TW202320815A - 眼科組成物 - Google Patents
眼科組成物 Download PDFInfo
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- TW202320815A TW202320815A TW111137266A TW111137266A TW202320815A TW 202320815 A TW202320815 A TW 202320815A TW 111137266 A TW111137266 A TW 111137266A TW 111137266 A TW111137266 A TW 111137266A TW 202320815 A TW202320815 A TW 202320815A
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- ophthalmic composition
- acid
- sodium
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- mass
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 72
- 239000011592 zinc chloride Substances 0.000 claims abstract description 37
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
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- 206010013774 Dry eye Diseases 0.000 claims description 8
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 7
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Abstract
本發明係關於一種眼科組成物,其含有:(A)氯化鋅、及(B)聚乙烯系高分子化合物。
Description
本發明係關於一種眼科組成物。
一般而言,複數次用量之滴眼劑包含具有抑制微生物增殖之作用之防腐劑,以防滴眼劑受到細菌、真菌等微生物污染。另一方面,防腐劑亦包含具有細胞毒性之成分,有因頻繁或長期使用包含防腐劑之滴眼劑而引起角膜上皮損傷之報告。因此,必須進行於不使用防腐劑之情況下抑制微生物增殖,且降低角膜上皮損傷之風險之滴眼劑之配方設計。
作為此種無防腐劑之滴眼劑之配方設計,報告有一種於眼科組成物中摻合氯化鋅等鋅鹽之技術(例如,專利文獻1)。
[先前技術文獻]
[專利文獻]
專利文獻1:日本特表2010-504358號公報
[發明所欲解決之課題]
然而,含有鋅鹽之無防腐劑之滴眼劑於保存效果(防腐力)之強度之方面仍有進一步改善之餘地。本發明之目的在於提供一種無防腐劑且保存效果優異之眼科組成物。
[解決課題之技術手段]
本發明人等發現,同時含有氯化鋅及聚乙烯吡咯啶酮等聚乙烯系高分子化合物之眼科組成物之保存效果顯著增強。本發明係基於該見解者,提供以下各發明。
[1]
一種眼科組成物,其含有:(A)氯化鋅、及(B)聚乙烯系高分子化合物。
[2]
如[1]所記載之眼科組成物,其中,(B)聚乙烯系高分子化合物為聚乙烯吡咯啶酮。
[3]
如[2]所記載之眼科組成物,其中,上述聚乙烯吡咯啶酮之含量以眼科組成物之總量為基準為0.001~5 w/v%。
[4]
如[2]或[3]所記載之眼科組成物,其中,上述聚乙烯吡咯啶酮之黏性特性值為10~150。
[5]
如[1]至[4]中任一項所記載之眼科組成物,其進而含有(C)選自由黏多醣類及纖維素系高分子化合物所組成之群中之至少一種。
[6]
如[1]至[5]中任一項所記載之眼科組成物,其不含有氯化苄烷銨。
[7]
如[1]至[6]中任一項所記載之眼科組成物,其pH為5.0~8.0。
[8]
如[1]至[7]中任一項所記載之眼科組成物,其用以抑制眼睛乾澀或乾眼症。
[9]
如[1]至[8]中任一項所記載之眼科組成物,其用於隱形眼鏡。
[10]
如[1]至[8]中任一項所記載之眼科組成物,其用於軟性隱形眼鏡。
[發明之效果]
根據本發明,能夠提供一種無防腐劑且保存效果優異之眼科組成物。
以下,對本發明就實施方式詳細地進行說明。但,本發明並不限定於以下之實施方式。
於本說明書中,除非另有記載,否則含量之單位「%」表示「w/v%」,與「g/100 mL」同義。
[1.眼科組成物]
本實施方式之眼科組成物含有氯化鋅(亦簡稱為「(A)成分」)及聚乙烯系高分子化合物(亦簡稱為「(B)成分」)。
氯化鋅只要是醫藥上、藥理學上(製藥上)或生理學上所容許者則並無特別限制。氯化鋅亦可使用市售者。
本實施方式之眼科組成物中之(A)成分之含量並無特別限定,係根據其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。(A)成分之總含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.000001 w/v%以上、0.00005 w/v%以上、或0.0001 w/v%以上,可為0.05 w/v%以下、0.025 w/v%以下、或0.015 w/v%以下,亦可為0.000001~0.05 w/v%、0.00005~0.025 w/v%、或0.0001~0.015 w/v%。
聚乙烯系高分子化合物只要是醫藥上、藥理學上(製藥上)或生理學上所容許者,則並無特別限制。
作為聚乙烯系高分子化合物,例如可例舉:羧乙烯聚合物、聚乙烯醇(完全或部分皂化物)、聚乙烯吡咯啶酮及其等之鹽。關於可用於本發明之聚乙烯系高分子,其分子量並無限制,例如可使用重量平均分子量為0.5萬~500萬,較佳為1萬~300萬,更佳為1萬~100萬左右者。聚乙烯吡咯啶酮之黏性特性值(K值)並無特別限制,可較佳地使用其為10~150者,可更佳地使用其為20~100者。該等之中,從更進一步提高本發明之效果之觀點而言,較佳為聚乙烯吡咯啶酮,更佳為聚乙烯吡咯啶酮K25、聚乙烯吡咯啶酮K30、聚乙烯吡咯啶酮K90,進而較佳為聚乙烯吡咯啶酮K30、聚乙烯吡咯啶酮K90。
聚乙烯系高分子化合物亦可使用市售者。聚乙烯系高分子化合物可單獨使用一種,亦可組合使用兩種以上。
本實施方式之眼科組成物中之(B)成分之含量並無特別限定,係根據(B)成分之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。(B)成分之含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.0001 w/v%以上、0.0005 w/v%以上、0.001 w/v%以上、或0.005 w/v%以上,可為10 w/v%以下、5 w/v%以下、3 w/v%以下、或1 w/v%以下,亦可為0.0001~10 w/v%、0.0005~5 w/v%、0.001~3 w/v%、或0.005~1 w/v%。
於使用聚乙烯吡咯啶酮作為(B)成分之情形時,本實施方式之眼科組成物中之聚乙烯吡咯啶酮之含量並無特別限定,係根據聚乙烯吡咯啶酮之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。聚乙烯吡咯啶酮之含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.0001 w/v%以上、0.0005 w/v%以上、0.001 w/v%以上、0.005 w/v%以上、或0.01 w/v%以上,可為10 w/v%以下、5 w/v%以下、3 w/v%以下、1 w/v%以下、或0.5 w/v%以下,亦可為0.0001~10 w/v%、0.0005~5 w/v%、0.001~3 w/v%、0.005~1 w/v%、或0.01~0.5 w/v%。
本實施方式之眼科組成物中之(B)成分相對於(A)成分之含有比率並無特別限定,係根據(B)成分之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。關於(B)成分相對於(A)成分之含有比率,從更進一步提高本發明之效果之觀點而言,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,(B)成分之總含量可為0.002質量份以上、0.01質量份以上、0.06質量份以上、或0.1質量份以上,可為2000000質量份以下、100000質量份以下、10000質量份以下、或1000質量份以下,亦可為0.002~2000000質量份、0.01~100000質量份、0.06~10000質量份、或0.1~1000質量份。
於使用聚乙烯吡咯啶酮作為(B)成分之情形時,聚乙烯吡咯啶酮相對於(A)成分之含有比率並無特別限定,係根據聚乙烯吡咯啶酮之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。關於聚乙烯吡咯啶酮相對於(A)成分之含有比率,從更進一步提高本發明之效果之觀點而言,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,聚乙烯吡咯啶酮之總含量可為0.002質量份以上、0.01質量份以上、0.06質量份以上、0.1質量份以上、或0.1質量份以上,可為500質量份以下、300質量份以下、200質量份以下、100質量份以下、或未達100質量份,亦可為0.002~500質量份、0.01~300質量份、0.06~200質量份、0.1~100質量份、或0.1質量份以上且未達100質量份。
本實施方式之眼科組成物亦可進而含有(C)選自由黏多醣類及纖維素系高分子化合物所組成之群中之至少一種(亦稱作「(C)成分」)。藉由使眼科組成物進而含有(C)成分,本發明之效果會得以更加顯著地發揮。
黏多醣類只要是醫藥上、藥理學上(製藥上)或生理學上所容許者,則並無特別限制。
