CN106794183B - 含有细胞周期蛋白抑制剂的药物制剂及其制备方法 - Google Patents
含有细胞周期蛋白抑制剂的药物制剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种以6‑乙酰基‑8‑环戊基‑5‑甲基‑2‑(5‑哌嗪‑1‑基‑吡啶‑2‑基氨基)‑8H‑吡啶并[2,3‑d]嘧啶‑7‑酮或其盐为活性成分的药物制剂,所述盐包括盐酸盐、羟乙基磺酸盐,所述药物剂型包括片剂、胶囊剂。所述剂型均具有良好的稳定性以及优异的溶出行为。
Description
技术领域
本发明属于药物制剂领域,具体涉及用于细胞周期蛋白抑制剂的药物制剂及其制备方法。
背景技术
细胞周期蛋白依赖性激酶(CDK)共有13个成员,都属丝氨酸/苏氨酸蛋白激酶家族,依赖与细胞周期蛋白(cyclin)的结合,促进细胞周期时相转变,启动DNA合成以及调控细胞转录等关键功能。
CDKs在所有细胞包括健康和肿瘤细胞的增殖与死亡中所起的关键作用,广谱的CDK抑制剂,尤其是针对未经过基因筛选的患者很难展现较高的治疗窗口。剂量大了毒性太高,而小了又没有药效。所以选择性地抑制部分CDK就变得格外重要。当然因为大部分CDK亚型具有相对近似的化学结构,如何提高CDK抑制剂的选择性又是另外一个挑战。
CDK4/6作为抗肿瘤靶点的优势在于:①CDK4/6的抑制剂不表现出“泛-CDK抑制剂”的细胞毒性,如骨髓抑制和肠道反应;②细胞cyclin D水平升高或者P161NK4a失活,能够增加细胞对药物的敏感性,肿瘤细胞相对于正常细胞存在上述现象,所以一定程度上增加了药物的靶向性。
式I化合物是一种靶向性CDK4/6抑制剂,能够选择性抑制细胞周期蛋白依赖性激酶4和6(CDK4/6),恢复细胞周期控制,阻断肿瘤细胞增殖。其作用于MDA-MB-435乳腺癌细胞,能有效降低Rb在Ser780和Ser795位点磷酸化,IC50分别为66nM和63nM。
乳腺癌是女性最常见的恶性肿瘤之一,具有发病率高,颇具侵袭性,但病程进展缓慢。据国际癌症研究中心公布的数据显示,2012年全球约有167万新发病例,占所有癌症的25%。美国国家癌症中心流行病学调查和最终结果(SEER)统计,2013年美国估计性乳腺癌发病率为123.8/10万人,2005~2009年亚裔人群女性乳腺癌发病率为94.5/10万人;我国无官方数据,据估计我国有60%~70%的乳腺癌患者雌激素或孕激素受体呈阳性,推算我国雌激素受体阳性乳腺癌2005~2009年发病率为56.7~66.15/10万人。Thomson预测,本品上市后销售额将大幅上升,2019年销售额将达20.27亿美元。
发明内容
本发明的目的在于提供一种含有6-乙酰基-8-环戊基-5-甲基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-8H-吡啶并[2,3-d]嘧啶-7-酮及盐的药物制剂及其制备方法。
本发明的技术方案是通过下列方式实现的:
药物组合物,其包括式I化合物或其盐,以及药学上可接受的赋形剂作为载体,所述盐型包括盐酸盐、羟乙基磺酸盐。
优选的,式I化合物占所述组合物重量的10%~80%,优选15~60%,进一步优选20~40%。
优选的,所述组合物包括式I化合物或其盐及赋形剂,所述赋形剂包括崩解剂、稀释剂、粘合剂、表面活性剂、润滑剂中一种或多种,优选的,各组分重量比如下:
任选的,所述组合物中还可以包含矫味剂、着色剂或包衣材料,最优选的,上述各组分的重量百分比之和为100%。
进一步优选的,所述的药物制剂,各组分的重量百分比如下:
任选的,所述组合物中还可以包含矫味剂、着色剂或包衣材料,最优选的,上述各组分的重量百分比之和为100%。
更优选的,所述的药物制剂,各组分的重量百分比如下:
优选的,所述稀释剂选自淀粉、糖粉、糊精、乳糖、预胶化淀粉、磷酸氢钙、硫酸钙、碳酸钙、甘露醇、山梨醇、微晶纤维素的至少一种,进一步优选的,所述稀释剂选自乳糖、微晶纤维素、淀粉或甘露醇中的至少一种,更优选的,所述稀释剂选自乳糖和微晶纤维素。
