CN105764486B - 冷-温石膏 - Google Patents
冷-温石膏 Download PDFInfo
- Publication number
- CN105764486B CN105764486B CN201480050997.XA CN201480050997A CN105764486B CN 105764486 B CN105764486 B CN 105764486B CN 201480050997 A CN201480050997 A CN 201480050997A CN 105764486 B CN105764486 B CN 105764486B
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- CN
- China
- Prior art keywords
- composition
- percent
- menthol
- butyl ether
- pain
- 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.)
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- 239000011505 plaster Substances 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 48
- 229940041616 menthol Drugs 0.000 claims abstract description 24
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 22
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229940078465 vanillyl butyl ether Drugs 0.000 claims abstract description 22
- VLDFMKOUUQYFGF-UHFFFAOYSA-N 4-(butoxymethyl)-2-methoxyphenol Chemical compound CCCCOCC1=CC=C(O)C(OC)=C1 VLDFMKOUUQYFGF-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000017 hydrogel Substances 0.000 claims abstract description 17
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- 230000000552 rheumatic effect Effects 0.000 claims abstract description 5
- 230000008733 trauma Effects 0.000 claims abstract description 5
- 208000000112 Myalgia Diseases 0.000 claims abstract description 4
- 208000002193 Pain Diseases 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000009637 wintergreen oil Substances 0.000 claims description 13
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims description 9
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
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- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 claims description 3
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
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- URYWXMHZLSZSNE-UHFFFAOYSA-N (2,2-diethoxy-2-methoxyethyl) 2-methylprop-2-enoate Chemical compound CCOC(OCC)(OC)COC(=O)C(C)=C URYWXMHZLSZSNE-UHFFFAOYSA-N 0.000 description 2
