CN1209065A - 耳用微生物联合用药 - Google Patents
耳用微生物联合用药 Download PDFInfo
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- A61P31/02—Local antiseptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明公开了一种用于治疗耳部感染的耳用组合物,包含有治疗效果的联合使用的抗菌素如喹诺酮或其盐以及磺胺嘧啶银,用于治疗动物的耳部感染。
Description
发明背景
发明领域：
本发明涉及耳用制剂和抗微生物药剂，更具体说，涉及含有联合使用的抗微生物药剂如喹诺酮和磺胺嘧啶银的耳用制剂。
现有技术简述：
美国专利4,404,197公开了在治疗烧伤时使用某些喹诺酮和磺胺嘧啶银。更具体说，该专利公开了含有磺胺嘧啶银和1-乙基-6-氟-1，4-二氢-4-氧代-7-(1-哌嗪基)-3-喹诺酮羧酸或其金属盐，比如银盐、锌盐、钴盐或铈盐的组合物。显然，该专利教导了这些组合物在治疗烧伤方面的应用，以及在治疗局部的表面或皮肤感染方面的应用，包括微生物和真菌感染等方面的应用。然而，该专利没有教导或建议该组合物在耳部的应用。
美国专利3,761,590公开了磺胺嘧啶银单独在治疗烧伤方面的应用。磺胺嘧啶银，优选以在可水分散的亲水性载体中的制剂应用于烧伤。
荷兰林堡(Limburg)大学微生物医学系的伯加德(Bogaard)等人公开了磺胺嘧啶银霜膏在治疗狗的外耳道慢性假单孢菌感染方面的应用。
正如人们所认识到的，需要有一种有效的组合物用于治疗耳部感染。本发明提供一种用于治疗耳部感染治疗有效的活性成分联合用药。
发明概要
如前所述，本发明包括一种用于治疗动物的耳部感染的组合物，所述的组合物含有有治疗效果的联合使用的抗微生物药剂如抗菌剂，优选为喹诺酮或其盐类，以及磺胺嘧啶银。本发明还包括含有有治疗效果的联合使用的抗微生物药剂如抗菌剂，优选为喹诺酮或其盐类，以及磺胺嘧啶银的组合物在治疗耳部感染方面的应用。
本发明也包括了通过给动物，特别是小动物比如狗施用该组合物治疗耳部感染的方法。含有有治疗效果的联合使用的抗微生物药剂如抗菌剂，优选为喹诺酮或其盐类，以及磺胺嘧啶银的组合物可以单独使用，或者与生理上可接受的载体如水包油乳液一起使用。
该组合物可以安全而有效地用来治疗耳部感染，比如外耳道的感染。该组合物特别可以用于治疗由于假单孢菌细菌或厚皮马拉色霉菌引起的感染。下面将更详细地叙述本发明。
发明详述
如上所述，本发明涉及用于治疗耳部感染的组合物。该组合物含有有治疗效果的联合使用抗微生物药剂如抗菌剂，优选为喹诺酮或其盐类，以及磺胺嘧啶银。一般说来，该喹诺酮是氟取代的喹诺酮。下面专门就喹诺酮说明有效的联合使用。不过，本发明包括联合使用磺胺嘧啶银和可以与磺胺嘧啶银联合使用的其他抗微生物剂，以联合使用磺胺嘧啶银和喹诺酮的方式，提供对耳部感染的有效治疗。
氟代喹诺酮的非限定性的例子可以选自恩氟沙星、6-氟-1，4-二氢二氢-1-(甲基氨基)-7-(4-甲基-1-哌嗪基)-4-氧代-3-喹诺酮羧酸(氨氟沙星)、Benofloxacin、6-氟-1-(4-氟苯基)-1，4-二氢-7-(4-甲基-1-哌嗪基)-4-氧代-3-喹诺酮羧酸(二氟沙星)、Flerofloxacin、6，8-二氟-1-(2-氟-乙基)-1，4-二氢-7-(4-甲基-1-哌嗪基)-4-氧代-3-喹诺酮羧酸(氟罗沙星)、1-乙基-6，8-二氟-1，4-二氢-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹诺酮羧酸(洛美氟沙星)、马波沙星、1-乙基-6-氟-1，4-二氢-4-氧代-7-(哌嗪基)-3-喹诺酮羧酸(诺氟沙星)、9-氟-2，3-二氢-3-甲基-10-(4-甲基-1-哌嗪基)-7-氧代-7H-吡啶并[1，2，3-de]-1，4-苯并噁嗪-6-羧酸(氧氟沙星)、全氟沙星(Perfloxacin)、芦氟沙星、沙氟沙星和替马氟沙星。优选的氟代喹诺酮是恩氟沙星。引在本文中作为参考的美国专利4,556,658专门就恩氟沙星及其制备方法对喹诺酮进行了说明而非限定性的叙述。
喹诺酮或其盐类以及磺胺嘧啶银的用量要足以提供出有药物效果的组合物。以组合物的重量计，喹诺酮或其盐的用量为0.005-1.5％，优选0.1-1％。以组合物的重量计，磺胺嘧啶银的用量为0.05-2％，优选0.5-1.5％。
在制备该组合物时，可以以任何常规方式合并喹诺酮和磺胺嘧啶银。比如，可以将研成细粉的磺胺嘧啶银和喹诺酮相互混合。该组合物可以直接使用，或者优选以与可药用的生理载体配伍使用。
