CN114099444A - 含聚乙烯醇的造粒产品和固体制剂 - Google Patents
含聚乙烯醇的造粒产品和固体制剂 Download PDFInfo
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
本发明提供了一种造粒产品(GP),其包含选自活性成分、赋形剂和崩解剂的至少一种,和基于GP的质量为0.1质量%至5.0质量%的皂化度为60mol%至77mol%的聚乙烯醇;包含该GP的固体制剂;和在该GP不包含活性成分的情况下的活性成分;以及生产GP的方法,该方法包括造粒的造粒步骤,同时添加至少包含水的第二组分、包含选自活性成分、赋形剂和崩解剂中的至少一种的第一组分以获得GP,其中所述第一组分和/或所述第二组分包含基于GP的质量为0.1质量%至5.0质量%的量的皂化度为60mol%至77mol%的聚乙烯醇。
Description
技术领域
本发明涉及一种含有聚乙烯醇的造粒产品,和含有该造粒产品且在医药品或保健食品领域中在崩解方面表现优异的固体制剂。
背景技术
用于医药品和保健食品(例如声称具有营养功能的食品)领域中的活性成分的口服给药剂型包括固体制剂,例如片剂、颗粒剂和胶囊;以及液体制剂,例如酏剂、悬浮液和乳液。其中,片剂是通过将粉末压片成恒定形状获得的固体制剂,并且具有易于处理和易于服用等优点。尤其是在医药品领域,片剂占总产值为约50%并且最为常用。
用于生产片剂的方法的实例包括干法直接压片、干法造粒压片、挤压造粒压片和湿法造粒压片。湿法造粒压片比干法直接压片(其中,例如药物和赋形剂按原样混合并压片)更复杂。然而,更常用的是湿法造粒压片,因为通过造粒操作可以大大改善可压缩性、可流动性和药物含量的均匀性。湿法造粒压片是这样的方法:其中通过利用粘合剂溶液或溶剂(例如水)的粘附将例如药物和赋形剂的混合物制成颗粒;干燥;并将所得造粒产品压片以生产片剂。湿法造粒压片包括使用搅拌造粒机的湿法搅拌造粒压片和使用流化床造粒机的流化床造粒压片。
其中所获得的造粒产品作为未压片的药品或保健食品口服给药的固体制剂称为颗粒剂。通过用造粒产品填充胶囊获得的固体制剂称为胶囊。
在湿造粒压片中的造粒期间使用的粘合剂的主要实例包括聚乙烯吡咯烷酮(以下也称为“PVP”)、羟丙基纤维素(以下也称为“HPC”)和羟丙基甲基纤维素(以下也称为“HPMC”)。
然而,所述粘合剂的结合强度可能不足,以致可能无法获得具有预定粒径的造粒产品,可能无法获得具有所需片剂硬度的片剂,或者在压片过程中可能出现压片故障,例如揭盖。当增加所述粘合剂的量以增强粘合强度时,存在崩解劣化的问题。
因此,希望开发一种造粒产品,其具有足够粒径而不增加粘合剂的量,并且能够提供具有高片剂硬度和压片时的短崩解时间的片剂;以及在不使用特殊技术或设备的情况下生产造粒产品的方法。
当PVP、HPC或HPMC导致缺乏粘合强度时,聚乙烯醇(以下也称为“PVA”)可用作具有高粘合强度的粘合剂。例如,与使用HPC或HPMC的造粒产品相比,通过使用符合日本药用辅料的PVA通过湿法搅拌造粒获得的造粒产品已知具有减少的细颗粒量和低压实度以及优异的可流动性;与通过将含有HPC或HPMC的造粒产品压片获得的片剂相比,通过将含有PVA的造粒产品压片获得的片剂已知具有更高的片剂硬度和更低的易碎性(Proceedings of30th Symposium on Particulate Preparations and Designs,2013,pages38 to 39)。
为了提高难溶性药物的溶解度和分解度,PVA也用作固体分散体的载体,其中药物在载体中非晶化并在分子水平上分散(WO 2018/199281A和WO 2018/199282A)。
发明内容
然而,当PVA用作通过湿法造粒(包括湿法搅拌造粒)获得的造粒产品中的粘合剂时,与使用其他粘合剂相比,崩解时间可能延迟。
本发明是鉴于上述情况而做出的,本发明的目的是提供一种造粒产品,即使其含有PVA作为粘合剂时也具有优异的崩解性;用于生产所述造粒产品的方法;以及一种包含所述造粒产品的固体制剂。由于本发明涉及造粒产品,因此与固体分散体相反,晶体药物不会在造粒产品的生产过程中变为非晶态。造粒产品不包括固体分散体,但固体分散体造粒的情况除外。
作为解决上述问题的广泛研究的结果,发明人发现,在湿法造粒压片中的造粒期间,使用皂化度为60mol%至77mol%的PVA可获得硬度和崩解性优异的片剂,并完成本发明。
在本发明的一个方面中,提供一种造粒产品,该造粒产品包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种;和基于造粒产品的质量为0.1质量%至5.0质量%的皂化度为60mol%至77mol%的聚乙烯醇。
在本发明的另一个方面中,提供一种固体制剂,其包含造粒产品,以及在造粒产品不包含活性成分的情况下的所述活性成分。
在本发明的又一个方面中,提供一种用于生产造粒产品的方法,该方法包括造粒的造粒步骤,同时添加至少包含水的第二组分、包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种的第一组分以获得造粒产品,其中第一组分和/或第二组分包含基于造粒产品的质量为0.1质量%至5.0质量%的量的皂化度为60mol%至77mol%的聚乙烯醇。
在本发明的又一个方面中,提供一种用于生产片剂的方法,该方法包括将包含造粒产品和润滑剂的粉末压片以获得片剂的步骤。
根据本发明,可生产硬度和崩解性优异的高品质固体制剂,以便在填充、运输等过程中抑制裂纹和碎屑的出现;并且口服给药时药物功效可能会迅速显现。
具体实施方式
(1)造粒产品
造粒产品包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种;和基于造粒产品的质量为0.1质量%至5.0质量%的皂化度为60mol%至77mol%的聚乙烯醇作为粘合剂。
活性成分不受特别限制,只要其是一种能够口服给药的活性成分。活性成分的实例包括药品中使用的药物和保健食品(例如具有营养功能声明的食品、用于特定保健用途的食品和具有功能声明的食品)中使用的活性成分。
药品中使用的药物的实例包括用于中枢神经系统的药物、用于心血管系统的药物、用于呼吸系统的药物、用于消化系统的药物、抗生素、镇咳祛痰药、抗组胺药、解热消炎镇痛药、利尿剂、植物神经系统药、抗疟药、止泻药、精神药物、以及维生素及其衍生物。
