JP2013136602A - 栄養組成物 - Google Patents
栄養組成物 Download PDFInfo
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- JP2013136602A JP2013136602A JP2013023027A JP2013023027A JP2013136602A JP 2013136602 A JP2013136602 A JP 2013136602A JP 2013023027 A JP2013023027 A JP 2013023027A JP 2013023027 A JP2013023027 A JP 2013023027A JP 2013136602 A JP2013136602 A JP 2013136602A
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Abstract
【解決手段】ホエイタンパク質加水分解物、脂質代謝改善作用を有するレシチンおよび高オレイン酸含有油脂、ならびにインスリン節約効果を有するパラチノースを必須成分として含む栄養組成物が、ガラクトサミン肝障害の発症を抑制する。また、該栄養組成物中に含まれるホエイタンパク質加水分解物が、マクロファージにおけるエンドトキシン誘導性TNF-αおよびインターロイキン6(IL-6)産生を抑制する。
【選択図】図1
Description
本発明は、肝疾患患者の栄養管理および栄養治療に有用な栄養組成物に関する。また本発明は、手術や感染、熱傷などの生体侵襲下の患者における代謝・栄養管理に有用な栄養組成物に関する。さらにまた本発明は、炎症性疾患患者の病態改善に有用な栄養組成物に関する。
肝疾患の栄養病態は、糖質代謝では一般に解糖系酵素活性の変化と、末梢におけるインスリン感受性の低下により耐糖能異常が高頻度にみられる。とくに、肝硬変ではエネルギー消費が亢進し、エネルギー基質として糖質利用率も低下する。タンパク質代謝では肝炎や肝硬変で、血漿アミノ酸の不均衡(分枝鎖アミノ酸/芳香族アミノ酸の比(Fischer比)の低下)、タンパク質異化の亢進、負の窒素出納による低タンパク血症、高アンモニア血症がみられる。さらに、脂質代謝では多価飽和脂肪酸の減少、脂溶性ビタミンの低下が顕在化する。
本発明は、肝不全患者の栄養管理および栄養治療に有用な栄養組成物を提供することを課題とする。また本発明は、手術や感染、熱傷などの高度生体侵襲下にある患者の代謝・栄養管理に有用な栄養組成物を提供することを課題とする。さらにまた本発明は、炎症性疾患患者の病態改善に有用な栄養組成物を提供することを課題とする。
(1)タンパク質として乳タンパク質の加水分解物および発酵乳由来タンパク質、脂質として高オレイン酸含有油脂ならびにミルクレシチン及び/又は大豆レシチン、および糖質としてパラチノースを含む、肝疾患患者用栄養組成物、
(2)乳タンパク質が、カゼイン、乳タンパク質濃縮物(MPC)、ホエイタンパク質濃縮物(WPC)、ホエイタンパク質分離物(WPI)、α-ラクトアルブミン、β-ラクトグロブリンおよびラクトフェリンからなる群より選択される、(1)の肝疾患患者用栄養組成物、
(3)発酵乳由来タンパク質が発酵乳よりホエイを減少させた組成物に由来する、(1)の肝疾患患者用栄養組成物、
(4)発酵乳由来タンパク質がフレッシュチーズに由来する、(1)の肝疾患患者用栄養組成物、
(5)フレッシュチーズがクワルクである、(4)の肝疾患患者用栄養組成物、
(6)乳タンパク質の加水分解物が、ホエイタンパク質分離物(WPI)をバシラス・リシェニフォルムス(Bacillus licheniformus)由来のアルカラーゼで加水分解およびブタ膵臓由来のトリプシンで加水分解して得られうる、(1)の肝疾患患者用栄養組成物、
(7)分画分子量10,000の限外濾過膜でさらに処理して得られる透過画分(パーミエイト)である、(6)の肝疾患患者用栄養組成物、
(8)逆相HPLCで分離したときのクロマトグラムが図1で示される、(7)の肝疾患患者用栄養組成物、
