CN110996954A - 低剂量的溴莫尼定组合及其用途 - Google Patents
低剂量的溴莫尼定组合及其用途 Download PDFInfo
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- CN110996954A CN110996954A CN201880052027.1A CN201880052027A CN110996954A CN 110996954 A CN110996954 A CN 110996954A CN 201880052027 A CN201880052027 A CN 201880052027A CN 110996954 A CN110996954 A CN 110996954A
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- glaucoma
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Abstract
本发明涉及组合物,其包含低剂量溴莫尼定以及第二种青光眼药物、抗组胺药和非甾体抗炎药中的任一者。本发明进一步涉及通过施用本发明的组合物来治疗青光眼或过敏或者减轻炎症的方法。
Description
技术领域
本发明涉及组合物,其包含低剂量溴莫尼定以及第二种青光眼药物、抗组胺药和非甾体抗炎药中的任一者。本发明进一步涉及通过施用本发明的组合物治疗青光眼或过敏或减轻炎症的方法。
背景技术
青光眼是一种多因素疾病,其涵盖范围从眼内压升高(“IOP”)到视神经的血管灌注减少的一系列疾病。
尽管有许多因素被认为是青光眼的病因,但目前现有的青光眼治疗方法在降低IOP方面效果有限,和/或伴有许多副作用,例如疲劳、镇静、眼睑过敏、局部过敏和/或发红。超过10%的青光眼患者遭受充血的特征(stigma)(即眼睛发红)。由于这些副作用,青光眼治疗的另一个主要问题是患者按处方服用药物的依从性。
超过40%的青光眼患者需要两种或更多种药物来令人满意地控制其眼内压。其中,前列腺素/类前列腺素(包括(拉坦前列素;Xalatan是Pfizer Health AB的注册商标)、(曲伏前列素;Travatan是Novartis AG的注册商标)和(比马前列素;Lumigan是Allergan,Inc.的注册商标))之所以成为领先药物,是因为它们显著降低IOP、特别是在高眼压眼(21mm Hg或更高)中,IOP通常降低30%以上,并且葡萄膜巩膜流出的持续时间延长。为了发挥最大作用,这两种药物应具有不同的作用机理。
溴莫尼定是一种已知的α-2(α-2)肾上腺素能受体激动剂,目前可以商品名(Alphagan是Allergan,Inc.的注册商标)购得,其形式为0.1%、1.5%和0.2%的酒石酸溴莫尼定。溴莫尼定通常会在眼部高压眼中使IOP峰值降低约20-25%,在血压正常眼中(低于21mm Hg)降低6-18%。其最大作用是在滴注后2小时内,其作用持续时间通常少于12小时,并且其中等效力通常需要每天服用2-3次。它是领先的次级药物之一,具有水抑制作用的机制,可补充前列腺素/前列腺素类葡萄膜巩膜流出的增强,从而具有显著的附加益处,但与其他二线青光眼药物(例如,β-受体阻滞剂和碳酸酐酶抑制剂)大体相当。当与β受体阻滞剂或碳酸酐酶抑制剂(特别是与前列腺素)组合使用时,发现0.2%溴莫尼定可使IOP降低1-2mm Hg。
然而,0.15-0.2%溴莫尼定可能在10-25%的使用者中引起实质性的局部副作用,例如结膜充血(即发红)、睑缘炎、过敏、结膜水肿、结膜滤泡、异物感、灼热或模糊。这些副作用仅由最新的溴莫尼定制剂适度改善,导致浓度降低,在更碱性的下眼内吸收增加。通常,α-2激动剂(包括溴莫尼定,其前身可乐定和更具选择性的右美托咪定),如果被吸收进入循环系统,会产生实质性的全身作用,并且众所周知,这种作用会增加疲劳、降低血压(即低血压)并降低心率(即心动过缓)。溴莫尼定由于其相对的α2/α1特异性(约900:1的比例)仍在眼内引入α1激动剂活性,长期任何诱导的局部缺血均可潜在地加速视神经丧失。
