TWI429424B - Ophthalmic compositions and the stabilization of vitamin A - Google Patents

Ophthalmic compositions and the stabilization of vitamin A Download PDF

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TWI429424B
TWI429424B TW98121635A TW98121635A TWI429424B TW I429424 B TWI429424 B TW I429424B TW 98121635 A TW98121635 A TW 98121635A TW 98121635 A TW98121635 A TW 98121635A TW I429424 B TWI429424 B TW I429424B
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vitamin
ophthalmic composition
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acid
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TW98121635A
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TW201100071A (en
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Nobuhito Tabuchi
Chieko Inoue
Manabu Hattori
Miyuki Miyake
Hazuki Fukuoka
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Lion Corp
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眼科用組成物及維生素A之安定化方法Ophthalmic composition and vitamin A stabilization method

本發明係有關含有高濃度維生素A之眼科用組成物。The present invention relates to an ophthalmic composition containing a high concentration of vitamin A.

維生素A係作為預防、治療角膜、結膜、皮膚黏膜之角化症等之有效成份倍受矚目。另外,脂溶性維生素之維生素A對於空氣、光、熱、酸、金屬離子等極為敏感,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。Vitamin A is attracting attention as an effective ingredient for preventing and treating cornea, conjunctiva, and keratosis of the skin and mucous membranes. Further, the vitamin A of the fat-soluble vitamin is extremely sensitive to air, light, heat, acid, metal ions, etc., and is extremely unstable in an aqueous solution, and therefore it is extremely difficult to stably mix with an ophthalmic composition such as an eye drop.

作為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:以聚乙烯硬化萞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、包裝面之穩定化技術(如:特開平6-40907號公報:專利文獻3、特開2003-113078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。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 or a packaging surface (e.g., JP-A-6-40907) Japanese Patent Laid-Open Publication No. JP-A No. 2002-332225 (Patent Document 5). However, in the advanced technology, when the concentration is high (50,000 units or more), 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.

[特許文獻1]特開平5-331056號公報[Patent Document 1] Japanese Patent Publication No. 5-331056

[特許文獻2]特開平6-247853號公報[Protocol 2] Unexamined-Japanese-Patent No. 6-247853

[特許文獻3]特開平6-40907號公報[Property Document 3] Unexamined Patent Publication No. 6-40907

[特許文獻4]特開2003-113078號公報[Patent Document 4] JP-A-2003-113078

[特許文獻5]特開2002-332225號公報[Patent Document 5] JP-A-2002-332225

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之安定化方法為目的。In view of the above problems, the present invention provides an ophthalmic composition containing a high concentration of vitamin A for stabilizing vitamin A, and a method for stabilizing vitamin A.

本發明者,為達成該目的而進行精密研討後,結果發現,於含有50,000單位/100mL以上之維生素A之眼科用組成物中,配合0.4W/V%以上之聚氧化乙烯聚氧化丙烯二醇與trometamol後,可明顯提昇維生素A之安定性,進而完成本發明。In order to achieve the object, the inventors of the present invention found that 0.40/V% or more of polyoxyethylene polyoxypropylene diol is blended in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A. After trometamol, the stability of vitamin A can be significantly improved, and the present invention is completed.

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。Accordingly, the present invention provides an ophthalmic composition described below and a method for stabilizing vitamin A.

[1]含有(A)50,000單位/100mL以上之維生素A與(B)0.4W/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。[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, and (C) trometamol.

[2](A)成份之含量為100,000單位/100mL以上之[1]所載之眼科用組成物。[2] The ophthalmic composition contained in [1] of the component (A) having a content of 100,000 units/100 mL or more.

[3](A)成份之含量為200,000單位/100mL以上之[1]所載之眼科用組成物。[3] The ophthalmic composition contained in [1] of the component (A) having a content of 200,000 units/100 mL or more.

[4](A)成份之含量為300,000單位/100mL以上之[1]所載之眼科用組成物。[4] The ophthalmic composition contained in [1] of the component (A) having a content of 300,000 units/100 mL or more.

[5]進一步含有(D)抗氧化劑之[1]所載之眼科用組成物。[5] Further comprising the ophthalmic composition contained in (D) an antioxidant [1].

[6](D)成份為維生素E及/或二丁基羥基甲苯之[5]所載之眼科用組成物。[6] (D) The ophthalmic composition contained in vitamin E and/or dibutylhydroxytoluene [5].

[7](A)成份為維生素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。[7] (A) The ophthalmic composition contained in the vitamin A palmitate, vitamin A acetate or vitamin A acid [1].

[8](B):(C)所代表之(B)成份與(C)成份之質量比為1:30~30:1之[1]所載之眼科用組成物。[8] (B): The ophthalmic composition contained in [1] [1] represented by (C) and (C) has a mass ratio of 1:30 to 30:1.

[9]於含有50,000單位/100mL以上之維生素A之眼科用組成物中,配合0.4W/V%以上之聚氧化乙烯聚氧化丙烯二醇、與(C)trometamol者為其特徵之維生素A之安定化方法。[9] In the 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 are used as vitamin A. Stability method.

