201143763 六、發明說明： 【發明所屬之技術領域】 本發明係關於-種可於佩戴軟式隱形眼鏡時使用之點眼 劑。 义 【先前技術】 隱形眼鏡之佩戴者有逐年增加之趨勢。特別是軟式隱形 眼鏡，由於其使用感良好而被許多人使用，且可想到今後 使用者亦不斷增加。因此，期望開發出可於佩戴軟式隱形 眼鏡之狀態下直接使用之點眼劑。 然而’於「眼科用藥銷售（進口）許可標準」（非專利文獻 1)一項之功能.效果之解說中記載：「為使人工淚液及隱形眼 鏡佩戴液取得對軟式隱形眼鏡之功能或效果，必須隨附以 下資料進Μ請：證實適合制於各種軟式隱形眼鏡之資 料’例如與點目請之㈣成分制是添加物（防㈣等）之吸 附、濃縮或吸收、釋出對隱形眼鏡之物性（顏色、形狀、牢 固度、脆弱度等)造成之影響及佩戴時之安全性相關的資 料」’設料於佩戴軟式隱形眼鏡之狀直接制之點眼 劑並不容易。 因此目刖可於佩戴軟式隱形眼鏡之狀態下直接使用之 點眼劑限於以人工淚淡炎由 戍液為中心之一部分產品，不可謂滿足 使用者之要求於軟式隱形眼鏡佩戴者使用點眼劑之情形 時，通常必須取出鏡片德& Ρ 兄乃设占眼’而有不僅由於鏡片之佩戴 或取出引起鏡片破損，％ # 而且由手指上之細菌引起污染或異 物專之混入、對眼睛造成傷宝之可处地 月 < 取楊告之可能性。於1天點眼3次以 153907.doc 201143763 上之點眼劑之情形時，其風險變高。 由於此種it况’期望開發出調配藥效成分 '可於佩戴軟 式隱形眼鏡之狀態下直接點眼之點眼劑，而進行了調配各 種藥效成分之嘗試（專利文獻i〜4)。 另一方面，點眼劑雖為無菌製劑，但除了 一次性之單次 使用者以外均係於開封後反覆使用，故通常使用防腐劑。 然而，已知軟式隱形眼鏡中防腐劑容易被鏡片吸收而蓄 積。特別s報告有被廣泛用作點眼劑之防腐劑的氣化苯二 曱烴銨或對羥基苯曱酸酯容易蓄積於軟式隱形眼鏡（非專 利文獻2)。 近年來，由於電腦之普及等，眼疲勞之人不斷增加，作 為其治療之第一選擇藥’一直使用調配有氰鈷胺素之點眼 劑。已知氰鈷胺素使睫狀肌之功能活化，緩解眼疲勞。然 而’可於佩戴軟式隱形眼鏡之狀態下直接點眼之調配有氰 鈷胺素之點眼劑則尚不知曉。 [先前技術文獻] [專利文獻] [專利文獻1]日本專利特開2001-158734號公報 [專利文獻2]日本專利特開2002-249445號公報 [專利文獻3]日本專利特開2005-84558號公報 [專利文獻4]曰本專利特開2007-70350號公報 [非專利文獻]201143763 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to an eyedrop that can be used when wearing a soft contact lens. [Prior Art] The wearer of contact lenses has a tendency to increase year by year. In particular, soft contact lenses are used by many people because of their good feeling of use, and it is conceivable that users will continue to increase in the future. Therefore, it has been desired to develop an eye drop which can be directly used while wearing a soft contact lens. However, the function of the "Ophthalmology Drug Sales (Import) License Standard" (Non-Patent Document 1) is explained in the explanation of the effect: "In order to make artificial tears and contact lens wear liquids function or effect on soft contact lenses, Must be accompanied by the following information: Confirm the information suitable for a variety of soft contact lenses 'For example, please contact (4) ingredients are additives (anti-(four), etc.) adsorption, concentration or absorption, release of contact lenses Information on the effects of physical properties (color, shape, firmness, fragility, etc.) and the safety of wearing "" It is not easy to set the eyedrops directly on the wearing of soft contact lenses. Therefore, the eye-dropping agent that can be directly used in the state of wearing the soft contact lens is limited to one part of the product which is centered on the sputum liquid by artificial tearing, and it is not necessary to satisfy the user's requirement to use the eye-dropping agent for the soft contact lens wearer. In the case of the case, it is usually necessary to take out the lens and the 兄 兄 乃 设 设 ' ' 而 而 而 而 而 而 而 而 而 而 而 而 而 而 而 而 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片 镜片The treasure of the injury can be used in the month < The risk is higher when the eyedrops on 153907.doc 201143763 are taken 3 times a day. In view of the fact that it is expected to develop a formulated medicinal ingredient, it is possible to apply various medicinal ingredients by directly applying an eye-dropping