CN101212960A - 包括黄原胶和萜类化合物的滴眼制剂 - Google Patents
包括黄原胶和萜类化合物的滴眼制剂 Download PDFInfo
- Publication number
- CN101212960A CN101212960A CNA2006800239849A CN200680023984A CN101212960A CN 101212960 A CN101212960 A CN 101212960A CN A2006800239849 A CNA2006800239849 A CN A2006800239849A CN 200680023984 A CN200680023984 A CN 200680023984A CN 101212960 A CN101212960 A CN 101212960A
- Authority
- CN
- China
- Prior art keywords
- xanthan gum
- terpenoid
- ophthalmic solution
- menthol
- content
- 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.)
- Granted
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- 229920001285 xanthan gum Polymers 0.000 title claims abstract description 71
- 239000000230 xanthan gum Substances 0.000 title claims abstract description 70
- 235000010493 xanthan gum Nutrition 0.000 title claims abstract description 70
- 229940082509 xanthan gum Drugs 0.000 title claims abstract description 70
- 150000003505 terpenes Chemical class 0.000 title claims abstract description 49
- 239000003889 eye drop Substances 0.000 title description 15
- 238000002360 preparation method Methods 0.000 title description 5
- 239000002997 ophthalmic solution Substances 0.000 claims abstract description 71
- 229940054534 ophthalmic solution Drugs 0.000 claims abstract description 70
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 47
- 229940025250 camphora Drugs 0.000 claims description 23
- 239000010238 camphora Substances 0.000 claims description 23
- 229940041616 menthol Drugs 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 229920003023 plastic Polymers 0.000 claims description 7
- 239000004033 plastic Substances 0.000 claims description 7
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 5
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims 1
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 55
- -1 polyethylene terephthalate Polymers 0.000 description 34
- 230000000052 comparative effect Effects 0.000 description 22
- 150000003839 salts Chemical class 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 230000002401 inhibitory effect Effects 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 229920000139 polyethylene terephthalate Polymers 0.000 description 10
