CN115666571A - 含有阿扑吗啡的经皮吸收型制剂 - Google Patents
含有阿扑吗啡的经皮吸收型制剂 Download PDFInfo
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- CN115666571A CN115666571A CN202180036299.4A CN202180036299A CN115666571A CN 115666571 A CN115666571 A CN 115666571A CN 202180036299 A CN202180036299 A CN 202180036299A CN 115666571 A CN115666571 A CN 115666571A
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- apomorphine
- percutaneous absorption
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Images
Classifications
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Abstract
本发明的课题在于提供一种使阿扑吗啡盐酸盐高浓度地溶解,由此能够以短时间吸收对治疗而言为足量的阿扑吗啡,并且能够持续地给药的经皮吸收型制剂。作为本发明,例如可举出阿扑吗啡或其盐、碳原子数6以下的多元醇和/或低分子量聚乙二醇、以及包含碳酸丙烯酯的经皮吸收型制剂。根据本发明,可以制备高浓度的含有阿扑吗啡的液体,能够使足量的阿扑吗啡在短时间内从皮肤吸收到体内,并且能够持续地给药。
Description
技术领域
(相关申请的交叉引用)
本申请主张在2020年5月20日向日本专利局申请的日本申请号第2020-87793号的权益。该日本申请的申请文件(说明书、权利要求书、附图及说明书摘要)的整体如本说明书中说明的那样,出于整体的目的,通过参照而援引于本说明书。
本发明涉及一种包含阿扑吗啡或其盐作为活性成分的经皮吸收型制剂。特别是涉及一种以高浓度包含阿扑吗啡或其盐,能够将对治疗而言为足量的阿扑吗啡进行经皮给药的经皮吸收型组合物。
背景技术
阿扑吗啡是多巴胺D1样和D2样受体激动剂,对纹状体刺激该受容体而对帕金森病的关期(OFF)症状显示出快速的改善效果。特别是作为由L-DOPA药效不足带来的显示出关期症状时的抢救药品,临床上可使用皮下注射等。例如提出了包含1)作为活性成分的阿扑吗啡、2)水溶性的共溶剂、3)抗氧化剂、以及4)水,且pH超过4的用作注射剂的医药组合物(专利文献1)。
然而,对于大多数的患者而言,不仅在白天,在给药困难的夜间、早晨也出现由L-DOPA的药效不足导致的关期症状,干扰睡眠、起床时的活动。
因此,为了改善在夜间、早晨产生的关期症状,需要一种经皮吸收型制剂,其能够在就寝前贴附,并且在就寝后到早晨为止持续地给予阿扑吗啡。
用于抢救夜间、早晨的关期症状的经皮吸收型制剂中,需要阿扑吗啡的快速且持续的皮肤透过性。特别是为了实现贴附后的快速的皮肤透过性,基本是在制剂中高浓度地溶解药物。然而,目前未开发出以足够的浓度使阿扑吗啡溶解的方法。
现有技术文献
专利文献
专利文献1:日本特开2017-81947号公报
发明内容
