JP4011638B2 - Oral enteral nutrition composition - Google Patents
Oral enteral nutrition composition Download PDFInfo
- Publication number
- JP4011638B2 JP4011638B2 JP33788394A JP33788394A JP4011638B2 JP 4011638 B2 JP4011638 B2 JP 4011638B2 JP 33788394 A JP33788394 A JP 33788394A JP 33788394 A JP33788394 A JP 33788394A JP 4011638 B2 JP4011638 B2 JP 4011638B2
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- Japan
- Prior art keywords
- composition
- arginine
- amino acid
- weight
- enteral nutrition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
【０００１】
【産業上の利用分野】
本発明は、術後などの侵襲期、あるいは腸疾患や腸管障害時などの各種病態期に発生する低栄養状態の患者に対し、経口もしくは経腸投与される栄養組成物に関する。
本発明の経口経腸栄養組成物は、低栄養状態患者の栄養管理において、窒素源、糖質及び脂質などの各種栄養素の腸管からの吸収率及び体内利用率を高め、病状の早期治癒や回復促進の効果を有する。
【０００２】
【従来の技術】
従来、ヒトにおけるアミノ酸の体外摂取必要量の決定に際しては、バランスのとれた必須アミノ酸の摂取に重点が置かれており、非必須アミノ酸（可欠アミノ酸）の体外摂取は、Roseによる動物の成長速度や窒素平衡保持を指標とした実験により、特に必要ではないとされてきた〔Physiol. Rev., vol.18, pp.109-136 (1938)〕。
【０００３】
近年、生体が生理的に最適な反応を示すために必要なアミノ酸の種類と量は、窒素平衡などで推定されたものより多いことが指摘されている。特に、各種病態下においては、例えば、侵襲期における分岐鎖アミノ酸（ロイシン、イソロイシン、バリン）（以下、特に指定していないアミノ酸については、グリシンを除きすべてＬ形アミノ酸である）やグルタミン要求量の増大が挙げられる。そして、 Seifterらは、アルギニンの摂取により創傷治癒日数が短縮されることを明らかにしており、これは、アルギニンが肉芽形成に必要なコラーゲンの構成成分であるプロリンに変換され供給されると共に、創傷治癒に効果を及ぼすインスリン、グルカゴンなどのホルモン分泌を刺激する作用を有するためであると報告している〔Surgery, vol.84, pp.224-230 (1978)〕。また、Barbulらは、正常人に 30gのアルギニンを投与することにより免疫機能の亢進を認め〔Surgery, vol.90, pp.244-251 (1981)〕、さらに、 Reynoldらも、アルギニンが細胞毒性Ｔリンパ球の分化促進などの免疫への作用を有していることを報告している〔Surgery, vol.104, pp.142-151 (1988) 〕。これらのことは、アルギニンはが単に体蛋白の構成成分であるばかりでなく、生理的機能の保持に必要であることを示唆している。そのため、アルギニンの生体維持に必要な量は、Roseの古典的な基準では的確でなく、さらに高いものと考えられる〔若林保良ら，外科と代謝・栄養，vol.25, pp.398-404 (1991) 〕。したがって、アルギニンの体内合成量が疾病などにより低下したり、疾病期の栄養管理において供給されるアルギニン量が必要量より少なかったりすると、疾病に対する治癒回復の遅延や症状の増悪、合併症の併発などが危惧される。
【０００４】
また、正常動物においては、全ての細胞で一様に十分量のアルギニンは合成されず、基本的にグルタミン酸から小腸と腎臓の主要臓器の分担のもと７種類の酵素により合成されて体内各部に送られ、蛋白合成や尿素回路、その他に消費されると言われている〔若林保良ら，外科と代謝・栄養，vol.25, pp.398-404 (1991) 〕。そのため、小腸の大量切除術や短腸症候群などの腸管障害を有する患者、外傷や熱傷などの高度侵襲を受け蛋白代謝が異常に亢進した患者、あるいは抗癌剤投与時の副作用として見られる腸管障害や腸管萎縮を有する患者などでは、アルギニンの合成臓器機能が著しく低下しており、アルギニンが必須となる可能性は極めて高く、通常の栄養組成物での栄養管理においてもアルギニン不足の状態を呈し、症状の憎悪や回復の遅延が危惧される。
【０００５】
