TWI463978B - Ophthalmic composition - Google Patents
Ophthalmic composition Download PDFInfo
- Publication number
- TWI463978B TWI463978B TW099121495A TW99121495A TWI463978B TW I463978 B TWI463978 B TW I463978B TW 099121495 A TW099121495 A TW 099121495A TW 99121495 A TW99121495 A TW 99121495A TW I463978 B TWI463978 B TW I463978B
- Authority
- TW
- Taiwan
- Prior art keywords
- ophthalmic composition
- oil
- component
- vitamin
- composition according
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 69
- -1 polyoxyethylene Polymers 0.000 claims description 53
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- 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 claims description 3
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- 229960000420 polidronium chloride Drugs 0.000 description 1
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- 235000012207 sodium gluconate Nutrition 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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- 239000011576 zinc lactate Substances 0.000 description 1
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- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
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- 239000002076 α-tocopherol Substances 0.000 description 1
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- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 1
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Description
本發明係有關混合維他命A,且具有乾眼症治療效果之眼科用組成物。
近年來伴隨著因空調普及造成的室內乾燥,電腦等VDT作業增加,及隱形眼鏡使用者增加等各式各樣的生活與社會環境的變化,乾眼症患者急遽增加。乾眼症係因淚液膜的質或量的異常,而造成眼球表面上角膜與結膜受到傷害之狀態。淚液膜係由脂肪層、水液層及黏液層等三層構成,當該三層構造的質或量的平衡被破壞時,淚液膜便會變得不安定,角膜受到損傷而引起乾眼症。故於治療乾眼症時使該淚液膜之脂肪層、水液層及黏液層等三層構造恢復,以及治療角膜損傷十分重要。
