CN116687842A - 一种拉坦前列素滴眼液及其制备方法 - Google Patents
一种拉坦前列素滴眼液及其制备方法 Download PDFInfo
- Publication number
- CN116687842A CN116687842A CN202210185081.1A CN202210185081A CN116687842A CN 116687842 A CN116687842 A CN 116687842A CN 202210185081 A CN202210185081 A CN 202210185081A CN 116687842 A CN116687842 A CN 116687842A
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- China
- Prior art keywords
- latanoprost
- eye drops
- polyethylene glycol
- acid
- latanoprost eye
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 title claims abstract description 79
- 229960001160 latanoprost Drugs 0.000 title claims abstract description 77
- 239000003889 eye drop Substances 0.000 title claims abstract description 44
- 229940012356 eye drops Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims abstract description 38
- 230000003204 osmotic effect Effects 0.000 claims abstract description 12
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- 239000002736 nonionic surfactant Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 15
- 239000000600 sorbitol Substances 0.000 claims description 15
- 235000010356 sorbitol Nutrition 0.000 claims description 15
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- 239000004584 polyacrylic acid Substances 0.000 claims description 14
- -1 polyoxyethylene Polymers 0.000 claims description 12
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 10
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
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- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
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- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 claims description 2
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- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 claims description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
本发明属于药物制剂领域，具体涉及一种无防腐剂、单位剂量的拉坦前列素滴眼液及其制备方法。所述的拉坦前列素滴眼液包含渗透压调节剂、粘稠剂、非离子表面活性剂、稳定剂、pH值调节剂，新组方中无添加防腐剂，添加表面活性剂聚乙二醇4000，避免了防腐剂为角膜结膜疾病的主要病原，抑制树脂类容器吸附作用，可快速溶解得到分散均匀的拉坦前列素滴眼液，降低拉坦前列素难溶解的程度，增加水溶性滴眼液的稳定性，适用于工业生产。
Description
技术领域
本发明属于药物制剂领域，尤其涉及一种一种拉坦前列素滴眼液及其制备方法。
背景技术
青光眼主要是由眼压增高引起的机械性压迫和视神经缺血进而引发的眼部障碍疾病。眼压增高的原因有很多，但主要的原因是眼部房水动态循环遭到破坏而失去了平衡。临床上房水动态循环被破坏的原因主要有两种，一种是房水分泌过多，一种是房水流出机制发生障碍，后者情况在临床上占大多数。要知道，青光眼是导致失明的三大致盲性眼部疾病之一，也是不可逆转的致盲性眼病之首。同时，我国也是青光眼疾病的高发地区。
