CN112236146A - 稳定性优良的固体制剂 - Google Patents
稳定性优良的固体制剂 Download PDFInfo
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- CN112236146A CN112236146A CN201980038190.7A CN201980038190A CN112236146A CN 112236146 A CN112236146 A CN 112236146A CN 201980038190 A CN201980038190 A CN 201980038190A CN 112236146 A CN112236146 A CN 112236146A
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Abstract
本发明提供一种固体制剂,其含有式(I)所示化合物或其药学上可接受的盐、稳定剂、糖醇及/或糖类、水溶性聚合物、以及无机物,前述固体制剂的稳定性、水中悬浮性及流动性良好。
Description
[技术领域]
本发明涉及一种含有多环性吡啶酮化合物且稳定性及水中悬浮性优良的制剂。即,涉及一种固体制剂,其含有稳定剂、糖醇及/或糖类、水溶性聚合物、以及无机物,详细而言,涉及一种制剂,其含有多环性吡啶酮化合物,并且含有作为稳定剂的氯化钠、作为糖醇及/或糖类的麦芽糖醇(maltitol)及甘露醇、作为水溶性聚合物的羟丙基甲基纤维素(hypromellose)、以及作为无机物的轻质无水硅酸及滑石,而提高多环性吡啶酮化合物的稳定性、在水中的制剂的悬浮性、以及制剂的流动性。
[先前技术]
流行性感冒是由感染流行性感冒病毒所致的急性呼吸器感染症。在日本每年冬天有数百万人的疑似流行性感冒患者的报告,流行性感冒伴随着高的罹患率及死亡率。
就抗流行性感冒药而言,已知有抑制病毒的脱核过程的Symmetrel(商品名:金刚胺(Amantadine))及Flumadine(商品名:龟刚胺(Rimantadine))、抑制病毒的细胞的出芽/放出的属于神经氨酸酶(neuraminidase)抑制剂的Oseltamivir(商品名:达菲(Tamiflu))及Zanamivir(商品名:瑞乐沙旋达碟(Relenza))。但是,因仍有抗性株的出现及副作用的问题、以及病原性及致死性高的新型流行性感冒病毒的世界性的大流行等的疑虑,故期望能开发出新机制的抗流行性感冒药。
Cap依赖性核酸内切酶(Cap-Dependent Endonuclease)为源自流行性感冒病毒的酶,其为病毒增殖所必需,并且是宿主所没有的病毒特异性的酶活性,所以被认为适于作为抗流行性感冒药的标靶。
在专利文献1中记载下述式(II)所示化合物为作为抑制Cap依赖性核酸内切酶的化合物,其为有用于作为具有抗病毒作用(尤其是对流行性感冒病毒的抑制增殖活性)的化合物。
在将式(II)所示化合物对生体投药(例如经口投药)时,必须提供更有效率地在体内被吸收而显现高的药理效果且同时缩短流行性感冒患病期间的化合物,为了达成这些目的,而提供式(I)所示化合物,其为式(II)所示化合物的前药。在专利文献1中也有公开式(I)所示化合物。
但是,在专利文献1并未公开式(I)所示化合物的具体制剂。
流行性感冒是对于乳幼儿、高龄者等高危险群为特别重要的疾病。尤其是现在于市售的抗流行性感冒药中,内服用小儿制剂只有Oseltamivir(商品名:达菲),期望可开发抗流行性感冒药的内服用小儿制剂。
就内服用制剂而言,有干糖浆(dry syrup)、细粒、片剂、糖浆等。若该制剂中的药物浓度低,则在实施经时稳定性试验时,视药物而会有类似物量增多的情况。此外,内服用小儿制剂在为了要给小儿服用时有将制剂悬浮于水的情况,在水中的悬浮性若不好,药物会有堆滞在容器底部的情况。再者,干糖浆或细粒的流动性若不好,对其制造有造成阻碍的情况。于是,需要开发一种内服用小儿制剂,其为在经时稳定性试验后,类似物量少,并且水中悬浮性及流动性良好。
在专利文献2至4中公开含有氯化钠而抑制苦味或改善药物吸收性的颗粒。但是,专利文献2至4所使用的化合物为与式(I)所示化合物在化学构造上大不相同,无法得知以专利文献2至4公开的制剂处方能否改善式(I)所示化合物的稳定性,在该文献中也毫无公开或提示。
此外,在专利文献5中公开含有特定化合物、羟丙基甲基纤维素(hypromellose)及甘露醇的粉末。但是,专利文献5所使用的化合物为与式(I)所示化合物在化学构造上大不相同,无法得知以专利文献5记述的制剂处方能否使含有式(I)所示化合物的固体制剂获得优良的水中悬浮性,在该文献中也毫无公开或提示。
[先前技术文献]
[专利文献]
[专利文献1]国际公开第2016/175224号小册
[专利文献2]日本特开2008-07420号公报
[专利文献3]日本特开2016-79102号公报
[专利文献4]日本特表2001-512433号公报
[专利文献5]日本特表2014-534215号公报
[发明内容]
[发明要解决的课题]
本发明的课题是要找出使式(I)所示化合物的稳定性优良且水中悬浮性优良的固体制剂。
[解决课题的手段]
本发明者等为了要解决上述课题而精心重复研究,结果发现通过含有作为稳定剂的选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上、糖醇及/或糖类、水溶性聚合物、以及无机物,则可提高多环性吡啶酮化合物的稳定性、在水中的制剂的悬浮性、以及制剂的流动性,而完成本发明。以下,本发明所完成的制剂有时为称为“本发明制剂”。
即,
(1)一种固体制剂,其含有:式(I)所示化合物或其药学上可接受的盐,以及选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上;
(2)如上述(1)所述的固体制剂,其含有碱金属氯化物,该碱金属氯化物是氯化钠及/或氯化钾。
(3)如上述(1)所述的固体制剂,其含有有机酸,该有机酸是抗坏血酸及/或富马酸。
(4)如上述(1)所述的固体制剂,其含有多元醇酯,该多元醇酯为选自由Miglyol、柠檬酸三乙酯及聚氧乙烯山梨醇酐单油酸酯(polyoxyethylene sorbitan monooleate)所成的群组中的1种以上。
(5)如上述(1)所述的固体制剂,其含有脂肪酸酯,该脂肪酸酯是三乙酸甘油酯(triacetin)。
(6)如上述(1)至(5)中任一项所述的固体制剂,其还含有糖醇及/或糖类。
(7)如上述(6)所述的固体制剂,其中,糖醇及/或糖类为选自由异麦芽酮糖醇(isomalt)、还原麦芽糖水饴(麦芽糖醇)、甘露醇、木糖醇、赤藻糖醇(erythritol)、山梨糖醇、乳糖、蔗糖、果糖、麦芽糖、精制白糖及海藻糖(trehalose)所成的群组中的1种以上。
(8)如上述(1)至(7)中任一项所述的固体制剂,其还含有水溶性聚合物。
(9)如上述(8)所述的固体制剂,其中,水溶性聚合物是纤维素类聚合物。
(10)一种固体制剂,其含有:式(I)所示化合物或其药学上可接受的盐,以及纤维素类聚合物;
但在固体制剂的覆盖层中不含纤维素类聚合物。
(11)如上述(9)或(10)所述的固体制剂,其中,纤维素类聚合物为选自由羟丙基甲基纤维素(hypromellose)、羟丙基纤维素、甲基纤维素、羧甲基纤维素、羧甲基乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯(hypromellose phthalate)及羟丙基甲基纤维素乙酸酯琥珀酸酯所成的群组中的1种以上。
(12)如上述(11)所述的固体制剂,其中,纤维素类聚合物是羟丙基甲基纤维素。
(13)如上述(1)至(12)中任一项所述的固体制剂,其还含有无机物,但固体制剂的覆盖层中不含无机物。
(14)如上述(13)所述的固体制剂,其中,无机物为选自由含水二氧化硅、轻质无水硅酸及滑石所成的群组中的1种以上。
(15)如上述(1)至(14)中任一项所述的固体制剂,其中,在第17改正日本药局方所规定的溶出试验法(桨法(paddle method))中的溶出试验开始15分钟后的式(I)所示化合物或其药学上可接受的盐的溶出率为在80%以上。
(16)如(1)至(15)中任一项所述的固体制剂,其含有1至80mg的式(I)所示化合物;
(17)如(1)至(16)中任一项所述的固体制剂,其为颗粒剂或干糖浆剂。
[发明的效果]