作為黏多醣類,例如可例舉:肝素類似物質、肝素、硫酸肝素、硫酸乙醯肝素(heparan sulfate)、類肝素(heparinoid)、玻尿酸及其鹽、硫酸軟骨素及其鹽。作為此種鹽,例如可例舉與有機鹼之鹽(胺鹽、精胺酸等之鹼性銨鹽等)、與無機鹼之鹽(銨鹽;鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土類金屬鹽;鋁鹽等)等,其中,更佳為鈉鹽、鉀鹽、鈣鹽,尤佳為鈉鹽。黏多醣類之中,較佳為玻尿酸及其鹽、硫酸軟骨素及其鹽,更佳為硫酸軟骨素及其鹽。
於使用黏多醣類作為(C)成分之情形時,本實施方式之眼科組成物中之黏多醣類之含量並無特別限定,係根據黏多醣類之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。黏多醣類之含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.00001 w/v%以上、0.0001 w/v%以上、0.0005 w/v%以上、或0.001 w/v%以上,可為10 w/v%以下、5 w/v%以下、3 w/v%以下、或1 w/v%以下,亦可為0.00001~10 w/v%、0.0001~5 w/v%、0.0005~3 w/v%、或0.001~1 w/v%。
於使用黏多醣類作為(C)成分之情形時,本實施方式之眼科組成物中之黏多醣類相對於(A)成分之含有比率並無特別限定,係根據黏多醣類之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。關於黏多醣類相對於(A)成分之含有比率,從更進一步提高本發明之效果之觀點而言,例如,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,黏多醣類之總含量可為0.0002質量份以上、0.001質量份以上、0.02質量份以上、或0.1質量份以上,可為2000000質量份以下、200000質量份以下、10000質量份以下、或1000質量份以下,亦可為0.0002~2000000質量份、0.001~200000質量份、0.02~10000質量份、或0.1~1000質量份。
纖維素系高分子化合物只要是醫藥上、藥理學上(製藥上)或生理學上所容許者,則並無特別限制。
作為纖維素系高分子化合物,例如可例舉:甲基纖維素、乙基纖維素、羥乙基纖維素、羥甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素(hypromellose、羥丙甲纖維素)、羧甲基纖維素、羧乙基纖維素、及其等之鹽。作為此種鹽,例如可例舉與有機鹼之鹽(胺鹽、精胺酸等之鹼性銨鹽等)、與無機鹼之鹽(銨鹽;鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土類金屬鹽;鋁鹽等)等,其中,更佳為鈉鹽、鉀鹽、鈣鹽,尤佳為鈉鹽。纖維素系高分子化合物之中,較佳為羥乙基纖維素、羥丙基甲基纖維素、及其等之鹽,更佳為羥丙基甲基纖維素及其鹽。
纖維素系高分子化合物亦可使用市售者。纖維素系高分子化合物可單獨使用一種,亦可組合使用兩種以上。
於使用纖維素系高分子化合物作為(C)成分之情形時,本實施方式之眼科組成物中之纖維素系高分子化合物之含量並無特別限定,係根據纖維素系高分子化合物之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。纖維素系高分子化合物之含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.00001 w/v%以上、0.0001 w/v%以上、0.0005 w/v%以上、0.001 w/v%以上、0.005 w/v%以上、或0.01 w/v%以上,可為10 w/v%以下、5 w/v%以下、3 w/v%以下、1 w/v%以下、0.8 w/v%以下、或0.5 w/v%以下,亦可為0.00001~10 w/v%、0.0001~5 w/v%、0.0005~3 w/v%、0.001~1 w/v%、0.005~0.8 w/v%、或0.01~0.5 w/v%。
於使用纖維素系高分子化合物作為(C)成分之情形時,本實施方式之眼科組成物中之纖維素系高分子化合物相對於(A)成分之含有比率並無特別限定,係根據纖維素系高分子化合物之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。關於纖維素系高分子化合物相對於(A)成分之含有比率,從更進一步提高本發明之效果之觀點而言,例如,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,纖維素系高分子化合物之總含量可為0.0002質量份以上、0.001質量份以上、0.02質量份以上、或0.1質量份以上,可為2000000質量份以下、200000質量份以下、10000質量份以下、或1000質量份以下,亦可為0.0002~2000000質量份、0.001~200000質量份、0.02~10000質量份、或0.1~1000質量份。
本實施方式之眼科組成物亦可進而含有緩衝劑。藉由使眼科組成物進而含有緩衝劑,本發明之效果會得以更進一步顯著地發揮。緩衝劑只要是醫藥上、藥理學上(製藥上)或生理學上所容許者,則並無特別限制。作為緩衝劑,例如可例舉:來自無機酸之緩衝劑即無機緩衝劑、以及來自有機酸或有機鹼之緩衝劑即有機緩衝劑。
作為無機緩衝劑,例如可例舉:硼酸緩衝劑、磷酸緩衝劑、碳酸緩衝劑等。作為硼酸緩衝劑,可例舉:硼酸或其鹽(硼酸鹼金屬鹽、硼酸鹼土類金屬鹽等)。作為磷酸緩衝劑,可例舉:磷酸或其鹽(磷酸鹼金屬鹽、磷酸鹼土類金屬鹽等)。作為碳酸緩衝劑,可例舉:碳酸或其鹽(碳酸鹼金屬鹽、碳酸鹼土類金屬鹽等)。又,作為硼酸緩衝劑、磷酸緩衝劑或碳酸緩衝劑,亦可使用硼酸鹽、磷酸鹽或碳酸鹽之水合物。關於更具體之例,作為硼酸緩衝劑,可例示硼酸或其鹽(硼酸鈉、四硼酸鉀、偏硼酸鉀、硼酸銨、硼砂等);作為磷酸緩衝劑,可例示磷酸或其鹽(磷酸氫二鈉、磷酸二氫鈉、磷酸二氫鉀、磷酸三鈉、磷酸三鉀、磷酸氫鈣、磷酸二氫鈣等);作為碳酸緩衝劑,可例示碳酸或其鹽(碳酸氫鈉、碳酸鈉、碳酸銨、碳酸鉀、碳酸鈣、碳酸氫鉀、碳酸鎂等)等。
作為有機緩衝劑,例如可例舉:乙酸緩衝劑、乳酸緩衝劑、琥珀酸緩衝劑、Tris緩衝劑、AMPD緩衝劑等。作為乙酸緩衝劑,可例舉:乙酸或其鹽(乙酸鹼金屬鹽、乙酸鹼土類金屬鹽等)。作為乳酸緩衝劑,可例舉:乳酸或其鹽(乳酸鹼金屬鹽、乳酸鹼土類金屬鹽等)。作為琥珀酸緩衝劑,可例舉:琥珀酸或其鹽(琥珀酸鹼金屬鹽等)。又,作為乙酸緩衝劑、乳酸緩衝劑或琥珀酸緩衝劑,亦可使用乙酸鹽、乳酸鹽或琥珀酸鹽之水合物。關於更具體之例,作為乙酸緩衝劑,可例示乙酸或其鹽(乙酸銨、乙酸鈉、乙酸鉀、乙酸鈣等)等;作為乳酸緩衝劑,可例示乳酸或其鹽(乳酸鈉、乳酸鉀、乳酸鈣等)等;作為琥珀酸緩衝劑,可例示琥珀酸或其鹽(琥珀酸單鈉、琥珀酸二鈉等)等。作為Tris緩衝劑,例如可例舉:胺丁三醇(trometamol)或其鹽(胺丁三醇鹽酸鹽等)。作為AMPD緩衝劑,例如可例舉:2-胺基-2-甲基-1,3-丙二醇或其鹽。
作為緩衝劑,較佳為硼酸緩衝劑(例如,硼酸與硼砂之組合等),更佳為硼酸及其鹽,進而較佳為硼酸與硼砂之組合。
緩衝劑亦可使用市售者。緩衝劑可單獨使用一種,亦可組合使用兩種以上。
本實施方式之眼科組成物中之緩衝劑之含量並無特別限定,係根據緩衝劑之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。緩衝劑之總含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.0001 w/v%以上、0.001 w/v%以上、或0.005 w/v%以上,可為10 w/v%以下、5 w/v%以下、或3 w/v%以下,亦可為0.0001~10 w/v%、0.001~5 w/v%、或0.005~3 w/v%。
本實施方式之眼科組成物中之緩衝劑相對於(A)成分之含有比率並無特別限定,係根據緩衝劑之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。作為緩衝劑相對於(A)成分之含有比率,從更進一步提高本發明之效果之觀點而言,例如,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,緩衝劑之總含量可為0.002質量份以上、0.02質量份以上、或0.1質量份以上,可為2000000質量份以下、50000質量份以下、或2000質量份以下,亦可為0.002~2000000質量份、0.02~50000質量份、或0.1~2000質量份。
作為緩衝劑,亦可使用檸檬酸緩衝劑(檸檬酸或其鹽,具體而言:檸檬酸;檸檬酸鈉、檸檬酸鉀、檸檬酸二氫鈉、檸檬酸二鈉等檸檬酸鹼金屬鹽;檸檬酸鈣等檸檬酸鹼土類金屬鹽)。於此情形時,本實施方式之眼科組成物中之檸檬酸緩衝劑之含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0 w/v%以上、0.0001 w/v%以上、或0.005 w/v%以上,可為0.1 w/v%以下、0.08 w/v%以下、或0.05 w/v%以下,可為0~0.1 w/v%、0.0001~0.08 w/v%、或0.005~0.05 w/v%,亦可不含有檸檬酸緩衝劑(0 w/v%)。
本實施方式之眼科組成物亦可進而含有界面活性劑。藉由使眼科組成物進而含有界面活性劑,本發明之效果會得以更進一步顯著地發揮。界面活性劑只要是醫藥上、藥理學上(製藥上)或生理學上所容許者則並無特別限制,可為非離子性界面活性劑、兩性界面活性劑、陰離子性界面活性劑、陽離子性界面活性劑中之任一者。
