CN1438898A - 防腐剂 - Google Patents
防腐剂 Download PDFInfo
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- CN1438898A CN1438898A CN01811388A CN01811388A CN1438898A CN 1438898 A CN1438898 A CN 1438898A CN 01811388 A CN01811388 A CN 01811388A CN 01811388 A CN01811388 A CN 01811388A CN 1438898 A CN1438898 A CN 1438898A
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- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
- A01N59/14—Boron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Dentistry (AREA)
- Pest Control & Pesticides (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Agronomy & Crop Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Plant Pathology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明的目的是通过组合液体制剂的常用添加剂提供一种安全的防腐剂。优选的防腐剂是通过组合硼酸和/或硼砂、乙二胺四乙酸或其盐和聚乙烯吡咯烷酮获得的。通过向防腐剂中进一步加入纤维素类聚合物防腐效果可以提高。
Description
技术领域
本发明涉及包含硼酸、乙二胺四乙酸和聚乙烯吡咯烷酮之组合的防腐剂，以及进一步含有纤维素类聚合物的防腐剂。这些防腐剂适合用于水性液体制剂，如滴眼液和接触镜片(隐形眼镜)用溶液。
背景技术
苯扎氯铵、苄索氯铵、山梨酸等已经用作滴眼液和接触镜片用溶液的防腐剂。
虽然苯扎氯铵和苄索氯铵具有优异的防腐效果，但它们依浓度不同可能造成角膜疾病，因此使用浓度受到限制。另外，这些化合物易于被吸附到镜片和塑料容器上。
山梨酸被广泛用作接触镜片眼用溶液的防腐剂，虽然它很少有副作用并且不易吸附到接触镜片和塑料容器上，但它有防腐效果弱的问题。
另一方面，可用于药物如滴眼液的防腐剂成分是有限的。
发明内容
本发明人精心研究力图找到通过将已经用于滴眼液等水性制剂的成分相互结合来显示防腐效果的防腐剂。硼酸和/或硼砂广泛用作缓冲剂，乙二胺四乙酸或其盐用作滴眼液中的稳定剂。由于注意到这些化合物具有防腐效果，但效果都弱，本发明人进行研究以便改善防腐效果。结果，本发明人发现，向(A)硼酸和/或硼砂和(B)乙二胺四乙酸中加入(C)聚乙烯吡咯烷酮(广泛用作增稠剂)，防腐效果显著提高，从而完成了本发明。还发现，再向这种组合中加入纤维素类聚合物，防腐效果进一步提高。
本发明的防腐剂包含三种必需的成分。第一种成分是硼酸和/或硼砂。硼酸和/或硼砂的量优选是0.05％到3.0％(重量)，更优选是0.5％到2.0％(重量)。当第一种成分的量太小时，不能获得足够的防腐效果。太大的量对于眼睛安全来说不是优选的。
本发明的第二种成分是乙二胺四乙酸或其盐。四钠盐或二钠盐(依地酸二钠)适合作为这样的盐。乙二胺四乙酸或其盐的量优选为0.01％到0.3％(重量)，更优选0.05％到0.2％(重量)。当第二种成分的量太小时，不能获得足够的稳定性和防腐效果。太大的量对于眼睛安全而言不是优选的。
本发明的第三种成分是聚乙烯吡咯烷酮(PVP)。例如，可以使用“PVP K-25”(平均分子量：25000)、“PVP K-30”(平均分子量：40000)和“PVP K-90”(平均分子量：360000)。PVP的量优选为0.02％到4.0％(重量)，更优选为0.1％到2.0％(重量)。当第三种成分的量太小时，不能获得足够的防腐效果。太大的量不是优选的，因为会产生令人不愉快的粘滞感。
向上述本发明的三种成分中加入纤维素类聚合物，防腐效果进一步增加。纤维素类聚合物的例子有羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素和羟乙基纤维素。特别优选的是羟丙基甲基纤维素。纤维素类聚合物的量优选为0.01％到0.5％(重量)，更优选为0.05％到0.3％(重量)，但不限于这些范围。
因为本发明的防腐剂对人体是安全的，而且不易吸附到接触镜片和塑料容器上，它们适用于水性液体制剂，如滴眼液和接触镜片用溶液。为了制备这些水性液体制剂，可能适当地向上述成分中加入其他添加成分，如等渗调节剂、pH调节剂、稳定剂和另一种防腐剂。
可以使用这些水性液体制剂的药物的非限制性例子有各种维生素(维生素B2、维生素B6、维生素B12、维生素E、泛醇等)、减充血剂(盐酸四氢唑啉、盐酸萘甲唑啉等)、抗炎药(甘草酸二钾、ε-氨基己酸等)、抗组胺药(马来酸氯苯那敏、盐酸苯海拉明等)、抗过敏药(色甘酸钠等)、抗微生物药(磺胺甲唑等)、氨基酸(L-天冬氨酸钾、氨基乙磺酸、硫酸软骨素钠等)、透明质酸钠、甲基硫酸新斯的明等。
等渗调节剂的例子有甘油、丙二醇、氯化钠、氯化钾、山梨醇和甘露醇。
pH调节剂的例子有盐酸、柠檬酸、磷酸、乙酸、氢氧化钠、氢氧化钾、碳酸钠和碳酸氢钠。
增溶剂的示例有聚山梨酯80、聚氧乙烯氢化蓖麻油60和聚乙二醇4000。
