【発明の詳細な説明】「産業上の利用分野」本発明は酸化をグルタチオンまたはその塩類を主成分と
する角膜疾患治療用点眼剤に関する。DETAILED DESCRIPTION OF THE INVENTION "Field of Industrial Application" The present invention relates to eye drops for treating corneal diseases that contain oxidized glutathione or its salts as a main component.
「従来技術、発明が解決しようとする課題および課題を
解決するための手段」還元塵グルタチオンはＳＨ酵素系を介して組織内呼吸の
円滑な運転に関与しているが、角膜潰瘍、角膜上皮剥離
、角膜炎などの角膜疾患時にその濃度が減少することが
知られている。（あたらしい眼科２．２１（１９８５）
）そこで、これらの角膜疾患に対し、還元型グルタチオ
ン点眼剤を用いてグルタチオ／を補給し、角膜上皮組織
の修復を促進する方法が行なわれている。"Prior art, problems to be solved by the invention, and means for solving the problems" Reduced dust glutathione is involved in the smooth operation of tissue respiration through the SH enzyme system, but it has been shown to cause corneal ulcers and corneal epithelial detachment. It is known that its concentration decreases during corneal diseases such as keratitis. (New Ophthalmology 2.21 (1985)
) Therefore, methods have been used to treat these corneal diseases by using reduced glutathione eye drops to replenish glutathione and promote repair of the corneal epithelial tissue.
ところが、還元型グルタチオンは製剤中での安定性が悪
く、点眼剤では使用時に還元型グルタチオンの錠剤や顆
粒を溶解して用いなければならなかった。However, reduced glutathione has poor stability in formulations, and reduced glutathione tablets or granules must be dissolved before use in eye drops.
このことから、角膜疾患の治療に有用で、かつ安定性に
優れた点眼剤を検討する必要があった。For this reason, it was necessary to investigate eye drops that are useful for the treatment of corneal diseases and have excellent stability.
そこで、本発明者らはこの問題について鋭意検討した結
果、酸化型グルタチオン点眼剤が創傷治癒促進作用を有
しており、角膜潰瘍等の角膜疾患に有用であることを見
い出した。又、酸化型グルタチオン点眼剤は安定性の点
において、還元型グルタチオンよシもはるかに優れてい
ることを見い出した。The inventors of the present invention conducted extensive studies on this problem and found that oxidized glutathione eye drops have a wound healing promoting effect and are useful for corneal diseases such as corneal ulcers. We have also found that oxidized glutathione eye drops are far superior to reduced glutathione in terms of stability.
「発明の開示」本発明は酸化型グルタチオンまたはその塩類（以下酸化
型グルタチオンと総称する）を主成分とする角膜疾患治
療用点眼剤に関する。"Disclosure of the Invention" The present invention relates to an eye drop for treating corneal diseases, which contains oxidized glutathione or its salts (hereinafter collectively referred to as oxidized glutathione) as a main ingredient.
上記の塩としては医薬として許容されるものであればよ
く、例えばナトリウム、カリウム、カルシウム、マグネ
シウムなどの金属塩や有機アミン塩などが含まれる。The above-mentioned salts may be any pharmaceutically acceptable salts, and include, for example, metal salts such as sodium, potassium, calcium, and magnesium, and organic amine salts.
又、本発明でいう角膜疾患とは角膜潰瘍、角膜上皮剥離
、角膜炎などをいう。Furthermore, the term "corneal disease" as used in the present invention refers to corneal ulcer, corneal epithelial detachment, keratitis, and the like.
還元型グルタチオンはＳＨ酵素系を介して組織内呼吸の
円滑な運転に関与しているが、角膜潰瘍、角膜上皮剥離
、角膜炎などの角膜疾患時にその濃度が減少することが
知られている。（あたらしい眼科２．２１ （１９８５
））そこで、とれらの角膜疾患に対し、還元型グルタチオン
点眼剤を用いてグルタチオンを補給し、角膜上皮組織の
修復を促進する方法が行なわれている。Reduced glutathione is involved in the smooth operation of tissue respiration via the SH enzyme system, but its concentration is known to decrease during corneal diseases such as corneal ulcers, corneal epithelial abrasion, and keratitis. (New Ophthalmology 2.21 (1985)
)) Therefore, methods are being used to treat these corneal diseases by using reduced glutathione eye drops to replenish glutathione and promote repair of the corneal epithelial tissue.