なお、病態下におけるアルギニンの作用としては、創傷治癒効果や免疫賦活効果以外にも、窒素節約効果、アンモニア解毒、内分泌系刺激、クレアチン・ポリアミン合成などが知られている。そして、これらの効果を利用するものとして、例えば、アンモニア解毒作用を利用した肝不全患者用アミノ酸製剤〔特開平 1-83017号公報〕、免疫賦活作用を利用した免疫刺激性組成物〔特開平2-191213号公報〕、免疫刺激剤〔特表平5-502881号公報〕、癌用アミノ酸製剤〔特公平 5-79049号公報、特開平 3-68514号公報、特開平 6-40900号公報〕などが提案されている。
【０００６】
さらに、最近の研究により、Ｌ−アルギニン−一酸化窒素経路によってアルギニンから生成した一酸化窒素は血管拡張作用を有し、アルギニン投与量の増大に伴い、一酸化窒素の産生が著しく高まることが明らかとなり、また、一酸化窒素は局所の細胞機能の調節や細胞間の連絡に重要な役割を果たしていることが判ってきた。しかし、このアルギニンから生成される一酸化窒素は、生体内では上記の免疫賦活効力を発揮する一方、一般的にはラジカルな気体であるため、細胞障害や発癌性などの毒性作用も有し、生体に対して善悪の二面性を有する。また、アルギニンの経口もしくは経腸による過剰投与は、一酸化窒素合成やサイクリックＧＭＰ合成を介して下痢が発生することが知られており、下痢による栄養素の腸管からの吸収障害により全身の栄養状態を低下させることが懸念される。すなわち、過剰投与時のアルギニンは病態下において「両刃の剣」的な物質であり、アルギニンやアルギニンの誘導体であるオルニチンなどのこれらの作用をコントロールすることが、治療上重要な課題となってきている。
【０００７】
一方、栄養療法において、経口もしくは経腸栄養療法は、輸液などの経静脈栄養療法と比較して、投与経路がより生理的であり、安全性も高いばかりでなく、凝固機能障害、肝機能障害、呼吸障害、網内系への脂肪沈着、免疫機能に及ぼす障害、脂肪塞栓などの合併症が発生し難いなどの特徴があり注目されている。特に、経静脈栄養療法時に発生する腸管萎縮によるバクテリアルトランスロケーションは、経腸栄養療法では起こり難いことから、医療における経口もしくは経腸栄養療法のウエイトは高まってきている。
【０００８】
そこで、本発明者らは、上述したアルギニンの有用性を経口もしくは経腸栄養療法に応用すべく栄養組成物を調製し、小腸広範囲切除ラットなどの病態モデル動物を用いて実験を重ねてきた。しかし、それらの栄養組成物の栄養効果や創傷治癒効果などの病態回復効果は、市販の栄養剤と比較して悪い結果しか得られなかった。従来提案されているようなアルギニンを過剰に配合した栄養組成物を実験動物に投与すると投与開始後の早い時期から激しい下痢の症状を呈し、それに伴う栄養素の腸管での吸収不良が生体の栄養効果を著しく低下させたものと考えられた。また、窒素出納や体内アミノ酸プールのアミノ酸組成の分析結果から、アルギニン過剰配合によるアミノ酸インバランスが、病態下の窒素の代謝に悪影響を及ぼしたとも考えられた。そして、これらの実験から、従来提案されているようなアルギニンを過剰に配合した栄養組成物では、経口もしくは経腸栄養療法において、アルギニンの有用性を得ることができず、マイナスの効果しか現れないことが判った。すなわち、経口もしくは経腸栄養組成物においては、投与経路の違いから、これまでに公開されている文献などに記載されている輸液などの実験結果を応用できないので、アルギニンによる副作用が発生せず、かつ全体のアミノ酸バランスを考慮しながら病気の治癒や回復に適当なアルギニンの投与量を設定することは重要な課題であった。
【０００９】
【発明が解決しようとする課題】
本発明者らは、上述の課題や問題点を鑑み、経口もしくは経腸栄養療法において、アルギニンの有用性を最大限に発揮させることができ、かつ下痢などの副作用が発生しない栄養組成物について鋭意検討を進めていたところ、窒素源として一定の範囲で各アミノ酸を配合し、 L- グルタミン酸及び L- グルタミンに対する L- アルギニンの割合が重量比で１〜３とすることにより、術後などの侵襲期、あるいは腸疾患や腸管障害時などの各種病態期に発生する低栄養状態患者に対し、窒素源、糖質及び脂質などの各種栄養素の腸管からの吸収率及び体内利用率を高め、病状の早期治癒や回復を促進することができることを見出し、本発明を完成した。したがって、本発明は、各種病態期に発生する低栄養状態の患者を対象とする経口もしくは経腸投与に適した栄養組成物を提供することを課題とする。
【００１０】
【課題を解決するための手段】
本発明者らは、上述の課題を解決するべく、各種のアミノ酸組成を有する栄養組成物を調製して検討を重ねた。そして、経口もしくは経腸投与する栄養組成物においてアルギニンの有用性を最大限に発揮させるために必要なアミノ酸組成を見出した。
本発明の経口経腸栄養組成物の窒素源としてのアミノ酸組成物を以下の条件に従って調製する。
（１）必須アミノ酸組成をヒトやウシなどの乳蛋白質、あるいは卵白などの卵蛋白質の必須アミノ酸組成に近似した割合とする。その必須アミノ酸組成を表１に示す。
【００１１】
【表１】
─────────────────────────────────
必須アミノ酸 全アミノ酸組成に対する割合
─────────────────────────────────
L-イソロイシン 4.0 〜 8.0（重量％）
