JP6241681B2 - 水酸化脂肪酸を含む腸管保護剤 - Google Patents
水酸化脂肪酸を含む腸管保護剤 Download PDFInfo
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- JP6241681B2 JP6241681B2 JP2015501420A JP2015501420A JP6241681B2 JP 6241681 B2 JP6241681 B2 JP 6241681B2 JP 2015501420 A JP2015501420 A JP 2015501420A JP 2015501420 A JP2015501420 A JP 2015501420A JP 6241681 B2 JP6241681 B2 JP 6241681B2
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- A61K31/201—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 one or two double bonds, e.g. oleic, linoleic acids
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- A—HUMAN NECESSITIES
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- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Description
上記のような腸管保護剤は報告されているものの、腸管バリア機能の損傷又はそれに起因する疾患の予防又は治療に用いることのできる、新たな腸管保護剤の開発が望まれている。
[1]10位及び/又は12位に水酸基を有する炭素数18の水酸化脂肪酸を含む、腸管保護剤。
[2]水酸化脂肪酸が、水酸化不飽和脂肪酸である、[1]に記載の剤。
[3]水酸化不飽和脂肪酸が、12位にシス型二重結合を有する、[2]に記載の剤。
[4]水酸化不飽和脂肪酸が、10-ヒドロキシ-シス-12-オクタデセン酸である、[2]に記載の剤。
[5]腸管バリア機能の損傷に起因する疾患の予防又は改善に使用される[1]−[4]のいずれかに記載の剤。
[6]腸管バリア機能の損傷に起因する疾患が、炎症性腸疾患、潰瘍及び腸過敏性症候群からなる群から選択される少なくとも1種の疾患の予防又は改善に使用される、[5]に記載の剤。
[7]食品もしくは食品添加物である、[1]−[6]のいずれかに記載の剤。
[8]医薬品である、[1]−[6]のいずれかに記載の剤。
[9]飼料もしくは飼料添加物である、[1]−[6]のいずれかに記載の剤。
[10]温血動物における腸管バリア機能の損傷又はそれに起因する疾患を予防又は治療する方法であって、有効量の10位及び/又は12位に水酸基を有する炭素数18の水酸化脂肪酸を、該哺乳動物に投与することを含む、方法。
[11]腸管保護剤として使用するための、10位及び/又は12位に水酸基を有する炭素数18の水酸化脂肪酸。
[12]腸管保護剤の製造のための、10位及び/又は12位に水酸基を有する炭素数18の水酸化脂肪酸の使用。
本発明において「腸管保護」効果を有する、「腸管バリア機能の損傷を予防又は改善する」とは、上記いずれかの手法の少なくとも1つによる腸管バリア機能の評価が、被検水酸化脂肪酸の投与により有意に改善されることを意味する。
より具体的には、10-ヒドロキシ-シス-12-オクタデセン酸(HYA)、10-ヒドロキシ-シス-12,シス-15-オクタデカジエン酸(以下、「αHYA」ともいう)、10-ヒドロキシ-シス-6,シス-12-オクタデカジエン酸(以下、「γHYA」ともいう)、10-ヒドロキシ-シス-6,シス-12,シス-15-オクタデカトリエン酸(以下、「sHYA」ともいう)、10,12-ジヒドロキシオクタデカン酸(以下、「rHYA」ともいう)、10-ヒドロキシオクタデカン酸(以下、「HYB」ともいう)、10-ヒドロキシ-シス-15-オクタデセン酸(以下、「αHYB」ともいう)、10-ヒドロキシ-シス-6-オクタデセン酸(以下、「γHYB」ともいう)、10-ヒドロキシ-シス-6,シス-15-オクタデカジエン酸(以下、「sHYB」ともいう)、12-ヒドロキシオクタデカン酸(以下、「rHYB」ともいう)、リシノール酸(以下、「RA」ともいう)、10-ヒドロキシ-トランス-11-オクタデセン酸(以下、「HYC」ともいう)、10-ヒドロキシ-トランス-11,シス-15-オクタデカジエン酸(以下、「αHYC」ともいう)、10-ヒドロキシ-シス-6,トランス-11-オクタデカジエン酸(以下、「γHYC」ともいう)、10-ヒドロキシ-シス-6,トランス-11,シス-15-オクタデカトリエン酸(以下、「sHYC」ともいう)等が挙げられるが、これらに限定されない。
