CN109414431A - 用副交感神经剂和抗交感神经剂治疗干眼病 - Google Patents
用副交感神经剂和抗交感神经剂治疗干眼病 Download PDFInfo
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Abstract
提供了用于治疗和/或预防干眼病(DED)的方法和组合,其通过用有效治疗所述干眼病的至少一种副交感神经剂和至少一种抗交感神经剂的组合来治疗有此需要的受试者。
Description
技术领域
提供了治疗和/或预防干眼病(DED)的方法,其通过用副交感神经剂和抗交感神经剂的组合治疗有此需要的受试者来进行。具体地,该组合通过模拟生理性副交感神经稳态转变(parasympathetic homeostatic shift)而起作用。
背景技术
DED是一种常见疾病,影响全球约15-35%的人口(Xiao X,He H,Lin Z,等人Therapeutic effects of epidermal growth factor on benzalkonium chloride-induced dry eye in a mouse model.Invest Ophthalmol Vis Sci 2012;53:191-7)。在病因学上有两种类型的DED(Nichols KK.The international workshop on meibomiangland dysfunction:Introduction.Invest Ophthalmol Vis Sci2011;52:1917-21)-较常见的睑板腺功能障碍(MGD)型,以及相当罕见的泪腺受损型(水液缺乏性DED)(Lemp MA,Crews LA,Bron AJ,Foulks GN,Sullivan BD.Distribution of aqueous-deficient andevaporative dry eye in a clinic-based patient cohort:A retrospectivestudy.Cornea 2012;31:472-8)。在159个可分类的DED病例中,只有14%是纯的水液缺乏型的(Lemp MA,Crews LA,Bron AJ,Foulks GN,Sullivan BD.Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort:Aretrospective study.Cornea 2012;31:472-8)。MGD型DED患者具有角化过度和厚的异常的睑脂。
关于这种疾病的具体特征有大量信息。然而,这种丰度似乎没有合并为对DED基本发病机制的充分理解。似乎默认DED是由多种原因引起的,并且没有一种基本潜在的发病机制。与此相符,最近列出了二十五个“甚至更多个”DED原因(Mantelli F,Massaro-GiordanoM,Macchi I,Lambiase A,Bonini S.The cellular mechanisms of dry eye:frompathogenesis to treatment.J Cell Physiol 2013;228:2253-6)。
大多数DED病例似乎是由全身性原因和局部原因综合引起的。例如,DED似乎与以下疾病之间似乎存在关系:(1)类风湿性关节炎(见,例如,(Barendregt PJ,van derHeijde GL,Breedveld FC,Markusse HM.Parasympathetic dysfunction in rheumatoidarthritis patients with ocular dryness.Ann Rheum Dis 1996;55:612-5),(2)干燥综合征(Sjogren's syndrome)(Tsifetaki N,Kitsos G,Paschides CA,等人Oralpilocarpine for the treatment of ocular symptoms in patients with Sjogren'ssyndrome:A randomized 12week controlled study.Ann Rheum Dis 2003;62:1204-7),(3)衰老(Tsubota K,Kawashima M,Inaba T,等人The antiaging approach for thetreatment of dry eye.Cornea 2012;31:S3-S8),(4)压力(Tsubota K,Kawashima M,Inaba T,等人The antiaging approach for the treatment of dry eye.Cornea 2012;31:S3-S8.;Galor A,Feuer W,Lee DJ,Depression,post-traumatic stress disorder,and dry eye syndrome:a study utilizing the national United States VeteransAffairs administrative database.Am J Ophthalmol 2012;154:340-6),(5)高血压(Uchino