CN1275081A - 含水液体药物组合物 - Google Patents

含水液体药物组合物 Download PDF

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CN1275081A
CN1275081A CN99801408A CN99801408A CN1275081A CN 1275081 A CN1275081 A CN 1275081A CN 99801408 A CN99801408 A CN 99801408A CN 99801408 A CN99801408 A CN 99801408A CN 1275081 A CN1275081 A CN 1275081A
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gatifloxacin
disodiumedetate
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安枝真一
稻田胜弘
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Abstract

本发明提供含有Gatifloxacin(化学命名:(±)－1－环丙基－6－氟－1,4－二氢－8－甲氧基－7－(3－甲基－1－哌嗪基)－4－氧代－3－喹啉羧酸)或者其盐和乙二胺四乙酸二钠的含水液体药物组合物。此外,本发明提供通过向含有Gatifloxacin或者其盐的含水液体制剂中掺入乙二胺四乙酸二钠来提高Gatifloxacin的角膜渗透性的方法,防止Gatifloxacin晶体沉淀的方法,和防止Gatifloxacin变色的方法。

Description

含水液体药物组合物
发明领域
本发明涉及含有喹诺酮羧酸衍生物Gatifloxacin(化学命名：(±)-1-环丙基-6-氟-1，4-二氢-8-甲氧基-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸)作为主要成分的含水液体药物组合物。此外，本发明涉及提高Gatifloxacin的角膜渗透性的方法，防止Gatifloxacin晶体沉淀的方法，和防止Gatifloxacin变色的方法。
发明背景
Gatifloxacin是一种新的喹诺酮抗微生物剂，已认识到该化合物具有强的抗微生物活性，不仅抗革兰氏阴性细菌而且抗革兰氏阳性细菌，厌氧微生物和支原体。之后，其被建议用于眼科感染疾病，例如结膜炎，泪囊炎，麦粒肿等等和耳鼻科感染疾病，例如外耳炎，中耳炎，窦炎等等(参见JP-B8-9597)。
为了设计含有抗微生物剂的滴眼液形式的药物制剂，一种指标是要提高药剂的角膜渗透性以提高药剂转移到体液中的量。但是，一般情况下，对眼施用的药剂由于眼泪的稀释和角膜的屏障作用而很难进入眼睛内部。因此，曾建议过使用吸收增强剂的方法作为提高药剂角膜渗透性的方法。另外，曾建议过使用粘性基质材料的方法来提高眼节段前部处的药剂滞留性。
发明目的
关于Gatifloxacin，尽管建议过其应用于眼科或耳鼻科感染疾病，但是还没有报道过其含水液体药物组合物能够实际性对眼施用例如进入到眼睛内部的局部给药，稳定性等等的研究。
在这样的背景下，本发明的一个目的是允许在眼科或耳鼻科领域实际性施用Gatifloxacin，特别是，提供含有有效成分Gatifloxacin的含水液体药物组合物。
发明概述
本发明人充分研究了在眼科领域应用Gatifloxacin，结果发现Gatifloxacin和乙二胺四乙酸二钠的共同存在能实现该目的。
乙二胺四乙酸二钠被认为降低角膜上皮细胞中的钙浓度并且扩张细胞间隙，从而促进水溶解性药物进入眼睛内部。但是药物角膜渗透性的提高取决于乙二胺四乙酸二钠的浓度(药物科学杂志(Journalof Pharmaceutical Science)，77：3-14，1988)，并且当前一般情况下，一般以0.5％这样高的浓度使用乙二胺四乙酸二钠(InvestigativeOphthalmology & Visual Science，26：110-113，1985；ExperimentalEye Research，54：747-757，1992；Pharmaceutical Research，12：1146-1150)。不管怎样，本发明人发现可以在低乙二胺四乙酸二钠浓度下提高Gatifloxacin的角膜渗透性。
此外，已知Gatifloxacin的溶解度取决于pH，并且其在大约生理pH处的溶解度非常低。因此，为了在含水液体药物组合物中溶解足够量的Gatifloxacin，组合物的pH应该调节到酸性或碱性范围，这在局部施用时会引起刺激之类的问题。但是，本发明人也发现在大约生理pH处的Gatifloxacin的溶解度由于其与乙二胺四乙酸二钠的共同存在而提高。
本发明是在本发明人这些新的发现的基础上完成的，根据本发明，提供含有Gatifloxacin或者其盐和乙二胺四乙酸二钠的含水液体药物组合物。特别是，本发明含水液体药物组合物是含有Gatifloxacin或者其盐和乙二胺四乙酸二钠的水溶液。
此外，本发明提供提高Gatifloxacin的角膜渗透性的方法，该方法包括将乙二胺四乙酸二钠掺入到含有Gatifloxacin或者其盐的滴眼液中；防止Gatifloxacin晶体沉淀的方法，该方法包括将乙二胺四乙酸二钠掺入到含有Gatifloxacin或者其盐的含水液体制剂中；和防止Gatifloxacin变色的方法，该方法包括将乙二胺四乙酸二钠掺入到含有Gatifloxacin或者其盐的含水液体制剂中。
根据下面的描述，本发明的该目的以及其它目的和本发明的优点对于本领域技术人员变得清楚。
发明详述
