CN105106931A - 冻干的或可冻干形式的lkktet和/或lkktnt肽组合物 - Google Patents
冻干的或可冻干形式的lkktet和/或lkktnt肽组合物 Download PDFInfo
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- CN105106931A CN105106931A CN201510532998.4A CN201510532998A CN105106931A CN 105106931 A CN105106931 A CN 105106931A CN 201510532998 A CN201510532998 A CN 201510532998A CN 105106931 A CN105106931 A CN 105106931A
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- peptide
- peptide reagent
- lkktnt
- reagent
- amino acid
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Abstract
本发明涉及冻干的或可冻干形式的LKKTET和/或LKKTNT肽组合物,具体而言,本发明涉及包括肽试剂的组合物,所述肽试剂包括氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂、或者包括刺激LKKTET或LKKTNT肽或其保守变异体产生的刺激试剂,该组合物包括氨基酸稳定剂或冻干填充剂中的至少一种,该组合物是冻干形式或能够被冻干的形式。
Description
本申请是申请号为200680021662.0,申请日为2006年6月19日,发明名称为“冻干的或可冻干形式的LKKTET和/或LKKTNT肽组合物”的中国专利申请的分案申请。
发明背景
相关申请的交叉引用
本发明要求2005年6月17日提交的美国临时申请60/691,261和2006年2月28日提交的美国临时申请60/776,947的权益。
技术领域
本发明涉及LKKTET和/或LKKTNT组合物及方法的领域。
背景技术
胸腺素β4起初被认为是在体外内皮细胞迁移和分化期间被上调的蛋白。胸腺素β4最初从胸腺分离,是一个具有43个氨基酸、4.9KDa、在多种组织中普遍存在的多肽。归于该蛋白的几种功能包括在内皮细胞分化和迁移、T细胞分化、肌动蛋白隔离、血管形成和伤口愈合中的功能。
已经鉴定了许多Tβ4异构体,其与已知的Tβ4氨基酸序列具有约70%、或约75%、或约80%或更高的同源性。这些异构体包括,例如Tβ4ala、Tβ9、Tβ10、Tβ11、Tβ12、Tβ13、Tβ14和Tβ15。与Tβ4相似,Tβ10和Tβ15异构体也表现出能隔离肌动蛋白的活性。Tβ4、Tβ10和Tβ15,以及这些其他异构体共有一个氨基酸序列LKKTET或LKKTNT,其似乎参与调节肌动蛋白的隔离或结合。尽管不希望被任何特定的理论所限制,但本文中描述的肽试剂的活性至少部分地归因于这些试剂的抗炎活性。β-胸腺素也调节了肌动蛋白聚合(例如,β胸腺素似乎通过隔离游离的G-肌动蛋白而解聚F-肌动蛋白)。Tβ4调节肌动蛋白聚合的能力可归因于其通过LKKTET序列结合或隔离肌动蛋白的能力。
本领域需要LKKTET和/或LKKTNT的组合物和方法。
发明内容
根据一个具体实施方式,组合物包括含氨基酸序列LKKTET或LKKTNT或其保守变异体的肽试剂,或者包括刺激LKKTET或LKKTNT肽或其保守变异体产生的刺激试剂,该组合物包括至少一种氨酸稳定剂,该组合物是冻干的形式或能够被冻干的形式。
根据另一具体实施方式,组合物包括含氨基酸序列LKKTET或LKKTNT或其保守变异体的肽试剂,或者刺激LKKTET或LKKTNT肽或其保守变异体产生的刺激试剂,以及包括冻干填充剂或氨基酸稳定剂中的至少一种,所述组合物是冻干的形式。
具体实施方式
为多种目的而对受试者施用的许多组合物含有一种或多种可能导致受试者损伤的组分。
例如,防腐剂,如用在许多眼用和化妆产品的苯扎氯铵(BAK),在施用该产品时可引起表面刺激和/或伤害。综合症包括发红和不适。
长期使用含有季铵盐(如BAK)的滴眼液会产生显著且逐渐严重的眼睛表面刺激和细胞凋亡。患者经常发展为诸如发红和通常的眼部不适这样的症状。本发明的肽试剂,例如胸腺素β4(Tβ4),在与季铵盐(如BAK)一起接触眼组织对受试者施用时,可用于治疗或阻止对眼组织的伤害或受损。
可以用于本发明的季铵盐的实例包括BAK、西曲溴铵(cetrimide)、苯佐氯铵(benzoxonium)及其类似物。
根据具体实施方式,该肽试剂与作为同一个制剂一部分的铵盐如BAK一起施用,例如作为添加剂加入到含BAK或其他季铵盐的制剂中。季铵盐如BAK在许多眼溶液,如青光眼滴眼液中常用作防腐剂。
在另一个具体实施方式中,该肽试剂可在施用季铵盐如BAK之前,和/或施用季铵盐如BAK期间,和/或施用季铵盐如BAK之后施用。
根据具体实施方式,本发明尤其可用于阻止对眼角膜上皮的眼组织的伤害,其包括阻止这类眼组织中的细胞凋亡。例如,本发明也用作抗青光滴眼液或其他滴眼液的佐剂。
本发明一方面提供了眼用组合物,其包括含氨基酸序列LKKTET或LKKTNT的肽试剂或其保守变异体。
本发明另一方面提供了治疗眼组织的方法,其包括对所述眼组织局部施用眼用组合物,该组合物包括氨基酸序列LKKTET或LKKTNT的肽试剂或其保守变异体
在具体实施方式中,本发明提供了通过将眼组织与有效量的含本文描述的肽试剂的组合物接触的治疗方法。直接施用的实施例包括,例如直接应用含本文描述的肽制剂的溶液、洗剂、油膏、凝胶、乳膏、糊剂、喷雾剂、悬浮液、分散液、水凝胶、软膏、油或泡沫与组织接触。
未发现适于任何特定理论,肌动蛋白-隔离肽,如胸腺素β4(Tβ4或TB4)和其他包括肌动蛋白-隔离肽或肽片段的试剂可以促进眼组织健康,其中肌动蛋白-隔离肽或肽片段含氨基酸序列LKKTET或LKKTNT或其保守变异体。
胸腺素β4起初被认为是内皮细胞迁移和体外分化期间被上调的蛋白。胸腺素β4最初从胸腺分离,是一个具有43个氨基酸、4.9Kda、在多种组织中普遍存在的多肽。归于该蛋白的几种功能包括在内皮细胞分化和迁移、T细胞分化、肌动蛋白隔离、血管形成和伤口愈合中的功能。
根据具体实施方式,本发明优选地适用于胸腺素β4、和/或Tβ4异构体、类似物或衍生物,其中包括KLKKTET、LKKTETQ、氧化的Tβ4、Tβ4亚砜、Tβ4的N-端变异体和C-端变异体。
根据具体实施方式,可用于本发明的组合物包括肽试剂,例如胸腺素β4、和/或Tβ4异构体、类似物或衍生物,其中包括Tβ4的氧化形式(包括Tβ4亚砜)、Tβ4的N-端变异体和C-端变异体、以及包含或基本上由氨基酸序列LKKTET及其保守性变异体组成的多肽或肽片段。国际申请PCT/US99/17282公开了可用于本发明的Tβ4的异构体,以及可用于本发明的氨基酸序列LKKTET或LKKTNT和其保守变异体,该申请通过引用的方式纳入本文。国际申请PCT/GB99/00833(WO99/49883)公开了可用于本发明的氧化的胸腺素β4,该申请通过引用的方式纳入本文。尽管本发明在下文中主要针对Tβ4和Tβ4异构体进行描述,但应当理解为以下描述同样适用于氨基酸序列LKKTET或LKKTNT、包含或基本上由LKKTET、LKKTNT组成的肽和片段、它们的保守变异体,和/或Tβ4异构体、类似物或衍生物,其中包括氧化的Tβ4、Tβ4的N-端变异体和C-端变异体。
根据具体实施方式,本发明的组合物以每天、每两天、每两周、每两个月等的频率施用,其中在施用的每日,可进行单次或多次用药,例如每施用当日用药2、3、4或更多次。