- 239000005020 polyethylene terephthalate Substances 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 210000001508 eye Anatomy 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
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- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 7
- 239000004327 boric acid Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- 239000004743 Polypropylene Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 6
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- 239000001509 sodium citrate Substances 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 4
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 4
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 4
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
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- 229960003291 chlorphenamine Drugs 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
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- 229960000458 allantoin Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000607 artificial tear Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
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- 239000008103 glucose Substances 0.000 description 3
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- 229940068988 potassium aspartate Drugs 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 3
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 3
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- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明提供含有黄原胶和萜类化合物的眼用溶液剂，其通过将黄原胶加入到含有萜类化合物的眼用溶液剂中，表现出抑制所述萜类化合物含量的减少。
Description
技术领域
本发明涉及包括黄原胶和萜类化合物的眼用溶液剂，其表现出抑制所述萜类化合物含量的减少。
背景技术
许多普通的眼用溶液剂含有作为清凉剂的萜类化合物，如薄荷醇、樟脑、冰片等，以便在滴入时提供凉爽的感觉和清新的感觉。虽然通常对所述眼用溶液剂使用塑料容器，但是已知将含有萜类化合物的药物装入塑料容器并保存时，萜类化合物含量会减少。为了解决这个问题，JP-A-2000-273061公开了塑料容器中的水包油型乳剂眼用溶液剂，其中萜类化合物含量的降低受到抑制。另外，JP-A-2002-003364公开了一种抑制清凉剂如薄荷醇等吸附到容器的方法，所述方法包括将多价醇加入到单位剂量(一次性的)的滴眼液容器中。
已知泪液具有假塑性。即，当通过眨眼而施加力时，泪液的粘度降低，且当不施加力时增加。因此，泪液具有独特的性质，由于在眨眼过程中具有低粘度并变稀，从而帮助眨眼，而在眨眼之前或之后，它变为高粘性，从而覆盖在眼睛表面用于保护。已知黄原胶为表现出所述假塑性的聚合物化合物。