專利文件
專利文件1:特開2008-222638號公報
已知維他命A係上皮細胞增殖與分化之必須物質,具有促進黏液產生作用及治療角膜創傷作用。因此,維他命A正被期待發揮「回復淚液膜的黏膜層」及「治療角膜結膜損傷」之效果,作為治療乾眼症之有效藥物。
進而,由於維他命A為脂溶性,若與水性劑型之眼科用組成物混合,可補充淚液膜的脂肪層及水液層。因此,混合維他命A之眼科用組成物,由於其對於治療乾眼症最重要的回復淚液膜的脂肪層、水液層及黏液層等三層構成,以及治療角膜損傷有效,而適用作為眼藥水。
然而,目前存在尚未明確得知僅藉由維他命A是否可充分補足淚液膜的脂肪層,以及當維他命A與許多眼科用組成物混合時可能對眼睛造成刺激等副作用等問題點。另外,當維他命A無法充分補足淚液膜的脂肪層時,考慮輔助性地混合油性成分,但由於該混合必然會增加界面活性劑,因而出現後述之對眼睛造成刺激此問題點。
綜上所述,期望可開發於混合了維他命A的組成物中,混合可充分補充淚液膜的脂肪層之油性成分,且不會造成眼睛刺激之具有乾眼症治療效果之眼科用組成物。
另一方面,考慮將維他命A用於油性眼藥水及點眼軟膏。為補充淚液膜的脂肪層,以投藥油性眼藥水及點眼軟膏為最有效的方法。然而,直接對眼睛投藥油性成分時,因其特有的刺激及黏性,而產生「疼痛」、「模糊」、「朦朧」等視線不良,以及「黏膩感」等不愉快感等問題點。另外於隱形眼鏡使用者,存在油份是容易造成隱形眼鏡模糊不清及污垢的主要原因之問題點。
另外,油性成分藉由界面活性劑而可溶於水,或可進行乳化。然而,許多油性成分使用較為少量的界面活性劑進行乳化,而成為乳白色的製劑,該製劑雖然具有對眼睛刺激性較低之優點,但經長時間保存時,會出現油性成分分離等難以保持安定性、均勻性之問題點。反之,使用大量的界面活性劑使油性成分溶化的澄清的眼藥水,雖然具有點眼液中的油性成分可安定存在之優點,但界面活性劑對角膜或結膜具有刺激性,無法認定其可充分發揮乾眼症的預防或改善效果。另外於配戴隱形眼鏡時,該等問題點會更為顯著。綜上所述,目前正期待具有改善乾眼症效果,且可抑制對眼睛的刺激,及外觀保存安定性佳之眼科用組成物。
本發明有鑑於上述現況,以提供具有改善乾眼症效果,且可抑制對眼睛的刺激,及外觀保存安定性佳之眼科用組成物為目的。
本發明團隊為達成上述目的進行專心檢討後,發現含有(A)維他命A之外,藉由混合(C)植物油等油性成分,可充分補足淚液膜的脂肪層,提高改善乾眼症效果,同時可抑制對眼睛的刺激。另外,亦發現藉由混合(B)聚氧乙烯聚氧丙二醇,可使併用了(A)成分與(C)成分之本發明之眼科用組成物變為澄清,提高外觀保存安定性,可更發揮改善乾眼症效果。進而,藉由混合(D)抗氧化劑,可再提升外觀保存安定性,且發現藉由適量混合(E)聚氧乙烯硬化蓖麻子油或聚氧乙烯脂肪酸山梨醇酐酯,不會對眼睛產生刺激,可獲得澄清且具有良好的外觀保存安定性之眼科用組成物,本發明遂至完成。
因此,本發明係提供下述眼科用組成物。
[1]. 一種眼科用組成物,其係含有(A)維他命A、(B)聚氧乙烯聚氧丙二醇及(C)選自蓖麻油,大豆油、芝麻油、花生油、橄欖油、甜杏仁油、小麥胚芽油、玉米油、油菜籽油、葵花籽油、純化羊毛脂及烴凝膠所成群之油性成分。
[2]. 如[1]項之眼科用組成物,其中(A)成分係視黃醇棕櫚酸酯、視黃醇乙酸酯或視黃酸。
[3]. 如[1]或[2]項之眼科用組成物,其中(B)成分之含量係0.1~20W/V%。
[4]. 如[1]、[2]或[3]項之眼科用組成物,其中(C)成分之含量係0.01~5W/V%。
[5]. 如[1]~[4]項中任一項之眼科用組成物,其中進而含有(D)抗氧化劑。
[6]. 如[5]項中之眼科用組成物,其中(D)成分係維他命E或二丁基羥基甲苯。