拉坦前列素化学名称为异丙基-(Z)-7[(1R,2R,3R,5S)3,5-二羟基-2-[(3R)-3-羟基-5-苯戊基]环戊基]-5-庚烯酸酯，化学分子结构式如下：
拉坦前列素是具有生理活性的前列腺素F2α类似物。对前列腺素受体即FP受体有高选择性，具有使房水的葡萄膜巩膜流出量增加而使眼压降低的效果，因此拉坦前列素水性滴眼液可作为青光眼的治疗剂，其广泛用作青光眼治疗。
市场上销售的拉坦前列素的滴眼液基本为含0.005％，浓度较低，通常采用塑料容器灌装，比如低密度聚乙烯瓶，这种树脂容器内壁易吸附有效成分，因接触溶液的面积较大，吸附程度更为严重，导致浓度本来就很较低的拉坦前列素浓度会更加的低，影响药品的有效性。
市场上销售的拉坦前列素滴眼液比如进口药品Xalatan，其附带的说明书所述，滴眼液的pH值设定为6.7，含有的添加剂为苯扎氯铵、氯化钠、一水磷酸二氢钠、无水磷酸氢二钠。其中防腐剂为0.02％苯扎氯铵，防腐剂苯扎氯铵不仅对细菌、真菌具有抗菌效果，还具有防止拉坦前列素降解和抑制其被树脂容器壁吸附的作用，但防腐剂0.02％苯扎氯铵也已知为角膜结膜疾病的主要病原，并且为安全起见优选尽可能低的苯扎氯铵类防腐剂，但因为其稳定化作用使其部分被树脂容器内壁吸附，浓度本来就很较低的苯扎氯铵浓度会更低，影响防腐作用。
拉坦前列素为前列腺素F2α类似物，为亲脂性物质，不溶于水，配制其水性溶液是一个难题，通过物理溶解方法和添加表面活性剂，改善拉坦前列素溶解性，也增加了溶液的稳定性。
另外，市场上销售的拉坦前列素滴眼液均为多剂量，多次开瓶使用有感染细菌、真菌的风险。
发明内容
针对上述提到的技术问题，本发明开发了一种单位剂量、无防腐剂的拉坦前列素滴眼液，每瓶为一次使用量，避免多次开瓶染菌的风险，为患者使用提供便利。
防腐剂虽具有防止拉坦前列素降解和抑制其被树脂容器壁吸附的作用，但其为角膜结膜疾病的主要病原，对患者健康造成威胁。
首先，在新的组方中无添加防腐剂，而另外添加表面活性剂聚乙二醇4000，可抑制树脂类容器吸附作用。
其次，拉坦前列素为脂溶性药物，配制其水溶性溶液难度高，在此基础上，提供开发了一种能够操作简单、溶解快速的方法，即增加表面活性剂聚乙二醇4000，并使用超声波超声溶解，可快速溶解得到分散均匀的拉坦前列素滴眼液。
再次，拉坦前列素为前列腺素F2α类似物，结构中含有羟基、双键等不稳定官能团，易受高温、光照及微生物的影响而发生分解反应，为保证其稳定性，发明的新组方中添加稳定剂依地酸二钠，有利于拉坦前列素滴眼液长期保存。
综上所述，本发明提供了一种单位剂量、无防腐剂的拉坦前列素滴眼液，所述的拉坦前列素滴眼液包含渗透压调节剂、粘稠剂、非离子表面活性剂、稳定剂、pH值调节剂。
所述渗透压调节剂为甘油、山梨醇、甘露醇、丙二醇、氯化钙、氯化钾、氯化钠；优选为山梨醇。
所述粘稠剂为羟丙基甲基纤维素、羧甲纤维素钠、甲基纤维素，聚乙烯吡咯烷酮、聚乙烯醇、葡聚糖和聚丙烯酸；优选为聚丙烯酸974P。
所述非离子表面活性剂为聚乙二醇4000、聚山梨酯60、聚山梨酯40、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、聚氧乙烯、聚乙二醇4000、普朗尼克F127、普朗尼克F68、聚乙二醇40硬脂酸酯和蔗糖脂肪酯；优选聚乙二醇4000。
所述稳定剂为亚硝酸钠、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、巯基乙酸钠、硫代苹果酸钠、天然维生素E、依地酸二钠；优选为依地酸二钠。
所述pH值调节剂为盐酸、硼酸、醋酸、氢氧化钠、碳酸氢钠、磷酸盐缓冲液、磷酸缓冲液、醋酸盐缓冲液；优选为氢氧化钠。
其中，所述聚乙二醇4000的量为0.05％-0.5％；优选为0.1％-0.5％；更优选为0.1％。
其中，所述依地酸二钠的量为0.005％-0.2％；优选为0.05％-0.1％；更优选0.1％。
其中，所述拉坦前列素滴眼液为水性溶液滴眼液，包含：
所述溶液为水溶性溶液，用于治疗高眼压和青光眼的拉坦前列素滴眼液。
本发明所提供了一种拉坦前列素滴眼液为水性溶液滴眼液，并且为单位剂量、无防腐剂，采用BFS技术(吹灌封三合一体无菌灌装技术)，使用低密度聚乙烯(LDPE)一次灌装成无防腐剂、单位剂量型滴眼液。
相对现有技术，本发明取得了有益效果如下：
(1)新组方中无添加防腐剂，避免了防腐剂为角膜结膜疾病的主要病原，对患者健康造成威胁；
(2)添加表面活性剂聚乙二醇4000，抑制树脂类容器吸附作用，可快速溶解得到分散均匀的拉坦前列素滴眼液；
(3)采用了独特的BFS技术制备方法，相对于传统灌装方法，减少生产过程中的染菌风险，灌装量为一次性使用量，也便于患者使用。
具体实施方式
为了使本发明的目的，技术方案更加清楚明白，以下结合实施例，对本发明做进一步的说明，但是本发明的保护范围并不限于这些实施例，实施例仅用于解释本发明。本领域技术人员应该理解的是，凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
1、表面活性剂加入量探究实验
新组方中无防腐剂，添加非离子表面活性剂，以解决拉坦前列素溶解问题和树脂类容器吸附问题，但加入量过多会产生腹泻的不良反应，加入量过少，起不到应有的作用，非离子表面活性剂的使用量一般为0.05％-0.5％，通过本实施例实验验证非离子表面活性剂加入量，设计实验如下：
实施例1-1