作为含有黄原胶的眼用组合物，已经报告了如下内容。例如，公开了含有碘依可酯和黄原胶的眼用组合物，且报告了黄原胶增强碘依可酯的治疗作用(美国专利号4136177)。另外，公开了含有黄原胶和碳酸酐酶抑制剂的眼用组合物，其中黄原胶用于改进碳酸酐酶抑制剂的眼科生物利用率(JP-T-2001-508035，JP-T-2002-501017，JP-T-2002-506461)。为了改进药物眼科生物利用率的目的，使用黄原胶，并公开了含有碳酸酐酶抑制剂、前列腺素衍生物和黄原胶的眼用组合物(JP-T-2002-501533，JP-T-2002-521332，JP-T-2002-521333)。公开了含有四元含氮的乙氧基化糖苷和黄原胶的眼用组合物，其用于治疗干眼症(JP-T-2001-516713)。另外，公开了含有黄原胶的眼用组合物(JP-T-2002-510654)，其在与眼睛接触时被凝胶化。另外，美国专利号6623751与皮肤贴相联系报告了处于水相中的含有亲水性凝胶系统的贴，其中所述皮肤贴可以适应于眼睛、前额、鼻、和口周围的形状。美国专利号6623751的实施例3报告了含有黄原胶和薄荷醇的贴。
然而，不存在对包含黄原胶和萜类化合物的眼用溶液剂的报告。而且，未曾报道过在眼用溶液剂中黄原胶对萜类化合物含量减少的抑制。
发明内容
本发明的目的是提供含有萜类化合物的眼用溶液剂，所述眼用溶液剂表现出抑制所述萜类化合物含量的减少。本发明的另一个目的是提供抑制包含萜类化合物的眼用溶液剂中的萜类化合物含量减少的方法。
本发明人已经实施了深入细致的研究，以试图实现上述目的，并发现将黄原胶加入到包含萜类化合物的眼用溶液剂中可以抑制所述萜类化合物含量的减少。本发明人基于这个发现进行了进一步的研究，并完成了本发明。
因此，本发明涉及
(1)眼用溶液剂，所述眼用溶液剂包含黄原胶和萜类化合物；
(2)以上(1)的眼用溶液剂，其中所述萜类化合物是薄荷醇和/或樟脑；
(3)以上(1)或(2)的眼用溶液剂，其中所述黄原胶的浓度是0.2-0.7w/v％；
(4)以上(1)-(3)中任一项的眼用溶液剂，其中所述萜类化合物的浓度是0.002-0.05w/v％；
(5)以上(1)-(4)中任一项的眼用溶液剂，其中为此使用的容器是塑料容器；和
(6)抑制萜类化合物含量减少的方法，所述方法包括将黄原胶加入到含有萜类化合物的眼用溶液剂中。
按照本发明，通过加入黄原胶，可以提供表现出抑制所述萜类化合物含量减少的眼用溶液剂。而且，可以提供抑制眼用溶液剂中萜类化合物含量减少的方法，所述方法包括将黄原胶加入到含有萜类化合物的眼用溶液剂中。此外，本发明的眼用溶液剂由于其组合提供的无粘着性的粘性感觉和清新感觉而在使用过程中提供极好的感觉，因为它包含黄原胶和薄荷醇。
实施本发明的最佳方式
将本发明更详细地描述如下。
本发明的眼用溶液剂包含可以施用于眼睛的水性剂型，例如水性眼用溶液剂和水性眼用混悬剂。
虽然用于本发明眼用溶液剂的容器不受特殊限制，只要它可以用于该水性剂型，但是塑料容器是优选的。塑料容器材料的实例包括聚对苯二甲酸乙二醇酯、聚乙烯、聚丙烯，等。聚对苯二甲酸乙二醇酯是特别优选的。
用于本发明的眼用溶液剂的黄原胶通常具有100000-50000000，优选200000-20000000，并且特别优选1000000-10000000的平均分子量。使用下列各项作为黄原胶：可以从DAINIPPON SUMITOMOPHARMACEUTICAL CO.LTD.商购的ECHO GUM系列，如ECHO GUMT，ECHO GUM F等；可以从San-Ei Gen F.F.I.Inc.商购的SAN-ACE系列，如SAN-ACE NXG-S等；可以从Sansho Co.Ltd.商购的KELTROL系列，如KELTROL CG，KELTROL CG-T等；以及诸如此类，优选ECHO GUM T和KELTROL CG-T。
鉴于对萜类化合物含量减少的抑制作用，本发明的眼用溶液剂中的黄原胶具有通常0.01-1.5w/v％的浓度，优选0.1-1w/v％，更优选0.15-1w/v％，特别优选0.2-0.7w/v％和尤其优选0.2-0.6w/v％。可以容易地生产含有黄原胶浓度为1.5w/v％或以下的眼用溶液剂，原因在于其具有合适的粘度，且容许在一般条件下过滤灭菌。
用于本发明的眼用溶液剂的萜类化合物的实例包括薄荷醇(l-薄荷醇，d-薄荷醇，dl-薄荷醇等)；樟脑(l-樟脑，d-樟脑，dl-樟脑等)；单萜(冰片，香叶醇，桉油精(cineol)，茴香脑，柠檬烯，丁香酚等)；倍半萜(法呢醇，橙花叔醇等)；二萜(叶绿醇，松柏烯(cembrene)等)；等，优选为薄荷醇和樟脑。这些以其一种或多种的组合的形式使用。
本发明的眼用溶液剂的萜类化合物的浓度在制备时一般是0.0002-0.2w/v％，优选地，0.001-0.1w/v％，并且特别优选地，0.002-0.05w/v％。
为了抑制所述萜类化合物含量的减少，当萜类化合物的浓度是0.001-0.1w/v％时，本发明的眼用溶液剂中萜类化合物与黄原胶的重量比在制备时优选为1∶1000-1∶1，并且更优选1∶100-1∶10。当萜类化合物的浓度是0.002-0.05w/v％时，该重量比优选为1∶350-1∶4，和更优选1∶100-1∶10。
