CN105380928B - 口腔内薄膜状基剂和制剂 - Google Patents
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Abstract
本发明涉及口腔内薄膜状基剂和制剂,其目的在于,提供具有口腔内的迅速的溶解曲线、充分的薄膜强度、指触时的触感、口腔内的食感、味道等也良好、对需要限制糖分的人也容易给药的口腔内薄膜状基剂和制剂。本发明为含有可食性高分子和选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的口腔内薄膜状基剂,前述可食性高分子可溶于水和溶解度参数为9.7以上的有机溶剂,前述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒以颗粒的状态分散于前述口腔内薄膜状基剂中。
Description
技术领域
本发明涉及在口腔内迅速溶解的薄膜状基剂和制剂(药剂),更详细而言,涉及通过在口腔内迅速溶解,从而以使药物被消化器官或口腔粘膜吸收为目的的口服用的薄膜状基剂和制剂。
背景技术
在口腔内不咬碎而使其仅由唾液崩解或溶解而服用的薄膜状、带状或片状的药剂在海外已经被一般用药品(OTC药品)销售了10种产品以上,在日本也作为医疗用药品被销售了多种产品。
这样的薄膜状制剂在薄膜状基剂中分散或溶解有药物,例如,可以如下制造:使水溶性高分子溶解于溶剂中,且使药物分散或溶解,形成所得分散液或溶液的薄膜,进行干燥,从而制造。
作为这样的薄膜状制剂,提出了以下制剂:在包含羟丙基纤维素或羟丙基纤维素与聚乙烯吡咯烷酮的混合物、和由丹宁物质得到的薄膜的基剂中配合有药剂的制剂(专利文献1);含有药剂、可食性的水溶性薄膜形成剂、和低取代度羟丙基纤维素的薄膜状制剂(专利文献2);含有药物和可食性高分子物质、该薄膜的断裂强度和拉伸强度在规定的范围内、且在口腔内在60秒以内溶解的速溶性薄膜状制剂(专利文献3);包含在室温下具有约小于1g/4mL的水溶性的活性成分的含水率约小于15重量%的可溶性的薄膜(专利文献4)等。
另外,虽然不是薄膜状,但专利文献5中记载了一种迅速溶解性制剂,其可以如下得到:将药物、糖类和聚乙烯吡咯烷酮溶解/分散于有机溶剂,得到悬浮液,接着将该悬浮液填充至制剂用模具,然后去除有机溶剂,从而得到。
然而,迄今为止公开的薄膜状制剂为了确保薄膜强度等大多含有糖或糖醇作为赋形剂,糖或糖醇以溶解于溶剂的状态或重结晶的状态而含有,因此在口腔内呈现由水溶性高分子导致的粘感。另外,作为指触时的触感粘腻也成为问题。
针对这样的问题,专利文献6中记载了以下方法:在口腔内薄膜状基剂和制剂中,通过使糖或糖醇的颗粒分散在含有可食性高分子的薄膜中,从而防止糖或糖醇的溶解和重结晶且改善口腔内的崩解性。另外,关于添加到薄膜状制剂中的颗粒的大小也进行了各种研究(例如,专利文献7~9)。
现有技术文献
专利文献
专利文献1:日本专利第3496727号
专利文献2:日本特开2008-169138号公报
专利文献3:日本特开2004-43450号公报
专利文献4:日本特表2007-528876号公报
专利文献5:日本特开平11-116465号公报
专利文献6:国际公开第2010/087032号
专利文献7:国际公开第2004/066986号
专利文献8:国际公开第2004/045537号
专利文献9:国际公开第2010/103539号
发明内容
发明要解决的问题
然而,使用糖或糖醇作为赋形剂时,伴随着糖分吸湿的粘腻对触感造成不良影响,另外产生必须避免对需要限制糖分的人(例如,需要控制血糖值的人)给药的情况。另外,对于添加到薄膜状制剂中的颗粒的大小进行了各种研究(例如,专利文献7~9),但对控制粒径、颗粒形态的方法尚未进行充分地研究。
鉴于上述现状,本发明的目的在于,提供具有口腔内的迅速的溶解曲线、充分的薄膜强度、指触时的触感、口腔内的食感、味等也良好、对需要限制糖分的人也容易给药的口腔内薄膜状基剂和制剂。
用于解决问题的方案
为了解决上述问题,本发明人等进行了深入研究,结果发现:使用可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子作为可食性高分子,使选自由氨基酸、二肽和核苷酸组成的组中的至少1种以颗粒的状态分散在口腔内薄膜状基剂中,从而可以得到具有口腔内的迅速的溶解曲线、充分的薄膜强度、指触时的触感、口腔内的食感、味道等也良好、对需要限制糖分的人也容易给药的口腔内薄膜状基剂和制剂,从而完成了本发明。