M,Nishiwaki Y,Michikawa T,等人Prevalence and risk factors of dry eyedisease in Japan:Koumi Study Ophthamology 2011;1118:2361-7),(6)心肌梗塞UchinoM,Nishiwaki Y,Michikawa T,等人Prevalence and risk factors of dry eye diseasein Japan:Koumi Study.Ophthamology 2011;1118:2361-7),(7)吸烟(Altinors DD,AkcaS,Akova YA,等人Smoking associated with damage to the lipid layer of theocular surface.Am J Ophthalmol 2006;141:1016-21),(8)糖尿病(Li B,Sheng M,XieL,等人Tear proteomic analysis of patients with type 2diabetes and dry eyesyndrome by two-dimensional nano-liquid chromatography coupled withtandemmass spectrometry.Invest Ophthalmol Vis Sci 2014;55:177-86),(9)血脂异常(Jalbert I.Diet,nutraceuticals and the tear film.Exp Eye Res 2013;117:138-46,Chun YH,Kim HR,Han K,Park YG,Song HJ,Na KS.Total cholesterol and lipoporoteincomposition are associated with dry eye disease in Korean women.Lipids HealthDis 2013;12:84),和(10)炎症(Henrich CF,Ramulu PY,Akpek EK.Association of dryeye and inflammatory systemic diseases in a tertiary care-baed sample.Cornea2014;33:819-25)。
DED和青光眼之间似乎也存在关系。已经发现,在患有青光眼的个体中治疗DED改善了眼内压控制(Batra R,Tailor R,Mohamed S,Ocular surface disease exacerbatedglaucoma:optimizing the ocular surface improves intraocular pressurecontrol.J Glaucoma 2014;23:56-60)。此外,事实上,伴有青光眼的DED/MGD的发病率更高(Lee SY,Wong TT,Chua J,Boo C,Soh YF,Tong L.Effect of chronic anti-glaucomamedications and trabeculectomy on tear osmolality.Eye 2013;27:1142-50;Viso E,Gude F,Rodriguez-Ares MT.The association of meibomian gland dysfunction andother common ocular diseases with dry eye:a population-based study inSpain.Cornea 2011;30:1-6,Arita R,Itoh K,Maeda S,等人Comparison of the long-term effects of various topical antiglaucoma medications on meibomianglands.Cornea 2012;31:1229-34)。
然而,现在已经认识到,与青光眼滴剂一起使用的滴眼剂防腐剂,例如苯扎氯铵(Xiao X,He H,Lin Z,等人Therapeutic effects of epidermal growth factor onbenzalkonium chloride-induced dry eye in a mouse model.Invest Ophthalmol VisSci 2012;53:191-7和Lee SY,Wong TT,Chua J,Boo C,Soh YF,Tong L.Effect ofchronic anti-glaucoma medications and trabeculectomy on tear osmolarity.Eye2013;27:1142-50),有利于DED(Arita R,Itoh K,Maeda S,等人Comparison of the long-term effects of various topical antiglaucoma medications on meibomianglands.Cornea 2012;31:1229-34)并且治疗青光眼的前列腺素衍生物引起结膜充血、浅层点状角膜病和睑缘炎(Arita R,Itoh K,Maeda S,等人Comparison of the long-termeffects of various topical antiglaucoma medications on meibomianglands.Cornea 2012;31:1229-34)。