[7]. 如[1]~[6]項中任一項之眼科用組成物,其中進而含有(E)聚氧乙烯硬化蓖麻子油及/或聚氧乙烯脂肪酸山梨醇酐酯0.001~0.5W/V%。
[8]. 如[7]項之眼科用組成物,其中(B)成分及(E)成分之合計含量係1.1 W/V%以上。
[9]. 如[1]~[8]項中任一項之眼科用組成物,其係未混合防腐劑。
[10]. 如[1]~[9]中任一項之眼科用組成物,其係隱形眼鏡用眼藥水。
根據本發明,可提供具有改善乾眼症效果,同時可抑制對眼睛的刺激,及外觀保存安定性佳之眼科用組成物。
以下針對本發明進行詳細的說明。
本發明之眼科用組成物係含有(A)維他命A、(B)聚氧乙烯聚氧丙二醇及(C)選自蓖麻油、大豆油、芝麻油、花生油、橄欖油、甜杏仁油、小麥胚芽油、玉米油、油菜籽油、葵花籽油、純化羊毛脂及烴凝膠所成群之油性成分之眼科用組成物。
(A)維他命A
維他命A除了本身以外,可使用例如維他命A油等含維他命A之混合物、維他命A脂肪酸酯等維他命A衍生物等。可單獨使用1種或適當地組合2種以上使用。具體而言可舉出視黃醇棕櫚酸酯、視黃醇乙酸酯、視黃醇、視黃酸、視黃質等。其中以視黃醇棕櫚酸酯、視黃醇乙酸酯、視黃酸為佳。一般視黃醇棕櫚酸酯有100萬~180萬國際單位(以下簡寫為I.U.)之市售品,具體而言可舉出Roche Vitamin Japan股份有限公司製之視黃醇棕櫚酸酯(170萬I.U./g)等。
(A)成分之含有量係相對於全量眼科用組成物,以50,000~500,000單位/100mL為佳,50,000~300,000單位/100mL更佳,100,000~200,000單位/100mL更佳。以W(質量)/V(體積)%(g/100mL)表示時,混合之維他命A亦相同,上述含維他命A之成分以0.03~0.3 W/V%為佳,0.03~0.18 W/V%更佳,0.06~0.12 W/V%最佳。雖然維他命A具有角膜與結膜損傷治療效果,及對改善乾眼症、眼睛疲勞、視力模糊具有改善效果,但未達50,000單位/100mL時,可能無法獲得充分的角膜與結膜損傷治療效果,而超過500,000單位/100mL時,則有可能發生副作用。
(B)聚氧乙烯聚氧丙二醇
並未限定特別的聚氧乙烯聚氧丙二醇,可使用醫藥品添加物規格(藥添規)所記載者。乙烯氧之平均聚合度以4~200為佳,20~200更佳,丙烯氧之平均聚合度以5~100為佳,20~70更佳,可為團聯式共聚物或無規式共聚物。(B)成分可單獨使用1種或適當地組合2種以上使用。藉由使用(B)成分此特定的界面活性劑,可使併用了(A)成分與(C)成分之本發明之眼科用組成物變為澄清,提高外觀保存安定性,可更發揮改善乾眼症效果。另外,即使大量混合(B)成分,亦不易對眼睛造成刺激。
具體而言可舉出聚氧乙烯(200)聚氧丙烯(70)乙二醇:Lutrol F127(BASF公司製)、Unilub 70DP-950B(日油(股)製)等、聚氧乙烯(120)聚氧丙烯(40)乙二醇(Pluronic F-87)、聚氧乙烯(160)聚氧丙烯(30)乙二醇(Pluronic F-68,別名-Poloxamer 188)、Puronon#188P(日油(股)製)等、聚氧乙烯(42)聚氧丙烯(67)乙二醇(Pluronic P123,別名-Poloxamer 403)、聚氧乙烯(54)聚氧丙烯(39)乙二醇(Pluronic P85)、Puronon#235P(日油(股)製)等、聚氧乙烯(20)聚氧丙烯(20)乙二醇(Pluronic L-44)、Tetronic等。其中以聚氧乙烯(200)聚氧丙烯(70)乙二醇、聚氧乙烯(160)聚氧丙烯(30)乙二醇、聚氧乙烯(54)聚氧丙烯(39)乙二醇為佳。
