CN111212642A - 眼用组合物及使用方法 - Google Patents
眼用组合物及使用方法 Download PDFInfo
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- CN111212642A CN111212642A CN201980001967.2A CN201980001967A CN111212642A CN 111212642 A CN111212642 A CN 111212642A CN 201980001967 A CN201980001967 A CN 201980001967A CN 111212642 A CN111212642 A CN 111212642A
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- Prior art keywords
- ophthalmic
- nanoemulsion
- ocular
- group
- formulation
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Abstract
本发明涉及一种眼用组合物,包括至少两种活性药物成分。具体地,所述活性药物成分选自以下项组成的组:α2肾上腺素能受体激动剂;β‑肾上腺素能受体激动剂;免疫抑制剂;淋巴细胞相关抗原拮抗剂;抗炎剂;β‑阻断剂;前列腺素类似物;组胺受体拮抗剂;碳酸酐酶抑制剂;和,抗生素。在一些实施方式中,本发明的组合物是纳米乳制剂。在一个具体实施方式中,第一活性药物成分是α2肾上腺素能受体激动剂。本发明还提供了使用本发明的组合物治疗与眼障碍或眼病相关的各种临床疾病的方法。
Description
技术领域
本发明涉及包括至少两种活性药物成分的眼用组合物。具体地,所述活性药物成分选自由以下项组成的组:α2肾上腺素能受体激动剂;β-肾上腺素能受体激动剂;免疫抑制剂;淋巴细胞相关抗原拮抗剂;抗炎剂;β-阻断剂;前列腺素类似物;组胺受体拮抗剂;碳酸酐酶抑制剂;和,抗生素。在一些实施方式中,本发明的组合物是纳米乳制剂。本发明还提供了使用本发明的组合物,治疗与眼障碍或眼病相关的各种临床病症的方法。
背景技术
干眼综合征是一种多因素疾病。干眼综合征引起炎症和眼表面刺激。因此,治疗干眼综合征的目的在于改善患者的眼部舒适度,使眼表面和泪液组成恢复到它们的基本和健康状态。
对干眼综合征的传统治疗包括(i)滴注人工泪液来补充和刺激泪液,以及(ii)使用抗炎药来减少眼表面的炎症。目前干眼治疗一般涉及局部施用人工泪液产品/润滑剂、保存泪液管理、泪眼分泌刺激、局部施用抗生素(例如,红霉素或杆菌肽软膏)、口服给药四环素类(例如四环素、强力霉素或米诺环素)、施用钙调磷酸酶抑制剂免疫抑制剂(如环孢素和皮质类固醇)。这些治疗通常耗费时间、令患者沮丧,并且常常没有疗效或疗效不稳定。
一种目前可用于治疗干眼综合征的制剂是环孢素(市场上作为(加尼福利亚州欧文,阿勒根(Allergan,Irvine,CA)销售)。虽然环孢素一定程度上减少了干眼综合征的症状,它也具有许多不期望的副作用,如灼烧和刺痛感。本发明的目的之一是为了降低局部副作用,提升患者的舒适度。用于治疗干眼综合征的另一个产品是立他司特(Lifitegrast)(市场上作为的5%眼用溶液销售,希尔美国股份有限公司(ShireUS Inc.),马萨诸塞州莱克星顿(Lexington,MA))。据报道,与安慰剂相比,立他司特(化学名称:N-{[2-(1-苯并呋喃-6-基羰基)-5,7-二氯-1,2,3,4-四氢-6-异喹啉基]羰基}-3-(甲磺酰基)-L-苯丙氨酸)眼用溶液5.0%当每日给药两次时,能改善眼部不适和眼干的症状(Sheppard et al.,Ophthalmology,2014,121(2),pp.475-483)。
干眼病(“DED”)是会导致不适、视觉障碍和泪膜不稳定,并伴有眼表面受损的眼表面多因素疾病。DED通常被分为两组:1)水液缺乏型DED和2)蒸发过强型DED。DED通常是泪腺功能单元或LFU变化的结果。LFU由泪腺、角膜、眼睑、睑板腺、结膜、杯状细胞和眼神经构成。LFU负责持续生产足够的泪膜,以持续润滑眼表面。LFU的结构变化可导致泪膜的不稳定和功能不全,这反过来会导致泪液具有高渗透压。对于眼表面的各种压力,如环境因素、传染、内源性压力、抗原、遗传因素,均被确定为主要的致病触发原因。源于泪膜的慢性渗透压可以激活眼表面上皮细胞的应激相关途径,从而触发涉及趋化因子、细胞因子和基质金属蛋白酶混合物的促炎反应。随后眼表面上抗原呈递细胞的成熟,导致了自身反应性T淋巴细胞以及其他LFU中的白细胞类的迁移、激活和扩增。促炎性白细胞向眼表面上的不断募集可能造成小磨损和上皮屏障缺陷形式的上皮损伤。这些损伤可最终发展为浅层点状角膜炎、鳞状上皮化生、细胞外基质(“ECM”)沉积、杯状细胞分化减少、上皮细胞更新增加(上皮病变),和显著的眼表面神经损伤和神经病变。因此,导致炎症、疼痛、组织损伤、免疫应答亢进的各种细胞和生理过程,均与DED的病理生理学相关,暗示了不同分子通路的作用。
治疗DED的传统疗法专注于用单一的活性药物成分。这极大地限制了作用方式,对患者来说效果不佳。因此,尚未满足治疗DED来处理涉及不同作用方式的多种病理生理过程的需要。
目前DED治疗的另一显著不足在于,没有传统眼用制剂,其允许活性药物成分优先分配到目标泪腺组织中。没有能力靶向泪腺组织,这极大地降低了传统眼用制剂的效果。
相应地,存在对干眼综合征以及其他眼障碍和/或疾病进行有效治疗的组合物和方法的持续需求。
发明内容
本发明涉及一种组合制剂,组成为两种或更多种APIs,其具有DED发病机理的不同分子靶标。单一制剂中两种或更多种具有不同作用机制的APIs的组合,提供了对多于一种分子通路的调节,并且为DED患者带来了显著益处。具体地,本发明的一些实施方式涉及组合制剂中的APIs的选择,其中组合制剂靶向参于病理生理学眼表面疾病、眼前段疾病以及与眼部手术相关的疼痛和炎症的多种分子通路。
本发明的一个特定方面在于提供包括至少两种活性药物成分的眼用组合物。在一个实施方式中,所述至少两种活性药物成分选自于不同的类别。在一个具体的实施方式中,所述活性药物成分选自于下列类别的活性药物成分:α2肾上腺素能受体激动剂;β-肾上腺素能受体激动剂;免疫抑制剂;淋巴细胞相关抗原拮抗剂;抗炎剂;β-阻断剂;前列腺素类似物;组胺受体拮抗剂;碳酸酐酶抑制剂;以及,抗生素。
在一些实施方式中,本发明的组合物是纳米乳制剂。相比于非纳米乳制剂,本发明的纳米乳制剂提供了各种令人惊奇的、意想不到的益处,包括但是不限于活性药物成分的延时释放,活性药物成分向预期细胞的渗透谱更好,在角膜中的停留时间增加等等。
在一个具体实施方式中,本发明的组合物是眼用纳米乳制剂。在一些实施方式中,第一活性药物成分是所述α2肾上腺素能激动剂,第二活性药物成分选自于以下项组成的组:所述免疫抑制剂、所述淋巴细胞相关抗原激动剂、所述皮质类固醇、所述β-阻断剂、所述前列腺素类似物、所述碳酸酐酶抑制剂,及其组合。在一个具体的实施方式中,α2肾上腺素能激动剂包括溴莫尼定(brimonidine)、其药用盐或其组合。
在一些实施方式中,所述免疫抑制剂选自于由环孢素、他克莫司(tacrolimus)及其组合组成的组。在其他实施方式中,所述淋巴细胞相关抗原激动剂包括立他司特。在另外一些实施方式中,所述皮质类固醇选自于由泼尼松龙(prednisolone)、甲基泼尼松龙(methylprednisolone)、二氟泼尼酯、醋酸泼尼松龙(prednisone acetate)、泼尼松龙磷酸钠(prednisolone sodium phosphate)、曲安西龙(triamcinolone)、氟轻松(fluocinolone)、氟米龙(fluorometholone)、倍他米松(betamethasone)、甲羟松(medrysone)及其组合组成的组。在其他实施方式中,实施抗炎剂选自于由皮质类固醇,非甾体抗炎药(“NSAID”)、胸腺素β4及其组合组成的组。在一个具体例子中,所述NSAID选自于由双氯芬酸、氟比洛芬(flubiprofen)、酮咯酸、酮咯酸氨丁三醇(ketorolacthromethamine)、溴芬酸、奈帕芬胺(nepafenac)、氟比洛芬(flurbiprofen)及其组合组成的组。在又一实施方式中,所述β-肾上腺素能受体激动剂选自于由多培沙明(Dopexamine)、肾上腺素(Epinephrine)、喘息定(Isoprenaline)、异丙肾上腺素(isoproterenol)、左旋沙丁胺醇(levalbuterol)、舒喘宁(Salbutamol)、沙丁胺醇(albuterol)及其组合组成的组。在另外一些实施方式中,所述β-阻断剂选自于由噻吗洛尔(Timolol)、普萘洛尔(Propranolo)、索他洛尔(Sotalol)、纳多洛尔(nadolol)及其组合组成的组。在另外一些实施方式中,所述前列腺素类似物选自于由拉坦前列素(latanoprost)、比马前列素(bimatoprost)、曲伏前列素(travoprost)、他氟前列素(tafluprost)及其组合组成的组。在另外一些实施方式中,所述碳酸酐酶抑制剂选自于由多佐胺(dorzolamide)、醋甲唑胺(methazolamide)、布林唑胺(brinzolamide)、双氯非那胺(dichlorphenamide)及其组合组成的组。