由于含有选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上的稳定剂、糖醇及/或糖类、水溶性聚合物及无机物,而可减少多环性吡啶酮化合物的类似物,并且可提高制剂的流动性及在水中的制剂的悬浮性。
[附图说明]
图1是式(I)所示化合物的结晶的粉末X线衍射图形。
图2是经时保存试验开始时及经时保存试验开始经过一定期间后的式(I)所示化合物的溶出状况。
[具体实施方式]
本发明制剂中的有效成分为使用式(I)所示化合物或其药学上可接受的盐。
式(I)所示化合物、其药学上可接受的盐的制法为公开在专利文献1中。
式(I)所示化合物或其药学上可接受的盐,为在生体内被变换为式(II)所示化合物,具有Cap依赖性核酸内切酶抑制作用。所以,式(I)所示化合物或其药学上可接受的盐为有用于作为流行性感冒的治疗剂及/或预防剂。
式(I)所示化合物或其药学上可接受的盐是有用于由流行性感冒病毒所诱发的症状及/或疾病。例如,对于伴随着发烧、恶寒、头痛、肌肉痛、全身倦怠感等的类似感冒症状,以及咽头痛、鼻水、鼻塞、咳嗽、痰等气道炎症状,腹痛、呕吐、下痢等胃肠症状,急性脑症、肺炎等伴随着二次感染的合并症的治疗及/或预防、改善症状为有效。即,本发明所用的化合物可用于流行性感冒病毒感染症的治疗及/或预防。
式(I)所示化合物或其药学上可接受的盐为有效于缩短流行性感冒患病期间。例如,对于流行性感冒患病期间可缩短约20至40小时、约25至30小时。具体而言,可使直到“咳嗽”、“喉咙痛”、“头痛”、“鼻塞”、“发烧或恶寒”、“肌肉或关节痛”、“疲劳感”有所改善为止的时间被缩短。尤其是有用于缩短直到“鼻塞”、“肌肉或关节痛”、“疲劳感”、“发烧或恶寒”、“头痛”有所改善为止的时间。再者,有用于缩短直到“鼻塞”及“肌肉或关节痛”有所改善为止的时间。
式(I)所示化合物或其药学上可接受的盐具备作为医药的有用性。式(I)所示化合物或其药学上可接受的盐是前药,经口吸收性高,显现良好的生物有效性及清除性(clearance),具有肺移行性高等优点,可成为优良的药品。
式(I)所示化合物或其药学上可接受的盐为代谢稳定性及经口吸收性高,显现良好的生物有效性及清除性。此外,式(I)所示化合物或其药学上可接受的盐为肺移行性高,半衰期长。再者,式(I)所示化合物或其药学上可接受的盐为有例如非蛋白键结率高,hERG通道抑制及CYP抑制低,确认有CPE(CytoPathic Effect,细胞病变效果)抑制效果,及/或在光毒性试验、Ames试验、遗传毒性试验中显示阴性,或是无肝障碍等毒性等优点。因而,本发明所用的化合物的药物组合物可成为优良的药品。
式(I)所示化合物或其药学上可接受的盐的投药量为依据投药方法、患者的年龄、体重、状态及疾病的种类而有所不同,但通常在经口投药的情况时,成人每1日为约0.05mg至3000mg,优选为约0.1mg至1000mg,更优选为约10mg至80mg,必要时可分割投药。此外,在非经口投药的情况时,成人每1日为约0.01mg至1000mg,优选为约0.05mg至500mg,更优选为投药约1mg至80mg。可将其予以1日1次或分成数次投药。具体而言,式(I)所示化合物或其药学上可接受的盐的含量是10mg、20mg、40mg或80mg。在此情形下,10mg为表示9.0至11.0mg,优选为9.5至10.5mg的范围,20mg为表示18.0至22.0mg,优选为19.0至21.0mg的范围,40mg为表示36.0至44.0mg的范围,优选为38.0至42.0mg的范围,80mg为表示72.0至88.0mg,优选为76.0至84.0mg的范围。
式(I)所示化合物或其药学上可接受的盐,可在以增强该化合物的作用或减少该化合物的投药量等为目的的情况下,与其他药剂等(以下简称为“并用药剂”)组合使用。例如,对于流行性感冒的疾病,可与神经氨酸酶抑制剂(例如oseltamivir、zanamivir、peramivir及Inavir等)、RNA依赖性RNA聚合酶抑制剂(例如favipiravir)、M2蛋白抑制剂(例如amandazin)、PB2 Cap键结抑制剂(例如VX-787)、抗HA抗体(例如MHAA4549A)、或免疫作用药(例如nitazoxanide)组合使用。这时,本发明所用的化合物及并用药剂的投药时期没有限定,可对于投药对象同时投药这些药物,也可隔一段时间再投药。再者,与式(I)所示化合物或其药学上可接受的盐的并用药剂,为能以含有各自的活性成分的2种以上的制剂的形式来投药,也能以含有全部活性成分的单一制剂的形式来投药。
并用药剂的投药量为能以临床上所用的用量作为基准来适宜选择。此外,式(I)所示化合物或其药学上可接受的盐与并用药剂的调配比率为可依据投药对象、投药路径、对象疾病、症状、组合等而适宜选择。例如,当投药对象是人时,相对于式(I)所示化合物或其药学上可接受的盐1重量份,并用药剂可使用0.01至100重量份。
式(I)所示化合物或其药学上可接受的盐,其对于Cap依赖性核酸内切酶的抑制活性高,由于其为病毒特异性的酶,所以有选择性高等效果,故可成为减轻副作用的药品。
以下,说明鉴定式(I)所示化合物或其结晶、或式(II)所示化合物的方法。
如无特别注明,本说明书中及申请专利范围所记载的数值是大概的数值。数值的变动由装置校正、装置误差、物质的纯度、结晶大小、试样大小或其他因素所导致。
本说明书中所用的“结晶”是指具有使构成固体的原子、离子、分子等以规则方式排列而成的结构,且结果具有周期性、异向性(anisotropy)的结构。结晶形态及结晶度为可通过例如包括粉末X线衍射测定、水分吸脱附测定、示差扫描热量测定、示差热热重量同时测定、溶液比色测定、溶解特性的多种技术而测定。
化合物的NMR分析为以300MHz实施,使用DMSO-d6、CDCl3测定。
粉末X线衍射图形的测定
遵照在日本药局方的一般试验法中所记载的粉末X线衍射测定法,对各实施例所得的结晶实施粉末X线衍射测定。以下列示测定条件。
(装置)
Rigaku公司制MiniFlex600
(操作方法)
检测器:高速一维检测器(D/TecUltra2)及可变刀口
测定法:反射法
光源的种类:Cu
波长:CuKα线
管电流:15mA
管电压:40kV
试料板:硅无反射试料板
X线的入射角(θ):4-40°,取样幅度:0.02°
一般而言,在粉末X线衍射中的衍射角度(2θ)可在±0.2°的范围内产生误差,衍射角度的值亦包含±0.2°左右的范围内的数值。因此,本发明制剂中,不仅可使用在粉末X线衍射中的峰的衍射角度完全一致的结晶,也可使用峰的衍射角度一致存在±0.2°左右的误差的结晶。
本发明制剂中的式(I)所示化合物或其药学上可接受的盐的调配量,相对于制剂总量为0.1至80重量%,优选为0.5至8重量%,更优选为1至4重量%。
本发明制剂可含有稳定剂。本说明书中,就稳定剂而言,可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书所收载的稳定剂,尤其是可使用可将式(I)所示化合物或其药学上可接受的盐在经时保存下予以稳定化的稳定剂。
就稳定剂而言,只要是可将类似物(特别是式(II)所示化合物)的量减少的物质即可,具体上可列举如碱金属氯化物、有机酸、多元醇酯及脂肪酸酯等。
碱金属氯化物是指以M为碱金属,X为氯,并以化学式MX表示的无机化合物。具体而言,可列举如氯化钠及氯化钾等,优选氯化钠。
有机酸是指具有羧基的有机化合物(羧酸)、具有磺酸基的有机化合物(磺酸)、具有羟基、硫醇基、烯醇作为特征基团的有机化合物。具体而言,可列举如甲酸、草酸、乙酸、柠檬酸、抗坏血酸及富马酸等,优选抗坏血酸、富马酸,更优选富马酸。
多元醇酯是指分子内具有2个以上的羟基的醇的酯体,在多元醇中,羟基分别附在不同的碳原子上。具体而言,可列举如Miglyol(即中链脂肪酸甘油三酯)、柠檬酸三乙酯及聚氧乙烯山梨醇酐单油酸酯等,优选Miglyol。
脂肪酸酯是指由脂肪酸的羧基与醇进行酯键结而成的化合物。具体而言,可列举如三乙酸甘油酯(triacetin,即glyceryl triacetate)、脂肪酸甘油酯、酰基甘油(acylglycerol)、单甘油酯衍生物及脂肪酸聚甘油酯等,优选三乙酸甘油酯。
本发明制剂的稳定剂可调配于制剂中,也可覆盖在制剂的表面,优选为调配于制剂中。若调配于制剂中,则可提高制剂中所含有的式(I)所示化合物的稳定性,并减少类似物(尤其是式(II)所示化合物)的量。
本发明制剂中的稳定剂的调配量,相对于制剂总量为0.01至10重量%,优选为0.05至7.5重量%,更优选为0.1至5重量%。比此量少时,则有使类似物量增加的可能性。