(9)タンパク質として乳タンパク質の加水分解物および発酵乳由来タンパク質、脂質として高オレイン酸含有油脂ならびにミルクレシチン及び/又は大豆レシチン、および糖質としてパラチノースを含む、生体高度侵襲患者用栄養組成物、
(10)乳タンパク質が、カゼイン、乳タンパク質濃縮物(MPC)、ホエイタンパク質濃縮物(WPC)、ホエイタンパク質分離物(WPI)、α-ラクトアルブミン、β-ラクトグロブリンおよびラクトフェリンからなる群より選択される、(9)の生体高度侵襲患者用栄養組成物、
(11)発酵乳由来タンパク質が発酵乳よりホエイを減少させた組成物に由来する、(9)の生体高度侵襲患者用栄養組成物、
(12)発酵乳由来タンパク質がフレッシュチーズに由来する、(9)の生体高度侵襲患者用栄養組成物、
(13)フレッシュチーズがクワルクである、(12)の生体高度侵襲患者用栄養組成物、
(14)乳タンパク質の加水分解物が、ホエイタンパク質分離物(WPI)をバシラス・リシェニフォルムス由来のアルカラーゼで加水分解およびブタ膵臓由来のトリプシンで加水分解して得られうる、(9)の生体高度侵襲患者用栄養組成物、
(15)分画分子量10,000の限外濾過膜でさらに処理して得られる透過画分(パーミエイト)である、(14)の生体高度侵襲患者用栄養組成物、
(16) 逆相HPLCで分離したときのクロマトグラムが図1で示される、(15)の生体高度侵襲患者用栄養組成物。
1-1 乳タンパク質加水分解物
原料タンパク質として、カゼイン、ホエイタンパク質(ホエイタンパク質濃縮物(WPC)、ホエイタンパク質分離物(WPI)、α-ラクトアルブミン(α-La)、β-ラクトグロブリン(β-Lg))、乳タンパク質濃縮物(MPC、総乳タンパク質=TMPともいう)等を用いることができる。
予備加熱:65〜90℃
E/S:0.01〜0.2
pH:2〜10
加水分解温度:30〜65℃
加水分解時間:3〜20時間未満
1)エンド型プロテアーゼ
B. リシェニホルミス由来:アルカラーゼ(Alcalase)
B. レントゥス(B. lentus)由来:エスペラーゼ
枯草菌由来:ニュートラーゼ(Neutrase)
バクテリア由来:プロタメックス
豚膵臓由来:PTN(トリプシン)
2)エキソ型プロテアーゼ
アスペルギルス・オリゼ(Aspergillus oryzae)由来:フレーバーザイム
豚あるいはウシ内臓由来:カルボキシペプチダーゼ
発酵乳(ヨーグルト)由来タンパク質は、アミノ酸スコアが100で、発酵によりタンパク質の消化吸収性が高められており栄養価が高い。配合原料としては、発酵乳(ヨーグルト)から水分(ホエイ)を減少させたもの(例えば、日本特許第3,179,555号)をあげることができる。
発酵乳由来タンパク質の配合量はタンパク質として製品100 mL当たり2〜6 g好ましくは2.5〜4.5 gと考えられる。
2-1 リン脂質
リン脂質として乳由来レシチンと大豆由来レシチンあるいは卵黄レシチンの組み合わせを用いる。乳由来レシチン単独でもよい。レシチンという用語は、生化学、医学、薬学などの分野ではホスファチジルコリンだけに使用しているが、商業的あるいは工業的には、ホスファチジルコリン、ホスファチジルエタノールアミン、ホスファチジルイノシトール、ホスファチジン酸および他のリン脂質の混合物の総称として使われている。食品添加物公定書第7版(1999)では、レシチンは、「油糧種子又は動物原料から得られたもので、その主成分は、リン脂質である」、と定義されている。本発明では乳由来のリン脂質も一括して「乳由来レシチン」と称する。
乳リン脂質(ミルクレシチン)は、スフィンゴミエリン(SM)、ホスファチジルコリン(PC)、ホスファチジルエタノールアミン(PE)、ホスファチジルイノシトール(PI)、ホスファチジルセリン(PS)、リゾホスファチジルコリン(LPC)からなり、乳脂肪球皮膜(MFGM)のみに局在している。MFGMリン脂質画分の成分組成を表1(乳業技術 Bulletin of Japan Dairy Technical Association, Vol. 50:pp. 58-91, 2000)に示す。
