CN113874011A - 外用制剂 - Google Patents
外用制剂 Download PDFInfo
- Publication number
- CN113874011A CN113874011A CN202080039407.9A CN202080039407A CN113874011A CN 113874011 A CN113874011 A CN 113874011A CN 202080039407 A CN202080039407 A CN 202080039407A CN 113874011 A CN113874011 A CN 113874011A
- Authority
- CN
- China
- Prior art keywords
- acid
- external preparation
- dexmedetomidine
- component
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 64
- 229960004253 dexmedetomidine Drugs 0.000 claims abstract description 49
- -1 fatty acid ester Chemical class 0.000 claims abstract description 44
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- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 19
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- 239000000194 fatty acid Substances 0.000 claims abstract description 15
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- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 6
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 claims abstract 4
- 239000002253 acid Substances 0.000 claims description 7
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明提供一种可在制剂中抑制右美托咪定的结晶析出且经皮吸收性良好的含右美托咪定的非水系外用制剂。一种非水系外用制剂，其含有(A)右美托咪定或其盐、(B)碳原子数10～12的脂肪族醇、(C)丙二醇单碳原子数6～16的脂肪酸酯、(D)有机酸和(E)有机酸盐。
Description
技术领域
本发明涉及一种含有作为镇静剂有用的右美托咪定或其盐的非水系外用制剂。
背景技术
右美托咪定或其盐是α2肾上腺素受体的激动剂，具有镇静作用、镇痛作用、交感神经抑制作用，被用作镇静剂。目前在日本用于重症监护室人工呼吸期间和退出后的镇静，但在其他国家被广泛用作镇静剂和止痛剂。作为该右美托咪定的给药方式，仅确认了静脉内给药。
作为右美托咪定的给药方式，研究了多种经皮吸收制剂。例如，报告有：具有衬里层、固定粘接剂层、多孔性中间层、接触粘接层和剥离衬垫的非水系贴剂(专利文献1)；储库型贴剂(专利文献2)；使用环糊精衍生物的贴剂(专利文献3)；以与羧酸的盐的形式配合有右美托咪定的贴剂(专利文献4)；含有右美托咪定或其盐与水溶性高分子的含水型贴剂(专利文献5)；包含右美托咪定与感压粘接剂的经皮输送装置(专利文献6)。
现有技术文献
专利文献
专利文献1：日本专利第3043064号公报
专利文献2：日本专利第3011459号公报
专利文献3：日本专利第3734267号公报