优选的,所述乳糖和微晶纤维素的重量比为1∶2~2∶1,优选1∶1。
优选的,所述粘合剂选自淀粉浆、羟丙甲纤维素、羟丙纤维素、聚维酮、甲基纤维素、羧甲基纤维素钠、聚乙二醇的至少一种,更优选的,所述稀释剂选自羟丙基纤维素或聚维酮的至少一种。
优选的,所述崩解剂选自交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、干淀粉、低取代羟丙基纤维素的至少一种,更优选的,所述崩解剂选自交联聚维酮、羧甲淀粉钠、交联羧甲基纤维素钠中的至少一种。
优选的,所述润滑剂选自硬脂酸镁、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯、胶态二氧化硅、滑石粉、二氧化硅中的至少一种,更优选的,所述润滑剂选自硬脂酸、山嵛酸甘油酯、胶态二氧化硅中的至少一种。
优选的,所述表面活性剂为十二烷基硫酸钠、吐温80和泊洛沙姆,更优选的,所述表面活性剂为十二烷基硫酸钠。
另一方面,本发明提供了制备式(I)化合物或其盐的制备方法,所述制备工艺包括湿法制粒、干法制粒、直接混合等工艺,所述剂型包括片剂、胶囊。
优选的,所述组合物是通过湿法制粒完成的,所述方法包括以下步骤:
(1)在湿法混合制粒机中预混合式I化合物或其盐与部分润滑剂,获得预混合物;
(2)添加制粒液体,优选的,所述制粒液体为水,将步骤(1)的预混合物制粒;
(3)在流化床干燥器或干燥箱中干燥步骤(2)的颗粒;
(4)任选的,干燥筛分步骤(3)的干燥的颗粒;
(5)混合步骤(4)的干燥的颗粒与剩余赋形剂,获得最终混合物;
(6)任选的,通过合适的胶囊灌装机灌装上述步骤(5)的混合物,制备胶囊剂;
(7)任选的,通过在合适的压片机上压制上述步骤(5)的混合物,将其压片,从而制得片芯;
(8)任选的,用膜包衣对步骤(7)的片芯进行薄膜包衣。
优选的,所述组合物是通过干法制粒完成的,所述方法包括以下步骤:
(1)在料斗混合机中混合所述式I化合物或其盐和包括粘合剂在内的大多数赋形剂,获得预混合物;
(2)在合适的滚筒压制机中压实步骤(1)的混合物;
(3)通过合适的研磨或筛分步骤,将步骤(2)期间获得的带状物碎成颗粒;
(4)任选的,在混合机中混合步骤(3)和剩余赋形剂,获得最终混合物;
(5)任选的,通过合适的胶囊灌装机灌装上述步骤(4)的混合物,制备胶囊剂;
(6)任选的,通过在合适的压片机上压制上述步骤(4)的混合物,将其压片,从而制得片芯;
(7)任选的,用膜包衣对步骤(6)的片芯进行薄膜包衣。
本发明提供了一种稳定的,适合医药应用的6-乙酰基-8-环戊基-5-甲基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-8H-吡啶并[2,3-d]嘧啶-7-酮及盐的药物制剂,该药物制剂具有优异的溶出行为和好的稳定性,符合临床应用需求,能够使活性成分实现良好的体内生物利用度。
具体实施方式
下面将结合具体实施例,对本发明的实施方案进行详细描述。下面实施例仅用于说明本发明,而不应视为限定本发明的范围。
实施例1
1.1单位处方组成
注:“/”代表未添加。
1.2制备
将上述1000片处方量式I化合物和除硬脂酸镁外其他赋形剂投入料斗混合机混匀,加润湿剂润湿制粒,45℃流化床干燥10min,1.0mm筛整粒,加硬脂酸镁总混10min,中控含量,灌装胶囊。或压制成片。
1.3溶出数据
各处方在0.1mol/L HCl中溶出度,详见下表。
处方1 | 处方2 | 处方3 | 处方4 | 处方5 | 处方6 | 处方7 | 处方8 | |
10min | 35 | 40 | 32 | 27 | 22 | 42 | 41 | 37 |
15min | 62 | 66 | 68 | 56 | 55 | 66 | 69 | 65 |