大豆レシチンは天然の食品添加物として、食品分野で広く使われる一方、ポリエンホスファチジルコリンは医薬品(適応:慢性肝疾患における肝機能の改善、脂肪肝、高脂質血症)としても使われている。大豆レシチンの生理作用として、(1) 生体膜の形態と機能の調整、(2) 肺機能改善、(3) 動脈硬化症の改善、(4) 脂質代謝の改善、(5) 肝臓脂質代謝の改善および(6)神経機能の改善・向上、があげられている(食品と開発, Vol. 29(3):18-21, 1994 )。
厚生省(厚生労働省)は、飽和脂肪酸(SFA:パルミチン酸、ステアリン酸等):一価不飽和脂肪酸(MUFA:オレイン酸等):多価不飽和脂肪酸(PUFA:リノール酸、リノレン酸等)の望ましい摂取比率を従来の1:1.5:1から3:4:3となるよう、また、n-6系脂肪酸:n-3系脂肪酸の比率が4:1となるよう勧告している。わが国において、MUFAの摂取比を1.5倍まで高めた食生活の実施は難しいということが理由の一つである。そこで、脂質の脂肪酸組成中一価不飽和脂肪酸(MUFA)の含量を高める。そのために一価不飽和脂肪酸であるオレイン酸を脂肪酸組成中30%以上、好ましくは30〜60%配合する。オレイン酸を多く含む脂質源としては、例えば、高オレイン酸のハイオレイックヒマワリ油、ナタネ油、オリーブ油、高オレイン酸ベニバナ油、大豆油、コーン油、パーム油などが挙げられる。またオレイン酸を含む脂質源として栄養調製油脂(日本油脂(株))が挙げられる。ヒマワリ油、ナタネ油、オリーブ油、およびオリーブ油との混合物も用いることができる。オレイン酸の配合量は製品100 g当たり適切な配合量は1〜6 gで選択される。さらに、DHA、EPA、アラキドン酸等の多価不飽和脂肪酸、カプリル酸、カプリン酸、ラウリン酸等の中鎖脂肪酸を加えて、飽和脂肪酸:一価不飽和脂肪酸:多価不飽和脂肪酸の比率を3:4:3に近くなるように調整する。
糖質としては、パラチノースを主とする。その他の糖質としては、糖アルコール(ソルビトール、キシリトール、マルチトールなど)、ハチミツ、グラニュー糖、ブドウ糖、果糖、転化などがあげられる。
現在ビタミンは13種類が知られている。そのうち肝臓に深いかかわりをもつことが知られているのは、ビタミンA、B群(B1、B2、ニコチン酸、B6、パントテン酸、葉酸、B12、ビオチン)およびKである。肝障害との関連においては、Aの欠乏症と過剰症、B群の欠乏症、Kの過剰症が主として問題になる。
体液管理を行う場合に通常問題となる電解質は、ナトリウム、塩素、カリウム、リン、カルシウムおよびマグネシウムである。ミネラルの処方を組み立てるさいには、(1) 細胞内に取り込まれるミネラルが十分に配分されているか、(2) 患者の内分泌環境が、投与しようとしている栄養基質の量とと種類に十分対応できるか、(3) 腎に対する浸透圧物質負荷量の推測と適正な尿浸透圧を維持するための投与水分量はどうか、の3点に配慮する。
以下、本発明を実施例および試験例により具体的に説明するが、本発明はこれらに限定されるものではない。
乾燥物として約90%のタンパク質含量のホエイタンパク質分離物(WPI、ダビスコ社)を、8%(w/v)のタンパク質含有量で蒸留水に溶解した。溶液は85℃2分間の加熱処理しタンパク質を変性させた。この加熱後の溶液のpHは約7.5であった。加水分解は、アルカラーゼ2.4L(酵素、ノボザイムス社)を基質に対して2.0%の濃度で添加し3時間55℃で反応させた。次に、豚由来のトリプシンである PTN 6.0S(ノボザイムズジャパン)を基質に対して3.0%の濃度で添加し3時間55℃で反応させた。全加水分解時間は6時間であった。反応終了時のpHは約7.0であった。ホエイタンパク質加水分解物は、遠心処理(20,000×g、10分)後、分画分子量10,000のUF膜処理(ミリポア社ウルトラフリー-MC)を行った。
条件
試料 :ホエイタンパク質加水分解物のUFパーミエイト
