CN112839641A - 眼科用组合物 - Google Patents
眼科用组合物 Download PDFInfo
- Publication number
- CN112839641A CN112839641A CN201980067557.8A CN201980067557A CN112839641A CN 112839641 A CN112839641 A CN 112839641A CN 201980067557 A CN201980067557 A CN 201980067557A CN 112839641 A CN112839641 A CN 112839641A
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- CN
- China
- Prior art keywords
- ophthalmic composition
- eye
- oil
- polyoxyethylene
- salt
- Prior art date
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- Pending
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- 239000000203 mixture Substances 0.000 title claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims abstract description 18
- 229960001802 phenylephrine Drugs 0.000 claims abstract description 17
- 150000003505 terpenes Chemical class 0.000 claims abstract description 8
- -1 polyhexamethylene guanidine Polymers 0.000 claims description 69
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 41
- 239000004359 castor oil Substances 0.000 claims description 33
- 235000019438 castor oil Nutrition 0.000 claims description 33
- 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 33
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- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 claims description 5
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- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 claims description 3
- 208000006550 Mydriasis Diseases 0.000 abstract description 32
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- 206010013774 Dry eye Diseases 0.000 description 32
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- 206010065062 Meibomian gland dysfunction Diseases 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
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- 239000008213 purified water Substances 0.000 description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
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- 206010015958 Eye pain Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 150000001720 carbohydrates Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