用于中枢神经系统的药物的实例包括安定、艾地苯醌、萘普生、吡罗昔康、吲哚美辛、舒林酸、劳拉西泮、硝基安定、苯妥英、对乙酰氨基酚、乙水杨胺、酮洛芬和氯氮卓。
用于心血管系统的药物的实例包括吗多明、长春西汀、普萘洛尔、甲基多巴、潘生丁、呋塞米、氨苯蝶啶、硝苯地平、阿替洛尔、螺内酯、美托洛尔、吲哚洛尔、卡托普利、硝酸异山梨酯、盐酸地拉普利、盐酸甲氯芬酯、盐酸地尔硫卓、盐酸依替福林、洋地黄毒苷和盐酸阿普洛尔。
用于呼吸系统的药物示例包括氨来呫诺、右美沙芬、茶碱、伪麻黄碱、沙丁胺醇和愈创甘油醚。
用于消化系统的药物的实例包括具有抗溃疡作用的苯并咪唑药物,例如2-[[3-甲基-4-(2,2,2-三氟乙氧基)-2-吡啶基]甲基亚磺酰基]苯并咪唑和5-甲氧基-2-[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基亚磺酰基]苯并咪唑;西咪替丁;雷尼替丁;盐酸哌仑西平;胰酶;比沙可啶;和5-氨基水杨酸。
抗生素的实例包括盐酸酞氨西林、盐酸卡巴西林、头孢克洛和红霉素。
镇咳祛痰药的实例包括盐酸那可汀、柠檬酸喷托维林、异柠檬酸4-二甲氨基-2,2-异丙基苯基戊腈(isoaminile citrate)和磷酸二甲啡烷。
抗组胺药的实例包括马来酸氯苯比胺、盐酸苯海拉明和盐酸异丙嗪。
解热抗炎镇痛药的实例包括布洛芬、双氯芬酸钠、氟芬那酸、安乃近(sulpyrine)、阿司匹林和酮洛芬。
利尿剂的实例包括咖啡因。
植物神经系统药的实例包括磷酸二氢可待因、dl-甲基麻黄素盐酸盐、硫酸阿托品、氯化乙酰胆碱和新斯的明。
抗疟药的实例包括盐酸奎宁。
止泻剂的实例包括盐酸洛哌丁胺。
精神药物的实例包括氯丙嗪。
维生素及其衍生物的实例包括维生素A、维生素B1、呋喃硫胺、维生素B2、维生素B6、维生素B12、维生素C、维生素D、维生素E、维生素K、泛酸钙和氨甲环酸。
保健食品中使用的活性成分实例包括上述维生素及其衍生物、矿物质、类胡萝卜素、氨基酸及其衍生物、植物提取物和保健食品材料。
矿物质的实例包括钙、镁、锰、锌、铁、铜、硒、铬、硫和碘。
类胡萝卜素的例子包括β-胡萝卜素、α-胡萝卜素、叶黄素、隐黄质、玉米黄质、番茄红素、虾青素和多胡萝卜素。
氨基酸的实例包括酸性氨基酸、碱性氨基酸、中性氨基酸和酸性氨基酸酰胺。
酸性氨基酸的实例包括天冬氨酸和谷氨酸。
碱性氨基酸的实例包括赖氨酸、精氨酸和组氨酸。
中性氨基酸的实例包括直链脂肪族氨基酸,如丙氨酸和甘氨酸;支链脂肪族氨基酸,如缬氨酸、亮氨酸和异亮氨酸;羟基氨基酸,如丝氨酸和苏氨酸;含硫氨基酸,如半胱氨酸和蛋氨酸;芳香族氨基酸,如苯丙氨酸和酪氨酸;杂环氨基酸,如色氨酸;以及亚氨基酸,如脯氨酸。
酸性氨基酸酰胺的实例包括天冬酰胺和谷氨酰胺。
氨基酸衍生物的实例包括乙酰谷氨酰胺、乙酰半胱氨酸、羧甲基半胱氨酸、乙酰酪氨酸、乙酰羟脯氨酸、5-羟脯氨酸、谷胱甘肽、肌酸、S-腺苷甲硫氨酸、甘氨酰甘氨酸、甘氨酰谷氨酰胺、多巴、丙氨酰谷氨酰胺、卡尼丁和γ-氨基丁酸。
植物提取物的实例包括芦荟提取物、蜂胶提取物、伞菌属(agaricus)提取物、人参提取物、银杏叶提取物、姜黄提取物、姜黄素、发芽糙米提取物、香菇菌丝体提取物、甜茶(Rubus suavissimus)提取物、甜绣球叶提取物、桑黄提取物、芝麻提取物、大蒜提取物、玛卡(Lepidium meyenii)提取物、虫草(Cordyceps sinensis)提取物、甘菊提取物和红辣椒提取物。
保健食品材料的实例包括蜂王浆;膳食纤维;蛋白质;双歧杆菌;乳酸菌;壳聚糖;酵母;氨基葡萄糖;卵磷脂;多酚;动物、鱼类和贝类的软骨;甲鱼;乳铁蛋白;淡水蛤;二十碳五烯酸;锗;酶;肌酸;肉碱;柠檬酸;覆盆子酮;辅酶Q10;甲磺酰甲烷;以及与磷脂结合的大豆肽。
可根据下文所述片剂中活性成分的含量确定活性成分的量。如有必要,可使用两种或更多种类型的活性成分。可使用市售活性成分。
赋形剂的实例包括糖,如绵白糖、乳糖、葡萄糖和麦芽糖;糖醇,如D-甘露醇、山梨醇和麦芽糖醇;淀粉,如小麦淀粉、大米淀粉、马铃薯淀粉和玉米淀粉;糊精;粉状纤维素;微晶纤维素;碳酸钙;磷酸钙;和硫酸钙。
可根据下文所述固体制剂中活性成分的含量确定赋形剂的量。如有必要,可使用两种或更多种类型的赋形剂。可使用市售赋形剂。
崩解剂的实例包括低取代羟丙基纤维素;淀粉,如小麦淀粉、大米淀粉、马铃薯淀粉和玉米淀粉;部分预糊化淀粉;羟基乙酸淀粉钠;羧甲基纤维素;羧甲基纤维素钙;交联羧甲基纤维素钠;微晶纤维素;和交聚维酮。
例如,从崩解的角度来看,低取代羟丙基纤维素(以下也称为“L-HPC”)中羟丙氧基的含量优选为5质量%至16质量%,更优选7质量%至15质量%。低取代羟丙基纤维素中羟丙氧基的含量可通过日本药典第十七版“低取代羟丙基纤维素”一节中所述的测定来确定。
可根据预期固体制剂中崩解剂的含量确定崩解剂的量。如有必要,可使用两种或更多种类型的崩解剂。可使用市售崩解剂。
PVA是一种水溶性聚合物,用作粘合剂。通常,PVA是通过聚合乙酸乙烯酯单体,然后用碱使所得聚合物皂化而制备的。PVA的皂化度为60mol%至77mol%,优选60mol%至74mol%,更优选60mol%至72mol%,并特别优选62mol%至72mol%。当皂化度小于60mol%时,在水中的溶解度降低,从而导致相分离和沉淀,或可压缩性不足。此外,当用量超过77mol%时,在固体制剂中使用时崩解变得不足。
PVA的皂化度可根据JIS K6726中描述的皂化度测量方法进行测量。
20℃时4质量%的PVA水溶液的粘度为1.5mPa·s至100.0mPa·s,优选2.0mPa.s至80.0mPa·s,更优选3.0mPa.s至50.0mPa·s。当粘度小于1.5mPa·s时,无法获得足够的粘合强度。当粘度超过100mPa·s时,造粒进展过度以产生团块,或当用于固体制剂时崩解变得不足。
可根据JIS K6726中所述的粘度测量方法测量4质量%的PVA水溶液在20℃时的粘度。
造粒产品中的PVA含量为0.1质量%至5.0质量%,优选0.2质量%至4.0质量%,并更优选0.5质量%至3.0质量%。当含量小于0.1质量%时,无法获得足够的粘合强度。当含量超过5.0质量%时,造粒进展过度以产生团块,或当用于固体制剂时崩解变得不足。
造粒产品可包括除PVA外的可选粘合剂和除活性成分、赋形剂和崩解剂外的可选的其他添加剂(以下也称为“其他添加剂”)。
除PVA外的可选粘合剂的实例包括羟丙基纤维素、聚乙烯吡咯烷酮、羟丙基甲基纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯醇-丙烯酸-甲基丙烯酸甲酯共聚物和乙酸乙烯酯树脂-乙烯基吡咯烷酮共聚物。
