JP2017119637A - 涙液分泌促進組成物 - Google Patents
涙液分泌促進組成物 Download PDFInfo
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- JP2017119637A JP2017119637A JP2015256199A JP2015256199A JP2017119637A JP 2017119637 A JP2017119637 A JP 2017119637A JP 2015256199 A JP2015256199 A JP 2015256199A JP 2015256199 A JP2015256199 A JP 2015256199A JP 2017119637 A JP2017119637 A JP 2017119637A
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Abstract
Description
ceptor-2/プロテアーゼ活性化受容体2)を活性化させるペプチドに涙液分泌促進作用があることが開示されており(特許文献5,6)、今後新たな涙液分泌促進製剤の開発が期待される。
組成物の製造のためのセロトニン5−HT3受容体の作動薬の使用が提供される。
症候群、角結膜炎などが含まれ、好ましくはドライアイである。
症候群、角結膜炎などが含まれ、好ましくはドライアイである。
(1)賦形剤:デンプン類、乳糖、白糖、ブドウ糖、マンニトール、硫酸カルシウム、炭酸カルシウム、タルク、トレハロース、キシリトール。
(2)結合剤:デンプン、セルロース、ゼラチン、アルギン酸ナトリウム、ポリビニルアルコール、ポリビニルピロリドン、アラビアゴム、デキストリン。
(3)滑沢剤:ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ワックス類、ステアリン酸及びその塩類。
(4)安定化剤:アスコルビン酸、キレート剤、還元性物質、トコフェロール、亜硫酸水素ナトリウム。
(5)保存剤:安息香酸及びその塩類、パラオキシ安息香酸エステル類、クロロブタノール。
(6)溶剤:精製水、生理食塩水、エタノール、グリセリン、植物油類。
(7)基剤:ワセリン、植物油類、タルク、マクロゴール。
(8)コーティング剤:白糖、ゼラチン、ヒドロキシプロピルメチルセルロース。
(9)矯味剤:白糖、ブドウ糖、サッカリン、キシリトール、アスコルビン酸、クエン酸、メントール。
(10)着色剤:水溶性食用色素。
れらに限定されるものではない。
<方法>
モデル動物として、8週齢の雌の C57BL/6マウス(CLEA Japanより購入)を用いた。実験は、慶應義塾大学医学部の動物実験倫理委員会の承認の下で行った。
動物は実験の1週間前に隔離及び順化を、温度23±2℃、湿度 60 ± 10%、12時間明暗サイクル(午前8時から午後8時)の条件下で、飼料及び水は自由に摂取させた。
標準食としてはAIN93G(オリエンタル酵母)の組成に基づく飼料を用いた。トリプトファン欠乏食としては、トリプトファン(Trp)を除去したAIN93Gを用いた。
順化期間中は標準食を与えて、その後トリプトファン欠乏食に切り替えた。対照(Control)は、トリプトファン欠乏食に切り替えずに標準食を与え続けた。
涙液分泌能をトリプトファン欠乏食を与えた7日間にわたり測定した。
マウスの左右の外眼角に綿糸(ZONE-QUICK(登録商標)、昭和薬品化工株式会社)を15秒間挿入し、綿糸が涙液の浸透により褐色変色した長さを、0.5mmの精度で測定した。左右眼の平均を個体の涙液分泌量とした。
腹大動脈から採決した血中の5-HT濃度を、HPLC法により測定した。
結果を図1に示す。血中の5-HT濃度はトリプトファン欠乏食への切り替えから1日後に徐々に減少をし、7日目には切り替え前と比べて約70%減少した(図1A)。この間、涙液量も徐々に減少し、3日目から7日目にかけては切り替え前から約20%減少でプラトーに達した(図1B)。
実施例1のトリプトファン欠乏食を摂取させたマウスに、5-HTを腹腔内注射した。トリプトファン欠乏食への切り替え後2日後に5-HTを腹腔内注射した。その後、5分間隔で涙液分泌量を測定した。
結果を図2に示す。投与した5-HTの量に依存して、涙液分泌が促進された。促進効果は、投与後5〜10分の間に観察され、0.1及び1 mg/kg投与の場合に顕著な効果が観察された。
マウスへのセロトニン5−HT3受容体の作動薬及び拮抗薬の投与の効果を評価した。
対照として、セロトニン5−HT1a受容体の拮抗薬Way-100635、セロトニン5−HT2a受容体の拮抗薬及びセロトニン5−HT7受容体の拮抗薬SB269970を用いた。
セロトニン5−HT3受容体の作動薬としてSR57227Aを用いた。作動薬の投与量は72 μg/kg/dayとした。
結果を図3に示す。
セロトニン5−HT3受容体作動薬の涙腺における細胞内カルシウムイオン濃度([Ca2+]i)への影響を評価した。
細胞内カルシウムイオン濃度測定
[Ca2+]iの測定は、Sprague-Dawleyラットから採取した涙腺を用いて、文献:Imada T, Nakamura S & Kitamura N et al. PLoS One 9, e106338 (2014).に記載の方法に準じて行った。
図4Aに示すように、5-HT3(0.1〜10 μM)の添加により、涙腺の腺房細胞(acinar cells)における細胞内カルシウムイオン濃度([Ca2+]i)を上昇させる。本願発明者は、図4Bに示すようにSR57227Aの添加によっても、[Ca2+]iが上昇することを見出した。