カラム:C18 SG120(資生堂社)4.6 mmφ×250 mm
溶離液:A;0.1%トリフルオロ酢酸水溶液/アセトニトリル5/95
B;0.1%トリフルオロ酢酸水溶液/アセトニトリル32/68
A→B 60分の直線濃度勾配
流速 :1 mL/min
検出 :215 nm(紫外/可視検出器)
表3に示す成分を含む栄養組成物を常法により調製した。ホエイタンパク質加水分解物は実施例1で調製したものを用いた。パラチノースは新三井製糖(株)、新調製油脂は日本油脂株式会社、乳由来リン脂質は、例えば、特開平7-173182に記載の方法に準じて得ることができる。以下に一例を述べる。
本発明の栄養組成物および比較対照としてメイバランスCの、ラットガラクトサミン肝炎に対する抑制効果を調べた。メイバランスC(明治乳業株式会社)は、半消化態の総合流動栄養食である。
Sprague-Dawley系雄ラット(6週齡、日本SLC(株))を1週間予備飼育後、体重により、表3に示す栄養組成物飼育群(n=8)およびメイバランスC飼育群(n=8)に群分けした。
実験動物は6週齡Balb/cマウスを日本SLC(株)より購入、1週間AIN-93M(オリエンタル酵母社製)で予備飼育後、体重で各群8匹に群分けを行った。群分け後、表7の組成で混合し、缶容器に充填後レトルト殺菌を行い、凍結乾燥した栄養組成物、へパス(森永クリニコ社製)で 8日間飼育した。飼育8日目にPBSに溶かしたD-ガラクトサミン(和光純薬)をマウス体重1kgあたり400 mg、次にLPS(和光純薬)をマウス体重1kgあたり10μgで腹腔内に投与した。投与後8時間後に尾静脈から採血し、翌日にエーテル麻酔下で動脈から採血を行った。飼料と水は自由摂取とした。血液は遠心を行い血清を分離し、富士ドライケムでGOT、GPTを測定した。結果は平均±SEで示し、Mann-Whitney検定を用い有意差検定を行った(*:p<0.05)。
実験動物は6週齡Balb/cマウスを日本SLC(株)より購入、1週間AIN-93Mで予備飼育後、体重で各群10匹に群分けを行った。群分け後、WPI(Davisco社)、実施例1で作製したホエイタンパク質加水分解物を飼料中蛋白質含量の25或いは50%の割合でAIN-93M(14%カゼインを含む)中のカゼインと置換した実験飼料に変え14日間飼育した。飼育14日目にPBSに溶かしたConA(Sigma)をマウス体重1kgあたり15 mgになるように静脈に注射した。投与後2、4、8時間後に尾静脈から採血し、翌日にエーテル麻酔下で動脈から採血を行った。飼料と水は自由摂取とした。血液は遠心を行い血清を分離し、富士ドライケムでGOT、GPTを測定した。サイトカインはTNF-αをELISA法(Amersham、Bioscience社)で測定した。結果は平均±SEで示し、Mann-WhitneyのU検定を用い有意差検定を行った(*:p<0.05)。
方法
6週齢のICR系雄マウス(日本エスエルシー(株))を1週間予備飼育後、体重の平均値が等しくなるように3群(各群6匹)に分けた。タンパク質源として、100%カゼイン(対照群)、50%カゼイン+50% WPI(Davisco Foods社)、あるいは50%カゼイン+50%ホエイタンパク質加水分解物(実施例1で調製したもの)を精製飼料(AIN93M)に14%(重量)添加した実験飼料を各群に与え7日間飼育した。
LPS投与後のTNF-α産生量は、カゼイン群(対照群)に対して、WPI群では抑制傾向がみられ、ホエイタンパク質加水分解物群では有意(p=0.033)に抑制された(図7)。
1.肝疾患とTNF-αとの関連について
TNF-α、IL-1、IL-6は炎症や免疫反応に際し、主にマクロファージ系細胞と内皮細胞により産生され、それ自身が発熱物質として作用するとともに肝細胞に直接働き、急性期タンパク質(CRP)の産生を促す(Hepatology 23: 909-916, 1996;J. Immunol., 146: 3032-3037, 1991;Intensive Care Med., 24: 224-229, 1998;Hepatology 9: 497-499, 1989)。