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- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 3
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- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
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Abstract
一种眼科用组合物,含有:(A)选自去氧肾上腺素及其盐中的一种以上,以及(B)选自类萜中的一种以上,其能提高泪液层稳定效果,并且即使在短时间内频繁滴眼,也能在维持由去氧肾上腺素所引起的泪液层稳定效果的状态下抑制散瞳。
Description
技术领域
本发明涉及一种含有去氧肾上腺素的眼科用组合物。
背景技术
干眼症是患病率高的疾病或症状。此外,据报道,包括日本在内的亚洲的患病率高于欧美。进一步地,预计由于作为干眼症风险因素的“年龄增长”、“隐形眼镜佩戴”、“长时间的电脑操作”而引起的有症状者数量在未来会持续增加。
泪液层的破坏(不稳定化)是由于泪液油层的异常、液层的水分量减少或分泌型粘蛋白的异常或者上皮的水润湿性降低而引起的。目前,在日本,产生了“从眼表面的不足成分中寻求引起干眼症的泪液层破坏原因并通过对其补充来治疗干眼症”这样的新型干眼症的诊断和治疗理念(分别为TFOD(tear film oriented diagnosis(泪膜定位诊断):眼表面的层化诊断)以及TFOT(tear film oriented therapy(泪膜定位治疗):眼表面的层化治疗)),这被认为对干眼症诊疗非常有用。
作为干眼症的治疗药物,以往,医疗用和一般用医药品的治疗中,含有无机盐类(如氯化钠或氯化钾等)的人工泪液已被广泛使用,但这些只起到以补充泪液为目的的暂时性效果。近年来,混入了透明质酸钠、地夸磷索钠(diquafosol sodium)和瑞巴派特(rebamipide)等对干眼症有效的成分的滴眼剂也已经开始销售了。据报道,一方面,这些成分具有促进粘蛋白或水分的显现、稳定泪液层的作用,另一方面,地夸磷索钠中,作为成分特有的副作用而产生眼眵的产生或眼痛,瑞巴派特中,作为成分特有的副作用而产生味觉障碍(参照专利文献1和2)。
如上所述,针对干眼症的有效成分种类少,有时副作用也成为问题,因而,期待新的干眼症治疗药物开发。
现有技术文献
专利文献
专利文献1:日本专利第6267003号公报
专利文献2:日本专利第6060168号公报
发明内容
发明要解决的问题
鉴于上述情况,本发明人发现,去氧肾上腺素在泪液层稳定效果和睑脂分泌促进效果方面是优良的。去氧肾上腺素在泪液层稳定效果和睑脂分泌促进效果方面是优良的,作为干眼症预防剂或治疗剂是有用的。对于去氧肾上腺素,在医疗用途方面,5w/v%(质量/体积%,g/100mL,以下相同,以下记载为%)的滴眼剂以眼底检查时的散瞳为目的而被使用。另一方面,在非处方药中,批准基准最大调配浓度为0.1%,通常用法中,几乎不会产生散瞳。然而,已经明确的是,在短时间内频繁点眼时,会产生弱的散瞳。基于以上所述,本发明的目的在于提供一种眼科用组合物,其能提高泪液层稳定效果,并且即使在短时间内频繁点眼,也能在维持由去氧肾上腺素所引起的泪液层稳定效果的状态下抑制散瞳。
解决问题的手段
为了达成上述目的,本发明人经专心研究后发现,通过在(A)选自去氧肾上腺素及其盐中的一种以上中并用(B)选自类萜(terpenoid)中的一种以上(优选与(C)选自季铵盐、山梨酸及其盐、聚己缩胍(polihexanide)及其盐、以及对羟基苯甲酸酯中的一种以上),能解决上述问题,从而完成了本发明。
因而,本发明提供下述眼科用组合物。
1.一种眼科用组合物,其含有:(A)选自去氧肾上腺素及其盐中的一种以上;以及(B)选自类萜中的一种以上。
2.根据上述1记载的眼科用组合物,其中,眼科用组合物还含有:(C)选自季铵盐、山梨酸及其盐、聚己缩胍及其盐、以及对羟基苯甲酸酯中的一种以上。
3.根据上述1或2记载的眼科用组合物,其中,眼科用组合物还含有:(D)选自聚氧乙烯氢化蓖麻油、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇、马来酸氯苯那敏、ε-氨基己酸、天冬氨酸及其盐、以及乙二胺四乙酸及其盐中的一种以上。