已经鉴定了许多Tβ4异构体,其与已知的Tβ4氨基酸序列具有约70%、或约75%、或约80%或更高的同源性。这些异构体包括,例如Tβ4ala、Tβ9、Tβ10、Tβ11、Tβ12、Tβ13、Tβ14和Tβ15。与Tβ4相似,异构体Tβ10和Tβ15也表现出能隔离肌动蛋白的活性。Tβ4、Tβ10和Tβ15,以及其他异构体共有氨基酸序列LKKTET或LKKTNT,其似乎参与调节肌动蛋白的隔离或结合。Tβ4具有抗炎活性,并且也能调节肌动蛋白聚合(例如,β胸腺素似乎通过隔离游离的G-肌动蛋白而解聚F-肌动蛋白)。Tβ4调节肌动蛋白聚合的能力可归因于其通过LKKTET或LKKTNT序列结合或隔离肌动蛋白的能力。这样,与Tβ4一样,其他抗炎性蛋白和/或结合或隔离肌动蛋白,或者调节肌动蛋白聚合的蛋白(其中包括具有氨基酸序列LKKTET的Tβ4异构体)很可能如本文说明的那样单独或与Tβ4组合而发挥作用。
因此,可以明确预期已知的Tβ4异构体,例如Tβ4ala、Tβ9、Tβ10、Tβ11、Tβ12、Tβ13、Tβ14和Tβ15,以及还未鉴定的Tβ4异构体可用于本发明的方法。这样,Tβ4异构体可用于本发明的方法,其中包括在受试者中采用的方法。本发明从而进一步提供了包括Tβ4,以及Tβ4异构体Tβ4ala、Tβ9、Tβ10、Tβ11、Tβ12、Tβ13、Tβ14和Tβ15,以及眼用载体的药物组合物。
另外,如在适当的隔离、结合、动员或聚合分析中所显示的那样或如通过具有调节肌动蛋白结合的氨基酸序列(例如LKKTETR、LKKTNT)所确认的那样,其他具有抗炎活性和/或肌动蛋白隔离或结合能力,或能够动员肌动蛋白或调节肌动蛋白聚合的试剂或蛋白质,可相似地用于本发明的方法。这样的蛋白包括例如凝溶胶蛋白、维生素D结合蛋白(DBP)、抑制蛋白(profilin)、cofilin、蚕食蛋白(depactin)、DNA酶I、绒毛蛋白(villin)、截断蛋白(fragmin)、肌割蛋白(severin)、加帽蛋白(cappingprotein)、β-肌动蛋白和肌动调解蛋白(acumentin)。因此,方法包括已用于受试者的那些方法。本发明进一步提供了药物组合物,其包括本文提到的凝溶胶蛋白、维生素D结合蛋白(DBP)、抑制蛋白(profilin)、cofilin、蚕食蛋白(depactin)、DNA酶I、绒毛蛋白(villin)、截断蛋白(fragmin)、肌割蛋白(severin)、加帽蛋白(cappingprotein)、β-肌动蛋白和肌动调解蛋白(acumentin)。因此,本发明包括含有氨基酸序列LKKTET、或LKKTNT和其保守变异体的多肽的应用。
本文所使用的术语“保守变异体”或其语法上的变体是指氨基酸残基被另一种生物学上相似的残基替换。保守变异体的实例包括疏水残基例如异亮氨酸、缬氨酸、亮氨酸或甲硫氨酸替换另一个疏水性残基,极性残基替换另一个极性残基,例如用精氨酸替换赖氨酸、谷氨酸替换天门冬氨酸、或谷氨酰胺替换天门冬酰胺以及类似的替换。
根据具体实施方式,本发明的组合物是滴眼液制剂。
根据具体实施方式,用于本发明的组合物包含本文所描述的肽试剂,其中肽试剂的浓度范围是大约0.001-1000毫克每毫升(mcg/ml),更优选的是0.1-100mcg/ml,最优选的是大约1-10mcg/ml。在特别优选的具体实施方式中,该肽试剂是Tβ4。
根据具体实施方式,本发明用于治疗或预防眼组织由于与季铵盐如BAK接触造成的损害或损伤,季铵盐浓度范围是大约0.0001-1wt%,优选的浓度范围是大约0.001-0.1wt%,更优选的浓度范围是0.002-0.05wt%。在一个具体实施方式中,季铵盐的浓度是大约0.005-0.02wt%。
根据具体实施方式,本发明也包括含本文中所描述的肽试剂的药物组合物,该肽试剂在可眼用载体中。这样的载体包括,例如本文中所列的载体。
根据具体实施方式,提供治疗的实际剂量或试剂、制剂或组合物依赖许多因素,包括受试者的大小和健康状况。然而,本领域普通技术人员能够使用在PCT/US99/17282(见前)和本文中引用的参考文献中所描述的用于确定临床剂量的方法和技术来确定合适的使用剂量。
根据具体实施方式,本文中描述的方法和组合物所使用或包括的肽试剂可通过与可眼用的无毒赋形剂或载体混合来制成组合物。
根据具体实施方式,包括活性化合物的外用制剂也包括生理相容性载体,眼科领域的技术人员可使用常规标准选择该载体。该载体可选自已知的眼用载体,其包括但不局限于盐溶液;聚醚水溶液(waterpolyethers)(例如聚乙二醇);聚乙烯(例如聚乙烯醇和聚乙烯吡咯酮(povidone));纤维素衍生物,例如甲基纤维素和羟丙基甲基纤维素;石油衍生物,例如矿物油和白凡士林;动物脂肪例如羊毛脂;丙烯酸聚合物例如卡波姆胶(carboxypolymethylenegel);植物脂肪,例如花生油;以及多糖,例如葡聚糖;以及粘多糖(glycosaminogiycans),例如透明质酸钠;和盐,例如氯化钠和氯化钾。
根据具体实施方式,眼用组合物有利于局部用于眼睛,尤其是以溶液、悬浮液、软膏、凝胶或泡沫的形式。
根据具体实施方式,用于相应眼用组合物的常规药学可接受赋形剂和添加剂是本领域技术人员已知的,例如下文中提到的那些,尤其是载体、稳定剂、增溶剂、渗透促进剂、缓冲物质、防腐剂、增稠剂、复合剂和其他赋形剂。这样的添加剂和赋形剂的实例可见美国专利5,134,124和4,906,613。这些组合物以各自已知的方法制备,比如通过将活性组分与相应的赋形剂和/或添加剂混合形成相应的眼用组合物。活性组分优选地以滴眼液的形式施用,活性组分常规地溶解在例如载体中。该溶液可适当地调节和/或缓冲到所需的pH值,并且,适当时添加稳定剂、增溶剂或渗透促进剂。适当时,向眼用组合物中添加防腐剂和/或其他赋形剂。
本发明中所使用的载体通常适用于外用或普通给药,并且例如是水、水和易与水混溶的溶剂的混合液,例如C1-C7-烷醇、含0.5-5wt%羟乙基纤维素的植物油或矿物油、油酸乙酯、羧甲基纤维素、聚乙烯吡咯烷酮和其他眼用的无毒水溶性聚合物,例如纤维素衍生物如甲基纤维素、羧甲基纤维素的碱金属盐、羟甲基纤维素、羟乙基纤维素、甲基羟丙基纤维素和羟丙基纤维素、丙烯酸酯/盐或甲基丙烯酸酯/盐,如聚丙烯酸的盐或丙烯酸乙酯、聚丙烯酰胺,天然物质如明胶、藻酸盐、果胶、黄芪胶、梧桐树胶、黄原胶、角叉胶、琼脂和阿拉伯树胶,淀粉衍生物如淀粉醋酸酯和羟丙基淀粉,其他合成产物如聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯甲醚、聚氧化乙烯,优选的交联聚丙烯酸如中性卡波姆,或者这些聚合物的混合物。优选的载体是水、纤维素衍生物如甲基纤维素、羧甲基纤维素的碱金属盐、羟甲基纤维素、羟乙基纤维素、甲基羟丙基纤维素和羟丙基纤维素、中性卡波姆或者其混合物。
根据具体实施方式,用于本发明眼用组合物的增溶剂是,例如泰洛沙泊、脂肪酸甘油聚低级烷二醇酯(fattyacidglycerolpoly-loweralkyleneglycolesters)、脂肪酸聚低级烷二醇酯(fattyacidpoly-loweralkyleneglycolesters)、聚乙二醇(polyethyleneglycols)、甘油醚(glycerolethers)或这些化合物的混合物。所添加的量通常足以溶解活性组分。例如,增溶剂的浓度是活性组分浓度的0.1-5000倍。低级烷二醇中的亚烷基是指最多包括7个碳原子的亚烷基,例如为亚甲基、亚乙基、1,3-亚丙基、1,2-亚丙基、1,5-亚戊基、2,5-亚己基或1,7-亚庚基。低级亚烷基优选的是最多包括4个碳原子的线性或支链亚烷基。
缓冲物质的实例是醋酸盐、抗坏血酸盐、硼酸盐、碳酸氢盐/碳酸盐、柠檬酸盐、葡萄糖酸盐、乳糖酸盐、磷酸盐、丙酸盐和TRIS(氨丁三醇)缓冲液。氨丁三醇和硼酸盐缓冲液是优选的缓冲液。所添加缓冲物质的量,例如是确保和维持生理耐受pH范围所需要的量。该pH范围通常为5-9,优选为6-8.2,更优选为6.8-8.1。