可药用的生理载体的非限定性的例子可以是水包油乳液。一般说来，这种油是无刺激性的润滑油，其用以说明而非限定性的例子可以选自矿物油、植物油和已知组成的改性植物油。这种油的更具体而非限定性的例子可以选自花生油、芝麻油、棉籽油等，以及Huls AmericaInc.公司生产的中等链长(C6～C12)的三甘油酯(如Miglyol NeutralOils 810、812、818、829、840等)。在此使用的典型的乳化剂可以选自Span 60和Tween 60，前者是一种缩水山梨糖醇一硬脂酸酯，后者是聚乙氧基醚60，两者都来自ICI Americas公司。乳化剂优选非离子型乳化剂。乳化剂的用量可以是组合物重量的1.5～6.5％，优选3.0～5.0％。乳液的疏水相的用量可以是组合物重量的15.0～25.0％，优选18.0～22.0％。
本发明的区别特征是本发明的组合物可以配制成含有在本文中叙述的水包油乳液的乳液基形式。在此以前，磺胺嘧啶银一直被配制成霜基形式或固体状合成敷料形式用以治疗烧伤。有关的硝酸银溶液被认为是不希望的。
除了上述的组分以外，本发明组合物的制剂可以含有其他的组分，比如防腐剂(苯甲醇、对羟基苯甲酸酯类或苯甲酸盐类)、稳定剂(鲸蜡硬脂醇、甘油酯)、遮味剂和着色剂等。
下面是提供本发明组合物方法的说明性而非限定性的叙述。在一个适当安装的容器中，在油中加热乳化剂和脂肪醇形成悬浮液，在此悬浮液中加入活性组分。在另一个容器中，在热水中加入乳化剂形成水溶液。在剧烈搅拌下向此溶液中加入防腐剂和悬浮液。得到的含有本发明组合物的混合物具有治疗耳部感染的效果。
在治疗耳部感染时，该组合物优选在局部涂敷有药效量施用。该组合物的涂敷剂量可以是每只耳朵5～20滴，优选为每只耳朵8～12滴，以涂敷耳道。
在下面的非限定性实施例进一步说明本发明，其中除非另有说明，所有的份数和百分数都是按重量计的。
实施例
下面的实施例说明本发明的耳用组合物及其制备和使用方法，在本发明的这些实施方案中磺胺嘧啶银和喹诺酮按如下方法合并。
在50～60℃的温度下，在一个SS夹套槽中，在水中加入聚乙氧基醚60(Tween 60)。把得到的水溶液加热到61～75℃。在66℃的温度下将防腐剂(苯甲醇)加入到水溶液中，同时搅拌3～10分钟。
在75℃的温度下，在3～5分钟的时间内，在另一个容器中向Mygliol Oil油中加入恩氟沙星和磺胺嘧啶银。在油状混合物中加入缩水山梨糖醇一硬脂酸酯(Span 60)和鲸蜡硬脂醇。将得到的油状混合物加热到62～75℃。然后在3～5分钟内，在66℃和剧烈的搅拌下将此油状混合物加入到水溶液中。将得到的组合物冷却到35～45℃，借助于高剪切乳化机混合和通过均化机进行均化。将组合物进一步冷却至25～30℃。用适当的容器包装最终的组合物。
实施例1～3叙述了使用上述的方法和如下所列的重量份的各组分来制备含有本发明组合物的制剂。
实施例1：
组分
重量份
恩氟沙星 0.005～1.5
磺胺嘧啶银(SSD) 0.05～2.0
聚乙氧基醚60 0.5～3.5
缩水山梨糖醇一硬脂酸酯 0.5～3.0
鲸蜡硬脂醇 0.5～3.0
苯甲醇 1.0～3.0
Miglyol Oil油 8～18
水 89.4～68
实施例2：
组分
重量份
恩氟沙星 0.5～1.0
磺胺嘧啶银(SSD) 0.5～1.5
聚乙氧基醚60 1.0～3.0
缩水山梨糖醇一硬脂酸酯 1.0～2.0
鲸蜡硬脂醇 1.0～2.0
苯甲醇 1.5～2.5
Miglyol Oil油 12～16
水 85～74
实施例3
组分
重量份
恩氟沙星 0.5
磺胺嘧啶银(SSD) 1.0
聚乙氧基醚60 2.5
缩水山梨糖醇一硬脂酸酯 1.5
鲸蜡硬脂醇 1.5
苯甲醇 2.0
Miglyol Oil油 14.5
水 76.5
实施例4
用多种犬耳病原体对合用恩氟沙星(喹诺酮)和磺胺嘧啶进行体外微生物学的研究。在国家临床实验室标准委员会(NCCLS)指南的指导下，对于每一种测试的琼脂板使用ATCC对照生物体进行研究。开始时，确定每一种活性组分的最低抑制浓度(MIC)。在MIC的基础上，恩氟沙星和磺胺嘧啶银(SSD)对普通的皮(耳)病原体都是有活性的。虽然两者都是杀细菌的，但是作用模式不同。不同的作用模式降低了对耐药形成的可能性。另外，在测试的浓度下，恩氟沙星对马拉色霉菌或念珠菌是无效的。而磺胺嘧啶银对两者都是有效的。以前磺胺嘧啶银对马拉色霉菌活性的证据未见报道。
使用MIC数据，用标准方格检查板系统制备了含有一系列稀释的合用抗生素的琼脂板。为了确定在恩氟沙星和磺胺嘧啶银之间的可能的相互作用，制备了稀释样，它们大多是从各抗生素MIC以上的三种稀释度到各抗生素MIC以下的三种稀释度。在暴露于各种抗菌素之后，比较单个的分离菌的生长(抑制)模式。具有相同反响的单个菌属的分离菌被归为一组。然后对所有的分离菌进行数学计算，以示这些抗菌素是否具有拮抗或协同作用，或是介于两者之间。称作分级抑制浓度(FIC)指数的标准计算表示如下：
式中X等于药物X的浓度，是在其检查板的行中的最低抑制浓度，而Y等于药物Y在其检查板行上的浓度。
FIC指数等于或小于0.5表示是有协同性的；
FIC指数等于或大于2.0表示是有拮抗性的；