此外,用于青光眼的多种药物有利于MGD和浅层点状角膜病的症状,有利于DED(Arita R,Itoh K,Maeda S,等人Comparison of the long-termeffects of various topical antiglaucoma medications on meibomianglands.Cornea 2012;31:1229-34)。
由于传统上将DED视为具有多个独立的机制,因此DED的治疗只能是对症的(综述于Geerling G,Tauber J,Baudouin C,等人The international workshop on meibomiangland dysfunction:Report of the subcommittee on management and treatment ofmeibomian gland dysfunction.Invest Ophthalmol Vis Sci 2011;52:2050-64)。目前,治疗包括,例如,使用热敷和按摩来液化睑脂并有利于其排出,局部用抗炎剂如环孢菌素或皮质类固醇,抗生素和润滑滴眼剂(例如,人造泪液,见,例如美国专利号4,131,651和美国专利号3,947,573)。毛果芸香碱(pilocarpine),一种用于治疗青光眼的胆碱能剂,被发现是干眼病的一种有效的系统性治疗方法。已经发现局部用毛果芸香碱制剂会引起调节痉挛(综述于美国专利号6,277,855)。然而,最近发现低剂量局部用毛果芸香碱(0.05%)刺激泪液产生,治疗两个月后瞳孔尺寸没有任何变化(Urriquia TB and Marin,Jr.JDF.Efficacyof Topical Pilocarpine in the Management of Primary Aqueous Tear Deficiency:An Initial Study.Philip J Ophthalmol 2014;39:6-11)。
提议的其他治疗包括使用乙酰胆碱酯酶(AchE)抑制剂(美国专利号6,273,092),烟碱样乙酰胆碱受体激动剂(美国专利号6,277,885),神经递质如乙酰胆碱,ATP,甘氨酸,谷氨酸,多巴胺,去甲肾上腺素,肾上腺素,章鱼胺,血清素(5-羟色胺),β-丙氨酸,组胺,γ氨基丁酸(GABA),牛磺酸,天冬氨酸和一氧化氮和神经肽(美国专利申请公开号20060270592和20080261890)。
发明内容
本发明提供了用于治疗和/或预防有此需要的受试者的干眼病的方法和组合物。在一个具体实施方案中,所述受试者可以是哺乳动物(例如,狗、猫、人);在一个甚至更具体的实施方案中,所述受试者可以是人类患者。该方法包括施用有效治疗所述干眼病的量的至少一种拟副交感神经剂和至少一种抗交感神经剂。在一个具体的实施方案中,受试者被施用的所述拟副交感神经剂和/或抗交感神经剂的量比用于治疗青光眼或其他眼病的已知有效剂量低至少约10%。在一个更加具体的实施方案中,受试者被施用的所述拟副交感神经剂和/或抗交感神经剂的量比用于治疗青光眼或其他眼病的剂量低至少约50%至约80%。在另一个具体的实施方案中,药剂被局部施用,因此该组合物是局部用组合物。
还提供了所述拟副交感神经剂和至少一种抗交感神经剂在配制用于治疗干眼病的药物中的用途。在一个具体的实施方案中,拟副交感神经剂和/或抗交感神经剂的存在量比用于治疗青光眼或其他眼病的已知有效剂量低至少约10%或者至少约50%至约80%。
在一个具体的实施方案中,所述DED是隐形眼镜诱导的DED。在一个相关方面,所述副交感神经剂和交感神经剂被施用于隐形眼镜。在又一个相关方面,提供了一种用于预防和/或治疗有此需要的受试者的DED特别是隐形眼镜诱导的DED的方法,其包括向所述受试者施用隐形眼镜,所述隐形眼镜包含有效治疗所述DED特别是隐形眼镜诱导的DED的量的至少一种拟副交感神经剂和任选地至少一种抗交感神经剂。在另一个相关方面,提供了一种隐形眼镜,其包含有效治疗和/或预防DED特别是隐形眼镜诱导的DED的量的至少一种拟副交感神经剂和至少一种抗交感神经剂。还提供了一种制造所述隐形眼镜的方法,包括施用有效治疗和/或预防DED的量的至少一种拟副交感神经剂和任选的至少一种抗交感神经剂。
在一个更加具体的实施方案中,所述方法和组合物通过模拟副交感神经稳态转变起作用。副交感神经稳态转变的基本原理可以在Hellstrom HR.The altered homeostatictheory:A hypothesis proposed to be useful in preventing ischemic heartdisease,hypertension,and diabetes-including reducing the risk of age andatherosclerosis.Med Hypotheses.2007;68:415-433中找到。这种稳态改变理论认为风险因素有利于有害的交感神经稳态转变和疾病,并且预防因素有利于有益的副交感神经稳态转变和健康。例如,以上列出的多种风险因素被认为是通过有害的交感神经稳态转变而有利于DED,并且在本发明中使用的DED的治疗有利于有益的副交感神经稳态转变和DED的改善。有益的副交感神经稳态转变包括副交感神经活动增加和交感神经活动减少。因此,使用拟副交感神经剂和抗交感神经剂的组合。