agent in a state in which a soft contact lens is worn (Patent Documents i to 4). On the other hand, although the ophthalmic agent is a sterile preparation, it is usually used in addition to a one-time single-use user, and a preservative is usually used. However, it is known that preservatives in soft contact lenses are easily absorbed by the lens to accumulate. In particular, it has been reported that vaporized benzodiazepine or p-hydroxybenzoate which is widely used as a preservative for eye drops is easily accumulated in soft contact lenses (Non-patent Document 2). In recent years, due to the popularity of computers, the number of people with eye fatigue has been increasing, and the first choice for their treatment has been the use of eye drops formulated with cyanocobalamin. It is known that cyanocobalamin activates the function of the ciliary muscle and relieves eye fatigue. However, it is not known that eye drops which are formulated with cyanocobalamin directly in the state of wearing soft contact lenses. [Prior Art Document] [Patent Document 1] Japanese Patent Laid-Open Publication No. 2001-158734 (Patent Document 2) Japanese Patent Laid-Open Publication No. 2002-249445 (Patent Document 3) Japanese Patent Laid-Open No. 2005-84558 [Patent Document 4] Japanese Patent Laid-Open Publication No. 2007-70350 [Non-Patent Document]
[非專利文獻1]一般用醫藥品製造（進口）許可標準2000年 版，JIHO 153907.doc 201143763 [非專利文獻2]日本隱形眼鏡學會雜誌 35:178-182, 1993 【發明内容】 [發明所欲解決之問題] 本發明之課題在於提供一種含有對於眼疲勞之減輕有用 之氰鈷胺素、且可於佩戴軟式隱形眼鏡時使用之點眼劑。 [解決問題之技術手段] 因此，本發明者為開發出含有氰鈷胺素、可於佩戴軟式 隱形眼鏡時使用之具有減輕眼疲勞之功能之點眼劑，以點 眼劑對軟式隱形眼鏡造成之影響（藥物之鏡片蓄積性或鏡 片之變形等）、與防腐劑之相互作用、使用感及眼疲勞之減 輕作用為指標，對佩戴軟式隱形眼鏡時亦可使用之點眼劑 之製劑設計進行了努力研究，結果發現，藉由在氰鈷胺素 中以特定量之範圍調配作為防腐劑之山梨酸或其鹽，進而 以特定量之範圍調配硼酸或其鹽及乙二胺四乙酸或其鹽， 可獲得達成上述所有指標之點眼劑，從而完成了本發明。 即’本發明提供-種可於佩戴軟式隱形眼鏡時使用之點 眼劑，其含有（A)氰鈷胺素、（B)山梨酸或其鹽〇 〇2〜〇 2 w/v%、（C)蝴酸或其鹽〇5〜2〇 w/v%、及（D)乙二胺四乙酸或 其鹽 0.01 〜0.2 w/v%。 [發明之效果] 本發明之點眼劑由於含有氰録胺素，故眼疲勞之減輕效 果優異’且即便於佩戴軟式隱形眼鏡時使用亦不對軟式隱 形眼鏡造成影響’使用性優異。根據本發明，首次可提供 153907.doc 201143763 含有氰鈷胺素之可於佩戴軟式隱形眼鏡時使用之點眼劑。 又，於在本發明之點眼劑中調配牛磺酸及硫酸軟骨素鈉之 情形時’《為具有更良好之使用感之點眼劑。 【實施方式】 本發明之點眼劑含有（A)氱鈷胺素、（B)山梨酸或其鹽 0·02〜0_2 w/v%、（C)蝴酸或其鹽〇 5〜2 〇 wv%、及（d)乙二胺 四乙酸或其鹽0.01〜0.2 w/ν%。 (A)氰鈷胺素係亦稱被為維生素b丨2之水溶性維生素之一 種已知其具有眼疲勞治療作用。含有氛始胺素之點眼劑 已為人所b ’但必須轉認其不會對軟式隱形眼鏡造成影響 而可安全地使用’可於佩戴軟式隱形眼鏡時使用之含有氛 姑胺素之點眼劑則並不知曉。關於本發明點眼财氰敍胺 ，之3量&眼疲勞之減輕作用 ' 對軟式隱形眼鏡之影響、 安全性.副作用之方面而言，較佳為0.004〜0.05 w/v%，尤佳 為 0·006〜0·〇2 w/v%。 本發明中所使用之（B)山梨酸或其鹽具有保存作用’且並 無與軟式隱形眼鏡之相互作用，特別是與氛錄胺辛併用 時，不會對氰録胺素之穩定性造成不良影響。作為山梨酸 之鹽’尤佳為山梨酸鈉、山梨酸鉀等山梨酸鹼金屬 併用山梨酸與其鹽。 了 關於本發明點眼劑中山梨酸或其鹽之含量， 點眼劑所要求之保存效力、抑 ”有作為 而言，重要的是0.㈣.2w/v%，進而佳為G抓G :面 尤佳為 0.05〜0.2 w/v%。 V/〇 ’ I53907.doc 201143763 作為本發明中所使用之（c)硼酸或其鹽，可列舉硼酸、硼 酸鈉、硼酸鉀等硼酸鹼金屬鹽、硼砂。其中，較佳為併用 棚酸及侧砂。 關於本發明點眼劑中硼酸或其鹽之含量，就藉由與山梨 酸或其鹽併用而實現之保存效力之增強作用、氰鈷胺素之 穩定性、安全性及使用感之方面而言，重要的是〇 〇 w/ν%，較佳為 本毛月中所使用之（D)乙二胺四乙酸或其鹽係藉由與硼 酸或其鹽併用而具有氰鈷胺素之穩定性及山梨酸或其鹽之 保存效力之增強作用。作為乙二胺四乙酸之鹽，可列舉乙 二胺四乙酸鈉、乙二胺四乙酸鉀等乙二胺四乙酸鹼金屬鹽。 關於本發明點眼劑中乙二胺四乙酸或其鹽之含量，就氰 始胺素之穩定性、上述保存效力之增強作用、安全性及使 用感之點而言’重要的从㈣2 w/v%，進而佳為⑽〜〇 2 w/v%’ 尤佳為〇.〇4〜〇.i5w/v〇/。。 =而，本發明點眼劑可藉由併用（丑）牛磺酸及/或（f)硫酸 軟=納而確保氰姑胺素之穩定性、改善使用感。牛橫酸 篁較佳為0.05〜1.0 w/v%，尤佳為〇」〜〇 5 w/v%。硫酸 軟^素鈉之含量較佳為G㈣5 w/v%，尤佳為〇卜〇 $ 尤佳為併用牛續酸及硫酸軟骨素鈉。 