CN101909602A - 口服粉粒状抗肿瘤剂 - Google Patents
口服粉粒状抗肿瘤剂 Download PDFInfo
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- CN101909602A CN101909602A CN2008801233887A CN200880123388A CN101909602A CN 101909602 A CN101909602 A CN 101909602A CN 2008801233887 A CN2008801233887 A CN 2008801233887A CN 200880123388 A CN200880123388 A CN 200880123388A CN 101909602 A CN101909602 A CN 101909602A
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- Prior art keywords
- antitumor agent
- powder
- granular
- oral powder
- ftorafur
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Abstract
本发明提供一种口服粉粒状抗肿瘤剂，该口服粉粒状抗肿瘤剂能够使因高药理活性而在操作上危险较多的抗肿瘤剂安全服用，且与胶囊剂和片剂具有同等的稳定性。一种口服粉粒状抗肿瘤剂，其特征在于，由除纤维素衍生物以外的糖类包覆含有抗肿瘤剂的粉粒状组合物而得到。
Description
技术领域
本发明涉及以糖类的包衣膜包覆的口服粉粒状抗肿瘤剂。
背景技术
根据国立癌中心癌对策情报中心的《最新癌统计》，癌症罹患率(2000年)，64岁前的男性为11％、女性为10％，74岁前的男性为27％、女性为17％。另外，根据厚生劳动省大臣官房统计情报部的《人口动态统计》，从昭和56年起，癌症占日本国死因的第1位，在平成16年死亡320,315人，占总死亡人数的31.1％。
作为对众多国民所罹患的癌症的治疗方法，可以列举外科疗法、化学疗法、放射线疗法、基因疗法、免疫疗法等。
其中，化学疗法是使用抗肿瘤剂进行的药物疗法，抗肿瘤剂有注射剂、片剂、胶囊剂、干糖浆剂、颗粒剂等剂型。
使用注射剂的治疗方法大多使用点滴慢慢给药，患者被迫受到长时间的限制。另一方面，胶囊剂、片剂等口服剂由于在家庭和工作场所等医院以外的地方也能够服用，所以具有不会显著影响日常生活的很大优点。因此，对于手术后不能长期住院治疗的患者而言，也大多可以作为出院后的辅助疗法使用。
但是，在临床上，癌症罹患率高的高龄者大多伴随吞咽功能的下降而难以吞咽片剂或胶囊剂。另外，在癌症患者中，还存在以胃瘘、饲管等摄取营养，因此在物理上不能服用片剂或胶囊剂的人。因此，目前的现状是，由药剂师进行片剂粉碎或者取出胶囊剂内容物的操作，作为粉粒状制剂给药。
一般而言，显示抗肿瘤效果的活性成分大多药理活性很高而被分类为烈性药，对其处理需要充分注意。但是，通过粉碎片剂或取出胶囊剂内容物的操作而制备得到的抗肿瘤剂，药物处于剥出状态，所以，经常存在着药理活性高的药物导致污染的危险性，该污染不仅波及到药剂师，而且可能波及到服用的患者和服药辅助者。
另一方面，以往，作为粉粒状制剂，上市了散剂、干糖浆剂、细粒剂、颗粒剂等。但是，作为施加了表面处理以使药物不被剥出的粉粒状抗肿瘤剂，目前为止仅已知施加了肠溶性包衣的颗粒剂(专利文献1)，因为包衣的目的主要是减轻副作用，所以，以安全服用为主要着眼点而施加包衣的粉粒状抗肿瘤剂尚不存在。认为这对于患者、辅助者和医疗从业者处理药理活性高的抗肿瘤剂而言是考虑不周的。