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.25g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.05g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.05％聚乙二醇4000的拉坦前列素溶液。
实施例1-2
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.25g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.25g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.1％聚乙二醇4000的拉坦前列素溶液。
实施例1-3
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.25g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.2％聚乙二醇4000的拉坦前列素溶液。
实施例1-4
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.25g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 2.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.5％聚乙二醇4000的拉坦前列素溶液。
实施例1-5
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.25g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得无聚乙二醇4000的拉坦前列素溶液。
将实施例1-1～1-5所得拉坦前列素溶液分别用BFS吹灌封设备灌装至低密度聚乙烯瓶中，另取多瓶进口拉坦前列素滴眼液Xalatan，取出溶液倒入已成型的吹灌封低密度聚乙烯瓶中，人工密封，与上述溶液一起放入25℃40％RH条件下加速6个月，考察pH值、含量、拉坦前列素酸、微生物变化情况，结果如表1。
拉坦前列素酸
取本品作为供试品溶液。另取在室温下真空干燥至少15小时至恒重的拉坦前列素酸对照品约5mg，精密称定，置200ml量瓶中加乙腈溶解并稀释至刻度，摇匀；再精密量取上述溶液2ml，置100ml量瓶中，加流动相A稀释至刻度，摇匀，作为对照品溶液。照高效液相色谱法测定，用十八烷基硅烷键合硅胶为填充剂；以0.025mol/L磷酸盐缓冲液(0.025mol/L磷酸二氢钠溶液用0.025mol/L磷酸调节pH值至2.5)-乙腈(70:30)为流动相A，0.025mol/L磷酸盐缓冲液(0.025mol/L磷酸二氢钠溶液用0.025mol/L磷酸调节pH值至2.5)-乙腈(20:80)为流动相B，按下表进行梯度洗脱：
检测波长为200nm；柱温为60℃，对照品溶液连续进样6次，其峰面积的相对标准偏差应小于3.0％，拉坦前列素酸峰与相邻峰的分离度不得小于1.0。取对照品溶液50μl注入液相色谱仪，调节检测灵敏度，使拉坦前列素酸色谱峰的峰高约为满量程的20～30％。再精密量取对照品溶液和供试品溶液各50μl，分别注入液相色谱仪，记录结果。
含量测定
精密量取本品适量，用流动相稀释制成每1ml含拉坦前列素5μg的溶液，作为供试品溶液，取于室温下真空干燥至少15小时至恒重的拉坦前列素对照品适量，精密称定，加乙腈溶解制成每1ml约含拉坦前列素0.5mg的溶液，用Chiralcel OD-R色谱柱；以0.025mol/L磷酸盐缓冲液(0.025mol/L磷酸二氢钠溶液用0.025mol/L磷酸调节pH值至2.5)-乙腈(55：45)为流动相；检测波长200nm，柱温35℃，流速0.5ml/分钟。理论板数按拉坦前列素峰计算应不低于3000，拉坦前列素峰与苯扎氯铵C14峰的分离度应大于2.4。精密量取对照品溶液和供试品溶液各20μl分别注入液相色谱仪，记录结果，按外标法以峰面积计算。
表1加速实验结果
结论：如表1结果所示，在25℃40％RH条件下加速6个月，拉坦前列素酸基本均在相同的水平，添加0.01％和0.05％聚乙二醇4000的样品含量有明显的下降，未添加聚乙二醇4000的样品含量下降尤为明显，而添加0.1％和0.5％聚乙二醇4000的样品含量基本无明显下降，说明0.1％和0.5％的聚乙二醇4000明显抑制了树脂类容器对拉坦前列素的吸附，优选0.1％的聚乙二醇4000。
2、稳定剂加入量实验
新组方中添加稳定剂，以解决拉坦前列素氧化降解成拉坦前列素酸的问题，但加入量过多会产生恶心、呕吐、腹痛等不良反应，加入量过少，起不到应有的作用，稳定剂的使用量一般为0.005％-0.2％，通过本实验验证稳定剂加入量，设计实验如下。
实施例2-1
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.025g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.2％聚乙二醇4000的拉坦前列素溶液。
实施例2-2
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.1g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.2％聚乙二醇4000的拉坦前列素溶液。