可选其他添加剂的实例包括调味剂、甜味剂、流化剂和用于活性成分的助溶剂。
调味剂的实例包括薄荷醇、薄荷油和香兰素。
甜味剂的实例包括阿斯巴甜、乙酰磺胺酸钾、三氯蔗糖、甜菊糖(stevia)和索马甜。
流化剂的实例包括轻质无水硅酸、水合二氧化硅和镁铝硅酸盐。
活性成分的助溶剂的实例包括有机酸,如富马酸、琥珀酸、苹果酸、酒石酸和己二酸;和有机酸的碱金属盐。
如有必要,可使用两种或更多种类型的其他添加剂。可使用市售的其他添加剂。待使用的其他添加剂的量将在下文中以固体制剂中的含量来描述。
造粒产品的平均粒径因应用而异。用于片剂时从可压片性和片剂之间的质量变化的角度来看,优选为60μm至300μm、更优选70μm至200μm、进而更优选80μm至150μm。
在分散压力为2巴、散射强度为2%至10%的条件下,可使用基于夫琅和费衍射理论的干法,使用激光衍射型粒径分布测量仪(Malvern生产的Master Sizer 3000)测量造粒产品的平均粒径,其中,在基于体积的累积粒径分布曲线中与50%累积尺寸对应的值用作平均粒径。
(2)生产造粒产品的方法
首先,将描述一种用于生产造粒产品的方法,该造粒产品包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种;和基于造粒产品的质量为0.1质量%至5.0质量%的皂化度为60mol%至77mol%的聚乙烯醇作为粘合剂。
造粒产品例如,可通过一种方法(下文也称为“生产造粒产品的方法A”)生产,该方法包括造粒步骤,同时添加包含水和皂化度为60mol%至77mol%的PVA的第二组分、包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种的第一组分以获得造粒产品。
造粒产品可通过一种方法(下文也称为“生产造粒产品的方法B”)生产,该方法包括造粒步骤,同时添加包含水的第二组分、包含皂化度为60mol%至77mol%的PVA,以及选自由活性成分、赋形剂和崩解剂组成的组的至少一种的第一组分。
此外,造粒产品可通过一种方法(下文也称为“生产造粒产品的方法C”)生产,该方法包括造粒步骤,同时添加包含水和皂化度为60mol%至77mol%的PVA的第二组分、包含皂化度为60mol%至77mol%的PVA以及选自由活性成分、赋形剂和崩解剂组成的组的至少一种的第一组分。
用于生产造粒产品的方法A中的第一组分包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种。用于生产造粒产品的方法B或方法C中的第一组分包含PVA和选自由活性成分、赋形剂和崩解剂组成的组的至少一种。
用于生产造粒产品的方法A或方法C中的第二组分是包含PVA和水的水性组合物。用于生产造粒产品的方法B中的第二组分包含水。
当PVA用于第二组分时,PVA的平均粒径不受特别限制。从制备含PVA的水性组合物的过程中的溶解速率的角度来看,它优选为20μm至5000μm、更优选50μm至2000μm。当PVA用于第一组分时,从造粒过程中的溶解度的角度来看,PVA的平均粒径优选为10μm至200μm、更优选20μm至150μm。
在分散压力为2巴、散射强度为2%至10%的条件下,可使用基于夫琅和费衍射理论的干法,使用激光衍射型粒径分布测量仪(Malvern生产的Master Sizer 3000)测量PVA的平均粒径,其中,在基于体积的累积粒径分布曲线中与50%累积尺寸对应的直径用作PVA的平均粒径。作为选择,可根据JIS Z 8815:1994(试验筛分一般要求)中所述的干式机械筛分法进行筛分。可使用Rosin-Rammler图绘制筛上累积残渣的百分比,当筛上累积残渣的百分比为50%时,可确定粒径为平均粒径。当平均粒径为1000μm以下时,优选使用激光衍射粒径分布测量仪测量平均粒度。当平均粒径大于1000μm时,优选根据JIS Z 8815:1994测量平均粒径。
水的实例包括纯化水。
水的量不受特别限制。当使用能够同时喷雾和干燥的造粒机(例如,流化床造粒机)时,从生产力和可操作性的角度来看,水的量相对于100质量份的包含第一和第二组分且不包含水的造粒产品,优选为10质量份至500质量份,更优选20质量份至200质量份。
当使用不能同时喷雾和干燥的造粒机(例如,湿式搅拌造粒机)时,从粒度的角度来看,水的量相对于100质量份的包含第一和第二组分且不含水的造粒产品,优选为5质量份至100质量份,更优选10质量份至50质量份。
第二组分可任选地包含活性成分、赋形剂和/或崩解剂,无论第一组分的组成如何。第一和第二组分之一或二者可包含除PVA外的可选的其他粘合剂和/或除含活性成分、赋形剂和崩解剂外的可选的其他添加剂(以下也称为“其他添加剂”)。
可使用造粒机进行造粒。造粒机的实例包括流化床造粒机、搅拌造粒机、翻滚流化床造粒机和喷雾干燥造粒机。
当通过使用流化床造粒机作为示例来解释用于生产造粒产品的方法A中的造粒操作时,可通过将包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种的粉末形式的第一组分放置在流化床造粒机中,然后造粒第一组分,同时添加(优选喷雾)包含预定PVA和水的水性组合物作为第二组分而获得造粒产品。
当通过使用湿式搅拌造粒机作为示例来解释用于生产造粒产品的方法B中的造粒操作时,可通过放置预定PVA和选自由活性成分、赋形剂和崩解剂组成的组的至少一种作为第一组分在湿式搅拌造粒机中,然后造粒第一组分,同时添加(优选喷雾)包含水的第二组分而获得造粒产品。
当获得的造粒产品在能够同时喷雾和干燥的造粒机(如流化床造粒机)中干燥时,无需进一步干燥。当获得的造粒产品未在该造粒机中干燥时,或在不能同时喷雾和干燥的造粒机(例如,湿式搅拌造粒机)中获得造粒产品时,优选通过已知方法进行干燥。
可使用干燥器(例如干燥烤箱)进行干燥。干燥器的实例包括流化床干燥器、闪蒸干燥器、箱式干燥器、振动干燥器、自然对流式恒温干燥器、强制对流式恒温干燥器和强制对流式恒温恒湿干燥器。干燥温度优选为40℃至120℃。
从片剂稳定性的角度来看,干燥的造粒产品的水含量优选为5.0质量%以下,更优选2.0质量%以下。可使用加热和干燥法水分分析仪(A&D Company Ltd.生产的MX-50)在5g造粒产品、105℃加热温度和60分钟加热时间的条件下测定造粒产品的水含量。
(3)固体制剂