本发明制剂可含有赋形剂。本说明书中,赋形剂为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书所收载的赋形剂。优选为可为使制剂在水中悬浮性良好,制剂对容器的附着少,并且制剂的细粒产率高,堆积密度小的赋形剂。具体而言,可列举如糖醇及糖类。
糖醇为相当于日本消费者厅公告的食品标示基准的糖质,是由醛糖或酮糖的羰基还原而生成的糖的一种。具体而言,可列举如异麦芽酮糖醇、赤藻糖醇、D-甘露醇、木糖醇、山梨糖醇、还原麦芽糖水饴(麦芽糖醇)、乳糖醇、寡糖醇等,优选D-甘露醇、还原麦芽糖水饴(麦芽糖醇)。
糖类为相当于日本消费者厅公告的食品标示基准的糖类,具体而言,可列举如单糖类及二糖类,更具体而言,有木糖、葡萄糖(glucose)、果糖(fructose)、麦芽糖(maltose)、乳糖(lactose)、蔗糖(sucrose)、果糖、海藻糖、异构化糖、水饴、精制白糖、白糖、精制白糖球状颗粒、无水乳糖、白糖/淀粉球状颗粒等,优选精制白糖、白糖。
在本发明制剂中的赋形剂,为可将糖醇及糖类混合使用。此时,可将糖醇及糖类组合,也可将糖醇及其他糖醇组合,且亦可将糖类及其他糖类组合。组合的糖醇及糖类的种类、调配比率,只要是可改善制剂的水中悬浮性、制剂对容器的附着性、并使制剂的细粒产率高、堆积密度小的种类及调配比率即可。关于具体的组合,有精制白糖与还原麦芽糖水饴(麦芽糖醇)、精制白糖与D-甘露醇、还原麦芽糖水饴(麦芽糖醇)与D-甘露醇等,优选还原麦芽糖水饴(麦芽糖醇)与D-甘露醇。此外,调配比率是以重量比计而为99:1至1:99,优选90:10至10:90,更优选80:20至20:80,特别优选75:25至25:75。更具体而言,还原麦芽糖水饴(麦芽糖醇)与D-甘露醇为30:70至50:50的比率。
在本发明制剂中,也可含有糖醇及糖类以外的赋形剂。具体而言,可列举如相当于“日本消费者厅公告的食品标示基准的糖质”的寡糖、糊精、淀粉等多糖类、半消化态淀粉、葡萄糖水合物、结晶纤维素、微结晶纤维素、聚三葡萄糖(pullulan)、β-环糊精、氨基乙基磺酸、饴粉、氯化钠、柠檬酸、柠檬酸钠、甘氨酸、葡萄糖酸钙、L-谷氨酰胺、酒石酸、酒石酸氢钾、碳酸铵、聚葡萄糖(dextran)40、糊精、乳酸钙、聚维酮(povidone)、Macrogol(聚乙二醇)1500、Macrogol 1540、Macrogol 4000、Macrogol 6000、无水柠檬酸、DL-苹果酸、磷酸氢钠、磷酸二氢钾、磷酸二氢钠、L-天冬氨酸、海藻酸(alginic acid)、羧甲基纤维素钠(carmellose sodium)、含水二氧化硅、交联聚维酮(crospovidone)、甘油磷酸钙,硅酸铝酸镁、硅酸钙、硅酸镁、轻质无水硅酸、合成硅酸铝、小麦粉、小麦淀粉、小麦胚芽粉、小麦胚芽油、米粉、米淀粉、邻苯二甲酸乙酸纤维素(cellulose acetate phthalate)、氧化钛、氧化镁、二羟基铝氨基乙酸酯、磷酸三钙、滑石、碳酸钙、碳酸镁、沉淀碳酸钙、天然硅酸铝、玉米淀粉、玉米淀粉造粒物、马铃薯淀粉、羟丙基纤维素、羟丙基淀粉、无水磷酸氢钙、无水磷酸氢钙造粒物、磷酸二氢钙等。
本发明制剂中的赋形剂的调配量,相对于制剂总量为1至99.5重量%,优选5至99重量%,更优选10至98.5重量%。比此量多时,有不能调配其他成分之虞;比此量少时,对制剂的外观有给予影响的可能性。
可将本发明制剂悬浮于水中,并服用其悬浮液。尤其是对小儿投药时,可实施这样的服用方法。但是,在没有悬浮剂的情况下,难以将本发明制剂予以悬浮。因此,可在本发明制剂中调配悬浮剂。悬浮剂为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书中所收载的悬浮剂。具体而言,有羧甲基纤维素(carmellose)、羧甲基纤维素钠、结晶纤维素/羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素(hypromellose,即hydroxy propyl methyl cellulose)、甲基纤维素、羧甲基乙基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、富马酸/硬脂酸/聚乙烯乙缩醛二乙基氨基乙酸酯/羟丙基甲基纤维素混合物等纤维素类聚合物、丙烯酸乙酯/甲基丙烯酸甲酯共聚物分散液、甲基丙烯酸胺烷酯共聚物、甲基丙烯酸共聚物、2-甲基-5-乙烯吡啶丙烯酸甲酯/甲基丙烯酸共聚物、干燥甲基丙烯酸共聚物、甲基丙烯酸二甲基氨基乙酯/甲基丙烯酸甲酯共聚物等丙烯酸类聚合物、聚乙烯吡咯烷酮(polyvinyl pyrrolidone)、交联聚维酮、羧乙烯聚合物、聚乙烯乙缩醛二乙基氨基乙酸酯、聚乙烯醇、聚乙烯醇/甲基丙烯酸甲酯/丙烯酸共聚物及聚乙烯醇共聚物等乙烯类聚合物、海藻酸钠、鹿角菜胶、羧乙烯聚合物、干燥氢氧化铝凝胶、黄原胶、硅酸铝镁、聚磷酸钠、Macrogol 4000、Macrogol 6000等,优选羧甲基纤维素、羧甲基纤维素钠、结晶纤维素/羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮,更优选羟丙基甲基纤维素。此外,悬浮剂也具有作为使本发明制剂分散在水中的分散剂的角色。但在固体制剂有形成覆盖层时,在固体制剂的覆盖层中不含纤维素类聚合物。
在本发明制剂中的悬浮剂的调配量,相对于制剂总量为0.01至10重量%,优选0.05至7.5重量%,更优选0.1至5重量%。比此量多时,在水中有起泡的可能性;比此量少时,制剂在水中有不能悬浮的可能性。
在本发明制剂中,为了提高制剂的流动性,可调配流化剂(fluidizer)。此外,依据流化剂而有使杂质或类似物增加的可能性,所以必须选择不会增加杂质或类似物的流化剂。流化剂为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书中所收载的流化剂,主要是以选择无机物或脂肪酸,很多情况下选择其盐。具体而言,有轻质无水硅酸、含水二氧化硅、硬脂酸、硬脂酸镁、硬脂酸钙、滑石等,优选轻质无水硅酸、含水二氧化硅,更优选轻质无水硅酸。但当流化剂是无机物且在固体制剂中有形成覆盖层时,在固体制剂的覆盖层中不含无机物。
在本发明制剂中的流化剂的调配量,相对于制剂总量为0.01至10重量%,优选0.05至7.5重量%,更优选0.1至5重量%。比此量多时,类似物有增加的可能性;比此量少时,有制剂不流动而在制造时造成障碍之虞。
在本发明制剂中,为了提高制剂的润滑性,可调配润滑剂。关于润滑剂的选择的指标包括休止角,休止角越小则流动性越良好。润滑剂为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书中所收载的润滑剂,主要是以选择无机物或脂肪酸,很多情况下选择其盐。具体而言,有轻质无水硅酸、含水二氧化硅、蔗糖脂肪酸酯、硬脂醇、硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠(sodium stearyl fumarate)、滑石等,优选轻质无水硅酸、含水二氧化硅、滑石,更优选滑石。但当润滑剂是无机物且在固体制剂中有形成覆盖层时,固体制剂的覆盖层中不含无机物。
本发明制剂中的润滑剂的调配量,相对于制剂总量为0.001至1重量%,优选0.005至0.75重量%,更优选0.01至0.5重量%。比此量多时,类似物有增加的可能性;比此量少时,有制剂不流动而在制造时造成障碍之虞。
在本发明制剂中,为了添加到有苦味等味道不好的药物中而矫正其味道,可调配矫味剂。矫味剂为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书中所收载的矫味剂。具体而言,有抗坏血酸、天冬氨酸、阿斯巴甜(aspartame)、三氯蔗糖(sucralose)、甘氨酸、氯化钠、氯化镁、盐酸、稀盐酸、柠檬酸及其盐、无水柠檬酸、L-谷氨酸及其盐、琥珀酸及其盐、乙酸、酒石酸及其盐、碳酸氢钠、富马酸及其盐、苹果酸及其盐、冰乙酸、肌苷酸二钠、蜂蜜、还原麦芽糖水饴(麦芽糖醇)、甘草末等,优选氯化钠。
本发明制剂中的矫味剂的调配量,相对于制剂总量为0.01至10重量%,优选0.05至7.5重量%,更优选0.1至5重量%。比此量多或少,在服用制剂时都有产生令人不快的味道之虞。
