CN102933573B - 包含酰胺衍生物或其可药用盐的药物组合物 - Google Patents
包含酰胺衍生物或其可药用盐的药物组合物 Download PDFInfo
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Abstract
本发明涉及包含酰胺衍生物或其可药用盐以及酸性添加剂的药物组合物。由于稳定性(甚至是在长期贮藏之后的稳定性)提高,该组合物适于抑制癌细胞的生长。
Description
技术领域
本发明涉及贮藏稳定性提高的包含酰胺衍生物或其可药用盐的药物组合物。
背景技术
细胞中有很多种信号转导系统,其功能上彼此相联系以控制细胞的增殖、生长和凋亡(Kaelin,Nature Reviews Cancer,2005,5:689)。由遗传或环境因素所引起的细胞内控制系统的故障引起信号转导的异常扩增或破坏,这导致肿瘤细胞的产生(Hanahan and Weinberg,Cell,2000,100:57)。
蛋白质酪氨酸激酶在这样的细胞内信号转导中发挥重要作用(Melnikova and Golden,Nature Reviews Drug Discovery,2004,3:993),并且在癌细胞中经常观察到蛋白质酪氨酸激酶的异常表达或突变。蛋白质酪氨酸激酶是催化磷酸基团从ATP向蛋白质底物上酪氨酸转移的蛋白质酪氨酸激酶。很多生长因子受体蛋白质充当酪氨酸激酶以转运细胞信号。生长因子及其受体之间的相互作用对于正常地控制细胞生长是必需的,但此类受体的突变或过量表达所引起的异常信号转导经常诱导肿瘤细胞和癌症。
蛋白质酪氨酸激酶已根据其生长因子类型而被分成很多个家族,并且尤其是已经深入地研究了表皮细胞生长因子(EGF)及其EGF受体(EGFR)酪氨酸激酶(Hynes and Lane,Nature Reviews Cancer,2005,5:341)。EGFR酪氨酸激酶(一种跨膜蛋白质)由受体和酪氨酸激酶构成,其将细胞外信号通过细胞膜递送至细胞核。多种EGFR酪氨酸激酶根据其结构特征而分成EGFR(Erb-B1)、Erb-B2、Erb-B3和Erb-B4,其中每一种可形成同二聚体信号递送复合物或与其他亚型一起形成异二聚体信号递送复合物。已有报道称在恶性疾病中过量表达两种或更多种此类异二聚体可导致转突变(transmutation)增加。在恶性肿瘤中经常观察到此类过量表达。
作为用于抑制EGFR酪氨酸激酶之小分子而开发的吉非替尼(Gefitinib)或埃罗替尼(Erlotinib)选择性地且可逆地抑制EGFR(Erb-B1)(EGFR的亚型),并且已被用作用于非小细胞肺癌(NSCLC)的治疗剂。2007年由美国食品及药物管理局(FDA)批准作为乳腺癌治疗剂的拉帕替尼(Lapatinib)可逆地抑制EGFR亚型中的Erb-B1和Erb-B2。
此外,用于抑制EGFR酪氨酸激酶的数种药物(例如,不可逆抑制剂如卡奈替尼(Canertinib)、HKI-272、BIBW-2992和PF00299804,以及可逆抑制剂如AEE-788、CP24714、ARRY334543和AV-412)目前正在进行临床试验。开发这些抑制剂以选择性地抑制Erb-B2,同时抑制两种或更多种EGFR亚型,包括Erb-B1或EGFR以及其他受体。
通过治疗NSCLC的临床测试结果,这些不可逆抑制剂表现出与常规可逆抑制剂相比提高的药物活性。但是,此类药物对患有抗药性癌症的患者未提供显著的治疗作用。
因此,对于开发与常规不可逆抑制剂相比有效治疗此类抗性癌症而不引起不良副作用的新药有持续的需要。根据需要,本发明的发明人开发了新化合物,其选择性地且有效地抑制癌细胞的生长和由EGFR及EGFR突变体所引起之药物抗性的产生而没有副作用,如韩国专利公开(Laid-open Publication)No.2008-0107294中所公开的那样。
