CN1147472C - 具有组蛋白脱乙酰酶抑制剂活性的苯甲酰胺制剂 - Google Patents
具有组蛋白脱乙酰酶抑制剂活性的苯甲酰胺制剂Info
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Abstract
提供了具有改进口服吸收性的药物制剂和注射液,它们含有高浓度的可以用作组蛋白脱乙酰酶抑制剂的苯甲酰胺衍生物和其药物上可接受的盐作为活性成分。通过将苯甲酰胺衍生物或其药物上可接受的盐溶于有机溶剂和/或酸性液体中制备药物溶液,而通过加入表面活性剂、酸性物质和/或聚乙二醇制备药物制剂。本发明可以使苯甲酰胺衍生物或其药物上可接受的盐以高浓度溶解而制备实用的注射液和口服液体制剂并改进口服给药的吸收性。
Description
发明领域
本发明涉及一种具有增加的溶解性且含有苯甲酰胺衍生物或其药物上可接受的盐的药物制剂,其可用作药物,尤其是抗癌药。具体而言,本发明涉及含有高浓度活性成分且具有改进的口服吸收性的药物制剂,它们还可用作注射液。
背景技术
用于本发明的苯甲酰胺衍生物及其药物上可接受的盐具有组蛋白脱乙酰酶抑制作用且可用作与细胞生长有关的疾病的治疗和/或改善剂,用作基因疗法的效果增强剂,以及用作免疫抑制剂。它们作为抗癌药具有特别强的作用且对造血组织肿瘤和实体瘤有效(日本未审专利公报(公开)No.平-10-152462)。
不过,尽管用于本发明的苯甲酰胺衍生物在口服给药于小鼠和大鼠时具有非常令人满意的吸收性,但在狗中发现了一些低吸收性的情况。甚至在使用常见添加剂如乳糖、玉米淀粉、羧甲基纤维素、轻质硅酸酐、硅酸铝镁、硬脂酸镁和二氧化钛制备制剂时也发现一些低口服给药吸收性的情况。因此,一直认为仅用含有苯甲酰胺衍生物或其盐作为活性成分的口服给药制剂难以达到稳定的血液浓度。
还尝试将苯甲酰胺衍生物或其药物上可接受的盐溶于水、磷酸盐缓冲液等中以制备液体药物或注射液,但它们的低溶解性使得不可能得到足够浓度的制剂。
因此,含有苯甲酰胺衍生物或其盐作为活性成分的注射液由于活性成分的溶解性差而必须具有非常大的体积且因此难以将其以药物提供。
发明公开
本发明的目的是提供具有增加的溶解性且对可用作组蛋白脱乙酰酶抑制剂的苯甲酰胺衍生物及其药物上可接受的盐具有改进的口服吸收性的制剂,并提供含有高浓度活性成分的注射液。
为了克服上述问题,本发明的发明人对向苯甲酰胺衍生物及其药物上可接受的盐中加入各种添加剂以改进溶解性和吸收性进行了广泛的研究,结果发现该目的可以通过使用某些类型的添加剂达到,并因此完成了本发明。
换句话说,本发明提供了
[1]一种药物制剂,包含式(1)所示的苯甲酰胺衍生物:
其中A代表由下式(2)中任意一种所示结构:
或其药学上可接受的盐,和选自表面活性剂、酸性物质、有机溶剂和聚乙二醇中的一种或多种;
[2]根据[1]的药物制剂,还包含水;
[3]根据[1]或[2]的药物制剂,其中苯甲酰胺衍生物如式(3)所示:
[4]根据[1]至[3]中任意一项的药物制剂,其中表面活性剂为选自阴离子表面活性剂和非离子表面活性剂中的一种或两种;
[5]根据[1]至[4]中任意一项的药物制剂,其中酸性物质为选自无机酸、羧酸、磺酸、酸性多糖、酸性氨基酸以及氨基酸和无机酸的盐中的一种或多种;
[6]根据[1]至[5]中任意一项的药物制剂,其中有机溶剂为选自甲醇、乙醇、丙二醇、甘油、碳酸亚丙酯和二甲基乙酰胺中的一种或多种;
[7]根据[1]至[6]中任意一项的药物制剂,其中聚乙二醇的分子量为200-20,000;
[8]根据[4]至[7]中任意一项的药物制剂,其中阴离子表面活性剂为月桂基硫酸钠;