在其他实施方式中,所述活性药物成分包括:(i)溴莫尼定,其药学上可接受的盐,或者其组合;(ii)环孢素;以及,(iii)立他司特或氯替泼诺(Loteprednol)。
本发明的一个特定方面提供了眼用水性溶液,包括(i)溴莫尼定,其药学上可以接受的盐类,或者其组合;和,(ii)环孢素。在一些实施方式中,所述眼用水性溶液是纳米乳溶液。
本发明的组合物还可以包括药学上可以接受的赋形剂。在一个具体实施方式中,所述药学上可以接受的赋形剂包括:乳液稳定聚合物、水溶性聚合物、表面活性剂、张力调节剂或稳定剂、粘度调节剂,或其组合。在一个具体实施方式中,实施药学上可以接受的赋形剂包括:(i)乳液稳定聚合物;(ii)表面活性剂;(iii)张力调节剂或稳定剂,选自于由多元醇、非还原性双糖及其组合组成的组;或,(iv)它们的组合。在其他实施方式中,所述药学上可以接受的赋形剂包括聚山梨醇酯80、卡波姆共聚物A类、多元醇或其组合。在另外的实施方式中,所述药学上可以接受的赋形剂包括聚山梨醇酯80、卡波姆共聚物B类、多元醇或其组合。在又一些实施方式中,所述张力调节剂或稳定剂选自于由多元醇、非还原性双糖及其组合组成的组。在又一些实施方式中,所述粘度调节剂选自于由卡波姆均聚物A类、卡波姆均聚物B类、卡波姆均聚物C类以及其组合组成的组。在又一些实施方式中,所述表面活性剂选自于由以下项组成的组:(i)非离子表面活性剂,如月桂酸甘油酯、聚山梨酯、司盘(spans)、泊洛沙姆(poloxamers)、壬苯醇醚-9;(ii)阳离子表面活性剂,如苯扎氯铵、苄索氯铵、苯扎溴铵、西曲溴铵、西曲氯铵、四甲基氢氧化铵、劳拉氯铵;(iii)两性离子表面活性剂,如卵磷脂;以及(iv)它们的组合。在另外一些实施方式中,所述药学上可以接受的赋形剂包括(i)乳液稳定聚合物,(ii)表面活性剂,(iii)张力调节剂或稳定剂,选自于由多元醇、非还原性双糖及其组合组成的组,或(iv)它们的组合。
本发明的又一方面提供了用来治疗与眼睛相关的临床病症,如眼障碍或眼病的方法。所述方法包括:向需要这种治疗的受试者给药治疗有效量的本发明的组合物。在一些实施方式中,与眼睛相关的临床病症选自于由以下项组成的组:干眼综合征(如干燥性角结膜炎)、舍格林氏综合征(sjogren’s syndrome)、先天性无泪、干性眼炎(xerophthalmia)(维生素A缺乏引起的干眼)、角膜软化症、甲状腺眼病、眼红斑痤疮、眼睑障碍、睑板腺疾病、睑板腺功能障碍、睑外翻、睑缘炎、睑皮松垂症、结节病、麦粒肿(stye)、睑腺炎(hordeolum)、霰粒肿、上睑下垂、翼状胬肉、眼睑水肿、眼睑皮炎、倒睫、睫毛脱落、泪腺炎、史蒂芬斯-强森(stevens-johnson)综合征、眼部移植物抗宿主病、泪囊炎、结膜炎、角膜结膜炎、眼睑结膜炎、睑角膜结膜炎、过敏性结膜炎、春季结膜炎、结膜充血、结膜松弛症、结膜下出血、翼状胬肉、结膜黄斑、结膜水肿、虹膜炎、虹膜睫状体炎、前葡萄膜炎、青光眼、高眼压、红眼、角膜炎、巩膜炎、浅层巩膜炎、周围溃疡性角膜炎、神经营养性角膜炎、神经营养性眼病、角膜溃疡、溃疡性角膜炎、角膜擦伤、光角膜炎、紫外线角膜炎、暴露性角膜炎、浅层点状角膜炎、泰格森(thygeson’s)浅层点状角膜炎、带状疱疹性角膜炎、红斑痤疮、角膜新血管形成、角膜营养不良、上皮基底膜营养不良、福克斯氏(fuch’s)营养不良、后部多形性角膜营养不良、黄斑角膜营养不良、睫状体炎、葡萄膜炎、虹膜炎,眼部手术(即眼睑手术、白内障手术、角膜手术、屈光手术包括屈光性角膜切除术、青光眼手术、泪腺手术、结膜手术、眼肌手术)后的术后炎症,由化学灼伤、热烧伤或物理创伤引起的眼表面疾病,由以下自身免疫或血管疾病引起的眼表面疾病:类风湿性关节炎、幼年类风湿性关节炎、强直性脊柱炎、赖特(reiter’s)综合征、肠病性关节炎、银屑病关节炎、盘状和系统性红斑狼疮、多发性硬化症、格雷夫斯(graves’)病、抗磷脂综合征、结节病、韦格纳(wegner’s)肉芽肿、白塞(behcet’s)综合征、结节性多动脉炎、高安(takayasu’s)动脉炎、皮肌炎、银屑病、复发性多发性软骨炎、血管炎、镰状细胞性贫血、II型糖尿病、糖尿病视网膜病变,及其组合。
在一些实施方式中,眼障碍选自于由以下项组成的组:(i)干眼综合征;(ii)眼部移植物抗宿主病;(iii)眼红斑痤疮;(iv)过敏性结膜炎;(v)自身免疫性眼表面疾病;(vi)泰格森浅层点状角膜炎;(vii)带状疱疹性角膜炎;(viii)史蒂芬斯-强森综合征;(ix)角膜炎;(x)结膜炎;(xi)睑缘炎;(xii)睑皮松垂症;(xiii)结膜松弛症;(xiv)眼睑结膜炎;(xv)睑角膜结膜炎;(xvi)眼部手术引起的术后炎症或疼痛;(xvii)巩膜炎;(xviii)浅层巩膜炎;(xix)前葡萄膜炎;(xx)虹膜炎;(xxi)睫状体炎;(xxii)眼表面血管疾病;(xxiii)溃疡性角膜炎;(xxiv)光角膜炎;(xxv)泪囊炎;(xxvi)眼睑障碍;(xxvii)先天性无泪;(xxviii)干性眼炎;(xxix)泪囊炎;以及,(xxx)由化学灼伤、热烧伤、隐形眼镜的使用或物理创伤引起的眼表面疾病。
在又一些实施方式中,所述干眼综合征选自于由舍格林氏综合征、睑板腺功能障碍和角膜结膜炎组成的组。在另外一些实施方式中,所述眼睑障碍包括眼睑炎症、疼痛和/或水肿。
在一些实施方式中,所述组合物局部给药于所述受试者的眼睛上。在一个实施方式中,所述组合物被配制为均相眼用水性制剂。在另一实施方式中,所述组合物被配制为非均相眼用水性溶液。在一些例子中,所述非均相眼用水性溶液包括乳液、悬浊液或其组合。
附图说明
图1是示出了本发明的一些眼用制剂所测量的粒径分布[Dx(50)]的中值直径的表格。
图2是示出了在不同温度(RT是室温)下,第0、36和66天的酒石酸溴莫尼定和依碳酸氯替泼诺(loteprednol etabonate)的眼用纳米乳制剂的粒径分布[Dx(50)]的中值直径的表格。
图3是示出了在不同温度下,第0和14天所测量的以下制剂的粒径分布[Dx(50)]的中值直径的表格:(i)酒石酸溴莫尼定(0.2%w/w)和环孢素(0.05%w/w)组合的眼用纳米乳制剂,以及(ii)酒石酸溴莫尼定(0.2%w/w)和环孢素(0.1%w/w)的眼用纳米乳制剂。
图4是示出了以下制剂的酒石酸溴莫尼定和环孢素在各相,油相和水相中分配的表格:(i)酒石酸溴莫尼定(0.2%w/w)和0.05%w/w环孢素眼用纳米乳制剂的组合以及(ii)酒石酸溴莫尼定(0.2%w/w)和0.1%w/w环孢素眼用纳米乳制剂的组合。
图5示出了在不同温度下,由活性药物成分酒石酸溴莫尼定和环孢素组成的本发明的眼用纳米乳制剂的稳定性数据。
图6A是示出了本发明的眼用纳米乳制剂的粒径分布[Dx(50)]的图,其中眼用纳米乳制剂具有活性药物成分酒石酸溴莫尼定和依碳酸氯替泼诺。
图6B是示出了本发明的眼用纳米乳制剂的粒径分布[Dx(50)]的图,其中眼用纳米乳制剂具有活性药物成分酒石酸溴莫尼定(0.2%w/w)和0.05%w/w环孢素。
图6C是示出了本发明的眼用纳米乳制剂的粒径分布[Dx(50)]的图,其中眼用纳米乳制剂具有活性药物成分酒石酸溴莫尼定(0.2%w/w)和0.1%w/w环孢素。
具体实施方式
本发明的一个方面提供了一种包括至少两种活性药物成分的纳米乳眼用组合物。如本文所使用的,术语“纳米乳”指中值乳液液滴粒径(即Dx(50))约250nm或更小,通常为大约220nm或更小,经常为大约200nm或更小,最经常为大约100nm或更小的乳液。
在一个具体的实施方式中,所述活性药物成分选自于下列活性药物成分的类别:α2肾上腺素能受体激动剂、β-肾上腺素能受体激动剂、免疫抑制剂、淋巴细胞相关抗原拮抗剂、抗炎剂、β-阻断剂、前列腺素类似物、组胺受体拮抗剂、碳酸酐酶抑制剂以及抗生素。在一个具体实施方式中,本发明的组合物包括α2肾上腺素能受体激动剂,与钙调磷酸酶抑制剂(如环孢素)和淋巴细胞功能相关抗原拮抗剂(如立他司特)中的一种或多种的组合。在另一实施方式中,本发明的组合物包括α2肾上腺素能受体激动剂与皮质类固醇的组合。本发明的另一方面提供了一种组合物,其包括α2肾上腺素能受体激动剂与下列组分中的一种或多种结合:(i)钙调磷酸酶抑制剂;(ii)淋巴细胞功能相关抗原拮抗剂;(iii)抗炎剂(例如皮质类固醇,包括氯替泼诺、胸腺素β4等);(iv)钠通道阻断剂;(v)非甾体抗炎药(即NSAID);和,(vi)抗组胺剂。
在一些实施方式中,实施抗炎剂为皮质类固醇。在另外的实施方式,所述抗炎剂是NSAID。在又一些实施方式中,所述抗炎剂是胸腺素β4。
在一些实施方式中,本发明的组合物是非均相溶液制剂,在所述制剂中含有治疗有效量的活性药物组分的组合。在另外的实施方式中,本发明的组合物是均相水性制剂,在所述制剂中含有治疗有效量的活性药物组分的组合。
本发明的组合物或制剂可以仅含有两种活性成分或含有多于两种的活性成分。在一些实施方式中,至少一种活性成分是α2肾上腺素能受体激动剂,如溴莫尼定,或其药学上可接受的盐,或它们的组合。
