CN1320035A - 治疗眼、耳和鼻的抗生素组合物 - Google Patents

治疗眼、耳和鼻的抗生素组合物 Download PDF

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CN1320035A
CN1320035A CN99811509A CN99811509A CN1320035A CN 1320035 A CN1320035 A CN 1320035A CN 99811509 A CN99811509 A CN 99811509A CN 99811509 A CN99811509 A CN 99811509A CN 1320035 A CN1320035 A CN 1320035A
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G·卡格尔
R·L·阿布希尔
D·W·斯特罗曼
J·M·扬尼
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Abstract

本发明公开了含一类新型抗生素(例如莫氟沙星)的眼、耳和鼻用组合物。所述组合物优选还含有一种或多种消炎剂。可以利用所述组合物通过将所述组合物涂敷到受影响的组织上治疗眼、耳和鼻病症。

Description

治疗眼、耳和鼻的抗生素组合物
本发明涉及治疗眼、耳和鼻感染，特别是细菌感染的局部抗生素药用组合物，以及通过将这些组合物施加到所述受影响的组织来治疗眼、耳和鼻感染的方法。本发明的组合物和方法是基于一类新抗生素的用途。本发明的组合物还可以含有一种或多种消炎剂。
使用喹诺酮抗生素治疗感染代表了眼药组合物和治疗方法领域中现行的技术状态。例如，含有喹诺酮环丙沙星的眼药组合物是由AlconLaboratories公司以名称CILOXANTM(环丙沙星0.3％)眼药液销售的。在眼用抗生素组合物中还利用了以下喹诺酮类：
喹诺酮            产品             厂商
氧氟沙星          OCUFLOXTM        Allergan
诺氟沙星          CHIBROXINTM      Merck
洛美沙星          LOMEFLOXTM       Senju
前面的喹诺酮抗生素组合物通常在治疗眼感染中是有效的，并且与较早的眼用抗生素组合物，特别是具有相对有限的抗生活性范围的那些，如：主要用于抗革兰氏阴性病原体的新霉素、多粘菌素B、庆大霉素和妥布霉素以及主要具有抗革兰氏阳性病原体活性的杆菌肽、短杆菌肽和红霉素相比具有明显的益处。尽管目前可以获得眼用喹诺酮治疗的一般功效，但是需要基于使用抗生素类的改进组合物和治疗方法，这些抗生素比现有抗生素抗关键眼科病原体更有效且不易因这些病原体产生耐药性。
对用于治疗耳和鼻感染，特别是细菌感染的有效的局部组合物和方法的需求日益增加。使用口服抗生素治疗小孩的耳感染的功效有限，并且带来抗口服抗生素的病原体耐药性的严重危险。
眼、耳和鼻感染经常伴随着感染的眼、耳和鼻组织以及可能甚至周围组织发炎。类似地，带来微生物感染危险的眼、耳和鼻手术过程还经常使受影响的组织发炎。因此，还需要将所述一种或多种抗生素的抗感染活性与一种或多种甾类或非甾类试剂的消炎活性组合在单一组合物中的眼、耳和鼻的药用组合物。
本发明基于一类有效治疗眼、耳和鼻感染的新抗生素的用途，以及眼、耳或鼻组织手术或其它外伤之后这些抗生素的预防性用途。为了预防或减轻手术后感染，还可以在眼、耳或鼻手术过程中将本发明的组合物给投到受影响的组织上。
优选所述组合物还含有一种或多种消炎剂，从而治疗与眼、耳或鼻组织感染有关的炎症。所述组合物中的消炎组分还对治疗与眼、耳或鼻组织的物理外伤有关的炎症，包括手术过程所致的炎症，有用。因此本发明的组合物对治疗与眼、耳或鼻组织的外伤有关的炎症特别有用，所述组织中或者存在外伤所致的感染或者存在外伤所致感染的危险。
可以用本发明的组合物治疗的眼病症的例子包括结膜炎、角膜炎、睑炎、泪囊炎、睑腺炎和角膜溃疡。本发明的组合物还可以预防性地用于与带来感染危险的各种眼外科手术结合。
可以用本发明的组合物治疗耳病症的例子包括外耳炎和中耳炎。就中耳炎的治疗而言，本发明的组合物主要对鼓膜已破裂并已植入鼓膜穿刺管的情况有用。所述组合物还可用于治疗与如鼓膜穿刺术的耳手术过程有关的感染，或者用于预防这些感染。
为了局部施加到眼、耳和鼻组织，本发明的组合物经过特定配制。所述组合物优选无菌，且具有特别适宜施加到眼、耳和鼻组织(包括已因先前存在的疾病、外伤或其它物理条件受损的组织)的物理性能(例如同渗重量摩尔浓度和pH)。