[9]根据[4]至[8]中任意一项的药物制剂,其中非离子表面活性剂为聚氧乙烯脱水山梨醇脂肪酸酯或糖酯;
[10]根据[9]的药物制剂,其中聚氧乙烯脱水山梨醇脂肪酸酯为聚山梨酸酯80;
[11]根据[9]的药物制剂,其中糖酯为脂肪酸的蔗糖酯;
[12]根据[5]至[11]中任意一项的药物制剂,其中无机酸为盐酸、硫酸或磷酸;
[13]根据[5]至[11]中任意一项的药物制剂,其中羧酸为柠檬酸、富马酸、己二酸、酒石酸、苹果酸或乙酸;
[14]根据[5]至[11]中任意一项的药物制剂,其中磺酸为氨基乙磺酸;
[15]根据[5]至[11]中任意一项的药物制剂,其中酸性多糖为藻酸;
[16]根据[5]至[11]中任意一项的药物制剂,其中酸性氨基酸为天冬氨酸或谷氨酸;
[17]根据[5]至[11]中任意一项的药物制剂,其中氨基酸和无机酸的盐为甘氨酸盐酸盐、天冬氨酸盐酸盐或谷氨酸盐酸盐。
附图简述
图1说明实施例2-4和对比例1中得到的制剂在用20ml水口服给药于禁食雄性比格犬(beagle)时血浆浓度的系列变化。
实施本发明的方式
现在更加详细地解释本发明。通常通过将一种或多种添加剂引入活性成分中来制备制剂。
本发明式(1)所示用作制剂的活性成分的苯甲酰胺衍生物例举于表1中且这些化合物可以通过例如日本未审专利公开平-10-152462所述的方法生产。
表1
化合物2
化合物3
用于本发明的表面活性剂没有特别限制,包括阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂、两性表面活性剂等;优选单独或结合使用月桂基硫酸钠、聚山梨酸酯80、脂肪酸的蔗糖酯等。
用于本发明的酸性物质包括无机酸如盐酸、硫酸和磷酸;羧酸如乙酸、乳酸、富马酸、酒石酸、琥珀酸、柠檬酸、草酸、丙二酸、马来酸、dl-苹果酸、硬脂酸和己二酸;磺酸如氨基乙磺酸;酸性多糖如藻酸;酸性氨基酸如谷氨酸和天冬氨酸;以及氨基酸和无机酸的盐,如甘氨酸盐酸盐、天冬氨酸盐酸盐和谷氨酸盐酸盐。
可以将一种或多种酸性物质用于本发明中。
这些酸性物质可以与表面活性剂、有机溶剂、聚乙二醇和/或类似物一起与活性成分配制,但它们还可以以在水中的溶液使用。
用于本发明的有机溶剂包括甲醇、乙醇、丙二醇、甘油、二甲基甲酰胺和碳酸亚丙酯,且可以使用它们中的一种或多种,任选以在水中的溶液形式。
用于本发明的聚乙二醇就其分子量而言并无特别限制,但优选其分子量为200-20,000,更优选200-600。可以选择使用一种或多种类型,任选以在水中的溶液形式。
本发明的包封液体的软胶囊和包封液体的硬胶囊等可以通过将合适量的苯甲酰胺衍生物或其药物上可接受的盐溶解于
(i)包含选自有机溶剂、聚乙二醇和表面活性剂中的一种或多种的液体中;
(ii)包含水和选自有机溶剂、聚乙二醇和表面活性剂中的一种或多种的液体中;
(iii)包含一种或多种酸性物质、水和选自有机溶剂、聚乙二醇和表面活性剂中的一种或多种的液体中;或
(iv)包含一种或多种酸性物质和水的液体中,并按照本领域熟练技术人员常用的方法制成包封液体的软胶囊和包封液体的硬胶囊等而制备。
用于制备软胶囊和硬胶囊等的有机溶剂包括甲醇、乙醇、丙二醇、甘油、二甲基甲酰胺和碳酸亚丙酯;用于制备软胶囊和硬胶囊等的聚乙二醇包括分子量为200-600的聚乙二醇;用于制备软胶囊和硬胶囊等的表面活性剂包括聚山梨酸酯80;而用于制备软胶囊和硬胶囊等的酸性物质包括无机酸如盐酸、硫酸和磷酸;羧酸如乙酸、乳酸、富马酸、酒石酸、琥珀酸、柠檬酸、草酸、丙二酸、马来酸、dl-苹果酸、硬脂酸和己二酸;磺酸如氨基乙磺酸;酸性多糖如藻酸;酸性氨基酸如谷氨酸和天冬氨酸;以及氨基酸和无机酸的盐如甘氨酸盐酸盐、天冬氨酸盐酸盐和谷氨酸盐酸盐。
