JP2018518460A - 網膜色素上皮の細胞を保護するためのノルビキシン含有組成物 - Google Patents
網膜色素上皮の細胞を保護するためのノルビキシン含有組成物 Download PDFInfo
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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Abstract
【選択図】図1
Description
1:ビキシン及びノルビキシンの調製
95重量%純粋なビキシンを、ベニノキの種子の有機抽出物由来で85重量%より高いビキシン濃度の市販品(Annatto B)から調製する。精製は、連続的な再結晶化により行う。
in vitro試験を、A2Eの存在下に置かれたRPE細胞に対する様々な天然物質の光保護効果を研究するために行った。分子の光保護効果を、A2Eでの処理、それに続く青色光線の照射により惹起される光毒性の細胞モデルで評価する。「青色放射線」という語は、可視光スペクトルの青色バンドに対応する、すなわち435〜490nmの波長を有する放射線を意味するものとする。
図1は、ビキシン及びノルビキシン(20μM)が、A2Eを使用したコントロールと比較して、A2Eの存在下で惹起された光毒性からRPE細胞を効果的に保護することを示す。ベニノキの種子の粗抽出物(ビキシン20μMになるまで希釈)は高い光保護活性を有する。極めて純粋な濃度20μMのビキシンの使用により、この成分が実際に際立った光保護活性を有すること(図1)、またビキシンと同じ量になるように希釈したBixilia(登録商標)抽出物の活性のかなりの部分の説明になることを示すことができた。匹敵する活性はノルビキシンでも見られ、ノルビキシンはビキシンの主要循環代謝物である(Levy et al.,1997)。これらの結果は、同じ化合物の、ヒトの皮膚の光保護について過去に実証された光保護活性と一致している(Veillet et al.,2009)。
Bixilia(登録商標)はフェノール性の他の光保護化合物を含有し、その存在が、ビキシン単体より粗抽出物のほうが活性が高い理由であると考えられる(ある同一ビキシン濃度に関して)。ベニノキの種子の殻の連続抽出を連続的にシクロヘキサン、ジクロロメタン及びメタノール(各1L/種子100g)で行った。シクロヘキサンでの抽出後、ビキシン濃度0.65μMの画分が得られる。ジクロロメタンでの抽出後、ビキシン濃度1485μMを有する画分が得られ、メタノールでの抽出後、ビキシン濃度45μMを有する画分が得られる。次に前回のin vitro試験を繰り返す。図2では、97%のビキシンを含有するジクロロメタン画分は活性が高かったが、フェノール化合物が豊富なメタノール抽出物は極めて高い活性を有することも注目される(C=シクロヘキサン、D=ジクロロメタン、M=メタノール)。
ビキシン及びノルビキシンの生体利用能についての研究をC57BI/6マウスで行った。化合物を経口で投与した(50mg/kg)。血液サンプルを0.25、0.5、1、3、6、8及び24時間後に採取し、HPLC−DAD(UV460nm)−MS/MSで分析した。表1及び図3aは、経口摂取されたビキシンが速やかにノルビキシンに変換され、これら2種の化合物が類似の濃度で循環することを開示している。これらの化合物は8時間後には検出されない。さらに、経口摂取されたノルビキシンの生体利用能はビキシンよりはるかに高いことも注目される。
Maeda et al.(2008)が開発した遺伝子改変マウスモデルを用いてノルビキシンの光保護活性を試験した。このマウスモデルにおいては、視物質サイクルに関わる2つの遺伝子(ABCA4及びRDH8)を失活させており、これが眼におけるA2Eの早期蓄積をもたらす(図5)。結果的に、この動物モデルは、齧歯類と霊長類との眼の構造における違いとの関係で当然限界はあるものの、ヒトの病態に類似している。
「ラット青色光線」モデルは、ラットを6時間にわたって強力な青色光線に曝露することで眼に損傷を引き起こし、その損傷を網膜電図検査及び組織学的分析を行うことで7日後に評価することから成る。抗酸化化合物であるPBN(フェニル−N−tert−ブチルニトロン)をポジティブコントロールとして使用する(Ranchon et al.,2001;Tomita et al.,2005)。光保護活性を測定しようとする化合物を、照射フェーズ前及びその最中に注射する(腹腔内)。この照射フェーズは、Philipsブルーネオン管(4.2mW/cm2)を使用して6時間にわたって行われる。実験プロトコルを図8Aに示す。
0.3mg/gの純粋なノルビキシンを含有する飼料を用意し、ダブルKOマウス(ABCA4-/-、RDH8-/-)に3ヶ月間にわたって与えた。
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Claims (10)
- Bixa Orellana種子の抽出物からの精製で得られるノルビキシンを90重量%を超えて含む、哺乳動物において網膜色素上皮(RPE)の細胞の光保護に使用するための組成物。
