TW201100071A

TW201100071A - Ophthalmic composition and vitamin A stabilization method

Info

Publication number: TW201100071A
Application number: TW98121635A
Authority: TW
Inventors: Nobuhito Tabuchi; Chieko Inoue; Manabu Hattori; Miyuki Miyake; Hazuki Fukuoka
Original assignee: Lion Corp
Priority date: 2009-06-26
Filing date: 2009-06-26
Publication date: 2011-01-01
Also published as: TWI429424B

Abstract

This invention provides an ophthalmic composition containing: (A) more than 50,000 units/100 ml vitamin A, (B) ophthalmic 0.4 W/V% polyethylene oxide (PEO) and polyoxypropyleneglycol (PPG), and (C) trometamol. By this way, the stability of vitamin A with high concentration is significantly increased to effectively cure cornea damage, keratoconjunctivitis sicca (KCS) or dry eye syndrome (DES), and to reduce the irritation to eyes. The best mass ratio of the (B) 0.4 W/V% of Polyethylene oxide (PEO) and Polyoxypropyleneglycol (PPG) to the (C) trometamol is 1:10 to 3:1.

Description

201100071 六、發明說明：【發明所屬之技術領域】本發明係有關含有高濃度維生素A之眼科用組成物。【先前技術】維生素A係作爲預防、治療角膜、結膜、皮膚黏膜之角化症等之有效成份倍受囑目。另外，脂溶性維生素之維 Q 生素A對於空氣、光、熱、酸、金屬離子等極爲敏感，特別是於水溶液中極不穩定，因此極不易穩定配合於點眼劑等之眼科用組成物。作爲將此不穩定之維生素A進行穩定化技術者，先行技術中，被揭示有：以聚乙烯硬化蓖麻子油等之非離子界面活性劑（如：特開平5-331056號公報：專利文獻1)、疏水性抗氧化劑之維生素E類進行穩定化之方法（如：特開平6-247853號公報：專利文獻2)、及由容器、包裝面 Q 之穩定化技術（如：特開平6-40907號公報：專利文獻3 、特開2003- 1 1 3078號公報：專利文獻4)、藉由高能量乳化所製造之穩定化技術（如：特開2002-332225號公報 :專利文獻5 )。惟，先行技術中，於高濃度系（50,000 單位以上）時，並無法充分滿足醫藥品水準所需要之穩定性。因此，被期待一種配合高濃度維生素A之眼科用組成物中，進一步提昇維生素A安定化之技術。〔特許文獻1〕特開平5 -3 31056號公報〔特許文獻2〕特開平6-247853號公報 201100071 〔特許文獻3〕特開平6-40907號公報〔特許文獻4〕特開2003- 1 1 3078號公報〔特許文獻5〕特開2002-332225號公報【發明內容】本發明鑑於上述課題而提供一種使維生素A進行安定化之配合高濃度維生素A之眼科用組成物，及維生素a 之安定化方法爲目的。本發明者，爲達成該目的而進行精密硏討後，結果發現，於含有50,000單位/100 mL以上之維生素A之眼科用組成物中，配合0.4 W/V%以上之聚氧化乙烯聚氧化丙烯二醇與trometamoI後，可明顯提昇維生素A之安定性，進而完成本發明。因此，本發明係提供一種下述之眼科用組成物及維生素A之安定化方法。〔1〕含有（A) 50,000單位/100 mL以上之維生素A 與（B ) 0.4 W/V%以上之聚氧化乙烯聚氧化丙烯二醇’以及（C) trometamol之眼科用組成物。〔2〕（A)成份之含量爲1〇〇,〇〇〇單位/100 mL以上之〔1〕所載之眼科用組成物。〔3〕（A)成份之含量爲200,000單位/1〇〇 mL以上之〔1〕所載之眼科用組成物。〔4〕（A)成份之含量爲300,000單位/1〇〇 mL以上之〔1〕所載之眼科用組成物。 -6- 201100071 〔5〕進一步含有（D)抗氧化劑之〔1〕所載之眼科用組成物。〔6〕（D)成份爲維生素E及/或二丁基羥基甲苯之〔5〕所載之眼科用組成物。〔7〕（A)成份爲維生素A棕櫚酸酯、維生素A乙酸酯或維生素A酸之〔1〕所載之眼科用組成物。〔8〕 ( B ) ： ( C )所代表之（B )成份與（C )成份 Q 之質量比爲1: 30~30: 1之〔1〕所載之眼科用組成物。〔9〕於含有50,000單位/100 mL以上之維生素A之眼科用組成物中，配合0.4 W/V%以上之聚氧化乙烯聚氧化丙嫌二醇、與（C) trometamol者爲其特徵之維生素A 之安定化方法。藉由本發明，即使配合高濃度之維生素A，仍可提供一種使維生素A安定化之含有維生素A之眼科用組成物，及維生素A之安定化方法。〇【實施方式】〔發明實施之最佳形態〕以下，針對本發明進行詳細說明。本發明之眼科用組成物係含有（A) 50,000單位/100 mL以上之維生素A與 (B ) 0.4 W/V%以上之聚氧化乙烯聚氧化丙烯二醇、與（ C) trometamol。另外，更作爲本發明之另一課題者係提供一種具有改善乾眼症效果之眼科用組成物，本發明更有另一效果爲改善乾眼症之效果。 201100071201100071 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to an ophthalmic composition containing a high concentration of vitamin A. [Prior Art] Vitamin A is attracting attention as an effective ingredient for preventing and treating cornea, conjunctiva, and keratosis of the skin and mucous membranes. In addition, vitamin A, a fat-soluble vitamin, is extremely sensitive to air, light, heat, acid, metal ions, etc., and is extremely unstable in an aqueous solution, so that it is extremely difficult to stably mix an ophthalmic composition such as an eye drop. . As a technique for stabilizing the unstable vitamin A, a non-ionic surfactant such as a hardened castor oil such as polyethylene is disclosed in the prior art (for example, Japanese Patent Publication No. Hei 5-331056: Patent Document 1 A method for stabilizing a vitamin E type of a hydrophobic antioxidant (for example, JP-A-6-247853: Patent Document 2), and a stabilization technique by a container and a packaging surface Q (e.g., JP-A-6-40907) Japanese Patent Laid-Open Publication No. JP-A-2002-332225 (Patent Document 5). However, in the advanced technology, when the high concentration system (50,000 units or more) is used, the stability required for the pharmaceutical level cannot be sufficiently satisfied. Therefore, it is expected that an ophthalmic composition containing a high concentration of vitamin A can further enhance the technology of vitamin A stabilization. [Patent Document 1] Japanese Laid-Open Patent Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. In view of the above problems, the present invention provides an ophthalmic composition containing a high concentration of vitamin A, which stabilizes vitamin A, and a stabilization of vitamin A. The method is for the purpose. The present inventors have found that, in order to achieve the object, it is found that a polyoxyethylene polyoxypropylene of 0.4 W/V% or more is blended in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A. After the diol and trometamo I, the stability of vitamin A can be remarkably improved, and the present invention is completed. Accordingly, the present invention provides an ophthalmic composition and a method for stabilizing vitamin A. [1] An ophthalmic composition containing (A) 50,000 units/100 mL or more of vitamin A and (B) 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol diol and (C) trometamol. [2] (A) The ophthalmic composition contained in [1], the content of which is 1 〇〇, 〇〇〇 unit / 100 mL or more. [3] (A) The ophthalmic composition contained in [1] of the component content of 200,000 units / 1 〇〇 mL or more. [4] (A) The ophthalmic composition contained in [1] of the component content of 300,000 units / 1 〇〇 mL or more. -6- 201100071 [5] Further comprising the ophthalmic composition contained in (D) the antioxidant [1]. [6] (D) The ophthalmic composition contained in vitamin E and/or dibutylhydroxytoluene [5]. [7] The component (A) is an ophthalmic composition contained in [1] of vitamin A palmitate, vitamin A acetate or vitamin A acid. [8] (B): The mass ratio of (B) represented by (C) to (C) component Q is 1:30~30:1 [1]. [9] In an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A, a vitamin of 0.4 W/V% or more of polyoxyethylene polyoxypropylene propylene glycol and (C) trometamol A method of stabilization. According to the present invention, even if a high concentration of vitamin A is blended, an ophthalmic composition containing vitamin A which stabilizes vitamin A and a method for stabilizing vitamin A can be provided. [Embodiment] [Best Mode for Carrying Out the Invention] Hereinafter, the present invention will be described in detail. The ophthalmic composition of the present invention contains (A) 50,000 units/100 mL or more of vitamin A and (B) 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol, and (C) trometamol. Further, as another subject of the present invention, an ophthalmic composition having an effect of improving dry eye is provided, and another effect of the present invention is to improve the effect of dry eye. 201100071

