CN1289061C - 用于预防和治疗臭汗症的药剂 - Google Patents
用于预防和治疗臭汗症的药剂 Download PDFInfo
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Abstract
本发明涉及肉毒杆菌毒素在制造用于预防及/或治疗臭汗症的药剂以及在制造用于改善体臭的化妆工具中的用途。
Description
技术领域
本发明涉及肉毒杆菌毒素(botulinus toxin)在制造用于预防及/或治疗臭汗症(bromhidrosis)的药剂以及在制造用于改善体臭的化妆工具(cosmetic means)中的用途。
背景技术
于化妆学中，有多种方法使用外来物质(香料)来产生令人愉悦的气味；于医学中，也有方法用来减低病理性的、难闻的体臭(臭汗症(bromhydrosis))。不过，两者都不外乎用来增加体味的品质等级或可接受性之可能性。
体臭系一种一般已知且广布的现象。其可能在类似的状况下以非常不同的强度发生于不同的个体且会给罹患的人本身及其同伴不同的感觉。
与通常的观念不同的是，体汗，亦即外分泌汗腺的分泌物，是完全无味的。所以过度的出汗不能与过度的体味混淆。于其组成中，汗液为一种透明的水性液体，主要包括钠、钾、钙、镁和氯等离子且除此之外还含有乳酸盐、尿素与微量氨基酸、生物胺类(biogenic amines)及维生素。在特殊情况中也可能透过出汗而排出药剂例如灰黄霉素(griseofulvin)与酮康唑(ketokonazol)，不过这些对于体臭并没有明显的作用。产生的汗液愈多，例如在极端情况像在蒸气浴室中，汗会更为稀释，亦即，所有的汗会变得更为水性。在正常生理状况下过度非自然性的汗产生即称为一种病态，所谓的多汗症(hyperhidrosis)。所以过度的出汗(多汗)不是体味的直接原因。相反地，在医学教科书和刊物中明确地强调患有过度腋下出汗(腋多汗(Hyperhidrosis axillaris))的病人通常不会发展出强烈体臭[4]。此点可以由巨量流出的汗好似从皮肤“冲洗掉”味道产生性物质之事实予以解释。不过，与分泌汗腺不同，所谓的气味腺(the scent ligand)(顶泌腺(apocrine ligand)与顶-外分泌腺(apo-eccrinegland)可能释放出可辨出的嗅觉性分泌物。此种分泌物可能转而在皮肤表面上被细菌转化成恶臭物质。所以可以指称气味腺于体臭发生中具有肇始作用。气味腺可能数目巨大，例如在人体的腋窝内，不过其通常是在青春期以后才具有活性。因此，在成人期通常具有比儿童期远较为强烈的体臭。
简言之，体臭可能由两项必要因素所产生：
1.由气味腺产生的分泌物显示出会被其它人以非常不同的程度所觉察出之特性味道。
2.气味腺的分泌物、类固醇衍生物与其它身体物质例如皮肤的油脂，可能被皮肤上的微生物区系(microflora)所降解，产生一系列的分解产物。此等由细菌产生的分解产物可能产生例如刺鼻性或腐臭气味。某些氨基酸也可能造成体臭。
因此总的说来体臭大部份为多种不同成分的混合物质，其组成尚未被完全分析过且不同个体之间可能非常地不同。因此，有关体臭的分析，不是仅仅通过生物化学测量而进行，而是由进行体臭评定的独立的人员采用他们的嗅觉器官进行，且以此方式在平分表上指出某一气味的强烈程度或使人不愉快的程度。
对于极端强烈且使人不愉快的情况，体臭被定义为一种称为“臭汗症”的疾病。不过，体臭也可能在从使人不愉快、讨厌到讨人喜欢或甚至于使人着迷或兴奋的广泛范围内为人所察觉。因此，于行为心理学中，体臭的影响不仅由强度(某物质嗅起来多强烈)而且也由情绪价(emotional valence)(某物质嗅起来多好或多坏)予以判断。
于今所知要获得讨人喜欢的体味之方法基本上包括使用来覆盖本身体味的香水、香料、物质与除臭剂。
此外，减低讨厌的体臭所用的治疗法主要针对皮肤细菌及其在皮肤上的分解活性。因此，于有臭汗症的情况中，建议例如下列事项：
·经常洗涤及更换内衣
·经常使用肥皂或合成洗涤剂(syndets)以洗清有强烈味道的物质
·使用除臭剂
·使用消毒剂或皮肤清洁剂以分别地减低或破坏皮肤菌群。