L-ロイシン 7.0 〜 14.0
L-リジン 5.0 〜 10.0
L-メチオニン及びL-シスチン 3.0 〜 6.0
L-フェニルアラニン及びL-チロシン 6.0 〜 9.0
L-スレオニン 4.0 〜 6.0
L-トリプトファン 1.0 〜 2.0
L-バリン 5.0 〜 10.0
L-ヒスチジン 2.0 〜 4.0
─────────────────────────────────
【００１２】
（２）非必須アミノ酸組成については、アルギニンが全アミノ酸に対して10〜30重量％の割合、好ましくは12〜20重量％の割合とする。
（３）リジンに対するアルギニンの割合が重量比で１〜４とする。
（４）アルギニンを除く非必須アミノ酸組成をヒトやウシなどの乳蛋白質、あるいは卵白などの卵蛋白質、さらには大豆蛋白質の非必須アミノ酸組成に近似した割合とする。その非必須アミノ酸組成を表２に示す。
【００１３】
【表２】
さらに、好ましくは、グルタミン酸及びグルタミンに対するアルギニンの割合を重量比で１〜３とする。
本発明の経口経腸栄養組成物においては、表１に示した必須アミノ酸組成の範囲で、術後の栄養管理に十分なアルギニンの有効性を引き出すことが可能となる。すなわち、表１の必須アミノ酸の組成範囲において、一種類のアミノ酸がその範囲を外れた組成である栄養組成物では、アルギニンの有効性が著しく減じるばかりか、成長の抑制や生体の窒素保持の低下を引き起こす危険性が極めて高いので、表１の範囲内の必須アミノ酸組成であることは重要である。特に、分岐鎖アミノ酸であるロイシン、イソロイシン、バリンの組成比率が表１に対して低値となる栄養組成物では著しい成長の低下が認められるので注意を要する。
また、リジンとアルギニンは、腸管からの吸収や細胞膜間の輸送において、相互に拮抗障害を起こすために、その比率は１〜４が好ましい。この範囲を外れるとアルギニンの有効性の低下やリジンの利用低下による栄養状態の不良がみられるので、その率は重要である。
一方、表２に示した非必須アミノ酸組成の範囲で、輸液等の経静脈用の栄養組成物と異なる本発明の特徴は、アスパラギン酸及びアスパラギンの組成比とグルタミン酸及びグルタミンの組成比であり、経静脈栄養療法でみられるアスパラギン酸やグルタミン酸の投与による痙攣や頻脈等の副作用の発生が、本発明の経口経腸栄養組成物では表２の範囲内においてはみられないどころか、成長促進や窒素出納の改善作用を有し、術後の栄養管理に十分なアルギニンの有効性を引き出すことが可能となる。
さらに、本発明者らの研究によれば、アルギニンの有効性や下痢等の副作用において、グルタミン酸及びグルタミンの組成比率が密接に関与していることがわかった。好ましいグルタミン酸及びグルタミンに対するアルギニンの割合は１〜３であり、この範囲を外れるとアルギニンの有効性の低下や下痢等の副作用の発生が高くなる危険性がある。その理由は不明であるが、おそらく、グルタミン酸もしくはグルタミンがアルギニンの代謝を制御していることが推察される。
【００１５】
以上のような条件に従って窒素源を配合することにより、本発明の経口経腸栄養組成物は、広範囲の疾患患者に対し、蛋白代謝亢進に伴う体内のアルギニン不足状態を速やかに解消させ、栄養状態の改善、病状の早期治癒や回復を促進すると共に、下痢などの副作用や体内のアミノ酸インバランスも発生しない状態で、アルギニンの有する生理作用、すなわち、免疫賦活作用、窒素節約作用、内分泌系の刺激作用などを最大限に発揮させることができる。
【００１６】
本発明の経口経腸栄養組成物に用いる窒素源としては、遊離型の結晶アミノ酸やその薬理学的に許容される塩、例えば、ナトリウム塩などの金属塩、塩酸塩などの鉱酸塩、酢酸塩などの有機酸塩の形態のものが使用可能である。また、遊離型の結晶アミノ酸の一部もしくは全部をＮ−アシル誘導体の形態としたものを使用してもよく、２種類のアミノ酸が塩結合した物質、例えば、Ｌ−アルギニン−Ｌ−グルタミン酸塩やＬ−リジン−Ｌ−アスパラギン酸塩などを使用してもよい。さらに、カゼインやホエー蛋白質などの乳蛋白質、あるいは卵白などの卵蛋白質、またはそれらの加水分解物をベースとして、遊離のアルギニンやアルギニンを含む合成ペプチド、あるいは、魚類の白子蛋白質であるプロタミンなどのアルギニンを高度に含有している蛋白質やその加水分解物などで補正したものを使用してもよい。特に、遊離の結晶アミノ酸のみから成る窒素源や乳蛋白質加水分解物あるいは卵蛋白質加水分解物をベースとして、遊離のアルギニンやアルギニンを含むペプチドで補正したペプチド及び遊離のアミノ酸を主体とした窒素源を使用すると、腸管からの吸収が速やかであるため、さらに良好な効果を得ることが期待できる。
【００１７】
本発明の経口経腸栄養組成物は、上記した窒素源を混合することにより調製することができるが、糖質、脂質、ビタミン及びミネラルなどの栄養素を適当量、すなわち、必要量添加配合した栄養剤とすることが実際上好ましい。
【００１８】
