JP4813682B2 - Ophthalmic agent - Google Patents
Ophthalmic agent Download PDFInfo
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- JP4813682B2 JP4813682B2 JP2001133915A JP2001133915A JP4813682B2 JP 4813682 B2 JP4813682 B2 JP 4813682B2 JP 2001133915 A JP2001133915 A JP 2001133915A JP 2001133915 A JP2001133915 A JP 2001133915A JP 4813682 B2 JP4813682 B2 JP 4813682B2
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- JP
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- Prior art keywords
- ophthalmic
- present
- eye
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- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
【0001】
【発明の属する技術分野】
本発明は、深層水を配合した眼科用剤に関し、更に詳細には、ドライアイ等の角膜上皮障害の治療に有利に用いられる眼科用剤に関する。
【0002】
【従来の技術】
近年、情報機器の普及に伴い、長時間ディスプレイ装置に向かうことにより目を酷使する人が増えており、これに比例してドライアイ等による角膜上皮障害の患者も増えている。
【0003】
従来、これらの角膜上皮障害の治療には、ヒアルロン酸やコンドロイチン硫酸などのムコ多糖類を有効成分とした点眼剤が用いられているが、これらの点眼剤は、副作用などの理由から1日あたり数回の投与に限定されている。
【0004】
しかしながら、ドライアイにおける眼球の乾燥やそれにより生ずる痛みは、点眼剤の投与では一時的な効果しか得られないため、一日数回の投与では症状を十分に解消できないという問題があった。
【0005】
【発明が解決しようとする課題】
従って、ドライアイ等の角膜上皮障害を有効に予防・治療することができ、しかも頻繁に使用したとしても安全性の問題の生じない眼科用剤の提供が求められていた。
【0006】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく眼科用剤に配合しうる成分について鋭意検索を行っていたところ、硝酸態窒素、リン酸態リンおよびケイ酸態ケイ素を表層海水に比べ10〜20倍多く含む海洋深層水は角膜修復作用があり、これを含有せしめた眼科用剤はドライアイなどに伴う角膜上皮障害に有効であることを見出した。また、更に天然の抗菌性化合物であるフラボノイド類やテルペン類を添加することにより、防腐剤として汎用される第4級アンモニウム性陽イオン界面活性剤を添加しなくても保存安定性を高めることができることを見出し、本発明を完成した。
【0007】
すなわち本発明は、深層水を含有する眼科用剤を提供するものである。
【0008】
また本発明は、更に抗菌剤としてフラボノイド類またはテルペン類を含有する上記眼科用剤を提供するものである。
【0009】
【発明の実施の形態】
本発明の眼科用剤において使用される深層水は、無機塩類等の栄養分に富んでいることが注目され、さまざまな分野での応用が検討されている海洋における深層水である。この深層水は、海洋の深度200mより深い部分から汲み上げられた海水を指称し、既に飲料水や化粧品の分野では深層水を配合した商品が上市されており、また、アトピー性皮膚炎などの皮膚疾患に効果があることも報告されているが(特開平9−67258号、特開平9−110702号)、この深層水を眼科領域に応用することについては報告がない。
【0010】
本発明の眼科用剤において使用される深層水の採取場所については特に制約はなく、現在採取が行われている富山県、沖縄県、高知県等の沖合で採取された深層水のいずれもが使用できる。また、眼科用剤に対する深層水の配合量も特に限定されるものではない。例えば、深層水をそのままで点眼もしくは洗眼しても眼刺激はさほど強くないことが確認されている。しかしながら、深層水の浸透圧比は概ね3.5程度であるため、これを精製水を用いて3〜4倍程度に希釈して用いることが望ましい。
【0011】
本発明の眼科用剤では、実質的に深層水が有効成分となるが、その他の眼科分野での有効成分、例えば、ヒアルロン酸ナトリウム、コンドロイチン硫酸ナトリウム、エリスロマイシン、オフロキサン、インドメタシン、イプシロンアミノカプロン酸、アライトイン、グリチルリチン酸二カリウム、マレイン酸クロルフェニラミン、硫酸亜鉛、アスパラギン酸塩、各種ビタミン類等を配合することを妨げるものではない。
【0012】
また、本発明の眼科用剤には、抗菌剤、溶解補助剤、清涼化剤、等張化剤、安定化剤、緩衝剤等、一般に眼科用剤に使用されうる添加剤を配合することができる。