本发明的组合物可用于各种眼障碍或眼病的治疗,包括但不限于:干眼综合征(如干燥性角膜结膜炎)、舍格林氏综合征、先天性无泪、干性眼炎(xerophthalmia)(维生素A缺乏引起的干眼)、角膜软化症、甲状腺眼病、眼红斑痤疮、眼睑障碍、睑板腺疾病、睑板腺功能障碍、睑外翻、睑缘炎、睑皮松垂症、结节病、麦粒肿(stye)、睑腺炎(hordeolum)、霰粒肿、上睑下垂、翼状胬肉、眼睑水肿、眼睑皮炎、倒睫、睫毛脱落、泪腺炎、史蒂芬斯-强森(stevens-johnson)综合征、眼部移植物抗宿主病、泪囊炎、结膜炎、角膜结膜炎、眼睑结膜炎、眼睑角膜结膜炎、过敏性结膜炎、春季结膜炎、结膜充血、结膜松弛症、结膜下出血、翼状胬肉、结膜黄斑、结膜水肿、虹膜炎、虹膜睫状体炎、前葡萄膜炎、青光眼、高眼压、红眼、角膜炎、巩膜炎、浅层巩膜炎、周围溃疡性角膜炎、神经营养性角膜炎、神经营养性眼病、角膜溃疡、溃疡性角膜炎、角膜擦伤、光角膜炎、紫外线角膜炎、暴露性角膜炎、浅层点状角膜炎、泰格森(thygeson’s)浅层点状角膜炎、带状疱疹性角膜炎、红斑痤疮、角膜新血管形成、角膜营养不良、上皮基底膜营养不良、福克斯氏(fuch’s)营养不良、后部多形性角膜营养不良、黄斑性角膜营养不良、睫状体炎、葡萄膜炎、虹膜炎、眼部手术(即眼睑手术、白内障手术、角膜手术、屈光手术包括屈光性角膜切除术、青光眼手术、泪腺手术、结膜手术、眼肌手术)后的术后炎症,由化学灼伤、热烧伤或物理创伤引起的眼表面疾病,由以下自身免疫或血管疾病引起的眼表面疾病:类风湿性关节炎、幼年类风湿性关节炎、强直性脊柱炎、赖特(reiter’s)综合征、肠病性关节炎、银屑病关节炎、盘状和系统性红斑狼疮、多发性硬化症、格雷夫斯(graves’)病、抗磷脂综合征、结节病、韦格纳(Wegener’s)肉芽肿、白塞(behcet’s)综合征、结节性多动脉炎、高安(takayasu’s)动脉炎、皮肌炎、银屑病、复发性多发性软骨炎、血管炎、镰状细胞-贫血、II型糖尿病、糖尿病视网膜病变,及其组合。
本发明的一些方面提供了使用本文公开的组合物治疗干眼综合征的方法。干眼综合征有两种主要类别:(i)水液缺乏型干眼(ADDE)和(ii)蒸发过强型干眼(EDE)。也有混合机制的干眼病例(即ADDE和EDE都有)。ADDE主要是由于泪腺的泪液分泌障碍。ADDE可以进一步地细分为舍格林氏干眼综合征(其中泪腺和唾液腺被自身免疫过程靶向,例如类风湿性关节炎)和非舍格林氏(non-Sjogren's)干眼综合征(泪腺功能障碍,但舍格林氏综合征的系统性自身免疫特征除外,例如年龄相关性干眼症)。相反地,EDE主要是由于在泪腺分泌功能正常的情况下,过多的水分从暴露的眼表面处流失。其原因可能是外在的(例如,由于一些外在的暴露,隐形眼镜的磨损或维生素A缺乏造成的眼表面疾病),或内在的(例如,睑板腺功能障碍和眼睑孔径(eyelid aperture)异常)。睑板腺分泌脂类和其他成分的混合物,形成眼前泪膜的外层。该脂质层的作用是减少泪膜蒸发。睑板腺功能障碍(MGD)导致蒸发过强型干眼疾病。在MGD中最知名的临床发现之一是存在大量横穿眼睑边缘的毛细血管扩张性血管。MGD也可以伴随水液缺乏型干眼疾病,如在眼部移植物抗宿主病(oGVHD)中所见。可以使用本发明的组合物治疗的其他具体的干眼综合征包括角膜结膜炎,结膜炎造成的干眼,过敏性结膜炎造成的干眼,睑缘炎造成的干眼,角膜炎造成的干眼,泪腺炎造成的干眼,眼红斑痤疮造成的干眼,博姆(boehm)综合征造成的干眼,结膜松弛症造成的干眼,眼睑结膜炎造成的干眼,眼睑角膜结膜炎造成的干眼症,浅层点状角膜炎造成的干眼,泰格森浅层点状角膜炎造成的干眼,oGVHD造成的干眼,舍格林氏干眼综合征,史蒂芬斯-强森干眼综合征,MGD,睑板腺疾病造成的干眼,维生素A缺乏引发的干眼,药理性引发的干眼(即激素替代疗法、血压药物、抗组胺药、抗抑郁药、抗胆碱能药物、青光眼药物、抗高血压药、利尿剂、镇静剂、异维甲酸、鼻减充血剂、口服避孕药、β-阻断剂、吩噻嗪、阿托品、止痛麻醉剂),妊娠引发的干眼,LASIK手术或屈光手术引发的干眼,胶原血管病引发的干眼(即系统性红斑狼疮、韦格纳肉芽肿、类风湿性关节炎、复发性多发性软骨炎),肿瘤或结节病对泪腺的浸润造成的干眼,放疗后的泪腺纤维化造成的干眼,泪腺、睑板腺或杯状细胞消融造成的干眼,感觉性去神经支配造成的干眼,热或化学烧伤造成的干眼,潜在的糖尿病造成的干眼,病毒、真菌或细菌感染造成的干眼,长时间使用隐形眼镜造成的干眼,眼睑障碍或眼睑损伤造成的干眼(即眼睛凸出,眼睑下垂),角膜营养不良造成的干眼,自身免疫性疾病造成的干眼,年龄引发的干眼,以及它们的组合。
在一些实施方式中,治疗干眼综合征的方法包括治疗需要治疗睑板腺功能异常(MGD)的患者。在另外的实施方式中,治疗干眼综合征的方法包括治疗需要治疗水液缺乏型干眼(ADDE)的患者。在一些例子中,治疗ADDE的方法包括治疗需要治疗舍格林氏干眼综合征、眼移植物抗宿主病(oGVHD)或非舍格林氏干眼综合征的患者。在另外的实施方式中,对干眼综合征的治疗方法包括治疗需要治疗蒸发过强型干眼(EDE)的患者。在其他实施方式中,本发明的方法包括治疗需要治疗由ADDE和EDE组成的混合机制干眼症的患者。在又一些实施方式中,本发明的方法包括治疗患干眼综合征的患者,所述干眼综合征是由屈光眼手术的并发症引起,或可归因于以下一种或多种原因:维生素A缺乏、眼表面疾病、过敏、衰老、隐形眼镜使用、药物使用或眼睑障碍。
在一些实施方式中,本发明的组合物包括阿尔法2(α2)肾上腺素能受体激动剂。示例性的α2肾上腺素能受体激动剂包括,但不限于溴莫尼定、4-NEMD、7-甲基-麻噻尼定(marsanidine)、胍丁胺、阿可乐定(apraclonidine)、大麻萜酚、可乐定(clonidine)、地托咪定(detomidine)、右旋美托咪定(dexmedetomidine)、法度咪定(fadolmidine)、氯苄氨胍、胍法辛、洛非西定(lofexidine)、麻噻尼定(marsanidine)、美托咪定(medetomidine)、甲基苯丙胺、米伐西醇(mivazerol)、利美尼定(rilmenidine)、罗米非定(romifidine)、他利克索(talipexole)、替扎尼定(tizanidine)、托洛尼定(tolonidine)、噻拉嗪、噻洛唑啉,以及包括其药学上可接受的盐等等。在一个具体的实施方式中,α2肾上腺素能受体激动剂是溴莫尼定(5-溴-N-(4,5-二氢-1H-咪唑-2-基)喹喔啉-6-胺),其药学上可接受的盐,或它们的组合。
化合物的“药学上可接受的盐”指药学上可接受的并且具有母体化合物所期望的药理活性的盐。此种盐包括:(1)酸加成盐,由无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成;或由有机酸如乙酸、三氟乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、4-甲基双环[2.2.2]-辛-2-烯-1羧酸、葡萄糖庚酸、3-苯丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、粘康酸等形成;或(2)当母体化合物中存在的酸性质子被金属离子取代,例如碱金属离子、碱土金属离子或铝离子;或与有机碱如乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺等配位时形成的盐。溴莫尼定药学上可接受的盐的具体的例子包括,但不限于,酒石酸盐、三氟乙酸盐、盐酸盐、乙酸盐、草酸盐,以及本文公开的和/或本领域技术人员已知的其它盐类。
α-2肾上腺素能受体激动剂是那些使α-2肾上腺素能受体活化的化合物。这种受体有三种亚型,命名为A、B和C。可以激活任何或所有这些受体亚型的α-2肾上腺素能受体激动剂可以用于本发明。然而,在本发明的一些实施方式中,与其对α-2B受体亚型(例如溴莫尼定及其盐类)的活性相比,α2肾上腺素能受体激动剂对α-2A肾上腺素能受体亚型具有更高的活性或功效。在一些实施方式中,与α2B激动剂活性相比,本发明组合物中的所述α2肾上腺素能激动剂具有更高的α2A激动剂活性。在一些例子中,所述α2肾上腺素能激动剂的α2A激动剂活性比其α2B激动剂活性高至少大约10%,通常高至少大约20%,经常高至少大约30%。如本文所用,术语“大约”当涉及数值时,指数值±20%,通常指±10%,经常指±5%,最经常指±2%。
在一个实施方式中,所述第二药物活性化合物包括钙调磷酸酶抑制剂、淋巴细胞功能相关抗原拮抗剂或其组合。钙调磷酸酶(CaN)是钙调蛋白和钙依赖性丝氨酸/苏氨酸蛋白磷酸酶(也被称为蛋白磷酸酶3,和钙依赖性丝氨酸-苏氨酸磷酸酶)。它激活免疫系统的T细胞,并且可以被一类叫做钙调磷酸酶抑制剂的药物所阻断,包括环孢素、他克莫司(tacrolimus)、吡美莫司(pimecrolimus)、沃洛斯饱菌素(voclosporin),以及其它被本领域技术人员所知的药物。任何已知的钙调磷酸酶抑制剂(例如,环孢素)或那些被本领域技术人员开发的,均可以应用于本发明的组合物中。淋巴细胞功能相关抗原(LFA)-1/细胞间粘附分子(ICAM)-1的相互作用,在免疫应答的过程中,介导了若干重要的步骤。示例性的淋巴细胞功能相关抗原拮抗剂包括,但不限于立他司特(lifitegrast)(即(S)-2-(2-(苯并呋喃-6-羰基)-5,7-二氯-1,2,3,4-四氢异喹啉-6-甲酰胺基)-3-(3-(甲磺酰基)苯基)丙酸),它是阻断LFA-1与ICAM-1结合的水溶性药物,以及被本领域技术人员所知的其他淋巴细胞功能相关抗原拮抗剂。任何淋巴细胞功能相关抗原拮抗剂均可以用于本发明的组合物。