作為非離子性界面活性劑,例如可例舉:POE(20)山梨醇酐單月桂酸酯(聚山梨醇酯20)、POE(20)山梨醇酐單棕櫚酸酯(聚山梨醇酯40)、POE(20)山梨醇酐單硬脂酸酯(聚山梨醇酯60)、POE(20)山梨醇酐三硬脂酸酯(聚山梨醇酯65)、POE(20)山梨醇酐單油酸酯(聚山梨醇酯80)等POE山梨醇酐脂肪酸酯;POE(40)氫化蓖麻油(聚氧乙烯氫化蓖麻油40)、POE(60)氫化蓖麻油(聚氧乙烯氫化蓖麻油60)等POE氫化蓖麻油;POE(3)蓖麻油(聚氧乙烯蓖麻油3)、POE(10)蓖麻油(聚氧乙烯蓖麻油10)、POE(35)蓖麻油(聚氧乙烯蓖麻油35)等POE蓖麻油;POE(9)月桂醚等POE烷基醚;POE(20)POP(4)十六醚等POE-POP烷基醚;聚乙二醇硬脂酸酯40等聚乙二醇單硬脂酸酯;POE(196)POP(67)二醇(Poloxamer 407、Pluronic F127)、POE(200)POP(70)二醇等POE-POP嵌段共聚物等。再者,於上述所例示之化合物中,POE表示聚氧乙烯,POP表示聚氧丙烯,以及,括弧內之數字表示加成莫耳數。
作為兩性界面活性劑,例如可例舉:烷基二胺基乙基甘胺酸或其鹽(例如,鹽酸鹽等)等。
作為陰離子性界面活性劑,例如可例舉:烷基苯磺酸鹽、烷基硫酸鹽、聚氧乙烯烷基硫酸鹽、脂肪族α-磺基甲酯、α-烯烴磺酸等。
作為陽離子性界面活性劑,例如可例舉:氯化十六烷基吡啶、氯化苄烷銨、氯化苯索寧等。
該等界面活性劑之中,較佳為非離子性界面活性劑,更佳為POE山梨醇酐脂肪酸酯、POE氫化蓖麻油、POE蓖麻油、聚乙二醇單硬脂酸酯、POE-POP嵌段共聚物。
界面活性劑亦可使用市售者。界面活性劑可單獨使用一種,亦可組合使用兩種以上。
本實施方式之眼科組成物中之界面活性劑之含量並無特別限定,係根據界面活性劑之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。界面活性劑之總含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0.001 w/v%以上、0.005 w/v%以上、或0.01 w/v%以上,可為5 w/v%以下、3 w/v%以下、或1 w/v%以下,亦可為0.001~5 w/v%、0.005~3 w/v%、或0.01~1 w/v%。
本實施方式之眼科組成物中之界面活性劑相對於(A)成分之含有比率並無特別限定,係根據界面活性劑之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。作為界面活性劑相對於(A)成分之含有比率,從更進一步提高本發明之效果之觀點而言,例如,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,界面活性劑之總含量可為0.002質量份以上、0.1質量份以上、或1質量份以上,可為60000質量份以下、10000質量份以下、或1000質量份以下,亦可為0.002~60000質量份、0.1~10000質量份、或1~1000質量份。
本實施方式之眼科組成物亦可進而含有螯合劑。螯合劑只要是醫藥上、藥理學上(製藥上)或生理學上所容許者則並無特別限制。
作為螯合劑,例如可例舉:乙二胺四乙酸(EDTA;edetic acid)、乙二胺二乙酸(EDDA)、乙二胺三乙酸、N-(2-羥乙基)乙二胺三乙酸(HEDTA)、二伸乙基三胺五乙酸(DTPA)、及其等之鹽。作為此種鹽,例如可例舉與無機鹼之鹽(銨鹽;鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土類金屬鹽;鋁鹽等)等,其中,更佳為鈉鹽、鉀鹽,尤佳為鈉鹽。螯合劑之中,較佳為乙二胺四乙酸及其鹽,更佳為乙二胺四乙酸鈉、乙二胺四乙酸二鈉、乙二胺四乙酸四鈉,進而較佳為乙二胺四乙酸二鈉。
本實施方式之眼科組成物中之螯合劑之含量並無特別限定,係根據螯合劑之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。螯合劑之含量從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,可為0 w/v%以上,可為0.01 w/v%以下、0.001 w/v%以下、或0.0001 w/v%以下,可為0~0.01 w/v%、0~0.001 w/v%、或0~0.0001 w/v%,亦可不含有螯合劑(0 w/v%)。
本實施方式之眼科組成物中螯合劑相對於(A)成分之含有比率並無特別限定,係根據螯合劑之種類、其他組成成分之種類及含量、眼科組成物之用途及製劑形態等而適當設定。螯合劑相對於(A)成分之含有比率從更進一步提高本發明之效果之觀點而言,例如,相對於本實施方式之眼科組成物中所包含之(A)成分之總含量1質量份,螯合劑之總含量可為0質量份以上,可為2000質量份以下、100質量份以下、或20質量份以下,亦可為0~2000質量份、0~100質量份、或0~20質量份。
本實施方式之眼科組成物之pH只要處於醫藥上、藥理學上(製藥上)或生理學上所容許之範圍內則並無特別限定。本實施方式之眼科組成物之pH可為4.0以上、4.5以上、5.0以上、或5.5以上,可為9.5以下、9.0以下、8.0以下、7.5以下、7.0以下、或未達7.0,亦可為4.0~9.5、4.5~9.0、5.0~8.0、5.5~7.5、或5.5~7.0。作為本實施方式之眼科組成物之pH,從使本發明之效果得以更加顯著地發揮之觀點而言,亦可為5.0以上且未達7.0、或5.5以上且未達7.0。
本實施方式之眼科組成物可視需要調節為生物體所容許之範圍內之滲透壓比。合適之滲透壓比可根據眼科組成物之用途、製劑形態、使用方法等而適當設定,例如可為0.4以上、0.6以上、0.8以上,可為5.0以下、3.0以下、2.2以下、或2.0以下,亦可為0.4~5.0、0.6~3.0、0.8~2.2、或0.8~2.0。滲透壓比係基於日本藥典第十七修訂版,設為試樣之滲透壓相對於286 mOsm(0.9 w/v%氯化鈉水溶液之滲透壓)之比,滲透壓係參考日本藥典記載之滲透壓測定法(凝固點降低法)而測定。再者,滲透壓比測定用標準溶液(0.9 w/v%氯化鈉水溶液)能夠以如下方式製備:於500~650℃將氯化鈉(日本藥典標準試劑)乾燥40~50分鐘後,於乾燥器(矽膠)中放冷,準確地稱量其0.900 g,使之溶解於純化水中,準確地製成100 mL;或者,可使用市售之滲透壓比測定用標準溶液(0.9 w/v%氯化鈉水溶液)。
本實施方式之眼科組成物之黏度只要處於醫藥上、藥理學上(製藥上)或生理學上所容許之範圍內則並無特別限定。關於本實施方式之眼科組成物之黏度,例如,利用旋轉黏度計(TV-20型黏度計,東機產業公司製造,轉子;1°34'×R24)所測得之於20℃之黏度可為1 mPa・s以上、或1.1 mPa・s以上,可為10000 mPa・s以下、8000 mPa・s以下、1000 mPa・s以下、100 mPa・s以下、20 mPa・s以下、或17 mPa・s以下,亦可為1~10000 mPa・s、1~8000 mPa・s、1~1000 mPa・s、1~100 mPa・s、1~20 mPa・s、或1.1~17 mPa・s。
本實施方式之眼科組成物只要處於不損害本發明之效果之範圍內,則除了上述成分以外,亦可組合選自各種藥理活性成分及生理活性成分中之成分而含有適當量。該成分並無特別限制,例如可例示需指導・一般用醫藥品製造銷售許可基準2017年版(一般社團法人Regulatory Science學會 監修)中所記載之眼科用藥中之有效成分。作為眼科用藥中所使用之成分,具體而言,例如可例舉如下成分。
抗過敏劑:例如,色甘酸鈉(sodium cromoglicate)、曲尼司特(tranilast)、吡嘧司特鉀(pemirolast potassium)、阿紮司特(acitazanolast)、胺來呫諾(amlexanox)、異丁司特(ibudilast)等。
抗組織胺劑:例如,氯菲安明或其鹽(例如,氯菲安明馬來酸鹽)、苯海拉明或其鹽(例如,鹽酸苯海拉明)、異丙海汀(iproheptine)或其鹽(例如,鹽酸異丙海汀)、左卡巴司汀(levocabastine)或其鹽(例如,鹽酸左卡巴司汀)、可多替芬(ketotifen)或其鹽(例如,富馬酸可多替芬)、吡嘧司特鉀(pemirolast potassium)、奧洛他定(olopatadine)或其鹽(例如,鹽酸奧洛他定)等。
消炎劑:例如,水楊酸甲酯、水楊酸乙二醇酯、尿囊素、傳明酸、溶菌酶、氯化溶菌酶、吲哚美辛、普拉洛芬、伊布洛芬、皮考伊布洛芬吡(ibuprofenpiconol)、酮洛芬、聯苯乙酸、苄達酸、匹洛西卡、丁苯羥酸、氟芬那酸丁酯、ε-胺基己酸、氯化小檗鹼、硫酸小檗鹼、薁磺酸鈉、甘草酸或其鹽(例如,甘草酸二鉀、甘草酸單銨)等。
類固醇:例如,丙酸氟替卡松、糠酸氟替卡松、糠酸莫美他松、丙酸倍氯米松、氟尼縮松等。
充血去除劑:例如,鹽酸四氫唑啉(tetrahydrozoline hydrochloride)、硝酸四氫唑啉(tetrahydrozoline nitrate)、鹽酸萘甲唑啉、硝酸萘甲唑啉、腎上腺素、鹽酸腎上腺素、鹽酸麻黃鹼、鹽酸去氧腎上腺素、dl-鹽酸甲基麻黃鹼等。
眼肌調節藥劑:例如,具有與乙醯膽鹼類似之活性中心的膽鹼酯酶抑制劑,具體而言,甲基硫酸新斯的明、托品醯胺、土木香素(helenien)、硫酸阿托品(atropine sulfate)、鹽酸毛果芸香鹼(pilocarpine hydrochloride)等。
維生素類:例如,乙酸視黃醇酯、棕櫚酸視黃醇酯、乙酸生育酚酯、黃素腺嘌呤二核苷酸鈉、維生素B12、吡哆醇鹽酸鹽、泛醇、泛酸鈣、抗壞血酸、抗壞血酸鈉、鹽酸噻胺等。
胺基酸類:例如,L-精胺酸、麩胺酸、甘胺酸、丙胺酸、離胺酸、γ-胺基丁酸、γ-胺基戊酸、三甲基甘胺酸、牛磺酸、天冬胺酸及其等之鹽等。
收斂劑:例如,鋅白、乳酸鋅、硫酸鋅等。
其他:例如,磺胺甲異唑、磺胺異唑、磺胺二甲嘧啶及其等之鹽等。
本實施方式之眼科組成物中,只要處於不損害本發明之效果之範圍內,則亦可根據其用途及製劑形態,依照通常方法,適當選擇各種添加物,併用一種或一種以上而含有適當量。作為此種添加物,例如可例示醫藥品添加物事典2016(日本醫藥品添加劑協會編輯)中所記載之各種添加物。作為代表成分,可例舉以下添加物。
載體:例如,水、含水乙醇等水性溶劑。
基劑:例如,辛基十二烷醇、氧化鈦、溴化鉀、Plastibase等。
pH調節劑:例如,鹽酸、乙酸、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、三乙醇胺、單乙醇胺、二異丙醇胺等。