专利文献1：日本特开平4-36237号公报
发明内容
本发明的目的在于提供一种口服粉粒状抗肿瘤剂，该口服粉粒状抗肿瘤剂能够使因高药理活性而在操作上危险较多的抗肿瘤剂安全服用，且与胶囊剂和片剂具有同等的稳定性。
另外，在本说明书中，所谓“能够安全服用”，指的是药物不剥出，从而在配药和服用时不发生药物污染。
本发明的发明人为了解决上述课题，尝试使用迅速溶解的各种包衣基剂制造能够口服给药的粉粒状抗肿瘤剂。
其结果，虽然将药物进行包覆避免了药物污染的危险性，但可以确认包含以往的剂型中没有的新有关物质的总有关物质量增加，稳定性显著下降的问题变得明显。
因此，尽管具认为使用迅速溶解的包衣基剂得到包覆表面且具有和以往剂型同等稳定性的粉粒状物是不可能的，本发明的发明人仍然继续进行了各种研究，得到如下见解：
(a)如果在包衣基剂中不使用水溶性高分子而使用糖类，则能够确保和以往剂型同等的稳定性。
(b)这样得到的粉粒状物，由于包衣膜的物理性磨损少，所以在配药和服用时不必担心药物附着而能够安全服用。此外，由于包衣膜迅速溶解，所以不会导致生物利用度的下降。
本发明就是基于这样的见解而完成的发明。
即，本发明提供一种口服粉粒状抗肿瘤剂，其特征在于，由除纤维素衍生物以外的糖类包覆含有抗肿瘤剂的粉粒状组合物而得到。
在本说明书中，所谓“粉粒状物”，指的是将医药品制成为粉状或粒状的制剂。根据这些制成为粉状或粒状的医药品的粒度分布，分为散剂、细粒剂、颗粒剂等类别。
发明的效果
如果根据本发明，则发挥以下优异的效果。
(a)如果在包衣基剂中不使用水溶性高分子而使用糖类，则能够确保和以往剂型同等的稳定性。
(b)这样得到的粉粒状物，由于包衣膜的物理性磨损少，所以在配药和服用时不必担心药物附着而能够安全服用。此外，由于包衣膜迅速溶解，所以不会导致生物利用度的下降。
(c)因此，根据本发明，能够得到一种口服粉粒状抗肿瘤剂，该口服粉粒状抗肿瘤剂能够使因高药理活性而在操作上危险较多的抗肿瘤剂安全服用，且与胶囊剂和片剂具有同等的稳定性。
具体实施方式
作为本发明中的抗肿瘤剂，只要是包含显示抗肿瘤效果的药效成分的制剂，则没有特别限制，例如，可以列举烷基化剂、代谢拮抗剂、抗肿瘤性抗生素、抗肿瘤性植物成分制剂等。
作为烷基化剂，具体而言，可以列举氯乙胺类抗肿瘤剂、乙撑亚胺类抗肿瘤剂、磺酸酯类抗肿瘤剂等。
作为代谢拮抗剂，具体而言，可以列举巯基嘌呤类抗肿瘤剂、甲氨蝶呤类抗肿瘤剂、氟尿嘧啶类抗肿瘤剂、胞嘧啶类抗肿瘤剂等。
作为抗肿瘤性抗生素，具体而言，可以列举丝裂霉素C、放线菌素D、博来霉素类抗肿瘤剂、蒽环类抗生素、新制癌菌素类抗肿瘤剂等。
另外，作为其它，可以列举醋葡内酯、阿那曲唑、依西美坦、法倔唑盐酸盐水合物、甲基苄肼盐酸盐、他莫昔芬柠檬酸盐、托瑞米芬柠檬酸盐、吉非替尼、索布佐生、他米巴罗汀、维A酸、比卡鲁胺、氟他胺、伊马替尼甲磺酸盐、厄洛替尼盐酸盐、索拉非尼甲苯磺酸盐、舒尼替尼苹果酸盐等。
在抗肿瘤剂中，从药效和安全性的观点出发，优选能够口服给药的抗肿瘤剂。在本说明书中，所谓“能够口服给药的抗肿瘤剂”，只要是含有通过口服而显示抗肿瘤效果的药效成分的抗肿瘤剂，则没有特别限定，但优选含有现在作为口服剂而上市的药效成分的抗肿瘤剂。
在能够口服给药的抗肿瘤剂中，从改善药剂稳定性的观点出发，优选代谢拮抗剂，特别优选其复方制剂。作为代谢拮抗剂，可以列举巯基嘌呤、甲氨蝶呤、卡培他滨、卡莫氟、替加氟、脱氧氟尿苷、氟尿嘧啶、阿糖胞苷十八烷基磷酸盐(Cytarabine Ocfosfate)、羟基脲、替加氟-尿嘧啶、替加氟-吉莫斯特-奥替拉西钾复方制剂，特别优选替加氟-吉莫斯特-奥替拉西钾复方制剂，更优选它们的摩尔比为1∶0.4∶1的复方制剂。