より具体的には、本発明の水酸化脂肪酸の製造原料もしくは中間体として、10-オキソ-シス-12-オクタデセン酸(「KetoA」ともいう)、10-オキソ-シス-12,シス-15-オクタデカジエン酸(以下、「αKetoA」ともいう)、10-オキソ-シス-6,シス-12-オクタデカジエン酸(以下、「γKetoA」ともいう)、10-オキソ-シス-6,シス-12,シス-15-オクタデカトリエン酸(以下、「sKetoA」ともいう)等の10-oxo,cis-12脂肪酸、10-オキソオクタデカン酸(「KetoB」ともいう)、10-オキソ-シス-6-オクタデセン酸(以下、「γKetoB」ともいう)、10-オキソ-シス-15-オクタデセン酸(以下、「αKetoB」ともいう)、10-オキソ-シス-6,シス-15-オクタデカジエン酸(以下、「sKetoB」ともいう)等の10-oxo,11,12-飽和化脂肪酸、10-オキソ-トランス-11-オクタデセン酸(「KetoC」ともいう)、10-オキソ-シス-6,トランス-11-オクタデカジエン酸(以下、「γKetoC」ともいう)、10-オキソ-トランス-11,シス-15-オクタデカジエン酸(以下、「αKetoC」ともいう)、10-オキソ-シス-6,トランス-11,シス-15-オクタデカトリエン酸(以下、「sKetoC」ともいう)等の10-oxo,trans-11脂肪酸などが使用され得る。
反応1の「基質」は、9位にシス型二重結合を有する炭素数18の不飽和脂肪酸であれば特に制限されず、例えばモノエン酸(18:1)、ジエン酸(18:2)、トリエン酸(18:3)、テトラエン酸(18:4)、ペンタエン酸(18:5)等が挙げられる。ジエン酸、トリエン酸、又はテトラエン酸がより好ましく、ジエン酸類、又はトリエン酸類が特に好ましい。尚、本明細書において「脂肪酸」という場合、遊離の酸のみならず、エステル体、塩基性化合物との塩等をも包含する。
ジエン酸としては、例えば、リノール酸、シス-9,トランス-11-オクタデカジエン酸等が挙げられる。
トリエン酸類としては、例えば、α−リノレン酸、γ−リノレン酸等が挙げられる。
テトラエン酸としては、例えば、ステアリドン酸等が挙げられる。
さらに、酵素反応に「活性化剤」を用いてよく、例えば、モリブデン酸カリウム、モリブデン(VI)酸二ナトリウム無水和物、モリブデン(VI)酸二ナトリウム二水和物、オルトバナジン(V)酸ナトリウム、メタバナジン(V)酸ナトリウム、タングステン(VI)酸カリウム、タングステン(VI)酸ナトリウム無水和物、及びタングステン(VI)酸ナトリウム二水和物からなる群から選ばれる1又は2以上の化合物が挙げられる。その添加濃度は水和反応が効率良く進む濃度であればよい。好ましくは0.1〜20 mM、より好ましくは1〜10 mMである。
一方、12-hydroxy脂肪酸は、例えば、それを構成脂肪酸として含むトリグリセリドエステルを主成分とする天然油から、加水分解により得ることができる。例えば、RAはヒマシ油、rHYBは硬化ヒマシ油の加水分解により得ることができる。
さらに、酵素反応に「活性化剤」を用いてよく、例えば、上記反応1で例示されたのと同様の化合物を、同様の添加濃度で使用することができる。
化学的酸化としては、自体公知の方法、例えばクロム酸酸化、好ましくはジョーンズ酸化等が挙げられる。クロム酸としては、無水クロム酸CrO3、クロム酸H2CrO4、二クロム酸H2Cr2O7といった化合物の塩や錯体を使用することができる。
反応3の「基質」としては、上記反応1及び2により、9位及び12位にシス型二重結合を有する炭素数18の不飽和脂肪酸から誘導される10-oxo,cis-12脂肪酸であれば特に制限されず、リノール酸から誘導されるKetoA、α−リノレン酸から誘導されるαKetoA、γ−リノレン酸から誘導されるγKetoA、ステアリドン酸から誘導されるsKetoA等が挙げられる。当該基質は反応1及び2以外の方法により得られたものであってもよい。
反応4の「基質」としては、上記反応3により生成し得る10-oxo,trans-11脂肪酸であれば特に制限されず、KetoAから誘導されるKetoC、αKetoAから誘導されるαKetoC、γKetoAから誘導されるγKetoC、sKetoAから誘導されるsKetoC等が挙げられる。当該基質は反応3以外の方法により得られたものであってもよい。
(a)配列番号2に示されるアミノ酸配列からなる酵素タンパク質、
(b)配列番号2に示されるアミノ酸配列において、1又は複数個のアミノ酸が欠失及び/又は置換及び/又は挿入及び/又は付加されたアミノ酸配列を含み、かつ上記反応4を触媒する酵素活性を有するタンパク質、あるいは