本发明的眼用溶液剂可以酌情含有多种添加剂，如缓冲剂、等渗性试剂、防腐剂、增溶剂、稳定剂、螯合剂、增稠剂、pH调节剂等。
作为缓冲剂，可以提及，例如，硼酸或其盐(硼酸钠，等)，柠檬酸或其盐(柠檬酸钠，等)，酒石酸或其盐(酒石酸钠，等)，葡糖酸或其盐(葡糖酸钠，等)，乙酸或其盐(乙酸钠，等)，磷酸或其盐(磷酸氢钠，磷酸二氢钠，等)，多种氨基酸，如谷氨酸，ε-氨基己酸等，和tris缓冲剂，等。它们以其一种或多种的组合的形式使用。
作为等渗性试剂，可以提及，例如，山梨糖醇，葡萄糖，甘露醇，甘油，丙二醇，氯化钠，氯化钾，等。
作为防腐剂，可以提及，例如，对羟基苯甲酸酯(paraoxybenzoates)，苯扎氯铵，苄索氯铵，苯甲醇，山梨酸或其盐，氯己定或其盐，脱氢乙酸钠，西吡氯铵，烷基二氨乙基甘氨酸盐酸盐，三氯叔丁醇，等。它们以其一种或多种的组合的形式使用。
作为增溶剂，可以提及，例如，非离子表面活性剂如聚氧乙烯山梨聚糖脂肪酸酯(sorbitan polyoxyethylene fatty acid esters)(聚山梨酯80，等)，聚氧乙烯氢化蓖麻油，聚氧乙烯单硬脂酸酯(聚乙二醇酯，等)，水溶性聚合物如聚乙二醇(聚乙二醇4000，等)，聚乙烯吡咯烷酮等，丙二醇，环糊精，等。
作为稳定剂，可以提及，例如，依地酸二钠，硫代硫酸钠，抗坏血酸，环糊精，浓缩的磷酸或其盐，亚硫酸盐，柠檬酸或其盐，二丁基羟基甲苯，等。
作为螯合剂，可以提及，例如，依地酸钠，柠檬酸钠，浓缩的磷酸或其盐(浓缩的磷酸钠，等)，等。
作为增稠剂，可以提及，例如，甲基纤维素，羟乙基纤维素，羟丙基纤维素，羟丙甲基纤维素，羧甲基纤维素钠，聚乙烯吡咯烷酮，聚乙烯醇，聚乙二醇，透明质酸，等。
作为pH调节剂，可以提及，例如，氢氧化钠，氢氧化钾，碳酸钠，碳酸氢钠，硼酸或其盐(硼酸钠)，盐酸，柠檬酸或其盐(柠檬酸钠，柠檬酸二氢钠等)，磷酸或其盐(磷酸二氢钠，磷酸二氢钾等)，乙酸或其盐(乙酸钠，乙酸铝等)，酒石酸或其盐(酒石酸钠等)，等。
将本发明的眼用溶液剂制备成具有pH3-10，并且优选pH5-8。
只要本发明的目的不被削弱，本发明的眼用溶液剂可以含有一种或多种药用成分，所述药用成分选自：抗炎药(尿囊素，普拉洛芬等)，减充血药(盐酸萘甲唑林等)，眼肌调节剂(甲硫酸新斯的明等)，收敛剂(硫酸锌等)，抗组胺剂(扑尔敏等)，抗过敏剂(色甘酸钠等)，维生素(泛醇)，氨基酸，等。
作为氨基酸，可以提及，例如，甘氨酸，丙氨酸，缬氨酸，亮氨酸，异亮氨酸，苯丙氨酸，脯氨酸，丝氨酸，苏氨酸，酪氨酸，天冬酰胺，谷氨酰胺，赖氨酸，精氨酸，色氨酸，组氨酸，半胱氨酸，甲硫氨酸，天冬氨酸，谷氨酸，氨基乙基磺酸，及其药用盐。作为所述盐，可以提及，例如，钠盐，钾盐，钙盐和镁盐。这些以其一种或多种的组合的形式使用。
本发明的眼用溶液剂的投药时期不受限制。可以将所述眼用溶液剂以作为标准的临床使用量为基础施用于投药受试者。考虑到投药受试者、靶疾病、症状、组合等，可以适当的选择本发明的眼用溶液剂和上述药用成分的混合比例。例如，当投药受试者是人时，上述药用成分可以以相对于本发明眼用溶液剂0.0006-5w/v％的比例使用。
本发明的眼用溶液剂可以用作处方药物或非处方药物。另外，它还可以用作佩戴隐形眼镜时所使用的用于隐形眼镜或隐形眼镜溶液的眼用溶液剂。本发明的眼用溶液剂还可以用作预防或改善眼睛疲劳，眼睛干燥，视力模糊，眼睛发痒，结膜充血，佩戴隐形眼镜所引起的不适，等。而且，本发明的眼用溶液剂还可以用作补充泪液(眼睛干燥)的人工泪液，等。
例如，当本发明的眼用溶液剂用于成人时，优选地，作为含有萜类化合物的眼用溶液剂，以2-3滴/滴注(installation)，5或6次/天的量进行施用，其中所述萜类化合物所占的比例优选为0.001-0.1w/v％，并且特别优选为0.002-0.05w/v％。
本发明的眼用溶液剂表现出无粘着性的粘性感觉，原因在于它含有黄原胶，该黄原胶表现假塑性。而且，本发明的眼用溶液剂还提供凉爽的感觉和清新的感觉，其原因在于它含有作为清凉剂的萜类化合物。
本发明提供用于抑制所述萜类化合物含量减少的方法，所述方法包括将黄原胶加入到含有萜类化合物的眼用溶液剂中。
实施例
虽然以下通过参考实施例和试验例来详细描述本发明，但是不将它们解释为限制。
[试验例1]在聚对苯二甲酸乙二醇酯滴眼液容器中，黄原胶对萜类化合物含量减少的抑制作用。
1.制备方法
将氯化钠在环境温度溶解于纯化的水中。当在均相混合机(T.K.Robomix，Tokushu Kika Kogyo Co.Ltd.)中温和地搅拌该水性溶液时，逐渐地加入黄原胶(ECHO GUM T：注册商标，DAINIPPON SUMITOMOPHARMACEUTICAL CO.LTD.)，并以15,000rpm搅拌该混合物1小时。将l-薄荷醇(日本药典第十四版(The Japanese Pharmacopoeia FourteenthEdition))或dl-樟脑(日本药典第十四版(The Japanese PharmacopoeiaFourteenth Edition))在室温下加入到该水性溶液中，并以8,000rpm搅拌该混合物10分钟，以使其溶解。经过膜滤器(0.45μm的孔直径，压力过滤器(Pressure Filter)，由Millipore制造)过滤该水性溶液，从而获得实施例1-4的眼用溶液剂。另外，以相同的方式操作，不同之处在于加入黄原胶，获得比较例1和2的眼用溶液剂。
