CN102711762A - 口服用固体医药组合物 - Google Patents
口服用固体医药组合物 Download PDFInfo
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- CN102711762A CN102711762A CN2010800597883A CN201080059788A CN102711762A CN 102711762 A CN102711762 A CN 102711762A CN 2010800597883 A CN2010800597883 A CN 2010800597883A CN 201080059788 A CN201080059788 A CN 201080059788A CN 102711762 A CN102711762 A CN 102711762A
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- Prior art keywords
- acid
- compound
- pharmaceutical composition
- oral administration
- solid pharmaceutical
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明涉及一种口服用固体医药组合物,其含有(A)2-[4-[2-(苯并咪唑-2-基硫代)乙基]哌嗪-1-基]-N-[2,4-双(甲基硫代)-6-甲基-3-吡啶基]乙酰胺(化合物a)或其酸加成盐、和(B)选自酒石酸、苹果酸、抗坏血酸和苯甲酸中的有机酸。根据本发明,能够改善作为高胆固醇血症、动脉硬化等的治疗药有用的化合物a的溶出性。
Description
技术领域
本发明涉及溶出性得到提高的口服用固体医药组合物。
背景技术
2-[4-[2-(苯并咪唑-2-基硫代)乙基]哌嗪-1-基]-N-[2,4-双(甲基硫代)-6-甲基-3-吡啶基]乙酰胺(以下,称为化合物a)或其酸加成盐,已知具有优异的酰基辅酶A胆固醇酰基转移酶(ACAT)抑制作用、细胞内胆固醇输送抑制作用,作为高胆固醇血症、动脉硬化和急性心肌梗塞等的治疗剂有用(专利文献1~2)。
现有技术文献
专利文献
专利文献1:WO1998/054153
专利文献2:WO2005/020996
发明内容
发明所要解决的课题
高胆固醇血症或动脉硬化等的患者多为高龄者,并且,这些疾病的治疗需要长时间。因此,作为这些疾病的治疗药,希望是能够长时间稳定地给药的口服用医药组合物。通常的口服用医药组合物,在口服后,在胃等的上部消化道,药效成分快速从组合物中开始溶出而被吸收,产生药效。
然而,上述化合物a,在从弱酸性到碱性的溶解性低(例如,对水的溶解性为0.05%(W/V))。因此,在高龄者等中多发的胃酸缺乏症患者时,有在胃中化合物a从医药组合物的溶出性不够,给药物的有效性带来差别的担心。
因此,本发明的课题在于提供含有改善了消化道中的溶出性的化合物a的口服用固体医药组合物。
用于解决课题的方法
因此,本发明的发明人对含有化合物a的固体组合物的溶出性的改善进行了各种研究,结果发现,在各种添加物中,酸性物质改善化合物a的溶出性,进一步研究的结果发现,在各种酸性物质中,酒石酸、苹果酸、抗坏血酸或苯甲酸具有特别优异的化合物a的溶出性改善效果,从而完成了本发明。
即,本发明提供一种口服用固体医药组合物,其含有:(A)2-[4-[2-(苯并咪唑-2-基硫代)乙基]哌嗪-1-基]-N-[2,4-双(甲基硫代)-6-甲基-3-吡啶基]乙酰胺(化合物a)或其酸加成盐、和(B)选自酒石酸、苹果酸、抗坏血酸和苯甲酸中的有机酸。
另外,本发明提供上述的组合物,其中,成分(A)中的化合物a和成分(B)的含有质量比(A/B)为10/3~1/20。
另外,本发明提供一种高胆固醇血症或动脉硬化等的治疗方法,其特征在于,口服含有(A)化合物a或其酸加成盐和(B)选自酒石酸、苹果酸、抗坏血酸、苯甲酸中的有机酸的固体医药组合物。
发明的效果
本发明的固体医药组合物,由于消化道中的化合物a的溶出性良好,因此通过口服快速且稳定地发挥高胆固醇血症和动脉硬化等的治疗效果。
附图说明