本发明的发明人还开发了多种形式的制剂,其包含韩国专利公开No.2008-0107294中所公开的式(I)的1-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)丙-2-烯-1-酮作为活性成分。但是,通过使用常规可药用添加剂而制备的制剂导致了降低量的化合物,并且减少了贮存期间式(II)化合物(杂质E)的形成。
活性成分的纯度是制备安全且有效的药物组合物的重要因素。尤其是应用于免疫系统非常弱的患有癌症之患者的抗癌药物需要包含具有最大纯度的活性成分。除了在活性成分的制备过程中能够被除去的杂质之外,药物的杂质(例如,由多种环境因素(例如,温度、湿度和光)所诱导的来自最终药物产物的降解产物)可引起对被治疗患者的多种副作用。
因此,本发明的发明人已通过抑制任何杂质的形成而努力提高式(I)化合物的稳定性,并且发现酸性添加剂有效地提高本发明活性成分的稳定性。
发明概述
本发明的一个目的是提供具有提高的稳定性的包含酰胺衍生物或其可药用盐的药物组合物。
根据本发明的一个方面,提供了包含式(I)化合物或其可药用盐以及酸性添加剂的药物组合物:
附图简述
当结合附图时,通过本发明的以下描述,本发明的上述和其他目的及特征将变得清楚,所述附图分别示出:
图1:根据实施例1至7以及比较实施例1制备的制剂在60℃时的稳定性;
图2:根据酸性添加剂之量的制剂稳定性;
图3:根据实施例1和比较实施例2至5制备的制剂在60℃时的稳定性;以及
图4:根据实施例11和12以及比较实施例6制备的制剂在60℃时的稳定性。
发明详述
本发明提供包含式(I)化合物或其可药用盐以及酸性添加剂的药物组合物:
根据本发明的药物组合物可通过使用酸性添加剂以及抑制杂质形成而提高所述活性成分的稳定性。包含式(I)化合物作为活性成分的药物组合物由于在贮藏期间形成杂质而显示出低稳定性。但是,与通过降低水分含量或在制备过程中添加特定赋形剂或稳定剂而制备的药物组合物相比,通过使用酸性添加剂而制备的本发明药物组合物可更有效地抑制杂质形成。
以下详细地描述本发明药物组合物的每种成分。
(1)活性成分
本发明药物组合物中使用的活性成分是式(I)的1-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)丙-2-烯-1-酮或其可药用盐。
式(I)的化合物已作为新化合物而公开,其可选择性且有效地抑制癌细胞的生长和由EGFR及EGFR突变体所引起之药物抗性的产生,但不引起不良的副作用(见韩国专利公开No.2008-0107294)。
在本发明中,可药用盐包括但不限于无机酸或有机酸的酸加成盐,或者金属盐。优选地,无机酸加成盐的实例可包括盐酸、磷酸、硫酸或焦硫酸的盐;有机酸盐的实例可包括苹果酸、马来酸、柠檬酸、富马酸、苯磺酸(besylic acid)、樟磺酸(camsylic acid)或乙二磺酸(edisylic acid)的盐;且金属盐的实例可包括钙盐、钠盐、镁盐、锶盐或钾盐。
每1制剂单位的所述组合物中可包含量为0.1mg至1,000mg的本发明活性成分。
(2)酸性添加剂
用于本发明药物组合物的酸性添加剂可以是作为可药用赋形剂的选自以下的至少一种:(1)具有COOH或SO3H基团的C2-20有机酸或脂肪酸;(2)选自磷酸、硫酸、硼酸及其混合物的无机酸;以及(3)当以1至5%(w/v)的浓度溶解或分散于水中时显示出pH 1至6的任何物质。
具体地,具有COOH基团之酸性添加剂的实例可包括但不限于乙酸、己二酸(adipic acid)、柠檬酸、抗坏血酸、赤藻糖酸(erythorbic acid)、乳酸、丙酸、酒石酸、富马酸、甲酸、草酸、樟磺酸、苹果酸、马来酸、乙二磺酸、棕榈酸或硬脂酸。
当以1至5%(w/v)的浓度溶解或分散于水中时显示出pH 1至6之物质的实例可包括但不限于海藻酸(arginic acid)或SiO2。
在本发明的药物组合物中,可以基于按重量计1份式(I)化合物以按重量计0.1至100份(优选按重量计0.25至50份)的量使用所述酸性添加剂。
可在式(I)化合物以及可药用赋形剂(例如,崩解剂、润滑剂、稀释剂等)的湿法或干法制粒过程期间或者甚至在制粒过程之后添加所述酸性添加剂。此外,其可添加至式(I)化合物与可药用赋形剂的混合物,以用于直接压片或填充胶囊。
(3)其他成分