(A) 維生素A 作爲維生素A者，除維生素A本身之外，如：維生素 A油等之含有維生素A之混合物、維生素A脂肪酸酯等之維生素A衍生物等例。具體而言如：維生素A棕櫚酸酯、維生素A乙酸酯、維生素A、維生素A酸、retinoid等例。其中又以維生素A棕櫚酸酯、維生素A乙酸酯、維生素A酸爲較佳者。維生素A棕櫚酸酯通常市售者爲100 萬〜180萬國際單位（以下以單位或I.U.記之），具體例如 :羅氏、維生素、日本股份公司製「棕櫚酸維生素A」（ 170 萬 I.U./g)等例。 (A)成份可單獨使用1種，或適當組合2種以上使用，其含量對於眼科用組成物總量而言，爲50,000單位 /100 mL以上。維生素A係具有治療角膜、結膜損傷之效果，改善乾眼症、改善眼睛疲勞、視力模糊之效果，作成 50,000單位/100 mL以上後，可更明顯發揮此等效果。由此等效果面視之，（A)成份之量爲100,000單位/100 mL 以上者宜，較佳者爲200,000單位/100 mL以上，更佳者爲300,000單位/100 mL以上。由穩定性之面視之，上限爲500,000單位/100 mL以下者宜。上述之量以W (質量 )/V (體積）％ ( g/100 mL )代表後，依所配合之維生素 A之單位而異，一般爲0.03〜0.3 W/V%者宜。 (B) 聚氧化乙烯聚氧化丙烯二醇 -8 - 201100071 本發明中，使用（B)聚氧化乙烯聚氧化丙烯二醇後，含有500, 〇〇〇單位/100 mL以上之維生素A之眼科用組成物，仍可維持其穩定性’同時對於眼睛之刺激性亦少’ 可提昇角膜損傷之治療及治療乾眼症之效果。此等效果如 :常用於點眼劑之山梨聚糖脂肪酸酯’聚氧化乙烯硬化蓖麻子油等之界面活性劑中並不足。聚氧化乙烯聚氧化丙烯二醇並未特別受限，可使用醫藥品添加物規格（醫藥品添 ¢) 加物規格）所載者。環氧乙烷之平均聚合度爲4〜200者宜，20〜200更佳，環氧丙烷之平均聚合度爲5~100者宜，更佳者爲20~70，可爲嵌段共聚物，亦可爲無規聚合物。具體而言如，聚氧化乙烯（200 )聚氧化丙烯（7〇 ) 二醇：Lutrol F127 ( BASF 製）、Unilub 70 DP-950B (日油（股份）製）等，聚氧化乙烯（12〇 )聚氧化丙烯（40 )二醇（Prulonic F-87 )、聚氧化乙烯（160 )聚氧化丙嫌（30)二醇（Prulonic F-68、別名 Polocthamer 188): Q Pronon #188P (日油（股份））等、聚氧化乙烯（42)聚氧化丙稀（67)二醇（Prulonic P123、別名 Polocthamer 403 )、聚氧化乙烯（54 )聚氧化丙烯（39 )二醇（ PrulonicP85) : Pronon#235P (日油（股份））等、聚氧化乙烯（20)聚氧化丙烯（20)二醇（Prulonic L-44)、 tetronic等例。其中又以聚氧化乙烯（200 )聚氧化丙烯（ 70)二醇、聚氧化乙烯（160)聚氧化丙烯（30)二醇、聚氧化乙烯（54)聚氧化丙烯（39)二醇爲較佳者。 (B)成份可單獨使用1種或適當組合2種以上使用 201100071 之，其含量，對於眼科用組成物總量而言，爲〇·4 w/v% 以上者宜，較佳者爲〇·4〜5 W/V%，更佳者爲〇·5~3 W/V% ，特別理想者爲〇·6〜2 W/V%，最爲理想者1〜2 W/V%。當未達0.4 W/V%時，則維生素A的可溶化變得不易’由維生素A之保存穩定性之面視之，爲5 W/V %以下者宜。由維生素A保存安定化之觀點視之，以〔（A )維生素A單位/100 mL〕/〔（B)聚氧化乙烯聚氧化丙烯二醇 g/100 mL〕所代表之（A )成份與（B )成份之比率爲 1 0,000~ 1 5 0,000者宜，較佳者爲1 5,000〜10〇,〇〇〇，更佳者爲 25,000〜50,000 。 (C ) trometamol 本發明之眼科用組成物中，由提昇維生素A之保存安定性之面視之，以添加 trometamol者宜。於 trometamol 中可提昇維生素A之保存安定性之效果係本發明的新發現。此機序並未明朗’而可由以下被推測。聚氧化乙烯聚氧化丙烯二醇係具有聚氧化乙烯（EO)鏈與聚氧化丙烯（ p〇)鏈之非離子性界面活性劑。使E〇鏈爲外側、P0鏈爲內側’包住維生素A ’形成膠粒。與trometamol共存後，存在於trometamol中之-NH2基直接與EO鍵之釀鍵鍵結，故使膠粒之構造極爲強固。trometamo1更藉由與膠粒外側之EO鏈鍵結，強固膠粒之構造後’降低自由度’其結果，降低膠粒內部之P〇鏈的分子運動性。由上述’可認定trometamol可賦予維生素A與聚氧化乙烯聚氧化丙烯 -10- 201100071 二醇所形成之膠粒的安定化，其結果亦賦予維生素A 存安定性。 (C ) trometamol之含量對於眼科用組成物總量，爲0.01〜5 W/V%者宜，較佳者爲0.05〜5 W/V%，更爲0.1〜3 W/V%，特別理想者爲0.5〜2 W/V%。當未達 W/V%時，則恐使維生素A之保存安定化效果不足，，超出5 W/V%則恐對於眼睛產生刺激感。又，由維 0 A保存安定化之觀點視之，（B) : (C)所代表之成份與（C)成份之質量比爲1 : 30~30 ; 1者宜，較爲1:20〜20:1，更佳者爲1:10〜1〇:1，最佳者爲 1 0 〜3 : 1。 (D )抗氧化劑本發明之眼科用組成物中，由提昇維生素A之保定性之面視之，以添加抗氧化劑者宜。作爲抗氧化劑〇如：d-α-生育酚、d-々-生育酚、d-r-生育酚、d-5-酚、dl-α-生育酚、乙酸d-α-生育酚、乙酸dl-α-生、乙酸dl-y3-生育酚、乙酸dl-r-生育酚、乙酸dl-育酚' 煙鹼酸dl-α-生育酚等之維生素E類、二丁基甲苯、丁基羥基茴香醚等之脂溶性抗氧化劑、維生素氫輥、半胱氨酸、谷胱甘肽等之水溶性抗氧化劑等例中又以維生素Ε等之脂溶性抗氧化劑者較佳，更佳者酸d-a-生育酚、二丁基羥基甲苯，最佳者爲乙酸d-育酚。又，倂用維生素E及二丁基羥基甲苯亦可。之保而言佳者 0.01 反之生素 (B ) 佳者 1 ：存安者， -生育育酚 5 ·生羥基 C、，其爲乙 α -生 -11 - 201100071 抗氧化劑可單獨使用1種，亦可適當組合2種以上使用之’其含量對於眼科用組成物總量而言，爲〇.〇〇5~5 W/V %者宜，於此範圍內，可進一步提昇維生素a之保存安定性’ 0.005〜1 W/V%爲較佳者，更佳者爲〇.005〜〇·2 W/V%。本發明之眼科用組成物中，在不損及本發明效果之範圍下’除上述成份之外，可配合添加於眼科用組成物中之各種成份。作爲此等成份者，如：多元醇、（B )成份以外之界面活性劑、緩衝劑 '黏稠劑' 糖類、pH調整劑、防腐劑、等張化劑、穩定化劑、清涼化劑、藥物、水等例。此等可單獨使用1種，或適當組合2種以上使用之，可適量配合。作爲多價醇者，如：甘油、丙二醇、丁二醇、聚乙二醇等例。多價醇之含量對於眼科用組成物總量而言，爲 0.0 1〜5 W/V%者宜，更佳者爲〇.〇5〜3 W/V%。亦可倂用（B )成份以外之界面活性劑，如：聚氧化乙烯硬化蓖麻子油、聚氧化乙烯山梨聚糖脂肪酸酯（聚山梨酸酯80)等例。經由倂用後，進一步提昇更安定的安定性。此等含量對於眼科用組成物總量而言，爲0.0001〜5 W/V%者宜，更佳者爲0.005〜3 W/V%。另外，由治療角膜、結膜損傷之效果，治療乾眼症之面視之，此等界面活性劑之量愈少愈好，以0.5 W/V%以下者宜。作爲緩衝劑者，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）、 -12- 201100071 酒石酸或其鹽（酒石酸鈉等）、葡糖酸或其鹽（葡糖等）、乙酸或其鹽（乙酸鈉等），其中又以倂用硼酸砂後，特別可得到高度防腐效果最爲理想。緩衝劑之對於眼科用組成物總量而言，爲0.001〜10 w/v%者宜佳者爲0.01〜5 W/V%。又，藉由配合硼酸、檸檬酸後意圖使維生素A更安定化。作爲黏稠劑者，如：聚乙烯吡咯烷酮、羥乙基纖 0 、羥丙基甲基纖維素、甲基纖維素、聚乙烯醇、玻尿、軟骨素硫酸鈉、聚丙烯酸、羧基乙烯聚合物等例。配合此等後，提高滯留性，進一步提昇治療角膜、結傷之效果。黏稠化劑對於眼科用組成物總量之含量 0.001〜10 W/V%者宜，較佳者爲0.001~5 W/V%，更佳 0.01 〜3 W/V%。作爲糖類者，如：葡萄糖、環糊精、木糖醇、山醇、甘露糖醇等例。另外，此等可任意爲D體、L 〇 DL體。糖類對於眼科用組成物總量之含量， 0.00 1~1 0 W/V%者宜，較佳者爲0.005〜5 W/V%，更佳 0.01-3 W/V%。作爲pH調整劑者，以使用無機酸或無機鹼劑者無機酸之例如：（烯）鹽酸之例。無機鹼劑之例如：化鈉、氫氧化鉀、碳酸鈉、碳酸氫鈉等例。其中又以、氫氧化鈉爲較佳。本發明之眼科用組成物之pH ( )爲4.0〜9·0者宜，較佳者爲5.0〜8.0，更佳者爲6.C 。另外，本發明中，ρ Η之測定係於2 0 °C下利用ρ Η 酸鈉、硼含量，更，可維素酸鈉藉由膜損如：者爲梨糖體或如：者爲宜。氫氧鹽酸 2 〇oc I 〜8.0 滲透 -13- 201100071 壓計（HOSM-l，東亞DKK (股份））進行之。pH調整劑對於眼科用組成物總量之含量如：0.0000 1〜10 W/V%者宜，較佳者爲〇.〇〇〇1〜51/¥%，更佳者爲0.001〜3冒/¥%。作爲防腐劑者，如：烷基二甲基苄基氯化銨、苄乙胺、山梨酸或其鹽、對羥基苯甲酸酯（對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯等）、 chlorhexidine glucenate、metilosal、苯乙醇、鹽酸垸二胺乙基甘胺酸、polyhexanide hydrochloride、polydronium chloride等例。防腐劑對於眼科用組成物總量之含量爲： 0.00001〜5 W/V%者宜，較佳者爲0.0001〜3 W/V%，更佳者爲 0.001 〜2 W/V%。另外，由治療角膜、結膜損傷之效果及改善乾眼症之面觀之，本發明中使選自烷基二甲基苄基氯化銨，苄乙銨之陽離子性界面活性劑（部份爲陽離子性防腐劑）、選自對羥基苯甲酸酯（對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯等）及氯丁醇之疏水性防腐劑之含量作成0.004 W/V%以下者宜，更佳者爲0.003 W/V%以下，未含此等，作成無添加者更爲理想。此等阻擾治療角膜、結膜損傷之效果機序雖未明朗，而可由下述推測。（B) 聚氧化乙烯聚氧化丙烯二醇係使EO鏈爲外側、PO鏈爲內側，形成包覆維生素A之膠粒。該膠粒吸附於角膜表面’ 維生素A於角膜內部被吸收。陽離子性界面活性劑經由界面活性能，又，疏水性防腐劑藉由高疏水性，改變了膠粒表面之狀態，故阻擾對於維生素A角膜的吸附，其結果被 -14- 201100071 認爲阻礙角膜、結膜損傷治療效果及乾眼症的改善。另外，山梨酸或其鹽等之親水性高者並不影響膠粒表面之狀態，因此，不會阻礙維生素A的促進吸收效果。又，上述成份爲防腐劑的一部份，而無添加防腐劑時之防腐力可配合 1種以上或適當組合2種以上之選自乙烯二胺四乙酸二鈉、硼酸及trometamol。又，作成unit doors容器，附濾器之容器時，亦可無添加防腐劑。 0 作爲等張化劑者，如：氯化鈉、氯化鉀等例。等張化劑對於眼科用組成物總量之含量爲0.001-5 W/V%者宜，較佳者爲〇.〇1~3 W/V%，更佳者爲0.1〜2 W/V%。作爲安定化劑者，如：乙烯二胺四乙酸二鈉，環糊精、亞硫酸鹽、二丁基羥基甲苯等例。另外，本發明中配合穩定化劑後，更提昇維生素A之安定性。隱定化劑對於眼科用組成物總量之含量爲〇.〇〇1~5 W/V%者宜，較佳者爲 0.01 〜3 W/V%，更佳者爲 0 1 〜2 W/V%。〇作爲清涼化劑者，如：薄荷醇、樟腦、冰片、香葉醇、沈香醇、桉樹腦等例。清涼化劑對於眼科用組成物總量之含量，以化合物總量爲0.0001-5 W/V%者宜’較佳者爲 0.001~2 W/V%，更佳者爲 0.005-1 W/V%，特別以 0.007〜0.8 W/V%爲最佳。作爲藥物（藥學的有效成份）者，可適當配合如：充血去除劑（如：鹽酸萘唑啉、鹽酸四氫化萘唑啉、鹽酸脫氫腎上腺素、腎上腺素、鹽酸麻黃素、dl-鹽酸甲基麻黃素、硝酸四氫化萘唑啉、硝酸萘唑琳等）、消炎、收歛劑（ -15- 201100071 如：甲基硫酸新斯的明、ε -胺基己酸、尿囊素、氯化小檗鹼、硫酸鋅、乳酸鋅、氯化溶菌酶、甘草酸二鉀、甘草酸錢、甘草酸、水楊酸甲酯、tranexamicacid、甘菊環磺酸鈉等）、抗組織胺劑（如：Iproheptin hydrochloride、鹽酸2-二苯甲氧基-Ν，Ν·二甲基乙胺、2-二苯甲基-N，N-二甲基乙胺、鹽酸異二苄酯、馬來酸氯苯丙胺等）、水溶性維生素（活化型維生素B2、維生素B6、維生素B12等）、胺基酸（如：L-天冬胺酸鉀、L-天冬胺酸鎂、胺基乙基磺酸、軟骨素硫酸鈉等）、硫化劑、殺菌劑（如：硫、異丙甲酣、日扁柏醇等）、抗.過敏劑（cromoglicate、 ketotifen fumarate、tranilaste 等）、局部麻醉劑（如：利多卡因、鹽酸利多卡因、鹽酸普魯卡因、鹽酸奴白卡因等 )、散瞳劑（cyclopentolate hydrochloride、tropicamide 等）、白內障治療劑（pirenoxine、谷胱甘酞等）。此等成份之含量可因應製劑之種類、藥物之種類等進行適當選擇、各種成份之含量於該技術領域中爲公知者。如：對於眼科用組成物總量而言，可由0.0001〜30 W/V% ，較佳者0.001~10 W/V%之範圍進行適當選擇。更具體者，各成份對於眼科用組成物總量之含量爲如下。充血去除劑，如：0.000 1〜0.5 W/V%者宜，較佳者爲 0·0005~0·3 W/V%，更佳者爲 0.001~0·1 W/V%。消炎·收歛劑，如：0.000 1〜10 w/ν%者宜，較佳者爲 0.000 1 〜5 W/V%。抗組織胺劑，如：0.000 1〜10 w/ν%者宜，較佳者爲 -16- 201100071 0.001 〜5 W/V%。水溶性維生素，如：0.000 1〜1 w/v%者宜，較佳者爲 0.000 1 〜0.5 W/V%。胺基酸，如：0.0001〜10 w/ν%者宜，較佳者爲 0.001 〜3 W/V%。硫化劑，殺菌劑，如：0.0 0 0 0 1 ~ 1 0 w / V %者宜，較佳者爲 0.0001 〜10 w/ν%。〇抗過敏劑，如：0.0001〜10 w/ν%者宜，較佳者爲 0.001 〜5 W/V%。局部麻醉劑、散瞳劑、白內障治療劑，如：0.001〜1 ^/乂％者宜，較佳者爲〇.〇〇5〜1\^/乂％。本發明之眼科用組成物可直接作成液劑，亦可調製成懸浮劑、凝膠劑等。作爲使用形態者，具體例如：點眼劑 (如：一般用點眼劑、隱形眼鏡用點眼劑等）、洗眼劑（一般用洗眼劑，取出隱眼鏡後所使用之洗眼劑等）、裝載〇隱形眼鏡之裝載液，取出隱形眼鏡之取出液等例。本發明之眼科用組成物爲液狀，點眼劑時，黏度爲 1〜lOOmPa . S者宜，較佳者爲1〜50mPa · S，更佳者爲 1〜30mPs· s。另外，黏度測定係於20°C下，利用E型黏度計（VISCONIC FLD-R，東京計器（股份））進行測定〇本發明之眼科用組成物，有關其調製方法並未特別限制，一般如：使維生素A由聚氧化乙烯聚氧化丙烯二醇於滅菌精製水中進行可溶化，接著，加入trometamol、各配 -17- 201100071 合成份，進行調整pH後可得到。之後，於適當的容器，如：聚對苯二甲酸乙二醇酯製之容器等中進行無菌塡充。藉由本發明，即使配合50,000單位/100 mL以上之維生素 A，仍可經由配合聚氧化乙烯聚氧化丙烯二醇、 trometamol，使維生素A安定化。本發明之維生素A安定化之方法有：於含有50,000 單位/100 mL以上維生素A之眼科用組成物中，配合0.4 W/V%以上之聚氧化乙烯聚氧化丙烯二醇、與（C) trometamol之維生素A的安定化方法，適當的成份、含量與上述眼科用組成物相同。又，本發明係提供一種含有 50,000單位/100 mL以上維生素A之眼科用組成物配合用，由聚氧化乙稀聚氧化丙嫌二醇及trometamol所成之該維生素A之穩定化劑。此時，聚氧化乙烯聚氧化丙烯二醇係於含有50,000單位/100 mL以上之維生素A之眼科用組成物中配合0.4 W/V%以上之量。又，本發明使維生素A以高濃度配合後，更進一步發揮效果適用於角膜損傷治療用眼科用組成物、乾眼症治療劑。另外，乾眼症係經由淚液之質或量的異常，使得眼球表面上之角結膜受到阻礙之狀態。淚液係由油層、水層及黏蛋白層之三層所構成，該三層構造之質、量均衡受破壞，導致淚液不穩定，於角膜出現障礙，造成乾眼症。乾眼症治療中，其重點在於使該淚液之油層、水層、黏蛋白層之三層構造恢復，及治療角膜障礙。又，隱形眼鏡使用者，容易導致乾眼，故本發明之眼科用組成物係適用於隱形 -18- 201100071 眼鏡用點眼劑、取出隱形眼鏡後之洗眼劑、隱形眼鏡裝載液、隱形眼鏡取出液等。適用於乾眼症治療劑時，藉由點眼1次30〜60 gL、1日3〜6次後，可進一步發揮其效果。〔實施例〕以下顯示實施例與·比較例，進行本發明具體的說明，惟本發明並未受限於下述之實施例。另外，表中之量，其 0 他係代表成份之純份量。〔實施例1〜28、比較例1〜5〕將表1〜7所示之組成的眼科用組成物（點眼劑）於8 5 t下使維生素A、聚氧化乙烯聚氧化丙烯二醇、必要時之抗氧化劑，進行預備溶解，該預備溶解物加溫至85 °C之滅菌精製水中進行可溶化，冷卻後，加入trometamol等之水溶性配合成份，調整pH ( 20°C )爲7.0，得到眼科用組成 Q 物。將1 5 mL之所得到眼科用組成物塡充於1 5 mL用點眼容器（聚對苯二甲酸乙二醇酯製）。實施例之眼科用組成物具有充足的防腐力。〈維生素A棕櫚酸酯殘存率（％)〉於製造後，及40°C、75%RH保存6個月後（嚴格試驗）測定眼科用組成物中維生素A棕櫚酸酯之含量。測定係使用高速液體色譜法進行測定。依下述式爲基準’由得到之維生素A棕櫚酸酯含量’算出維生素A棕櫚酸酯殘 -19- 201100071 存率（％)。維生素A棕櫚酸酯殘存率（％)=保存後的維生素A棕櫚酸酯含量/製造後之維生素A棕櫚酸酯含量xl 00 〔表1〕組成(W/V%) 實施例比較例 1 1 2 3 4 5 ㈧維生素A棕櫚酸酯 50,000 單位 50,000 單位 50,000 單位 50,000 單位 50,000 單位 50,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 1 1 0.1 - - - (C) trometamol 1 1 - - 1 其他聚氧化乙烯硬化蓖麻子油60 _ - 1 _ - 聚山梨酸酯80 • _ . 1 1 氯化鈉 0.9 0.9 0.9 0.9 0.9 0.9 稀鹽酸/氫氧化鈉(pH=7) 適量適量適量適量適量適量精製水殘部殘部殘部殘部殘部殘部合計 100mL lOOmL lOOmL lOOmL lOOmL lOOmL 維生素A棕櫚酸酯殘存率(％) 66.5 59.7 不可溶化 57.2 57.0 57.2 (A)單位/(B)g 50,000 50,000 50,000 50,000 50,000 50,000 (B)：(C) 1:1 - 1:10 - - - -20- 201100071 〔表2〕組成(w/v%) 實方晒 2 3 4 5 ㈧維生素A棕櫚酸酯 50,000 單位 50,000 單位 50,000 單位 50,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 0.4 1.5 3 5 (C) trometamol 1 1 1 1 其他氯化鈉 0.9 0.9 0.9 0.9 稀鹽酸/氣氧化鈉(pH=7) 適量適量適量適量精製水殘部殘部殘部殘部合計 lOOmL lOOmL 100mL lOOmL 維生素A棕櫚酸酯殘存率(％) 64.3 66.4 65.5 64.1 (A 揮位/(B)g 125,000 33,333 16,667 10,000 (BMC) 1:2.5 1.5:1 3:1 5:1 〔表3〕組成(w/v%) 實施例 6 7 8 9 10 (A) 維生素A棕櫚酸酯 50,000 單位 50,000 單位 50,000 單位 50,000 單位 50,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 1 1 1 1 1 (C) trometamol 0.05 0.1 0.5 3 5 其他氯化鈉 0.9 0.9 0.9 0.9 0.9 稀鹽酸/氣氧化鈉(pH=7) 適量適量適量適景 i商量精製水殘部殘部殘部殘部殘部合計 100mL 100mL lOOmL lOOmL lOOmL 維生素Λ棕櫚酸酯殘存率(％) 65.3 65.8 66.4 66.7 66.9 (Α)單位/(B)g 50,000 50,000 50,000 50,000 50,000 (B)：(C) 20:1 10:1 2:1 1:3 1:5 -21 - 201100071 〔表4〕組成(w/v%) 實施例 11 12 13 (A) 維生素A棕櫚酸酯 50,000 單位 50,000 單位 50,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 1 1 1 (C) trometamol 1 1 1 (D) 乙酸d-α -生育酚 0.05 0.05 二丁基羥基甲苯 0.005 0.005 其他聚氧化乙烯硬化箆麻子油60 _ _ 氯化鈉 0.9 0.9 0.9 稀鹽酸/氫氧化鈉(pH=7) 適量鑪滴量精製水殘部殘部殘部合計 lOOmL lOOmL 100mL 維生素A棕櫚酸酯殘存率(％) 68.5 68.7 70.9 (A 谭位/(B)g 50,000 50,000 50,000 (B):(C) 1:1 1:1 1:1 -22- 201100071 〔表5〕組 l^(W/V%) 實方酬 14 15 16 17 18 19 (A) 維生素A棕櫚酸酯 50,000 單位 50,000 單位 50,000 單位 100,000 單位 200,000 單位 300,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 1 1 1 3 5 5 (C) trometamol 0.1 0.5 2 2 3 5 (D) 乙酸d-α -生育酚 0.05 0.05 0.05 0.2 0.05 0.05 二丁基羥基甲苯 0.005 0.005 0.005 0.005 0.005 0.005 其他玻尿_ _ 0.02 • 0.02 馬尿甲基纖維素 0.1 _ 0.1 聚乙烯吡咯烷酮 • 0.1 一 0.1 軟骨素硫酸鈉 0.1 - - 0.1 _ - 牛磺酸 0.1 0.1 . 0.1 L-天冬氨酸鉀 1 - 1 硼酸 0.5 0.5 0.5 0.5 0.5 0.5 硼砂 - - 0.2 - 1-薄荷醇 - 0.005 - - - r dl-樟腦 - 0.002 - • • d-冰片 • 0.003 - - - - 乙烯二胺四乙酸鈉 0.1 0.1 0.1 0.1 0.1 0.1 山梨睛 • 0.1 • - Γ 甘油 - 0.5 - - - 氯化鈉 0.9 0.9 0.9 0.9 0.9 0.9 稀鹽酸/氫氧化鈉(ΡΗ=7) 適畺精製水殘部合計 100mL 100mL 100mL lOOmL lOOmL lOOmL 維生素A掠樞酸醋殘存率(%) 70.5 70.6 70.8 67.3 66.5 66.1 (A)單位/_ 50,000 50,000 50,000 33,333 40,000 60,000 _ (B):(C)__ 10:1 2:1 1:2 1.5:1 1.7:1 1:1 -23- 201100071 〔表6〕組成(w/v%) 實施例 20 21 22 23 24 (A) 維生素A棕櫚酸酯 50,000 單位 50,000 單位 50,000 單位 50,000 單位 100,000 單位 (B) 聚氧化乙烯(2〇〇)聚氧化丙烯 (70)二醇 0.4 1 2 5 3 (C) trometamol 1 1 2 2 0.5 (D) 乙酸d-α -生育酚 0.05 0.05 0.1 0.05 1 二丁基經基甲苯 0.005 0.005 0.005 0.005 0.005 tetrahydrozoline hydrochloride 0.05 _ 0.05 - - neostigmine methylsulfate 0.005 - 0.005 - - 氯苯吡胺馬來酸鹽 0.03 0.03 0.03 0.03 0.03 維生素B6鹽酸鹽 0.05 0.05 0.05 0.05 甘草酸二鉀 _ - _ - 0.25 玻尿酸鈉 0.02 _ _ 0.02 硼酸 1 1 1 1 1 硼砂 0.5 0.5 0.5 0.5 0.5 其 1-薄荷醇 0.005 _ • - 0.005 他 dl-樟腦 0.002 _ - 0.002 d_冰片 0.003 一 - 一 0.003 乙烯二胺四乙酸鈉 0.1 0.1 0.1 0.1 0.1 山梨酸鉀 _ - 0.1 甘油 . _ - 0.2 葡萄糖 _ - _ _ 0.1 氯化鈉 0.9 0.9 0.9 0.9 0.9 稀鹽酸/氫氧化鈉_=7) 適量精製水殘部合計 100mL lOOmL lOOmL lOOmL lOOmL 維生素A棕櫚酸酯殘存率(％) 70.1 70.5 70.6 70.7 67.1 (A)單位/(B)g 125,000 50,000 25,000 10,000 33,333 (B)：(C) 1:2.5 1:1 1:1 2.5:1 6:1 -24- 201100071 〔表7〕組成(w/v%) 實方 _ 25 26 27 28 (A) 維生素A棕櫚酸酯 200,000 單位 300,000 單位 300,000 單位 500,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 5 5 2.5 2.5 聚氧化乙烯(160)聚氧化丙嫌 (30)二醇 - - 2.5 - 聚氧化乙烯(54)聚氧化丙烯(39) 二醇 - - - 2.5 (C) trometamol 2 5 3 3 (D) 乙酸d-α -生育酣 0.05 0.05 0.05 0.05 二丁基羥基甲苯 0.005 0.005 0.005 0.005 其他 tetrahydrozoline hydrochloride 0.05 - 0.05 neostigmine methylsulfate 0.005 _ 0.005 氯苯吡胺馬來酸鹽 0.03 0.03 0.03 0.03 維生素B6鹽酸鹽 0.05 0.05 0.05 0.05 甘草酸二鉀 0.25 _ . 