4.根据上述1~3中任一项记载的眼科用组合物,其中,(B)成分是选自薄荷脑、冰片、樟脑、香叶醇、胡椒薄荷油(peppermint oil)、留兰香油和桉叶油中的一种以上。
发明效果
根据本发明,可提供以下的眼科用组合物:提高由去氧肾上腺素或其盐所引起的泪液层稳定效果,并且即使在短时间内频繁使用,也能在维持泪液层稳定效果的状态下不产生散瞳。
具体实施方式
以下,对本发明进行详细说明。
[(A)成分]
(A)成分为选自去氧肾上腺素及其盐中的一种以上,可单独使用一种或适当将两种以上组合使用。例如,作为去氧肾上腺素盐,可举出:盐酸去氧肾上腺素等医药上可接受的盐。从泪液层稳定效果方面来看,在眼科用组合物中,(A)成分的混合量为0.01~5%,优选为0.025~5%,更优选为0.1~5%。另外,从散瞳抑制效果方面来看,更优选为0.01~1%,进一步优选为0.1~0.5%。
[(B)成分]
(B)成分为选自类萜中的一种以上,可单独使用一种或适当将两种以上组合使用。本发明中的类萜是指具有以异戊二烯单元为构成单元的结构的化合物,例如,可举出:萜烯烃、萜烯醇、萜烯醛和萜烯酮等。另外,根据碳原子数分类,有单萜烯、倍半萜烯、二萜烯、三萜烯和四萜烯。具体而言,可举出:薄荷脑(薄荷醇)、薄荷酮、樟脑、冰片、龙脑、香叶醇、桉叶素、芳樟醇、香茅醇和柠檬烯等单萜烯;视黄醇和视黄醛等二萜烯;以及类胡萝卜素等四萜烯等。其中,优选使用单萜烯。这些类萜可使用d体、l体或dl体中的任一种。另外,本发明中,作为类萜,也可使用含有上述化合物的精油。作为此类精油,例如,可举出:桉叶油、佛手柑油、茴香油、玫瑰油、亚洲薄荷油(mint oil)、胡椒薄荷油(椒样薄荷油)、留兰香油(绿薄荷油)和龙脑香科植物的精油、迷迭香油、薰衣草油等。其中,优选薄荷脑、冰片、樟脑、香叶醇、胡椒薄荷油、留兰香油和桉叶油。
从泪液层稳定效果和散瞳抑制效果方面来看,在眼科用组合物中,(B)成分的混合量优选为0.00005~0.3%,更优选为0.0001~0.2%,进一步优选为0.0005~0.1。另外,从泪液层稳定效果方面来看,(B)成分的混合量上限特别优选为0.03%以下。
各成分在眼科用组合物中的优选范围如下所述。
当混入薄荷脑时,优选为0.00005~0.2%,更优选为0.0001~0.1%,进一步优选为0.0005~0.03%,特别优选为0.001~0.03%,最优选为0.019~0.03%。
当混入冰片时,优选为0.00005~0.2%,更优选为0.0001~0.1%,进一步优选为0.0005~0.03%,特别优选为0.001~0.03%,最优选为0.009~0.03%。
当混入樟脑时,优选为0.0001~0.1%,更优选为0.0005~0.05%,进一步优选为0.001~0.01%,特别优选为0.002~0.01%。
当混入香叶醇时,优选为0.0001~0.1%,更优选为0.0005~0.05%,进一步优选为0.001~0.03%,特别优选为0.009~0.03%。
当混入胡椒薄荷油、留兰香油时,优选为0.0001~0.1%,更优选为0.0005~0.05%,进一步优选为0.001~0.03%,特别优选为0.009~0.03%。
当混入桉叶油时,优选为0.0002~0.2%,更优选为0.001~0.1%,进一步优选为0.002~0.03%,特别优选为0.009~0.03%,最优选为0.009~0.02%。
从提高泪液层稳定效果、散瞳抑制效果方面来看,以(B)/(A)表示的含有质量比优选为0.001~1,更优选为0.005~0.5,进一步优选为0.01~0.3。另外,上述比率为w/v%比,但为与质量比相同的值。
[(C)成分]
(C)成分为选自季铵盐、山梨酸及其盐、聚己缩胍及其盐、以及对羟基苯甲酸酯中的一种以上,可单独使用一种或适当将两种以上组合使用。例如,作为季铵盐,可举出:苯扎氯铵和苄索氯铵等;作为山梨酸盐,可举出:山梨酸钾等;作为聚己缩胍,可举出:聚己缩胍盐酸盐;作为对羟基苯甲酸酯,可举出:对羟基苯甲酸甲酯和对羟基苯甲酸乙酯等。通过混合这些,散瞳抑制效果进一步提高,即使在(A)成分的混合量高时,也能进一步获得散瞳抑制效果。
从散瞳抑制效果方面来看,在眼科用组合物中,(C)成分的混合量优选为0.00005~1%,更优选为0.0001~1%,进一步优选为0.0005~0.5%,特别优选为0.001~0.3%。
各成分在眼科用组合物中的优选范围如下所述。
当混入季铵盐时,优选为0.0001~0.1%,更优选为0.0005~0.05%,进一步优选为0.001~0.01%。
当混入山梨酸及其盐时,优选为0.005~1.0%,更优选为0.01~0.5%,进一步优选为0.05~0.3%。
当混入聚己缩胍及其盐时,优选为0.00005~0.05%,更优选为0.0001~0.02%,进一步优选为0.0001~0.01%。