专利文献4：日本专利第3483881号公报
专利文献5：国际公开第2015/093503号手册
专利文献6：日本专利特表2016-532642号公报
发明内容
发明所要解决的技术问题
然而，现有的含右美托咪定的外用制剂为了获得高的经皮吸收性而使用复杂的制剂构成或释放机制，或者将右美托咪定制成特殊的盐。另外，在专利文献5中，由于是含水型贴剂，所以粘接性存在限度。另外，在非水系的外用制剂中，存在右美托咪定的结晶会在制剂中析出的问题。
因此，本发明的课题在于提供一种可在制剂中抑制右美托咪定的结晶析出且经皮吸收性良好的含右美托咪定的非水系外用制剂。
用于解决技术问题的技术方案
因此，本发明的发明人为了获得在右美托咪定的非水系外用制剂中抑制右美托咪定的结晶析出且经皮吸收性良好的制剂而进行了各种研究，结果发现，通过在含有右美托咪定的非水系基剂中配合碳原子数10～12的脂肪族醇、丙二醇单碳原子数6～16的脂肪酸酯、有机酸和有机酸盐这四种，能够实现右美托咪定的结晶析出抑制与良好的经皮吸收性，从而完成了本发明。
即，本发明提供以下的[1]～[3]。
[1]一种非水系外用制剂，其含有(A)右美托咪定或其盐、(B)碳原子数10～12的脂肪族醇、(C)丙二醇单碳原子数6～16的脂肪酸酯、(D)有机酸和(E)有机酸盐。
[2]如[1]所述的外用制剂，其中，非水系外用制剂为软膏剂或非水系贴剂。
[3]如[1]或[2]所述的外用制剂，其中，非水系外用制剂为非水系贴剂。
发明效果
本发明的外用制剂可抑制制剂中的右美托咪定的结晶析出，且经皮吸收性良好，故而可长时间稳定地获得右美托咪定作为镇静剂以及其他基于中枢性α2肾上腺素受体激动作用的各种适应症(例如，可列举ADHD(注意缺陷与多动障碍)、焦虑症、失眠症、酒精以及其他的戒断综合症、疼痛管理等，但并不限定于这些)的药剂的效果。
具体实施方式
本发明的非水系外用制剂的特征在于，含有(A)右美托咪定或其盐、(B)碳原子数10～12的脂肪族醇、(C)丙二醇单碳原子数6～16的脂肪酸酯、(D)有机酸和(E)有机酸盐。
成分(A)右美托咪定或其盐是本发明的外用制剂的有效成分。右美托咪定的化学名为(+)-(S)-4-[1-(2,3-二甲基苯基)乙基]-1H-咪唑，为中枢性α2肾上腺素受体的激动剂。作为该右美托咪定的盐，可列举酸加成盐，优选为盐酸、硫酸、硝酸、磷酸等无机酸加成盐，特别优选为盐酸盐。
就结晶析出抑制效果、经皮吸收促进效果和皮肤刺激性减低效果的方面而言，在非水系外用制剂中(在贴剂的情况下为膏体中)，右美托咪定或其盐的含量优选为0.1～10质量％，更优选为0.1～7质量％，进一步优选为0.1～5质量％。
关于成分(B)碳原子数10～12的脂肪族醇与成分(C)丙二醇单碳原子数6～16的脂肪酸酯，通过组合配合这两种成分而特别发挥右美托咪定或其盐的结晶析出抑制效果。
作为(B)碳原子数10～12的脂肪族醇，可列举癸醇(decanol)、月桂醇(dodecanol)，特别优选为月桂醇。其中，碳原子数10～12的脂肪族醇可使用一种或两种以上。
就右美托咪定或其盐的结晶析出抑制效果、经皮吸收促进效果和皮肤刺激性减低效果的方面而言，在非水系外用制剂中(在贴剂的情况下为膏体中)，成分(B)的含量优选为0.5～10质量％，更优选为1～8质量％，进一步优选为1～6质量％。
作为成分(C)丙二醇单碳原子数6～16的脂肪酸酯，可列举：丙二醇单己酸酯、丙二醇单辛酸酯、丙二醇单癸酸酯、丙二醇单月桂酸酯、丙二醇单肉豆蔻酸酯、丙二醇单棕榈酸酯。这些之中，更优选丙二醇单碳原子数8～14的脂肪酸酯，进一步优选丙二醇单碳原子数8～12的脂肪酸酯。这些丙二醇单碳原子数6～16的脂肪酸酯可使用一种或两种以上。
就右美托咪定或其盐的结晶析出抑制效果、经皮吸收促进效果的方面而言，在非水系外用制剂中(在贴剂的情况下为膏体中)，成分(C)的含量优选为1～12质量％，更优选为1～10质量％，进一步优选为1～8质量％。
关于成分(D)有机酸与成分(E)有机酸盐，通过组合配合这2种成分，能够提高右美托咪定或其盐的经皮吸收性。另外，通过使成分(B)、成分(C)与这些成分(D)和成分(E)组合，能够发挥右美托咪定或其盐的结晶析出抑制效果。