【0013】
なお、本発明の眼科用剤がドライアイ患者に用いられる時には、一日に何回も点眼、塗布もしくは洗眼されることが想定されるので、上記の有効成分や添加剤として、副作用の懸念される成分の配合量は極力少なくすることが好ましい。
【0014】
例えば、一般的な眼科用剤には、防腐剤として抗菌作用を有する塩化ベンザルコニウム等の第4級アンモニウム性陽イオン界面活性剤が配合されることが多いが、これらの界面活性剤には角膜障害作用が報告されており、本発明の効果を減少させる恐れがある。従って本発明においては、抗菌剤として、天然の抗菌性化合物、特にカテキン、カテコール、テアフラビン等のフラボノイド類化合物やテルピネン−4−オール、リナロール、ナポール、カルボン(carvon)等のテルペン類を用いることが好ましい。これらの抗菌剤は、眼科用剤中、0.0005から0.2質量%(以下、「%」とする)程度添加することが好ましく、特に好ましくは0.003から0.1%程度程度である。
【0015】
かくして得られる本発明の眼科用剤は、種々の形態、例えば、点眼剤、眼軟膏、洗眼剤などとすることができる。そして、深層水の副作用はきわめて小さいものと考えられるので、本発明の眼科用剤は頻繁に使用することが可能である。
【0016】
【実施例】
以下に実施例を挙げて本発明を更に詳しく説明するが、本発明はこれら実施例に何ら制約されるものではない。
【0017】
実 施 例 1
点 眼 液 1:
富山県沖で採取された深層水(以下単に「深層水」という)100mlを点眼液容器に充填し、点眼液を得た。この点眼液の浸透圧比(生理食塩水に対する)は3.48、pHは7.7であった。
【0018】
実 施 例 2
点 眼 液 2:
深層水を精製水で3.5倍に希釈した溶液100mlを点眼液容器に充填し、点眼液を得た。この点眼液の浸透圧比は1.08、pHは7.6であった。
【0019】
実 施 例 3
点 眼 液 3:
カテキン0.03gに深層水を加え、全量を100mlとした後、これを点眼液容器に充填し、点眼液を得た。この点眼液の浸透圧比は3.53、pHは7.5であった。
【0020】
実 施 例 4
点 眼 液 4:
カテキン0.03gに、深層水の精製水による3.5倍希釈液を加え、全量を100mlとした後、これを点眼液容器に充填し、点眼液を得た。この点眼液の浸透圧比は1.10、pHは7.3であった。
【0021】
比 較 例 1
比較点眼液:
生理食塩水100mlを点眼液容器に充填し、比較点眼液を得た。この点眼液の浸透圧比は1.00、pHは6.6であった。
【0022】
試 験 例 1
角膜上皮障害防止試験:
長野らの方法(長野敬ほか:あたらしい眼科,13,267-270,1996)をもとに家兎強制開瞼ドライアイモデルを作製して実施例および比較例の各点眼剤の作用を調べた。すなわち、家兎をカルバミド酸エチル麻酔下(2g/kg s.c.)、開瞼器を装着した状態で強制的に3時間開瞼することによりドライアイモデルを作製した。
【0023】
涙液の薬効評価への影響をできるだけ少なくするため、強制開瞼約30分前にアトロピンを2滴点眼した。開瞼開始直後に生理食塩液にて眼球を洗浄した。各点眼液は強制開瞼開始時より1時間ごとに100μLずつの計3回点眼した。
【0024】
3時間の強制開瞼後、過剰のネンブタール注射液を静注することにより安楽死させ、眼球を摘出した。摘出した眼球の角膜を1%メチレンブルーにより染色後、生理食塩液で洗浄し、角膜を切り出した。切り出した角膜は飽和硫酸ナトリウム・アセトン混液(3:7)3mLに一晩浸漬した。翌日振盪器により10分間振盪することによりメチレンブルーを抽出した。抽出したメチレンブルーは分光光度計により660nm付近の最大吸収波長における吸光度を測定し、色素量を求めた。この結果を表1に示す。
【0025】
( 結 果 )
【表1】
【0026】
表1に示すように、角膜上皮障害の指標として障害部位を染色する色素量を測定した結果、実施例1、実施例2および実施例3は比較例1と比して統計的有意に色素量の減少を認めた。本モデルは角膜上皮組織像は、ヒトドライアイの状態と酷似したものであり、本モデルで効果の認められた深層水を配合した本発明の眼科用剤は、ドライアイもしくは角膜上皮障害の治癒効果が期待できる有用な薬剤であると判断された。
【0027】
【発明の効果】
本発明の眼科用剤に配合される深層水は、ドライアイなどに伴う角膜上皮障害に有効であるとともに、副作用の極めて弱いものと考えられており、頻繁に投与したとしても問題が生じる虞がないものである。
【0028】
従って、本発明の眼科用剤は目の酷使により生じるドライアイ等を防止する点眼剤等として広く使用することが可能なものである。
以 上[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an ophthalmic agent formulated with deep water, and more particularly to an ophthalmic agent that is advantageously used for the treatment of corneal epithelial disorders such as dry eye.