玻尿酸鈉 - - - 0.02 硼酸 1 1 1 1 硼砂 0.05 0.05 0.05 0.05 1-薄荷醇 0.005 0.2 dl-樟腦 0.002 - - d-冰片 • 0.003 - 乙烯二胺四乙酸鈉 0.1 0.1 0.1 0.1 山梨酸鉀 _ _ 0.1 丙二醇 • 0.1 _ - 葡萄糖 - - 0.1 - 氯化鈉 0.9 0.9 0.9 0.9 稀鹽酸/氫氧化鈉(pH=7) 適量精製水殘部合計 100mL 100mL lOOmL lOOmL 維生素A棕櫚酸酯殘存率(％) 66.8 66.2 66.4 66.1 (A)單位/(B)g 40,000 60,000 120,000 200,000 (B):(C) 2.5:1 1:1 1:1.2 1:1.2 -25- 201100071 〔比較例6、7〕依實施例1爲基準’調製表8所不之組成之眼科用組成物（點眼劑）’以下述方法評定角膜、結膜損傷之治療效果及眼睛刺激性’作爲治療乾眼症之指標。結果倂入實施例1之結果示於表中。〈角膜、結膜損傷之治療效果〉使用庚醇處理之兔子角膜、結膜上皮障礙模型之角膜、結膜損傷之治療效果試驗。於兔子進行庚醇處理（使庚醇/乙醇=8: 2混合液滴入單眼200 μΙ〇，製作於兔子角膜、結膜上皮受損之模型。之後’使試料連續進行點眼1 1天（6次（1〇〇 μι/次）/天 )。點眼期間，定期進行熒光素染色（2%熒光素單眼滴入 5 0 μί)，依Lenp判定基準，以15分滿分（將庚醇處理後之分數作成15分，依其有效改善度降分）進行評定。顯示第5天之評定結果。〈眼睛刺激性〉以50 次、間隔5分鐘，於兔子進行15次超頻次點眼試驗。點眼15次之後，進行熒光素染色（2%熒光素單眼滴入50 A) ’依下述基準評定角膜損傷範圍。評分4:於角膜全體面積之2/3以上出現染色評分3:於角膜全體面積之1/3以上未達2/3出現染色 -26- 201100071 評分2:於角膜全體面積出現之染色未達1/3 評分1 :稍有染色評分0:未出現染色(A) Vitamin A As the vitamin A, in addition to the vitamin A itself, for example, a vitamin A-containing mixture such as vitamin A oil or a vitamin A derivative such as a vitamin A fatty acid ester. Specifically, for example, vitamin A palmitate, vitamin A acetate, vitamin A, vitamin A acid, retinoid and the like. Among them, vitamin A palmitate, vitamin A acetate, and vitamin A acid are preferred. Vitamin A palmitate is usually marketed at 1 million to 1.8 million international units (hereinafter referred to as units or IU), for example: Roche, vitamins, and "Potassium Palmitate" manufactured by Nippon Stock Co., Ltd. (1.7 million IU/g) ) et al. (A) The components may be used singly or in combination of two or more kinds, and the content thereof is 50,000 units/100 mL or more for the total amount of the ophthalmic composition. Vitamin A has the effect of treating corneal and conjunctival damage, improving dry eye, improving eye fatigue, and blurring vision. After making 50,000 units/100 mL or more, these effects can be more apparent. From the above effects, the amount of the component (A) is preferably 100,000 units/100 mL or more, preferably 200,000 units/100 mL or more, more preferably 300,000 units/100 mL or more. From the perspective of stability, the upper limit is 500,000 units / 100 mL or less. The above amount is represented by W (mass) / V (volume) % ( g / 100 mL ), and it is preferably in the range of 0.03 to 0.3 W/V% depending on the unit of vitamin A to be blended. (B) Polyoxyethylene polyoxypropylene diol-8 - 201100071 In the present invention, after (B) polyoxyethylene polyoxypropylene diol, ophthalmic use containing 500, 〇〇〇 unit / 100 mL or more of vitamin A The composition can still maintain its stability 'at the same time, it is less irritating to the eyes', which can improve the treatment of corneal damage and the effect of treating dry eye. Such effects are not sufficient in surfactants such as sorbitan fatty acid esters of the eye drops, polyoxyethylene hardened ramie oil, and the like. The polyoxyethylene polyoxypropylene diol is not particularly limited, and may be used in the specification of a pharmaceutical additive (medical product). The average degree of polymerization of ethylene oxide is preferably from 4 to 200, more preferably from 20 to 200, and the average degree of polymerization of propylene oxide is from 5 to 100, more preferably from 20 to 70, which may be a block copolymer. It can also be a random polymer. Specifically, for example, polyoxyethylene (200) polyoxypropylene (7 oxime) diol: Lutrol F127 (manufactured by BASF), Unilub 70 DP-950B (manufactured by Nippon Oil Co., Ltd.), polyoxyethylene (12 〇) Polypropylene oxide (40) diol (Prulonic F-87), polyethylene oxide (160) poly oxidized propylene (30) diol (Prulonic F-68, alias Polocthamer 188): Q Pronon #188P (Nippon Oil (shares) )), etc., polyethylene oxide (42) polyoxypropylene (67) diol (Prulonic P123, alias Polocthamer 403), polyethylene oxide (54) polyoxypropylene (39) diol (Pulonic P85): Pronon #235P ( Examples of polyoxyethylene (20) polyoxypropylene (20) diol (Prulonic L-44) and tetronic, such as Nippon Oil (share). Among them, polyoxyethylene (200) polyoxypropylene (70) diol, polyethylene oxide (160) polyoxypropylene (30) diol, polyethylene oxide (54) polyoxypropylene (39) diol is preferred. By. (B) The components may be used alone or in combination of two or more. 201100071, and the content thereof is preferably 〇·4 w/v% or more for the total amount of the ophthalmic composition, preferably 〇· 4~5 W/V%, more preferably 〇·5~3 W/V%, especially ideal 〇·6~2 W/V%, ideally 1~2 W/V%. When it is less than 0.4 W/V%, the solubilization of vitamin A becomes difficult. From the viewpoint of the storage stability of vitamin A, it is preferably 5 W/V% or less. From the viewpoint of preservation and stability of vitamin A, the composition of (A) is represented by [(A) vitamin A unit / 100 mL] / [(B) polyoxyethylene polyoxypropylene diol g / 100 mL] B) The ratio of ingredients is preferably from 1 000,000 to 1,500,000, preferably from 1 5,000 to 10 〇, and more preferably from 25,000 to 50,000. (C) trometamol The ophthalmic composition of the present invention is preferably added to trometamol by enhancing the preservation stability of vitamin A. The effect of enhancing the preservation stability of vitamin A in trometamol is a novel finding of the present invention. This sequence is not clear' and can be inferred from the following. The polyoxyethylene polyoxypropylene diol is a nonionic surfactant having a polyoxyethylene (EO) chain and a polyoxypropylene (p) chain. The E chain is made to the outside, and the P0 chain is inside. The vitamin A is encapsulated to form a colloidal particle. After coexistence with trometamol, the -NH2 group present in trometamol is directly bonded to the EO bond, so that the structure of the colloidal particles is extremely strong. Trometamo1 further reduces the molecular mobility of the P〇 chain inside the colloid by binding the EO chain on the outer side of the colloid, strengthening the structure of the colloid and reducing the degree of freedom. The above-mentioned identifiable trometamol can impart stability to the colloidal particles formed by the vitamin A and the polyoxyethylene polyoxypropylene-10-01000071 diol, and the result also imparts stability to the vitamin A. (C) The content of trometamol is preferably 0.01 to 5 W/V% for the total amount of the ophthalmic composition, preferably 0.05 to 5 W/V%, more preferably 0.1 to 3 W/V%, and particularly desirable. It is 0.5~2 W/V%. When it is less than W/V%, it may cause insufficient effect on the preservation of vitamin A. If it exceeds 5 W/V%, it may cause irritation to the eyes. Moreover, the viewpoint of maintaining stability by dimension 0 A is regarded as (B): the mass ratio of the component represented by (C) to the component (C) is 1: 30~30; 1 is suitable, more 1:20~ 20:1, the better is 1:10~1〇:1, and the best is 1 0~3: 1. (D) Antioxidant The ophthalmic composition of the present invention is preferably added to the surface of the ophthalmic composition to enhance the protective properties of vitamin A. As an antioxidant such as: d-α-tocopherol, d-々-tocopherol, dr-tocopherol, d-5-phenol, dl-α-tocopherol, acetic acid d-α-tocopherol, acetic acid dl-α - Vitamin E, dibutyl toluene, butylated hydroxyanisole, raw, acetic acid dl-y3-tocopherol, acetic acid dl-r-tocopherol, acetic acid dl-tocopherol nicotinic acid dl-α-tocopherol Examples of the water-soluble antioxidants such as fat-soluble antioxidants, vitamin hydrogen rolls, cysteine, and glutathione are preferably fat-soluble antioxidants such as vitamins and the like, and more preferably acid-to-fertility. Phenol, dibutylhydroxytoluene, the most preferred is d-tocopherol acetate. Also, vitamin E and dibutylhydroxytoluene may be used. In the case of the protection, the better is 0.01, the opposite is the raw material (B), the best one: the depositor, the parent, the phenol, the hydroxy group C, the hydroxy group C, which is the acetyl group - 201100071. It is also suitable for the combination of two or more types. For the total amount of ophthalmic composition, it is suitable for 〇.〇〇5~5 W/V%. In this range, the preservation and stability of vitamin A can be further improved. The sex '0.005~1 W/V% is better, and the better is 〇.005~〇·2 W/V%. The ophthalmic composition of the present invention can be blended with various components added to the ophthalmic composition in addition to the above components without impairing the effects of the present invention. As such components, such as: polyol, surfactants other than (B), buffers, 'viscosifiers', sugars, pH adjusters, preservatives, isotonic agents, stabilizers, cooling agents, drugs , water and other examples. These may be used singly or in combination of two or more kinds as appropriate, and may be blended in an appropriate amount. Examples of the polyvalent alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. The content of the polyvalent alcohol is preferably 0.1 1 to 5 W/V% for the total amount of the ophthalmic composition, and more preferably 〇.