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。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.

[發明實施之最佳形態][Best form of implementation of the invention]

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/100mL以上之維生素A與(B)0.4W/V%以上之聚氧化乙烯聚氧化丙烯二醇、與(C)trometamol。另外,更作為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為改善乾眼症之效果。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 the present invention has an effect of improving dry eye.

(A)維生素A(A) Vitamin A

作為維生素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酸為較佳者。維生素A棕櫚酸酯通常市售者為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。Examples of the vitamin A include, in addition to the vitamin A itself, a vitamin A-containing mixture such as a 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 the unit or IU), for example: Roche, vitamins, "Potassium palmitate" manufactured by Nippon Stock Co., Ltd. (1.7 million IU/g) ) et al.

(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,為50,000單位/100mL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/100mL以上後,可更明顯發揮此等效果。由此等效果面視之,(A)成份之量為100,000單位/100mL以上者宜,較佳者為200,000單位/100mL以上,更佳者為300,000單位/100mL以上。由穩定性之面視之,上限為500,000單位/100mL以下者宜。上述之量以W(質量)/V(體積)%(g/100mL)代表後,依所配合之維生素A之單位而異,一般為0.03~0.3W/V%者宜。The component (A) 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 syndrome, improving eye fatigue and blurred vision. After making 50,000 units/100mL or more, these effects can be more apparent. From the viewpoint of such effects, the amount of the component (A) is preferably 100,000 units/100 mL or more, preferably 200,000 units/100 mL or more, and more preferably 300,000 units/100 mL or more. From the perspective of stability, the upper limit is 500,000 units / 100mL or less. The above amount is represented by W (mass) / V (volume)% (g / 100mL), and it is preferably in the range of 0.03 to 0.3 W/V% depending on the unit of the vitamin A to be blended.

(B)聚氧化乙烯聚氧化丙烯二醇(B) Polyoxyethylene polyoxypropylene diol

本發明中,使用(B)聚氧化乙烯聚氧化丙烯二醇後,含有500,000單位/100mL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,聚氧化乙烯硬化萞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為4~200者宜,20~200更佳,環氧丙烷之平均聚合度為5~100者宜,更佳者為20~70,可為嵌段共聚物,亦可為無規聚合物。In the present invention, after the (B) polyoxyethylene polyoxypropylene diol is used, the ophthalmic composition containing 500,000 units/100 mL or more of vitamin A can maintain its stability and is less irritating to the eyes. Improve the treatment of corneal damage and the effect of treating dry eye. Such effects are not sufficient for surfactants such as sorbitan fatty acid esters which are commonly used for eye drops, and polyoxyethylene hardened castor oil. The polyoxyethylene polyoxypropylene diol is not particularly limited, and those contained in the pharmaceutical additive specifications (pharmaceutical additive specifications) can be used. 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.

具體而言如,聚氧化乙烯(200)聚氧化丙烯(70)二醇:Lutrol F127(BASF製)、Unilub 70 DP-950B(日油(股份)製)等,聚氧化乙烯(120)聚氧化丙烯(40)二醇(Prulonic F-87)、聚氧化乙烯(160)聚氧化丙烯(30)二醇(Prulonic F-68、別名Polocthamer 188):Pronon #188P(日油(股份))等、聚氧化乙烯(42)聚氧化丙烯(67)二醇(Prulonic P123、別名Polocthamer 403)、聚氧化乙烯(54)聚氧化丙烯(39)二醇(Prulonic P85):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)二醇為較佳者。Specifically, for example, polyoxyethylene (200) polyoxypropylene (70) diol: Lutrol F127 (manufactured by BASF), Unilub 70 DP-950B (manufactured by Nippon Oil Co., Ltd.), polyoxyethylene (120) polyoxidation Propylene (40) diol (Prulonic F-87), polyethylene oxide (160) poly propylene oxide (30) diol (Prulonic F-68, alias Polocthamer 188): Pronon #188P (Nippon Oil (share)), etc. Polyethylene oxide (42) polyoxypropylene (67) diol (Prulonic P123, alias Polychethamer 403), polyethylene oxide (54) polyoxypropylene (39) diol (Prulonic P85): Pronon #235P (Nippon Oil (shares) )), etc., examples of polyoxyethylene (20) polyoxypropylene (20) diol (Prulonic L-44), tetronic, and the like. Among them, polyoxyethylene (200) polyoxypropylene (70) diol, polyethylene oxide (160) polyoxypropylene (30) diol, polyethylene oxide (54) polyoxypropylene (39) diol is preferred. By.