本发明的课题在于提供一种使阿扑吗啡或其盐高浓度地溶解,由此以短时间吸收对治疗而言为足量的阿扑吗啡,并且能够持续地给药的经皮吸收型制剂。
本发明人等为了解决上述课题重复进行了深入的研究,其结果发现通过组合特定的多元醇和碳酸丙烯酯,由此能够制备高浓度的阿扑吗啡或其盐的含有液。并且,能够成功地使用该高浓度的阿扑吗啡或其盐的含有液来制备能够经皮给予足量的阿扑吗啡的制剂,从而完成了本发明。
作为本发明,例如可举出下述的方式。
[1]一种经皮吸收型制剂,其包含阿扑吗啡或其盐、碳原子数6以下的多元醇和/或低分子量聚乙二醇、以及碳酸丙烯酯。
[2]根据上述[1]所述的经皮吸收型制剂,其中,包含2重量%以上的上述阿扑吗啡或其盐。
[3]根据上述[1]所述的经皮吸收型制剂,其中,包含4重量%以上的上述阿扑吗啡或其盐。
[4]根据上述[1]~[3]中任一项所述的经皮吸收型制剂,其中,在5重量%~40重量%的范围内包含上述碳酸丙烯酯。
[5]根据上述[1]~[4]中任一项所述的经皮吸收型制剂,其中,将上述碳酸丙烯酯的重量设为1时,上述多元醇与低分子量聚乙二醇的合计的重量在1~10的范围内。
[6]根据上述[5]所述的经皮吸收型制剂,其中,上述多元醇为选自丙二醇、甘油以及1,3-丁二醇中的1种以上。
[7]根据上述[1]~[6]中任一项所述的经皮吸收型制剂,其进一步包含抗氧化剂。
[8]根据上述[7]所述的经皮吸收型制剂,其中,上述抗氧化剂为焦亚硫酸钠。
[9]根据上述[1]~[8]中任一项所述的经皮吸收型制剂,其进一步包含有机酸或者水。
[10]根据上述[9]所述的经皮吸收型制剂,其中,上述有机酸为异硬脂酸或者油酸。
[11]根据上述[1]~[10]中任一项所述的经皮吸收型制剂,其进一步包含乳化剂。
[12]根据上述[1]~[11]中任一项所述的经皮吸收型制剂,其中,剂型为液剂、凝胶剂或者软膏剂。
[13]一种贴剂,是使上述[12]所述的经皮吸收型制剂含浸于载体中而成的。
[14]根据上述[1]~[12]中任一项所述的经皮吸收型制剂或者上述[13]所述的贴剂,其用于改善帕金森病的关期症状。
根据本发明,能够提供制备含有高浓度的阿扑吗啡的液体,以短时间使足够量的阿扑吗啡从皮肤吸收到体内,并且可持续地给药的经皮吸收型制剂。
附图说明
图1中显示了针对实施例1~3的制剂,进行使用了弗朗兹细胞(Franz cell)的阿扑吗啡盐酸盐的体内皮肤透过性试验的结果。纵轴表示透过量(μg/cm2),横轴表示经过时间(小时)。图内的数值(1.5、3以及5)表示阿扑吗啡盐酸盐在制剂中的含量(重量%)。
图2中显示了针对实施例4的制剂,进行了使用弗朗兹细胞的阿扑吗啡盐酸盐的体内皮肤透过性试验的结果。纵轴表示透过量(μg/cm2),横轴表示经过时间(小时)。图内的数值(10)表示阿扑吗啡盐酸盐在制剂中的含量(重量%)。
具体实施方式
对于本发明的经皮吸收型制剂而言,作为一个实施方式,包含阿扑吗啡或其盐、碳原子数6以下的多元醇和/或低分子量聚乙二醇、以及碳酸丙烯酯。包含该组合的液体能够使阿扑吗啡或其盐以约5重量%以上、或者约10重量%的高浓度溶解。即使在向该高浓度的溶液进一步加入其它成分而制备的亲水性制剂中,也能够将阿扑吗啡或其盐的浓度维持在足够的高浓度。如此能够得到含有具有快速持续的皮肤透过性的阿扑吗啡或其盐的经皮吸收型制剂。
对于本发明的经皮吸收型制剂而言,包含阿扑吗啡或其盐作为有效成分。本发明的经皮吸收型制剂的阿扑吗啡或其盐的含量例如可以为约2重量%以上、约3重量%以上、或者约4重量%以上。阿扑吗啡或其盐的含量的上限例如可以为约15重量%、约12重量%、或者约10重量%。在一个实施方式中,本发明的经皮吸收型制剂不包含阿扑吗啡或其盐以外的有效成分。