图1表示试验例1的溶出试验的结果。
具体实施方式
作为本发明的医药组合物的有效成分(A)化合物a,如上述专利文献1所记载,已知具有优异的ACAT抑制作用、细胞内胆固醇输送抑制作用,作为高胆固醇血症、动脉硬化等的治疗药有用。作为化合物a的酸加成盐,可以列举盐酸、硫酸、硝酸等的无机酸的加成盐和乙酸、乳酸、琥珀酸等的有机酸的加成盐,其中优选盐酸盐。另外,化合物a可以为水合物的形态。另外,化合物a能够通过上述专利文献1所记载的制造方法制备。
从治疗效果的观点出发,本发明的医药组合物中的化合物a的含量优选为10mg~300mg,更优选为25mg~200mg。所使用的化合物a的粒径没有特别限定,但从溶出性、吸收性等的观点出发,优选平均粒径为0.1~200μm,更优选为1~150μm。
本发明的医药组合物含有(A)化合物a和(B)选自酒石酸、苹果酸、抗坏血酸和苯甲酸中的有机酸(下面,也称为有机酸(B))。这些有机酸(B)具有显著改善化合物a从医药组合物中的溶出性的作用。
作为酒石酸,可以列举DL(±)-酒石酸、L(+)-酒石酸和D(-)-酒石酸,但优选L(+)-酒石酸。作为苹果酸,可以列举dl-苹果酸、d-苹果酸、l-苹果酸,但优选dl-苹果酸。作为抗坏血酸优选L(+)-抗坏血酸。作为这些有机酸(B)的市售品,例如,能够购得L(+)-酒石酸(和光纯药工业株式会社制)、日本药典酒石酸(太平化学产业株式会社制)、DL-苹果酸、L(-)-苹果酸(和光纯药工业株式会社制)、L(+)-抗坏血酸(关东化学株式会社制)、苯甲酸(和光纯药工业株式会社制)、日本药典苯甲酸(株式会社伏见制药所制)等。这些有机酸(B)之中,从化合物a的溶出性、味道等的观点出发,特别优选酒石酸和苹果酸。另外,这些有机酸(B)既可以单独使用,也可以组合2种以上使用。另外这些有机酸(B)的平均粒径,从化合物a的溶出性改善效果的观点出发,优选为1000μm以下,特别优选500μm以下。
从化合物a的溶出性的观点出发,有机酸(B)的含量优选相对于化合物a的1质量份为大于0.2质量份的量,更优选为0.3质量份以上。另外,有机酸(B)的含量的上限没有特别限定,但从固体组合物的制造方面的观点出发,优选相对于化合物a的1质量份为20质量份以下,更优选为5质量份。因此,优选使医药组合物中的成分(A)中的化合物a和(B)各种有机酸的质量比(A/B)在5/1~1/20的范围内,更优选在10/3~1/20的范围内,更加优选在2/1~1/5的范围内。
本发明的医药组合物,在成分(A)中的化合物a和(B)有机酸以外,还含有(C)崩解剂,由此化合物a的溶出性进一步改善。作为这样的崩解剂,可以列举交聚维酮、交联羧甲基纤维素钠、α化淀粉、部分α化淀粉、羧甲基淀粉钠、羧甲基纤维素、羧甲基纤维素钠、低取代度羟丙基纤维素、羟丙基淀粉等。
其中,特别优选交聚维酮、交联羧甲基纤维素钠、α化淀粉、部分α化淀粉及羧甲基淀粉钠。
交聚维酮是N-乙烯基-2-吡咯烷酮的交联聚合物。作为交聚维酮,优选使用平均粒径为5~100μm的交聚维酮。作为交联羧甲基纤维素钠,是羧甲基纤维素钠的交联聚合物。α化淀粉是将淀粉和水加热α化后快速干燥得到的淀粉。部分α化淀粉是将玉米淀粉与水一起在常压下或加压下加热,将淀粉粒部分α化后干燥得到的淀粉。羧甲基淀粉钠(也称为淀粉羟乙酸钠)是淀粉的羧甲基醚的钠盐。
这些(C)崩解剂之中,从化合物a的溶出性改善效果的观点出发,特别优选使用交聚维酮、α化淀粉。作为交聚维酮的市售品,例如能够购得Polyplasdone XL、Polyplasdone XL-10、Polyplasdone INF-10(ISPJAPAN株式会社制)、Kollidon CL、Kollidon CL-F、Kollidon CL-SF、Kollidon CL-M(BASF JAPAN株式会社制)等。另外,作为α化淀粉的市售品,例如,能够购得SWELSTAR PD-1(旭化成化学株式会社制)、LYCATAB PGS(Roquette Japan株式会社制)、AMICOL(日淀化学株式会社制)等。
优选(C)崩解剂的含量相对于1质量份成分a为0.1~1质量份,更优选为0.2~0.8质量份。
本发明的医药组合物为口服用固体组合物,具体而言,可以列举片剂、颗粒剂、细粒剂、胶囊剂、散剂、丸剂等,但其中优选片剂、颗粒剂和胶囊剂,从服用性的方面特别优选片剂。