又本發明之點眼劑中可調配其他藥效成分，例如甘草 酸-：、ε-胺基己酸、尿囊素、奠磺酸鈉、硫酸鋅等消炎 劑/素腺嘌呤雙核苷酸鈉、吡哆醇鹽酸鹽、泛醇等維生 素類，L-天冬胺酸鉀等胺基酸類等。於調配該等有效成分之 153907.doc 201143763 情形時，必須考慮製劑設計以不對敕 双式隱形眼鏡造成影響》 又，除此之外，本發明之點眼劑中亦 調配例如氯化鉀、 氣化鈣、氣化鈉、碳酸氫鈉、碳醆鋼、 久α夂坰、乾燥碳酸鈉、硫酸 鎮等無機鹽’磷酸氫鈉、磷酸二氫鈉 乳納、磷酸二氫鉀、檸檬 酸、榖胺酸等緩衝劑；聚乙^㈣相、經 乙基纖維素、玻尿義、甲基纖維素1聚糖等增稠劑， 甘油、葡萄糖、D-甘露醇、D-山梨醇、海藻糖等之等張劑， 乙醇、丙二醇等溶解助劑’亞硫酸氫納、亞硫酸鈉、硫代 硫酸鈉等穩定劑，L·薄荷腦等清㈣卜再者，《維持氛钻 胺素之穩定性或保存效力，較佳為不調配聚氧乙烯氫化萬 麻油、聚山梨醇酯等非離子性界面活性劑，或限於少量而 調配。 本發明之點眼劑較佳為以水溶液之形態製成點眼液，亦 可調配pH調整劑。作為pH調整劑，可使用氫氧化鈉或氫氧 化鉀等。關於本發明之點眼劑之pH值，就氰鈷胺素之穩定 性及使用感之點而言’較佳為5 5〜7 5，尤佳為5.8〜6.8。 [實施例] 以下列舉實施例對本發明加以更詳細說明。 試驗例1 按照常法使實施例1〜4及比較例卜丨3之調配成分溶解於 純化水中’製備各點眼劑，以無菌方式填充至塑膠製點眼 谷器中’將所得者作為試驗樣品。按照以下之試驗法，對 各樣品之「刺痛感之程度」、「眼疲勞之減輕效果」及「保 存效力試驗」進行試驗。 153907.doc 201143763 (試驗法） 使8位佩戴軟式隱形眼鏡之試驗對象1天佩戴鏡片丨〇小時 以上’當眼睛感到疲勞時丨次點眼1至2滴，點眼次數以1天8 次為上限’點眼間隔係隔開1小時以上，點眼後休息丨〇分 鐘。點眼後立即評價「刺痛感之程度」，點眼丨0分鐘後評價 「眼疲勞之減輕效果」。評價基準如下。 (評價基準） 「刺痛感之程度」 1 :刺痛 2 :稍許刺痛 3 :略微刺痛 4 :幾乎不刺痛 5 :完全不刺痛 「眼疲勞之減輕效果」 1 :眼疲勞幾乎未改善 2 :眼疲勞略微改善 3 :眼疲勞稍許改善 4 :眼疲勞改善 5 :眼疲勞頗為改善 眼疲勞之減輕效果係根據8位試驗對象之評分之平均值 如以下般進行評價，結果示於表i。 「8位試驗對象之評分之平均值」 X : 1以上〜小於2 △ : 2以上〜小於3 153907.doc 201143763 〇：3以上〜小於4 ◎ : 4以上 又’按照日本藥典之參考資訊保存效力試驗對各點眼劑 確認保存效力》 (保存效力試驗法） 保存效力係依據日本藥典第十五次修訂版之保存效力試 驗法進行評價。作為試驗菌，使用大腸桿菌（Escherichia coli)、綠膿桿菌（pseU(jomonas aeruginosa)、金黃色葡萄球 菌（Staphylococcus aureus)之細菌類及念珠菌（Candida albicans)、黑鍾菌（Aspergillus niger)之真菌類，根據以下之 評價基準評價各點眼劑之保存效力。 (評價基準） 〇 :所有細菌類於培養2週後之菌數之比例下降至小於接 種菌數之0.1%，且所有真菌類於培養2週後之菌數之比例與 接種菌數相比較下降之情形。 △.細菌類中，培養2週後之菌數之比例未達到小於接種 菌數之0· 1 /〇者有1個菌種以上，但其菌數比例下降至小於 之睛形，或者對真菌類培養2週後之菌數超過與接種菌 數相同之水準者不存在，與該水準相比較未下降者有丨個菌 種以上之情形。 、、田菌類中，培養2週後之菌數比例未下降至小於接種 菌數之1%者冑1個菌種以上之情形；或者對真菌類培養：週 後之菌數比例超過接種菌數之水準者有W菌種以上之情形。 結果示於表1。 153907.doc 201143763 ro 0.125] 〇.〇1 I 卜 〇 適量 0.05 I I 0.05 I 0.005 I 0.005 I 〇.〇1 I 00 〇 Ο < X 〇 (N ο 00 〇 適量 0.05 0.45 0.08 ο < < X ο 〇 VO 適量| 〇 〇 〇 ο 寸 ν〇 X < 〇 Ο VO 〇 適量| 〇 0.55 0.05 ο X X 〇 | 0.006 I 〇 (N 〇 適量 10.05 I 10.55 | 0.05 | ο 00 ν〇 〇 〇 X 00 ί 0.006 1 00 〇 適量 | 0.05 j m 〇 | 0.05 I 00 〇 〇 X 比較例 卜 0.02 適量 〇 o c5 m 〇 〇 X 0.01 CN 適量| 0.15 00 〇 〇 X 0.01 寸 〇 適量 〇 m 〇 0.05 ο 00 〇 < X 寸 0.006] 〇〇 〇 適量1 0.0051 m ο | 0.05] 0.02^ 00 〇 < X m 0.006 | 〇 適量 | 0.25 1 CN Ο < X 〇 (N 0.006 (Ν 適量 | 0.05 | m c> [0.05 j Ο 00 ν〇 < X 〇 0.02 (Ν 適量| 〇 (N 〇 o cn ο m νο <! X 〇 實施例 寸 | 0.004 | 適量 d o o ο \ό < 〇 〇 m 0.006 | 〇〇· ο 適量 | 0.05 ] m O 1 0.05 1 Τ—Η Ο 00 ν〇 〇 〇 〇 CN 0.02 VO 適量| 〇 r—H o o ο m νο ◎ 〇 〇 r—H 0.01 (Ν 適量 0.04 0.15 0.08 00 〇 〇 〇 成分(w/v%) 氰鈷胺素 牛磺酸 硫酸軟骨素鈉 甘草酸二钟 °比哆醇鹽酸鹽 硼酸 硼砂 聚氧乙烯聚氧丙烯二醇 聚氧乙稀氫化蓖麻油60 . L-薄荷腦 d_掉腦 磷酸二氫鈉 填酸氮納 氫氧化鈉 乙二胺四乙酸鈉 氯化納 氯化鉀 山梨酸 山梨酸鉀 pH值 眼疲勞之減輕效果 刺痛感之程度 保存效力試驗 153907.doc -11 - 201143763 根據表1明顯確認到，藉由在氰鈷胺素中調配一定量之山 梨酸或其鹽、硼酸或其鹽及乙二胺四乙酸或其鹽，可獲得 刺痛感之程度較少且具有眼疲勞之減輕效果及充分之保存 力的點眼劑。 試驗例2 按照常法使實施例5〜11及比較例14〜16之調配成分溶解 屯化水中，製備各點眼劑，以無菌方式填充至塑膠製點 眼容器中’將所得者作為試驗樣品。按照以下之試驗法， 對各樣品之「刺痛感之程度」及「異物感」進行調查。 (試驗法） 鏡片’進行點 異物感」。評價 使8位佩戴軟式隱形眼鏡之試驗對象佩戴 眼。點眼後立即評價「刺痛感之程度」及「 基準如下。 (評價基準） 「刺痛感之程度 1 :刺痛 2:稍許刺痛 3 :略微刺痛 4 :幾乎不刺痛 5 :完全不刺痛 異物感」 1 :感覺到異物感 2 :稍許感覺到異物感 3 :略微感覺到異物感 153907.doc •12· 201143763 4 :幾乎感覺不到異物感 5:完全感覺不到異物感 刺痛感之程度及異物感係根據8名試驗對象之評分之平 均值如以下般進行評價，結果示於表2。 