(B)成分之含量,相對於眼科用組成物之全量,以0.1~20 W/V%為佳,0.2~15 W/V%更佳,以0.5~10W/V%更佳,1.1~10 W/V%特佳,3~10 W/V%最佳。未達0.1W/V%時,油性成分難以溶化。超過20 W/V%時可能對眼睛產生刺激,但即使大量混合(B)成分,亦不易對眼睛造成刺激。另外,將(B)成分作為可溶化劑單獨混合時,藉由使用0.4 W/V%以上,可容易使油性成分變為可溶化。
(C)油性成分
油性成分可舉出選自蓖麻油、大豆油、芝麻油、花生油、橄欖油、甜杏仁油、小麥胚芽油、玉米油、油菜籽油、葵花籽油、純化羊毛脂及烴凝膠所成群之油性成分,可單獨使用1種或適當地組合2種以上使用。其中以蓖麻油、芝麻油、橄欖油、大豆油、花生油為佳,蓖麻油、芝麻油、大豆油、花生油更佳,蓖麻油、芝麻油、大豆油最佳。藉由併用(A)維他命A與(C)油性成分,提高乾眼症改善效果。
(C)成分的含量,自改善乾眼症及外觀安定性之點,以相對於眼科用組成物全量為0.01~5 W/V%為佳,0.05~3 W/V%更佳。未達0.01 W/V%時,難以獲得良好的使用感,超過5 W/V%則有時會無法獲得澄清的眼藥水。
(D)抗氧化劑
自提高維他命A的保存安定性以及外觀保存安定性之點,以混合抗氧化劑為佳。抗氧化劑可舉出d-α-生育醇、d-β-生育醇、d-γ-生育醇、d-δ-生育醇、dl-α-生育醇、d-α-生育醇醋酸酯、dl-α-生育醇醋酸酯、dl-β-生育醇醋酸酯、dl-γ-生育醇醋酸酯、dl-δ-生育醇醋酸酯、dl-α-生育醇尼古丁酸酯等之維他命E及其衍生物、二丁基羥基甲苯、丁基羥基苯甲醚等脂溶性抗氧化劑、維他命C、對苯二酚、半胱胺酸、穀胱甘肽等水溶性抗氧化劑等。可將該等物質單獨使用1種,或適當地組合2種以上而使用。其中以維他命E等脂溶性抗氧化劑為佳,d-α-生育醇醋酸酯、二丁基羥基甲苯更佳,d-α-生育醇醋酸酯最佳。
(D)成分之含量為相對於眼科用組成物全量以0.001~0.5 W/V%為佳,0.005~0.3 W/V%更佳。
(E)聚氧乙烯硬化蓖麻子油及/或聚氧乙烯脂肪酸山梨醇酐酯
本發明之眼科用組成物中,自提高外觀保存安定性之點,以混合聚氧乙烯硬化蓖麻子油及/或聚氧乙烯脂肪酸山梨醇酐酯為佳。聚氧乙烯硬化蓖麻子油係可舉出聚氧乙烯硬化蓖麻子油(E. O.)5、聚氧乙烯硬化蓖麻子油10、聚氧乙烯硬化蓖麻子油20、聚氧乙烯硬化蓖麻子油40、聚氧乙烯硬化蓖麻子油50、聚氧乙烯硬化蓖麻子油60、聚氧乙烯硬化蓖麻子油100等,聚氧乙烯脂肪酸山梨醇酐酯則可舉出聚氧乙烯(20)山梨醇酐酯月桂酸酯(聚山梨醇酯20)、聚氧乙烯(20)山梨醇酐單油酸酯(聚山梨醇酯80)、聚氧乙烯山梨醇酐單硬酯酸酯(聚山梨醇酯60)、聚氧乙烯山梨醇酐三硬酯酸酯(聚山梨醇酯65)等,可將該等物質單獨使用1種,或適當地組合2種以上而使用。其中以聚山梨醇酯80、聚氧乙烯硬化蓖麻子油60為佳。
(E)成分可於不產生眼睛刺激之範圍內進行混合。其含量為相對於眼科用組成物全量,以0.001~0.5 W/V%為佳,0.01~0.4 W/V%更佳,0.05~0.3 W/V%最佳。
(B)成分及(E)成分之合計含量,自提高外觀保存安定性之點,以1.1 W/V%以上為佳,2 W/V%以上更佳。自對眼睛造成刺激此點而言,則以25 W/V%以下為佳。另外如上所述,自改善乾眼症及抑制對眼睛的刺激而言,(E)成分以0.5 W/V%以下為佳。
於本發明之眼科用組成物中,除前述之成分外,可於不損及本發明效果的範圍內,混合其他可混合於眼科用組成物之各種成分。該等成分可舉出多元醇、(B)成分及(E)成分以外之界面活性劑、緩衝劑、黏稠劑、糖類、pH調整劑、防腐劑、等張化劑、安定化劑、清涼化劑、藥物、水等。該等物質可分別單獨使用1種,或適當地組合2種以上使用,可適量混合。
多元醇可舉出甘油、丙二醇、丁二醇、聚乙二醇等。多元醇之含量以於眼科用組成物中為0.01~5 W/V%為佳,0.05~3W/V%更佳。
