JP6086373B2 - 難消化性オリゴ糖類の使用 - Google Patents
難消化性オリゴ糖類の使用 Download PDFInfo
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- JP6086373B2 JP6086373B2 JP2015200855A JP2015200855A JP6086373B2 JP 6086373 B2 JP6086373 B2 JP 6086373B2 JP 2015200855 A JP2015200855 A JP 2015200855A JP 2015200855 A JP2015200855 A JP 2015200855A JP 6086373 B2 JP6086373 B2 JP 6086373B2
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- indigestible
- oligosaccharide
- oligosaccharides
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Description
この例では、参照の図は以下のとおりである:
本発明の別の態様によれば、それを必要とする被験体の増殖性障害の予防および/または治療の方法が提供され、この方法は、この被験体に対して治療上有効な量の難消化性オリゴ糖を投与する工程を包含する。
本発明の別の態様によれば、それを必要とする被験体の過剰増殖性障害の予防および/または治療の方法が提供され、この方法は、この被験体に対して治療上有効な量の難消化性オリゴ糖を投与する工程を包含する。
(式1)
[A]−[B]n
ここで、
[A]および[B]は各々が独立して、5員または6員の糖単位であり、かつ
nが2〜10である、難消化性オリゴ糖またはその塩の使用が提供される。
(a)透明な、低粘度の、水様の、安定な、すぐ使える(ready−to−use)、瓶詰めの、炭酸飲料もしくは非炭酸飲料;または再構成用の濃縮透明液(難消化性オリゴ糖を含有する);
(b)水または他の経口の摂取可能な液体と、飲用可能な液体として再構成される粉末/顆粒混合物(難消化性オリゴ糖を含有する);
(c)食料品(例えば、食物バーなど)中に混合される粉末/顆粒混合物。
ラフィノースファミリーのオリゴ糖類(RFO類)は、スクロースのα−ガラクトシル誘導体であって、最も一般的には、三糖ラフィノース、四糖スタキオースおよび五糖ベルバスコースである。RFO類は植物界でほぼ偏在性であって、多くの異なる科の広範な種々の種子に見出される。
ヒトおよび他の単胃動物(ブタおよび鳥類)は、RFO類を破壊するα−GAL酵素を保有せず、これらのオリゴ糖は、胃および腸上部を未消化のまま通過する。
ヨーロッパ細胞培養コレクション(European cell Culture collection)(ECACC番号86010202,Porton Down,UK)から入手したCaco−2細胞を、高グルコース(4.5g/l)、10%ウシ胎仔血清、2Mmグルタミン、1%非必須アミノ酸および50IU/mlのペニシリン/50μg/mlのストレプトマイシン(Invitrogen,Paisley,UK)含有のダルベッコ改変イーグル培地(DMEM)中で維持した。これらの細胞(継代41〜50)を、75cm2のT−フラスコ(Fisher,UK)中で、37℃で5%のCO2中で、一定湿度の環境で、1週に培地を3回置き換えて培養した。単層が80%コンフルエンシーの領域に達した時、0.05%のトリプシン/0.02%のEDTAを用いて1:10の分割比で分割した。
経上皮電気抵抗(TEER)は、細胞の単層を横切る電気抵抗を測定することを包含する。電気抵抗は、単層がイオンを透過させる程度の指標であり、従って、密着結合完全性の代用として用いることができる。抵抗が高ければ、密着結合が閉じていることを示し、その逆もまた同様である。
REKおよびCaco−2細胞を、無血清培地中に24時間置いて、次に種々の濃度および/または時間で難消化性オリゴ糖で処理した。難消化性オリゴ糖を、水中のストック溶液として1モル(M)の濃度で調製した。陰性コントロールのスクロースを同様に処理した。
高含量スクリーニングによって、プロテインキナーゼC(これは活性化されると細胞内で移動する)の活性を観察する。プロテインキナーゼCの活性は、多数の細胞活性を変更し得る細胞内のシグナル伝達カスケードの開始点である。細胞調節因子PKCの活性によって、多くの細胞活性が難消化性オリゴ糖類に応答して変更されることが示唆される。caco−2細胞は、96ウェルプレート上で100%コンフルエントまで増殖させた。実験前に、細胞を無血清培地(SFM)でインキュベートして、インキュベーター内に一晩置いた。翌日、細胞を、オリゴフルクトース(50mMまたは100mM)またはメリビオース(50mMまたは100mM)のいずれかで5分、10分、20分、40分または60分間処理した。全ての実験を三連で行った。同様に、コントロールとしてある程度の細胞を、難消化性オリゴ糖類と同じ時間、50mMまたは100mMのいずれかのスクロースで処理した。この後、2%のホルムアルデヒドを室温で20分間細胞上に置いた。次いで、この細胞をPBSで2回洗浄して、実験のために100μlのPBS溶液とともに置いた。