固体制剂包括上述造粒产品,并在造粒产品不含活性成分的情况下包含活性成分。固体制剂的实例包括片剂、颗粒剂和胶囊。
固体制剂中或造粒产品中活性成分的含量不受特别限制。从药物作用或功效的角度来看,其优选为0.01质量%至99.40质量%。
固体制剂中或造粒产品中赋形剂的含量不受特别限制。从控制片剂的硬度和崩解时间的角度来看,其优选为0.00质量%至99.39质量%,更优选0.00质量%至95.00质量%。
从崩解和储存稳定性的角度来看,固体制剂中或造粒产品中崩解剂的含量优选为0.5质量%至30.0质量%,更优选1.0质量%至20.0质量%,进而更优选2.0质量%至10.0质量%。
从控制片剂的硬度和崩解时间的角度来看,固体制剂中或造粒产品中除PVA外的其他粘合剂的含量优选为0质量%至10质量%,更优选0质量%至5质量%。
固体制剂中或造粒产品中其他添加剂的含量不受特别限制。从控制片剂的风味、控制用于压片的粉末的可流动性或控制活性成分的溶解性的角度来看,其优选为0质量%至10质量%。
活性成分、赋形剂、崩解剂、粘合剂和/或添加剂可以在上述片剂中每种含量范围内包含在粉末状第一组分和第二组分之一或两者中;或可通过可选地将获得的造粒产品与活性成分、赋形剂、崩解剂、粘合剂和/或添加剂混合而包含在内。在造粒之前,粘合剂不仅可以包含在水性组合物中,而且可以包含在粉末组合物中。
片剂将被描述为固体制剂的实例。
从处理和施用的角度来看,片剂的直径优选为6mm至12mm。
片剂的重量优选为每片70mg至700mg。
在填充、运输或从PTP(压装)片材移除片剂时,从防止开裂、碎屑等的角度来看,片剂的硬度优选为60N至300N,更优选80N至250N,进而更优选100N至200N。片剂的硬度可使用片剂硬度计(ERWEKA GmbH生产的TBH-125)测量,且以1mm/s的速率在直径方向上向片剂施加载荷直到片剂断裂时获得为最大断裂强度。
从药物作用发展的角度来看,片剂的崩解时间优选在130秒内,更优选在100秒内,进而更优选在80秒内。片剂的崩解时间可根据日本药典第十七版的崩解试验(试验溶液:水,无补充板)使用崩解试验仪(Toyama Sangyo Co.,Ltd.生产的NT-400)确定。
从药物作用发展的角度看,作为固体制剂的颗粒或胶囊的实例优选包括满足日本药典第十七版溶解试验的那些。
(4)用于生产固体制剂的方法
接下来,描述一种用于生产固体制剂的方法,该固体制剂包含造粒产品,并且在造粒产品不包含活性成分的情况下,包含活性成分。将描述其中通过使用所获得的造粒产品来生产作为固体制剂的片剂的方法。
当造粒产品不含活性成分时,将造粒产品与活性成分混合。此时,造粒产品可任选地与例如赋形剂、崩解剂、粘合剂或其他添加剂混合。当使用内部润滑方法时,可将其与润滑剂混合。
混合方法不受特别限制。可使用混合机进行混合。混合机的实例包括V型混合机、带式混合机、容器混合机和滚筒混合机。
生产片剂的方法将被描述为生产固体制剂的方法的实例。
片剂可通过至少包括以下步骤的方法生产:至少将润滑剂添加至造粒产品以获得混合物(内部润滑法),并将混合物压片。通过按照下面描述的外部润滑方法放置润滑剂并压片,也可以不向造粒产品中添加润滑剂而生产片剂。
如有必要,可将造粒产品转化为用于压片的粉末。用于压片的粉末可通过将造粒产品与选自由活性成分、赋形剂、崩解剂、粘合剂、添加剂和下述润滑剂组成的组的至少一种混合的步骤获得。混合方法不受特别限制。可使用混合机进行混合。混合机的实例包括V型混合机、带式混合机、容器混合机和滚筒混合机。
当不向造粒产品中添加任何物质时,造粒产品本身可用作压片用粉末。
可使用压片机进行压片。压片机的实例包括旋转压片机和单冲压片机。
作为添加润滑剂的方法(以下也称为“润滑方法”),可选择内部润滑法或外部润滑法。
根据内部润滑法,使用配备有冲头和模具的压片机压片含有润滑剂的粉末,其中冲头和模具的粉末接触部分均不存在润滑剂。另一方面,根据外部润滑法,使用配备有冲头和模具的压片机压片不含润滑剂的粉末或造粒产品,其中润滑剂存在于冲头的粉末(或造粒产品)接触部分和/或模具的粉末(或造粒产品)接触部分。
当使用压片机(如旋转压片机或单冲压片机)通过内部润滑方法生产片剂时,可将含有粉末的润滑剂放置在无润滑剂的模具中,并在预定压力下通过无润滑剂的上下冲头按压。
当使用与外部润滑喷雾系统(ELS-P1,由Kikusui Seisakusho Ltd.生产)相连的旋转压片机等通过外部润滑法生产片剂时,可将不含润滑剂的粉末或造粒产品放置在模具中,并在预定压力下通过上下冲头按压,其中润滑剂存在于模具和冲头的每个粉末(或造粒产品)接触部分。将润滑剂放置在冲头的粉末(或造粒产品)接触部分和/或模具的粉末(或造粒产品)接触部分的方法的实例包括喷雾或涂覆。
润滑剂的实例包括滑石;硬脂酸镁;硬脂酸钙;硬脂酰富马酸钠;蔗糖脂肪酸酯;蜡,如石蜡和巴西棕榈蜡;以及硬化油,如硬化蓖麻油、硬化菜籽油和硬化牛脂油。
从抑制压片失败、崩解延迟和片剂硬度降低的角度来看,内部润滑法中的润滑剂量相对于100质量份的不含润滑剂的片剂(即,用于压片的造粒产品或粉末),优选为0.2质量份至5.0质量份,更优选0.4质量份至3.0质量份。
从抑制压片失败和防止崩解延迟以及降低片剂硬度的角度来看,外部润滑法中的润滑剂量相对于100质量份的不含润滑剂的片剂(即,用于压片的造粒产品或粉末),优选为0.01质量份至2.0质量份,更优选0.05质量份至1.0质量份。
从片剂硬度、崩解时间和抑制压片失败的角度来看,压片压力优选为20MPa至400MPa。
生产颗粒的方法的实例包括上述生产造粒产品的方法相同的实例。获得的造粒产品用作未压片的颗粒。
生产胶囊的方法包括,例如,上述生产造粒产品的方法所包括的每个步骤,以及将获得的造粒产品填充到胶囊中的步骤。
实施例
将参考实施例和比较例来解释本发明。不应解释为本发明限于这些实施例或由这些实施例限制。
<生产PVA粉末A>
将市售的聚乙酸乙烯酯树脂(JMR-30LL,由日本VAM&POVALC0.,LTD.生产)在100℃真空干燥以除去水分,然后溶解在甲醇中,以获得51质量%的聚乙酸乙烯酯树脂的甲醇溶液。通过将250g(500质量份)甲醇溶液加热至40℃进行皂化反应;向其中添加6.5g(13质量份)3质量%的氢氧化钠的甲醇溶液(35℃);使用螺旋桨式搅拌叶片充分搅拌所得混合物,直到混合物变得均匀;然后使均匀的混合物在40℃静置40分钟。将所得凝胶粉碎;浸入由325g(650质量份)甲醇、165g(330质量份)乙酸甲酯和8.5g(17质量份)水组成的混合溶剂中;缓慢搅拌;然后加入1质量%的乙酸水溶液,加入的量使所得混合物的pH值为8至9,作为中和。中和后,分离固体物质和液体,并在60℃干燥固体物质8小时以获得PVA颗粒。
