JP6861806B2 - オレアノール酸アセテートを有効成分として含む、薬剤により誘発される腎臓毒性の予防、改善または治療用の組成物 - Google Patents
オレアノール酸アセテートを有効成分として含む、薬剤により誘発される腎臓毒性の予防、改善または治療用の組成物 Download PDFInfo
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- JP6861806B2 JP6861806B2 JP2019518209A JP2019518209A JP6861806B2 JP 6861806 B2 JP6861806 B2 JP 6861806B2 JP 2019518209 A JP2019518209 A JP 2019518209A JP 2019518209 A JP2019518209 A JP 2019518209A JP 6861806 B2 JP6861806 B2 JP 6861806B2
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- oleanolate
- acetate
- cisplatin
- renal toxicity
- induced
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Description
本発明の他の目的は、オレアノール酸アセテートまたはその食品学的に許容される塩を有効成分として含む、薬剤により誘発される腎臓毒性に対する予防または改善用の健康機能食品を提供することにある。
本発明で用いられる用語、「MCP−1」とは、単球走化性タンパク質−1(monocyte chemoattractant protein−1)の略語であって、炎症性ケモカインの一種をいう。
実施例1−1:赤小豆抽出物の製造
赤小豆(小豆またはしま蔓小豆)を水で清潔に洗浄し陰で乾燥した後、ワーリングブレンダーで粉末化した。粉末化された赤小豆20kgをメタノール100Lに入れ、室温で3日間冷浸抽出した後、濾紙(ワットマン、米国)で減圧濾過した後、濾過抽出物は真空回転濃縮機を用いて室温でメタノール溶媒を除去した後に抽出された残渣として赤小豆抽出物450gを製造した。
前記製造された赤小豆抽出物から活性分画物を分離するために、赤小豆抽出物を水1Lに懸濁し、等量のn−ヘキサンを加えて混合して分画し、この過程を4回繰り返し行って、水可溶性分画物1Lとn−ヘキサン可溶性分画物4Lを得た。その次に、前記n−ヘキサン可溶性分画物を減圧濃縮してn−ヘキサン可溶抽出物50gを得た。
前記実施例1−1および1−2で得られた各々の赤小豆抽出物および分画物を対象にHPLC分析を行った。
前記実施例1−2で得られたn−ヘキサン分画物80gをヘキサン:エチルアセテート(100:1→1:1)で構成されたステップグラジエント(step gradient)溶媒システムを用いてシリカゲルカラムクロマトグラフィー(silica gel column chromatography)に適用して5個の活性分画(Fr.1−5)を得た。前記活性分画のうち3番および4番の分画にメタノールを加えて再結晶過程を行うことによって、白色粉末状の2種の化合物を精製した。
オレアノール酸とオレアノール酸アセテートの細胞毒性を比較するために、ヒト腎臓細胞株とマウス腹腔マクロファージ、脾臓primary細胞を用いて確認した。
ヒト胎児腎臓細胞(Human embryonic kidney cell)であるHEK−293T細胞は、熱により不活性化した10% FBSが添加されたGibco社製(米国)のDulbecco’s modified eagle medium(Cat No.12800−017)で培養した。
培養が終わった細胞の生存率はMTT還元方法を用いて測定した。MTT溶液は、生きている細胞でミトコンドリアのデヒドロゲナーゼ(dehydrogenases)によりホルマザン(formazan)を形成して細胞の生存有無を確認することができる。細胞毒性を確認するために、cellを96ウェルプレートに5×104細胞/ウェルで37℃で培養した後、オレアノール酸とオレアノール酸アセテートを濃度別に処理し、24時間培養した。24時間後、各ウェルに20μlのMTT溶液を添加し、さらに2時間培養した後に培養液を除去し、100μlのジメチルスルホキシド(dimethylsulfoxide)を添加した後に570nmで吸光度を測定した。
オレアノール酸とオレアノール酸アセテートの細胞毒性を比較評価するために、ヒト腎臓細胞株と腹腔マクロファージ、脾臓細胞を用いてMTT assayを確認した。その結果、ヒト腎臓細胞株では、濃度依存的にオレアノール酸よりオレアノール酸アセテートの細胞毒性が少なく、最高濃度1000μg/mlにおいて、オレアノール酸は27%、オレアノール酸アセテートは43%の細胞生存率を示しており、オレアノール酸アセテートの方が細胞毒性が少なく誘発するのを確認した(図1a)。
オレアノール酸アセテートのシスプラチン誘発腎臓毒性の抑制効果を確認するために動物実験を行った。