香料或清涼劑:例如,薄荷腦、薄荷酮、樟腦、龍腦、香葉草醇、桉樹腦、香茅醇、香旱芹酮、大茴香腦、丁香酚、檸檬烯、沈香醇、乙酸沈香酯、瑞香草酚、異丙甲苯、松油醇、蒎烯、莰烯、異龍腦、葑烯、橙花醇、月桂油烯、香葉烯醇、乙酸沈香醇、薰衣草醇、桉葉油、香柑油、胡椒薄荷油、涼薄荷油、綠薄荷油、薄荷油、茴香油、桂皮油、玫瑰油、樟腦油等。該等可為d體、l體或dl體中之任一者。
增黏劑:例如,澱粉;甲殼素及其衍生物;聚葡萄胺糖及其衍生物;角叉菜膠;葡萄糖等單糖類等。
穩定劑:例如,甲醛次硫酸氫鈉(Rongalite、雕白粉)、單硬脂酸鋁、單硬脂酸甘油酯、環糊精、單乙醇胺、二丁基羥基甲苯、亞硫酸氫鈉、焦亞硫酸鈉等。
防腐劑:例如,烷基聚胺基乙基甘胺酸類、四級銨鹽(例如,氯化苄烷銨、氯化苯索寧等)、葡萄糖酸洛赫西定、泊利氯銨、苯甲酸鈉、乙醇、氯丁醇、山梨酸、山梨酸鉀、去氫乙酸鈉、對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯、對羥苯甲酸丁酯、硫酸羥基喹啉、苯乙醇、苄醇、雙胍化合物(具體而言,鹽酸聚己縮胍(聚六亞甲基雙胍)、阿來西定等)、Glokill(Rhodia公司製造,商品名)等。
等張劑:例如,氯化鉀、氯化鈣、氯化鈉、氯化鎂、乙酸鉀、乙酸鈉、碳酸氫鈉、碳酸鈉、硫代硫酸鈉、硫酸鎂、甘油、丙二醇、亞硫酸氫鈉、亞硫酸鈉等。
糖醇類:例如,木糖醇、山梨醇、甘露醇、甘油等。該等可為d體、l體或dl體中之任一者。
油類:例如,芝麻油、蓖麻油、大豆油、橄欖油等植物油;角鯊烷等動物油;液態石蠟、凡士林等礦物油等。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有氯化苄烷銨,更佳為不含有選自由氯化苄烷銨、對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯及對羥苯甲酸丁酯所組成之群中之至少一種,進而較佳為不含有選自由雙胍化合物、烷基聚胺基乙基甘胺酸類、葡萄糖酸洛赫西定、山梨酸鹽、四級銨鹽、對羥苯甲酸甲酯、對羥苯甲酸乙酯、對羥苯甲酸丙酯及對羥苯甲酸丁酯所組成之群中之至少一種。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有防腐劑。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有選自由水楊酸甲酯、水楊酸乙二醇酯、傳明酸、溶菌酶、吲哚美辛、伊布洛芬、皮考伊布洛芬吡、酮洛芬、聯苯乙酸、苄達酸、匹洛西卡、丁苯羥酸、氟芬那酸丁酯、及其等之鹽所組成之群中之至少一種,更佳為不含有選自由尿囊素、ε-胺基己酸、小檗鹼、薁磺酸、甘草酸、普拉洛芬、水楊酸甲酯、水楊酸乙二醇酯、傳明酸、溶菌酶、吲哚美辛、伊布洛芬、皮考伊布洛芬吡、酮洛芬、聯苯乙酸、苄達酸、匹洛西卡、丁苯羥酸、氟芬那酸丁酯、及其等之鹽所組成之群中之至少一種。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有消炎劑。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有選自由腎上腺素、麻黃鹼、去氧腎上腺素、甲基麻黃鹼、及其等之鹽所組成之群中之至少一種,更佳為不含有選自由四氫唑啉、萘甲唑啉、腎上腺素、麻黃鹼、去氧腎上腺素、甲基麻黃鹼、及其等之鹽所組成之群中之至少一種。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有充血去除劑。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有選自由托品醯胺、土木香素、阿托品、毛果芸香鹼、及其等之鹽所組成之群中之至少一種,更佳為不含有選自由新斯的明、托品醯胺、土木香素、阿托品、毛果芸香鹼、及其等之鹽所組成之群中之至少一種。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有眼肌調節藥劑。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有選自由泛酸、噻胺、及其等之鹽所組成之群中之至少一種,更佳為不含有選自由吡哆醇、泛醇、維生素B12、乙酸生育酚酯、乙酸視黃醇酯、棕櫚酸視黃醇酯、黃素腺嘌呤二核苷酸、抗壞血酸、泛酸、噻胺、及其等之鹽所組成之群中之至少一種。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有維生素類。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有選自由乳酸鋅及鋅白所組成之群中之至少一種,更佳為不含有選自由硫酸鋅、乳酸鋅、及鋅白所組成之群中之至少一種,進而較佳為不含有除了氯化鋅以外之鋅化合物。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有收斂劑。
本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有瑞巴派特(rebamipide)。又,本實施方式之眼科組成物從能夠使本發明之效果得以顯著地發揮之觀點而言,較佳為不含有凡士林、海藻酸及其鹽、以及山梨醇,更佳為不含有凡士林以及海藻酸及其鹽、或者凡士林及山梨醇,進而較佳為不含有凡士林。
於本實施方式之眼科組成物含有水之情形時,作為水之含量,從使本發明之效果得以更加顯著地發揮之觀點而言,以眼科組成物之總量為基準,水之含量可為80 w/v%以上、85 w/v%以上、或90 w/v%,可為未達100 w/v%、99.5 w/v%以下、或99.2 w/v%以下,亦可為80 w/v%以上且未達100 w/v%、85 w/v%以上99.5 w/v%以下、或90 w/v%以上99.2 w/v%以下。
本實施方式之眼科組成物中所使用之水只要是醫藥上、藥理學上(製藥上)或生理學上所容許者即可。作為此種水,例如可例舉:蒸餾水、普通水、純化水、殺菌純化水、注射用水及注射用蒸餾水等。其等之定義係基於日本藥典第十七修訂版。
本實施方式之眼科組成物可藉由以成為所需濃度之方式添加所需量之(A)成分、(B)成分、及視需要之其他成分加以混和而製備。例如,可藉由使其等成分溶解或分散於純化水中,調整為特定之pH及滲透壓,利用過濾殺菌等進行殺菌處理而製備。
本實施方式之眼科組成物可視目的而採用各種製劑形態。作為製劑形態,例如可例舉:液劑、凝膠劑、半固體劑(軟膏等)等。
本實施方式之眼科組成物例如可用作:滴眼劑(亦稱作滴眼液或滴眼藥。又,滴眼劑中包含可於配戴有隱形眼鏡時滴眼之滴眼劑)、人工淚液、洗眼劑(亦稱作洗眼液或洗眼藥。又,洗眼劑中包含可於配戴有隱形眼鏡時洗眼之洗眼劑)、隱形眼鏡用組成物[隱形眼鏡配戴液、隱形眼鏡護理用組成物(隱形眼鏡消毒劑、隱形眼鏡用保存劑、隱形眼鏡用清潔劑、隱形眼鏡用清潔保存劑)、隱形眼鏡包裝液等]。再者,「隱形眼鏡」包含硬性隱形眼鏡、軟性隱形眼鏡(包含離子性及非離子性兩者,包含聚矽氧水凝膠隱形眼鏡及非聚矽氧水凝膠隱形眼鏡兩者)。本實施方式之眼科組成物從使本發明之效果得以更加顯著地發揮之觀點而言,較佳為隱形眼鏡用眼科組成物。又,本實施方式之眼科組成物從改善配戴軟性隱形眼鏡時之剛滴眼後之擴散容易性或配戴感(乾燥感之減輕等)之觀點而言,更佳為軟性隱形眼鏡用眼科組成物。
本實施方式之眼科組成物從能夠使本發明之效果更加顯著地發揮之方面而言,較佳為滴眼劑(包含可於配戴有隱形眼鏡時滴眼之滴眼劑)。於本實施方式之眼科組成物為滴眼劑之情形時,作為其用法、用量,只要是能發揮效果且副作用較少之用法、用量則並無特別限定,例如,於成人(15歲以上)及7歲以上之兒童之情形時,可例示1次1~3滴、1~2滴、或2~3滴,1天滴眼2~4次、或5~6次而使用之方法。
本實施方式之眼科組成物如後述之實施例中所確認,具有抑制隱形眼鏡之乾燥之效果、減少摩擦之效果、增大黏度效果、及提升角膜上皮細胞於乾燥條件下之存活率之效果,因此,能夠合適地用於抑制眼睛乾澀或乾眼症。
本實施方式之眼科組成物收容於任意容器而提供。收容本實施方式之眼科組成物之容器並無特別限制,例如,可為玻璃製,又,亦可為塑膠製。較佳為塑膠製。作為塑膠,例如可例舉:聚對苯二甲酸乙二酯(PET)、聚芳酯、聚萘二甲酸乙二酯、聚碳酸酯、聚乙烯、聚丙烯、聚醯亞胺及構成該等之單體之共聚物、以及混合該等中之兩種以上而成者。較佳為聚對苯二甲酸乙二酯。又,收容本實施方式之眼科組成物之容器可為能夠看見容器內部之透明容器,亦可為難以看見容器內部之不透明容器。較佳為透明容器。此處,所謂「透明容器」,包含無色透明容器及有色透明容器兩者。
亦可於收容本實施方式之眼科組成物之容器中安裝噴嘴。噴嘴之材質並無特別限制,例如,可為玻璃製,又,亦可為塑膠製。較佳為塑膠製。作為塑膠,例如可例舉:聚對苯二甲酸丁二酯、聚乙烯、聚丙烯、聚對苯二甲酸乙二酯、聚萘二甲酸乙二酯及構成該等之單體之共聚物、以及混合該等中之兩種以上而成者。作為噴嘴之材質,從更進一步提高本發明之效果之觀點而言,較佳為聚丙烯、聚乙烯、聚對苯二甲酸乙二酯、聚對苯二甲酸丁二酯、聚萘二甲酸乙二酯,更佳為聚乙烯。
收容本實施方式之眼科組成物之容器可為收容有複數次之使用量的多劑量型,亦可為收容有單次之使用量的單一劑量型,但從發揮本發明之效果之觀點而言,較佳為多劑量型。
本實施方式之眼科組成物較佳為填充至內容積為4~30 mL之容器而成,更佳為填充至內容積為5~20 mL之容器而成,進而較佳為填充至內容積為6~16 mL之容器而成,進而更佳為填充至內容積為10~15 mL之容器而成。又,可填充至內容積為0.1~3 mL之容器,亦可填充至內容積為0.2~1 mL之容器。
[2.增強眼科組成物之保存效果之方法]
本實施方式之滴眼劑藉由含有(A)成分及(B)成分,保存效果得到提升。因此,作為本發明之一實施方式,提供一種增強該眼科組成物之保存效果之方法,其包含於眼科組成物中摻合(A)氯化鋅及(B)聚乙烯系高分子化合物。
該方法中之(A)成分及(B)成分之種類及含量等、其他成分之種類及含量等、眼科組成物之製劑形態及用途等如[1.眼科組成物]中之說明所示。