即,本发明为一种口腔内薄膜状基剂,其为含有可食性高分子和选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的口腔内薄膜状基剂,前述可食性高分子可溶于水和溶解度参数为9.7以上的有机溶剂,前述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒以颗粒的状态分散于前述口腔内薄膜状基剂中。
优选上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的平均粒径为0.1~60μm。
优选上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子在常温下为固体。
优选上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子为聚乙烯吡咯烷酮和/或羟丙基纤维素。
优选上述聚乙烯吡咯烷酮的重均分子量为2500~300万。
优选上述羟丙基纤维素的重均分子量为1万~115万。
优选上述羟丙基纤维素的羟基丙氧基的取代度为50~100%。
优选本发明的口腔内薄膜状基剂是使用溶解度参数为9.7以上的有机溶剂而制造的。
另外,本发明为一种口腔内薄膜状制剂,在本发明的口腔内薄膜状基剂中进一步分散或溶解有药物。
以下,对本发明详细说明。
本发明的口腔内薄膜状基剂含有可食性高分子和选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒,前述可食性高分子可溶于水和溶解度参数为9.7以上的有机溶剂。上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒以颗粒的状态分散于本发明的口腔内薄膜状基剂中。
本发明的口腔内薄膜状基剂具有这样的结构,因此具有口腔内的迅速的溶解曲线、充分的薄膜强度,指触时的触感、口腔内的食感、味道等也良好。另外,本发明的口腔内薄膜状基剂含有选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒,因此与含有糖或糖醇的情况相比,改善伴随着糖分吸湿的触感恶化(粘腻),且对需要限制糖分的人也容易给药。
需要说明的是,本说明书中,“以颗粒的状态分散”是指维持颗粒的状态的同时分散,而不是溶解的状态、也不是重结晶的状态。在口腔内薄膜状基剂中以重结晶的状态含有的氨基酸等、和以颗粒的状态分散的氨基酸等对于本领域技术人员来说可以通过例如显微镜观察等容易且明确地区分。
即,在口腔内薄膜状基剂中以重结晶的状态含有的氨基酸等是氨基酸等在口腔内薄膜状基剂中自然发生而形成的,因此具有有时也被称为无定形的不规则且不均匀的形状和尺寸。与此相对,对于在口腔内薄膜状基剂中以颗粒的状态分散的氨基酸等,制造者在制造时控制粒径,因此具有人为的形状和尺寸。
图1为示出本发明的口腔内薄膜状基剂的实施方式的一例的示意图,如图1所示那样,本发明的口腔内薄膜状基剂中,选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒1a以颗粒的状态分散于由可食性高分子形成的可食性薄膜1b中。
上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒是为了确保薄膜强度等而作为赋形剂添加的。
上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒优选为不溶于溶解度参数为9.7以上的有机溶剂。使用具有上述溶解特性的物质作为上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒,另一方面,如后述那样,使用可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子,进而使用溶解度参数为9.7以上的有机溶剂作为制造时的溶剂,从而可以使上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种以颗粒的状态分散,可以控制其粒径、颗粒形态。