次いで細胞を、プロテインキナーゼC(PKC)に対して惹起された蛍光抗体でチャレンジして、プレート読み取り蛍光顕微鏡を用いる高含量スクリーニング(High Content Screening)(HCS)によって分析した。プレート読み取りベースの蛍光顕微鏡によって、目的のいくつかの抗原について染色された細胞の迅速な獲得および定量が可能になり、それによって、シグナル伝達事象、例えば、リン酸化反応および/または細胞内タンパク質再分配を多様性解析で定量することが可能になる。高含量スクリーニング(High Content Screening)(HCS)によって、染色強度の定量、および画像データをグラフ形式に変換することを可能にする細胞内局在パターンが可能になる。高含量スクリーニング(HCS)は、Imagen Biotech Ltd.によって行った。
REK細胞を、1ウェルあたり3000個の細胞で96ウェルプレートにプレートした。24時間後、この細胞を、5%のウシ胎仔血清(FBS)および50mMの難消化性オリゴ糖を含有する培地中に入れた。この細胞を4日間増殖させ、次いで細胞数を、製造業者の指示に従ってCelltitre 96(商標)アッセイ(promega)を用いて測定した。
ヒト皮膚は、顔のシワ取りのための待機手術を受けている同意したボランティアから得た。皮膚は、最大7日間まで臓器培養液中で維持し、オリゴフルクトースで処理した。次いで組織を「急速(snap)」凍結し、薄片にして、増殖マーカーについて適切な抗体Ki67、またはアポトーシスのマーカーTUNELで染色した。
オリゴフルクトースは、caco−2細胞の単層において経上皮電気抵抗を低下した。
Tanswell(商標)フィルター上で増殖しているcaco−2単層を50mMのオリゴフルクトースまたは同じ濃度のスクロースを用いて、先端面に対してオリゴフルクトースまたはスクロースを添加することによって処理した。TEER測定は、未処理のコントロールの測定とともに2時間行った。その結果を図1に示しており、これによって、コントロールの単層のTEER測定が、スクロースのコントロールと同様にこの期間の間、影響されていないままであることが示される。しかし、TEER測定は、難消化性の多糖での処理によって有意に減少された。オリゴフルクトースは、TEERを出発値の約35%まで低下した。TEERの低下は、難消化性多糖が先端面に添加された場合にのみ生じた。基底面の処理は、細胞に影響を有さなかった。TEERの減少によって、細胞は、難消化性オリゴ糖類を認識すること、および密着結合が開放されることが示される。
96ウェルプレート上で増殖しているコンフルエントなcaco−2細胞を、5分〜60分の間で変化する時間にわたりスクロースまたはオリゴフルクトースでチャレンジした。高含量のスクリーニング、(抗体を用いて細胞質から細胞内の膜への重要なタンパク質の移動をモニターする蛍光ベースの技術)を用いて、プロテインキナーゼC(PKC)の動きを、オリゴフルクトース添加の数分以内に観察した。
96ウェルプレート中で増殖するラット表皮のケラチン生成細胞を、50mMの難消化性オリゴ糖を含有する血清減少(5%)培地に供し、次いで4日間インキュベートした。細胞増殖は、Celltitre96を用いてモニターした。
上記で考察されるデータによって、難消化性オリゴ糖類は、モデル腸細胞と直接相互作用し、その活性に変化をもたらすことが示される。caco−2細胞に対する難消化性オリゴ糖類添加の5分内に、ベースラインを上回って膜でのPKC染色の強度における約4倍の増大が観察された。活性化の際に、PKCは、原形質膜に遊走し、ここでPKCは、それらを通常はリン酸化することによって他のタンパク質と相互作用する。従って、膜に対する移動は、PKC活性化の代用である。これによって、難消化性オリゴ糖類は、caco−2細胞におけるPKCの活性化を誘導し得ることが示唆される。難消化性オリゴ糖類に応答するcaco−2細胞における密着結合の開放もまた観察された。最初の測定は、治療の1時間後に行い、これによって、密着結合開放の代用であるTEERは、ベースラインのレベルの約40%まで低下されることが示された。2時間まで、TEERは、さらにわずかに低下された。後の時点で、さらなる減少は明らかにならず、これによって、密着結合開放が2時間までに最大となったことが示唆される。消化性糖類、スクロースは、密着結合を開放することもなく、PKC活性を誘発することもなく、このことは、これらの効果が難消化性オリゴ糖類に特異的であることを示唆する。
臨床研究のために、乾癬のプラークに加えられた物質がそれらの特徴を変化するか否かを評価するためにデザインされている、Scholtz−Dumasバイオアッセイと呼ばれる技術を用いた。この研究では、少量のクリームを、14日の間に6回、小面積(約2cm2)の患者の皮膚に対して、種々の量の天然に存在する難消化性オリゴ糖類を含有するテンプレートにまたがって適用した。クリームはまた、難消化性オリゴ糖類の存在なしに適用し、また乾癬に対して有効であることが公知の軽度のステロイドを含むクリームもコントロールとして適用した。2セットの反復適用を行った;1セットは、被覆(閉塞)して天然に存在する化合物の皮膚への浸透を最大にし、他のセットは被覆しないままにした。