アルコール性肝硬変では、血中IL-6値と末梢血単核球のIL-6産生は増えており、その程度はIgA値と正の、IL-2やIFN-γ産生とは負の相関を示す(Clin. Exp. Immunol., 77: 221-225, 1989)。慢性肝炎の急性増悪時にも血中IL-6活性は上昇しており(Am. J. Gastroenterol., 86: 1804-1808, 1991)、血中IL-6値と末梢血単核球の非刺激時のIL-6産生は、それぞれ肝内の炎症の程度をよく反映するものと思われる。
サイトカインによる侵襲時の代謝異常や臓器障害を防止するには局所のサイトカインは正常に産生させるが、全身へのこの波及を防止することは合理的と考えられる。そこで、栄養投与経路の相違で侵襲時のサイトカイン産生を修飾することが可能かどうかについて議論がなされている。侵襲のない健康成人では経腸栄養あるいは経静脈栄養の1週間の施行で、血中のTNFやIL-6値に明らかな相違は生じない(New Horizon 2: 164-174, 1994)。しかし、健康成人で経腸栄養あるいは経静脈栄養の7日間施行した後、エンドトキシンを静注すると、そのさいの発熱やTNF、侵襲ホルモン分泌などの全身生体反応は経静脈栄養より経腸栄養で軽微であることが報告されている(Ann. Surg., 210: 449-457, 1989)。斉藤らも栄養投与経路の異なる腹腔内細菌投与ラットを用いて、栄養投与経路とサイトカイン産生の関係を検討した結果、経腸栄養では経静脈栄養に比べて、サイトカイン産生の修飾が生体反応にとって有利な方向に向かうことを確認している(Ann. Surg., 223: 84-93, 1996)。
本発明の栄養組成物を経口摂取すると、エンドトキシン誘導性のTNF-αおよびIL-6の血中濃度上昇が有意に抑制された。その抑制作用は、主として栄養組成物中に含まれるホエイタンパク質加水分解物によるものであり、血中におけるTNF-αおよびIL-6濃度上昇抑制は経口摂取による修飾によるものと考えられる。
本発明の栄養組成物は、急性肝炎(劇症肝炎)、慢性肝炎、代償性肝硬変、非代償性肝硬変の栄養管理に有用である。とくに肝性脳症の発現の可能性を有する慢性肝不全の栄養管理に有用である。慢性肝不全において、食事摂取が可能な例では、摂取タンパク質量の制限が基本である。しかし高度のタンパク質制限が長期間に及ぶと食欲を阻害し、タンパク質の異化を亢進させ、低栄養状態をさらに悪化させる。そこで何らかの栄養補充が必要となる。本発明の食品タイプの栄養組成物は食品タイプであり、栄養組成物を毎食に付加給与することのより、慢性肝不全の栄養状態の改善が期待できる。
Claims (16)
- タンパク質として乳タンパク質の加水分解物および発酵乳由来タンパク質、脂質として高オレイン酸含有油脂ならびにミルクレシチン及び/又は大豆レシチン、および糖質としてパラチノースを含む、肝疾患患者用栄養組成物。
- 乳タンパク質が、カゼイン、乳タンパク質濃縮物(MPC)、ホエイタンパク質濃縮物(WPC)、ホエイタンパク質分離物(WPI)、α-ラクトアルブミン、β-ラクトグロブリンおよびラクトフェリンからなる群より選択される、請求項1記載の肝疾患患者用栄養組成物。
- 発酵乳由来タンパク質が発酵乳よりホエイを減少させた組成物に由来する、請求項1記載の肝疾患患者用栄養組成物。
- 発酵乳由来タンパク質がフレッシュチーズに由来する、請求項1記載の肝疾患患者用栄養組成物。
- フレッシュチーズがクワルクである、請求項4記載の肝疾患患者用栄養組成物。
- 乳タンパク質の加水分解物が、ホエイタンパク質分離物(WPI)をバシラス・リシェニフォルムス(Bacillus licheniformus)由来のアルカラーゼで加水分解およびブタ膵臓由来のトリプシンで加水分解して得られうる、請求項1記載の肝疾患患者用栄養組成物。