当混入对羟基苯甲酸酯时,优选为0.001~0.3%,更优选为0.005~0.2%,进一步优选为0.01~0.1%。
从散瞳抑制效果和眼刺激抑制效果方面来看,以((B)+(C))/(A)表示的含有质量比优选为0.001~3,更优选为0.005~2,进一步优选为0.01~1,特别优选为0.02~0.7。另外,上述比率为w/v%比,但为与质量比相同的值。
[(D)成分]
(D)成分为选自聚氧乙烯氢化蓖麻油、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇、马来酸氯苯那敏、ε-氨基己酸、天冬氨酸及其盐、以及乙二胺四乙酸及其盐中的一种以上,可单独使用一种或适当将两种以上组合使用。通过混合这些,散瞳抑制效果进一步提高,即使在(A)成分的混合量高时,也能进一步获得散瞳抑制效果。其中,优选聚氧乙烯氢化蓖麻油、聚氧乙烯脱水山梨醇脂肪酸酯和聚氧乙烯聚氧丙烯二醇。
聚氧乙烯氢化蓖麻油(POE氢化蓖麻油)是通过在氢化蓖麻油上加成聚合氧化乙烯而得的化合物,并已知有氧化乙烯的平均加成摩尔数不同的一些种类。对于聚氧乙烯氢化蓖麻油中的氧化乙烯的平均加成摩尔数,并没有特别限定,可示例出5~100摩尔。具体而言,可举出:聚氧乙烯氢化蓖麻油5(EO平均加成摩尔数为5)、聚氧乙烯氢化蓖麻油10(EO平均加成摩尔数为10)、聚氧乙烯氢化蓖麻油20(EO平均加成摩尔数为20)、聚氧乙烯氢化蓖麻油30(EO平均加成摩尔数为30)、聚氧乙烯氢化蓖麻油40(EO平均加成摩尔数为40)、聚氧乙烯氢化蓖麻油50(EO平均加成摩尔数为50)、聚氧乙烯氢化蓖麻油60(EO平均加成摩尔数为60)、聚氧乙烯氢化蓖麻油80(EO平均加成摩尔数为80)和聚氧乙烯氢化蓖麻油100(EO平均加成摩尔数为100)等。其中,优选聚氧乙烯氢化蓖麻油60。
作为聚氧乙烯脱水山梨醇脂肪酸酯(POE脱水山梨醇脂肪酸酯),可举出:聚氧乙烯(20)脱水山梨醇单月桂酸酯(聚山梨醇酯20)、聚氧乙烯(20)脱水山梨醇单棕榈酸酯(聚山梨醇酯40)、聚氧乙烯(20)脱水山梨醇单硬脂酸酯(聚山梨醇酯60)、聚氧乙烯(20)脱水山梨醇三硬脂酸酯(聚山梨醇酯65)和聚氧乙烯(20)脱水山梨醇单油酸酯(聚山梨醇酯80)。其中,优选聚氧乙烯(20)脱水山梨醇单油酸酯(聚山梨醇酯80)。
聚氧乙烯聚氧丙烯二醇(POEPOP二醇)并没有特别限定,可使用医药品添加物规格(药添规)中记载的物质。氧化乙烯的平均聚合度优选为4~200,更优选为20~200;氧化丙烯的平均聚合度优选为5~100,更优选为20~70;可为嵌段共聚物或无规聚合物。具体而言,可举出:
聚氧乙烯(200)聚氧丙烯(70)二醇:Lutrol F127(BASF公司制造)和Unilube70DP-950B(日本油脂株式会社制造)等;
聚氧乙烯(120)聚氧丙烯(40)二醇:Pluronic F-87(BASF公司制造);
聚氧乙烯(160)聚氧丙烯(30)二醇:Pluronic F-68(BASF公司制造)和Pronon#188P(日本油脂株式会社制造)等;
聚氧乙烯(42)聚氧丙烯(67)二醇:Pluronic P123(BASF公司制造);
聚氧乙烯(54)聚氧丙烯(39)二醇:Pluronic P85(BASF公司制造)和Pronon#235P(日本油脂株式会社制造)等;以及
聚氧乙烯(20)聚氧丙烯(20)二醇:Pluronic L-44和Tetronic(BASF公司制造)等(日本油脂株式会社制造)等。
其中,优选聚氧乙烯(200)聚氧丙烯(70)二醇。
马来酸氯苯那敏作为一种抗组胺剂被熟知。ε-氨基己酸作为一种消炎-收敛剂被熟知。作为天冬氨酸及其盐中的天冬氨酸盐,可举出:天冬氨酸钾等。作为乙二胺四乙酸及其盐中的乙二胺四乙酸盐,可举出:乙二胺四乙酸钠和乙二胺四乙酸钠水合物等。
在眼科用组合物中,(D)成分的混合量优选为0.0001~20%,更优选为0.0005~10%,进一步优选为0.001~2%。
各成分在眼科用组合物中的优选范围如下所述。
当混入聚氧乙烯氢化蓖麻油时,优选为0.001~1%,更优选为0.005~0.5%,进一步优选为0.01~0.2%。
当混入聚氧乙烯脱水山梨醇脂肪酸酯时,优选为0.001~0.5%,更优选为0.005~0.4%,进一步优选为0.01~0.2%。
当混入聚氧乙烯聚氧丙烯二醇时,优选为0.01~20%,更优选为0.05~10%,进一步优选为0.1~1%。
当混入马来酸氯苯那敏时,优选为0.0001~0.1%,更优选为0.0005~0.05%,进一步优选为0.001~0.03。
当混入ε-氨基己酸时,优选为0.01~5%,更优选为0.05~4%,进一步优选为0.1~2%。
当混入天冬氨酸或其盐时,优选为0.01~3%,更优选为0.03~2%,进一步优选为0.05~1%。