本发明制剂可含有粘合剂。粘合剂为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书等所收载的粘合剂。具体而言,可列举如羟丙基纤维素、玉米淀粉、α化淀粉、部分α化淀粉、阿拉伯树胶、阿拉伯树胶末、明胶、洋菜、糊精、聚三葡萄糖、聚乙烯吡咯烷酮、聚乙烯醇、结晶纤维素、甲基纤维素、乙基纤维素、羧甲基乙基纤维素、羧甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素等,优选聚乙烯吡咯烷酮。
本发明制剂中的粘合剂的含量,相对于制剂总量为0.1至20重量%,优选0.25至15重量%,更优选0.5至10重量%。比此量多时,制剂的粒径有变太大的虑;比此量少时,制剂的粒径有变得太小的可能性。
本发明制剂可含有崩解剂。崩解剂为可使用日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书等所收载的崩解剂。具体而言,可列举如交联羧甲基纤维素钠、交联聚维酮、羧甲基纤维素钙、羧甲基淀粉钠、低交换度羟丙基纤维素等。
本发明制剂中的崩解剂的含量,相对于制剂总量为0.5至20重量%,优选0.75至15重量%,更优选1至10重量%。
本发明制剂可含有聚合物。聚合物为可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书中所收载的聚合物。具体而言,可列举如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、羧甲基乙基纤维素、羧甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟乙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、富马酸/硬脂酸/聚乙烯乙缩醛二乙基氨基乙酸酯/羟丙基甲基纤维素混合物等纤维素类聚合物、丙烯酸乙酯/甲基丙烯酸甲酯共聚物分散液、甲基丙烯酸胺烷酯共聚物、甲基丙烯酸共聚物、2-甲基-5-乙烯基吡啶丙烯酸甲酯/甲基丙烯酸共聚物、干燥甲基丙烯酸共聚物、甲基丙烯酸二甲基氨基乙酯/甲基丙烯酸甲酯共聚物等丙烯酸类聚合物、聚乙烯吡咯烷酮、交联聚维酮、羧乙烯聚合物、聚乙烯乙缩醛二乙基氨基乙酸酯、聚乙烯醇、聚乙烯醇/甲基丙烯酸甲酯/丙烯酸共聚物及聚乙烯醇共聚物等的乙烯类聚合物、巴西棕榈蜡(Carnauba wax)、硬脂醇、虫胶、鲸蜡醇等,优选羟丙甲纤维素(羟丙基甲基纤维素)。
本发明制剂可含有着色剂。着色剂为可使用在日本药局方、日本药局方外药品规格或药品添加物规格等所收载的着色剂。具体而言,可列举如氧化铁、焦油色素及天然色素等。就氧化铁而言,有三氧化二铁、黄色氧化铁、黄色三氧化二铁、黑色氧化铁等。就焦油色素而言,有食用黄色4号铝色淀、食用蓝色1号铝色淀、食用红色3号铝色淀、食用蓝色1号、食用蓝色2号、食用黄色4号、食用黄色5号、食用红色102号、食用红色2号、食用红色3号等。就天然色素而言,有姜黄萃取液、β-胡萝卜素、胡萝卜素液、铜叶绿酸钠(sodium copperchlorophyllin)、铜叶绿素、青稞(naked barley)绿叶萃取末、青稞绿叶青汁干燥粉末、青稞绿叶萃取物、氧化钛、滑石等。色素也包含作为光稳定剂使用的色素。
本发明制剂还可视需要而含有上述以外的添加剂,可使用在日本药局方、日本药局方外药品规格、药品添加物规格及食品添加物公定书中所收载的添加剂。此外,这些添加剂的含量可为任意的比率。上述以外的添加剂为具体地可列举如香料、甜味剂等。
香料具体地可列举如柑橙香精(orange essence)、橙油(orange oil)、焦糖(caramel)、樟脑(camphor)、桂皮油(cinnamon oil)、绿薄荷油(spearmint oil)、草莓香精(strawberry essence)、巧克力香精(chocolate essence)、樱桃风味剂(cherry flavor)、橙皮油(orange peel oil)、松油(pine oil)、薄荷油、香草风味剂(vanilla flavor)、草莓风味剂(strawberry flavor)、苦味香精(bitter essence)、水果风味剂(fruit flavor)、胡椒薄荷香精(peppermint essence)、混合风味剂(mix flavor)、薄荷风味剂(mintflavor)、薄荷醇(menthol)、柠檬粉末(lemon powder)、柠檬油(lemon oil)、玫瑰油(roseoil)等,优选草莓风味剂。
甜味剂具体地可列举如阿斯巴甜、还原麦芽糖水饴(麦芽糖醇)、甘草、木糖醇、甘油、糖精(saccharin)、三氯蔗糖、D-山梨糖醇、乙酰磺氨酸钾(acesulfame potassium)、甜菊、索马甜(thamatin)、爱德万甜(advantame)等,优选三氯蔗糖。
本发明制剂只要是固体制剂即可。具体而言,只要是颗粒剂、干糖浆剂、细粒剂、片剂、散剂、胶囊剂、丸剂等即可,优选颗粒剂、干糖浆剂、细粒剂,更优选颗粒剂。
本发明制剂中的颗粒剂的制造方法为无特别限制,具体而言是将有效成分、粘合剂、赋形剂等添加剂予以混合而制造混合粉末后将该混合粉末予以造粒的方法,优选添加水、含有粘合剂的水、溶剂等而造粒的湿法造粒法,以及经压缩成形而不使用水的干法造粒法及熔融造粒法。用以混合有效成分及添加剂等的机械,可使用破碎型造粒机(powermill)、V型混合机、容器混合机(container blender)等。此外,造粒的机械为可使用湿式挤压造粒机、流动层造粒机、搅拌造粒机,干式破碎造粒机及熔融挤压造粒机等。
当本发明制剂是颗粒剂时,颗粒剂的平均粒径是在1至1000μm的范围。
以下,记述优选的方面。
(1)提供一种固体制剂,其含有:式(I)所示化合物或其药学上可接受的盐,以及(2)选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上。碱金属氯化物具体地可列举如氯化钠及/或氯化钾,优选氯化钠,有机酸具体地可列举如抗坏血酸及/或富马酸,优选富马酸,多元醇酯具体地可列举如Miglyol、柠檬酸三乙酯、聚氧乙烯山梨醇酐单油酸酯,脂肪酸酯具体地可列举如三乙酸甘油酯。
另一方面为提供一种固体制剂,其含有:(1)式(I)所示化合物或其药学上可接受的盐,(2)选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上,以及(3)糖醇及/或糖类。碱金属氯化物具体地可列举如氯化钠及/或氯化钾,优选氯化钠,有机酸具体地可列举如抗坏血酸及/或富马酸,优选富马酸,多元醇酯具体地可列举如Miglyol、柠檬酸三乙酯、聚氧乙烯山梨醇酐单油酸酯,脂肪酸酯具体地可列举如三乙酸甘油酯。糖醇及/或糖类于具体为选自由异麦芽酮糖醇、还原麦芽糖水饴(麦芽糖醇)、甘露醇、木糖醇、赤藻糖醇、山梨糖醇、乳糖、蔗糖、果糖、麦芽糖、精制白糖及海藻糖所成的群组中的1种以上,优选选自由精制白糖、还原麦芽糖水饴及D-甘露醇所成的群组中的1种以上,更优选者可列举如还原麦芽糖水饴、D-甘露醇,特别是优选为还原麦芽糖水饴及D-甘露醇的混合物。
另一方面为提供一种固体制剂,其含有:(1)式(I)所示化合物或其药学上可接受的盐,(2)选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上,(3)糖醇及/或糖类,以及(4)水溶性聚合物。碱金属氯化物具体地可列举如氯化钠及/或氯化钾,优选者可列举如氯化钠,有机酸具体地可列举如抗坏血酸及/或富马酸,优选富马酸,多元醇酯具体地可列举如Miglyol、柠檬酸三乙酯、聚氧乙烯山梨醇酐单油酸酯,脂肪酸酯具体地可列举如三乙酸甘油酯。糖醇及/或糖类于具体为选自由异麦芽酮糖醇、还原麦芽糖水饴(麦芽糖醇)、甘露醇、木糖醇、赤藻糖醇、山梨糖醇、乳糖、蔗糖、果糖、麦芽糖、精制白糖及海藻糖所成的群组中的1种以上,优选选自由精制白糖、还原麦芽糖水饴(麦芽糖醇)及D-甘露醇所成的群组中的1种以上,更优选者可列举如还原麦芽糖水饴、D-甘露醇,尤其是特别优选为还原麦芽糖水饴(麦芽糖醇)及D-甘露醇的混合物。水溶性聚合物于具体为纤维素类聚合物、丙烯酸类聚合物、聚乙烯类聚合物,优选者可列举如纤维素类聚合物。作为纤维素类聚合物,更具体而言,是羧甲基纤维素、羧甲基纤维素钠、结晶纤维素/羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羧甲基乙基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、富马酸/硬脂酸/聚乙烯乙缩醛二乙基氨基乙酸酯/羟丙基甲基纤维素混合物等,优选者可列举如羟丙基甲基纤维素。