在本发明中，Gatifloxacin或者其盐被用作有效成分。本发明中使用的Gatifloxacin的盐的例子包括与无机酸例如盐酸，硫酸，磷酸等的那些盐；与有机酸例如甲磺酸，乳酸，草酸，乙酸等的那些盐；或者与钠，钾，镁，钙，铝，铯，铬，钴，铜，铁，锌，铂，银等的那些盐。
一般情况下，在本发明的含水液体药物组合物中配制的Gatifloxacin或者其盐(下文有时简单称之为“Gatifloxacin”)的量根据具体患者感染的程度而不同，但是，一般情况下，在0.1-1.0w/v％，优选0.1-0.8w/v％，更优选0.3-0.5w/v％的范围内配制Gatifloxacin。
一般情况下，以0.001-0.2w/v％，优选0.005-0.1w/v％，更优选0.01-0.1w/v％的量配制乙二胺四乙酸二钠。
一般情况下，本发明的含水液体药物组合物被调节到pH5-8，优选pH5.5-7.5，更优选pH6-7。
如果需要，本发明的含水液体药物组合物可以进一步含有合适的添加剂，例如等渗剂(例如氯化钠，氯化钾，硼酸，甘油，丙二醇，甘露糖醇，山梨糖醇，葡萄糖等等)；缓冲液(例如磷酸盐缓冲溶液，乙酸盐缓冲溶液，硼酸盐缓冲溶液，柠檬酸盐缓冲溶液，谷氨酸，ε-氨基己酸等等)；防腐剂(例如氯苄烷铵，氯苄乙铵，葡萄糖酸洗必太，氯丁醇，苄醇，脱氢乙酸钠，对羟基苯甲酸盐等等)，增稠剂(例如甲基纤维素，羟乙基纤维素，羟丙基甲基纤维素，羧甲基纤维素，透明质酸钠，羧基乙烯基聚合物，聚乙烯醇，聚乙烯吡咯烷酮，Macrogol(聚乙二醇)等等)，pH调节剂(例如盐酸，氢氧化钠，乙酸，磷酸等等)等等。
本发明的含水液体药物组合物能够通过本身已知的方法制备。例如，可以通过第十三版日本药典，制品通则，“眼科溶液”或“液体和溶液”部分中描述的方法制备。
本发明的含水液体药物组合物具有抗微生物活性并且能够用于预防和治疗睑炎，麦粒肿，泪腺炎，结膜炎，睑板炎，角膜炎，角膜溃疡，术后感染等等。为了该目的，以每次一滴的剂量每天大约三次向眼中滴入组合物。对于外耳炎或中耳炎，一般情况下以每次6-10滴的剂量每天两次向耳中滴入组合物。此外，对于鼻窦炎，一般情况下以每次2-4ml的剂量一周中隔天三次喷入或吸入组合物，或者可以以每次1ml的剂量每周一次在上颌骨窦中施用。使用剂量可以根据具体疾病症状的程度而加大或减小。
通过下面的实验和实施例进一步详细描述本发明，但是本发明不局限于此。
实验1
乙二胺四乙酸二钠对Gatifloxacin转移到体液的影响
方法
根据表1的配方，制备Gatifloxacin的滴眼液(配方A-C)。向雄性日本白兔(体重：大约2千克)的眼中一次滴入其中一种滴眼液(50μl/眼)。滴入后1小时，采集体液，并且通过HPLC测定Gatifloxacin浓度。
表1
    配方      A      B      C
Gatifloxacin     0.5g     0.5g     0.5g
乙二胺四乙酸二钠     -     -     0.05g
氯化钠     0.9g     0.9g     0.9g
盐酸     适量     适量     适量
氢氧化钠     适量     适量     适量
灭菌纯化水  至总量100ml  至总量100ml  至总量100ml
pH     7.0     6.0     6.0
结论
表2给出了滴入后1小时时，体液中Gatifloxacin的浓度。
当pH降低时，转移到体液的Gatifloxacin的量减少。与用作对照物的配方A(pH7.0)和B(pH6.0)相比，对于调节到pH6.0的配方(配方C)，转移到体液中的量分别增加大约1.2倍和1.5倍。
由于通常用于提高角膜渗透性的乙二胺四乙酸二钠的浓度是0.5w/v％，这些结果表明，即使使用占通常使用量的1/10量的乙二胺四乙酸二钠也提高了Gatifloxacin的角膜渗透性。
表2
   配方     体液中Gatifloxacin的浓度(μg/ml)
    A               1.61±0.43
    B               1.30±0.42
    C               1.93±0.95
实验2
乙二胺四乙酸二钠对Gatifloxacin结晶沉淀的影响
方法
根据表3的配方，制备Gatifloxacin的含水液体制剂(配方B-D)。每一种溶液装入5ml玻璃安瓿中。使安瓿在-30℃下冷冻(过夜)，然后在室温下融化并重复如此操作，以观察Gatifloxacin结晶的沉淀作用。
表3
    配方      B      C      D
Gatifloxacin     0.5g     0.5g     0.5g
乙二胺四乙酸二钠     -     0.05g     0.1g
氯化钠     0.9g     0.9g     0.9g
盐酸     适量     适量     适量
氢氧化钠     适量     适量     适量
灭菌纯化水 至总量100ml 至总量100ml 至总量100ml
pH     6.0     6.0     6.0
结论
在其中没有配入乙二胺四乙酸二钠的制剂(配方B)中，当冷冻和融化重复两次至三次时晶体沉淀。相反，当配入乙二胺四乙酸二钠(配方C和D)时，即使冷冻和融化重复10次也没有发现晶体沉淀。
这些结果表明在Gatifloxacin的含水液体制剂中配入乙二胺四乙酸二钠，可防止低温贮存条件下Gatifloxacin晶体的沉淀作用。
实验3
乙二胺四乙酸二钠对防止Gatifloxacin变色的影响
方法
向8cm直径不锈钢(SUS316)烧杯的灭菌纯化水(80ml)中加入氯化钠(0.86g)和0.1mol/升盐酸(5.2ml)，并且搅拌混合物。然后将Gatifloxacin(0.32g)和乙二胺四乙酸二钠(终浓度是0％，0.001％，0.005％，0.01％或0.05％)加入并溶解于其中。用0.1mol/升氢氧化钠将溶液调节到pH6.5，并且将总体积补足至100ml，得到Gatifloxacin的含水液体制剂。用差示比色计(Minolta生产的Chroma meterCT-210C，光源Lab平台系统)测定含水液体制剂和灭菌纯化水之间的色差。作为对照，使用在玻璃烧杯中制备的Gatifloxacin的含水液体制剂。