根据本发明,可以通过如下方式制备固体制剂如粉剂、颗粒、片剂、丸剂和胶囊:根据本领域熟练技术人员常用的方法,向活性成分中加入一种或多种选自如下的物质:表面活性剂如月桂基硫酸钠和脂肪酸的蔗糖酯;聚乙二醇如聚乙二醇4000和聚乙二醇6000;包括无机酸如盐酸、硫酸和磷酸;羧酸如乙酸、乳酸、富马酸、酒石酸、琥珀酸、柠檬酸、草酸、丙二酸、马来酸、dl-苹果酸、硬脂酸和己二酸;磺酸如氨基乙磺酸;酸性多糖如藻酸;酸性氨基酸如谷氨酸和天冬氨酸;以及氨基酸和无机酸的盐如甘氨酸盐酸盐、天冬氨酸盐酸盐和谷氨酸盐酸盐在内的酸性物质,并且还使用用于制剂的赋形剂、粘合剂、崩解剂、润滑剂、包衣剂等。
用于本发明的赋形剂包括D-甘露糖醇、乳糖、蔗糖、玉米淀粉、结晶纤维素等。用于本发明的粘合剂包括羟丙基纤维素、聚乙烯基吡咯烷酮、明胶、甘油、水等。
用于本发明的崩解剂包括羧甲基纤维素(carmellose)、羧甲基纤维素钙、羧甲基淀粉钠、低取代的羟丙基纤维素、部分预胶凝淀粉等。用于本发明的润滑剂包括硬脂酸镁、硬脂酸钙等。
用于本发明的包衣剂包括羟丙基甲基纤维素、甲基丙烯酸共聚物、羟丙基甲基纤维素邻苯二甲酸酯等。
片剂可以是必要时包有常用包衣的片剂,如糖包衣片剂、明胶包封片剂、肠衣片剂或包膜片剂。此外,片剂可以是双层或多层片剂,其具有活性成分、酸性物质和表面活性剂等的分离层。
本发明的注射液可以通过将合适量的苯甲酰胺衍生物或其药物上可接受的盐溶解于
(i)包含选自有机溶剂、聚乙二醇和表面活性剂中的一种或多种的液体中;
(ii)包含水和选自有机溶剂、聚乙二醇和表面活性剂中的一种或多种的液体中;
(iii)包含一种或多种酸性物质、水和选自有机溶剂、聚乙二醇和表面活性剂中的一种或多种的液体中;或
(iv)包含一种或多种酸性物质和水的液体中,并按照本领域熟练技术人员常用的方法制成注射液而制备。
用于制备注射液的有机溶剂包括甲醇、乙醇、丙二醇、甘油、二甲基甲酰胺和碳酸亚丙酯;用于制备注射液的聚乙二醇包括分子量为200-600的聚乙二醇;用于制备注射液的表面活性剂包括聚山梨酸酯80;而用于制备注射液的酸性物质包括无机酸如盐酸、硫酸和磷酸;羧酸如乙酸、乳酸、富马酸、酒石酸、琥珀酸、柠檬酸、草酸、丙二酸、马来酸、dl-苹果酸、硬脂酸和己二酸;磺酸如氨基乙磺酸;酸性多糖如藻酸;酸性氨基酸如谷氨酸和天冬氨酸;以及氨基酸和无机酸的盐如甘氨酸盐酸盐、天冬氨酸盐酸盐和谷氨酸盐酸盐。
另外,在将选自这些酸性物质中的一种或多种溶解于水中之后,可以将合适量的苯甲酰胺衍生物或其药物上可接受的盐溶解于其中,得到由本领域熟练技术人员常用的方法制备的注射液。此时,可以与其一起使用表面活性剂如月桂基硫酸钠和/或脂肪酸的蔗糖酯,和/或聚乙二醇如聚乙二醇4000和/或聚乙二醇6000来改进苯甲酰胺衍生物的溶解性。
对本发明药物制剂的给药方法没有特别的限制,且可以通过一种适合于制剂形式、患者的年龄、性别和症状严重性以及其它因素的方法给药。例如,片剂、丸剂、液体药物、糖浆、悬浮液、乳液、颗粒和胶囊经口服给药,而注射液单独或与包含葡萄糖、氨基酸等的常规液体溶液混合经静脉内给药;若需要,它们可经肌内、皮下或腹内给药。
本发明的这些药物制剂的剂量可以基于给药方法、患者的年龄、性别和症状严重性以及其它因素进行适当选择。然而,大多数活性成分的剂量可以为约0.0001-100mg/天/kg体重。单位剂型的活性成分用量优选在约0.001-1000mg范围内。
实施例
现在通过实施例和对比例来详细说明本发明。不过请注意,本发明无论如何也不局限于这些实施例。
实施例1