另一方面为提供一种固体制剂,其含有:(1)式(I)所示化合物或其药学上可接受的盐,(2)选自由碱金属氯化物、有机酸、多元醇酯及脂肪酸酯所成的群组中的1种以上,(3)糖醇及/或糖类,(4)水溶性聚合物,以及(5)无机物。碱金属氯化物具体地可列举如氯化钠及/或氯化钾,优选者可列举如氯化钠,有机酸具体地可列举如抗坏血酸及/或富马酸,优选富马酸,多元醇酯的优选例为Miglyol、柠檬酸三乙酯、聚氧乙烯山梨醇酐单油酸酯,脂肪酸酯具体地可列举如三乙酸甘油酯。糖醇及/或糖类于具体为选自由异麦芽酮糖醇、还原麦芽糖水饴(麦芽糖醇)、甘露醇、木糖醇、赤藻糖醇、山梨糖醇、乳糖、蔗糖、果糖、麦芽糖、精制白糖及海藻糖所成的群组中的1种以上,优选选自由精制白糖、还原麦芽糖水饴(麦芽糖醇)及D-甘露醇所成的群组中的1种以上,更优选者可列举如还原麦芽糖水饴(麦芽糖醇)、D-甘露醇,尤其是特别优选为还原麦芽糖水饴(麦芽糖醇)及D-甘露醇的混合物。水溶性聚合物于具体为纤维素类聚合物、丙烯酸类聚合物、聚乙烯类聚合物,优选者可列举如纤维素类聚合物。作为纤维素聚合物,更具体而言,是羧甲基纤维素、羧甲基纤维素钠、结晶纤维素/羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羧甲基乙基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、富马酸/硬脂酸/聚乙烯乙缩醛二乙基氨基乙酸酯/羟丙基甲基纤维素混合物等,优选者可列举如羟丙基甲基纤维素。无机物具体地可列举如轻质无水硅酸、含水二氧化硅、硬脂酰富马酸钠、滑石,优选者可列举如轻质无水硅酸、滑石。
另一方面为提供一种固体制剂,其含有:(1)式(I)所示化合物或其药学上可接受的盐,以及(2)纤维素类聚合物。但当固体制剂有形成覆盖层时,覆盖层中不含纤维素类聚合物。纤维素聚合物于具体为羧甲基纤维素、羧甲基纤维素钠、结晶纤维素/羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羧甲基乙基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、富马酸/硬脂酸/聚乙烯乙缩醛二乙基氨基乙酸酯/羟丙基甲基纤维素混合物等,优选者可列举如羟丙基甲基纤维素。
另一方面为提供一种固体制剂,其含有:(1)式(I)所示化合物或其药学上可接受的盐,(2)纤维素类聚合物,以及(3)无机物。但当固体制剂有形成覆盖层时,覆盖层中不含纤维素类聚合物及无机物。纤维素聚合物于具体为羧甲基纤维素、羧甲基纤维素钠、结晶纤维素/羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羧甲基乙基纤维素、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素乙酸酯琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯、富马酸/硬脂酸/聚乙烯乙缩醛二乙基氨基乙酸酯/羟丙基甲基纤维素混合物等,优选者可列举如羟丙基甲基纤维素。无机物具体地可列举如轻质无水硅酸、含水二氧化硅、硬脂酰富马酸钠、滑石,优选者可列举如轻质无水硅酸、滑石。
本发明制剂即使在使用时添加水并放置长时间,也会维持水中悬浮性。例如,悬浮液为可通过将本发明制剂及水混合而调制。在另一方面中,悬浮液为可通过在本发明制剂2g中添加水20ml混合而调制。此外,在另一方面中,悬浮液为可通过对于放在瓶中的本发明制剂添加水20ml,并轻轻摇动混合以使本发明制剂及水确实混合而调制。
水中悬浮性是指对于本发明制剂约1g添加水9.5mL时以目视确认为均匀的悬浮剂的意思。有时在本说明书中为将这些物理性质统称为“均匀分散性”。
本发明制剂在投入至容器时几乎不会附着于容器表面。
本发明制剂可防止在保存后的制剂彼此间的固着。就制剂的固着的指标而言,可在容器中充填制剂并依据翻转后的制剂的流动性来确认。
本发明制剂可提高流动性并增大制造的作业效率。可使用休止角作为制剂的流动性的指标。
本发明制剂中,在第17改正日本药局方所规定的溶出试验法(桨法)的溶出试验开始15分钟后的式(I)所示化合物或其药学上可接受的盐的溶出率为在75%以上,优选为80%以上,更优选为85%以上。
本发明制剂可直接经口服用,也可将本发明制剂以水或白开水悬浮后将本发明制剂的悬浮液予以服用。本发明制剂不只是成人可服用,小儿也可服用,尤其是对于小儿,为可在使本发明制剂悬浮在水或白开水后再服用本发明制剂的悬浮液。
[实施例]
以下,列举实施例、比较例及参考例以详细说明本发明,但本发明并不受这些例的任何限制。化合物II为可依照国际公开第2016/175224号小册所公开的方法来制造。
实施例A化合物I的制造方法
对于化合物II(4.0g,8.3mmol)添加碳酸钾(1483.4mg,10.7mmol)及碘化钾(549.5mg,3.3mmol)、四氢呋喃(33.1g)、N,N-二甲基乙酰胺(3.8g)及水(80.3mg)并搅拌。升温至60℃,添加碳酸氯甲酯甲酯(1758.9mg,14.2mmol)。在60℃搅拌9小时,冷却至20℃。添加乙酸(822.0mg)、2-丙醇(3.1g)及水(20.0g),以四氢呋喃(1.8g,8.9g)萃取2次。通过减压浓缩而馏去溶剂直到液重量成为约32g为止。升温至45℃后,添加2-丙醇(1.6g),冷却至20℃。添加由乙酸钠(339.0mg)及水(46.0g)调制的乙酸钠水溶液后,冷却至5℃。在5℃搅拌3小时后,滤取所产生的淡黄白色沉淀物。以2-丙醇(4.7g)及水(6.0g)的混合液清洗所得的固体后,以2-丙醇(6.3g)再度清洗固体。对于所得的淡黄白色固体添加二甲基亚砜(30.9g)并搅拌。升温至60℃,添加二甲基亚砜(2.2g)及水(4.8g)的混合液。再添加二甲基亚砜(19.9g)及水(28.4g)的混合液,冷却至20℃。在20℃搅拌3小时后,滤取所生成的白色沉淀物。以二甲基亚砜(8.0g)及水(4.8g)的混合液清洗所得的固体后,以水(12.0g)再度清洗固体。干燥所得的固体,得到化合物I(4.21g)的白色结晶。
1H-NMR(DMSO-D6)δ:2.91-2.98(1H,m),3.24-3.31(1H,m),3.44(1H,t,J=10.4Hz),3.69(1H,dd,J=11.5,2.8Hz),3.73(3H,s),4.00(1H,dd,J=10.8,2.9Hz),4.06(1H,d,J=14.3Hz),4.40(1H,d,J=11.8Hz),4.45(1H,dd,J=9.9,2.9Hz),5.42(1H,dd,J=14.4,1.8Hz),5.67(1H,d,J=6.5Hz),5.72-5.75(3H,m),6.83-6.87(1H,m),7.01(1H,d,J=6.9Hz),7.09(1H,dd,J=8.0,1.1Hz),7.14-7.18(1H,m),7.23(1H,d,J=7.8Hz),7.37-7.44(2H,m)
粉末X线衍射2θ(°):在8.6°±0.2°、14.1°±0.2°、17.4°±0.2°、20.0°±0.2°、24.0°±0.2°、26.3°±0.2°、29.6°±0.2°及35.4°±0.2°有特征性的峰。
将化合物I的粉末X线衍射图形示于图1。
(1)稳定剂的探讨
为了探讨稳定剂,将示于表2至表4的稳定剂及式(I)所示化合物进行湿法造粒,在制造的颗粒剂的经时稳定性试验后,评价作为类似物的式(II)所示化合物的增加量。将示于表1的处方的制剂以搅拌造粒法进行制造。
[表1]
调配量(mg) | |
式(I)所示化合物 | 2.0 |
精制白糖 | 488.0 |
还原麦芽糖水饴(麦芽糖醇) | 500.0 |
稳定剂 | 30.0 |
羟丙基纤维素 | 10.0 |
合计 | 1030.0 |
(制剂的制造法)
将示于表1的式(I)所示化合物、精制白糖、粉末还原麦芽糖水饴(麦芽糖醇)、稳定剂及羟丙基纤维素,以高速混合机(high speed mixer)(FS-GS SJT 10高速混合机,深江Powtech Co.)混合,添加水,进行搅拌造粒。其后,将造粒物以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,以流动层造粒机(WSG2&5fluid bed dryer granulator,大川原制作所)在65至70℃进行干燥。干燥后,以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,得到颗粒剂。高速混合机的造粒条件如下所述。