作为(D)有机酸，例如可列举：乙酸、丙酸、丁酸等C2～C5单羧酸；己二酸、马来酸、琥珀酸等二羧酸；乳酸、酒石酸、苹果酸、柠檬酸等羟基羧酸；乙酰乙酸、乙酰丙酸等酮羧酸；辛酸、癸酸、己酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、油酸、亚麻酸、次亚麻酸、山萮酸等高级脂肪酸等。
作为(E)有机酸盐，可列举上述有机酸的碱金属盐。这些(D)有机酸和(E)有机酸盐可分别使用一种或两种以上。另外，(D)有机酸与(E)有机酸盐可以为相同的有机酸与其盐，也可以为不同的有机酸与其盐。
这些成分(D)有机酸中，更优选为选自C2～C5单羧酸、C2～C8二羧酸、C2～C8羟基羧酸、C4～C8酮羧酸、C6～C24脂肪酸中的一种或两种以上。另外，作为(E)有机酸盐，更优选为选自C2～C5单羧酸盐、C2～C8二羧酸盐、C2～C8羟基羧酸盐、C4～C8酮羧酸盐中的一种或两种以上。
就右美托咪定或其盐的经皮吸收促进效果的方面而言，在非水系外用制剂中(在贴剂的情况下为膏体中)，成分(D)的含量优选为0.1～5质量％，更优选为0.1～3质量％，进一步优选为0.1～2质量％。
就右美托咪定或其盐的经皮吸收促进效果的方面而言，在非水系外用制剂中(在贴剂的情况下为膏体中)，成分(E)的含量优选为0.05～5质量％，更优选为0.05～3质量％，进一步优选为0.05～2质量％。
本发明的外用制剂为非水系外用制剂，具体而言，可列举软膏剂等非水系经皮吸收用剂、非水系贴剂。可配合在本发明的非水系外用制剂中的所述成分(A)～(E)以外的成分根据这些剂型而不同。
在为软膏剂等皮肤涂布用剂的情况下，除成分(A)～(E)以外，还可以配合各种软膏用基剂。作为这些成分，可列举：凡士林、石蜡、树脂基质(Plastibase)、有机硅等矿物性基剂；植物油、猪脂、牛脂、蜡等动植物基剂等。
在为非水系贴剂的情况下，可配合非水系基剂、增粘剂、增塑剂、溶解剂、上述以外的吸收促进剂、稳定化剂、紫外线吸收剂、填充剂、着色剂、着香剂、刺激抑制剂(胆固醇、尿素等)等。
其中，作为非水系基剂，可列举橡胶基剂和丙烯酸系基剂。作为橡胶基剂，可列举：苯乙烯-异戊二烯-苯乙烯嵌段共聚物(SIS)、聚异戊二烯、聚异丁烯(PIB)、苯乙烯-丁二烯-苯乙烯嵌段共聚物(SBS)、苯乙烯-丁二烯共聚物(SBR)、天然橡胶、有机硅系橡胶等。作为丙烯酸系基剂，可列举：丙烯酸/丙烯酸辛酯共聚物、丙烯酸酯/乙酸乙烯酯共聚物、丙烯酸2-乙基己酯/乙烯基吡咯啶酮共聚物、丙烯酸2-乙基己酯/甲基丙烯酸2-乙基己酯/甲基丙烯酸十二烷基酯共聚物、丙烯酸甲酯/丙烯酸2-乙基己酯共聚物、甲基丙烯酸/丙烯酸正丁酯共聚物等。其中，更优选橡胶系基剂。
作为增粘剂，可列举：石油系树脂(脂肪族烃树脂、脂环族烃树脂)、萜烯树脂、松香树脂、萜烯酚树脂、香豆酮树脂、二甲苯树脂、苯乙烯树脂等。
作为增塑剂，可列举：液体石蜡、轻质液体石蜡、聚丁烯、肉豆蔻酸异丙酯、肉豆蔻酸辛基十二烷基酯、棕榈酸异丙酯、硬脂酸丁酯、乳酸肉豆蔻酯、己二酸二辛酯、癸二酸二乙酯、癸二酸二异丙酯、癸二酸二辛酯、己二酸二异丙酯、琥珀酸二辛酯、辛基十二烷醇、己基癸醇、蓖麻油、柠檬酸三乙酯等。
作为溶解剂，可列举：甘油、丙二醇、三乙二醇、聚乙二醇(分子量200～4000)、1,3-丁二醇、克罗米通、角鲨烷、角鲨烯、丙二醇脂肪酸酯、中链脂肪酸甘油三酯、甘油脂肪酸酯、碳酸亚丙酯、三乙酸甘油酯、聚桂醇等。
作为成分(A)～(E)以外的吸收促进剂，可列举：辛酸、癸酸、己酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、亚麻酸、次亚麻酸、月桂酸甲酯、肉豆蔻酸异丙酯、肉豆蔻酸肉豆蔻酯、肉豆蔻酸辛基十二烷基酯、棕榈酸鲸蜡酯、乳酸鲸蜡酯、棕榈酸异丙酯、山梨糖醇酐单油酸酯、甘油单月桂酸酯、甘油单油酸酯、山梨糖醇酐单月桂酸酯、聚山梨醇酯20、聚山梨醇酯80、聚乙二醇单月桂酸酯、聚乙二醇单硬脂酸酯、聚氧乙烯硬化蓖麻油、α-单异硬脂基甘油酯等。