本发明的固体组合物,除了化合物a、有机酸(B)和崩解剂(C),还能够添加赋形剂、粘合剂、润滑剂等,制成各种形态。作为赋形剂可以列举乳糖、玉米淀粉、结晶纤维素、白糖、葡萄糖、甘露醇、山梨糖醇、碳酸钙等。作为粘合剂,可以列举羟丙基纤维素、羟丙甲纤维素、羟乙基乙基纤维素、羧乙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇等。作为润滑剂,可以列举硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石等。
本发明的医药组合物的赋形剂、粘合剂和润滑剂的含量,若考虑化合物a的溶出性,则优选相对于化合物a的1质量份,设为赋形剂0.2~4质量份、粘合剂0.05~1质量份、润滑剂0.01~0.08质量份。
本发明的固体医药组合物的制造法,没有特别限定,例如在为片剂时,能够将上述各成分均匀地混合,利用通用的湿式颗粒压缩法或直接粉末压缩法等制造。另外,还能够对得到的片剂实施包膜、糖衣、缓释性包衣等。此时,作为包衣剂,例如可以列举羧丙甲纤维素、羟丙基纤维素、聚乙烯醇、氧化钛、滑石、聚乙二醇、柠檬酸三乙酯、硬脂酸、含水二氧化硅、轻质硅酸酐等。作为糖衣剂,例如,可以列举阿拉伯胶、精制明胶、明胶、精制白糖、白糖、沉降碳酸钙、滑石、磷酸二氢钙水合物等,作为缓释性包衣剂,例如,可以列举甲基丙烯酸共聚物LD、乙基纤维素、氨基烷基甲基丙烯酸酯共聚物RS、羧丙甲纤维素等。
本发明的医药组合物,化合物a对水的溶解性低也没有关系,通过有机酸(B)的添加使化合物a从组合物的溶出性显著改善。其理由仍不清楚,但可以认为是由于在化合物a与水接触时,通过有机酸(B)的配合,微观中的化合物a的附近的pH降低的缘故。但是,从后述实施例和比较例的对比可知,如果仅由于pH降低,则在水杨酸或邻苯二甲酸酐中化合物a的溶出性应该得到改善,但在这些有机酸中却得不到良好的溶出性的改善效率,因此可以认为有pH以外的某种因素参与。即,本发明的效果可以认为是由化合物a和有机酸(B)的组合物带来的特有的效果。
实施例
接着,列举实施例详细地说明本发明,但本发明不受这些实施例任何限制。
在下面的实施例中,使用化合物a的1盐酸盐(下面,称为化合物a盐酸盐)进行。其中,化合物a盐酸盐使用上述专利文献1所记载的方法和公知的方法合成。
实施例1
将53.65mg的化合物a盐酸盐(作为化合物a为50mg)和L(+)-酒石酸50mg在乳钵中粉碎、混合,得到试样2(103.65mg)。
实施例2
将53.65mg的化合物a盐酸盐和dl-苹果酸50mg在乳钵中粉碎、混合,得到试样4(103.65mg)。
实施例3
将53.65mg的化合物a盐酸盐和苯甲酸50mg在乳钵中粉碎、混合,得到试样1(103.65mg)。
实施例4
将53.65mg的化合物a盐酸盐和L(+)-抗坏血酸50mg在乳钵中粉碎、混合,得到试样3(103.65mg)。
比较例1
将53.65mg的化合物a盐酸盐在乳钵中粉碎,得到试样5(53.65mg)。
比较例2
将53.65mg的化合物a盐酸盐和水杨酸50mg在乳钵中粉碎,得到试样6(103.65mg)。
比较例3
将53.65mg的化合物a盐酸盐和山梨酸50mg在乳钵中粉碎,得到试样7(103.65mg)。
比较例4
将53.65mg的化合物a盐酸盐和邻苯二甲酸酐50mg在乳钵中粉碎,得到试样8(103.65mg)。
比较例5
将53.65mg的化合物a盐酸盐和硼酸50mg在乳钵中粉碎,得到试样9(103.65mg)。
试验例1溶出试验
关于试样1~9的溶出性,按照日本药典一般试验法溶出试验法第2方法(桨法)确认。
在900mL日本药典溶出试验第2液体中分别加入103.65mg(仅试样5为53.65mg)试样1~9,在温度为37±0.5℃、桨转速为50rpm的条件下进行试验,测定5、10、15、30、45、60分钟后的化合物a的浓度。用细孔径0.45μm的PTFE制膜过滤器(东洋滤纸制DISMIC-25HP)过滤在各试验采集的试验溶液,通过使用反相柱(野村化工制:Develosil ODS-HG-5)的高性能液相色谱法测定,算出溶出率。在表1和图1中表示结果。