本発明の経口経腸栄養組成物の調製法は、通常の経口経腸栄養組成物の調製法と実質的には異ならず、例えば、上記した成分を含有する原材料を粉体混合して調製したり、溶解して液剤に調製したり、適当な乳化剤を添加して乳化液剤に調製することができる。さらに、必要に応じて、エリソルビン酸などの安定化剤、クエン酸、リンゴ酸、炭酸ナトリウムなどのpH調整剤、あるいはその他の添加剤を加えることもできる。なお、液剤においては、加熱滅菌または無菌濾過などの手段により無菌化しておくことが望ましい。また、粉体においては、投与直前に水または温湯で溶解もしくは懸濁して投与することができる形態にしておくことが望ましい。
【００１９】
本発明の経口経腸栄養組成物については、窒素源濃度が２〜12重量％の溶液となるように調製して投与することが望ましい。また、糖質や脂質などのエネルギー源を配合する場合、窒素源由来の窒素量に対する糖質や脂質由来のカロリー量の比率（Non-protein Cal/N 比) を90〜200 の範囲に納まるよう調製し、かつ糖質や脂質の濃度を 0.5〜2kcal/mlの範囲内に調製し、投与することが望ましい。
【００２０】
本発明の経口経腸栄養組成物に配合することができる糖質としては、特に限定されるものではなく、グルコース、フルクトース及びデキストリンなどを使用すればよい。特に、デキストリンを使用すると経口経腸栄養組成物の浸透圧を低く抑えることができ、投与時の高浸透圧に由来する下痢の発生を減少させることができる。
【００２１】
本発明の経口経腸栄養組成物に配合することができる脂質としては、特に限定されるものではなく、大豆油、サフラワー油、コーン油、シソ油などを使用すればよい。なお、脂質は必須脂肪酸であるリノール酸の供給源となることが望ましいので、リノール酸を含有する大豆油やサフラワー油などを配合することが好ましい。その配合量については特に限定されないが、総カロリーに対して２〜４カロリー％のリノール酸を配合すると必須脂肪酸は欠乏しない。また、近年、もう一つの必須脂肪酸であることが確認されているn-３系の多価不飽和脂肪酸であるα−リノレン酸をリノール酸と共に、好ましくは、α−リノレン酸／リノール酸比で 1/5〜1/3 程度の比率でするとよい。すなわち、α−リノレン酸を配合すると、臨床的にn-３系多価不飽和脂肪酸の欠乏症状として認識されているしびれ、まひ、筋力低下、視力障害などの発生が防止できる。
【００２２】
本発明の経口経腸栄養組成物は、経口もしくは経腸投与されるが、その投与量は、通常の経口経腸栄養組成物の投与量と同様にすればよく、一般的には、成人で１日当たり窒素源量で20〜120gとすればよい。また、糖質や脂質などを任意に配合した経口経腸栄養組成物で、それらの配合量が1kcal/mlとなるよう調製したものであれば、 200〜2,400ml を目安とし、投与される患者の病態、栄養状態、年齢、体重などに応じて適宜に増減させればよい。
【００２３】
以下、実施例を示し、本発明を詳しく説明する。
【実施例１】
表３、表４及び表５の配合表に従い、表６の実施例１の欄に示したアミノ酸組成の窒素源をその他の原料と共に溶解、懸濁し、クエン酸でpHを中性付近に調整した後、高圧ホモジナイザーで乳化した。次いで、この乳化液剤を合成樹脂バッグに充填し、空間部を窒素置換した後、密封し、常法により加熱滅菌して目的の経口経腸栄養組成物を製造した。
【００２４】
【表３】
【００２５】
【表４】
────────────────────────────────
リン酸一カリウム 64 (g/100l)
リン酸二カリウム 77
クエン酸ナトリウム・一水和物 382
塩化カリウム 137
塩化カルシウム・二水和物 43
グルコン酸カルシウム・二水和物 475
硫酸マグネシウム・七水和物 193
硫酸亜鉛・七水和物 3
硫酸マンガン・五水和物 0.6
グルコン酸鉄 6.5
硫酸銅・五水和物 0.5
ヨウ化カリウム 0.008
────────────────────────────────
【００２６】
【表５】
────────────────────────────────
ビタミンＡ油 1.15 (g/100l)
ビタミンＤ油 0.13
トコフェロール 0.70
フィトナジオン 0.06
塩酸チアミン 0.60
塩酸ピリドキシン 0.50
アスコルビン酸 30.0
リン酸リボフラビンナトリウム 0.35
ニコチン酸アミド 2.60
パントテン酸カルシウム 1.10
シアノコバラミン 0.00032
葉酸 0.042
ビオチン 0.004
────────────────────────────────
【００２７】
【表６】
【比較例１】
表３、表４及び表５の配合表に従って、表６の比較例１の欄に示したアミノ酸組成の窒素源をその他の原料と共に溶解、懸濁し、クエン酸でpHを中性付近に調整した後、高圧ホモジナイザーで乳化した。次いで、この乳化液剤を合成樹脂バッグに充填し、空間部を窒素置換した後、密封し、常法により加熱滅菌して目的の経口経腸栄養組成物を製造した。
なお、この経口経腸栄養組成物は、一般に使用されている経口経腸栄養組成物の例である。この経口経腸栄養組成物には、アルギニンが全アミノ酸組成に対する重量比で７％配合されている。
【００２９】
【比較例２】