図4Cに示すように、Ca2+フリー及びオンダンステロンの添加により[Ca2+]iの上昇が見られなくなったため、5-HT3受容体及びCa2+を介して涙液分泌が起きていると考えられる。
なお、Ca2+フリーは、通常の方法おけるsaline solution (140 mM NaCl, 5 mM KCl, 10 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM dextrose [pH 7.4])に替えて、CaCl2を含まない溶液を使用した。
正常個体におけるセロトニン5−HT3受容体作動薬の効果を検証した。
標準食を摂取するマウスに、実施例2と同様にしてSR57227Aを0.1mg/kgの用量で単回投与を行った。投与経路は腹腔内とした。
投与前及び投与後5分間隔で30分後まで涙液測定を行った。
結果を図5に示す。セロトニン5−HT3受容体作動薬の投与10分後に、投与前(0)と比較し有意に涙液分泌量が増加した。その後減少し転じ、投与30分後には投与前の値に復した。
マウスストレス性ドライアイモデルを用いて、セロトニン5−HT3受容体作動薬のドライアイ予防効果を評価した。
低下処置(ストレス処置)
文献:Nakamura, S., Tanaka, J., Imada, T.et al. Journal of Functional Foods 10, 346-354 (2014)の記載に従って、雌の8週齢C57BL/6マウスに拘束ストレスを与えた。マウスを、1日4時間、呼吸/排泄可能な処置を施したポリプロピレン製遠沈管(容量約60ml)内に拘束する。拘束中はマウス顔面に送風(風速0.5~1.0 m/s)を行った。拘束処置時間以外はケージ内で餌と飲料は自由摂取とした。
セロトニン5−HT3受容体の作動薬(SR57227A)をストレス処置前日、ストレス処置直前に10mg/kgの用量で投与を行った。投与経路は腹腔内とした。
実施例1と同様にして、ストレス処置前、投与期間中の適時実施した。
結果を図6に示す。ストレス処置により溶媒対照では、涙液分泌量が約1/4に減少したのに対し、SR57227A投与により、その低下が溶媒対照に比較し有意に抑制された。この結果は、セロトニン5−HT3受容体作動薬の投与により、ドライアイ予防効果(涙液分泌低下を抑制)が期待できることを示している。
Claims (9)
- セロトニン5−HT3受容体の作動薬又は拮抗薬を有効成分として含有する、涙液分泌調整組成物。
- セロトニン5−HT3受容体の作動薬を有効成分とする涙液分泌促進組成物である、請求項1に記載の組成物。
- セロトニン5−HT3受容体の作動薬がSR 57227Aである、請求項2に記載の組成物。
- セロトニン5−HT3受容体の拮抗薬を有効成分とする涙液分泌抑制組成物である、請求項1に記載の組成物。
- セロトニン5−HT3受容体の拮抗薬がオンダセトロン又はその薬学的に許容されうる塩である、請求項4に記載の組成物。
- 経口剤である、請求項1〜5のいずれか一項に記載の涙液分泌促進組成物。
- セロトニン5−HT3受容体の作動薬を有効成分として含有する、角結膜障害の予防又は治療剤。
- 角結膜障害がドライアイである請求項6に記載の予防又は治療剤。
- セロトニン5−HT3受容体の拮抗薬を有効成分として含有する、流涙症の予防又は治療薬。
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JPH1067684A (ja) * | 1996-06-17 | 1998-03-10 | Mitsubishi Chem Corp | 涙液分泌促進剤 |
US20080261890A1 (en) * | 2004-03-19 | 2008-10-23 | Ousler George W | Use of neurotransmitters and neuropeptides for the treatment of dry eye diseases and related conditions |
US20110217262A1 (en) * | 2010-03-05 | 2011-09-08 | Kornfield Julia A | Treatment of Ocular Surface Disorders by Increasing Conjunctival Vascular Permeability |
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JPH1067684A (ja) * | 1996-06-17 | 1998-03-10 | Mitsubishi Chem Corp | 涙液分泌促進剤 |
US20080261890A1 (en) * | 2004-03-19 | 2008-10-23 | Ousler George W | Use of neurotransmitters and neuropeptides for the treatment of dry eye diseases and related conditions |
US20110217262A1 (en) * | 2010-03-05 | 2011-09-08 | Kornfield Julia A | Treatment of Ocular Surface Disorders by Increasing Conjunctival Vascular Permeability |
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