因此,在本领域中需要组合青光眼治疗,其在减少副作用的同时至少保持加和作用。
过敏性疾病是世界范围内的主要健康问题。此外,在大多数国家,过敏性疾病的患病率正在增加。过敏的两种主要形式包括过敏性鼻炎和眼部过敏。当免疫系统对过敏原的存在做出反应并产生组胺时,就会发生过敏反应。然后,组胺会引起过敏的主要症状,包括“流鼻涕”或“痒痒”的鼻子、打喷嚏、“水汪汪的”眼睛、喉咙发痒等。
在过敏性鼻炎中,过敏反应发生在鼻子中。响应于反应而释放的组胺引起局部血管扩张,导致毛细血管压力增加以及毛细血管渗透性增加。这两种作用都会导致液体迅速渗漏到鼻子组织中,并且鼻腔内膜变得肿胀和分泌。
响应组胺的释放,眼部过敏或过敏性结膜炎常伴有过敏性鼻炎。眼睛的过敏体征和症状包括瘙痒、发红、肿胀、流泪、灼热和刺痛。
经常用滴眼剂治疗眼部过敏,包括(0.02675%盐酸萘甲唑啉和0.315%马来酸非那敏;Opcon A是Bausch&Lomb Incorporated的注册商标)、(0.025%盐酸萘甲唑啉和0.3%马来酸苯那敏;Naphcon-A是AlconResearch Ltd的注册商标)和(0.05%萘甲唑啉盐酸盐和0.5%磷酸安他唑啉;Vasocon是Novartis AG的注册商标)和AlbalonTM(0.05%萘甲唑啉盐酸盐,Albalon可从Allergan Pharmaceuticals获得)。
然而,处方或施用的用于治疗眼过敏和/或过敏性鼻炎的许多抗组胺药可治疗组胺引起的瘙痒和不适,但不能完全缓解伴随的症状,包括特别是继发于血管渗漏和充血(眼睛充血)引起的肿胀,既保持不适感又不健康。因此,在本领域中进一步需要组合过敏治疗,其导致更大程度地减轻包括眼红的伴随症状。
发明内容
在一个实施方案中,本发明涉及一种用于治疗青光眼的眼科组合物,其包含浓度为约0.01%至约0.050%w/v的溴莫尼定和第二种青光眼药物。
在另一个实施方案中,本发明涉及一种治疗青光眼的方法,其包括向有此需要的受试者施用包含约0.01%至约0.050%w/v的浓度的溴莫尼定和第二种青光眼药物的组合物。
在另一实施方案中,本发明涉及一种治疗青光眼的方法,其中该方法进一步提供减少眼睛发红。
在另一实施方案中,本发明涉及一种治疗青光眼的方法,其中该方法进一步提供眼睛美白。
在另一实施方案中,本发明涉及一种治疗青光眼的方法,其中该方法进一步提供减少结膜肿胀、减少充血和眼睛美白。
在一个实施方案中,本发明涉及一种用于治疗过敏的眼科组合物,其包含浓度为约0.01%至约0.050%w/v的溴莫尼定和组胺拮抗剂。
在另一个实施方案中,本发明涉及一种治疗过敏的方法,其包括向有此需要的受试者施用包含约0.005%至约0.050%w/v的浓度的溴莫尼定和组胺拮抗剂的组合物。
在另一个实施方案中,本发明涉及一种治疗过敏的方法,其中该方法进一步提供眼睛美白和或减轻的炎症。
在另一个实施方案中,本发明涉及用于一种减轻炎症的眼科组合物,其包含约0.005%至约0.050%w/v的溴莫尼定和有效量的非甾体抗炎药(“NSAID”)。
在另一个实施方案中,本发明涉及一种减轻炎症的方法,其包括向有此需要的受试者施用包含约0.005%至约0.050%w/v的浓度的溴莫尼定和NSAID的组合物。
附图说明
图1-施用0.005%拉坦前列素(0小时,白条)后IOP降低的先例,相对于施用0.03%溴莫尼定和0.005%拉坦前列素后(4、6和8小时,黑条)的IOP降低。
具体实施方式