上面所提及的作法之缺点在于：愈广泛地使用这些措施，愈导致其对皮肤的刺激以及对皮肤作为屏障的功能之干扰，其可能导致讨厌的似湿疹反应而伴随着发红与搔痒。此外，在除臭剂内的香料物质特别会展现出高变态反应性(allergenic power)而促成一种免疫性变态反应性作用(immunological allergisation)导致毕生存在的变态反应。
虽然有建议采用对汗分泌的压制，例如经由使用含金属盐如氯化铝的溶液，来促成对汗腺通道的机械性堵塞，由此抑制流汗。不过，这些与类似的治疗法也时常会导致对皮肤产生讨厌的刺激作用。再者，考虑到上面所提及的汗的无味特点，这些方法也不适合于用来直接影响体臭，反而最好是对皮肤环境产生间接的改变。
因此，总而言之，所有常规作法都忽视气味腺以及对其进行操作以改善体臭的重要性。
所以，本发明的问题包括提供用于治疗臭汗症所用的药剂以及提供用于改善体臭的化妆工具。
这些问题由本申请的权利要求书中所界定的主题予以解决。
发明内容
本发明的一方面涉及肉毒杆菌毒素在制造用于预防或治疗臭汗症的药剂中的用途。本发明的另一方面涉及肉毒杆菌毒素在制造用于改善体臭的化妆剂中的用途。
因此，本发明涉及一种新的处理体臭之方法，例如使体臭减轻(较不强烈)和改善(感觉更令人喜悦)的方法。由于汗液是一种无味的流体，因此该方法不仅仅是要减少汗液的分泌，而是要改变产生可察觉的且令人讨厌的臭味的腋窝或其它皮肤部位的气味的特征。
附图说明
本发明要用下面的图式予以示范说明。
图1显示出使用肉毒杆菌毒素于一侧处理后的体臭强度评估(0＝没有可察觉的气味，6＝最强烈的气味)。对照处理腋窝：n＝16，中位数＝2.88，SD＝1.43。肉毒杆菌毒素-A-处理腋窝：n＝16，中位数＝1.75，SD＝0.86。显著性差异(Wilcoxon-test)：p＝0.02。BTA指肉毒杆菌毒素-A。
图2显示出使用肉毒杆菌毒素一侧处理后的体臭品质等级(价)评估(-3＝极端讨厌；+3＝极端令人喜悦)。对照处理腋窝：n＝16，中位数＝-1.13，SD＝0.89。肉毒杆菌毒素-A处理腋窝：n＝16，中位数＝0.5，SD＝0.75。显著性差异(Wilcoxon-test)：p＝0.001。BTA指肉毒杆菌毒素-A。
具体实施方式
肉毒杆菌毒素是由肉毒杆菌(Clostridium botulinum)在厌氧(anaerobic)条件下产生的一组高效力细菌毒素。自1989年之后在美国且自1991与1993年之后在德国，亚型肉毒杆菌毒素-A即分别经认可作为一种药用剂用以治疗选定的神经肌肉疾病。于德国，肉毒杆菌毒素-A的商品名有Botox(Merz，Frankfurt公司所经销；制造：Allergan，IrvineCa.，USA)与Dysport(Ispen-pharma，Ettlingen公司所经销)之下取得。自2001年之后，出现了名称为NeuroBloc(company Elan，Munich)的含有亚型肉毒杆菌毒素-B的另一种制剂。
肉毒杆菌毒素的药理学、药剂制造以及许多临床应用都在技术文献中有详细地说明[1，2]。肉毒杆菌毒素的临床效应在于其对乙酰胆碱(acetylcholine)释放的阻断。如此一来，使用乙酰胆碱作为递质(transmitter)的所有神经末端都可能被阻断。
肉毒杆菌毒素-A在过度发汗(多汗症)治疗中的成功应用已经在技术文献中有重复地述及[3]。但是，对于体臭的影响则至今尚未听闻。事实上，倒是在一篇有关多汗症的治疗之科学文章中讨论到肉毒杆菌毒素的注射对于体臭没有影响[3]。
不过，本发明人在临床观察中惊讶地发现肉毒杆菌毒素对于臭汗症的情况有效用且甚至可改善健康人的体臭。后者绝对不是成功的臭汗症治疗之必然结果，因为讨厌的、甚至是病理性的体臭的减轻应该只是会导致较低困扰性或最多不过是中性的体味，而不会导致产生一种不同的、正面的体味。
所以，本发明的一方面在于提供一种物质，其导致身体本身的气味对其同伴分别显示出逐渐增强的正面及更愉悦的影响且因而在所有嗅觉起着一种直接或间接的影响的人际关系的情况中给使用者产生竞争优势。