「8位試驗對象之評分之平均值」 X : 1以上〜小於2 △ : 2以上〜小於3 〇：3以上〜小於4 ◎ : 4以上 153907.doc -13- 201143763 ι〇 ο tt㈣ 倒 (Ν 〇 〇 〇 s c5 φ| 帘 KTi ο »/Ί »—Μ c> 〇 〇 寸 X 〇 yri <N c5 Ο Ο 卜 ο tt(&l S 〇 S 〇 S 〇 d 〇 〇 o o 00 ο (N X 〇 寸 S o 寸 ο o φ| ο ο (N 〇 〇 m ^ό X X τ^Η g o vq ♦t ο Ο cn ^ό 〇 < 〇 o o <Ν φ4 o ο Μ d> 00 〇 < ON o o uo CN ♦1 g o ο g ο 00 in 〇 〇 oo o o in ο (Ν ^-Η ΦΙ 智 g o ο g ο 00 vi 〇 〇 卜 ^D o o (Ν Ο s Ο οο ο φΐ s o cn ο S ο 00 ^0 ◎ 〇 s o Ο Ο ν〇 〇Η ο 1·^ ο r™H m ^d ◎ ◎ r-H c5 <η ο m ο CN 1—4 ♦1 智 o ^η ί—Η <ό g ο 00 yn 〇 ◎ > 苍 φρ 物< m Ί 额 额 f 键 f Ρ W 鮏 Ί tO 〇 Ό taS ；〇 0 敏 漆 *5 鉍 犟 μ _ t τΐ) ves tO s 绪 Ί N〇 ；〇 签 蘇 潜 雜 Ψ tO 制 ί4 p( 怒 奪 m « 怒 Μ 茶 雄 % 迴 X Dh 燦 荽 wlc -14- 153907.doc 201143763 由表2可確認’本發明之點眼劑之刺痛感之程度及異物感 較少而使用感良好。特別可確認，若調配牛績酸及硫酸軟 骨素納，則该等效果變顯著。 I53907.doc -15-[Non-Patent Document 1] General Pharmaceutical Manufacturing (Import) License Standard 2000 Edition, JIHO 153907.doc 201143763 [Non-Patent Document 2] Japanese Journal of Contact Lens Society 35: 178-182, 1993 [Summary of the Invention] [Invented Solution to Problem] An object of the present invention is to provide an eyedrop containing a cyanocobalamin which is useful for reducing eye fatigue and which can be used when wearing a soft contact lens. [Technical means for solving the problem] Therefore, the present inventors have developed an eyedrop agent containing cyanocobalamin which can be used for wearing a soft contact lens and which has a function of reducing eye fatigue, and an eyedrop agent for a soft contact lens. The effect (the lens accumulation of the drug or the deformation of the lens, etc.), the interaction with the preservative, the feeling of use, and the reduction of the eye fatigue are indicators, and the formulation of the eyedrops which can also be used when wearing the soft contact lens is designed. In an effort to study, it has been found that a sorbic acid or a salt thereof as a preservative is formulated in a specific amount in cyanocobalamin, and a boric acid or a salt thereof and ethylenediaminetetraacetic acid or a compound thereof can be formulated in a specific amount. Salt, an eye drop agent which achieves all of the above indexes can be obtained, thereby completing the present invention. That is, the present invention provides an eye drop agent which can be used when wearing a soft contact lens, which comprises (A) cyanocobalamin, (B) sorbic acid or its salt 〇〇2 to 〇2 w/v%, ( C) caudate acid or its salt 〇 5~2〇w/v%, and (D) ethylenediaminetetraacetic acid or its salt 0.01~0.2 w/v%. [Effects of the Invention] Since the eyedrops of the present invention contain cyanocyanin, the effect of reducing eye fatigue is excellent, and the use of the soft contact lens does not affect the soft contact lens. According to the present invention, for the first time, 153907.doc 201143763 an eyedrop containing cyanocobalamin which can be used when wearing a soft contact lens can be provided. Further, in the case where taurine and chondroitin sulfate are formulated in the eye drops of the present invention, "the eyedrops having a better feeling of use are used." [Embodiment] The eyedrop agent of the present invention contains (A) sphingosine, (B) sorbic acid or a salt thereof, 0. 