本发明的发现是,与α1血管收缩剂相比,低剂量溴莫尼定可以选择性地减少毛细血管后静脉渗漏。不希望受特定理论的束缚,据信α1激动剂比低剂量溴莫尼定更大程度地收缩较大的血管,例如小动脉。较大血管的收缩会导致局部缺血,反复使用会引起炎症和反弹性充血。毛细血管后小静脉的渗漏与血管内皮VE钙粘蛋白的短暂损失有关,导致间隙连接并沿毛细血管后小静脉壁渗漏。然而,令人惊讶地发现,通过低剂量溴莫尼定收缩小血管,特别是所述没有缺血的毛细血管后小静脉,可以减少这种渗漏,而没有四氢唑啉、羟甲唑啉或其他α1激动剂的缺血,减轻了发红和肿胀和发红的临床后遗症,其并非完全缓解,这使低剂量溴莫尼定与抗组胺药的结合特别有效。
当与青光眼药物结合时,特别是但不限于前列腺素/类前列腺素,可减轻表面炎症、肿胀和充血。进一步降低了IOP。本发明发现较低浓度的溴莫尼定可提供有效的降低IOP的第二种药物的益处,但还可能减少视神经缺血,而没有较高浓度的溴莫尼定的伴随的α1激动剂活性。
术语“溴莫尼定”包括但不限于溴莫尼定盐和其他衍生物,并且具体包括但不限于酒石酸溴莫尼定、5-溴-6-(2-咪唑啉-2-基氨基)喹喔啉D-酒石酸盐、(Alphagan是Allergan,Inc.的注册商标)和UK 14,304。
术语“青光眼药物”或“第二种青光眼药物”包括但不限于所有用于治疗青光眼的药物,包括那些除溴莫尼定以外用于降低眼压的药物。
术语“组胺拮抗剂”包括已发现能拮抗至少一种组胺受体的所有化学物质,包括组胺H1和组胺H2。
术语“过敏”(“allergy”或“allergies”)或“过敏反应”是指过敏性鼻炎和/或眼部过敏。过敏性鼻炎是鼻气道的过敏性炎症,伴有以下症状,包括但不限于鼻漏、鼻塞、鼻痒、打喷嚏、眼部瘙痒症。眼部过敏是眼睛的任何过敏性疾病,包括但不限于季节性/常年性过敏性结膜炎、春季角膜结膜炎、巨乳头状结膜炎、常年性过敏性结膜炎和特应性角膜结膜炎。
术语“药学上可接受的盐”是指包括活性化合物的盐,该活性化合物是用相对无毒的酸或碱制备的,这取决于本文所述化合物上发现的特定取代基。当本发明的化合物含有相对酸性的官能团时,可以通过使这类化合物的中性形式与足量的所需碱(无论是纯净的还是在惰性溶剂中)接触而获得碱加成盐。药学上可接受的碱加成盐的实例包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物含有相对碱性的官能团时,可以通过使这类化合物的中性形式与足量的所需酸(无论是净的还是在惰性溶剂中)接触而获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自无机酸例如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢氟酸或亚磷酸等的那些盐,以及衍生自相对无毒的有机酸例如乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、姜黄扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等的那些盐。还包括氨基酸的盐,例如精氨酸盐等,以及有机酸的盐,例如葡萄糖醛酸或半乳糖醛酸等(参见例如Berge,S.M.,等人,"Pharmaceutical Salts",Journal of Pharmaceutical Science,1977,66,1-19)。本发明的某些特定化合物同时包含碱性和酸性官能团,这使得该化合物可以转化为碱或酸加成盐。
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来记录。化合物的母体形式在某些物理性质(例如在极性溶剂中的溶解度)方面与各种盐形式不同,但是对于本发明的目的,盐与化合物的母体形式等效。
除盐形式外,本发明提供前药形式的化合物。本文所述化合物的前药是那些在生理条件下容易发生化学变化以提供本发明化合物的化合物。另外,可以在离体环境中通过化学或生化方法将前药转化为本发明的化合物。例如,当将前药与合适的酶或化学试剂一起置于透皮贴剂储库中时,可以将其缓慢转化为本发明的化合物。前药通常是有用的,因为在某些情况下,它们可能比母体药物更易于管理。通过口服给药,它们可能是生物可利用的,而母体药物则不是。与母体药物相比,前药在药理学组合物中的溶解度也可能提高。多种前药衍生物是本领域已知的,例如依赖于前药的水解裂解或氧化活化的那些衍生物。前药的一个实例但不限于此,是本发明的化合物,其以酯(“前药”)的形式给药,但随后被代谢水解为羧酸,即活性实体。另外的实例包括本发明化合物的肽基衍生物。