(B)成份可單獨使用1種或適當組合2種以上使用之,其含量,對於眼科用組成物總量而言,為0.4W/V%以上者宜,較佳者為0.4~5W/V%,更佳者為0.5~3W/V%,特別理想者為0.6~2W/V%,最為理想者1~2W/V%。當未達0.4W/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,為5W/V%以下者宜。(B) The component may be used singly or in combination of two or more kinds, and the content thereof is preferably 0.4 W/V% or more for the total amount of the ophthalmic composition, preferably 0.4 to 5 W/V. %, preferably 0.5~3W/V%, especially ideally 0.6~2W/V%, ideally 1~2W/V%. When it is less than 0.4 W/V%, the solubilization of vitamin A becomes difficult, and it is preferable that it is 5 W/V% or less from the viewpoint of the storage stability of vitamin A.

由維生素A保存安定化之觀點視之,以[(A)維生素A單位/100mL]/[(B)聚氧化乙烯聚氧化丙烯二醇g/100mL]所代表之(A)成份與(B)成份之比率為10,000~150,000者宜,較佳者為15,000~100,000,更佳者為25,000~50,000。From the viewpoint of preservation and stability of vitamin A, (A) and (B) represented by [(A) vitamin A unit / 100 mL] / [(B) polyoxyethylene polyoxypropylene diol g / 100 mL] The ratio of ingredients is 10,000 to 150,000, preferably 15,000 to 100,000, and more preferably 25,000 to 50,000.

(C)trometamol(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(PO)鏈之非離子性界面活性劑。使EO鏈為外側、PO鏈為內側,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鏈之醚鍵鍵結,故使膠粒之構造極為強固。trometamol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PO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二醇所形成之膠粒的安定化,其結果亦賦予維生素A之保存安定性。In the ophthalmic composition of the present invention, it is preferred to add trometamol by enhancing the preservation stability of vitamin A. The effect of enhancing the preservation stability of vitamin A in trometamol is a novel discovery 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 (PO) chain. The EO chain is the outer side and the PO chain is the inner side, and the vitamin A is encapsulated to form a colloidal particle. After coexistence with trometamol, the -NH 2 group present in trometamol is directly bonded to the ether bond of the EO chain, so that the structure of the colloidal particles is extremely strong. Trometamol further reduces the degree of freedom by bonding the EO chain to the outer side of the colloidal particles, thereby reducing the molecular mobility of the PO chain inside the colloidal particles. From the above, it can be confirmed that trometamol can impart stability to the colloidal particles formed by vitamin A and polyoxyethylene polyoxypropylene diol, and as a result, the preservation stability of vitamin A is also imparted.

(C)trometamol之含量對於眼科用組成物總量而言,為0.01~5W/V%者宜,較佳者為0.05~5W/V%,更佳者為0.1~3W/V%,特別理想者為0.5~2W/V%。當未達0.01W/V%時,則恐使維生素A之保存安定化效果不足,反之,超出5W/V%則恐對於眼睛產生刺激感。又,由維生素A保存安定化之觀點視之,(B):(C)所代表之(B)成份與(C)成份之質量比為1:30~30;1者宜,較佳者為1:20~20:1,更佳者為1:10~10:1,最佳者為1:10~3:1。(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%, and more preferably 0.1 to 3 W/V%, which is particularly desirable. The value is 0.5~2W/V%. When it is less than 0.01 W/V%, it is feared that the preservation effect of vitamin A is insufficient, and if it exceeds 5 W/V%, it may cause irritation to the eyes. Moreover, from the viewpoint of preservation and stability of vitamin A, (B): (C) represents a mass ratio of (B) component to (C) component of 1:30 to 30; one is preferred, preferably 1:20~20:1, the better is 1:10~10:1, and the best is 1:10~3:1.

(D)抗氧化劑(D) Antioxidants

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,以添加抗氧化劑者宜。作為抗氧化劑者,如:d-α-生育酚、d-β-生育酚、d-γ-生育酚、d-δ-生育酚、dl-α-生育酚、乙酸d-α-生育酚、乙酸dl-α-生育酚、乙酸dl-β-生育酚、乙酸dl-γ-生育酚、乙酸dl-δ-生育酚、煙鹼酸dl-α-生育酚等之維生素E類、二丁基羥基甲苯、丁基羥基茴香醚等之脂溶性抗氧化劑、維生素C、氫輥、半胱氨酸、谷胱甘肽等之水溶性抗氧化劑等例,其中又以維生素E等之脂溶性抗氧化劑者較佳,更佳者為乙酸d-α-生育酚、二丁基羥基甲苯,最佳者為乙酸d-α-生育酚。又,併用維生素E及二丁基羥基甲苯亦可。In the ophthalmic composition of the present invention, it is preferred to add an antioxidant to enhance the preservation stability of vitamin A. As antioxidants, such as: d-α-tocopherol, d-β-tocopherol, d-γ-tocopherol, d-δ-tocopherol, dl-α-tocopherol, d-α-tocopherol acetate, Vitamin E, dibutyl acetate, dl-β-tocopherol acetate, dl-β-tocopherol acetate, dl-γ-tocopherol acetate, dl-δ-tocopherol acetate, nicotinic acid dl-α-tocopherol Examples of water-soluble antioxidants such as hydroxytoluene and butyl hydroxyanisole, vitamin C, hydrogen roller, cysteine, glutathione, etc., among which are fat-soluble antioxidants such as vitamin E. More preferably, it is preferably d-α-tocopherol acetate or dibutylhydroxytoluene, and the most preferred one is acetic acid d-α-tocopherol. Also, vitamin E and dibutylhydroxytoluene may be used in combination.