本发明的防腐剂可以与已经广泛使用的防腐剂结合使用，例如山梨酸、山梨酸钾、苯扎氯铵、苄索氯铵、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯和三氯叔丁醇。由于本发明的防腐剂与常用防腐剂结合时可以补充这些常用防腐剂的防腐效果，因此本发明的防腐剂还有显著减少常用防腐剂用量的有益效果。
当本发明的液体制剂用作滴眼液时，最好将pH调到约7.0，将渗透压比调节到约1.0。
现给出以下实施例来详细描述本发明，但这些实施例并不限制本
发明的范围。发明的最佳实施方式
按下述方法进行防腐效果试验，以研究本发明防腐剂的防腐效果。
防腐效果试验
在实施例1-4和对比实施例1-3中，用常规方法将表1中显示的制剂成分加入到蒸馏水中，制备液体制剂。向各液体制剂中加入作为等渗调节剂的氯化钠将渗透压调到1.0，需要时再向液体制剂中加入氢氧化钠调节pH至7.0。按照第13版日本药典的防腐效果试验方法进行防腐效果试验。用金黄色葡萄球菌作为试验菌，按以下算式计算细菌的存活率。所得的结果见表1。
存活率(％)＝[(两周后的细菌数目)/(起始细菌数目)]×100
表1
| 实施例 | 比较实施例 | ||||||
| 制剂成分(％重量) | 1 | 2 | 3 | 4 | 1 | 2 | 3 |
| 硼酸 | 1.5％ | 1.39％ | 1.5％ | 1.39％ | 1.5％ | - | - |
| 硼砂 | - | 0.18％ | - | 0.18％ | - | - | - |
| 依地酸钠 | 0.1％ | 0.1％ | 0.1％ | 0.1％ | 0.1％ | ||
| PVP*1 | 1.0％ | 0.2％ | 1.0％ | 1.0％ | - | 1.0％ | - |
| HPMC*2 | - | - | 0.2％ | 0.3％ | - | - | 0.1％ |
| 存活率(％) | 0.50 | 0.59 | 0.19 | 0.03 | 1.7 | 6.2 | 7.9 |
*1PVP：聚乙烯吡咯烷酮
*2HPMC：羟丙基甲基纤维素
表1清楚地显示，本发明实施例1和2与比较实施例1-3相比，防腐效果显著改善。另外加入了HPMC的实施例3和4与实施例1和2相比防腐效果又有提高。因此，含有(A)硼酸和/或硼砂、(B)乙二胺四乙酸或其盐和(C)聚乙烯吡咯烷酮的本发明防腐剂的防腐效果由于这些成分的协同作用而得以提高。通过进一步加入纤维素类聚合物，本发明的防腐效果可以进一步提高。因为本发明用于改进液体制剂防腐效果的防腐剂是通过混合已分别广泛用作缓冲剂、稳定剂和增稠剂的化合物制备的，这些防腐剂对人体安全，适合药用。本发明的防腐剂还可以与苯扎氯铵或山梨酸这些常用防腐剂一起使用，由于这种组合常用防腐剂的用量可以减少。
工业实用性
本发明提供含有硼酸、乙二胺四乙酸和聚乙烯吡咯烷酮的防腐剂，这些防腐剂还可以进一步含有纤维素类聚合物。这些防腐剂适用于水性液体制剂，如滴眼液和接触镜片用溶液。
Claims (7)
1.一种防腐剂，其含有(A)硼酸和/或硼砂、(B)乙二胺四乙酸或其盐和(C)聚乙烯吡咯烷酮的组合。
2.权利要求1所述的防腐剂，其特征在于其中还含有(D)一种纤维素类聚合物。
3.一种水性液体制剂，其含有权利要求1或2所述的防腐剂。
4.权利要求3所述的水性液体制剂，其剂型为滴眼液。
5.一种水性液体制剂，其中含有(A)0.05％到3.0％(重量)的硼酸和/或硼砂，(B)0.01％到0.3％(重量)的乙二胺四乙酸或其盐，和(C)0.02％到4.0％(重量)的聚乙烯吡咯烷酮的组合作为防腐剂。
6.权利要求5所述的水性液体制剂，其中还含有(D)0.01％到0.5％(重量)的纤维素类聚合物。
7.权利要求2所述的防腐剂或权利要求6所述的水性液体制剂，其中纤维素类聚合物是羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素或羟乙基纤维素。
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| CN101951868B (zh) * | 2007-11-30 | 2014-03-12 | 托尔特克制药有限责任公司 | 用于治疗阴道感染和致病性阴道生物被膜的组合物和方法 |
| US9999593B2 (en) | 2008-05-30 | 2018-06-19 | Santen Pharmaceutical Co., Ltd. | Method and composition for treating ocular hypertension and glaucoma |
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| WO2003073858A2 (fr) * | 2002-03-01 | 2003-09-12 | Realco 2001 S.A. | Procede de lutte contre les maladies des vegetaux par inhibition des enzymes extracellulaires des microorganismes contaminants |
| TW200501987A (en) * | 2002-12-11 | 2005-01-16 | Santen Pharmaceutical Co Ltd | Ophthalmic solution preservatives |