本发明的某些化合物能够以非溶剂化物形式以及包括水合形式的溶剂化物形式存在。通常,溶剂化形式等同于非溶剂化形式,并且旨在包括在本发明的范围内。本发明的某些化合物可以多种结晶或无定形形式存在。通常,所有物理形式对于本发明预期的用途是等同的,并且旨在包括在本发明的范围内。
在优选的实施方案中,本发明的组合物可包含非离子表面活性剂、增粘剂,优选羟丙基甲基纤维素(“HPMC”)或羧甲基纤维素、缓冲剂和任选的山梨酸酯。
适用于本发明的非离子表面活性剂包括但不限于聚山梨酯、泊洛沙姆、聚氧基、烷基芳基聚醚、环糊精、生育酚聚乙二醇琥珀酸酯、葡糖基二烷基醚和冠醚、酯连接的表面活性剂。非离子表面活性剂可以约1%至约5%w/v的浓度存在于本发明的组合物中。
适用于本发明的聚山梨酸酯包括但不限于聚山梨酸酯20(聚氧乙烯(20)脱水山梨醇单月桂酸酯)、聚山梨酸酯40(聚氧乙烯(20)脱水山梨醇单棕榈酸酯)、聚山梨酯60(聚氧乙烯(20)脱水山梨醇单硬脂酸酯)和聚山梨酯80(聚氧乙烯(20)脱水山梨醇单油酸酯)。
本发明组合物中存在的聚山梨酸酯的浓度可以为约1%至约5%w/v,更优选为约2%至约3%w/v,最优选为约2.5%w/v。
泊洛沙姆包括但不限于泊洛沙姆103、泊洛沙姆123和泊洛沙姆124、泊洛沙姆407、泊洛沙姆188、泊洛沙姆338和任何泊洛沙姆类似物或衍生物。
聚氧基包括但不限于35、78、98、700(聚氧乙烯二醇烷基醚)和Spans(脱水山梨糖醇酯)和20-80(脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单棕榈酸酯、脱水山梨糖醇单硬脂酸酯和脱水山梨醇单油酸酯)。
增粘剂(优选HPMC)可以以约0.1%至约1.2%w/v、优选约1.2%w/v的浓度存在于本发明的组合物中。
用于本发明的缓冲剂包括但不限于柠檬酸盐缓冲剂和磷酸盐缓冲剂。缓冲剂可以以约1毫摩尔(“mM”)至约10mM、优选约2mM至约6mM、更优选约3mM至约4mM的浓度存在于本发明的组合物中。
本发明组合物中存在的山梨酸酯的浓度可以为约0.01%至约0.5%w/v,优选为约0.05%至约0.25%w/v,最优选为约0.1%w/v。
如本文所用,被定义为“约”每个特定值的与数量、重量等有关的所有数值均加上或减去10%。例如,短语“约5%w/v”应理解为“4.5%至5.5%w/v”。因此,权利要求的范围涵盖在所要求的值的10%以内的量。
如本文所用,“%w/v”是指总组合物的重量百分比。
如本文所用,术语“受试者”和“患者”可互换使用,并且是指但不限于人或其他动物。
如本文所用,术语“预防”(“prevent”或“preventing”)是指排除(preclude)、转移(avert)、避免(obviate)、防止(forestall)、终止(stop)或阻止(hinder)某些事情的发生,特别是通过提前动作。
如本文所用,术语“治疗”(“treat”或“treating”)是指逆转、减轻或减缓此类术语所适用的疾病、病症或病况或此类疾病、病症或病况的一种或多种症状的进展。
如本文所用,术语“施用”(“administration”或“administering”)是指通过局部施用、注射或植入物的施用。
除非上下文另外明确指出,否则冠词“一个(a)”、“一种(an)”和“该(the)”旨在包括复数和单数。
与青光眼药物合用
本发明的发现是,与常规的第二种青光眼药物联合使用时,溴莫尼定的浓度低至目前可得的制剂中与第二种青光眼药物联合使用时的浓度的约五分之一能够相比于单独使用第二种青光眼药物大大降低眼内压,同时单独使用溴莫尼定或迄今为止的固定组合青光眼药物相关的回弹充血大大减轻和或消除了。这种极低剂量的溴莫尼定(“ELDB”)与第二种青光眼药物的局部应用显示出眼内压降低与全强度溴莫尼定组合相似或可能更好,并且可能比单独使用任何一种药物都具有协同作用。