在一个具体实施方案中,抗交感神经剂是β-阻断剂,可包括但不限于尼普地洛(niprodilol)、奈必洛尔(nebivolol)、普萘洛尔(propranolol),更特别地,是尼普地洛和奈必洛尔。在另一个具体实施方案中,拟副交感神经剂选自由毛果芸香碱和卡巴胆碱(carbachol)组成的组。在一个特别的实施方案中,可以给受试者施用包含(a)卡巴胆碱和(b)尼普地洛和/或奈必洛尔和/或普萘洛尔的组合或组合物。
在另一个具体实施方案中,还提供了血管紧张素阻断剂(血管紧张素转化酶(ACE)抑制剂和血管紧张素II受体阻断剂)。这些药剂可被视为抗交感神经剂,因为它们可阻断肾素-血管紧张素-醛固酮系统(Slomka T,Lennon ES,Akbar H,等人Effects of Renin-Angiotensin-Aldosterone System Blockade in Patients with End-Stage RenalDisease.Am J Med Sci 2016;351:309-16)。特别地,ACE抑制剂(Hirooka K,ShiragaF.Potential role for angiotensin-converating enzyme inhibitors in thetreatment of glaucoma.Clin Ophthalmol 2007;1:217-23)和血管紧张素II受体阻断剂(Burnier M.Angiotensin II receptor antagonists.Lancet 2000;355:637-45)阻断血管紧张素II–并且血管紧张素II增加交感神经激活(Reid IA.Interactions between ANGII,sympathetic nervous system,and baroreceptor reflexes in regulation ofblood pressure.Am J Physiol 1992;262:E63-E78)。因此,血管紧张素阻断剂减少交感神经激活并另外促进副交感神经激活(Hellstrom HR.The altered homeostatic theory:ahypothesis proposed to be useful in understanding and preventing ischemicheart disease,hypertension,and diabetes-including reducing the risk of ageand atherosclerosis.Med Hypotheses 2007;68:415-33)。应该注意的是,肾素-血管紧张素调节存在于眼睛中(Hirooka K,Shiraga F.Potential role for angiotensin-converating enzyme inhibitors in the treatment of glaucoma.Clin Ophthalmol2007;1:217-23)。此外,已发现ACE抑制剂与较低的DED风险有关(Anonymous.AmericanAcademy of Ophthalmology Cornea/External Disease Panel.Preferred PracticeGuidelines.Dry Eye Syndrome.American Academy ofOphthalmology.2013.http://one.aao.org/preferred-practice-pattern/dry-eye-syndrome-ppp—2013.Accessed February 15,2015.Approved September 21,2013)并促进副交感神经激活。还发现ACE抑制剂可改善糖尿病视网膜病变(Chaturvedi N,SjolieAK,Stephenson JM,等人Effect of lisinopril on progression of retinopathy innormotensive people with type 1diabetes.The EUCLID Study Group.EURODIABControlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus.Lancet1998;351:28-31),并降低青光眼的眼内压(Hirooka K,Shiraga F.Potential role forangiotensin-converating enzyme inhibitors in the treatment of glaucoma.ClinOphthalmol 2007;1:217-23)。
