CN108883060A - 用于预防/阻止人轴性近视的抗过敏剂与毒蕈碱拮抗剂和/或多巴胺能激动剂的组合 - Google Patents
用于预防/阻止人轴性近视的抗过敏剂与毒蕈碱拮抗剂和/或多巴胺能激动剂的组合 Download PDFInfo
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Abstract
使用毒蕈碱拮抗剂或多巴胺激动剂滴眼液用于控制眼生长和预防近视的主要问题之一是不可接受的医源性结膜炎或皮炎的比率。本发明涉及那些活性成分与抗过敏成分的结合。可选地，同时具有抗毒蕈碱和/或多巴胺能作用以及抗组胺功能的分子的眼用用途。
Description
发明领域
本发明涉及用于在预防/阻止人近视中使用的药物活性成分或多功能活性成分的组合的领域。
技术状态
近视可以被定义为眼需要凹透镜以将图像聚焦在视网膜平面上。存在近视的许多亚组，散布最广的是由于眼球(ocular bulb)的过度伸长的轴性近视。在大多数西方儿童中，眼的生长持续进行，且眼在生理上保持些许远视，但在一些儿童(主要是6至14岁之间的儿童)中，眼伸长更快并导致近视。重要的生物学过程仍知之甚少，遗传和环境因素有助于其发展。已知近视在亚洲是在西方国家的3倍更普遍，一些研究将状况的发展与室内学习的小时数或者反过来与在室外花费的时间联系起来。在实验模型鸡或小型哺乳动物中，过度的眼生长可以通过眼睑缝合(lid suture)或者使用半透明的透镜退化图像来引发(形觉剥夺性近视(form deprivation myopia)或FDM)，或者，有趣的是，通过并置凹透镜来引发(透镜诱导的近视或LIM)。还可得的是具有自发的异常眼生长的小鼠品种。
许多人不认为近视是一种疾病，因为其在大多数情况中通过眼镜或隐形眼镜被可接受地矫正，但它可以被认为是眼生长的功能异常。此外，隐形眼镜佩戴者经受过敏或异物反应，或可引起视觉丧失的更严重的角膜感染。此外，近视的眼更易经受视网膜退化和视网膜裂孔，其可以导致视网膜脱落、青光眼、近视性黄斑劈裂(foveoschisis)和黄斑裂孔，所有疾病都可导致失明。因此，需要用于预防近视的有效疗法，以不仅用于审美目的，也为了预防成人期的失明性疾病。
从R.Bedrossian(Ophthalmology,May 1979,Vol 86,pp.713-717)的研究开始，越来越多的证据表明，在实验模型(形觉剥夺性近视或透镜诱导的近视)和人类二者中，阻断眼中的M1毒蕈碱受体使眼的轴向伸长停止。
在过去的30年中，许多研究探索了不同浓度的阿托品滴眼液的风险和益处或者阿托品滴眼液与其他装置例如隐形眼镜或多焦眼镜结合的风险和益处，以寻找用于近视预防的有效制剂。这些在Cochrane综合分析中分析(a Cochrane meta analysis)(Walline JJ等人,Interventions to slow progression of myopia in children.CochraneDatabase of Systematic Reviews 2011,Issue 12.Art.No.:CD004916)。更好的结果从ATOM(用于治疗近视的阿托品(Atropine for Treatment Of Myopia))I期和II期研究获得。在第一个研究(公开于2006年)(Chua W.H.等人,Atropine for the Treatment ofChildhood Myopia,Ophthalmology 2006；113:2285–2291)中，作者证明，在安慰剂对照的大的中国儿童团体中，入睡时滴注一滴1％阿托品洗眼液通过阻止眼球伸长而使90％的受试者中的轴性近视的发展停止。由于阻碍该药物的广泛使用的主要因素是由于散瞳导致的视力模糊(这在ATOM I期研究中也被大量抱怨)，在第二个研究(Chia A.