JP2019038783A - Dry eye therapeutic agent - Google Patents
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- JP2019038783A JP2019038783A JP2017162912A JP2017162912A JP2019038783A JP 2019038783 A JP2019038783 A JP 2019038783A JP 2017162912 A JP2017162912 A JP 2017162912A JP 2017162912 A JP2017162912 A JP 2017162912A JP 2019038783 A JP2019038783 A JP 2019038783A
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- 208000003556 Dry Eye Syndromes Diseases 0.000 title claims abstract description 33
- 206010013774 Dry eye Diseases 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title abstract description 10
- 229940124597 therapeutic agent Drugs 0.000 title abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- AMZWNNKNOQSBOP-UHFFFAOYSA-M [n'-(2,5-dioxoimidazolidin-4-yl)carbamimidoyl]oxyaluminum;dihydrate Chemical compound O.O.NC(=O)NC1N=C(O[Al])NC1=O AMZWNNKNOQSBOP-UHFFFAOYSA-M 0.000 claims abstract description 19
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- 230000001225 therapeutic effect Effects 0.000 abstract description 4
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- 239000003889 eye drop Substances 0.000 description 13
- 239000002997 ophthalmic solution Substances 0.000 description 11
- 229940054534 ophthalmic solution Drugs 0.000 description 11
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- 229940012356 eye drops Drugs 0.000 description 9
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- 230000006378 damage Effects 0.000 description 7
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- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 6
- 229960000458 allantoin Drugs 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000004561 lacrimal apparatus Anatomy 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
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- 230000000694 effects Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
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- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
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- OWTGMPPCCUSXIP-FNXFGIETSA-J tetrasodium;[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [[[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].N1([C@@H]2O[C@@H]([C@H]([C@H]2O)O)COP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@H]([C@@H](O2)N2C(NC(=O)C=C2)=O)O)O)C=CC(=O)NC1=O OWTGMPPCCUSXIP-FNXFGIETSA-J 0.000 description 2
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- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical compound C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
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- 239000000556 agonist Substances 0.000 description 1
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- 230000004064 dysfunction Effects 0.000 description 1
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
【課題】本発明は、ドライアイの治療に有用な医薬組成物を提供することを課題とする。【解決手段】本発明は、本発明は、ドライアイの治療に有用な医薬組成物に関する。さらに詳しくは、アルジオキサ（ジヒドロキシアルミニウムアラントイナート）を含有する、ドライアイの治療に有用な医薬組成物に関する。本発明の医薬組成物は、ドライアイにおける角膜上皮障害の治療効果を有する。したがって、本発明の医薬組成物は、ドライアイ治療の治療剤として有用である。【選択図】図１An object of the present invention is to provide a pharmaceutical composition useful for the treatment of dry eye. The present invention relates to a pharmaceutical composition useful for the treatment of dry eye. More particularly, the present invention relates to a pharmaceutical composition useful for the treatment of dry eye, which contains aldioxa (dihydroxyaluminum allantoate). The pharmaceutical composition of the present invention has a therapeutic effect on corneal epithelial disorder in dry eye. Therefore, the pharmaceutical composition of the present invention is useful as a therapeutic agent for dry eye treatment. [Selection] Figure 1
Description
本発明は、ドライアイの治療に有用な医薬組成物に関する。 The present invention relates to pharmaceutical compositions useful for the treatment of dry eye.
さらに詳しくは、本発明は、アルジオキサ（ジヒドロキシアルミニウムアラントイナート）を含有する、ドライアイの治療に有用な医薬組成物に関する。 More particularly, the present invention relates to a pharmaceutical composition useful for the treatment of dry eye comprising aldioxa (dihydroxyaluminum allantoate).
近年、空調の普及、VDT（visual display terminals）作業者の増加等により、ドライアイの患者数は急増している。そのため、ドライアイ治療の重要性が高まっている（非特許文献１）。 In recent years, the number of dry eye patients has been rapidly increasing due to the spread of air conditioning, the increase of VDT (visual display terminals) workers, and the like. Therefore, the importance of dry eye treatment is increasing (Non-Patent Document 1).
ドライアイの薬物治療には、水分補給を目的とした人工涙液、水分保持作用を有するヒアルロン酸ナトリウム点眼液等が用いられている。日本国内においては、近年、ジクアホソルナトリウム又はレバミピドを有効成分とするドライアイ治療剤が販売されている。しかしながら、ドライアイの治療剤は、他疾患の治療剤に比べ選択肢が少なく、新たなドライアイ治療剤の開発が望まれている。 For the treatment of dry eye, artificial tears for the purpose of rehydration, sodium hyaluronate ophthalmic solution having a water retaining action, and the like are used. In Japan, dry eye therapeutic agents containing diquafosol sodium or rebamipide as an active ingredient have recently been marketed. However, therapeutic agents for dry eye have fewer options than therapeutic agents for other diseases, and development of new therapeutic agents for dry eye is desired.