如先前更详细地讨论的,拟副交感神经剂和/或抗交感神经剂的量比用于治疗青光眼或其他眼病的量少至少约10%。Niprovilol(Mizuno KI,Koide T,Yoshimura M,AraieM.Neuroprotective effect and intraocular penetration of nipradilol,a beta-blocker with nitric oxide donative action Invest Ophth Vis Sci.2001;42:688-92)和奈必洛尔(Zhang A,Ding L,Jin Z,等人Nebivolol protects against myocardialinfarction injury via stimulation of beta 3-adrenergic receptors and nitricoxide signaling.PlosONE.2014;9:e98179)可以在具体实施方案中使用,因为它们具有能治愈的一氧化氮(NO)供给作用(nitric oxide(NO)donative action)。这是相关的,因为功能性泪腺单元包括氮能神经支配(Bolekova A,Kluchov D,Tomasova L,HvizdosovaN.Effect of retinoic acid on the nitrergic innervation of meibomian glands inrats.Eur J Histochem.2012;56:e50)。
定义
当提供了值的范围时,应该理解的是,在所述范围的上限与下限之间的每个中间值到下限单位的十分之一(除非上下文另有明确指出),以及所述范围内的任意其他所述的值或中间值都包含在本发明中。这些较小范围的上限和下限可以独立地包括在较小范围内,并且也包括在本发明内,受所述范围内任何具体排除的界限的限制。当所述范围包括一个或两个界限时,排除这两个界限的范围也包括在本发明中。
除非另外定义,否则本文所使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。尽管与本文描述的那些类似或等同的任意方法和材料也可用于本发明的实践或测试,但现在描述的是优选的方法和材料。
本公开内容中援引的所有出版物和专利均通过引用整体并入。本文中的任何内容均不应被解释为承认本发明无权凭借在先发明而先于此类公开。如果通过引用并入的材料与本说明书相矛盾或不一致,则说明书将取代任何此类材料。
必须注意的是,如本文和所附权利要求中所使用的,单数形式“一”、“一个”和“该”包括复数指代,除非上下文另有明确说明。
除非另有说明,否则在一系列元素之前的术语“至少”应理解为指代该系列中的每个元素。本领域技术人员会意识到或能够仅使用常规的实验确定本文所述的本发明的具体实施方案的许多等同物。这样的等同物旨在由本发明所包含。在整个说明书和随后的权利要求中,除非上下文另有要求,否则词语“包含”(comprise)以及诸如“包含”(comprises)和“包含”(comprising)等变体,将被理解为表示包括所述整数或步骤或一组整数或步骤,但不排除任何其他的整数或步骤或一组整数或步骤。因此,术语“包含”、“包括”、“含有”、“具有”等应以扩充性或开放性的无限制的方式来理解。当在本文中使用时,术语“包含”可以用术语“含有”代替,或者有时当在本文中使用时用术语“具有”代替。
如本文所定义,术语“干眼”、“干眼病”或“干眼综合症”是指对功能性泪腺单元也就是对润滑眼睛的泪膜的质量产生不利影响的任意疾病或病症或病况。疾病或病症可以是眼睛本身,或者是身体的另一部分,只要它对润滑眼睛的泪膜的质量产生不利影响。例如,本文所用的“干眼”包括干眼症、赖利-戴综合征(Riley Day Syndrome)和干燥性角膜结膜炎(keratoconjunctivities sicca),以及由例如以下的其他病况、因素和现象引起的干眼:糖尿病,长时间佩戴隐形眼镜,高龄,循环激素,各种自身免疫性疾病(例如干燥综合征和系统性红斑狼疮),眼科手术,包括PRK或LASIK,许多药物,环境状况,视觉任务,如计算机使用,眼疲劳,机械影响,如角膜敏感性,眼睑闭合不全(partial lid closure),表面不规则(例如翼状胬肉),和眼睑不规则(例如上睑下垂,睑内翻/外翻,结膜黄斑)。
短语“有效量”(“effective amount”或“amount effective”)是本领域公认的术语,并且指的是当将其掺入到本文所述的组合物中时,在适用于任何医学治疗的合理的收益/风险比率下产生一些所需效果的药剂的量。在某些实施方案中,该术语是指消除、减轻或维持干眼症状(例如,防止干眼症状的蔓延),或预防或治疗干眼所必需或足够的量。有效量可以根据诸如所治疗的疾病或病况、所施用的具体组合物或疾病或病况的严重性等因素而变化。本领域技术人员可凭经验确定具体药剂的有效量,而无需过多的实验。
如本文所定义的,“生理性副交感神经稳态转变”意指将稳态转变为副交感神经优势,其中副交感神经活动增加并且交感神经活动相应减少。
如本文所定义,术语“治疗”(“treat”、“treatment”和“treating”)应相应地理解为包括预防和治疗或改善疾病症状以及治疗疾病的起因。
详细说明