在又一实施方式中,本发明的组合物被配制为水性溶液,可以是均相的或非均相的溶液。在这些实施方式中,本发明的组合物包括至少两种活性成分。在一个具体的实施例中,制剂包括一种水溶性的活性成分,以及另一种亲脂的活性成分。在另一个具体的实施方式中,所述制剂包括两种或多种水溶性的活性成分。在另一个具体的实施方式中,所述制剂包括两种或多种亲脂的活性成分。在另外的实施方式中,本发明的组合物被配制为眼用水性溶液。如上所述,所述眼用水性溶液可以是均相的或非均相的,并且可以包括水性悬浊液或分散液,其中至少一些活性成分在水性溶液中以悬浊液或分散液的形式存在。所述眼用水性溶液,可以是基本上地均相的水性溶液,其中基本上全部的(即≥85%、通常≥90%、经常≥95%,最经常≥97%)活性成分均溶于水性溶液中。
在一个具体的实施方式中,其中一种活性成分是溴莫尼定,其药学上可接受的盐,或它们的组合。所述组合物包括第二活性成分,可以是环孢素、立他司特或其组合。
如本文所用,术语“活性成分”和“活性药物(的)成分”在本文中可以互换使用,是指被本领域技术人员所使用的或所知的用来治疗眼障碍,如干眼综合征的化合物。因此,尽管水和油可以存在于一些制剂中,但它们并非主要出于作为治疗眼障碍的目的使用,而是用作运载活性成分的溶媒。一般地,活性成分作用于特定的受体或细胞,或已经被美国食品和药物管理局(“FDA”)批准用来治疗眼障碍。
在一个具体的实施方式中,术语“活性成分”指α2肾上腺素能受体激动剂、β-肾上腺素能受体激动剂、免疫抑制剂、淋巴细胞相关抗原拮抗剂、抗炎剂(如皮质类固醇、NSAID、胸腺素β4等)、β-阻断剂、前列腺素类似物、组胺受体拮抗剂、碳酸酐酶抑制剂以及抗生素。在另外的实施方式中,术语“活性成分”指的是:α2肾上腺素能激动剂、钙调磷酸酶抑制剂、淋巴细胞功能相关抗原拮抗剂、皮质类固醇、CRGP受体拮抗剂、抗CGRP受体单克隆抗体、肾上腺髓质素抑制剂、血清素、组织蛋白酶抑制素或神经肽、钠通道阻断剂、抗组胺药、抗组胺药和/或非甾体抗炎药。可存在于本发明的制剂/组合物的其它成分,主要地用作药学上可接受的赋形剂或溶媒,如pH调节剂、张力调节剂或稳定剂、表面活性剂、乳液稳定剂等。
本发明组合物中活性成分的治疗有效量,可以由本领域技术人员容易地确定。在一些实施方式中,本发明的组合物被配制为非均相水性溶液。在一个具体的实施方式中,本发明的组合物包括从大约0.01到大约5mg/mL(大约0.001%至大约0.5%w/v),通常大约0.2w/v或更少(例如,0.05~0.2%,经常为0.07~0.15%)的溴莫尼定或其盐(例如,酒石酸溴莫尼定和三氟乙酸羟基溴莫尼定)。成分的量以%重量/体积(%w/v)或重量/重量(%w/w)的单位表示。在一个具体的实施方式中,酒石酸溴莫尼定被用作α2肾上腺素能激动剂。在一个实施方式中,存在于组合物中的酒石酸溴莫尼定的量是从大约0.01%w/w到大约1%w/w,通常是从0.01%w/w到大约0.7%w/w,经常是从大约0.02%w/w到大约0.5%w/w。
在一些实施方式中,第二治疗活性化合物包括环孢素。在一个具体的实施方式中,第二治疗活性化合物包括环孢素A。存在于本发明组合物中的环孢素A的通常量是从大约0.005%w/w到大约0.5%w/w,经常是从0.01%w/w到大约0.3%w/w。
在另一实施方式中,第二治疗活性化合物包括在一个具体的实施方式中,存在于本发明的组合物中的立他司特是从大约0.1%w/w到大约20%w/w,通常是从大约0.2%w/w到大约15%w/w,经常是从大约0.3%w/w到大约10%w/w。
在另一些实施方式中,第二治疗活性化合物包括皮质类固醇。示例性的皮质类固醇包括,但不限于,甲基泼尼松龙、氢化可的松、倍他米松、地塞米松和依碳酸氯替泼诺。在一个具体的实施方式中,用于本发明的组合物中的皮质类固醇是依碳酸氯替泼诺(loteprednol etabonate)。在一些实施方式中,存在于本发明的组合物中的依碳酸氯替泼诺的量是从大约0.01%w/w到2%w/w,通常是从大约0.05%w/w到1%,经常是从大约0.1%到大约0.3%。
在另一实施方式中,第二治疗活性化合物包括钠通道阻断剂和/或溶粘液剂。被本领域技术人员所知的用于治疗眼障碍的合适的钠通道阻断剂和/或溶粘液剂,包括例如在美国专利号9,586,911、9,346,753、8,980,898、8,673,340、8,058,278、7,875,619、7,868,010、7,842,697、7,820,678、7,410,968、7,399,766、7,388,013、7,375,107、7,368,451、7,368,450、7,368,447、7,375,107、7,368,451、7,368,447、7,345,044、7,332,496、7,317,013、7,247,637、7,247,636、7,241,766、7,192,959、7,192,958、7,189,719、7,186,833、7,064,129、7,030,177、7,026,325、6,995,160、6,903,105、6,858,615和6,858,614中公开的那些,其均通过引用整体并入本文。用于本发明的合适的钠通道阻断剂的具体例子包括,但不限于阿米洛利(amiloride)、苯扎米尔(benzamil)、非那米尔(phenamil)、阿米洛利(amiloride)类似物,以及例如在美国专利号9,586,911、9,346,753、8,980,898、8,673,340、8,058,278、7,875,619、7,868,010、7,842,697、7,820,678、7,410,968、7,399,766、7,388,013、7,375,107、7,368,451、7,368,450、7,368,447、7,375,107、7,368,451、7,368,447、7,345,044、7,332,496、7,317,013、7,247,637、7,247,636、7,241,766、7,192,959、7,192,958、7,189,719、7,186,833、7,064,129、7,030,177、7,026,325、6,995,160、6,903,105、6,858,615和6,858,614中公开的那些。
在又一实施方式中,第二治疗活性化合物包括非甾体抗炎药(即NSAID)。用于治疗眼障碍的合适的NSAID,包括酮咯酸(0.05~0.3%)、双氯芬酸(0.01~1%)、氟比洛芬(0.01~1%)、溴芬酸(0.01~0.5%)、奈帕芬胺(0.05~0.5%)等。这些NSAID中的一些是商业上可获得的,如安贺拉(Acular)、Acular PF和Acular LS(酮咯酸氨丁三醇,爱力根(Allergan)),欧可芬(Ocufen)(氟比洛芬钠,爱力根),扶他林(Voltaren)(双氯芬酸钠,诺华(Novartis)),Xibrom(溴芬酸眼用溶液,ISTA制药公司),Prolensa(溴芬酸眼用溶液,博士伦(Bausch&Lomb)),和奈帕芬胺(Nevanac)(奈帕芬胺,爱尔康(Alcon))。
在进一步的实施方式中,第二治疗活性化合物包括抗组胺药。用于治疗眼障碍的合适的抗组胺药,包括阿卡他定(alcaftadine)(0.01%至0.5%)、氮卓斯汀(azelastine)(0.001%至0.2%)、贝他斯汀(bepotastine)(0.1%至3%)、依美斯汀(emedastine)(0.001%至0.2%)、依匹斯汀(epinastine)(0.001%至0.2%)、酮替芬(ketotifen)(0.001%至0.2%)和奥洛他定(olopatadine)(0.01%至1.5%)。这些抗组胺药中的一些是商业上可获得的,如Lastacaft(阿卡他定,爱力根)、Optivar(盐酸氮卓斯汀,美达制药(Meda Pharmaceuticals))、Bepreve(苯磺酸贝他斯汀,Bausch&Lomb)、Emadine(富马酸依美斯汀,爱尔康)、Elestat(盐酸依匹斯汀,爱力根)、Alaway(富马酸酮替芬,Baush&Lomb)、Zaditor(富马酸酮替芬,爱尔康)、Pazeo(盐酸奥洛他定,爱尔康)、Pataday(盐酸奥洛他定,爱尔康)和Patanol(盐酸奥洛他定,爱尔康)。
在其他实施方式中,第二治疗活性化合物包括胸腺素β4。在一些实施方式中,存在于本发明的组合物中的胸腺素β4的量是从大约0.01%w/w到2%w/w,通常是从大约0.05%w/w到1%,经常是从大约0.0.05%到大约0.3%。