此外,治疗青光眼的主要障碍是患者的依从性。由于伴随的副作用包括结膜充血和反弹性充血(即眼睛发红),许多患者停止给予青光眼治疗。本发明的发现是,结合使用ELDB可治疗青光眼,同时大大降低副作用,例如与全强度溴莫尼定浓度有关的结膜充血。最后,ELDB能够使眼睛的巩膜增白,超出受试者的基线白度,这可能导致更大的患者依从性。
不希望受到特定理论的束缚,ELDB可以减少青光眼药物的全身递送,从而减少全身副作用,并导致青光眼药物在眼表面的更多保留。这种更多的保留可能导致青光眼药物的眼内吸收更大,从而减少给药的量和/或频率,从而导致患者的进一步依从性。
在一个实施方案中,本发明涉及用于治疗青光眼的眼科组合物,其包含浓度为约0.01%至约0.050%w/v的溴莫尼定和第二种青光眼药物。
溴莫尼定的浓度可以为约0.005%至约0.050%w/v,优选约0.005%至约0.050%w/v、约0.01%至约0.050%w/v、约0.025%至约0.045%w/v、约0.025%至约0.035%w/v和约0.025%、约0.035%或约0.04%w/v。
可用于本发明的除溴莫尼定以外的青光眼药物包括但不限于前列腺素、岩石(rock)抑制剂、β-阻滞剂和碳酸酐酶抑制剂(“CAI”)。前列腺素包括但不限于拉坦前列素、比马前列素、曲伐前列素、他氟前列素及其药学上可接受的盐。Rho激酶抑制剂包括但不限于奈塔舒地尔。β-受体阻滞剂包括但不限于:卡替洛尔、蒂莫替尼、替莫洛尔、贝他洛尔、左布诺洛尔、美替洛尔及其药学上可接受的盐。CAI包括但不限于布林佐胺、多佐胺、乙酰唑胺、醋甲唑胺及其药学上可接受的盐。
除溴莫尼定以外的青光眼药物的浓度可以为约0.001%至约5%w/v。优选地:前列腺素的浓度为约0.001%至约0.1%w/v,更优选约0.0015%至约0.03%w/v;β受体阻滞剂的浓度为约0.1%至约1%w/v,更优选约0.25%至约0.5%w/v;rho激酶抑制剂的浓度为约0.01%至约1%w/v,优选约0.01%至约0.05%w/v,并且CAI的浓度为约0.5%至约5%w/v,更优选约1%至约2%w/v。目前,用于眼科给药的青光眼药物以以下有效成分浓度销售:0.004%的曲伐前列素;0.01%和0.03%的比马前列素;0.0015%的他氟前列素;0.005%的拉坦前列素;0.02%的耐舒地尔;0.25%和0.5%的马来酸替莫洛尔;0.25%和0.5%的替莫洛尔半水合物;0.25%和0.5%的盐酸(“HCl”)贝他洛尔;0.25%和0.5%的盐酸左布诺洛尔;1%的布林佐胺;和2%的多佐胺。
溴莫尼定和第二种青光眼药物的具体组合包括但不限于约0.035%至0.050%w/v的溴莫尼定和约0.005%w/v的拉坦前列素;约0.035%至0.050%w/v的溴莫尼定和约0.050%w/v的比马前列素;约0.035%至约0.050%w/v的溴莫尼定和约0.5%w/v的替莫洛尔;和约0.035%至约0.050%w/v的溴莫尼定和约2%w/v的多佐胺。
本发明的组合物的pH对于溴莫尼定青光眼组合药物为约5.0至约8.0,更优选约6.0至约7.5,甚至更优选约7.2至约7.7并且甚至更优选约7.4至约7.6。
在优选的实施方案中,本发明涉及一种组合物,其包含:
约0.001%w/v的拉坦前列素;
约0.050%w/v的溴莫尼定;
约2.5%w/v的聚山梨酯;
约1.2%w/v羟丙基甲基纤维素("HPMC");
约5mM的硼酸;和
任选地,约0.1%w/v的山梨酸酯,
其中组合物的pH为约7.4。
在另一优选的实施方案中,本发明涉及一种组合物,其包含:
约0.05%w/v的替莫洛尔;
约0.050%w/v的溴莫尼定;
约2.5%w/v的聚山梨酯;
约1.2%w/v的HPMC;
