CN1352558B - 即释型口服用药物组合物 - Google Patents

即释型口服用药物组合物 Download PDF

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CN1352558B
CN1352558B CN998167657A CN99816765A CN1352558B CN 1352558 B CN1352558 B CN 1352558B CN 998167657 A CN998167657 A CN 998167657A CN 99816765 A CN99816765 A CN 99816765A CN 1352558 B CN1352558 B CN 1352558B
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大内清久
金子薰
金田健
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Abstract

本发明涉及可用作糖尿病治疗剂的含有作为有效成分的下式

Description

即释型口服用药物组合物
技术领域
本发明涉及可用作糖尿病治疗剂的即释型口服用药物组合物。 
背景技术
已知作为本发明药物组合物的有效成分的下式 
Figure GWB00000008830300011
表示的苄基琥珀酸衍生物(化学名:(2S)-2-苄基-3-(顺-六氢-2-异二氢氮杂茚基羰基)丙酸)的钙盐或其水合物是一种具有显著的降血糖作用、可用作糖尿病治疗剂的化合物(日本特许公开公报1992年第356459号)。 
现在在糖尿病治疗中经常使用的格列本脲、格列齐特等磺酰脲类药物(SU药物)要显示其效果,需要较长的时间,且作用持续数小时,因此,已被指出的一个问题是,其反而会引起低血糖症状的危险性很大。例如,饭后服用足以充分抑制高血糖的量的SU药物时,无法避免在两餐之间引起低血糖的问题。然而,本发明的化合物由于其作用效果的持续时间短,因此,它有望成为一种仅纠正饭后的高血糖状态而不会引起两餐之间的低血糖症状的高血糖症治疗用药。 
要仅纠正饭后的高血糖状态而不会引起两餐之间的低血糖症状,除了有效成分须及早从血中排泄出来之外,还要服用后能迅速被吸收。为此,在饭后的高血糖治疗中,需要开发药物组合物的崩解性和有效成分的溶出性优异的即释型制剂。一般要求即释型制剂在服用后通常20分钟内释放出约75%以上的药物(药物溶出性)(医药品的开发,第11卷,第65-77页,广川书店发行),本发明的化合物难溶于水,在溶出性方面令人担忧。因此,为了解决此问题,非常希望能及早开发出优异的即释型制剂。 
发明内容
本发明涉及即释型口服用药物组合物的制备方法,该组合物为片剂; 
所述制备方法包括将作为有效成分的下式 
表示的苄基琥珀酸衍生物的钙盐的二水合物与作为崩解剂的二氧化硅、结晶纤维素、乳糖和玉米淀粉混合的工序,并采用直接粉末压缩法或湿式颗粒压缩法制成片剂的工序;所述二氧化硅占组合物总重量的0.5-5%。 
本发明还涉及用上述方法制成的即释型口服用药物组合物。 
附图说明
图1示出以上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物为有效成分的实施例1、2和参考例1中所述的各种片剂的溶出性,纵坐标为有效成分的溶出率(%),横坐标为试验开始后的经过时间(分钟)。 
图2示出以上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物为有效成分的实施例3-6和参考例2-9中所述的各种片剂的溶出性,纵坐标为有效成分的溶出率(%),横坐标为试验开始后的经过时间(分钟)。 
具体实施方式
本发明者为了得到含有作为有效成分的上述式(I)表示的苄基琥珀酸衍生物的钙盐或其水合物、可用作糖尿病治疗剂的具有优异崩解性和溶出性的即释型口服用药物组合物,进行了深入的研究,结果发现,在药物组合物中至少添加二氧化硅或部分α化淀粉,可提高药物组合物的崩解性,且溶出性得以飞跃性改善,由此完成了本发明。 
在以含有作为有效成分的上述式(I)表示的苄基琥珀酸衍生物的钙盐或其水合物的口服用药物组合物中添加羧甲基淀粉钠、低取代的羟丙基纤维素等常用崩解剂时,即使用一般认为崩解性良好的干法(直接粉末压缩法)制造片剂,仍完 全得不到溶出性良好的制剂。所得制剂不仅溶出迟缓,而且,溶出率异常地低。但添加一般用作润滑剂的二氧化硅,则令人惊异的是,所制得片剂显示出极优异的溶出效率,例如,在使用日本药典第1液的溶出试验中,从试验刚开始起,就观察到快速溶出,最大溶出率也极高。 
