CN101340882B - 含有药物的蜡基质粒子的制造方法、用于该方法的挤出机、及含有西洛他唑的缓释制剂 - Google Patents
含有药物的蜡基质粒子的制造方法、用于该方法的挤出机、及含有西洛他唑的缓释制剂 Download PDFInfo
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- CN101340882B CN101340882B CN200680048206.5A CN200680048206A CN101340882B CN 101340882 B CN101340882 B CN 101340882B CN 200680048206 A CN200680048206 A CN 200680048206A CN 101340882 B CN101340882 B CN 101340882B
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- Prior art keywords
- wax
- particle
- extruder
- cilostazol
- slow releasing
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Abstract
本发明的目的在于提供一种以简便的方法制造含有药物的蜡基质粒子特别是平均粒径1mm以下的含有药物的蜡基质粒子,且在从熔融至喷雾的工序中不发生由熔融药物的重结晶导致的液体阻塞。经过以下工序(i)及(ii),制造含有药物及蜡的含有药物的蜡基质粒子:工序(i):向挤出机中供给所述药物及蜡,所述挤出机中滚筒(1)及冲模的温度设定为所述蜡的熔点以上的温度;工序(ii):一边在所述挤出机内熔融混炼所述药物及蜡,一边从喷嘴(5)向温度低于所述蜡的熔点的环境气体中喷雾排出所述药物及蜡的熔融混炼物,由此成型为粒子状,所述喷嘴(5)直接安装在冲模部(3)上,所述冲模部(3)设置在所述挤出机滚筒(1)的前端。
Description
技术领域
本发明涉及一种含有药物的蜡基质粒子的制造方法。另外,本发明涉及一种用于制造含有药物的蜡基质粒子的挤出机(extruder)。
本发明还涉及一种含有西洛他唑(cilostazol)的缓释制剂。更详细而言,本发明涉及下述缓释制剂,所述缓释制剂是包含含有西洛他唑的蜡基质粒子的制剂,在空腹给药和进食后给药的情况下西洛他唑释放或血中浓度变化的差异小,具有优异的缓释性。
背景技术
作为口服缓释制剂,已知有片剂之类的一单元型、和颗粒之类的多单元型,人们期待一种体内药物释放及血中浓度分布的个体间差异小的多单元型制剂。另外,作为缓释制剂,使用羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、聚氧乙烯(PEO)等水溶性高分子的亲水性水凝胶制剂较为适用,但上述亲水性水凝胶制剂存在药物释放速度易受食物影响的倾向。另外,pH依赖型或pH非依赖型的高分子膜包衣,可以调节制剂的溶解性且片剂和颗粒均适用,但上述膜包衣受胃内酸性度差异的影响不能忽略,且对于粒径小的颗粒特别是粒径在100μm以下的微小粒子在制造适用性(涂布时间、收率、组间差异)方面存在很多问题。另外,乙基纤维素(EC)之类水不溶性高分子的膜包衣制剂,存在下述缺点,即不仅难以适用于微小粒子,而且也不适用于难溶性药物的缓释化。
另外,已知通过使用水不溶性油脂性物质作为基质基剂也可以使其具有缓释性,含有上述基质基剂的粒子(以下,有时也称为蜡基质粒子)作为缓释制剂有用。
目前,作为具有蜡基质的制剂,已知有从1mm以下的粒子状制剂到数mm以上的颗粒状或片剂状制剂,作为其制造方法,可以采用熔融法、喷雾法、加热熔融喷雾法、混炼挤出法等。上述现有方法中,作为制造平均粒径1mm以下的蜡基质粒子的方法,已知有在熔点以上的温度下加热熔融低熔点物质,添加药物及其他添加剂混合后,使用大型喷雾冷却器喷雾冷却的方法(加热熔融喷雾法)(参见专利文献1)。此加热熔融喷雾法适于形成球状基质粒子,但存在以下缺点:(1)必需有用于喷雾冷却的大型装置;(2)必需有用于将原料在加热熔融贮罐内均匀混合的装置;(3)必须对连接贮罐和喷雾冷却装置所需的管路、泵等进行温度控制等。并且,采用加热熔融喷雾法大量生产时必须加热处理大量原料,原料不可避免地长时间暴露于高温下,因此可能会由热导致药物或添加剂的稳定性被破坏。进而,加热熔融喷雾法还存在下述缺陷:在溶解于熔融混合物中的药物易析出时,在贮罐内熔融混合液的表面或与贮罐壁面的浸液面、输液管、旋转盘、喷嘴等喷雾部分等发生因药物析出固化而导致的问题。
另外,专利文献2中公开了使用多螺杆型挤出机制造蜡基质粒子的方法。此专利文献2的方法中,将来自冲模(die)的排出物的温度控制在蜡的熔点以下(优选低于熔点10~20℃的较低温度),一边将排出物冷却固化一边用高速切刀切割成颗粒状,然后通过用辊式造粒机(roll granulator)等粉碎,得到平均粒径1mm以下的蜡基质粒子。然而,即使此方法可以采用多螺杆型挤出机仅通过一个步骤即可使原料形成基质状,却存在以下缺陷,即,为了形成1mm以下的粒子,必须另外进行粉碎处理,同时采用粉碎处理不能得到球状粒子。
进而,作为使用挤出机制造蜡基质制剂的方法,已知有下述方法:用高速切刀将来自挤出机的排出物切断,成型为圆形的方法(例如,参见专利文献3);将来自挤出机的排出物成型为叶状片剂的方法(例如,参见专利文献4);将来自挤出机的排出物用研磨机粉碎,一边用水、空气冷却一边用高速切刀进一步切断的方法(例如,参见非专利文献1)。然而,上述使用挤出机的方法,与上述专利文献1的方法 相同,存在为了得到平均粒径在1mm以下的蜡基质粒子,需要另外进行粉碎处理的缺陷,除此之外,还存在形状不均匀、不能得到球状粒子的问题。另外,目前还公开了使用双螺杆挤出机熔融混合原料,用泵输送至雾化器进行喷雾的方法(参见专利文献5)。然而,此方法必须通过泵进行输液,在管路连接部产生由于熔融的药物结晶化导致液体阻塞等不良情况,因此,存在装置保养的负担增大、制造效率降低等缺陷。
鉴于上述现有技术,迫切期望确立一种方法,该方法能够以简便的方法制造含有药物的蜡基质粒子、特别是平均粒径1mm以下的含有药物的蜡基质粒子,而在从熔融至喷雾的工序中不发生由于熔融的药物重结晶导致的液体阻塞。
另外,现有的含有药物的蜡基质粒子不仅存在上述制造方面的问题,而且还存在配合的药物受限制的缺陷,因此,临床上的应用范围受限。具体而言目前的状况为,由于在有限的于消化管内移动的时间内蜡基质粒子完全释放且被吸收是很重要的,所以仅限于在水中的溶解度为约0.6w/v%左右的溶解度较高的茶碱之类药物。另外,一般认为,蜡基质粒子通过消化管内的消化作用,蜡基质基剂迅速崩解,因此在空腹给药和进食后给药的情况下药物释放或血中浓度变化的差异增加的倾向变大。虽然上述缺陷可以通过严密地设定制剂的给药时间来消除,但是需要让患者自己遵守制剂给药时间,从制剂特性的观点考虑仍期望消除上述缺陷。
另一方面,为难溶性药物的西洛他唑,作为具有末梢血管扩张作用的抗血小板药物,可以用于治疗以慢性动脉闭塞症为基础的溃疡、或改善锐痛及寒冷等缺血性各症状。目前为止,专利文献6中公开了将西洛他唑制成缓释制剂的技术,但对于作为蜡基质粒子进行制剂化的技术尚无报道。另外,对于含有西洛他唑的缓释制剂,为了有效地呈现所期望的药效,使西洛他唑在消化管下部释放是十分重要的,因此,一般认为使缓释制剂含有粒径为数μm的西洛他唑是有效的。
因此,人们还迫切期望开发出一种蜡基质粒子,所述蜡基质粒子 含有西洛他唑,在空腹给药和进食后给药的情况下西洛他唑释放或血中浓度变化的差异小,具有优异的缓释性。
专利文献1:专利第2973751号说明书
专利文献2:专利第2616252号说明书
专利文献3:特开平10-57450号公报
专利文献4:特表平10-511289号公报
专利文献5:特开2005-162733号公报
专利文献6:特开2001-163769号公报
非专利文献1:Pharmaceutical Extrusion Technology、edited by IsaacGhebre-Sellassie、Charles Martin、DRUGS AND THEPHARMACEUTICAL SCIENCE VOL.133、MARCEL DEKKER、INC、2003、Chapter 9pages 171~181
发明内容
本发明的目的在于提供一种简便地制造含有药物的蜡基质粒子、特别是平均粒径1mm以下的含有药物的蜡基质粒子的方法,该方法在从熔融至喷雾的工序中不发生因熔融的药物重结晶而导致的液体阻塞。另外,本发明的目的在于提供一种可简便地制造含有药物的蜡基质粒子的装置。进而,本发明的目的还在于提供一种缓释制剂,所述缓释制剂是包含含有西洛他唑的蜡基质粒子的制剂,在空腹给药和进食后给药的情况下西洛他唑释放或血中浓度变化的差异小、且具有优异的缓释性。
本发明人为了解决上述课题进行了潜心研究,发现使用直接安装了可喷雾排出原料的喷嘴的挤出机,可以制造粒子状的含有药物的蜡基质。即,向挤出机供给药物及蜡,将滚筒及冲模的温度设定为蜡的熔点以上的温度,一边将药物及蜡熔融混炼,一边从喷嘴向空气中喷雾排出,在空中冷却固化,由此可以制造粒子状的含有药物的蜡基质,所述喷嘴安装在设置于上述挤出机滚筒前端的冲模部。
进而,本发明人等发现组合含有(A)西洛他唑结晶和(B)脂肪 酸甘油酯及/或聚甘油脂肪酸酯、且含有平均粒径为40~200μm的蜡基质粒子的制剂,具有优异的西洛他唑缓释性,且在空腹给药和进食后给药的情况下西洛他唑释放或血中浓度变化的差异减小。本发明是基于上述发现,通过进一步反复改良而完成的。