本发明的口服粉粒状抗肿瘤剂由除纤维素衍生物以外的糖类包覆含有上述抗肿瘤剂的粉粒状组合物而得到。
作为本发明中的糖类，只要是除纤维素衍生物以外的作为医药品添加剂通常所使用的糖类，则没有特别限制，例如，可以列举单糖类、寡糖、多糖类等。
作为单糖类，可以列举三碳糖(甘油醛、二羟丙酮等)、四碳糖(赤藓糖、苏糖等)、五碳糖(木糖、阿拉伯糖、核糖、脱氧核糖等)、六碳糖(葡萄糖、果糖、半乳糖、甘露糖等)、脱氧糖(岩藻糖、鼠李糖、硫代葡萄糖等)、氨基糖(氨基葡糖、氨基半乳糖等)、糖醇(甘露糖醇、肌醇等)、糖醛酸(葡糖醛酸、半乳糖醛酸等)、醛糖糖酸(葡糖酸等)等。
作为寡糖，可以列举二糖类(海藻糖、曲二糖、黑曲霉糖、麦芽糖、异麦芽糖、蜜二糖、槐二糖、昆布二糖、龙胆双糖、纤维二糖、乳糖、松二糖、蔗糖、明串珠菌二糖、异麦芽酮糖等)、三糖类(6-蔗果三糖、1-蔗果三糖、新蔗果三糖、松三糖、蜜三糖、潘糖、异潘糖、低聚乳果糖等)、四糖类(水苏糖、大蒜糖等)、五糖类(毛蕊糖等)和其它(环糊精、环果聚糖、环状糊精等)。
作为多糖类，可以列举淀粉、琼脂糖、角叉菜胶、壳多糖等。
其中，这些糖类可以单独使用或者组合两种以上使用。
在本发明的糖类中，从改善药剂稳定性和包衣膜的物理性磨损度的观点出发，优选单糖类或寡糖，特别优选糖醇或二糖类，更加优选甘露糖醇或蔗糖。
其中，在本发明中，从糖类中除外纤维素和纤维素衍生物，作为所除外的纤维素衍生物，可以列举甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙甲纤维素等。
作为这些糖类的包覆对象的粉粒状组合物，可以列举使用抗肿瘤剂和公知的制剂添加物由通常的造粒方法造粒得到的粉粒状组合物。作为造粒方法，例如，可以列举使用流动层造粒法、搅拌造粒法、转动流动层造粒法、挤出造粒法、喷雾干燥造粒法等将核心颗粒造粒的方法。
作为在本发明中使用的粉粒状组合物的典型的制造方法，例如，可以列举利用挤出造粒装置，使用制剂添加物，将含有能够口服给药的抗肿瘤剂的核心颗粒造粒的方法。
上述制剂添加物在使用时，在不妨碍本发明效果的范围内使用。作为这样的制剂添加物，只要是在粉粒状制剂的制造中通常所使用的各种制剂添加物，则没有特别问题，例如，可以列举赋形剂、崩解剂、粘合剂、润滑剂、着色剂、着香剂、矫味剂等。作为赋形剂，可以列举糖类、轻质无水硅酸和硅酸钙等。作为崩解剂，可以列举低取代度羟丙基纤维素、羧甲基纤维素、交聚维酮、羧甲基纤维素钙和交联羧甲基纤维素钠等。作为粘合剂，可以列举羟丙基纤维素、羟丙甲纤维素、聚乙烯醇、聚乙烯吡咯烷酮等。作为润滑剂，可以列举硬脂酸镁、硬脂酸钙、滑石和蔗糖脂肪酸酯等。作为着色剂，可以列举食用黄色5号色素、食用红色2号色素、食用蓝色2号色素、食用色淀色素、黄色三氧化二铁和氧化钛等。作为着香剂，可以列举橙、柠檬各种香料等。作为矫味剂，可以列举L-薄荷醇、樟脑、薄荷等。
作为所得到的造粒物(粉粒状组合物)的包覆方法，可以列举使用流动层、包覆盘等的方法。
更优选的可以列举使用流动层造粒包覆装置，向核心颗粒上喷雾溶解有糖类的水溶液而进行包覆的方法。
另外，由糖类包覆的比例只要在不妨碍本发明效果的范围内，则没有特别限制，优选为全部包覆量的70～100质量％，其比例特别优选为90～100质量％的范围，特别优选只以糖类包覆。
另外，包覆时的包覆量只要在不妨碍本发明效果的范围内，则没有特别限制，相对于粉粒状抗肿瘤剂的总量，优选为1～20质量％，更优选为2～15质量％，特别优选为3～10质量％。