于此种情况中肉毒杆菌毒素不仅可以用其野生型形式而且可以用其衍生物、片段或有经过各种各样改变例如化学修饰的肉毒杆菌毒素。于此“衍生物”意指肉毒杆菌毒素的氨基酸序列可能包含取代、缺失、插入或添加。于此，“片段”意指只有某些部份的肉毒杆菌毒素可以使用，只要该部份显示出野生型肉毒杆菌毒素所具生物活性即可。
优选地，肉毒杆菌毒素系经由皮内注射而导入皮肤之内。这可以经由使用例如分别附有紧急皮下针头与常规针头(例如30号针)的注射器或以任何别的注射方法(例如分别为高压注射与无针头注射)予以完成。注射要在欲处理的皮肤部位上面均匀地分布例如以0.5至5厘米的距离分布。也可以使用其它种注射法例如皮下或表皮内注射。
其它的施用形式例如敷用一种适当的、有或没有辅助皮肤渗透的添加剂的制剂(例如凝胶、乳膏、软膏、喷剂)中的肉毒杆菌毒素，也适合所用，只要能提供活性剂的透皮吸收即可。同样地，可以使用水浴或含溶剂的浴于有或没有施加微弱的电流之下(离子电渗法(iontophoresis))将活性剂分别施加到皮肤上并导入皮肤内。
优选地制备成即用型肉毒杆菌毒素注射溶液。此类溶液可以经由例如将一包装单位的制剂Botox或制剂Dysport溶解在无菌生理盐水溶液(例如自由决定的1-10毫升体积)之内而制备成。或者使用已经可以取得为溶解形式的制剂Neurobloc。或者分别使用任何亚型的肉毒杆菌毒素(例如A、B、C、D、E、F、G)及这些肉毒杆菌毒素的衍生物、片段或有任何方面的改变之形式。或者分别使用适合于上面所提施药方式的数种肉毒杆菌毒素亚型的组合或与其它物质和辅助性物质的组合。活性剂在溶液中的浓度(以小鼠单位/毫升测定)可以根据个别需要与经验而自由地选用。
优选地，腋窝为适合治疗的部位，不过，任何其它身体区位都可以用其来治疗，例如鼠蹊区、臀部、足部。任何形式的支持性预-处理或后-处理，例如敷用止痛膏、冷却、皮肤浸渍或会改变气味的乳膏或软膏、或任何类型的外部施药，都可以与上面所提诸种施药形式之一组合地使用。
下面的实施例用来阐明本发明而不可误解为要用来限制本发明。
实施例
实施例1-医案研究(casuistics)
一个患有从腋窝散发出的强烈体臭之患者接受使用溶解在2毫升NaCl内的50单位Botox分布在每腋窝10个皮内注射点之治疗。于一星期之后，虽然还是具有相同的卫生习惯，不过检查到其体臭强度有显著地减低。
实施例2-初步研究
对一组16个试验人员于教育与以书写形式同意之后进行检测。对每一试验人员都要求不要使用除臭剂、香水或香皂等，不要食用洋葱、龙须菜或大蒜且与伴侣不亲密或亲近接触三天。于第三天要求每一试验人员穿上一件白色的T恤(100％棉，预先洗过)从中午到中午共24小时。于此之后，将T恤腋下部份切下并分开地放置到可气密地封锁住之玻璃烧瓶之内。将这些样品匿名地标记后，呈现给参与者作为嗅觉样品，每一参与者都嗅所有的嗅觉样品，但都不知道样品是从何人所得。于此之后，每一参与者都接受在两腋窝中每侧10切入点之注射治疗。于其中一侧系施用溶解在2毫升等张NaCl溶液内的100单位肉毒杆菌毒素-A(Dysport)而于另一侧系施用2毫升的等张生理盐水溶液。医师或参与者都不知道那一侧是用活性剂处理或用对照溶液处理(双盲式)。于一星期之后，在完全相同的条件之下重复T-恤嗅觉试验。在统计分析之后，发现在两边之间具有高度显著性差异：用肉毒杆菌毒素处理的腋窝与T恤切片分别嗅起来都比对照分别较不强烈且较不令人讨厌与更令人愉悦。
实施例3-初步研究
要求56个女人评估前面16个供应者的嗅觉样品。嗅觉样品的准备所用方法类似于实施例2，亦即从每一供应者得到2个样品：一者系来自经肉毒杆菌毒素-处理的腋窝；另一者系得自未经处理的腋窝。
所有女人都被要求评估下列诸项：
1.两个样品中哪一个嗅起来较为令人愉悦(双盲方式)？
2.嗅觉品质如何：(7分范围，从-3＝非常令人讨厌，经过0＝中性，到+3＝非常愉悦)？
3.你如何描述该气味(给出正面或负面形容词以供选择，例如花香相对于脓臭，水果香相对于腐臭味等)？
4.在觉察此气味时你的感觉如何(9分价)？
5.你能想要拥有此种气味的伴侣吗？
6.有关此气味你心理会出现什幺？
分析：对重复的象征性数据点(nominal data point)所得测量值利用McNemarχ2-试验计算配对式比较。
