CN102083413A - 用于治疗高眼压和青光眼的方法和组合物 - Google Patents
用于治疗高眼压和青光眼的方法和组合物 Download PDFInfo
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- CN102083413A CN102083413A CN2009801197245A CN200980119724A CN102083413A CN 102083413 A CN102083413 A CN 102083413A CN 2009801197245 A CN2009801197245 A CN 2009801197245A CN 200980119724 A CN200980119724 A CN 200980119724A CN 102083413 A CN102083413 A CN 102083413A
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- aqueous solution
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Abstract
本发明涉及含有PGF2α类似物用于治疗高眼压和青光眼的眼用含水组合物,通过给予需要这种治疗的受试者所述的组合物治疗高眼压和青光眼的方法,以及增加含水组合物中PGF2α类似物的水溶性和稳定性的方法。
Description
技术领域
本发明涉及含有前列腺素(以下称为PG) F2α类似物用于治疗高眼压和青光眼的不含防腐剂的眼用含水组合物,通过给予需要这种治疗的受试者所述的组合物治疗高眼压和青光眼的方法,以及增加含水组合物中PGF2α类似物的水溶性和改善其稳定性的方法。
背景技术
由于PGF2α类似物降低眼内压的作用和它们低的全身性副作用,PGF2α类似物已经被广泛用于治疗青光眼和高眼压。PGF2α类似物包括所有已知的PGF2α类似物,例如他氟前列素(tafluprost)、拉坦前列素(latanoprost)、异丙基乌诺前列酮(isopropyl unoprostone)、曲伏前列素(travoprost)、比马前列素(bimatoprost)以及US 5,886,035、US 5,807,892、US 6,096,783中所示的类似物。
他氟前列素是新一代氟化的PGF2α异丙酯类似物,其为有效的降眼压剂(EP 0 850 926)。
PGF2α类似物用于治疗青光眼的浓度是非常低的。例如,已经发现他氟前列素在眼用组合物中的有效浓度0.0005-0.005 (w/v),优选约0.0015%足以用于治疗高眼压和青光眼。然而作为亲脂性物质,PGF2α类似物例如他氟前列素容易被通常用于储存眼用溶液的树脂(塑料) 容器或瓶吸收,因此可能进一步降低眼用溶液中已经很低的药物浓度。
防腐剂
对细菌和真菌显示充分抗菌作用的防腐剂传统上已被用于眼用组合物中。除此之外,需要防腐剂是稳定的,并且优选通过与组分相互作用匀化和稳定组合物,例如通过将组分均匀地分散或溶解于载体或基质中 (参见EP 0 969 846、EP 1 916 002和EP 1 547 599)。如今在商业可获得的眼用溶液中最常用的防腐剂为苯扎氯铵(BAK) 和其他季铵盐。其他药学可接受的用于眼用溶液的防腐剂为例如硼酸-多元醇-氯化锌 (EP 1 115 406) 或氧化氯化合物 (EP 1 905 453)、葡萄糖酸氯己定、苄索氯铵、山梨酸、山梨酸钾、对羟基苯甲酸乙酯和对羟基苯甲酸丁酯。