[實施例]
以下,基於試驗例對本發明具體地進行說明,但本發明並不限定於該等。
〔試驗例1:保存效果試驗(1)〕
以表1及2中所示之組成依照通常方法製備各眼科組成物,製成試驗溶液。表1及2中之各成分之單位為w/v%。將大腸桿菌(Escherichia coli)(ATCC8739)接種於大豆-酪蛋白-消化物斜面培養基之表面,於33℃培養24小時。利用白金接種環無菌地採集培養菌體,使其懸浮於適量之殺菌生理食鹽水中,製備包含約1×10
7CFU/mL之生菌的細菌懸浮液。再者,懸浮液之生菌數係另行培養而計測。繼而,向15 mL之CORNING錐形管(PET)填充所製備之各眼科組成物各10 mL。以生菌數(最終濃度)成為約10
5CFU/mL之方式,將大腸桿菌菌液(懸浮於生理食鹽水中)接種於該等各眼科組成物,充分進行攪拌而製成試樣。將包含菌之試樣於遮光下且於23℃保存5天。其後,以成為適於計數之濃度之方式調整包含菌之試樣,於3M
TMPetrifilm
TM生菌數迅速測定用板(RAC板)上接種1 mL,於33℃培養2天後,對所觀察到的菌落數進行計數,藉此求出生菌數。將剛接種後之生菌數與保存5天後之試樣中之生菌數加以比較,以Log Reduction(對數減少)算出菌數之減少量。再者,用於計數之菌之培養係於33℃實施2天。將結果示於表1及2。
[表1]
| 成分名 | 試驗液1-1 | 試驗液1-2 | 試驗液1-3 | 試驗液1-4 | 試驗液1-5 | 試驗液1-6 | 試驗液1-7 | 試驗液1-8 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 | - | - | - | 0.2 |
| 聚乙烯吡咯啶酮(K值=25) | - | - | - | - | 0.2 | 0.2 | - | - |
| 氯化鋅 | - | 0.003 | - | 0.003 | - | 0.003 | 0.05 | 0.05 |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| 菌數減少量(Log Reduction) | 1.03 | 2.41 | 1.95 | 5.81 | 3.21 | 5.81 | 3.51 | 5.81 |
[表2]
| 成分名 | 試驗液1-9 | 試驗液1-10 | 試驗液1-11 | 試驗液1-12 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 |
| 聚乙烯吡咯啶酮(K值=25) | - | - | - | - |
| 氯化鋅 | - | 0.003 | - | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 |
| 硫酸軟骨素酯鈉 | 0.5 | 0.5 | 0.5 | 0.5 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 |
| 菌數減少量(Log Reduction) | 0.33 | 0.66 | -0.25 | 2.58 |
確認了於使用作為革蘭氏陰性菌之大腸桿菌作為菌之情形時,與含有氯化鋅或聚乙烯吡咯啶酮中之任一者之眼科組成物相比,含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物之保存效果顯著提升。又,已知於含有硫酸軟骨素酯鈉之情形時,保存效果會降低,但確認了即使於摻合有硫酸軟骨素酯鈉之情形時,與含有氯化鋅或聚乙烯吡咯啶酮中之任一者之眼科組成物相比,含有氯化鋅及聚乙烯吡咯啶酮之眼科組成物之保存效果亦顯著提升。
〔試驗例2:保存效果試驗(2)〕
以表3中所示之組成依照通常方法製備各眼科組成物,製成試驗溶液。表3中之各成分之單位為w/v%。將金黃色葡萄球菌(Staphylococcus aureus)(ATCC6538)接種於大豆-酪蛋白-消化物斜面培養基之表面,於33℃培養24小時。利用白金接種環無菌地採集培養菌體,使其懸浮於適量之殺菌生理食鹽水中,製備包含約1×10
7CFU/mL之生菌的細菌懸浮液。再者,懸浮液之生菌數係另行培養而計測。繼而,向15 mL之CORNING錐形管(PET)填充所製備之各眼科組成物各10 mL。以生菌數(最終濃度)成為約10
5CFU/mL之方式,將金黃色葡萄球菌菌液(懸浮於生理食鹽水中)接種於該等各眼科組成物,充分進行攪拌而製成試樣。將包含菌之試樣於遮光下且於23℃保存3天。其後,以成為適合計數之濃度之方式調整包含菌之試樣,於3M
TMPetrifilm
TM生菌數迅速測定用板(RAC板)上接種1 mL,於33℃培養2天後,對所觀察到的菌落數進行計數,藉此求出生菌數。將剛接種後之生菌數與保存3天後之試樣中之生菌數加以比較,以Log Reduction(對數減少)算出菌數之減少量。再者,用於計數之菌之培養係於33℃實施2天。將結果示於表3。
[表3]
| 成分名 | 試驗液2-1 | 試驗液2-2 | 試驗液2-3 | 試驗液2-4 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 |
| 硫酸軟骨素酯鈉 | 0.5 | 0.5 | 0.5 | 0.5 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 |
| 菌數減少量(Log Reduction) | 0.36 | 1.63 | -0.09 | 2.13 |
確認了即使於使用作為革蘭氏陽性菌之金黃色葡萄球菌作為菌之情形時,與含有氯化鋅或聚乙烯吡咯啶酮中之任一者之眼科組成物相比,含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物之保存效果亦顯著提升。
〔試驗例3:摩擦試驗〕
以表4及5中所示之組成依照通常方法製備各眼科組成物,製成試驗溶液。表4及5中之各成分之單位為w/v%。使用靜動摩擦測定器Tribomaster(型號:TL201Sa(Trinity-Lab(股)製造),接觸件:觸覺接觸件,單模(single mode),speed(速度):1 mm/sec,vertical load(垂直負載):20 g,distance(距離):100 mm)對所製備之試驗溶液就靜摩擦係數進行評價。具體而言,於測定器之平台側設置人工皮革,於人工皮革上塗抹100 μL之各試驗液,對該狀態下之靜摩擦係數進行測定。將結果示於表4及5。
[表4]
| 成分名 | 試驗液 3-1 | 試驗液 3-2 | 試驗液 3-3 | 試驗液 3-4 | 試驗液 3-5 | 試驗液 3-6 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 | - | - |
| 聚乙烯吡咯啶酮(K值=25) | - | - | - | - | 0.2 | - |
| 聚乙烯吡咯啶酮(K值=30) | - | - | - | - | - | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 | 0.003 | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 | 100 | 100 |
| 靜摩擦係數(Fs) | 1.01 | 1.11 | 1.31 | 1.07 | 1.06 | 0.92 |
[表5]
| 成分名 | 試驗液 3-7 | 試驗液 3-8 | 試驗液 3-9 | 試驗液 3-10 | 試驗液 3-11 | 試驗液 3-12 |
| 聚乙烯吡咯啶酮(K值=90) | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 | - | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 |
| 硫酸軟骨素酯鈉 | 0.5 | 0.5 | - | - | - | - |
| 玻尿酸鈉 | - | - | 0.05 | 0.05 | - | - |
| 羥丙基甲基纖維素 | - | - | - | - | 0.2 | 0.2 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 | 100 | 100 |
| 靜摩擦係數(Fs) | 1.81 | 1.51 | 1.53 | 0.79 | 1.58 | 1.42 |
確認了與含有聚乙烯吡咯啶酮之眼科組成物相比,含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物之靜摩擦係數顯著降低。又,進而含有硫酸軟骨素酯鈉、玻尿酸鈉或羥丙基甲基纖維素之眼科組成物亦確認有同樣之趨勢。含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物能夠減輕眼睛乾澀或乾眼症時眨眼之困難或眨眼時之不適感。
〔試驗例4:隱形眼鏡乾燥試驗〕
以表6中所示之組成依照通常方法製備各眼科組成物,製成試驗溶液。表6中之各成分之單位為w/v%。於加熱至90~100℃之水中加入5 g之瓊脂,一面攪拌一面使其充分溶解後,一面攪拌一面冷卻至50~60℃。使已冷卻之瓊脂液流入至眼球模具(根據日本人之平均眼球形狀而製成之模具:眼睛大小ϕ24 mm:基礎曲線8.65 mm),於4℃冷卻3小時以上而使之凝固。自模具取出已充分凝固之瓊脂凝膠,製作眼球模型。以4 mL/孔向12孔板(BD Falcon,No. 35-3043)分注磷酸緩衝生理食鹽水(氯化鈉0.60%,磷酸氫鈉(十二水合物)0.60%,磷酸二氫鈉(二水合物)0.05%,pH為7.4±0.1)。以2片/孔將隱形眼鏡(2-WEEK ACUVUE(Johnson & Johnson股份有限公司))浸漬於各孔,於室溫靜置4小時以上。進而同樣地以4 mL/孔向另一12孔板分注下述表6中所記載之各試驗液,用無絨紙輕輕擦拭之前浸漬過之隱形眼鏡後,以2片/孔浸漬於各孔,於室溫下靜置4小時。用無絨紙輕輕地擦去浸漬過之隱形眼鏡之水分後,將隱形眼鏡靜置於上述製作之眼球模型之前端(角膜部分)。自靜置眼鏡之時起計測時間,根據下述觀察基準,進行外觀觀察。將結果示於表6。
