CN101137383B - 增强型比马前列素眼用溶液 - Google Patents
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Abstract
本文公开了一种组合物,包括以重量百分比计0.005%至0.02%的比马前列素和100ppm至250ppm的苯扎氯胺,其中所述组合物是按配方配制的用于眼用给药的水成液。此外本文也公开了一种可用于治疗青光眼或相关的高眼压症的方法。
Description
技术领域
本发明涉及到包括比马前列素的药物组合物。
背景技术
相关技术说明
比马前列素,如下所示,为一种市售的用于治疗青光眼和高眼压症的前列腺酰胺(prostamide)。
化学式I
苯扎氯胺(BAK)为一种防腐剂,用于很多市售眼用产品来防止在多次使用产品中的微生物污染。市售滴眼剂(Bimatoprost,Allergan,Irc.,Irvine,CA)含有0.03%比马前列素和0.005%BAK。尽管现在没有其它市售的用于治疗青光眼的比马前列素,但是有几种市售的含有BAK作为防腐剂的前列腺素类似物。这些前列腺素类似物包括拉坦前列素(Xalatan)、曲伏前列素(Travatan)和异丙基乌诺前列酮(Rescula),这些前列腺素需要相当多的150至200ppm的BAK,,来达到美国和欧洲的抗菌效果测试的要求。
美国专利No.6,596,765 B2公开了一种组合物,含有0.005%或0.0005%的拉坦前列素和0.2mg/mL的BAK。
美国专利No.6,646,001 B2公开了组合物,含有0.03%的比马前列素和0.01%的BAK或“0.01%+5%过量”的BAK。
附图说明
图1为一幅给出了在几种制剂的局部给药后,比马前列素母酸的房水浓度的图。
图2为一幅给出了在几种不同制剂中,比马前列素的膜渗透性的图。
发明内容
本文公开了一种组合物,包括以重量百分比计0.005%至0.02%的比马前列素和100ppm至250ppm的苯扎氯胺,其中所述组合物是按配方配制的用于眼部给药的水成液。
此外本文也公开了一种可用于治疗青光眼或相关的高眼压症的方法。
配制出了一种按配方配制用于眼用给药的水成液,使得它可以被局部给药至眼部。应尽可能地使被给药者感到舒适,但是有时出于配方的考虑(如药物稳定性)可能无法达到最佳的舒适感。
在某些组合物中比马前列素的浓度为0.01%至0.02%。在另一些组合物中比马前列素的浓度为0.015%至0.02%。
在某些组合物中BAK的浓度为150ppm至200ppm。在另一些组合物中BAK的浓度为150ppm至200ppm。在另一些组合物中BAK的浓度为150ppm至250ppm。
在眼用组合物中,可以使用一种螯合剂来增强防腐剂效果。适宜的螯合剂在本领域中是已知,并非为了限制,乙二胺四乙酸盐(EDTA)为可用的螯合剂。
在某些组合物中EDTA的浓度为至少0.001%。在另一些组合物中EDTA的浓度为至少0.01%。在另一些组合物中EDTA的浓度为0.15%或更少。在另一些组合物中EDTA的浓度为0.1%或更少。在另一些组合物中EDTA的浓度为0.05%或更少。
某些组合物包含150至250ppm的BAK和有效量的EDTA。
如本领域中已知的,经常使用缓冲液将pH值调整到一个所需的适于眼用的范围。通常需要6-8左右的pH值,而且在某些组合物中需要7.4的pH值。已知许多包括无机酸盐的缓冲液,如磷酸盐,硼酸盐和硫酸盐。
另外一种在眼用组合物中常用的赋形剂为粘度增强剂或增稠剂。使用增稠剂可出于各种原因,包括从改良制剂形式以方便给药,到增加与眼球接触以提高生物利用度。粘度增强剂可以包括含亲水基团的聚合物,亲水基团如单糖、多糖、环氧乙烷基团、羟基基团、羧酸或其他带电官能团。并非为了限制本发明的范围,一些有用的粘度增强剂的实例为羧甲基纤维素钠、羟丙基甲基纤维素、聚维酮、聚乙烯醇和聚乙二醇。
在眼用溶液中,经常使用张度剂将制剂的组成调整到所需的等渗范围。张度剂是本领域熟知的,一些实例包括丙三醇、甘露醇、山梨糖醇、氯化钠和其它电解质。
一种组合物的pH值为7.4,且基本由0.015%比马前列素、200ppm苯扎氯胺、0至0.03%的EDTA、磷酸盐缓冲液、NaCl和水组成。
另一种组合物的pH值为7.4,且包括0.02%比马前列素、200ppm苯扎氯胺、0至0.03%的EDTA、磷酸盐缓冲液、NaCl和水。
另一种组合物的pH值为7.4,且由0.01%比马前列素、200ppm苯扎氯胺、0至0.03%的EDTA、磷酸盐缓冲液、NaCl和水组成。
在下面的实例中描述了制造和使用本发明组合物的最好方式。这些实例只是为如何制造和使用本发明组合物提供了方向和指导,并不意在以任何方式限制本发明的范围。
一个实施方案包括0.01%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水,其中pH值为7.3。
另一个实施方案包括0.015%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水,其中pH值为7.3。