(c)配列番号1に示される塩基配列の相補鎖配列からなる核酸と、ストリンジェントな条件下でハイブリダイズする塩基配列によってコードされ、かつ上記反応4を触媒する酵素活性を有するタンパク質である。
上記のようにアミノ酸が欠失、置換又は挿入されている場合、その欠失、置換、挿入の位置は、上記酵素活性が保持される限り、特に限定されない。
さらに、酵素反応に「活性化剤」を用いてよく、例えば、上記反応1で例示されたのと同様の化合物を、同様の添加濃度で使用することができる。
反応5の「基質」としては、上記反応3により生成し得る10-oxo,trans-11脂肪酸であれば特に制限されず、KetoAから誘導されるKetoC、αKetoAから誘導されるαKetoC、γKetoAから誘導されるγKetoC、sKetoAから誘導されるsKetoC等が挙げられる。当該基質は反応3以外の方法により得られたものであってもよい。
一方、反応6の「基質」としては、上記反応4により生成し得る10-oxo,11,12-飽和化脂肪酸であれば特に制限されず、KetoCから誘導されるKetoB、αKetoCから誘導されるαKetoB、γKetoCから誘導されるγKetoB、sKetoCから誘導されるsKetoB等が挙げられる。当該基質は反応4以外の方法により得られたものであってもよい。
さらに、酵素反応に「活性化剤」を用いてよく、例えば、上記反応1で例示されたのと同様の化合物を、同様の添加濃度で使用することができる。
腸管バリア機能の損傷を起こす原因は、例えば、ストレス、手術等の外科的要因、薬物、毒素などが挙げられるが、これらに限定されない。
当該医薬品の剤型としては、散剤、顆粒剤、丸剤、ソフトカプセル、ハードカプセル、錠剤、チュアブル錠、速崩錠、シロップ、液剤、懸濁剤、座剤、軟膏、クリーム剤、ゲル剤、粘付剤、吸入剤、注射剤等が挙げられる。これらの製剤は常法に従って調製されるが、水酸化脂肪酸等は水に難溶性であるため、植物性油、動物性油等の非親水性有機溶媒に溶解するか又は、乳化剤、分散剤もしくは界面活性剤等とともに、ホモジナイザー(高圧ホモジナイザー)を用いて水溶液中に分散、乳化させて用いる。
本発明の医薬品の投与量又は本発明の食品の摂取量は、患者又は摂取者の年齢及び体重、症状、投与時間、剤型、投与方法、薬剤の組み合わせ等に依存して適宜決定できる。例えば、本発明の医薬品を経口投与する場合、有効成分である本発明の水酸化脂肪酸の総量として、成人1日当たり0.02〜100mg/kg体重、好ましくは0.2〜50mg/kg体重の範囲で、また、非経口的に投与する場合は0.002mg〜50mg/kg体重、好ましくは0.02〜50mg/kg体重の範囲で、一日1回もしくは数回(2〜5回)に分けて投与することができる。また、食品として摂取する場合には、有効成分である本発明の水酸化脂肪酸の総量が、成人1人1日当たり1〜6000mgの範囲、好ましくは10〜3000mgの範囲の摂取量となるように、食品に配合することができる。本発明の飼料の摂取量についても、それぞれ上記食品の摂取量及び上記医薬品の投与量に準じて適宜決定することができる。
Caco-2細胞:ATCCでの受託番号HTB-37、40〜60代継代したものを使用した。
培地:10%牛胎子血清、1%非必須アミノ酸、100 IU/mLペニシリン、100 μg/mLストレプトマイシン、及び50 μg/mLゲンタマイシン含有ダルベッコ改変イーグル培地(培地及び添加物はいずれもLife Technologies製)
Caco-2細胞の調製
75 cm2の組織培養フラスコにCaco-2細胞を入れ、約80%のコンフルエンスになるまで、37℃で培養した。当該細胞を、12穴トランズウェル(Transwell(登録商標))細胞培養チャンバー(透過性膜;直径12mm、孔径0.4μm)に、2×105 cells/cm2の細胞濃度で接種し、5% CO2雰囲気下、37℃にて14日間培養しCaco-2単層細胞を得た。さらに、タイトジャンクションが充分に形成されているか否かを検証するため、経上皮電気抵抗(TER)が約900〜1,000Ω・cm2以上のCaco-2単層細胞をアッセイに用いた。各ウェルはクラスタープレート上に設置し、外側培養液(基底側、1.5 mL)及び内側培養液(管腔側、0.5 mL)を満たした。48時間毎に新鮮な培地に交換してCaco-2単層細胞を培養した。
上述の方法で調製したCaco-2単層細胞の各ウェルの内側培養液に、HYA、HYB、KetoA、KetoBまたはKetoC、各々50 μM濃度の溶液を500 μL添加して24時間培養した。次に、外側培養液に、最終濃度が50 ng/mLになるようにIFN-γを添加して24時間培養後、外側培地を一旦取り除き、50 ng/mLになるようにTNF-αを加え、さらに6時間培養した後、後述の腸管バリア保護効果の評価を行った。その際、被検脂肪酸液無添加でIFN-γ及びTNF-αのみを添加したウェル、若しくは、被検脂肪酸液、IFN-γ及びTNF-αのいずれも添加しないウェル(以下、コントロールともいう)も設けた。