当混入乙二胺四乙酸或其盐时,优选为0.0001~1.5%,更优选为0.0005~1%,进一步优选为0.001~0.1%。
[其他成分]
在不损害本发明效果的范围内,本发明的眼科用组合物中可适量混入其他成分。作为其他成分,可举出:水、油性成分、除(D)成分以外的表面活性剂、除(C)成分以外的防腐剂、糖类、缓冲剂、pH调节剂、等张剂、除(D)成分以外的稳定剂、多元醇、增稠剂、除(A)成分和(D)成分以外的药物等。这些成分可单独混入一种或适当将两种以上组合混入。下述所示成分的混合量,为混合时的优选范围。另外,水的混合量可为眼科用组合物的余量。
作为油性成分,例如,可举出:液体石蜡、蓖麻油、大豆油、橄榄油、芝麻油、玉米油、椰油、杏仁油、中链脂肪酸甘油三酯、白凡士林、混合生育酚和羊毛脂等。混入油成分时,其在眼科用组合物中的混合量优选为0.001~1.0%,更优选为0.001~0.5%,进一步优选为0.001~0.25%。
作为表面活性剂,例如,可举出:下述非离子表面活性剂。
聚氧乙烯蓖麻油(POE蓖麻油)是通过在蓖麻油上加成聚合氧化乙烯而得的化合物,并已知有氧化乙烯的平均加成摩尔数不同的一些种类。对于聚氧乙烯蓖麻油中的氧化乙烯的平均加成摩尔数,并没有特别限定,可示例出3~60摩尔。具体而言,可举出:聚氧乙烯蓖麻油3(数值表示氧化乙烯的平均加成摩尔数,以下相同)、聚氧乙烯蓖麻油10、聚氧乙烯蓖麻油20、聚氧乙烯蓖麻油35、聚氧乙烯蓖麻油40、聚氧乙烯蓖麻油50和聚氧乙烯蓖麻油60等。
作为聚乙二醇脂肪酸酯,可举出:聚乙二醇-25硬脂酸酯和聚乙二醇-40硬脂酸酯等,其中,优选聚乙二醇-40硬脂酸酯。
当混入(D)成分以外的表面活性剂时,其在眼科用组合物中的混合量优选为0.01~2.0%,更优选为0.05~1.5%,进一步优选为0.1~1.2%。
作为(C)成分以外的防腐剂,可为具有如烷基链或苯环等疏水部的防腐剂,其可举出:硫柳汞、苯乙醇、烷基氨基乙基甘氨酸和葡萄糖酸氯己定等。当混入防腐剂时,其在眼科用组合物中的混合量优选为0.0001~0.5%。其中,当混入防腐剂时,其在眼科用组合物中的混合量优选为0.1%以下,更优选为0.01%以下。
作为糖类,例如,可举出:葡萄糖、环糊精、木糖醇、山梨糖醇和甘露糖醇等。另外,这些可为d体、l体或dl体中的任一种。当混入糖类时,其在眼科用组合物中的混合量优选为0.001~5.0%,更优选为0.001~1%,进一步优选为0.001~0.1%。
作为缓冲剂,例如,可举出:柠檬酸、柠檬酸钠、硼酸、硼砂、磷酸、磷酸氢钠、磷酸二氢钠、冰醋酸、氨丁三醇和碳酸氢钠等。当混入缓冲剂时,其在眼科用组合物中的混合量优选为0.001~5.0%,更优选为0.001~2%,进一步优选为0.001~1%。
作为pH调节剂,可举出:无机酸或无机碱剂。例如,作为无机酸,可举出(稀)盐酸。作为无机碱剂,可举出:氢氧化钠、氢氧化钾、碳酸钠和碳酸氢钠等。眼科用组合物的pH优选为3.5~8.0,更优选为5.5~8.0。另外,在25℃下,用pH计(HM-25R,东亚DKK株式会社)进行pH的测定。
作为等张剂,例如,可举出:氯化钠、氯化钾、氯化钙、碳酸氢钠、碳酸钠、干燥碳酸钠、硫酸镁、磷酸氢钠、磷酸二氢钠和磷酸二氢钾等。从更加改善泪液油层不稳定引起的诸多症状方面来看,优选混入氯化钠或氯化钾,使之等张化。眼科用组合物对于生理盐水渗透压比优选为0.60~2.00,更优选为0.60~1.55,最优选为0.83~1.20。另外,在25℃下,使用自动渗透压计(A2O,Advanced Instruments公司)进行渗透压的测定。
作为(D)成分以外的稳定剂,例如,可举出:环糊精、亚硫酸盐和二丁基羟基甲苯等。当混入稳定剂时,其在眼科用组合物中的混合量优选为0.001~5.0%,更优选为0.001~1%,进一步优选为0.001~0.1%。
作为多元醇,例如,可举出:甘油、丙二醇、丁二醇和聚乙二醇等。当混入多元醇时,其在眼科用组合物中的混合量优选为0.001~5.0%,更优选为0.001~1%,进一步优选为0.001~0.1%。
作为增稠剂,例如,可举出:聚乙烯吡咯烷酮、羟乙基纤维素、羟丙基甲基纤维素、甲基纤维素、聚乙烯醇、透明质酸钠、硫酸软骨素钠、聚丙烯酸和羧基乙烯基聚合物等。当混入增稠剂时,其在眼科用组合物中的混合量优选为0.001~5.0%,更优选为0.001~1%,进一步优选为0.001~0.1%。