アラントインの誘導体であるアルジオキサは、胃潰瘍、十二指腸潰瘍、及び胃炎の症状改善を効能・効果に有する薬剤として知られている。また、アルジオキサを含有する軟膏剤の皮膚炎症に対する効果が報告されている（非特許文献2）。しかしながら、アルジオキサがドライアイの治療剤として有用であることは、前記文献には記載されていない。 Aldioxa, which is a derivative of allantoin, is known as a drug having an effect and an improvement of symptoms of gastric ulcer, duodenal ulcer and gastritis. In addition, the effect of aldioxa-containing ointments on skin inflammation has been reported (Non-patent Document 2). However, the usefulness of aldioxa as a therapeutic agent for dry eye is not described in the above-mentioned reference.
本発明は、ドライアイの治療に有用な医薬組成物を提供することを課題とする。 An object of the present invention is to provide a pharmaceutical composition useful for the treatment of dry eye.
本発明は、下記の〔１〕及び〔２〕等に関する。
〔１〕アルジオキサを含有する、ドライアイの治療用医薬組成物。
〔２〕ドライアイにおける角膜上皮障害の治療用医薬組成物である、前記〔１〕に記載の医薬組成物。
The present invention relates to the following [1] and [2] and the like.
[1] A pharmaceutical composition for treating dry eye, which comprises aldioxa.
[2] The pharmaceutical composition according to the above-mentioned [1], which is a pharmaceutical composition for treating a corneal epithelial disorder in dry eye.
本発明の医薬組成物は、ドライアイにおける角膜上皮障害の治療効果を有する。したがって、本発明の医薬組成物は、ドライアイの治療剤として有用である。 The pharmaceutical composition of the present invention has a therapeutic effect on corneal epithelial disorders in dry eye. Therefore, the pharmaceutical composition of the present invention is useful as a therapeutic agent for dry eye.
以下、本発明の実施の形態についてより詳細に説明する。 Hereinafter, embodiments of the present invention will be described in more detail.
本発明において、各用語は、特に断らない限り、以下の意味を有する。 In the present invention, each term has the following meaning, unless otherwise specified.
本発明において、「ドライアイ」は、眼不快感や視機能異常等を伴う、涙液及び角結膜上皮の慢性疾患である。その診断や治療効果の評価には、例えば、非特許文献1に記載の定義及び診断基準、NEI（National Eye Institute）の定義（Lempら、「CLAO J」、1995年、第21巻、p.221-232）等を用いることもできる。
In the present invention, "dry eye" is a chronic disease of tear fluid and keratoconjunctival epithelium accompanied by eye discomfort and visual dysfunction. For the diagnosis and evaluation of therapeutic effects, for example, the definitions and diagnostic criteria described in
本発明のアルジオキサは、公知の方法で製造することができる。また、市販されているアルジオキサを用いることもできる。 The aldioxa of the present invention can be produced by known methods. In addition, commercially available aldioxa can also be used.
本発明の医薬組成物は、例えば、点眼剤（点眼液、眼軟膏等）の形態で投与することもできる。 The pharmaceutical composition of the present invention can also be administered, for example, in the form of eye drops (eye drops, eye ointment, etc.).
本発明の医薬組成物は、常法により、アルジオキサ及び少なくとも1つの医薬品添加剤を用いて調製することができる。添加剤としては、例えば、緩衝剤、等張化剤、防腐剤、安定化剤、pH調整剤、溶解補助剤、界面活性剤等が挙げられる。 The pharmaceutical composition of the present invention can be prepared in a conventional manner using aldioxa and at least one pharmaceutical additive. Examples of the additive include a buffer, a tonicity agent, an antiseptic, a stabilizer, a pH adjuster, a solubilizing agent, a surfactant and the like.
本発明の医薬組成物における有効成分の含有量は、患者の体重、年齢、性別、疾患の程度等に応じて定めればよい。点眼剤の場合、有効成分の含有量は、例えば、0.01 ％（w/v）〜1 ％（w/v）である。一つの実施態様として、本発明は、有効成分の含有量が0.01％（w/v）、0.1％（w/v）又は1％（w/v）である点眼剤である。なお、「w/v」は、重量／容量を表す。 The content of the active ingredient in the pharmaceutical composition of the present invention may be determined according to the weight, age, sex, degree of disease, etc. of the patient. In the case of eye drops, the content of the active ingredient is, for example, 0.01% (w / v) to 1% (w / v). In one embodiment, the present invention is an eye drop wherein the content of the active ingredient is 0.01% (w / v), 0.1% (w / v) or 1% (w / v). "W / v" represents weight / volume.