渗透促进剂(tonicityenhancingagent)例如是离子化合物,如碱金属或碱土金属的卤化物,例如是CaCl2、KBr、KCl、LiCl、NaBr、NaCl或硼酸。非离子渗透促进剂例如是尿素、丙三醇、山梨醇、甘露醇、丙二醇或葡萄糖右旋糖。例如添加足够的渗透促进剂制成即用的眼用组合物,其渗透压大约是50-1000mOsmol,优选的是100-400mOsmol,更优选的是200-400mOsmol,再更优选的是280-350mOsmol。
防腐剂的实例是季铵盐,例如西曲溴铵、苯扎氯铵、苯佐氯铵、硫代水杨酸的烷基汞盐,例如硫柳汞、硝酸苯汞、醋酸苯汞或硼酸苯汞;对羟苯甲酸酯类,例如对羟苯甲酸甲酯或对羟苯甲酸丙酯;醇类如氯丁醇、苯甲醇或苯乙醇;胍衍生物,如氯己啶或聚六亚甲基双胍,或者山梨酸。优选的防腐剂是西曲溴铵、苯扎氯铵、苯佐氯铵和对羟苯甲酸酯类。适当地向眼用组合物中添加足量防腐剂以确保防止使用中由细菌和真菌造成的二次污染。
根据具体实施方式,该眼用组合物可进一步包括无毒赋形剂,例如乳化剂、湿润剂或填充剂,比如聚乙二醇200、300、400和600,或者Carbowax1000、1500、4000、6000和10000。如果需要,其他可以使用的赋形剂列表如下,但它们不以任何方式用于限制可用赋形剂的范围。它们尤其是络合剂,如EDTA二钠或EDTA;抗氧化剂,如抗坏血酸、乙酰半胱氨酸、半胱氨酸、亚硫酸氢钠、丁基羟基茴香醚、丁基羟基甲苯或α-生育酚醋酸酯;稳定剂,如环糊精、硫脲、硫代山梨醇、琥珀酸二辛酯磺酸钠或单硫代甘油;或其他赋形剂,如月桂酸山梨醇酯、三乙醇胺油酸酯或棕榈酸酯。优选的赋形剂是络合剂,例如EDTA二钠,以及稳定剂,如环糊精。所添加赋形剂的量和类型要根据特定的需求并且通常在大约0.0001至大约90wt%的范围内。环糊精含有多个葡萄糖单位,其中每个葡萄糖都含有3个游离羟基。具体实施方式中使用的环糊精的量优选是0.01-20wt%,更优选是0.1-15wt%,再更优选是1-10wt%。
根据具体实施方式,本发明也涉及眼用组合物,其包括治疗有效量的本文中所描述的肽试剂、载体、增溶剂和其他治疗有效的药学试剂,这些药学试剂可以是,例如抗生素、抗过敏药、麻醉剂、其他的消炎剂、皮质类固醇、适用于降低眼内压(IOP)的试剂、或其他药物。
pH(氢离子浓度)
根据具体实施方式,本发明制剂的pH应当尽可能接近泪膜的pH。眼泪的生理pH大约是7.4±0.2。这样,出于对舒适、耐受力和安全的考虑,这是最佳的眼用制剂的pH。
刺激眼泪分泌和眨眼会导致pH值降低。当眼睑张开过长时间,泪膜会与周围空气中的CO2分压相平衡而被碱化,pH值会大于9。pH降低和升高都不会有不良后果。因此,当表述发明的制剂在大约pH7.4时,该pH有一定的变动范围。
而且,当对眼睛施用制剂时,其刺激流出眼泪。流泪能够快速稀释和缓冲少量的添加物质,说明眼睛能够耐受特定制剂造成的相对宽的pH范围。
因此,眼用制剂的pH值可以在大约3.5-11.5的范围内。然而,眼用制剂可以显示出更窄的3.5-9的pH范围,优选的是4.5-8,最优选的是55.-7.8。最优选的pH范围得益于本发明组合物的预期溶解度、化学稳定性和治疗活性,并且该范围是对阻止角膜损害有用的、相对窄的范围。
缓冲系统
根据具体实施方式,缓冲系统由弱酸或弱碱及其共轭盐组成。系统中成分所具有的缓冲能力,使得无论添加酸或碱以及受温度、压力、体积、氧化还原势、体液和眼泪的外部影响,pH将维持基本恒定。尽管缓冲能力应足够大以抵抗在合理的保存期(即在储存条件下)内产品pH的变化(即pH漂移),但本发明眼用制剂的缓冲能力即使低也足以能在眼部施用时,即能快速地再调整产品到生理pH。根据具体实施方式,眼用产品的缓冲能力应当在0.05-1.0范围内,对特定发明组合物优选的和最优选的缓冲能力分别在0.02-0.2和0.01-0.1的范围内。缓冲能力通过以下公式确定:
*β=ΔB/ΔpH
其中β是缓冲能力,ΔB是强酸/强碱改变1升缓冲溶液的pH所相当的克数,ΔpH是添加强酸/强碱所造成的pH变化量。
根据具体实施方式,合适的缓冲系统可以是以下酸的钠盐:醋酸、抗坏血酸、硼酸、碳酸、磷酸、柠檬酸、葡萄糖酸、乳酸和丙酸。碳酸或丙酸的钙盐以及磷酸的钾盐都可形成合适的缓冲系统。Tris缓冲液(氨丁三醇)作为矫正代谢酸毒症的碱化剂在静脉中使用,其也是用于本发明的优选缓冲剂之一。其他优选的缓冲剂是醋酸盐、磷酸盐、柠檬酸盐和硼酸盐。在特定实例中,包括蛋白质的氨基酸残基的质子供体和质子受体的缓冲系统比酸-碱或氨-碱缓冲剂更优选。
缓冲物质的具体用量会变化并依赖于维持适于本发明组合物稳定性的pH环境并确保和维持生理可耐受pH范围所必须的量。
高渗剂(tonicityagent)
本文中所列的高渗剂,其目的是针对天然眼泪调节本发明眼用组合物的渗透压大约至生理渗透压(例如0.9%盐水)。例如,可向本发明肽试剂制剂中添加氯化钠、氯化钾、氯化钙、葡萄糖右旋糖和/或甘露醇。高渗剂的量会变化,并依赖于所要加入的具体试剂。大体上,特定的发明组合物含有的高渗剂的量足以使最终的组合物具有眼用可接受的渗透压,渗透压优选的是150-450mOsm,最优选的是250-350mOsm。
优选的高渗剂是钠盐和钾盐,尤其是氯化钠和氯化钾。最优选的高渗剂是氯化钠。
润滑剂/润湿剂/粘度增强剂
根据具体实施方式,本发明包括如下化合物,其中该化合物能够使眼睛润滑,降低其他疏水上皮角膜表面的表面张力和提高其湿润度(接触),与眼泪具有大致的一致性。这样的化合物也可增强本发明组合物的粘度,使得本发明的制剂在眼睛内停留时间更长从而使肽试剂有更多的时间发挥其治疗活性或被吸收而达到所需的靶点。
眼用制剂中合适的粘度增强剂和其在本发明的某些组合物中的浓度范围包括但不局限于:(a)单体多元醇,例如泰洛沙泊(tyloxapol)(0.1-1%)、丙三醇(0.2-1%)、丙二醇(0.2-1%)、乙二醇(0.2-1%);(b)聚合多元醇,例如聚乙二醇(例如PEG300和PEG400)(0.2-1%);(c)纤维素衍生物(纤维素家族的多聚体),例如羟乙基纤维素(0.2-2.5%)、羟丙甲纤维素(0.2-2.5%)、羟丙基甲基纤维素(0.2-2.5%)、甲基纤维素(0.2-2.5%)、羧甲基纤维素钠(0.2-2.5%)、羟丙基纤维素(0.2-2.5%);(d)葡聚糖,例如葡聚糖70(当与另一个润湿剂一起使用时,其是0.1%);(e)水溶性蛋白,例如明胶(0.01%);(f)乙烯基聚合物,例如聚乙烯醇(0.1-4%)、聚乙烯吡咯烷酮(0.1-4%);(g)其他多元醇,例如聚山梨醇酯80(0.2-1%)、聚乙烯吡咯酮(0.1-2%);(h)卡波姆,例如卡波姆934P、卡波姆941、卡波姆940和卡波姆974P;以及(i)多糖/糖胺聚糖,例如透明质酸(透明质酸/透明质酸盐)(0.1-3%)、硫酸软骨素(0.1-3%)。
可向本发明组合物中添加多于一种粘度增强剂来提高载体的粘度。本发明肽试剂制剂的载体中的优选增强剂是羧甲基纤维素。
粘度
粘度描述了物质在施压后,抵抗流动或形状改变的内力。物质(溶液、半粘性凝胶,悬浮液、油脂软膏和软凝胶(粘性凝胶))的粘性以单位泊表示。单位厘泊(“cp”或其复数形式“cps”)等于0.01泊并且经常在药学应用领域使用。用来增强粘度的化合物有多种级别,如15cps、100cps等。该级别数是指固定百分比液体溶液的增强剂制成后产生的粘度。通常,溶液是1%或2%;然而在特定增强剂内溶液可以高到4%。在20或25℃测量粘度。
眼用溶液的合适粘度在25至50厘泊(cps)之间。为产生所需粘度而需要的增强剂的实际浓度依赖于增强剂的级别。例如,如果使用甲基纤维素25cps,那么1%的溶液将产生25cps的粘度。如果使用甲基纤维素4000cps,那么0.25%的溶液可提供所需的粘度。标准参照给出了百分比溶液和组分级别所产生的粘度的列表。
