CN101896175B - 含有环氧洛芬的水性贴剂 - Google Patents
含有环氧洛芬的水性贴剂 Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
提供一种制剂，其是含有环氧洛芬的水性贴剂，其具备环氧洛芬的良好的稳定性与优异的透皮吸收性；一种水性贴剂，其特征在于，由含有环氧洛芬或其盐与三乙酸甘油酯而成；具体地，水性贴剂，其特征在于，相对于膏体重量，含有环氧洛芬或其盐0.1～5重量％、三乙酸甘油酯0.5～5重量％、水溶性高分子1～30重量％、交联剂0.01～5重量％、纯水10～90重量％和无机粉末0～20重量％。
Description
技术领域
本发明涉及含有环氧洛芬的水性贴剂，其中，环氧洛芬的制剂中的稳定性良好、且该水性贴剂具备优异的透皮吸收性。
背景技术
环氧洛芬作为苯丙酸系的非甾类化合物消炎镇痛剂具有优异的药效，并作为内服药而被广泛使用。此外，还提出了数种外用制剂，例如，专利文献1中，作为配合环氧洛芬的贴剂，公开了配合环氧洛芬与克罗米通的贴剂。
该贴剂的目标在于提供含有环氧洛芬的贴剂，其通过在水性贴剂基质中配合克罗米通，而提高制剂中的环氧洛芬溶解性，同时制剂的稳定性高、皮肤刺激降低，但是，其在有效成分环氧洛芬的透皮吸收性上效果并不充分。
[专利文献1]日本特开平10-120560号公报
因此，当前状况是要求环氧洛芬的制剂中的稳定性优异，同时透皮吸收性优异的、含有环氧洛芬的外用贴剂的进一步改良。
发明内容
鉴于上述现状，本发明的课题是提供下述制剂，其是含有环氧洛芬的水性贴剂，其具备环氧洛芬的良好的制剂稳定性、和优异的透皮吸收性。
本发明人等为解决所述课题反复深入研究，结果初次发现：通过在配合三乙酸甘油酯而成的膏体中，溶解环氧洛芬或其盐，从而将环氧洛芬稳定地溶解于膏体中，由此可提供具备环氧洛芬的良好的稳定性、和优异的透皮吸收性的贴剂，从而完成了本发明。
因此，本发明作为其基本方案是水性贴剂，其特征在于，由含有环氧洛芬或其盐与三乙酸甘油酯而成。
更具体地，本发明是水性贴剂，其特征在于，环氧洛芬或其盐的配合量为膏体重量的0.1～5重量％，且三乙酸甘油酯的配合量为膏体重量的0.5～5重量％。
进一步具体地，本发明是水性贴剂，其特征在于，相对于膏体重量，含有环氧洛芬或其盐0.1～5重量％、三乙酸甘油酯0.5～5重量％、水溶性高分子1～30重量％、交联剂0.01～5重量％、纯水10～90重量％、和无机粉末0～20重量％。
本发明提供的水性贴剂，通过在配合了三乙酸甘油酯的基质中，配合环氧洛芬或其盐，可使环氧洛芬稳定地溶解于膏体中。
由于该稳定的溶解性，使得可提供下述水性贴剂，其具备以往的含有环氧洛芬的水性贴剂所无法获得的、环氧洛芬的优异透皮吸收性与良好的制剂的稳定性。
附图说明
[图1]是基于试验例1的、显示环氧洛芬的体外皮肤渗透量的图。
具体实施方式
本发明的水性贴剂中，作为用作有效成分的环氧洛芬或其盐，可举出：钠盐、钾盐、锂盐之类的碱金属盐；钙盐、镁盐之类的碱土类金属盐；铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等金属盐；铵盐；叔辛基胺盐、二苄基胺盐、吗啉盐、葡萄糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙基胺盐、三乙基胺盐、二环己基胺盐、N，N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙胺盐、哌嗪盐、四甲基铵盐、三(羟甲基)氨基甲烷盐之类的有机盐等胺盐；以及，甘氨酸盐、赖氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐之类的氨基酸盐。优选水溶性的盐，更优选钠盐。