本発明の医薬組成物の投与方法は、患者の体重、年齢、性別、疾患の程度等に応じて適宜定めればよい。点眼剤の場合、成人における点眼方法は、例えば、片眼あたり1回1滴、1日1〜6回投与である。なお、投与間隔は、適宜定めることができ、例えば、3〜4時間である。 The administration method of the pharmaceutical composition of the present invention may be appropriately determined according to the weight, age, sex, degree of disease, etc. of the patient. In the case of eye drops, the eye drop method in adults is, for example, once a drop per eye, 1 to 6 times a day. The administration interval can be appropriately determined, and is, for example, 3 to 4 hours.
以下に、本発明を実施例にもとづいてさらに詳細に説明するが、本発明はその内容に限定されるものではない。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the contents.
実施例１：ドライアイモデル1（涙腺摘出モデル）
１．試験方法
7週齢の雄性SDラットを2%イソフルラン吸入麻酔下で、左右耳下部分を切開し、眼窩外涙腺を摘出後、切開部を縫合しラットドライアイモデルを作製した（Fujihara T，et al. Improvement of corneal barrier function by the P2Y2 agonist INS365 in a rat dry eye model. Invest Ophthalmol Vis Sci. 2001，42，p.96-100）。また、正常群（Normal）のラットには、眼窩外涙腺の摘出以外同様の手術を実施した（偽手術）。眼窩外涙腺摘出翌日に、1%（w/v）のアルジオキサ点眼液又はcontrolとしてアルジオキサ点眼液基剤（クエン酸溶液：pH 7.3）を1日4回（3時間間隔）で6日間、両眼に5 μLずつ点眼投与した（各群7〜8例）。正常群（8例）にはアルジオキサ点眼液基剤を同様に点眼投与した。最終点眼投与翌日に、イソフルラン麻酔下にて1%リサミングリーン溶液を両眼に各1μL点眼後、角膜の障害の程度をスコア化した。角膜障害スコアは、角膜全体に点状染色が認められた場合を4点、角膜全体に対して1/2以上3/4未満の場合を3点、1/4以上1/2未満の場合を2点、1/4未満の場合を1点及び染色が認められない場合を0点とし、左右の角膜スコアの合計をその個体の角膜上皮障害スコアとした。なお、上記スコア評価は盲検化にて実施した。
また、比較例としてアラントインの1%（w/v）点眼液を作製し、上記と同様の方法でアラントイン点眼液の効果を評価した。
２．結果
1％（w/v）のアルジオキサ点眼液を投与した涙腺摘出ドライアイモデルにおいて、角膜上皮障害の有意な改善が認められた（図１）。一方、1％（w/v）のアラントイン点眼液を投与した涙腺摘出ラットにおいて、角膜上皮障害の有意な改善は認められなかった。
Example 1: Dry eye model 1 (a lacrimal gland extraction model)
1. Test method
A 7-week-old male SD rat was dissected under 2% isoflurane inhalation anesthesia, the left and right parotid area was incised, the extraorbital lacrimal gland was removed, and the section was sutured to prepare a rat dry eye model (Fujihara T, et al. Invest Ophthalmol Vis Sci. 2001, 42, p. 96-100), the improvement of the corneal barrier function by the P2Y2 agonist INS 365 in a rat dry eye model. In addition, in the normal group (Normal), a similar operation except for removal of extraorbital lacrimal gland was performed (sham operation). On the next day of extraorbital lacrimal gland excision: 1% (w / v) aldioxa ophthalmic solution or aldioxa ophthalmic solution base (citric acid solution: pH 7.3) as control for 4 days (3 hour interval) for 6 days, both eyes 5 .mu.L each to eye drops (7 to 8 cases in each group). Aldioxa eye drop base was similarly administered to the normal group (8 cases). On the day after the last instillation, 1 μL each of 1% lissamine green solution was instilled in both eyes under isoflurane anesthesia, and the degree of corneal damage was scored. The corneal injury score is 4 points when point-like staining is observed throughout the cornea, 3 points when 1⁄2 or more and less than 3⁄4 of the whole cornea, and 1⁄4 or more and less than 1⁄2. A score of 2 points, less than 1⁄4 was regarded as 1 point and a case where no staining was observed was regarded as 0 point, and the sum of the corneal scores on the left and right sides was regarded as the corneal epithelial injury score of the individual. In addition, the said score evaluation was implemented by blinding.