需要说明的是,本说明书中,“溶解度参数”(也称为SP值)是指1mol容量的液体蒸发所需的蒸发热(cal/cm3)的平方根((cal/cm3)1/2)。另外,“不溶”于溶剂是指在20℃下溶解1g溶质的溶剂的量必须为100mL以上的情况,“可溶”于溶剂是指在20℃下溶解1g溶质的溶剂的量小于5mL的情况。需要说明的是,在20℃下溶解1g溶质的溶剂的量小于3mL时,使用“易溶”的表述。
另外,上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒由于可以容易地形成颗粒,优选在常温下为固体。
需要说明的是,本说明书中“在常温下为固体”是指在20℃下不具有流动性。
上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒优选在本发明的口腔内薄膜状基剂中作为其本身的颗粒分散,例如不是通过微囊化等而被覆。这样的颗粒由于未被覆,因此在给药时显示出即效性,且无需复杂的制造方法。
上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒只要为颗粒状就对其粒径没有特别限定,优选平均粒径为0.1~60μm。小于0.1μm时,有颗粒凝集的可能性,有口腔内薄膜状基剂的柔软性变得因部位不同而不均匀的可能性。另一方面,超过60μm时,含有在实用厚度的口腔内薄膜状基剂中时,有柔软性变得因部位不同而不均匀的可能性。平均粒径更优选为0.5~40μm。
需要说明的是,本说明书中,选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的平均粒径是指,通过激光散射式粒度分布测定装置测定的50体积%平均粒径。
上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的平均粒径在上述范围外时,可以利用使平均粒径为上述范围的方式进行整粒而得到的颗粒。平均粒径的调整可以通过利用粉碎、干式粉碎法、湿式造粒法等的造粒、使用筛、分级机等的分级等来进行。
作为上述氨基酸,没有特别限定,可以适合使用甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、丝氨酸、苏氨酸、半胱氨酸、蛋氨酸、天门冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、苯丙氨酸、酪氨酸、色氨酸、羟基脯氨酸、和它们的药学上允许的盐。这些氨基酸可以单独使用也可以组合2种以上使用。
作为上述二肽,只要为2个氨基酸经肽键而成的分子就没有特别限定,上述氨基酸中,可以适合使用相同或不同种类的氨基酸经肽键而成的分子、和其药学上允许的盐。这些二肽可以单独使用也可以组合2种以上使用。
作为上述核苷酸,没有特别限定,可以适合使用腺苷酸、胸苷酸、鸟苷酸、胞苷酸、肌苷酸、和它们的药学上允许的盐。这些核苷酸可以单独使用也可以组合2种以上使用。
上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的配合量优选在本发明的口腔内薄膜状基剂或制剂中所含的固体成分总重量中为5~80重量%。小于5重量%时,有时无法得到口腔内的迅速的溶解曲线、充分的薄膜强度。另一方面,超过80重量%时,有时选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的粒径只要不是相当地小,就会逐步出现产品的保型性等问题。配合量更优选为10~60重量%。
作为上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子,只要是可溶于水和溶解度参数为9.7以上的有机溶剂且分子量大至一定程度从而具有薄膜形成能力、具有可食性,就没有特别限定,优选在常温下为固体。
这样的可食性高分子的重均分子量优选为2000~400万。小于2000时,薄膜成型性缺乏,有难以维持口腔内薄膜状基剂的形状的可能性。另一方面,超过400万时,口腔内薄膜状基剂的溶解性变差,实用上有成为问题的可能性。重均分子量更优选为2500~300万。
作为上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子,具体而言,可以适合使用聚乙烯吡咯烷酮(以下记作“PVP”)和/或羟丙基纤维素(以下记作“HPC”)。