作为稳定化剂，可列举：L-抗坏血酸、L-抗坏血酸棕榈酸酯、L-抗坏血酸硬脂酸酯、L-抗坏血酸-2-葡萄糖苷、L-抗坏血酸钠、L-抗坏血酸钙、L-抗坏血酸磷酸酯镁、异抗坏血酸、异抗坏血酸钠、二丁基羟基甲苯、丁基羟基苯甲醚、没食子酸丙酯、没食子酸辛酯、没食子酸月桂酯、去甲二氢愈创木酸、三羟基丁酰苯、叔丁基氢醌、4-羟基甲基-2,6-二叔丁基苯酚、焦亚硫酸钠、亚硫酸氢钠、亚硫酸钠、焦亚硫酸钾等亚硫酸盐、巯基苯并咪唑等。
在为软膏剂的情况下，可通过如下方式来制造：向上述软膏基剂中配合成分(A)～(E)，视需要进行加热熔融，混合至整体变得均质为止并加以融合。
在为非水系贴剂的情况下，例如可利用如下方法中的任一种来制造：向将基剂成分热熔融而得到的物质中添加药物的溶解液，并将所获得的物质加以延展的热熔法；以及向将基剂成分溶解在有机溶剂中而得到的物质中添加药物的溶解液，并对所获得的物质进行涂敷干燥的溶剂法。其中，就不会对药物施加高热负荷的方面而言，优选为溶剂法。关于溶剂法中所使用的溶剂，可列举：甲苯、二甲苯、己烷、乙酸乙酯、四氢呋喃、二氯甲烷等。就有机溶剂的毒性的方面而言，优选为乙酸乙酯(医药品的残留溶剂指南：医药通报第307号)。
在为溶剂法的情况下，例如可按照下述程序来制造。
向液体石蜡中添加右美托咪定盐酸盐、有机酸盐和有机酸，进行充分搅拌，直至右美托咪定或其盐溶解或油状物化，制成有效成分混合液。
在有机酸盐为结晶性化合物等的情况下，为了缩短有效成分混合液的制备时间，可添加水和乙醇的两者或其中一者，或者进行超声波处理。
在添加水、乙醇的情况下，若有效成分混合液中的水、乙醇的量多，则存在如下情况：在将有效成分混合液投入后述的基剂成分溶解液中时，基剂成分凝聚。
在这种情况下，视需要，通过加温、减压、喷吹惰性气体等而将有效成分混合液中的水、乙醇蒸馏去除，藉此可避免基剂成分的凝聚。
向有机溶剂中加入橡胶基剂、增粘剂、增塑剂、溶解剂、包含成分(B)和成分(C)的吸收促进剂、稳定化剂和其他添加物并加以溶解，制成基剂成分溶解液。
向基剂成分溶解液中添加有效成分混合液，并进行均匀搅拌，将所获得的物质作为涂敷溶液。
将涂敷溶液以规定的厚度涂敷在衬垫上后，吹送暖风等而加以干燥，将支撑体贴合在所获得的粘接层后，裁断成规定的大小，从而获得制剂。
其中，作为支撑体，可列举：聚对苯二甲酸乙二醇酯、聚丙烯、聚乙烯等塑料膜和对这些塑料膜的表面进行放电电晕处理或喷砂处理而获得的塑料膜；以及对这些塑料膜层压由聚对苯二甲酸乙二醇酯、聚丙烯、聚乙烯等形成的无纺布而获得的膜。
另外，作为衬垫，可列举对由聚对苯二甲酸乙二醇酯、聚乙烯、聚丙烯形成的膜实施有机硅处理或氟处理而获得的衬垫。
关于本发明的非水系外用制剂，即使长期保存，也没有右美托咪定或其盐的结晶析出且稳定，并且经皮吸收性良好。因此，若使用本发明的非水系外用制剂，则可长时间稳定地获得右美托咪定的作为镇静剂以及其他基于中枢性α2肾上腺素受体刺激作用的各种适应症(例如，可列举ADHD、焦虑症、失眠症、酒精以及其他的戒断综合症、疼痛管理等，但并不限定在这些)的药剂的效果。
实施例
接下来，列举实施例更详细地说明本发明，但本发明并不限定在这些实施例。
(非水系贴剂的制造法)
按照下述程序获得表1～表3所示配方(质量％)的制剂。
(i)基剂溶液的制备
向乙酸乙酯(适量)中添加表中记载的基剂成分，并进行搅拌溶解，将所获得者设为基剂溶液。
(ii)有效成分混合液的制备
向液体石蜡中添加有机酸、有机酸盐和右美托咪定盐酸盐，并进行搅拌溶解，将所获得的混合液作为有效成分混合液。在溶解时，视需要添加适量的水/乙醇，并进行超声波处理。进而，在有机酸、有机酸盐和右美托咪定盐酸盐溶解后，视需要将水/乙醇蒸馏去除。
此外，在比较例1中，向液体石蜡中添加右美托咪定盐酸盐，并进行超声波分散，将所获得的混合液作为有效成分混合液。
(iii)涂敷溶液的制备
向基剂溶液中添加表中记载的其他成分，进行搅拌，继而，添加有效成分混合液并加以搅拌，将所获得的溶液作为涂敷溶液。