然而,防腐剂还被认为是角结膜障碍的主要病因,并且为了安全起见,优选防腐剂例如苯扎氯铵(BAK)的浓度尽可能地低。还已经研发了不含防腐剂的眼用溶液。
另一方面,BAK有助于防止前列腺素降解和抑制前列腺素被树脂容器壁吸收。他氟前列素和其他PGF2α类似物被树脂容器壁吸收已经成为问题,尤其是使用聚乙烯制造的容器。由于其性质,例如足够的弹性、柔软性、良好的可制造性和使用者友好性,聚乙烯是优选的用于包装眼用组合物,尤其是单位剂量形式的眼用组合物的材料。
此外,PGF2α类似物被树脂容器壁吸收取决于容器壁的表面积。单位剂量制剂含有非常少量的眼用组合物,制剂与容器的接触面积非常大。因此,PGF2α类似物被容器壁吸收对于单位剂量制剂而言是严重的问题。
因此,在本发明之前实践中不可能制备稳定的、不含防腐剂的眼用溶液,所述溶液含有PGF2α类似物并且可以包装并储存于基本上由聚乙烯组成的容器中。根据EP 1011728,包装于聚丙烯容器中的含水前列腺素组合物比包装于聚乙烯容器中的更稳定。基于所述出版物的稳定性结果,不鼓励技术人员选择聚乙烯,而且可能会禁止其作为容器材料,尤其是对于所有高亲脂性化合物例如PGF2α类似物。包含聚乙烯作为次要成分的聚丙烯-聚乙烯共聚物也是可能的,但并非暗示聚乙烯作为唯一的材料或作为主要的树脂组分 (EP 1 829 545)。
此外,几乎所有的PGF2α类似物是几乎不溶于水的。因此为了在眼用溶液尤其是单位剂量制剂中配制PGF2α类似物,还需要解决对水的溶解性问题。在EP 1 321 144和US 2007/248697中,已经将非离子表面活性剂添加到眼用溶液中以防止前列腺素衍生物被树脂容器吸附。解决在水中配制高亲脂性前列腺素类似物的难题的其他尝试描述于例如EP 0 969 846、EP 1 666 043、EP 1 011 728和WO 2007/042262中,但是它们没有提及任何不含防腐剂的组合物。
因此本发明的目的在于提供一种包含PGF2α类似物并且基本上不含防腐剂的眼用含水溶液,其中防止PGF2α类似物被基本上由聚乙烯组成的树脂容器吸收,并且其中所述的类似物在不含防腐剂的制剂中保持溶解、稳定以及可生物利用。由于目前青光眼患者对不含防腐剂的前列腺素滴眼剂的临床需求未得到满足,因此根据本发明的眼用含水溶液提供显著的临床优势。
发明内容
本发明涉及包含PGF2α类似物作为其有效成分用于治疗高眼压和青光眼的眼用含水溶液,该溶液在基本上由聚乙烯组成的容器中含有非离子表面活性剂、稳定剂,并且基本上不含防腐剂。
本发明还涉及一种治疗高眼压和青光眼的方法,该方法包含给予需要所述治疗的受试者包含PGF2α类似物作为其有效成分的含水眼用溶液,其中该眼用溶液含有非离子表面活性剂、稳定剂,并且基本上不含防腐剂。
此外,本发明涉及PGF2α类似物在制备用于治疗高眼压和青光眼的眼用含水溶液中的用途,其中所述溶液含有非离子表面活性剂、稳定剂,基本上不含防腐剂并且储存在基本上由聚乙烯组成的容器中。
本发明的另一目的是增加眼用含水溶液中PGF2α类似物的水溶性和改善其稳定性的方法,包含制备含有PGF2α类似物、非离子表面活性剂、稳定剂并且基本上不含防腐剂的眼用含水溶液,以及将不含防腐剂的眼用溶液包装在基本上由聚乙烯组成的容器中的步骤。
在本说明书中,“基本上不含防腐剂”或“不含防腐剂”是指溶液完全不含有防腐剂,或者溶液含有检测不到的浓度的防腐剂或者不提供防腐效果。
