JP2015027959A - 白色脂肪細胞の褐色様脂肪細胞分化誘導剤組成物 - Google Patents
白色脂肪細胞の褐色様脂肪細胞分化誘導剤組成物 Download PDFInfo
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Abstract
Description
したがって、本発明の課題は、これまでレスベラトロールには見られない新しい効果である、優れた白色脂肪細胞の褐色様脂肪細胞への分化誘導作用を有し、且つ安全安価に作製することが可能な白色脂肪細胞の褐色様脂肪細胞の分化誘導剤組成物、ならびに該組成物を含有する医薬品及び医薬部外品を提供することにある。
[1]レスベラトロールをアルカリ性条件下で加熱して得られることを特徴とする、白色脂肪細胞の褐色様脂肪細胞への分化誘導剤組成物、
[2]式(1):
[3]前記[1]又は[2]記載の白色脂肪細胞の褐色様脂肪細胞への分化誘導剤組成物を含有する医薬品又は医薬部外品
に関する。
また、本発明の組成物は、本件出願人が先に提出した特願2013−071836に記載しているような化合物の単離精製工程を行わなくても優れた白色脂肪細胞から褐色様脂肪細胞への分化誘導作用を有しているため、前記先願発明より生産性がよく、より安価に白色脂肪細胞から褐色様脂肪細胞への分化誘導剤を提供することが可能である。
加えて、本発明の組成物を医薬品又は医薬部外品に配合することで、新規なメタボリックシンドローム予防又は改善用の医薬品又は医薬部外品を提供することができる。
前記環化反応を効率的に進ませるために、レスベラトロール含有溶液の加熱温度は110℃以上に調整することが好ましい。また、使用する溶媒の沸点から考え、加圧加熱が望ましい。例えば、開放容器にレスベラトロール含有溶液を入れ、溶媒の沸点を超える高温で前記容器を加熱する、密閉容器にレスベラトロール含有溶液を入れ、前記容器を加熱する、レトルト装置やオートクレーブを用いて加圧加熱する、超臨界装置やプレッシャークッカー等の装置を用い加圧加熱する等、少なくとも部分的にレスベラトロール含有溶液の温度が110℃以上に達するように加熱することが好ましい。前記レスべラトロール重合化合物などの回収効率面から、レスベラトロール含有溶液の温度が均一に120℃〜180℃になることが、さらに好ましい。加熱時間も加熱温度と同様に限られたものではなく、効率的に目的の反応が進行する時間条件とすればよい。特に、加熱時間は加熱温度との兼ね合いによるものであり、加熱温度に応じた加熱時間にすることが望ましい。例えば、130℃付近で加熱する場合は、10分〜120分の加熱時間が望ましい。また、加熱は、一度でもよいし、複数回に分けて繰り返し加熱してもよい。複数回に分けて加熱する場合、溶媒を新たに追加して行うことが好ましい。
なお、前記式(1)〜(3)で表されるレスベラトロール重合化合物の生成量については、本発明の組成物中に多いほど白色脂肪細胞の褐色様脂肪細胞への分化誘導作用が強くなるので好ましいが、具体的には、それぞれの総量が本発明の組成物中に1重量%以上であればよい。
また、式(1)、式(2)、式(3)で表されるレスベラトロール重合化合物のそれぞれの含有比率については特に限定はない。
中でも、合成吸着剤を用いることで、前記式(1)〜(3)で表されるレスベラトロール重合化合物を吸着させ、その後、溶出することで容易に濃縮、精製ができる。前記合成吸着剤としては、例えば、三菱化学株式会社製のダイヤイオン(登録商標)HPシリーズ、セパビーズ(登録商標)SPシリーズなどの芳香族系合成吸着剤、オルガノ株式会社製のアンバーライト(登録商標)XADシリーズなどのスチレン系合成吸着剤などが挙げられる。
結合剤としては、例えば、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、ポリビニルアルコール、ポリビニルエーテル、ポリビニルピロリドン、カルボキシメチルセルロース、セラック、メチルセルロース、エチルセルロース、水、エタノール、リン酸カリウム及びこれらの混合物等が挙げられる。
安定化剤としては、例えば、ピロ亜硫酸ナトリウム、エチレンジアミン四酢酸、チオグリコール酸、チオ乳酸及びこれらの混合物等が挙げられる。
pH調整剤及び緩衝剤としては、例えば、クエン酸ナトリウム、クエン酸、酢酸ナトリウム、リン酸ナトリウム及びこれらの混合物等が挙げられる。
レスベラトロール重合化合物を含有する組成物の作製、及び精製を以下の手順で行った。トランス−レスベラトロール((株)TECNO SCIENCE社製)1gをエタノール10mLに溶解し、10%炭酸水素ナトリウム(和光純薬工業(株)社製)水溶液を10mL加えて、レスベラトロール含有溶液(pH9.9)を得た。このレスベラトロール含有溶液をオートクレーブ(三洋電機製、「SANYO LABO AUTOCLAVE」、以下同じ)にて130℃、90分間加熱し、レスベラトロール重合化合物含有溶液を作製した。