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,為0.005~5W/V%者宜,於此範圍內,可進一步提昇維生素A之保存安定性,0.005~1W/V%為較佳者,更佳者為0.005~0.2W/V%。The antioxidant may be used singly or in combination of two or more kinds, and the content thereof is preferably 0.005 to 5 W/V% for the total amount of the ophthalmic composition. In this range, the vitamin A can be further improved. The storage stability is preferably 0.005~1W/V%, and more preferably 0.005~0.2W/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。作為此等成份者,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。In the ophthalmic composition of the present invention, various components added to the ophthalmic composition can be blended in addition to the above components without departing from the effects of the present invention. As such components, such as: polyol, surfactants other than (B) components, buffers, thickeners, 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.

作為多價醇者,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,為0.01~5W/V%者宜,更佳者為0.05~3W/V%。Examples of the polyvalent alcohol include glycerin, propylene glycol, butylene glycol, and polyethylene glycol. The content of the polyvalent alcohol is preferably 0.01 to 5 W/V% for the total amount of the ophthalmic composition, and more preferably 0.05 to 3 W/V%.

亦可併用(B)成份以外之界面活性劑,如:聚氧化乙烯硬化萞麻子油、聚氧化乙烯山梨聚糖脂肪酸酯(聚山梨酸酯80)等例。經由併用後,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,為0.0001~5W/V%者宜,更佳者為0.005~3W/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0.5W/V%以下者宜。Surfactants other than the component (B) may be used in combination, such as polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid ester (polysorbate 80), and the like. After being used together, it will further enhance the stability of stability. These contents are 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, and the treatment of dry eye syndrome, the less the amount of these surfactants, the better, 0.5W / V% or less.

作為緩衝劑者,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)、酒石酸或其鹽(酒石酸鈉等)、葡糖酸或其鹽(葡糖酸鈉等)、乙酸或其鹽(乙酸鈉等),其中又以併用硼酸、硼砂後,特別可得到高度防腐效果最為理想。緩衝劑之含量對於眼科用組成物總量而言,為0.001~10W/V%者宜,更佳者為0.01~5W/V%。又,藉由配合硼酸、檸檬酸後,可意圖使維生素A更安定化。As a buffer, for example, boric acid or a salt thereof (borax or the like), citric acid or a salt thereof (such as sodium citrate), phosphoric acid or a salt thereof (such as sodium phosphate), tartaric acid or a salt thereof (sodium tartrate, etc.), Gluconic acid or a salt thereof (sodium gluconate or the like), acetic acid or a salt thereof (sodium acetate or the like), and in combination with boric acid and borax, a highly highly anticorrosive effect is particularly preferable. The content of the buffering agent is preferably 0.001 to 10 W/V% for the total amount of the ophthalmic composition, and more preferably 0.01 to 5 W/V%. Further, by blending boric acid or citric acid, it is intended to make vitamin A more stable.

作為黏稠劑者,如: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、軟骨素硫酸鈉、聚丙烯酸、羧基乙烯聚合物等例。藉由配合此等後,提高滯留性,進一步提昇治療角膜、結膜損傷之效果。黏稠化劑對於眼科用組成物總量之含量如:0.001~10W/V%者宜,較佳者為0.001~5W/V%,更佳者為0.01~3W/V%。As a thickener, such as: polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, carboxyvinyl polymer, etc. example. By coordinating with these, the retention is improved, and the effect of treating corneal and conjunctival damage is further enhanced. The content of the viscosifying agent for the total amount of the ophthalmic composition is preferably 0.001 to 10 W/V%, preferably 0.001 to 5 W/V%, and more preferably 0.01 to 3 W/V%.

作為糖類者,如:葡萄糖、環糊精、木糖醇、山梨糖醇、甘露糖醇等例。另外,此等可任意為D體、L體或DL體。糖類對於眼科用組成物總量之含量,如:0.001~10W/V%者宜,較佳者為0.005~5W/V%,更佳者為0.01~3W/V%。Examples of the sugar include glucose, cyclodextrin, xylitol, sorbitol, and mannitol. Further, these may be any D body, L body or DL body. The content of the sugar for the total amount of the ophthalmic composition is, for example, 0.001 to 10 W/V%, preferably 0.005 to 5 W/V%, and more preferably 0.01 to 3 W/V%.