可併用(B)成分及(E)成分以外之界面活性劑,例如烷基二胺乙基甘胺酸等甘胺酸型兩性界面活性劑、烷基四級銨鹽(具體而言可舉出氯化苯二甲烴銨、甲苄索氯銨、等陽離子界面活性劑)。該等之含量於眼科用組成物中,以0.0001~10W/V%為佳,0.005~5 W/V%更佳。
緩衝劑可舉出例如硼酸或其鹽(硼砂等)、檸檬酸或其鹽(檸檬酸鈉等)、磷酸或其鹽(磷酸氫鈉等)、酒石酸或其鹽(酒石酸鈉等)、葡萄糖酸或其鹽(葡萄糖酸鈉等)、乙酸或其鹽(乙酸鈉等)、各種胺基酸等(6-氨基己烯酸、天門冬氨酸鉀、氨基乙磺酸、麩胺酸、麩胺酸鈉等)、氨丁三醇等。其中,自低刺激性且具有組成物之防腐效果之觀點,以氨丁三醇為佳。進而合併使用硼酸、硼砂,可獲得更高的防腐效果。且於本發明中,混合硼酸、氨丁三醇、檸檬酸或其鹽時,可進而提升維他命A之安定性。緩衝劑之含量以佔眼科用組成物中之0.001~10 W/V%為佳,0.01~5 W/V%更佳。
黏稠劑可舉出聚乙烯吡咯烷酮、羥乙基纖維素、羥丙基甲基纖維素、甲基纖維素、聚乙烯醇、玻尿酸鈉、硫酸軟骨素鈉、聚丙烯酸、羧乙烯基聚合物等。藉由混合該等物質,可提高滯留性並提升角膜與結膜損傷治療效果。黏稠劑之混合量以例如0.001~10 W/V%為佳,0.001~5 W/V%更佳,0.01~3 W/V%最佳。
糖類可舉出葡萄糖、環糊精、木糖醇、山梨糖醇、甘露糖醇等。該等糖類可為右旋體(d-form)、左旋體(l-form)或dl-form之任一種。糖類之混合量可為例如0.001~10 W/V%為佳,0.005~5 W/V%更佳,0.01~3 W/V%最佳。
pH調整劑以使用無機酸或無機鹼劑為佳。例如無機酸可舉出(稀)鹽酸。無機鹼劑可舉出氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸氫鈉等。其中以鹽酸、氫氧化鈉為佳。本發明之眼科用組成物之pH(20℃)以4.0~9.0為佳,5.0~8.0更佳,6.0~8.0最佳。且於本發明中,pH之測定係於20℃,使用pH滲透壓計(HOSM-1,東亞TKK(股)製)。pH調整劑之混合量以例如0.00001~10 W/V%為佳,0.0001~5 W/V%更佳,0.001~3 W/V%最佳。
防腐劑可舉出例如氯化苯二甲烴銨、甲苄索氯銨、山梨酸或其鹽、對苯甲酸酯(Methylparaben、Ethylparaben、Propylparaben等)、氯己定葡糖酸鹽、硫柳汞、苯乙醇、鹽酸烷基二胺基乙基甘胺酸、鹽酸聚己縮胍、POLYQUAD(polidronium chloride)等。可於不損及本發明效果的範圍內混合防腐劑,但本發明之眼科用組成物,著眼於會對眼部造成刺激此點,以不含防腐劑之無防腐劑為佳。
本發明中,自改善乾眼症之觀點,選自氯化苯二甲烴銨、甲苄索氯銨之陽離子性界面活性劑(一部分為陽離子性防腐劑)、對苯甲酸酯(Methylparaben、Ethylparaben、Propylparaben等)及選自氯丁醇之疏水性防腐劑之含量以0.004 W/V%以下為佳,0.003W/V%以下更佳,且以不含該等防腐劑,不混合防腐劑為最佳。該等防腐劑阻礙角膜與結膜損傷治療效果之機轉雖尚未解明,但推測如後所述。(B)聚氧乙烯聚氧丙二醇係以EO鏈於外側,PO鏈於內側之方式包住維他命A而形成微胞。該微胞附著於角膜表面,而使維他命A被吸收入角膜內部。由於陽離子性界面活性劑會改變界面活性能,及由於疏水性防腐劑之疏水性高,使微胞表面的狀態改變,而阻礙維他命A被角膜吸收,結果阻礙了角膜與結膜損傷之治療效果以及對乾眼症之改善。反之,山梨酸或其鹽等親水性高之防腐劑,由於不會對微胞表面狀態造成影響,不會阻礙維他命A之吸收促進效果。且上述成分為防腐劑的一部分,未混合防腐劑時之防腐力,可適宜地組合混合EDTA鈉、硼酸及氨丁三醇之1種以上或2種以上。另外於使用單一劑量(unit dose)容器或附有過濾膜之容器之情況,亦可不使用防腐劑。