ところが、還元型グルタチオンは製剤中での安定性が悪
く、点眼剤では使用時に還元型グルタチオンの錠剤や顆
粒を溶解して用いなければならなかった。However, reduced glutathione has poor stability in formulations, and reduced glutathione tablets or granules must be dissolved before use in eye drops.
このことから、角膜疾患の治療に有用で、かつ安定性に
優れた点眼剤を検討する必要があった。For this reason, it was necessary to investigate eye drops that are useful for the treatment of corneal diseases and have excellent stability.
そこで、本発明者らはこの問題について鋭意検討を行な
った。その結果、酸化型グルタチオン点眼剤が創傷治癒
促進作用を有しておυ、角膜潰瘍等の角膜疾患に有用で
あることを見い出した。Therefore, the inventors of the present invention conducted extensive studies on this problem. As a result, we found that oxidized glutathione eye drops have a wound healing promoting effect and are useful for corneal diseases such as corneal ulcers.
醸化型グルタチオンは２分子の還元減グルタチオンの一
８Ｈ基が酸化されて−５−８−結合した化合物であるが
、眼疾患に対する酸化型グルタチオンの作用については
知られておらず、酸化型グルタチオンが角膜疾患に有効
である事を本発明で初めて明らかにしたものである。Fermented glutathione is a compound in which two molecules of reduced-reduced glutathione's 18H groups are oxidized and bonded to -5-8, but the effects of oxidized glutathione on eye diseases are not known. The present invention revealed for the first time that this method is effective for treating corneal diseases.
本発明者らは角膜疾患の治療剤として酸化型グルタチオ
ンの点眼剤を用いることを検討し、その有用性の指標と
して酸化型グルタチオンの角膜創傷治癒促進効果につい
て調べた。詳しくは薬理試験の項で述べるが、酸化型グ
ルタチオンを含有する本発明点眼剤は、対照の基剤と比
較して明らかに角膜創傷治癒促進作用を有しており、角
膜疾患の治療剤として有用であることが明らかとなつ九
又、本発明点眼剤は安定性試験の項で述べるように非常
に安定であり、還元型グルタチオンの水溶液を室温１ケ
月保存したものの定量値が約９゜チとなシ組成に変化を
きたすのに対し、同じ条件で本発明点眼剤を保存したも
のの定量値はほとんど低下しておらず、組成の変化は認
められなかった。The present inventors investigated the use of oxidized glutathione eye drops as a therapeutic agent for corneal diseases, and investigated the corneal wound healing promoting effect of oxidized glutathione as an indicator of its usefulness. As will be described in detail in the pharmacological test section, the eye drops of the present invention containing oxidized glutathione clearly have a corneal wound healing promoting effect compared to the control base, and are useful as therapeutic agents for corneal diseases. It has become clear that the eye drops of the present invention are very stable, as described in the stability test section, and the quantitative value of an aqueous solution of reduced glutathione stored at room temperature for one month was approximately 9°. However, when the eye drops of the present invention were stored under the same conditions, the quantitative value hardly decreased, and no change in composition was observed.
以上のように、本発明点眼剤は角膜創傷治癒促進作用を
有し、かつ安定性にも優れたものである。As described above, the eye drops of the present invention have a corneal wound healing promoting effect and also have excellent stability.
本発明点眼剤の酸化型グルタチオンの濃度はその効果が
発揮できるものであればよく、０．５〜５チのものが好
ましいが、症状、年令などによって適宜選択すればよい
。The concentration of oxidized glutathione in the eye drops of the present invention may be any concentration as long as it can exhibit its effects, and is preferably 0.5 to 5%, but may be appropriately selected depending on symptoms, age, etc.
ｐＨは眼科製剤に許容される範囲内にあればよいが、４
〜７の範囲が好ましい。The pH may be within the range acceptable for ophthalmic preparations, but
The range of 7 to 7 is preferable.