FIC指数等于或大于0.5，但是小于2.0表示没有影响。
为了进行比较，恩氟沙星也和克霉唑一起使用。克霉唑也有抗霉活性，但是对细菌基本没有活性。使用同样的一系列病原体以对两种抗菌素的组合进行评价。表明了两种组合方式所观察的反响的研究得到的FIC数据列于下表(表1)。
表1
相互作用的抗菌范围
分级抑制浓度指数
生物体 Enro*+SSD Enro+Clotr
绿脓杆菌(15)** 0.507～0.75 1.167～2.67
中间葡萄球菌(12) 1.5 1.5
大肠杆菌(7) 0.36～1.5 0.8～1.8
肺炎杆菌(5) 0.62～1.5 1.8～2.3
β血液葡萄球菌(9) 0.625～1.5 0.75～2.25
马拉色霉菌属(12) 1.5 0.56～1.5
念珠菌属(4) 1.5～1.75 1.5
*药物的缩写是Enro＝恩氟沙星 SSD＝磺胺嘧啶银
Clotr＝克霉唑
**括弧内的数字表示测试的分离菌株数。
至于上面所报道的分离菌株，合并使用恩氟沙星和磺胺嘧啶银的值均未在拮抗性范围内。许多细菌的分离菌株的FIC指数小于1表明了明显的增效作用倾向。而对马拉色霉菌和念珠菌则较少有增效作用倾向。
因为联合使用具有不同活性模式的抗菌素刚好容易表现出对抗性，所以恩氟沙星和磺胺嘧啶银的增效作用是无法预见的。比如联合使用恩氟沙星和克霉唑明显地表现出拮抗性。在上面报道的5个细菌属中的3个计算出评分大于2。克霉唑没有抗菌活性，数据仍然表明该药物明显地干扰了恩氟沙星的抗菌效能。
虽然在前面出于说明的目的详细地叙述了本发明，应该理解，这些细节只是为了这样的目的，本领域的专业人员在不背离由权利要求所限定的本发明精神和不超出本发明的范围的情况下可以进行变化。
Claims (17)
1.一种用于治疗耳部感染组合物，含有有治疗效果的联合使用的抗菌素和磺胺嘧啶银，以治疗动物的耳部感染。
2.如权利要求1的组合物，其中的抗菌素是喹诺酮或其盐类。
3.如权利要求2的组合物，其中的喹诺酮是氟代喹诺酮，氟代喹诺酮的酯或者氟代喹诺酮的盐。
4.如权利要求3的组合物，其中的氟代喹诺酮选自氨氟沙星、Benofloxacin、二氟沙星、恩氟沙星、Flerofloxacin、氟罗沙星、洛美氟沙星、马波沙星、诺氟沙星、氧氟沙星、全氟沙星、沙氟沙星和替马氟沙星。
5.如权利要求4的组合物，其中的氟代喹诺酮是恩氟沙星。
6.如权利要求1的组合物，其中抗菌素的用量为组合物重量的0.005～1.5％。
7.如权利要求6的组合物，其中抗菌素的用量为组合物重量的0.1～1％。
8.如权利要求1的组合物，其中的磺胺嘧啶的用量为组合物重量的0.05～2％。
9.如权利要求8的组合物，其中的磺胺嘧啶的用量为组合物重量的0.5～1.5％。
10.如权利要求1的组合物，其中还含有可药用的载体。
11.如权利要求10的组合物，其中的载体含有乳液。
12.如权利要求11的组合物，其中的乳液是水包油乳液。
13.如权利要求11的组合物，其中的乳液含有乳化剂，其用量是组合物重量的1.5～6.5％。
14.如权利要求11的组合物，其中的乳液含有非水相，其含量为组合物重量的15～25％。
15.治疗动物耳部感染的方法，包括给耳部感染的动物施用权利要求1的组合物。
16.如权利要求15的方法，其中组合物以药物有效量施用。
17.如权利要求15的方法，其中每天施用组合物两次。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/579,461 | 1995-12-27 | ||
| US08/579,461 US5753269A (en) | 1995-12-27 | 1995-12-27 | Otic microbial combinations |
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| Publication Number | Publication Date |
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| CN1209065A true CN1209065A (zh) | 1999-02-24 |
| CN1191069C CN1191069C (zh) | 2005-03-02 |
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| CNB961999942A Expired - Lifetime CN1191069C (zh) | 1995-12-27 | 1996-12-10 | 耳用微生物联合用药 |
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| US (1) | US5753269A (zh) |
| EP (1) | EP0869795A1 (zh) |
| JP (1) | JP2000502703A (zh) |