如上所述,提供了用于预防和/或治疗干眼病的给药方法和组合物,其包含有效预防和/或治疗所述干眼病的量的一种或多种拟副交感神经剂和至少一种抗交感神经剂。还提供了有效量的至少一种拟副交感神经剂和至少一种抗交感神经剂预防和/或治疗干眼病和/或配制用于预防和/或治疗干眼病的药物的用途。
拟副交感神经剂
存在多种拟副交感神经剂,并且有几种被配制用于局部使用。这些包括但不限于提到过的毛果芸香碱、卡巴胆碱、碘依可酯(ecothiopate)、地美溴铵(demecariumbromide)和氟磷酸二异丙酯。在一个具体实施方案中,拟副交感神经剂可以是卡巴胆碱、碘依可酯(echothiophate iodide)、毒扁豆碱和/或地美溴铵。可以使用一种以上的拟副交感神经剂来确保更广泛的结果。
交感神经阻断剂/抗交感神经剂
交感神经阻断剂是α或β选择性的。α阻断剂可能没有帮助。例如,α阻断剂坦索罗辛(tamsulosin)可在眼外科手术期间引起虹膜松弛综合症(Chang DF,Campbell JR,ColinJ,Schweitzer C.Prospective masked comparison of intraoperative floppy irissyndrome severity with tamsulosin versus alfuzosin.Ophthalmology 2014;121:829-34),也可引起逆行射精(Agrawal M,Gupta M,Gupta A等人Prospective randomizedtrial comparing efficacy of alfuzosin and tamsulosin in management of lowerereteral stones.Urology 2009;73:706-9)。然而,为了确保更生理性的交感神经激活的阻断,可能会在相当低的剂量下使用α阻断剂。
在另一个具体的实施方案中,交感神经阻断剂或抗交感神经剂可以是β-阻断剂。β-阻断剂可以是β-选择性或非选择性药剂,可以包括但不限于普萘洛尔(非选择性)噻吗洛尔(timolol)(非选择性)、倍他洛尔(betaxolol)(β1选择性拮抗剂)、左布诺洛尔(levobunolol)(非选择性β1和2阻断剂)、卡替洛尔(carteolol)(非选择性β阻断剂)、美替洛尔(metipranolol)(非选择性β阻断剂)左倍他洛尔(levobetaxolol)(β1抑制剂)以及一氧化氮(NO)供体如尼普地洛(nipradilol)(不可选择的β阻断剂)和奈必洛尔(β选择性阻断剂),和另外地,具有ISA或内在交感神经作用的物质,如氧烯洛尔(oxyprenolol)和吲哚洛尔(pindolol)。
剂量水平
如上文更详细地描述的那样,在一个实施方案中,至少一种上述药剂以低于针对青光眼或其它眼病的任意已知治疗剂量水平的剂量施用。在一个具体实施方案中,至少一种药剂以比用于治疗青光眼或其他眼病的剂量低至少约10%的剂量施用。在一个甚至更具体的实施方案中,至少一种所述药剂以比用于治疗青光眼或其他眼病的已知有效剂量低至少约50%至约80%的剂量施用,并且在甚至另一个更具体的实施方案中,所述药剂以比用于治疗青光眼或其它眼病的已知有效剂量低至少约40%至约25%的剂量施用。
上述药剂可一天施用一次、两次或三次。在一个实施方案中,两种药剂将在一种制剂中施用或一起施用。在一个具体实施方案中,两种药剂在一种制剂中施用。
在一个具体的实施方案中,卡巴胆碱(一种刺激毒蕈碱受体和烟碱受体的拟副交感神经剂)可以以约0.25%w/v至约0.5%w/v的剂量施用,并且尼普地洛(一种具有硝酸甘油样血管舒张活性的β阻断剂)可以以约0.05%至约0.1%w/v的剂量施用。或者,可以使用具有一些内在拟交感神经活性的β阻断剂卡替洛尔。它可以以约0.25%w/v至约0.35%w/v之间的剂量施用。
血管紧张素阻断剂
还提供了血管紧张素阻断剂,其包括但不限于ACE抑制剂和血管紧张素II受体阻断剂。如上所述,血管紧张素阻断剂可以作为抗交感神经剂以及拟副交感神经剂起作用。ACE抑制剂的实例包括但不限于苯那普利(benazepril),卡托普利(captopri!),依那普利(enalapril),福辛普利(fosinopril),赖诺普利(lisinopril),莫西普利(moexipril),培哚普利(perindopril),喹那普利(quinapril),雷米普利(ramipril)和Ixandolapril。血管紧张素II受体拮抗剂的实例包括但不限于氯沙坦(Losartan),缬沙坦(Valsartan),厄贝沙坦(Irbesartan),坎地沙坦(Candesartan),替米沙坦(Telmisartan),依普罗沙坦(Eprosartan)。
组合物/制剂
在某些实施方案中,该组合物包含至少一种拟副交感神经剂和至少一种抗交感神经剂。优选地,该组合物将在药学上可接受的载体、佐剂或媒介物中被配制成用于局部眼科施用的溶液、悬浮液和其他剂型。基于易于配制,以及患者通过在受影响的眼睛中滴入一至两滴溶液而容易地施用这些组合物的能力,通常优选水溶液。然而,组合物也可以是悬浮液、粘性或半粘性凝胶或其他类型的固体或半固体组合物。