02 to 0_2 w/v%, (C) a butterfly acid or a salt thereof, 5 to 2 〇 Wv%, and (d) ethylenediaminetetraacetic acid or a salt thereof is 0.01 to 0.2 w/v%. (A) Cyanocobalamin is also known as one of the water-soluble vitamins of vitamin b2, which is known to have an eye fatigue treatment effect. Eyedrops containing serotonin have been made for people's but must be recognized as not affecting soft contact lenses and safe to use 'the point of serotonin that can be used when wearing soft contact lenses Eye drops are not known. Regarding the effect of the present invention, the amount of <a reduction in eye fatigue' is preferably 0.004 to 0.05 w/v% in terms of the influence, safety and side effects of the soft contact lens. It is 0·006~0·〇2 w/v%. (B) sorbic acid or a salt thereof used in the present invention has a preservative effect and does not interact with a soft contact lens, and particularly when used in combination with amphotericin, does not cause stability to cyanamide Bad effects. The salt of sorbic acid is particularly preferably an alkali metal sorbate such as sodium sorbate or potassium sorbate, and sorbic acid and a salt thereof. Regarding the content of sorbic acid or a salt thereof in the eyedropting agent of the present invention, the preservation efficiency required for the eye drop agent, and the "action", it is important that it is 0. (4). 2w/v%, and further preferably G G The surface is particularly preferably 0.05 to 0.2 w/v%. V/〇' I53907.doc 201143763 The (b) boric acid or a salt thereof used in the present invention may, for example, be an alkali metal borate such as boric acid, sodium borate or potassium borate. Borax. Among them, linoleic acid and side sand are preferably used in combination. Regarding the content of boric acid or a salt thereof in the eye drop of the present invention, the preservation effect by the combination with sorbic acid or a salt thereof, the cyanide cobalt In terms of the stability, safety and feeling of use of the amine, it is important that 〇〇w/ν%, preferably used in the month of the month (D) ethylenediaminetetraacetic acid or a salt thereof In combination with boric acid or a salt thereof, it has the stability of cyanocobalamin and the reinforcing effect of the storage efficiency of sorbic acid or a salt thereof. As the salt of ethylenediaminetetraacetic acid, sodium edetate or ethylenediamine is mentioned. An alkali metal salt of ethylenediaminetetraacetic acid such as potassium acetate. Ethylenediaminetetraacetic acid or a salt thereof in the eyedrop of the present invention The content, in terms of the stability of cyanogenic amine, the enhancement of the above-mentioned preservation efficacy, the safety and the sense of use, are important from (4) 2 w/v%, and thus preferably (10) to 〇2 w/v%'.佳为〇.〇4~〇.i5w/v〇/. =, and the eyedrop of the present invention can ensure cyanocyanin by using (ugly) taurine and/or (f) sulfuric acid soft = nano The stability and the feeling of use are improved. The lanthanum lanthanum is preferably 0.05 to 1.0 w/v%, and more preferably 〇"~〇5 w/v%. The content of sodium sulphate is preferably G (four) 5 w / v%, especially preferably 〇 〇 尤 尤 尤 尤 尤 尤 尤 尤 尤 尤 尤 尤 尤 。 