CN1684688A - 以拉坦前列素为有效成分的稳定的滴眼液 - Google Patents
以拉坦前列素为有效成分的稳定的滴眼液 Download PDFInfo
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- CN1684688A CN1684688A CNA038226960A CN03822696A CN1684688A CN 1684688 A CN1684688 A CN 1684688A CN A038226960 A CNA038226960 A CN A038226960A CN 03822696 A CN03822696 A CN 03822696A CN 1684688 A CN1684688 A CN 1684688A
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- latanoprost
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- 229960001160 latanoprost Drugs 0.000 title claims abstract description 78
- 239000004480 active ingredient Substances 0.000 title 1
- 239000006210 lotion Substances 0.000 title 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229960002684 aminocaproic acid Drugs 0.000 claims abstract description 25
- 239000003889 eye drop Substances 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 8
- 239000004615 ingredient Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 abstract description 13
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- 239000002997 ophthalmic solution Substances 0.000 abstract 2
- 229940110775 latanoprost ophthalmic solution Drugs 0.000 abstract 1
- 239000012530 fluid Substances 0.000 description 25
- 239000012153 distilled water Substances 0.000 description 21
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- 230000004410 intraocular pressure Effects 0.000 description 1
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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Abstract
本发明提供一种可在室温下保存的、稳定性优良的拉坦前列素滴眼液。本发明的滴眼液是以拉坦前列素为有效成分的滴眼液，其特征为利用选自下述1)和2)中的至少一种方法将拉坦前列素稳定至可在室温下保存，所述方法为1)将pH调整至5.0～6.25的方法，2)添加ε－氨基己酸的方法。
Description
技术领域
本发明提供一种能够保存于室温下的拉坦前列素滴眼液。
背景技术
拉坦前列素(latanoprost)为以化学名(Z)-7[(1R，2R，3R，5S)3，5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]-5-庚酸异丙酯表示的前列腺素类青光眼治疗药。拉坦前列素为选择性的FP受体激动剂，通过促进房水流出而降低眼压(日本专利第2721414号公报)。拉坦前列素的给药途径为滴眼给药，市场有售含0.005％拉坦前列素的滴眼液(商品名：Xalatan滴眼液)(以下称为“市售滴眼液”)。如其附带的说明书所述，该市售滴眼液的pH设定为6.7，含有的添加剂为苯扎氯铵、氯化钠、磷酸二氢钠·一水合物、以及无水磷酸氢二钠。
但是，上述市售滴眼液的稳定性差，因此保存条件为避光环境中阴冷处(2～8℃)保存。
已有报道上述市售滴眼液对温度及光稳定性的论文(Journal ofGlaucoma，10(5)，401-405，2001)。但是还没有关于含拉坦前列素的滴眼液的稳定化方法的报道。
发明内容
如上所述，由于上述市售滴眼液不便保存，因而希望开发出能够在室温下保存、稳定性优良的拉坦前列素滴眼液。