而且,即使用一般被认为在崩解性方面差的湿法(湿式颗粒压缩法)制造片剂时,添加二氧化硅的片剂与添加羧甲基淀粉钠、低取代的羟丙基纤维素等常用崩解剂的片剂相比,显示出令人惊异的显著的溶出效率,例如,在使用日本药典第1液的溶出试验中,从试验刚开始起,就观察到快速溶出,最大溶出率也极高。此外,用湿法制造片剂时,添加羧甲基淀粉钠、低取代的羟丙基纤维素等常用崩解剂的片剂即使在经过相当长时间后,其溶出率依然低,溶出性出现显著差异,无法令人满意,而添加部分α化淀粉作为崩解剂、用湿法制得的片剂与添加二氧化硅时一样,显示出良好的溶出性。此外,添加羧甲醚纤维素作为崩解剂的制剂虽然显示出与本发明的药物组合物同样高的溶出效率,但由于与作为有效成分的上述式(I)表示的苄基琥珀酸衍生物的钙盐不相容,药物组合物变成淡黄色,而且,有效成分分解,因此,其稳定性差,不符合要求。 
即,本发明涉及以至少含有二氧化硅或部分α化淀粉为特征、含有作为有效成分的上述式(I)表示的苄基琥珀酸衍生物的钙盐或其水合物的即释型口服用药物组合物,它具有卓越的崩解性和活性成分溶出性,且与上述式(I)表示的苄基琥珀酸衍生物的钙盐相容,长期保存性优异。 
在本发明中,含有作为有效成分的上述式(I)表示的苄基琥珀酸衍生物的钙盐和其水合物可用文献记载的方法或与其同样的方法等制造(例如,日本特许公开公报1992年第356459号)。 
对本发明中使用的二氧化硅无特别限定,例如,可以是轻质无水硅酸、水合二氧化硅等。对二氧化硅的掺入量无特别限定,但占制剂总重量的0.5-5%即足够。 
可在本发明中使用的部分α化淀粉可以是各种α化度的淀粉,例如,可以是市售的商品名为PCS(注册商标)的部分α化淀粉。对部分α化淀粉的掺入量无特别限定,但占制剂总重量的5-20%即足够。 
本发明的口服用药物组合物可采用各种剂型,代表性的剂型例如有颗粒剂、微粒剂、散剂、片剂、胶囊。 
例如,颗粒剂、微粒剂和散剂可按常法制造。片剂可按常法,用颗粒或微粒制造,也可按常法,用干法(直接粉末压缩法)直接造粒而加以制造。胶囊可按 常法,将颗粒、微粒或混合粉末直接充入胶囊中加以制造。 
制造本发明的药物组合物时,还可视需要,使用适合各制剂的添加剂,如赋形剂、粘合剂、表面活性剂、润滑剂、助流剂、涂层材料、增湿剂、着色剂、香料等。这些添加剂只要是制剂学上通常使用的物质,不会对上述式(I)表示的苄基琥珀酸衍生物的钙盐或其水合物的溶出性、相容性等产生不良影响即可,可以是任何物质。 
赋形剂例如可以是结晶纤维素等纤维素或纤维素衍生物,玉米淀粉、小麦淀粉、环糊精等淀粉或淀粉衍生物,乳糖、D-甘露糖醇等糖或糖醇,干燥氢氧化铝凝胶、沉淀碳酸钙、偏硅酸铝酸镁、磷酸氢钙等无机赋形剂。 
粘合剂例如可以是羟丙基纤维素、甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、糊精、支链淀粉、羟丙基淀粉、聚乙烯醇、阿拉伯胶、琼脂、明胶、黄蓍胶、聚乙二醇等。 
表面活性剂例如可以是脂肪酸蔗糖酯、硬脂酸聚烃氧基酯、聚氧乙烯氢化蓖麻油、聚氧乙烯聚氧丙二醇、失水山梨糖醇倍半油酸酯、失水山梨糖醇三油酸酯、失水山梨糖醇单硬脂酸酯、失水山梨糖醇单棕榈酸酯、失水山梨糖醇单月桂酸酯、聚山梨醇酯、单硬脂酸甘油酯、月桂基硫酸钠、月桂基聚乙二醇等。 
润滑剂例如可以是硬脂酸、硬脂酸钙、硬脂酸镁、滑石粉等。 
助流剂例如可以是干燥氢氧化铝凝胶、硅酸镁等。 
涂层材料例如可以是羟丙基甲基纤维素2910、甲基丙烯酸氨基烷酯共聚物E、聚乙烯醇缩乙醛二乙基氨基乙酸酯、聚乙二醇6000、氧化钛等。 
增塑剂例如可以是柠檬酸三乙酯、三醋精、聚乙二醇6000等。 
本发明的药物组合物非常稳定,即使在高温高湿度的苛刻条件下放置1周,外观也不变化,也未观察到有效成分分解且未发现溶出率变化。 
下面通过参考例、实施例和试验例对本发明的内容作更详细的说明,但本发明不限于这些内容。 
参考例1 
Figure DEST_PATH_GFW00000038621100041
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)75.0g与结晶纤维素412.5g、乳糖430.5g、玉米淀粉150.0g、低取代的羟丙基纤维素(商品名:L-HPC/LH-11,信越化学工业株式会社产品)45.0g和硬脂酸钙12.0g混合后,用直径6mm的圆面(5R)冲头以约700kg的压力加压成形,制得上述组成的片剂。 
参考例2 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和羧甲醚纤维素(商品名:NS-300(注册商标),五德药品工业株式会社产品)0.8g混合后,添加羟丙基纤维素6重量%水溶液4g(换算成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例3 
Figure DEST_PATH_GFW00000038621100043
Figure DEST_PATH_GFW00000038621100051