。 。 。 。 。 。 。 。 。 。 。 。 Further, the eyedrop agent of the present invention may be formulated with other medicinal ingredients, such as glycyrrhizic acid-:, ε-aminohexanoic acid, allantoin, sodium sulfonate, zinc sulfate, etc., an anti-inflammatory agent/adenine dinucleotide sodium And vitamins such as pyridoxine hydrochloride and panthenol, and amino acids such as L-aspartate. In the case of 153907.doc 201143763 in which the active ingredients are formulated, the formulation design must be considered so as not to affect the double-contact lens. In addition, in addition, the eye drops of the present invention are also formulated with, for example, potassium chloride and gas. Calcium, gasified sodium, sodium bicarbonate, carbon steel, long-term α夂坰, dry sodium carbonate, sulfuric acid and other inorganic salts 'sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate, citric acid, cesium Buffering agent such as amine acid; thickening agent such as polyethylene (tetra) phase, ethyl cellulose, hyaluronic acid, methyl cellulose 1 glycan, glycerin, glucose, D-mannitol, D-sorbitol, trehalose Such as isotonic agent, alcohol, propylene glycol and other dissolution aids such as sodium bisulfite, sodium sulfite, sodium thiosulfate and other stabilizers, L · menthol and other clear (four) Bu, "maintain the stability of astringentamine or The storage efficiency is preferably not formulated with a nonionic surfactant such as polyoxyethylene hydrogenated perylene oil or polysorbate, or limited to a small amount. The eye drop agent of the present invention is preferably made into an eye drop in the form of an aqueous solution, and may also be formulated with a pH adjuster. As the pH adjuster, sodium hydroxide, potassium hydroxide or the like can be used. The pH of the eyedropting agent of the present invention is preferably from 5 5 to 7 5, particularly preferably from 5.8 to 6.8, in terms of stability and feeling of use of cyanocobalamin. [Examples] Hereinafter, the present invention will be described in more detail by way of examples. Test Example 1 The formulation components of Examples 1 to 4 and Comparative Example 3 were dissolved in purified water according to a usual method. Each eyedrop was prepared and aseptically filled into a plastic dot-eye barn. sample. The "stinging degree", "eye fatigue reduction effect" and "preservation effectiveness test" of each sample were tested according to the following test methods. 153907.doc 201143763 (Test method) 8 subjects wearing soft contact lenses wear lenses for more than 1 hour. 'When the eyes are tired, 1 to 2 drops are taken, and the number of eye points is 8 times a day. The upper limit 'eye-to-eye interval is separated by more than 1 hour, and the eye is rested for a minute. Immediately after the eye, the "degree of tingling sensation" was evaluated. After 0 minutes, the "reduction effect of eye fatigue" was evaluated. The evaluation criteria are as follows. (Evaluation Criteria) "The degree of tingling" 1 : Stinging 2: Slightly tingling 3: Slightly tingling 4: Almost