CN1138542C - 通过特定应用的抗氧化剂稳定药物组合物的方法 - Google Patents
通过特定应用的抗氧化剂稳定药物组合物的方法 Download PDFInfo
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- CN1138542C CN1138542C CNB998047163A CN99804716A CN1138542C CN 1138542 C CN1138542 C CN 1138542C CN B998047163 A CNB998047163 A CN B998047163A CN 99804716 A CN99804716 A CN 99804716A CN 1138542 C CN1138542 C CN 1138542C
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- Prior art keywords
- dimethyl ethyl
- antioxidant
- polymeric material
- composition
- pharmaceutical composition
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Abstract
本发明具体公开了通过使所述组合物与含有抗氧化剂的聚合物材料相接触来稳定药物组合物的方法。
Description
本发明特别涉及一种通过使组合物与含有抗氧化剂的聚合物材料相接触稳定药物组合物的方法。
药物组合物，特别是含水药物组合物，具体如水滴眼剂需要得到稳定，以使该组合物可以对抗因加热、光照和/或在氧下暴露引起的分解而保持稳定。
按照本发明的主权利要求已经解决了上述问题，具体而言，通过应用其中含有抗氧化剂的塑料瓶解决了上述问题。所述稳定化方法的优点在于省略了须向此类药物组合物中另外加入抗氧化剂和/或稳定剂的可能性。因此，所述药物组合物通常表现出比常规稳定化的组合物更高的耐受性，这归因于不需在要求这种药物组合物的生物体中加入抗氧化剂。
因此，本发明的目的是尤其是按照主权利要求所述的使药物组合物稳定化的方法，例如通过应用含有抗氧化剂的塑料瓶。
在本发明中，稳定化作用涉及在暴露于保藏、氧和/或空气(氧游离基)、光(UV)和/或热(例如在121℃下的灭菌步骤)时药物组合物整体的稳定性，特别是其活性组分的稳定性。加热灭菌等于是指热压灭菌。
术语“聚合物材料”涉及优选不溶于本发明的液体药物组合物中的聚合物，并且所述聚合物材料可以进一步是无规模塑制品形式。所述模塑料的实例具体为颗粒状物、珠粒、柱形、棒状、片状、管型或小瓶，更优选大瓶。优选的聚合物材料含有或由聚乙烯(PE)、聚丙烯(PP)和/或其混合物组成。
所以，术语“塑料瓶”特别是指聚乙烯(PE)和/或聚丙烯(PP)瓶。它们还可以任选地含有辅剂，例如光吸收材料，例如二氧化钛、着色颜料和/或UV吸收剂等等。
本发明中的术语“抗氧化剂”应被理解为选自如下的化合物：2，2’，2”，6，6’，6”-六-(1，1-二甲基乙基)-4，4’，4”-[(2，4，6-三甲基-1，3，5-苯三苯甲基)-三亚甲基]-三酚(Irganox 1330)、1，3，5，三[3，5-二(1，1-二甲基乙基)-4-羟基苄基]-1H，3H，5H-1，3，5-三嗪-2，4，6-三酮、四[3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]-丙酸]季戊四醇酯、十八烷基-3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]丙酸酯、三[2，4-二(1，1-二甲基乙基)-苯基]-亚磷酸酯、2，2’-二(十八烷基氧基)-5，5’-螺二(1，3，2-二氧杂phosphorinane)、二硫化双十八烷、双十二烷基-3，3’-硫代二丙酸酯、双十八烷基-3，3’-硫代二丙酸酯、丁基羟基甲苯、双[3，3-二[3-(1，1-二甲基乙基)-4-羟基苯基]-丁酸]亚乙酯及其混合物。优选的抗氧化剂是Irganox 1330。