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和羧甲基淀粉钠(商品名:Primogel(注册商标),松谷化学工业株式会社产品)0.8g混合后,添加羟丙基纤维素6重量%水溶液4g(换算成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例4 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和低取代的羟丙基纤维素(商品名:L-HPC/LH-11,信越化学工业株式会社产品)0.8g混合后,添加羟丙基纤维素6重量%水溶液4g(换算成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例5 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和低取代的羟丙基纤维素(商品名:L-HPC/LH-22,信越化学工业株式会社产品)0.8g混合后,添加羟丙基纤维素6重量%水溶液4g(换算成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例6 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和部分α化淀粉(商品名:PCS,旭化成工业株式会社产品)0.8g、羟丙基纤维素0.24g和硬脂酸钙0.12g混合后,用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例7 
Figure DEST_PATH_GFW00000038621100071
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和羧甲基淀粉钠(商品名:Primogel(注册商标),松谷化学工业株式会社产品)0.8g、羟丙基纤维素0.24g和硬脂酸钙0.12g混合后,用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例8 
Figure DEST_PATH_GFW00000038621100072
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和低取代的羟丙基纤维素(商品名:L-HPC/LH-11,信越化学工业株式会社产品)0.8g、羟丙基纤维素0.24g和硬脂酸钙0.12g混合后,用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
参考例9 
Figure DEST_PATH_GFW00000038621100081
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和低取代的羟丙基纤维素(商品名:L-HPC/LH-22,信越化学工业株式会社产品)0.8g、羟丙基纤维素0.24g和硬脂酸钙0.12g混合后,用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
实施例1 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)50.0g与结晶纤维素275.0g、乳糖279.0g、玉米淀粉100.0g、低取代的羟丙基纤维素(商品名:L-HPC/LH-11,信越化学工业株式会社产品)30.0g、硬脂酸钙8.0g和轻质无水硅酸(商品名:Adsolider(注册商标)101,Freund产业株式会社产品)8.0g混合后,用直径6mm的圆面(5R)冲头以700kg的压力加压成形,制得上述组 成的片剂。 
实施例2 
Figure DEST_PATH_GFW00000038621100091
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)50.0g与结晶纤维素275.0g、乳糖273.0g、玉米淀粉100.0g、低取代的羟丙基纤维素(商品名:L-HPC/LH-11,信越化学工业株式会社产品)30.0g、硬脂酸钙8.0g和轻质无水硅酸(商品名:Adsolider(注册商标)101,Freund产业株式会社产品)14.0g混合后,用直径6mm的圆面(5R)冲头以700kg的压力加压成形,制得上述组成的片剂。 
实施例3 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.6g、玉米淀粉2.4g、结晶纤维素1.32g和部分α化淀粉(商品名:PCS,旭化成工业株式会社产品)0.8g混合后,添加羟丙基纤维素6重量%水溶液4g(换算 成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