等張化劑可舉出例如氯化鈉、氯化鉀等。等張化劑之混合量以例如0.001~5 W/V%為佳,0.01~3 W/V%更佳,0.1~2 W/V%最佳。
安定化劑可舉出例如乙二胺四醋酸鈉、環糊精、亞硫酸鹽、二丁基羥基甲苯等。於本發明中,混合安定化劑時,可進而提升維他命A之安定性。安定化劑之混合量以例如0.001~5 W/V%為佳,0.01~3 W/V%更佳,0.1~2 W/V%最佳。
清涼化劑可舉出例如薄荷腦、樟腦、冰片、香葉醇、桉油醇、沈香醇等。清涼化劑之混合量以0.0001~5 W/V%為佳,0.001~2 W/V%更佳,0.005~1 W/V%亦佳,0.007~0.8 W/V%特佳。
藥物(藥學上之有效成分)可舉出適當地混合例如消除充血劑(例如鹽酸萘甲唑啉、鹽酸四氫唑啉、鹽酸去氧腎上腺素、腎上腺素、鹽酸麻黃鹼、dl-甲基鹽酸麻黃鹼、硝酸四氫唑啉、硝酸萘甲唑啉等);消炎及收斂劑(例如硫酸甲酯新斯狄明、6-氨基己烯酸、尿囊素、鹽酸黃連素、硫酸鋅、乳酸鋅、溶菌酶素、甘草酸二鉀、甘草酸銨、甘草酸、甲基水楊酸、傳明酸、薁磺酸鈉等);抗組織胺劑(例如鹽酸異丙海汀、鹽酸二苯胺明、二苯胺明、鹽酸異西噴地、縮水蘋果酸氯菲尼拉明等);抗過敏劑(例如色甘酸鈉等);水溶性維他命(活化型維他命B2
、維他命B6
、維他命B12
等);胺基酸(例如L-天門冬氨酸鉀、L-天門冬氨酸鎂、胺基乙基磺酸、硫酸軟骨素鈉等、穀胱甘肽等);磺胺劑、殺菌劑(例如硫磺、異丙基甲基酚、檜木醇等);局部麻醉劑(例如利多卡因、鹽酸利多卡因、鹽酸普羅卡因、鹽酸及普卡因等);散朣劑(例如挫匹卡邁等)。
眼科用組成物中該等物質之混合量可適當地因應製劑種類、藥物種類等選擇,各成分之混合量於相關技術範圍內為已知者。例如可選擇相對於製劑全成分為0.0001~30W/V%為佳,0.001~10W/V%之範圍更佳。更具體而言,各成分相對於眼科用組成物全量之混合量,係如下所述。
消除充血劑為例如以0.0001~0.5W/V%為佳,0.0005~0.3 W/V%更佳,0.001~0.1W/V%最佳。消炎及收斂劑為例如以0.0001~10W/V%為佳,0.0001~5 W/V%更佳。抗組織胺劑為例如以0.0001~10W/V%最佳,0.001~5W/V%更佳。水溶性維他命為例如以0.0001~1 W/V%為佳,0.0001~0.5W/V%更佳。胺基酸為例如以0.0001~10W/V%為佳,0.001~3 W/V%更佳。磺胺劑、殺菌劑為例如以0.00001~10W/V%為佳,0.0001~10 W/V%更佳。局部麻醉劑為例如以0.001~1W/V%為佳,0.01~1 W/V%更佳。
本發明之眼科用組成物,可直接使用液劑,亦可調製為懸濁劑、凝膠劑等。眼科用組成物可舉出為眼藥水、洗眼劑等,且最適合作為隱形眼鏡用。「隱形眼鏡用」係指配戴隱形眼鏡時所使用者。具體而言可舉出眼藥水(包含可於配戴隱形眼鏡時使用之隱形眼鏡用眼藥水)、洗眼劑(包含可於配戴隱形眼鏡時可進行洗眼之隱形眼鏡用洗眼劑),以隱形眼鏡用眼藥水為佳。並未特別限定隱形眼鏡的種類,可舉出可為硬式、半透氧式、軟式、拋棄式、矽水凝膠(Silicone Hydrogel)式等。
本發明藉由混合高濃度之維他命A,而適用作為治療角膜損傷之眼科用組成物,及乾眼症治療劑。乾眼症係因淚液膜的質或量的異常,而造成眼球表面上角膜與結膜受到傷害之狀態。淚液膜係由脂肪層、水液層及黏液層等三層所構成,當該三層構造的質或量的平衡被破壞時,淚液膜便會變得不安定,使角膜受到損傷而引起乾眼症。故於治療乾眼症時,使該淚液膜之脂肪層、水液層及黏液層等三層構造恢復,以及治療角膜損傷十分重要。另外,由於隱形眼鏡使用者容易產生乾眼症,本發明之眼科用組成物,適用為隱形眼鏡用眼藥水、取下隱形眼鏡後使用之洗眼劑、配戴隱形眼鏡用液、取下隱形眼鏡用液等。使用為乾眼症治療劑時,1次30~60μL,每日點眼3~6次,可更發揮其效果。