抗氧化剂在该聚合物材料中的含量通常介于Ph.Eur.所推荐的范围内，并且-般为0.05-1.0％(重量)，更优选0.1-0.7％(重量)，更优选0.12-0.55％(重量)。
其他抗氧化剂，例如抗坏血酸、乙酰基半胱氨酸、半胱氨酸、亚硫酸氢钠、丁羟基苯甲醚，和醋酸α-生育酚也可以存在。
本发明所述的含在聚合物材料中的抗氧化剂的优点在于，所述抗氧化剂一般很少释放或基本不释放至与该聚合物材料相接触的药物组合物中，特别是含水眼科用组合物。这可以使药物组合物基本不含有所述抗氧化剂。
聚合物材料的制备过程中常采用抗氧化剂用来避免分解和/或氧化作用。所以，此类聚合物尤其属于本发明所指的范围内，换言之是指含有抗氧化剂的聚合物材料。
药物活性组分例如可选自：氯化乙酰胆碱、无环鸟苷、肾上腺素、丁卡因、氨基己酸、磷酸安他唑啉、花生四烯酸、阿托品、倍他洛尔、布比卡因、卡巴胆碱、卡替洛尔、氯霉素、金霉素、糜蛋白酶(chymatrypsin)、可乐定、可卡因、柯楠次碱、色甘酸、环戊四醇酯、地美卡林、地塞米松、地布托林、双氯非那胺、双氯芬酸、地匹福林、echodtiophate、麻黄碱、红霉素、乙胺丁醇、依替卡因、尤卡托品、fluoromethalone、氟米龙、庆大霉素、短杆菌肽、H-胸腺嘧啶核苷、后马托品、透明质酸、氢化可的松、碘苷、消炎痛、异氟磷、异山梨醇、痛力克、酮替芬、苯醇酸铵乙酯(1aches ine)、左布诺洛尔、左卡巴司汀、利多卡因、赛罗卡因、6α-甲-11-羟孕酮、甲哌卡因、醋甲胆碱、醋甲唑胺、萘甲唑啉、那他霉素、新霉素、新斯的明、去甲肾上腺素、氧氟沙星、普鲁卡因、氧甲唑啉、奥芬溴铵(oxyphenonium)、屈米通、苯福林、毒扁豆碱、匹鲁卡品、多粘菌素B、泼尼松龙、丙对卡因、丙美卡因(proxymethacaine)、甲氧苯二胺、视黄酸、维生素A、醋酸维生素A、棕榈酸维生素A、东莨菪碱、索比尼尔、磺胺醋酰、他莫昔芬、丁卡因、四环素、四氢唑啉、噻吗洛尔、三氟尿苷、托品酰胺、阿糖腺苷，和它们的药学上可接受的盐，及其混合物。
优选的药学活性化合物选自：倍他洛尔、氯霉素、双氯芬酸、地匹福林、麻黄碱、红霉素、庆大霉素、消炎痛、酮替芬、左布诺洛尔、左卡巴司汀、氧氟沙星、普鲁卡因、多粘菌素B、泼尼松龙、视黄酸、维生素A、醋酸维生素A、棕榈酸维生素A、四环素和它们药学上可接受的盐。
更优选的药学活性化合物选自：倍他洛尔、氯霉素、双氯芬酸、酮替芬、左布诺洛尔、左卡巴司汀、匹鲁卡品、视黄酸、维生素A、醋酸维生素A、棕榈酸维生素A和它们药学上可接受的盐。
特别优选：酮替芬、视黄酸、维生素A、醋酸维生素A、棕榈酸维生素A和它们药学上可接受的盐。
极其优选酮替芬及其药学上可接受的盐。
在本发明中，药物组合物的特征在于所述载体，所述药物活性化合物混合、悬浮、溶解和/或部分溶解其中，并且选自：水、水和可与水混溶的溶剂如C1-C7烷醇的混合物、植物油或矿物油，含有0.5-5％(重量)羟乙基纤维素、油酸乙酯、羧甲基纤维素、聚乙烯基吡咯烷酮和其它无毒水溶性聚合物，尤其是适合眼用的载体，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；丙烯酸酯或甲基丙烯酸酯，如聚丙烯酸的盐或丙烯酸乙酯；聚丙烯酰胺；天然产物，如明胶、藻酸盐、果胶，黄耆胶、刺梧桐胶、黄原胶、角叉菜胶、琼脂、金合欢；淀粉衍生物，如醋酸淀粉和羟丙基淀粉；和其它合成产物，如聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯甲基醚、聚环氧乙烷；优选交联聚丙烯酸，如中性Carbopol，或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Carbopol，或它们的混合物。特别优选的载体是水。载体的浓度通常是活性组分浓度的1-100000倍。术语“含水”一般表示含水组合物，其中所述载体的水份含量＞50％(重量)，更优选＞75％(重量)，特别优选＞90％(重量)。
在本发明的术语中，术语“组合物”具体是指溶液、悬浮液、凝胶、软膏、乳液和/或其混合物。