30min | 78 | 82 | 77 | 70 | 73 | 79 | 82 | 79 |
45min | 89 | 91 | 93 | 83 | 80 | 87 | 89 | 83 |
60min | 95 | 96 | 98 | 88 | 91 | 99 | 96 | 95 |
实施例2
2.1单位处方组成
处方9 | 处方10 | 处方11 | 处方12 | |
式I化合物 | 75 | 75 | 100 | 125 |
微晶纤维素 | 38.7 | 10.8 | 93.9 | 117.3 |
乳糖 | 54.3 | 18.8 | 49.7 | 65.7 |
羟丙纤维素 | / | / | / | 17.5 |
聚维酮 | 10.5 | 3.5 | 14 | / |
羧甲淀粉钠 | / | 10.5 | 14 | 17.5 |
交联羧甲基纤维素钠 | 21 | / | / | / |
十二烷基硫酸钠 | 2.1 | / | 2.8 | / |
滑石粉 | 2.1 | 0.7 | 2.8 | 3.5 |
硬脂酸镁 | 2.1 | 0.7 | 2.8 | 3.5 |
重量 | 210 | 120 | 280 | 350 |
注:“/”代表未添加。
2.2制备
将上述1000片处方量式I化合物和除硬脂酸镁外其他赋形剂投入料斗混合机混匀,采用滚筒压制机压成带状物,将带状物碎成颗粒,加硬脂酸镁总混10min,中控含量,灌装胶囊。或压制成片。
2.3溶出数据
处方9 | 处方10 | 处方11 | 处方12 | |
10min | 44 | 38 | 35 | 38 |
15min | 69 | 63 | 64 | 70 |
30min | 76 | 74 | 75 | 81 |
45min | 93 | 90 | 89 | 90 |
60min | 98 | 98 | 93 | 92 |
实施例3
3.1单位处方组成
处方13 | 处方14 | 处方15 | |
式I化合物 | 75 | 75 | 75 |
微晶纤维素 | 71.8 | / | 50 |
乳糖 | 35.9 | 25.8 | 15.7 |
羟丙纤维素 | 10.5 | 6.0 | 9.0 |
羧甲淀粉钠 | 10.5 | 6.0 | 5.0 |
交联聚维酮 | / | 3.0 | 4.0 |
十二烷基硫酸钠 | 2.1 | / | 2.1 |
滑石粉 | 2.1 | 2.1 | 2.1 |
硬脂酸镁 | 2.1 | 2.1 | 2.1 |
重量 | 210 | 120 | 165 |
注:“/”代表未添加。
3.2制备
将上述1000片处方量式I化合物和赋形剂投入料斗混合机混匀,中控含量,灌装胶囊。或压制成片。
3.3溶出数据
实施例4
4.1单位处方组成
处方16 | 处方17 | 处方18 | |
API<sup>2</sup> | 125 | 125 | 125 |
微晶纤维素 | 124.3 | 64.5 | 27.1 |
乳糖 | 62.2 | 64.6 | 27.1 |
羟丙纤维素 | 17.5 | 8.4 | 16.8 |
交联聚维酮 | / | 14 | 10.5 |
交联羧甲基纤维素钠 | 17.5 | / | / |
硬脂酸镁 | 3.5 | 3.5 | 3.5 |
重量 | 350 | 280 | 210 |
注1:“/”代表未添加。
注2:API指的是式I化合物盐酸盐或羟乙基磺酸盐。
4.2制备
将上述1000片处方量API和除硬脂酸镁外其他赋形剂投入料斗混合机混匀,加润湿剂润湿制粒,流化床45℃干燥10min,1.0mm筛整粒,加硬脂酸镁总混10min,中控含量,灌装胶囊。或压制成片。
4.3溶出数据
处方16 | 处方17 | 处方18 | |
5min | 70 | 73 | 71 |
15min | 95 | 92 | 91 |
30min | 98 | 97 | 98 |
实施例5
5.1单位处方组成
处方19 | 处方20 | 处方21 | 处方22 | |