体重20〜25gの8週齢のC57BL/6雄マウス(オリエンタルバイオ、ソウル、韓国)を購入して、無作為に生理食塩水投与群(Control、CON)、オレアノール酸アセテート投与群(OAA)、シスプラチン単独投与群(CP)、シスプラチンとオレアノール酸アセテートの併用投与群(CP+OAA)に分けた。実験のために、これらのマウスを一定の温度(23±3℃)、湿度(55±15%)および照射量(7:00時から19:00時まで)下で飼育した。購入後、マウスをSPF動物飼育室で1週間安定させた後に実験に用いた。シスプラチン(Sigma、St.Louis、MO、USA)は、生理食塩水に2mg/mlの濃度で溶かした後に20mg/kgの容量で腹腔投与し、オレアノール酸アセテートは、蒸留水に溶かして50mg/mlの容量で、シスプラチン投与1時間前、投与してから1日目、3日目、5日目に経口投与した。全ての群のマウスは、シスプラチン投与してから5日目にマウスを犠牲死させた。
マウスの犠牲後に体重を測定し、腎臓を分離し、心臓からは血液を採取して腎臓毒性と関連した生化学的指標である血中尿素窒素(blood urea nitrogen、BUN)を測定した。採取したマウス血液は、遠心分離機を用いて4℃、3000rpm、15分間遠心分離して血清のみを分離した後、自動分析装置(automatic analyzer)(Fuji Dry−Chem NX500i、Tokyo、Japan)を用いてBUNを測定した。
血液内の炎症性サイトカイン(TNF−α、IL−6)を測定するために血液から血清を分離して用い、TNF−α、IL−6はマウスELISAキット(R&D system、Minneapolis、MN、USA)を用いて分析した。ELISA発色程度は、450nm波長でVarioskanTM LUXマルチモードマイクロプレートリーダー(Thermofisher、Sunnyvale、CA、USA)を用いて測定した。
マウス犠牲後、腎臓を分離してTrizol reagent(Invitrogen、Carlsbad、CA、USA)を添加して均質化した。それにクロロホルムを添加してRNAを抽出し、イソプロパノールを添加して沈殿させた。RNA沈殿物を75%エタノールで洗浄した後、RNAの濃度と純度は2100 Bioanalyzer system(Agilent Technologies、Santa Clara、CA、USA)を用いて測定し、Taqman reverse transcription reagents kit(Applied Biosystems、Foster City、CA、USA)を用いてcDNAを合成した。炎症因子の発現程度は、SYBR Green PCR master mix kit(Applied Biosystem、Foster City、CA、USA)を用いてReal−time PCRを通じて測定した。
オレアノール酸アセテート、それを含む赤小豆抽出物または前記抽出物の分画物0.1g、乳糖1.5gおよびタルク0.5gを混合し、気密布に充填して散剤を製造した。
オレアノール酸アセテート、それを含む赤小豆抽出物または前記抽出物の分画物0.1g、ラクトース7.9g、結晶性セルロース1.5gおよびマグネシウムステアレート0.5gを混合し、直接打錠法(direct tableting method)により有効成分を50mgとして含む500mgの錠剤を製造した。
オレアノール酸アセテート、それを含む赤小豆抽出物または前記抽出物の分画物0.1g、トウモロコシデンプン5gおよびカルボキシセルロース4.9gをよく混合して粉末を製造し、硬質カプセルに前記粉末500mgを入れてカプセル剤を製造した。
通常の注射剤の製造方法に従い、オレアノール酸アセテート、それを含む赤小豆抽出物または前記抽出物の分画物0.1gと適量の注射用滅菌蒸留水およびpH調節剤を含む2ml容量の注射用アンプルを製造した。
通常の液剤の製造方法に従い、精製水にオレアノール酸アセテート、それを含む赤小豆抽出物または前記抽出物の分画物0.1g、異性化糖10gおよびマンニトール5gを加えて溶解させ、レモン香りを適量加えてから前記成分を混合した後、精製水を加えて全体100mlに調節した後、琥珀色の薬瓶に充填し滅菌して液剤を製造した。
Claims (10)
- 前記腎臓毒性を誘発する薬剤は、シスプラチン(cisplatin)、カルボプラチン(carboplatin)、オキサリプラチン(oxaliplatin)およびネダプラチン(nedaplatin)からなる群より選択される一つ以上の白金系抗癌剤;または抗生剤である、請求項1に記載の薬学的組成物。
- 前記薬学的組成物は、腎臓組織内の炎症因子の発現阻害活性を有する、請求項1に記載の薬学的組成物。
- 前記炎症因子は、TNF−α、IL−6、COX−2およびMCP−1からなる群より選択される一つ以上である、請求項3に記載の薬学的組成物。
- 前記抗癌補助剤は、シスプラチン(cisplatin)、カルボプラチン(carboplatin)、オキサリプラチン(oxaliplatin)およびネダプラチン(nedaplatin)からなる群より選択される一つ以上の白金系抗癌剤と併用投与される、請求項5に記載の抗癌補助剤。
- 前記抗癌補助剤は、腎臓組織内の炎症因子の発現阻害活性を有する、請求項5に記載の抗癌補助剤。
- 前記炎症因子は、TNF−α、IL−6、COX−2およびMCP−1からなる群より選択される一つ以上である、請求項7に記載の抗癌補助剤。
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