- DAVVKEZTUOGEAK-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethyl 2-methylprop-2-enoate Chemical compound COCCOCCOC(=O)C(C)=C DAVVKEZTUOGEAK-UHFFFAOYSA-N 0.000 description 2
- YXYJVFYWCLAXHO-UHFFFAOYSA-N 2-methoxyethyl 2-methylprop-2-enoate Chemical compound COCCOC(=O)C(C)=C YXYJVFYWCLAXHO-UHFFFAOYSA-N 0.000 description 2
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- ZYTMANIQRDEHIO-KXUCPTDWSA-N isopulegol Chemical compound C[C@@H]1CC[C@@H](C(C)=C)[C@H](O)C1 ZYTMANIQRDEHIO-KXUCPTDWSA-N 0.000 description 2
- 239000004745 nonwoven fabric Substances 0.000 description 2
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000001871 (1R,2R,5S)-5-methyl-2-prop-1-en-2-ylcyclohexan-1-ol Substances 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- OLQFXOWPTQTLDP-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCOCCO OLQFXOWPTQTLDP-UHFFFAOYSA-N 0.000 description 1
- PSJBSUHYCGQTHZ-UHFFFAOYSA-N 3-Methoxy-1,2-propanediol Chemical compound COCC(O)CO PSJBSUHYCGQTHZ-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
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- 241001073507 Callicarpa Species 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Abstract
一种用于局部用药的组合物,其特征在于其包括在水凝胶基底中的香草基丁基醚和薄荷醇。此处所述的组合物提供了冷感和温感的有序开发,得到特别适用于治疗神经和/或肌肉源疼痛疾病的作用。该组合物进一步具有增湿和舒缓的作用,其共同作用对风湿性和肌肉疼痛、创伤和挫伤形成非简单对症的疗效。该组合物能与任意用药形式相容,优选且有利地配制成石膏。
Description
技术领域
本发明属于可用于治疗神经和/或肌肉源疼痛疾病(例如风湿性疼痛、腰痛、头颈僵直疲劳、创伤和挫伤)的用于局部用药的组合物(即具有局限性作用的产品)的领域,进一步属于适于其(特别是含药石膏)施用(administration)的设备的领域。
背景技术
神经或肌肉源疼痛疾病是普遍存在的。其可以具有慢性(例如风湿性疼痛)或急性(例如在创伤或挫伤之后)的起因。其是强度或强或弱的疾病,通常难以治疗,尤其是在最严重的阶段。这些疾病的治疗通常是基于抗炎药的全身用药或在可行的情况下在患病部位局部用药的。
所有这些治疗通常都包括使用显著剂量的抗炎药,其可能具有不适合的副作用,尤其是在长期大量用药的情况中。因此存在持续的努力以降低或甚至消除对这些药的依赖。
上述疾病也能够用局部冷敷(例如用水、冰或通过产生冷觉的物质(例如薄荷醇、薄荷烷和衍生物等))来治疗,由此得到的冷却降低了疼痛的刺激,或者至少降低了对其的感知。可替代地,形成温觉也可能会产生益处,促进患病肌肉区域的缓解和收缩。