作为(A)成分和(D)成分以外的药物(药学上的有效成分),例如,可举出:充血去除成分(例如,肾上腺素、甲基去甲肾上腺素、去甲肾上腺素、盐酸肾上腺素、麻黄碱、甲基麻黄碱、伪麻黄碱、盐酸麻黄碱、盐酸四氢唑啉、盐酸萘甲唑啉、硝酸萘甲唑啉、dl-甲基麻黄碱盐酸盐、羟甲唑啉、甲氧胺(methoxamine)、苯丙醇胺、依替福林、米多君、曲马唑啉、辛弗林、西拉唑啉、赛洛唑啉以及它们的药学上可接受的盐等);消炎-收敛剂(例如,甲基硫酸新斯的明、尿囊素、盐酸小檗碱水合物、硫酸小檗碱水合物、薁磺酸钠、甘草酸二钾、硫酸锌、乳酸锌和盐酸溶菌酶等);抗组胺剂(例如,盐酸苯海拉明等);水溶性维生素类(黄素腺嘌呤二核苷酸钠、氰钴胺素、盐酸吡哆醇、泛醇、泛酸钙和泛酸钠等);脂溶性维生素类(乙酸视黄醇、棕榈酸视黄醇和生育酚乙酸酯等);氨基酸类(例如,氨基乙基磺酸等);以及磺胺(制)剂(sulfa drug)等。当混入药物时,药物的混合量可选择各药物的有效适应性量,在眼科用组合物中优选为0.001~5%,更优选为0.001~1%,进一步优选为0.001~0.1%。
[制造方法]
本发明的眼科用组合物制造方法并没有特别限定,例如,可通过下述方法获得:将水性成分溶解于纯化水中,调节pH后,用纯化水调节总体积。混合方法可为一般的方法,可使用波轮(pulsator)、螺旋桨叶片、桨式叶片和涡轮叶片等适当进行,转速并没有特别限定,优选设定为不激烈地起泡的程度。各液体的混合温度并没有特别限定,具体而言,从20~95℃的范围进行适当选择。
[眼科用组合物]
从容易适应于眼睛的方面来看,本发明的眼科用组合物优选为液体,并且从容易与泪液混合的方面来看,20℃下的粘度优选为20mPa·s以下,更优选为10mPa·s以下,进一步优选为5mPa·s以下,特别优选为2mPa·s以下。另外,粘度的测定方法是采用锥板型粘度计(DV2T,英弘精机株式会社)进行的。粘度的下限并没有特别限定,可为1mPa·s。
本发明的眼科用组合物可适宜作为滴眼剂、隐形眼镜用滴眼剂和洗眼剂等使用,从干眼症的预防或治疗效果方面来看,可适宜作为滴眼剂、隐形眼镜用滴眼剂(隐形眼镜佩戴者用滴眼剂)等滴眼剂使用。作为隐形眼镜,并没有特别限定,可为硬性隐形眼镜和软性隐形眼镜,详细地,可为硅水凝胶软性隐形眼镜、O2硬性隐形眼镜和彩色隐形眼镜等。据报道,隐形眼镜会影响睑板腺的形态变化,成为干眼症的一个原因,因而,本发明的眼科用组合物特别适合作为隐形眼镜用滴眼剂。
本发明的眼科用组合物能抑制由于短时间内频繁使用(每小时滴眼(或洗眼)6次以上)所引起的散瞳,其使用方法并没有特别限定。例如,作为滴眼剂或隐形眼镜用滴眼剂使用时,优选每次滴眼10~100μL、1~6滴(优选为1~3滴),每日滴眼1~6次;更优选每次滴眼10~50μL、1~6滴(优选为1~3滴),每日滴眼1~6次;进一步优选每次滴眼10~30μL、1~6滴(优选为1~3滴),每日滴眼1~6次。作为洗眼剂使用时,优选每次洗眼3~6mL,每日洗眼3~6次。
另外,可在将所得的眼科用组合物填充于树脂制容器后,进一步通过包装体进行密封,并将氮气等不活泼气体封入在上述容器和上述包装体之间所形成的空间中,也可在将眼科用组合物填充于树脂制容器后,通过包装体与脱氧剂一起密封。
<泪液层稳定化>
由于去氧肾上腺素或其盐具有泪液层稳定效果,因而,本发明的眼科用组合物具有泪液层稳定效果,适合作为泪液层稳定剂。对于泪液层稳定效果的测定,例如,可用NI(Non-invasive)BUT(非侵入性泪液层破裂时间;non-invasive tear film break uptime)进行测定。具体地,为后述的实施例的方法。
当获得泪液层稳定效果时,可适宜用作干眼症的预防剂或治疗剂。干眼症的定义是“由于各种因素而泪液层稳定性降低的疾病或症状,有时会产生眼部不适感或视觉功能异常并伴有眼表面障碍”,其诊断基准为以下两项:自觉症状和荧光素BUT(泪液层破裂时间)为5秒以下。对于BUT的测定,尽管通常使用荧光素进行测定,但必须向眼内施用染色剂,虽为少许,但泪液量也会有变化,并且染色剂可能会附着在脸部或衣服上;而调查非侵入性的直至泪液层破裂为止的时间(non-invasive breakup time:NIBUT)的方法也是众所周知的。与荧光素BUT相比,通常NIBUT更长。
特别地,去氧肾上腺素或其盐对BUT缩短型干眼症表现出显著的效果。BUT缩短型干眼症是指以下的干眼症:泪液分泌或角结膜上皮大体上正常,但检测到BUT缩短,并以此为原因,会产生眼疲劳、眼睛干涩、戴隐形眼镜时的不适感和眼模糊、异物感、眼痛、目眩、眼睛沉重、眼睛不适感、眼眵和流泪等症状。本发明的泪液层稳定剂可伴有或不伴有泪液分泌量的增加,即使无泪液分泌量的增加,也能表现出显著的干眼症预防或治疗效果。
作为由泪液层不稳定所产生的疾病或症状,可举出如下所述的症状,并且本发明的泪液层稳定剂可适合用作下述疾病或症状的预防剂或治疗剂。