附图说明
图 1-3显示在5℃、25℃和40℃下在三种不同的聚山梨酯浓度下聚山梨酯80 (吐温80; TW) 分别对不含防腐剂的他氟前列素被低密度的聚乙烯容器吸收的作用。
图4显示在单次滴注BAK-防腐的0.0015%他氟前列素的眼用溶液[BAK(+)],含有0.20%吐温80的非-防腐的0.0015%他氟前列素眼用溶液[BAK(-) 0.2%吐温80],或含有0.05%吐温80的非-防腐的0.0015%他氟前列素眼用溶液[BAK(-) 0.05%吐温80]后家兔房水中酸式他氟前列素的浓度。棒表示在每个时间点他氟前列素酸式浓度的平均值的标准误,星号表示BAK(-) 0.2%吐温80 和BAK(-) 0.05%吐温80 溶液之间他氟前列素酸式浓度的统计学显著性差异(p<0.05,N=8)。
具体实施方式
非离子表面活性剂由于其增溶作用而被添加到本发明的眼用溶液中并且用于防止PGF2α类似物被容器的树脂壁吸收。非离子表面活性剂的实例为聚氧乙烯脂肪酯,例如聚山梨酯80[聚(氧乙烯)脱水山梨糖醇单油酸酯]、聚山梨酯60[聚(氧乙烯)脱水山梨糖醇单硬脂酸酯]、聚山梨酯40[聚(氧乙烯)脱水山梨糖醇单棕榈酸酯]、聚(氧乙烯)脱水山梨糖醇单月桂酸酯、聚(氧乙烯)脱水山梨糖醇三油酸酯和聚山梨酯65[聚(氧乙烯)脱水山梨糖醇三硬脂酸酯],聚氧乙烯氢化蓖麻油类,例如聚氧乙烯氢化蓖麻油10、聚氧乙烯氢化蓖麻油40、聚氧乙烯氢化蓖麻油50和聚氧乙烯氢化蓖麻油60,聚氧乙烯聚氧丙烯二醇类,例如聚氧乙烯(160)聚氧丙烯(30)二醇[普朗尼克(Pluronic)F68]、聚氧乙烯(42)聚氧丙烯(67)二醇[普朗尼克P123]、聚氧乙烯(54)聚氧丙烯(39)二醇[普朗尼克P85]、聚氧乙烯(196)聚氧丙烯(67)二醇[普朗尼克F127]和聚氧乙烯(20)聚氧丙烯(20)二醇[普朗尼克L-44],聚乙二醇40硬脂酸酯和蔗糖脂肪酯。非离子表面活性剂可以单独或组合使用。优选的非离子表面活性剂的实例为聚山梨酯80[聚(氧乙烯)脱水山梨糖醇单油酸酯]。其他优选的非离子表面活性剂为聚氧乙烯氢化蓖麻油60和聚乙二醇40硬脂酸酯。
可以根据前列腺素类似物的量和类型以及具体的表面活性剂选择本发明的眼用溶液中的非离子表面活性剂的量,并且在本领域技术人员的能力内。对于聚山梨酯80,其浓度为例如0.05-0.5%(w/v) 的范围内,甚至更优选0.05-0.1%,以及最优选约0.075%。本发明人还已发现过高浓度的非离子表面活性剂对角膜上皮层有刺激作用,对眼用溶液中前列腺素的生物利用度有不利作用。例如在他氟前列素的情况中,非离子表面活性剂聚山梨酯80 0.5%的上限是合适的。
根据本发明的眼用溶液还含有稳定剂以抑制眼用溶液中PGF2α类似物的分解。优选的稳定剂的实例为乙二胺四乙酸及其盐类,例如依地酸二钠和二丁基羟基甲苯。还可以使用其它稳定剂,例如亚硝酸钠、抗坏血酸、L-抗坏血酸硬脂酸酯、亚硫酸氢钠、α硫代甘油(alphathioglycerin)、异抗坏血酸、盐酸半胱氨酸、柠檬酸、醋酸生育酚、二氯异氰尿酸钾、2,6-二叔丁基-4-甲酚、大豆卵磷脂、巯基乙酸钠(sodium thioglycollate)、硫代苹果酸钠、天然维生素E、生育酚、ascorbyl pasthyminate、焦亚硫酸钠、丁基羟基茴香醚、1,3-丁二醇、季戊四醇(pentaerythtyl)四[3-(3,5-二叔丁基-4-羟苯基)]丙酸酯、没食子酸丙酯、2-巯基苯并咪唑和硫酸羟基喹啉。