(造粒条件)
·造粒机:FS-GS SJT 10高速混合机
·搅拌机(agitator)转数:250转/分钟
·切碎机(chopper)转数:2500转/分钟
·液注加速度:21±2g/分钟
·水分量:4至6.5重量%
·成块(massing)时间:1分钟±5秒
(制剂的经时稳定性试验)
将所制造的制剂在60℃保存2周,测定作为类似物的式(II)所示化合物的增加量。
(稳定剂)
就稳定剂而言,如表2至表4所示,使用氯化钠(关东化学)、氯化钾(和光纯药)、抗坏血酸(Nacalai Tesque)、富马酸(Merck)、中链脂肪酸甘油三酯Miglyol(三叶贸易)、柠檬酸三乙酯(Merck)、亚硝酸钠(Nacalai Tesque)、甘油(关东化学)、维生素E(Merck)。
[表2]
实施例1 | 实施例2 | 实施例3 | 实施例4 | |
稳定剂 | 氯化钠 | 氯化钾 | 抗坏血酸 | 富马酸 |
[表3]
实施例5 | 实施例6 | 比较例1 | 比较例2 | |
稳定剂 | 中链脂肪酸甘油三酯Miglyol | 柠檬酸三乙酯 | 亚硝酸钠 | 甘油 |
[表4]
比较例3 | 比较例4 | |
稳定剂 | 维生素E | 无 |
(式(II)所示化合物的测定法)
依照下述的方法、条件,以液相色谱仪测定式(II)所示化合物的量。
·检测器:紫外分光光度计(测定波长260nm)
·管柱:XBridge C18,3.5μm,3.0×150mm
·管柱温度:35℃附近的一定温度
·流动相A:0.1%三氟乙酸/0.2mM EDTA溶液,流动相B:乙腈
·流动相的送液:将流动相A及流动相B的混合比依照表5所示而改变以控制浓度梯度。
[表5]
·流量:约0.6mL/分钟
·注入量:5μL
·试样冷却器温度:约5℃
·自动注射器清洗液:乙腈/甲醇混液(1:3)
·面积测定范围:试料溶液注入后50分钟
·式(II)所示化合物的量的计算式
式(II)所示化合物的量(%)=(ATII/ΣAT)×100
ATII:试料溶液的式(II)所示化合物的峰面积
ΣAT:试料溶液的峰面积的合计(除去空白及系统峰)
(结果)
将对于实施例1至6、比较例1至4制剂进行经时稳定性试验时的式(II)所示化合物的增加量(%)示于表6至表8。结果,实施例1至6的颗粒剂的式(II)所示化合物的增加量(%),相较于比较例4的不含稳定剂的颗粒剂而为较低。尤其是实施例1的含有氯化钠的颗粒剂、实施例3的含有抗坏血酸的颗粒剂、实施例4的含有富马酸的颗粒剂及实施例5的含有中链脂肪酸甘油三酯Miglyol的颗粒剂,相较于比较例4的不含稳定剂的颗粒剂,而显现式(II)所示化合物的增加量为相当少。
[表6]
[表7]
[表8]
比较例3 | 比较例4 | |
稳定剂 | 维生素E | 无 |
式(II)所示化合物的增加量(%) | 3.56 | 1.35 |
(2)赋形剂的探讨
为了探讨赋形剂,将示于表9至表11的赋形剂及式(I)所示化合物进行湿法造粒,在所制造的颗粒剂的经时稳定性试验后,评价作为类似物的式(II)所示化合物的增加量。
(制剂的制造法)
将示于表9至表11赋形剂及式(I)所示化合物以1:1在袋内混合后,以30网目(线径0.22mm)的筛进行过筛。将过筛的混合粉末以研钵混合后,以使造粒水分相对于原料的装填量而成为约5重量%的方式缓缓添加精制水,使用研棒进行捏合。对于捏合后的物质,以手于16网目(线径0.55mm)的金属网进行挤压并实施湿式整粒。将经整粒的造粒物,以通气式干燥机干燥,以手于20网目(线径0.40mm)的金属网进行挤压并实施调粒。
(制剂的经时稳定性试验)
将所制造的制剂在60℃保存2周,测定作为类似物的式(II)所示化合物的增加量。
(赋形剂)
就赋形剂而言,如表9至表11所示,使用精制白糖(Merck)、还原麦芽糖水饴(麦芽糖醇,ROQUETTE)、D-甘露醇(ROQUETTE)、乳糖水合物(DMV-Fonterra)、山梨糖醇(Merck)、赤藻糖醇(ROQUETTE)、木糖醇(ROQUETTE)、异麦芽酮糖醇(Beneo palatinit)。
[表9]
[表10]
参考例1 | 参考例2 | 参考例3 | |
赋形剂 | 乳糖水合物 | 山梨糖醇 | 赤藻糖醇 |
[表11]
参考例4 | 参考例5 | |
赋形剂 | 木糖醇 | 异麦芽酮糖醇 |
(结果)
将对于实施例7至9、参考例1至5的制剂进行经时稳定性试验时的式(II)所示化合物的增加量(%)及各赋形剂的熔点示于表12至表14。结果,实施例7至9的颗粒剂的式(II)所示化合物的增加量(%),相较于参考例1、2及5的颗粒剂稍低。此外,参考例3及4的颗粒剂的式(II)所示化合物的增加量(%),与实施例7至9的颗粒剂几乎相同,但熔点为低于实施例7至9,有固着的可能性。因此,就赋形剂而言,可认为精制白糖、还原麦芽糖水饴(麦芽糖醇)及D-甘露醇为优选。
[表12]
[表13]
参考例1 | 参考例2 | 参考例3 | |
赋形剂 | 乳糖水合物 | 山梨糖醇 | 赤藻糖醇 |
熔点(℃) | 160至186 | 145 | 166至168 |
式(II)所示化合物的增加量(%) | 0.17 | 0.15 | 0.08 |
[表14]
参考例4 | 参考例5 | |
赋形剂 | 木糖醇 | 异麦芽酮糖醇 |
熔点(℃) | 92至96 | 141至161 |
式(II)所示化合物的增加量(%) | 0.04 | 0.38 |
(3)赋形剂的组合的探讨
虽然选择了精制白糖、还原麦芽糖水饴(麦芽糖醇)及D-甘露醇作为优选的赋形剂,但为了探讨这些赋形剂的组合,故将表15、表16所示的赋形剂的组合及式(I)所示化合物进行湿法造粒,评定所制造的颗粒剂的(a)作为类似物的式(II)所示化合物的增加量、(b)水中悬浮性、(c)容器附着性、(d)细粒产率、(e)堆积密度。将表15及表16所示的处方的制剂以搅拌造粒法进行制造。
[表15]
[表16]
(制剂的制造法)
将示于表15、表16的式(I)所示化合物、赋形剂及聚乙烯吡咯烷酮以高速混合机(LFS-GS-2J高速混合机,深江Powtech)混合,添加水,进行搅拌造粒。其后,将造粒物以破碎型造粒机(P-3S型,昭和机械工作所)进行整粒,以流动层造粒机(MP-01Fluid bed dryergranulator,Powrex)在65至70℃进行干燥。干燥后,以破碎型造粒机(P-3S型,昭和机械工作所)进行整粒,得到颗粒剂。高速混合机的造粒条件为如下所述。
(造粒条件)
·造粒机:LFS-GS-2J高速混合机
·搅拌机转数:333转/分钟
·切碎机转数:2500转/分钟
·液注加速度:20±3.5g/分钟
·水分量:3至7.5重量%
·成块时间:1至2分钟±5秒
(制剂的水中悬浮性试验)
记录在对于本发明制剂约1g添加水9.5mL时以目视确认达到均匀的悬浮剂时所需的翻转混合次数。
(制剂的容器附着性)
在本发明制剂的制造时,以目视确认在造粒后于搅拌造粒机的内壁所附着的造粒物的量。容器附着性的指标是:依据刮落后的附着的有无来评定。
(制剂的细粒产率测定)
将本发明制剂100g以30号及140号的筛网进行过筛,算出“通过30号的筛但残留于140号的筛上的颗粒剂的量”相对于“筛选的颗粒剂总量”的比率。
(制剂的堆积密度测定)
将本发明制剂流入容积100mL的容器中直到溢出为止,从容器的上表面将过剩的制剂小心擦去。从预先扣除的容器重量而得到容器内的制剂重量的值,依据下述的式求出堆积密度。
堆积密度=容器内的制剂重量/100
(赋形剂)
就赋形剂而言,如表15、表16所示,为将精制白糖(Merck)、还原麦芽糖水饴(麦芽糖醇,ROQUETTE)、D-甘露醇(ROQUETTE)组合而使用。
(结果)
将实施例10至12、比较例5、6制剂的水中悬浮性、容器附着性、细粒产率及堆积密度示于表17、表18。结果,赋形剂是还原麦芽糖水饴(麦芽糖醇)及D-甘露醇的混合物的实施例10至12的制剂为水中悬浮性优良、对容器的附着性也少、堆积密度也在0.5g/mL以上。尤其是实施例10及11为细粒产率亦高达90%以上。另一方面,赋形剂是精制白糖及还原麦芽糖水饴(麦芽糖醇)、精制白糖及D-甘露醇的混合物的比较例5及6则是水中悬浮性比实施例差,容器附着性也大。尤其是比较例6为细粒产率也低。
[表17]
[表18]
(4)粘合剂的探讨