在其他实施方式中,第二治疗活性化合物包括前列腺素类似物。用于本发明组合物的示例性的前列腺素类似物包括,但不限于拉坦前列素、比马前列素、曲伏前列素和他氟前列素。当存在时,本发明的组合物中的前列腺素类似物的量是从大约0.001%w/w到1%w/w,通常是从大约0.005%w/w到0.5%,经常是从大约0.005%到大约0.1%。
在一些实施方式中,本发明的组合物被用作眼用制剂。这类眼用制剂可以是均相的或非均相的制剂。在这些实施方式中,被配制的组合物包括油或脂肪酸酯。脂肪酸酯具有本领域普遍理解的含义,是在醇和脂肪酸之间形成的酯。用于本发明的制剂的示例性的脂肪酸酯包括,但不限于,通常被称为植物油的甘油三酯、脂肪酸的单和二甘油酯、脂肪酸甲酯,以及其他被本领域技术人员所知的脂肪酸酯。应该被理解的是,脂肪酸酯可以是若干种化学化合物的混合物或基本上是纯化合物。通常地,所述脂肪酸酯是植物油。可以被应用的植物油的具体的例子包括,但不限于蓖麻油、芝麻油、大豆油、棉籽油、橄榄油、花生油、红花油、葵花油、棕榈油、棕榈仁油、菜籽油和Miglyol在一个具体的实施方式中,脂肪酸酯是蓖麻油。
各种溶媒可以被用于本发明的眼用制剂中。这些溶媒包括,但不限于,纯净水(水)、聚乙烯醇、聚维酮、羟丙基甲基纤维素、泊洛沙姆、羧甲基纤维素、羟乙基纤维素、环糊精及其两种或多种的混合物。制剂中以所需的量使用溶媒,来提供本文所公开的活性化合物的浓度。在一个具体的实施方式中,所述溶媒包括水。
在本发明的一些实施方式中,使用了乳液稳定聚合物。尽管不打算限制本发明的范围,但乳液稳定聚合物通常包括亲水基团,如纤维素、糖、环氧乙烷、氢氧化物、羧酸或其他聚电解质。不受任何理论的限定,人们相信这些聚合物通过增加制剂的粘度,以及降低界面张力来帮助稳定乳液。用于本发明中的乳液稳定聚合物的一些例子包括,但不限于,卡波姆、羧甲基纤维素钠、羟丙基甲基纤维素、聚维酮、聚乙烯醇、聚乙二醇,及其中两种或更多种的混合物。
在本发明的另一个实施方式中,所述制剂包括表面活性剂。不受任何理论的限定,表面活性剂用来帮助促进乳液形成和改善其稳定性。可以使用任何种类的表面活性剂,包括阴离子的、阳离子的、两性的、两性离子的、非离子的,及其中两种或更多种的混合物。在一个具体的实施方式中,本发明的所述制剂包括非离子表面活性剂。示例性的非离子表面活性剂包括,但不限于,聚山梨醇酯、泊洛沙姆、聚氧乙烯醚、乙二醇-丙二醇嵌段共聚物、脂肪酸酰胺、烷基酚聚氧乙烯酯、磷脂,及其中两种或混合物。在一个具体的实施方式中,所述表面活性剂是聚山梨酯80(ICI美洲公司,威尔明顿,特拉华(ICI Americas,Inc.,Wilmington,DE))。
只要所得的制剂是眼科上可以接受的,则可以使用各种调节pH的缓冲剂和方式。相应地,有用的缓冲剂包括,但不限于醋酸盐缓冲液、柠檬酸盐缓冲液、磷酸盐缓冲液和硼酸盐缓冲液。在一个具体的实施方式中,缓冲剂被用于将pH维持在治疗上地有用的4~10的pH范围,通常是大约5~8的pH范围,经常是6.5~8.0的pH范围,更经常是7.0~8.0的pH范围,最经常是7.2~7.6的pH范围。然而应理解的是,本发明的范围并不限定于这些具体的pH范围。一般地,任何让活性成分适当渗透到眼睛中的pH范围都可以使用。通常使用本领域技术人员所知的缓冲剂,包括,但不限于乙酸酯、硼酸盐、三羟甲基氨基甲烷、碳酸盐、柠檬酸盐、组氨酸、琥珀酸盐和磷酸盐。在一个具体的实施方式中,缓冲剂包括硼酸。在另一个实施方式中,缓冲剂包括柠檬酸钠。
为了给眼用制剂提供与眼液的pH基本上相对应的pH,或可接受的生理pH,如上所述,眼用制剂的pH可以通过加入足以达到所期望的pH的酸或碱来调节。pH的调节可以通过使用各种化学物质达到,如盐酸、氢氧化钠、柠檬酸、柠檬酸钠、醋酸、醋酸钠、醋酸铵、琥珀酸、乳酸、乳酸钙、乳酸钠、富马酸钠、丙酸钠、硼酸、三羟甲基氨基甲烷碱、硼酸铵、马来酸、磷酸、硫酸和硫酸钾铝等等。可以用于调节水性缓冲眼用制剂的pH的酸的具体例子是1N盐酸。可以用于调节水性缓冲眼用制剂的pH的碱的具体例子是1N氢氧化钠。然而,应该被理解的是,本发明的范围并不限定于具体的酸和碱。一般地,任何药学上可接受的酸和碱都可以用来调节pH。在一个具体的实施方式中,本发明的眼用制剂包括二碱式和单碱式磷酸盐或硼酸和硼酸钠的组合-作为缓冲剂。例如,所述制剂包括足以在6.5~8.0或7.5~8.0的pH范围内缓冲制剂的量的硼酸和硼酸钠,或足以在6.5~8.0或7.0~8.0或7.5~8.0的pH范围内缓冲制剂的二碱式和单碱式磷酸盐。
在另一个实施方式中,张力剂(张力-调节剂)被用作调节制剂的组成,达到所期望的等渗范围。所述张力-调节剂可以是多元醇或双糖,包括非还原性双糖。此类张力剂是被本领域技术人员所知的,包括,但不限于甘油、甘露醇、山梨醇、海藻糖、木糖醇、氯化钠和其它电解质。在一个具体的实施方式中,所述张力剂是甘油。
如果需要,本发明的制剂中可以包括胶体和树脂,包括例如,聚丙烯酸钠、纤维素醚、海藻酸钙、聚羧乙烯、乙烯-丙烯酸共聚物、乙烯基吡咯烷酮聚合物、乙烯醇-乙烯基吡咯烷酮共聚物、氮取代丙烯酰胺聚合物、聚丙烯酰胺、阳离子聚合物如阳离子瓜尔胶、二甲基丙烯酸铵聚合物、丙烯酸-甲基丙烯酸共聚物、聚氧乙烯-聚丙烯共聚物、聚乙烯醇、支链淀粉、琼脂、明胶、壳聚糖、罗望子多糖、黄原胶、卡拉胶、高甲氧基果胶、低甲氧基果胶、瓜尔胶、阿拉伯树胶、微晶纤维素、阿拉伯半乳聚糖、刺梧桐树胶、黄蓍胶、海藻酸盐、白蛋白、酪蛋白、凝胶多糖、结冷胶、葡聚糖、纤维素、聚乙烯亚胺、高聚合聚乙二醇、阳离子硅氧烷聚合物、合成乳胶、丙烯酸硅氧烷、三甲基硅氧乙烯基硅酸酯和氟化硅树脂。
在一些实施方式中,所述制剂是不含防腐剂的。在另外的实施方式中,使用了防腐剂。防腐剂被用来,例如,预防多次使用的眼用制剂中的细菌污染。示例性的防腐剂包括,但不限于,苯扎氯铵、稳定的氯氧络合物(也被称为)、乙酸苯汞、氯丁醇、苯甲醇、对羟基苯甲酸酯和硫柳汞。在一个具体的实施方式中,所述防腐剂是
本发明的眼用制剂中还可以包括的其他的赋形剂组分或成分,是螯合剂和抗生素。合适的螯合剂是本领域所知的。有用的螯合剂的具体的实例包括,但不限于,乙二胺四乙酸盐如乙二胺四乙酸二钠、乙二胺四乙酸钙二钠、乙二胺四乙酸钠、乙二胺四乙酸三钠和乙二胺四乙酸二钾。在一个具体的实施方式中,所述螯合剂是乙二胺四乙酸二钠。应理解的是,也可以用其他螯合剂来代替乙二胺四乙酸二钠,或与乙二胺四乙酸二钠一起使用。本发明的制剂可以包括一些抗生素的例子,包括但不限于硫酸甲氧苄啶/硫酸多粘菌素B、加替沙星、盐酸莫西沙星、妥布霉素、替考拉宁、万古霉素、阿奇霉素、克拉霉素、阿莫西林、青霉素、氨苄青霉素、羧苄青霉素、环丙沙星、左氧氟沙星、阿米卡星、庆大霉素、卡那霉素、新霉素和链霉素。
本发明的制剂可以包装成眼科局部用药领域已知的多种包装形式。在一个实施方式中,所述制剂被包装在无菌的、不含防腐剂的一次性包装或小瓶或容器(即单位剂量瓶)中。每一个小瓶,例如小到0.9ml,可以由低密度聚乙烯制成,从而容纳少量的制剂,例如单次使用的0.4ml。在这种情况下,当药物组合物进行无菌化并装载于以滴液形式供局部使用的一次性单剂量容器中时,可以将一组30个小瓶、60个小瓶等形式的多个小瓶包装在带盖托盘中,例如,带有铝制可剥盖的聚丙烯托盘。每一个托盘的全部内容物可以完整出售,每次使用一个小瓶或包装,并在每次使用完后都立刻丢弃。例如,塑料安瓿瓶或小瓶或容器可以用吹-灌-封(BFS)的技术制造。所述BFS工艺在一次连续性操作中可以涉及塑料挤出、成型、无菌填充和密封,并且这些流程是本领域所已知的。在另一个实施方式中,所述制剂被包装在多剂量的小瓶中,每次使用专门的容器/封盖对材料进行无菌分配,从而保持了无菌完整性。然而在另一个实施方式中,所述制剂被包装在传统的小瓶/容器中,作为无菌的产品。
在一些实施方式中,本发明的剂型是非均相水性溶液的滴眼液,滴眼液制剂包括两种或多种活性成分,其中第一活性成分是α2肾上腺素能受体激动剂,第二活性成分选自于由钙调磷酸酶抑制剂、淋巴细胞功能相关抗原拮抗剂、皮质类固醇、NSAID、钠通道阻断剂、抗组胺药,以及其两种或更多种的组合组成的组。例如,滴眼液制剂可以包括溴莫尼定或酒石酸溴莫尼定和环孢素,或溴莫尼定或酒石酸溴莫尼定和立他司特,或环孢素和立他司特的组合,或溴莫尼定或酒石酸溴莫尼定、环孢素和立他司特。根据本发明,滴眼液通常包括,活性成分在药学上可接受的载体和/或赋形剂中的水性/油性悬浊液。在一些实施方式中,所用活性成分的粒径是大约10μm或更小,通常是5μm或更小,经常是1μm或更小,更经常是0.5μm或更小,仍然更经常是0.2μm或更小,最经常是0.15μm或更小。
在另一个方面,本发明涉及通过向患者的眼睛给予本文所公开的眼用制剂,来治疗患有眼障碍(例如,干眼综合征)的受试者或患者的方法。例如,在一些实施方式中,用于治疗眼障碍的制剂包括:(i)溴莫尼定或其药学上可接受的盐(如酒石酸溴莫尼定)和环孢素;(ii)溴莫尼定或其药学上可接受的盐和立他司特;(iii)环孢素和立他司特的组合;或,(iv)所有的三种活性物质,即溴莫尼定或其药学上可接受的盐、环孢素和立他司特。本发明的组合物的另外的实例,包括溴莫尼定或其药学上可接受的盐和氯替泼诺;溴莫尼定、其药学上可接受的盐和NSAID的组合;以及,溴莫尼定、其药学上可接受的盐和钠通道阻断剂,和溴莫尼定或其药学上可接受的盐和抗组胺药的组合。
