CN101072571A - 用于治疗耳感染的组合物 - Google Patents
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Abstract
包含莫西沙星或其药用水合物或盐和蛋白水解酶的局部耳用药物组合物。该组合物促进治疗水平的莫西沙星的经鼓膜递送。
Description
本申请要求2004年12月10号提交的美国临时申请60/635,218的优先权。
发明领域
本发明总的说来涉及用于治疗或预防耳感染的局部抗生素药物组合物和更具体地涉及用于治疗或预防中耳或内耳感染的莫西沙星组合物。
相关领域的描述
几乎70%的美国儿童在两岁前发生中耳炎(中耳感染)。这些儿童中的一半具有反复的发作。中耳炎是听力丧失的最常见原因,且其通常阻碍儿童的发育和学习过程。
通常开全身性抗生素处方治疗中耳炎。一般的治疗方案使用全身性抗生素长达14天,且在该治疗过程中副作用相当普遍。
也可获得用于治疗外耳炎(外耳感染)和中耳炎的局部抗生素。示例性产品包括可从Alcon Laboratories,Inc.of Fort Worth,Texas商购获得的CIPROHC(相当于0.2%环丙沙星的盐酸环丙沙星;1%氢化考的松);可从Alcon Laboratories,Inc.商购获得的CIPRODEX(0.3%环丙沙星;0.1%地塞米松)滴耳混悬剂;和可从DaiichiPharmaceutical Corporation of Japan商购获得的FLOXIN(0.3%氧氟沙星)耳用溶液。CIPROHC滴耳混悬剂标明是用于治疗急性外耳炎的。CIPRODEX滴耳混悬剂用于急性外耳炎和使用鼓膜造孔插管治疗急性中耳炎。FLOXIN耳用溶液用于治疗急性外耳炎、及使用鼓膜造孔插管治疗急性中耳炎和治疗具有穿孔鼓膜的慢性化脓性中耳炎。然而,一般接受的常规治疗剂不穿过鼓膜。因此,用于治疗中耳的现有产品都需要通过门诊病人的手术操作预先放置鼓膜造孔插管或预先存在的鼓膜穿孔以递送药物至中耳或内耳。在可对滴耳剂产生恐惧和由于感染的疼痛导致激动的婴儿或小儿中通过鼓膜造孔插管精确滴放滴剂已证明是相当困难的。
属于Petrus的美国专利5,954,682公开了具有可用一种或多种治疗剂浸渍的多孔介质4的治疗施药器2。参见′682专利,图1;第3栏,第59至61行;第6栏,第24至57行。′682专利也公开了允许药物和化学试剂渗透耳道的膜和内皮的酶和非酶渗透促进剂。参见,例如,′682专利,第6栏,第58行至第7栏,第35行。′682专利特别地公开了“非酶渗透促进剂促进生物活性剂例如药物和化学物质通过耳道的膜和内皮10的渗透”。′682专利,第7栏,第19至22行。
该文献也报导了胰蛋白酶,一种蛋白水解酶已被用于含有盐酸四环素/多粘菌素B(polymixinB)/倍他米松磷酸钠和丁卡因的滴耳液。参见Laboratories Cusi S-A,November1992的“Otocusi Enzimatico”手册。该溶液用于治疗外耳和中耳的化脓性或非化脓性疼痛炎性病症。手册声称“胰蛋白酶是促成坏死组织、脓膜和结痂破坏/消除的蛋白水解酶”。
国际公开号WO03/003976,其在此引用作为参考,公开了用于帮助除去人耳垢的组合物,该组合物包含用于在外耳道软化、驱除、分散和/或分解人耳垢的耳垢裂解(cerumenolytically)可接受酶。优选的耳垢裂解可接受酶包括脂酶、蛋白酶和淀粉酶。优选的蛋白酶或蛋白水解酶包括胰酶、胰蛋白酶、枯草杆菌蛋白酶、胶原蛋白酶、角蛋白酶、羧肽酶、木瓜蛋白酶、菠萝蛋白酶、氨基肽酶、弹性蛋白酶、Aspergillo肽酶、链霉蛋白酶E(来自灰色链霉菌(S.griseus))、中性蛋白酶(来自多粘芽胞杆菌(Bacillus polymyxa))和其混合物。参见WO03/003976,第11页,第1至19行。最优选的蛋白水解酶是甲基胰蛋白酶。WO03/003976,第13页,第9行。
美国专利6,716,830,其在此引用作为参考,公开了有效的新一类抗生素治疗眼、耳和鼻感染的用途,以及这些抗生素在术后或眼、耳和鼻组织的其他损伤之后的预防性用途。也可在眼、耳和鼻手术过程中给受影响的组织施用公开的组合物以预防或减轻术后感染。公开的优选的抗生素是莫西沙星。
有效地用于预防或治疗中耳或内耳感染的改进的莫西沙星组合物以及递送该组合物的方法仍然是想要的。
发明概述
本发明包括包含莫西沙星或其药用水合物或盐和蛋白水解酶的局部耳用药物组合物。所述组合物促进治疗水平的莫西沙星的经鼓膜递送。
优选的实施方案的详述
除非另外指出,以百分比列出的所有组分浓度以重量/体积百分比的单位来表示。