作為pH調整劑者,以使用無機酸或無機鹼劑者宜。無機酸之例如:(烯)鹽酸之例。無機鹼劑之例如:氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸氫鈉等例。其中又以鹽酸、氫氧化鈉為較佳。本發明之眼科用組成物之pH(20℃)為4.0~9.0者宜,較佳者為5.0~8.0,更佳者為6.0~8.0。另外,本發明中,pH之測定係於20℃下利用pH滲透壓計(HOSM-1,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:0.00001~10W/V%者宜,較佳者為0.0001~5W/V%,更佳者為0.001~3W/V%。As the pH adjuster, it is preferred to use an inorganic acid or an inorganic base. Examples of inorganic acids are, for example, (alkenyl) hydrochloric acid. Examples of the inorganic alkali agent include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogencarbonate. Among them, hydrochloric acid and sodium hydroxide are preferred. The pH of the ophthalmic composition of the present invention (20 ° C) is preferably 4.0 to 9.0, preferably 5.0 to 8.0, more preferably 6.0 to 8.0. Further, in the present invention, the pH is measured by a pH osmometer (HOSM-1, East Asia DKK (share)) at 20 °C. The content of the pH adjusting agent for the total amount of the ophthalmic composition is preferably 0.00001 to 10 W/V%, preferably 0.0001 to 5 W/V%, and more preferably 0.001 to 3 W/V%.

作為防腐劑者,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、鹽酸烷二胺乙基甘胺酸、polyhexanide hydrochloride、polydronium chloride等例。防腐劑對於眼科用組成物總量之含量為:0.00001~5W/V%者宜,較佳者為0.0001~3W/V%,更佳者為0.001~2W/V%。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, alkyldiamine ethylglycolic acid, 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%, and more preferably 0.001 to 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(部份為陽離子性防腐劑)、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0.004W/V%以下者宜,更佳者為0.003W/V%以下,未含此等,作成無添加者更為理想。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鏈為外側、PO鏈為內側,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,其結果被認為阻礙角膜、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,上述成份為防腐劑的一部份,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。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 the better one is 0.003 W/V% or less. It is not included, and it is more desirable to make it without adding. The effect of these disturbances on the treatment of corneal and conjunctival damage is not clear, but can be inferred as follows. (B) Polyoxyethylene polyoxypropylene glycol is a rubber particle coated with vitamin A, which has an EO chain as an outer side and a PO chain as an inner side. The colloidal particles are adsorbed on the surface of the cornea, and vitamin A is absorbed inside the cornea. The cationic surfactant can change the state of the surface of the colloid by high interfacial activity through the interfacial activity, and the hydrophobic preservative hinders the adsorption of the vitamin A cornea. The result is considered to hinder the treatment of corneal and conjunctival injury. The effect and improvement of dry eye syndrome. Further, since the hydrophilicity of sorbic acid or a salt thereof does not affect the state of the surface of the colloidal particles, the effect of promoting the absorption of vitamin A is not inhibited. 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. Moreover, when the unit doors container is provided and the container of the filter is attached, no preservative may be added.

作為等張化劑者,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為0.001~5W/V%者宜,較佳者為0.01~3W/V%,更佳者為0.1~2W/V%。As the isotonic agent, such as sodium chloride, potassium chloride and the like. The isotonic agent is preferably used in an amount of 0.001 to 5 W/V% for the total ophthalmic composition, preferably 0.01 to 3 W/V%, more preferably 0.1 to 2 W/V%.

作為安定化劑者,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為0.001~5W/V%者宜,較佳者為0.01~3W/V%,更佳者為0.1~2W/V%。As the stabilizer, for example, disodium ethylenediaminetetraacetate, cyclodextrin, sulfite, dibutylhydroxytoluene and the like. In addition, in the present invention, after the stabilizer is added, the stability of vitamin A is further enhanced. The content of the cryptic agent for the total amount of the ophthalmic composition is preferably 0.001 to 5 W/V%, preferably 0.01 to 3 W/V%, and more preferably 0.1 to 2 W/V%.

作為清涼化劑者,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,以化合物總量為0.0001~5W/V%者宜,較佳者為0.001~2W/V%,更佳者為0.005~1W/V%,特別以0.007~0.8W/V%為最佳。Examples of the cooling agent include menthol, camphor, borneol, geraniol, linalool, and eucalyptus. The amount of the cooling agent for the total amount of the ophthalmic composition is preferably 0.0001 to 5 W/V% of the total amount of the compound, preferably 0.001 to 2 W/V%, more preferably 0.005 to 1 W/V%, and particularly The best is 0.007~0.8W/V%.

作為藥物(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、硝酸萘唑啉等)、消炎、收歛劑(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、甘草酸銨、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-N,N-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、異丙甲酚、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)、散朣劑(cyclopentolate hydrochloride、tropicamide等)、白內障治療劑(pirenoxine、谷胱甘酞等)。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, naphthyl nitrate, etc., anti-inflammatory, astringent (eg: neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, chlorinated bismuth Alkali, zinc sulfate, zinc lactate, chlorinated lysozyme, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhizic acid, methyl salicylate, tranexamic acid, sodium sulphate, etc.), antihistamines (eg, Iproheptin hydrochloride, 2-Diphenylmethoxy-N,N-dimethylethylamine, 2-diphenylmethyl-N,N-dimethylethylamine, iso-dibenzyl hydroxychloride, chloramphelam maleate, etc.) Water-soluble vitamins (activated vitamin B 2 , vitamin B 6 , vitamin B 12, etc.), amino acids (eg, L-aspartate, L-aspartate, aminoethyl sulfonate, cartilage) Sodium sulphate, etc.), vulcanizing agents, bactericides (eg sulfur, isopropyl cresol, hinokitiol, etc.), anti-allergic agents (cromoglicate, ketotifen fumarate, tranilas Te et al), local anesthetics (eg lidocaine, lidocaine hydrochloride, procaine hydrochloride, leucocaine hydrochloride, etc.), sputum (cyclopentolate hydrochloride, tropicamide, etc.), cataract treatment (pirenoxine, valley) Cysteine, etc.).