为了探讨粘合剂,将示于表19的粘合剂及式(I)所示化合物进行湿法造粒,评定所制造的制剂的(a)经时稳定性试验后的作为类似物的式(II)所示化合物的增加量及(b)堆积密度。将示于表19的处方的制剂以搅拌造粒法进行制造。粘合剂为使用聚乙烯吡咯烷酮K25(BASF)、羟丙基纤维素SL(信越化学工业)。
[表19]
(制剂的制造法)
将示于表19的式(I)所示化合物、精制白糖、还原麦芽糖水饴(麦芽糖醇)、及作为粘合剂的羟丙基纤维素SL(日本曹达)或聚乙烯吡咯烷酮K25以高速混合机(LFS-GS-2J高速混合机,深江Powtech)混合,添加水,进行搅拌造粒。其后,将造粒物以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,以流动层造粒机(MP-01Fluid bed dryer granulator,Powrex)在65至70℃进行干燥。干燥后,以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,得到颗粒剂。高速混合机的造粒条件如下所述。
(造粒条件)
·造粒机:LFS-GS-2J高速混合机
·搅拌机转数:333转/分钟
·切碎机转数:2500转/分钟
·液注加速度:20±3.5g/分钟
·水分量:3至7.5重量%
·成块时间:1至2分钟±5秒
(制剂的经时稳定性试验)
将所制造的制剂在60℃保存2周,测定作为类似物的式(II)所示化合物的增加量。
(制剂的堆积密度测定)
将本发明制剂流入容积100mL的容器中直到溢出为止,从容器的上表面将过剩的制剂小心擦去。从预先扣除的容器重量而得到容器内的制剂重量的值,依据下述的式求出堆积密度。
堆积密度=容器内的制剂重量/100
(结果)
将实施例13、14及参考例6的制剂的经时稳定性试验时的式(II)所示化合物的增加量(%)及堆积密度示于表20。结果,相较于含有羟丙基纤维素的参考例6制剂,含有聚乙烯吡咯烷酮的实施例12及13制剂的式(II)所示化合物的增加量(%)为较低。此外,相较于聚乙烯吡咯烷酮的量为3重量%的实施例13制剂,其量为1重量%的实施例12制剂为在经时稳定性试验时的式(II)所示化合物的增加量(%)较低,堆积密度也低。
[表20]
实施例13 | 实施例14 | 参考例6 | |
式(II)所示化合物的增加量(%) | 0.12 | 0.15 | 0.20 |
堆积密度(g/mL) | 0.72 | 0.77 | - |
(5)流化剂的探讨
为了探讨流化剂,而评定(a)将制剂经时保存后的类似物量、(b)制剂彼此间的固着性。将示于表21、表22的处方的制剂以搅拌造粒法进行制造。流化剂为使用轻质无水硅酸(Cab-o-sil,CABOT)1%、3%,含水二氧化硅(RxCIPIENTS)1%、3%及硬脂酰富马酸钠(PRUV,JRSPHARMA)1%、3%。
[表21]
[表22]
(制剂的制造法)
将示于表21、表22的式(I)所示化合物、还原麦芽糖水饴(麦芽糖醇)、D-甘露醇、聚乙烯吡咯烷酮K25、三氯蔗糖、流化剂(轻质无水硅酸、含水二氧化硅、硬脂酰富马酸钠中的任一者)及草莓风味剂以高速混合机(LFS-GS-2J高速混合机,深江Powtech)混合,添加水,进行搅拌造粒。其后,将造粒物以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,以流动层造粒机(MP-01Fluid bed dryer granulator,Powrex)在65至70℃进行干燥。干燥后,以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,得到颗粒剂。高速混合机的造粒条件如下所述。
(造粒条件)
·造粒机:LFS-GS-2J高速混合机
·搅拌机转数:333转/分钟
·切碎机转数:2500转/分钟
·液注加速度:20±3.5g/分钟
·水分量:3至7.5重量%
·成块时间:1至2分钟±5秒
(制剂的经时稳定性试验)
将所制造的本发明制剂在60℃保存2周,测定作为类似物的式(II)所示化合物的增加量。
(制剂的固着性试验)
在4mL的褐色瓶中充填1g的制剂,将该瓶翻转3次时位于底部的制剂有流动的情形为评定为○,将该瓶翻转3次时上部的制剂有流动的情形为评定为△,将该瓶翻转3次时制剂完全不流动的情形为评定为×。
(结果)
将对于实施例15至18及比较例7、8制剂进行经时稳定性试验时的式(II)所示化合物的增加量(%)及制剂的固着性示于表23、表24。结果,实施例15至18制剂的式(II)所示化合物的增加量(%),与含有硬脂酰富马酸钠的比较例7及8制剂几乎相同,即使变更流化剂的量也是结果几乎相同。
另一方面,探讨实施例15至18、比较例7、8制剂的固着性的结果,相较于比较例7、8制剂,实施例15至18制剂的固着性较低。
[表23]
实施例15 | 实施例16 | 实施例17 | |
式(II)所示化合物的增加量(%) | 0.64 | 0.51 | 0.34 |
固着性 | △ | ○ | ○ |
[表24]
实施例18 | 比较例7 | 比较例8 | |
式(II)所示化合物的增加量(%) | 0.58 | 0.51 | 0.45 |
固着性 | ○ | × | × |
(6)悬浮剂的探讨
为了探讨悬浮剂,而评定制剂的水中悬浮性。将表25所示的处方的本发明制剂以搅拌造粒法进行制造。悬浮剂为使用羟丙基甲基纤维素(TC-5,信越化学工业)、羟丙基纤维素(HPC-L,日本曹达)、甲基纤维素(SM-4,信越化学工业)。
[表25]
(制剂的制造法)
将示于表25的式(I)所示化合物、D-甘露醇、还原麦芽糖水饴(麦芽糖醇)、氯化钠及聚乙烯吡咯烷酮K25以立式造粒机(vertical granulator)(VG-50型,Powrex)混合,添加水,进行搅拌造粒。其后,将造粒物以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,以流动层造粒机(GPGC-15&30fluid bed dryer granulator,Powrex)在65至70℃进行干燥。干燥后,以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒。经整粒的造粒物及三氯蔗糖及悬浮剂(羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素中的任一者)、轻质无水硅酸及草莓风味剂以V型混合机(130L V type blender,德寿工作所公司制)混合,制成颗粒剂。
(造粒条件)
·造粒机:立式造粒机VG-50型
·搅拌机转数:200转/分钟
·切碎机转数:2500转/分钟
·液注加速度:105±3g/分钟
·水分量:4.5至7.5重量%
·成块时间:1至3分钟±5秒
(制剂的水中悬浮性试验)
将本发明制剂1g投入至已装有9.5mL的水的带盖的容器中,将带盖的容器往返翻转40次后,立即从容器的上部及下部采取液。此外,容器翻转结束后,在室温放置10分钟,从容器中央部采取液。测定所采取的液中的式(I)所示化合物浓度。
(式(I)所示化合物的测定法)
依照下述的方法、条件,以液相色谱仪测定式(I)所示化合物的量。
·检测器:紫外分光光度计(测定波长260nm)
·管柱:ACQUITY UPLC BEH C18 1.7μm,2.1×50mm(Waters)
·管柱温度:35℃附近的一定温度
·流动相A:0.1%三氟乙酸/0.2mM EDTA溶液,流动相B:乙腈
·流动相的送液:将流动相A及流动相B的混合比依照如表26所示而改变以控制浓度梯度。
[表26]
注入后的时间(分钟) | 流动相A(vol%) | 流动相B(vol%) |
0至2.3 | 62 | 38 |
2.3至3 | 62→20 | 38→80 |
3至4 | 20 | 80 |
·流量:约0.6mL/分钟
·注入量:4μL
·试样冷却器温度:约5℃
·自动注射器清洗液:乙腈
·面积测定范围:试料溶液注入后8分钟
·式(I)所示化合物的量的计算式
式(I)所示化合物的量(%)=MS/C×AT/AS×100
MS:质量(mg)
C:制剂中表示量(mg/mL)
AS:由标准溶液所得的峰面积
AT:由试料溶液所得的峰面积
(水中悬浮性的评定)
依据下述式来评定制剂的悬浮性。
容器翻转10分钟后的容器的位于中央的悬浮液中的式(I)所示化合物量的比率(%)=(容器翻转10分钟后的容器的位于中央的悬浮液中的式(I)所示化合物浓度/容器刚翻转后的容器的位于中央的悬浮液中的式(I)所示化合物浓度)×100(%)