(表1)
| 加入的成分(g/100mL) | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 比较例1 | 比较例2 |
| 黄原胶 | 0.2 | 0.5 | 0.7 | 0.5 | - | - |
| 氯化钠 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 |
| l-薄荷醇 | 0.01 | 0.01 | 0.01 | - | 0.01 | - |
| dl-樟脑 | - | - | - | 0.01 | - | 0.01 |
| 纯化的水 | 平衡量 | 平衡量 | 平衡量 | 平衡量 | 平衡量 | 平衡量 |
2.测试方法
将实施例1-4和比较例1和2的眼用溶液剂分别装入15mL的聚对苯二甲酸乙二醇酯滴眼液容器中，并在60℃保存2天。在保存之前和之后测量了每种样品的l-薄荷醇和dl-樟脑的含量。l-薄荷醇和dl-樟脑的量化方法如下。
精确测量样品(2mL)，并且向其中精确加入2mL的氯仿。然后剧烈振荡该混合物，将氯仿层分离并用作样品溶液。分别地，精确测量了0.02g的l-薄荷醇标准产品，并向其中加入氯仿，以达到准确的20mL。精确量出该溶液(2mL)，向其中加入氯仿，以达到准确的20mL，并且该溶液用作l-薄荷醇标准溶液。另外，精确测量了0.02g的dl-樟脑的标准产品，并将氯仿加入其中，以达到准确的20mL。精确量出该溶液(2mL)，向其中加入氯仿，以达到准确的20mL，并且该溶液用作dl-樟脑标准溶液。通过气相色谱法测试了所述样品溶液和标准溶液(5μL)。由l-薄荷醇和dl-樟脑的峰面积确定了它们的含量。
l-薄荷醇和dl-樟脑在样品溶液中的含量(W/V％)＝测量到的标准产品的量(g)×AT/AS/2
AT：样品溶液中的l-薄荷醇和dl-樟脑的峰面积
AS：标准溶液中的l-薄荷醇和dl-樟脑的峰面积
气相色谱法条件
系统：GC-2010(Shimadzu Corporation)
检测器：氢焰离子化检测器
柱：PEG 20M 20％Gaschrom Q 60/80筛目3mm×2m玻璃柱(GLScience)
柱温度：150℃
检测器温度：200℃
注射温度：200℃
流速：安排成达到约8分钟的l-薄荷醇保留时间
3.测试结果
如图2中所示，与比较例1相比，实施例1-3中的l-薄荷醇残留比增加。在相应浓度为0.2-0.7％时，观察到了黄原胶对l-薄荷醇含量减少的抑制作用。而且，与比较例2相比，实施例4中的dl-樟脑残留比增加，并观察到了黄原胶对dl-樟脑含量减少的抑制作用。
(表2)
在聚对苯二甲酸乙二醇酯滴眼液容器中，黄原胶对萜类化合物含量减少的抑制作用
(60℃，保存2天)
| 黄原胶含量(％) | l-薄荷醇残留比(％) | dl-樟脑残留比(％) | |
| 实施例1 | 0.2 | 80.4 | - |
| 实施例2 | 0.5 | 86.8 | - |
| 实施例3 | 0.7 | 89.2 | - |
| 实施例4 | 0.5 | - | 95.9 |
| 比较例1 | 0 | 74.7 | - |
| 比较例2 | 0 | - | 80.3 |
[试验例2]在聚对苯二甲酸乙二醇酯滴眼液容器中，黄原胶对萜类化合物含量减少的抑制作用
(表3)
| 加入的成分(g/100mL) | 实施例5 | 实施例6 | 实施例7 | 比较例3 | 比较例4 | 比较例5 |
| 黄原胶 | 0.5 | 0.5 | 0.5 | - | - | - |
| 氯化钠 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 |
| l-薄荷醇 | 0.002 | 0.03 | 0.05 | 0.002 | 0.03 | 0.05 |
| 聚山梨酯80 | - | - | 0.2 | - | - | 0.2 |
| 纯化的水 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 |
1.测试方法
将实施例5-7和比较例3-5的眼用溶液剂分别装入15mL的聚对苯二甲酸乙二醇酯滴眼液容器中，并在60℃保存2天。，以与试验例1中相同的方式，测量了保存之前和之后的每种样品的l-薄荷醇的含量。
2.测试结果
如表4中所示，与比较例3-5相比，实施例5-7中的l-薄荷醇残留比增加。在任意l-薄荷醇浓度时，观察到了黄原胶对l-薄荷醇含量减少的抑制作用。
(表4)
黄原胶对薄荷醇含量减少的抑制作用(60℃，保存2天)
| 黄原胶含量(％) | l-薄荷醇含量(％) | l-薄荷醇残留比(％) | |
| 实施例5 | 0.5 | 0.002 | 90.1 |
| 实施例6 | 0.5 | 0.03 | 91.5 |
| 实施例7 | 0.5 | 0.05 | 97.7 |