约4mM的硼酸;和
任选地,约0.1%w/v的山梨酸酯,
其中组合物的pH为约7.4。
用于治疗青光眼的本发明的组合物可以通过眼内注射或通过眼内植入物局部施用于眼睛,优选通过局部施用进行。
与组胺拮抗剂合用
当前可用的抗组胺药(即组胺拮抗剂)不能完全缓解所有过敏症状,特别是与细胞因子诱导的血管舒张相关的眼睛发红。本发明的发现是,使用极低剂量的溴莫尼定(“ELDB”)与抗组胺药相结合,与使用单独使用抗组胺药相比,不仅导致更大程度的发红减少,而且还减轻了诸如结膜肿胀之类的过敏症状。
在一个实施方案中,本发明涉及用于治疗过敏的眼科组合物,其包含浓度为约0.005%至约0.050%w/v的溴莫尼定和组胺拮抗剂。
溴莫尼定的浓度可以为约0.005%至约0.050%w/v,优选约0.01%至约0.050%w/v,更优选约0.025%至约0.035%w/v和约0.025%、约0.035%或约0.04%w/v。
可用于本发明的组胺拮抗剂包括但不限于萘甲唑啉、蒽唑啉、氮斯汀、卡莫沙明、赛庚啶、依美斯汀、羟嗪、左旋卡巴汀、溴苯那敏、氯苯那敏、氯马汀、苯海拉明、酮替芬、氯雷他定、地氯雷他汀、西替利嗪、非索非那定、奥洛他定、阿昔瓦汀、依巴斯汀、降冰片碱、左西替利嗪、咪唑斯汀、苯那敏、其药学上可接受的盐及其组合。
组胺拮抗剂的浓度可以为约0.01%至约1%w/v,优选为约0.025%至约0.7%w/v。目前,用于以鼻科或眼科给药的组胺拮抗剂以以下有效成分浓度销售:0.05%的盐酸萘甲唑啉;0.05%的盐酸萘甲唑啉和0.5%的磷酸蒽唑啉的组合;0.05%的盐酸萘甲唑啉和0.3%的马来酸苯那敏的组合;0.02675%的盐酸萘甲唑啉和0.315%的马来酸苯那敏的组合;0.1%和0.15%氮斯汀;0.05%的依美斯汀;0.05%的盐酸左旋卡巴汀;0.025%的酮替芬;和0.1%、0.2%和0.7%的奥洛他定。
在优选的实施方案中,本发明涉及一种组合物,其包含:
约0.0035%w/v富马酸酮替芬;
约0.035%w/v的溴莫尼定;
约2.5%w/v的聚山梨酯;
约0.1%至约1.2%w/v的HPMC;
约4mM柠檬酸盐缓冲液;和
任选地,约0.1%w/v的山梨酸酯,
其中组合物的pH为6.5。
与非甾体类抗炎药合用
当前可用的非甾体抗炎药(“NSAID”)不能完全减轻所有炎症。本发明的发现是,与单独使用NSAID相比,与NSAID组合使用极低剂量溴莫尼定(“ELDB”)可导致更大程度的炎症减轻。此外,存在相当大的炎症、充血和刺激,主要是细胞因子诱导的,其中低剂量溴莫尼定和低强度NSAID(例如0.025%的酮咯酸)的组合可同时缓解充血和减轻炎症。据信,与单独使用两种产品相比,这种组合可以更好地改善患有慢性眼部过敏的人的生活质量。
在一个实施方案中,本发明涉及用于减轻炎症的眼科组合物,其包含浓度为约0.005%至约0.050%w/v的溴莫尼定和NSAID。
溴莫尼定的浓度可以为约0.005%至约0.050%w/v,优选约0.01%至约0.050%w/v,更优选约0.025%至约0.035%w/v和约0.025%、约0.035%或约0.04%w/v。
可用于本发明的NSAID包括但不限于酮咯酸、阿司匹林、塞来昔布、地氟尼醛、依托度酸、布洛芬、吲哚美辛、酮洛芬、萘丁美酮、萘普生、奥沙普嗪、水杨酸盐、舒林酸、托美汀及其药学上可接受的盐及其组合。
NSAID的浓度可以为约0.01%至约10%w/v,优选约0.01%至约1%w/v,更优选约0.02%至约0.50%w/v。
用于减轻炎症的本发明的组合物可以通过滴剂或喷雾剂局部施用于眼睛或鼻腔。
实施例
实施例1-预示性降低眼内压
方法
将具有血压正常的基线眼内压(“IOP”;<21mm Hg)的受试者连续5天进行预治疗,每天每只眼每滴2滴含0.035%溴莫尼定、0.005%的拉坦前列素的组合物,以及0.03%溴莫尼定和0.005%拉坦前列素的组合。在三个治疗周期的每个周期之间观察到1周的冲洗期。在上午8:30滴注,然后在第1、3和5天滴注30秒的点滴闭塞(punctual occlusion)。