在局部制剂中可以使用多种载体的任意一种,包括水,水和水混溶性溶剂的混合物,例如CI-至C7-链烷醇,植物油或含有从0.5至5%无毒水溶性聚合物的矿物油,天然产品,如明胶,海藻酸盐,果胶,黄蓍胶,刺梧桐树胶,黄原胶,角叉菜胶,琼脂和阿拉伯树胶,淀粉衍生物,如淀粉乙酸酯和羟丙基淀粉,以及其他合成产品,如聚乙烯醇,聚乙烯吡咯烷酮,聚乙烯甲醚,聚环氧乙烷,优选交联的聚丙烯酸,例如中性Carpool,或这些聚合物的混合物。载体的浓度通常为活性成分浓度的1至100,000倍。
可包括在制剂中的另外的成分包括张力增强剂,防腐剂,增溶剂,无毒赋形剂,缓和剂,多价螯合剂,pH调节剂,共溶剂和增粘剂。
为了调节pH,优选调节至生理pH,缓冲剂可能特别有用。本溶液的pH应保持在4.0至8.0,更优选约4.0至6.0,更优选约6.5至7.8的范围内。可以加入的合适的缓冲剂,例如硼酸,硼酸钠,柠檬酸钾,柠檬酸,碳酸氢钠,TRIS和多种混合磷酸盐缓冲剂(包括Na2HPO4、NaH2PO4和KH2PO4的组合)及其混合物。优选的是硼酸盐缓冲剂。通常,缓冲剂的用量范围为约0.05至2.5重量百分比,优选0.1至1.5百分比。
如果需要,通常通过张力增强剂调节张力。这些试剂可以是例如离子型和/或非离子型的。离子型张力增强剂的实例是碱金属或碱土金属卤化物,诸如,例如,CaCl2、KBr、KC1、LiCl、Nal、NaBr或NaCl、Na2SO4或硼酸。非离子型张力增强剂是例如尿素,甘油,山梨糖醇,甘露醇,丙二醇或右旋糖。通常用张力剂调节本发明的水溶液以接近正常泪液的渗透压,该渗透压相当于0.9%的氯化钠溶液或2.5%的甘油溶液。优选的是约225至400mOsm/kg的渗透压,更优选的是280至320mOsm。
在某些实施方案中,局部用制剂另外包含防腐剂。防腐剂通常可选自季铵化合物,诸如如苯扎氯铵、苯佐氯铵或其类似物。苯扎氯铵更好地描述为:N-苄基-N-(C8-C18烷基)-N,N-二甲基氯化铵。不同于季铵盐的防腐剂的实例是硫代水杨酸的烷基汞盐,诸如,例如,硫柳汞、硝酸苯汞、醋酸苯汞或硼酸苯汞,过硼酸钠,亚氯酸钠,对羟基苯甲酸酯类,诸如,例如,对羟基苯甲酸甲酯或对羟基苯甲酸丙酯,醇类,诸如,例如,氯丁醇、苯甲醇或苯乙醇,胍衍生物,诸如,例如,氯己定或聚六亚甲基双胍,过硼酸钠,或山梨酸。优选的防腐剂是季铵化合物,特别是苯扎氯铵或其衍生物如Polyquad(见美国专利号4,407,791)、烷基汞盐和对羟基苯甲酸酯类。在适当的情况下,向眼用组合物中加入足量的防腐剂,以确保在使用过程中防止由细菌和真菌引起的二次污染。
在另一个实施方案中,局部用制剂不包含防腐剂。这样的制剂可用于戴隐形眼镜的患者,或使用几种局部用滴眼液的那些患者和/或眼睛表面已经受损的那些患者,其中限制暴露于防腐剂可能是更合乎需要。
在一个具体实施方案中,可以使用本领域已知的方法将所述副交感神经剂和交感神经剂掺入、附着或携带在隐形眼镜上。在用于预防和/或治疗DED特别是隐形眼镜诱导的DED的具体实施方案中,本发明包括以适于预防和治疗DED特别是隐形眼镜诱导的DED的剂量将拟副交感神经剂和抗交感神经剂装载到药物洗脱隐形眼镜(如水凝胶隐形眼镜)之中或其上。作为药物洗脱隐形眼镜(如水凝胶隐形眼镜)的药物装载的一个实例,青光眼治疗的一项初步研究使用了装载到药物洗脱隐形眼镜诸如硅-水凝胶隐形眼镜中的β阻断剂噻吗洛尔(见,例如,Jung HJ,Abou-Jaoude M,Carbia BE,Plummer C,Chauhan A.Glaucomatherapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses.J Controlled Release 2013;165:82-9)。有趣的是,在药物洗脱隐形眼镜的另一项初步研究中,使用了两种药剂来治疗青光眼(Hsu KH,Carbia BE,Plummer C,Chauhan A.Dual drug delivery from vitamin E loaded contact lensesfor glaucoma therapy.Eur J Pharmaceut Biopharmaceut 2015;94:312-21)。
局部用制剂可能另外需要增溶剂的存在,特别是如果活性或非活性成分倾向于形成悬浮液或乳液。适用于上述组合物的增溶剂,例如,选自由以下组成的组:泰洛沙泊(tyloxapol),脂肪酸甘油聚乙二醇酯,脂肪酸聚乙二醇酯,聚乙二醇,甘油醚,环糊精(例如α-、β-或γ-环糊精,例如,烷基化的、羟烷基化的、羧烷基化的或烷氧基羰基-烷基化的衍生物,或单-或二糖基-α-、β-或γ-环糊精,单-或二麦芽糖基-α-、β-或γ-环糊精或潘糖基(panosyl)-环糊精),聚山梨酯20,聚山梨酯80或这些化合物的混合物。增溶剂的具体实例是蓖麻油和环氧乙烷的反应产物,例如商业产品Cremophor或Cremophor蓖麻油和环氧乙烷的反应产物已被证明是特别好的增溶剂,其可被眼睛极好地耐受。另一种增溶剂选自泰洛沙泊和环糊精。使用的浓度尤其取决于活性成分的浓度。添加量通常足以溶解活性成分。例如,增溶剂的浓度为活性成分浓度的0.1至5000倍。
制剂可包含其他无毒赋形剂,诸如,例如,乳化剂、润湿剂或填充剂,诸如,例如,指定为200、300、400和600的聚乙二醇,或指定为1000、1500、4000、6000和10000的Carbowax。所添加的赋形剂的量和类型根据具体要求而定,通常在约0.0001至约90重量%的范围内。