试验例2pH值的测定
在烧杯中分别加入103.65mg(仅试样5为53.65mg)试样1~9,然后加入纯化水50mL,边以磁力搅拌器进行搅拌边以玻璃电极式氢离子浓度计(东亚电波工业株式会社制:HM-50V)测定溶液的pH。再加入纯化水50mL后,同样进行pH的测定。在表1中表示结果。
[表1]
如上所述,化合物a在单体时几乎不溶出,另外,在与各有机酸或硼酸的配合中也没有发现溶出率的改善,仅在与L(+)-酒石酸、dl-苹果酸、苯甲酸或L(+)-抗坏血酸的配合时在作为判断的标准的30分钟后溶出率就达到超过40%的数值。其中,通过与L(+)-酒石酸或dl-苹果酸的配合,可以发现显著的溶出率的改善效果。
Claims (2)
1.一种口服用固体医药组合物,其特征在于,含有:
(A)2-[4-[2-(苯并咪唑-2-基硫代)乙基]哌嗪-1-基]-N-[2,4-双(甲基硫代)-6-甲基-3-吡啶基]乙酰胺(化合物a)或其酸加成盐,和(B)选自酒石酸、苹果酸、抗坏血酸及苯甲酸中的有机酸。
2.如权利要求1所述的组合物,其特征在于:
成分(A)中的化合物a和成分(B)的含有质量比(A/B)为10/3~1/20。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29073609P | 2009-12-29 | 2009-12-29 | |
US61/290,736 | 2009-12-29 | ||
PCT/JP2010/073497 WO2011081117A1 (ja) | 2009-12-29 | 2010-12-27 | 経口投与用固形医薬組成物 |
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CN102711762A true CN102711762A (zh) | 2012-10-03 |
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CN2010800597883A Pending CN102711762A (zh) | 2009-12-29 | 2010-12-27 | 口服用固体医药组合物 |
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US (1) | US20120289517A1 (zh) |
EP (1) | EP2520299A1 (zh) |
JP (1) | JPWO2011081117A1 (zh) |
KR (1) | KR20120123289A (zh) |
CN (1) | CN102711762A (zh) |
WO (1) | WO2011081117A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1258283A (zh) * | 1997-05-26 | 2000-06-28 | 兴和株式会社 | 新的环状二胺化合物及含有它的药物 |
WO2003057675A1 (fr) * | 2001-12-28 | 2003-07-17 | Kowa Co., Ltd. | Procedes pour produire des composes de diamine cyclique ou des sels de ceux-ci |
CN1845737A (zh) * | 2003-08-29 | 2006-10-11 | 兴和株式会社 | 富脂质斑的稳定化方法和破裂的预防方法 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
YU183988A (en) * | 1988-09-30 | 1990-08-31 | Lek Tovarna Farmacevtskih | Process for preparing dispersion pills of dihydroergotoxine |
DE4001622A1 (de) * | 1990-01-20 | 1991-07-25 | Thomae Gmbh Dr K | Orale arzneimittelformen von pimobendan |