表３、表４及び表５の配合表に従って、表６の比較例２の欄に示したアミノ酸組成の窒素源をその他の原料と共に溶解、懸濁し、クエン酸でpHを中性付近に調整した後、高圧ホモジナイザーで乳化した。次いで、この乳化液剤を合成樹脂バッグに充填し、空間部を窒素置換した後、密封し、常法により加熱滅菌して目的の経口経腸栄養組成物を製造した。
なお、この経口経腸栄養組成物は、癌用アミノ酸製剤として提案された輸液剤〔特公平 5-79049号公報〕のアミノ酸組成に準じて調製されたものであり、アルギニンを高度に含有し、免疫賦活作用や抗癌作用を有する経口経腸栄養組成物の例である。この経口経腸栄養組成物には、アルギニンが全アミノ酸組成に対する重量比で30％配合されている。
【００３０】
【試験例１】
実施例１及び比較例１、比較例２で調製した経口経腸栄養組成物を用い、動物実験を行った。
体重 150〜160gのＳＤ系ラット（１群12匹）に小腸広範囲切除術（小腸トライツ靱帯の10cm肛門側から回盲部の５cm口側までの小腸を切除し、残存腸管を端々吻合法により縫合）及び十二指腸カテーテル留置術を施した。
術後、一晩絶食絶飲し、翌日から十二指腸に留置したカテーテルより、各経口経腸栄養組成物を無拘束下に10日間持続投与した。投与期間中、毎日、体重及び投与量を測定し、縫合部の治癒状態及び糞便の性状を観察した。また、投与早期（投与２〜４日目）と後期（投与８〜10日目) の各３日間の糞便及び尿を採取し、糞便及び尿中の窒素排泄量を測定し、窒素出納を求めた。
【００３１】
投与終了後、一晩絶食させて解剖を行い、血液、大腿骨骨格筋及び胸腺を採取し、血清生化学検査、血漿及び骨格筋中遊離アミノ酸組成の分析、胸腺重量の測定を実施した。なお、血清生化学検査は、日立7150型血清自動分析装置を用いて行った。また、血漿中遊離アミノ酸組成の分析は、血漿に４重量％のスルホサリチル酸溶液を等量添加して除蛋白処理し、日立L-8500型アミノ酸自動分析計を用いて行った。さらに、骨格筋中遊離アミノ酸組成の分析は、骨格筋をホモジネートした後、４重量％のスルホサリチル酸溶液を等量添加して除蛋白処理し、日立L-8500型アミノ酸自動分析計を用いて行った。
【００３２】
図１に投与期間中における各群の投与カロリーと体重変化率を示す。これによると、各群の投与カロリーには差はなかったが、体重変化率については、実施例１の経口経腸栄養組成物投与群が投与早期から高値を示した。
【００３３】
図２に投与早期（投与２〜４日目）と後期（投与８〜10日目) における窒素出納を示す。これによると、窒素の体内保持量についても実施例１の経口経腸栄養組成物投与群が比較例１及び２に対して高値を示した。
【００３４】
表７に血清生化学検査の結果を示す。
【表７】
なお、健常ラット群は、動物実験に供したラットと同一週齢の未手術ラットに通常のラット固形飼料CRF-1(オリエンタル酵母工業株式会社) を自由摂取させ、同様に飼育した群（６匹）であり、参考値とした。健常ラット群の血清中アルブミン量を正常値と見なすことができる。
【００３６】
以上の結果から、本発明の経口経腸栄養組成物は、優れた栄養効果を示すことが判った。
【００３７】
表８に投与期間中における手術時の縫合部不良（傷口の再開口）が生じた割合を示す。
【表８】
【００３８】
図３に投与期間中における糞便性状の経時的変化を示す。これによると、実施例１の経口経腸栄養組成物投与群は、下痢及び軟便の発生頻度について明らかに最低値を示した。特に、術後早期においてその傾向は顕著であった。
図４に投与期間中における糞便重量を示す。これによると、実施例１の経口経腸栄養組成物投与群は、投与早期（投与２〜４日目）において、湿重量及び乾燥重量共に最低値を示した。
以上の結果から、本発明の経口経腸栄養組成物は、下痢の発生頻度が低く、かつ腸管からの栄養吸収率が高いことが判った。
【００３９】
表９に胸腺重量の測定結果を示す。
【表９】
なお、健常ラット群は、動物実験に供したラットと同一週齢の未手術ラットに通常のラット固形飼料CRF-1(オリエンタル酵母工業株式会社) を自由摂取させ、同様に飼育した群（６匹）であり、参考値とした。健常ラット群の胸腺重量を正常値と見なすことができる。
小腸切除術施行後、各栄養剤で飼育したラットは、健常ラットと比較して、いずれの群も胸腺の萎縮を示した。
しかし、健常ラットに対する各栄養剤投与群の胸腺平均重量対比は、比較例１および比較例２投与群がそれぞれ46％および59％であるのに対して、実施例１では68％となり、実施例１において胸腺萎縮の度合いはもっとも抑制されていた。この結果から、本発明の経口経腸栄養組成物は、胸腺の萎縮に伴う免疫能低下を抑制することが判った。
【００４１】
表10に骨格筋の遊離アミノ酸組成中のアルギニン、プロリン、オルニチン及びリジン濃度を示す。
【表１０】
なお、健常ラット群は、動物実験に供したラットと同一週齢の未手術ラットに通常のラット固形飼料CRF-1(オリエンタル酵母工業株式会社) を自由摂取させ、同様に飼育した群（６匹）であり、健常ラット群のアミノ酸濃度を正常値と見なすことができる。また、アルギニン、プロリン、オルニチン、リジン以外のアミノ酸濃度はいずれの群間においても顕著な差は認められなかった。