本製剤には点眼剤として通常に用いられる添加物、例え
ばバラオキシ安息香酸エステル、塩化ベンザルコニウム
などの防腐剤、塩化ナトリウム、グリセリン、マンニト
ールなどの等張化剤、ε−アミノカプロン酸、酢酸ナト
リウム、リン酸ナトリウムなどの緩衝化剤、エデト酸ナ
トリウムなどの安定化剤、ポリビニルアルコールなどの
ｆｉｎ（ビ剤、希塩酸、水酸化ナトリウムなどのｐＨ調
節剤等を必要に応じて用いることができる。This preparation contains additives commonly used in eye drops, such as preservatives such as roseoxybenzoic acid ester and benzalkonium chloride, isotonic agents such as sodium chloride, glycerin, and mannitol, ε-aminocaproic acid, sodium acetate, Buffering agents such as sodium phosphate, stabilizing agents such as sodium edetate, fins such as polyvinyl alcohol (vinyl alcohol, pH adjusting agents such as dilute hydrochloric acid, sodium hydroxide, etc.) can be used as necessary.
このようにして得られた点眼剤は、通常１回１滴〜数滴
、１日１回〜数回投与することができる。The eye drops thus obtained can usually be administered from one drop to several drops at a time, once to several times a day.
尚、本発明点眼剤の剤型は点眼液、眼軟膏のいずれでも
よい。以下に実施例としてその製剤例をあげる。The dosage form of the eye drops of the present invention may be either an eye drop or an eye ointment. Examples of the formulation are given below as examples.
「実施例」実施例１（点眼液）処方１１００献中酸化型グルタチオンε−アミノカプロン酸塩化ナトリウム塩化ベンザルコニウム水酸化ナトリウム滅菌精製水製法滅菌精製水８ｏｔ！ｉに酸化型グルタチオン、Ｃ−アミ
ノカプロン酸、塩化ナトリウム、塩化ベンザルコニウム
を加えて溶解した後、水酸化ナトリウムを用いてｐＨを
５．０に調節する。滅菌２゜Ｏｙ０．２２０．６ｙｏ、ｏ ｏ ｓ ｙ適量精製水を加えて全量を１００ｄとする。"Example" Example 1 (Eye Drops) Prescription 1100 Oxidized glutathione ε-aminocaproic acid Sodium chloride Benzalkonium chloride Sodium hydroxide Sterile purified water production method Sterile purified water 8 ots! After adding and dissolving oxidized glutathione, C-aminocaproic acid, sodium chloride, and benzalkonium chloride in i, the pH is adjusted to 5.0 using sodium hydroxide. Sterilize 2°Oy 0.22 0.6y o, oosy Add an appropriate amount of purified water to make a total volume of 100d.
上記の同様の方法を用いて処方２〜４の点眼液を調製し
た。Eye drops of formulations 2-4 were prepared using a similar method as described above.
処方２ １００ｍｆｆ中 （ＰＨ６，０）酸化型グルタ
チオン ２．０ ？酢酸ナトリウム
０．２７塩化ナトリウム ０．６ｙ
塩化ベンザルコニウム ｏ、ｏ ｏ ｓ ｙエデ
ト酸ナトリウム ｏ、ｏ ｉ ｙ希塩酸もしく
は水酸化ナトリウム 適量滅菌精製水処方３１００−中 （ｐＨ５，０）酸化型グル、タチオン ２．０ ｙ酢酸ナトリ
ウム ０．２ｊ；’グリセリン
２．０９パラオキシ安息香酸メチル ｏ、ｏ ｏ ｓ ｙ
パラオキシ安息香酸プロピル ０．０１ ｐ水酸化
ナトリウムもしくは希塩酸 適量滅菌精製水処方４１００ｍｅ中 （ｐＨ５，２）酸化屋グルタチオン ２．０ ？ポリビニルア
ルコール １．０ｙマンニトール
３．５２塩化ベンザルコニウム ｏ、ｏ ｏ
ｓ ｙ水酸化ナトリウム 適量滅菌精製水実施例２処方５（眼軟膏）１００ｙ中酸化型グルタチオン ２．Ｏｆ流動パラフィン
１０ｆ白色ワセリン ８８２製法流動パラフィンの中に酸化型グルタチオンを加えて分散
させる。これを８０°Ｃに熱した白色パラフィン中に加
え、脱気しながらゆっくりと撹拌し室温まで冷却する。Prescription 2 100mff (PH6,0) Oxidized glutathione 2.0? sodium acetate
0.27 Sodium chloride 0.6y
Benzalkonium chloride o, o o sy Sodium edetate o, o i y Dilute hydrochloric acid or sodium hydroxide Appropriate amount in sterile purified water (pH 5,0) Oxidized glu, tathion 2.0 y Sodium acetate 0.2j ;'Glycerin