结论
测定的色差见表4。
玻璃烧杯中制备的并且用作对照的含水液体制剂具有1.9-2.0的色差并且是淡黄色的。另一方面，不锈钢烧杯中制备的含水液体制剂在不加入乙二胺四乙酸二钠情况下具有3.17的色差，在加入0.01％乙二胺四乙酸二钠情况下具有2.42的色差。其分别具有浅黄色和淡黄色。因此，它们是由于配入乙二胺四乙酸二钠而褪色。
从这些结果来看，认为从不锈钢烧杯制备中溶解的金属离子使Gatifloxacin变色。此外这些结果表明，加入乙二胺四乙酸二钠可以防止Gatifloxacin变色。
表4
  乙二胺四乙酸二钠的浓度(％)      色差       色差
  不锈钢烧杯     玻璃烧杯
    0     3.17     1.90
    0.001     3.08     1.93
    0.005     3.05     2.02
    0.01     2.42     1.94
    0.05     2.19     1.93
实施例1
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                        量
Gatifloxacin                                0.5g
乙二胺四乙酸二钠                            0.1g
氯化钠                                      0.9g
盐酸                                        适量
氢氧化钠                                    适量
灭菌纯化水                                  至100ml
pH                                          7.0
实施例2
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                        量
Gatifloxacin                                0.5g
乙二胺四乙酸二钠                           0.05g
氯化钠                                     0.9g
盐酸                                       适量
氢氧化钠                                   适量
灭菌纯化水                                 至100ml
pH                                         7.0
实施例3
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                       量
Gatifloxacin                               0.5g
乙二胺四乙酸二钠                           0.1g
磷酸二氢钠                                 0.1g
氯化钠                                     0.9g
盐酸                                       适量
氢氧化钠                                   适量
灭菌纯化水                                 至100ml
pH                                         7.0
实施例4
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                       量
Gatifloxacin                               0.3g
乙二胺四乙酸二钠                           0.05g
氯化钠                                     0.9g
盐酸                                       适量
氢氧化钠                                   适量
灭菌纯化水                                 至100ml
pH                                         6.0
实施例5
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                       量
Gatifloxacin                               0.5g
乙二胺四乙酸二钠                           0.01g
甘油                                       2.6g
氯苄烷铵                                   0.005g
盐酸                                       适量
氢氧化钠                                   适量