更优选的是适合眼部给药的药物组合物。因此，所述组合物适宜含有其它组分以满足眼用耐受性所必备的必要条件。所以，在一个具体方面中，本发明涉及眼用组合物的稳定化，特别是含水眼用组合物的稳定化。
这些附加组分可以包括张度促进剂、防腐剂和pH调节剂。
为了调节pH，优选调至生理pH，尤其可以应用缓冲剂。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、葡糖酸盐、乳酸盐、磷酸盐、丙酸盐和TRIS(氨基三丁醇)缓冲剂。氨基三丁醇和硼酸缓冲剂是优选的缓冲剂。缓冲物质的加入量一般是用于达到和维持在生理可耐受pH范围内所必需的量。所述pH范围通常为4至9，优选是4.5至8.5，更优选是5.0至8.2。
如果必要，通过张度促进剂来调节张度。张度促进剂可以例如是离子和/或非离子型的。离子张度促进剂的实例例如是碱金属或碱土金属的卤化物，如CaCl2、KBr、KCl、LiCl、NaI、NaBr或NaCl、Na2SO4或硼酸。非离子张度促进剂例如是脲、甘油、山梨糖醇、甘露醇、丙二醇或葡萄糖。通常，加入足够量的张度促进剂可以令上述眼用组合物约50至1000mOsmol，优选100-400mOsmol，更优选200-400mOsmol，特别优选250-350mOsmol的等渗重量摩尔浓度(osmolality)。
防腐剂一般选自季铵化合物，例如苯扎氯铵、benzoxoniumchloride等。苯扎氯铵更应称作：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，例如硫柳汞、硝酸苯汞、乙酸苯汞或硼酸苯汞；对羟基苯甲酸酯，例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯；醇，例如氯丁醇、苄醇或苯基乙醇；胍类衍生物，例如洗必泰或聚亚己基双胍；过硼酸钠、GermalII或山梨酸。优选的防腐剂是季铵化合物，特别是苯扎氯铵、烷基汞盐和对羟基苯甲酸酯。如果适宜，向眼用组合物中加入足够量的防腐剂以便确保在使用期间保护组合物对抗由细菌和真菌引起的二次污染。
药物组合物中还可以存在增溶剂，尤其是当活性或非活性组分趋于形成悬浮液或乳液时。适用于本发明组合物的增溶剂例如可选自泰洛沙泊、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、羟烷基化、羧基烷基化或烷氧基羰基-烷基化衍生物，或一或二葡基-α-、β-或γ-环糊精，一或二麦芽糖基-α-、β-或γ-环糊精或潘糖基环糊精)、聚山梨酸酯20、聚山梨酸酯80或这些化合物的混合物。特别优选的增溶剂的具体实例是蓖麻油和环氧乙烷的反应产物，例如市售产品Cremophor EL或Cremophor RH 40。业已证明，蓖麻油和环氧乙烷的反应产物是特别良好的增溶剂，眼睛对该化合物具有极其优异的耐受性。另一种优选的增溶剂选自泰洛沙泊和环糊精。所用浓度具体取决于活性组分的浓度。增溶剂的加入量一般应足以令活性组分溶解。例如，增溶剂的浓度是活性组分浓度的0.1至5000倍。
上述药物组合物可以含有其它非毒性赋形剂，例如乳化剂、湿润剂或填充剂，如聚乙二醇200、300、400和600或Carbowax 1000、1500、4000、6000和10000。根据需要应用的其它赋形剂如下文所列，但它们不以任何方式对可能的赋形剂的范围构成限定。所加入的赋形剂的用量和类型是根据具体要求，并且一般是在约0.0001至约90％(重量)的范围内。
本发明的其它目的是那些公开在全部独立权利要求和从属权利要求中的目的。
本发明的另一个目的是如实施例所述的塑料瓶在稳定此处所述组合物中的应用。
实施例1：0.025％的酮替芬滴眼剂
实施例2：0.05％的酮替芬滴眼剂
| 在10mlPE-瓶中(不含抗氧化剂) | 在10mlPP-瓶中(加Irganox 1330) | |
| 0-值 | ||
| 酮替芬富马酸氢盐的百分含量 | 97.7 | 97.7 |
| pH | 5.06 | 5.06 |
| 等渗重量摩尔浓度(mOsmol) | 247 | 247 |
