TW202033186A - 眼科用組成物 - Google Patents
眼科用組成物 Download PDFInfo
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- TW202033186A TW202033186A TW108147884A TW108147884A TW202033186A TW 202033186 A TW202033186 A TW 202033186A TW 108147884 A TW108147884 A TW 108147884A TW 108147884 A TW108147884 A TW 108147884A TW 202033186 A TW202033186 A TW 202033186A
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- Prior art keywords
- oil
- polyoxyethylene
- ophthalmic composition
- eye
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Abstract
藉由製成含有(A)選自脫羥腎上腺素及其鹽中的一種以上、以及(B)選自萜類化合物中的一種以上的眼科用組成物,可提高淚液層穩定效果,進而,即便於短時間內頻繁點眼,亦可於維持脫羥腎上腺素帶來的淚液層穩定效果的狀態下抑制散瞳。
Description
本發明是有關於一種含有脫羥腎上腺素(phenylephrine)的眼科用組成物。
乾眼症(dry eye)為患病率高的疾病或症狀。此外,報告指出包括日本在內的亞洲的患病率比歐美高。進而,預測因作為乾眼症的風險因子(risk factor)的「高齡」、「隱形眼鏡(contact lenses)佩戴」、「長時間的電腦作業」引起的有症狀者的數量將來會持續增加。
淚液層的破壞(不穩定化)是由淚液油層的異常、液層的水分量的減少或分泌型黏蛋白(mucin)的異常、或者上皮的水潤濕性的降低引起的。目前,在日本產生有於眼表面的不足成分中尋求引起乾眼症的淚液層的破壞的原因並對其加以彌補而治療乾眼症的新的乾眼症的診斷、治療觀念(分別為:TFOD(tear film oriented diagnosis(淚膜定向診斷):眼表面的層化診斷)、以及TFOT(tear film oriented therapy(淚膜定向治療):眼表面的層化治療)),且對乾眼症診療極其有用。
作為乾眼症的治療藥,先前,於醫療用藥及非處方藥的治療中,廣泛使用含有氯化鈉或氯化鉀等無機鹽類的人工淚液,該些僅有以補充淚液為目的的暫時性效果。近年來,亦開始售賣調配有如玻尿酸鈉(hyaluronic acid sodium)、地誇磷索鈉(diquafosol sodium)、瑞巴派特(rebamipide)般對乾眼症有效的成分的點眼藥。該些成分具有促進黏蛋白或水分的顯現並使淚液層穩定化的作用,另一方面,報告指出:地誇磷索鈉中,作為成分特有的副作用而產生眼眵的產生或眼痛,瑞巴派特中,作為成分特有的副作用而產生味覺障礙(參照專利文獻1、專利文獻2)。
如上所述,針對乾眼症的有效成分的種類少,且有時副作用亦成為問題,因此期望開發一種新的乾眼症治療藥。
[現有技術文獻]
[專利文獻]
[專利文獻1]日本專利第6267003號公報
[專利文獻2]日本專利第6060168號公報
[發明所欲解決之課題]
鑑於所述狀況,本發明者等人得知脫羥腎上腺素的淚液層穩定效果、瞼脂(meibum)分泌促進效果優異。關於脫羥腎上腺素,淚液層穩定效果、瞼脂分泌促進效果優異,作為乾眼症預防劑或治療劑有用。關於脫羥腎上腺素,於醫療用藥中,5 w/v%(質量/體積%,g/100 mL,以下相同,以下以%來記載)的點眼液是以眼底檢查時的散瞳為目的來使用。另一方面,於非處方藥中,許可基準最大調配濃度為0.1%,在通常的用法中,幾乎不會發生散瞳。但是,已明確的是,於在短時間內頻繁點眼的情況下,會發生弱的散瞳。根據以上情況,目的在於提供一種眼科用組成物,其提高淚液層穩定效果,進而,即便於短時間內頻繁點眼,亦可於維持脫羥腎上腺素帶來的淚液層穩定效果的狀態下抑制散瞳。
[解決課題之手段]
本發明者等人為了達成所述目的而進行了努力研究,結果得知,藉由對(A)選自脫羥腎上腺素及其鹽中的一種以上併用(B)選自萜類化合物(terpenoid)中的一種以上、以及較佳的(C)選自四級銨鹽、山梨酸及其鹽、聚己雙胍(polihexanide)及其鹽、以及對羥基苯甲酸酯中的一種以上,可解決所述課題,從而完成了本發明。
因此,本發明提供下述眼科用組成物。
1. 一種眼科用組成物,含有:(A)選自脫羥腎上腺素及其鹽中的一種以上、以及(B)選自萜類化合物中的一種以上。
2. 如1所述的眼科用組成物,其進而含有:(C)選自四級銨鹽、山梨酸及其鹽、聚己雙胍及其鹽、以及對羥基苯甲酸酯中的一種以上。
3. 如1或2所述的眼科用組成物,其進而含有:(D)選自聚氧乙烯硬化蓖麻油、聚氧乙烯脫水山梨糖醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇、氯菲安明馬來酸鹽(chlorpheniramine maleate)、ε-胺基己酸、天冬胺酸及其鹽、以及依地酸(edetic acid)及其鹽中的一種以上。
4. 如1至3中任一項所述的眼科用組成物,其中(B)成分為選自薄荷醇(menthol)、冰片(borneol)、樟腦、香葉草醇(geraniol)、歐薄荷油(peppermint oil)、綠薄荷油(spearmint oil)及桉葉油(eucalyptus oil)中的一種以上。
[發明的效果]
根據本發明,可提供一種眼科用組成物,其提高脫羥腎上腺素或其鹽帶來的淚液層穩定效果,進而,即便於短時間內的頻繁使用時,亦維持淚液層穩定效果,且於該狀態下不會發生散瞳。
以下,對本發明進行詳細說明。
[(A)成分]
(A)成分為選自脫羥腎上腺素及其鹽中的一種以上,可單獨使用一種或將兩種以上適宜組合來使用。例如,作為脫羥腎上腺素鹽,可列舉脫羥腎上腺素鹽酸鹽等醫藥上所允許的鹽。就淚液層穩定效果的方面而言,(A)成分的調配量於眼科用組成物中為0.01%~5%,較佳為0.025%~5%,更佳為0.1%~5%。另外,就散瞳抑制效果的方面而言,更佳為0.01%~1%,進而佳為0.1%~0.5%。
[(B)成分]
(B)成分為選自萜類化合物中的一種以上,可單獨使用一種或將兩種以上適宜組合來使用。所謂本發明中的萜類化合物,是具有將異戊二烯單元作為構成單元的結構的化合物,例如可列舉:萜烯烴、萜烯醇、萜烯醛、萜烯酮等。另外,根據碳數,有單萜烯、倍半萜烯、二萜烯、三萜烯、四萜烯。具體而言,可列舉:薄荷醇、薄荷酮(menthone)、樟腦、冰片、龍腦、香葉草醇、桉油醇(cineol)、沈香醇(linalool)、香茅醇(citronellol)及檸檬烯(limonene)等單萜烯,視黃醇(retinol)及視黃醛(retinal)等二萜烯,類胡蘿蔔素(carotenoid)等四萜烯等。其中,較佳為使用單萜烯。該些萜類化合物亦可使用d體、l體或dl體的任一種。再者,於本發明中,作為萜類化合物,亦可使用含有所述化合物的精油。作為此種精油,例如可列舉:桉葉油、香柑油(bergamot oil)、小茴香油、玫瑰油、亞洲薄荷油(mint oil)、歐薄荷油、綠薄荷油、以及龍腦香科(Dipterocarpaceae)植物的精油、迷迭香油(rosemary oil)、薰衣草油(lavender oil)等。其中,較佳為薄荷醇、冰片、樟腦、香葉草醇、歐薄荷油、綠薄荷油、桉葉油。