灭菌纯化水                                 至100ml
pH                                         7.5
实施例6
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                       量
Gatifloxacin                               0.5g
乙二胺四乙酸二钠                           0.05g
氯化钠                                     0.9g
盐酸                                       适量
氢氧化钠                                   适量
灭菌纯化水                                 至100ml
pH                                         5.5
实施例7
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                       量
Gatifloxacin                               0.3g
乙二胺四乙酸二钠                           0.05g
氯化钠                                     0.9g
羟丙基甲基纤维素                           0.1g
对羟基苯甲酸甲酯                           0.026g
对羟基苯甲酸丙酯                           0.014g
盐酸                                       适量
氢氧化钠                                   适量
灭菌纯化水                                至100ml
pH                                        6.0
实施例8
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                      量
Gatifloxacin                              0.5g
乙二胺四乙酸二钠                          0.01g
氯化钠                                    0.83g
氯苄烷铵                                  0.005g
盐酸                                      适量
氢氧化钠                                  适量
灭菌纯化水                                至100ml
pH                                        5.5
实施例9
根据常规方法制备具有下面配方的滴眼水溶液，滴耳水溶液和滴鼻水溶液。
成分                                      量
Gatifloxacin                              0.3g
乙二胺四乙酸二钠                          0.01g
氯化钠                                    0.86g
氯苄烷铵                                  0.005g
盐酸                                      适量
氢氧化钠                                  适量
灭菌纯化水                                至100ml
pH                                        6.0
如实验1所示，根据本发明的滴眼液，即使使用通常使用量的1/10的量的乙二胺四乙酸二钠也能提高有效成分Gatifloxacin的角膜渗透性。此外，如实验2所示，本发明的含水液体制剂能够防止如低温的贮存条件下的Gatifloxacin晶体的沉淀作用。此外，如实验3所示，能够防止金属离子引起的Gatifloxacin变色。因此，本发明的含水液体制剂是非常有用的。

Claims (8)

1.含水液体药物组合物，其含有Gatifloxacin或者其盐和乙二胺四乙酸二钠。
2.权利要求1的含水液体药物组合物，其中组合物的pH在5-8范围内。
3.权利要求1或2的含水液体药物组合物，其中组合物是滴眼液形式。
4.权利要求1或2的含水液体药物组合物，其中组合物是滴耳液形式。
5.权利要求1或2的含水液体药物组合物，其中组合物是滴鼻液形式。
6.一种提高Gatifloxacin的角膜渗透性的方法，其包括向含有Gatifloxacin或者其盐的滴眼液中掺入乙二胺四乙酸二钠。
7.一种防止Gatifloxacin结晶沉淀的方法，其包括向含有Gatifloxacin或者其盐的含水液体制剂中掺入乙二胺四乙酸二钠。
8.一种防止Gatifloxacin变色的方法，其包括向含有Gatifloxacin或者其盐的含水液体制剂中掺入乙二胺四乙酸二钠。
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