(结果)
将实施例19、参考例7、8及比较例9制剂的水中悬浮性示于表27。结果,相较于不含悬浮剂的比较例9,实施例19及参考例7、8的悬浮液中的式(I)所示化合物量的比率较高。尤其是含有羟丙基甲基纤维素的实施例19制剂的悬浮液中的式(I)所示化合物量的比率高,水中悬浮性良好。
[表27]
(7)润滑剂的探讨
为了探讨润滑剂,而评定作为制剂的流动性的指标的休止角。将表28所示的处方的制剂以搅拌造粒法进行制造。润滑剂是使用滑石(Merck,LUB)。
[表28]
(制剂的制造法)
将示于表28的式(I)所示化合物、D-甘露醇、还原麦芽糖水饴(麦芽糖醇)、氯化钠、聚乙烯吡咯烷酮K25及羟丙基甲基纤维素以立式造粒机(FM-VG50型,Powrex)混合,添加水,进行搅拌造粒。其后,将造粒物以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒,以流动层造粒机(GPGC-15&30fluid bed dryer granulator,Powrex)在65至70℃进行干燥。干燥后,以破碎型造粒机(P-3S型,昭和化学机械工作所)进行整粒。经整粒的造粒物及滑石、三氯蔗糖、轻质无水硅酸及草莓风味剂以V型混合机(130L V type blender,德寿工作所)混合,成为颗粒剂。
(造粒条件)
·造粒机:立式造粒机VG-50型
·搅拌机转数:200转/分钟
·切碎机转数:2500转/分钟
·液注加速度:105±3g/分钟
·水分量:4.5至7.5重量%
·成块时间:1至3分钟±5秒
(制剂的休止角的测定)
将所制造的制剂以粉末测试器(细川Micron)依照下述条件测定休止角。
动作时间:170秒,减慢(slow down):10秒,振幅:1.5mm
(结果)
将实施例20、比较例10制剂的休止角示于表29。结果,相较于不含滑石的比较例10制剂,含有滑石的实施例20制剂的休止角较小,可知含有滑石时可提高制剂的流动性。
[表29]
实施例20 | 比较例10 | |
休止角(°) | 33.7 | 36.2 |
(8)溶出率的测定
将示于表28的实施例20制剂进行SP(铝)包装,在25℃于相对湿度60%下保存3、6、9及12个月,测定式(I)所示化合物的溶出率。
(制剂的溶出性试验)
将所制造的制剂在25℃于相对湿度60%下保存一定时期后,依照日本药局方的溶出试验法(第2法,桨法)测定式(I)所示化合物的溶出率。溶出试验法中所使用的液为使用溶出第2液(含有溴化鲸蜡基三甲基铵),桨的转数设定为50rpm。
(结果)
如图2所示,关于实施例20制剂的溶出率,刚调制后的制剂的溶出率与在25℃于相对湿度60%下保存3、6、9及12个月后的制剂几乎没有差异。
(9)含有不同化合物量的制剂
调制表29所示的实施例21的制剂作为另一方面。实施例21为与实施例20同样地以搅拌造粒法进行制造。
[表30]
[产业上的可利用性]
含有式(I)所示化合物的本发明制剂,在各项探讨中提高了稳定性、水中悬浮性、流动性等。由此,可将本发明制剂在水中悬浮,并使小儿也可容易服用本发明制剂。
Claims (17)
2.如权利要求1所述的固体制剂,其含有碱金属氯化物,该碱金属氯化物是氯化钠及/或氯化钾。
3.如权利要求1所述的固体制剂,其含有有机酸,该有机酸为抗坏血酸及/或富马酸。
4.如权利要求1所述的固体制剂,其含有多元醇酯,该多元醇酯为选自由Miglyol、柠檬酸三乙酯及聚氧乙烯山梨醇酐单油酸酯所成的群组中的1种以上。
5.如权利要求1所述的固体制剂,其含有脂肪酸酯,该脂肪酸酯是三乙酸甘油酯。
6.如权利要求1至5中任一项所述的固体制剂,其还含有糖醇及/或糖类。
7.如权利要求6所述的固体制剂,其中,糖醇及/或糖类为选自由异麦芽酮糖醇、还原麦芽糖水饴、甘露醇、木糖醇、赤藻糖醇、山梨糖醇、乳糖、蔗糖、果糖、麦芽糖、精制白糖及海藻糖所成的群组中的1种以上。
8.如权利要求1至7中任一项所述的固体制剂,其还含有水溶性聚合物。
9.如权利要求8所述的固体制剂,其中,水溶性聚合物为纤维素类聚合物。
11.如权利要求9或10所述的固体制剂,其中,纤维素类聚合物为选自由羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羧甲基纤维素、羧甲基乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯及羟丙基甲基纤维素乙酸酯琥珀酸酯所成的群组中的1种以上。
12.如权利要求11所述的固体制剂,其中,纤维素类聚合物是羟丙基甲基纤维素。
13.如权利要求1至12中任一项所述的固体制剂,其还含有无机物,但固体制剂的覆盖层中不含无机物。
14.如权利要求13所述的固体制剂,其中,无机物为选自由含水二氧化硅、轻质无水硅酸及滑石所成的群组中的1种以上。
15.如权利要求1至14中任一项所述的固体制剂,其中,依照第17改正日本药局方所规定的溶出试验法(桨法)中的溶出试验开始15分钟后的式(I)所示化合物或其药学上可接受的盐的溶出率为在80%以上。
17.如权利要求1至16中任一项所述的固体制剂,其为颗粒剂或干糖浆剂。
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JP2018-083006 | 2018-04-24 | ||
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PCT/JP2019/017146 WO2019208540A1 (ja) | 2018-04-24 | 2019-04-23 | 安定性に優れた固形製剤 |
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JP (1) | JP6618099B2 (zh) |
KR (1) | KR102501180B1 (zh) |
CN (1) | CN112236146A (zh) |
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AU (1) | AU2019259686B2 (zh) |
BR (1) | BR112020021059B1 (zh) |
CA (1) | CA3098006A1 (zh) |
MX (1) | MX2022009094A (zh) |
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WO2021230308A1 (ja) | 2020-05-15 | 2021-11-18 | 塩野義製薬株式会社 | 不純物の生成を抑制した医薬組成物 |
JP2022108727A (ja) * | 2021-01-13 | 2022-07-26 | 日曹商事株式会社 | フマル酸含有固形製剤 |
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AU2019259686B2 (en) | 2023-05-25 |
AU2019259686A1 (en) | 2020-10-29 |
KR20200144127A (ko) | 2020-12-28 |
TWI822498B (zh) | 2023-11-11 |
BR112020021059B1 (pt) | 2022-08-30 |
TWI788557B (zh) | 2023-01-01 |
KR102501180B1 (ko) | 2023-02-21 |
CA3098006A1 (en) | 2019-10-31 |
JP6618099B2 (ja) | 2019-12-11 |
TW202000206A (zh) | 2020-01-01 |
WO2019208540A1 (ja) | 2019-10-31 |
MX2022009094A (es) | 2022-08-18 |
US20210106589A1 (en) | 2021-04-15 |
US11925648B2 (en) | 2024-03-12 |
JP2019189635A (ja) | 2019-10-31 |
AR115354A1 (es) | 2020-12-23 |
TW202313057A (zh) | 2023-04-01 |
BR112020021059A2 (pt) | 2021-02-17 |
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