所述活性成分以,向给药组合物的眼障碍患者提供所期望的治疗益处的有效量存在。治疗有效量应该足以在治疗后能缓解眼障碍。受试者或患者的眼睛可以是整个眼睛结构,或是在眼睛中或眼睛周围的组织或腺体,如患者的眼组织、眼睑、眼睑边缘,眼表面。所述眼科药物制剂是局部地给药和/或对眼睛中、上或周围进行给药。所述干眼综合征可以是水液缺乏型干眼(ADDE),或蒸发过强型干眼(EDE),或由ADDE和EDE组成(混合机制的干眼)。ADDE可以是舍格林氏干眼综合征(其中泪腺和唾液腺被自身免疫过程靶向,例如类风湿性关节炎)和非舍格林氏干眼综合征(泪腺功能障碍,但舍格林氏综合征的系统性自身免疫特征除外,如年龄相关性干眼)。本发明的活性化合物的实际剂量取决于具体的化合物,以及将要治疗的疾病;对于合适的剂量的选择完全在技术人员的知识范围内。
通过下列实施例的验证,本发明的额外的目的、优势和新的特征,对于本领域技术人员将变得显而易见,但这些实施例并非旨在限制。在实施例中,结构性地简化为实践的步骤用现在时态描述,在实验室中已经实施的步骤用过去时态阐述。
实施例
局部用非均相眼用溶液(其具有用于治疗眼障碍(例如,干眼综合征)的各种成分(w/w))的实施例如下所述:含量为0.02%至0.2%重量、优选大约0.075%的酒石酸溴莫尼定,和0.01至0.1%重量的环孢素,大约0.02%至2%重量的表面活性剂如聚山梨酯80,或大约0.1%和0.25%重量的泊洛沙姆/泰洛沙泊;大约0.05%重量的卡波姆共聚物(A型或B型);大约2.2%重量的张力剂(甘油或包括甘油);pH 6.0~8.0的磷酸盐(二碱式和单碱式组合)缓冲液(或其他缓冲液,如Tris或柠檬酸钠缓冲液);含量大约0.02%重量或更少的EDTA钠;含量大约1.25%重量的油(例如蓖麻油)。或者,用于油相中的油是中链甘油三酯,范围是从0.5~4%,通常是大约2%。为制备这种制剂,可加入所有水溶性组分,并加热(大约60~70℃)以制成含缓冲液的水相。亲脂性溶液是使用亲脂溶剂(例如,蓖麻油)并加热到大约60~70℃来制备。非均相溶液是通过将亲脂性溶液迅速加入水相中,随后进行高剪切力混合来形成。最终的溶液通过0.22微米的过滤器进行消毒。或者,也可以通过在大约121℃下高压灭菌20分钟的方式进行消毒。经消毒的非均相溶液通过BFS等技术填充到单剂量的一次性管中。
制备本发明的包括非均相水性溶液的组合物的另一常用方法如下所述:
1.混合油相:将适量的蓖麻油和聚山梨酯80混合,直到均匀;
2.混合水相:将所需量的Pemulen、水和甘油混合,直到均匀;
3.将来自步骤1和步骤2中的油相和水相混合物进行初次混合;
4.将来自步骤3的混合物进行高剪切混合并且均质化。
5.通过工艺测试确定眼用溶液的性质。
局部眼用纳米乳制剂(其具有用于治疗眼障碍(例如,干眼综合征)的各种组分(w/w))的另一个实施例如下所述:它含有平均粒径等于或小于0.2μm且大于0.02μm的胶体颗粒,并且具有被界面膜包裹的油核。胶体颗粒的尺寸总体分布可以是单峰的。溶液含有从0.05%至0.5%(例如0.2%)任何范围的α2肾上腺素能受体激动剂、0.01%至0.3%(例如0.075%)的环孢素以及0.5至4%w/w(例如1.25%w/w)的蓖麻油或中链甘油酯。它包括表面活性剂,优选0.5~4%重量的聚山梨酯80(例如大约1.0%重量);丙烯酸酯/C10-30丙烯酸烷基酯交联聚合物(大约0.05%重量)。局部眼用溶液包括张力剂或缓和剂组分(例如,甘油,含量可以是大约2.2%重量)、缓冲液,如柠檬酸钠,Tris-碱来调节pH。本局部眼用溶液的pH范围可以是大约6.0到大约8.0。该局部眼用溶液对于增加眼泪产生是有治疗效果的。
局部眼用水性溶液(其具有用于治疗眼障碍(例如,干眼综合征)的各种组分(w/w))的另一实施例如下所述:它包括平均粒径等于或小于0.2μm且大于0.02μm的胶体颗粒,并且具有被界面膜包裹的油核。胶体颗粒的尺寸总体分布可以是单峰的。溶液含有重量占油相总重量(w/w)的0.05%至0.2%(例如0.075%)的任何范围的α2肾上腺素能受体激动剂(例如溴莫尼定或其盐),0.01%至0.3%(例如,0.1%)的环孢素,0.5至4%w/w(例如2%w/w)的中链甘油三酯,0.02%w/w的苯扎氯铵或单剂量无菌容器中不含苄烷铵(不含防腐剂),和表面活性剂。该表面活性剂,例如,由量为0.3%w/w的泰洛沙泊和量为0.1%w/w的泊洛沙姆的混合物组成。该眼用溶液可以包括一种或多种油,选自于蓖麻油、橄榄油、大豆油、玉米油、矿物油、棉籽油、红花油和芝麻油。该溶液不包括能产生负电荷和/或磷脂的任何显著量(≤1%,通常≤0.5%,经常≤0.1%,最经常≤0.01%)的物质。该眼用非均相溶液可以用来治疗干眼综合征。
局部眼用纳米乳制剂(其具有用于治疗眼障碍的各种组分(w/w))的又一实施例如下所述:它包括量为大约0.2%的酒石酸溴莫尼定;0.3%至10%重量,优选4%重量的立他司特;聚山梨醇80(例如大约1.0%重量);丙烯酸/C10-30丙烯酸烷基酯交联聚合物(大约0.05%重量);水适量;和,量为大约1.25%重量的蓖麻油。局部眼用溶液包括张力剂或缓和剂组分(例如,甘油,其含量可以是大约2.2%重量),缓冲液,如柠檬酸钠,Tris-碱来调节pH。本局部眼用溶液的pH范围可以是大约6.0至大约8.0。本局部眼用溶液对于增加眼泪产生是有治疗效果的。
局部眼用水性溶液(其具有用于治疗眼障碍的各种组分(w/w))的又一实施例如下所述:它包括量大约是0.02%的酒石酸溴莫尼定;0.3%至10%重量,优选3%重量的立他司特,聚山梨醇80(例如大约1.0%重量);丙烯酸/C10-30丙烯酸烷基酯交联聚合物(大约0.05%重量);水适量;和,含量是大约1.25%重量的蓖麻油。所述α2肾上腺素能受体激动剂立他司特是在局部眼用溶液中存在的唯一的活性剂,但包括张力剂或缓和剂组分(例如,甘油,其含量可以是大约2.2%重量),缓冲液。本局部眼用溶液的pH的范围可以是在大约6.0至大约8.0。本局部眼用溶液对于增加眼泪产生是有治疗效果的。
局部眼用水性溶液(具有各种组分(w/w))的又一实施例如下所述:它包括量的范围从大约0.01%至大约0.5%,通常含量大约0.2%重量的酒石酸溴莫尼定;0.01%至大约0.2%,通常含量是大约0.075%重量的环孢素;0.3%至10%重量,通常4%重量的立他司特;大约0.2至大约0.6%,通常含量是大约0.4%或大约0.25%的B类卡波姆均聚物,和/或大约0.4至大约5%,通常含量是大约4%或大约2.5%的C类卡波姆均聚物,和/或大约0.2至大约0.5%,通常大约0.4%或大约0.2%的聚卡波非(polycarbophil);大约0.5%至大约1%,通常大约0.9%的甘油;大约0.003%至大约0.01%,通常大约0.007%的苯扎氯铵;大约0.03%至大约0.07%,通常大约0.05%的乙二胺四乙酸钠;多达大约0.09%,通常大约0.06%,或适量至等渗的的氯化钠,或适量至等渗的甘露醇,或不含有等渗调节剂氯化钠和甘露醇;大约0.3%至大约0.6%,通常大约是0.5%的丙二醇;水适量,到100gms,和氢氧化钠或盐酸适量以将pH调节到pH6.0到约8.0的范围。局部眼用溶液对于治疗干眼综合征是治疗有效的。虽然在非限制性实施例中,本发明的制剂可以使用如苯扎氯铵等防腐剂,但制剂通常是不含防腐剂的。
局部眼用水性溶液(具有用于治疗眼障碍(例如,干眼综合征)的各种组分(w/w))的另一个实施例如下所述:0.02%到0.3%重量,通常大约0.1到0.2%的酒石酸溴莫尼定;0.02到0.6%重量,通常大约0.1到0.3%的依碳酸氯替泼诺;表面活性剂,如大约0.02%~2%重量的聚山梨酯80或大约0.1%和0.25%重量的泊洛沙姆/泰洛沙泊;大约0.05%重量的卡波姆共聚物(A类或B类);大约2.2%重量的张力剂(甘油或包括甘油);pH 6.0~8.0的柠檬酸钠和Tris缓冲液;含量是大约0.02%重量或更少的EDTA钠;含量大约是1.25%重量的油(例如蓖麻油)。或者,油相中的油是0.5~4%,通常是大约2%的中链甘油三酯。为了制备这种制剂,可以添加所有的水溶性组分并且加热(大约60~70℃)。油相:所述油(例如蓖麻油)被加热到大约60~70℃。非均相的粗溶液是通过将油快速加入到水相中,随后用高剪切力混合来形成的。最终的非均相溶液通过0.22微米的过滤器进行消毒。或者,也可以通过在大约121℃下高压灭菌20分钟的方式来消毒。经消毒的非均相溶液通过BFS等技术填充到单剂量的一次性管中。
局部眼用制剂组合物(具有用于治疗眼障碍(例如,干眼综合征)的各种组分(w/w))的另一个实施例如下所述:含量是0.02%到0.3%重量,优选是大约0.1到0.2%的酒石酸溴莫尼定;含量是0.02到0.6%重量,优选是大约0.1到0.3%的依碳酸氯替泼诺;大约0.6%重量的聚维酮;大约0.1%和0.25%重量的泊洛沙姆/泰洛沙泊;大约1到3%重量的张力剂(甘油或包括甘油);pH 6.0~8.0的柠檬酸钠和Tris缓冲液;含量是大约0.02%重量或更少的EDTA钠。
制剂实施例:眼用药物组合物可以用下表所示的组合物配制。非均相溶液制剂可以根据下面所述的工艺配制,其中将不溶于水的活性物质加入到油相(例如蓖麻油)中,然后将油相引入到水相中。