【００４２】
表10から明らかのように骨格筋中のアルギニン、プロリン、オルニチン、リジン濃度は比較例１で最低値を示し、比較例２で最高値となった。その中で実施例１の各アミノ酸濃度が、正常値（健常ラット群）と最も近い値を示し、各アミノ酸の組成比率も実施例１が正常値ともっとも近似した値となった。
この結果から、本発明の経口経腸栄養組成物は、術後の栄養管理において既存品（比較例１および２）と比べ、体内の主アミノ酸貯蔵プールである骨格筋中のアミノ酸組成を変動させることが少ない。特に、アルギニン、プロリン、オルニチン、リジンの過不足が実施例１において最も少なくアミノ酸バランスが優れていることが判った。
【００４３】
【試験例２】
実施例１および比較例１、比較例２で調製した経口経腸栄養組成物を用い、試験例１の対照となる動物実験を行った。
すなわち、小腸広範囲切除術を行わないこと以外は試験例１と同様の手順で実験を実施した。また、栄養剤の投与方法及び投与量も試験例１と同一とした。この試験例２で飼育したラットは、小腸広範囲切除術を施行しないために、消化管手術の侵襲をほとんど受けていない健常のラットと見なすことができる。
図５に試験例２における飼育10日間の摂取カロリーと体重変化率を示した。各群の投与カロリーに差がなく、しかも、試験例１とも差がないものの、試験例１の結果と異なり、体重変化率は実施例１、比較例１及び比較例２ともに投与早期から飼育期間を通じて同様に推移し、差はみられなかった。
一方、窒素出納に関しては、比較例１に対して実施例１は投与早期から高値を示したが、比較例２との間には差が認められなかった。
これらの結果から、実施例１の経口経腸栄養組成物は消化管術後等の侵襲期の栄養管理において顕著に効果を発揮することがわかった。
【００４４】
【発明の効果】
本発明の経口経腸栄養組成物は、術後などの侵襲期、あるいは腸疾患や腸管障害時などの各種病態期に発生する低栄養状態の患者に対し、窒素源、糖質及び脂質などの各種栄養素の腸管からの吸収率及び体内利用率を高めることができ、即効性の栄養療法として、病状の早期治癒や回復を促進することを目的とする栄養組成物として有用である。
【図面の簡単な説明】
【図１】試験例１における術後１０日間の摂取カロリーと体重変化率を示す。
【符号の説明】
＊ 実施例に対して危険率0.05で有意差あり
【図２】試験例１における各投与期間中の窒素出納を示す。
【符号の説明】
＊ 有意差あり
Ａ 比較例１
Ｂ 実施例１
Ｃ 比較例２
【図３】試験例１における糞便性状の経時的変化を示す。
【図４】試験例１における糞便の湿重量及び乾燥重量を示す。
【符号の説明】
＊ 有意差あり
Ａ 比較例１
Ｂ 実施例１
Ｃ 比較例２
【図５】試験例２における摂取カロリーと体重変化率を示す。[0001]
[Industrial application fields]
The present invention relates to a nutritional composition to be administered orally or enterally to patients with an undernutrition occurring in an invasive phase such as after surgery or in various pathological phases such as intestinal diseases or intestinal disorders.
The oral enteral nutrition composition of the present invention increases the absorption rate and in-vivo utilization rate of various nutrients such as nitrogen sources, carbohydrates and lipids in the nutritional management of patients with malnutrition, and early cure and recovery of disease states Has a promoting effect.
[0002]
[Prior art]
Traditionally, the determination of the in vitro intake of amino acids in humans has focused on balanced intake of essential amino acids, and in vitro intake of non-essential amino acids (essential amino acids) is the rate of animal growth by Rose. And experiments using nitrogen equilibrium as an index have been found to be unnecessary (Physiol. Rev., vol.18, pp.109-136 (1938)).