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為公知者。如:對於眼科用組成物總量而言,可由0.0001~30W/V%,較佳者0.001~10W/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為如下。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.

充血去除劑,如:0.0001~0.5W/V%者宜,較佳者為0.0005~0.3W/V%,更佳者為0.001~0.1W/V%。The blood-removing remover, such as: 0.0001~0.5W/V%, preferably 0.0005~0.3W/V%, and more preferably 0.001~0.1W/V%.

消炎‧收歛劑,如:0.0001~10W/V%者宜,較佳者為0.0001~5W/V%。Anti-inflammatory ‧ astringent, such as: 0.0001 ~ 10W / V% should be preferred, preferably 0.0001 ~ 5W / V%.

抗組織胺劑,如:0.0001~10W/V%者宜,較佳者為0.001~5W/V%。Antihistamines, such as: 0.0001 ~ 10W / V%, preferably 0.001 ~ 5W / V%.

水溶性維生素,如:0.0001~1W/V%者宜,較佳者為0.0001~0.5W/V%。Water-soluble vitamins, such as: 0.0001 ~ 1W / V% should be preferred, preferably 0.0001 ~ 0.5W / V%.

胺基酸,如:0.0001~10W/V%者宜,較佳者為0.001~3W/V%。Amino acids, such as: 0.0001 ~ 10W / V%, preferably 0.001 ~ 3W / V%.

硫化劑,殺菌劑,如:0.00001~10W/V%者宜,較佳者為0.0001~10W/V%。Vulcanizing agent, fungicide, such as: 0.00001 ~ 10W / V% should be preferred, preferably 0.0001 ~ 10W / V%.

抗過敏劑,如:0.0001~10W/V%者宜,較佳者為0.001~5W/V%。Anti-allergic agents, such as: 0.0001 ~ 10W / V% should be preferred, preferably 0.001 ~ 5W / V%.

局部麻醉劑、散瞳劑、白內障治療劑,如:0.001~1W/V%者宜,較佳者為0.005~1W/V%。Local anesthetics, mydriatic agents, cataract therapeutic agents, such as: 0.001 ~ 1W / V% should be preferred, preferably 0.005 ~ 1W / V%.

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。作為使用形態者,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)、裝載隱形眼鏡之裝載液,取出隱形眼鏡之取出液等例。The ophthalmic composition of the present invention can be directly used as a liquid preparation, or can be prepared into a suspension, a gel, and the like. Specific examples of the form of use include eye-dropping agents (such as general eye drops, eye drops for contact lenses, etc.), eye washes (generally used eye wash, eye wash used after taking out the hidden glasses, etc.), and loading The contact liquid of the contact lens, the removal liquid of the contact lens, and the like.

本發明之眼科用組成物為液狀,點眼劑時,黏度為1~100mPa‧s者宜,較佳者為1~50mPa‧s,更佳者為1~30mPs‧s。另外,黏度測定係於20℃下,利用E型黏度計(VISCONIC FLD-R,東京計器(股份))進行測定。The ophthalmic composition of the present invention is in the form of a liquid, and when the eye drops are used, the viscosity is preferably from 1 to 100 mPa ‧ s, preferably from 1 to 50 mPa ‧ s, and more preferably from 1 to 30 mP s s. Further, the viscosity measurement was carried out at 20 ° C using an E-type viscometer (VISCONIC FLD-R, Tokyo Keiki Co., Ltd.).

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填充。The ophthalmic composition of the present invention is not particularly limited in terms of its preparation method. Generally, vitamin A is solubilized from polyoxyethylene polyoxypropylene diol in sterilized purified water, followed by adding trometamol and each component. It can be obtained after adjusting the pH. Thereafter, aseptic filling is carried out in a suitable container such as a container made of polyethylene terephthalate or the like.

藉由本發明,即使配合50,000單位/100mL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。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.

本發明之維生素A安定化之方法有:於含有50,000單位/100mL以上維生素A之眼科用組成物中,配合0.4W/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/100mL以上維生素A之眼科用組成物配合用,由聚氧化乙烯聚氧化丙烯二醇及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/100mL以上之維生素A之眼科用組成物中配合0.4W/V%以上之量。The method for stabilizing vitamin A of the present invention comprises: blending 0.4 W/V% or more of polyoxyethylene polyoxypropylene diol with (C) trometamol in an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A; 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 ophthalmic composition comprising 50,000 units/100 mL or more of vitamin A, which is a stabilizer for vitamin A obtained from polyoxyethylene polyoxypropylene diol 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.