就淚液層穩定效果、散瞳抑制效果的方面而言,(B)成分的調配量於眼科用組成物中較佳為0.00005%~0.3%,更佳為0.0001%~0.2%,進而佳為0.0005%~0.1%。再者,就淚液層穩定效果的方面而言,上限特佳為0.03%以下。
各成分於眼科用組成物中的較佳範圍為如下所述。
於調配薄荷醇的情況下,較佳為0.00005%~0.2%,更佳為0.0001%~0.1%,進而佳為0.0005%~0.03%,特佳為0.001%~0.03%,最佳為0.019%~0.03%。
於調配冰片的情況下,較佳為0.00005%~0.2%,更佳為0.0001%~0.1%,進而佳為0.0005%~0.03%,特佳為0.001%~0.03%,最佳為0.009%~0.03%。
於調配樟腦的情況下,較佳為0.0001%~0.1%,更佳為0.0005%~0.05%,進而佳為0.001%~0.01%,特佳為0.002%~0.01%。
於調配香葉草醇的情況下,較佳為0.0001%~0.1%,更佳為0.0005%~0.05%,進而佳為0.001%~0.03%,特佳為0.009%~0.03%。
於調配歐薄荷油、綠薄荷油的情況下,較佳為0.0001%~0.1%,更佳為0.0005%~0.05%,進而佳為0.001%~0.03%,特佳為0.009%~0.03%。
於調配桉葉油的情況下,較佳為0.0002%~0.2%,更佳為0.001%~0.1%,進而佳為0.002%~0.03%,特佳為0.009%~0.03%,最佳為0.009%~0.02%。
就淚液層穩定效果提高、散瞳抑制效果的方面而言,(B)/(A)所表示的含有質量比較佳為0.001~1,更佳為0.005~0.5,進而佳為0.01~0.3。再者,所述比率為w/v%比,為與質量比相同的值。
[(C)成分]
(C)成分為選自四級銨鹽、山梨酸及其鹽、聚己雙胍及其鹽、以及對羥基苯甲酸酯中的一種以上,可單獨使用一種或將兩種以上適宜組合來使用。例如,四級銨鹽可列舉氯化苄烷銨(benzalkonium chloride)、氯化苯索寧(benzethonium chloride)等,山梨酸鹽可列舉山梨酸鉀等,聚己雙胍可列舉鹽酸聚己雙胍,對羥基苯甲酸酯可列舉對羥基苯甲酸甲酯、對羥基苯甲酸乙酯等。藉由調配該些成分,散瞳抑制效果進一步提高,即便於(A)成分的調配量高的情況下,亦可進一步獲得散瞳抑制效果。
就散瞳抑制效果的方面而言,(C)成分的調配量於眼科用組成物中較佳為0.00005%~1%,更佳為0.0001%~1%,進而佳為0.0005%~0.5%,特佳為0.001%~0.3%。
各成分於眼科用組成物中的較佳範圍為如下所述。
於調配四級銨鹽的情況下,較佳為0.0001%~0.1%,更佳為0.0005%~0.05%,進而佳為0.001%~0.01%。
於調配山梨酸及其鹽的情況下,較佳為0.005%~1.0%,更佳為0.01%~0.5%,進而佳為0.05%~0.3%。
於調配聚己雙胍及其鹽的情況下,較佳為0.00005%~0.05%,更佳為0.0001%~0.02%,進而佳為0.0001%~0.01%。
於調配對羥基苯甲酸酯的情況下,較佳為0.001%~0.3%,更佳為0.005%~0.2%,進而佳為0.01%~0.1%。
就散瞳抑制效果及眼刺激抑制效果的方面而言,((B)+(C))/(A)所表示的含有質量比較佳為0.001~3,更佳為0.005~2,進而佳為0.01~1,特佳為0.02~0.7。再者,所述比率為w/v%比,為與質量比相同的值。
[(D)成分]
(D)成分為選自聚氧乙烯硬化蓖麻油、聚氧乙烯脫水山梨糖醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇、氯菲安明馬來酸鹽、ε-胺基己酸、天冬胺酸及其鹽、以及依地酸及其鹽中的一種以上,可單獨使用一種或將兩種以上適宜組合來使用。藉由調配該些成分,散瞳抑制效果進一步提高,即便於(A)成分的調配量高的情況下,亦可進一步獲得散瞳抑制效果。其中,較佳為聚氧乙烯硬化蓖麻油、聚氧乙烯脫水山梨糖醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇。
聚氧乙烯硬化蓖麻油(POE(polyoxyethylene)硬化蓖麻油)為藉由對氫化蓖麻油加成聚合氧化乙烯而獲得的化合物,已知有氧化乙烯的平均加成莫耳數不同的若干種類。關於聚氧乙烯硬化蓖麻油中的氧化乙烯的平均加成莫耳數,並無特別限定,可例示5莫耳~100莫耳。具體而言,可列舉:聚氧乙烯硬化蓖麻油5(環氧乙烷(ethylene oxide,EO)平均加成莫耳數5)、聚氧乙烯硬化蓖麻油10(EO平均加成莫耳數10)、聚氧乙烯硬化蓖麻油20(EO平均加成莫耳數20)、聚氧乙烯硬化蓖麻油30(EO平均加成莫耳數30)、聚氧乙烯硬化蓖麻油40(EO平均加成莫耳數40)、聚氧乙烯硬化蓖麻油50(EO平均加成莫耳數50)、聚氧乙烯硬化蓖麻油60(EO平均加成莫耳數60)、聚氧乙烯硬化蓖麻油80(EO平均加成莫耳數80)、聚氧乙烯硬化蓖麻油100(EO平均加成莫耳數100)等。其中,較佳為聚氧乙烯硬化蓖麻油60。
作為聚氧乙烯脫水山梨糖醇脂肪酸酯(POE脫水山梨糖醇脂肪酸酯),可列舉:單月桂酸聚氧乙烯(20)脫水山梨糖醇(聚山梨醇酯(polysorbate)20)、單棕櫚酸聚氧乙烯(20)脫水山梨糖醇(聚山梨醇酯40)、單硬脂酸聚氧乙烯(20)脫水山梨糖醇(聚山梨醇酯60)、三硬脂酸聚氧乙烯(20)脫水山梨糖醇(聚山梨醇酯65)、單油酸聚氧乙烯(20)脫水山梨糖醇(聚山梨醇酯80)。其中,較佳為單油酸聚氧乙烯(20)脫水山梨糖醇(聚山梨醇酯80)。
聚氧乙烯聚氧丙烯二醇(POEPOP(polyoxyethylene polyoxypropylene)二醇)並無特別限定,可使用醫藥品添加物規格(藥添規)中所記載者。環氧乙烷的平均聚合度較佳為4~200,更佳為20~200,環氧丙烷的平均聚合度較佳為5~100,更佳為20~70,可為嵌段共聚物,亦可為無規聚合物。具體而言,可列舉:聚氧乙烯(200)聚氧丙烯(70)二醇:魯特魯(Lutrol)F127(巴斯夫(BASF)公司製造)、尤尼盧布(Uni-Loob)70DP-950B(日本油脂(股)製造)等、聚氧乙烯(120)聚氧丙烯(40)二醇:普羅尼克(Pluronic)F-87(巴斯夫(BASF)公司製造)、聚氧乙烯(160)聚氧丙烯(30)二醇:普羅尼克(Pluronic)F-68(巴斯夫(BASF)公司製造)、普羅農(Pronon)#188P(日本油脂(股)製造)等、聚氧乙烯(42)聚氧丙烯(67)二醇:普羅尼克(Pluronic)P123(巴斯夫(BASF)公司製造)、聚氧乙烯(54)聚氧丙烯(39)二醇:普羅尼克(Pluronic)P85(巴斯夫(BASF)公司製造)、普羅農(Pronon)#235P(日本油脂(股)製造)等、聚氧乙烯(20)聚氧丙烯(20)二醇:普羅尼克(Pluronic)L-44、泰特尼庫(Tetronic)(巴斯夫(BASF)公司製造)等。其中,較佳為聚氧乙烯(200)聚氧丙烯(70)二醇。