即,本发明提供如下所示的发明:
项1、含有至少1种药物及至少1种蜡的含药物蜡基质粒子的制造方法,包含以下工序,
工序(i):向挤出机中供给上述至少1种药物及至少1种蜡,所述挤出机中的滚筒及冲模的温度设定为上述蜡的熔点以上的温度,及
工序(ii):一边在所述挤出机内熔融混炼上述药物及蜡,一边从喷嘴向温度低于上述蜡的熔点的环境气体中喷雾排出熔融混炼的上述药物及蜡的混合物,由此成型为粒子状,所述喷嘴直接安装在冲模部,所述冲模部设置在上述挤出机滚筒的前端。
项2、如项1所述的制造方法,其中,所述喷嘴为单流体喷嘴、加压喷嘴、双流体喷嘴或多流体喷嘴。
项3、如项1所述的制造方法,其中,所述挤出机为单螺杆挤出机、双螺杆挤出机或三螺杆以上的多螺杆挤出机。
项4、如项1所述的制造方法,其中,含有药物的蜡基质粒子为球形。
项5、如项4所述的制造方法,其中,含有药物的蜡基质粒子的平均粒径为1mm以下。
项6、如项1所述的制造方法,其中,药物为选自茶碱、西洛他唑、酮基布洛芬、萘普生、双氯酚酸钠、伊曲康唑、吡罗昔康、苯妥英、维拉帕米、丙丁酚、及托伐普坦中的至少1种。
项7、如项1所述的制造方法,其中,蜡为选自石蜡、微晶蜡、地蜡、日本蜡、可可脂、巴西棕榈蜡、蜂蜡、鲸蜡醇、十八烷醇、肉豆蔻酸、棕榈酸、硬脂酸、脂肪酸甘油酯、聚甘油脂肪酸酯、甘油有机酸脂肪酸酯、丙二醇脂肪酸酯、失水山梨糖醇脂肪酸酯、及硬化油中的至少1种。
项8、如项1所述的制造方法,其中,含有药物的蜡基质粒子基于该粒子总量含有0.001~90重量%药物、0.1~99.99重量%蜡。
项9、如项1所述的制造方法,其中,药物为(A)西洛他唑,蜡为(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯,制造的含有药物的蜡基质粒子的平均粒径为40~200μm。
项10、如项9所述的制造方法,其中,还包含工序(iii):在40~55℃的温度条件下对所述工序(ii)中得到的粒子进行加热处理。
项11、如项10所述的制造方法,其中,所述工序(iii)是在使惰性粉末附着在所述工序(ii)得到的粒子的表面后,在40~55℃的温度条件下进行加热处理的工序。
项12、一种含有药物的蜡基质粒子制造用挤出机,其特征在于,具有以下部分:
配备了温度控制装置的滚筒;
向所述滚筒内供给至少1种药物和至少1种蜡的供给口;
设置在所述滚筒上的出口冲模部;
配置在所述滚筒内、用于配制熔融混炼的所述药物和蜡的混合物并将该混合物输送至所述出口冲模部的挤出螺杆;
直接安装在所述出口冲模部上、可将熔融混炼的药物和蜡的混合物喷雾排出的喷嘴。
项13、如项12所述的含有药物的蜡基质粒子制造用挤出机,其特征在于,还具有用于使从所述喷嘴喷雾的熔融混炼的药物和蜡的混合物固化、形成粒子的粒子形成用腔,。
项14、一种缓释制剂,其特征在于,所述缓释制剂包含含有(A)西洛他唑结晶、及(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯的粒子,该粒子的平均粒径为40~200μm。
项15、如项14所述的缓释制剂,其中,所述(A)西洛他唑结晶的平均粒径为10μm以下。
项16、如项14所述的缓释制剂,其中,相对于缓释制剂中所述粒子的总量,含有5~60重量%(A)西洛他唑结晶、及30~95重量%(B) 脂肪酸甘油酯及/或聚甘油脂肪酸酯。
项17、如项14所述的缓释制剂,其中,还含有水溶性纤维素衍生物。
项18、如项17所述的缓释制剂,其中,水溶性纤维素衍生物为羟丙基甲基纤维素。
项19、如项17所述的缓释制剂,其中,相对于缓释制剂的总量,含有总量为1~15重量%的水溶性纤维素衍生物。
项20、如项18所述的缓释制剂,其中,相对于缓释制剂的总量,含有1~15重量%羟丙基甲基纤维素。
项21、如项14所述的缓释制剂,其中,含有所述(A)及(B)成分的粒子是通过使所述(A)及(B)成分的熔融混合物固化而制得的粒子。
项22、如项14所述的缓释制剂,其中,惰性粉末附着在所述粒子的表面。
项23、如项22所述的缓释制剂,其中,所述惰性粉末是选自滑石、轻质二氧化硅、氧化钛、及纤维素类聚合物中的至少1种。
项24、如项14所述的缓释制剂,其中,所述(B)成分为选自甘油硬脂酸酯、聚甘油硬脂酸酯、甘油山嵛酸酯、及聚甘油山嵛酸酯中的至少1种。
项25、如项14所述的缓释制剂,其中,所述(B)成分是选自甘油山嵛酸酯、二甘油硬脂酸酯、及三甘油半山嵛酸酯中的至少1种。
项26、如项14所述的缓释制剂,通过以下工序(i)及(ii)制造:
工序(i):向挤出机中供给(A)西洛他唑、及(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯,所述挤出机将滚筒及冲模的温度设定为所述(B)成分的熔点以上的温度,及
工序(ii):一边在所述挤出机内将所述(A)及(B)成分熔融混炼,一边从喷嘴向温度低于所述(B)成分熔点的环境气体中喷雾排出熔融混炼的所述(A)及(B)成分的混合物,由此成型为粒子状,所述喷嘴直接安装在冲模部,所述冲模部设置在所述挤出机滚筒 的前端。
项27、如项26所述的缓释制剂,其中,在所述工序(i)中除了所述(A)及(B)成分之外还供给(C)水溶性纤维素衍生物。
项28、如项26所述的缓释制剂,其中,进一步经过下述工序(iii)进行制造,所述工序(iii)为在40~55℃的温度条件下对所述工序(ii)得到的粒子进行加热处理。
项29、如项26所述的缓释制剂,其中,还包含下述工序,即在所述工序(iii)中于加热处理前使惰性粉末附着在所述工序(ii)所得粒子的表面。
根据本发明的制造方法及挤出机,可以制造含有药物的蜡基质粒子、特别是平均粒径1mm以下的含有药物的蜡基质粒子,且不发生由熔融的药物重结晶导致的输液管(管路)阻塞等。另外,根据本发明的制造方法及挤出机,不需粉碎处理等工序,仅通过一个工序即可简便地制造含有药物的蜡基质粒子,因此,从其工业应用方面考虑有用性也很高。
并且,本发明的缓释制剂中所含的粒子(蜡基质粒子)的必须结构为:(1)含有西洛他唑结晶(优选平均结晶粒径为10μm以下)、(2)作为蜡基质基剂使用脂肪酸甘油酯及/或聚甘油脂肪酸酯、及(3)成型为蜡基质粒子的平均粒径为40~200μm的粒子状。本发明的缓释制剂通过采用上述结构,使难溶性的西洛他唑具有优异的缓释性,在空腹给药和进食后给药的情况下西洛他唑释放或血中浓度变化的差异减小。所以,根据本发明的缓释制剂,可以更有效地呈现西洛他唑的药理效果,作为药物制剂有用。
另外,本发明的缓释制剂,通过进一步含有水溶性纤维素衍生物、特别是羟丙基甲基纤维素,能够在确保缓释性的同时,具有高生物学利用度,因此,临床上的有用性极高。
具体实施方式
本发明中,所谓含有药物的蜡基质,是指在为连续相的蜡内药物 溶解或分散而被包埋的蜡基质。另外,本发明中,所谓“缓释制剂”,是通过口服给药,所含药物显示缓释性的制剂。以下,详细说明本发明。
1.含有药物的蜡基质粒子的制造方法
挤出机
本发明的制造方法使用挤出机实施,所述挤出机在设置于滚筒前端的出口冲模部安装了喷嘴。
对在本发明制造方法中优选使用的挤出机(含有药物的蜡基质粒子制造用挤出机)的方案,进行具体地说明。
上述挤出机在滚筒(cylinder)上配备温度控制装置。此温度控制装置可以将供给到滚筒内的蜡加热到熔点以上的温度。另外,该温度控制装置优选还具有冷却功能。如上所述通过具有冷却功能,能够更适当地控制滚筒内的原料温度。作为上述温度控制装置的具体例,可以举出可加热及/或冷却的滚筒套管。
在上述挤出机的滚筒内,在其上游侧设置了用于供给原料的供给口、在其下游侧设置了用于将熔融混炼的原料(熔融混炼原料)排出的出口冲模部。
在上述挤出机的滚筒内,配置了挤出螺杆,用于将从供给口投入的原料配制成熔融混炼原料,并将该熔融混炼原料输送至上述出口冲模部。对于挤出螺杆的数量,没有特殊的限定,可以为单螺杆式、双螺杆式、或三螺杆以上的多螺杆式中的任一种,优选为双螺杆式。
另外,螺杆只要能够将从供给口投入的原料配制成熔融混炼原料,且输送熔融混炼原料即可,对其形状没有特殊的限制。例如可以举出输送螺杆、捏和螺杆、混合螺杆、或它们的组合。
上述挤出机在出口冲模部安装喷嘴,此喷嘴形成了能够将经螺杆输送到出口冲模部的熔融混炼原料向外部喷雾排出的结构。
对上述喷嘴的喷雾排出的方式没有特殊的限制,可以为加压喷嘴、双流体喷嘴、或双流体以上的多流体喷嘴中的任一种。另外,对于喷嘴的排出孔的形状只要能够喷雾排出熔融混炼原料即可,没有限 制,但作为优选例可以举出圆形。排出孔为圆形时,作为其内径,例如可以举出为0.1~20mm、优选为0.2~15mm、更优选为0.2~10mm。
另外,上述挤出机中优选配备加热装置,用于将供给到喷嘴的喷雾气体(为了喷雾使用的空气)加热。
进而,上述挤出机优选配备粒子形成用腔,用于使从喷嘴喷雾的熔融混炼原料固化形成粒子。配备该粒子形成用腔时,只要形成使熔融混炼原料从喷嘴的排出孔部分排出到该粒子形成用腔内的结构即可,没有特殊的限制,例如,将该粒子形成用腔配置成喷嘴的排出孔部分被组装入该粒子形成用腔内。另外,该粒子形成用腔只要能够在腔内使熔融混炼原料固化形成粒子即可,对其形态没有特殊的限制。例如,该粒子形成用腔可以形成熔融混炼原料被从喷嘴喷雾到腔内的气体环境气体中的结构。另外,可以在腔内保持液氮等液体,通过该液体控制腔内温度。进而,该粒子形成用腔内还配备蜡基质粒子回收部,用于回收在腔内形成的蜡基质粒子。另外,该粒子形成用腔优选配置温度控制装置,用于对喷雾到腔内的熔融混炼原料的环境气体温度进行控制,进而,还优选配置排气装置,用于将导入腔内的喷雾气排出。需要说明的是,为了回收残存在排出气体中的蜡基质粒子,也可以在该排气装置中配置排气中蜡基质粒子的回收部。