已知有不同的装置可用于患者的身体以产生冷觉或温觉。例如,已知包含具有高热容量的液体的包,其可以预防性地加热或冷却,然后应用到需要治疗的身体部分上,以产生相应的温度效果。现有技术EP 988852显示了基于选自薄荷醇、异蒲勒醇、3-甲氧基丙-1,2-二醇、p-薄荷烷-3,8-二醇的组分与香草基丁基醚混合的冷却组合物,第二种组分已知能产生温觉,然而,此处描述的组合物仅仅用于冷却,而未达到加热作用,或者仅能偶尔以偶然的在统计学上无意义的方式达到加热作用。
公开文件WO-A2-2010045415描述了一种局部用药的NSAID组合物,其中感觉剂(例如香草基丁基醚)的添加提高了NSAID的吸收率;该文件进一步描述了整个NSAID组合物的疼痛缓解活性;对于感觉剂本身公开了没有特定的疼痛缓解活性;对可能的增温/冷却效果的时机选择没有研究。
因为温/冷效果明确相反,因此在单一装置中调和冷和热的产生存在困难。而且,甚至对于能够通常产生这两种感知的装置,仍然很难控制其在可用于有效治疗疼痛疾病的方式和时间方面的开发。而且,对于开发能避免或大大降低对常规抗炎药剂的使用的对疼痛状态局部有效的治疗方法仍存在挑战。
发明内容
描述了一种用于局部用药的新型组合物,其特征在于其包括在水凝胶基底中的香草基丁基醚和薄荷醇。这两种组分,在分散在水凝胶相中时,以其特定的相互和绝对重量比,可以有序开发冷感和温感,由此得到特别适用于治疗神经和/或肌肉源疼痛疾病的作用。该组合物一旦施涂到皮肤上,就会产生立即的冷感,然后以有序的且在统计学上可重复性的方式产生温感。最初的冷却作用抑制了急剧的疼痛症状,使病人处于良好的状态,然后,在疼痛刺激降低/抑制之后,该组合物开发了令人愉悦的温感并促进患病部分的缓解和收缩。进一步地,该组合物具有增湿和舒缓的作用,其与上述有序的冷/温感协同作用,由此共同作用对风湿性和肌肉疼痛、创伤和挫伤形成非简单对症的疗效。该组合物能与任意用药形式相容,优选且有利地配制成石膏。
发明详述:
此处所用的术语“水凝胶”表示由一种或多种中性或离子均聚物或共聚物的水合得到的胶凝相,该均聚物或共聚物典型地包括亲水基团(例如羟基)、具有三维网络结构,且通常由交联反应得到。任何与皮肤相容的合成或天然水凝胶都可以用作分散本发明的薄荷醇和香草基丁基醚的基底。在合成水凝胶中,可以提及例如以下的水凝胶:聚丙烯酸酯,例如甲基丙烯酸羟乙酯(HEMA)、甲基丙烯酸羟基乙氧基乙基酯(HEEMA)、甲基丙烯酸羟基二乙氧基乙基酯(HDEEMA)、甲基丙烯酸甲氧基乙基酯(MEMA)、甲基丙烯酸甲氧基乙氧基乙基酯(MEEMA)、甲基丙烯酸甲氧基二乙氧基乙基酯(MDEEMA)的聚合物,或聚丙烯酸钠;聚乙二醇及其衍生物,例如聚乙二醇丙烯酸酯、聚乙二醇二丙烯酸酯、聚乙二醇甲基丙烯酸酯、聚乙二醇二甲基丙烯酸酯;聚乙烯基醇;交联或非交联的聚乙烯基吡咯烷酮;聚酰亚胺;聚丙烯酰胺;聚氨酯;纤维素凝胶或其衍生物,例如羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、纤维素乙酸酯、羧甲基纤维素(羧甲醚纤维素钠)等。在天然水凝胶中,可以使用例如以下的水凝胶:透明质酸、壳聚糖、明胶、琼脂、胶原蛋白、右旋糖酐等。优选的水凝胶是基于明胶、聚乙烯基吡咯烷酮、聚丙烯酸钠和羧甲基纤维素的那些。
该水凝胶的干相(即除水之外所用的所有胶凝剂的总和)与香草基丁基醚和薄荷醇(热活性成分)的总和之间以35:1-2:1之间的重量比存在。本发明的组合物的混合物中的水合率(水占总组合物的重量百分比)通常在20%-55%之间,优选在25%-50%之间,更优选为约40%。
典型地,在本发明中,与加温剂香草基丁基醚相比,冷却剂薄荷醇的含量更高。特别地,香草基丁基醚与薄荷醇以在1:2-1:25之间,优选在1:3-1:15之间的相对重量比存在。在最终的水合组合物中,香草基丁基醚优选以在0.01-1%之间的重量百分比存在,薄荷醇优选以在0.1-10%之间的重量百分比存在。
根据已知,薄荷醇和香草基丁基醚用于其各自的冷却和加热性质。然而,两种不同感知的开发时间对于该组合物对治疗目的的有效性具有关键的作用,可使这两种组分对神经/肌肉源疼痛症状进行有效的祛除性治疗。特别地,已经发现这两种组分在依照本发明以特定比例均匀分散在水凝胶相中时,得到了有序且可重复性的冷/温感开发:特别地,首先立即得到冷感,其降低/抑制了施涂区域的神经或肌肉疼痛症状;然后在施涂约20-30分钟之后,继而产生温感;该温感在此处以特别令人愉悦的方式被感知,因为其是在疼痛症状通过第一冷却步骤已经降低/抑制时形成的。典型地,在本发明的组合物中,在该冷感停止之后,该疼痛降低/抑制作用持续一段时间,由此得到更宽的疼痛降低/抑制时间窗口,在此期间温感能够最好地执行其缓解作用。不希望被理论束缚,我们详细本发明的水凝胶基底实现了类似的组织增湿作用,提高了冷却步骤的强度/效能,由此增强了对疼痛刺激的抑制;冷却作用的增强避免了温感可能过早的形成,温感过早的形成将会是较为无益的,其的感知仍在剧烈疼痛阶段期间。