本发明提供的水性贴剂中，贴剂中含有的环氧洛芬或其盐的配合量只要能够进行制剂，则没有特别限定，可在相对于膏体重量，优选0.1～5重量％、更优选0.5～2重量％的范围内进行配合。
制剂中的环氧洛芬或其盐的含量不足0.1重量％时，透皮吸收性不充分，不能获得目的的消炎、镇痛效果。此外，超过5重量％进行配合时，则引起制剂中的结晶化和药物利用率降低等问题，故不优选。
本发明在下述方面具有特征：通过在配合三乙酸甘油酯而成的膏体中，溶解环氧洛芬或其盐，从而使环氧洛芬稳定地溶解于膏体中，由此可提供具备环氧洛芬的良好的稳定性与优异的透皮吸收性的贴剂。
该三乙酸甘油酯用作环氧洛芬或其盐的溶解剂。
本发明中的三乙酸甘油酯的配合量，可相对于膏体重量，在0.5～5重量％、优选1～2重量％的范围内进行配合。三乙酸甘油酯的配合量不足0.5重量％时，环氧洛芬的或其盐在膏体中的溶解变得不充分，不能获得高透皮吸收性。此外，超过5重量％进行配合时，贴剂剥离后，在皮肤表面发生膏体残留等，产生对制剂物性不优选的影响。
另外，对于本发明提供的水性贴剂，只要不对其它造成影响，则可使用通常的水性贴剂中所用的各种基质。
作为所述基质并无特别限定，可举出例如：通常所使用的聚丙烯酸钠、聚丙烯酸、羧基乙烯基聚合物、羧甲基纤维素钠、聚乙烯醇、明胶等水溶性高分子；甘油、丙二醇、聚乙二醇等多元醇类；氢氧化铝、硫酸铝钾、甘氨酸铝等交联剂；高岭土、氧化钛等无机粉末；柠檬酸、酒石酸等pH调节剂；聚氧乙烯失水山梨糖醇单油酸酯、失水山梨糖醇单油酸酯、聚氧乙烯单油酸酯、甘油脂肪酸酯、聚甘油脂肪酸酯、聚氧乙烯脂肪酸酯、失水山梨糖醇脂肪酸酯、聚氧乙烯失水山梨糖醇脂肪酸酯、聚氧乙烯山梨糖醇脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯烷基醚等表面活性剂；以及纯水等。
进一步地，可根据需要添加吸收促进剂、防腐剂、抗氧化剂、调味剂、着色剂等。
对于上述各成分，特别是在本发明提供的水性贴剂中，明确了优选在基质中分别配合水溶性高分子1～30重量％、多元醇类1～50重量％、交联剂0.01～5重量％、纯水10～90重量％、无机粉末0～20重量％。
作为本发明的水性贴剂中的载体，只要是具有柔软性的机织织物、无纺织物、膜、片，则没有特别限定，可使用例如：将人造丝、聚酯、聚烯烃、聚氨酯等纤维制成的机织织物或无纺织物，或聚合物膜、发泡体片等。
特别优选使用在各方向上具有伸缩性的载体。
作为被覆粘着基质即膏体的表面的剥离片，可使用各种塑料膜。作为这类塑料膜，可举出聚乙烯、聚丙烯、聚酯膜，此外，还可举出用有机硅对它们进行脱模处理得到的塑料膜。
本发明提供的水性贴剂的制法没有特别限定，例如，作为环氧洛芬或其盐使用环氧洛芬钠时，可以将该环氧洛芬钠溶解于水中，添加至预先制备好的由浓甘油等多元醇、聚丙烯酸等水溶性高分子、无机粉末与纯水构成的混合液中，充分搅拌后，向其中添加三乙酸甘油酯、pH调节剂、表面活性剂、交联剂等，进一步充分混合，由此得到膏体，将该膏体涂敷在载体上，并用塑料膜被覆该膏体表面，从而制造所期望的贴剂。
所得的本发明的贴剂剪断为适当的大小，并根据需要放入气密容器等中保存。
实施例
以下通过实施例更加详细地说明本发明，但本发明不受以下实施例的限定。
应予说明，实施例和比较例中，若无特别指出则以“重量％”表示。
[实施例1～4]
基于下述表1中记载的配方，按照上述制造方法，制造本发明的水性贴剂。
[比较例1]
使用市售的环氧洛芬钠巴布剂100mg(制造·销售：Lead Chemical公司)。该市售的环氧洛芬钠巴布剂是基于专利文献1的配合配方。
[比较例2、3]
基于以下表1中记载的配方，按照上述制造方法，制造比较例的水性贴剂。
应予说明，比较例2是不含三乙酸甘油酯的贴剂，比较例3是代替三乙酸甘油酯而配合克罗米通的贴剂。
[表1]