以下参照附图说明上述挤出机的优选例之一。
图1所示的挤出机中在滚筒1上作为温度控制装置配备4个可控制温度的滚筒套管1a(从上游侧开始编号为1a-1、1a-2、1a-3、及1a-4)。另外,滚筒1中在上游侧设置用于供给原料的供给口2,另外在下游侧设置出口冲模部3。在滚筒1内配置螺杆4,用于一边将从供给口2投入的原料熔融混炼一边将其输送至出口冲模部3。该螺杆4形成可以被发动机4a驱动的结构。进而,在出口冲模部3安装喷嘴5,此喷嘴5配备用于加热喷雾气体的加热装置5a及用于排出熔融混炼原料的排出孔5b。
进而,图2表示配备粒子形成用腔6的挤出机的一例,所述粒子形成用腔6形成熔融混炼原料被从喷嘴喷雾到气体环境气体中的结构。 需要说明的是,图2中,为方便起见,按照与实际不同的比率给出挤出机和粒子形成用腔6的尺寸。在图2的挤出机中,设置粒子形成用腔6,使喷嘴5的排出孔5b部分被组装在内部。在粒子形成用腔6的底部,设置蜡基质粒子回收部6a,用于回收由于重力落下而积聚在底部的蜡基质粒子。另外,在粒子形成用腔6内,于喷嘴5的排出孔5b部分的相反侧设置排气装置7,可将导入腔内的喷雾气体排出。接下来,在排气装置7中设置排气扇7a和用于回收排出气体中蜡基质粒子的回收部7b,使其在排出粒子形成用腔6内的气体的同时,可以回收残存在排出气体中的蜡基质粒子。
原料的供给及熔融混炼
本发明的方法中,向挤出机中供给规定量的原料,将上述原料熔融混炼。供给到挤出机中的原料是配合在制造的含有药物的蜡基质粒子中的成分,具体而言,可以举出至少1种药物、及至少1种蜡。另外,本发明中制造的含有药物的蜡基质粒子中除药物及蜡之外还可以含有其他添加剂,如上所述含有添加剂时,作为原料,将添加剂与药物及蜡一同供给到挤出机中。
用挤出机进行熔融混炼时的滚筒及冲模的温度,设定为所配合的蜡的熔点以上的温度,优选设定为比所配合的蜡的熔点高5~200℃的温度、更优选设定为比所配合的蜡的熔点高10~200℃的温度。需要说明的是,此设定温度在不影响添加的药物、蜡、其他添加剂的稳定性的范围内。另外,滚筒的上述设定温度设定为从上游侧(原料供给口侧)到下游侧(出口冲模部侧)温度逐步升高,优选在下游侧最终达到上述温度。
对于供给的原料在滚筒内的滞留时间、螺杆的旋转速度、原料的供给速度等可以适当地设定,使熔融混炼原料在挤出机的出口冲模部形成。
熔融混炼物的喷雾排出及粒子的形成
在上述条件下一边将原料(药物、蜡、及根据需要添加的添加剂)熔融混炼,一边从安装在挤出机冲模部的喷嘴向温度低于上述蜡的熔 点的环境气体中喷雾排出熔融混炼原料。作为使熔融混炼原料从喷嘴向上述温度环境气体中喷雾排出时的排出速度,需要考虑最终得到的含有药物的蜡基质粒子的粒径、熔融混炼原料的粘度等,进而根据喷嘴的形状、喷嘴排出孔的孔径、双流体以上的多流体喷嘴时喷雾气体的空气量等适当地确定。
具体而言,作为上述熔融混炼原料从上述挤出机中的排出速度,通常可以举出冲模的每1个排出孔为0.1~1000kg/小时、优选为0.5~700kg/小时、更优选1~400kg/小时。通过采用上述排出速度,可以制造具有下述粒径范围的含有药物的蜡基质粒子。喷雾气体量、喷嘴孔径相同时,具有排出速度越快粒径越大的倾向,另外,存在排出速度越慢粒径越小的倾向。另外,不使用喷雾气体时,存在排出速度越快粒径越小的倾向,排出速度越慢粒径越大的倾向。
对于使熔融混炼原料排出喷雾时使用的喷雾气体温度,没有特殊的限制。例如,喷嘴为双流体以上的多流体喷嘴时,作为该喷雾气体温度,可以举出在所配合的蜡的熔点附近以上,优选在所配合的蜡的熔点的-10~+300℃左右、较优选在所配合的蜡的熔点的-10~+250℃左右、更优选在蜡的熔点的±0~+200℃左右。
在上述条件下排出到温度低于上述蜡的熔点的环境气体中的熔融混炼原料,在该环境气体中冷却,形成球状粒子。作为使上述熔融混炼原料排出的环境气体温度,只要低于上述蜡的熔点,为上述熔融混炼原料固化的温度即可,例如可以举出-196~50℃、优选-196~40℃。上述温度的环境气体可以通过常用的温度控制装置进行调制,可以是使用液氮制作的气体环境气体。作为优选实施方案,可以举出在低于上述蜡的熔点的气体环境气体中将上述熔融混炼原料喷雾排出的方法。
在上述条件下,通过在温度低于上述蜡的熔点的环境气体中排出熔融混炼原料将其冷却,制造规定粒径的含有药物的蜡基质粒子。根据本发明的制造方法,可以制造平均粒径在1.5mm以下、优选0.01~1.5mm、较优选0.02~1.0mm、更优选0.03~0.9mm的含有药物的蜡基 质粒子。本发明的制造方法中,含有药物的蜡基质粒子的平均粒径,可以通过适当地控制所用原料的种类或配合量、熔融混炼原料的排出速度、喷雾空气量等适当地调节。需要说明的是,此处所谓的平均粒径,是50%累积直径,即,在粒度分布图中从0μm积分的体积为50%时的粒径,是通过利用激光衍射·散射法的粒度分布测定机测定的值。
通过现有技术制造具有上述范围的平均粒径的球状的含有药物的蜡基质粒子时,存在熔融的药物在管路内或管路连接部或雾化器部重结晶,发生管路阻塞等不良情况的问题。而根据本发明的制造方法可以解决上述现有技术的问题,故作为制造具有上述范围的平均粒径的球状的含有药物的蜡基质粒子的方法,是有用的。
蜡基质粒子中药物结晶的形成
蜡基质粒子内药物没有完全结晶时,可以通过生成药物的结晶,使药物具有稳定的释放控制特性。
因此,可以通过对上述所得的含有药物的蜡基质粒子进行常温保存或加热处理,使所期望的结晶粒径的药物结晶在蜡基质粒子中析出。从在短时间内使所期望的药物结晶析出的观点考虑,优选进行加热处理。
在上述加热处理前,优选使规定量的下述惰性粉末附着在含有药物的蜡基质粒子的表面。如上所述通过使惰性粉末附着,能够防止蜡基质粒子之间凝集,可以提高制造效率。为了使惰性粉末附着在上述蜡基质粒子上,将两者混合的方法较为简便。
作为上述加热处理条件,没有特殊的限定,通常为室温以上且蜡的熔点以下的温度、优选在40~55℃下、更优选在45~54℃下进行。另外,作为加热时间,根据加热温度等不同而改变,通常可以为1分钟~24小时、优选5分钟~20小时、更优选10分钟~15小时。
在药物为西洛他唑时,在上述蜡基质粒子内生成药物的结晶特别有效。
药物
作为本发明的制造方法中使用的药物,只要为药学允许的药物、 并且显示药理活性作用即可,没有特殊的限制,可以为水溶性、脂溶性或水难溶性中的任一种。作为该药物的一例,可以举出血管紧张素2受体拮抗剂(ARB)、胃肠药、营养剂、营养性油、阿片类镇痛药、钙(Ca)拮抗剂、膀胱过度活动症治疗药、角质溶解药、强心药、肌肉松弛剂、抗恶性肿瘤药、抗病毒药、抗炎症药、抗菌药、抗心绞痛药、驱虫药、抗抑郁药、精神分裂症治疗药、抗癫痫药、抗心律失常药、镇痛药、抗真菌药、抗凝血药、抗糖尿病药、抗痛风药、抗高血压药、抗尿失禁药、抗疟药、抗偏头痛药、抗毒蕈碱药、抗帕金森药、抗组胺药物、抗肥胖药、抗焦虑药、抗心律失常药、抗良性前列腺肥大药、兴奋剂、骨质疏松症治疗药、类固醇、CCR5受体拮抗剂(HIV侵入抑制剂)、脂质调节药、抗惊厥药、勃起功能障碍改善药、免疫抑制药、抗原虫药、抗甲状腺药、Cox-2抑制剂、催眠药、肌肉松弛剂、性激素、镇静药、识别增强剂(recognition enhancer)、排尿障害改善药、β阻断药、必需脂肪酸、非必需脂肪酸、蛋白酶抑制剂、大环内酯类抗生素、利尿药、白三烯拮抗药等各种制剂中配合的常用药物。本发明中,药物可以单独使用1种,另外也可以任意组合2种以上进行使用。
作为本发明中使用的药物的具体例,可以举出阿维A脂(acetretin)、阿苯哒唑、沙丁胺醇、氨鲁米特、胺碘酮、氨氯地平、安非他命、两性霉素B、阿托伐他汀、阿托伐醌、阿奇霉素、巴氯芬、倍氯米松、贝那普利、苯佐那酯、倍他米松、比卡鲁胺、布地奈德、安非他酮、白消安、布替萘芬、骨化二醇、卡泊三醇、骨化三醇、喜树碱、坎地沙坦、辣椒碱、卡马西平、胡萝卜素、塞来昔布、西伐他丁、西替利嗪、氯苯那敏、维生素D3、西洛他唑、西咪替丁、桂利嗪、环丙沙星、西沙比利、克拉霉素、氯马斯汀、氯米芬、氯米帕明、氯吡格雷、可待因、辅酶Q10、胺苯环庚烯、环孢素、达那唑、达者仑、右氯苯那敏(dexchlorpheniramine)、双氯酚酸、双香豆素、地高辛、普拉睾酮、双氢麦角胺、双氢速甾醇、地红霉素、多奈哌齐、依法韦仑、依普沙坦、维生素D2、麦角胺、必需脂肪酸供给源、依托度酸、 依托泊苷、法莫替丁、非诺贝特、芬太尼、非索那定、非那雄胺、氟康唑、氟比洛芬、氟伐地汀、磷苯妥英、夫罗曲坦、呋喃唑酮、加巴喷丁、吉非贝齐、格列本脲、格列吡嗪、格列本脲、格列美脲、灰黄霉素、氯氟菲醇、布洛芬、依贝沙坦、伊立替康、硝酸异山梨醇酯、异维甲酸、伊曲康唑、伊维菌素、酮康唑、酮咯酸、拉莫三嗪、兰索拉唑、来氟洛米、赖诺普利、洛哌丁胺、氯雷他定、洛伐他汀、L-甲状腺素、叶黄素、番茄红素、甲羟孕酮、米非司酮、甲氟喹、甲地孕酮、美沙酮、甲氧补骨脂素、甲硝唑、咪康唑、咪达唑仑、米格列醇、咪诺地尔、米托蒽醌、孟鲁司特、萘普酮、纳布啡、奈非那韦、硝苯地平、尼索地平、尼鲁米特(nilutanide)、呋喃妥因、尼扎替丁、奥美拉唑、奥普瑞白介素(oprelvekin)、雌二醇、奥沙普嗪、紫杉醇、旁卡西醇、帕罗西汀、镇痛新、吡格列酮、苯唑替吩、普伐他汀、泼尼松龙、丙丁酚、黄体酮、伪麻黄素(pseudoephedrine)、吡斯的明、雷贝拉唑、雷洛昔芬、罗非克西、瑞格列奈、利福布汀、利福喷汀、利美索龙、利托那韦(ritanovir)、利扎曲普坦、罗格列酮、沙奎那韦、舍曲林、西布茶明、柠檬酸西地那非、辛伐他汀、西罗莫司、螺内酯、舒马曲坦、他克林、他克莫司、他莫昔芬、他索洛辛、蓓萨罗丁(targretin)、他佐罗汀、替米沙坦、替尼泊苷、特比萘芬、特拉唑嗪、四氢大麻酚、硫加宾、噻氯匹定、替罗非班、替扎尼定、托吡酯、拓扑替康、托瑞米芬、曲马多、维甲酸、曲格列酮、曲伐沙星、泛癸利酮、缬沙坦、文拉法辛、维替泊芬、氨己烯酸、维生素A、维生素D、维生素E、维生素K、扎鲁司特、弃白通、佐米曲坦、唑吡坦、佐匹克隆、阿卡波糖、阿昔洛韦、乙酰半胱氨酸、氯乙酰胆碱、阿拉沙星、阿仑特罗、阿糖塞姆(alglucerase)、盐酸金刚胺、安贝氯铵、阿米斯丁、盐酸阿米洛利、氨基己酸、两性霉素B、抑肽酶、门冬酰胺酶、阿替洛尔、安托肌松、阿托品、阿奇霉素、氨曲南、BCG卡介苗、杆菌肽、贝卡普勒明、颠茄、盐酸苄普地尔、硫酸博来霉素、人降钙素、鲑降钙素、卡铂、卡培他滨、硫酸卷曲霉素、头孢孟多酯钠、头孢唑啉钠、盐酸头孢吡肟(cefepime