[0003]
In recent years, it has been pointed out that the types and amounts of amino acids necessary for a living body to exhibit a physiologically optimal reaction are more than those estimated by nitrogen equilibrium. In particular, under various pathological conditions, for example, branched chain amino acids (leucine, isoleucine, valine) in the invasive phase (hereinafter, amino acids not specifically designated are all L-form amino acids except glycine) and glutamine requirements. Increase. Seifter et al. Have shown that ingestion of arginine shortens the wound healing days, which means that arginine is converted and supplied to proline, a collagen component necessary for granulation, and wounds. It has been reported that it has the effect of stimulating the secretion of hormones such as insulin and glucagon that have an effect on healing [Surgery, vol.84, pp.224-230 (1978)]. Barbul et al. Also showed that immune function was enhanced by administering 30 g of arginine to normal individuals (Surgery, vol. 90, pp. 244-251 (1981)), and Reynold et al. It has been reported that it has an effect on immunity such as promotion of T lymphocyte differentiation [Surgery, vol. 104, pp. 142-151 (1988)]. These facts suggest that arginine is not only a component of body protein but also necessary for maintaining physiological functions. Therefore, the amount of arginine required to maintain the living body is not accurate according to Rose's classical standard, and is considered to be even higher [Wakabayashi Y. et al., Surgery and Metabolism / Nutrition, vol.25, pp.398-404 ( 1991)]. Therefore, if the amount of arginine synthesized in the body decreases due to diseases, etc., or if the amount of arginine supplied in nutritional management during the disease stage is less than the required amount, delayed recovery from symptoms, worsening of symptoms, complications, etc. Is concerned.
[0004]
In normal animals, a sufficient amount of arginine is not synthesized uniformly in all cells. Basically, it is synthesized from glutamic acid by seven kinds of enzymes under the division of the main organs of the small intestine and kidneys, and then is synthesized in various parts of the body. It is said that it is sent to and consumed by protein synthesis, urea cycle, etc. [Wakabayashi Y. et al., Surgery and metabolism / nutrition, vol.25, pp.398-404 (1991)]. Therefore, patients with intestinal disorders such as massive resection of the small intestine and short bowel syndrome, patients with severely invasive injuries such as trauma and burns, or abnormally increased protein metabolism, or intestinal disorders or intestinal tracts seen as a side effect when anticancer drugs are administered In patients with atrophy, arginine's synthetic organ function is remarkably reduced, arginine is very likely to be essential, and arginine is deficient even in nutritional management with normal nutritional compositions. There is concern about hatred and delayed recovery.
[0005]
As the action of arginine under pathological conditions, in addition to the wound healing effect and immunostimulatory effect, nitrogen saving effect, ammonia detoxification, endocrine stimulation, creatine / polyamine synthesis, etc. are known. Examples of utilizing these effects include amino acid preparations for patients with hepatic failure utilizing ammonia detoxification (JP-A-1-83017), immunostimulatory compositions utilizing immunostimulatory action [JP-A-2 No. -191213], immunostimulant [Japanese Patent Publication No. 5-502881], amino acid preparation for cancer [Japanese Patent Publication No. 5-79049, Japanese Patent Publication No. 3-68514, Japanese Patent Publication No. 6-40900], etc. Has been proposed.
[0006]
Furthermore, recent studies reveal that nitric oxide produced from arginine by the L-arginine-nitric oxide pathway has a vasodilatory effect, and the production of nitric oxide increases markedly with increasing arginine dosage. In addition, it has been found that nitric oxide plays an important role in the regulation of local cell functions and communication between cells. However, nitric oxide produced from this arginine exerts the above-described immunostimulatory effect in vivo, but generally has a toxic effect such as cell damage and carcinogenicity because it is a radical gas, Has a good and evil duality to the living body. In addition, it is known that arginine overdose orally or enterally causes diarrhea through nitric oxide synthesis or cyclic GMP synthesis, and due to impaired absorption of nutrients from the intestinal tract due to diarrhea, systemic nutritional status There is a concern that this may be reduced. In other words, arginine at the time of overdose is a “double-edged sword” substance under pathological conditions, and controlling these actions such as arginine and ornithine, a derivative of arginine, has become an important therapeutic issue. Yes.
[0007]
On the other hand, in nutritional therapy, oral or enteral nutrition therapy is not only more physiological and safer than intravenous parenteral therapy such as infusion, but also coagulation dysfunction and liver dysfunction. It has been attracting attention because it has features such as respiratory failure, fat deposition in the reticuloendothelial system, disorder on immune function, and difficulty in complications such as fat embolism. In particular, since bacterial translocation due to intestinal atrophy that occurs during parenteral nutrition therapy is unlikely to occur in enteral nutrition therapy, the weight of oral or enteral nutrition therapy in medicine is increasing.