根据具体实施方式,本发明制剂也表现出大于1至100,000厘泊(cps)或更高的粘度。本发明的软膏组合物(油脂凝胶或粘性凝胶)可具有大于100,000cps的粘度级别。这是因为眼用软膏需要粘稠一些,这样才能阻止其从需要施用的区域流走。在应用后随时间的推移,这些软膏附着处的结膜囊内或眼睛表面的温度会导致这些软膏“熔化”并开始流动。
多种本发明制剂类型的优选粘度范围见下表:
制剂类型粘度范围(cps)
水溶液 | >1至<1000 |
悬浮液 | >1至<1000 |
凝胶 | >3至40,000 |
软膏,凝胶 | >20,000至100,000 |
软膏,油脂性 | >20,000至100,000 |
还原剂/抗氧化剂/氧隔离剂
本发明的某些组合物具有被氧化降解的可能。因此,制作过程中,操作和包装本发明组合物可包括:通过(1)用氮气或高浓度惰性气体如氩替换氧,(2)添加还原剂以使氧化作用最小化,(3)加入诱饵分子保护本发明的化合物免受氧化作用的影响。
可用于眼用制剂的常见抗氧化(还原)剂的浓度可达0.1%或更高,它们是硫酸钠、硫代亚硫酸钠、亚硫酸氢钠、偏亚硫酸氢钠和硫脲。亚硫酸盐可引起一些人的过敏反应;因此,在用含此抗氧化剂的本发明组合物治疗前应当询问服用此类抗氧化剂的患者关于此类可能反应的问题。其他适用于本发明组合物的可用抗氧化剂是抗坏血酸、EDTA/乙二胺四乙酸二钠、醋酸、柠檬酸、谷胱甘肽和乙酰半胱氨酸。这些试剂也被视为稳定剂。
诱饵分子或氧隔离保护试剂可作为稳定剂添加到本发明制剂中以最小化对本发明制剂的氧化作用。分子诱饵必须具有至少与本发明制剂相同的被氧化能力。对于含甲硫氨酸的本发明制剂,这样的诱饵就是甲硫氨酸本身。在含甲硫氨酸的本发明试剂中所添加的游离甲硫氨酸会在被氧化成甲硫氨酰的过程中竞争氧。游离氧消耗剂是阻止本发明组合物/肽中的氧活性氨基酸被氧化的试剂。为实现特定的发明组合物的目的,并不局限于游离氧消耗剂是甲硫氨酸。
眼用软膏/油脂软化基质
眼用软膏易于使活性试剂与眼睛接触的时间长于悬浮液,当然也比溶液的时间长。多数软膏由于不易被流泪去除,所以趋于使视觉模糊。这样,软膏通常在晚上使用作为日用滴眼液的辅助治疗。
本发明组合物的油脂软膏基质是矿物油、凡士林和羊毛脂的混合物,它们都具有和体温相近的熔点。对本发明的化合物下,该组合物可包括矿物油、凡士林或羊毛脂。根据具体实施方式,优选的组合物包括凡士林、矿物油和羊毛脂的组合。最优选的组合物是含白凡士林、矿物油和羊毛脂(无水)的软膏组合物。
含氨基酸序列LKKTET或LKKTNT或其保守变异体的肽试剂溶解在少量的纯水或0.9%的盐水以影响溶出度。此水溶液加入到无水羊毛脂中,然后这样的“水”羊毛脂(至多10%)与其余的软膏/油脂软化基质组分,矿物油(至多30%)和白凡士林(至多60%)相混合。
眼用软膏管通常少量地含有大约1-5克的软膏,优选的是3.5克,并配有细头,该细头可挤出英寸计细条的软膏或其小段,以用于对药剂进行定量。
防腐剂
无菌是所有眼用制剂的绝对要求。污染的制剂会导致眼睛感染,从而最终导致失明,尤其是,如果含有铜绿假单胞菌微生物(P.aeruginosa),情况则更是如此。因此,本文中描述的眼用制剂必须使用确保本发明组合物的溶液、凝胶、悬浮液和软膏无菌的技术。无菌制剂必须包装在无菌容器里。多数外用眼用产品通常以多剂量形式包装。因此,需要防腐剂来阻止使用过程中无菌产品的微生物污染。合适的防腐剂包括:季铵化合物(盐),如苯扎氯铵(0.001-0.02%)、氯苄乙铵、西他氯铵、西曲溴铵、苯度溴铵和苯佐氯铵;硫代水杨酸的烷基汞盐,例如硫柳汞(0.001-0.005%);对羟基苯甲酸酯类,例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯;螯合剂,如乙二胺四乙酸二钠、葡萄糖酸钠、丙酸钠;其他试剂,例如三氯叔丁醇、硼酸、山梨酸、苯乙醇(0.25%);二氧化氯;polyquatemium-1(0.001%)和肉豆蔻酰胺丙基二乙胺(myristamidopropyldiethylamine)(0.005%)或其他本领域技术人员已知的试剂。
这些防腐剂通常以0.001%-0.1%(w/v)的水平使用以确保防止使用中由细菌、霉菌和真菌造成的二次微生物污染。
以下所选的现已证明可在眼用制剂中使用的防腐剂的最大浓度见下表:
来源:FDA顾问团的OTC眼用药物产品,最终报告,1979年12月
合适防腐剂的选择是基于其对所选发明组合物的抗微生物效率。用于本发明制剂的优选防腐剂是对羟基苯甲酸甲酯(0.080%-1%)和对羟基苯甲酸丙酯(0.016%-0.024%)的组合、苯扎氯铵(BAK)(0.005%-0.02%,其中0.01%w/v是最优选的)、BAK和EDTA(0.01-0.5%)的组合,它们在一起施用时有协同作用。
本发明的单位剂量组合物是无菌的但未防腐处理。这样的组合物多数不含防腐剂。因此,这些组合物不能反复使用,一旦打开必须丢弃。
填充/稳定剂
填充/稳定剂对在长时间储存期间维持本发明组合物中的润滑剂、软化剂或载体增强剂的水合状态是有益的。缔合似乎发生在这些物质的多聚链之内或之间,这些缔合随时间促成了这些链的水合状态的减少。这些缔合可以是多聚链之内或之间的氢键形式,其可以证明本发明的眼用制剂/组合物的粘度和质地的变化。冷冻干燥填充剂,主要是糖,也可以看作是压力保护剂,用来在冷冻周期内保护化合物。大幅减低或消除这种降低的水合状态的试剂是一类稳定或水合增强试剂,即,0.2-5wt%浓度的多元醇。这些多元醇的代表是甘露醇、山梨醇、丙三醇、蔗糖、相关的糖和类似物。最优选的稳定剂是吸水的甘露醇,其浓度在0.2-5wt%范围内。
另外,50mM氨基酸稳定剂,如丙氨酸(Ala)、赖氨酸(Lys)、甘氨酸(Gly)和谷氨酸(Glu),也加入到含序列LKKTET或LKKTNT或其保守变异体的制成肽制剂中以提高冷冻后从再生水溶液的恢复。优选的氨基酸稳定剂是精氨酸和甘氨酸,而最优选的50mM氨基酸是甘氨酸。
本发明肽的施用
实例性外用给药(用于表面作用效果)
为达到局部效果,将含序列LKKTET或LKKTNT或其保守变异体的肽制剂施用到眼睛表面,以治疗例如:
1.由,但不限于由化学灼伤、复发性角膜糜烂、手术中的上皮清创术、角膜表面重修手术、激光辅助原位角膜磨镶术(LASIK)造成的角膜上皮创伤;
2.由季铵盐(如BAK和类似物)造成的角膜上皮变薄;
3.眼部发炎(单独或与皮质类固醇激素一起使用),从而治疗例如,结膜炎、眼睑炎、角膜炎、眼色素层炎、巩膜炎、视网膜炎、视神经炎和颞动脉炎;
4.治疗微生物感染(单独,或者与抗细菌、抗真菌或抗病毒试剂一起或者与抗微生物及抗炎症试剂一起使用);
5.干眼综合症(眼球干燥症);
6.红眼(单独或者与眼睛解充血剂(结膜的肾上腺能血管收缩药),例如麻黄素、萘唑啉、苯肾上腺素、四氢萘咪唑啉和抗组胺药,例如马来酸非尼拉敏)一起使用来使眼睛变白);
7.眼内压(IOP)高和青光眼;以及
8.跌打损伤或外科手术之后的发炎或刺激状况,或多种眼部刺激紊乱中的发炎或刺激状况。
本发明外用肽试剂制成溶液、悬浮液、凝胶和软膏。本发明肽试剂制剂可以直接或间接的通过胶原海绵、插入或相似的方法来施用。包括外用眼药在内的每种眼用产品应当在其最终容器内是无菌的,以阻止对眼睛的微生物感染。当制剂包装在多剂量容器内用于多次使用时,为在容器打开后保持无菌,应向制剂中添加防腐剂。眼用制剂需要仔细的控制其pH、缓冲能力、粘度和渗透压。本文中描述了优选的pH范围、缓冲剂、粘度和渗透压。
实例性制剂:用于滴眼液的外用溶液
每毫升外用的本发明肽制剂包括含氨基酸序列LKKTET或LKKTNT或保守变异体的下述肽试剂:
肽的浓度范围是大约0.001-1,000mg/ml,优选的是大约0.01-600mg/ml,更优选的是大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle):20mM柠檬酸钠;50mM甘氨酸;3%蔗糖;用于调解pH的NaOH或HCI;USP纯化水。
实例性制剂:用于滴眼液的外用悬浮液
对于包括含氨基酸序列LKKTET或LKKTNT的肽试剂的眼用悬浮液,其颗粒必须小于10微米以最小化对眼睛的刺激。固体未溶解颗粒往往会粘附到结膜上。当药物被吸收后,这些颗粒会溶解从而补充被吸收了的药物。与溶液相比,这种蓄积或储存作用提高了悬浮液的接触时间和作用时长。
每毫升外用的本发明肽制剂包括含氨基酸序列LKKTET或LKKTNT或保守变异体的下述肽试剂:
肽的浓度范围是大约0.001-1,000mg/ml,优选的是大约0.01-600mg/ml,更优选的是大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle):聚(丙交酯-乙交酯)PLGA微球形式的肽包囊;20mM柠檬酸钠;50mM甘氨酸;3%蔗糖;用于调节pH的NaOH或HCI;USP纯化水。
实例性制剂:用于滴眼液的外用凝胶
每毫升外用的本发明肽制剂包括含氨基酸序列LKKTET或LKKTNT或保守变异体的下述肽试剂:
肽的浓度范围是大约0.001-1,000mg/ml,优选的是大约0.01-600mg/ml,更优选的是大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle):羧甲基纤维素钠(0.5-1%);磷酸二钠;氯化钠;丙二醇;对羟基苯甲酸甲酯;对羟基苯甲酸丙酯;用于调节pH的NaOH或HCI;USP纯化水。
实例性制剂:外用软膏
每毫升外用的本发明肽制剂包括含氨基酸序列LKKTET或LKKTNT或保守变异体的下述肽试剂:
肽的浓度范围是大约0.001-1,000mg/ml,优选的是大约0.01-600mg/ml,更优选的是大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle)(1):羧甲基纤维素钠(2.5%);磷酸二钠;丙二醇;对羟基苯甲酸甲酯;对羟基苯甲酸丙酯;氯化钠;用于调节pH的NaOH或HCI;USP纯化水。
优选的载体(carrier/vehicle)(2):“水”羊毛脂(10%);矿物油(30%)和白凡士林(60%)。
节约类固醇作用的实例性外用给药
皮质类固醇抑制了对多种刺激性试剂的抗炎症反应。
●地塞米松眼用悬浮剂(0.1%);地塞米松眼用软膏(0.05%);和地塞米松磷酸钠眼用溶液(0.1%)
●氟米龙眼用软膏(0.1%);氟米龙眼用悬浮液(0.25-1%);和氟米龙醋酸盐眼用悬浮液(0.1%)
●氯替泼诺(0.5%)
●甲羟松眼用悬浮液(1%)
●醋酸强的松龙眼用悬浮液(0.12-1%)和强的松龙磷酸钠眼用溶液(0.125-1%)
●利美索龙眼用悬浮液(1%)
然而,这些试剂可以提高眼内压(IOP),可以诱导易感个体的青光眼从而损伤视神经、使视觉准确度和视野受损、形成后囊下白内障。白内障的形成更似乎是与高剂量、长时间使用相伴的并发症。一些皮质类固醇,例如醋酸氟米龙、甲羟松和氯替泼诺比其他皮质类固醇引起较小的IOP升高。长期使用也会抑制宿主的免疫反应从而帮助了从眼组织释放的真菌和病毒形成二次眼部感染。已知外用皮质类固醇延缓或减慢创伤的愈合。
施用包括含氨基酸序列LKKTET或LKKTNT或保守变异体的本发明肽试剂的外用滴眼液或软膏来抑制对刺激试剂的炎症反应具有节约类固醇的潜能。
实例性眼内给药-结膜/巩膜滴注
外用结膜进入途径在药物渗透入眼前节中起到重要作用。而且,已发现外用药物从结膜进入巩膜。通过巩膜转运或扩散的可能性依赖于该组织大而且可透过的表面区域、以及其不随年龄显著降低的高水合性、高度细胞过少和高通透性。因此,可以想到本发明的组合物可以通过此非侵入给药途径找到到达眼前节的通路。数据说明巩膜甚至对大分子量的化合物(~150kD)也是易于穿透的,这远大于含氨基酸序列LKKTET或LKKTNT或其保守变异体的肽试剂。最新的发现:外用奈帕芬胺通过降低VEGF的产生来抑制脉络膜和视网膜的新生血管形成,大分子量肽如胰岛素(5.8kD)能在外用给药后在视网膜和视神经处积累,这说明外用本发明的组合物,其分子量都<150kD,不仅能穿过结膜到到眼前节,而且它们也具有治疗作用。在上文中描述的含氨基酸序列LKKTET或LKKTNT或保守变异体的肽试剂的外用溶液、悬浮液、凝胶或软膏是外用于结膜和巩膜的合适制剂。
另外,通过注射含氨基酸序列LKKTET或LKKTNT或其保守变异体的肽试剂的本发明组合物来进行结膜下施用可用于递送抗炎症和抗微生物疗法(并对本发明的化合物是敏感的),可用于治疗严重的眼部炎症和眼部感染,例如葡萄膜炎、眼内炎和青光眼。
优选的可注射制剂:每ml含氨基酸序列LKKTET或LKKTNT或保守变异体的肽试剂包含:
肽的浓度范围在大约0.001-1,000mg/ml,优选的在大约0.01-600mg/ml,更优选的在大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle):20mM柠檬酸钠;50mM甘氨酸;3%蔗糖;用于调节pH的NaOH或HCI;USP纯化水。
实例性眼内给药-透角膜滴注
外用药物通过疏水角膜渗透入眼内环境;然而,透角膜转运不是最有效的方式,原因是其只使十分之一到十分之三的剂量渗透入眼睛而大多数药物残留在上皮层的表面。本发明肽组合物通过角膜的被动扩散在很大程度上受它们的溶解度、分子量和离子化程度的影响。制成外用药物的本发明的肽试剂由于具有净负电和相对高的分子量,从而很难穿透完整的角膜。位于角膜上皮细胞之间的孔隙只允许约500分子量或更小的小分子细胞旁路穿过的事实支持这一观点。然而,当完整角膜被腐蚀所破坏时,例如或是暴露于能打开上皮细胞间紧密连接的某种物质或穿透试剂,本发明的组合物可以更有效的穿过角膜进入眼内空间。
如上文所述的含氨基酸序列LKKTET或LKKTNT或保守变异体的肽试剂的外用溶液、凝胶或软膏是透角膜滴注的合适制剂。
实例性眼内给药-眼周注射
在眼部炎症不应答单独的外用滴眼液以及在炎症状况如前葡萄膜炎、后葡萄膜炎、眼内炎和视神经炎情况下,使用本发明肽试剂的眼周注射制剂。该肽试剂注射入结膜下或者筋膜囊(Tenon’scapsule)下的空间。从而,吸收会更多,结果是所期望靶点有更多的药物。眼周注射是外用治疗的补充,但其不方便且不适用于首选治疗。
优选的可注射制剂:每ml含氨基酸序列LKKTET或LKKTNT或保守变异体的肽试剂包含:
肽的浓度范围是大约0.001-1,000mg/ml,优选的是大约0.01-600mg/ml,更优选的是大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle):20mM柠檬酸钠;50mM甘氨酸;3%蔗糖;用于调节pH的NaOH或HCI;USP纯化水。
实例性眼内给药-玻璃体内/房水内(IntraAqueous)施用
作为透角膜、透结膜和透巩膜转运的替代,本发明肽试剂的送入眼内组织可通过注射入玻璃体或房水腔内实现。玻璃体是由水凝胶(水、透明质酸和胶原)构成,其填充了视网膜和晶状体之间的腔,而房水是填充晶状体和虹膜之间腔的水性流体。将制成溶液的本发明肽试剂注射到玻璃体和房水内可使眼内组织迅速暴露于肽试剂。试剂会快速从玻璃体中清除掉,所以为实现本发明试剂在眼内持续存在,就需要重复注射,而重复注射提高了患眼内炎、损害晶状体以及造成视网膜脱落的风险,并且难以忍受。为克服这一障碍,本发明的肽试剂可以包裹到磷脂膜内,即脂质体、生物可降解微球、纳米颗粒或生物可降解内酯为基质的多聚体,其包括由L-丙交酯、乙交酯、己内酯、二氧杂环己酮、环状碳酸酯和它们的衍生物缩聚而制成的聚酯。聚交酯和聚乙交酯,也分别称为聚(乳酸)PLA和聚(乙醇酸)PGA,尤其是它们的共聚物聚乳酸/乙醇酸共聚物PLGA是研究最多的生物可降解多聚体,其也可用作本发明肽试剂的载体。另外,肽-聚合物的结合物如含LKKTET或LKKTNT或其变异体的肽试剂与合成及天然多聚物如聚乙二醇(PEG)和葡聚糖(包括环葡聚糖)的共价连接,可改善药代动力学模式,从而导致降低了对本发明肽的清除。