- 分画分子量10,000の限外濾過膜でさらに処理して得られる透過画分(パーミエイト)である、請求項6記載の肝疾患患者用栄養組成物。
- 逆相HPLCで分離したときのクロマトグラムが図1で示される、請求項7記載の肝疾患患者用栄養組成物。
- タンパク質として乳タンパク質の加水分解物および発酵乳由来タンパク質、脂質として高オレイン酸含有油脂ならびにミルクレシチン及び/又は大豆レシチン、および糖質としてパラチノースを含む、生体高度侵襲患者用栄養組成物。
- 乳タンパク質が、カゼイン、乳タンパク質濃縮物(MPC)、ホエイタンパク質濃縮物(WPC)、ホエイタンパク質分離物(WPI)、α-ラクトアルブミン、β-ラクトグロブリンおよびラクトフェリンからなる群より選択される、請求項9記載の生体高度侵襲患者用栄養組成物。
- 発酵乳由来タンパク質が発酵乳よりホエイを減少させた組成物に由来する、請求項9記載の生体高度侵襲患者用栄養組成物。
- 発酵乳由来タンパク質がフレッシュチーズに由来する、請求項9記載の生体高度侵襲患者用栄養組成物。
- フレッシュチーズがクワルクである、請求項12記載の生体高度侵襲患者用栄養組成物。
- 乳タンパク質の加水分解物が、ホエイタンパク質分離物(WPI)をバシラス・リシェニフォルムス由来のアルカラーゼで加水分解およびブタ膵臓由来のトリプシンで加水分解して得られうる、請求項9記載の生体高度侵襲患者用栄養組成物。
- 分画分子量10,000の限外濾過膜でさらに処理して得られる透過画分(パーミエイト)である、請求項14記載の生体高度侵襲患者用栄養組成物。
- 逆相HPLCで分離したときのクロマトグラムが図1で示される、請求項15記載の生体高度侵襲患者用栄養組成物。
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JP5688818B2 (ja) | 2015-03-25 |
DE60332760D1 (de) | 2010-07-08 |
AR042107A1 (es) | 2005-06-08 |
CA2506603C (en) | 2011-06-28 |
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CN100393243C (zh) | 2008-06-11 |
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US8778404B2 (en) | 2014-07-15 |
US7563458B2 (en) | 2009-07-21 |
ATE468762T1 (de) | 2010-06-15 |
NZ540775A (en) | 2007-08-31 |
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CA2506603A1 (en) | 2004-06-10 |
JP2006515287A (ja) | 2006-05-25 |
ES2344640T3 (es) | 2010-09-02 |
MY169519A (en) | 2019-04-22 |
TW200412990A (en) | 2004-08-01 |
BR0316512A (pt) | 2005-10-04 |
EP1575379A1 (en) | 2005-09-21 |
HK1083174A1 (en) | 2006-06-30 |
DK1575379T3 (da) | 2010-09-13 |
US20090233865A1 (en) | 2009-09-17 |
AU2003283831A1 (en) | 2004-06-18 |
EP1575379B1 (en) | 2010-05-26 |
WO2004047566A1 (en) | 2004-06-10 |
TWI317636B (en) | 2009-12-01 |
KR101038354B1 (ko) | 2011-06-01 |
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