[0002]
[Prior art]
In recent years, with the widespread use of information equipment, the number of people who overuse their eyes by going to display devices for a long time has increased, and in proportion to this, the number of patients with corneal epithelial disorders due to dry eyes and the like has also increased.
[0003]
Conventionally, eye drops containing mucopolysaccharides such as hyaluronic acid and chondroitin sulfate as active ingredients have been used for the treatment of these corneal epithelial disorders. However, these eye drops are used daily for reasons such as side effects. Limited to several doses.
[0004]
However, the dry eye and the pain caused by the dry eye have a problem that the symptoms cannot be sufficiently resolved by administration several times a day since the administration of the eye drops can provide only a temporary effect.
[0005]
[Problems to be solved by the invention]
Accordingly, there has been a demand for providing an ophthalmic agent that can effectively prevent and treat corneal epithelial disorders such as dry eye and that does not cause safety problems even if it is frequently used.
[0006]
[Means for Solving the Problems]
The present inventors have been diligently searching for components that can be blended in an ophthalmic agent in order to solve the above-mentioned problems. As a result, nitrate nitrogen, phosphate phosphorus, and silicate silicon are 10 to 20 in comparison with surface seawater. It has been found that the deep ocean water containing twice as much has a corneal repairing effect, and the ophthalmic agent containing this is effective for corneal epithelial disorder associated with dry eye. Furthermore, by adding flavonoids and terpenes, which are natural antibacterial compounds, storage stability can be improved without adding a quaternary ammonium cationic surfactant that is widely used as a preservative. The present invention has been completed by finding out what can be done.
[0007]
That is, the present invention provides an ophthalmic agent containing deep water.
[0008]
The present invention further provides the above ophthalmic agent containing a flavonoid or a terpene as an antibacterial agent.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The deep water used in the ophthalmic preparation of the present invention is deep water in the ocean, which is attracting attention as being rich in nutrients such as inorganic salts and is being studied for application in various fields. This deep water refers to seawater pumped from a depth of 200m deeper in the ocean, and products containing deep water are already on the market in the drinking water and cosmetics fields, and skin such as atopic dermatitis. Although it has been reported that it is effective for diseases (Japanese Patent Application Laid-Open Nos. 9-67258 and 9-110702), there is no report on the application of this deep water to the ophthalmic field.
[0010]
There are no particular restrictions on the location of the deep water used in the ophthalmic preparation of the present invention, and any of the deep water collected offshore such as Toyama, Okinawa, Kochi, etc., currently being collected. Can be used. Further, the blending amount of the deep layer water with respect to the ophthalmic agent is not particularly limited. For example, it has been confirmed that the eye irritation is not so strong even if the eye is washed or washed with the deep layer water as it is. However, since the osmotic pressure ratio of the deep water is about 3.5, it is desirable to dilute it with purified water about 3 to 4 times.