试验例1：含有环氧洛芬的水性贴剂的体外皮肤渗透试验
对于实施例1和比较例1～3的贴剂，进行使用大鼠皮肤的体外皮肤渗透试验。
将去毛雄性大鼠(Wistar系、7周龄)的背部摘出皮肤固定在保温于37℃的立式渗透试验用扩散池中，将试验贴剂贴于摘出皮肤的角质层侧，在内侧(真皮层侧)添加磷酸缓冲生理盐水10mL作为接受液。之后，经时性地采集接受液，通过液相色谱法测定环氧洛芬的摘出皮肤渗透量。
其结果示于图1。
由图1所示结果可知，实施例1的贴剂相对于未添加三乙酸甘油酯的比较例2的贴剂，显示出约1.8倍的皮肤渗透性。
此外，相对于添加克罗米通2重量％的制剂，即比较例3的贴剂，也显示出约1.7倍的皮肤渗透性。
即，可理解本发明的贴剂与这些比较例的贴剂相比，显示出环氧洛芬的良好渗透性。
试验例2：含有环氧洛芬的水性贴剂的稳定性试验
将实施例1与比较例2及3的各贴剂密封于铝袋中后，在40℃的条件下保存1个月，通过高效液相色谱法对上述各贴剂中的环氧洛芬含量的变化进行测定。
其结果示于下述表2。
结果以保存开始时贴剂中的环氧洛芬含量为100％，表示为相对于初始值％。
此外，*表示环氧洛芬的结晶在膏体中析出。
| 初始值 | 40℃1个月 | |
| 实施例1 | 100 | 98.3 |
| 比较例2 | 100 | 97.7* |
由表2所示结果可知，本发明的实施例1的贴剂相较于比较例的贴剂，显示出膏体中的环氧洛芬的良好的稳定性。
产业实用性
如上所述，本发明提供的水性贴剂，通过在配合三乙酸甘油酯的基质中配合环氧洛芬或其盐，而将环氧洛芬稳定地溶解，由此可提供下述水性贴剂，其具备以往含有环氧洛芬的水性贴剂所无法获得的、环氧洛芬的优异的透皮吸收性和良好的制剂的稳定性。
Claims (5)
1.水性贴剂，其特征在于，含有环氧洛芬或其盐与三乙酸甘油酯。
2.权利要求1所述的水性贴剂，其特征在于，环氧洛芬或其盐的配合量为膏体重量的0.1～5重量％。
3.权利要求1或2所述的水性贴剂，其特征在于，三乙酸甘油酯的配合量为膏体重量的0.5～5重量％。
4.权利要求1或2所述的水性贴剂，其特征在于，相对于膏体重量，含有环氧洛芬或其盐0.1～5重量％、三乙酸甘油酯0.5～5重量％、水溶性高分子1～30重量％、交联剂0.01～5重量％、纯水10～90重量％、和无机粉末0～20重量％，其中所述无机粉末为高岭土或氧化钛。
5.权利要求3所述的水性贴剂，其特征在于，相对于膏体重量，含有环氧洛芬或其盐0.1～5重量％、三乙酸甘油酯0.5～5重量％、水溶性高分子1～30重量％、交联剂0.01～5重量％、纯水10～90重量％、和无机粉末0～20重量％，其中所述无机粉末为高岭土或氧化钛。
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| JP5800417B2 (ja) * | 2011-07-12 | 2015-10-28 | 帝國製薬株式会社 | 外用貼付剤 |
| JP6344947B2 (ja) * | 2013-03-29 | 2018-06-20 | 興和株式会社 | ロキソプロフェン含有外用固形剤 |
| JP7049258B2 (ja) * | 2016-10-12 | 2022-04-06 | 帝國製薬株式会社 | 水性貼付剤 |
| KR102000435B1 (ko) * | 2018-01-18 | 2019-07-16 | 대화제약 주식회사 | 하이드로겔 패치 형태의 경피투여용 약학 조성물 |
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| KR101539801B1 (ko) | 2015-07-27 |
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