本发明人等首先着眼于上述市售滴眼液的pH被设定为6.7的事实，深入研究了pH对拉坦前列素稳定性的影响。结果发现，拉坦前列素在pH偏碱性或者过于偏酸性时稳定性均变差，而将pH调整至特定的范围5.0～6.25时较为稳定，能够得到可在室温下保存的拉坦前列素滴眼液。
另外还着眼于添加剂，深入地研究了各种添加剂对拉坦前列素稳定性的影响，结果发现添加ε-氨基己酸时拉坦前列素较为稳定，能够得到可在室温下保存的拉坦前列素滴眼液。
即，通过本发明，可提供一种稳定的滴眼液，是以拉坦前列素为有效成分的滴眼液，其特征为通过利用选自下述1)和2)中的至少一种方法，可在室温下保存拉坦前列素。
1)将pH调整至5.0～6.25的方法
2)添加ε-氨基己酸的方法
本发明的滴眼液中有效成分拉坦前列素的浓度优选为0.001～0.01％(W/V)，特别优选为0.005％(W/V)。
本发明的滴眼液的特征之一为将pH调整至5.0～6.25使拉坦前列素稳定化。该pH范围为滴眼液允许的pH范围。在实施例项的试验例中进行了详细说明，可知拉坦前列素的稳定性受pH改变的影响较大。
为了将pH调整至5.0～6.25，可以使用pH调整剂。作为pH调整剂，例如可以举出盐酸、枸橼酸、磷酸、醋酸、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠等。
另外，除了调整pH，也可以通过添加ε-氨基己酸使拉坦前列素稳定化。ε-氨基己酸的浓度根据拉坦前列素的浓度决定，通常为0.1～2％(W/V)，特别优选为0.2～1％(W/V)。还发现采用该添加ε-氨基己酸的方法时，即使在更接近中性、即pH7.0附近也能够保持稳定性。
可以使用各种添加剂使滴眼液稳定化，从后述稳定化试验项中可以明确，众多添加剂中特别是ε-氨基己酸显示出了优良的拉坦前列素稳定化效果。
显然，也可以将pH调整至5.0～6.25并配合ε-氨基己酸作为添加剂，这样可期待二者的协同效果。
配制本发明的滴眼液时，除了上述pH调整剂及ε-氨基己酸之外，可以根据需要加入缓冲剂、等渗剂、助溶剂、防腐剂、增粘剂等添加剂。
作为缓冲剂例如可以举出磷酸及其盐、硼酸及其盐、枸橼酸及其盐、醋酸及其盐、酒石酸及其盐、氨基丁三醇等。
作为等渗剂例如可以举出甘油、丙二醇、氯化钠、氯化钾、山梨糖醇、甘露醇等。
作为助溶剂例如可以举出聚山梨酯80、聚氧乙烯硬化蓖麻油60、聚乙烯二醇4000等。
作为防腐剂例如可以举出苯扎氯铵、苄索氯铵、山梨酸、山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯代丁醇等。
增粘剂例如可以举出羟丙甲基纤维素、羟丙基纤维素、聚乙烯基醇、羧乙烯聚合物、聚乙烯基吡咯烷酮等。
通过将有效成分为拉坦前列素的滴眼液的pH设定在5.0～6.25的范围内可使拉坦前列素稳定化。由此可提供能够在室温下保存、稳定性优良的拉坦前列素滴眼液。
另外，通过在拉坦前列素水溶液中添加ε-氨基己酸也可使拉坦前列素稳定化。由此可提供能够在室温下保存、稳定性优良的拉坦前列素滴眼液。
附图说明
图1为拉坦前列素滴眼液在60℃下保存时各种pH条件下的残存率经时变化的曲线图。
图2为拉坦前列素滴眼液在70℃下保存时各种pH条件下的残存率经时变化的曲线图。
图3为将在拉坦前列素中添加各种添加剂得到的试验液保存于50℃时的残存率经时变化的曲线图。
图4为将在拉坦前列素中添加各种添加剂得到的试验液保存于80℃时的残存率经时变化的曲线图。
具体实施方式
以下为本发明的实施例。实施例中配制的滴眼液在室温下均显示优良的稳定性。
实施例1
将1g结晶磷酸二氢钠溶解在约80ml的蒸馏水中，添加1N的氢氧化钠水溶液调整pH为5.0，继续添加蒸馏水使总量为100ml，以此为基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解。确认上述溶液冷至室温后pH为5.0。
实施例2
将1g结晶磷酸二氢钠溶解在约80ml的蒸馏水中，添加1N的氢氧化钠水溶液调整pH为5.5，继续添加蒸馏水使总量为100ml，以此为基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解。确认上述溶液冷至室温后pH为5.5。
实施例3
将1g结晶磷酸二氢钠溶解在约80ml的蒸馏水中，添加1N的氢氧化钠水溶液调整pH为6.0，继续添加蒸馏水使总量为100ml，以此为基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解。确认上述溶液冷至室温后pH为6.0。
实施例4
将1g结晶磷酸二氢钠溶解在约80ml的蒸馏水中，添加1N的氢氧化钠水溶液调整pH为6.25，继续添加蒸馏水使总量为100ml，以此为基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解。确认上述溶液冷至室温后pH为6.25。
实施例5
将1g结晶磷酸二氢钠、0.4g氯化钠、0.02g苯扎氯铵溶解在约80ml的蒸馏水中，调整pH为6.0，继续添加蒸馏水使总量为100ml，以此为基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解。确认了上述溶液冷至室温后pH为6.0。