玻璃体内或房水内施用本发明的肽试剂可以在眼部炎症、眼部感染(细菌、真菌或病毒的)以及青光眼的治疗中,通过控制流出通路细胞中F-肌动蛋白的构建而展现(ReadATetal.,ExpEyeRes,2006Jun:82(6):974-85)。
优选的可注射制剂:每ml含氨基酸序列LKKTET或LKKTNT或保守变异体的肽试剂包含:
肽的浓度范围是大约0.001-1,000mg/ml,优选的是大约0.01-600mg/ml,更优选的是大约0.1-60mg/ml,最优选的肽浓度是大约1-6mg/ml。
优选的载体(carrier/vehicle):1):20mM柠檬酸钠;50mM甘氨酸;3%蔗糖;用于调节pH的NaOH或HCI;USP纯化水。
优选的载体(carrier/vehicle)(2):PLGA微球形式的肽包囊;20mM柠檬酸钠;50mM甘氨酸;3%蔗糖;用于调节pH的NaOH或HCI;USP纯化水。。
实例性制剂剂量
外用溶液和悬浮液
建议每次施用一滴并至少间隔5分钟再次施用。向眼睛中滴注一滴后立即压迫泪囊1-2分钟以减少通过此通路的药物流失速度。可注射剂量:使用27-30规格的针,0.5英寸长度。
根据具体实施方式的组合物可以是冻干形式,或者能够被冻干的形式,其包括含氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂,或者包括刺激LKKTET或LKKTNT肽、或其保守变异体产生的刺激试剂,该组合物进一步包括至少一种氨基酸稳定剂。该组合物可包括含氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂,或者包括刺激LKKTET或LKKTNT肽、或其保守变异体产生的刺激试剂,以及冻干填充剂或氨基酸稳定剂中至少一种,所述组合物处于冻干形式。该组合物进一步包括酸性或碱性pH调节剂中的一种,该pH调剂能够在含水介质内调节组合物的pH到所需的生理可接受pH水平,以及在所述含水介质内基本稳定上述所需pH的缓冲剂。氨基酸稳定剂可包括丙氨酸、赖氨酸、甘氨酸或谷氨酸中的至少一种。氨基酸稳定剂可包括至少一种50mM的氨基酸稳定剂。氨基酸稳定剂可包括50mM甘氨酸。该组合物可进一步包括填充试剂,该填充试剂包括碳水化合物、糖醇、单糖、二糖、多糖、多元醇、甘露醇、山梨醇、丙三醇、蔗糖或葡萄糖右旋糖中的至少一种。pH调节剂可包括NaOH或HCl中的至少一种。缓冲剂可包括醋酸、抗坏血酸、硼酸、碳酸、磷酸、柠檬酸、葡萄糖酸、乳酸或丙酸中至少一种的钠盐,碳酸或丙酸的钙盐,磷酸钾盐,Tris缓冲液,醋酸,磷酸,柠檬酸盐或硼酸盐缓冲液中的至少一种。缓冲剂可以是柠檬酸钠。缓冲剂的缓冲能力是大约0.05-1.0。缓冲剂的缓冲能力是大约0.02-0.2,或大约0.01-0.1。所需的pH水平的范围可以是大约3.5-11.5,大约3.5-9,大约4.5-8,或大约5.0-7.8。所需pH水平可以是大约5.5。肽试剂包括氨基酸序列KLKKTET、氨基酸序列LKKTETQ、Tβ4、Tβ4的N-末端变异体、Tβ4的C-末端变异体、或Tβ4的异构体。组合物可进一步包括含水介质,其中所述的肽试剂在所述含水介质内的浓度范围是大约0.001-1,000mg/ml。组合物可进一步包括至少一种类固醇。
根据另一具体实施方式的组合物用于对受试者皮肤组织施用,并包括含氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂,或者包括在所述组织内刺激LKKTET或LKKTNT肽、或其保守变异体产生的刺激试剂,该组合物进一步包括季铵盐和应用于所述受试者的皮肤组织的外用载体。该肽试剂可包括氨基酸序列LKKTET、氨基酸序列LKKTETQ、Tβ4、Tβ4的N-末端变异体或Tβ4的异构体。季铵盐可包括苯扎氯铵。肽试剂的浓度可以是大于0.001-1,000mg/ml,所述季铵盐在所述组合物内大约是0.001-1wt%。该组合物可以是溶液、凝胶、乳膏、糊剂、洗剂、喷雾剂、悬浮液、分散液、油膏,水凝胶、软膏或泡沫制剂的形式。该组合物可以是化妆品制剂。
根据另一个具体实施方式的药学或化妆品的组合,其包括含氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂,或者包括刺激LKKTET或LKKTNT肽、或其保守变异体产生的刺激试剂,该组合物进一步包括季铵盐,其中所述试剂和所述盐可分别或一起对受试者施用。该肽试剂可包括氨基酸序列LKKTET、氨基酸序列LKKTETQ、Tβ4、Tβ4的N-末端变异体或Tβ4的异构体。季铵盐可包括苯扎氯铵。该组合可包括药学、眼用或化妆品组合物,其所含肽试剂的浓度可以是大于0.001-1,000mg/ml,其中所述季铵盐在所述组合物内大约是0.001-1wt%。该组合可包括眼用组合物,该眼用组合物进一步包括可眼用载体。该组合物可包括滴眼液组合物。
根据另一个具体实施方式,治疗、阻止、抑制或降低组织由于对受试者施用季铵盐所造成的衰退、受损或损害的处理方法包括对所述受体施用所述季铵盐以及对所述受试者施用含氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂、或者在所述组织内刺激LKKTET或LKKTNT肽或其保守变异体产生的刺激试剂。该试剂可在所述季铵盐施用之前、同时或之后对受试者施用。该试剂和所述盐可作为组合物同时施用。该组合物可进一步包括可眼用载体。该组合物可包括滴眼液组合物。该组合物可包括化妆品可接受的载体。该组合物可以是溶液、凝胶、乳膏、糊剂、洗剂、喷雾剂、悬浮液、分散液、油膏,水凝胶、软膏或泡沫制剂的形式。肽试剂可包括氨基酸序列KLKKTET、氨基酸序列LKKTETQ、Tβ4、Tβ4的N-末端变异体、Tβ4的C-末端变异体或Tβ4的异构体。季铵盐可包括苯扎氯铵。包括在所述组合物中的肽试剂的浓度可以是大约0.001-1,000mg/ml,所述季铵盐在所述组合物内大约是0.001-1wt%。
根据另一个具体实施方式的组合物,其包括含氨基酸序列LKKTET或LKKTNT或其变异体的肽试剂、或者刺激LKKTET或LKKTNT肽或其保守变异体产生的刺激试剂、以及可眼用载体、抗微生物作用的防腐剂、为所述组合物提供眼睛可接受渗透压的高渗剂、舒适增强剂、能够调节组合物pH到所需眼用可接受pH水平的酸性或碱性pH调节剂中的至少一种、以及基本维持上述所需pH水平的缓冲剂。该组合物可进一步包括抗氧化剂或氧隔离试剂中的一种。抗氧化剂或氧隔离试剂可包括亚硫酸钠、硫代亚硫酸钠、亚硫酸氢钠、焦亚硫酸氢钠、硫脲、抗坏血酸、EDTA/乙二胺四乙酸二钠、醋酸、柠檬酸、谷胱甘肽、乙酰半胱氨酸或甲硫氨酸。抗氧化剂或氧隔离试剂在所述组合物内的浓度范围是大约0.0001-1.0wt%。抗微生物作用的防腐剂可包括以下中的一种:季铵化合物:苯扎氯铵、氯苄乙铵、西他氯铵、西曲溴铵、苯度溴铵、苯佐氯铵;硫代水杨酸的烷基汞盐:硫柳汞、硝酸苯汞、醋酸苯汞、硼酸苯汞;对羟基苯甲酸酯类:对羟基苯甲酸甲酯、对羟基苯甲酸丙酯;螯合剂、乙二胺四乙酸二钠、葡萄糖酸钠、丙酸钠;醇类、三氯叔丁醇、苯甲醇、苯乙醇;胍衍生物:氯己啶(chlorohexidine)、聚亚己基缩二胍(polyhexamethylenebiguanide)、山梨酸、硼酸、二氧化氯、聚咪唑啉季铵盐(polyquatemium)或肉豆蔻酰胺丙基二乙胺(myristamidopropyldiethylamine)。