选自如下的疾病或症状:泪液减少症、年龄增加的干性眼、少泪症、眼睛干燥症、综合征、干性角结膜炎、Stevens-Johnson综合征、眼类天疱疮、眼睑边缘炎、闭眼不全、感觉神经麻痹、过敏性结膜炎相关的干眼症、病毒性结膜炎后的干眼症、白内障手术后的干眼症、VDT(视频显示终端;Visual Display Terminal)操作相关的干眼症以及隐形眼镜佩戴相关的干眼症。
选自如下的疾病或症状:因干眼症而引起的眼疲劳、眼睛干涩、眼睛劳累、戴隐形眼镜时的不适感、眼模糊、LWE(Lid Wiper Epitheliopathy:眼睑刷上皮病变)、角结膜上皮障碍、角膜上皮剥离、角膜上皮糜烂、角膜溃疡以及眼感染症。
进一步地,作为由泪液层不稳定所产生的疾病或症状,可举出如下所述的症状,并且本发明的泪液层稳定剂适合用作下述症状的预防剂或治疗剂。
眼疲劳、眼睛干涩、戴隐形眼镜时的不适感和眼模糊、异物感、眼痛、目眩、眼睛沉重、眼睛不适感、眼眵和流泪。
<睑脂分泌促进剂>
由于去氧肾上腺素或其盐具有睑脂分泌促进效果,因而,本发明的眼科用组合物具有睑脂分泌促进效果,并适合作为睑脂分泌促进剂。睑脂是由睑板腺所分泌的成分,通过促进睑脂分泌,泪液油层增加。睑脂分泌促进效果是通过测定泪液油层的厚度来评价的。
存在于眼睑内的睑板腺能分泌脂质,作为泪液油层的供给源而重要。该泪液油层因降低泪液的表面张力和防止泪液的蒸发等,故而泪液作为膜是稳定的,因而是重要的。然而,关于睑板腺分泌机制的报道很少,并且尚未充分阐明。
作为由于来自睑板腺的睑脂分泌障碍所产生的疾病或症状,除上述干眼症以外,还存在睑板腺功能障碍和睑腺炎(麦粒肿、霰粒肿)等。
睑板腺功能障碍(meibomian gland dysfunction;MGD)定义为由睑板腺的分泌障碍所引起的泪液和眼表面的异常。可根据以下3个方面进行诊断:自觉症状与睑板腺开口部周围异常观察结果以及睑板腺阻塞观察结果。MGD患者的自觉症状是多种的,且诉诸有异物感、干燥感、眼睛疲劳感和灼热感等。对于治疗,为了改善睑板腺的阻塞,而进行有:温热疗法或者通过施加物理力来进行的压出、在海外用细铁丝样器具直接解除睑板腺的阻塞的方法等。另外,近年来,已经开发了一种通过干涉图像来评价泪液油层并从内侧以温热和按摩效果来对眼睑进行治疗的系统、Lipiview/Lipiflow系统,并且今后的治疗效果受到关注。然而,这些方法全部成为在医疗机构内的处置,因而,期待简便的治疗方法。
通常称为睑腺炎的麦粒肿和霰粒肿是发生在睑板腺中的疾病或症状。麦粒肿是由细菌感染引起的急性化脓性炎症。对于治疗,存在药物疗法和手术疗法。药物疗法是在发现脓点的自毁/排脓时,施用抗菌剂。对于手术疗法,当脓点不在浅层且无法自毁/排脓时,采用注射针等进行穿刺/切开以促进排脓。也就是说,治疗需要从睑板腺中排脓,但直到现在,仅有的选择是等待自然排脓或有侵入性的强制排脓。霰粒肿被称为对脂质的异物反应,并非感染症。基本以手术进行治疗。也就是说,尽管麦粒肿和霰粒肿需要从睑板腺排出脓或脂质,但迄今为止并无除手术外的其他方法。
本发明的睑脂分泌促进剂可适合用作与上述泪液层稳定剂相同的症状的预防剂或治疗剂。进一步地,通过本发明的睑脂分泌促进剂,能增加睑脂分泌,因而,能预防或治疗MGD或干眼症、麦粒肿和霰粒肿(睑腺炎)。
<散瞳抑制剂>
对于本发明,即使在短时间内频繁使用(滴眼),也可在维持由去氧肾上腺素所引起的泪液层稳定效果的状态下抑制去氧肾上腺素所引起的散瞳,因而,适宜作为能抑制短时间内频繁使用所引起的散瞳的散瞳抑制剂。适宜的成分和混合量等与上述相同。另外,本发明中,短时间内频繁使用意味着每小时滴眼(或洗眼)6次以上。此外,每次的眼科用组合物量适宜在10~100μL的范围内进行选定,可为50μL。
【实施例】
以下,通过实施例和比较例对本发明进行具体说明,但本发明并不局限于下述实施例。另外,下述例子中,无特别说明时,组成的“%”表示w/v%,比率表示质量比(与w/v%比相同的值)。
[实施例、比较例]
将(B)成分与丙二醇混合并溶解在纯化水中后,将(A)成分~(D)成分以及其他水溶性成分溶解在纯化水中,调节pH后,用纯化水将总体积调整至100mL。另外,所得眼科用组合物在25℃下的pH示出在表中。此外,25℃下的组合物粘度在1~20mPa·s的范围内。对所得眼科用组合物进行下述评价。结果也一并显示在表中。
<试验1:散瞳抑制效果>
3名受试者在1小时内将样品滴眼6次(一次一滴(50μL))。在滴眼前和滴眼后,根据下述基准,评价散瞳程度。为了评价散瞳程度,使用数码相机,设定至预闪光模式,在即将拍摄之前,引发光适应(缩瞳),进行拍摄。散瞳率越低,表示散瞳抑制效果越高。
散瞳率(缩瞳抑制率)=(D2-D1)/D1×100(%)
D1=滴眼前(初始状态)的瞳孔直径(mm)
D2=滴眼后的瞳孔直径(mm)
根据3名受试者的散瞳率平均值,按照下述评价基准,对散瞳抑制效果进行评价。以“○”和“◎”作为合格。
[散瞳抑制效果]
◎:散瞳率的平均值小于10%