这些可食性高分子充分显示出可溶于水和溶解度参数为9.7以上的有机溶剂,满足以下两个条件:在口腔内迅速溶解;和制造口腔内薄膜状基剂时可以使用选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒为不溶性的溶剂。由此,可以使选自由氨基酸、二肽和核苷酸组成的组中的至少1种以颗粒的状态均匀地分散、负载。
上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子中,更优选为HPC。与PVP相比,HPC的对于相对湿度的吸湿性低,从实用上的观点出发,可以认为优选。这些可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子可以单独使用也可以组合2种以上使用。
上述PVP的重均分子量优选为2500~300万。小于2500时,有稳定性和吸湿性变差的担心。另一方面,超过300万时,有溶解性变差的担心。重均分子量更优选为2500~120万。
上述HPC的重均分子量优选为1万~115万。小于1万时,有吸湿性和稳定性变差的担心。另一方面,超过115万时,有溶解性变差的担心。重均分子量更优选为1万~37万。
需要说明的是,本说明书中,分子量是指重均分子量,重均分子量是指通过凝胶渗透色谱分析得到的分子量。
上述HPC的羟基丙氧基的取代度优选为50~100%。小于50%时,有对有机溶剂的溶解性变差的担心。羟基丙氧基的取代度更优选为53.4%以上。
需要说明的是,羟基丙氧基的取代度的测定方法基于第十五版修订日本药典/药品各条/羟丙基纤维素/定量法。
本发明的口腔内薄膜状基剂中除了上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子以外,还可以含有适量的其他可食性高分子。
作为上述其他可食性高分子,例如可以举出:仅可溶于水的可食性高分子、不溶于水以及溶解度参数为9.7以上的有机溶剂的可食性高分子等,具体而言,例如可以举出:聚乙烯醇、羧乙烯聚合物、羟丙甲基纤维素(以下记作“HPMC”)、羟乙基纤维素、甲基纤维素、乙基纤维素、低取代度羟丙基纤维素、结晶纤维素、羧甲基纤维素钠、羧甲基纤维素钙、羧甲基纤维素、羧甲基淀粉钠等合成高分子;由藻酸钠、葡聚糖、酪蛋白、普鲁兰多糖、果胶、瓜尔豆胶、黄原胶、黄蓍胶、***树胶、***胶、淀粉等天然物得到的高分子等。
上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子、与上述其他可食性高分子的配合量的总计在本发明的口腔内薄膜状基剂或制剂所含的固体成分总重量中优选为1~80重量%。小于1重量%时,有时选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的配合量变得过多,有时它们的粒径只要不是相当地小,就会逐步出现产品的保型性等问题。另一方面,超过80重量%时,有时无法得到口腔内的迅速的溶解曲线、充分的薄膜强度。配合量更优选为10~70重量%。
本发明的口腔内薄膜状基剂中除了上述各物质以外可以根据期望适当含有香料、矫味剂、甜味剂、着色剂、防腐剂、抗氧化剂、稳定化剂、表面活性剂、增塑剂(聚乙二醇(PEG)等)等。本发明的口腔内薄膜状基剂含有上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒作为赋形剂,因此优选不含有以往用作赋形剂的糖或糖醇。但是,在不有损本发明的效果的范围内可以含有糖或糖醇。
本发明的口腔内薄膜状制剂在本发明的口腔内薄膜状基剂中进一步分散或溶解有药物。
上述药物可以分散于本发明的口腔内薄膜状基剂中,也可以溶解于本发明的口腔内薄膜状基剂中。上述药物分散时,上述药物优选不溶于溶解度参数为9.7以上的有机溶剂,为了可以容易地形成药物颗粒,更优选在常温下为固体。
上述药物只要能够口服给药就没有特别限定,例如可以举出:镇静剂、祛痰剂、泻药、抗癌剂、糖尿病药、抗帕金森病药、抗抑郁药、精神稳定剂、痴呆症药、降压剂、高脂血浆药、偏头痛药、骨质疏松治疗药、低血压治疗药、镇咳剂、消化性溃疡用剂、尿频·排尿障碍药、尿失禁药、抗溃疡药、过敏药、5-HT3受体拮抗药(止吐药)等。另外,上述药物没有苦味是适合的,但可以有苦味,可以通过苦味掩盖技术(例如,微囊化、添加苦味遮蔽剂、甜味剂、矫味剂和芳香剂等)而适合使用。
