其中2只小鼠肿瘤体积完全消失，各实施例中以实施例10药效最为显著，平均肿瘤体积由458.16mm3缩小至2.11mm3，其中7只小鼠肿瘤完全消失。与阳性药组相比，仅有实施例10药效显著优于阳性药(p<0.01)，其余实施例药效均较阳性药差(p<0.01)。
Claims (1)
1. 含有吡唑并嘧啶衍生物的组合物的口服制剂，其特征在于，包括如下重量份的组分：吡唑并嘧啶衍生物 5～15份、乳糖60～90份、低取代羟丙基纤维素1～5份、十二烷基硫酸钠2～8份、硬脂酸镁0.2～0.7份、肠溶型薄膜包衣预混悬剂6~12份；
其中，先将吡唑并嘧啶衍生物、乳糖、低取代羟丙纤维素、十二烷基硫酸钠混匀，然后加入硬脂酸镁混合，压制成片芯；所述肠溶型薄膜包衣预混悬剂配成包衣液喷涂于片芯上，干燥即得肠溶片剂；
所述吡唑并嘧啶衍生物为以下结构式所示：
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