然后，检查不同pH时拉坦前列素滴眼液的稳定性。
[拉坦前列素的稳定性试验1]
<试验方法>
1)称取0.0025g拉坦前列素置于50ml的烧杯中，加入50ml预先配制的各种pH的磷酸缓冲液(4.0、5.0、5.5、6.0、6.25、6.5、6.7、8.0)，全部以磁力搅拌器搅拌。在约为80℃的水浴中加热搅拌约30分钟使拉坦前列素溶解。
2)确认拉坦前列素已经溶解并确认pH值。
3)将各配制液分别取2.5ml填充至玻璃安瓶中熔封。
4)将其在60℃或者70℃下保存。
5)从开始保存后到第28天为止进行经时采样，利用高效液相色谱法测定拉坦前列素的含量，计算残存率。稳定性的判断标准为，60℃·28天保存后的残存率为95％或95％以上、70℃·28天保存后的残存率为90％或90％以上时认为是稳定的。
<结果>
60℃及70℃下保存的残存率经时变化分别在图1及图2中给出。保存28天后的残存率在表1中示出。由表1可知，保存于60℃下残存率为95％或95％以上的稳定样品的pH在5.0～6.25的范围内。同样，保存于70℃下残存率为90％或90％以上的稳定样品的pH也在5.0～6.25的范围内。
由以上结果可知，拉坦前列素滴眼液的pH设定为5.0～6.25时，可使拉坦前列素稳定化，能够在室温下保存。
另外，pH6.7的样品与前述市售滴眼液的pH相同，但pH为6.7时，70℃下保存28天的拉坦前列素残存率不足80％。
表1
拉坦前列素的稳定性(保存28天后的残存率％)
| pH4.0 | pH5.0 | pH5.5 | pH6.0 | pH6.25 | pH6.5 | pH6.7 | pH8.0 | |
| 60℃70℃ | 87.476.7 | 98.994.9 | 98.094.6 | 98.993.1 | 95.092.0 | 92.482.7 | 93.478.1 | 30.0*14.1** |
*第21天的值 **第12天的值
实施例6
将1gε-氨基己酸、1.8g浓甘油、及0.01g苯扎氯铵溶解在约80ml的蒸馏水中，调整pH为6.7，继续添加蒸馏水使总量为100ml，得到基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解在基液中。确认得到的溶液冷至室温后pH为6.7。
实施例7
将0.2gε-氨基己酸、2.3g浓甘油、0.01g苯扎氯铵溶解在约80ml的蒸馏水中，调整pH为6.7，继续添加蒸馏水使总量为100ml，得到基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解在基液中。确认得到的溶液冷至室温后pH为6.7。
实施例8
将1gε-氨基己酸、1.8g浓甘油、0.01g苯扎氯铵溶解在约80ml的蒸馏水中，调整pH为6.0，继续添加蒸馏水使总量为100ml，得到基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解在基液中。确认得到的溶液冷至室温后pH为6.0。
实施例9
将1gε-氨基己酸、1.8g浓甘油、0.01g苯扎氯铵溶解在约80ml的蒸馏水中，调整pH为7.0，继续添加蒸馏水使总量为100ml，得到基液。在5mg拉坦前列素中加入100ml基液，并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解在基液中。确认得到的溶液冷至室温后pH为7.0。
[拉坦前列素的稳定性试验2]
研究了各种添加剂对拉坦前列素稳定性的影响。使用结晶磷酸二氢钠、聚乙二醇400(PEG400)、聚乙二醇、海藻糖、异丙醇、α-环糊精、枸橼酸钠、ε-氨基己酸作为添加剂。为了避免pH改变产生的影响，在无缓冲能力的添加剂处方中加入结晶磷酸二氢钠。
<试验方法>
将添加剂分别溶解在约80ml蒸馏水中使其达到表2所示的浓度，调整pH为7.0，继续添加蒸馏水使总量为100ml，得到基液。分别在5mg拉坦前列素中加入100ml各种基液并在约80℃的水浴中边加温边搅拌使拉坦前列素溶解在基液中。确认得到的溶液冷至室温后pH为7.0。以该溶液作为试验液。在玻璃安瓶中分别装入约2.5ml各试验液，在恒温器中于50℃及80℃下保存。在规定时间后对试验液进行采样，利用高效液相色谱法测定拉坦前列素的含量，求出相对于保存前含量的残存率。
表2
| 处方1 | 处方2 | 处方3 | 处方4 | 处方5 | 处方6 | 处方7 | 处方8 | |
| 拉坦前列素 | 0.005％ | 0.005％ | 0.005％ | 0.005％ | 0.005％ | 0.005％ | 0.005％ | 0.005％ |
| 结晶磷酸二氢钠 | 1％ | 1％ | 1％ | 1％ | 1％ | 1％ | - | - |
| PEG400 | - | 1％ | - | - | - | - | - | - |
| 丙二醇 | - | - | 1％ | - | - | - | - | - |
| 海藻糖 | - | - | - | 1％ | - | - | - | - |