[0011]
In the ophthalmic preparation of the present invention, the deep-layer water is substantially the active ingredient, but other active ingredients in the ophthalmic field, such as sodium hyaluronate, sodium chondroitin sulfate, erythromycin, ofloxane, indomethacin, epsilon aminocaproic acid, allite in It does not prevent the addition of dipotassium glycyrrhizinate, chlorpheniramine maleate, zinc sulfate, aspartate, various vitamins and the like.
[0012]
In addition, the ophthalmic agent of the present invention may be blended with additives that can generally be used in ophthalmic agents, such as antibacterial agents, solubilizers, cooling agents, tonicity agents, stabilizers, and buffering agents. it can.
[0013]
When the ophthalmic preparation of the present invention is used for dry eye patients, it is assumed that it is instilled, applied or washed many times a day, so there is a concern about side effects as the above active ingredients and additives. It is preferable to reduce the blending amount of the components as much as possible.
[0014]
For example, in general ophthalmic agents, a quaternary ammonium cationic surfactant such as benzalkonium chloride having an antibacterial action as an antiseptic is often blended. Corneal damage has been reported and may reduce the effects of the present invention. Therefore, in the present invention, natural antibacterial compounds, in particular, flavonoid compounds such as catechin, catechol and theaflavin, and terpenes such as terpinen-4-ol, linalool, napol and carvon can be used as the antibacterial agent. preferable. These antibacterial agents are preferably added in an amount of about 0.0005 to 0.2% by mass (hereinafter referred to as “%”) in the ophthalmic agent, and particularly preferably about 0.003 to 0.1%. is there.
[0015]
The ophthalmic preparation of the present invention thus obtained can be in various forms, such as eye drops, eye ointments, eyewashes, and the like. And since the side effect of deep water is considered to be extremely small, the ophthalmic preparation of the present invention can be used frequently.
[0016]
【Example】
EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.
[0017]
Example 1
Ophthalmic solution 1:
An ophthalmic solution container was filled with 100 ml of deep layer water (hereinafter simply referred to as “deep layer water”) collected off Toyama Prefecture. This ophthalmic solution had an osmotic pressure ratio (relative to physiological saline) of 3.48 and a pH of 7.7.
[0018]
Example 2
Ophthalmic solution 2:
An ophthalmic solution container was filled with 100 ml of a solution obtained by diluting the deep layer water 3.5 times with purified water to obtain an ophthalmic solution. This ophthalmic solution had an osmotic pressure ratio of 1.08 and a pH of 7.6.
[0019]
Example 3
Ophthalmic solution 3:
Deep water was added to 0.03 g of catechin to make the total amount 100 ml, which was then filled into an ophthalmic solution container to obtain an ophthalmic solution. This ophthalmic solution had an osmotic pressure ratio of 3.53 and a pH of 7.5.
[0020]
Example 4
Ophthalmic solution 4:
A 3.5-fold diluted solution of purified water of deep layer water was added to 0.03 g of catechin to make a total volume of 100 ml, which was then filled into an ophthalmic solution container to obtain an ophthalmic solution. The ophthalmic solution had an osmotic pressure ratio of 1.10 and a pH of 7.3.
[0021]
Comparative Example 1
Comparative ophthalmic solution:
An eye drop container was filled with 100 ml of physiological saline to obtain a comparative eye drop. The ophthalmic solution had an osmotic pressure ratio of 1.00 and a pH of 6.6.
[0022]
Test example 1
Corneal epithelial disorder prevention test:
Based on the method of Nagano et al. (Takashi Nagano et al .: New Ophthalmology, 13,267-270, 1996), a rabbit's forced open eye dry eye model was prepared, and the action of each eye drop in Examples and Comparative Examples was examined. That is, a dry eye model was prepared by forcibly opening a rabbit for 3 hours under anesthesia with ethyl carbamate (2 g / kg sc) and wearing a cleaver.
[0023]
In order to minimize the effect of tears on drug efficacy evaluation, two drops of atropine were instilled approximately 30 minutes before forced opening. Immediately after the opening of the eyelids, the eyeball was washed with physiological saline. Each ophthalmic solution was instilled three times, 100 μL each hour from the start of forced eye opening.