在一个实施方式中,阿扑吗啡或其盐例如可举出阿扑吗啡游离体、阿扑吗啡与有机酸的盐、或者阿扑吗啡与无机酸的盐等。也可以为阿扑吗啡盐酸盐。另外,阿扑吗啡或其盐可以为阿扑吗啡游离体或阿扑吗啡的盐的水合物、溶剂合物。
在一个实施方式中,本发明的经皮吸收型制剂可以单独包含碳原子数6以下的多元醇和低分子量聚乙二醇中的任一者,或包含两者。
对于碳原子数6以下的多元醇与低分子量聚乙二醇的量,只要是溶解了充分量的阿扑吗啡或其盐,就没有特别限定,以合计来计算,例如可以为经皮吸收型制剂的约20重量%以上、约30重量%以上、约40重量%以上、约50重量%以上、或者约60重量%以上,可以为约90重量%以下、约85重量%以下、或者约80重量%以下的范围。从皮肤透过性的观点考虑,碳原子数6以下的多元醇与低分子量聚乙二醇的量越少越好,从皮肤刺激性的观点考虑,越多越好。
这里,碳原子数6以下的多元醇(以下称为“该多元醇”)例如为具有2个~8个或是6个左右的羟基(OH)的醇,只要是这样的多元醇,则没有特别限制。作为该多元醇,可举出二元醇、三元醇。该多元醇的碳原子数例如可以为5以下或者3以下。具体而言,作为该多元醇,例如可举出丙二醇、1,3-丙二醇、1,3-丁二醇、1,4-丁二醇、戊二醇、己二醇、甘油。在它们之中,优选为丙二醇、1,3-丁二醇、甘油。本发明的经皮吸收型制剂中,可以包含这些制剂中的1种,也可以包含任意的2种以上。
该多元醇为甘油(99%以上)的情况下,该含量例如可以为经皮吸收型制剂的约1重量%~约50重量%、约5重量%~约40重量%、或者约10重量%~约30重量%的各范围内。在该多元醇为1,3-丁二醇的情况下,该含量例如可以为经皮吸收型制剂的约0.5重量%~约30重量%、或者约1重量%~约25重量%的各范围内。在该多元醇为丙二醇的情况下,该含量例如可以为经皮吸收型制剂的约1重量%~约60重量%、或者约3重量%~约55重量%的各范围内。
作为低分子量聚乙二醇,例如可举出分子量为约200~约600的聚乙二醇,可以使用分子量为约200~约300的聚乙二醇。
碳酸丙烯酯的量例如可以为经皮吸收型制剂的约1重量%~约40重量%、约2重量%~约30重量%、约5重量%~约25重量%的各范围内。
对于该多元醇和/或低分子量聚乙二醇与碳酸丙烯酯的重量比,例如在将碳酸丙烯酯设为1时,可以将该多元醇与低分子量聚乙二醇的合计设在约1~约10的范围内、约2~约9、或者约3~约8的范围内。
在一个实施方式中,本发明的经皮吸收型制剂可以包含抗氧化剂。通过加入抗氧化剂,由此阿扑吗啡或其盐可以不着色地、稳定地保存。作为该抗氧化剂,可例示生育酚乙酸酯、依地酸钠、异抗坏血酸、1,3-丁二醇、二丁基羟基甲苯、抗坏血酸、没食子酸丙酯、亚硫酸钠、焦亚硫酸钠等。
该抗氧化剂的含量只要可得到阿扑吗啡或其盐的稳定性就没有特别限定,例如可以为约0.01重量%~约0.5重量%、约0.02重量%~约0.3重量%、或者约0.05重量%~约0.2重量%的各范围内。
在一个实施方式中,本发明的经皮吸收型制剂可以包含有机酸。通过加入有机酸,由此提高阿扑吗啡或其盐的皮肤透过性。该有机酸的种类没有特别限定,例如可举出油酸、异硬脂酸、癸酸、山梨酸、乙酰丙酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸。