上述药物的配合量根据使用的药物的性质等而不同,在本发明的口腔内薄膜状制剂中所含的固体成分总重量中,优选为0.1~60重量%。超过60重量%时,有时药物的粒径只要不是相当地小,就会逐步出现产品的保型性等问题。
作为本发明的口腔内薄膜状基剂和制剂的厚度,没有特别限定,优选为30~300μm。小于30μm时,从薄膜强度和产品的操作性的观点出发,有成为问题的可能性。另一方面,超过300μm时,口腔内的溶解耗费时间,有不容易溶解的可能性。
作为本发明的口腔内薄膜状基剂和制剂的平面形状,没有特别限定,例如可以举出:长方形、正方形、圆形等任意形状。
本发明的口腔内薄膜状基剂和制剂例如可以通过以下方法制造。
即,首先,将规定量的可食性高分子溶解于溶剂(例如,乙醇、丙醇、丙酮等)。在制剂的情况下,使药物分散或溶解于该溶液,另外,利用粉碎、造粒、分级装置等调整粒径,使所得规定量的选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒均匀地分散,制备分散液。然后,将适当量的该分散液在剥离薄膜上展延干燥形成薄膜,从而可以制造本发明的口腔内薄膜状基剂和制剂。进而,将干燥后的口腔内薄膜状基剂和制剂裁切成期望的大小,根据需要进行密封包装,形成产品。
上述分散液的制备中产生泡时,优选放置一晚、进行真空脱泡。
对于本发明的口腔内薄膜状基剂和制剂的制造时所使用的溶剂,虽然上述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒为不溶性的,但只要上述可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子为可溶性的,就没有特别限定,可以适合使用溶解度参数为9.7以上的有机溶剂。
即,本发明的口腔内薄膜状基剂和制剂优选使用溶解度参数为9.7以上的有机溶剂来制造。
上述溶解度参数为9.7以上的有机溶剂的溶解度参数优选为9.7~20、更优选为9.7~15。溶解度参数超过20时,有选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒根据种类而发生溶解的担心。
作为上述溶解度参数为9.7以上的有机溶剂,具体而言,可以适合使用乙醇、丙醇、丙酮,更优选为乙醇。这些溶解度参数为9.7以上的有机溶剂可以单独使用也可以组合2种以上使用。另外,如果为微量则可以向这些溶解度参数为9.7以上的有机溶剂中加入水(纯化水)。
需要说明的是,将水和溶解度参数为9.7以上的有机溶剂的溶解度参数(SP值)示于表1。
[表1]
溶剂 | 溶解度参数(SP值) |
甲醇 | 14.5~14.8 |
乙醇 | 12.7 |
异丙醇 | 11.5 |
丙二醇 | 14.3 |
二氯甲烷 | 9.7 |
丙酮 | 10 |
水 | 23.4 |
发明的效果
本发明的口腔内薄膜状基剂和制剂具有口腔内的迅速的溶解曲线、充分的薄膜强度,指触时的触感、口腔内的食感、味道等也良好。另外,本发明的口腔内薄膜状基剂和制剂含有选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒,因此与含有糖或糖醇的情况相比,改善伴随着糖分吸湿的触感恶化(粘腻),且对需要限制糖分的人也容易给药。
另外,制造本发明的口腔内薄膜状基剂和制剂时,没有必要使选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒暂时溶解于溶液,可以以颗粒的状态分散、负载,因此可以高效地制造本发明的口腔内薄膜状基剂和制剂,可以控制其粒径、颗粒形态。
附图说明
图1为示出本发明的口腔内薄膜状基剂的实施方式的一例的示意图。
图2为示出粘着持续时间试验的方式的示意图。
附图标记说明
1a 选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒
1b 可食性薄膜
2a 探针
2b 双面胶带
2c 试验片
2d 胶原蛋白薄膜
2e 橡胶
2f 试验台
具体实施方式
根据以下的实施例具体地说明本发明,但本发明不限定于这些实施例。
作为实施例和比较例中使用的氨基酸、二肽或核苷酸微粒,使用粉碎后用32μm、50μm或90μm的筛过筛而得到的微粒。通过激光散射式粒度分布测定装置测定这些微粒的50体积%平均粒径,将其作为平均粒径。表2示出实施例和比较例中使用的氨基酸、二肽或核苷酸微粒的50体积%平均粒径。
[表2]