随后,使用漫游式搅拌机(Osaka Chemical Co.,Ltd.生产的WB-1)将PVA颗粒粉碎,然后通过开口为150μm的JIS试验用筛子进行筛分以获得PVA粉末A。
根据JIS K6726中所述的皂化度测量方法和粘度测量方法,测量所得PVA粉末A的皂化度及其4质量%的水溶液在20℃时的粘度。其平均粒径也使用激光衍射型粒径分布测量装置测量。结果显示在表1中。
<生产PVA粉末B>
PVA粉末B以与PVA粉末A的生产相同的方式生产,不同之处在于将3质量%的量的氢氧化钠的甲醇溶液(35℃)变为5.5g(11质量份)。
以与PVA粉末A相同的方式测量所得PVA粉末B的皂化度、其4质量%的量的水溶液在20℃时的粘度及其平均粒径。结果显示在表1中。
<PVA粉末C的制备>
PVA粉末C以与PVA粉末A的生产相同的方式生产,不同之处在于将3质量%的量的氢氧化钠的甲醇溶液(35℃)变为5.0g(10质量份)。
以与PVA粉末A相同的方式测量所得PVA粉末C的皂化度、其4质量%的量的水溶液在20℃时的粘度及其平均粒径。结果显示在表1中。
<PVA粉末D的制备>
PVA粉末D以与PVA粉末A的生产相同的方式生产,不同之处在于将3质量%的量的氢氧化钠的甲醇溶液(35℃)变为4.5g(9质量份)。
以与PVA粉末A相同的方式测量所得PVA粉末D的皂化度、其4质量%的量的水溶液在20℃时的粘度及其平均粒径。结果显示在表1中。
<PVA粉末E的制备>
PVA粉末E以与PVA粉末A的生产相同的方式生产,不同之处在于将3质量%的量的氢氧化钠的甲醇溶液(35℃)变为4.0g(8质量份)。
以与PVA粉末A相同的方式测量所得PVA粉末E的皂化度、其4质量%的量的水溶液在20℃时的粘度及其平均粒径。结果显示在表1中。
<PVA粉末F的制备>
PVA粉末F以与PVA粉末A的生产相同的方式生产,不同之处在于将3质量%的量的氢氧化钠的甲醇溶液(35℃)变为3.5g(7质量份)。
以与PVA粉末A相同的方式测量所得PVA粉末F的皂化度、其4质量%的量的水溶液在20℃时的粘度及其平均粒径。结果显示在表1中。
<PVA粉末G的制备>
PVA粉末G以与PVA粉末A的生产相同的方式生产,不同之处在于将3质量%的量的氢氧化钠的甲醇溶液(35℃)变为2.5g(5质量份)。
以与PVA粉末A相同的方式测量所得PVA粉末G的皂化度、其4质量%的量的水溶液在20℃时的粘度及其平均粒径。结果显示在表1中。
表1
实施例1
通过将6g PVA粉末B(皂化度为76mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为96μm)作为粘合剂溶解在144g纯化水中制备水性组合物(以下也称为“水性粘合剂溶液”)。
接下来,将60g对乙酰氨基酚(细粉级,由Yamamoto Kagaku Kogyo Co.,Ltd.生产)作为活性成分、219g乳糖(Pharmatose 200M,由DFE Pharma生产)作为赋形剂和15g低取代羟丙基纤维素(羟丙氧基含量为11质量%)作为崩解剂放置在流化床造粒机(MP-01,由Powrex Corporation生产)中,并以0.6m3/min至0.7m3/min的空气流量混合以获得粉末组合物。
在同一造粒机中,在入口空气温度为80℃、出口空气温度为35℃至38℃、空气流量为0.5m3/min至0.6m3/min、喷雾速率为10g/min和喷雾空气压力为200kPa的条件下喷雾上述粘合剂水溶液时进行造粒。喷雾完成后,在同一造粒机中,在入口空气温度为80℃和空气流量为0.5m3/min至0.6m3/min的条件下干燥混合物,直到出口空气温度达到45℃,然后通过开口为710μm的JIS试验用筛进行筛分以获得造粒产品。所得造粒产品的组分、平均粒径和水含量显示在表2中。
接下来,在100g(100质量份)的所得造粒产品中添加0.5g(0.5质量份)硬脂酸镁(蔬菜级,TAIHEI CHEMICAL INDUSTRIALCO.,LTD.生产)作为润滑剂,并混合以获得用于压片的粉末。
然后,使用配有一对直径为8mm和曲率半径为12mm的冲头和孔径为8mm的模具的桌面压片机(单冲头压片机HANDTAB-100,由Ichihashi Seiki Co.,Ltd.生产),将201mg用于压片的粉末装料并在10.0kN(约199.0MPa)的压力下压片,以根据内部润滑法生产201mg片剂。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例2
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末C(皂化度为73mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为104μm)用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例3
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末D(皂化度为70mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为107μm)用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例4
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末E(皂化度为66mol%、以4质量%水溶液测定的20℃粘度为5.3mPa·s、且平均粒径为111μm)用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中
实施例5
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末F(皂化度为63mol%、以4质量%水溶液测定的20℃粘度为3.8mPa·s、且平均粒径为108μm)用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例6