本发明的优选的组合物包括莫西沙星或其药用水合物和盐以及促进莫西沙星穿过完整的鼓膜递送的渗透促进剂。在美国专利5,607,942中提供了关于莫西沙星的结构、制备和物理性质的更详细内容,所述专利在此引用作为参考。莫西沙星优选地以0.1-1%的量,和最优选地0.5%的量存在。优选的渗透促进剂包括蛋白水解酶例如胰蛋白酶、胶原蛋白酶和胃蛋白酶。胰蛋白酶优选地以0.1-10mg/ml和最优选地5mg/ml的量存在。胶原蛋白酶优选地以0.1-10mg/ml和最优选地5mg/ml的量存在。胃蛋白酶优选以0.1-10mg/ml,最优选以5mg/ml的量存在。优选的缓冲剂包含醋酸钠.3H2O、氯化钠、氯化钙.2H2O、水和pH调节剂。优选的pH调节剂是氢氧化钠或盐酸。醋酸钠3H2O优选地以0.1-1%和最优选地0.68%的量存在。氯化钠优选地以0.1-1%和最优选地0.60%的量存在。氯化钙.2H2O优选地以0.01-1%和最优选地0.05%的量存在。以足以产生想要的体积的量加入水。以足以使组合物的pH达到6至8和最优选地7.5的量加入pH调节剂。
已令人意外地发现,在该组合物中,蛋白水解酶是优于常规的皮肤渗透促进剂例如二甲亚砜(″DMSO″)和纯化的二乙二醇单乙醚(TranscutolP)的莫西沙星的经鼓膜递送的渗透促进剂。此外,令人意外地发现,胶原蛋白酶是优于胰蛋白酶或胃蛋白酶的莫西沙星的经鼓膜递送的渗透促进剂。
专门地配制用于给耳组织局部施用的本发明的组合物。所述组合物优选地是无菌的且具有特别适合于给耳组织施用的物理性质,所述耳组织包括由于预先存在的疾病、创伤、手术或其他身体状况而受到损害的组织。
优选地将本发明的组合物包装在瓶中,可挤压所述瓶子,通过喷管将成滴的组合物分配入用户的耳中,或所述瓶子具有可开动以将组合物的喷雾递送入用户的耳内的泵。用于分配本发明的组合物的某些优选的装置描述于美国专利5,474,209和5,782,345,以及国际公开号WO03/003976中,其在此引用作为参考。
通常以多剂量形式包装耳用药剂。可能需要防腐剂以在使用期间预防微生物污染。合适的防腐剂包括:聚季铵盐-1(polyquaternium-1)、氯化苯甲烃铵、硫柳汞、三氯叔丁醇、尼泊金甲酯、尼泊金酸丙酯、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他试剂。聚季铵盐-1作为抗菌防腐剂的用途是优选的。一般地以0.001%至1.0%的水平使用这些防腐剂。
可通过组合物中的表面活性剂或其他合适的共溶剂增加本发明组合物的组分的溶解性。这些共溶剂包括聚山梨醇酯20、60和80;聚氧乙烯/聚氧丙烯嵌段共聚物表面活性剂(例如,PluronicF-68和Tetronic1304);环糊精;或本领域技术人员已知的其他试剂。一般地,以0.01%至2%的水平使用这些共溶剂。
使用粘性增强剂为本发明的组合物提供大于单纯的水溶液的粘性的粘性,从而增加在耳内的滞留时间是理想的。这些粘性构建剂(building agent)包括,例如聚乙烯醇、聚乙烯吡咯烷酮、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他试剂。通常以0.01%至2%的水平使用这些试剂。
下列实施例意在举例说明,但绝非限制本发明。
实施例1
使用从靠近鼓膜处采集的新西兰白兔耳片建立实验室模型。在模拟耳解剖结构的简单装置中维持培养所述片。兔耳的内部皮肤侧为“供体侧”,而除去皮肤层的兔耳的皮毛侧是“受体侧”。选择0.5%的莫西沙星作为治疗剂,使其和例如不同的渗透促进剂混合在一起。向具有0.68%醋酸钠.3H2O、0.60%氯化钠、0.05%氯化钙.2H2O、适量的水和适量的pH调节剂的醋酸盐缓冲剂中加入莫西沙星和一种渗透促进剂,使组合物的pH达到7.5。将所得的组合物用于片的供体侧。表1显示2小时后通过HPLC测量的耳片的受体侧上缓冲剂中的莫西沙星水平。
表1
0.5%莫西沙星+ | 兔耳受体侧上的莫西沙星的浓度 |
醋酸盐缓冲剂 | 0.17ppm |
DMSO10%+醋酸盐缓冲剂 | 0.22ppm |
Transcutolp50%+醋酸盐缓冲剂 | 0.49ppm |
胰蛋白酶5mg/ml+醋酸盐缓冲剂 | 0.93ppm |
胶原蛋白酶5mg/ml+醋酸盐缓冲剂 | 1.81ppm |
胃蛋白酶5mg/ml+醋酸盐缓冲剂 | 1.51ppm |
全身性剂量递送(例如口服递送@500mg/天)期间抗生素的中耳液浓度通常在1至10ppm的范围之内,其依赖于特定的抗生素。一般地,对于许多通常和耳感染关联的细菌,莫西沙星的MIC水平是1至2ppm。选择DMSO和TranscutolP作为典型的常规皮肤渗透促进剂。DMSO和TranscutolP都是非酶渗透促进剂。如由表1所示的,与单独的莫西沙星和缓冲剂的组合物相比,莫西沙星、非酶渗透促进剂(例如DMSO或TranscutolP)和缓冲剂的组合物确实在兔耳的受体侧上产生更高的莫西沙星浓度。然而,莫西沙星、酶渗透促进剂(例如,胰蛋白酶、胶原蛋白酶或胃蛋白酶)的组合物意外地导致显著更高的莫西沙星浓度,该浓度处于或高于莫西沙星对于许多通常和耳感染相关的细菌的MIC水平。莫西沙星的这些浓度代表治疗水平。
根据上面,可认识到,本发明提供了有效地预防或治疗中耳或内耳感染的改进的莫西沙星组合物和递送该组合物的方法。据认为,根据上述描述本发明的实施和建立将变得明显。尽管上面显示或描述的组合物和方法已被表征为优选的,但在其中可产生各种变化和改变而不背离下列权利要求中确定的本发明的精神和范围。