可以根据具体的稳定剂选择本发明的眼用溶液中稳定剂的量,并且在本领域技术人员的能力内。例如,当稳定剂为依地酸二钠时,其浓度通常为0.005-0.2%(w/v),优选0.01-0.1%,甚至更优选约0.05%。
优选的用于本发明的眼用含水溶液中的PGF2α类似物为他氟前列素。然而,还可以使用所有已知的PGF2α类似物,尤其是其他ω链苯环取代的PGF2α类似物例如拉坦前列素、曲伏前列素和比马前列素或两种或多种前列腺素的混合物。用于本发明的眼用含水溶液中的替代药物为其他的前列腺素及其衍生物,例如前列腺素E 及其类似物(参见US 6,344,477和其中的参考文献)。前列腺素或类似物与其他眼科药物例如β-阻断剂如噻吗洛尔的组合也是合适的。
可以根据具体的上述前列腺素、所治疗的疾病及其症状,选择本发明的眼用溶液中PGF2α类似物的量。对于他氟前列素,例如0.0001-0.01%,优选约0.0005-0.0025%,甚至更优选0.0010-0.0025%(w/v)的量被认为是充分的。其他PGF2α类似物用于治疗青光眼的优选浓度为曲伏前列素0.001-0.004%、拉坦前列素约0.005%、比马前列素约0.03%和乌诺前列酮约0.15%。
本发明的眼用溶液还可以包含用于眼用组合物中的常规辅料,例如缓冲剂、溶剂、pH 调节剂、张度剂(tonicity agent)等。合适的缓冲剂的实例包括但不限于磷酸二氢钠二水合物、硼酸、硼砂、柠檬酸或ε-氨基已酸。张度剂的具体实例包括但不限于甘油、山梨醇、甘露醇和其他糖醇、丙二醇、氯化钠、氯化钾和氯化钙。
本发明的眼用含水溶液的pH优选为4-8,更优选5-7。对于pH 调节剂,可以使用常规的pH 调节剂,例如氢氧化钠和/或盐酸。
树脂容器的材料基本上由聚乙烯组成。容器材料可以含有少量的除聚乙烯外的其他材料,例如聚丙烯、聚对苯二甲酸乙二醇酯、聚氯乙烯、丙烯酸树脂、聚苯乙烯、聚甲基丙烯酸甲酯和尼龙6。所述材料的量优选不超过总容器材料的约5-10%。聚乙烯根据其密度被分为多种类型,即低密度聚乙烯(LDPE)、中密度聚乙烯(MDPE)、高密度聚乙烯(HDPE)等,这些聚乙烯都包括在本发明中。优选的聚乙烯为LDPE。
用于包装和储存本发明的眼用含水溶液的容器包括所有适用于使用者友好地局部眼用递送的容器形式。因此,该容器可以选自例如单次单位剂量形式或多剂量形式的瓶、管、安瓿、吸量管和流体分配器。根据本发明优选的实施方案,眼用含水溶液为单剂量或单位剂量形式。
用于本发明的眼用溶液的容器优选通过挤出吹塑成型方法制造。与通常用于制造例如聚乙烯多剂量瓶的注射吹塑成型相比,挤出吹塑成型生成更平滑的容器内表面。与通过注射吹塑成型制造的聚乙烯容器相比,更平滑的内表面得到前列腺素在聚乙烯容器中更好的化学稳定性。此外,当使用单剂量容器时,它们在成型过程中通过加热进行灭菌,不需要对容器另外灭菌,这也改善前列腺素在单剂量容器中的稳定性 (参见EP 1 825 855和EP 1 349 580)。
通常,通过吹塑成型方法制造的单位剂量眼用容器的容积约1 ml,填充约0.2-0.5 ml的溶液。已知这类容器的形状种类繁多。典型的实例参见US 5,409,125和US 6,241,124。
虽然就本发明的目的而言单位剂量容器是优选的,但是本发明的眼用含水溶液在用于分配微量无菌流体的流体分配器中或任何其他眼用含水溶液与基本上由聚乙烯组成的容器材料接触的容器类型中,也保持溶解、稳定以及可生物利用。这类流体分配器公开于例如US 5,614,172中。