JP2000514100A (ja) * | 1997-07-01 | 2000-10-24 | ファイザー・プロダクツ・インク | 可溶化されたセルトラリン組成物 |
EP1571144A4 (en) * | 2002-12-12 | 2007-08-01 | Kowa Co | HYDROXYALKYLATED CYCLIC DEDIAMINE COMPOUND |
MY140618A (en) * | 2003-02-28 | 2009-12-31 | Kowa Co | Method for preparing acid addition salts of polyacidic basic compounds |
WO2004106323A1 (ja) * | 2003-05-28 | 2004-12-09 | Kowa Co., Ltd. | 環状ジアミン誘導体又はその塩の製造法 |
EP1767527A4 (en) * | 2004-06-30 | 2009-11-11 | Kowa Co | PROCESS FOR PRODUCING CYCLIC DIAMINE DERIVATIVE |
TW200619204A (en) * | 2004-12-10 | 2006-06-16 | Kowa Co | Method for reduction, stabilization and prevention of rupture of lipid rich plaque |
-
2010
- 2010-12-27 US US13/519,333 patent/US20120289517A1/en not_active Abandoned
- 2010-12-27 KR KR1020127016512A patent/KR20120123289A/ko not_active Application Discontinuation
- 2010-12-27 EP EP10840973A patent/EP2520299A1/en not_active Withdrawn
- 2010-12-27 CN CN2010800597883A patent/CN102711762A/zh active Pending
- 2010-12-27 JP JP2011547679A patent/JPWO2011081117A1/ja active Pending
- 2010-12-27 WO PCT/JP2010/073497 patent/WO2011081117A1/ja active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1258283A (zh) * | 1997-05-26 | 2000-06-28 | 兴和株式会社 | 新的环状二胺化合物及含有它的药物 |
WO2003057675A1 (fr) * | 2001-12-28 | 2003-07-17 | Kowa Co., Ltd. | Procedes pour produire des composes de diamine cyclique ou des sels de ceux-ci |
CN1845737A (zh) * | 2003-08-29 | 2006-10-11 | 兴和株式会社 | 富脂质斑的稳定化方法和破裂的预防方法 |
Also Published As
Publication number | Publication date |
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EP2520299A1 (en) | 2012-11-07 |
JPWO2011081117A1 (ja) | 2013-05-09 |
US20120289517A1 (en) | 2012-11-15 |
WO2011081117A1 (ja) | 2011-07-07 |
KR20120123289A (ko) | 2012-11-08 |
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