防腐剂在所述组合物内的浓度范围是大约0.0001-5.0%(w/v)。该组合物可进一步包括至少一种眼用可接受稳定剂。稳定剂可包括多元醇、甘露醇、山梨醇、丙三醇、蔗糖、氨基酸稳定剂丙氨酸(Ala)、赖氨酸(Lys)、或谷氨酸(Glu)中的至少一种。稳定剂在所述组合物中的浓度范围是大约0.01-10wt%。高渗剂包括离子化合物、碱金属卤代物、碱土金属卤代物、CaCl2、KBr、KCl、LiCl、NaBr、NaCl、硼酸、非离子化合物、尿素、丙三醇、山梨醇、甘露醇、丙二醇或葡萄糖右旋糖中的至少一种。该组合物的渗透压的范围可以是50-1000mOsmol。调节剂可包括NaOH或HCl中的至少一种。缓冲剂可包括醋酸钠盐、抗坏血酸钠盐、硼酸钠盐、碳酸钠盐、磷酸钠盐、柠檬酸钠盐、葡萄糖酸钠盐、乳酸钠盐、丙酸钠盐、碳酸钙盐、丙酸钙盐、磷酸钾盐、Tris缓冲液、醋酸缓冲液、磷酸缓冲液、柠檬酸盐缓冲液或硼酸盐缓冲液中的至少一种。所需的pH水平的范围是大约3.5-11.5。缓冲剂具有的缓冲能力是大约0.05-1.0。肽试剂可包括氨基酸序列KLKKTET、氨基酸序列LKKTETQ、Tβ4、Tβ4的N-末端变异体、Tβ4的C-末端变异体或Tβ4的异构体。该化合物进一步包括水介质,其中所述的肽试剂在所述含水介质中的浓度范围是0.001-1,000mg/ml。该组合物可以是溶液、凝胶、乳膏、糊剂、洗剂、喷雾剂、悬浮液、分散液、油膏,水凝胶、软膏或泡沫制剂的形式。该组合物可包括滴眼液组合物。肽试剂可在所述组合物中,组合物被磷脂膜、脂质体、微球、纳米颗粒或生物可降解多聚体中的至少一种所包裹,或者以肽-聚合物的结合物形式存在。
实施例
胸腺素β4(Tβ4),是一个含43个氨基酸的分子,其促进了眼部创伤的愈合,降低了眼部炎症,并对角膜上皮具有抗细胞凋亡作用。在本研究中,检测了Tβ4对暴露于苯扎氯铵(BAK)的培养人角膜上皮细胞的存活的作用。
大约80%汇合的人角膜上皮细胞在用0%、0.001%、0.01%或0.1%的BAK处理15分钟。在培养基内恢复3和24小时后,使用比色BrdU渗入分析来检测细胞增值。使用比色膜联蛋白为基础的细胞死亡分析来检测细胞凋亡。在1mcg/mlTβ4中重复实验,该剂量在几个已发表的研究中显示有效。为进一步评估Tβ4阻止细胞凋亡的能力,角膜上皮细胞用0.01%BAK±Tβ4处理超过5天。
在所有使用过的BAK浓度下,与对照相比,角膜上皮细胞在3和24小时的恢复时间的增殖被抑制了,细胞凋亡被提高了。在3和24小时的时间点,Tβ4没有消除BAK的有害作用;Tβ4也没有促进细胞增殖并且细胞凋亡没有被抑制。然而,在更长的培养时间(2-5天)时,Tβ4处理显著抑制了BAK诱导的上皮细胞凋亡。另外,与只在培养基内培养5天的细胞相比,Tβ4处理的细胞的细胞凋亡降低了。
BAK是在许多市售眼用溶液中使用的防腐剂,其在培养中诱导了上皮细胞的凋亡,说明长时间的暴露对角膜健康是有害的。本文报道的研究说明Tβ4能够克服BAK的有害细胞凋亡前作用。因为许多含BAK的滴眼液通常在很长一段时间内使用,所以Tβ4是含此种防腐剂的溶液的有用添加剂。
Claims (10)
1.肽试剂在制备用于治疗受试者青光眼或干眼综合症的药物中的应用,其中所述药物被配制成具有pH6.8-8.1的眼用可接受的组合物,其中所述肽试剂包括氨基酸序列LKKTET或其保守变异体,LKKTNT或其保守变异体、KLKKTET、LKKTETQ或胸腺素β4(Tβ4),并且其中所述药物含有浓度约0.001mg/mL~约1000mg/mL的所述肽试剂,并且所述组合物适合每日施用两次或更多次。
2.根据权利要求1所述的应用,其中所述肽试剂包含氨基酸序列LKKTET或其保守变异体、LKKTNT或其保守变异体。
3.根据权利要求1所述的应用,其中所述肽试剂包含氨基酸序列KLKKTET、氨基酸序列LKKTETQ、Tβ4。
4.根据权利要求1所述的应用,其中所述肽试剂是Tβ4。
5.根据权利要求1所述的应用,其还进一步包括药学可接受的载体,其为溶液、悬浮液、凝胶、软膏、局部插入物,或在脂质体、微球、纳米颗粒或生物可降解内酯为基质的多聚体中的包裹体。
6.根据权利要求1所述的应用,其中所述组合物包括含水介质。
7.根据权利要求1所述的应用,其中所述肽试剂的浓度范围是大约0.01mg/mL-600mg/mL。
8.根据权利要求1所述的应用,其中所述肽试剂的浓度范围是大约0.1mg/mL-60mg/mL。
9.根据权利要求1所述的应用,其中所述肽试剂的浓度范围是大约1mg/mL-6mg/mL。
10.根据权利要求1所述的应用,其用于治疗干眼综合征,其中所述肽试剂是Tβ4。
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CN201510532998.4A Pending CN105106931A (zh) | 2005-06-17 | 2006-06-19 | 冻干的或可冻干形式的lkktet和/或lkktnt肽组合物 |
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US (8) | US20090131313A1 (zh) |
EP (4) | EP3326647A1 (zh) |
JP (3) | JP2008543877A (zh) |
KR (3) | KR20080021782A (zh) |
CN (1) | CN105106931A (zh) |
AU (3) | AU2006261156B2 (zh) |
CA (3) | CA2612522A1 (zh) |
HK (1) | HK1218248A1 (zh) |
IL (4) | IL187522A0 (zh) |
MX (3) | MX2007015957A (zh) |
WO (3) | WO2006138707A1 (zh) |
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CN110430866A (zh) * | 2017-03-03 | 2019-11-08 | Gtreebnt科技有限公司 | 含有胸腺素β-4作为有效成分的稳定外用剂 |
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EP3117210A4 (en) | 2014-03-12 | 2017-11-01 | University Of Virginia Patent Foundation | Compositions and methods for treating eye infections and disease |
AU2015336396B2 (en) | 2014-10-22 | 2020-12-10 | HLB Therapeutics Co., Ltd. | Composition containing thymosin beta 4, and pharmaceutical formulation comprising same |
KR20170021667A (ko) | 2015-08-18 | 2017-02-28 | 주식회사 지트리비앤티 | 티모신 β4를 유효성분으로 포함하는 신경영양성각막염 치료용 조성물 |
US9867868B2 (en) | 2015-08-18 | 2018-01-16 | G-Treebnt Co., Ltd. | Pharmaceutical composition for treating or preventing corneal wound comprising thymosin β4 and citric acid |