实施例4 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖6.07g、玉米淀粉2.6g、结晶纤维素1.32g和轻质无水硅酸(商品名:Adsolider(注册商标)101,Freund产业株式会社产品)0.13g混合后,添加羟丙基纤维素6重量%水溶液4g(换算成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
实施例5 
Figure DEST_PATH_GFW00000038621100102
Figure DEST_PATH_GFW00000038621100111
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)2.2g与乳糖5.47g、玉米淀粉2.4g、结晶纤维素1.32g、部分α化淀粉(商品名:PCS,旭化成工业株式会社产品)0.8g和轻质无水硅酸(商品名:Adsolider(注册商标)101,Freund产业株式会社产品)0.13g混合后,添加羟丙基纤维素6重量%水溶液4g(换算成羟丙基纤维素,为0.24g),在乳钵中搅拌造粒,用筒式干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.95%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
实施例6 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物(活性成分)220g与乳糖569g、玉米淀粉244g、结晶纤维素140g和部分α化淀粉(商品名:PCS,旭化成工业株式会社产品)90g混合后,添加羟丙基纤维素6重量%水溶液416.7g(换算成羟丙基纤维素,为25g),用高速混合搅拌造粒机搅拌造粒,并用流化床干燥器干燥后过筛,制成30目(500μm)以下的颗粒。将该颗粒与硬脂酸钙混合,使硬脂酸钙的量达到0.92%,然后用直径7mm的圆面(9.5R)冲头以500kg的压力加压成形,制得上述组成的片剂。 
试验例1 
溶出试验(1) 
按日本药典第13版记载的溶出试验第2法(用浆搅拌法),用日本药典第1液900mL作为试验液以50rpm对实施例1~2和参考例1的片剂进行溶出试验(定量方法:HPLC,检测波长:220nm)。这些片剂的溶出试验结果见图1。与参考例1的片剂相比,实施例1~2的片剂显示出优异的溶出性。 
试验例2 
溶出试验(2) 
按日本药典第13版记载的溶出试验第2法(用浆搅拌法),用日本药典第1液900mL作为试验液以50rpm对实施例3~6和参考例2~9的片剂进行溶出试验(定量方法:UV吸光度测定,检测波长:205nm)。这些片剂的溶出试验结果见图2。与参考例3~9的片剂相比,实施例3~6和参考例2的片剂显示出优异的溶出性。 
试验例3 
相容性试验 
将上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物1g与下述各添加剂1g分别混合,将混合物在60℃、相对湿度80%的条件下放置2周后观察外观。 
添加剂 
部分α化淀粉(商品名:PCS(注册商标),旭化成工业株式会社产品)羧甲醚纤维素(商品名:NS-300(注册商标),五德药品工业株式会社产品) 
羧甲醚纤维素钙(商品名:ECG-505(注册商标),五德药品工业株式会社产品) 
羧甲醚纤维素钠(商品名:Ac-Di-Sol,旭化成工业株式会社产品) 
轻质无水硅酸(商品名:Adsolider(注册商标)101,Freund产业株式会社产品) 
其结果见下面的表1。上述式(I)的苄基琥珀酸衍生物的钙盐的二水合物在与部分α化淀粉或轻质无水硅酸配伍时是稳定的,但与羧甲醚纤维素、羧甲醚纤维素钙或羧甲醚纤维素钠配伍时则会变色。 
表1 
试验例4 
稳定性试验 
将实施例3~4和参考例2的片剂在60℃、相对湿度80%的条件下放置1周后检查片剂外观、分解物的量和在日本药典第1液中的溶出时间的变化。结果,含有羧甲醚纤维素的参考例2的片剂的外观变成微黄色,显示分解物增加,而使用部分α化淀粉的实施例3的片剂和使用轻质无水硅酸的实施例4的片剂则未检测出任何变化,溶出时间也无变化,表明片剂非常稳定。 

Claims (2)

1.即释型口服用药物组合物的制备方法,该组合物为片剂;
所述制备方法包括将作为有效成分的下式
表示的苄基琥珀酸衍生物的钙盐的二水合物与作为崩解剂的二氧化硅、结晶纤维素、乳糖和玉米淀粉混合的工序,并采用直接粉末压缩法或湿式颗粒压缩法制成片剂的工序;所述二氧化硅占组合物总重量的0.5-5%。
2.即释型口服用药物组合物,采用权利要求1所述的制备方法制成。
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