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于将3g PVA粉末D作为粘合剂溶解在147g纯化水中以制备粘合剂水溶液,并将放置在流化床造粒机中的乳糖的量变为222g。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例7
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于将1.5g PVA粉末D作为粘合剂溶解在148.5g纯化水中以制备粘合剂水溶液,并将放置在流化床造粒机中的乳糖的量变为223.5g。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例8
通过将6g PVA粉末C(皂化度为73mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为104μm)作为粘合剂溶解在144g纯化水中制备水性粘合剂溶液。
接下来,将60g对乙酰氨基酚(细粉级,由Yamamoto Kagaku Kogyo Co.,Ltd.生产)作为活性成分和219g D-甘露醇(PEARLITOL25C,由Roquette生产)作为赋形剂放置在流化床造粒机(MP-01,由PowrexCorporation生产)中,并以0.6m3/min至0.7m3/min的空气流量混合以获得粉末组合物。
在同一造粒机中,在入口空气温度为80℃、出口空气温度为35℃至38℃、空气流量为0.5m3/min至0.6m3/min、喷雾速率为10g/min和喷雾空气压力为200kPa的条件下喷雾上述粘合剂水溶液时进行造粒。喷雾完成后,在同一造粒机中,在入口空气温度为80℃和空气流量为0.5m3/min至0.6m3/min的条件下干燥混合物,直到出口空气温度达到45℃,然后通过开口为710μm的JIS试验用筛进行筛分以获得造粒产品。所得造粒产品的组分、平均粒径和水含量显示在表2中。
接下来,将95g(95质量份)的所得造粒产品和5g(5质量份)低取代羟丙基纤维素(羟丙氧基含量为11质量%)作为崩解剂混合,然后添加0.5g(0.5质量份)硬脂酸镁(蔬菜级,TAIHEI CHEMICAL INDUSTRIAL CO.,LTD.生产)作为润滑剂,并混合以获得用于压片的粉末。
然后,使用配有一对直径为8mm和曲率半径为12mm的冲头和孔径为8mm的模具的桌面压片机(单冲头压片机HANDTAB-100,由Ichihashi Seiki Co.,Ltd.生产),将201mg用于压片的粉末装料并在7.5kN(约149.3MPa)的压力下压片,以根据内部润滑法生产201mg片剂。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例9
以与实施例8中相同的方式生产造粒产品和片剂,不同之处在于将实施例8中获得的95g(95质量份)造粒产品和5g(5质量份)羟基乙酸淀粉钠(Primojel,由DFE Pharma生产)作为崩解剂混合。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例10
通过将6g PVA粉末D(皂化度为70mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为107μm)作为粘合剂溶解在144g纯化水中制备粘合剂水溶液。
接下来,将279g D-甘露醇(PEARLITOL 25C,由Roquette生产)作为赋形剂和15g低取代羟丙基纤维素(羟丙氧基含量为11质量%)作为崩解剂放置在流化床造粒机(MP-01,由PowrexCorporation生产)中,并以0.6m3/min至0.7m3/min的空气流量混合以获得粉末组合物。
在同一造粒机中,在入口空气温度为80℃、出口空气温度为35℃至38℃、空气流量为0.5m3/min至0.6m3/min、喷雾速率为10g/min和喷雾空气压力为200kPa的条件下喷雾上述粘合剂水溶液时进行造粒。喷雾完成后,在同一造粒机中,在入口空气温度为80℃和空气流量为0.5m3/min至0.6m3/min的条件下干燥混合物,直到出口空气温度达到45℃,然后通过开口为710μm的JIS试验用筛进行筛分以获得造粒产品。所得造粒产品的组分、平均粒径和水含量显示在表2中。
接下来,将90g(90质量份)的所得造粒产品和10g(10质量份)对乙酰氨基酚(细粉级,由Yamamoto Kagaku Kogyo Co.,Ltd.生产)作为活性成分混合,然后添加0.5g(0.5质量份)硬脂酸镁(蔬菜级,TAIHEI CHEMICAL INDUSTRIAL CO.,LTD.生产)作为润滑剂,并混合以获得用于压片的粉末。
然后,使用配有一对直径为8mm和曲率半径为12mm的冲头和孔径为8mm的模具的桌面压片机(单冲头压片机HANDTAB-100,由Ichihashi Seiki Co.,Ltd.生产),将201mg用于压片的粉末装料并在10.0kN(约199.0MPa)的压力下压片,以根据内部润滑法生产201mg片剂。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例11
通过将6g PVA粉末D(皂化度为70mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为107μm)作为粘合剂溶解在144g纯化水中制备粘合剂水溶液。
接下来,将294g对乙酰氨基酚(细粉级,由Yamamoto Kagaku Kogyo Co.,Ltd.生产)作为活性成分放置在流化床造粒机(MP-01,由PowrexCorporation生产)中,并以0.6m3/min至0.7m3/min的空气流量流动以获得粉末组合物。
在同一造粒机中,在入口空气温度为80℃、出口空气温度为35℃至38℃、空气流量为0.5m3/min至0.6m3/min、喷雾速率为10g/min和喷雾空气压力为200kPa的条件下喷雾上述粘合剂水溶液时进行造粒。喷雾完成后,在同一造粒机中,在入口空气温度为80℃和空气流量为0.5m3/min至0.6m3/min的条件下干燥混合物,直到出口空气温度达到45℃,然后通过开口为710μm的JIS试验用筛进行筛分以获得造粒产品。所得造粒产品的组分、平均粒径和水含量显示在表2中。