| 比较例3 | 0 | 0.002 | 78.6 |
| 比较例4 | 0 | 0.03 | 71.4 |
| 比较例5 | 0 | 0.05 | 86.2 |
[试验例3]在聚丙烯或聚乙烯滴眼液容器中，黄原胶对薄荷醇含量减少的抑制作用
1.测试方法
将实施例2和比较例1的眼用溶液剂分别装入15mL的聚丙烯滴眼液容器和15mL的聚乙烯滴眼液容器中，并在60℃保存6小时。以与试验例1中相同的方式，测量了保存之前和之后的每种样品的l-薄荷醇的含量。
2.测试结果
如表5中所示，与比较例1相比，实施例2中，在聚丙烯滴眼液容器和聚乙烯滴眼液容器中的l-薄荷醇残留比均增加。由此，观察到了黄原胶对l-薄荷醇含量减少的抑制作用。
(表5)
在聚丙烯或聚乙烯滴眼液容器中，黄原胶对薄荷醇含量减少的抑制作用(60℃，保存6小时)
| 黄原胶含量(％) | l-薄荷醇残留比(％) | ||
| 聚丙烯 | 聚乙烯 | ||
| 实施例2 | 0.5 | 53.0 | 23.5 |
| 比较例1 | 0 | 47.2 | 15.5 |
[试验例4]在聚对苯二甲酸乙二醇酯滴眼液容器中，黄原胶对薄荷醇含量减少的抑制作用
1.测试方法
将实施例2和比较例1的眼用溶液剂(每种5mL)装入5mL玻璃安瓿中，将一块聚对苯二甲酸乙二醇酯容器(从容器体切割下来的约3g，约5mm×25mm的断片)浸没于其中，并在60℃保存该安瓿1天。以与试验例1中相同的方式，测量了保存之前和之后的每种样品的l-薄荷醇的含量。另外，以相同的方式处理了一个无容器断片浸没的样品。
2.测试结果
如表6中所示，与比较例1相比，实施例2中的l-薄荷醇残留比增加。由该结果，认为黄原胶所抑制的薄荷醇对所述容器的吸附是该抑制含量减少作用的一种机制。
(表6)
在聚对苯二甲酸乙二醇酯滴眼液容器中，黄原胶对薄荷醇含量减少的抑制作用(60℃，保存1天)
| 黄原胶含量(％) | l-薄荷醇残留比(％) | ||
| 无容器断片 | 有容器断片 | ||
| 实施例2 | 0.5 | 100.4 | 96.7 |
| 比较例1 | 0 | 100.1 | 91.1 |
本发明的包括黄原胶和萜类化合物的眼用溶液剂的剂型实施例如下所示。
[实施例8]含有黄原胶和l-薄荷醇的人工泪液
按照常规方法制备了如下配方的人工泪液。
l-天冬氨酸钾 0.5g
氨基乙基磺酸 0.5g
氯化钠 0.5g
氯化钾 0.15g
硼酸 0.3g
硼砂 适量
黄原胶 0.5g
苯扎氯铵 0.005g
l-薄荷醇 0.005g
纯化的水 适量
总量 100ml(pH7.2)
[实施例9]含有黄原胶和l-薄荷醇的隐形眼镜眼用溶液剂
按照常规方法制备了如下配方的隐形眼镜眼用溶液剂。
氯化钠 0.55g
氯化钾 0.15g
葡萄糖 0.005g
硼酸 0.6g
硼砂 适量
黄原胶 0.3g
山梨酸钾 0.1g
l-薄荷醇 0.01g
聚乙二醇 40000.3g
依地酸钠(Sodium edentate) 0.1g
纯化的水 适量
总量 100ml(pH6.5)
[实施例10]含有黄原胶和l-薄荷醇的隐形眼镜眼用溶液剂
按照常规方法制备了如下配方的隐形眼镜眼用溶液剂。
l-天冬氨酸钾 0.1g
氯化钠 0.3g
氯化钾 0.05g
葡萄糖 0.005g
硼酸 1g
硼砂 适量
柠檬酸钠 0.5g
三氯叔丁醇 0.1g
黄原胶 0.3g
山梨酸 0.1g
l-薄荷醇 0.035g
聚乙二醇4000 0.3g
纯化的水 适量
总量 100ml(pH6.5)
[实施例11]含有黄原胶和l-薄荷醇的非处方眼用溶液剂
按照常规方法制备了如下配方的非处方眼用溶液剂。
甲硫酸新斯的明 0.005g
泛醇 0.1g
l-天冬氨酸钾 1g
尿囊素 0.1g
扑尔敏 0.03g
氯化钠 0.45g
l-谷氨酸钠 0.2g
聚氧乙烯氢化蓖麻油60 0.3g
l-薄荷醇 0.008g
冰片 0.002g
盐酸 适量
苯扎氯铵 0.005g
三氯叔丁醇 0.2g
黄原胶 0.5g
纯化的水 适量
总量 100ml(pH5.5)
[实施例12]含有黄原胶、dl-樟脑和l-薄荷醇的非处方眼用溶液剂
按照常规方法制备了如下配方的非处方眼用溶液剂。
萘唑啉盐酸盐 0.002g
尿囊素 0.1g
硫酸锌 0.1g
扑尔敏 0.03g
氨基乙基磺酸 0.1g
硼酸 0.7g
ε-氨基己酸 0.2g
氯化钠 0.45g
三氯叔丁醇 0.15g
对羟基苯甲酸甲酯 0.02g
l-薄荷醇 0.03g
dl-樟脑 0.003g
桉树油 0.0009g
香叶醇 0.0009g
聚乙二醇4000 0.3g
黄原胶 0.2g
纯化的水 适量
总量 100ml(pH5.8)
实施例13：含有黄原胶和l-薄荷醇的非处方眼用溶液剂
按照常规方法制备了如下配方的非处方眼用溶液剂。
色甘酸钠 1g
扑尔敏 0.015g
普拉洛芬 0.05g
硼酸 1.8g
硼砂 0.35g
依地酸钠 0.01g
l-薄荷醇 0.005g
聚山梨酯80 0.2g
黄原胶 0.3g
纯化的水 适量
总量 100ml(pH7)
工业实用性