〇:散瞳率的平均值为10%以上且小于20%
△:散瞳率的平均值为20%以上且小于30%
×:散瞳率的平均值为30%以上
<试验2:眩光(无眩光的程度)评价>
3名受试者在1小时内将各样品滴眼6次(一次一滴(50μL))。滴眼后,根据下述基准,评价眩光程度。点数越低,表示越没有眩光。以“○”和“◎”作为合格。
[眩光]
0点:完全没有症状。
1点:症状并不痛苦,但有时会有症状。对日常生活几乎没有障碍。
2点:症状并不那么痛苦,但常常会有症状。对日常生活有轻微障碍。
3点:症状相当痛苦,但勉强可忍受。对日常生活非常有障碍。
4点:症状非常痛苦且为难以忍受的程度。无法进行日常生活。
[无眩光的程度]
◎:小于0.5
○:0.5以上且小于1.0
△:1.0以上且小于1.5
×:平均值为1.5以上
<试验3:泪液层稳定性:NI(Non-invasive)BUT(非侵入性泪液层破裂时间)>
3名受试者在1小时内将样品滴眼6次(一次一滴(50μL))。在滴眼前和滴眼后(最后滴眼经过5分钟以上后),按照以下步骤进行测定。
NIBUT的评价中,使用DR-1(兴和制造)。
使用DR-1观察泪液干涉图像,睁开眼睑后,测定直到泪液层破裂(均匀的灰色或白色的干涉图像消失)为止的时间(秒)(NIBUT;非侵入性泪液层破裂时间),并算出其平均值。NIBUT长者的泪液层稳定性效果高。
测定滴眼实施例和比较例时的NIBUT,并算出平均值。
另外,算出实施例的平均值与比较例的平均值之间的差,并按照下述基准,评价泪液层稳定性效果。另外,盐酸去氧肾上腺素浓度为0.1%时,其为与比较例2之间的差;盐酸去氧肾上腺素浓度为1%时,其为与比较例3之间的差。此外,比较例中,记载NIBUT;非侵入性泪液层破裂时间。将“●”、“○”和“◎”作为合格。
◎:平均值之差为1.5秒以上
○:平均值之差为1秒以上且小于1.5秒
●:平均值之差小于1秒
×:无泪液层稳定性效果
【表1】
【表2】
【表3】
【表4】
【表5】
【表6】
上述例子中所使用的原料如下所述。另外,除非另有说明,表中各成分的量为纯度换算量。
POE(聚氧乙烯)氢化蓖麻油(聚氧乙烯氢化蓖麻油60:HCO-60,日本Surfactant工业株式会社制造)
POE(聚氧乙烯)脱水山梨醇脂肪酸酯(聚山梨醇酯80,Rheodol TW-O120V,花王株式会社制造)
EOPO(聚氧乙烯(196)聚氧丙烯(67)二醇)(Lutrol F127,BASF日本株式会社制造)
Claims (4)
1.一种眼科用组合物,其特征在于,含有:(A)选自去氧肾上腺素及其盐中的一种以上;以及(B)选自类萜中的一种以上。
2.根据权利要求1所述的眼科用组合物,其中,眼科用组合物还含有:(C)选自季铵盐、山梨酸及其盐、聚己缩胍及其盐以及对羟基苯甲酸酯中的一种以上。
3.根据权利要求1或2所述的眼科用组合物,其中,眼科用组合物还含有:(D)选自聚氧乙烯氢化蓖麻油、聚氧乙烯脱水山梨醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇、马来酸氯苯那敏、ε-氨基己酸、天冬氨酸及其盐以及乙二胺四乙酸及其盐中的一种以上。
4.根据权利要求1~3中任一项所述的眼科用组合物,其中,(B)成分是选自薄荷脑、冰片、樟脑、香叶醇、胡椒薄荷油、留兰香油和桉叶油中的一种以上。
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- 2019-12-25 KR KR1020217000919A patent/KR20210107607A/ko unknown
- 2019-12-25 WO PCT/JP2019/050751 patent/WO2020138135A1/ja active Application Filing
- 2019-12-25 CN CN201980067557.8A patent/CN112839641A/zh active Pending
- 2019-12-25 JP JP2020563334A patent/JPWO2020138135A1/ja active Pending
- 2019-12-26 TW TW108147884A patent/TW202033186A/zh unknown
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KR20210107607A (ko) | 2021-09-01 |
TW202033186A (zh) | 2020-09-16 |
JPWO2020138135A1 (ja) | 2021-11-11 |
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