2.09 Methyl paraoxybenzoate o, o o s y
Propyl paraoxybenzoate 0.01 p Sodium hydroxide or dilute hydrochloric acid in 4100ml of sterile purified water (pH 5,2) Oxidized glutathione 2.0 ? Polyvinyl alcohol 1.0y mannitol
3.52 Benzalkonium chloride o, o o
sy Sodium hydroxide Appropriate amount Sterile purified water Example 2 Prescription 5 (eye ointment) 100y Medium oxidized glutathione 2. Of Liquid Paraffin 10f White Petrolatum 882 Production Method Add oxidized glutathione to liquid paraffin and disperse. This is added to white paraffin heated to 80°C, stirred slowly while degassing, and cooled to room temperature.
安定性試験本発明点眼剤の安定性を調べるため、ｐＨを６に調整し
た２％の酸化型グルタチオン水溶液と還元型グルタチオ
ン水溶液を作り、室温で１ケ月間保存した後、その残存
率を測定した。Stability test In order to examine the stability of the eye drops of the present invention, a 2% aqueous oxidized glutathione solution and a reduced glutathione aqueous solution were prepared with pH adjusted to 6, and after storing them at room temperature for one month, the residual rate was measured. .
その結果、還元型グルタチオン水溶液の残存率が約９０
％であったのに対して、酸化型グルタチオン水溶液では
残存率の低下はほとんど認められなかった。As a result, the residual rate of the reduced glutathione aqueous solution was approximately 90%.
%, whereas in the oxidized glutathione aqueous solution, almost no decrease in the residual rate was observed.
このことから本発明点眼剤が還元型グルタチオン点眼剤
に比べて安定性がはるかに優れていることがわかる。This shows that the eye drops of the present invention have much better stability than the reduced glutathione eye drops.
薬理試験角膜疾患の治療剤としての有用性を検討するため、本発
明点眼剤の角膜創傷治癒促進作用について調べた。薬物
の角膜創傷治癒促進作用を調べる方法としては、ｎ−ヘ
プタツールを用いた角膜上皮剥離法が知られているので
この方法を用いた。Pharmacological Test In order to examine its usefulness as a therapeutic agent for corneal diseases, the corneal wound healing promoting effect of the eye drops of the present invention was investigated. A corneal epithelial ablation method using n-heptatool is known as a method for examining the corneal wound healing promoting effect of drugs, and this method was used.
（実験方法）実験はＣ１ｎｔｒｏｎらの方法（Ｏｐｈｔｈａｌｍｉａ
Ｒｅａ、。(Experimental method) The experiment was conducted using the method of C1ntron et al. (Ophthalmia
Rea,.
１１．９０（１９７９））を用いて行なった。酸化型グ
ルタチオンを生理食塩液（０，９％塩化ナトリウム液）
に溶かし、ｐＨ６，０に調製したものをウサギの角膜上
皮剥離後、１回１滴、１日４回点眼した。創傷面積を測
定することによシ角膜創傷治癒促進作用を調べた。尚、
対照として生理食塩液を用いた。11.90 (1979)). Oxidized glutathione in physiological saline (0.9% sodium chloride solution)
After abrasion of the corneal epithelium of a rabbit, one drop of the solution was adjusted to pH 6.0 and instilled into the eyes of the rabbit, four times a day. The corneal wound healing promoting effect was investigated by measuring the wound area. still,
Physiological saline was used as a control.