〇 5 to 3 W/V%. Surfactants other than the component (B) such as polyoxyethylene hardened castor oil and polyoxyethylene sorbitan fatty acid ester (polysorbate 80) may also be used. After the use, it will further enhance the stability of stability. The content is preferably 0.0001 to 5 W/V% for the total amount of the ophthalmic composition, and more preferably 0.005 to 3 W/V%. In addition, the effect of treating cornea and conjunctival damage is the side of the treatment of dry eye. The less the amount of these surfactants, the better, 0.5 W/V% or less. As a buffer, such as: boric acid or a salt thereof (borax, etc.), citric acid or a salt thereof (sodium citrate, etc.), phosphoric acid or a salt thereof (sodium phosphate, sodium hydrogenate, etc.), -12-201100071 tartaric acid or a salt thereof (tartaric acid) Sodium, etc.), gluconic acid or a salt thereof (glucose, etc.), acetic acid or a salt thereof (sodium acetate, etc.), and in particular, after using boric acid sand, it is particularly preferable to obtain a highly antiseptic effect. The buffering agent is preferably from 0.01 to 5 W/V%, preferably from 0.001 to 10 w/v%, based on the total amount of the ophthalmic composition. Further, it is intended to make vitamin A more stable by blending boric acid and citric acid. As a thickener, such as: polyvinylpyrrolidone, hydroxyethylcellulose 0, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, hyaluronic acid, sodium chondroitin, polyacrylic acid, carboxyvinyl polymer, etc. example. After coordinating with this, the retention is improved, and the effect of treating cornea and bruise is further enhanced. The viscosifying agent is preferably used in an amount of 0.001 to 10 W/V% of the total ophthalmic composition, preferably 0.001 to 5 W/V%, more preferably 0.01 to 3 W/V%. Examples of the saccharide include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. Further, these may be any D body or L 〇 DL body. The content of the saccharide for the total amount of the ophthalmic composition is preferably 0.001 to 10 W/V%, preferably 0.005 to 5 W/V%, more preferably 0.01 to 3 W/V%. As the pH adjuster, an inorganic acid or an inorganic alkali agent is used, for example, an (alkenyl) hydrochloric acid. Examples of the inorganic alkali agent include sodium, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like. Among them, sodium hydroxide is preferred. The pH ( ) of the ophthalmic composition of the present invention is preferably 4.0 to 9·0, preferably 5.0 to 8.0, more preferably 6.C. In addition, in the present invention, the measurement of ρ 系 is carried out at 20 ° C using sodium citrate, boron content, and more, sodium can be obtained by film loss such as: pear saccharide or such as: . Hydrogen Peroxide Hydrochloric acid 2 〇oc I ~ 8.0 Infiltration -13- 201100071 Pressure gauge (HOSM-l, East Asia DKK (share)) carried out. The content of the pH adjusting agent for the total amount of the ophthalmic composition is, for example, 0.0000 1 to 10 W/V%, preferably 〇.〇〇〇1 to 51/¥%, and more preferably 0.001 to 3/ ¥%. As a preservative, such as: alkyl dimethyl benzyl ammonium chloride, benzyl ethylamine, sorbic acid or its salt, p-hydroxybenzoic acid ester (methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, pair Examples of propyl hydroxybenzoate, chlorhexidine glucenate, metilosal, phenylethyl alcohol, guanidine diamine ethylglycine, polyhexanide hydrochloride, polydronium chloride, and the like. The content of the preservative for the total amount of the ophthalmic composition is 0.00001 to 5 W/V%, preferably 0.0001 to 3 W/V%, more preferably 0.001 to 2 W/V%. In addition, in the treatment of the cornea, conjunctival damage and the improvement of dry eye, in the present invention, a cationic surfactant selected from the group consisting of alkyl dimethyl benzyl ammonium chloride and benzyl ammonium chloride (partially a cationic preservative), a content of a hydrophobic preservative selected from the group consisting of a paraben (methylparaben, ethylparaben, propylparaben, etc.) and chlorobutanol. W/V% or less is preferable, and more preferably 0.003 W/V% or less. It is not preferable, and it is more desirable to make it without adding. The effect of these disturbances on the treatment of corneal and conjunctival lesions is not clear, but can be inferred as follows. (B) The polyoxyethylene polyoxypropylene diol has an EO chain as an outer side and a PO chain as an inner side, and forms a rubber particle coated with vitamin A. The micelles are adsorbed on the surface of the cornea. Vitamin A is absorbed inside the cornea. The cationic surfactant passes through the interfacial activity energy, and the hydrophobic preservative changes the state of the surface of the colloidal particles by high hydrophobicity, so that the adsorption of the vitamin A cornea is hindered, and the result is considered to be hindered by the use of the -140007. Corneal and conjunctival injury treatment effects and improvement of dry eye syndrome. Further, the high hydrophilicity of sorbic acid or a salt thereof does not affect the state of the surface of the colloidal particles, and therefore does not hinder the promoting absorption effect of vitamin A. Further, the above-mentioned components are a part of the preservative, and the antiseptic property in the case where no preservative is added may be used in combination of one or more kinds or a combination of two or more kinds selected from the group consisting of disodium ethylenediaminetetraacetate, boric acid and trometamol. Further, when a unit door container is provided and a container for the filter is attached, no preservative may be added. 0 as an isotonic agent, such as: sodium chloride, potassium chloride and the like. The content of the isotonic agent for the total amount of the ophthalmic composition is preferably 0.001 to 5 W/V%, preferably 〇.〇1 to 3 W/V%, more preferably 0.1 to 2 W/V%. . As the stabilizer, for example, disodium ethylenediaminetetraacetate, cyclodextrin, sulfite, dibutylhydroxytoluene, and the like. Further, in the present invention, after the stabilizing agent is blended, the stability of vitamin A is further enhanced. The content of the cryptic agent for the total amount of the ophthalmic composition is 〇.〇〇1~5 W/V%, preferably 0.01 to 3 W/V%, and more preferably 0 1 to 2 W/ V%. 〇 As a cooling agent, such as menthol, camphor, borneol, geraniol, linalool, eucalyptus and the like. The amount of the cooling agent for the total amount of the ophthalmic composition is preferably 0.001 to 2 W/V%, more preferably 0.005-1 W/V, based on the total amount of the compound of 0.0001-5 W/V%. %, especially 0.007~0.8 W/V% is the best. As a drug (pharmaceutical active ingredient), it can be appropriately blended with, for example, a hyperemia removing agent (eg, naphtholine hydrochloride, tetrahydronaphthyl hydrochloride, dehydrogenated adrenaline, adrenaline, ephedrine hydrochloride, dl-hydrochloric acid). Methyl ephedrine, tetrahydronaphthyl nitrate, naphtholine nitrate, etc.), anti-inflammatory, astringent ( -15- 201100071 such as: neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, Berberine chloride, zinc sulfate, zinc lactate, chlorinated lysozyme, dipotassium glycyrrhizinate, glycyrrhizic acid, glycyrrhizic acid, methyl salicylate, tranexamic acid, sodium sulphate, etc.), antihistamines (eg :Iproheptin hydrochloride, 2-diphenylmethoxy-oxime hydrochloride, hydrazine-dimethylethylamine, 2-diphenylmethyl-N,N-dimethylethylamine, iso-dibenzyl chloride hydrochloride, chlorine maleate Amphetamine, etc., water-soluble vitamins (activated vitamin B2, vitamin B6, vitamin B12, etc.), amino acids (such as: L-aspartate, L-aspartate, aminoethyl sulfonic acid, Chondroitin sodium sulfate, etc.), vulcanizing agents, fungicides (eg sulfur, metformin, hinokitiol, etc.) Anti-allergic agents (cromoglicate, ketotifen fumarate, tranilaste, etc.), local anesthetics (eg lidocaine, lidocaine hydrochloride, procaine hydrochloride, leucocaine hydrochloride, etc.), sputum (cyclopentolate hydrochloride, tropicamide) Etc.), cataract therapeutics (pirenoxine, glutathione, etc.). The content of these components can be appropriately selected depending on the kind of the preparation, the kind of the drug, and the like, and the contents of the various components are well known in the art. For example, the total amount of the ophthalmic composition can be appropriately selected from the range of 0.0001 to 30 W/V%, preferably 0.001 to 10 W/V%. More specifically, the content of each component for the total amount of the ophthalmic composition is as follows. The blood-removing remover, such as: 0.000 1~0.5 W/V%, preferably 0.0005~0·3 W/V%, and more preferably 0.001~0·1 W/V%. An anti-inflammatory astringent such as 0.000 1 to 10 w/ν%, preferably 0.000 1 to 5 W/V%. An antihistamine agent, such as: 0.000 1~10 w/ν%, preferably -16-201100071 0.001 〜5 W/V%. Water-soluble vitamins, such as: 0.000 1~1 w/v%, preferably 0.000 1 to 0.5 W/V%. The amino acid is preferably, for example, 0.0001 to 10 w/v%, preferably 0.001 to 3 W/V%. A vulcanizing agent or a bactericide such as 0.00 0 0 1 ~ 1 0 w / V % is preferred, preferably 0.0001 to 10 w/ν%. 〇 Anti-allergic agents, such as: 0.0001~10 w/ν%, preferably 0.001~5 W/V%. Local anesthetics, mydriatic agents, cataract therapeutic agents, such as: 0.001 ~ 1 ^ / 乂% should be preferred, preferably 〇. 〇〇 5~1 \ ^ / 乂%. The ophthalmic composition of the present invention can be directly used as a liquid preparation, or can be prepared into a suspension, a gel, or the like. Specific examples of the use form include eye drops (for example, general eye drops, eye drops for contact lenses, etc.), eye wash (generally used eye wash, eye wash used after taking out the hidden glasses, etc.), and loading 〇 The contact liquid of the contact lens, the removal liquid of the contact lens, and the like. The ophthalmic composition of the present invention is in the form of a liquid, and when the eye drops are used, the viscosity is 1 to 100 mPa. Preferably, it is preferably 1 to 50 mPa·s, more preferably 1 to 30 mPs·s. Further, the viscosity measurement was carried out at 20 ° C, and the ophthalmic composition of the present invention was measured by an E-type viscometer (VISCONIC FLD-R, Tokyo Keiki Co., Ltd.), and the preparation method thereof is not particularly limited, and generally, : Vitamin A is solubilized from polyoxyethylene polyoxypropylene diol in sterilized purified water, and then trometamol and each -17-201100071 synthetic component are added to adjust the pH. Thereafter, aseptic filling is carried out in a suitable container, such as a container made of polyethylene terephthalate or the like. According to the present invention, even if 50,000 units/100 mL or more of vitamin A is blended, vitamin A can be stabilized by blending polyoxyethylene polyoxypropylene diol or trometamol. The vitamin A stabilization method of the present invention comprises: in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A, 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol, and (C) trometamol The method for stabilizing vitamin A has the same composition and content as the above ophthalmic composition. Further, the present invention provides a stabilizer for the vitamin A which is prepared by using an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A and comprising polyoxyethylene polyoxypropylene propylene glycol and trometamol. In this case, the polyoxyethylene polyoxypropylene diol is blended in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A in an amount