本发明的不含防腐剂的眼用含水溶液可以在室温下在包括单位剂量吸量管和分配器的上述合适的容器中储存。稳定性研究已经表明本发明的不含防腐剂的含水眼用他氟前列素溶液在聚乙烯容器中长期、在25℃下至少12个月以及在5℃下至少30个月内是稳定的。
优选的本发明的实施方案为用于治疗高眼压和青光眼的含水眼用溶液,其在基本上由聚乙烯组成的容器中包含:
0.0001 – 0.01%w/v PGF2α类似物;
0.05 – 0.5%w/v 非离子表面活性剂,
0.005 – 0.2%w/v 稳定剂,
基本上不含防腐剂,和
任选的眼用溶液中常规使用的缓冲剂、pH调节剂和张度剂。
下列实施例对本发明进行了说明,而不以任何方式限定本发明。
实施例 1
研究非离子表面活性剂在5℃、25℃和40℃下在20周内对不含防腐剂的他氟前列素被低密度聚乙烯容器吸收的作用。使用三种不同的聚山梨酯80 (吐温80) 浓度,即0.05%、0.075%和0.1%。除了聚山梨酯80外,不含防腐剂的含水他氟前列素制剂的组合物为0.0015%他氟前列素、2.25%甘油、0.2%磷酸二氢钠二水合物、0.05%依地酸二钠以及调节pH至5.0 – 6.7的氢氧化钠和/或盐酸。
将上述制备的0.3 ml 组合物填充到单位剂量容器(LDPE)的主体部分,通过加热容器(LDPE)的上部进行密封。单位剂量容器的内部容积为约1 ml。将容器包装在纸涂布的铝-聚乙烯箔中并且储存于冰箱或保温箱中。
通过HPLC测量他氟前列素的剩余浓度。结果显示于图1-3中。该结果表明聚山梨酯的浓度对他氟前列素被聚乙烯吸收具有影响。聚山梨酯(0.05-0.1%)抑制他氟前列素的吸收,尤其是在升高的温度(40℃)下。0.075-0.1%量的聚山梨酯对他氟前列素的吸收显示良好的抑制作用。
实施例 2
研究在单次滴注
1) 含有0.01%BAK和0.05%聚山梨酯80的防腐的0.0015%他氟前列素眼用溶液,或
2) 含有0.20%聚山梨酯80的非-防腐的0.0015%他氟前列素眼用溶液,或
3) 含有0.05%聚山梨酯80的非-防腐的0.0015%他氟前列素眼用溶液后家兔房水中他氟前列素游离酸的浓度。
除聚山梨酯80外,非-防腐的溶液中成分的浓度如下:2.25%甘油,0.2%磷酸二氢钠二水合物,0.05%依地酸二钠以及调节pH至5.0 – 6.7的氢氧化钠和/或盐酸。
家兔接受上述眼用溶液。在每个时间点处死家兔(每个时间点每种处理4只动物)并提取房水样本。使用验证的LC-MS/MS方法测量他氟前列素酸形式的浓度。
结果 (每个时间点每种测试溶液N= 8) 显示于图4中。
由结果可以看出,非离子表面活性剂的量对眼部生物利用度有影响。当非离子表面活性剂的量超过一定限度时,活性剂向房水的渗透开始降低。因此需要平衡非离子表面活性剂的量,一方面最小化PGF2α类似物被容器壁吸收,另一方面,最大化眼部生物利用度。
Claims (22)
1.一种用于治疗高眼压和青光眼的眼用含水溶液,包含PGF2α类似物作为有效成分,其中所述眼用含水溶液在基本上由聚乙烯组成的容器中含有非离子表面活性剂、稳定剂,并且基本上不含防腐剂。
2.根据权利要求1的眼用含水溶液,其中PGF2α类似物选自拉坦前列素、异丙基乌诺前列酮、曲伏前列素、比马前列素和他氟前列素或其两种或多种的混合物。
3.根据权利要求1的眼用含水溶液,其中PGF2α类似物为他氟前列素。
4.根据权利要求1-3任一所述的眼用含水溶液,所述容器包含少量的聚丙烯、聚对苯二甲酸乙二醇酯、聚氯乙烯、丙烯酸树脂、聚苯乙烯、聚甲基丙烯酸甲酯或尼龙6。