用于本发明的组合物和方法的抗生素类具有以下结构式及其药用上有用的水合物和盐：其中：
A为CH、CF、CCl、C-OCH3或N；
X1为H、卤素、NH2或CH3；
R1为C1-C3烷基、FCH2CH2、环丙基或苯基，选择性地被一个、二个或三个卤素取代，或者A与R1一起可以形成式C-O-CH2-CH(CH3)的桥；
R2为H、C1-C3烷基(选择性地被OH、卤素或NH2取代)、或者5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基-甲基；和
B选自以下基团：其中：
Y为O或CH2；
R3为C2-C5烷氧基、CH2-CO-C6H5、CH2CH2CO2R’、R’O2C-CH=C-CO2R’、CH=CH-CO2R’或CH2CH2-CN，
其中：
R’为H或C1-C3烷基；
R4为H、C1-C3烷基、C2-C5烷氧基、CH2-CO-C6H5、CH2CH2CO2R’、R’O2C-CH=C-CO2R’、CH=CH-CO2R’、CH2CH2-CN或5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基-甲基，其中：
R’为H或C1-C3烷基。最优选化合物莫氟沙星(Moxifloxacin)。莫氟沙星的结构如下：
Figure A9981150900071
在美国专利5607942中提供了式(Ⅰ)的莫氟沙星及其它化合物的更详细结构、制备方法和物理性能。
本发明组合物中的式(Ⅰ)抗生素的浓度将根据组合物的预定用途(例如治疗现有的感染或预防手术后感染)和所选具体抗生素的相关抗微生物活性而变化。所述抗生素的抗微生物活性通常可以抑制特定病原体生长所需的最小浓度来表示。该浓度还被称之为“最小抑制浓度”或“MIC”。术语“MIC90”是指抑制一个种中90％菌株生长所需的抗生素最小浓度。完全杀死指定细菌所需的抗生素的浓度被称之为“最小杀菌浓度”或“MBC”。下表提供了用于通常与眼、耳和鼻感染有关的几种细菌的莫氟沙星的最小抑制浓度：微生物                     MIC90金黄色葡萄球菌/甲氧西林敏  0.13感的金黄色葡萄球菌/耐甲氧西林  4.0的金黄色葡萄球菌/耐喹诺酮的  4.0表皮葡萄球菌/甲氧西林敏感  0.25的表皮葡萄球菌/耐甲氧西林的  4.0肺炎链球菌/甲氧西林敏感的  0.25肺炎链球菌/耐甲氧西林的    0.25绿脓假单胞菌               8.0流感嗜血菌/β-内酰胺酶阳性  0.06的流感嗜血菌/β-内酰胺酶阴性  0.06的
前面的所有浓度都以微生物/毫升(″mcg/ml″)计。
眼用组合物的适宜抗生素浓度通常是一种或多种式(Ⅰ)抗生素的量足以使在眼中眼房水和泪液中的浓度等于或大于所选抗生素相对通常与眼感染有关的革兰氏阴性和革兰氏阳性生物体的MIC90水平。耳和鼻用组合物的适宜浓度通常是一种或多种式(Ⅰ)抗生素的量足以使在所感染的组织中的浓度等于或大于所选抗生素相对通常与耳或鼻感染有关的革兰氏阴性和革兰氏阳性生物体的MIC90水平。这些量在本文中被称之为“抗微生物有效量：本发明的组合物典型地含有一种或多种式(Ⅰ)化合物，其浓度为组合物重量的约0.1-约1.0wt％。
本发明的组合物还可以含有一种或多种消炎剂。用于本发明的所述消炎剂广义上被分成甾类或非甾类。优选的甾类消炎剂为糖皮质激素类。
眼和鼻用的优选糖皮质激素类包括地塞米松、氯替泼诺、利美索龙、泼尼松龙、氟米龙和氢化可的松。鼻用的优选糖皮质激素类包括莫米松、氟替卡松、倍氯米松、氟尼缩松、去炎松和布地奈德。
尤其在治疗眼炎的组合物中，美国专利5223493(Boltralik)中描述的地塞米松衍生物还是优选的甾类消炎剂。特别优选以下化合物：
Figure A9981150900081
这些化合物在本文中被称之为“地塞米松的21-醚衍生物”。特别优选其21-苄醚衍生物(即化合物AL-2512)。
优选的非甾类消炎剂有：前列腺素H合成酶抑制剂(CoxⅠ或CoxⅡ)，还将其称之为环加氧酶Ⅰ型和Ⅱ型抑制剂，如双氯芬酸、氟比洛芬、酮咯酸、舒洛芬、nepafenac、氨芬酸、消炎痛、萘普生、布洛芬、溴芬酸、酮洛芬、甲氯芬那盐、吡罗昔康、舒林酸、甲芬那酸、二氟尼柳、奥沙普秦、托美丁、非诺洛芬、苯噁洛芬、那布米酮、依托度酸、保泰松、阿斯匹林、羟布宗、NCX-4016、HCT-1026、NCX-284、NCX-456、滕诺息卡和卡洛芬；环加氧酶Ⅱ型选择性抑制剂，如NS-398、vioxx、celecoxib、P54、依托度酸、L-804600和S-33516；PAF拮抗剂，如SR-27417、A-137491、ABT-299、阿帕泛、贝帕泛、米诺帕泛、E-6123、BN-50727、纽帕泛和莫地帕泛；PDE Ⅳ抑制剂，如ariflo、托巴茶碱、咯利普兰、filaminast、piclamilast、cipamfylline、CG-1088、V-11294A、CT-2820、PD-168787、CP-293121、DWP-205297、CP-220629、SH-636、BAY-19-8004和roflumilast；细胞因子生成抑制剂，如NFkB转录因子抑制剂；或本领域技术人员已知的其它消炎剂。