(觀察基準)
將隱形眼鏡發生下述任一現象之時間作為「直至隱形眼鏡乾燥之時間」進行記錄,結束試驗。
・隱形眼鏡貼於眼球模型。
・隱形眼鏡之周緣部變形或者捲縮。
[表6]
| 成分名 | 試驗液4-1 | 試驗液4-2 | 試驗液4-3 | 試驗液4-4 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 |
| 鹽酸 | 適量 | 適量 | 適量 | 適量 |
| 氫氧化鈉 | 適量 | 適量 | 適量 | 適量 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 |
| pH | 7 | 7 | 7 | 7 |
| 滲透壓(mOsm) | 170 | 170 | 170 | 170 |
| 直至乾燥之時間 | 5分鐘 | 5分鐘 | 2小時 | 2小時30分鐘以上 |
確認了與含有氯化鋅或聚乙烯吡咯啶酮中之任一者之眼科組成物相比,利用使用含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物時,直至隱形眼鏡乾燥之時間顯著延長。
再者,試驗液4-4與試驗液4-3相比,於滴入至配戴有軟性隱形眼鏡之眼睛時,剛滴眼後之擴散良好,滴眼5分鐘後眼睛之乾燥感減輕。
〔試驗例5:流變試驗〕
以表7及8中所示之組成依照通常方法製備各眼科組成物,製成試驗溶液。表7及8中之各成分之單位為w/v%。對於所製備之試驗溶液,使用旋轉黏度計(RE550型,東機產業(股)製造,轉子;1°34'×R24),於試驗液5-1~5-8及5-13~5-16之情形時,於20℃以50 rpm之轉速測定1分鐘,於試驗液5-9~5-12之情形時於20℃以20 rpm之轉速測定1分鐘。將結果示於表7及8。
[表7]
| 成分名 | 試驗液 5-1 | 試驗液 5-2 | 試驗液 5-3 | 試驗液 5-4 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 |
| 黏度(mPa・s) | 1.23 | 1.19 | 1.62 | 1.84 |
[表8]
| 成分名 | 試驗液 5-5 | 試驗液 5-6 | 試驗液 5-7 | 試驗液 5-8 | 試驗液 5-9 | 試驗液 5-10 | 試驗液 5-11 | 試驗液 5-12 | 試驗液 5-13 | 試驗液 5-14 | 試驗液 5-15 | 試驗液 5-16 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 | - | - | 0.2 | 0.2 | - | - | 0.2 | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 | - | 0.003 | - | 0.003 | - | 0.003 | - | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 |
| 硫酸軟骨素酯鈉 | 0.5 | 0.5 | 0.5 | 0.5 | - | - | - | - | - | - | - | - |
| 玻尿酸鈉 | - | - | - | - | 0.05 | 0.05 | 0.05 | 0.05 | - | - | - | - |
| 羥丙基甲基纖維素 | - | - | - | - | - | - | - | - | 0.2 | 0.2 | 0.2 | 0.2 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| 黏度(mPa・s) | 1.69 | 1.72 | 2.29 | 2.67 | 6.66 | 8.90 | 14.20 | 15.93 | 2.4 | 2.91 | 3.51 | 3.89 |
確認了與含有氯化鋅或聚乙烯吡咯啶酮中之任一者之眼科組成物相比,含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物之黏度增加。又,進而含有硫酸軟骨素酯鈉、玻尿酸鈉或羥丙基甲基纖維素之眼科組成物亦確認有同樣之趨勢。藉由提高眼科組成物之黏度,能夠提升眼睛中之滯留性。
〔試驗例6:細胞乾燥試驗〕
以表9所示之組成依照通常方法製備各眼科組成物,製成試驗溶液。表9中之各成分之單位為w/v%。於96孔板(Corning公司)接種人類角膜上皮細胞株HCE-T細胞,於設定為37℃、5%CO
2之濃度的CO
2培養箱中進行培養。於37℃、5%CO
2、濕度90%之條件下培養至融合。作為增殖培養基,使用於DMEM/F12(Thermo Fisher公司)中以FCS(DS Pharma公司)成為5%,DMSO(和光純藥公司)成為0.5%,重組人類(recombinant human)EGF(R & D公司)成為10 ng/mL,人類胰島素溶液(insulin solution human)(SIGMA公司)成為5 μg/mL之方式進行添加而成者。自培養開始經過2~4天而使細胞融合後,自各孔吸引去除增殖培養基,將各眼科組成物以50 μL/孔加入至各孔,於37℃、5%CO
2之條件下培養15分鐘。自各孔吸引去除各眼科組成物後,於清潔台內放置20分鐘,藉此施加乾燥壓力,其後,對活細胞數進行測定。活細胞數之測定係向各孔對於培養基100 μL添加10 μL之細胞數測定試劑Cell counting kit-8(同仁化學公司),於37℃、5%CO
2、濕度90%之條件下培養2~3小時後,使用吸光度計(MOLECULAR DEVICES公司)測定於450 nm之吸光度,藉此測定活細胞數。針對各眼科組成物,將作為相對於試驗液6-1之吸光度之比而算出之結果示於表9。再者,活細胞數越多,吸光度越大。
[表9]
| 成分名 | 試驗液 6-1 | 試驗液 6-2 | 試驗液 6-3 | 試驗液 6-4 | 試驗液 6-5 | 試驗液 6-6 |
| 聚乙烯吡咯啶酮(K值=90) | - | - | 0.2 | 0.2 | 0.2 | 0.2 |
| 氯化鋅 | - | 0.003 | - | 0.003 | 0.003 | 0.003 |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 |
| 硼砂 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 | 0.08 |
| 硫酸軟骨素酯鈉 | - | - | - | - | 0.5 | - |
| 玻尿酸鈉 | - | - | - | - | - | 0.05 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量(mL) | 100 | 100 | 100 | 100 | 100 | 100 |
| 相對於試驗液6-1之比 | 1.00 | 1.14 | 1.35 | 1.46 | 1.74 | 1.68 |
確認了與含有氯化鋅或聚乙烯吡咯啶酮中之任一者之眼科組成物相比,利用含有氯化鋅及聚乙烯吡咯啶酮兩者之眼科組成物時,角膜上皮細胞於乾燥條件下之存活率提升。又,確認了利用除了氯化鋅及聚乙烯吡咯啶酮以外,進而含有硫酸軟骨素酯鈉或玻尿酸鈉之眼科組成物時,角膜上皮細胞於乾燥條件下之存活率更進一步地提升。
〔製劑例〕
以下述表10~12中所記載之配方,依照通常方法製備滴眼劑。再者,下述表10~12中之各成分量之單位除了表中標明者以外,均為w/v%。
[表10]
| 成分名 | 配方例1 | 配方例2 | 配方例3 | 配方例4 | 配方例5 | 配方例6 | 配方例7 | 配方例8 | 配方例9 | 配方例10 |
| 氯化鋅 | 0.001 | 0.003 | 0.0003 | 0.005 | 0.003 | 0.001 | 0.003 | 0.0003 | 0.005 | 0.003 |
| 聚乙烯吡咯啶酮(K90) | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 1 | 1 | 1 | 1 | 1 |
| 聚乙烯吡咯啶酮(K30) | - | - | - | - | - | - | - | - | - | - |
| 聚乙烯吡咯啶酮(K25) | - | - | - | - | - | - | - | - | - | - |
| 羧乙烯聚合物 | - | - | - | - | - | - | - | - | - | - |
| 聚乙烯醇 | - | - | - | - | - | - | - | - | - | - |
| 硫酸軟骨素鈉 | 1 | - | - | - | - | - | - | 1 | - | - |
| 玻尿酸鈉 | - | 0.05 | - | 0.01 | 0.01 | 0.01 | 0.01 | - | 0.05 | - |
| 羥丙基甲基纖維素 | - | - | 0.5 | - | 0.1 | - | 0.1 | - | - | 0.5 |
| 羥乙基纖維素 | - | - | - | 1 | - | 1 | - | - | - | - |
| 新斯的明甲基硫酸鹽 | - | 0.005 | - | - | - | - | - | - | 0.005 | - |
| 馬來酸氯菲安明 | 0.03 | - | - | - | - | 0.03 | - | - | - | 0.03 |
| 甘草酸二鉀 | - | - | - | 0.5 | - | 0.5 | - | - | - | 0.5 |
| 乙酸d-α-生育酚酯 | - | - | - | - | - | 0.2 | - | - | - | - |
| 硫酸鋅 | 0.1 | - | - | - | - | - | - | 0.3 | - | - |
| 吡哆醇鹽酸鹽 | - | - | - | - | - | 0.1 | - | 0.1 | - | - |