dihydrochloride)、头孢克肟、 头孢尼西钠、头孢哌酮、头孢替坦二钠、头孢氨噻、头孢西丁钠、头孢唑肟、头孢曲松、头孢呋辛酯、头孢氨苄、头孢吡硫钠、霍乱菌苗、西多福韦、顺铂、克拉屈滨、溴化可利啶、克林霉素及克林霉素衍生物、环丙沙星、氯屈膦酸二钠、多粘菌素E甲磺酸钠、硫酸多粘菌素E、促皮质素、二十四肽促皮质素、色甘酸钠、阿糖胞苷、达肝素钠、达那帕罗、去铁胺、地尼白介素2、去氨加压素、泛影葡胺、泛影钠、双环维林、地达诺新、地红霉素、盐酸多巴胺、去氧核糖核酸酶α、多沙氯铵、阿霉素、依替膦酸二钠、依那普利拉、脑啡肽、依诺沙星、依诺肝素钠、麻黄碱、肾上腺素、红霉素、盐酸艾司洛尔、法昔洛韦、氟达拉滨、氟西汀、膦甲酸钠(foscarnet sodium)、更昔洛韦、庆大霉素、胰高血糖素、格隆溴铵、高那瑞林、硫酸吲哚那韦、流感病毒疫苗(influenza virus vaccines)、异丙托溴铵、异环磷酰胺、拉米夫定、甲酰四氢叶酸钙、醋酸亮丙瑞林、左旋氧氟沙星、林可霉素及林可霉素衍生物、洛布卡韦、洛美沙星、氯拉卡比、溴化甲哌酯、美沙拉秦、乌洛托品、甲氨蝶呤、甲基东莨菪碱、盐酸甲福明、美托洛尔、美洛西林钠、氯化米库氯铵、奈多罗米钠、溴新斯的明、甲硫酸新斯的明、加巴喷丁、氟哌酸、醋酸奥曲肽、氧氟沙星、奥帕膦酸钠(olpadronate)、催产素、帕米膦酸二钠、泮库溴铵、帕罗西汀、甲氟哌酸、依西酸喷他脒(pentamidine isethionate)、喷司他丁、己酮可可碱、喷昔洛韦、五肽胃泌素、甲基磺酸酚妥拉明、苯丙氨酸、水杨酸毒扁豆碱、鼠疫菌苗、哌拉西林钠、硫酸多粘菌素B、氯磷定、普兰林肽、普加巴林、普罗帕酮、溴丙胺太林、溴吡斯的明、狂犬病疫苗、利塞膦酸钠、利巴韦林、盐酸金刚乙胺、沙美特罗昔萘酸酯、辛卡酯、索他洛尔(solatol)、生长激素释放抑制因子、司帕沙星、大观霉素、司他夫定、链激酶、链脲霉素、氯化琥珀胆碱、盐酸他克林、硫酸特布他林、噻替派(thiopeta)、替卡西林、替鲁膦酸钠、噻吗洛尔、群多普利、葡萄糖酸三甲曲沙(trimetrexate gluconate)、托司哌丁霉素(trospectinomycin)、曲伐沙星、氯化筒箭毒碱、尿素、尿激酶、万古霉素、伐昔洛韦、缬沙坦、加压素及加压素衍生物、维 库溴铵、长春碱、长春新碱、长春烯碱、维生素B12、华法林钠、扎西胞苷、扎那米韦、择泰(zolendronate)、齐多夫定、茶碱、葛帕沙星、卡替洛尔、丙卡特罗、雷巴米特、阿立哌唑、托伐普坦、扑热息痛、酮基布洛芬、萘普生、吡罗昔康、苯妥英、维拉帕米、它们的药学上允许的盐、它们的异构体、衍生物等。本发明中,上述药物可以单独使用1种,另外也可以任意组合2种以上进行使用。
由于含有药物的蜡基质粒子可以具有缓释性,所以,作为本发明中使用的药物优选必须具有缓释性的药物。从上述观点考虑,作为本发明中使用的药物,优选举出茶碱、西洛他唑、酮基布洛芬、萘普生、双氯酚酸钠、伊曲康唑、吡罗昔康、苯妥英、维拉帕米、丙丁酚、托伐普坦;更优选举出茶碱、西洛他唑、丙丁酚、托伐普坦。
本发明中,即使对于在基剂成分(蜡)熔融的状态下易析出结晶的药物,也能够在不使药物析出结晶的前提下制造含有药物的蜡基质粒子。鉴于上述本发明的效果,作为本发明中使用的药物的优选例之一,可以举出在基剂成分(蜡)熔融的状态下易析出结晶的药物(例如、熔点在100~200℃左右的药物)。作为上述药物的具体例,可以举出西洛他唑。
制造的含有药物的蜡基质粒子中药物的浓度,根据所用药物的种类或药效、给药对象的性别或年龄等而不同,例如,可以举出相对于该蜡基质粒子的总量为0.001~90重量%、优选为0.05~95重量%、更优选为0.1~90重量%。
蜡
作为本发明制造方法中使用的蜡(蜡基质基材),只要是药学上允许的蜡、并且在常温(30℃)下呈固态的蜡即可,没有特殊的限制,可以是熔点为40~120℃、优选为40~90℃的来自动物、来自植物、合成、或半合成中的任一种。对于该熔点,根据“第14版日本药典一般试验法14.凝固点测定法”进行测定。
作为蜡的具体例,可以举出石蜡、微晶蜡、地蜡、日本蜡、可可脂、巴西棕榈蜡、蜂蜡、鲸蜡醇、十八烷醇、肉豆蔻酸、棕榈酸、硬 脂酸、脂肪酸甘油酯、聚甘油脂肪酸酯、甘油有机酸脂肪酸酯、丙二醇脂肪酸酯、失水山梨糖醇脂肪酸酯、硬化油等。
脂肪酸甘油酯是甘油和各种脂肪酸的单酯、二酯、三酯。作为构成该脂肪酸甘油酯的脂肪酸,可以举出C6~C22脂肪酸。作为上述脂肪酸,例如可以举出硬脂酸、山嵛酸、棕榈酸、油酸、亚油酸、亚麻酸、肉豆蔻酸、月桂酸、蓖麻油酸、辛酸、癸酸等。作为脂肪酸甘油酯的具体例,可以举出单硬脂酸甘油酯、二硬脂酸甘油酯、三硬脂酸甘油酯、单山嵛酸甘油酯、二山嵛酸甘油酯、三山嵛酸甘油酯、甘油单硬脂酸单山嵛酸酯等。
聚甘油脂肪酸酯是2个以上甘油聚合形成的聚甘油中键合1个以上脂肪酸形成的酯。该聚甘油脂肪酸酯中包括脂肪酸与聚甘油的全部羟基成酯键的聚甘油全脂肪酸酯、及脂肪酸与聚甘油的大约一半羟基成酯键的聚甘油半脂肪酸酯等。所谓聚甘油半脂肪酸酯,具体而言是指聚甘油的酯化的羟基数的平均值(NE)是未被酯化的聚甘油本身具有的全部羟基数(N)的大约一半的化合物或其混合物,例如可以举出0.3≤NE/N≤0.7、优选0.35≤NE/N≤0.65的范围的化合物。例如,三甘油半山嵛酸酯是指山嵛酸与3分子甘油脱水缩合形成的具有5个羟基的三甘油形成2个或3个酯键的化合物或它们的混合物、即、三甘油山嵛酸(二或三)酯。
作为构成聚甘油脂肪酸酯的脂肪酸,可以举出C6~C22脂肪酸,其具体例与上述脂肪酸甘油酯的构成脂肪酸相同。作为聚甘油脂肪酸酯的具体例,可以举出二甘油-单或二硬脂酸酯;二甘油-单或二棕榈酸酯;二甘油-单或二月桂酸酯;二甘油-单或二油酸酯;二甘油-单或二亚油酸酯;二甘油-单或二辛酸酯;二甘油-单或二山嵛酸酯;三甘油-单、二、三、四或五硬脂酸酯;三甘油-单、二、三、四或五棕榈酸酯;三甘油-单、二、三、四或五月桂酸酯;三甘油-单、二、三、四或五油酸酯;三甘油-单、二、三、四或五-亚油酸酯;三甘油-单、二、三、四或五辛酸酯;三甘油-单、二、三、四或五山嵛酸酯;四甘油-单、二、三、四、五或六硬脂酸酯;四甘油 -单、二、三、四、五或六棕榈酸酯;四甘油-单、二、三、四、五或六月桂酸酯;四甘油-单、二、三、四、五或六油酸酯;四甘油-单、二、三、四、五或六亚油酸酯;四甘油-单、二、三、四、五或六辛酸酯;四甘油-单、二、三、四、五或六山嵛酸酯;五甘油-单、二、三、四、五或六硬脂酸酯;五甘油-单、二、三、四、五或六硬脂酸酯;五甘油-单、二、三、四、五或六棕榈酸酯;五甘油-单、二、三、四、五或六月桂酸酯;五甘油-单、二、三、四、五或六油酸酯;五甘油-单、二、三、四、五或六亚油酸酯;五甘油-单、二、三、四、五或六辛酸酯;五甘油-单、二、三、四、五或六山嵛酸酯;六甘油-单、二、三、四、五、六或七硬脂酸酯;六甘油-单、二、三、四、五、六或七棕榈酸酯;六甘油-单、二、三、四、五、六或七月桂酸酯;六甘油-单、二、三、四、五、六或七油酸酯;六甘油-单、二、三、四、五、六或七亚油酸酯;六甘油-单、二、三、四、五、六或七辛酸酯;六甘油-单、二、三、四、五、六或七山嵛酸酯;七甘油-单、二、三、四、五、六、七或八硬脂酸酯;七甘油-单、二、三、四、五、六、七或八棕榈酸酯;七甘油-单、二、三、四、五、六、七或八月桂酸酯;七甘油-单、二、三、四、五、六、七或八油酸酯;七甘油-单、二、三、四、五、六、七或八亚油酸酯;七甘油-单、二、三、四、五、六、七或八辛酸酯;七甘油-单、二、三、四、五、六、七或八山嵛酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一硬脂酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一棕榈酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一月桂酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一油酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一亚油酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一辛酸酯;十甘油-单、二、三、四、五、六、七、八、九、十或十一山嵛酸酯等。另外,除上述之外,还可以举出由硬脂酸、山嵛酸、棕榈酸、油酸、亚油酸、亚麻酸、肉豆蔻酸、月桂酸、蓖麻油酸、辛酸、癸酸中的2种以上脂肪酸和聚甘油的酯构成的聚甘油脂肪酸酯。