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30~60μL、1日3~6次後,可進一步發揮其效果。Further, in the present invention, after the vitamin A is blended at a high concentration, 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 eyeball is hindered by the abnormality of the quality or amount of the tear fluid. 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, the water layer and the mucin layer of the tear, and treating the corneal disorder. Further, since the contact lens user is likely to cause dry eye, the ophthalmic composition of the present invention is suitable for eye contact for contact lenses, eye wash after taking out contact lenses, contact lens loading solution, contact lens take-out solution, and the like. When applied to a dry eye treatment, it can be further exerted by eye-dropping once 30 to 60 μL and 3 to 6 times a day.

[實施例][Examples]

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,其他係代表成份之純份量。The following examples and comparative examples are given to illustrate the invention, but the invention is not limited to the examples described below. In addition, the amount in the table, the other represents the pure amount of ingredients.

[實施例1~28、比較例1~5][Examples 1 to 28, Comparative Examples 1 to 5]

將表1~7所示之組成的眼科用組成物(點眼劑)於85℃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℃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℃)為7.0,得到眼科用組成物。將15mL之所得到眼科用組成物填充於15mL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。The ophthalmic composition (eyedrop) of the composition shown in Tables 1 to 7 was preliminarily dissolved at 85 ° C by using vitamin A, polyoxyethylene polyoxypropylene diol, and, if necessary, an antioxidant. The sterilized purified water heated to 85 ° C was solubilized, and after cooling, a water-soluble complex component such as trometamol was added thereto, and the pH (20 ° C) was adjusted to 7.0 to obtain an ophthalmic composition. 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.

〈維生素A棕櫚酸酯殘存率(%)〉<Residual rate of vitamin A palmitate (%)>

於製造後,及40℃、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。依下述式為基準,由得到之維生素A棕櫚酸酯含量,算出維生素A棕櫚酸酯殘存率(%)。After the production, the content of vitamin A palmitate in the ophthalmic composition was measured after storage for 6 months at 40 ° C and 75% RH (rigid test). The measurement was carried out using high speed liquid chromatography. The vitamin A palmitate residual ratio (%) was calculated from the obtained vitamin A palmitate content based on the following formula.

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×100Residual rate of vitamin A palmitate (%) = vitamin A palmitate content after storage / vitamin A palmitate content after manufacture × 100

[比較例6、7][Comparative Examples 6, 7]

依實施例1為基準,調製表8所示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,作為治療乾眼症之指標。結果併入實施例1之結果示於表中。The ophthalmic composition (eyedrop) having the composition shown in Table 8 was prepared on the basis of Example 1, and the therapeutic effects of corneal and conjunctival damage and eye irritation were evaluated by the following methods as an index for treating dry eye. Results The results of incorporation into Example 1 are shown in the table.

〈角膜、結膜損傷之治療效果〉<Therapeutic effect of corneal and conjunctival injury>

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。The therapeutic effect test of corneal cornea, hemorrhage of conjunctival epithelial disorder model, and conjunctival injury using heptanol treatment.

於兔子進行庚醇處理(使庚醇/乙醇=8:2混合液滴入單眼200μL),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11天(6次(100μL/次)/天)。點眼期間,定期進行熒光素染色(2%熒光素單眼滴入50μL),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。The rabbit was subjected to heptanol treatment (dropping of heptanol/ethanol = 8:2 into 200 μL of a single eye) to prepare a rabbit corneal and conjunctival epithelial damaged model. Thereafter, the sample was continuously subjected to a blind eye for 11 days (6 times (100 μL/time)/day). During the eye-pointing period, fluorescein staining was performed regularly (2% fluorescein monocular instillation of 50 μL), and according to the Lenp criterion, 15 points (with a score of 15 points after heptanol treatment, according to the effective improvement score) assessment. The results of the evaluation on the 5th day are displayed.

〈眼睛刺激性〉<eye irritation>

以50μL/次、間隔5分鐘,於兔子進行15次超頻次點眼試驗。Fifteen overclocking eye tests were performed on rabbits at 50 μL/time at intervals of 5 minutes.

點眼15次之後,進行熒光素染色(2%熒光素單眼滴入50μL),依下述基準評定角膜損傷範圍。After 15 eyes were spotted, fluorescein staining (2% fluorescein monocular drop of 50 μL) was performed, and the corneal damage range was evaluated according to the following criteria.

評分4:於角膜全體面積之2/3以上出現染色Score 4: Staining occurs 2/3 or more of the entire area of the cornea

評分3:於角膜全體面積之1/3以上未達2/3出現染色Score 3: less than 2/3 of the total area of the cornea

評分2:於角膜全體面積出現之染色未達1/3Score 2: less than 1/3 of the staining in the entire area of the cornea

評分1:稍有染色Score 1: Slightly stained

評分0:未出現染色Score 0: no staining

[實施例29~33][Examples 29 to 33]

依實施例1為基準,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。結果併入表中。The ophthalmic composition of Table 9 was prepared on the basis of Example 1, and the residual rate of vitamin A palmitate, the therapeutic effect of corneal and conjunctival damage, and eye irritation were evaluated by the above method. The results are incorporated into the table.