将100mg化合物1与各为10ml的0.05N盐酸溶液、甲醇、乙醇、碳酸亚丙酯、聚山梨酸酯80、聚乙二醇400、聚乙二醇300、甘油、二甲基乙酰胺或丙二醇在室温下彻底掺混,分离出通过离心分离各混合物得到的上层清液并将其用作药物溶液。还通过用各为10ml的纯化水、pH4.0的乙酸钠缓冲液或pH6.8的磷酸钠缓冲液在室温下彻底溶解100mg化合物1并通过离心分离分离出上层清液而制备对比用对照样品。表2示出了通过HPLC分析测量各样品中化合物1浓度的结果。所有本发明的样品含有以5mg/ml或更高的浓度溶解的化合物1,该浓度足以用于注射。另一方面,所有对比用对照样品含有以0.2mg/ml或更低的浓度溶解的化合物1,因此不能保证注射所必需的浓度。
表2:化合物1在溶剂中的溶解性对比
溶剂 | 化合物1浓度(mg/ml) | |
对比用对照样品 | 水乙酸钠缓冲液,pH4.0磷酸盐缓冲液,pH6.8 | 0.040.20.04 |
本发明样品 | 0.05N盐酸溶液甲醇乙醇碳酸亚丙酯聚山梨酸酯80聚乙二醇400聚乙二醇300甘油二甲基乙酰胺丙二醇 | 14.09.95.417.529.977.769.110.0>10054.6 |
实施例2
将10.13g聚乙二醇400、1.08g聚山梨酸酯80和200mg化合物1混在一起,通过超声处理30分钟并不时混合使混合物彻底溶解。将溶液填充到硬明胶胶囊中以使剂量基于给药前狗的体重为1.5mg/kg,由此制备药物制剂。
实施例3
称重200mg化合物1、700mg聚乙二醇4000、800mg聚乙二醇6000、600mg月桂基硫酸钠和1200mg脂肪酸的蔗糖酯并在玛瑙研钵中混合,再用研杵粉化混合物。将混合的粉末填充到硬明胶胶囊中以使剂量基于给药前狗的体重为1.5mg/kg,由此制备药物制剂。
实施例4
称重200mg化合物1、1350mg谷氨酸盐酸盐和1950mgD-甘露糖醇并在玛瑙研钵中混合,再用研杵粉化混合物。将混合的粉末填充到硬明胶胶囊中以使剂量基于给药前狗的体重为1.5mg/kg,由此制备药物制剂。
对比例1
称重200mg化合物1和1000mgD-甘露糖醇并在玛瑙研钵中混合,再用研杵粉化混合物。将混合的粉末填充到硬明胶胶囊中以使剂量基于给药前狗的体重为1.5mg/kg,由此制备药物制剂。
实施例5
在水中的溶解性评价试验
将在实施例2-4和对比例1中得到的各药物制剂与水混合,通过HPLC测量化合物1的浓度或观察上层清液中的透明性和颜色来评价溶解性。表3示出了基于在实施例2-4和对比例1中得到的各制剂(化合物1的量为20mg)与1-1000ml纯化水混合后HPLC测量化合物1的浓度或观察各上层清液中的透明性和颜色的溶解性评价结果。根据实施例2的结果,在与水以任意比例混合下没有发现化合物1的沉淀。对于实施例3和4,发现溶解性分别为对比例1的约4倍和约100倍。
表3:各药物制剂在水中的溶解性
水的量 | ||||
1ml | 10ml | 250ml | 1000ml | |
实施例2实施例3实施例4对比例1 | ○××× | ○×○× | ○○○× | ○○○○ |
在表中,符号×表示化合物1没有溶解,符○表示化合物1彻底溶解。
口服吸收性评价试验
将实施例2-4和对比例1中得到的药物制剂用20ml水口服给药于禁食的雄性比格犬。在给药15、30和45分钟以及1、2、4、6和9小时后将约2.5ml血液从静脉内取样到肝素化容器中并离心血液,收集血浆。通过固相萃取从血浆中分离活性成分并由高效液相色谱测量浓度。结果示于图1中。实施例2-4均具有高于对比例1的吸收性。