作为甘油有机酸脂肪酸酯,为有机酸及脂肪酸与甘油键合形成的酯。作为构成该甘油有机酸脂肪酸酯的脂肪酸,可以举出C6~C22脂肪酸,其具体例与上述脂肪酸甘油酯的构成脂肪酸相同。作为甘油有机酸脂肪酸酯的具体例,可以举出甘油柠檬酸脂肪酸酯、甘油乙酸脂肪酸酯、甘油乳酸脂肪酸酯、甘油琥珀酸脂肪酸酯、甘油富马酸脂肪酸酯、甘油酒石酸脂肪酸酯、甘油二乙酰基酒石酸脂肪酸酯、聚甘油柠檬酸脂肪酸酯、聚甘油乙酸脂肪酸酯、聚甘油乳酸脂肪酸酯、聚甘油琥珀酸脂肪酸酯、聚甘油富马酸脂肪酸酯、聚甘油酒石酸脂肪酸酯及聚甘油二乙酰基酒石酸脂肪酸酯等。
作为构成失水山梨糖醇脂肪酸酯的脂肪酸,可以举出C6~C22脂肪酸,其具体例与上述脂肪酸甘油酯的构成脂肪酸相同。作为失水山梨糖醇脂肪酸酯的具体例,可以举出失水山梨糖醇月桂酸酯、失水山梨糖醇棕榈酸酯、失水山梨糖醇油酸酯、失水山梨糖醇硬脂酸酯等。
作为构成脂肪酸丙二醇酯的脂肪酸,可以举出C6~C22脂肪酸,其具体例与上述脂肪酸甘油酯的构成脂肪酸相同。作为脂肪酸丙二醇酯的具体例,可以举出肉豆蔻酸丙二醇酯、硬脂酸丙二醇酯、月桂酸丙二醇酯、油酸丙二醇酯、癸酸丙二醇酯等。另外,除上述物质之外,还可以举出2种以上脂肪酸组合键合形成的脂肪酸丙二醇酯。
作为硬化油,具体而言可以举出蓖麻油、棉子油、大豆油、菜籽油、牛脂等。
上述蜡中,优选举出脂肪酸甘油酯、聚甘油脂肪酸酯。
上述蜡可以单独使用1种,另外也可以任意组合2种以上进行使用。
制造的含有药物的蜡基质粒子中蜡的浓度,例如可以举出相对于该蜡基质粒子的总量为0.1~99.99重量%、优选为0.5~99重量%、更优选为1~90重量%。
任意配合成分(添加剂)
另外,本发明的制造方法中,作为原料,除上述药物及蜡之外,还可以配合适当量的表面活性剂。作为上述表面活性剂,可以举出烷基葡糖苷、烷基麦芽糖苷、烷基硫代葡糖苷、聚乙二醇月桂酸甘油酯(lauryl macrogol glycerides)、聚氧乙烯烷基醚、聚氧乙烯烷基酚、聚乙二醇脂肪酸酯、聚乙二醇脂肪酸甘油酯、聚氧乙烯失水山梨糖醇脂肪酸酯、聚氧乙烯聚氧丙烯烷基醚、聚氧乙烯-聚氧丙烯嵌段共聚物、聚氧乙烯甘油酯、聚氧乙烯甾醇(polyethylene sterols)、其衍生物、聚氧乙烯植物油、聚氧乙烯固化植物油、生育酚聚乙二醇琥珀酸酯(TPGS)、糖酯、糖醚、蔗糖甘油酯(sucroglycerides)、低级醇(C2~C4)和脂肪酸(C8~C18)的酯等。
作为上述表面活性剂,更具体而言可以举出聚氧乙烯十二烷基醚、聚氧乙烯十六烷基醚、聚氧乙烯十八烷基醚、聚氧乙烯油基醚、聚氧乙烯二十二烷基醚等聚氧乙烯烷基醚;月桂酸聚乙二醇酯、硬脂酸聚乙二醇酯、油酸聚乙二醇酯、棕榈酸聚乙二醇酯、聚乙二醇-脂肪酸单及二酯混合物等聚乙二醇脂肪酸酯;聚乙二醇甘油月桂酸酯、聚乙二醇甘油硬脂酸酯、聚乙二醇甘油油酸酯等聚乙二醇脂肪酸甘油酯;聚氧乙烯植物甾醇酯、聚氧乙烯胆甾醇酯、聚氧乙烯胆甾烷醇酯等聚氧乙烯甾醇及其衍生物;聚乙二醇失水山梨糖醇月桂酸酯、聚乙二醇失水山梨糖醇油酸酯、聚乙二醇失水山梨糖醇棕榈酸酯等聚乙二醇失水山梨糖醇脂肪酸酯;聚氧乙烯聚氧丙烯十六烷基醚、聚氧乙烯聚氧丙烯癸基十四烷基醚等聚氧乙烯聚氧丙烯烷基醚;POLOXAMER105、108、122、123、124、181、182、183、184、185、188、212、215、217、231、234、235、237、238、282、284、288、331、334、335、338、401、402、403、407等、Pluronic(注册商标)系列(BASF)、Emkalyx、Lutrol(BASE)、Supronic、Monolan、Pluracare、及Plurodac等聚氧乙烯-聚氧丙烯嵌段共聚物;蔗糖-单或二-硬脂酸酯、蔗糖-单或二棕榈酸酯、蔗糖-单或二月桂酸酯等糖酯;油酸乙酯、肉豆蔻酸异丙基酯、棕榈酸异丙基酯、亚麻酸乙酯、亚麻酸异丙基酯等低级醇(C2~C4)和脂肪酸(C8~C18)的酯等。
进而,本发明的制造方法中,也可以在原料中配合适当量的可熔融或分散在熔融混炼的蜡中的水溶性高分子、水不溶性高分子、肠溶性高分子、胃溶性高分子等高分子物质。作为上述高分子物质,具体而言可以举出羟基纤维素、羟丙基甲基纤维素、醋酸羟丙基甲基纤维素琥珀酸酯、醋酸纤维素邻苯二甲酸酯、乙基纤维素、醋酸纤维素、聚乙烯基吡咯烷酮、羟基乙基纤维素、甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羧甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、环糊精、环糊精衍生物、甲基丙烯酸氨基烷基酯共聚物E、甲基丙烯酸烷基酯共聚物RS、甲基丙烯酸酯共聚物L、甲基丙烯酸酯共聚物S、卡波普(carboxyvinyl polymer)、聚乙烯醇缩乙醛二乙基胺乙酸酯(polyvinyl acetal diethyl amine acetate)、聚乙烯醇、藻酸钠、藻酸丙二醇酯、明胶、紫胶等。
另外,除上述物质之外,作为可作为原料配合的添加剂,可以举出惰性粉末、离子交换树脂、可溶化剂、增塑剂、稀释剂、甜味料、润滑剂、赋型剂或充填剂、酶抑制剂、抗粘结剂、抗凝固剂、消泡剂、粘合剂、pH调节剂或缓冲剂、螯合剂、凝析剂、吸收促进剂、粘合剂、香料减感剂、矫味剂、保存剂、抗氧化剂、防冻结剂、着色剂、不透明化剂、冷却剂、溶剂、增稠剂、崩解剂等。作为上述添加剂的具体例,可以举出卵磷脂、溶血卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酸、磷脂酰丝氨酸、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、溶血磷脂酰甘油、溶血磷脂酸、溶血磷脂酰丝氨酸、PEG-磷脂酰乙醇胺、PVP-磷脂酰乙醇胺、脂肪酸的乳酸酯、硬脂基-2-乳酸酯(stearyl-2-lactate)、乳酸十八烷基酯(stearyl lactate)、琥珀酸单甘油酯(succinylated monoglyceride)、单/二甘油酯的单/二乙酰化酒石酸酯、单/二甘油酯的柠檬酸酯、胆酸、牛磺胆酸、甘氨胆酸、脱氧胆酸、牛磺脱氧胆酸、鹅脱氧胆酸、甘氨脱氧胆酸、甘氨鹅脱氧胆酸、牛磺鹅去氧胆酸、乌索脱氧胆酸(ursodeoxycholate)、牛磺熊脱氧胆酸(Tauroursodeoxycholic acid)、甘氨乌索脱氧胆酸、胆酸肌氨酸、N-甲基牛磺胆酸、己酸、辛酸、癸酸、月桂酸、油酸、蓖麻油酸、亚油酸、亚麻酸、硫酸十二烷基酯、硫酸十四烷基酯、多 库酯(docusate)、月桂酰肉碱、棕榈酰肉碱、肉豆蔻酰肉碱、己酸钠、辛酸钠、月桂酸钠、肉豆蔻酸钠、肉豆蔻脑酸钠、棕榈酸钠、棕榈油酸钠、油酸钠、蓖麻油酸钠、亚油酸钠、亚麻酸钠、硬脂酸钠、十二烷基硫酸钠、十四烷基硫酸钠、月桂基肌氨酸钠、二辛基硫酸琥珀酸钠(DOSS)、胆汁酸钠、胆酸钠、牛磺胆酸钠、甘醇酸钠、脱氧胆酸钠、牛磺脱氧胆酸钠、甘氨脱氧胆酸钠、乌索脱氧胆酸钠、鹅脱氧胆酸钠、心磷脂、聚乙二醇400、聚乙二醇4000、聚乙二醇600、聚乙二醇10000、聚乙二醇6000、乳糖、白糖、甘露糖醇、氯化钠、葡萄糖、碳酸钙、高岭土、结晶纤维素、纤维素类聚合物、轻质二氧化硅、硅酸盐、水、乙醇、单糖浆、葡萄糖液、淀粉液、明胶液、糊精、普鲁兰多糖(pullulan)、柠檬酸、柠檬酸酐、柠檬酸钠、柠檬酸钠二水合物、无水磷酸一氢钠、无水磷酸二氢钠、磷酸氢钠、聚山梨醇酯80、季铵盐基团、十二烷基硫酸钠、精制滑石、硬脂酸盐、聚乙二醇、胶状硅酸、黄氧化铁、黄色三氧化二铁、三氧化二铁、β胡萝卜素、氧化钛、食用色素(例如、食用蓝色1号等)、叶绿素铜、核黄素、抗坏血酸、天冬甜素、甘茶(hydrangeae dulcis folium)、氯化钠、果糖、糖精、粉糖等。
需要说明的是,对于上述任意配合成分,可以通过与上述药物及蜡一同作为原料供给到挤出机内进行配合,也可以通过与形成的蜡基质粒子混合进行配合。
含有药物的蜡基质粒子
采用本发明的制造方法制造的含有药物的蜡基质粒子被用作药物制剂。该制剂可以为含有药物的蜡基质粒子本身的散剂或颗粒剂的形态,也可以采用填充到微囊、软胶囊、硬胶囊等中形成胶囊剂的形态。
2.含有西洛他唑的缓释制剂
进而,本发明提供一种包含含有西洛他唑的蜡基质粒子的缓释制剂。该缓释制剂中所含的含有西洛他唑的蜡基质粒子可以通过上述制造方法简便地制造,也可以通过其他制法制造,对其制法没有特殊的 限定。
本发明的缓释制剂,作为药物含有西洛他唑结晶(以下,有时也简单地表示为(A)成分)。对该西洛他唑结晶的平均粒径没有特殊的限制,可以举出为10μm以下、优选为0.1~10μm、更优选为0.5~8μm。西洛他唑是满足上述平均粒径的结晶时,能够在水分少的消化管下部更加稳定地进行西洛他唑的缓慢释放及吸收。
可以通过在常温下放置西洛他唑完全溶解的蜡基质粒子来生成上述平均粒径的西洛他唑的结晶,但通过对西洛他唑完全溶解的蜡基质粒子进行规定的加热处理,与在常温下放置的情况相比能够更加迅速地生成结晶。具体而言,可以按规定量混合下述(B)成分和西洛他唑,进行加热,使所得的熔融混合物固化成粒子状,然后,在室温以上且该(B)成分熔点以下的温度下、优选在40~55℃下、更优选在45~54℃下进行加热,由此在蜡基质粒子中生成上述平均粒径的西洛他唑结晶。需要说明的是,作为上述加热处理时间,没有特殊的限定,通常可以举出1分钟~24小时、优选5分钟~20小时、更优选10分钟~15小时。
西洛他唑结晶的平均粒径通过偏光显微镜进行观察加以测定。具体而言,在偏光显微镜中于视野内呈现出具有规定大小的直尺,观察结晶的大小,由此进行测定。
本发明的缓释制剂中,上述(A)成分的浓度根据该制剂的用途、给药对象的性别或年龄等而不同,例如可以举出相对于该制剂所含的蜡基质粒子的总量为5~60重量%、优选为10~50重量%、更优选为20~45重量%。