Claims (15)
1.包含莫西沙星或其药用水合物或盐和蛋白水解酶的局部耳用药物组合物。
2.权利要求1的组合物,其中所述蛋白水解酶是胰蛋白酶。
3.权利要求1的组合物,其中所述蛋白水解酶是胶原蛋白酶。
4.权利要求1的组合物,其中所述蛋白水解酶是胃蛋白酶。
5.权利要求1的组合物,其中所述组合物促进治疗水平的所述莫西沙星的经鼓膜递送。
6.权利要求1的组合物,还包含醋酸盐缓冲剂。
7.局部耳用药物组合物,其包含:
具有0.1-1%的莫西沙星浓度的莫西沙星或其药用水合物或盐;和
0.1-10mg/ml浓度的胰蛋白酶。
8.权利要求7的组合物,其中所述组合物促进治疗水平的所述莫西沙星的经鼓膜递送。
9.权利要求7的组合物,还包含醋酸盐缓冲剂。
10.局部耳用药物组合物,其包含:
具有0.1-1%的莫西沙星浓度的莫西沙星或其药用水合物或盐;和0.1-10mg/ml浓度的胶原蛋白酶。
11.权利要求10的组合物,其中所述组合物促进治疗水平的所述莫西沙星的经鼓膜递送。
12.权利要求10的组合物,还包含醋酸盐缓冲剂。
13.局部耳用药物组合物,其包含:
具有0.1-1%的莫西沙星浓度的莫西沙星或其药用水合物或盐;和0.1-10mg/ml浓度的胃蛋白酶。
14.权利要求13的组合物,其中所述组合物促进治疗水平的所述莫西沙星的经鼓膜递送。
15.权利要求13的组合物,还包含醋酸缓冲剂。
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US63521804P | 2004-12-10 | 2004-12-10 | |
US60/635,218 | 2004-12-10 |
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CN101072571A true CN101072571A (zh) | 2007-11-14 |
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US (1) | US20070212343A1 (zh) |
EP (1) | EP1824499A2 (zh) |
JP (1) | JP2008523060A (zh) |
KR (1) | KR20070089222A (zh) |
CN (1) | CN101072571A (zh) |
AU (1) | AU2005317228A1 (zh) |
BR (1) | BRPI0518891A2 (zh) |
CA (1) | CA2587081A1 (zh) |
MX (1) | MX2007005980A (zh) |
WO (1) | WO2006065301A2 (zh) |
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Cited By (2)
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CN102791270A (zh) * | 2010-01-07 | 2012-11-21 | 明尼苏达大学董事会 | 将莫西沙星应用于耳的方法和组合物 |
US8734836B2 (en) | 2002-11-27 | 2014-05-27 | Regents Of The University Of Minnesota | Methods and compositions for applying pharmacologic agents to the ear |
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US20120253267A1 (en) * | 2004-05-24 | 2012-10-04 | Reed Don C | Combined otic and medication dispenser and method for treating otic infections |
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 |
TW201010727A (en) * | 2008-09-03 | 2010-03-16 | Alcon Res Ltd | Pharmaceutical composition having relatively low ionic strength |
US20170071979A1 (en) * | 2011-05-11 | 2017-03-16 | Veloce Biopharma, Llc | Composition and method for treating otitis |