根據本發明,可使眼科用組成物呈現澄清狀態。且本發明中「澄清」係指沒有混濁且透明。
本發明之眼科用組成物係液狀,其黏度於使用為眼藥水時,以1~50mPa‧s為佳,1~20mPa‧s亦佳,1~5mPa‧s最佳。黏度測定係於20℃時使用E型黏度計(VISCONIC ELD-R,東京計器(股))進行。
由於本發明之眼科用組成物其調製方法並未特別被限定,例如維他命A可藉由聚氧乙烯聚氧丙二醇而可溶解於純水中,其次,再加入各成份後調整pH而可得。之後,可無菌填充於適當的容器例如聚對苯二甲二乙酯(PET,Polyethyleneterephthalate)製之容器等。
[實施例]
以下列以實施例及比較例具體說明本發明,但本發明並未被限制於下述實施例。且表中之量及其他係成分之純份量。
[實施例1~44,比較例1~4]
以下述方法調製表1~8所示組成之眼科用組成物(眼藥水)。將維他命A、聚氧乙烯聚氧丙二醇及油成分(可因應需要添加抗氧化劑)於85℃下預先溶解。再將該預先溶解物加熱至85℃使可溶解於純水中。待冷卻後,加入水溶性混合成分。針對所得之眼科用組成物(眼藥水)進行如下所述之評價。將結果併記於表中。另外,眼科用組成物之pH(20℃)測定係使用pH滲透壓計(HOSM-1,東亞TKK(股)製),結果示於表中。且實施例中之眼科用組成物均為澄清。
<外觀安定性>
將20mL之眼科用組成物填充於玻璃製之安瓶(20mL用)中,觀察於70℃保存7天後外觀的變化,並以下述標準進行評價。
<評價標準>
5:液體為澄清,幾乎沒有變色
4:液體為澄清,但稍有變色
3:液體為澄清,但有少許變色
2:液體不澄清
1:液體產生分離或沉澱
<乾眼症改善1>
對主訴乾眼症症狀(參照重症度1:The Ocular Surface,Vol 5,No. 2,2007)之患者,以眼科用組成物50μL點眼(點眼3次,每次間隔2小時),點眼3次後,於30分鐘後,根據下述標準評價乾眼症的改善程度(眼睛的乾燥感)。
<評價標準>
5:非常有改善
4:有改善
3:稍有改善
2:不清楚有沒有改善
1:沒有改善
<乾眼症改善2>
對主訴乾眼症症狀(重症度4)之患者(3位),以眼科用組成物50μL點眼(點眼3次,每次間隔2小時),點眼3次後,於30分鐘後,根據下述標準評價乾眼症的改善程度(眼睛的乾燥感)。結果表示為3位患者的平均值(小數點第一位四捨五入)。
<評價標準>
7:極有改善
6:非常有改善
5:有很大改善
4:有改善
3:稍有改善
2:不清楚有沒有改善
1:沒有改善
<對眼睛的刺激性>
將5mL眼科用組成物置入洗眼用杯,進行30秒洗眼。對進行洗眼中感覺到之眼部刺激以下述標準進行評價。且進行洗眼時以頭部朝上之姿勢,及洗眼中不使洗眼液自洗眼用杯流失而進行,每5秒眨眼一次,以使洗眼液覆蓋眼球表面全體之條件進行。
<評價標準>
5:未感覺到刺激感
4:不清楚有沒有刺激感
3:稍感覺到刺激感
2:感覺到刺激感
1:感覺到非常強的刺激感
如上所述,顯示本發明之眼科用組成物對乾眼症症狀(重症度4)症狀嚴重之患者具有特別顯著之效果。
實施例所使用之原料如下所示。
*1:Unilub 70DP-950B,藥添規,日油(股)或Lutrol F127,藥添規,BASF
*2:Puronon#188P,藥添規,日油(股)
*3:Puronon#235P,藥添規,日油(股)
Claims (10)
- 一種眼科用組成物,其係含有(A)維他命A、(B)乙烯氧之平均聚合度為20~200,丙烯氧之平均聚合度為20~70之聚氧乙烯聚氧丙二醇0.01~20W(質量)/V(體積)%(g/100mL)及(C)選自蓖麻油、大豆油、芝麻油、花生油、橄欖油、甜杏仁油、小麥胚芽油、玉米油、油菜籽油、葵花籽油及純化羊毛脂所成群之油性成分0.01~5W(質量)/V(體積)%(g/100mL)、(D)抗氧化劑、(E)聚氧乙烯硬化蓖麻子油及/或聚氧乙烯脂肪酸山梨醇酐酯0.001~1.0W(質量)/V(體積)%(g/100mL),其特徵為(B)成分及(E)成分之合計含量,為1.1W(質量)/V(體積)%(g/100mL)以上。