5.根据权利要求1-4任一所述的眼用含水溶液,其中非离子表面活性剂选自聚氧乙烯脂肪酯,例如聚山梨酯80[聚(氧乙烯)脱水山梨糖醇单油酸酯]、聚山梨酯60[聚(氧乙烯)脱水山梨糖醇单硬脂酸酯]、聚山梨酯40[聚(氧乙烯)脱水山梨糖醇单棕榈酸酯]、聚(氧乙烯)脱水山梨糖醇单月桂酸酯、聚(氧乙烯)脱水山梨糖醇三油酸酯和聚山梨酯65[聚(氧乙烯)脱水山梨糖醇三硬脂酸酯],聚氧乙烯氢化蓖麻油类,例如聚氧乙烯氢化蓖麻油 10、聚氧乙烯氢化蓖麻油 40、聚氧乙烯氢化蓖麻油 50和聚氧乙烯氢化蓖麻油60,聚氧乙烯聚氧丙烯二醇类,例如聚氧乙烯(160)聚氧丙烯(30)二醇[普朗尼克F68]、聚氧乙烯(42)聚氧丙烯(67)二醇[普朗尼克P123]、聚氧乙烯(54)聚氧丙烯(39)二醇[普朗尼克P85]、聚氧乙烯(196)聚氧丙烯(67)二醇[普朗尼克F127]和聚氧乙烯(20)聚氧丙烯(20)二醇[普朗尼克L-44],聚乙二醇40硬脂酸酯和蔗糖脂肪酯。
6.根据权利要求5的眼用含水溶液,其中非离子表面活性剂为聚山梨酯80或蓖麻油。
7.根据权利要求1-6任一所述的眼用含水溶液,其中非离子表面活性剂的量为0.05-0.5%(w/v),优选0.05-0.1%(w/v),甚至更优选约0.075%(w/v)。
8.根据权利要求1-7任一所述的眼用含水溶液,其中稳定剂选自乙二胺四乙酸及其盐类、亚硝酸钠、抗坏血酸、L-抗坏血酸硬脂酸酯、亚硫酸氢钠、α硫代甘油、异抗坏血酸、盐酸半胱氨酸、柠檬酸、醋酸生育酚、二氯异氰尿酸钾、2,6-二叔丁基-4-甲酚、大豆卵磷脂、巯基乙酸钠、硫代苹果酸钠、天然维生素E、生育酚、ascorbyl pasthyminate、焦亚硫酸钠、丁基羟基茴香醚、1,3-丁二醇、季戊四醇四[3-(3,5-二叔丁基-4-羟苯基)]丙酸酯、没食子酸丙酯、2-巯基苯并咪唑和硫酸羟基喹啉。
9.根据权利要求8的眼用含水溶液,其中稳定剂为依地酸二钠。
10.根据权利要求1-9任一所述的眼用含水溶液,其中稳定剂的量为0.005-0.2%,优选0.01-0.1%,甚至更优选约0.05%(w/v)。
11.根据权利要求1的眼用含水溶液,其为单剂量形式。
12.根据权利要求1-11任一所述的眼用含水溶液, 包含至少一种其它药学活性物质,例如噻吗洛尔。
13.一种眼用含水溶液,包含:
0.0001 – 0.01%w/v PGF2α类似物;
0.05 – 0.5%w/v 非离子表面活性剂,
0.005 – 0.2%w/v 稳定剂,和
任选的眼用溶液中常规使用的缓冲剂、pH调节剂和张度剂,并且基本上不含防腐剂,所述溶液在基本上由聚乙烯组成的容器中或与基本上由聚乙烯组成的容器材料接触。
14.一种眼用含水溶液,包含:
0.0010 – 0.0015%w/v 他氟前列素;
0.05 – 0.1%w/v 聚山梨酯80,
0.01 – 0.1%w/v 依地酸二钠,和
任选的眼用溶液中常规使用的缓冲剂、pH调节剂和张度剂,并且基本上不含防腐剂,所述溶液在基本上由聚乙烯组成的容器中或与基本上由聚乙烯组成的容器材料接触。
15.一种眼用含水溶液,包含:
0.0015%w/v 他氟前列素,
0.075%w/v 聚山梨酯80,
0.05%w/v 依地酸二钠,
2.25%w/v 甘油,
0.2%w/v 磷酸二氢钠二水合物,
pH调节剂,并且基本上不含防腐剂,所述溶液在基本上由聚乙烯组成的容器中或与基本上由聚乙烯组成的容器材料接触。