Moreover, 1% (w / v) eye drops of allantoin was prepared as a comparative example, and the effect of allantoin eye drops was evaluated by the same method as described above.
2. result
In the lacrimal gland excision dry eye model administered 1% (w / v) aldioxa ophthalmic solution, significant improvement of corneal epithelial disorder was observed (FIG. 1). On the other hand, no significant improvement of corneal epithelial damage was observed in lacrimal gland-extracted rats that received 1% (w / v) allantoin eye drop.
実施例２：ドライアイモデル2（n-heptanol角膜上皮障害モデル）
１．試験方法
7週齢の雄性SDラットを2%イソフルラン吸入麻酔下で、両眼の角膜中央に0.3μLのn-heptanolで湿らせた直径3mmのメンブランフィルターを1分間静置し、角膜上皮障害モデルを作製した。角膜上皮障害モデル作製後の角膜撮影直後、及びその後3時間間隔で合計4回、1%（w/v）のアルジオキサ点眼液又はcontrolとしてアルジオキサ点眼液基剤（クエン酸溶液：pH 7.3）を両眼に5 μLずつ点眼投与した（各群8例）。角膜上皮障害作製直後及び24時間後に、イソフルラン麻酔下にて1%フルオレセイン溶液を両眼に各1μL点眼後、デジタルカメラにて角膜を撮影した。撮影された写真を元に、画像解析装置を用いてフルオレセインで染色された面積を測定し、角膜上皮障害モデル作製直後の面積に対する24時間後の面積比率を算出し、治癒率とした。なお、上記スコア評価は盲検化にて実施した。
また、比較例としてアラントインの1%（w/v）点眼液を作製し、上記と同様の方法でアラントイン点眼液の効果を評価した。
治癒率（%）=（1-（24時間後の染色面積/作製直後の染色面積））X100
２．結果
1％（w／v）のアルジオキサ点眼液を投与したn-heptanol角膜上皮障害モデルにおいて、角膜上皮障害に対する治癒率の有意な向上が認められた（図２）。一方、1％（w/v）のアラントイン点眼液を投与したn-heptanol角膜上皮障害モデルにおいて、角膜上皮障害に対する治癒率の有意な向上は認められなかった。
Example 2 Dry Eye Model 2 (n-Heptanol Corneal Epithelial Disorder Model)
1. Test method
A 3-mm diameter membrane filter moistened with 0.3 μL of n-heptanol was placed at the center of both corneas under a 2% isoflurane inhalation anesthesia in a 7-week-old male SD rat for 1 minute to prepare a corneal epithelial injury model. did. Aldioxa ophthalmic solution as a 1% (w / v) ophthalmic solution or aldioxa ophthalmic solution base (citric acid solution: pH 7.3) both immediately after cornea imaging after preparation of the corneal epithelial disorder model and for a total of 4 times at 3 hour intervals thereafter. The eye was administered with 5 μL each (eight cases in each group). Immediately after and 24 hours after preparation of corneal epithelial disorder, 1 μl of 1% fluorescein solution was instilled in both eyes under isoflurane anesthesia, and the cornea was photographed with a digital camera. Based on the photograph taken, the area stained with fluorescein was measured using an image analysis device, and the area ratio after 24 hours to the area immediately after preparation of the corneal epithelial disorder model was calculated and used as the cure rate. In addition, the said score evaluation was implemented by blinding.
Moreover, 1% (w / v) eye drops of allantoin was prepared as a comparative example, and the effect of allantoin eye drops was evaluated by the same method as described above.
Cure rate (%) = (1-(stained area after 24 hours / stained area immediately after preparation))
2. result
In the n-heptanol corneal epithelial injury model treated with 1% (w / v) aldioxa ophthalmic solution, a significant improvement in the cure rate for corneal epithelial injury was observed (FIG. 2). On the other hand, in the n-heptanol corneal epithelial injury model treated with 1% (w / v) allantoin ophthalmic solution, no significant improvement in the cure rate for corneal epithelial injury was observed.
実施例１及び２の結果から、本発明の医薬組成物は、ドライアイにおける角膜上皮障害の治療効果を有し、ドライアイの治療剤として有用であることが示された。 The results of Examples 1 and 2 indicate that the pharmaceutical composition of the present invention has a therapeutic effect on corneal epithelial disorders in dry eye and is useful as a therapeutic agent for dry eye.
本発明の医薬組成物は、ドライアイの治療用医薬組成物として有用である。 The pharmaceutical composition of the present invention is useful as a pharmaceutical composition for treating dry eye.
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