按照本发明，可以提供包括黄原胶和萜类化合物的眼用溶液剂，其表现出抑制所述萜类化合物含量的减少。本发明的眼用溶液剂在使用过程中提供极好的感觉，原因在于无粘着性的粘性感觉和清新感觉。
虽然以上详述了本发明的一些实施方案，但是本领域中的普通技术人员在基本上不偏离本发明的新教导和优点的情况下，可以对所示特殊实施方案进行多种修改和改变。所述修改和改变包括于如所附权利要求所阐明的本发明的实质和范围内。
本申请基于在日本提交的申请号2005-201871，将其内容通过参考结合于此。
Claims (6)
1.包含黄原胶和萜类化合物的眼用溶液剂。
2.权利要求1的眼用溶液剂，其中所述萜类化合物是薄荷醇和/或樟脑。
3.权利要求1或2的眼用溶液剂，其中所述黄原胶的浓度是0.2-0.7w/v％。
4.权利要求1-3中任一项的眼用溶液剂，其中所述萜类化合物的浓度是0.002-0.05w/v％。
5.权利要求1-4中任一项的眼用溶液剂，其中为此使用的容器是塑料容器。
6.一种抑制萜类化合物含量减少的方法，所述方法包括将黄原胶加入到包含萜类化合物的眼用溶液剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005201871 | 2005-07-11 | ||
| JP201871/2005 | 2005-07-11 | ||
| PCT/JP2006/314129 WO2007007894A1 (ja) | 2005-07-11 | 2006-07-11 | キサンタンガムおよびテルペノイドを含有する点眼剤 |
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| CN101212960A true CN101212960A (zh) | 2008-07-02 |
| CN101212960B CN101212960B (zh) | 2011-04-13 |
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| US (1) | US7998942B2 (zh) |
| EP (1) | EP1911447B1 (zh) |
| JP (1) | JP4966854B2 (zh) |
| KR (1) | KR101322527B1 (zh) |
| CN (1) | CN101212960B (zh) |
| DE (1) | DE602006011330D1 (zh) |
| ES (1) | ES2337501T3 (zh) |
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| WO (1) | WO2007007894A1 (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085395A (zh) * | 2009-12-02 | 2011-06-08 | 日本乐敦制药株式会社 | 硅酮水凝胶隐形眼镜用眼科组合物 |
| CN110114119A (zh) * | 2016-10-12 | 2019-08-09 | Ps治疗有限公司 | 人工泪液、隐形眼镜和药物载体组合物及其使用方法 |
| CN114761022A (zh) * | 2019-11-29 | 2022-07-15 | 千寿制药株式会社 | 药物组合物 |
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| EP2014333A1 (en) | 2007-07-12 | 2009-01-14 | Hakiman Shargh Research Company | Use of cooling agents for treatment or prevention of lacrimation or eye burning |
| US8501800B2 (en) | 2009-03-05 | 2013-08-06 | Insite Vision Incorporated | Controlled-release ophthalmic vehicles |
| WO2011018800A2 (en) * | 2009-08-13 | 2011-02-17 | Fdc Limited | A novel in-situ gel forming solution for ocular drug delivery |
| BRPI1107166A2 (pt) * | 2011-10-17 | 2013-11-26 | Fbm Ind Farmaceutica Ltda | Solução limpadora de lentes contato |
| JPWO2015029924A1 (ja) * | 2013-08-26 | 2017-03-02 | ロート製薬株式会社 | 眼科用組成物 |
| CN103805069B (zh) * | 2014-01-27 | 2016-03-02 | 欧普康视科技股份有限公司 | 一种角膜接触镜抛光液及其制备方法 |