该组合物可以进一步包括活性剂冬绿油:这是一种芳香族精油,富含水杨酸甲酯,从白珠树属的植物浆果中提取出。申请人发现这种成分是一种高性能的舒缓和芳香组分,特别是与本发明的水凝胶结合时。在存在时,该冬绿油优选与薄荷醇和香草基丁基醚的总和相比以在5:1-1:5范围内的比例使用。
归因于其增强的治疗功效,所述的薄荷醇、香草基丁基醚和冬绿油(当存在时)是该组合物的“主要”活性剂,其中“主要”表示该组合物不包括其他对神经/肌肉源疼痛症状局部有效的有效成分;特别地,该组合物不包含其他抗炎剂;可替代地,该其他有效成分可以存在,尽管与薄荷醇、香草基丁基醚和冬绿油(当存在时)的总和相比以少量比例存在,特别地以低于1:8或低于1:10的比例存在;本发明事实上基于上述活性成分的重要治疗作用,其可以使得不需要其他治疗剂的存在。
本发明的组合物可以进一步包括非活性成分(赋形剂),其选择用于所需的用药形式。其中,可以提及保湿剂,例如多元醇,例如山梨糖醇或甘露醇或二醇;表面活性剂,例如聚山梨醇酯;防腐剂,例如尼泊金酯;螯合剂,例如EDTA;pH调节剂,例如酒石酸;矿物填料,例如高岭土;颜料,例如二氧化钛;交联剂,例如甘氨酸铝等。
特别但不专门为了用于实施含药物的石膏而设计的组合物以重量比包括:
-温/冷组分(香草基丁基醚+薄荷醇,以上述所示的相互比例):0.10-10%
-冬绿油:0-10%
-胶凝剂(不包括水):2-23%
-各种赋形剂:30-60%
-水:20-55%。
更优选的用于上述用途的组合物以重量比包括:
-温/冷组分(香草基丁基醚+薄荷醇,以上述所示的相互比例):0.20-5%
-冬绿油:0-5%
-胶凝剂(不包括水):2-16%
-各种赋形剂:30-60%
-水:20-55%。
甚至更优选的组合物除常规赋形剂之外以重量比包括:
-香草基丁基醚:0.01-1%
-薄荷醇:0.1-5%
-冬绿油:0.1-5%
-胶凝剂(不包括水):2-16%
-水:20-55%。
进一步优选的组合物除常规赋形剂之外以重量比包括:
-香草基丁基醚:0.04-0.8%
-薄荷醇:0.2-4%
-冬绿油:0.1-5%
-胶凝剂(不包括水):2-16%
-水:20-55%。
进一步的组合物示例在下面的实验实施例中。
本发明的组合物适用于对患神经或肌肉源疼痛症状的患者在患病区域进行局部用药。在被治疗的皮肤上感知到冷/温作用以及增湿和疼痛缓解作用,且其能够对肌肉块提供益处。预期了几种给药形式,包括以可扩散的凝胶形式用药、或者通过适合的持久系统(例如含药石膏)用药。依照本发明的优选实施方案的含药石膏具有以下优点:简单、快速、原位持久、精确预计量用药方式、不讲产品分散到与治疗相关皮肤区域相邻的皮肤区域上;水凝胶也用作温和的粘合剂:其可以将石膏在该皮肤上粘合足以开发冷/温作用的时间,然后可以将石膏温和且无痛地除去;因此可以避免使用含药石膏通常使用的其他粘合剂、胶和溶剂,这些粘合剂、胶和溶剂可能会刺激皮肤,在去除时可能需要皮肤的过度拉伸和/或在皮肤上遗留难以去除的残余物。本发明具有另一优点:可以提供用于治疗神经或肌肉源疼痛症状的治疗方法,其基本上不使用常规的抗炎剂(例如NSAID),大部分抗炎剂已知具有长期的毒性。
现在通过以下实施例以非限制的方式描述本发明。
实施例1
如下制备依照本发明制备的含药石膏的组合物:
原料 | 组分百分比 |
VBE | 0.5% |
薄荷醇 | 2.0% |
冬绿油(白珠油) | 2.0% |
明胶 | 3.0% |
聚乙烯吡啶酮 | 1.0% |
山梨糖醇 | 24.5% |
高岭土 | 2.5% |
丙二醇 | 4.0% |
羧甲纤维素钠(CMC) | 2.2% |
甘氨酸铝 | 0.1% |
1,3-丁二醇 | 8.0% |
聚丙烯酸钠 | 2.2% |
纯水 | 48.0% |
总计 | 100.0% |
将实施例1的组合物施涂到适合的载体(无纺织物)上,并用保护性聚丙烯衬里覆盖。
然后将该产品涂覆到6名志愿者的背部,要求在4小时的时期内定期记录在经治疗的皮肤区域上感知到的冷、中性和温感。不同的感知可在以下标准(F2)-(F1)-(0)-(C1)-(C2)上分类,其中0代表该作用的中性,F1/C1分别代表中等的冷/温作用;F2/C2分别代表强烈的冷/温作用。
结果示例在表1中:
表1中示例的结果显示:尽管在这类试验固有的通常变化性范围内,在施涂石膏之后的第一步中都一致地感知到冷感,然后在观察时期的第二部分中一致地感知到温感。
实施例2
如下制备依照本发明制备的含药石膏的组合物:
原料 | 组分百分比 |