第1群:局所用調製物のオープンの投与量設定試験。乾癬のための能動的局所への投薬からの2週間のウオッシュアウト期間後、クリームでの活性な範囲の用量を、12日の期間にわたって1日おきに、Scholtz−Dumasバイオアッセイ中の閉塞下の小領域の個々のプラークに適用した。各々の臨床上の来診の際、個々の領域をEISシステムを用いてスコア付けした。
被験体には、プラシーボまたはオリゴフルクトースのいずれかの局所用処方物を提供した。全ての被験体には、4週間にわたって毎日1回、2つの対称的プラークの各々に対して活性およびプラシーボの局所用処方物を適用するようにアドバイスした。この研究の間に、プラークは、EIS(紅斑、硬結およびスケーリングの標準の格付けシステム)およびTEWLについてモニターする。プラシーボ対活性プラークに対するEISおよび皮膚TEWLの比較測定によって、疾患および皮膚バリア機能に対する局所用のオリゴフルクトースの有益な効果を測定する。
被験体には、プラシーボまたはオリゴフルクトースのいずれかの固定用量を含む小袋を1日1回提供した。被験体には、シリアルにオリゴフルクトースを振りかけるかまたは、好ましくは、水に溶解して、飲料としてとるように求めた。8週後、経口治療をクロスオーバーさせて、プラシーボをとっている患者が活性剤をとるように、逆もまた同様にした。4週ごとに、比較の疾患PASI(乾癬の範囲と重症度インデックス(Psoriasis Area Severity Index))スコアおよびTEWL測定を行った。
粉末処方物は、5.0gの粉末のオリゴフルクトースおよび0.2gの標準の香味料の噴霧乾燥混合物を混合することによって調製した。
(a)3.5gの凍結乾燥したオリゴフルクトース(粉末)を、100mlのオレンジジュース(あるいはオレンジジュース濃縮物および水)に溶解した。
または
(b)2.5gの凍結乾燥したオリゴフルクトース(粉末)を、100mlのオレンジジュース(あるいはオレンジジュース濃縮物および水)に溶解した。
Claims (14)
- 被験体における乾癬による乾癬皮膚の表皮のケラチン生成細胞過剰増殖性の予防または治療用組成物の製造のための難消化性オリゴ糖またはその塩の抗過剰増殖剤としての使用であって、難消化性オリゴ糖が、主要な活性成分としてオリゴフルクトースまたはその塩を含有することを特徴とする使用。
- 組成物が局所皮膚適用製剤からなる請求項1に記載の使用。
- オリゴフルクトースまたはその塩を主要な活性成分として組成物中に0.5〜80質量%含むものである請求項1または2に記載の使用。
- 組成物中に、更に、薬学的に許容される希釈剤または担体を含有する請求項2または3に記載の使用。
- 局所皮膚適用製剤が、溶液、クリーム、軟膏、ゼリー、ゲル、シャンプー、スプレー、泡状物、粉末、リポソーム、水溶液、油性溶液及び懸濁液よりなる群から選ばれる一種以上の製剤である請求項2〜4のいずれかの項記載の使用。
- 組成物が経口用製剤からなる請求項1に記載の使用。
- 経口用製剤が0.5mg〜7gのオリゴフルクトースまたはその塩を活性成分として含有する請求項6に記載の使用。
- 主要な活性成分としてオリゴフルクトースまたはその塩を含有する乾癬による乾癬皮膚の表皮のケラチン生成細胞過剰増殖性の予防または治療用組成物。
- 組成物が局所皮膚適用製剤である請求項8に記載の組成物。
- オリゴフルクトースまたはその塩を主要な活性成分として組成物中に0.5〜80質量%含むものである請求項8または9に記載の組成物。
- 組成物中に、更に、薬学的に許容される希釈剤または担体を含有する請求項9または10に記載の使用。
- 局所皮膚適用製剤が、溶液、クリーム、軟膏、ゼリー、ゲル、シャンプー、スプレー、泡状物、粉末、リポソーム、水溶液、油性溶液及び懸濁液よりなる群から選ばれる一種以上の製剤である請求項9〜11のいずれかの項記載の組成物。
- 組成物が経口用製剤である請求項8に記載の組成物。
- 経口用製剤が0.5mg〜7gのオリゴフルクトースまたはその塩を活性成分として含有する請求項13に記載の組成物。
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US20150374607A1 (en) * | 2012-02-14 | 2015-12-31 | The Procter & Gamble Company | Topical use of a skin-commensal prebiotic agent and compositions containing the same |
EP3448398A4 (en) | 2016-04-21 | 2019-12-18 | Naked Biome, Inc. | COMPOSITIONS AND METHODS FOR THE TREATMENT OF SKIN DISORDERS |
AU2018241798B2 (en) * | 2017-03-30 | 2020-04-30 | Fruithy Holdings Limited | Lactulose glycoside compound and preparation method and use thereof |
KR20210135215A (ko) * | 2018-11-08 | 2021-11-12 | 디에스엠 아이피 어셋츠 비.브이. | 위장 항상성 유지를 지원하는 방법 |
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