| CN (1) | CN1191069C (zh) |
| AU (1) | AU709478B2 (zh) |
| BR (1) | BR9612325A (zh) |
| CA (1) | CA2193597C (zh) |
| HK (1) | HK1018592A1 (zh) |
| HU (1) | HU229339B1 (zh) |
| MX (1) | MX9606361A (zh) |
| NZ (1) | NZ326061A (zh) |
| WO (1) | WO1997024128A1 (zh) |
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| CN107920510A (zh) * | 2015-08-24 | 2018-04-17 | 史密夫和内修有限公司 | 中等极性油与抗菌剂的组合在细菌生物膜上的协同抗菌活性 |
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| US6361526B1 (en) * | 1993-11-01 | 2002-03-26 | Medtronic Xomed, Inc. | Antimicrobial tympanostomy tube |
| US20040191329A1 (en) * | 2000-07-27 | 2004-09-30 | Burrell Robert E. | Compositions and methods of metal-containing materials |
| US20030180379A1 (en) * | 2000-07-27 | 2003-09-25 | Burrell Robert E. | Solutions and aerosols of metal-containing compounds |
| US7098219B2 (en) | 2000-08-01 | 2006-08-29 | Wockhart Limited | Inhibitors of cellular efflux pumps of microbes |
| WO2002009758A2 (en) * | 2000-08-01 | 2002-02-07 | Wockhardt Limited | Inhibitors of cellular efflux pumps of microbes |
| CA2425749A1 (en) * | 2000-09-25 | 2002-04-04 | Daniel Ciszewski | Otic microbial combinations for treatment of animals with ruptured tympanic membrane |
| US6964966B2 (en) | 2001-04-25 | 2005-11-15 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
| US6878713B2 (en) | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
| WO2004006957A1 (en) * | 2002-07-15 | 2004-01-22 | Alcon, Inc. | Pharmaceutical compositions for otic use |
| ATE366734T1 (de) | 2003-09-04 | 2007-08-15 | Wockhardt Ltd | Benzochinolizin-2-carbonsäureargininsalz- tetrahydrat |
| US8003616B2 (en) | 2004-04-23 | 2011-08-23 | Albert Rory J | Composition for the treatment of ear infections and method |
| DE102005055385A1 (de) * | 2004-12-09 | 2006-06-14 | Bayer Healthcare Ag | Arzneimittel zur hygienischen Applikation im Ohr |
| EP1973587B1 (en) | 2005-12-12 | 2019-02-06 | AllAccem, Inc. | Methods and systems for preparing antimicrobial films and coatings |