氨基酸、二肽或核苷酸微粒 | 50体积%平均粒径[μm] |
L-谷氨酸钠微粒 | 15 |
L-天门冬氨酸钠微粒 | 12 |
L-丙氨酸微粒 | 15 |
甘氨酸微粒 | 14 |
L-赖氨酸盐酸盐微粒 | 13 |
L-谷氨酰胺L-赖氨酸微粒 | 20 |
L-谷氨酸L-精氨酸微粒 | 21 |
肌甙酸二钠微粒 | 16 |
鸟苷酸二钠微粒 | 13 |
(实施例1、2)
在乙醇(溶解度参数12.7)60.0重量份中加入HPC(可溶于水和溶解度参数为9.7以上的有机溶剂、分子量约3万、羟基丙氧基的取代度53.4~77.5%)或PVP(可溶于水和溶解度参数为9.7以上的有机溶剂、分子量105万~120万、PVP K-30)40.0重量份,搅拌溶解,制备HPC或PVP的乙醇溶液。
另外,在适量的乙醇中加入佐米曲坦(zolmitriptan)9.0重量份,搅拌溶解,加入预先用32μm的筛过筛的L-谷氨酸钠微粒40.0重量份,进行超声波搅拌。向其中加入HPC或PVP的乙醇溶液117.5重量份和聚乙二醇(PEG400)4.0重量份,搅拌混合、充分脱泡,从而制备分散液。
将该分散液在聚酯剥离薄膜上拉伸干燥,形成厚度约100μm的薄膜,将所得薄膜裁切成3cm2的长方形,得到分散有L-谷氨酸钠微粒的口腔内薄膜状制剂。
(比较例1、2)
向少量的乙醇中加入佐米曲坦9.0重量份进行加热溶解。
向普鲁兰多糖(仅可溶于水)或HPMC(仅可溶于水)47.0重量份中加入纯化水183.3重量份或200.0重量份、聚乙二醇(PEG400)4.0重量份、和预先用32μm的筛过筛的L-谷氨酸钠微粒40.0重量份,搅拌溶解,加入预先制备的佐米曲坦的乙醇溶液,在45℃下加热的同时进行搅拌溶解、充分脱泡,从而制备溶液。
将该溶液在聚酯剥离薄膜上拉伸干燥,形成厚度约100μm的薄膜,将所得薄膜裁切成3cm2的长方形,得到溶解有L-谷氨酸钠的口腔内薄膜状制剂。
[表3]
(实施例3~10)
变更氨基酸、二肽或核苷酸微粒的种类,使其为表4所示的组成,除此之外,利用与实施例1同样的步骤,得到分散有氨基酸、二肽或核苷酸微粒的口腔内薄膜状制剂。
[表4]
(实施例11~16)
变更药物的种类,使其为表5所示的组成,除此之外,利用与实施例1同样的步骤,得到分散有L-谷氨酸钠微粒的口腔内薄膜状制剂。
[表5]
(比较例3)
不使用L-谷氨酸钠微粒,使其为表6所示的组成,除此之外,利用与实施例1同样的步骤,得到不含氨基酸、二肽或核苷酸的口腔内薄膜状制剂。
(比较例4~13)
向纯化水65.0重量份中加入HPC(可溶于水和溶解度参数为9.7以上的有机溶剂、分子量约3万、羟基丙氧基的取代度53.4~77.5%)35.0重量份,搅拌溶解,制备HPC的纯化水溶液。
另外,向极少量的乙醇中加入佐米曲坦9.0重量份,搅拌溶解,加入预先用32μm的筛过筛的氨基酸、二肽或核苷酸微粒40.0重量份,进行超声波搅拌。向其中加入HPC的纯化水溶液134.3重量份和聚乙二醇(PEG400)4.0重量份,搅拌混合、充分脱泡,从而制备溶液。
将该溶液在聚酯剥离薄膜上拉伸干燥,形成厚度约100μm的薄膜,之后自聚酯剥离薄膜剥离,想要得到口腔内薄膜状制剂,但比较例4、6、8~13中,口腔内薄膜状制剂较脆且过度柔软,因此无法得到口腔内薄膜状制剂。比较例5、7中,将所得厚度约100μm的薄膜裁切成3cm2的长方形,得到溶解有氨基酸、二肽或核苷酸的口腔内薄膜状制剂。
[表6]
(比较例14~22)
使用糖或糖醇微粒代替L-谷氨酸钠微粒,使其为表7所示的组成,除此之外,利用与实施例1同样的步骤,得到分散有糖或糖醇微粒的口腔内薄膜状制剂。
需要说明的是,通过激光散射式粒度分布测定装置测定糖或糖醇微粒的50体积%平均粒径,结果D-甘露糖醇微粒A为17μm、D-甘露糖醇微粒B为15μm、D-甘露糖醇微粒C为16μm、D-甘露糖醇微粒D为14μm、麦芽糖微粒为20μm、葡萄糖微粒为19μm。
[表7]
[试验方法]
对于实施例和比较例中得到的口腔内薄膜状制剂制造时的剥离性、口腔内的溶解曲线、薄膜强度、指触时的触感、口腔内的食感、味道、对糖分限制的有效性,通过以下的试验方法进行评价。
(1)剥离性试验
对制造口腔内薄膜状制剂时自聚酯剥离薄膜剥离的剥离性进行评价。评价基准如下所述。
4:能够容易地剥离
3:能够剥离
2:设法能够剥离
1:设法能够剥离但破裂
0:完全无法剥离
(2)口腔内崩解性试验