该有机酸的含量只要可得到足够的阿扑吗啡或其盐的皮肤透过性就没有特别限定,可以设为经皮吸收型制剂的约0.1重量%~约5重量%、约0.2重量%~约4重量%、或者约0.3重量%~约3重量%的各范围内。
在一个实施方式中,本发明的经皮吸收型制剂可以包含水。由此,能够降低皮肤刺激性。该水的配合量例如可以在经皮吸收型制剂的约0.5重量%~约30重量%、约1重量%~约20重量%、或者约2重量%~约10重量%的各范围内。
在一个实施方式中,本发明的经皮吸收型制剂可以包含乳化剂。通过加入乳化剂,由此在经皮吸收型制剂包含水的情况下,可以使相对于碳酸丙烯酯、有机酸等水的溶解性低的物质在液剂中稳定地分散。作为该乳化剂,例如可举出阿拉伯胶、明胶、黄芪胶、卵磷脂(磷脂酰胆碱)、胆固醇等天然乳化剂;肥皂、烷基硫酸钠等阴离子性表面活性剂;单油酰基聚氧乙烯山梨糖醇酐等聚氧乙烯山梨糖醇酐脂肪酸酯;聚氧乙烯蓖麻油衍生物、聚氧乙烯固化蓖麻油、甘油单硬脂酸酯、山梨糖醇酐单油酸酯等甘油脂肪酸酯;山梨糖醇酐单硬脂酸酯、山梨糖醇酐倍半酸酯等山梨糖醇酐脂肪酸酯;聚氧乙烯十六烷基醚等聚氧乙烯高级醇醚;聚氧乙烯烷基苯酚、聚氧乙烯氧基丙烯共聚物(例如Pluronic(注册商标)等)等非离子性表面活性剂;十六烷基三甲基氯化铵等阳离子性表面活性剂;两性表面活性剂等。
在一个实施方式中,本发明的经皮吸收型制剂可以包含烷醇胺。作为烷醇胺,例如可举出碳原子数2~12的伯烷醇胺、仲烷醇胺、或者叔烷醇胺,具体而言,例如可举出二乙醇胺、三乙醇胺、二异丙醇胺、三异丙醇胺。该烷醇胺的含量例如可以选自经皮吸收型制剂的约0.005重量%~约0.4重量%、或者约0.01重量%~约0.3重量%的各范围内。
本发明的经皮吸收型制剂也可以根据需要包含用于外用剂或者化妆品的各种添加剂。这样的添加剂中包含香料、抗氧化剂、防腐剂、着色剂、缓冲剂、pH调整剂、紫外线吸收剂、抗菌剂等。作为防腐剂,可例示山梨酸、牛磺酸等。作为pH调节剂,可例示柠檬酸、乙酸、酒石酸等有机酸;磷酸、盐酸等无机酸。
本发明的经皮吸收型制剂的最终的剂型没有特别限定,作为该剂型,例如可举出液剂、凝胶剂、软膏剂、使这些剂型中的至少一种含浸于载体而成的剂型,本发明的经皮吸收型制剂被制剂化成使药物从皮肤吸收的各种外用制剂,通过涂布、喷雾应用于皮肤。另外,本发明的经皮吸收型制剂为例如液剂、凝胶剂的情况下,也可以通过将含浸有该制剂的载体(无纺布、发泡基质等)贴附于皮肤来应用,根据该方法,容易调节用量,操作性良好。
本发明的经皮吸收型制剂可以作为以阿扑吗啡或其盐作为有效成分的所谓的医药品来使用。由于吸收早且可得到持续的效果,因此例如可作为帕金森病的关期症状改善剂使用。
实施例
以下,举出实施例更详细地说明本发明,但本发明并不限于实施例。
1.阿扑吗啡盐酸盐的溶解性的研究
对阿扑吗啡盐酸盐相对于各种溶剂的溶解性进行了研究。将结果示于表1。
在水、1,3-丁二醇、聚乙二醇、丙二醇、甘油以及碳酸丙烯酯中任一者单独使用的情况下,阿扑吗啡盐酸盐的溶解性为3重量%以下。特别是对碳酸丙烯酯的溶解性极低,为0.25%。
另一方面,如果将低分子量聚乙二醇和碳酸丙烯酯组合,则能够制备8重量%的阿扑吗啡盐酸盐溶液。并且在丙二醇与碳酸丙烯酯的组合中,如果使用以碳酸丙烯酯的5倍以上的重量与丙二醇混合的溶剂,则能够制备10重量%的阿扑吗啡盐酸盐溶液。
另外,同样地,即使是使用将1,3-丁二醇和浓甘油(99%)分别以碳酸丙烯酯和5:1的重量比混合的溶剂,也能够制备10重量%的阿扑吗啡盐酸盐。