本发明的药物组合物还可包含至少一种选自稀释剂、粘合剂、崩解剂和润滑剂的赋形剂。稀释剂的实例可包括微晶纤维素、乳糖、甘露醇、磷酸钙等;粘合剂的实例可包括聚维酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯醇、羧甲基纤维素钠等;崩解剂的实例可包括交聚维酮(crospovidone)、交联羧甲纤维素钠(sodium croscarmellose)、淀粉乙醇酸钠(sodium starch glycolate)等;以及润滑剂的实例可包括硬脂酸镁、硬脂酸钙、硬脂富马酸钠(sodium stearyl fumarate)等。
优选地,基于所述组合物的总重量,可以以按重量计20至80%的量使用所述稀释剂,可以以按重量计1至10%的量使用所述粘合剂,可以以按重量计1至30%的量使用所述崩解剂,以及可以以按重量计0.5至5%的量使用所述润滑剂。
可配制本发明的药物组合物用于经口施用。用于经口施用之制剂的代表性实例可包括散剂、片剂、胶囊剂、颗粒剂或糖浆剂,优选片剂或胶囊剂,但不限于此。
可用包衣基质为本发明的药物组合物包衣以防止所述组合物与使用者的手或皮肤相接触。本发明中所使用的包衣基质可包括快速释放包衣基质,例如羟丙基纤维素、羟丙基甲基纤维素、聚乙烯醇、聚乙烯醇-聚乙二醇接枝聚合物(Kollocoat IR,BASF)等;肠溶包衣基质(enteric coatingsubstrate),例如(甲基)丙烯酸盐/酯共聚物(尤特奇(Eudragit),EVONIK)、羟丙基甲基纤维素邻苯二甲酸酯(hydroxypropylmethylcellulose phthalate)、邻苯二甲酸乙酸纤维素(cellulose acetatephthalate)等;以及持续释放包衣基质,例如乙酸纤维素、乙基纤维素、聚乙酸乙烯酯等。可以基于未包衣核心以按重量计1至50%(优选按重量计1至30%)的量使用所述包衣基质。
实施例
以下实施例旨在进一步举例说明本发明而不限制其范围。
实施例1至7:包含酸性添加剂的片剂的制备
根据表1中所描述的组合物,通过使用式(I)化合物(Hanmi Pharm.Co.,Ltd.,Korea)、甘露醇、聚维酮(BASF,Germany)、交聚维酮(BASF,Germany)、硬脂酸镁以及一种或更多种酸性添加剂(例如,柠檬酸、赤藻糖酸、磷酸、海藻酸(alginic acid)、硬脂酸和二氧化硅)制备具有式(I)化合物的片剂。将向湿颗粒组合物中添加的酸性添加剂(柠檬酸和磷酸)溶解或分散于水(结合溶液(binding solution))中。当在制粒之后添加或者添加至直接压片的混合物时,将酸性添加剂过筛通过30目筛。通过使用压片机将实施例1至7的每种片剂制备成硬度为6至12kp的片剂。
表1
实施例8至10:包含不同量酸性添加剂的片剂的制备
根据表2中描述的组合物,根据实施例1的流程制备实施例8至10的每一种片剂,只是使用不同量的柠檬酸作为酸性添加剂。
表2
比较实施例1至5:包含非酸性抗氧化剂或碱性稳定剂的片剂的制备
根据表3中描述的组合物,根据实施例1的流程制备比较实施例1的片剂而不使用任何酸性添加剂。此外,根据表3中描述的组合物,根据实施例1的流程制备比较实施例2至5的每种片剂,只是使用丁羟甲苯(butylated hydroxy toluene,BHT)或生育酚作为非酸性抗氧化剂或者使用碳酸钙(CaCO3)或葡甲胺作为碱性稳定剂,而不是使用酸性添加剂。
表3
实施例11和12以及比较实施例6:胶囊剂的制备
根据表4中描述的组合物,将式(I)化合物和赋形剂过筛通过30目筛并且随后混合。将含有8mg式(I)化合物的混合物装入0号尺寸的胶囊中以制备实施例11和12的每一种胶囊剂。根据实施例11的流程制备比较实施例6的胶囊剂,只是不添加任何酸性添加剂。
表4
实施例11 | 实施例12 | 比较实施例6 | |
式(I)化合物 | 8 | 8 | 8 |
甘露醇 | 97 | 97 | 97 |
聚维酮 | 3 | 3 | 3 |
交聚维酮 | 10 | 10 | 10 |