- 95重量%を超えるノルビキシンを含む、請求項1に記載のその使用のための組成物。
- 90重量%を超える式(I):
- 亜鉛、ビタミンC及びビタミンEから選択される少なくとも1種の要素を含む、請求項1〜3のいずれか一項に記載のその使用のための組成物。
- 栄養補助食品又は薬物の形態である、請求項1〜4のいずれか一項に記載のその使用のための組成物。
- 経口摂取、眼内注射、全身注射又は血中への注入が許容可能な担体を含む、請求項1〜5のいずれか一項に記載のその使用のための組成物。
- 哺乳動物に、1日あたり、0.48mg/kg(体重)〜48mg/kg(体重)、好ましくは0.6mg/kg(体重)〜20mg/kg(体重)の量で投与される、請求項1〜6のいずれか一項に記載のその使用のための組成物。
- 可視光スペクトルの青色バンドに対応し、435〜490nmの波長を有する青色放射線への曝露により引き起こされる前記網膜への損傷の防止に適用するための、請求項1〜7のいずれか一項に記載のその使用のための組成物。
- 哺乳動物において加齢黄斑変性(ARMD)の治療に適用するための、請求項1〜8のいずれか一項に記載のその使用のための組成物。
- 哺乳動物においてシュタルガルト病及び/又は網膜色素変性症の治療に適用するための、請求項1〜8のいずれか一項に記載のその使用のための組成物。
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FR1553957A FR3035589B1 (fr) | 2015-04-30 | 2015-04-30 | Composition pour la protection des cellules de l'epithelium pigmentaire retinien |
FR1553957 | 2015-04-30 | ||
PCT/FR2016/051001 WO2016174360A1 (fr) | 2015-04-30 | 2016-04-28 | Composition contenant de la norbixine pour la protection des cellules de l'epithelium pigmentaire retinien |
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EP (1) | EP3288551B1 (ja) |
JP (1) | JP6660401B2 (ja) |
KR (1) | KR102575312B1 (ja) |
CN (1) | CN107708685B (ja) |
AU (1) | AU2016256637A1 (ja) |
BR (1) | BR112017023264A2 (ja) |
CA (1) | CA2984405C (ja) |
ES (1) | ES2752061T3 (ja) |
FR (1) | FR3035589B1 (ja) |
IL (1) | IL255276A0 (ja) |
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FR3078252B1 (fr) * | 2018-02-28 | 2020-08-14 | Biophytis | Phytoecdysones pour leur utilisation dans la prevention de la perte de force musculaire lors d’une immobilisation |
KR20200134935A (ko) | 2019-05-24 | 2020-12-02 | (주)비지엔케어 | 커큐민을 유효성분으로 포함하는 인간 망막색소상피세포 증식 개선용 약학 조성물 |
FR3105790B1 (fr) | 2019-12-26 | 2022-01-14 | Biophytis | Composés chimiques ciblant l’œil et leur utilisation dans le traitement de maladies oculaires |
KR20210008884A (ko) | 2021-01-08 | 2021-01-25 | (주)비지엔케어 | 커큐민을 유효성분으로 포함하는 인간 망막색소상피세포 증식 개선용 조성물 및 기능성 식품 조성물 |
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JP2007521274A (ja) * | 2003-06-20 | 2007-08-02 | アルコン,インコーポレイテッド | 複数成分の組み合わせを用いる加齢性黄斑変性の処置 |
JP2008520576A (ja) * | 2004-11-16 | 2008-06-19 | ニュー‐ティーン カンパニー,インク. | 眼性血管新生症および黄斑変性の処置に有用な組成物 |
JP2008179632A (ja) * | 2006-12-29 | 2008-08-07 | Fuji Chem Ind Co Ltd | 抗酸化剤 |