[表1]
○:溶解
×:残留有结晶
-:未实施
BG:1,3-丁二醇
PEG:聚乙二醇
PG:丙二醇
GL:浓甘油
CP:碳酸丙烯酯
2.阿扑吗啡盐酸盐液剂的制备
根据上述1.的研究,制备以约3.7:1~约3.5:1(该多元醇:碳酸丙烯酯)的重量比包含该多元醇(丙二醇、浓甘油以及1,3-丁二醇)和碳酸丙烯酯的、阿扑吗啡盐酸盐的1.5%液剂(实施例1)、3%液剂(实施例2)、以及5%液剂(实施例3)。另外,制备以约7.9:1(该混合物:碳酸丙烯酯)的重量比包含该多元醇与低分子量聚乙二醇的混合物和碳酸丙烯酯的阿扑吗啡盐酸盐的10%液剂(实施例4)。将各组成(重量%)示于表2。在任一实施例中,阿扑吗啡盐酸盐均完全溶解。
[表2]
[皮肤透过性试验]
对于使实施例1~3的液剂(本发明的经皮吸收型制剂)含浸于载体的制剂(贴剂),进行了使用弗朗兹细胞的体内皮肤透过性试验。用于试验的皮肤为5周龄无毛鼠(雄)腹部摘出的皮肤。将试验开始后9小时的累积皮肤透过量(μg/cm2)示于图1。
虽然任一液剂均示出了皮肤透过量的持续的增加,但是,仍有如下启示:对于包含3重量%以上的阿扑吗啡盐酸盐的液剂,其经皮吸收起效快,短时间内就可得到药效。
因此,有如下启示:为了得到给药后早期的皮肤透过性,期望将制剂中的阿扑吗啡盐酸盐浓度设为3重量%以上。
对于使实施例4的液剂(本发明的经皮吸收型制剂)含浸于载体的制剂(贴剂),进行使用弗朗兹细胞的体内皮肤透过性试验。用于试验的皮肤为人类皮肤。将试验开始后9小时的累积皮肤透过量(μg/cm2)示于图2。
有如下启示:包含10重量%的阿扑吗啡盐酸盐的液剂的经皮吸收起效更快,在人类皮肤中,也可以在短时间内得到药效。
[皮肤刺激性试验]
将实施例3中得到的液剂(本发明的经皮吸收型制剂)含浸于载体的制剂(贴剂)并贴附于兔子皮肤表面24小时,基于Draize的判定基准评价剥离后的皮肤刺激性。其结果可知,皮肤刺激指数P.I.I为0.1,为皮肤刺激性足够低的制剂。
[稳定性试验]
将实施例3中得到的液剂(本发明的经皮吸收型制剂)含浸于载体的制剂(贴剂)密封填充于铝层压容器后,在25℃下恒温槽内保存6个月,并将保存后的结果示于表3。已知阿扑吗啡盐酸盐不稳定且容易变色,但是,可以确认本发明的经皮吸收型制剂或贴剂是稳定的。
[表3]
Claims (14)
1.一种经皮吸收型制剂,包含:
阿扑吗啡或其盐、
碳原子数6以下的多元醇和/或低分子量聚乙二醇、以及
碳酸丙烯酯。
2.根据权利要求1所述的经皮吸收型制剂,其中,包含2重量%以上的所述阿扑吗啡或其盐。
3.根据权利要求1所述的经皮吸收型制剂,其中,包含4重量%以上的所述阿扑吗啡或其盐。
4.根据权利要求1~3中任一项所述的经皮吸收型制剂,其中,在5重量%~40重量%的范围内包含所述碳酸丙烯酯。
5.根据权利要求1~4中任一项所述的经皮吸收型制剂,其中,将所述碳酸丙烯酯的重量设为1时,所述多元醇与低分子量聚乙二醇的合计的重量在1~10的范围内。
6.根据权利要求5所述的经皮吸收型制剂,其中,所述多元醇为选自丙二醇、甘油以及1,3-丁二醇中的1种以上。
7.根据权利要求1~6中任一项所述的经皮吸收型制剂,其进一步包含抗氧化剂。
8.根据权利要求7所述的经皮吸收型制剂,其中,所述抗氧化剂为焦亚硫酸钠。
9.根据权利要求1~8中任一项所述的经皮吸收型制剂,其进一步包含有机酸或水。
10.根据权利要求9所述的经皮吸收型制剂,其中,所述有机酸为异硬脂酸或者油酸。