AU2020365197A1 (en) | 2019-10-18 | 2022-06-02 | Topikos Scientific, Inc. | Antimicrobial organosilanes |
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JPS61282313A (ja) * | 1985-06-06 | 1986-12-12 | Nitto Electric Ind Co Ltd | 酵素含有貼付剤 |
US5061729A (en) * | 1988-06-08 | 1991-10-29 | Biogal Gyogyszergyar | Pharmaceutical composition and process for preparing the same |
EP0577200B1 (en) * | 1992-07-02 | 1996-07-03 | Laboratorios Cusi, S.A. | Pharmaceutical product container for two separate substances, having a device for mixing and dosed dispensation |
DK0736012T3 (da) * | 1993-12-21 | 2001-01-29 | Boehringer Ingelheim Pharma | Anellerede dihydropyridiner og deres anvendelse til fremstilling af farmaceutiske præparater |
US5397578A (en) * | 1994-03-29 | 1995-03-14 | Tovarischestvo S Ogranichennoi Otvetstvennostiju "Taurus" | Method of treatment of chronic purulent inflammations of ear in children |
ES2128220B1 (es) * | 1995-12-04 | 1999-12-16 | Cusi Lab | Envase farmaceutico de dos sustancias separadas, con dispositivo de mezcla, aplicacion dosificada y su proceso de montaje. |
US20040126515A1 (en) * | 1995-12-27 | 2004-07-01 | Yarmoska Bruce S. | Wood-plastic composite having improved strength |
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IT1284973B1 (it) * | 1996-10-11 | 1998-05-28 | A R D O Associazione Ricerca E | Uso del sodio 2-mercaptoetansolfonato (mesna) in chirurgia |
US20020136712A1 (en) * | 1997-10-31 | 2002-09-26 | Fischetti Vincent | Bacterial phage associated lysing enzymes for the prophylactic and therapeutic treatment of colonization and infections caused by streptococcus pneumoniae |
US6716830B2 (en) * | 1998-09-30 | 2004-04-06 | Alcon, Inc. | Ophthalmic antibiotic compositions containing moxifloxacin |
AR020661A1 (es) * | 1998-09-30 | 2002-05-22 | Alcon Lab Inc | Una composicion farmaceutica topica oftalmica, otica o nasal y el uso de la misma para la manufactura de un medicamento |
US6093417A (en) * | 1999-01-11 | 2000-07-25 | Advanced Medical Instruments | Composition to treat ear disorders |
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KR100338327B1 (ko) * | 2000-05-16 | 2002-08-07 | 주식회사 태평양 | 피부 외용제 내의 활성성분의 피부 흡수를 증진시킬 수있는 조성물 |