(iv)涂敷干燥裁断包装
将涂敷溶液涂敷在衬垫(进行了有机硅处理的PET膜)上并加以干燥。将支撑体贴合在所获得的粘接层，裁断成规定的大小(10cm2)，从而获得制剂。涂敷量调整为每一片制剂的右美托咪定盐酸盐的量成为1mg(1mg/10cm2)。支撑体使用对PET膜层压无纺布而成者，并使粘接层与无纺布面相接。
将所获得的制剂以一片为单位包装在铝袋中。
(皮肤透过性试验)
将无毛小鼠(雄性，7周龄)的腹部摘出皮肤装在弗朗茨(Franz)型扩散池(有效透过面积：0.92cm2，接受相容量：2.5mL)。在角质侧应用规定的制剂试样，在真皮层侧应用等张磷酸缓冲液(pH＝6.8)。试验中，将接受相内的等张磷酸缓冲液保持为32℃的恒定温度，以规定的时间采取1.0mL，并立即补充等容量的等张磷酸缓冲液。所采取的试样中的右美托咪定盐酸盐通过高效液相层析法来进行定量，并求出每单位面积的右美托咪定的累积透过量。
(结晶析出的确认方法)
将所包装的制剂在25℃下保管。保管后，剥离制剂的衬垫而使膏体面露出，使用光学显微镜(光透过，100～800倍、数字显微镜KH-8700，HIROX公司)自膏体侧观察第5天和第30天的制剂中有无右美托咪定的结晶，并依据下述评分来进行评价。
○：无结晶或极少
×：有结晶
[表1]
[表2]
[表3]
根据表1可知，在添加了所有的成分(B)～(E)的实施例1～6中，在制剂中未确认到右美托咪定的结晶，右美托咪定的经皮吸收性良好。另一方面，在未添加成分(D)和(E)的比较例1中，在制剂中右美托咪定结晶化，右美托咪定的经皮吸收性也低。
另外，实施例1和实施例2中所添加的有机酸为DL-苹果酸，但如实施例3、实施例4和实施例5那样，即使变更为不同的有机酸，也获得了相同的效果。同样，实施例1～5中所添加的有机酸盐为乙酸钠(无水合物)，但如实施例6那样，即使变更为不同的有机酸盐，也获得了相同的效果。
根据表2和表3可知，同样，在添加了所有的成分(B)～(E)的实施例7～9中，在制剂中未确认到右美托咪定的结晶，获得了良好的制剂。另一方面，如比较例2～11那样，在未添加成分(B)～(E)中的任意一种以上的情况下，在制剂中确认到右美托咪定的结晶。
特别而言，在将实施例7的月桂醇变更为肉豆蔻醇的情况下(比较例9)，无法抑制右美托咪定的结晶化。
同样，在不添加实施例9的成分(D)即DL-苹果酸的情况下(比较例8)，无法抑制右美托咪定的结晶化。在将实施例8的丙二醇单辛酸酯变更为丙二醇二辛酸酯的情况下(比较例11)，无法抑制右美托咪定的结晶化。
Claims (12)
1.一种非水系外用制剂，其特征在于，含有：
(A)右美托咪定或其盐、(B)碳原子数10～12的脂肪族醇、(C)丙二醇单碳原子数6～16的脂肪酸酯、(D)有机酸和(E)有机酸盐。
2.如权利要求1所述的外用制剂，其特征在于：
非水系外用制剂为软膏剂或非水系贴剂。
3.如权利要求1或2所述的外用制剂，其特征在于：
非水系外用制剂为非水系贴剂。
4.如权利要求1～3中任一项所述的外用制剂，其特征在于：
成分(B)为选自癸醇和月桂醇中的一种或两种。
5.如权利要求1～4中任一项所述的外用制剂，其特征在于：
成分(C)为选自丙二醇单碳原子数8～14的脂肪酸酯中的一种或两种以上。
6.如权利要求1～5中任一项所述的外用制剂，其特征在于：
成分(D)为选自C2～C5单羧酸、C2～C8二羧酸、C2～C8羟基羧酸、C4～C8酮羧酸和C6～C24脂肪酸中的一种或两种以上。
7.如权利要求1～6中任一项所述的外用制剂，其特征在于：
成分(E)为选自C2～C5单羧酸盐、C2～C8二羧酸盐、C2～C8羟基羧酸盐和C4～C8酮羧酸盐中的一种或两种以上。
8.如权利要求1～7中任一项所述的外用制剂，其特征在于：
成分(A)的含量为0.1～10质量％。
9.如权利要求1～8中任一项所述的外用制剂，其特征在于：
成分(B)的含量为0.5～10质量％。
10.如权利要求1～9中任一项所述的外用制剂，其特征在于：
成分(C)的含量为1～12质量％。