本发明组合物中所含的消炎剂的浓度将根据所选试剂和所治疗的炎症类型而变化。其浓度应在向眼、耳或鼻组织局部施加所述组合物之后将足以减轻这些组织中的炎症。在本文中这种量被称之为“消炎有效量”。本发明的组合物典型地含有一种或多种消炎剂，其量为约0.01-约1.0wt％。
典型地，通过每天1-4次局部施加1-4滴无菌液或悬浮液、或者可比较量的软膏、凝胶或其它固体或半固体组合物来将所述组合物给到受影响的眼、耳或鼻组织。但是，所述组合物还可以被配制成在手术过程中施加到受影响的眼、耳或鼻组织的冲洗液。
本发明的眼、耳和鼻用组合物含有药用上可接受的载体中和一种或多种式(Ⅰ)组合物并优选含有一种或多种消炎剂。所述组合物将典型地具有4.5-8.0的pH。所述眼用组合物还必需配制成具有与眼和眼组织中的眼房水一致的渗透值。这些渗透值通常为约200-约400毫渗克分子/kg水(“mOsm/kg”)，但是优选约300mOsm/kg。
典型地以多剂量形式包装眼、耳和鼻用药用产品。因此需要防腐剂以防止使用时微生物污染。适宜的防腐剂包括：多季铵鎓-1、苯扎氯铵、硫汞撒、氯丁醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯乙醇、乙二胺四乙酸二钠、山梨酸或本领域技术人员已知的其它试剂。优选使用多季铵鎓-1作为抗微生物防腐剂。典型地以0.001％-1.0wt％的浓度使用这些防腐剂。
可以通过将表面活性剂或其它适宜辅助溶剂加入本组合物中提高该组合物的组分的溶解度。这些辅助溶剂包括聚山梨酯20、60和80、聚氧化乙烯/聚氧化丙烯表面活性剂(例如Pluronic F-68、F-84和P-103)、环糊精或本领域技术人员已知的其它试剂。典型地以以0.01％-2wt％的浓度使用这些辅助溶剂。
可以根据需要使用粘度提高剂使本发明的组合物的粘度大于简单水溶液的粘度，从而通过所述靶组织提高活性化合物的眼吸收作用或增加在眼、耳或鼻中的保留时间。这些粘度增强剂包括例如，聚乙烯醇、聚乙烯基吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧甲基纤维素、羟丙基纤维素或本领域技术人员已知的其它试剂。这些试剂典型地以0.01％-2wt％的浓度使用。
提供以下实施例以进一步说明本发明的眼、耳和鼻用组合物。
实施例1
眼/耳/鼻溶液
组分        量(wt％)
莫氟沙星      0.35
乙酸钠        0.03
乙酸          0.04
甘露糖醇      4.60
EDTA          0.05
苯扎氯铵      0.006
水         适量，至100
     实施例2
  眼/耳/鼻悬浮液
组分              量(wt％)
莫氟沙星            0.3
地塞米松，微粒化    0.10
USP
苯扎氯铵            0.01
乙二胺四乙酸二钠，  0.01
USP
氯化钠，USP         0.3
硫酸钠，USP         1.2
泰洛沙泊，USP       0.05
羟乙基纤维素        0.25
硫酸和/或氢氧化适量，用于将pH调
钠，NF            整至5.5
纯水，USP       适量，至100
       实施例3
      眼软膏
组分             量(wt％)
莫氟沙星           0.35
矿物油，USP        2.0
白矿脂，USP    适量，至100
     实施例4
     眼软膏
组分            量(wt％)
莫氟沙星          0.3
氟甲孕松醋酸酯，       0.1
USP
氯丁醇，无水，NF       0.5
矿物油，USP             5
白矿脂，USP         适量，至100
本文已通过一些优选实施方式描述了本发明。但是，由于对其明显的改变对本领域技术人员来说是显而易见的，因此不应认为本发明就限于此。