API<sup>2</sup> | 75 | 75 | 75 | 100 |
微晶纤维素 | 74.6 | 37.3 | 34.9 | 74.6 |
乳糖 | 37.3 | 74.6 | 34.9 | 74.6 |
聚维酮 | 10.5 | 10.5 | 8.25 | 14 |
羧甲淀粉钠 | / | 10.5 | 5 | 14 |
交联羧甲基纤维素钠 | 10.5 | / | 3.25 | / |
硬脂酸镁 | 2.1 | 2.1 | 1.65 | 2.8 |
重量 | 210 | 210 | 165 | 280 |
注1:“/”代表未添加。
注2:API指的是式I化合物盐酸盐(注:上述处方同样适用于羟乙基磺酸盐,且发明人检测其溶出效果与盐酸盐作为API时效果非常接近)。
5.2制备
将上述1000片处方量API和除硬脂酸镁外其他赋形剂投入料斗混合机混匀,采用滚筒压制机压成带状物,将带状物碎成颗粒,加硬脂酸镁总混10min,中控含量,灌装胶囊。或压制成片。
5.3溶出数据
处方19 | 处方20 | 处方21 | 处方22 | |
5min | 76 | 70 | 68 | 69 |
15min | 99 | 94 | 97 | 91 |
30min | 98 | 99 | 99 | 97 |
实施例6
6.1单位处方组成
注1:“/”代表未添加。
注2:API指的是式I化合物盐酸盐(注:上述处方同样适用于羟乙基磺酸盐,且发明人检测其溶出效果与盐酸盐作为API时效果非常接近)。
6.2制备
将上述1000片处方量API和赋形剂投入料斗混合机混匀,中控含量,灌装胶囊。或压制成素片,包衣,控制包衣增重3%。
6.3溶出数据
处方23 | 处方24 | 处方25 | |
5min | 62 | 60 | 59 |
15min | 90 | 90 | 94 |
30min | 97 | 95 | 99 |
实施例7
7.1单位剂量处方
注1:式I化合物与盐酸盐折算系数为447.53/484.03=92.4%,75mg式I化合物对应81mg式I化合物盐酸盐;式I化合物与羟乙基磺酸盐折算系数为447.53/573.53=78.0%,75mg式I化合物对应96mg式I化合物羟乙基磺酸盐,其他规格对应折算。
7.2制备
处方26-28,1000粒处方量API和赋形剂投入料斗混合机混匀,中控含量,灌装胶囊。处方29-30,混合后直接压制成素片,包衣,控制包衣增重3%。7.3溶出数据
处方26 | 处方27 | 处方28 | 处方29 | 处方30 | |
5min | 40 | 60 | 82 | 85 | 40 |
15min | 82 | 85 | 95 | 95 | 73 |
30min | 97 | 100 | 103 | 98 | 99 |
实施例8
8.1单位剂量处方
处方31 | 处方32 | 处方33 | 处方34 | 处方35 | |
式I化合物 | 75 | 100 | 100 | 125 | 125 |
微晶纤维素 | 86.7 | 77.1 | 154.1 | 144.5 | 56.3 |
乳糖 | 86.7 | 154.1 | 77.1 | 144.5 | 232.7 |
羧甲淀粉钠 | 13.5 | 18 | 18 | 22.5 | 22.5 |
胶态二氧化硅 | 5.4 | 7.2 | 7.2 | 9.0 | 9.0 |
硬脂酸镁 | 2.7 | 3.6 | 3.6 | 4.5 | 4.5 |
重量 | 270 | 360 | 360 | 450 | 450 |
8.2制备
处方31-32,1000粒处方量API和赋形剂投入料斗混合机混匀,中控含量,灌装胶囊。处方33-34,混合后直接压制成素片,包衣,控制包衣增重3%。处方35,将式I化合物和除硬脂酸镁外其他赋形剂投入料斗混合机混匀,采用滚筒压制机压成带状物,将带状物碎成颗粒,加硬脂酸镁总混10min,中控含量,压制成片,包衣,控制包衣增重3%。
8.3溶出数据