11.如权利要求1～10中任一项所述的外用制剂，其特征在于：
成分(D)的含量为0.1～5质量％。
12.如权利要求1～11中任一项所述的外用制剂，其特征在于：
成分(E)的含量为0.05～5质量％。
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| TW201609200A (zh) * | 2013-12-18 | 2016-03-16 | 丸石製藥股份有限公司 | 含水型貼劑 |
| CN105764494A (zh) * | 2013-10-07 | 2016-07-13 | 帝国制药美国公司 | 右旋美托咪啶经皮递送装置及其使用方法 |
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| US5219877A (en) * | 1989-09-25 | 1993-06-15 | Bristol-Myers Squibb Company | Lauryl alcohol as skin penetration enhancer for topical imidazole agents |
| GB9111732D0 (en) | 1991-05-31 | 1991-07-24 | Orion Yhtymae Oy | The use of certain salts of medetomidine and its optically active enantiomers to regulate the rate of transdermal administration of the drugs |
| US5352456A (en) | 1991-10-10 | 1994-10-04 | Cygnus Therapeutic Systems | Device for administering drug transdermally which provides an initial pulse of drug |
| GB2290964A (en) | 1994-07-08 | 1996-01-17 | Arto Olavi Urtti | Transdermal drug delivery system |
| JP5503916B2 (ja) | 2008-08-04 | 2014-05-28 | 富士フイルム株式会社 | レジスト組成物及びそれを用いたパターン形成方法 |
| TWI629067B (zh) * | 2013-10-07 | 2018-07-11 | 美商帝國製藥美國股份有限公司 | 用於經皮輸送非鎮靜量右美托咪啶之方法及組成物 |
| WO2017037813A1 (ja) * | 2015-08-29 | 2017-03-09 | 株式会社メドレックス | 塩基性薬物とソルビン酸とを含有する経皮吸収組成物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5124157A (en) * | 1989-08-18 | 1992-06-23 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
| CN105764494A (zh) * | 2013-10-07 | 2016-07-13 | 帝国制药美国公司 | 右旋美托咪啶经皮递送装置及其使用方法 |
| TW201609200A (zh) * | 2013-12-18 | 2016-03-16 | 丸石製藥股份有限公司 | 含水型貼劑 |
| EP3087985A1 (en) * | 2013-12-18 | 2016-11-02 | Maruishi Pharmaceutical Co., Ltd. | Water-containing adhesive patch |
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