等人,Atropinefor the Treatment of Childhood Myopia:Safety and Efficacy of 0.5％,0.1％,and0.01％Doses(Atropine for the Treatment of Myopia 2),Ophthalmology 2012；119:347–354)中试验的相同的组将剂量降低至0,1％、0,05％和0,01％，证明了阿托品的剂量依赖性作用在较低浓度仍是可接受的。另外，在儿童群体中，约5％的少量的但仍是不可接受的数目的受试者发展眼发红和发痒。该作用被证明是由结膜的过敏反应引起的。(Yoshikawa K.,Kalahari S.Contact allergy to atropine and other mydriaticagents；CONTACT DERMATITIS 12(1):56-57,april 2006)。阻止眼伸长不由对视网膜的毒性作用介导，如在一些初始体外研究中以及一些体外分析中假定的，且针对人类受试者的mfERG不展示视网膜功能的任何改变(Chia A.等人.Full-field electroretinogramfindings in children in the atropine treatment for myopia(ATOM2)study；Documenta Ophthalmologica 126(3)·January 2013)。
为了尝试降低副作用特别是散瞳，对实验模型和人类二者尝试了其他毒蕈碱拮抗剂。主要尝试了哌仑西平(EP 0478694B1)，但效果无论如何与散瞳的程度相关，且眼表面致敏超过阿托品，因此放弃了这个方法。
进一步的研究(主要是在上世纪的最后10年里)更深入地探索了多巴胺(DA)在眼轴伸长的过程中的作用。在实验模型中，D1激动剂主要促进眼伸长，而D2激动剂和D1拮抗剂则阻断该过程。因此，近视可以被解释为两种受体活性之间的不平衡。人类中的结果不可得，且基于该药物类别的滴眼液的发展由于活性成分在生理pH的不良溶解性而是困难的。未能发现多巴胺能药物在人类中的人类研究，仅实验数据是可得的(Feldkaemper M.等人,An updated view on the role of dopamine in myopia,Experimental Eye Research114(2013)106-119)，并且多巴胺再摄取抑制剂针对近视诱导的实验模型是有活性的。现今，多巴胺激动剂在眼科被使用以恢复严重受损的眼中的生理眼压(IOP)，它们对健康的眼具有很小作用，并且在长期使用中未显示风险。
因此，明显的是，使用毒蕈碱拮抗剂或多巴胺激动剂滴眼液用于控制眼生长和预防近视的主要问题之一是不可接受的医源性结膜炎或皮炎的比率。
本发明的目的是提供一种用于预防/阻止儿童近视的眼科疗法，其具有减轻的使用毒蕈碱拮抗剂或多巴胺激动剂滴眼液所观察到的副作用。
定义和缩写
AM：轴性近视
FDM：形觉诱导性近视
LIM：透镜诱导性近视
mfERG：多焦视网膜电图
DA：多巴胺
IOP：眼压
发明概述
本发明通过以下解决了上述问题：将更多种药物活性成分组合在单一制剂中，其中将抗组胺成分与抗胆碱能成分和/或多巴胺能成分或单胺再摄取抑制剂组合；或
单一药物活性成分，其具有抗胆碱能(抗毒蕈碱)和抗组胺的组合活性，或抗胆碱能、抗组胺和多巴胺能或单胺再摄取抑制的组合活性；
所述更多种药物活性成分或单一药物活性成分用于在预防/阻止儿童轴性近视中使用。
令人惊讶的是，上述成分/活性的组合允许预防眼轴伸长，而不会产生如同通过单独施用阿托品观察到的散瞳和过敏性结膜炎或皮炎的缺点。
因此，本发明的另一个目的还是一种眼用制剂，所述眼用制剂用于在预防/阻止轴性近视中使用，所述眼用制剂包含：