柠檬酸 | 10 | - | - |
赤藻糖酸 | - | 10 | - |
硬脂酸镁 | 2 | 2 | 2 |
混合物的总重量 | 130 | 130 | 120 |
实验实施例1:评价实施例和比较实施例之每种制剂的贮藏稳定性
为了评价含有式(I)化合物的根据实施例1至12和比较实施例1至6制备之制剂的贮藏稳定性,测量了作为主要降解产物的式(II)化合物(杂质E)的量。将所述制剂各自与1g硅胶一起包装于HDPE瓶中,并贮藏于室(chamber)中(60℃),并在四周和八周之后测量杂质E的量。结果示于表5至表7以及图1至图4中。
表5
表6
表7
实施例11 | 实施例12 | 比较实施例6 | |
初始(0周) | 0.02 | 0.02 | 0.02 |
4周(60℃) | 0.07 | 0.07 | 0.49 |
8周(60℃) | 0.10 | 0.11 | 0.96 |
如表5至表7以及图1至图4所示,杂质E的产生降低了约4至10倍或更多倍,因此向所述制剂添加一种或更多种酸性添加剂提高了含有式(I)化合物之制剂的贮藏稳定性。根据人用药物注册技术要求国际协调会议(International Conference on Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for Human Use,ICH),未知杂质和已知杂质的限值分别为0.2%和0.5%。为此,添加一种或更多种酸性添加剂可提高含有式(I)化合物之片剂和胶囊剂的稳定性,因此可预期优良的贮藏稳定性。
但是,通常用作药物稳定剂的非酸性抗氧化剂(BHT或生育酚)或者碱性稳定剂(碳酸钙(CaCO3)或葡甲胺)并不提高稳定性或者对稳定性有不良的影响。
虽然本发明是相对于上述具体实施方案而描述的,但应当认识到的是,本领域技术人员可对本发明进行多种修改和改变,其也落入由所附权利要求书所限定的本发明的范围之内。
Claims (12)
1.酸性添加剂在提高药物组合物中式(I)化合物或其可药用盐之稳定性中的用途,所述药物组合物包含式(I)化合物或其可药用盐以及酸性添加剂:
其中所述酸性添加剂是海藻酸或SiO2。
2.权利要求1的用途,其中所述可药用盐是无机酸盐、有机酸盐或金属盐。
3.权利要求2的用途,其中所述无机酸盐是盐酸、磷酸、硫酸或焦硫酸的盐;所述有机酸盐是苹果酸、马来酸、柠檬酸、富马酸、苯磺酸、樟磺酸或乙二磺酸的盐;以及所述金属盐是钙盐、钠盐、镁盐、锶盐或钾盐。
4.权利要求1的用途,其中每1单位的所述组合物含有量为0.1mg至1000mg的所述式(I)化合物。
5.权利要求1的用途,其中基于按重量计1份所述式(I)化合物含有按重量计0.1至100份量的所述酸性添加剂。
6.权利要求5的用途,其中基于按重量计1份所述式(I)化合物含有按重量计0.25至50份量的所述酸性添加剂。
7.权利要求1的用途,其中以胶囊剂或片剂的形式配制所述组合物。
8.权利要求1的用途,其中所述组合物还包含选自稀释剂、粘合剂、崩解剂、润滑剂及其混合物的赋形剂。
9.权利要求8的用途,其中基于所述组合物的总重量,含有按重量计20至80%量的所述稀释剂,含有按重量计1至10%量的所述粘合剂,含有按重量计1至30%量的所述崩解剂,或者含有按重量计0.5至5%量的所述润滑剂。
10.权利要求1的用途,其中所述组合物包被有快速释放包衣基质、肠溶包衣基质、持续释放包衣基质、或其混合物。
11.权利要求10的用途,其中所述快速释放包衣基质是羟丙基纤维素、羟丙基甲基纤维素、聚乙烯醇、聚乙烯醇-聚乙二醇接枝聚合物或其混合物;所述肠溶包衣基质是(甲基)丙烯酸盐/酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯、邻苯二甲酸乙酸纤维素或其混合物;以及所述持续释放包衣基质是乙酸纤维素、乙基纤维素、聚乙酸乙烯酯或其混合物。
12.权利要求10的用途,其中基于未包衣核心总重量以按重量计1至50%的量使用所述包衣基质。
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