[0024]
After 3 hours of forced cleaving, an excess of Nembutal injection was intravenously injected to euthanize and the eyeball was removed. The cornea of the removed eyeball was stained with 1% methylene blue, washed with physiological saline, and the cornea was cut out. The cut cornea was immersed in 3 mL of a saturated sodium sulfate / acetone mixture (3: 7) overnight. The next day, methylene blue was extracted by shaking with a shaker for 10 minutes. The extracted methylene blue was measured for absorbance at a maximum absorption wavelength near 660 nm with a spectrophotometer to determine the amount of dye. The results are shown in Table 1.
[0025]
(Result)
[Table 1]
[0026]
As shown in Table 1, as a result of measuring the amount of dye that stains the damaged site as an index of corneal epithelial disorder, Example 1, Example 2, and Example 3 are statistically significantly more pigmentous than Comparative Example 1. Decreased. In this model, the corneal epithelial tissue image is very similar to the state of human dry eye, and the ophthalmic agent of the present invention containing the deep water that has been confirmed to be effective in this model can cure dry eye or corneal epithelial disorder. It was judged to be a useful drug that can be expected to be effective.
[0027]
【The invention's effect】
Deep water blended in the ophthalmic preparation of the present invention is effective for corneal epithelial disorders associated with dry eye and the like, and is considered to have extremely weak side effects, and may cause problems even if administered frequently. There is nothing.
[0028]
Therefore, the ophthalmic preparation of the present invention can be widely used as an eye drop for preventing dry eye and the like caused by overuse of the eyes.
more than
Claims (3)
Priority Applications (1)
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JP2001133915A JP4813682B2 (en) | 2001-05-01 | 2001-05-01 | Ophthalmic agent |
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JP2001133915A JP4813682B2 (en) | 2001-05-01 | 2001-05-01 | Ophthalmic agent |
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JP2002326941A JP2002326941A (en) | 2002-11-15 |
JP4813682B2 true JP4813682B2 (en) | 2011-11-09 |
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JP2001133915A Expired - Fee Related JP4813682B2 (en) | 2001-05-01 | 2001-05-01 | Ophthalmic agent |
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Cited By (1)
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JP7362008B1 (en) | 2023-04-19 | 2023-10-16 | 三菱電機株式会社 | Arc-extinguishing plates and circuit breakers |
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ITMI20022353A1 (en) * | 2002-11-06 | 2004-05-07 | Farmaceutici S R L | COMPOSITION OF A PREPARATION FOR THE EYES WITH ANTIALLERGIC, ANTIBACTERIAL AND DISARROSSING ACTIVITY. |
KR20050014254A (en) * | 2003-07-30 | 2005-02-07 | 임자 | Pharmaceutical composition comprising Bando Deep Ocean Water or the concentrate thereof having anti-cancer activity |
JP2008303182A (en) * | 2007-06-08 | 2008-12-18 | Goshu Yakuhin Kk | Isotonic solution |
KR101401854B1 (en) * | 2012-05-24 | 2014-05-29 | 가톨릭대학교 산학협력단 | Composition for cleaning eyeball comprising mineral water |
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JPH02276562A (en) * | 1989-04-19 | 1990-11-13 | Mitsui Norin Kk | Antimicrobial agent |
JPH0421606A (en) * | 1990-05-17 | 1992-01-24 | Shiono Koryo Kk | Volatile antibacterial and antifungal agent |
FR2778562B1 (en) * | 1998-05-14 | 2000-08-04 | Sephra | PHARMACEUTICAL, HYGIENIC AND / OR COSMETIC COMPOSITION CONTAINING SEAWATER AND ARGININE |
US6162393A (en) * | 1998-08-06 | 2000-12-19 | Ndt, Inc. | Contact lens and ophthalmic solutions |
JP2000247873A (en) * | 1999-02-24 | 2000-09-12 | Taisho Pharmaceut Co Ltd | Composition for erasing sense of incompatibility at mucosal site |
JP4687837B2 (en) * | 1999-09-29 | 2011-05-25 | ライオン株式会社 | Ophthalmic composition |
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JP7362008B1 (en) | 2023-04-19 | 2023-10-16 | 三菱電機株式会社 | Arc-extinguishing plates and circuit breakers |
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