抗组胺成分，所述抗组胺成分与抗胆碱能成分和/或多巴胺能成分或单胺再摄取抑制剂组合；或
单一药物活性成分，所述单一药物活性成分具有抗胆碱能和抗组胺的组合活性，或抗胆碱能、抗组胺和多巴胺能或单胺再摄取抑(特别是多巴胺)的组合活性。
发明详述
根据本发明的用于使用的活性成分的组合或单一(抗帕金森病)成分优选地经眼、通过外用(topically)或局部地(locally)施用至眼。
根据本发明，配制用于眼用用途的组合物可进一步包含缓冲剂、增溶剂(诸如环糊精、离子型或非离子型表面活性剂、磷脂胶束或类似物、微粒体或其他物质)、凝胶化剂(gelificant)(诸如透明质酸、羟甲基纤维素、羟丙基纤维素、羧甲基纤维素、黄原胶(Xantan gum)、罗望子多糖(tamarind seed polysaccharide)、聚维酮、卡波姆和/或其他物质)和防腐剂(诸如苯扎氯铵、苯佐氯铵、十六烷基吡啶、聚季铵盐(polyquad)和/或其他物质)。
根据本发明，上述组合物可以是适合于隐形眼镜吸收或(通过适当的缓冲剂)适合于眼离子透入法或用于包含在眼内、穹窿或泪腺内多孔固体插入物(生物可降解的或生物不可降解的)如聚乳酸或类似聚合物中的洗眼液或溶液。优选地，根据本发明，制剂可以是具有或不具有凝胶化剂(gelificant)的无菌滴眼液；适用于隐形眼镜浸渍的无菌溶液；适用于经巩膜离子透入法的无菌溶液；用于待被置于结膜下穹用于持续释放的固体多孔装置的浸渍的浓缩溶液。
根据本发明，优选地，抗组胺/抗过敏成分包括但不限于：色甘酸、酮替芬、吡嘧司特(pemirolast)、苯磺酸贝托司汀(bepotastine besilate)、氨茶碱(aminophylline)、阿司咪唑(astemizole)、溴苯那敏、卡比沙明、西替利嗪、氯苯那敏、克里马丁、苯海拉明、多西拉敏、依巴斯汀(ebastine)、恩布拉敏、非索非那定、左西替利嗪、氯雷他定、甲地拉嗪、咪唑斯汀(mizolastine)、卢帕他定、特非那定(terfenadine)、槲皮素(quercetin)、芦丁(rutine)、迷迭香酸、咖啡酸酯、十六酰胺乙醇(PEA)、木犀草素、紫苏叶提取物和三桠乌药(lindera obtusiloba)水提取物。
根据本发明，优选地，抗胆碱能成分包括但不限于：阿托品碱或其盐、莨菪碱或其盐、甲硝阿托品；溴甲辛托品、环喷托酯(cyclopentolate)、后马托品、8-苯基乙酰基芬托氯铵(8-phenylacetyl homatropinium chloride)、东莨菪碱(scopolamine)(东莨菪碱(hyoscine))、去甲东莨菪碱、甲基东莨菪碱或其盐、丁基东莨菪碱或其盐、异丙托铵碱或其盐、噻托铵(tiotropium)碱或其盐、氧托铵(oxitropium)碱或其盐、氟托铵(flutropium)碱或其盐、奥芬铵(oxyphenonium)碱或其盐、西克托铵(cyclotropium)碱或其盐、西托铵(cimetropium)碱或其盐、曲司铵(trospium)碱或其盐、珍托铵(xenytropium)碱或其盐、阿地铵(aclidinium)碱或其盐、克利铵(clidinium)碱或其盐、托吡卡胺、环戊丙醇、安克痉(biperiden)、托特罗定、消旋山莨菪碱、普鲁芬胺(ethopropazine)、索利那新、达非那新、美贝维林、丙环定、普鲁本辛碱或其盐、甘罗溴铵、异丙胺(isopropamide)碱或其盐、甲哌佐酯(mepenzolate)、曲地铵、甲硫己环铵、美索托明(methoctramine)、双环胺、黄酮哌酯、奥昔布宁、喜巴辛(himbacine)和类似物(参见例如WO 2005/118576；和WO 2006/076564)、地芬尼多(六氢化-硅烷-地芬尼多、p-氟代六氢化-硅烷-地芬尼多)、哌仑西平、替仑西平、奴文西平、利喷西平和茄科所包括的植物的提取物，特别是以下族(tribe)中包括的植物的提取物：曼陀罗族(Datureae)、天仙子族(Hyoscyameae)、茄参族(Mandragoreae)、Solandreae、茄族(Solaneae)。