Claims (10)

1．一种眼、耳或鼻的药用组合物，含有抗微生物有效量的一种或多种下式化合物及其药用上有用的水合物和盐，及其药用上可接受的载体：
其中：
A为CH、CF、CCl、C-OCH3或N；
X1为H、卤素、NH2或CH3；
R1为C1-C3烷基、FCH2CH2、环丙基或苯基，选择性地被一个、二个或三个卤素取代，或者A与R1一起可以形成式C-O-CH2-CH(CH3)的桥；
R2为H、C1-C3烷基，其选择性地被OH、卤素或NH2取代、或者5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基-甲基；和
B选自以下基团：
其中：Y为O或CH2；
R3为C2-C5烷氧基、CH2-CO-C6H5、CH2CH2CO2R’、R’O2C-CH=C-CO2R’、CH=CH-CO2R’或CH2CH2-CN,
其中：
R’为H或C1-C3烷基；
R4为H、C1-C3烷基、C2-C5烷氧基、CH2-CO-C6H5、CH2CH2CO2R’、R’O2C-CH=C-CO2R’、CH=CH-CO2R’、CH2CH2-CN或5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基-甲基，
其中：
R’为H或C1-C3烷基。
2．如权利要求1的局部组合物，其中所述组合物还含有消炎有效量的甾类或非甾类消炎剂。
3．如权利要求2的局部组合物，其中所述消炎剂包括糖皮质激素。
4．如权利要求3的局部组合物，其中所述糖皮质激素选自地塞米松、利美索龙、泼尼松龙、氟米龙、氢化可的松、莫米松、氟替卡松、倍氯米松、氟尼缩松、去炎松和布地奈德。
5．如权利要求2的局部组合物，其中所述消炎剂包括非甾类试剂，所述非甾类试剂选自前列腺素H合成酶抑制剂、PAF拮抗物和PDE Ⅳ抑制剂。
6．如权利要求2的局部组合物，其中所述式(Ⅰ)化合物包括莫氟沙星。
7．如权利要求6的局部组合物，其中所述消炎剂包括地塞米松。
8．一种治疗或预防眼、耳或鼻感染的方法，包括向受影响的眼、耳或鼻组织局部施加疗效量的权利要求1的组合物。
9．一种治疗或预防眼、耳或鼻感染及伴随的炎症的方法，包括向受影响的眼、耳或鼻组织局部施加疗效量的权利要求2的组合物。
10．一种治疗或预防眼、耳或鼻感染及伴随的炎症的方法，包括向受影响的眼、耳或鼻组织局部施加疗效量的权利要求6的组合物。
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