通过以下的口腔内崩解性试验进行口腔内的溶解曲线的评价。
向1000mL的玻璃培养皿中加入pH6.8磷酸盐缓冲液900mL,使不锈钢制筛(Φmm)上下倒置并沉入其中,用搅拌器搅拌(300rpm)。对该溶液的温度使用恒温水循环装置在37±2℃下管理,使试验片(3cm2)沉入其中,同时从上方以3cm2×3cm2的不锈钢制金属网(网孔尺寸5mm)为砝码使其载置。根据试验片沉入的时间,以目视确认至试验片崩解结束为止的时间,用秒表测定。
对各试验片重复测定3次,将其平均值作为口腔内崩解时间。将该口腔内崩解时间应用于以下评价基准进行评分。(1)剥离性试验中评价为完全无法剥离的情况,评价为0。
4:0~10秒
3:10~15秒
2:15~20秒
1:20秒以上
(3)拉伸强度试验和刚软度试验
通过以下的拉伸强度试验和刚软度试验进行薄膜强度的评价。
(3-1)拉伸强度试验
使切断成12mm×50mm的试验片在干燥器中充分干燥,然后使用小型桌上拉伸试验机(株式会社岛津制作所、EZ TEST-100M),基于“JIS K7127塑料薄膜和片的拉伸试验方法”进行试验。作为试验速度,使用每分钟60mm。试验片基本未见拉伸,因此求出通过测定得到的拉伸屈服强度作为拉伸强度。
对于各试验片重复测定3次,将其平均值作为拉伸强度。将该拉伸强度应用于以下评价基准进行得分化。(1)剥离性试验中评价为完全无法剥离的情况,评价为0。
4:10~20N
3:5~10N
2:2~5N
1:0~2N
(3-2)刚软度试验
本试验法基于“JIS L1096一般织物试验法、8.19刚软性、8.19.1A法(45°悬臂法)”的试验方法进行。
取20mm×150mm的试验片5张,使试验片的短边按照刻度的基线地将一端置于具有45°斜面的表面光滑的水平台上。接着,通过适当的方法,使试验片沿斜面的方向缓慢滑动,根据刻度读出试验片的一端的中央点与斜面接触时的另一端的位置。
刚软度用试验片移动时的长度(mm)表示,将5张试验片的表面背面、前后分别相反地进行测定,将其平均值作为刚软度。评价基准考虑以不含氨基酸、二肽或核苷酸的口腔内薄膜状制剂(比较例3)的刚软度约60mm作为基准,如下所述进行设定。(1)剥离性试验中评价为完全无法剥离的情况,评价为0。
4:基准值±10mm
3:基准值±20mm
2:基准值±30mm
1:基准值±40mm以上
(4)粘着持续时间试验和官能试验(触感)
通过以下的粘着持续时间试验和官能试验(触感)进行指触时的触感和口腔内的食感的评价。
(4-1)粘着持续时间试验
使用流变计(SUN SCIENTIFIC、CR-2000),在图2所示的环境下进行试验。
用双面胶带2b将Φ12mm的试验片2c粘贴在Φ12mm的探针2a上。另外,使橡胶2e载置于试验台2f上,在其上设置用水浸渍了的胶原蛋白薄膜2d。在试验片上添加200μL的纯化水,使粘贴有该试验片2c的探针2a下降,使之与胶原蛋白薄膜2d接触,之后使其上升。此时,通过记录纸使用游标卡尺测定探针2a从胶原蛋白薄膜2d剥离时得到的初始粘着后的粘着持续时间。评价基准如下所述。(1)剥离性试验中评价为完全无法剥离的情况,每个剥离薄膜地切断,将剥离薄膜侧用双面胶带粘贴于探针,同样地进行测定。
4:0~2mm
3:2~3mm
2:3~4mm
1:4mm以上
(4-2)官能试验(触感)
用手指以描绘圆的方式接触口腔内薄膜状制剂5秒,评价表面是否有粘腻的不适感。评价基准如下所述。
4:没有粘腻
3:不会担心的程度的粘腻感
2:粘腻感中感觉到不适感
1:相当粘腻,手指上残留薄膜
(5)官能试验(味道)
在口腔内保持口腔内薄膜状制剂至溶解为止,评价对味道的影响。评价基准如下所述。
4:呈现矫味
3:苦味或不适感没有或少
2:强烈感到苦味或不适感
1:苦味或不适感强烈,在口腔内的保持困难
(6)对糖分限制的有效性
根据糖分的含有状态评价口腔内薄膜状制剂的对糖分限制的有效性。评价基准如下所述。
4:完全不含糖分
3:含有三糖以上的糖分
2:含有作为二糖的糖分
1:含有作为单糖的糖分
[表8]
[表9]
比较例1、2、4~13中,作为制造口腔内薄膜状制剂时的溶剂主要使用纯化水,因此氨基酸、二肽或核苷酸微粒会溶解,无法得到分散有氨基酸、二肽或核苷酸微粒的口腔内薄膜状制剂。这样的口腔内薄膜状制剂无法得到口腔内的迅速的溶解曲线、充分的薄膜强度,指触时的触感和口腔内的食感也恶化(表8、9)。