另一个实施方案包括0.015%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、0.03%EDTA和水,其中pH值为7.3。
另一个实施方案包括0.02%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水,其中pH值为7.3。
另一个实施方案基本由0.01%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水组成,其中pH值为7.3。
另一个实施方案基本由0.015%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水组成,其中pH值为7.3。
另一个实施方案基本由0.015%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、0.03%EDTA和水组成,其中pH值为7.3。
另一个实施方案基本由0.02%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水组成,其中pH值为7.3。
另一个实施方案由0.01%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水组成,其中pH值为7.3。
另一个实施方案由0.015%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水组成,其中pH值为7.3。
另一个实施方案由0.015%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、0.03%EDTA和水组成,其中pH值为7.3。
另一个实施方案由0.02%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠和水组成,其中pH值为7.3。
另一个实施方案包括0.0125%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水。
另一个实施方案基本由0.0125%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水组成。
另一个实施方案由0.0125%的比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水组成。
实施例1
用本领域熟知的常规方法来制备制剂,这些制剂含有0.268%七水磷酸氢二钠、0.014%柠檬酸、0.83%氯化钠,在qs(质量安全)水中将pH调整至7.3,且比马前列素、BAK和EDTA的量列于下表1中。
表1
制剂 |
1.0.03%比马前列素(50ppm BAK)对照 |
2.0.03%比马前列素-200ppm BAK |
3.0.03%比马前列素-0.015%TPGS(无防腐剂) |
4.0.03%比马前列素-0.2%TPGS(无防腐剂) |
5.0.03%比马前列素-0.4%TPGS(无防腐剂) |
6.0.03%比马前列素-1.0%TPGS(无防腐剂) |
实施例2
在体内进行研究来测定苯扎氯胺(BAK)和d-α维生素E琥珀酸聚乙二醇1000酯(TPGS)对于比马前列素的眼部吸收的影响。在该体内实验中,对十八只雌兔的两眼各加一滴28μL眼药水,并且收集用药后60分钟时的房水样品(每种制剂分配n=3只动物6只眼睛)。两只兔子(4只眼睛)未被处理以作为未用药的生物分析对照。用液相色谱串联质谱(LC-MS/MS)法分析从房水和体外样品中提取的比马前列素及其母体羧酸,定量范围为0.25-60ng/mL。
由于比马前列素在兔眼中的广泛代谢,其母酸被用作代替品来测定比马前列素的眼部吸收。图1和下表2总结了用6种不同的比马前列素制剂单次给药后兔房水中的酸浓度。
表2
制剂 | 房水a(ng/mL) |
1.0.03%比马前列素(50ppm BAK)对照 | 51.0±9.4 |
2.0.03%比马前列素-200ppm BAK | 87.2±19.0* |
3.0.03%比马前列素-0.015%TPGS(无防腐剂) | 26.1±3.3* |
4.0.03%比马前列素-0.2%TPGS(无防腐剂) | 22.9±3.2* |
5.0.03%比马前列素-0.4%TPGS(无防腐剂) | 19.3±5.6* |
6.0.03%比马前列素-1.0%TPGS(无防腐剂) | 15.4±3.3* |
a平均值±SD。每个制剂,N=3只兔子(6只眼睛)
*与0.03%比马前列素相比的统计学差异(p<0.05)
与比马前列素对照相比,含有0.015%、0.2%、0.4%和1.0%TPGS的测试制剂使得房水羧酸浓度分别降低了52%、59%、62%和72%。相反,与比马前列素(50ppm BAK)相比,含200ppm BAK的0.03%比马前列素会导致房水AGN 191522浓度提高57%。
并非以任何方式或理论限制本发明,与比马前列素对照相比,含有TPGS的制剂会导致比马前列素渗透性的下降。相比而言,含较高BAK含量的制剂会导致较高的渗透性。
实施例3