进而,本发明的缓释制剂,除了上述(A)成分之外,还可以含有脂肪酸甘油酯及/或聚甘油脂肪酸酯(以下,有时也简单地表示为(B)成分)作为蜡(蜡基质基材)。
作为脂肪酸甘油酯、及聚甘油脂肪酸酯,使用与上述相同的物质。
上述(B)成分可以单独使用1种,另外也可以任意组合2种以上进行使用。
上述(B)成分中,从进一步改善缓释性、并且进一步降低进食对西洛他唑释放速度的影响的观点考虑,优选甘油山嵛酸酯、二甘油硬脂酸酯、三甘油半山嵛酸酯、三甘油半硬脂酸酯、及十甘油单硬脂酸酯,更优选为甘油山嵛酸酯、二甘油硬脂酸酯、及三甘油半山嵛酸酯。
本发明的缓释制剂中,作为上述(A)及(B)成分的配合比率,没有特殊的限制,通常可以举出相对于100重量份上述(A)成分,上述(B)成分为50~2000重量份、优选为70~1000重量份、更优选为100~500重量份的比率。通过满足上述比率,能够更有效地提高西洛他唑的缓释性,并且不易受到进食对释放特性的影响。
本发明的缓释制剂中,对于上述(B)成分的浓度,可以根据上述(A)及(B)成分的配合比率和上述(A)成分的配合量适当地设定,例如可以举出相对于该制剂所含的蜡基质粒子的总量为30~95重量%、优选为40~90重量%、更优选为50~80重量%。
进而,本发明的缓释制剂中所含的蜡基质粒子,除上述(A)及(B)成分之外,还可以含有(C)羟丙基甲基纤维素、醋酸羟丙甲纤维素琥珀酸酯、醋酸纤维素邻苯二甲酸酯、乙酸纤维素、聚乙烯基吡咯烷酮、羟基乙基纤维素、甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯等水溶性纤维素衍生物(水溶性纤维素醚)。其中优选为羟丙基纤维素或羟丙基甲基纤维素,更优选为羟丙基甲基纤维素。上述水溶性纤维素衍生物可以单独使用1种,另外也可以组合2种以上进行使用。如上所述通过进一步配合水溶性纤维素衍生物,可以在确保缓释性的同时,具有高的生物学利用度。本发明的缓释制剂中,配合水溶性纤维素衍生物时,作为其配合量,例如相对于该制剂所含的蜡基质粒子的总量,水溶性纤维素衍生物为1~15重量%、优选为2~12重量%、更优选为2~10重量%。
另外,本发明的缓释制剂中还可以进一步配合适当量的表面活性剂。对于可以配合的表面活性剂,与上述“1.含有药物的蜡基质粒子的制造方法”项中的内容相同。
进而,本发明的缓释制剂中,也可以配合适当量的其他水溶性高分子、水不溶性高分子、肠溶性高分子、胃溶性高分子等高分子物质。对于上述高分子物质的具体例,也与上述“1.含有药物的蜡基质粒子的制造方法”项中的内容相同。
另外,除上述物质之外,本发明的缓释制剂中也可以配合适当量的惰性粉末、离子交换树脂、可溶化剂、增塑剂、稀释剂、甜味料、润滑剂、赋形剂或充填剂、酶抑制剂、抗粘结剂、抗凝固剂、消泡剂、粘合剂、pH调节剂或缓冲剂、螯合剂、凝析剂、吸收促进剂、香料减感剂、矫味剂、保存剂、抗氧化剂、防冻结剂、着色剂、不透明化剂、冷却剂、溶剂、增稠剂、崩解剂等。对于上述添加剂的具体例,也与上述“1.含有药物的蜡基质粒子的制造方法”项中的内容相同。
需要说明的是,上述除(A)及(B)成分以外的配合成分,可以与上述(A)及(B)成分一同被包含在蜡基质粒子中,也可以通过与含有(A)及(B)成分的蜡基质粒子混合进行配合。
例如,也可以以附着的形态含有上述添加剂中的无化学或生物学活性的惰性粉末,使其被覆含有上述(A)及(B)成分的蜡基质粒子的表面。由上述惰性粉末被覆蜡基质粒子的表面可以起到在用于使西洛他唑生成结晶的加热处理时抑制粒子之间凝集的作用。
具体而言,作为上述惰性粉末,可以举出滑石;轻质二氧化硅;氧化钛;羟丙基甲基纤维素、羟丙基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙基纤维素等纤维素类聚合物;果糖、糖精、粉糖等糖类等。上述惰性粉末可以单独使用1种,另外也可以任意组合2种以上进行使用。对于上述惰性粉末的平均粒径,没有特殊的限制,例如理想情况为在10μm以下,优选为7~10μm。上述惰性粉末的平均粒径可以根据在粉末粒径的测定中通常使用的方法进行测定。
作为惰性粉末的附着量,没有特殊的限制,例如可以举出相对于100重量份含有(A)及(B)成分的蜡基质粒子,该惰性粉末的总量为0.5~15重量份,优选为1~10重量份,更优选为2~10重量份的量。
本发明的缓释制剂中所含的粒子,优选为如下制造的粒子,即, 将上述(A)成分、(B)成分、及根据需要添加的其他成分以规定量混合,加热,得到熔融混合物,将其调整至规定大小的粒径使其固化进行制造得到粒子。作为本发明的缓释制剂中所含的粒子,较优选使用上述(A)成分、(B)成分、及根据需要使用其他成分,可以举出采用上述“1.含有药物的蜡基质粒子的制造方法”项所述的方法制造的粒子。
本发明的缓释制剂中所含的蜡基质粒子的平均粒径为40~200μm。优选为50~150μm、更优选为60~130μm。通过具有上述平均粒径、且组合含有上述(A)及(B)成分,能够实现西洛他唑的所期望的缓释性、减轻进食对西洛他唑的释放特性的影响。需要说明的是,此处所谓的平均粒径是50%累积直径,即、粒度分布图中从0μm积分的体积为50%时的粒径,是通过利用激光衍射·散射法的粒度分布测定机测定得到的值。
本发明的缓释制剂中所含的蜡基质粒子,通过具有上述(A)及(B)成分、且具有上述平均粒径,可以具有优异的缓释性。对于本发明的缓释制剂中所含粒子的缓释性本身,没有特殊的限定,例如,在第14版日本药典的溶出试验第2法(桨法)中投入相当于15mg西洛他唑的量的粒子进行试验时,优选2小时后的溶出率为20%~35%、6小时后的溶出率为40~60%、12小时后的溶出率为60~80%、及18小时后的溶出率为60~90%,更优选2小时后的溶出率为25%~35%、6小时后的溶出率为45~60%、及12小时后的溶出率为60~80%、及18小时后的溶出率为65~90%。
本发明的缓释制剂可以是含有上述(A)及(B)成分的蜡基质粒子本身的散剂或颗粒剂的形态,也可以填充到微囊、软胶囊、硬胶囊等中形成胶囊剂的形态。
本发明的缓释制剂的给药量可以根据作为目的的医药用途、患者的年龄或性别等适当地设定。
实施例
以下,根据实施例详细地说明本发明,但本发明并不限定于这些实施例。
实施例1
使用图2所示结构的挤出机,制造蜡基质粒子。作为挤出机,结构及其操作条件如下所示。
挤出机类型:双螺杆挤出机(KEX-25、栗本铁工所制)
螺杆形状:从下游到上游侧,输送、捏和、混合部顺次连接的形状
喷嘴:双流体喷嘴
螺杆部长度:约50cm
螺杆的旋转速度:125rpm
喷嘴的排出孔的形状、孔径:圆形、 0.5mm
原料在滚筒内的滞留时间:约2分钟
滚筒温度的设定温度:滚筒套管1a-1为140℃、滚筒套管1a-2为150℃、滚筒套管1a-3及1a-4为160℃
喷雾气体的温度及导入速度:约200℃、25L/min
熔融混炼物的每1个排出孔的排出速度:50g/分钟
粒子形成用腔内的环境气体:空气、约30℃。
具体而言,将300g茶碱及700g脂肪酸甘油酯(甘油单山嵛酸酯;熔点约75℃)混合。一边以约50g/min的速度向上述挤出机的供给口内投入所得的混合原料,一边用上述结构及条件的挤出机制造蜡基质粒子,从粒子形成用腔的蜡基质粒子回收部回收蜡基质粒子。
所得蜡基质粒子在显微镜下观察的结果如图3所示。所得蜡基质粒子为圆球状,用激光衍射式粒度分布计(东日计算机应用(TohnichiComputer Applications))测定粒度分布时,10%累积直径为37μm、50%累积直径(平均粒径)为84μm、90%累积直径为165μm、99%累积直径为219μm。
需要说明的是,确认在该制造过程中未发生挤出机内茶碱析出、液体阻塞等不良情况。另外,所得蜡基质粒子中的茶碱含量相对于理论值约为100%。
实施例2
作为原料,混合300g茶碱、10g乙基纤维素、及690g脂肪酸甘油酯(甘油单山嵛酸酯;熔点约75℃),使用所得混合原料,在与上述实施例1相同的条件下制造蜡基质粒子。
所得蜡基质粒子为圆球状,采用激光衍射式粒度分布计(东日计算机应用)测定粒度分布时,10%累积直径为43μm,50%累积直径(平均粒径)为88μm,90%累积直径为160μm,99%累积直径为204μm。
需要说明的是,确认在该制造过程中未发生挤出机内茶碱析出、液体阻塞等不良情况。另外,所得蜡基质粒子中的茶碱含量相对于理论值约为100%。
实施例3
作为原料,混合300g茶碱、及700g硬化油(熔点:约86℃),使用所得混合原料,在与上述实施例1相同的条件下制造蜡基质粒子。所得蜡基质粒子为圆球状,采用激光衍射式粒度分布计(东日计算机应用)测定粒度分布时,10%累积直径为48μm、50%累积直径(平均粒径)为96μm、90%累积直径为169μm、99%累积直径为221μm。
需要说明的是,确认该制造过程中未发生挤出机内茶碱析出、液体阻塞等不良情况。另外,所得蜡基质粒子中的茶碱含量相对于理论值约为100%。
实施例4
作为原料,将1350g西洛他唑、1710g二甘油单硬脂酸酯(poem J-2081、理研维他命社制)、990g五甘油单硬脂酸酯(Sunsoft A-181E、太阳化学社制)、及450g聚乙烯基吡咯烷酮(Kollidon25、Povidone、BASF社制)混合,使用所得混合原料,在与上述实施例1相同的条件下制造蜡基质粒子。
所得蜡基质粒子为圆球状,采用激光衍射式粒度分布计(东日计算机应用)测定粒度分布时,50%累积直径(平均粒径)约为90μm。需要说明的是,确认该制造过程中未出现在挤出机内西洛他唑析出、液体阻塞等不良情况。另外,所得蜡基质粒子中的西洛他唑含量为100%。
实施例5
使用图2所示结构的挤出机,制造蜡基质粒子。作为挤出机,结构及其操作条件如下所示:
挤出机类型:双螺杆挤出机(KEX-25、栗本铁工所制)
螺杆形状:从下游到上游侧,输送、捏和、混合部顺次连接的形状
喷嘴:双流体喷嘴
螺杆部长度:约50cm
螺杆旋转速度:130rpm
喷嘴排出孔的形状、孔径:圆形、 0.5mm
原料在滚筒内的滞留时间:约2分钟
滚筒温度的设定温度:滚筒套管1a-1为140℃、滚筒套管1a-2为160℃、滚筒套管1a-3为165℃、及1a-4为160℃
喷雾气体的温度及导入速度:约200℃、25L/min
熔融混炼物每1个排出孔的排出速度:50g/分钟
粒子形成用腔内的环境气体:空气、约30℃。
具体而言,将240g平均粒径约20μm的西洛他唑、348g二甘油单硬脂酸酯(poemJ-2081、理研维生素)及12g三甘油半山嵛酸酯(TR-HB、理研维生素)混合。一边以约50g/min的速度向上述挤出机的供给口中投入所得的混合原料,一边用上述结构及条件的挤出机制造蜡基质粒子,从粒子形成用腔的蜡基质粒子回收部回收蜡基质粒子。
所得基质粒子附着性强,但通过添加·混合14.8g滑石,改善了流动性,通过网眼355μm的筛。然后,在50℃下对经整粒的基质粒子加热处理16小时。
所得蜡基质粒子用光学显微镜观察时,确认生成了10μm以下的西洛他唑结晶。另外,所得蜡基质粒子为圆球状,用激光衍射式粒度分布计(东日计算机应用)测定平均粒径(50%累积直径)时,为92μm。需要说明的是,确认该制造过程中未发生挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例6
作为原料,将240g平均粒径约20μm的西洛他唑、336g二甘油单硬脂酸酯(poem J-2081、理研维生素)及24g三甘油半山嵛酸酯(TR-HB、理研维生素)混合,使用所得混合原料,在与上述实施例1相同的条件下制造蜡基质粒子。
所得蜡基质粒子用光学显微镜观察时,确认生成10μm以下的西洛他唑结晶,另外该蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定其平均粒径(50%累积直径),为93μm。需要说明的是,确认该制造过程中未发生挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例7
作为原料,将240g平均粒径约20μm的西洛他唑、324g二甘油单硬脂酸酯(poem J-2081、理研维生素)及36g三甘油半山嵛酸酯(TR-HB、理研维生素)混合,使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。
用光学显微镜观察所得蜡基质粒子,确认生成10μm以下的西洛他唑结晶,另外该蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定其平均粒径(50%累积直径),为91μm。需要说明的是,确认该制造过程中未发生挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例8
作为原料,将240g平均粒径约20μm的西洛他唑、234g二甘油单硬脂酸酯(poem J-2081、理研维生素)、24g三甘油半山嵛酸酯(TR-HB、理研维生素)及102g甘油山嵛酸酯(poem B-100、理研维生 素)混合,使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。
用光学显微镜观察所得蜡基质粒子,确认生成10μm以下的西洛他唑结晶,另外,该蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定其平均粒径(50%累积直径)时,为79μm。需要说明的是,确认该制造过程中未发生挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例9
将240g平均粒径约20μm的西洛他唑、222g二甘油单硬脂酸酯(poem J-2081V、理研维生素)、24g三甘油半山嵛酸酯(TR-HB、理研维生素)、96g甘油山嵛酸酯(poem B-100、理研维生素)及18g羟丙基甲基纤维素(TC-5E、信越化学)混合。使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。其中,滚筒温度1a-1为120℃、1a-2为185℃、1a-3为185℃、1a-4为185℃;喷雾气体约为200℃、50L/min;熔融混合物每1个排出孔的排出速度为118g/分钟。向314g所得粒子中添加12.6g滑石,混合,在50℃下加热处理16小时。然后用网眼350μm的筛整粒。
用光学显微镜观察所得蜡基质粒子时,可以确认无粒径大于10μm的西洛他唑结晶。另外,所得蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定平均粒径(50%累积直径)时约为77μm。需要说明的是,确认该制造过程中未发生在挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例10
将240g平均粒径约20μm的西洛他唑、210g二甘油单硬脂酸酯(poem J-2081V、理研维生素)、24g三甘油半山嵛酸酯(TR-HB、理研维生素)、90g甘油山嵛酸酯(poem B-100、理研维生素)及36g羟丙基甲基纤维素(TC-5E、信越化学)混合。使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。其中,滚筒温度1a-1为120℃、1a-2为185℃、1a-3为185℃、1a-4为185℃;喷雾气 体约为200℃、40L/min;熔融混合物每1个排出孔的排出速度为175g/min。向353g所得粒子中添加14.1g滑石,混合,在50℃下加热处理16小时。然后,用网眼350μm的筛整粒。
用光学显微镜观察所得蜡基质粒子,可以确认无粒径大于10μm的西洛他唑结晶。另外,所得蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定平均粒径(50%累积直径)时约为104μm。需要说明的是,确认该制造过程中未发生在挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例11
将240g平均粒径约20μm的西洛他唑、198g二甘油单硬脂酸酯(poem J-2081V、理研维生素)、24g三甘油半山嵛酸酯(TR-HB、理研维生素)、84g甘油山嵛酸酯(poem B-100、理研维生素)及54g羟丙基甲基纤维素(TC-5E、信越化学)混合。使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。其中,滚筒温度1a-1为120℃、1a-2为185℃、1a-3为185℃、1a-4为185℃;喷雾气体约为200℃、50L/min;熔融混合物每1个排出孔的排出速度为120g/min。向267g所得粒子中添加10.7g滑石,混合,在50℃下加热处理16小时。然后,用网眼350μm的筛整粒。
用光学显微镜观察所得蜡基质粒子时,可以确认无粒径大于10μm的西洛他唑结晶。另外,所得蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定平均粒径(50%累积直径)时约为93μm。需要说明的是,确认该制造过程中未发生挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例12
将240g平均粒径约20μm的西洛他唑、222g二甘油单硬脂酸酯(poem J-2081V、理研维生素)、24g三甘油半山嵛酸酯(TR-HB、理研维生素)及60g羟丙基甲基纤维素(TC-5E、信越化学)混合。使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。其中,滚筒温度1a-1为130℃、1a-2为165℃、1a-3为175℃、1a-4 为170℃;喷雾气体约为200℃、50L/min;熔融混合物的每1个排出孔的排出速度为140g/min。向320g所得粒子中添加12.8g滑石,混合,在50℃下加热处理16小时。然后,用网眼350μm的筛整粒。
用光学显微镜观察所得蜡基质粒子时,可以确认无粒径大于10μm的西洛他唑结晶。另外,所得蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定平均粒径(50%累积直径)时约为98μm。需要说明的是,确认该制造过程中未发生挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例13
将240g平均粒径约20μm的西洛他唑、228g二甘油单硬脂酸酯(poem J-2081V、理研维生素)、48g三甘油半山嵛酸酯(TR-HB、理研维生素)、60g甘油山嵛酸酯(poem B-100、理研维生素)及24g卡波普(Carbopol 974P)混合。使用所得混合原料,在与上述实施例5相同的条件下制造蜡基质粒子。其中,滚筒温度1a-1为120℃、1a-2为185℃、1a-3为185℃、1a-4为185℃;喷雾气体约为200℃、45L/min;熔融混合物每1个排出孔的排出速度为128g/min。向384g所得粒子中添加15.4g滑石,混合,在50℃下加热处理16小时。然后,用网眼350μm的筛整粒。