接下来,将50g(50质量份)所得造粒产品、38g(38质量份)乳糖(S,由FreundCorporation生产)作为赋形剂、10g(10质量份)微晶纤维素(PH-101,由FMCCorporation生产)和2g(2质量份)交聚维酮(CL,由巴斯夫生产)作为崩解剂进行混合,然后添加0.5g(0.5质量份)硬脂酸镁(蔬菜级,TAIHEICHEMICAL INDUS TRIALCO.,LTD.生产)作为润滑剂,并混合以获得用于压片的粉末。
然后,使用配有一对直径为8mm和曲率半径为12mm的冲头和孔径为8mm的模具的桌面压片机(单冲头压片机HANDTAB-100,由Ichihashi Seiki Co.,Ltd.生产),将201mg用于压片的粉末装料并在10.0kN(约199.0MPa)的亚片压力下压片,以根据内部润滑法生产201mg片剂。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例12
通过将6g PVA粉末D(皂化度为70mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为107μm)作为粘合剂溶解在144g纯化水中制备粘合剂水溶液。
接下来,将205.8g乳糖(Pharmatose 200M,由DFE Pharma生产)和88.2g玉米淀粉(Nisshoku Cornstarch W,由Nihon Shokuhin KakoCo.,Ltd.生产)作为赋形剂放置在流化床造粒机(MP-01,由PowrexCorporation生产)中,并以0.6m3/min至0.7m3/min的空气流量混合以获得粉末组合物。
在同一造粒机中,在入口空气温度为80℃、出口空气温度为35℃至38℃、空气流量为0.5m3/min至0.6m3/min、喷雾速率为10g/min和喷雾空气压力为200kPa的条件下喷雾上述粘合剂水溶液时进行造粒。喷雾完成后,在同一造粒机中,在入口空气温度为80℃和空气流量为0.5m3/min至0.6m3/min的条件下干燥混合物,直到出口空气温度达到45℃,然后通过开口为710μm的JIS试验用筛进行筛分以获得造粒产品。所得造粒产品的组分、平均粒径和水含量显示在表2中。
接下来,将88g(88质量份)获得的造粒产品、和10g(10质量份)对乙酰氨基酚(细粉级,由Yamamoto Kagaku Kogyo Co.,Ltd.生产)作为活性成分,以及2g(2质量份)羧甲基纤维素钠(由FMC Corporation生产)作为崩解剂进行混合,然后添加0.5g(0.5质量份)硬脂酸镁(蔬菜级,TAIHEI CHEMICAL INDUSTRIALCO.,LTD.生产)作为润滑剂,并混合以获得用于压片的粉末。
然后,使用配有一对直径为8mm和曲率半径为12mm的冲头和孔径为8mm的模具的桌面压片机(单冲头压片机HANDTAB-100,由Ichihashi Seiki Co.,Ltd.生产),将201mg用于压片的粉末装料并在10.0kN(约199.0MPa)的压力下压片,以根据内部润滑法生产201mg片剂。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例13
通过将60g对乙酰氨基酚(细粉级,由Yamamoto Kagaku kogyo Co.,Ltd.生产)作为活性成分、210g乳糖(Pharmatose200M,由DFE Pharma生产)作为赋形剂、15g低取代羟丙基纤维素(羟丙氧基含量为11质量%)作为崩解剂和15g PVA粉末D在湿式搅拌造粒机(VG-05,由PowrexCorporation生产)中以450rpm的主叶片转速和3000rpm的交叉螺杆转速混合1分钟以获得粉末组合物。
随后,在同一造粒机中,向粉末组合物添加54g水,以450rpm的主叶片转速和3000rpm的交叉螺杆转速捏合5分钟,然后通过开口为1mm的JIS试验用筛进行筛分,以获得湿造粒产品。将湿造粒产品放置在流化床造粒干燥机(Multiplex MP-01,由PowrexCorporation生产)中,并在入口空气温度为80℃和空气流量为0.6m3/min至0.8m3/min的条件下干燥,直到出口空气温度达到45℃,并通过开口为710μm的JIS试验用筛进行筛分以获得造粒产品。所得造粒产品的组分、平均粒径和水含量显示在表2中。
接下来,在100g(100质量份)的所得造粒产品中添加0.5g(0.5质量份)硬脂酸镁(蔬菜级,TAIHEI CHEMICAL INDUSTRIALCO.,LTD.生产)作为润滑剂,并混合以获得用于压片的粉末。
然后,使用配有一对直径为8mm和曲率半径为12mm的冲头和孔径为8mm的模具的桌面压片机(单冲头压片机HANDTAB-100,由Ichihashi Seiki Co.,Ltd.生产),将201mg用于压片的粉末装料并在15.0kN(约298.6MPa)的压力下压片,以根据内部润滑法生产201mg片剂。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
实施例14
以与实施例13中相同的方式生产造粒产品和片剂,不同之处在于使用216g乳糖(Pharmatose 200M,由DFE Pharma生产)作为赋形剂,9g PVA粉末E作为粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的成分、片剂硬度和崩解时间显示在表3中。
实施例15
以与实施例14中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末F用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的成分、片剂硬度和崩解时间显示在表3中。
比较例1
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末A(皂化度为79mol%、以4质量%水溶液测定的20℃粘度为5.0mPa·s、且平均粒径为96μm)用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
比较例2
以与实施例1中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末G(皂化度为58mol%、以4质量%水溶液测定的20℃粘度为3.0mPa·s、且平均粒径为115μm)用作粘合剂。结果,相分离时出现的PVA凝胶状沉淀物堵塞喷雾喷嘴,使其难以继续喷雾,从而导致造粒操作停止。
比较例3