no tingling 5: No tingling at all "Reducing effect of eye fatigue" 1 : Eye fatigue is almost Improvement 2: slight improvement in eye fatigue 3: slight improvement in eye fatigue 4: improvement in eye fatigue 5: eye fatigue is quite effective in improving eye fatigue. The average of the scores of the eight subjects was evaluated as follows. Table i. "Average of the scores of the eight test subjects" X : 1 or more ~ less than 2 △ : 2 or more ~ less than 3 153907.doc 201143763 〇: 3 or more ~ less than 4 ◎ : 4 or more 'According to the Japanese Pharmacopoeia reference information preservation effect The test confirms the preservation efficacy for each ophthalmic agent" (preservation efficacy test method) The preservation effect is evaluated according to the preservation efficacy test method of the fifteenth revised edition of the Japanese Pharmacopoeia. As test bacteria, Escherichia coli, PseU (jomonas aeruginosa), Staphylococcus aureus bacteria, Candida albicans, and Aspergillus niger fungi were used. For the class, the preservation efficacy of each eyedrop was evaluated according to the following evaluation criteria. (Evaluation criteria) 〇: The proportion of bacteria in all bacteria after 2 weeks of culture decreased to less than 0.1% of the number of inoculated bacteria, and all fungi were The ratio of the number of bacteria after 2 weeks of culture decreased compared with the number of inoculated bacteria. △. In the bacteria, the proportion of the number of bacteria after 2 weeks of culture did not reach 0. 1 / 1 of the number of inoculated bacteria. More than the strain, but the proportion of the bacteria decreased to less than the shape of the eye, or the number of bacteria after the fungus culture for 2 weeks exceeded the same level as the number of inoculated bacteria did not exist, compared with the level did not decline In the case of above-mentioned strains, the proportion of bacteria in the field of bacteria after 2 weeks of culture does not fall to less than 1% of the number of inoculated bacteria, or more than one species; or culture of fungi: weeks after bacteria Number ratio The number of inoculated bacteria exceeds the number of W strains. The results are shown in Table 1. 153907.doc 201143763 ro 0.125] 〇.〇1 I Bu 〇 amount 0.05 II 0.05 I 0.005 I 0.005 I 〇.〇1 I 00 〇Ο < X 〇 (N ο 00 〇 量 0.05 0.45 0.08 ο << X ο 〇 VO 适 | 〇〇〇ο 〇 〇 〇 X < 〇Ο VO 〇 | | 〇 0.55 0.05 ο XX 〇 | 0.006 I 〇 (N 〇 quantity 10.05 I 10.55 | 0.05 | ο 00 ν〇〇〇X 00 ί 0.006 1 00 〇 量 | 0.05 jm 〇 | 0.05 I 00 〇〇X Comparative example 0.02 适 〇o c5 m 〇〇X 0.01 CN 适量 | 0.15 00 〇〇X 0.01 inch 〇 〇 〇m 〇0.05 ο 00 〇< X inch 0.006] 〇〇〇 量 1 0.0051 m ο | 0.05] 0.02^ 00 〇< X m 0.006 | 〇 量 | 0.25 1 CN Ο < X 〇 (N 0.006 (Ν Appropriate | 0.05 | m c> [0.05 j Ο 00 ν〇< X 〇0.02 (Ν Appropriate amount | (N 〇o cn ο m νο <! X 〇 Example inch | 0.004 | Appropriate amount doo ο \ό < 〇〇m 0.006 | 〇〇· ο Appropriate amount | 0.05 ] m O 1 0.05 1 Τ—Η Ο 00 ν 〇〇〇〇CN 0.02 VO Appropriate amount | 〇r—H oo ο m νο ◎ 〇〇r—H 0.01 (Ν Appropriate amount 0.04 0.15 0.08 00 〇〇〇 Ingredient (w/v%) Cyanocobalamin Taurine Sulfate