| JP2018111691A (ja) * | 2017-01-11 | 2018-07-19 | 千寿製薬株式会社 | 眼科用水性組成物、及び化合物の含量低下を抑制する方法 |
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| JP3570444B2 (ja) * | 1995-06-05 | 2004-09-29 | ライオン株式会社 | 洗口液 |
| DE69736521D1 (de) * | 1996-09-26 | 2006-09-28 | Rohto Pharma | Augentropfen |
| FR2754712B1 (fr) * | 1996-10-17 | 1999-09-03 | Merck Sharp Dohme Chibret Lab | Compositions ophtalmiques |
| US20020094981A1 (en) * | 1997-05-30 | 2002-07-18 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
| EP1024810A4 (en) | 1997-06-26 | 2003-06-11 | Merck & Co Inc | METHOD FOR OPTIMIZING RETINAL AND THE HEALTH OF THE OPTICAL NERVE |
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- 2006-07-11 DE DE602006011330T patent/DE602006011330D1/de active Active
- 2006-07-11 JP JP2007524724A patent/JP4966854B2/ja active Active
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- 2006-07-11 KR KR1020087000902A patent/KR101322527B1/ko not_active IP Right Cessation
- 2006-07-11 CN CN2006800239849A patent/CN101212960B/zh not_active Expired - Fee Related
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085395A (zh) * | 2009-12-02 | 2011-06-08 | 日本乐敦制药株式会社 | 硅酮水凝胶隐形眼镜用眼科组合物 |
| CN110114119A (zh) * | 2016-10-12 | 2019-08-09 | Ps治疗有限公司 | 人工泪液、隐形眼镜和药物载体组合物及其使用方法 |
| CN110114119B (zh) * | 2016-10-12 | 2022-05-31 | Ps治疗有限公司 | 人工泪液、隐形眼镜和药物载体组合物及其使用方法 |
| CN114761022A (zh) * | 2019-11-29 | 2022-07-15 | 千寿制药株式会社 | 药物组合物 |
| CN114761022B (zh) * | 2019-11-29 | 2024-02-13 | 千寿制药株式会社 | 药物组合物 |
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| Publication number | Publication date |
|---|---|
| EP1911447A4 (en) | 2009-03-25 |
| DE602006011330D1 (de) | 2010-02-04 |
| KR101322527B1 (ko) | 2013-10-25 |
| PL1911447T3 (pl) | 2010-03-31 |
| ES2337501T3 (es) | 2010-04-26 |
| US20090054531A1 (en) | 2009-02-26 |
| EP1911447A1 (en) | 2008-04-16 |
| WO2007007894A1 (ja) | 2007-01-18 |
| JP4966854B2 (ja) | 2012-07-04 |
| CN101212960B (zh) | 2011-04-13 |
| KR20080041621A (ko) | 2008-05-13 |
| JPWO2007007894A1 (ja) | 2009-01-29 |
| EP1911447B1 (en) | 2009-12-23 |
| US7998942B2 (en) | 2011-08-16 |
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