- 如申請專利範圍第1項之眼科用組成物,其中(A)成分係視黃醇棕櫚酸酯、視黃醇乙酸酯或視黃酸。
- 如申請專利範圍第1或2項之眼科用組成物,其中(A)成分之含量為50,000~500,000單位/100mL。
- 如申請專利範圍第1或2項之眼科用組成物,其中(B)成分之含量係0.2~10W(質量)/V(體積)%(g/100mL)。
- 如申請專利範圍第1或2項之眼科用組成物,其中(D)成分係維他命E或二丁基羥基甲苯。
- 如申請專利範圍第1或2項之眼科用組成物,(D)成分之含量為0.001~0.5W(質量)/V(體積)%(g/100mL)。
- 如申請專利範圍第1或2項之眼科用組成物,其中(B)成分及(E)成分之合計含量係1.1~20.001W(質量)/V(體積)%(g/100mL)。
- 如申請專利範圍第1或2項之眼科用組成物,其係未混合防腐劑。
- 如申請專利範圍第8項之眼科用組成物,其係進一步含有選自乙二胺四醋酸鈉、硼酸及氨丁三醇之1種以上或2種以上。
- 如申請專利範圍第1或2項之眼科用組成物,其係隱形眼鏡用眼藥水。
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CN103764168B (zh) * | 2011-07-08 | 2016-02-17 | 乐敦制药株式会社 | 水性眼科用组合物 |
JP6155863B2 (ja) * | 2012-06-08 | 2017-07-05 | ライオン株式会社 | 粘膜用組成物及びその製造方法 |
KR102068858B1 (ko) * | 2012-06-08 | 2020-01-21 | 라이온 가부시키가이샤 | 점막용 조성물 |
JP6179204B2 (ja) * | 2012-06-08 | 2017-08-16 | ライオン株式会社 | 粘膜用組成物及びその製造方法 |
JP6462201B2 (ja) * | 2012-06-14 | 2019-01-30 | ロート製薬株式会社 | 水性眼科組成物 |
JP5984531B2 (ja) * | 2012-06-27 | 2016-09-06 | ロート製薬株式会社 | 水性眼科組成物 |
JP5988855B2 (ja) | 2012-06-27 | 2016-09-07 | ロート製薬株式会社 | 水性眼科組成物 |
US9427473B2 (en) * | 2012-12-04 | 2016-08-30 | Rohto Pharmaceutical Co., Ltd. | Aqueous ophthalmic composition |
WO2018003796A1 (ja) * | 2016-06-30 | 2018-01-04 | ライオン株式会社 | 眼科用製品及び粘度低下抑制方法 |
CN109689161A (zh) * | 2016-08-19 | 2019-04-26 | 阿克里维斯塔有限责任公司 | 诊断和治疗干眼综合症的方法以及用于治疗人眼的组合物 |
KR20190065237A (ko) * | 2016-10-07 | 2019-06-11 | 라이온 가부시키가이샤 | 안과용 제품 및 점도 저하 억제 방법 |
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JP7192766B2 (ja) * | 2017-04-21 | 2022-12-20 | ライオン株式会社 | 眼科用組成物及びその製造方法 |
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