氯菲安明馬來酸鹽作為抗組織胺劑已被熟知。ε-胺基己酸作為消炎收斂劑已被熟知。天冬胺酸及其鹽即天冬胺酸鹽可列舉天冬胺酸鉀等。依地酸及其鹽即依地酸鹽可列舉依地酸鈉、依地酸鈉水合物等。
(D)成分的調配量於眼科用組成物中較佳為0.0001%~20%,更佳為0.0005%~10%,進而佳為0.001%~2%。
各成分於眼科用組成物中的較佳範圍為如下所述。
於調配聚氧乙烯硬化蓖麻油的情況下,較佳為0.001%~1%,更佳為0.005%~0.5%,進而佳為0.01%~0.2%。
於調配聚氧乙烯脫水山梨糖醇脂肪酸酯的情況下,較佳為0.001%~0.5%,更佳為0.005%~0.4%,進而佳為0.01%~0.2%。
於調配聚氧乙烯聚氧丙烯二醇的情況下,較佳為0.01%~20%,更佳為0.05%~10%,進而佳為0.1%~1%。
於調配氯菲安明馬來酸鹽的情況下,較佳為0.0001%~0.1%,更佳為0.0005%~0.05%,進而佳為0.001%~0.03%。
於調配ε-胺基己酸的情況下,較佳為0.01%~5%,更佳為0.05%~4%,進而佳為0.1%~2%。
於調配天冬胺酸或其鹽的情況下,較佳為0.01%~3%,更佳為0.03%~2%,進而佳為0.05%~1%。
於調配依地酸或其鹽的情況下,較佳為0.0001%~1.5%,更佳為0.0005%~1%,進而佳為0.001%~0.1%。
[其他成分]
可於無損本發明的效果的範圍內對本發明的眼科用組成物適量調配其他成分。作為其他成分,可列舉:水、油性成分、除(D)成分以外的界面活性劑、除(C)成分以外的防腐劑、糖類、緩衝劑、pH值調整劑、等張劑、除(D)成分以外的穩定劑、多元醇、黏稠劑、除(A)成分、(D)成分以外的藥物等。該些成分可單獨調配一種或將兩種以上適宜組合來調配。以下所示的成分的調配量為進行調配時的較佳範圍。再者,水的調配量可設為眼科用組成物的剩餘部分。
作為油性成分,例如可列舉:液體石蠟、蓖麻油、大豆油、橄欖油、芝麻油、玉米油、椰子油、扁桃油、中鏈脂肪酸三甘油酯、白色凡士林、混合生育酚、羊毛脂等。調配油成分時的調配量於眼科用組成物中較佳為0.001%~1.0%,更佳為0.001%~0.5%,進而佳為0.001%~0.25%。
作為界面活性劑,例如可列舉下述非離子界面活性劑。
聚氧乙烯蓖麻油(POE蓖麻油)為藉由對蓖麻油加成聚合氧化乙烯而獲得的化合物,已知有氧化乙烯的平均加成莫耳數不同的若干種類。關於聚氧乙烯蓖麻油中的氧化乙烯的平均加成莫耳數,並無特別限定,可例示3莫耳~60莫耳。具體而言,可列舉:聚氧乙烯蓖麻油3(數值為氧化乙烯的平均加成莫耳數,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、聚氧乙烯蓖麻油60等。
作為聚乙二醇脂肪酸酯,可列舉硬脂酸聚乙二醇-25、硬脂酸聚乙二醇-40等,其中較佳為硬脂酸聚乙二醇-40。
調配(D)成分以外的界面活性劑時的調配量於眼科用組成物中較佳為0.01%~2.0%,更佳為0.05%~1.5%,進而佳為0.1%~1.2%。
作為(C)成分以外的防腐劑,具有烷基鏈或苯環等疏水部的防腐劑可列舉:乙汞硫柳酸鈉(thimerosal)、苯基乙基醇、烷基胺基乙基甘胺酸、葡萄糖酸洛赫西定(chlorhexidine gluconate)等。調配防腐劑時的調配量於眼科用組成物中較佳為0.0001%~0.5%。其中,於進行調配的情況下,在眼科用組成物中較佳為0.1%以下,進而佳為0.01%以下。
作為糖類,例如可列舉:葡萄糖、環糊精、木糖醇(xylitol)、山梨糖醇、甘露醇(mannitol)等。再者,該些可為d體、l體或dl體的任一種。調配糖類時的調配量於眼科用組成物中較佳為0.001%~5.0%,更佳為0.001%~1%,進而佳為0.001%~0.1%。
作為緩衝劑,例如可列舉:檸檬酸、檸檬酸鈉、硼酸、硼砂、磷酸、磷酸氫鈉、磷酸二氫鈉、冰乙酸、胺基丁三醇(trometamol)、碳酸氫鈉等。調配緩衝劑時的調配量於眼科用組成物中較佳為0.001%~5.0%,更佳為0.001%~2%,進而佳為0.001%~1%。
作為pH值調整劑,可列舉無機酸或無機鹼劑。例如,作為無機酸,可列舉(稀)鹽酸。作為無機鹼劑,可列舉:氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸氫鈉等。眼科用組成物的pH值較佳為3.5~8.0,更佳為5.5~8.0。再者,pH值的測定是於25℃下使用pH值計(HM-25R,東亞DKK(股))來進行。
作為等張劑,例如可列舉:氯化鈉、氯化鉀、氯化鈣、碳酸氫鈉、碳酸鈉、乾燥碳酸鈉、硫酸鎂、磷酸氫鈉、磷酸二氫鈉、磷酸二氫鉀等。就進一步改善淚液油層不穩定化引起的諸症狀的方面而言,較佳為調配氯化鈉或氯化鉀來加以等張化。眼科用組成物的相對於生理食鹽水的滲透壓比較佳為0.60~2.00,更佳為0.60~1.55,最佳為0.83~1.20。再者,滲透壓的測定是於25℃下使用自動滲透壓計(A2O,先進儀器(Advanced instruments)公司)進行。
作為(D)成分以外的穩定劑,例如可列舉:環糊精、亞硫酸鹽、二丁基羥基甲苯等。調配穩定劑時的調配量於眼科用組成物中較佳為0.001%~5.0%,更佳為0.001%~1%,進而佳為0.001%~0.1%。
作為多元醇,例如可列舉:甘油、丙二醇、丁二醇、聚乙二醇等。調配多元醇時的調配量於眼科用組成物中較佳為0.001%~5.0%,更佳為0.001%~1%,進而佳為0.001%~0.1%。
作為黏稠劑,例如可列舉:聚乙烯基吡咯啶酮、羥基乙基纖維素、羥基丙基甲基纖維素、甲基纖維素、聚乙烯基醇、玻尿酸鈉、軟骨素硫酸鈉(sodium chondroitin sulfate)、聚丙烯酸、羧基乙烯基聚合物等。調配黏稠劑時的調配量於眼科用組成物中較佳為0.001%~5.0%,更佳為0.001%~1%,進而佳為0.001%~0.1%。