表4示出了将在实施例2-4和对比例1中得到的药物制剂用20ml水口服给药于禁食的雄性比格犬的药物动力学参数。实施例2-4均显示出高于对比例1的AUC和Cmax且具有改进的口服给药吸收性。
表4:各药物制剂的药物动力学参数
制剂 | AUCO 0-∞(μg·hr/ml) | Cmax(μg/ml) | Tmax(hr) |
实施例2实施例3实施例4 | 0.820.830.92 | 0.850.520.70 | 0.671.080.75 |
对比例1 | 0.31 | 0.25 | 0.42 |
表中的数值为n=3的平均值。
工业实用性
通过将苯甲酰胺衍生物或其药物上可接受的盐溶解于有机溶剂和/或酸性液体中制备药物溶液并通过将表面活性剂、酸性物质和/或聚乙二醇加入苯甲酰胺衍生物或其药物上可接受的盐中制备药物制剂,从而提供具有高口服吸收性的药物制剂和注射液,它们含有高浓度的可以用作组蛋白脱乙酰酶抑制剂的苯甲酰胺衍生物或其药物上可接受的盐作为活性成分。
Claims (9)
2.根据权利要求1的药物制剂,其中苯甲酰胺衍生物如式(3)所示:
3.根据权利要求1的药物制剂,其中聚乙二醇的分子量为200-20,000。
4.根据权利要求1的药物制剂,其中氨基酸和无机酸的盐为选自甘氨酸盐酸盐、天冬氨酸盐酸盐或谷氨酸盐酸盐中的一种或多种。
5.根据权利要求1的药物制剂,其中表面活性剂为选自阴离子表面活性剂和非离子表面活性剂中的一种或两种。
6.根据权利要求5的药物制剂,其中阴离子表面活性剂为月桂基硫酸钠。
7.根据权利要求5的药物制剂,其中非离子表面活性剂为选自聚氧乙烯脱水山梨醇脂肪酸酯和糖酯中的一种或两种。
8.根据权利要求7的药物制剂,其中聚氧乙烯脱水山梨醇脂肪酸酯为聚山梨酸酯80。
9.根据权利要求7的药物制剂,其中糖酯为脂肪酸的蔗糖酯。
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JP3354090B2 (ja) * | 1996-09-30 | 2002-12-09 | シエーリング アクチエンゲゼルシャフト | 分化誘導剤 |
US6174905B1 (en) * | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
JP4405602B2 (ja) * | 1998-04-16 | 2010-01-27 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | ヒストン脱アセチル化酵素阻害剤 |
JP2000256194A (ja) * | 1999-01-06 | 2000-09-19 | Mitsui Chemicals Inc | 核内レセプタ作動薬およびその効果増強剤 |
JP2001064177A (ja) * | 1999-08-16 | 2001-03-13 | Schering Ag | ベンズアミド誘導体を有効成分とする製剤 |
-
1999
- 1999-08-30 JP JP24244499A patent/JP2001081031A/ja active Pending
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2000
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- 2000-08-29 AR ARP000104493A patent/AR025434A1/es unknown
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