非均相溶液制剂-工艺流程:
1.油相:将适量的蓖麻油和聚山梨酯80混合,直到均匀;
2.水相:将所需量的Pemulen、水和甘油混合,直到均匀;
3.将来自步骤1和步骤2中的油相和水相混合物进行初次混合;
4.将来自步骤3的混合物进行高剪切混合,并且形成非均相溶液;
5.通过工艺测试,确认非均相溶液的性质。
上述工艺流程不需要以同样的顺序实施。
*例如,不同活性成分组合的制剂为:溴莫尼定或酒石酸溴莫尼定+环孢素;溴莫尼定或酒石酸溴莫尼定+立他司特;环孢素+立他司特的组合;溴莫尼定或酒石酸溴莫尼定+环孢素+立他司特;溴莫尼定或酒石酸溴莫尼定+依碳酸氯替泼诺等。
可以监控这些示例性的非均相制剂的物理稳定性。例如,这些非均相溶液可以允许在20到25℃下静置一段时间(例如6个月),然后测量非均匀性的大小。在实验误差范围内的非均匀性大小,应该在测试期结束时,与那些刚制备的非均相溶液所测量的结果相同,从而表明不存在明显的非均匀性聚集。此外,应没有活性物质的沉淀。这些结果显示这样制备的非均相制剂具有优异的物理稳定性。
水性制剂(均相和非均相的溶液):下面提供了生产本发明组合物的水性制剂的一般工艺。简单地,对于X体积(V)的最终制剂-完成以下步骤:
1(a).在X/4V的水中,混合羧甲基纤维素-钠。
1(b).在X/2V的水中,混合聚山梨酯、API(酒石酸溴莫尼定和立他司特)和稳定剂(海藻糖/甘露醇)。
2.混合来自1(a)和1(b)的混合物,直到形成均相或非均相的溶液。
3.向来自步骤2的最终混合物中加入10X的储备缓冲液(X/10V)。
4.通过向来自步骤3中的混合物中加入NaCl储备液,来调节渗透压。
5.通过向来自步骤4中的混合物中加入HCl/NaOH,来调节pH。
6.通过向来自步骤5中的混合物中加入水,使最终体积达到V。
7.进行过滤消毒。
8.填充(BFS)。
组合的水性制剂:酒石酸溴莫尼定与立他司特的水性制剂的组合产品的示例。
治疗实施例:用本文作为示例的给定制剂中的若干液滴,向患有干眼综合征的患者的眼睛进行给药。在合理的时间段内,症状显著减轻。在病情持续期间,每天重复一次或多次治疗。
组合制剂:用本文公开的工艺来制备活性药物成分组合的多种组合。使用粒度分析仪Mastersizer 3000TM(马尔文分析(Malvern Panalytical),马尔文,英国),来测定这些示例性的眼用乳液制剂(例如,均相的/非均相的溶液;或悬浊液)的颗粒或球状尺寸分布。在测量过程中,制剂被分散在水中,并将数据绘制为颗粒的体积密度(%)比尺寸。如图1~3中的表格所示,制剂中的球状物/颗粒的中值尺寸被报道为Dx(50)。这些数据表明了可以使用本申请中纳米乳制剂(图3)中所描述的工艺,来制备纳米级小球。
还使用尺寸分布分析,在各种温度下,长时间监控了纳米乳/溶液/悬浮液制剂的物理稳定性。例如,制剂在储存温度(例如,20℃到25℃)、升高的温度(例如,40℃)和苛刻的温度(例如60℃)下孵育一段时间(例如,1~3个月),然后测量尺寸的非均匀性。在实验误差范围内的所述尺寸的非均匀性,应该在测试期结束时,与那些刚制备的纳米乳/悬浊液/溶液所测量的结果相同。这种粒径的一致性表明,在储存温度下,不均匀性没有显著的聚集。即使在升高的稳定温度下,球状物/颗粒(图2和图3)的中值尺寸也没有明显变化。这些结果显示这样制备的纳米乳/悬浊液制剂具有优异的物理稳定性。
用RP-HPLC方法,来测定各种示例性纳米乳制剂(例如均相的/非均相的溶液;或悬浮液)中的有效药物成分的量。对于酒石酸溴莫尼定和环孢素的组合制剂,所述HPLC方法用乙腈和低pH缓冲液的混合物作洗脱剂。在不同温度下进行长时间孵育后,用HPLC方法,来测定纳米乳/溶液/悬浊液制剂中的APIs的化学稳定性。例如,制剂在储存温度(例如20到25℃)、增加的温度(例如40℃)和苛刻的温度(例如60℃)下孵育,然后用HPLC方法测定纯度。纯度在2周测试期结束时,基本上与那些刚制备的纳米乳制剂(图5)测量的结果是相同的,从而表明在储存温度、增加的温度和甚至苛刻的温度下,都没有明显的降解。
用PR-HPLC方法,测定活性药物的成分在这些示例性纳米乳制剂的油相和水相中的分布。对于酒石酸溴莫尼定和环孢素的组合制剂,HPLC方法使用乙腈和低pH缓冲液的混合物作为洗脱剂。在纳米乳制剂中,采用超滤装置,通过离心工艺,分离油相和水相。用HPLC方法,对这些油相和水相中的APIs的量进行定量。分析表明,溴莫尼定在纳米乳制剂的两个相中都有分布(~30%在油相中,~70%在水相中),同时环孢素基本上仅在油相中的分布。这些结果证实,对于不同物理化学特征的药物在均相或非均相的纳米乳制剂中的不同相中的分布,纳米乳制剂具有独特的差异性特征。
本发明的前述讨论用于说明和描述的目的。前述讨论不旨于将本发明限制为本文公开的一种或多种形式。虽然本发明的描述包括了对一种或多种实施方式的描述,以及特定的变化和修改,但其他变化和修改均在本发明的范围中,例如,在理解本公开后,可以在本领域技术人员的技术和知识范围内的变化和修改。意于在允许的范围内获得包括替代实施方式的权利,包括那些所要求保护的替换、可互换和/或等价的结构、功能、范围或步骤,而无论这些替换、可互换和/或等价的结构、功能、范围或步骤是否在本文公开,且不意于公开指定任何可专利的客体。本文所有的引用都通过引用整体并入本文中。
Claims (27)
1.一种眼用纳米乳制剂,由至少两种活性药物成分组成,所述至少两种活性药物成分选自于由以下项组成的组:
(a)α2肾上腺素能受体激动剂;
(b)β-肾上腺素能受体激动剂;
(c)免疫抑制剂;
(d)淋巴细胞相关抗原拮抗剂;
(e)抗炎剂;
(f)β-阻断剂;
(g)前列腺素类似物;
(h)组胺受体拮抗剂;
(i)碳酸酐酶抑制剂;
(j)抗生素。
2.根据权利要求1所述的眼用纳米乳制剂,其中,第一活性药物成分是所述α2肾上腺素能激动剂,
第二活性药物成分选自于由以下项组成的组:所述免疫抑制剂、所述淋巴细胞相关抗原拮抗剂、所述皮质类固醇、所述β-阻断剂、所述前列腺素类似物、所述碳酸酐酶抑制剂。
3.根据权利要求2所述的眼用纳米乳制剂,其中,所述免疫抑制剂选自于由环孢素、他克莫司及其组合组成的组。
4.根据权利要求2所述的眼用纳米乳制剂,其中,所述淋巴细胞相关抗原拮抗剂包括立他司特。
5.根据权利要求2所述的眼用纳米乳制剂,其中所述皮质类固醇选自于由泼尼松龙、甲基泼尼松龙、二氟泼尼酯、醋酸泼尼松龙、泼尼松龙磷酸钠、曲安西龙、氟轻松、氟米龙、倍他米松、甲羟松及其组合组成的组。
6.根据权利要求2所述的眼用纳米乳制剂,其中,所述抗炎剂选自于由皮质类固醇、非甾体抗炎药(“NSAID”)、胸腺素β4及其组合组成的组。
7.根据权利要求6所述的眼用纳米乳制剂,其中,所述NSAID选自于由双氯芬酸、氟比洛芬、酮咯酸、酮咯酸氨丁三醇、溴芬酸、奈帕芬胺、氟比洛芬及其组合组成的组。
8.根据权利要求2所述的眼用纳米乳制剂,其中,所述β-肾上腺素能受体激动剂选自于由多培沙明、肾上腺素、喘息定、异丙肾上腺素、左旋沙丁胺醇、舒喘宁、沙丁胺醇及其组合组成的组。
9.根据权利要求2所述的眼用纳米乳制剂,其中,所述β-阻断剂选自于由噻吗洛尔、普萘洛尔、索他洛尔、纳多洛尔及其组合组成的组。
10.根据权利要求2所述的眼用纳米乳制剂,其中,所述前列腺素类似物选自于由拉坦前列素、比马前列素、曲伏前列素、他氟前列素及其组合组成的组。
11.根据权利要求2所述的眼用纳米乳制剂,其中,所述碳酸酐酶抑制剂选自于由多佐胺、醋甲唑胺、布林唑胺、双氯非那胺及其组合组成的组。
12.根据权利要求1所述的眼用纳米乳制剂,其中,所述活性药物成分由以下项组成:
(i)溴莫尼定,其药学上可接受的盐,或者它们的组合;
(ii)环孢素;和
(iii)立他司特或氯替泼诺。
13.一种眼用水性溶液,包括:
(i)溴莫尼定,其药学上可接受的盐,或者它们的组合;和
(ii)环孢素。
14.根据权利要求13所述的眼用水性溶液,进一步包括药学上可接受的赋形剂。
15.根据权利要求14所述的眼用水性溶液,其中,所述药学上可接受的赋形剂包括:
(i)乳液稳定聚合物;
(ii)表面活性剂;
(iii)张力调节剂或稳定剂,选自于由多元醇、非还原双糖及其组合组成的组;或
(iv)它们的组合。
16.根据权利要求13所述的眼用水性溶液,其中,所述溶液是纳米乳溶液。
17.一种治疗眼障碍的方法,所述方法包括对需要这种治疗的受试者,给药治疗有效量的权利要求1所述的组合物。
18.根据权利要求17所述的方法,其中,所述眼障碍选自于由以下项组成的组:(i)干眼综合征;(ii)眼部移植物抗宿主病;(iii)眼红斑痤疮;(iv)过敏性结膜炎;(v)自身免疫性眼表面疾病;(vi)泰格森浅层点状角膜炎;(vii)带状疱疹性角膜炎;(viii)史蒂芬斯-强森综合征;(ix)角膜炎;(x)结膜炎;(xi)睑缘炎;(xii)睑皮松垂症;(xiii)结膜松弛症;(xiv)眼睑结膜炎;(xv)睑角膜结膜炎;(xvi)眼部手术引起的术后炎症或疼痛;(xvii)巩膜炎;(xviii)浅层巩膜炎;(xix)前葡萄膜炎;(xx)虹膜炎;(xxi)睫状体炎;(xxii)眼表面血管障碍;(xxiii)溃疡性角膜炎;(xxiv)光角膜炎;(xxv)泪囊炎;(xxvi)眼睑障碍;(xxvii)先天性无泪;(xxviii)干性眼炎;(xxix)泪囊炎;(xxx)高眼压;(xxxi)青光眼;和,(xxxii)由化学灼伤、热烧伤、隐形眼镜的使用或引起眼表物理创伤所引起的眼表障碍。