本发明的粉粒状抗肿瘤剂的剂型没有特别限定，例如，可以列举颗粒剂、散剂和细粒剂。其中，在颗粒剂、散剂和细粒剂中，包括在使用时溶解使用的干糖浆剂，另外，包括在口腔内迅速溶解、崩解、无水也可以服用的粉粒状物。在这里，本发明所称的粉粒状物的粒径优选为75～1400μm，在颗粒剂时更优选为250～1000μm。
在本发明中，当含有替加氟作为抗肿瘤剂时，1次替加氟的最低给药量预计为20mg左右，但药物浓度低于0.5质量％时，在服用相当于20mg替加氟量时，必须服用多于4g的粉粒状物，不容易服用，另外，药物浓度高于15质量％时，相当于20mg替加氟的量将少于133mg，该量以通常的分装装置非常难以充填，因此，在以包衣膜包覆替加氟而得到的粉粒状物中，优选包含0.5～15质量％，特别优选包含5～10质量％。
本发明的口服粉粒状抗肿瘤剂含有抗肿瘤剂和根据需要的上述制剂添加物，因为进行了表面处理以使药物不在表面剥出，所以不用担心药物附着，是能够安全服用的口服制剂。
实施例
以下，列举实施例和试验例更详细地说明本发明，但本发明不受这些实施例的限定。
实施例1
在捏合机(装置名称“Dalton万能混合搅拌机，25AM-02-rr”，株式会社Dalton生产)中加入150g替加氟、43.5g吉莫斯特、147g奥替拉西钾、2659.5g乳糖、60g羟丙基纤维素(商品名“HPC-M”，日本曹达株式会社生产)，加入300g精制水，以转速75分钟-1捏合5分钟。
使用安装有Φ0.5mm滤网的挤出造粒机(装置名称“Pelleter DoubleEXD-60”，Fuji Paudal Co.，Ltd.生产)将该捏合物造粒。以开孔1.5mm的筛子将该造粒物过筛后，使用流动层造粒包覆装置(装置名称“Multiplex MP-01”，Powrex Corporation生产)干燥。干燥后，将所得到的造粒物整粒为355～1000μm，得到颗粒剂。
比较例1
在441g精制水中加入23.5g羟丙甲纤维素(取代度类型2910，商品名TC-5R)、5.9g滑石，制成包衣液。在流动层造粒包覆装置(MultiplexMP-01)中加入800g实施例1的颗粒，以喷雾速度3.2g/分钟将上述包衣液喷雾，得到包衣颗粒。
比较例2～4
按照和比较例1同样的方法，以表1中记载的量使用在表1中所示的水溶性高分子，得到包衣颗粒。
试验例1
将实施例1和比较例1～4中得到的颗粒在60℃保存10日后，由日本药典一般试验法的物理性试验法收载的液体色谱法测定生成的总有关物质量。
[表1]
单位：重量份
根据表1的结果可以明确，判断在颗粒剂上包覆水溶性高分子使得总有关物质量增加，稳定性下降。
实施例2
在捏合机(装置名称“Dalton万能混合搅拌机，25AM-02-rr”)中加入300g替加氟、87g吉莫斯特、294g奥替拉西钾、2319g乳糖、60g羟丙基纤维素(商品名“HPC-L”，日本曹达株式会社生产)，加入300g精制水，以转速75分钟-1捏合10分钟。使用安装有Φ0.5mm滤网的挤出造粒机(装置名称“Pelleter Double EXD-60”)将该捏合物造粒。使用流动层造粒包覆装置(装置名称“Multiplex MP-01”)干燥。干燥后，将所得到的造粒物整粒为250～1000μm，得到颗粒剂。
另一方面，在135g精制水中溶解15g蔗糖，制成包衣液。在流动层造粒包覆装置(Multiplex MP-01)中加入500g上述颗粒，以喷雾速度9g/分钟将上述包衣液喷雾，得到包衣颗粒。
实施例3
按照和实施例2同样的方法，在225g精制水中溶解25g D-甘露糖醇，制成包衣液。在流动层造粒包覆装置(Multiplex MP-01)中加入500g上述颗粒，以喷雾速度12g/分钟将上述包衣液喷雾，得到包衣颗粒。