以与实施例1中相同的方式进行造粒,不同之处在于将18g PVA粉末D作为粘合剂溶解在132g纯化水中以制备粘合剂水溶液,并且将放置在流化床造粒机中的乳糖的量变为207g。结果,造粒进展过度,导致流动状态劣化,并在流化床造粒机中发生堵塞,从而导致造粒操作停止。
比较例4
以与实施例8中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末A用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
比较例5
以与实施例9中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末A用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
比较例6
以与实施例14中相同的方式生产造粒产品和片剂,不同之处在于PVA粉末A用作粘合剂。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
比较例7
以与实施例13中相同的方式生产造粒产品和片剂,不同之处在于将放置在湿式搅拌造粒机中的乳糖的量变为225g,并且不使用PVA粉末。所得造粒产品的组分、平均粒径和水含量显示在表2中。所得片剂的组分、片剂硬度和崩解时间显示在表3中。
在实施例1至5中,使用皂化度为63mol%至76mol%的PVA时,获得具有足够平均粒径的造粒产品,并获得具有良好硬度和崩解性的片剂。另外,结果表明,PVA的皂化度越降低时,其崩解性的改善程度越大。另一方面,在比较例1中,其中使用皂化度为79mol%的PVA,造粒和片剂硬度足够,但崩解不够。
PVA是一种高度亲水的水溶性粘合剂,其分子中含有大量羟基基团。然而,将PVA溶解在比较例1的片剂中花费了很长时间,并且崩解不够。这被认为是因为分子间氢键很强,所以溶解到水中的速度慢。另一方面,实施例1至5的片剂显示出随着皂化度降低,崩解时间加快的趋势。据认为当皂化度降低时,与羟基基团结合的疏水乙酰基基团的量变大,因此分子间氢键变弱,并且溶解到水中的速率增加。从比较例2(其中使用皂化度为58mol%的PVA)的结果可以明显看出,皂化度过低的PVA不适合用作粘合剂。这是因为疏水性的增加导致降低了在水中的溶解度,并且通过相分离出现的PVA凝胶状沉淀物堵塞喷雾喷嘴,阻碍了喷雾,并且不能获得造粒产品。
从使用皂化度为70mol%的PVA的实施例3、6和7的结果可以明显看出,当PVA的量较小时,造粒产品的平均粒径和片剂硬度变低,但具有足够的造粒性和片剂硬度,并且崩解得到改善。相反,当PVA的量较大时,造粒性和片剂硬度得到改善。然而,从比较例3的结果也可以明显看出,当PVA的量过大时,造粒进展到过度程度,从而使造粒期间的流动状态恶化,在流化床造粒机中发生堵塞,且造粒操作无法继续,因此无法获得造粒产品。因此,据认为PVA的添加量存在适当的范围。
从实施例8和比较例4的结果可以明显看出,其中使用了不同于实施例1至7的赋形剂,并且在造粒后外部添加崩解剂,而不是在造粒过程中内部添加崩解剂,通过降低PVA的皂化度来改善崩解,而与赋形剂的类型和崩解剂的添加方法(内部添加或外部添加)无关。此外,从使用不同于实施例8的崩解剂的实施例9和比较例5的结果可以明显看出,当PVA的皂化度降低时,崩解都得到改善,而与崩解剂的类型无关。
在全部实施例10(活性成分被外部添加到含有三种组分的造粒产品中:赋形剂、崩解剂和PVA)、实施例11(赋形剂和崩解剂被外部添加到含有两种组分的造粒产品中:活性成分和PVA)以及实施例12(活性成分和崩解剂被外部添加到含有两种组分的造粒产品中:赋形剂和PVA)中,均获得具有良好硬度和崩解性的片剂。从这些结果可以明显看出,可以获得具有良好特性的片剂,而与赋形剂、崩解剂和活性成分的添加方法(内部添加或外部添加)无关。
实施例13至15中也获得了具有足够粒径的造粒产品和具有良好硬度和崩解性的片剂,其中通过将水添加到活性成分、赋形剂、崩解剂和皂化度为70mol%至63mol%的PVA中进行造粒,这不同于实施例1至7中的造粒方法(将PVA水溶液添加到活性成分、赋形剂和崩解剂中)。另一方面,造粒产品具有足够的平均粒径和片剂硬度,但在比较例6(通过以与实施例13至15中相同的造粒方法使用皂化度为79mol%的PVA)中崩解性较差。由于粘合强度不足,无法获得具有足够粒径的造粒产品,并且在未添加PVA的比较例7中无法获得具有足够硬度的片剂。
Claims (8)
1.一种造粒产品,所述造粒产品包含:
选自由活性成分、赋形剂和崩解剂组成的组的至少一种;和
基于所述造粒产品的质量为0.1质量%至5.0质量%的皂化度为60mol%至77mol%的聚乙烯醇。
2.根据权利要求1所述的造粒产品,所述造粒产品包含选自由糖、糖醇、淀粉、糊精、粉状纤维素、微晶纤维素、碳酸钙、磷酸钙和硫酸钙组成的组的赋形剂。
3.根据权利要求1或权利要求2所述的造粒产品,所述造粒产品包含选自由低取代羟丙基纤维素、淀粉、部分预糊化淀粉、羟基乙酸淀粉钠、羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠、微晶纤维素和交聚维酮组成的组的崩解剂。
4.一种固体制剂,所述固体制剂包含:
权利要求1至3中任一项所要求的造粒产品;和
一种活性成分,此时所述造粒产品不包含所述活性成分。
5.根据权利要求4所述的固体制剂,其中所述固体制剂为片剂、颗粒剂或胶囊的形式。
6.一种用于生产造粒产品的方法,所述方法包括造粒的造粒步骤,同时添加至少包含水的第二组分、包含选自由活性成分、赋形剂和崩解剂组成的组的至少一种的第一组分以获得所述造粒产品,其中所述第一组分和/或第二组分包含基于所述造粒产品的质量为0.1质量%至5.0质量%的量的皂化度为60mol%至77mol%的聚乙烯醇。
7.根据权利要求6所述的生产造粒产品的方法,所述方法包括选自由糖、糖醇、淀粉、糊精、粉状纤维素、微晶纤维素、碳酸钙、磷酸钙和硫酸钙组成的组的赋形剂。
8.根据权利要求6或权利要求7所述的生产造粒产品的方法,所述方法包括选自由低取代羟丙基纤维素、淀粉、部分预糊化淀粉、羟基乙酸淀粉钠、羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠、微晶纤维素和交聚维酮组成的组的崩解剂。
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