在4小时、8小时、12小时、24小时、32小时中的一个或多个测量IOP,并定性评估舒适度和副作用状况。
结果
基于初步数据,与单独使用拉坦前列素相比,经测试的本发明制剂预示了更大的IOP降低。此外,降低IOP的峰值效果
滴注后约4至8小时达到预想的效果,滴注后24小时IOP仍低于基线。图1证明了施用0.005%拉坦前列素(0小时,白条)后IOP降低的先例,相对于施用0.03%溴莫尼定和0.005%拉坦前列素后(4、6和8小时,黑条)IOP降低。实际上,除了滴注之前,ELDB和拉坦前列素联合给药后眼内压的降低在所有时间和天数都可以预见地达到协同作用。协同作用将通过观察到的IOP减少量除以IOP的预期减少量得出“协同因子”来计算。大于1的协同因子表明协同作用。预期的IOP降低将使用以下公式计算,其中A是单独的ELDB的IOP降低,B是单独的拉坦前列素的IOP降低:A+B-(AB/100).因此,在类似的测试条件下,本发明的制剂预示性地显示了优于单独使用全强度溴莫尼定和拉坦前列素的改善的性能。最后,在单独测试拉坦前列素的过程中,受试者预示性地经历了眼充血,而在进行溴莫尼定或溴莫尼定和拉坦前列素组合的测试中未观察到眼充血,这表明极低剂量的溴莫尼定不仅能够增强眼压降低,而且还可以减轻青光眼药物的副作用。
总之,ELDB和第二种青光眼药物的组合预示性地提供了比单独使用第二种青光眼药物或第二种青光眼药物与全强度溴莫尼定组合提供的效果更好或更好的眼内压的增强和协同缓解。此外,ELDB和第二种青光眼药物的组合预示性地提供了减少或改善的副作用,该副作用通常在单独施用第二种青光眼药物时发生。
实施例2-预示性过敏缓解
方法
连续7天对患有鼻过敏的受试者预施用0.005%至0.050%w/v的溴莫尼定和0.025%至0.035%w/v的富马酸酮替芬或0.3%w/v的马来酸苯那敏的组合。
结果
与单独的酮替芬或苯那敏相比,所测试的本发明制剂预示性地实现了更大的细胞因子和炎症减少。此外,测试的本发明制剂预示性地减少了与酮替芬和苯那敏有关的眼睛发红。最后,所测试的本发明制剂预示受试者的眼睛变白,超过了基线白度。
Claims (36)
1.一种用于治疗青光眼的眼科组合物,其包括约0.01%至约0.050%w/v的溴莫尼定和有效量的第二种青光眼药物,其中w/v表示以所述组合物的总体积计的重量。
2.根据权利要求1所述的组合物,其中所述溴莫尼定的浓度为约0.035%至约0.050%w/v。
3.根据权利要求1所述的组合物,其中所述第二种青光眼药物选自由前列腺素、β受体阻滞剂、rho激酶抑制剂和碳酸酐酶抑制剂组成的组。
4.根据权利要求1所述的组合物,其中青光眼药物选自由拉坦前列素、比马前列素、曲伐前列素、他氟前列素、耐他舒地尔、卡替洛尔、蒂莫替尼、替莫洛尔、贝他洛尔、左布诺洛尔、美替洛尔、布林佐胺、多佐胺、乙酰唑胺、醋甲唑胺及其药学上可接受的盐组成的组。
5.根据权利要求1所述的组合物,其中所述第二种青光眼药物的浓度为约0.001%至约1.0%w/v。
6.根据权利要求3所述的组合物,其中所述第二种青光眼药物是浓度为约0.001%至约1.0%w/v的前列腺素或浓度为约0.01%至约1.0%w/v的rho激酶抑制剂或浓度为约0.1%至约1.0%w/v的β-受体阻滞剂或浓度为约0.5%至约5%w/v的碳酸酐酶抑制剂。
7.根据权利要求3所述的组合物,其中所述第二种青光眼药物是浓度为约0.0015%至约0.03%w/v的前列腺素、浓度为约0.01%至约0.05%w/v的rho激酶抑制剂、浓度为约0.25%至约0.5%w/v的β-受体阻滞剂或浓度为约1%至约2%w/v的碳酸酐酶抑制剂。
8.根据权利要求1所述的组合物,其中溴莫尼定的浓度为约0.050%w/v,并且所述第二种青光眼药物是浓度为约0.005%w/v的拉坦前列素。