| 异丙醇 | - | - | - | - | 1％ | - | - | - |
| α-环糊精 | - | - | - | - | - | 0.11％ | - | - |
| 枸橼酸钠 | - | - | - | - | - | - | 1％ | - |
| ε-氨基己酸 | - | - | - | - | - | - | - | 1％ |
| 稀盐酸 | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. | q.s | q.s. |
| 氢氧化钠 | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. |
| 蒸馏水 | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. | q.s. |
| pH | 7.0 | 7.0 | 7.0 | 7.0 | 7.0 | 7.0 | 7.0 | 7.0 |
q.s.：适量
<结果>
50℃及80℃保存的残存率经时变化分别在图3及图4中示出。50℃·8周及80℃·4周保存后的残存率在表3中示出。由表3可知，50℃下保存时，添加了ε-氨基己酸的处方的残存率为90％或90％以上，ε-氨基己酸显示出优于其它添加剂的稳定化效果。另外，80℃下保存时，相比其它处方的残存率为30％或30％以下，添加了ε-氨基己酸的处方的残存率为51.8％，与50℃下保存的情况相同，ε-氨基己酸显示出优良的稳定化效果。
从上述结果可以知道，在拉坦前列素中添加ε-氨基己酸能够使拉坦前列素稳定，可在室温下保存。
表3
| 添加剂 | 50℃·保存8周 | 80℃·保存4周 | |
| 处方1 | 结晶磷酸二氢钠 | 88.7％ | 24.0％ |
| 处方2 | PEG400 | 88.8％ | 25.9％ |
| 处方3 | 丙二醇 | 88.1％ | 26.1％ |
| 处方4 | 海藻糖 | 83.7％ | 26.4％ |
| 处方5 | 异丙醇 | 88.9％ | 28.9％ |
| 处方6 | α-环糊精 | 86.6％ | 22.1％ |
| 处方7 | 枸橼酸 | 87.1％ | 6.3％ |
| 处方8 | ε-氨基己酸 | 93.1％ | 51.8％ |
产业实用性
本发明提供一种可在室温下保存的、稳定性优良的拉坦前列素滴眼液。
Claims (4)
1.一种滴眼液，是以拉坦前列素为有效成分的滴眼液，其特征为利用选自下述1)和2)中的至少一种方法，将拉坦前列素稳定至可在室温下保存，
1)将pH调整至5.0～6.25的方法；
2)添加ε-氨基己酸的方法。
2.如权利要求1所述的滴眼液，其中拉坦前列素的浓度为0.001％～0.01％(W/V)。
3.如权利要求1所述的滴眼液，其中拉坦前列素的浓度为0.001％～0.01％(W/V)，ε-氨基己酸的浓度为0.1％～2％(W/V)。
4.如权利要求3所述的滴眼液，其中拉坦前列素的浓度为0.005％(W/V)，ε-氨基己酸的浓度为1％(W/V)。
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| US6646001B2 (en) * | 1997-12-19 | 2003-11-11 | Alcon Manufacturing, Ltd. | Use of non-steroidal anti-inflammatory agents in combination with prostaglandin FP receptor agonists to treat glaucoma and ocular hypertension |
| EP1011728B1 (en) * | 1998-07-14 | 2004-12-29 | Alcon Manufacturing, Ltd. | Polypropylene containers for prostaglandin products |
| JP2001081048A (ja) * | 1999-09-10 | 2001-03-27 | Wakamoto Pharmaceut Co Ltd | 眼圧降下剤 |
| JP4757970B2 (ja) * | 1999-10-14 | 2011-08-24 | 久光製薬株式会社 | 点眼剤組成物 |
| PE20020146A1 (es) * | 2000-07-13 | 2002-03-31 | Upjohn Co | Formulacion oftalmica que comprende un inhibidor de ciclooxigenasa-2 (cox-2) |
| JP3876355B2 (ja) * | 2000-09-13 | 2007-01-31 | 参天製薬株式会社 | 点眼液 |
| ES2357551T3 (es) * | 2000-09-13 | 2011-04-27 | Santen Pharmaceutical Co., Ltd. | Colirio. |