处方31 | 处方32 | 处方33 | 处方34 | 处方35 | |
5min | 85 | 77 | 76 | 83 | 70 |
15min | 94 | 85 | 91 | 95 | 85 |
30min | 98 | 100 | 97 | 99 | 99 |
8.4稳定性数据
将实施例8制备的胶囊采用市售包装,在40℃±2℃、相对湿度75%±5%条件下,放置6个月,检测结果见表1。
表1的稳定性研究结果
实施例9
9.1单位剂量处方
注1:式I化合物与盐酸盐折算系数为447.53/484.03=92.4%,75mg式I化合物对应81mg式I化合物盐酸盐;式I化合物与羟乙基磺酸盐折算系数为447.53/573.53=78.0%,75mg式I化合物对应96mg式I化合物羟乙基磺酸盐,其他规格对应折算。
9.2制备
将式I化合物盐和润滑剂外赋形剂进行湿法制粒,干燥后整粒,加润滑剂总混10min,中控含量。处方36-38,灌装胶囊,处方39-41,压制成片,包衣,控制包衣增重3%。
9.3溶出数据
处方36 | 处方37 | 处方38 | 处方39 | 处方40 | 处方41 | |
5min | 85 | 79 | 77 | 65 | 56 | 50 |
15min | 95 | 89 | 90 | 79 | 80 | 76 |
30min | 102 | 96 | 97 | 94 | 93 | 94 |
Claims (17)
2.一种如权利要求1所述的药物组合物的制备方法,其特征在于,是通过湿法制粒制备,所述方法包括以下步骤:
1)在湿法混合制粒机中预混合式Ⅰ化合物或其盐与部分赋形剂,获得预混合物;
2)添加制粒液体,将步骤1)的预混合物制粒;
3)在流化床干燥器或干燥箱中干燥步骤2)的颗粒。
3.根据权利要求2所述的制备方法,其特征在于,干燥筛分步骤3)的干燥的颗粒;混合干燥的颗粒与剩余赋形剂,获得最终混合物。
4.根据权利要求3所述的制备方法,其特征在于,通过合适的胶囊灌装机灌装权利要求3的最终混合物,制备胶囊剂。
5.根据权利要求3所述的制备方法,其特征在于,通过在合适的压片机上压制权利要求3的最终混合物,将其压片,从而制得片芯。
6.根据权利要求5所述的制备方法,其特征在于,用膜包衣对片芯进行薄膜包衣。
7.根据权利要求2所述的制备方法,其特征在于,所述制粒液体为水。
8.一种如权利要求1所述的药物组合物的制备方法,其特征在于,是通过干法制粒完成的,所述方法包括以下步骤:
1)在料斗混合机中混合所述式Ⅰ化合物或其盐和部分赋形剂,获得预混合物;
2)在合适的滚筒压制机中压实步骤1)的混合物;
3)通过合适的研磨或筛分步骤,将步骤2)期间获得的带状物碎成颗粒。
9.根据权利要求8所述的制备方法,其特征在于,在混合机中混合步骤3)和剩余赋形剂,获得最终混合物。
10.根据权利要求9所述的制备方法,其特征在于,通过合适的胶囊灌装机灌装权利要求9的最终混合物,制备胶囊剂。
11.根据权利要求9所述的制备方法,其特征在于,通过在合适的压片机上压制权利要求9的最终混合物,将其压片,从而制得片芯。
12.根据权利要求11所述的制备方法,其特征在于,用膜包衣对片芯进行薄膜包衣。
13.一种如权利要求1所述的药物组合物的制备方法,其特征在于,所述药物组合物是通过直接混合的方法制得。
14.根据权利要求13所述的制备方法,其特征在于,所述方法包括以下步骤:在料斗混合机中混合所述式Ⅰ化合物或其盐和其他所有赋形剂,获得混合物。
15.根据权利要求14所述的制备方法,其特征在于,通过胶囊灌装机灌装权利要求14的混合物,制备胶囊剂。
16.根据权利要求14所述的制备方法,其特征在于,通过在合适的压片机上压制权利要求14的混合物,将其压片,从而制得片芯。
17.根据权利要求16所述的制备方法,其特征在于,用膜包衣对片芯进行薄膜包衣。
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