次いで、レスベラトロール重合化合物含有溶液を蒸留水1Lで希釈・溶解させ、400gの合成吸着剤ダイヤイオン(登録商標)HP−20(三菱化学株式会社製)に全量供した。蒸留水1Lで洗浄後、100%エタノール1Lで溶出させた。減圧乾燥にて溶媒を除去し、レスベラトロール重合化合物含有組成物(以下、誘導体含有組成物という。)200mgを得た。得られた重合化合物組成物を2mg/mLの濃度でメタノールに溶解させ、そのうち10μLをHPLCにより分析した。
カラム:CAPCELL PAK UG80カラム(4.6mmI.D.×250mm、資生堂株式会社製)
移動相A:0.1%トリフルオロ酢酸(TFA、和光純薬株式会社製)/H2O
移動相B:0.1%TFA/アセトニトリル(和光純薬株式会社製)
勾配(容量%):100%A/0%Bから0%A/100%Bまで33分、0%A/100%Bを7分(すべて直線)
すなわち、高分解能Negative−FAB−MSによる測定値は647.2144であり、理論値との比較から、以下の分子式を得た。
理論値C42H31O7(M−H-):647.2148
分子式C42H32O7
値はδ、ppmで、溶媒はDMSO−d6で測定した。
(性状)
褐色粉末
(溶解性)
水:難溶
メタノール:溶解
エタノール:溶解
DMSO:溶解
クロロホルム:難溶
酢酸エチル:難溶
白色脂肪細胞の褐色様脂肪細胞分化誘導作用を評価するために、3T3−L1細胞(マウス由来前駆脂肪細胞)を用いて評価を行った。3T3−L1前駆脂肪細胞は通常、分化誘導過程を経て、白色脂肪細胞へと分化、成熟する。しかし、褐色様脂肪細胞へと分化誘導されることで白色脂肪細胞ではほとんど観察されないCidea遺伝子の発現や、褐色脂肪細胞及び褐色様脂肪細胞にて発現が亢進する転写コアクチベーターPGC−1β、ミトコンドリアに発現するCox7a1遺伝子の発現量の増加、及びUCP1遺伝子の発現亢進が観察されるようになる。加えて、非特許文献6に言及があるように、褐色様脂肪細胞への分化を促す因子の一つとしてFGF−21が知られており、FGF−21の発現亢進がもたらすいくつかの効果の一つとして、PGC−1αの発現亢進を促し、白色脂肪細胞が褐色用脂肪細胞へと誘導されると考えられている。そこで、FGF−21、PGC−1α及びCox7a1の各遺伝子の発現量を指標に、白色脂肪細胞の褐色様脂肪細胞への分化誘導を確認した。
実施例2では誘導体含有組成物が褐色様脂肪細胞へと白色脂肪細胞を分化誘導することを分化誘導直後の細胞を持ち評価したので、実施例3では該誘導細胞が成熟後も褐色様脂肪細胞の形質を維持していることを、成熟脂肪細胞を用い評価した。評価は、FGF−21、PGC−1α及び褐色様脂肪細胞マーカー遺伝子である細胞死誘導DFFA様エフェクターa(Cidea)の各遺伝子の発現量、加えて、褐色様脂肪細胞はアドレナリンによる刺激に応答し、UCP1遺伝子の発現量を亢進することから成熟化後の脂肪細胞にアドレナリンを添加した場合のUCP1遺伝子の発現量を指標に、白色脂肪細胞の褐色様脂肪細胞への分化誘導を確認した。
3T3−L1細胞を用いて見られた、白色脂肪細胞の褐色様脂肪細胞分化誘導作用を評価するために、ヒト皮下脂肪由来正常前駆脂肪細胞(ロンザ・ジャパン社)を用いて評価を行った。正常前駆脂肪細胞は通常白色脂肪細胞へと分化するが、褐色様脂肪細胞へと分化誘導されることで白色脂肪細胞ではほとんど観察されないUCP−1遺伝子の発現や、ミトコンドリアに発現するCox7a1遺伝子の発現量の増加、褐色脂肪細胞のマーカー遺伝子であるPGC−1β及び褐色様脂肪細胞特異的に発現するCBP/p300‐interacting transactivator(CITED1)遺伝子の発現亢進が観察されるようになる。そこで、CITED1、Cox7a1及びUCP1の各遺伝子の発現量を指標に、白色脂肪細胞の褐色様脂肪細胞への分化誘導を確認した。
また、誘導体含有組成物は、製造コストがかかる合成アゴニストであるロシグリタゾンと比べて、ワンステップで、食品成分から安価に調製することが可能である点でも優れていることがわかる。
実施例1と同様にして得られた誘導体含有組成物1gをエタノールに溶解し、得られた溶液を微結晶セルロースに吸着させて、減圧乾燥した。本発明品吸着体10部、コーンスターチ23部、乳糖12部、カルボキシメチルセルロース8部、微結晶セルロース32部、ポリビニルピロリドン4部、ステアリン酸マグネシウム3部、タルク8部を混合し打錠することで、本発明品を含む打錠剤を得た。
実施例1と同様にして得られた誘導体含有組成物1.2gをエタノールに溶解させて得られたエタノール溶液10mL、タウリン20g、ビタミンB1硝酸塩0.12g、安息香酸ナトリウム0.6g、クエン酸4g、砂糖60g及びポリビニルピロリドン10gを精製水に溶解し、全量を1000mLにメスアップした。なお、pHは、希塩酸を用いて3.2に調整した。得られた溶液1000mLのうち50mLをガラス瓶に充填し、80℃で30分間滅菌して、医薬部外品であるドリンク剤を得た。
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