根据本发明，优选地，主要作用于D2受体或作为多巴胺再摄取抑制剂的多巴胺能成分包括但不限于：阿朴吗啡、R(-)n-丙基去甲阿朴吗啡、麦角腈、卡麦角林、溴隐亭、2-溴-α-麦角隐亭、二氢麦角隐亭、培高利特、麦角乙脲、左旋多巴、3,4-二苯甲酰多巴胺、二丙基多巴胺、N-甲基多巴胺、3,4-二羟基苯乙酸(DOPAC)、喹吡罗、7,8-二羟基-5-苯基-八氢苯并[h]异喹啉、A-86929、dihydrexidine、dinapsoline、rotigotin、dinoxiline、doxanthrine、SKF-81297、SKF-82958、SKF-38393、非诺多泮、6-Br-APB、A-68930、A-77636、CY-208,243、SKF-89145、SKF-89626、N,N-Propyldihydrexidine、他利克索、吡贝地尔、普拉克索、喹吡罗(Quinelorane)、罗匹尼罗、Sumanirole、可卡因、安非他命、金刚烷胺、金刚乙胺和adapromine、安咪奈丁、bromantane、哌甲酯、右哌甲酯、苯托雷司、芬坎法明、左法哌酯、美地沙明、美索卡、诺米芬辛、哌苯甲醇、苯咯戊烷、吡咯戊酮。
根据本发明，优选地，主要作用于D1受体的多巴胺拮抗剂的多巴胺能成分包括但不限于：多潘立酮、metoclorpromide、甲氧氯普胺、舒必利、氟哌啶醇、紫堇碱、螺环哌啶酮(spiroperidol)、硫丙拉嗪、氟奋乃静、匹莫齐特、螺哌隆、SCH-23,390、SKF-83,959、依考匹泮(Ecopipam)(SCH-39,166)、依替必利、Fallypride、Desmethoxyfallypride、L-741,626(3-[4-(4-氯苯基)-4-羟基哌啶-1-基]甲基-1H-吲哚)、雷氯必利、羟嗪、依托必利、SV 293、分类为典型的或非典型的抗精神病药的药物和育亨宾。
根据本发明，优选地，具有抗胆碱能和抗组胺的组合活性或抗胆碱能、抗组胺和多巴胺能(也为DA再摄取抑制剂)的组合活性的成分可以在抗帕金森病剂和三环类抗抑郁药中选择，因此包括但不限于：苯扎托品碱或其盐如甲磺酸苯扎托品(甲磺酸盐)、乙苯托品苯海索、dibenzoephtropine、Ditran(JB-329)(70％1-乙基-2-吡咯烷基甲基-α-苯基环戊基乙醇酸酯/盐和30％1-乙基-3-哌啶基-α-苯基环戊基乙醇酸酯/盐)、1-乙基-3-哌啶基-α-苯基环戊基乙醇酸酯/盐、乙胺太林(methantheline)、二苯拉林、氯胺酮、哌替啶、曲吡那敏茶苯海明、丙咪嗪及其代谢物、阿米替林及其代谢产物、去甲替林、10-羟基去甲替林和地昔帕明。
根据本发明的用于使用的优选组合包含阿托品和紫苏叶提取物，或阿托品和富马酸酮替芬。
根据本发明的用于使用的优选的抗帕金森病成分是甲磺酸苯扎托品。
优选的缓冲剂是磷酸二氢钠和磷酸氢二钠。
优选的防腐剂是苯扎氯铵。
根据本发明的优选的眼用制剂包含：
-硫酸阿托品0,01％-1,0％，
-紫苏叶提取物0,01％-5％，
-磷酸二氢钠0,05M，
-磷酸氢二钠0,05M，
-苯扎氯铵0,025％-0,1％，
-纯化水作为剩余物，
其中百分比基于组合物的总重量。
根据本发明的另一个优选的眼用制剂包含：
-硫酸阿托品0,01％-1,0％，
-富马酸酮替芬0,01％-0,1％，
-磷酸二氢钠0,05M，
-磷酸氢二钠0,05M，
-苯扎氯铵0,025％-0,1％，
-纯化水作为剩余物，
其中百分比基于组合物的总重量。
根据本发明的另一个优选的眼用制剂包含：