比较例5
除了不进行使用蔗糖的包覆以外，和实施例2同样操作，得到颗粒。
试验例2
在实施例2、3和比较例5中得到的颗粒剂上施加防湿包装(HDPE瓶+硅胶)，在40℃、75％R.H.下保存6个月后，由日本药典一般试验法的物理学试验法收载的液体色谱法测定生成的总有关物质量。
[表2]
为了进行比较，一并表示在市售品(替加氟-吉莫斯特-奥替拉西钾胶囊，销售名称“TS-1胶囊”)的防湿包装(PTP+铝袋)品的总有关物质量。根据表2的结果可以明确，判断即使在颗粒剂上施加蔗糖或D-甘露糖醇的包衣，在总有关物质量上也没有大的差别。另外，在蔗糖和D-甘露糖醇中，尽管D-甘露糖醇的包覆量多，但总有关物质量少。
试验例3
根据下述评价法评价在实施例2、3中得到的包衣颗粒的磨损度。评价法：
将约30g将粒径整粒为355～710μm的包衣颗粒与4个铝制球同时加入安装有铝罐的行星球磨机(Pulverisette5，FRITSCH生产)中，以转速刻度6运转10分钟。从罐中取出颗粒，以开孔250μm的筛过筛。其中，磨损度由下式算出。
磨损度A(％)＝(加入量-开孔250μm筛上质量)/加入量×100
磨损度A越小，来自颗粒表面的磨损就越小，在包衣颗粒的情况下，意味着防止由药物产生的污染。
[表3]
以上述测定法另行测定的替加氟颗粒(“市售名称：SterozineGranules，寿制药株式会社生产”)的磨损度是7.4％。根据表3的结果可以明确，判断实施例2、3的包衣颗粒相比于现有的颗粒剂几乎没有磨损。
试验例4
根据日本药典一般试验法的制剂试验法收载的溶出试验法，对实施例2、3中得到的颗粒实施试验。
<测定条件>
溶出试验法：第2法(50分钟-1)
试液：水(900mL)
测定波长：λ＝262nm
取样：开始5分钟后
[表4]
根据表4的结果可以明确，药效成分(替加氟、吉莫斯特、奥替拉西钾)在5分钟内从实施例2、3的包衣颗粒中几乎全部溶出。
根据以上结果判断，如果在包衣基剂中不使用水溶性高分子而使用糖类，则能够确保和以往剂型同等的稳定性，并且包衣膜迅速溶解而释放药物，不必担心生物利用度下降。而且，由于包衣膜的物理磨损少，所以在配药和服用时不用担心药物附着，从而可以安全服用。
Claims (12)
1.一种口服粉粒状抗肿瘤剂，其特征在于：
由除纤维素衍生物以外的糖类包覆含有抗肿瘤剂的粉粒状组合物而得到。
2.如权利要求1所述的口服粉粒状抗肿瘤剂，其特征在于：
糖类是单糖类或寡糖。
3.如权利要求1或2所述的口服粉粒状抗肿瘤剂，其特征在于：
糖类是糖醇或二糖类。
4.如权利要求1～3中任一项所述的口服粉粒状抗肿瘤剂，其特征在于：糖类是甘露糖醇或蔗糖。
5.如权利要求1～4中任一项所述的口服粉粒状抗肿瘤剂，其特征在于：剂型是颗粒剂。
6.如权利要求1～5中任一项所述的口服粉粒状抗肿瘤剂，其特征在于：抗肿瘤剂是能够口服给药的抗肿瘤剂。
7.如权利要求6所述的口服粉粒状抗肿瘤剂，其特征在于：
抗肿瘤剂是代谢拮抗剂。
8.如权利要求6或7所述的口服粉粒状抗肿瘤剂，其特征在于：
抗肿瘤剂是含有替加氟的抗肿瘤剂。
9.如权利要求6～8中任一项所述的口服粉粒状抗肿瘤剂，其特征在于：抗肿瘤剂含有(a)替加氟、(b)吉莫斯特和(c)奥替拉西钾。
10.如权利要求9所述的口服粉粒状抗肿瘤剂，其特征在于：
以1∶0.4∶1的摩尔比含有(a)替加氟、(b)吉莫斯特和(c)奥替拉西钾。
11.如权利要求1～10中任一项所述的口服粉粒状抗肿瘤剂，其特征在于：在以包衣膜包覆的粉粒状物中，含有0.5～15质量％的替加氟。