| JP5383281B2 (ja) | 2009-03-30 | 2014-01-08 | 花王株式会社 | 農薬含有組成物 |
| CN111836627A (zh) * | 2018-03-13 | 2020-10-27 | 参天制药株式会社 | 花粉破裂抑制用组合物 |
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| US4728509A (en) * | 1985-08-19 | 1988-03-01 | Takeda Chemical Industries, Ltd. | Aqueous liquid preparation |
| JPH01294620A (ja) * | 1988-05-19 | 1989-11-28 | Kissei Pharmaceut Co Ltd | 水溶液製剤およびその製造方法 |
| CA1330923C (en) * | 1988-09-08 | 1994-07-26 | Guy J. Sherman | Cleaning, conditioning, storing and wetting system and method for rigid gas permeable contact lenses and other contact lenses |
| TW200402B (zh) * | 1990-08-13 | 1993-02-21 | Senju Pharma Co | |
| SK143893A3 (en) * | 1992-03-18 | 1994-05-11 | Cooper Vision Pharmaceuticals | Verapamil hci formulation and other opthalmic solutions with buffer system for ocular administration |
| US5505953A (en) * | 1992-05-06 | 1996-04-09 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
| CA2125060C (en) * | 1993-07-02 | 1999-03-30 | Henry P. Dabrowski | Ophthalmic solution for artificial tears |
| CN1185953A (zh) * | 1996-12-27 | 1998-07-01 | 刘伟中 | 富氧舒眼液及其生产工艺 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101951868B (zh) * | 2007-11-30 | 2014-03-12 | 托尔特克制药有限责任公司 | 用于治疗阴道感染和致病性阴道生物被膜的组合物和方法 |
| CN103933063A (zh) * | 2007-11-30 | 2014-07-23 | 托尔特克制药有限责任公司 | 用于治疗阴道感染和致病性阴道生物被膜的组合物和方法 |
| US9999593B2 (en) | 2008-05-30 | 2018-06-19 | Santen Pharmaceutical Co., Ltd. | Method and composition for treating ocular hypertension and glaucoma |
| US10864159B2 (en) | 2008-05-30 | 2020-12-15 | Santen Pharmaceutical Co., Ltd. | Method and composition for treating ocular hypertension and glaucoma |
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| Publication number | Publication date |
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| CA2413088C (en) | 2009-10-20 |
| EP1312380A4 (en) | 2003-08-06 |
| EP1312380B1 (en) | 2006-05-03 |
| ATE324910T1 (de) | 2006-06-15 |
| DE60119337D1 (de) | 2006-06-08 |
| AU2001264261A1 (en) | 2002-01-02 |
| US20030152631A1 (en) | 2003-08-14 |
| EP1312380A1 (en) | 2003-05-21 |
| US20050106265A1 (en) | 2005-05-19 |
| WO2001097852A1 (fr) | 2001-12-27 |
| CA2413088A1 (en) | 2002-12-17 |
| KR100791871B1 (ko) | 2008-01-07 |
| CN1232305C (zh) | 2005-12-21 |
| ES2263623T3 (es) | 2006-12-16 |
| DE60119337T2 (de) | 2007-03-29 |
| KR20030009540A (ko) | 2003-01-29 |
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