JP6996713B2 (ja) * | 2015-10-06 | 2022-02-04 | エイチエルビー・セラピューティクス・カンパニー・リミテッド | チモシンベータ4を含む眼科用製剤の製造方法 |
KR102115158B1 (ko) | 2016-11-29 | 2020-05-26 | 주식회사 지트리파마슈티컬 | 티모신 베타 4 를 함유하는 제형 |
EP3585412A4 (en) * | 2017-02-21 | 2020-12-09 | TearSolutions, Inc. | STABLE PEPTIDIC COMPOSITIONS |
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US10342824B2 (en) | 2017-07-17 | 2019-07-09 | Dr. Marlowe's Weight Loss Institute, P.L.L.C. | Supplement for treating side effects of medications which cause metabolic acidosis |
AU2018372396A1 (en) * | 2017-11-24 | 2020-06-25 | HLB Therapeutics Co., Ltd. | Composition for promoting goblet cell proliferation or mucin secretion comprising thymosin beta 4 or derivative thereof as active ingredient |
WO2024006653A2 (en) * | 2022-07-01 | 2024-01-04 | Tearsolutions, Inc. | Stable peptide compositions and methods of use thereof for treatment of moderate/severe dry eye-related ocular symptoms |
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- 2006-06-19 AU AU2006261156A patent/AU2006261156B2/en not_active Ceased
- 2006-06-19 AU AU2006261155A patent/AU2006261155A1/en not_active Abandoned
- 2006-06-19 EP EP06785092A patent/EP1906986A4/en not_active Ceased
- 2006-06-19 KR KR1020087000983A patent/KR20080021782A/ko not_active Application Discontinuation
- 2006-06-19 EP EP06785091A patent/EP1904080A4/en not_active Withdrawn
- 2006-06-19 KR KR1020087000980A patent/KR20080018268A/ko not_active Application Discontinuation
- 2006-06-19 CA CA002612522A patent/CA2612522A1/en not_active Abandoned
- 2006-06-19 CN CN201510532998.4A patent/CN105106931A/zh active Pending
- 2006-06-19 US US11/917,869 patent/US20090131313A1/en not_active Abandoned
- 2006-06-19 KR KR1020087000982A patent/KR20080033939A/ko not_active Application Discontinuation
- 2006-06-19 JP JP2008517206A patent/JP2008543877A/ja active Pending
- 2006-06-19 MX MX2007015957A patent/MX2007015957A/es active IP Right Grant
- 2006-06-19 US US11/917,848 patent/US8383576B2/en active Active
- 2006-06-19 CA CA002612410A patent/CA2612410A1/en not_active Abandoned
- 2006-06-19 EP EP06785093A patent/EP1896050A4/en not_active Withdrawn
- 2006-06-19 US US11/917,883 patent/US20080214456A1/en not_active Abandoned
- 2006-06-19 AU AU2006261157A patent/AU2006261157A1/en not_active Abandoned
- 2006-06-19 WO PCT/US2006/023758 patent/WO2006138707A1/en active Application Filing
- 2006-06-19 JP JP2008517207A patent/JP2008543878A/ja active Pending
- 2006-06-19 MX MX2007015956A patent/MX2007015956A/es not_active Application Discontinuation
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- 2006-06-19 MX MX2007015958A patent/MX2007015958A/es not_active Application Discontinuation
- 2006-06-19 WO PCT/US2006/023760 patent/WO2006138709A2/en active Application Filing
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2007
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2011
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2016
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---|---|---|---|---|
CN109789182A (zh) * | 2016-07-18 | 2019-05-21 | 雷根特里有限责任公司 | 治疗干眼综合征的方法 |
CN110430866A (zh) * | 2017-03-03 | 2019-11-08 | Gtreebnt科技有限公司 | 含有胸腺素β-4作为有效成分的稳定外用剂 |
CN110430866B (zh) * | 2017-03-03 | 2023-04-07 | Hlb医疗有限公司 | 含有胸腺素β-4作为有效成分的稳定外用剂 |
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