| 应激试验，15小时，80℃ | ||
| 酮替芬富马酸氢盐的百分含量 | 73.7 | 96.2 |
| 已知降解产物的百分比 | 2.6 | 0.04 |
| pH | 4.42 | 4.96 |
| 等渗重量摩尔浓度(mOsmol) | 247 | 248 |
| 在10mlPE-瓶中(白色)(不含抗氧化剂) | 在10mlPP-瓶中(白色)(加Irganox 1330) | |
| 0-值 | ||
| 酮替芬富马酸氢盐的百分含量 | 97.8 | 97.8 |
| pH | 5.30 | 5.30 |
| 等渗重量摩尔浓度(mOsmol) | 248 | 248 |
| 3个月，25℃ | ||
| 酮替芬富马酸氢盐的百分含量 | 96.0 | 99.2 |
| 已知降解产物的百分比 | 0.6 | 未检测出 |
| 未知降解产物的百分比 | 未检测出 | 未检测出 |
| pH | 5.0 | 5.64 |
| 3个月，30℃ | ||
| 酮替芬富马酸氢盐的百分含量 | 93.5 | 99.2 |
| 已知降解产物的百分比 | 1.6 | 未检测出 |
| 未知降解产物的百分比 | 0.5 | 未检测出 |
| pH | 4.93 | 5.62 |
| 3个月，40℃(20％相对湿度) | ||
| 酮替芬富马酸氢盐的百分含量 | 79.2 | 99.8 |
| 已知降解产物的百分比 | 7.5 | 未检测出 |
| 未知降解产物的百分比 | 3.2 | 未检测出 |
| pH | 4.57 | 5.35 |
| 3个月，40℃(75％相对湿度) | ||
| 酮替芬富马酸氢盐的百分含量 | 83.4 | 99.4 |
| 已知降解产物的百分比 | 4.3 | 未检测出 |
| 未知降解产物的百分比 | 1.6 | 未检测出 |
| pH | 4.66 | 5.55 |
实施例3：
含有0.025％酮替芬的眼用组合物中的组分：
| 组分名称 | (mg/ml) | 功能 | 参考标准 |
| 活性组分 | |||
| 酮替芬(作为酮替芬富马酸氢盐应用) | 0.25(0.345) | 抗变态反应药 | |
| 其他组分 | |||
| 苯扎氯铵 | 0.10 | 防腐剂 | Ph.Eur. |
| 甘油 | 21.25 | 等渗剂 | Ph.Eur. |
| 1M氢氧化钠 | ～0.75(调至pH约为5.3) | pH调节剂 | Ph.Eur. |
| 注射用水 | ～981.055(加至1.0ml) | 溶剂 | Ph.Eur. |
实施例4：
含有0.05％酮替芬的眼用组合物中的组分：
| 组分名称 | 配料(mg/ml) | 功能 | 参考标准 |
| 活性组分 | |||
| 酮替芬(作为酮替芬富马酸氢盐应用) | 0.50(0.69) | 抗变态反应药 | |
| 其他组分 | |||
| 苯扎氯铵 | 0.10 | 防腐剂 | Ph.Eur. |
| 甘油85％ | 25.00 | 张度调节剂 | Ph.Eur. |
| 1N氢氧化钠 | ～1.50(调至pH约为5.3) | pH调节剂 | Ph.Eur. |
| 注射用水 | ～976.2 1(加至1.0ml) | 溶剂 | Ph.Eur. |
实施例5：维生素A滴眼剂
| 在5mlPE-瓶中(不含抗氧化剂) | 在5mlPP-瓶中加Irganox 1330 | |
| 0-值 | ||
| 棕榈酸维生素A(IU)的含量 | 1272 | 1272 |
| pH | 6.67 | 6.67 |
| 等渗重量摩尔浓度(mOsmol) | 310 | 310 |
| 40℃，1个月，75％相对湿度 | ||
| 棕榈酸维生素A国际单位(IU)的含量 | 1097 | 1204 |
| pH | 6.67 | 6.67 |
| 等渗重量摩尔浓度(mOsmol) | 310 | 310 |
实施例6：
维生素A滴眼剂(凝胶)含有的组分：
| 化合物 | mg/ml | 功能 | 参考标准 |