需要说明的是,为了在氨基酸、二肽或核苷酸微粒溶解的情况下也不产生这样的问题,可以考虑减少氨基酸、二肽或核苷酸微粒的配合量。然而,利用该方法可食性高分子的配合量相对地增加,结果,有产生同样的问题的可能性。
产业上的可利用性
本发明的口腔内薄膜状基剂和制剂具有口腔内的迅速的溶解曲线、充分的薄膜强度,指触时的触感、口腔内的食感、味道等也良好。另外,本发明的口腔内薄膜状基剂和制剂含有选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒,因此与含有糖或糖醇的情况相比,改善伴随着糖分吸湿的触感恶化(粘腻),且对需要限制糖分的人也容易给药。
另外,制造本发明的口腔内薄膜状基剂和制剂时,无需将选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒暂时溶解于溶液,可以以颗粒的状态分散、负载,因此可以高效地制造本发明的口腔内薄膜状基剂和制剂,可以控制其粒径、颗粒形态。
Claims (9)
1.一种口腔内薄膜状基剂,其特征在于,其为含有可食性高分子和选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的口腔内薄膜状基剂,所述可食性高分子可溶于水和溶解度参数为9.7以上的有机溶剂,所述可食性高分子为聚乙烯吡咯烷酮和/或羟丙基纤维素,
所述选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒以颗粒的状态分散于所述口腔内薄膜状基剂中,
所述氨基酸选自由甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、丝氨酸、苏氨酸、半胱氨酸、蛋氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、苯丙氨酸、酪氨酸、色氨酸、羟基脯氨酸、它们的药学上允许的盐、天门冬氨酸的药学上允许的盐以及谷氨酸的药学上允许的盐组成的组中的至少1种氨基酸,
所述口腔内薄膜状基剂不含有糖和糖醇。
2.根据权利要求1所述的口腔内薄膜状基剂,其中,选自由氨基酸、二肽和核苷酸组成的组中的至少1种的颗粒的平均粒径为0.1~60μm。
3.根据权利要求1或2所述的口腔内薄膜状基剂,其中,可溶于水和溶解度参数为9.7以上的有机溶剂的可食性高分子在常温下为固体。
4.根据权利要求3所述的口腔内薄膜状基剂,其中,聚乙烯吡咯烷酮的重均分子量为2500~300万。
5.根据权利要求3所述的口腔内薄膜状基剂,其中,羟丙基纤维素的重均分子量为1万~115万。
6.根据权利要求3所述的口腔内薄膜状基剂,其中,羟丙基纤维素的羟基丙氧基的取代度为50~100%。
7.根据权利要求1、2、4、5或6所述的口腔内薄膜状基剂,其是使用溶解度参数为9.7以上的有机溶剂而制造的。
8.根据权利要求3所述的口腔内薄膜状基剂,其是使用溶解度参数为9.7以上的有机溶剂而制造的。
9.一种口腔内薄膜状制剂,其特征在于,在权利要求1、2、3、4、5、6、7或8所述的口腔内薄膜状基剂中进一步分散或溶解有药物。
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EP1522225A1 (en) * | 2003-10-10 | 2005-04-13 | ORB Co., Ltd. | Bilayer edible sheet |
WO2010002418A2 (en) * | 2008-07-01 | 2010-01-07 | The Johns Hopkins University | Quick-dissolving oral thin film for targeted delivery of therapeutic agents |
EP2462928A1 (en) * | 2010-12-10 | 2012-06-13 | Nitto Denko Corporation | Sheet-form preparation and method for producing the same |
CN103202822A (zh) * | 2012-01-11 | 2013-07-17 | 日东电工株式会社 | 口腔内薄膜状基剂及制剂 |
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