用光学显微镜观察所得蜡基质粒子时,可以确认无粒径大于10μm的西洛他唑结晶。另外,所得蜡基质粒子为圆球状,通过激光衍射式粒度分布计(东日计算机应用)测定平均粒径(50%累积直径)时约为135μm。需要说明的是,确认该制造过程中未发生在挤出机内西洛他唑析出、液体阻塞等不良情况。
实施例14
向260g实施例13所得的蜡基质粒子中进一步混合1.0g轻质二氧化硅(Adsolider 101/YKF),将261mg所得混合物填充到硬胶囊中,制造胶囊剂。
比较例1
向密闭式带有套管的搅拌贮罐内添加1350g西洛他唑、1710g poem J-2081(二甘油单硬脂酸酯、理研维他命社制)、990g Sunsoft A-181E(五甘油单硬脂酸酯、太阳化学社制)、及450g Povidone(Kollidon25、聚乙烯基吡咯烷酮、BASF社制),一边加热至150℃一边混炼,制成透明熔融液。通过加压将此熔融混炼液从贮罐内输送至旋转盘式喷雾冷却器(直径2.5m)中。虽然用电热带将从贮罐至盘的约60cm管路加热至约150℃,但在管路中间西洛他唑仍析出并阻塞管路,不能进行喷雾。由此结果可知,该比较例1的方法即使使用与实施例4相同的原料成分,仍不能制造蜡基质粒子。
比较例2
使用1000g西洛他唑、1800g poem J-2081(二甘油单硬脂酸酯、理研维他命社制)、400g Povidone(Kollidon25、聚乙烯基吡咯烷酮、BASF社制)及800g Sunsoft No.621G(甘油柠檬酸单硬脂酸酯、太阳化学社制),在与上述比较例相同的条件下配制熔融液,输送至喷雾冷却器,用旋转盘喷雾冷却造粒,结果可以得到微量蜡基质粒子。然而,在贮罐内的浸液面、旋转螺杆部及管路内析出西洛他唑结晶。另外,所得蜡基质粒子中的西洛他唑含量相对于理论值为45%。
试验例1溶出试验
使用实施例5-8的蜡基质粒子,对西洛他唑释放特性进行评价。具体而言,使用与15mg西洛他唑相当的量的蜡基质粒子(实施例5-8),使用900mL 1重量%聚山梨醇酯80水溶液作为溶出液,采用日本药典第14版溶出试验法第2法桨法,使桨旋转数为75rpm,进行溶出试验,经时地测定溶出液中溶出的西洛他唑量(257nm及325nm的双波长测定),求出从蜡基质粒子中溶出的西洛他唑的比例(溶出率)(%)。
所得结果如图4所示。由此结果可知,实施例5-8的蜡基质粒子作为缓释制剂均显示出理想的溶出行为。
试验例2药动学评价
将与100mg西洛他唑相当的量的实施例6或8的蜡基质粒子填充到明胶胶囊中,在空腹下或进食后口服给予3只比格犬1个此明胶胶囊, 经时采血,测定血中西洛他唑浓度。另外,相同地经口给予市售Pletal片(含有相当于100mg的西洛他唑、结晶纤维素、玉米淀粉、羧甲基纤维素钙、羟丙基甲基纤维素、及硬脂酸镁)(速释片),经时地采血测定血中西洛他唑浓度。所得血中浓度变化的比较如图5所示,另外,计算的药物动态参数如表1所示。
给予速释片时,空腹给药和进食后给药的Cmax及AUC差异较大,受食物影响大。另一方面,给予实施例6或8的蜡基质粒子时,空腹给药和进食后给药的Cmax及AUC的差异小,不易受食物影响。
[表1]
AUCt:血中浓度时间曲线下面积(梯形法)
AUC∞:至无限长时间内的血中浓度时间曲线下面积
Cmax:最高血中浓度
Tmax:达到最高血中浓度的时间
MRTt:平均滞留时间
试验例3药动学评价
将相当于100mg西洛他唑的实施例10或13的蜡基质粒子填充到明胶胶囊中,进食后经口给予3只比格犬1个此明胶胶囊,经时地采血测定血中西洛他唑浓度。根据所得血中西洛他唑浓度计算的药物动态参数如表2所示。
由此结果确认,实施例10及13的蜡基质粒子作为缓释制剂均可显示出特别优良的溶出行为。由此结果可知,除了西洛他唑结晶、及脂肪酸甘油酯及/或聚甘油脂肪酸酯之外,通过配合羟丙基甲基纤维素,能够更有效地实现缓释制剂所要求的溶出状态。
[表2]
AUCt:血中浓度时间曲线下面积(梯形法)
AUC∞:至无限长时间内的血中浓度时间曲线下面积
Cmax:最高血中浓度
Tmax:达到最高血中浓度的时间
MRTt:平均滞留时间
附图说明
[图1]用于制造含有药物的蜡基质粒子的挤出机之一例,省略一部分表示的侧面图。
[图2]具有粒子形成用腔的状态的用于制造含有药物的蜡基质粒子的挤出机之一例的侧面图。
[图3]显微镜观察实施例1所得蜡基质粒子的结果(显微镜照片)。图中所示的短线长度表示200μm。
[图4]表示试验例1中测定的蜡基质粒子(实施例5-8)的溶出特性。
[图5]表示试验例2中测定的蜡基质粒子(实施例6及8)、及速释片的平均血中西洛他唑浓度的经时变化。
符号说明
1滚筒
2供给口
3出口冲模部
4螺杆
5喷嘴
6粒子形成用腔
7排气装置
10从喷嘴的排出孔5b排出的蜡基质粒子
Claims (14)
1.一种缓释制剂,其特征在于,所述缓释制剂包含含有(A)西洛他唑结晶、(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯及(C)羟丙基甲基纤维素的粒子,该粒子的平均粒径为40~200μm,
所述西洛他唑结晶(A)的粒径为10μm以下,
所述粒子是通过将所述(A)西洛他唑结晶、(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯、以及羟丙基甲基纤维素的熔融混合物进行喷雾使其固化而制得的粒子。
2.如权利要求1所述的缓释制剂,其中,所述(A)西洛他唑结晶的平均粒径为10μm以下。
3.如权利要求1或2所述的缓释制剂,其中,相对于缓释制剂中所述粒子的总量,含有5~60重量%(A)西洛他唑结晶、及30~95重量%(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯。
4.如权利要求1或2所述的缓释制剂,其中,相对于缓释制剂的总量,含有1~15重量%羟丙基甲基纤维素。
5.如权利要求1或2所述的缓释制剂,其中,惰性粉末附着在所述粒子的表面。
6.如权利要求5所述的缓释制剂,其中,所述惰性粉末是选自滑石、轻质二氧化硅、氧化钛、及纤维素类聚合物中的至少1种。
7.如权利要求1或2所述的缓释制剂,其中,所述(B)成分为选自甘油硬脂酸酯、聚甘油硬脂酸酯、甘油山嵛酸酯、及聚甘油山嵛酸酯中的至少1种。
8.如权利要求1或2所述的缓释制剂,其中,所述(B)成分是选自甘油山嵛酸酯、二甘油硬脂酸酯、及三甘油半山嵛酸酯中的至少1种。
9.如权利要求1或2所述的缓释制剂,是经过以下工序(i)及(ii)制得的,
工序(i):向挤出机中供给(A)西洛他唑、(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯及(C)羟丙基甲基纤维素,所述挤出机中的滚筒及冲模的温度设定为所述(B)成分的熔点以上的温度,及
工序(ii):一边在所述挤出机内将所述(A)及(B)成分熔融混炼,一边从喷嘴向温度低于所述(B)成分的熔点的环境气体中喷雾排出熔融混炼的所述(A)及(B)成分的混合物,由此成型为粒子状,所述喷嘴直接安装在冲模部,所述冲模部设置在所述挤出机滚筒的前端。
10.如权利要求9所述的缓释制剂,其中,进一步经过下述工序(iii)进行制造,所述工序(iii)为在40~55℃的温度条件下对所述工序(ii)得到的粒子进行加热处理。
11.如权利要求10所述的缓释制剂,其中,还包含下述工序,即在所述工序(iii)中于加热处理前使惰性粉末附着在所述工序(ii)所得粒子的表面。
12.一种权利要求1或2所述的缓释制剂的制造方法,包括下述步骤:
工序(i):向挤出机中供给(A)西洛他唑、(B)脂肪酸甘油酯及/或聚甘油脂肪酸酯及(C)羟丙基甲基纤维素,所述挤出机中的滚筒及冲模的温度设定为所述(B)成分的熔点以上的温度,及
工序(ii):一边在所述挤出机内将所述(A)及(B)成分熔融混炼,一边从喷嘴向温度低于所述(B)成分的熔点的环境气体中喷雾排出熔融混炼的所述(A)及(B)成分的混合物,由此成型为粒子状,所述喷嘴直接安装在冲模部,所述冲模部设置在所述挤出机滚筒的前端。
13.如权利要求12所述的制造方法,其中,还包含工序(iii):在40~55℃的温度条件下对所述工序(ii)中得到的粒子进行加热处理。
14.如权利要求13所述的制造方法,其中,所述工序(iii)是在使惰性粉末附着在所述工序(ii)得到的粒子的表面后,在40~55℃的温度条件下进行加热处理的工序。
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CN112826798B (zh) * | 2019-11-25 | 2023-04-07 | 上海博志研新药物技术有限公司 | 布洛芬药物组合物、制备方法及应用 |
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CN101219115B (zh) * | 2003-06-27 | 2012-09-19 | 大塚制药株式会社 | 药物持续释放颗粒及其制备方法 |
US6984403B2 (en) * | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
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CN1509185A (zh) * | 2001-05-25 | 2004-06-30 | ��V��ҩ��ʽ���� | 医药用组合物 |
CN1697648A (zh) * | 2003-12-04 | 2005-11-16 | 辉瑞产品公司 | 减少了副作用的阿奇霉素剂型 |
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