顯示實施例所使用之原料。The materials used in the examples are shown.

聚氧化乙烯(200)聚氧化丙烯(70)二醇:Uniroob 70 DP-950B、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)Polyethylene oxide (200) Polyoxypropylene (70) diol: Uniroob 70 DP-950B, pharmaceutical additive specifications, Nippon Oil (share) or Lutrol F127, pharmaceutical additive specifications, BASF (shares)

聚氧化乙烯(160)聚氧化丙烯(30)二醇:Pronon # 188P、醫藥品添加物規格、日油(股份)Polyethylene oxide (160) polyoxypropylene (30) diol: Pronon # 188P, pharmaceutical additive specifications, Nippon Oil (shares)

聚氧化乙烯(54)聚氧化丙烯(39)二醇:Pronon # 235P、醫藥品添加物規格、日油(股份)Polyethylene oxide (54) Polyoxypropylene (39) diol: Pronon # 235P, pharmaceutical additive specifications, Nippon Oil (shares)

聚氧化乙烯硬化萞麻子油60:CHO-60(醫藥用)、醫藥品添加物規格、日光Chemicals(股份)Polyoxyethylene hardened castor oil 60: CHO-60 (medical), pharmaceutical additive specifications, daylight Chemicals (shares)

聚山梨酸酯80:reodol TW-0120V、日本藥局方、花王(股份)Polysorbate 80: reodol TW-0120V, Japanese Pharmacy, Kao (share)

hypromelose:metrose 65SH-4000、日本藥局方、信越化學工業(股份)Hypromelose: metrose 65SH-4000, Japan Pharmacy, Shin-Etsu Chemical Industry (shares)

聚乙烯吡咯烷酮:Ulidone 90F、日本藥局方、BASFPolyvinylpyrrolidone: Ulidone 90F, Japanese Pharmacopoeia, BASF

Claims (8)

一種眼科用組成物,其特徵係含有(A)50,000單位/100mL以上之維生素A、與(B)0.4~5W/V%之聚氧化乙烯聚氧化丙烯二醇(polyoxyethylene polyoxylene glycol),與(C)trometamol,且以(B):(C)表示之(B)成份與(C)成份之質量比為1:20~20:1。 An ophthalmic composition comprising (A) 50,000 units/100 mL or more of vitamin A, and (B) 0.4 to 5 W/V% of polyoxyethylene polyoxylene glycol, and (C) ) trometamol, and the mass ratio of the component (B) to the component (C) represented by (B): (C) is 1:20 to 20:1. 如申請專利範圍第1項之眼科用組成物,其中(A)成份之含量為100,000單位/100mL以上。 For example, in the ophthalmic composition of claim 1, wherein the content of the component (A) is 100,000 units/100 mL or more. 如申請專利範圍第1項之眼科用組成物,其中(A)成份之含量為200,000單位/100mL以上。 For example, in the ophthalmic composition of claim 1, wherein the content of the component (A) is 200,000 units/100 mL or more. 如申請專利範圍第1項之眼科用組成物,其中(A)成份之含量為300,000單位/100mL以上。 For example, in the ophthalmic composition of claim 1, wherein the content of the component (A) is 300,000 units/100 mL or more. 如申請專利範圍第1項之眼科用組成物,其中更含有(D)抗氧化劑。 For example, the ophthalmic composition of claim 1 further contains (D) an antioxidant. 如申請專利範圍第5項之眼科用組成物,其中(D)成份為維生素E及/或二丁基羥基甲苯。 An ophthalmic composition according to claim 5, wherein the component (D) is vitamin E and/or dibutylhydroxytoluene. 如申請專利範圍第1項之眼科用組成物,其中(A)成份為維生素A棕櫚酸酯、維生素A乙酸酯或維生素A酸。 The ophthalmic composition according to claim 1, wherein the component (A) is vitamin A palmitate, vitamin A acetate or vitamin A acid. 一種維生素A之安定化方法,其特徵係於含有50,000單位/100mL以上之維生素A之眼科用組成物中添加(B)0.4~5W/V%之聚氧化乙烯聚氧化丙烯二醇與(C)trometamol,且以(B):(C)表示之(B)成份與(C)成份之質量比為1:20~20:1。 A method for stabilizing vitamin A, characterized by adding (B) 0.4 to 5 W/V% of polyoxyethylene polyoxypropylene diol and (C) to an ophthalmic composition containing 50,000 units/100 mL or more of vitamin A Trometamol, and the mass ratio of the component (B) to the component (C) represented by (B): (C) is 1:20 to 20:1.
TW98121635A 2009-06-26 2009-06-26 Ophthalmic compositions and the stabilization of vitamin A TWI429424B (en)

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