VBE | 0.06% |
薄荷醇 | 0.4% |
冬绿油(白珠油) | 2.0% |
明胶 | 3.0% |
聚乙烯吡啶酮 | 1.0% |
山梨糖醇 | 25.5% |
高岭土 | 1.5% |
丙二醇 | 4.0% |
羧甲纤维素钠(CMC) | 1.0% |
甘氨酸铝 | 0.02% |
1,3-丁二醇 | 7.0% |
聚丙烯酸钠 | 10.0% |
纯水 | 44.52% |
总计 | 100.0% |
将实施例2的组合物施涂到适合的载体(无纺织物)上,并用保护性聚丙烯衬里覆盖。
然后将该产品涂覆到6名志愿者的背部,要求在4小时的时期内定期记录在经治疗的皮肤区域上感知到的冷、中性和温感。不同的感知可在以下标准(F2)-(F1)-(0)-(C1)-(C2)上分类,其中0代表该作用的中性,F1/C1分别代表中等的冷/温作用;F2/C2分别代表强烈的冷/温作用。
结果示例在表2中:
表2中示例的结果显示:尽管在这类试验固有的通常变化性范围内,在施涂石膏之后的第一步中都一致地感知到冷感,然后在观察时期的第二部分中一致地感知到温感。
Claims (11)
1.一种用于局部用药的组合物,包括分散在水凝胶中的香草基丁基醚和薄荷醇,其中香草基丁基醚与薄荷醇以在1:3-1:15之间的重量比存在,其中香草基丁基醚以该组合物总重量的0.01-1%之间的量存在,薄荷醇以该组合物总重量的0.1-10%之间的量存在。
2.如权利要求1所述的组合物,包括占总组合物的20-55%之间的百分比的水。
3.如权利要求1-2所述的组合物,其中该水凝胶包括以下中的一种或多种:明胶、聚乙烯基吡咯烷酮、聚丙烯酸钠和羧甲基纤维素。
4.如权利要求1-2所述的组合物,进一步包括冬绿油。
5.如权利要求1-2所述的组合物,进一步包括选自以下的一种或多种赋形剂:保湿剂、表面活性剂、防腐剂、螯合剂、pH调节剂、矿物填料、交联剂、颜料、香料。
6.如权利要求4所述的组合物,包括:
-香草基丁基醚+薄荷醇:0.10-10%
-冬绿油:0-10%
-胶凝剂(不包括水):2-23%
-各种赋形剂:30-60%
-水:20-55%。
7.如权利要求4所述的组合物,包括:
-香草基丁基醚+薄荷醇:0.20-5%
-冬绿油:0-10%
-胶凝剂(不包括水):2-16%
-各种赋形剂:30-60%
-水:20-55%。
8.如权利要求1-2所述的组合物,用于治疗神经和/或肌肉源的疼痛症状。
9.如权利要求8所述的组合物,用于治疗风湿性疼痛、肌肉痛、腰痛、头颈僵直疲劳、创伤和挫伤。
10.用于局部用药的装置,包含如权利要求1-2所述的组合物。
11.如权利要求10所述的装置,是含药石膏。
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IT001532A ITMI20131532A1 (it) | 2013-09-17 | 2013-09-17 | Cerotto freddo-caldo |
PCT/EP2014/002519 WO2015039748A1 (en) | 2013-09-17 | 2014-09-17 | Cold-warm plaster |
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CN101238203A (zh) * | 2005-06-21 | 2008-08-06 | 高砂香料工业株式会社 | 香味和芳香组合物 |
CN102186470A (zh) * | 2008-10-16 | 2011-09-14 | 诺瓦提斯公司 | 具有感觉组分的局部用nsaid组合物 |
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EP1568365B1 (en) * | 2002-11-27 | 2018-04-11 | Hisamitsu Pharmaceutical Co. Inc. | Warm poultice |
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CN102186470A (zh) * | 2008-10-16 | 2011-09-14 | 诺瓦提斯公司 | 具有感觉组分的局部用nsaid组合物 |
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WO2015039748A1 (en) | 2015-03-26 |
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