被検脂肪酸液による腸管バリア保護効果の比較は、経上皮電気抵抗(TER)値(Ω・cm2)及びIL-8産生(pg/mL)を指標に行なった。Ag/AgCl電極を用いた抵抗値測定システム(Millicell-ERS、Millipore)を用いて、TNF-αを添加後0、1、2、3、4、5、6時間での各TER値を測定した。さらに、各ウェルのTER値をコントロールのTER値で除してTER相対値(Relative TER)を算出した。各IL-8産生量は、培養後に採取した外側培養液をELISA法に供し、TNF-α添加後6時間の値を測定した。
上述の実施例同様、HYAを添加して6時間後に、Caco-2単層細胞をPBSで3回洗浄した後、当該細胞からTRIzol(登録商標)(Life Technologies社製)を用いてRNAを抽出した。当該RNAをhigh-capacity cDNA reverse transcription kit (Life Technologies)を用いて逆転写させcDNAを得、KAPA SYBR FAST ABI PRISM qPCR kit (Kapa Biosystems)を用いて、リアルタイムPCR解析を行った。プライマーは、IL-8については配列番号3及び4、Claudin-1については配列番号5及び6、ZO-1については配列番号7及び8、Occludinについては配列番号9及び10、MLCKについては配列番号11及び12でそれぞれ表されるヌクレオチド配列からなるオリゴDNA対を使用した。
BALB/cマウス (♀, 6週齢)はCharles River Japan (Kanagawa, Japan)から購入し、全ての実験計画は広島大学動物実験等規則に従って行った (No. C10-17)。急性大腸炎は3.5 % (w/v) DSS (分子量36000-50000; MP Biomedicals, Aurora, OH, USA)を5日間、自由飲水させることにより誘導した。HYAおよびHYBの大腸に対する効果を評価するために、マウスにHYAあるいはHYB (各100 nmol)の懸濁液100 μLを経口投与した。この投与はDSS投与前5日間と投与開始後5日間の全10日間、毎日行った。大腸炎の症状評価は、体重減少、糞便の状態および肛門からの出血によって毎日評価した 。5日間のDSS投与後、マウスを屠殺し、大腸長を測定した。その後、大腸組織からRNeasy Mini Kit (Qiagen, Maryland, MD, USA)を用いてRNA抽出を行った。また、大腸組織のパラフィン切片 (7 μm)を作製し、ヘマトキシリン-エオシンによって染色して、組織化学的評価を行った。また、抽出したRNAはhigh-capacity cDNA reverse transcription kit (Life Technologies)を用いて逆転写させcDNAを得、KAPA SYBR FAST ABI PRISM qPCR kit (Kapa Biosystems)を用いて、リアルタイムPCR解析を行った。プライマーは、Claudin-1については配列番号5及び 6、Claudin-3については配列番号13及び14、Claudin-4については配列番号15及び16、ZO-1については配列番号7及び8、ZO-2については配列番号17及び18、Occludinについては配列番号9及び10、MLCKについては、配列番号11及び12でそれぞれ表されるヌクレオチド配列からなるオリゴDNA対を使用した。
また、大腸切片の組織化学的評価(H&E染色)の結果を図9に示す。DSS処理は大腸の上皮細胞の損傷とクリプトの減少を顕著に誘導したが、HYAを投与したマウスでは組織損傷が回復した。
claudin-1, -3, -4, occludin, MLCK, ZO-1およびZO-2のmRNA発現を図10に示す。DSSマウスは、claudin-1, 3, 4, occludin, ZO-1およびZO-2のmRNA発現異常を有意に誘導した(MLCKは増加傾向であった)。しかし、HYAを経口投与したマウスでは、DSSマウスと比較して、occludinとMLCKのmRNA発現が有意に回復していた。一方、HYBは全てのTJ関連因子の発現異常を回復しなかった。
ここで述べられた特許及び特許出願明細書を含む全ての刊行物に記載された内容は、ここに引用されたことによって、その全てが明示されたと同程度に本明細書に組み込まれるものである。
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