用本领域熟知的常规方法来制备制剂,这些制剂含有0.268%七水磷酸氢二钠、0.014%柠檬酸、0.83%氯化钠,在qs(质量安全)水中将pH调整至7.3,且比马前列素、BAK和EDTA的量列于下面表3中。
表3
制剂 |
A.0.03%比马前列素(50ppm BAK)-对照 |
B.0.015%比马前列素(50ppm BAK) |
C.0.015%比马前列素(50ppm BAK)0.03%EDTA |
D.0.015%比马前列素(200ppm BAK) |
E.0.015%比马前列素(200ppm BAK)0.03%EDTA |
F.0.015%比马前列素(50ppm BAK)0.015%EDTA |
G.0.015%比马前列素(200ppm BAK)0.015%EDTA |
H.0.015%比马前列素(125ppm BAK) |
I.0.015%比马前列素(125ppm BAK)0.03%EDTA |
J.0.015%比马前列素(125ppm BAK)0.015%EDTA |
K.0.015%比马前列素(150ppm BAK) |
L.0.015%比马前列素(150ppm BAK)0.1%EDTA |
M.0.015%比马前列素 |
N.0.03%比马前列素 |
实施例4
苯扎氯胺(BAK)和乙二胺四乙酸(EDTA)对于比马前列素穿过兔角膜上皮细胞层(RCECL)原代培养系时的渗透性的影响。角膜上皮细胞采集自新西兰白兔,并在TranswellTM filters上培养至汇合(5天)。对于转运实验,细胞首先在37℃下用转运缓冲液平衡1小时。然后将含有0.015%或0.03%比马前列素和各个浓度BAK和EDTA的剂量溶液加到TranswellTM的顶区室(两个培养系;每个培养系n=3-4),且细胞在37℃下孵育。为测试从顶部到基底外侧的(AB)转运,在给药后30、60、90和120分钟时,分别从基底外侧室取出200μL样品。用液相色谱串联质谱(LC-MS/MS)来分析样品,定量范围为1-600ng/mL。
结果在图2中示出。
实施例5
每天一次,给一个患有青光眼的人的眼睛局部给药一滴制剂J。几小时后,观察到与制剂A相比,制剂J使眼内压下降更多,眼内充血更少。只要治疗一直持续,就可以一直保持较低的眼内压。
Claims (16)
1.一种组合物,包括以重量百分比计0.005%至0.02%的比马前列素和100ppm至250ppm的苯扎氯胺,其中所述组合物是按配方配制的用于眼用给药的一种水成液。
2.权利要求1的组合物,进一步包括EDTA。
3.权利要求2的组合物,其中苯扎氯胺的浓度为150ppm至200ppm。
4.权利要求1的组合物,其中比马前列素的浓度为0.01%至0.02%。
5.权利要求4的组合物,其中比马前列素的浓度为0.015%至0.02%。
6.权利要求5的组合物,其中苯扎氯胺的浓度为150ppm至200ppm。
7.权利要求6的组合物,其中苯扎氯胺的浓度为200ppm。
8.权利要求5的组合物,进一步包括EDTA。
9.权利要求8的组合物,pH值为7.4,其包括0.015%比马前列素、200ppm苯扎氯胺、0至0.03%的EDTA、磷酸盐缓冲液和NaCl。
10.权利要求9的组合物,pH值为7.4,所述组合物由0.015%比马前列素、200ppm苯扎氯胺、0至0.03%的EDTA、磷酸盐缓冲液、NaCl和水组成。
11.一种组合物,包括以重量百分比计0.005%至0.02%比马前列素和100ppm至250ppm苯扎氯胺,在制备用于治疗青光眼或高眼内压症的药剂中的用途。
12.权利要求2的组合物,包括0.001%至0.15%的EDTA。
13.权利要求12的组合物,包括0.01%至0.1%的EDTA。
14.权利要求13的组合物,包括0.01%至0.05%的EDTA。
15.权利要求2的组合物,包括150ppm至250ppm BAK。
16.权利要求4的组合物,包括0.0125%比马前列素、0.02%苯扎氯胺、0.268%七水磷酸氢二钠、0.014%一水柠檬酸、0.81%氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水。
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Non-Patent Citations (4)
Title |
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Hitoshi Sasaki, et.al.,.ophthalmic preservatives as absorption promoters foroculardrug delivery.j pharm pharmacol47 9.1995,47(9),703-707. * |
HitoshiSasaki et.al. |
董智.露泌根.中国新药杂志11 2.2002,11(2),172-174. |
董智.露泌根.中国新药杂志11 2.2002,11(2),172-174. * |
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