| ε-胺基己酸 | - | - | - | - | - | 1 | - | - | - | - |
| 牛磺酸 | - | - | 1 | - | - | 1 | - | - | - | - |
| L-天冬胺酸鉀 | - | - | - | - | 1 | - | - | - | 0.5 | - |
| 氯化鈣 | 0.01 | - | - | - | 0.1 | - | - | 0.01 | 0.2 | - |
| 氯化鉀 | 0.01 | 0.01 | 0.05 | 0.01 | - | 0.05 | 0.01 | 0.01 | - | 0.01 |
| 氯化鈉 | 0.5 | 1 | 0.1 | 1 | 1 | 0.1 | 1 | 0.5 | 1 | 1 |
| 碳酸氫鈉 | - | - | - | 0.01 | - | - | 0.01 | - | - | - |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | - | 1 |
| 硼砂 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | - | 0.1 |
| 磷酸二氫鈉 | - | - | - | - | - | - | - | - | 0.1 | - |
| 磷酸二氫鉀 | - | - | - | - | - | - | - | - | 0.1 | - |
| 磷酸氫鈉水合物 | - | - | - | - | - | - | - | - | 1 | - |
| 檸檬酸鈉 | 0.02 | 0.01 | - | 0.02 | 1 | 0.01 | - | 0.02 | 1 | 1 |
| 檸檬酸酐 | 0.001 | - | - | 0.02 | - | - | 0.02 | 0.001 | - | |
| 乙二胺四乙酸鈉 | 0.01 | 0.1 | 0.1 | - | 0.001 | 0.1 | 0.1 | - | 0.01 | 0.001 |
| 聚山梨醇酯80 | 0.2 | 0.1 | - | 0.5 | 0.1 | - | 0.1 | - | 0.1 | 0.05 |
| 聚氧乙烯氫化蓖麻油60 | - | 0.1 | 0.1 | - | 0.1 | 0.1 | 0.1 | 0.5 | 0.1 | - |
| 聚氧乙烯蓖麻油 | - | - | 0.01 | - | - | 0.05 | - | 0.05 | - | - |
| 聚氧乙烯(196)聚氧丙烯(67)二醇 | - | - | - | 0.10 | 0.05 | 0.01 | - | - | 0.05 | - |
| l-薄荷腦 | 0.01 | 0.030 | 0.001 | 0.01 | - | - | 0.001 | 0.01 | 0.01 | - |
| 樟腦 | - | 0.01 | - | - | - | 0.01 | - | - | - | - |
| 香柑油 | - | - | - | 0.001 | 0.001 | - | - | 0.001 | - | 0.001 |
| 香葉草醇 | - | - | - | - | - | 0.005 | - | 0.001 | - | - |
| 胡椒薄荷油 | - | - | - | 0.001 | 0.001 | - | - | 0.001 | - | 0.001 |
| 芝麻油 | - | - | 0.1 | - | 0.001 | - | 0.1 | - | - | 0.002 |
| 鹽酸聚己縮胍 | 0.0001 | - | 0.001 | - | - | - | - | - | - | - |
| 胺丁三醇 | - | - | - | - | - | - | 0.05 | - | - | - |
| 鹽酸 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
| 氫氧化鈉 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL |
| pH | 5.5 | 6 | 7 | 5.5 | 6 | 7 | 5.5 | 6 | 7 | 5.5 |
[表11]
| 成分名 | 配方例11 | 配方例12 | 配方例13 | 配方例14 | 配方例15 | 配方例16 | 配方例17 | 配方例18 | 配方例19 | 配方例20 |
| 氯化鋅 | 0.001 | 0.003 | 0.0003 | 0.005 | 0.003 | 0.001 | 0.003 | 0.0003 | 0.005 | 0.003 |
| 聚乙烯吡咯啶酮(K90) | 3 | 3 | 3 | 3 | 3 | - | - | - | - | - |
| 聚乙烯吡咯啶酮(K30) | - | - | - | - | - | 0.2 | - | - | - | - |
| 聚乙烯吡咯啶酮(K25) | - | - | - | - | - | - | 0.2 | - | - | - |
| 羧乙烯聚合物 | - | - | - | - | - | - | - | 0.1 | - | - |
| 聚乙烯醇 | - | - | - | - | - | - | - | - | 1 | - |
| 硫酸軟骨素鈉 | - | - | 1 | - | - | 1 | - | - | - | - |
| 玻尿酸鈉 | 0.05 | - | - | 0.01 | 0.01 | - | 0.01 | - | 0.05 | 0.01 |
| 羥丙基甲基纖維素 | - | 0.5 | - | - | 0.1 | - | - | 0.5 | - | 0.1 |
| 羥乙基纖維素 | - | - | - | 1 | - | - | 1 | - | - | - |
| 新斯的明甲基硫酸鹽 | 0.005 | - | - | - | - | 0.005 | - | - | 0.005 | - |
| 馬來酸氯菲安明 | - | - | - | 0.03 | - | - | 0.03 | - | - | - |
| 甘草酸二鉀 | - | 0.5 | - | - | - | - | - | 0.5 | - | 0.5 |
| 乙酸d-α-生育酚酯 | - | - | - | - | - | - | - | - | - | - |
| 硫酸鋅 | - | - | - | - | 0.1000 | - | 0.3 | - | - | - |
| 吡哆醇鹽酸鹽 | 0.1 | - | - | 0.1 | - | - | 0.1 | - | 0.1 | - |
| ε-胺基己酸 | - | - | - | - | - | - | - | - | - | - |
| 牛磺酸 | - | - | 0.2 | - | - | - | - | 0.2 | - | - |
| L-天冬胺酸鉀 | - | - | - | - | - | - | - | - | - | - |
| 氯化鈣 | 0.2 | 0.01 | - | - | - | 0.01 | - | - | 0.2 | - |
| 氯化鉀 | - | 0.01 | 0.05 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | - | 0.05 |
| 氯化鈉 | 1 | 0.5 | 0.1 | 1 | 1 | 0.5 | 1 | 1 | 1 | 0.1 |
| 碳酸氫鈉 | - | - | - | - | 0.01 | - | 0.1 | - | - | - |
| 硼酸 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | - | 1 | 1 |
| 硼砂 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | - | 0.1 | 0.1 |
| 磷酸二氫鈉 | - | - | - | - | - | - | - | 0.1 | - | - |
| 磷酸二氫鉀 | - | - | - | - | - | - | - | 0.1 | - | - |
| 磷酸氫鈉水合物 | - | - | - | - | - | - | - | 1 | - | - |
| 檸檬酸鈉 | 1 | 0.01 | 0.02 | 0.02 | - | 0.01 | 0.02 | 1 | - | 1 |
| 檸檬酸酐 | - | - | 0.001 | 0.02 | - | - | 0.02 | 0.001 | - | - |
| 乙二胺四乙酸鈉 | 0.001 | 0.1 | 0.01 | - | 0.1 | 0.1 | - | 0.01 | 0.1 | 0.001 |
| 聚山梨醇酯80 | - | 0.1 | 0.1 | - | 0.1 | 0.1 | - | 0.1 | 0.1 | - |
| 聚氧乙烯氫化蓖麻油60 | 0.1 | - | 0.1 | 0.1 | 0.1 | - | 0.1 | - | 0.1 | 0.1 |
| 聚氧乙烯蓖麻油 | 0.05 | - | - | 0.05 | - | - | 0.05 | - | - | 0.05 |
| 聚氧乙烯(196)聚氧丙烯(67)二醇 | 0.01 | 0.1 | 0.05 | 0.01 | - | - | - | 0.10 | 0.05 | 0.01 |
| l-薄荷腦 | 0.015 | - | 0.001 | 0.01 | 0.01 | 0.015 | 0.001 | 0.01 | 0.01 | - |
| 樟腦 | 0.01 | - | - | - | - | 0.01 | - | - | - | - |
| 香柑油 | - | 0.001 | - | - | 0.001 | - | - | 0.001 | - | 0.001 |
| 香葉草醇 | - | - | - | - | - | - | - | - | - | - |
| 胡椒薄荷油 | - | 0.001 | - | - | 0.001 | - | - | 0.001 | - | 0.001 |