Cartilage Sodium gluconic acid two minutes ° 哆 哆 盐 硼 硼 borate borax polyoxyethylene polyoxypropylene diol polyoxyethylene hydrogenated castor oil 60 . L-menthol d_ cerebral dihydrogen phosphate sodium hydride Sodium ethoxide diacetate sodium chloride sodium chloride potassium sorbate potassium sorbate pH eye fatigue reduction effect tingling degree preservation efficacy test 153907.doc -11 - 201143763 Obviously confirmed according to Table 1, by When a certain amount of sorbic acid or a salt thereof, boric acid or a salt thereof, and ethylenediaminetetraacetic acid or a salt thereof are blended in cyanocobalamin, the degree of tingling sensation is small, and the eye fatigue reduction effect and sufficient preservation power are obtained. Eye drops. Test Example 2 The formulation components of Examples 5 to 11 and Comparative Examples 14 to 16 were dissolved in deuterated water according to a usual method, and each eyedrop was prepared and filled aseptically into a plastic eye container. The obtained one was used as a test sample. . The "degree of tingling" and "foreign sensation" of each sample were investigated according to the following test methods. (Test method) The lens was subjected to a foreign body sensation. Evaluation Eight subjects wearing soft contact lenses were worn on the eyes. Immediately after the eye, the "degree of tingling" and "the benchmark are as follows. (Evaluation criteria)" "Level of tingling 1: Tilting 2: Slightly tingling 3: Slightly tingling 4: Almost no tingling 5: Complete No tingling foreign body sensation 1 : Feeling foreign body sensation 2 : Slightly sensation of foreign body sensation 3 : Slightly sensation of foreign body 153907.doc •12· 201143763 4 : I can hardly feel foreign body sensation 5: I can not feel foreign body sensation completely The degree of pain and the foreign body sensation were evaluated based on the average of the scores of the eight test subjects as follows. The results are shown in Table 2. "Average of the scores of the eight test subjects" X : 1 or more ~ less than 2 △ : 2 or more ~ less than 3 〇 : 3 or more ~ less than 4 ◎ : 4 or more 153907.doc -13- 201143763 ι〇ο tt (4) Down (Ν 〇〇〇s c5 φ| Curtain KTi ο »/Ί »—Μ c> 〇〇 inch X 〇yri <N c5 Ο Ο ο tt (&l S 〇S 〇S 〇d 〇〇oo 00 ο ( NX S S o ο ο N N N N N N N N N N v φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ON oo uo CN ♦1 go ο g ο 00 in 〇〇oo oo in ο (Ν ^-Η ΦΙ 智 go ο g ο 00 vi 〇〇 ^ ^D oo (Ν Ο s Ο οο ο φΐ so cn ο S ο 00 ^0 ◎ 〇so Ο Ο ν〇〇Η ο 1·^ ο rTMH m ^d ◎ ◎ rH c5 <η ο m ο CN 1—4 ♦1 智o ^η ί—Η <ό g ο 00 yn 〇 ◎ >苍φρ物< m Ί Amount f key f Ρ W 鮏Ί tO 〇Ό taS ;〇0 Sensitive paint *5 铋_ t τΐ) ves tO s Ί Ί N〇; 〇 sign Su Qian Ψ tO system ί4 p ( 怒 夺 m « Μ Μ 雄 雄 回 X X D D D D D D D D D D D 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 It is confirmed that the degree of tingling sensation of the eyedrop of the present invention and the feeling of foreign body are small, and the feeling of use is good. In particular, it has been confirmed that when bovine acid and chondroitin sulfate are blended, these effects become remarkable. I53907.doc - 15-