| WO2008085913A1 (en) * | 2007-01-04 | 2008-07-17 | Rib-X Pharmaceuticals, Inc. | Methods for treating, preventing, or reducing the risk of opthalmic, otic, and nasal infections |
| ES2522908T3 (es) | 2007-02-21 | 2014-11-19 | Allaccem, Inc. | Composiciones a base de compuestos policíclicos con puente para la inhibición y el alivio de enfermedades |
| US8188068B2 (en) * | 2007-08-10 | 2012-05-29 | Allaccem, Inc. | Bridged polycyclic compound based compositions for coating oral surfaces in pets |
| US8153617B2 (en) * | 2007-08-10 | 2012-04-10 | Allaccem, Inc. | Bridged polycyclic compound based compositions for coating oral surfaces in humans |
| US8153618B2 (en) * | 2007-08-10 | 2012-04-10 | Allaccem, Inc. | Bridged polycyclic compound based compositions for topical applications for pets |
| US20090074833A1 (en) * | 2007-08-17 | 2009-03-19 | Whiteford Jeffery A | Bridged polycyclic compound based compositions for controlling bone resorption |
| US20100004218A1 (en) * | 2008-06-20 | 2010-01-07 | Whiteford Jeffery A | Bridged polycyclic compound based compositions for renal therapy |
| US20100016270A1 (en) * | 2008-06-20 | 2010-01-21 | Whiteford Jeffery A | Bridged polycyclic compound based compositions for controlling cholesterol levels |
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| US3761590A (en) * | 1970-05-18 | 1973-09-25 | Research Corp | Silver sulfadiazine used in the treatment of burns |
| US4404197A (en) * | 1981-05-15 | 1983-09-13 | Fox Jr Charles L | Antimicrobial compositions containing 1-ethyl-6-fluoro-1,4-dihydro-4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid or metal salts thereof and silver sulfadiazine |
| IT1136624B (it) * | 1981-05-21 | 1986-09-03 | Erregierre Ind Chim Spa | Prodotti di salificazione di acidi colici,processo per la loro preparazione e composizioni terapeutiche che li comprendono come principio attivo |
| EP0154622A4 (en) * | 1983-09-12 | 1987-03-16 | Research Corp | ANTIMICROBIAL COMPOSITIONS CONTAINING 1-ETHYL-6-FLUOR-1,4-DIHYDROXY-4-OXO-7 (1-PIPERAZINYL) -3-QUINOLINE CARBONIC ACID OR THEIR METAL SALTS AND SILVER SULFADIAZINE. |
| JPH01258620A (ja) * | 1988-04-08 | 1989-10-16 | Dai Ichi Seiyaku Co Ltd | 耳疾患用局所製剤 |