16.根据权利要求13-15任一所述的眼用含水溶液,所述容器包含少量的聚丙烯、聚对苯二甲酸乙二醇酯、聚氯乙烯、丙烯酸树脂、聚苯乙烯、聚甲基丙烯酸甲酯或尼龙6。
17.根据权利要求13-15任一所述的眼用含水溶液,其为单剂量或单位剂量形式。
18.根据权利要求13-15任一所述的眼用含水溶液,其为流体分配器形式。
19.一种增加眼用含水溶液中PGF2α类似物的水溶性和改善其稳定性的方法,包含制备含有PGF2α类似物、非离子表面活性剂、稳定剂并且基本上不含防腐剂的眼用含水溶液,以及将不含防腐剂的眼用溶液包装于基本上由聚乙烯组成的容器中或与基本上由聚乙烯组成的容器材料接触的步骤。
20.PGF2α类似物在制备用于治疗高眼压和青光眼的眼用含水溶液中的用途,其中所述眼用溶液包含非离子表面活性剂、稳定剂,并且基本上不含防腐剂。
21.根据权利要求20的用途,其中所述眼用含水溶液包装于基本上由聚乙烯组成的容器中或与基本上由聚乙烯组成的容器材料接触。
22.一种治疗高眼压和青光眼的方法,其包含给予需要所述治疗的受试者包含PGF2α类似物作为其有效成分的眼用含水溶液,其中所述眼用溶液包含非离子表面活性剂、稳定剂,并且基本上不含防腐剂。
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EP08397513A EP2127638A1 (en) | 2008-05-30 | 2008-05-30 | Method and composition for treating ocular hypertension and glaucoma |
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PCT/JP2009/060211 WO2009145356A1 (en) | 2008-05-30 | 2009-05-28 | Method and composition for treating ocular hypertension and glaucoma |
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CN102716074A (zh) * | 2012-06-28 | 2012-10-10 | 武汉武药科技有限公司 | 一种贝美前列素滴眼剂及其制备方法 |
CN102716074B (zh) * | 2012-06-28 | 2013-10-16 | 武汉武药科技有限公司 | 一种贝美前列素滴眼剂及其制备方法 |
CN110022856A (zh) * | 2016-11-09 | 2019-07-16 | 株式会社泰俊制药 | 用于降低眼压的眼用组合物 |
CN111632025A (zh) * | 2020-03-04 | 2020-09-08 | 吉林大学第一医院 | 一种贝美前列素眼用温度敏感型原位凝胶及其制备方法与应用 |
CN111840225A (zh) * | 2020-08-12 | 2020-10-30 | 王信 | 一种用于治疗青光眼的滴眼剂及其制备方法 |
CN111840225B (zh) * | 2020-08-12 | 2021-09-14 | 陈丽娜 | 一种用于治疗青光眼的滴眼剂及其制备方法 |
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