of 0.4 W/V% or more. Further, in the present invention, vitamin A is compounded at a high concentration, and further, the effect is further applied to an ophthalmic composition for treating corneal damage and a therapeutic agent for dry eye. In addition, dry eye syndrome is a state in which the keratoconjunctiva on the surface of the eye is obstructed by the abnormality of the quality or amount of the tear. The tear system is composed of three layers of oil layer, water layer and mucin layer. The quality and quantity of the three-layer structure are damaged, resulting in unstable tears and obstacles in the cornea, causing dry eye syndrome. In the treatment of dry eye, the focus is on restoring the three-layer structure of the oil layer, water layer, and mucin layer of the tear, and treating corneal disorders. Moreover, the contact lens user is prone to dry eyes, so the ophthalmic composition of the present invention is suitable for invisible -18-201100071 eye drops for glasses, eye wash after taking out contact lenses, contact lens loading solution, contact lens removal Liquid, etc. When applied to a dry eye treatment, it can be further exerted by applying 30 to 60 gL once a day and 3 to 6 times a day. [Examples] The present invention will be specifically described below by way of examples and comparative examples, but the present invention is not limited to the examples described below. In addition, the amount in the table, which is 0, represents the pure amount of the ingredient. [Examples 1 to 28, Comparative Examples 1 to 5] The ophthalmic composition (eyedrop) of the compositions shown in Tables 1 to 7 was used to make vitamin A, polyoxyethylene polyoxypropylene diol at 85 Torr, If necessary, the antioxidant is preliminarily dissolved, and the preliminary dissolved material is solubilized in sterilized purified water heated to 85 ° C. After cooling, a water-soluble complex component such as trometamol is added to adjust the pH (20 ° C) to 7.0. Get the Q component for ophthalmology. 15 mL of the obtained ophthalmic composition was filled in a 15 mL eye-drop container (made of polyethylene terephthalate). The ophthalmic composition of the examples has sufficient antiseptic properties. <Residual rate of vitamin A palmitate (%)> The content of vitamin A palmitate in the ophthalmic composition was measured after storage for 6 months at 40 ° C and 75% RH (rigorous test). The measurement was carried out using high speed liquid chromatography. The vitamin A palmitate residue -19-201100071 (%) was calculated from the obtained vitamin A palmitate content based on the following formula. Residual rate of vitamin A palmitate (%) = vitamin A palmitate content after storage / vitamin A palmitate content after manufacture xl 00 [Table 1] Composition (W/V%) Example Comparative Example 1 1 2 3 4 5 (eight) Vitamin A palmitate 50,000 units 50,000 units 50,000 units 50,000 units 50,000 units 50,000 units (B) Polyethylene oxide (200) polyoxypropylene (70) diol 1 1 0.1 - - - (C) trometamol 1 1 - - 1 Other polyoxyethylene hardened castor oil 60 _ - 1 _ - Polysorbate 80 • _ . 1 1 Sodium chloride 0.9 0.9 0.9 0.9 0.9 0.9 Dilute hydrochloric acid / sodium hydroxide (pH = 7) Appropriate amount Appropriate amount of appropriate amount of refined water residue Residual residue Residual residue Total 100mL lOOmL lOOmL lOOmL lOOmL lOOmL Vitamin A palmitate residual rate (%) 66.5 59.7 Insoluble 57.2 57.0 57.2 (A) Unit / (B) g 50,000 50,000 50,000 50,000 50,000 50,000 (B): (C) 1:1 - 1:10 - - - -20- 201100071 [Table 2] Composition (w/v%) Real Sun 2 3 4 5 (8) Vitamin A Palmitate 50,000 Units 50,000 Units 50,000 Unit 50,000 units (B) Polyoxygen Ethylene (200) Polyoxypropylene (70) diol 0.4 1.5 3 5 (C) trometamol 1 1 1 1 Other sodium chloride 0.9 0.9 0.9 0.9 Dilute hydrochloric acid / gas sodium oxide (pH = 7) Appropriate amount of appropriate amount of refined water Residual residue Residual residue total lOOmL lOOmL 100mL lOOmL Vitamin A palmitate residual rate (%) 64.3 66.4 65.5 64.1 (A wave / (B) g 125,000 33,333 16,667 10,000 (BMC) 1:2.5 1.5:1 3:1 5: 1 [Table 3] Composition (w/v%) Example 6 7 8 9 10 (A) Vitamin A palmitate 50,000 units 50,000 units 50,000 units 50,000 units 50,000 units (B) Polyethylene oxide (200) polyoxypropylene ( 70) diol 1 1 1 1 1 (C) trometamol 0.05 0.1 0.5 3 5 Other sodium chloride 0.9 0.9 0.9 0.9 0.9 Dilute hydrochloric acid / gas sodium oxide (pH = 7) Appropriate amount of appropriate amount of interest i to discuss the remnants of the refining water residue Residual residue total 100mL 100mL lOOmL lOOmL lOOmL Vitamin Λ palmitate residual rate (%) 65.3 65.8 66.4 66.7 66.9 (Α) unit / (B) g 50,000 50,000 50,000 50,000 50,000 (B): (C) 20:1 10:1 2:1 1:3 1:5 -21 - 201100071 [Table 4] Composition (w/v%) Example 11 12 13 (A) Vitamin A palmitate 50,000 units 50,000 units 50,000 units (B) Polyethylene oxide (200) polyoxypropylene (70) diol 1 1 1 (C) trometamol 1 1 1 (D) acetic acid d- --tocopherol 0.05 0.05 Dibutylhydroxytoluene 0.005 0.005 Other polyoxyethylene hardened castor oil 60 _ _ Sodium chloride 0.9 0.9 0.9 Dilute hydrochloric acid / sodium hydroxide (pH = 7) Appropriate amount of furnace drops Refined water residue Residual parts Total lOOmL lOOmL 100mL Vitamin A palmitate residual rate (%) 68.5 68.7 70.9 (A Tan / (B) g 50,000 50,000 50,000 (B): (C) 1:1 1:1 1:1 -22- 201100071 〔 Table 5] Group l^(W/V%) Really paid 14 15 16 17 18 19 (A) Vitamin A palmitate 50,000 units 50,000 units 50,000 units 100,000 units 200,000 units 300,000 units (B) Polyethylene oxide (200) Polyoxypropylene (70) diol 1 1 1 3 5 5 (C) trometamol 0.1 0.5 2 2 3 5 (D) acetic acid d-α-tocopherol 0.05 0.05 0.05 0.2 0.05 0.05 Dibutylhydroxytoluene 0.005 0.005 0.005 0.005 0.005 0.005 Other hyaluronic _ _ 0.02 • 0.02 Horse urine methyl cellulose 0.1 _ 0.1 Polyethylene Pyrrolidone • 0.1-0.1 Chondroitin sulfate 0.1 - - 0.1 _ - Taurine 0.1 0.1 . 0.1 L-potassium aspartate 1 - 1 Boric acid 0.5 0.5 0.5 0.5 0.5 0.5 Borax - - 0.2 - 1-menthol - 0.005 - - - r dl- camphor - 0.002 - • • d-borneol • 0.003 - - - - Sodium ethylenediaminetetraacetate 0.1 0.1 0.1 0.1 0.1 0.1 Yamanashi • 0.1 • - Γ Glycerin - 0.5 - - - Sodium chloride 0.9 0.9 0.9 0.9 0.9 0.9 Dilute hydrochloric acid/sodium hydroxide (ΡΗ=7) Appropriate purified water residue total 100mL 100mL 100mL lOOmL lOOmL lOOmL Vitamin A gluconate vinegar residual rate (%) 70.5 70.6 70.8 67.3 66.5 66.1 (A) unit / _ 50,000 50,000 50,000 33,333 40,000 60,000 _ (B): (C)__ 10:1 2:1 1:2 1.5:1 1.7:1 1:1 -23- 201100071 [Table 6] Composition (w/v%) Implementation Example 20 21 22 23 24 (A) Vitamin A palmitate 50,000 units 50,000 units 50,000 units 50,000 units 100,000 units (B) Polyethylene oxide (2 〇〇) polyoxypropylene (70) diol 0.4 1 2 5 3 (C ) trometamol 1 1 2 2 0.5 (D) acetic acid d-α-tocopherol 0.05 0.05 0.1 0.05 1 dibutyl permethyl toluene 0.005 0.005 0.005 0.005 0.005 tetrahydrozoline hydrochloride 0.05 _ 0.05 - - neostigmine methylsulfate 0.005 - 0.005 - - chlorpheniramine maleate 0.03 0.03 0.03 0.03 0.03 Vitamin B6 hydrochloride 0.05 0.05 0.05 0.05 Dipotassium glycyrrhizinate _ - _ - 0.25 Hyaluronic acid Sodium 0.02 _ _ 0.02 Boric acid 1 1 1 1 1 Borax 0.5 0.5 0.5 0.5 0.5 Its 1-menthol 0.005 _ • - 0.005 He dl- camphor 0.002 _ - 0.002 d_ borneol 0.003 one - one 0.003 sodium ethylene diamine tetraacetate 0.1 0.1 0.1 0.1 0.1 Potassium Sorbate _ - 0.1 Glycerin. _ - 0.2 Glucose _ - _ _ 0.1 Sodium Chloride 0.9 0.9 0.9 0.9 0.9 Dilute Hydrochloric Acid / Sodium Hydroxide _=7) Appropriate Purified Water Residue Total 100mL lOOmL lOOmL lOOmL lOOmL Vitamin Residual rate of A palmitate (%) 70.1 70.5 70.6 70.7 67.1 (A) Unit / (B) g 125,000 50,000 25,000 10,000 33,333 (B): (C) 1:2.5 1:1 1:1 2.5:1 6:1 -24- 201100071 [Table 7] Composition (w/v%) Reality _ 25 26 27 28 (A) Vitamin A palmitate 200,000 units 300,000 units 300,000 units 500,000 units (B) Polyethylene oxide (200) polyoxygen Propylene (70) diol 5 5 2.5 2.5 Polyethylene oxide (160) Polyoxypropylene propylene (30) diol - - 2.5 - Polyethylene oxide (54) Polypropylene oxide (39) diol - - - 2.5 (C) Trometamol 2 5 3 3 (D) acetic acid d-α - fertility 0.05 0.05 0.05 0.05 dibutylhydroxytoluene 0.005 0.005 0.005 0.005 other tetrahydrozoline hydrochloride 0.05 - 0.05 neostigmine methylsulfate 0.005 _ 0.005 chlorpheniramine maleate 0.03 0.03 0.03 0.03 Vitamin B6 hydrochloride 0.05 0.05 0.05 0.05 Dipotassium glycyrrhizinate 0.25 _ . Sodium hyaluronate - - - 0.02 Boric acid 1 1 1 1 Borax 0.05 0.05 0.05 0.05 1-Menthol 0.005 0.2 dl-camphor 0.002 - - d-borneol • 0.003 - Sodium ethylenediaminetetraacetate 0.1 0.1 0.1 0.1 Potassium sorbate _ _ 0.1 Propylene glycol • 0.1 _ - Glucose - - 0.1 - Sodium chloride 0.9 0.9 0.9 0.9 Dilute hydrochloric acid / sodium hydroxide (pH = 7) Appropriate amount of refined water residue 100mL 100mL lOOmL lOOmL Vitamin A palmitate residual rate (%) 66.8 66.2 66.4 66.1 (A) unit / (B) g 40,000 60,000 120,000 200,000 (B): (C) 2.5:1 1:1 1:1.2 1:1.2 -25- 201100071 [Comparative Example 6 7] According to the first embodiment, the ophthalmic composition (eyedrop) which is not composed of the composition of Table 8 is used to evaluate the therapeutic effect of corneal and conjunctival damage and eye irritation as an indicator for treating dry eye. . Results The results of the incorporation into Example 1 are shown in the table. <Therapeutic effect of corneal and conjunctival injury> The therapeutic effect of corneal cornea and conjunctival epithelial disorder model corneal and conjunctival injury using heptanol treatment. The rabbit was subjected to heptanol treatment (the heptanol/ethanol = 8:2 mixture was dropped into a single eye 200 μΙ〇, and the rabbit cornea and the conjunctival epithelium were damaged. Then the sample was continuously drilled for 1 day (6 Times (1〇〇μι/time)/day. During the eye, regular fluorescein staining (2% fluorescein monocular drop 50 μί), according to the Lenp criterion, with 15 points (after heptanol treatment) The score was scored as 15 points, and the score was determined according to the effective improvement score. The results of the evaluation on the 5th day were displayed. <Eye irritation> 15 times of overclocking eye test was performed in rabbits at 50 times and at intervals of 5 minutes. After 15 eyes, fluorescein staining (2% fluorescein monocular instillation of 50 A) was used to assess the extent of corneal damage according to the following criteria. Score 4: Staining score of 2/3 or more of the entire area of the cornea 3: in the cornea More than 1/3 of the area did not reach 2/3 staining -26- 201100071 Score 2: The staining in the whole area of the cornea did not reach 1/3 Score 1: Slight staining score 0: No staining occurred