作為(A)成分及(D)成分以外的藥物(藥學性有效成分),例如可列舉:去充血成分(例如,腎上腺素(epinephrine)、甲基去甲腎上腺素(methyl norepinephrine)、去甲腎上腺素(norepinephrine)、鹽酸腎上腺素、麻黃素(ephedrine)、甲基麻黃素、擬麻黃素(pseudoephedrine)、麻黃素鹽酸鹽、鹽酸四氫唑啉、奈甲嘧唑啉鹽酸鹽、奈甲嘧唑啉硝酸鹽、dl-甲基麻黃素鹽酸鹽、羥間唑啉(oxymetazoline)、甲氧胺(methoxamine)、苯丙醇胺(phenylpropanolamine)、依替福林(etilefrine)、米多君(midodrine)、曲馬唑啉(tramazoline)、交感醇(synephrine)、西拉唑啉(cirazoline)、賽洛唑啉(xylometazoline)及該些的藥學上所允許的鹽等);消炎、收斂劑(例如,新斯的明甲基硫酸鹽(neostigmine methyl sulfate)、尿囊素(allantoin)、氯化小蘗鹼水合物(berberine chloride hydrate)、小蘗鹼硫酸鹽水合物、薁磺酸鈉、甘草酸二鉀(dipotassium glycyrrhizinate)、硫酸鋅、乳酸鋅、溶菌酶鹽酸鹽(lysozyme hydrochloride)等);抗組織胺劑(例如,苯海拉明鹽酸鹽(diphenhydramine hydrochloride)等);水溶性維生素類(黃素腺嘌呤二核苷酸鈉(flavin adenine dinucleotide sodium)、氰鈷維生素(cyanocobalamin)、吡哆醇鹽酸鹽(pyridoxine hydrochloride)、泛醇、泛酸鈣、泛酸鈉等);脂溶性維生素類(乙酸視黃醇、棕櫚酸視黃醇、乙酸生育酚等);胺基酸類(例如,胺基乙基磺酸等)、磺胺劑等。於調配藥物的情況下,藥物調配量可選擇各藥物的有效適應性量,於眼科用組成物中較佳為0.001%~5%,更佳為0.001%~1%,進而佳為0.001%~0.1%。
[製造方法]
本發明的眼科用組成物的製造方法並無特別限定,例如可藉由如下方式獲得:將水性成分溶解於精製水中,並於調整pH值後,利用精製水對總體積進行調整。混合方法可為通常的方法,可使用攪拌器(pulsator)、螺旋葉片、明輪輪葉(paddle blade)、渦輪葉片等適宜進行,轉數並無特別限定,較佳為設定為不會激烈地起泡的程度。各液體的混合溫度並無特別限定,具體而言,可自20℃~95℃的範圍適宜選定。
[眼科用組成物]
就容易適應於眼的方面而言,本發明的眼科用組成物較佳為液體,就容易進行與淚液的混合的方面而言,20℃下的黏度較佳為20 mPa·s以下,更佳為10 mPa·s以下,進而佳為5 mPa·s以下,特佳為2 mPa·s以下。再者,黏度的測定方法是使用錐板(cone plate)型黏度計(DV2T,英弘精機(股))來進行。下限並無特別限定,亦可設為1 mPa·s。
本發明的眼科用組成物可作為點眼劑、隱形眼鏡用點眼劑、洗眼劑等而適宜地使用,就乾眼症預防或治療效果的方面而言,可作為點眼劑、隱形眼鏡用點眼劑(隱形眼鏡佩戴者用點眼劑)等點眼劑而適宜地使用。作為隱形眼鏡,有硬性隱形眼鏡、軟性隱形眼鏡,詳細而言,有矽水凝膠軟性隱形眼鏡、O2
硬性隱形眼鏡、彩色隱形眼鏡等,並無特別限定。隱形眼鏡會對瞼板腺的形態變化造成影響,且報告有成為乾眼症的一個原因,從而尤其是作為隱形眼鏡用點眼劑而適宜。
本發明的眼科用組成物可抑制於短時間內頻繁使用(每小時點眼(或洗眼)6次以上)所致的散瞳,其使用方法並無限定。例如,於作為點眼劑或隱形眼鏡用點眼劑使用的情況下,較佳為每次以10 μL~100 μL點眼1滴~6滴(較佳為1滴~3滴)且每天點眼1次~6次,更佳為每次以10 μL~50 μL點眼1滴~6滴(較佳為1滴~3滴)且每天點眼1次~6次,進而佳為每次以10 μL~30 μL點眼1滴~6滴(較佳為1滴~3滴)且每天點眼1次~6次。於作為洗眼劑使用的情況下,較佳為每次以3 mL~6 mL且每天洗眼3次~6次。
另外,可於將獲得的眼科用組成物填充至樹脂製容器後,進而利用包裝體進行密封,且將氮氣等惰性氣體封入至所述容器與所述包裝體之間所形成的空間中,亦可於將眼科用組成物填充至樹脂製容器後,與脫氧劑一起由包裝體密封。
〈淚液層穩定化〉
脫羥腎上腺素或其鹽具有淚液層穩定效果,因此本發明的眼科用組成物具有淚液層穩定效果,作為淚液層穩定劑而適宜。淚液層穩定效果的測定例如可利用NI(Non-invasive)BUT(非侵入性淚液層破壞時間,Non-invasive tear film break-up time)來測定。具體而言,為後述的實施例的方法。
若獲得淚液層穩定效果,則可作為乾眼症預防劑或治療劑而適宜地使用。乾眼症被定義為「因各種因素而淚液層的穩定性降低的疾病或症狀,有時產生眼不適感或視功能異常並伴有眼表面的障礙」,其診斷基準為自覺症狀與螢光素(fluorescein)BUT(淚液層破壞時間)為5秒以下兩個項目。BUT的測定通常使用螢光素,但需要向眼內投予染色試劑,雖為少許但亦有淚液量發生變化、染色試劑附著於臉或衣服上的可能性,且亦廣泛已知調查非侵入性的直至淚液層的破壞為止的時間(non-invasive breakup time:NIBUT)的方法。與螢光素BUT相比,通常NIBUT長。
尤其是,脫羥腎上腺素或其鹽對於BUT縮短型乾眼症顯示出顯著的效果。所謂BUT縮短型乾眼症,是指雖然淚液分泌或角膜結膜上皮大體正常,但檢測出BUT的縮短,且因該情況而產生眼疲勞、眼乾、戴隱形眼鏡時的不適感及眼模糊、異物感、眼痛、目眩、眼沈、眼的不適感、眼眵以及流淚等症狀的乾眼症。本發明的淚液層穩定劑可伴有淚液分泌量的增加亦可不伴有淚液分泌量的增加,即便並無淚液分泌量的增加,亦可顯示出顯著的乾眼症預防或治療效果。
作為因淚液層不穩定化而產生的疾病或症狀,可列舉如下般的症狀,本發明的淚液層穩定劑可作為下述疾病或症狀的預防劑或治療劑而適宜地使用。
選自淚液減少症、高齡乾性眼、少淚症、眼乾燥症、休格倫氏症(Sjögren's syndrome)、乾性角膜結膜炎、Stevens-Johnson二氏症候群(Stevens-Johnson's syndrome)、眼類天胞瘡、眼瞼邊緣炎、閉眼不全、知覺神經麻痹、過敏性結膜炎相關聯的乾眼症、病毒性結膜炎後的乾眼症、白內障手術後的乾眼症、視頻顯示終端機(Video Display Terminals,VDT)作業相關聯的乾眼症及隱形眼鏡佩戴相關聯的乾眼症中的疾病或症狀。
選自乾眼症引起的眼疲勞、眼乾、眼勞累、戴隱形眼鏡時的不適感、眼模糊、眼瞼刷上皮病變(Lid-wiper epitheliopathy)、角膜結膜上皮障礙、角膜上皮剝離、角膜上皮糜爛、角膜潰瘍及眼感染症中的疾病或症狀。
進而,作為因淚液層不穩定化而產生的疾病或症狀,可列舉如下般的症狀,本發明的淚液層穩定劑可作為下述症狀的預防劑或治療劑而適宜地使用。
眼疲勞、眼乾、戴隱形眼鏡時的不適感及眼模糊、異物感、眼痛、目眩、眼沈、眼的不適感、眼眵以及流淚。
〈瞼脂分泌促進劑〉
脫羥腎上腺素或其鹽具有瞼脂分泌促進效果,因此本發明的眼科用組成物具有瞼脂分泌促進效果,作為瞼脂分泌促進劑而適宜。瞼脂為由瞼板腺分泌的成分,藉由促進瞼脂分泌而淚液油層增加。瞼脂分泌促進效果是測定淚液油層的厚度。
存在於眼瞼內的瞼板腺會分泌脂質,故作為淚液油層的供給源而重要。該淚液油層因降低淚液的表面張力、防止淚液的蒸發等,故淚液作為膜是穩定的,故而重要。但是,與瞼板腺的分泌機制相關的報告少,並未充分進行闡明。
作為因阻礙來自瞼板腺的瞼脂分泌而產生的疾病或症狀,除了所述乾眼症以外,亦存在瞼板腺功能不全、針眼(麥粒腫、霰粒腫)等。