9.根据权利要求1所述的组合物,其中溴莫尼定的浓度为约0.050%w/v,并且所述第二种青光眼药物是浓度为约0.05%w/v的比马前列素。
10.根据权利要求1所述的组合物,其中溴莫尼定的浓度为约0.050%w/v,并且所述第二种青光眼药物是浓度为约0.5%w/v的替莫洛尔。
11.根据权利要求1所述的组合物,其中溴莫尼定的浓度为约0.04%w/v,并且所述第二种青光眼药物是浓度为约2%w/v的多佐胺。
12.根据权利要求1所述的组合物,其还包含非离子表面活性剂、增粘剂、缓冲剂和任选的山梨酸酯。
13.根据权利要求12所述的组合物,其中所述非离子表面活性剂是浓度为约1%至约5%w/v的聚山梨酯。
14.一种治疗青光眼的方法,其包括将根据权利要求1所述的组合物施用于有此需要的受试者。
15.根据权利要求14所述的方法,其中所述方法还提供发红减轻。
16.根据权利要求14所述的方法,其中所述方法还提供眼睛美白。
17.根据权利要求14所述的方法,其中所述方法还提供结膜肿胀减轻、充血减轻、眼睛美白或其组合。
18.一种用于治疗过敏的眼科组合物,其包括约0.005%至约0.050%的溴莫尼定和有效量的组胺拮抗剂,其中w/v表示以所述组合物的总体积计的重量。
19.根据权利要求18所述的组合物,其中溴莫尼定的浓度为约0.025%至约0.035%w/v。
21.根据权利要求18所述的组合物,其中所述组胺拮抗剂的浓度为约0.025%至约0.7%w/v。
22.根据权利要求18所述的组合物,其还包括非离子表面活性剂、羟丙基甲基纤维素、缓冲剂和任选的山梨酸酯。
23.根据权利要求22所述的组合物,其中所述非离子表面活性剂是浓度为约1%至约5%w/v的聚山梨酯。
24.一种治疗或预防过敏反应的方法,其包括将根据权利要求16所述的组合物施用于有此需要的受试者。
25.根据权利要求24所述的方法,其中所述方法还提供眼睛美白。
26.根据权利要求24所述的方法,其中所述方法还提供较小血管的选择性血管收缩、减少毛细血管后小静脉渗漏、减少来自细胞因子、白三烯或其组合的炎症。
27.一种用于减轻炎症的眼科组合物,其包括约0.005%至约0.050%w/v的溴莫尼定和有效量的非甾体类抗炎药(NSAID),其中w/v表示以所述组合物的总体积计的重量。
28.根据权利要求27所述的组合物,其中所述溴莫尼定的浓度为约0.025%至约0.035%w/v。
29.根据权利要求27所述的组合物,其中所述NSAID选自由酮咯酸、阿司匹林、塞来昔布、地氟尼醛、依托度酸、布洛芬、吲哚美辛、酮洛芬、萘丁美酮、萘普生、奥沙普嗪、水杨酸盐、舒林酸、托美汀及其药学上可接受的盐及其组合组成的组。
30.根据权利要求29所述的组合物,其中所述NSAID是酮咯酸。
31.根据权利要求27所述的组合物,其中所述NSAID的浓度为约0.02%至约0.50%w/v。
32.根据权利要求27所述的组合物,其还包括非离子表面活性剂、增粘剂、缓冲剂和任选的山梨酸酯。
33.根据权利要求32所述的组合物,其中所述非离子表面活性剂是浓度为约1%至约5%w/v的聚山梨酯。
34.一种减轻炎症的方法,其包括将根据权利要求25所述的组合物施用于有此需要的受试者。
35.一种用于治疗青光眼的组合物,其包括:
约0.001%w/v的拉坦前列素或0.05%w/v的替莫洛尔;
约0.050%w/v的溴莫尼定;
约2.5%w/v的聚山梨酯;
约1.2%w/v的羟丙基甲基纤维素;
约5毫摩尔的硼酸;和
任选地,约0.1%w/v的山梨酸酯,
其中所述组合物的pH为约7.4。
36.一种用于治疗过敏性结膜炎的组合物,其包括:
约0.0035%w/v富马酸酮替芬;
约0.035%w/v的溴莫尼定;
约2.5%w/v的聚山梨酯;
约0.1%至约1.2%w/v的羟丙基甲基纤维素;
约4毫摩尔的柠檬酸盐缓冲液;和
任选地,约0.1%w/v的山梨酸酯,
其中所述组合物的pH为约6.5。
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