| KR20050057251A (ko) * | 2002-09-09 | 2005-06-16 | 산텐 세이야꾸 가부시키가이샤 | 라타노프로스트를 유효 성분으로 하는 투명한 점안액 |
-
2003
- 2003-08-22 ES ES03795230T patent/ES2294361T3/es not_active Expired - Lifetime
- 2003-08-22 CA CA2496540A patent/CA2496540C/en not_active Expired - Fee Related
- 2003-08-22 AT AT03795230T patent/ATE374031T1/de active
- 2003-08-22 KR KR1020107026777A patent/KR20100132557A/ko not_active Application Discontinuation
- 2003-08-22 KR KR1020057002941A patent/KR101027454B1/ko not_active IP Right Cessation
- 2003-08-22 DE DE60316574T patent/DE60316574T2/de not_active Expired - Lifetime
- 2003-08-22 WO PCT/JP2003/010607 patent/WO2004024164A1/ja active IP Right Grant
- 2003-08-22 AU AU2003262268A patent/AU2003262268A1/en not_active Abandoned
- 2003-08-22 DK DK03795230T patent/DK1532981T3/da active
- 2003-08-22 PT PT03795230T patent/PT1532981E/pt unknown
- 2003-08-22 CN CNB038226960A patent/CN100361661C/zh not_active Expired - Fee Related
- 2003-08-22 US US10/524,996 patent/US20050228048A1/en not_active Abandoned
- 2003-08-22 CN CN200710089422A patent/CN100591333C/zh not_active Expired - Fee Related
- 2003-08-22 EP EP03795230A patent/EP1532981B1/en not_active Expired - Lifetime
-
2011
- 2011-01-10 US US12/930,521 patent/US20110118348A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110721260A (zh) * | 2019-10-29 | 2020-01-24 | 深圳市瑞霖医药有限公司 | 一种新型拉坦前列素滴眼液 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1532981A1 (en) | 2005-05-25 |
| CN100361661C (zh) | 2008-01-16 |
| US20110118348A1 (en) | 2011-05-19 |
| DE60316574T2 (de) | 2008-07-03 |
| US20050228048A1 (en) | 2005-10-13 |
| CA2496540A1 (en) | 2004-03-25 |
| DK1532981T3 (da) | 2008-01-28 |
| EP1532981A4 (en) | 2005-10-12 |
| EP1532981B1 (en) | 2007-09-26 |
| KR20050038624A (ko) | 2005-04-27 |
| WO2004024164A1 (ja) | 2004-03-25 |
| CA2496540C (en) | 2011-01-25 |
| ATE374031T1 (de) | 2007-10-15 |
| CN100591333C (zh) | 2010-02-24 |
| AU2003262268A1 (en) | 2004-04-30 |
| KR101027454B1 (ko) | 2011-04-06 |
| PT1532981E (pt) | 2007-12-12 |
| DE60316574D1 (de) | 2007-11-08 |
| KR20100132557A (ko) | 2010-12-17 |
| ES2294361T3 (es) | 2008-04-01 |
| CN101023927A (zh) | 2007-08-29 |
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