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1995
- 1995-12-27 US US08/579,461 patent/US5753269A/en not_active Expired - Lifetime
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- 1996-12-10 WO PCT/US1996/019946 patent/WO1997024128A1/en not_active Application Discontinuation
- 1996-12-10 JP JP09524358A patent/JP2000502703A/ja active Pending
- 1996-12-10 NZ NZ326061A patent/NZ326061A/xx not_active IP Right Cessation
- 1996-12-10 HU HU9902206A patent/HU229339B1/hu unknown
- 1996-12-10 CN CNB961999942A patent/CN1191069C/zh not_active Expired - Lifetime
- 1996-12-10 BR BR9612325A patent/BR9612325A/pt not_active Application Discontinuation
- 1996-12-10 AU AU13342/97A patent/AU709478B2/en not_active Expired
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- 1996-12-13 MX MX9606361A patent/MX9606361A/es active IP Right Grant
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107920510A (zh) * | 2015-08-24 | 2018-04-17 | 史密夫和内修有限公司 | 中等极性油与抗菌剂的组合在细菌生物膜上的协同抗菌活性 |
| US11197476B2 (en) | 2015-08-24 | 2021-12-14 | Smith & Nephew, Inc. | Synergistic antibacterial activity of medium polarity oils in combination with antibacterial agents on bacterial biofilms |
| US11641856B2 (en) | 2015-08-24 | 2023-05-09 | Smith & Nephew, Inc. | Synergistic antibacterial activity of medium polarity oils in combination with antibacterial agents on bacterial biofilms |
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| Publication number | Publication date |
|---|---|
| CA2193597A1 (en) | 1997-06-28 |
| BR9612325A (pt) | 1999-07-13 |
| HU229339B1 (en) | 2013-11-28 |
| HUP9902206A2 (hu) | 1999-12-28 |
| US5753269A (en) | 1998-05-19 |
| EP0869795A1 (en) | 1998-10-14 |
| CA2193597C (en) | 2009-03-31 |
| NZ326061A (en) | 1999-11-29 |
| AU709478B2 (en) | 1999-08-26 |
| WO1997024128A1 (en) | 1997-07-10 |
| CN1191069C (zh) | 2005-03-02 |
| MX9606361A (es) | 1997-06-28 |
| HK1018592A1 (en) | 1999-12-30 |
| HUP9902206A3 (en) | 2000-01-28 |
| AU1334297A (en) | 1997-07-28 |
| JP2000502703A (ja) | 2000-03-07 |
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