甲磺酸苯扎托品0,001％-3,0％，
-磷酸二氢钠0,05M，
-磷酸氢二钠0,05M，
-苯扎氯铵0,025％-0,1％，
-纯化水作为剩余物，
其中百分比基于组合物的总重量。
Claims (10)
1.药物活性成分的组合或单一药物活性成分，用于在预防/阻止轴性近视中使用，其中所述组合包含抗组胺成分，所述抗组胺成分与抗胆碱能成分和/或多巴胺能成分或单胺再摄取抑制剂组合；其中所述单一活性成分具有抗胆碱能和抗组胺的组合活性，或抗胆碱能、抗组胺和多巴胺能或单胺再摄取抑制(特别是多巴胺)的组合活性。
2.根据权利要求1所述的用于使用的组合，包含硫酸阿托品和紫苏叶提取物；或硫酸阿托品和富马酸酮替芬。
3.根据权利要求1所述的用于使用的单一药物活性成分，其选自由抗帕金森病剂和三环类抗抑郁药组成的组。
4.根据权利要求3所述的用于使用的单一药物活性成分，其为苯扎托品或甲磺酸苯扎托品。
5.根据权利要求1-4中任一项所述的用于使用的药物活性成分的组合或单一药物活性成分，其通过外用或局部地施用至眼。
6.一种眼用制剂，所述眼用制剂包含抗组胺成分，所述抗组胺成分与抗胆碱能成分和/或多巴胺能成分或单胺再摄取抑制剂组合；或单一药物活性成分，所述单一药物活性成分具有抗胆碱能和抗组胺的组合活性，或抗胆碱能、抗组胺和多巴胺能或单胺再摄取抑制剂(特别是多巴胺)的组合活性。
7.根据权利要求6所述的眼用制剂，包含阿托品和紫苏叶提取物，或硫酸阿托品和富马酸酮替芬，或甲磺酸苯扎托品。
8.根据权利要求6-7中任一项所述的眼用制剂，还包含缓冲剂、增溶剂、凝胶化剂和/或防腐剂。
9.根据权利要求8所述的眼用制剂，其中缓冲剂是磷酸二氢钠和磷酸氢二钠和/或防腐剂是苯扎氯铵。
10.根据权利要求6-9中任一项所述的眼用制剂，用于在预防/阻止轴性近视中使用。
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| ITUB2016A000876A ITUB20160876A1 (it) | 2016-02-19 | 2016-02-19 | Combinazione di un agente antiallergico con un antagonista muscarinico e/o un agonista dopaminergico per l'uso in prevenzione/ arresto di miopia assiale nell’uomo |
| PCT/EP2017/053619 WO2017140846A1 (en) | 2016-02-19 | 2017-02-17 | Combination of an antiallergic agent with muscarinic antagonist and/or dopaminergic agonist for use in preventing/stopping of axial myopia in human |
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| CN114558069A (zh) | 2022-04-06 | 2022-05-31 | 杭州美依生物科技有限公司 | 一种眼部舒缓涂抹液及其制备方法 |
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| IL260893B2 (en) | 2023-08-01 |
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| BR112018016845A2 (pt) | 2018-12-26 |
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