| 合成棕榈酸维生素A，水可分散形式(100’000IU/g) | 10(1000IU) | 抗干眼病药 | Ph.Eur. |
| 苯扎氯铵 | 0.10 | 防腐剂 | Ph.Eur. |
| 醋酸α-生育酚，水可分散形式(0.5g/g) | 10.0 | 抗氧化剂 | |
| 硼酸 | 16.20 | 缓冲剂 | Ph.Eur. |
| 四硼酸钠 | 1.40 | 缓冲剂 | Ph.Eur. |
| 乙二胺四乙酸二钠 | 1.00 | 螯合剂 | Ph.Eur. |
| 甲基羟丙基纤维素 | 4.00 | 粘度促进剂 | Ph.Eur. |
| 注射用水 | 加至1.0ml | 载体(溶剂) | Ph.Eur. |
Ph.Eur.＝欧洲药典
IU＝国际单位
实施例7
实施例3(0.025％眼用组合物)的酮替芬滴眼剂的稳定性试验：
| 组成(mg/ml) | 批次-7A填充至含有Irganox 1330的PP-瓶中 | 批次-7B填充至含有Irganox 1330的PP-瓶中，填充前高压灭菌 | 批次-7C填充至含有BHT的PP-瓶中，填充前用环氧乙烷灭菌 |
| 酮替芬富马酸氢盐 | 0.345 | 和7A相同 | 和7A相同 |
| 苯扎氯铵 | 0.10 | 和7A相同 | 和7A相同 |
| 甘油 | 21.25 | 和7A相同 | 和7A相同 |
| 1M氢氧化钠 | ～0.75 | 和7A相同 | 和7A相同 |
| 注射用水 | ～981.055 | 和7A相同 | 和7A相同 |
0-值
| 酮替芬富马酸氢盐的百分含量 | 96.5 | 100.0 | 99.6 |
| pH | 5.12 | 5.38 | 5.55 |
| 等渗重量摩尔浓度(mOsmol) | 241 | 238 | 238 |
在40℃和75％相对湿度下的应激试验
| 12个月 | 3个月 | 3个月 | |
| 酮替芬富马酸氢盐的百分含量 | 99.9 | 99.2 | 98.2 |
| 降解产物的百分比 | ～2.8 | ＜0.1 | ＜0.05 |
| pH | 5.16 | 5.35 | 5.56 |
| 等渗重量摩尔浓度(mOsmol) | 244 | 240 | 242 |
BHT：丁羟基甲苯
Claims (20)
1.药物组合物稳定化的方法，所述组合物为了达到通过本方法达到的基本相同的稳定程度应需要加入抗氧化剂，其特征在于令不含抗氧化剂的该组合物与含有抗氧化剂的聚合物材料接触，所述抗氧化剂在该聚合物材料的制备过程中已混合在该聚合物材料中，所述聚合物材料不溶于所述药物组合物中并且该聚合物材料的制品形状选自管、小瓶和大瓶。
2.权利要求1的方法，其中所述药物组合物是含水组合物。
3.权利要求1或2的方法，其中所述药物组合物是眼用组合物。
4.权利要求1-3任一项的方法，其中所述组合物是溶液、悬浮液或凝胶，优选是溶液。
5.权利要求1-4任一项的方法，其中所述聚合物材料选自聚乙烯、聚丙烯和它们的混合物，和优选聚丙烯。
6.权利要求5的方法，其中所述聚合物材料的制品形状是大瓶。
7.权利要求1的方法，其中所述抗氧化剂选自2，2’，2”，6，6’，6”-六-(1，1-二甲基乙基)-4，4’，4”-[(2，4，6-三甲基-1，3，5-苯三苯甲基)-三亚甲基]-三酚(Irganox 1330)、1，3，5，三[3，5-二(1，1-二甲基乙基)-4-羟基苄基]-1H，3H，5H-1，3，5-三嗪-2，4，6-三酮、四[3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]-丙酸]季戊四醇酯、十八烷基-3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]丙酸酯、三[2，4-二(1，1-二甲基乙基)-苯基]-亚磷酸盐、2，2’-二(十八烷基氧基)-5，5’-螺二(1，3，2-二氧杂phosphorinane)、二硫化双十八烷、双十二烷基-3，3’-硫代二丙酸酯、双十八烷基-3，3’-硫代二丙酸酯、丁羟基甲苯、亚乙基双[3，3-二[3-(1，1-二甲基乙基)-4-羟基苯基]-丁酸酯]及其混合物。