可以向本发明的制剂中添加其他化合物以增加载体的粘度。粘度增强剂的实例包括但不限于:多糖,例如透明质酸及其盐,硫酸软骨素及其盐,葡聚糖,纤维素家族的多种聚合物和乙烯基聚合物。在其他实施方案中,根据本发明的药物组合物将被配制用于其他类型的施用,例如口服,肠胃外,吸入喷雾,鼻,口腔,或通过植入的储库。本文所用的术语肠胃外包括皮下,皮内,静脉内,肌肉内,关节内,滑膜内,胸骨内,鞘内,病灶内和颅内注射或输注技术。配制用于这些施用形式的药物组合物的方法是本领域技术人员所熟知的。
适于口服施用的制剂可以是胶囊,扁囊,丸剂,片剂,锭剂(lozenge)(使用调味基,通常是蔗糖和阿拉伯树胶或黄芪胶),粉剂,颗粒,或者在水性或非水性液体中的溶液或悬浮液,或者水包油或油包水的液体乳液,或酏剂或糖浆,或软锭剂(pastille)(使用惰性基,如明胶和甘油,或蔗糖和阿拉伯树胶),各自含有预定量的其分子作为活性成分。
本发明的组合物还可以作为大丸剂、药糖剂或糊剂施用。
在用于口服施用的固体剂型(胶囊,片剂,丸剂,糖衣丸,粉末,颗粒等)中,将颗粒与一种或多种药学上可接受的载体(诸如柠檬酸钠或磷酸二钙)和/或任意以下物质混合:(1)填充剂或增量剂,诸如淀粉,乳糖,蔗糖,葡萄糖,甘露醇和/或硅酸;(2)粘合剂,诸如羧甲基纤维素,藻酸盐,明胶,聚乙烯吡咯烷酮,蔗糖和/或阿拉伯胶;(3)保湿剂,诸如甘油;(4)崩解剂,诸如琼脂-琼脂,碳酸钙,马铃薯或木薯淀粉,海藻酸,某些硅酸盐和碳酸钠;(5)溶液缓凝剂(solution retarding agent),诸如石蜡;(6)吸收促进剂,诸如季铵分子;(7)润湿剂,诸如,例如,乙酰醇和单硬脂酸甘油酯;(8)吸收剂,诸如高岭土和膨润土;(9)润滑剂,诸如滑石,硬脂酸钙,硬脂酸镁,固体聚乙二醇,十二烷基硫酸钠及其混合物;和(10)着色剂。在胶囊、片剂和丸剂的情况下,组合物还可包含缓冲剂。类似类型的固体组合物也可用作使用了赋形剂诸如乳糖或牛乳糖以及高分子量聚乙二醇等的软填充和硬填充明胶胶囊中的填料。
片剂可以通过压缩或模塑制备,任选地含有一种或多种辅助成分。压制片剂可以使用粘合剂(例如,明胶或羟丙基甲基纤维素),润滑剂,惰性稀释剂,防腐剂,崩解剂(例如,羟基乙酸淀粉钠或交联的羧甲基纤维素钠),表面活性剂或分散剂制备。模制片剂可以通过在合适的机器中模塑用惰性液体稀释剂润湿的补充剂或其组分的混合物来制备。片剂和其它固体剂型,例如糖衣丸、胶囊、丸剂和颗粒可任选地用包衣和外壳例如肠溶包衣和药物配制领域熟知的其它包衣刻痕(score)或制备。
用于口服施用的液体剂型包括药学上可接受的乳液,微乳液,溶液,悬浮液,糖浆和酏剂。除化合物外,液体剂型可含有本领域常用的惰性稀释剂,诸如,例如,水或其它溶剂、增溶剂和乳化剂,如乙醇,异丙醇,碳酸乙酯,乙酸乙酯,苯甲醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,油(特别是棉籽油,花生油,玉米油,胚芽油,橄榄油,蓖麻油和芝麻油),甘油,四氢呋喃醇,聚乙二醇和脱水山梨糖醇的脂肪酸酯,及其混合物。
除化合物外,悬浮液可含有悬浮剂,例如乙氧基化异硬脂醇,聚氧乙烯山梨糖醇和脱水山梨糖醇酯,微晶纤维素,偏氢氧化铝,膨润土,琼脂-琼脂和黄芪胶,以及它们的混合物。
可用于本发明药物组合物的合适的水性和非水性载体的实例包括水,乙醇,多元醇(诸如甘油,丙二醇,聚乙二醇等)及其合适的混合物,植物油,诸如橄榄油,和可注射的有机酯,诸如油酸乙酯。例如,可以通过使用诸如卵磷脂的包衣材料,在分散体的情况下通过保持所需的微粒尺寸,以及通过使用表面活性剂来保持适当的流动性。
Claims (13)
1.至少一种拟副交感神经剂和至少一种抗交感神经剂在配制用于治疗干眼病(DED)的药物中的用途。
2.根据权利要求1所述的用途,其中所述抗交感神经剂是β-阻断剂,例如尼普地洛、奈必洛尔、普萘洛尔。
3.根据权利要求1所述的用途,其中所述拟副交感神经剂选自由毛果芸香碱和卡巴胆碱组成的组。
4.用于治疗和/或预防有此需要的受试者的干眼病的组合物或组合,其包含有效治疗所述干眼病的量的至少一种拟副交感神经剂和至少一种抗交感神经剂。
5.根据权利要求1所述的用途,其中所述DED是隐形眼镜诱导的DED。
6.根据权利要求1所述的用途,其中所述剂被应用于隐形眼镜。
7.根据权利要求4所述的组合物,其中所述组合物为滴剂的形式或隐形眼镜的形式,所述隐形眼镜包含至少一种拟副交感神经剂和至少一种抗交感神经剂。
8.一种隐形眼镜,其包含有效治疗和/或预防DED的量的至少一种拟副交感神经剂和至少一种抗交感神经剂。
9.根据权利要求8所述的隐形眼镜,其中所述DED是隐形眼镜诱导的DED。
10.一种制造权利要求8所述的隐形眼镜的方法,其包括施用有效治疗和/或预防DED的量的至少一种拟副交感神经剂和任选的至少一种抗交感神经剂。
11.根据权利要求1所述的用途,其中所述副交感神经剂和/或抗交感神经剂是血管紧张素阻断剂。
12.根据权利要求4所述的组合物或组合,其中所述副交感神经剂和/或抗交感神经剂是血管紧张素阻断剂。
13.根据权利要求8所述的隐形眼镜,其中所述副交感神经剂和/或抗交感神经剂是血管紧张素阻断剂。
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