JP2012097003A (ja) * | 2010-10-29 | 2012-05-24 | Gifu City | ビキシン誘導体及び細胞保護剤 |
JP2014514366A (ja) * | 2011-05-13 | 2014-06-19 | アンスティチュ・ビオフィティス・エスアーエス | 黄斑変性症の治療のためのビクサ・オレラナ由来組成物 |
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FR1154172A (fr) | 1955-07-05 | 1958-04-03 | Rollei Werke Franke Heidecke | étui de protection pour appareils photographiques |
WO2001085183A2 (en) * | 2000-05-08 | 2001-11-15 | N.V. Nutricia | Preparation for the prevention and treatment of ocular disorders |
US7887847B2 (en) * | 2004-05-08 | 2011-02-15 | Paul Jr Edward L | Nutritional supplement for treatment of ocular diseases |
JP5550854B2 (ja) * | 2009-06-10 | 2014-07-16 | 理研ビタミン株式会社 | 一重項酸素消去剤 |
FR2947173B1 (fr) * | 2009-06-25 | 2012-01-27 | Inst Biophytis | Composition alimentaire destinee a la protection solaire |
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2007521274A (ja) * | 2003-06-20 | 2007-08-02 | アルコン,インコーポレイテッド | 複数成分の組み合わせを用いる加齢性黄斑変性の処置 |
JP2008520576A (ja) * | 2004-11-16 | 2008-06-19 | ニュー‐ティーン カンパニー,インク. | 眼性血管新生症および黄斑変性の処置に有用な組成物 |
JP2008179632A (ja) * | 2006-12-29 | 2008-08-07 | Fuji Chem Ind Co Ltd | 抗酸化剤 |
JP2012097003A (ja) * | 2010-10-29 | 2012-05-24 | Gifu City | ビキシン誘導体及び細胞保護剤 |
JP2014514366A (ja) * | 2011-05-13 | 2014-06-19 | アンスティチュ・ビオフィティス・エスアーエス | 黄斑変性症の治療のためのビクサ・オレラナ由来組成物 |
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RU2715889C2 (ru) | 2020-03-04 |
US20180289651A1 (en) | 2018-10-11 |
CA2984405C (fr) | 2024-01-23 |
KR20180011777A (ko) | 2018-02-02 |
CA2984405A1 (fr) | 2016-11-03 |
AU2016256637A1 (en) | 2017-12-14 |
MX2017013918A (es) | 2018-04-24 |
EP3288551B1 (fr) | 2019-07-31 |
FR3035589A1 (fr) | 2016-11-04 |
WO2016174360A9 (fr) | 2017-11-16 |
US10314804B2 (en) | 2019-06-11 |
FR3035589B1 (fr) | 2019-12-13 |
IL255276A0 (en) | 2017-12-31 |
RU2017141462A3 (ja) | 2019-09-12 |
CN107708685B (zh) | 2021-09-21 |
ES2752061T3 (es) | 2020-04-02 |
JP6660401B2 (ja) | 2020-03-11 |
PL3288551T3 (pl) | 2020-04-30 |
CN107708685A (zh) | 2018-02-16 |
WO2016174360A1 (fr) | 2016-11-03 |
RU2017141462A (ru) | 2019-05-31 |
BR112017023264A2 (pt) | 2018-08-07 |
EP3288551A1 (fr) | 2018-03-07 |
KR102575312B1 (ko) | 2023-09-06 |
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