12.如权利要求1～10中任一项所述的口服粉粒状抗肿瘤剂，其特征在于：在以包衣膜包覆的粉粒状物中，含有5～10质量％的替加氟。
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| SG194922A1 (en) | 2011-05-25 | 2013-12-30 | Taiho Pharmaceutical Co Ltd | Dry-coated tablet containing tegafur, gimeracil and oteracil potassium |
| CA2856692C (en) * | 2011-11-24 | 2016-06-28 | Imuneks Farma Ilac Sanayi Ve Ticaret A.S. | Imatinib solid dosage forms reconstituted just before use |
| TWI608849B (zh) * | 2014-06-16 | 2017-12-21 | 國邑藥品科技股份有限公司 | 可調控釋放度之高載藥量之醫藥組合物及其製備方法 |
| CN107865871B (zh) * | 2016-09-23 | 2021-09-03 | 江苏恒瑞医药股份有限公司 | 一种替吉奥组合物及其制备方法 |
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| EP1757283B1 (en) * | 2004-06-09 | 2012-10-17 | Taiho Pharmaceutical Co., Ltd. | Antitumor effect fortifier, antitumor agent and method of therapy for cancer |
| CN100333726C (zh) * | 2004-12-23 | 2007-08-29 | 鲁南制药集团股份有限公司 | 含有替加氟、吉莫斯特和氧嗪酸钾的口腔崩解片 |
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| JPWO2009084216A1 (ja) | 2011-05-12 |
| TW200932286A (en) | 2009-08-01 |
| MY151207A (en) | 2014-04-30 |
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| JP5722967B2 (ja) | 2015-05-27 |
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| KR101503559B1 (ko) | 2015-03-17 |
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| EP2223683A1 (en) | 2010-09-01 |
| CN101909602B (zh) | 2012-06-13 |
| JP5611403B2 (ja) | 2014-10-22 |
| EP2223683B1 (en) | 2014-06-18 |
| US20100266706A1 (en) | 2010-10-21 |
| US20160151295A1 (en) | 2016-06-02 |
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