8.权利要求1或6的方法，其中所述聚合物材料选自聚丙烯和聚乙烯，和所述抗氧化剂选自2，2’，2”，6，6’，6”-六-(1，1-二甲基乙基)-4，4’，4”-[(2，4，6-三甲基-1，3，5-苯三苯甲基)-三亚甲基]-三酚(Irganox 1330)、1，3，5，三[3，5-二(1，1-二甲基乙基)-4-羟基苄基]-1H，3H，5H-1，3，5-三嗪-2，4，6-三酮、四[3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]-丙酸]季戊四醇酯、十八烷基-3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]丙酸酯、三[2，4-二(1，1-二甲基乙基)-苯基]-亚磷酸酯和2，2’-二(十八烷基氧基)-5，5’-螺二(1，3，2-二氧杂phosphorinane)。
9.权利要求1或6的方法，其中所述聚合物材料是聚丙烯，和所述抗氧化剂选自丁羟基甲苯，并且优选自2，2’，2”，6，6’，6”-六-(1，1-二甲基乙基)-4，4’，4”-[(2，4，6-三甲基-1，3，5-苯三苯甲基)-三亚甲基]-三酚(Irganox 1330)。
10.权利要求1的方法，其中所述组合物是眼用组合物，所述聚合物材料是聚丙烯，和所述抗氧化剂选自2，2’，2”，6，6’，6”-六-(1，1-二甲基乙基)-4，4’，4”-[(2，4，6-三甲基-1，3，5-苯三苯甲基)-三亚甲基]-三酚(Irganox 1330)并且优选自丁羟基甲苯。
11.权利要求10的方法，其中所述眼用组合物进一步含有选自酮替芬、视黄酸、维生素A、醋酸维生素A、棕榈酸维生素A及其药学上可接受盐的药物活性组分。
12.权利要求10的方法，其中所述组合物进一步含有缓冲剂、张度促进剂和特别是防腐剂。
13.在聚合物材料制备过程中已混合在聚合物材料中的抗氧化剂在选自溶液、悬浮液、凝胶、软膏、乳液及其混合物的药物组合物的稳定化中的应用，所述组合物没有为了达到通过所述应用产生的基本相当的稳定程度所需要加入的抗氧化剂。
14.权利要求13的应用，其中所述组合物含有选自酮替芬、视黄酸、维生素A、醋酸维生素A、棕榈酸维生素A及其药学上可接受盐的药物活性组分。
15.权利要求1-12任一项的方法得到的药物组合物。
16.权利要求15的含有酮替芬或其药学可接受盐的含水眼用组合物，其中抗氧化剂已混合在聚合物材料中，所述聚合物材料选自聚乙烯、聚丙烯及其混合物。
17.权利要求16的组合物， 其中所述抗氧化剂选自2，2’，2”，6，6’，6”-六-(1，1-二甲基乙基)-4，4’，4”-[(2，4，6-三甲基-1，3，5-苯三苯甲基)-三亚甲基]-三酚(Irganox 1330)、1，3，5，三[3，5-二(1，1-二甲基乙基)-4-羟基苄基]-1H，3H，5H-1，3，5-三嗪-2，4，6-三酮、四[3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]-丙酸]季戊四醇酯、十八烷基-3-[3，5-二(1，1-二甲基乙基)-4-羟基苯基]丙酸酯、三[2，4-二(1，1-二甲基乙基)-苯基]-亚磷酸酯、2，2’-二(十八烷基氧基)-5，5’-螺二(1，3，2-二氧杂phosphorinane)、二硫化双十八烷、双十二烷基-3，3’-硫代二丙酸酯、双十八烷基-3，3’-硫代二丙酸酯、丁羟基甲苯、亚乙基双[3，3-二[3-(1，1-二甲基乙基)-4-羟基苯基]-丁酸酯]及其混合物，和其中优选的抗氧化剂是Irganox1330。
18.一种制品，选自管、小瓶和大瓶，由包含在其制备过程中已混合在其中的抗氧化剂的聚合物材料制成，该制品内装有药物组合物，所述组合物中没有需要另外加入以使其基本上同样稳定的抗氧化剂。
19.权利要求18的制品，其中所述药物组合物是眼用组合物。
20.权利要求18或19的制品，其中所述聚合物材料选自聚乙烯、聚丙烯及其混合物，优选聚丙烯。
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