（実験結果）点眼直前の創傷面積を１００％として各時間での創傷面
積を表に示した。(Experimental Results) The wound area at each time point is shown in the table, with the wound area immediately before instillation taken as 100%.
表「発明の効果」表に示されているように本発明点眼剤を点眼したものは
明らかに対照群よりも創傷面積が小さく、創傷治癒の促
進作用が認められた。Table ``Effects of the Invention'' As shown in the table, the wound area of the eye drops treated with the eye drops of the present invention was clearly smaller than that of the control group, and the effect of promoting wound healing was observed.
この結果から、本発明点眼剤が角膜炎などの角膜疾患治
療剤として有用であることが示された。These results showed that the eye drops of the present invention are useful as a therapeutic agent for corneal diseases such as keratitis.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1011497AJPH0611704B2 (en) | 1989-01-19 | 1989-01-19 | Eye drops for corneal disease treatment |
| KR1019890011003AKR960013437B1 (en) | 1988-08-05 | 1989-08-01 | Oxidized glutathion eye-drops |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1011497AJPH0611704B2 (en) | 1989-01-19 | 1989-01-19 | Eye drops for corneal disease treatment |
| Publication Number | Publication Date |
|---|---|
| JPH02193931Atrue JPH02193931A (en) | 1990-07-31 |
| JPH0611704B2 JPH0611704B2 (en) | 1994-02-16 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1011497AExpired - LifetimeJPH0611704B2 (en) | 1988-08-05 | 1989-01-19 | Eye drops for corneal disease treatment |
| Country | Link |
|---|---|
| JP (1) | JPH0611704B2 (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| ES2136557A1 (en)* | 1997-08-22 | 1999-11-16 | Martinez Parra Aurelio Juan | Product for treatment of keratitis sicca. |
| WO2000076454A3 (en)* | 1999-06-14 | 2001-06-28 | Advanced Medicine Res Inst | Therapeutic compositions for ophthalmic use and therapeutic compositions for brain central lesions |
| JP2002506808A (en)* | 1998-03-19 | 2002-03-05 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | Glycogen-containing ophthalmic solution |
| US7371411B2 (en) | 1998-11-23 | 2008-05-13 | Novelos Therapeutics, Inc. | Methods for production of the oxidized glutathione composite with CIS-diamminedichloroplatinum and pharmaceutical compositions based thereof regulating metabolism, proliferation, differentiation and apoptotic mechanisms for normal and transformed cells |
| JP2011219446A (en)* | 2010-04-14 | 2011-11-04 | Rohto Pharmaceutical Co Ltd | Ophthalmic composition for contact lens |
| JP2011221464A (en)* | 2010-04-14 | 2011-11-04 | Rohto Pharmaceut Co Ltd | Ophthalmologic composition for contact lens |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH072647A (en)* | 1991-10-02 | 1995-01-06 | Ocular Res Of Boston Inc | Method for medical treatment and solution for dry eye |
| ES2136557A1 (en)* | 1997-08-22 | 1999-11-16 | Martinez Parra Aurelio Juan | Product for treatment of keratitis sicca. |
| JP2002506808A (en)* | 1998-03-19 | 2002-03-05 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | Glycogen-containing ophthalmic solution |
| US7371411B2 (en) | 1998-11-23 | 2008-05-13 | Novelos Therapeutics, Inc. | Methods for production of the oxidized glutathione composite with CIS-diamminedichloroplatinum and pharmaceutical compositions based thereof regulating metabolism, proliferation, differentiation and apoptotic mechanisms for normal and transformed cells |
| WO2000076454A3 (en)* | 1999-06-14 | 2001-06-28 | Advanced Medicine Res Inst | Therapeutic compositions for ophthalmic use and therapeutic compositions for brain central lesions |
| JP2011219446A (en)* | 2010-04-14 | 2011-11-04 | Rohto Pharmaceutical Co Ltd | Ophthalmic composition for contact lens |
| JP2011221464A (en)* | 2010-04-14 | 2011-11-04 | Rohto Pharmaceut Co Ltd | Ophthalmologic composition for contact lens |
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| JPH0611704B2 (en) | 1994-02-16 |
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