〔表8〕組成(W/V%) 實施例比較例 1 6 7 (A) 維生素A棕櫚酸酯 50,000 單位 - 50,000 單位 ⑼ 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 1 1 (C) trometamol 1 1 1 其他聚氧化乙烯硬化蓖麻子油60 1 聚山梨酸酯80 傷鲁氯化鈉 0.9 0.9 0.9 稀鹽酸/氫氧化鈉(pH=7) 適量適量谪量精製水殘部殘部殘部合計 100mL lOOmL lOOmL 角膜.結膜損傷治療效果 9 13 12 眼刺激性 0 0 0 〔實施例29〜33〕依實施例1爲基準’調製表9之眼科用組成物，以上述方法評定維生素A棕櫚酸酯殘存率、角膜、結膜損傷之治療效果及眼睛刺激性。結果倂入表中。 201100071 〔表9〕組成(W/V%) 實施例 29 30 31 32 33 ㈧維生素Λ棕櫚酸酯 100,000 單位 150,000 單位 200,000 單位 300,000 單位 500,000 單位 (B) 聚氧化乙烯(200)聚氧化丙烯 (70)二醇 2 1 5 5 5 (C) trometamol 1 1 1 5 5 (D) 乙酸d-a -生育酚 0.05 0.05 0.05 0.05 0.05 二丁基羥基甲苯 0.005 0.5 0.005 0.005 0.005 其他氯化鈉 0.9 0.9 0.9 0.9 0.9 稀鹽酸/氫氧化鈉(pH=7) 適量適量適量適量谪量精製水殘部殘部殘部殘部殘部合計 100mL 100mL lOOmL lOOmL lOOmL 維生素A棕櫚酸酯殘存率(％) 67.2 66.4 66.3 66.5 66.2 角膜.結膜損傷治療效果 9 8 8 6 6 眼刺激性 0 0 0 0 0 (A)單位/(B)g 50,000 150,000 40,000 60,000 100,000 (B)：(C) 2:1 1:1 5:1 1:1 1:1 顯示實施例所使用之原料。聚氧化乙烯（200)聚氧化丙烯（70)二醇：[Table 8] Composition (W/V%) Example Comparative Example 1 6 7 (A) Vitamin A palmitate 50,000 units - 50,000 units (9) Polyethylene oxide (200) Polyoxypropylene (70) diol 1 1 (C ) trometamol 1 1 1 Other polyoxyethylene hardened castor oil 60 1 Polysorbate 80 Injury sodium chloride 0.9 0.9 0.9 Dilute hydrochloric acid / sodium hydroxide (pH = 7) Appropriate amount of amount of refined water residue Residual residue total 100mL lOOmL lOOmL cornea. Conjunctival injury treatment effect 9 13 12 Eye irritation 0 0 [Examples 29 to 33] According to Example 1 as a reference, the ophthalmic composition of Table 9 was prepared, and the residual vitamin A palmitate was evaluated by the above method. Rate, treatment of corneal and conjunctival damage and eye irritation. The result is broken into the table. 201100071 [Table 9] Composition (W/V%) Example 29 30 31 32 33 (VIII) Vitamin palmitate 100,000 Unit 150,000 Unit 200,000 Unit 300,000 Unit 500,000 Unit (B) Polyethylene oxide (200) Polyoxypropylene (70) Diol 2 1 5 5 5 (C) trometamol 1 1 1 5 5 (D) acetic acid da-tocopherol 0.05 0.05 0.05 0.05 0.05 Dibutylhydroxytoluene 0.005 0.5 0.005 0.005 0.005 Other sodium chloride 0.9 0.9 0.9 0.9 0.9 Dilute hydrochloric acid /Sodium hydroxide (pH=7) Appropriate amount, appropriate amount, appropriate amount, amount of refined water residue, residual parts, residue, total 100mL, 100mL, lOOmL, lOOmL, lOOmL, vitamin A palmitate, residual rate (%) 67.2 66.4 66.3 66.5 66.2 corneal and conjunctival injury treatment effect 9 8 8 6 6 Eye irritation 0 0 0 0 0 (A) Unit / (B) g 50,000 150,000 40,000 60,000 100,000 (B): (C) 2:1 1:1 5:1 1:1 1:1 Display implementation The raw materials used in the examples. Polyoxyethylene (200) polyoxypropylene (70) diol:

Uniroob 70 DP-9 5 0B、醫藥品添加物規格、日油（股份）或Lutrol F127，醫藥品添加物規格、BASF (股份）聚氧化乙烯（160)聚氧化丙烯（30)二醇：Uniroob 70 DP-9 5 0B, pharmaceutical additive specifications, daily oil (shares) or Lutrol F127, pharmaceutical additive specifications, BASF (shares) polyoxyethylene (160) polyoxypropylene (30) diol:

Pronon # 188P、醫藥品添加物規格、日油（股份）聚氧化乙烯（54)聚氧化丙烯（39)二醇：Pronon # 188P, Pharmaceutical Additive Specifications, Nippon Oil (Shares) Polyethylene Oxide (54) Polyoxypropylene (39) Glycol:

Pronon # 23 5P、醫藥品添加物規格、日油（股份）聚氧化乙烯硬化蓖麻子油60: -28- 201100071 CHO-60 (醫藥用）、醫藥品添加物規格、日光 Chemicals (股份）聚山梨酸酯80 : reodol TW-0 120 V、日本藥局方、花王（股份） hypromelo se : metrose 65SH-4000、日本藥局方、信越化學工業（股份）聚乙烯吡咯烷酮：Pronon # 23 5P, Pharmaceutical Additive Specifications, Nippon Oil (Shares) Polyoxyethylene Hardened Castor Oil 60: -28- 201100071 CHO-60 (medical), Pharmaceutical Additive Specifications, Daylight Chemicals (Shares) Poly Yamanashi Acid ester 80 : reodol TW-0 120 V, Japanese Pharmacopoeia, Kao (share) hypromelo se : metrose 65SH-4000, Japanese Pharmacopoeia, Shin-Etsu Chemical Industry (shares) Polyvinylpyrrolidone:

Ulidone 90F ' 日本藥局方、BASF 〇 -29-Ulidone 90F 'Japan Pharmacy Bureau, BASF 〇 -29-

Claims

201100071 VII. Patent application scope: 1. A group of ophthalmic compositions characterized by containing (A) more than 50,000 units/100 00 mL of vitamin A, and (B) 0.4 W/V% or more of polyoxyethylene. Oxidized polyoxyethylene polyoxylene glycol, and (c) trometamol. 2 · For the ophthalmic composition according to item 1 of the patent application, the content of the component (A) is 100,000 units/100 mL or more. 3 · For the ophthalmic composition according to item 1 of the patent application, the content of the component (A) is 200,000 units/100 mL or more. 4. The ophthalmic composition according to item 1 of the patent application, wherein the content of the component (A) is 300,000 units/100 mL or more. 5 · The ophthalmic composition of claim 1 of the patent application, which further contains (D) an antioxidant. 6 The ophthalmic composition of claim 5, wherein the component (D) is vitamin E and/or dibutylhydroxytoluene. 7. The ophthalmic composition according to claim 1, wherein the component (a) is vitamin A palmitate, vitamin A acetate or vitamin A acid. 8 · For the ophthalmic composition of claim 1 of the patent scope, wherein (B): (C) represents a mass ratio of (B) component to (C) component i: 30~30:1. 9. A method for stabilizing vitamin A, characterized in that 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol is added to ophthalmic composition containing 50,000 units/100 mL or more of vitamin A and (c) -30- 201100071 trometamol °

〇 201100071 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: none

❹ 201100071 5 If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: none