实施例2-3
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.25g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.2％聚乙二醇4000的拉坦前列素溶液。
实施例2-4
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g、依地酸二钠0.5g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.2％聚乙二醇4000的拉坦前列素溶液。
实施例2-5
精密称取聚丙烯酸974P 1g，缓慢加入盛有250ml纯化水的烧杯中，边加入边搅拌至分散完全，精密称取山梨醇100g加入其中搅拌至完全溶解，精密称取拉坦前列素25mg、聚乙二醇4000 0.5g置于盛有100ml纯化水的烧杯中，将烧杯置于超声波清洗机中超声20分钟，后倒入上述500ml烧杯中，持续搅拌，后加纯化水定容至刻度，并用氢氧化钠溶液调节pH至6.7，即得0.2％聚乙二醇4000的拉坦前列素溶液。
将实施例2-1～2-5所得拉坦前列素溶液分别用BFS吹灌封设备灌装至低密度聚乙烯瓶中，放入30℃鼓风干燥箱中加速1个月于0、5、10、20、30天取样检测，考察澄清度、含量、拉坦前列素酸变化情况，结果如表2所示。
表2加速实验结果
结论：如表2的结果所示，在30℃40％RH条件下加速30天，添加0.005％和0.02％依地酸二钠的样品拉坦前列素酸有明显的增大情况，未添依地酸二钠的样品拉坦前列素酸增大趋势尤为明显，而添加0.05％和0.1％依地酸二钠的样品拉坦前列素酸基本无明显下降，说明0.05％和0.1％依地酸二钠的样品明显抑制了拉坦前列素的氧化反应，优选为0.05％的依地酸二钠。
3、其它辅料加入量探究
眼睛作为人体非常重要的感觉器官，它的结构精密，组织娇嫩，即使轻微损伤，对生活、学习产生极大的影响，眼用制剂虽然是外用制剂，但在质量要求方面越来越接近于注射制剂的要求，其中包括pH值、渗透压、粘度值等质量参数，渗透压方面，滴眼剂应与泪液等渗，虽眼睛对渗透压耐受性比较高，通常在210～320mOs mol/kg，但高渗透压可使角膜失去水分，使眼组织干燥不适，低渗透压可使角膜组织细胞胀大而不适，高低渗透压溶液滴用后，均可产生刺激性，从而增加泪液的分泌，使料液被稀释或冲掉，降低疗效。
本发明选择25％的山梨醇使拉坦前列素滴眼液渗透压在正常的范围内。
粘度值方面，滴眼剂应加入粘度剂以增加其粘度，可以减少因眨眼而损失滴眼剂药液，延长药物和眼组织的接触时间，同时也可减少刺激作用，通常2.0mPa·s～5.0mPa·s，本发明选择0.2％的的丙烯酸974P使拉坦前列素滴眼液粘度值在正常的范围内。
pH值对滴眼剂有重要的影响，由于pH值不当而引起的刺激性，可增加泪液的分泌，导致药物迅速流失，甚至损伤角膜，本发明选择氢氧化钠调节pH值至6.7，使pH值变化控制在一定的范围内。
Claims (10)
1.一种拉坦前列素滴眼液，其特征在于，所述的拉坦前列素滴眼液包含渗透压调节剂、粘稠剂、非离子表面活性剂、稳定剂、pH值调节剂。
2.根据权利要求1所述的拉坦前列素滴眼液，其特征在于，所述渗透压调节剂为甘油、山梨醇、甘露醇、丙二醇、氯化钙、氯化钾、氯化钠；优选为山梨醇。
3.根据权利要求1所述的拉坦前列素滴眼液，其特征在于，所述粘稠剂为羟丙基甲基纤维素、羧甲纤维素钠、甲基纤维素，聚乙烯吡咯烷酮、聚乙烯醇、葡聚糖和聚丙烯酸；优选为聚丙烯酸974P。
4.根据权利要求1所述的拉坦前列素滴眼液，其特征在于，所述非离子表面活性剂为聚乙二醇4000、聚山梨酯60、聚山梨酯40、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、聚氧乙烯、聚乙二醇4000、普朗尼克F127、普朗尼克F68、聚乙二醇40硬脂酸酯和蔗糖脂肪酯；优选聚乙二醇4000。
5.根据权利要求1所述的拉坦前列素滴眼液，其特征在于，所述稳定剂为亚硝酸钠、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、巯基乙酸钠、硫代苹果酸钠、天然维生素E、依地酸二钠；优选为依地酸二钠。
6.根据权利要求1所述的拉坦前列素滴眼液，其特征在于，所述pH值调节剂为盐酸、硼酸、醋酸、氢氧化钠、碳酸氢钠、磷酸盐缓冲液、磷酸缓冲液、醋酸盐缓冲液；优选为氢氧化钠。
7.根据权利要求4所述的拉坦前列素滴眼液，其特征在于，所述聚乙二醇4000的用量为0.05％-0.5％；优选为0.1％-0.5％。
8.根据权利要求5所述的拉坦前列素滴眼液，其特征在于，所述依地酸二钠的用量为0.005％-0.2％；优选为0.05％-0.1％。
9.根据权利要求7或8所述的拉坦前列素滴眼液，其特征在于，所述拉坦前列素滴眼液为水性溶液滴眼液，包含
10.一种根据权利要求9所述的拉坦前列素滴眼液的制备方法，其特征在于，所述拉坦前列素滴眼液为水性溶液滴眼液，并且为单位剂量、无防腐剂，采用吹灌封三合一体无菌灌装技术，使用低密度聚乙烯一次灌装成无防腐剂、单位剂量型滴眼液。
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