11.根据权利要求1~10中任一项所述的经皮吸收型制剂,其进一步包含乳化剂。
12.根据权利要求1~11中任一项所述的经皮吸收型制剂,其中,剂型为液剂、凝胶剂或者软膏剂。
13.一种贴剂,是使权利要求12所述的经皮吸收型制剂含浸于载体而成的。
14.根据权利要求1~12中任一项所述的经皮吸收型制剂或权利要求13所述的贴剂,其用于改善帕金森病的关期症状。
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WO1996019956A1 (en) * | 1994-12-23 | 1996-07-04 | Pentech Pharmaceuticals, Inc. | Transdermal administration of apomorphine |
JP2002087954A (ja) * | 2000-09-12 | 2002-03-27 | Mikasa Seiyaku Co Ltd | 経皮吸収型外用貼付剤 |
JP2011511088A (ja) * | 2008-02-08 | 2011-04-07 | キューピーエス リミテッド ライアビリティ カンパニー | 薬物制御送達用の非ポリマー組成物 |
JP2013213055A (ja) * | 2002-07-18 | 2013-10-17 | Helix Biopharma Corp | 癌細胞増殖を阻害するためのウレアーゼの使用 |
JP2015151380A (ja) * | 2014-02-18 | 2015-08-24 | 久光製薬株式会社 | 貼付剤 |
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EP2545905A1 (en) | 2011-07-11 | 2013-01-16 | Britannia Pharmaceuticals Limited | A new therapeutical composition containing apomorphine as active ingredient |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO1996019956A1 (en) * | 1994-12-23 | 1996-07-04 | Pentech Pharmaceuticals, Inc. | Transdermal administration of apomorphine |
JP2002087954A (ja) * | 2000-09-12 | 2002-03-27 | Mikasa Seiyaku Co Ltd | 経皮吸収型外用貼付剤 |
JP2013213055A (ja) * | 2002-07-18 | 2013-10-17 | Helix Biopharma Corp | 癌細胞増殖を阻害するためのウレアーゼの使用 |
JP2011511088A (ja) * | 2008-02-08 | 2011-04-07 | キューピーエス リミテッド ライアビリティ カンパニー | 薬物制御送達用の非ポリマー組成物 |
JP2015151380A (ja) * | 2014-02-18 | 2015-08-24 | 久光製薬株式会社 | 貼付剤 |
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