用肉毒杆菌毒素处理过的一侧之气味都高度显著地感觉为更令人愉悦(p＜0.001)且在直接比较与根据评分范围两者中都是如此。对于肉毒杆菌毒素处理过的样品更明显地使用到正面的形容词。于感受经肉毒杆菌毒素处理过的样品之情况中，女人都感觉高度明显地“更牢靠”(securer)与“更快乐”(happier)且相对于具有未处理样品所具气味者，她们也可能更明显地想象要拥有具有经肉毒杆菌毒素处理过的样品所具气味之伴侣。
参考文献
1.Huang W，Foster JA，Rogachefsky AS(2000)：Pharmacology ofbotulinum toxin.J Am Acad Dermatol 43：249-59
2.Munchau A，Bhatia KP(2000)：Uses of botulinum toxin injection inmedicine today.BMJ 320：161-5
3.Naumarm M，Hofmann U，Bergmann I，Hamm H，Toyka KV，ReinersK(1998)：Focal hyperhidrosis：effective treatment with intracutaneousbotulinum toxin[see comments].Arch Dermatol 134：301-4
4.Sato K，Kang WH，Saga K，Sato KT(1989)：Biology of sweat glandsand their disorders.II.Disorders of sweat gland function.J Am AcadDermatol 20：713-726
Claims (6)
1.肉毒杆菌毒素在制备用于预防臭汗症的药物中的用途。
2.肉毒杆菌毒素在制备用于治疗臭汗症的药物中的用途。
3.肉毒杆菌毒素在制备用于改善体臭的药物中的用途。
4.权利要求1-3中任一项的用途，其中所述肉毒杆菌毒素是肉毒杆菌毒素A、B、C、D、E、F和G型。
5.权利要求1-3中任一项的用途，其中所述肉毒杆菌毒素是肉毒杆菌毒素A型。
6.权利要求1-3中任一项的用途，其中所述肉毒杆菌毒素是肉毒杆菌毒素B型。
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| EP1545207B1 (en) | 2002-08-19 | 2018-03-14 | Ira Sanders | Treatment of holocrine gland dysfunction with clostridia neurotoxins |
| WO2004078199A1 (en) | 2003-03-06 | 2004-09-16 | Botulinum Toxin Research Associates, Inc. | Treatment of chronic chalazion and hordeolum with botulinum toxin |
| US8048423B2 (en) * | 2003-12-09 | 2011-11-01 | Allergan, Inc. | Botulinum toxin therapy for skin disorders |
| ZA200707352B (en) * | 2005-03-03 | 2009-04-29 | Revance Therapeutics Inc | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
| US9486408B2 (en) | 2005-12-01 | 2016-11-08 | University Of Massachusetts Lowell | Botulinum nanoemulsions |
| JP2010528981A (ja) | 2006-12-01 | 2010-08-26 | アンテリオス， インコーポレイテッド | 両親媒性実体ナノ粒子 |
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