瞼板腺功能不全(meibomian gland dysfunction;MGD)被定義為因瞼板腺的分泌障礙而引起的淚液及眼表面的異常。藉由自覺症狀與瞼板腺開口部周圍異常觀察結果、瞼板腺閉塞觀察結果三個項目來診斷。MGD患者的自覺症狀為多種且陳述有異物感、乾燥感、眼疲勞感、灼熱感等。關於治療,為了改善瞼板腺的閉塞而進行有如下方法:溫熱療法或藉由施加物理力而進行的壓出、在海外利用細鐵絲樣的器具直接使瞼板腺解除閉塞的方法等。另外,近年來,亦開發有利用干涉像評價淚液油層並對眼瞼自內側以溫熱或按摩效果進行治療的系統、Lipiview/Lipiflow系統,且今後的治療效果受到矚目。其中,該些方法全部成為醫療機構內的措施,因此期望簡便的治療法。
通常被稱為針眼的麥粒腫與霰粒腫為瞼板腺中產生的疾病或症狀。麥粒腫為細菌感染引起的急性化膿性炎症。治療有藥物療法與手術療法。藥物療法是於發現膿點的自然毀壞、排膿的情況下投予抗菌劑。手術療法是於膿點位於淺層且並未自然毀壞、排膿的情況下,使用注射針等進行穿刺、切開來促進排膿。即,治療時需要來自瞼板腺的排膿,但至此為止,只有等到自然排膿、或有侵入性的強制性排膿的選擇項。霰粒腫是指針對脂質的異物反應,並非感染症。治療基本為手術。即,麥粒腫與霰粒腫儘管需要排出來自瞼板腺的膿或脂質,但是至此為止並無手術以外的方法。
本發明的瞼脂分泌促進劑可作為與所述淚液層穩定劑相同的症狀的預防劑或治療劑而適宜地使用。
進而,藉由本發明的瞼脂分泌促進劑而提高瞼脂分泌,藉此可預防或治療MGD或乾眼症、麥粒腫與霰粒腫(針眼)。
〈散瞳抑制劑〉
關於本發明,即便於短時間內的頻繁使用(點眼)時,亦可於維持脫羥腎上腺素帶來的淚液層穩定效果的狀態下抑制脫羥腎上腺素所致的散瞳,因此作為可抑制短時間內的頻繁使用所致的散瞳的散瞳抑制劑而適宜。適宜的成分、調配量等與所述相同。再者,於本發明中,所謂於短時間內頻繁使用,是指每小時點眼(或洗眼)6次以上。再者,每次的眼科用組成物量可自10 μL~100 μL的範圍內適宜選定,可設為50 μL。
[實施例]
以下,示出實施例及比較例來具體說明本發明,但本發明不受下述實施例的限制。再者,於下述例子中,在並未特別標明的情況下,組成的「%」表示w/v%,比率表示質量比(與w/v%比相同的值)。
[實施例、比較例]
將(B)成分與丙二醇混合,溶解於精製水中,之後,將(A)成分~(D)成分及其他水溶性成分溶解於精製水中,調整pH值後,利用精製水將總體積設為100 mL。再者,將所得的眼科用組成物的25℃下的pH值示於表中。再者,25℃下的組成物的黏度為1 mPa·s~20 mPa·s的範圍。對所得的眼科用組成物進行下述評價。將結果一併記載於表中。
〈試驗1:散瞳抑制效果〉
3名小組成員於1小時內點眼6次(1次1滴(50 μL))樣品。於點眼前與點眼後,按照下述基準評價散瞳的程度。為了評價散瞳的程度,使用數位相機並設定為預發光模式,於即將拍攝之前引發光適應(縮瞳),進行拍攝。散瞳率越低,散瞳抑制效果越高。
散瞳率(縮瞳抑制率)=(D2-D1)/D1×100(%)
D1=點眼前(初期狀態)的瞳孔直徑(mm)
D2=點眼後的瞳孔直徑(mm)
根據3名小組成員的散瞳率的平均值,基於下述評價基準評價散瞳抑制效果。將「○」、「◎」設為合格。
[散瞳抑制效果]
◎:散瞳率的平均值小於10%
〇:散瞳率的平均值為10%以上且小於20%
△:散瞳率的平均值為20%以上且小於30%
×:散瞳率的平均值為30%以上
〈試驗2:眩光(沒有眩光的程度)的評價〉
3名小組成員於1小時內點眼6次(1次1滴(50 μL))各樣品。點眼後,按照下述基準評價眩光程度。分數越低,表示越沒有眩光。將「○」、「◎」設為合格。
[眩光]
0分:完全沒有症狀。
1分:症狀雖不痛苦,但有時會發生。對日常生活幾乎沒有障礙。
2分:症狀並不那麼痛苦,但時常會發生。對日常生活稍有障礙。
3分:症狀相當痛苦,但勉強能忍受。對日常生活頗有障礙。
4分:症狀非常痛苦且為無法忍受的程度。無法進行日常生活。
[沒有眩光的程度]
◎:小於0.5
○:0.5以上且小於1.0
△:1.0以上且小於1.5
×:平均值為1.5以上
〈試驗3:淚液層穩定性:NI(Non-invasive)BUT(非侵入性淚液層破壞時間)〉
3名小組成員於1小時內點眼6次(1次1滴(50 μL))樣品。於點眼前、與點眼後(最後進行點眼且經過5分鐘以上後),按照以下順序進行測定。
NIBUT的評價中使用DR-1(興和製造)。
使用DR-1,觀察淚液干涉像,開瞼後,測量直至淚液層破壞(均勻的灰色或白色的干涉像消失)為止的時間(秒)(NIBUT:非侵入性淚液層破壞時間),求出其平均值。NIBUT長的情況下,淚液層穩定性效果高。
測定點眼實施例與比較例時的NIBUT,並求出平均值。
另外,求出實施例平均值與比較例平均值的差,並按照下述基準評價淚液層穩定性效果。再者,脫羥腎上腺素鹽酸鹽濃度為0.1%的情況為與比較例2的差,為1%的情況為與比較例3的差。再者,比較例中記載有NIBUT:非侵入性淚液層破壞時間。將「●」、「○」、「◎」設為合格。
◎:平均值的差為1.5秒以上
○:平均值的差為1秒以上且小於1.5秒
●:平均值的差小於1秒
×:無淚液層穩定性效果
[表1]
組成(w/v%,g/100 mL) | 實施例 | ||||||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | ||
(A) | 脫羥腎上腺素鹽酸鹽 | 0.1 | 0.1 | 1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
(B) | 薄荷醇 | 0.015 | 0.03 | 0.03 | - | - | - | - | - | - | - |
冰片 | - | - | - | 0.005 | 0.03 | - | - | - | - | - | |
香葉草醇 | - | - | - | - | - | - | - | - | - | 0.005 | |
歐薄荷油 | - | - | - | - | - | 0.005 | 0.03 | - | - | - | |
桉葉油 | - | - | - | - | - | - | - | 0.005 | 0.03 | - | |
其他 | 胺基丁三醇 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
硼酸 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | |
氯化鈉 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
丙二醇 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
pH值調整劑(HCl/NaOH) | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | |
精製水 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | |
合計 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | |
pH值 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | |
(B)/(A) | 0.15 | 0.3 | 0.03 | 0.05 | 0.3 | 0.05 | 0.3 | 0.05 | 0.3 | 0.05 | |
(B)成分合計量 | 0.015 | 0.03 | 0.03 | 0.005 | 0.03 | 0.005 | 0.03 | 0.005 | 0.03 | 0.005 | |
試驗1 | 散瞳率 | 13.0 | 9.0 | 19.7 | 15.0 | 6.0 | 16.7 | 7.3 | 19.3 | 15.7 | 15.0 |
散瞳抑制效果 | 〇 | ◎ | 〇 | 〇 | ◎ | 〇 | ◎ | 〇 | 〇 | 〇 | |
試驗2 | 眩光 | 0.7 | 0.3 | 0.7 | 0.7 | 0.0 | 0.7 | 0.3 | 0.7 | 0.3 | 0.7 |
沒有眩光的程度 | 〇 | ◎ | 〇 | 〇 | ◎ | 〇 | ◎ | 〇 | ◎ | 〇 | |
試驗3 | 淚液層穩定性試驗 | 〇 | ◎ | 〇 | 〇 | ◎ | 〇 | ◎ | 〇 | ◎ | 〇 |
[表2]
組成(w/v%,g/100 mL) | 實施例 | |||||||||
11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | ||
(A) | 脫羥腎上腺素鹽酸鹽 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
(B) | 薄荷醇 | - | 0.005 | 0.001 | - | 0.001 | 0.001 | - | - | 0.02 |
冰片 | - | - | 0.001 | - | - | - | - | - | 0.005 | |
樟腦 | - | - | 0.001 | 0.001 | - | - | - | - | 0.01 | |
香葉草醇 | 0.03 | 0.005 | - | 0.001 | - | - | 0.001 | 0.0005 | - | |
歐薄荷油 | - | - | - | - | - | 0.001 | 0.001 | 0.0005 | - | |
桉葉油 | - | - | - | - | 0.001 | - | - | 0.0005 | - | |
其他 | 胺基丁三醇 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
硼酸 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | |
丙二醇 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
pH值調整劑(HCl/NaOH) | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | |
精製水 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | |
合計 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | |
pH值 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | |
(B)/(A) | 0.3 | 0.1 | 0.03 | 0.02 | 0.02 | 0.02 | 0.02 | 0.015 | 0.35 | |
(B)成分合計量 | 0.03 | 0.01 | 0.003 | 0.002 | 0.002 | 0.002 | 0.002 | 0.0015 | 0.035 | |
試驗1 | 散瞳率 | 8.3 | 8.0 | 7.7 | 9.7 | 7.3 | 8.0 | 7.0 | 8.0 | 7.7 |
散瞳抑制效果 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | |
試驗2 | 眩光 | 0.3 | 0.3 | 0.0 | 0.0 | 0.3 | 0.0 | 0.3 | 0.0 | 0.0 |
沒有眩光的程度 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | |
試驗3 | 淚液層穩定性試驗 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ● |
[表3]
組成(w/v%,g/100 mL) | 實施例 | |||||||||
20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 | 28 | ||
(A) | 脫羥腎上腺素鹽酸鹽 | 0.1 | 0.1 | 0.1 | 1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
(B) | 薄荷醇 | 0.015 | 0.015 | 0.015 | 0.03 | - | - | - | 0.015 | - |
冰片 | - | - | - | - | 0.005 | 0.005 | 0.005 | - | 0.005 | |
(C) | 氯化苄烷銨 | 0.001 | - | - | 0.01 | 0.001 | - | - | - | - |
山梨酸鉀 | - | 0.05 | - | - | - | 0.05 | - | - | - | |
對羥基苯甲酸甲酯 | - | - | 0.01 | - | - | - | 0.01 | - | - | |
鹽酸聚己雙胍 | - | - | - | - | - | - | - | 0.0001 | 0.0001 | |
其他 | 胺基丁三醇 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
硼酸 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | |
氯化鈉 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
丙二醇 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
pH值調整劑(HCl/NaOH) | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | |
精製水 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | |
合計 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | |
pH值 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | |
(B)/(A) | 0.15 | 0.15 | 0.15 | 0.03 | 0.05 | 0.05 | 0.05 | 0.15 | 0.05 | |
((B)+(C))/(A) | 0.16 | 0.65 | 0.25 | 0.04 | 0.06 | 0.55 | 0.15 | 0.151 | 0.051 | |
試驗1 | 散瞳率 | 9.7 | 9.3 | 9.7 | 16.3 | 9.3 | 9.7 | 9.7 | 9.3 | 9.3 |
散瞳抑制效果 | ◎ | ◎ | ◎ | 〇 | ◎ | ◎ | ◎ | ◎ | ◎ | |
試驗2 | 眩光 | 0.3 | 0.0 | 0.3 | 0.3 | 0.3 | 0.3 | 0.0 | 0.3 | 0.3 |
沒有眩光的程度 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | |
試驗3 | 淚液層穩定性試驗 | ◎ | ◎ | ◎ | 〇 | ◎ | ◎ | ◎ | ◎ | ◎ |
[表4]
組成(w/v%,g/100 mL) | 實施例 | ||||||||
29 | 30 | 31 | 32 | 33 | 34 | 35 | 36 | ||
(A) | 脫羥腎上腺素鹽酸鹽 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
(B) | 樟腦 | 0.001 | 0.001 | 0.001 | - | - | - | 0.001 | - |
香葉草醇 | - | - | - | - | - | 0.005 | - | - | |
歐薄荷油 | - | - | - | - | 0.005 | - | - | 0.005 | |
桉葉油 | - | - | - | 0.005 | - | - | - | - | |
(C) | 氯化苄烷銨 | 0.001 | - | - | 0.001 | - | - | - | - |
山梨酸鉀 | - | 0.05 | - | - | 0.05 | - | - | - | |
對羥基苯甲酸甲酯 | - | - | 0.01 | - | - | 0.01 | - | - | |
鹽酸聚己雙胍 | - | - | - | - | - | - | 0.0001 | 0.0001 | |
其他 | 胺基丁三醇 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
硼酸 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | |
氯化鈉 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
丙二醇 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
pH值調整劑(HCl/NaOH) | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | |
精製水 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | |
合計 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | |
pH值 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | |
(B)/(A) | 0.01 | 0.01 | 0.01 | 0.05 | 0.05 | 0.05 | 0.01 | 0.05 | |
((B)+(C))/(A) | 0.02 | 0.51 | 0.11 | 0.06 | 0.55 | 0.15 | 0.011 | 0.051 | |
試驗1 | 散瞳率 | 19.7 | 19.7 | 19.3 | 9.7 | 9.7 | 9.7 | 19.3 | 9.7 |
散瞳抑制效果 | 〇 | 〇 | 〇 | ◎ | ◎ | ◎ | 〇 | ◎ | |
試驗2 | 眩光 | 0.3 | 0.7 | 0.7 | 0.3 | 0.3 | 0.0 | 0.7 | 0.3 |
沒有眩光的程度 | ◎ | 〇 | 〇 | ◎ | ◎ | ◎ | 〇 | ◎ | |
試驗3 | 淚液層穩定性試驗 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ |
[表5]
組成(w/v%,g/100 mL) | 實施例 | ||||||||
37 | 38 | 39 | 40 | 41 | 42 | 43 | 44 | ||
(A) | 脫羥腎上腺素鹽酸鹽 | 0.1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
(B) | 薄荷醇 | 0.01 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 |
(C) | 氯化苄烷銨 | 0.001 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
(D) | POE硬化蓖麻油 | 0.1 | 0.1 | - | - | - | - | - | - |
POE脫水山梨糖醇脂肪酸酯 | - | - | 0.1 | - | - | - | - | - | |
EOPO | - | - | - | 0.5 | - | - | - | - | |
氯菲安明馬來酸鹽 | - | - | - | - | 0.01 | - | - | - | |
ε-胺基己酸 | - | - | - | - | - | 1 | - | - | |
天冬胺酸 | - | - | - | - | - | - | 1 | - | |
依地酸鈉水合物 | - | - | - | - | - | - | - | 0.005 | |
其他 | 胺基丁三醇 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
硼酸 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | 1.4 | |
氯化鈉 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
丙二醇 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | |
pH值調整劑(HCl/NaOH) | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | |
精製水 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | 剩餘 部分 | |
合計 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | |
pH值 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | |
(B)/(A) | 0.1 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | |
((B)+(C))/(A) | 0.11 | 0.04 | 0.04 | 0.04 | 0.04 | 0.04 | 0.04 | 0.04 | |
試驗1 | 散瞳率 | 9.7 | 9.7 | 9.3 | 9.0 | 9.7 | 9.7 | 9.3 | 9.7 |
散瞳抑制效果 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | |
試驗2 | 眩光 | 0.3 | 0.3 | 0.3 | 0.0 | 0.3 | 0.3 | 0.0 | 0.3 |
沒有眩光的程度 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | |
試驗3 | 淚液層穩定性試驗 | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ | ◎ |
[表6]
組成(w/v%,g/100 mL) | 比較例 | |||
1 | 2 | 3 | ||
(A) | 脫羥腎上腺素鹽酸鹽 | - | 0.1 | 1 |
其他 | 胺基丁三醇 | 0.1 | 0.1 | 0.1 |
硼酸 | 1.4 | 1.4 | 1.4 | |
氯化鈉 | 0.2 | 0.2 | 0.2 | |
丙二醇 | 0.2 | 0.2 | 0.2 | |
pH值調整劑(HCl/NaOH) | 適量 | 適量 | 適量 | |
精製水 | 剩餘部分 | 剩餘部分 | 剩餘部分 | |
合計 | 100 mL | 100 mL | 100 mL | |
pH值 | 7 | 7 | 7 | |
試驗1 | 散瞳率 | 0.5 | 39.3 | 45.0 |
散瞳抑制效果 | ◎ | × | × | |
試驗2 | 眩光 | 0.0 | 2.0 | 2.7 |
沒有眩光的程度 | ◎ | × | × | |
試驗3 | 淚液層穩定性試驗 NIBUT (平均值(秒)) | 4.3 | 8.0 | 11.0 |
以下示出所述例子中所使用的原料。再者,只要並未特別標明,則表中的各成分的量為純度換算量。
POE(聚氧乙烯)硬化蓖麻油(聚氧乙烯硬化蓖麻油60:HCO-60,日本界面活性劑工業(Nippon Surfactant Industries)(股)製造)
POE(聚氧乙烯)脫水山梨糖醇脂肪酸酯(聚山梨醇酯80,萊奧道魯(Rheodol)TW-O120V 花王(股)製造)
EOPO(聚氧乙烯(196)聚氧丙烯(67)二醇(魯特魯(Lutrol)F127,日本巴斯夫(BASF Japan)(股)製造)
無
Claims (4)
- 一種眼科用組成物,含有:(A)選自脫羥腎上腺素及其鹽中的一種以上、以及(B)選自萜類化合物中的一種以上。
- 如請求項1所述的眼科用組成物,其進而含有:(C)選自四級銨鹽、山梨酸及其鹽、聚己雙胍及其鹽、以及對羥基苯甲酸酯中的一種以上。
- 如請求項1或請求項2所述的眼科用組成物,其進而含有:(D)選自聚氧乙烯硬化蓖麻油、聚氧乙烯脫水山梨糖醇脂肪酸酯、聚氧乙烯聚氧丙烯二醇、氯菲安明馬來酸鹽、ε-胺基己酸、天冬胺酸及其鹽、以及依地酸及其鹽中的一種以上。
- 如請求項1至請求項3中任一項所述的眼科用組成物,其中(B)成分為選自薄荷醇、冰片、樟腦、香葉草醇、歐薄荷油、綠薄荷油及桉葉油中的一種以上。
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US5188826A (en) * | 1988-02-08 | 1993-02-23 | Insite Vision Incorporated | Topical ophthalmic suspensions |
JP2001187728A (ja) * | 1999-12-28 | 2001-07-10 | Lion Corp | 眼科用組成物 |
JP2003055220A (ja) * | 2001-08-09 | 2003-02-26 | Taisho Pharmaceut Co Ltd | イブジラスト含有眼科用組成物 |
JP2004217596A (ja) * | 2003-01-17 | 2004-08-05 | Taisho Pharmaceut Co Ltd | 点眼剤組成物 |
JP4979258B2 (ja) * | 2005-04-08 | 2012-07-18 | ロート製薬株式会社 | アシタザノラスト含有水性組成物 |
EP1967186B1 (en) * | 2005-12-27 | 2015-03-11 | Lion Corporation | Composition for soft contact lens and adsorption suppressing method |
TW201322982A (zh) | 2011-11-01 | 2013-06-16 | Otsuka Pharma Co Ltd | 用於治療前眼疾病之藥劑,該藥劑包含瑞巴派特及眼淚保持劑 |
JP6267003B2 (ja) | 2014-02-27 | 2018-01-24 | 参天製薬株式会社 | ジクアホソルまたはその塩およびレバミピドまたはその塩を組み合わせたことを特徴とする涙液分泌促進剤 |
JP7047768B2 (ja) * | 2016-12-08 | 2022-04-05 | ライオン株式会社 | 眼科用組成物 |
JP6962663B2 (ja) * | 2016-12-08 | 2021-11-05 | ライオン株式会社 | 眼科用組成物及びその製造方法 |
JP7404658B2 (ja) * | 2018-05-31 | 2023-12-26 | ライオン株式会社 | 涙液層安定化剤及びマイバム分泌促進剤 |
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- 2019-12-25 JP JP2020563334A patent/JPWO2020138135A1/ja active Pending
- 2019-12-25 CN CN201980067557.8A patent/CN112839641A/zh active Pending
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JPWO2020138135A1 (ja) | 2021-11-11 |
CN112839641A (zh) | 2021-05-25 |
KR20210107607A (ko) | 2021-09-01 |
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