US20040126414A1 (en) * | 2002-12-12 | 2004-07-01 | Michaelis Arthur F. | Methods and compositions for treating and preventing ear infections |
-
2005
- 2005-09-14 BR BRPI0518891-1A patent/BRPI0518891A2/pt not_active IP Right Cessation
- 2005-09-14 WO PCT/US2005/033094 patent/WO2006065301A2/en active Application Filing
- 2005-09-14 JP JP2007545442A patent/JP2008523060A/ja active Pending
- 2005-09-14 CN CNA2005800421616A patent/CN101072571A/zh active Pending
- 2005-09-14 MX MX2007005980A patent/MX2007005980A/es not_active Application Discontinuation
- 2005-09-14 ZA ZA200704775A patent/ZA200704775B/xx unknown
- 2005-09-14 EP EP05797905A patent/EP1824499A2/en not_active Withdrawn
- 2005-09-14 CA CA002587081A patent/CA2587081A1/en not_active Abandoned
- 2005-09-14 AU AU2005317228A patent/AU2005317228A1/en not_active Abandoned
- 2005-09-14 KR KR1020077015697A patent/KR20070089222A/ko not_active Application Discontinuation
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- 2007-04-20 US US11/737,835 patent/US20070212343A1/en not_active Abandoned
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8734836B2 (en) | 2002-11-27 | 2014-05-27 | Regents Of The University Of Minnesota | Methods and compositions for applying pharmacologic agents to the ear |
US9592196B2 (en) | 2002-11-27 | 2017-03-14 | Regents Of The University Of Minnesota | Methods and compositions for applying pharmacologic agents to the ear |
CN102791270A (zh) * | 2010-01-07 | 2012-11-21 | 明尼苏达大学董事会 | 将莫西沙星应用于耳的方法和组合物 |
CN106309356A (zh) * | 2010-01-07 | 2017-01-11 | 明尼苏达大学董事会 | 将莫西沙星应用于耳的方法和组合物 |
Also Published As
Publication number | Publication date |
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KR20070089222A (ko) | 2007-08-30 |
BRPI0518891A2 (pt) | 2008-12-16 |
WO2006065301A2 (en) | 2006-06-22 |
CA2587081A1 (en) | 2006-06-22 |
US20070212343A1 (en) | 2007-09-13 |
MX2007005980A (es) | 2007-07-10 |
ZA200704775B (en) | 2008-08-27 |
JP2008523060A (ja) | 2008-07-03 |
EP1824499A2 (en) | 2007-08-29 |
WO2006065301A3 (en) | 2006-09-08 |
AU2005317228A1 (en) | 2006-06-22 |
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