19.根据权利要求18所述的方法,其中,所述干眼综合征选自于由舍格林氏综合征、睑板腺功能异常和角膜结膜炎组成的组。
20.根据权利要求18所述的方法,其中,所述眼睑障碍包括眼睑炎症、疼痛和/或水肿。
21.一种眼科活性纳米乳,包括:
(i)药学上可接受的载体水性溶液;以及
(ii)治疗活性化合物,所述治疗活性化合物由(a)溴莫尼定、其药学上可接受的盐或它们的组合,(b)环孢素,和(c)可选的一种或多种第三药物活性化合物的混合物组成,其中所述第三药物活性化合物由以下项组成:
(a)β-肾上腺素能受体激动剂;
(b)淋巴细胞相关抗原拮抗剂;
(c)抗炎剂;
(d)β-阻断剂;
(e)前列腺素类似物;
(f)组胺受体拮抗剂;
(g)碳酸酐酶抑制剂;以及
(h)抗生素。
22.根据权利要求21所述的眼科活性纳米乳,其中,所述第三药物活性化合物包括立他司特。
23.根据权利要求21所述的眼科活性纳米乳,其中,所述第三药物活性化合物包括氯替泼诺。
24.根据权利要求21所述的眼科活性纳米乳,其中,所述治疗活性化合物由(a)溴莫尼定、其药学上可接受的盐或它们的组合,和(b)环孢素组成。
25.根据权利要求21所述的眼科活性纳米乳,其中,所述治疗活性化合物由酒石酸溴莫尼定、环孢素,和可选的一种或多种所述第三药物活性化合物组成。
26.根据权利要求25所述的眼科活性纳米乳,其中,所述第三药物活性化合物包括立他司特。
27.根据权利要求25所述的眼科活性纳米乳,其中,所述第三药物活性化合物包括氯替泼诺。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070105761A1 (en) * | 2005-11-09 | 2007-05-10 | Combinatorx, Incorporated | Methods, compositions, and kits for the treatment of opthalmic disorders |
US20160243116A1 (en) * | 2015-02-24 | 2016-08-25 | The Board Of Trustees Of The University Of Illinois | Methods and Compositions for Treating Dry Eye Disease and Other Eye Disorders |
WO2018064354A1 (en) * | 2016-09-28 | 2018-04-05 | Medicon Pharmaceuticals, Inc. | Compositions and methods for treating ophthalmic conditions |
US20180221278A1 (en) * | 2015-02-24 | 2018-08-09 | Ocugen, Inc. | Prsustained release opthalmic formuation and methods for using the same |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2094688B1 (es) * | 1994-08-08 | 1997-08-01 | Cusi Lab | Manoemulsion del tipo de aceite en agua, util como vehiculo oftalmico y procedimiento para su preparacion. |
WO2001041806A1 (fr) * | 1999-12-07 | 2001-06-14 | Rohto Pharmaceutical Co., Ltd. | Compositions ophtalmiques |
CA2578176C (en) * | 2004-11-09 | 2013-09-24 | Novagali Pharma Sa | Ophthalmic emulsions containing an immunosuppressive agent |
MX2007010025A (es) * | 2007-08-17 | 2009-02-25 | Arturo Jimenez Bayardo | Composición farmacéutica para tratamiento de hipertensión ocular. |
EP3569223A1 (en) * | 2009-10-30 | 2019-11-20 | Intratus, Inc. | Methods and compositions for sustained delivery of drugs |
ES2641621T3 (es) * | 2011-12-16 | 2017-11-10 | Allergan, Inc. | Composiciones oftálmicas que comprenden copolímeros de injerto de polivinil caprolactama-acetato de polivinilo-polietilenglicol (SOLUPLUS) |
EP2664329A1 (de) * | 2012-05-15 | 2013-11-20 | F. Holzer GmbH | Ophthalmologisches Vehikelsystem |
CN102895245A (zh) * | 2012-10-30 | 2013-01-30 | 河南牧翔动物药业有限公司 | 一种复方甲氧苄啶与盐酸多西环素纳米乳制剂及其制备方法 |
WO2016060921A1 (en) * | 2014-10-15 | 2016-04-21 | Rapid Pathogen Screening, Inc. | Formulations for histatin protectives and therapeutics |
WO2016063184A1 (en) * | 2014-10-20 | 2016-04-28 | Sentiss Pharma Private Limited | Ophthalmic solution |
US10751337B2 (en) * | 2015-02-24 | 2020-08-25 | Ocugen, Inc. | Preservative free ocular compositions and methods for using the same for treating dry eye disease and other eye disorders |
US9981041B2 (en) * | 2016-08-23 | 2018-05-29 | Ira Jason Salzman | Ophthalmic lubricating spray |
EP3554531A1 (en) * | 2017-01-24 | 2019-10-23 | MacRegen, Inc. | Treatment of age-related degeneration and other eye diseases with apolipoprotein mimetics |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070105761A1 (en) * | 2005-11-09 | 2007-05-10 | Combinatorx, Incorporated | Methods, compositions, and kits for the treatment of opthalmic disorders |
US20160243116A1 (en) * | 2015-02-24 | 2016-08-25 | The Board Of Trustees Of The University Of Illinois | Methods and Compositions for Treating Dry Eye Disease and Other Eye Disorders |
US20180221278A1 (en) * | 2015-02-24 | 2018-08-09 | Ocugen, Inc. | Prsustained release opthalmic formuation and methods for using the same |
WO2018064354A1 (en) * | 2016-09-28 | 2018-04-05 | Medicon Pharmaceuticals, Inc. | Compositions and methods for treating ophthalmic conditions |
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