| 芝麻油 | - | 0.005 | 0.1 | - | - | - | 0.1 | - | - | 0.01 |
| 鹽酸聚己縮胍 | - | - | - | - | - | 0.001 | - | 0.0001 | - | - |
| 胺丁三醇 | - | - | - | - | - | - | - | - | - | - |
| 鹽酸 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
| 氫氧化鈉 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL |
| pH | 6 | 7 | 5.5 | 6 | 7 | 5.5 | 6 | 7 | 5.5 | 6 |
[表12]
| 成分名 | 配方例21 | 配方例22 | 配方例23 | 配方例24 | 配方例25 | 配方例26 | 配方例27 |
| 氯化鋅 | 0.01 | 0.005 | 0.005 | 0.02 | 0.0001 | 0.001 | 0.001 |
| 聚乙烯吡咯啶酮(K90) | 0.1 | - | 0.5 | 1 | 0.3 | 0.5 | 0.5 |
| 聚乙烯吡咯啶酮(K30) | - | - | 0.1 | - | - | - | - |
| 聚乙烯吡咯啶酮(K25) | - | - | - | 0.05 | 0.2 | 0.05 | 0.05 |
| 羧乙烯聚合物 | - | 0.01 | - | - | - | 0.05 | 0.05 |
| 聚乙烯醇 | - | 0.5 | - | 0.01 | - | - | - |
| 硫酸軟骨素鈉 | 0.5 | 0.5 | 0.1 | 0.5 | - | 3 | 3 |
| 玻尿酸鈉 | 0.001 | 0.1 | 0.005 | - | 0.001 | 0.1 | 0.1 |
| 羥乙基纖維素 | - | 0.01 | - | - | - | 0.6 | 0.6 |
| 羥丙基甲基纖維素 | 0.05 | - | - | 0.01 | 0.3 | - | - |
| L-天冬胺酸鉀 | - | - | 1 | 1 | 0.5 | 0.5 | 0.5 |
| L-天冬胺酸鎂/鉀 | - | 0.5 | - | - | 0.5 | - | - |
| 牛磺酸 | - | 0.5 | - | 0.1 | - | 1 | 1 |
| 葡萄糖 | - | - | 0.005 | - | - | - | - |
| 氯化鉀 | - | - | 0.08 | - | - | 0.01 | 0.05 |
| 氯化鈉 | 0.6 | 0.4 | 0.44 | 0.3 | 0.45 | 0.4 | 0.4 |
| l-薄荷腦 | 0.04 | 0.002 | 0.005 | 0.015 | - | 0.005 | 0.005 |
| d-樟腦 | 0.01 | - | 0.003 | 0.003 | - | 0.003 | 0.003 |
| 香葉草醇 | 0.003 | - | - | - | - | - | - |
| 桉葉油 | - | 0.002 | - | - | - | - | - |
| 香柑油 | - | - | - | 0.001 | - | 0.001 | - |
| 胡椒薄荷油 | - | 0.001 | - | - | - | 0.001 | - |
| 薄荷油 | - | 0.002 | - | - | - | - | - |
| 聚氧乙烯氫化蓖麻油 | - | - | 0.2 | 0.1 | - | - | - |
| 聚氧乙烯蓖麻油 | - | - | - | 0.05 | 0.1 | - | - |
| 聚山梨醇酯80 | 0.3 | 0.2 | - | - | - | 0.2 | 0.2 |
| 聚乙二醇硬脂酸酯 | - | - | - | - | 0.1 | - | - |
| 聚氧乙烯聚氧丙烯二醇 | - | - | - | - | 0.05 | - | - |
| 氯化苄烷銨 | - | - | - | - | - | - | 0.0001 |
| 葡萄糖酸洛赫西定 | - | - | - | - | - | - | 0.0001 |
| 鹽酸聚己縮胍 | - | - | - | - | - | - | 0.0001 |
| 氯丁醇 | 0.15 | - | - | - | - | - | - |
| 乙二胺四乙酸鈉 | - | 0.001 | - | - | - | - | 0.01 |
| 硼酸 | 0.5 | 1 | 0.4 | 1 | - | 1 | 1 |
| 硼砂 | - | 0.1 | 0.1 | 0.2 | - | 0.2 | 0.2 |
| 磷酸氫鈉 | - | - | - | - | 0.15 | - | - |
| 磷酸二氫鈉 | - | - | - | - | 0.1 | - | - |
| 檸檬酸鈉 | - | - | 0.001 | - | - | 0.01 | 0.1 |
| 芝麻油 | - | 0.001 | - | - | 0.05 | - | - |
| 丙二醇 | - | - | - | - | 0.1 | - | - |
| 液態石蠟 | - | - | - | 0.05 | - | - | - |
| 濃甘油 | - | - | - | - | - | 0.1 | - |
| L-精胺酸 | - | 0.5 | - | - | - | - | - |
| 鹽酸 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
| 氫氧化鈉 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 | 適量 |
| 純化水 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 | 剩餘量 |
| 總量 | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL | 100 mL |
| pH | 7 | 6.8 | 6.8 | 6.3 | 7.5 | 7 | 6.8 |
無
無
Claims (5)
- 一種眼科組成物,其含有:(A)氯化鋅、及(B)聚乙烯系高分子化合物。
- 如請求項1之眼科組成物,其中,(B)聚乙烯系高分子化合物為聚乙烯吡咯啶酮。
- 如請求項2之眼科組成物,其中,上述聚乙烯吡咯啶酮之含量以眼科組成物之總量為基準為0.001~5 w/v%。
- 如請求項2或3之眼科組成物,其中,上述聚乙烯吡咯啶酮之黏性特性值為10~150。
- 如請求項1至4中任一項之眼科組成物,其用以抑制眼睛乾澀或乾眼症。
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| 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 |
| WO2013065720A1 (ja) * | 2011-11-01 | 2013-05-10 | ロート製薬株式会社 | 眼科用水性組成物 |
| JP6150510B2 (ja) * | 2011-12-12 | 2017-06-21 | ロート製薬株式会社 | 眼科用水性組成物 |
| JP6081173B2 (ja) * | 2011-12-12 | 2017-02-15 | ロート製薬株式会社 | 眼科用水性組成物 |
| TW201417814A (zh) * | 2012-09-28 | 2014-05-16 | Otsuka Pharma Co Ltd | 包括瑞巴派特之醫藥組成物 |
| JP6027866B2 (ja) * | 2012-11-22 | 2016-11-16 | ロート製薬株式会社 | オロパタジン含有水性組成物 |
| JP6611444B2 (ja) * | 2015-03-24 | 2019-11-27 | ロート製薬株式会社 | 眼科用組成物 |
| CN107614018A (zh) * | 2015-05-28 | 2018-01-19 | 乐敦制药株式会社 | 水性眼科组合物 |
| JP7104553B2 (ja) * | 2018-03-30 | 2022-07-21 | ロート製薬株式会社 | 眼科組成物 |
| JP7758466B2 (ja) * | 2019-11-07 | 2025-10-22 | ロート製薬株式会社 | 眼科組成物 |
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2022
- 2022-09-30 EP EP22876531.9A patent/EP4393510A4/en active Pending
- 2022-09-30 WO PCT/JP2022/036673 patent/WO2023054669A1/ja not_active Ceased
- 2022-09-30 TW TW111137266A patent/TW202320815A/zh unknown
- 2022-09-30 JP JP2023551894A patent/JPWO2023054669A1/ja active Pending
- 2022-09-30 US US18/695,745 patent/US20240390416A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP4393510A1 (en) | 2024-07-03 |
| US20240390416A1 (en) | 2024-11-28 |
| EP4393510A4 (en) | 2025-08-06 |
| WO2023054669A1 (ja) | 2023-04-06 |
| JPWO2023054669A1 (zh) | 2023-04-06 |
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