[0008]
Therefore, the present inventors have prepared a nutritional composition so as to apply the above-mentioned usefulness of arginine to oral or enteral nutrition therapy, and have repeatedly conducted experiments using pathological model animals such as rats with extensive excision of the small intestine. However, the pathological condition recovery effects such as the nutritional effects and wound healing effects of these nutritional compositions have only been obtained inferior results compared to commercially available nutrients. When a nutritional composition containing an excessive amount of arginine as proposed in the past is administered to experimental animals, symptoms of severe diarrhea are observed from the early stage after the start of administration, and the inadequate absorption of nutrients in the intestinal tract is accompanied by the nutritional effects of the living body. It was thought that the value was significantly reduced. Moreover, from the results of analysis of nitrogen balance and the amino acid composition of the amino acid pool in the body, it was considered that the amino acid imbalance caused by excessive arginine had an adverse effect on nitrogen metabolism under pathological conditions. From these experiments, the nutritional composition containing arginine in an excessive amount as conventionally proposed cannot obtain the usefulness of arginine in oral or enteral nutrition therapy, and has only a negative effect. I found out. That is, in the oral or enteral nutrition composition, because of the difference in administration route, since the experimental results such as infusion described in the literature published so far cannot be applied, no side effects caused by arginine occur, In addition, setting an appropriate dose of arginine for the healing and recovery of the disease while considering the overall amino acid balance was an important issue.
[0009]
[Problems to be solved by the invention]
In view of the above-mentioned problems and problems, the present inventors have earnestly devised a nutritional composition that can maximize the usefulness of arginine in oral or enteral nutrition therapy and does not cause side effects such as diarrhea. As a result of investigations, each amino acid was formulated within a certain range as a nitrogen source.And L- Glutamic acid and L- Against glutamine L- The ratio of arginine is 1 to 3 by weightThe absorption rate of various nutrients such as nitrogen sources, carbohydrates and lipids from the intestinal tract to patients with undernutrition that occurs in the invasive phase after surgery, etc., or in various pathological phases such as intestinal diseases or intestinal disorders In addition, the inventors have found that the utilization rate in the body can be increased and early healing and recovery of a medical condition can be promoted, and the present invention has been completed. Therefore, an object of the present invention is to provide a nutritional composition suitable for oral or enteral administration intended for patients who are undernourished in various pathological stages.
[0010]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventors have prepared and studied nutritional compositions having various amino acid compositions. The present inventors have found an amino acid composition necessary for maximizing the usefulness of arginine in a nutritional composition to be administered orally or enterally.
An amino acid composition as a nitrogen source of the oral enteral nutrition composition of the present invention is prepared according to the following conditions.
(1) The essential amino acid composition is set to a ratio that approximates the essential amino acid composition of milk proteins such as humans and cows, or egg proteins such as egg white. The essential amino acid composition is shown in Table 1.
[0011]
[Table 1]
─────────────────────────────────
Essential amino acids Percentage of total amino acid composition
─────────────────────────────────
L-isoleucine 4.0-8.0 (wt%)
L-Leucine 7.0 to 14.0
L-Lysine 5.0 to 10.0
L-methionine and L-cystine 3.0-6.0
L-Phenylalanine and L-Tyrosine 6.0-9.0
L-threonine 4.0-6.0
L-tryptophan 1.0-2.0
L-Valine 5.0 to 10.0
L-Histidine 2.0-4.0
─────────────────────────────────
[0012]
(2) Regarding the non-essential amino acid composition, arginine is 10 to 30% by weight, preferably 12 to 20% by weight, based on all amino acids.
(3) The ratio of arginine to lysine is 1 to 4 by weight.
(4) The non-essential amino acid composition excluding arginine is set to a ratio that approximates the non-essential amino acid composition of milk protein such as human and cow, egg protein such as egg white, and soy protein. The non-essential amino acid composition is shown in Table 2.
[0013]
[Table 2]
Further, preferably, the ratio of arginine to glutamic acid and glutamine is 1 to 3 in terms of weight ratio.
In the oral enteral nutrition composition of the present invention, the effectiveness of arginine sufficient for postoperative nutritional management can be derived within the essential amino acid composition range shown in Table 1. That is, in the composition range of the essential amino acids shown in Table 1, in the nutritional composition in which one kind of amino acid is out of the range, not only the effectiveness of arginine is remarkably reduced, but also growth suppression and reduction of living body nitrogen retention are reduced. The essential amino acid composition within the range of Table 1 is important. In particular, a nutritional composition in which the composition ratios of branched chain amino acids leucine, isoleucine, and valine are lower than those in Table 1 shows a significant decrease in growth, and therefore requires attention.
In addition, lysine and arginine preferably have a ratio of 1 to 4 in order to cause a mutual antagonistic damage in absorption from the intestinal tract and transport between cell membranes. Outside this range, the effectiveness of arginine and poor nutrition due to reduced use of lysine are seen, so the rate is important.
On the other hand, in the range of the non-essential amino acid composition shown in Table 2, the feature of the present invention different from the intravenous nutritional composition such as infusion is the composition ratio of aspartic acid and asparagine and the composition ratio of glutamic acid and glutamine. The occurrence of side effects such as convulsions and tachycardia due to the administration of aspartic acid and glutamic acid as seen in parenteral nutrition therapy is not observed within the scope of Table 2 in the oral enteral nutrition composition of the present invention. It has the effect of improving nitrogen balance, and it is possible to extract the effectiveness of arginine sufficient for postoperative nutritional management.
Furthermore, according to the studies by the present inventors, it has been found that the composition ratio of glutamic acid and glutamine is closely related to the effectiveness of arginine and side effects such as diarrhea. The preferable ratio of arginine to glutamic acid and glutamine is 1 to 3, and if it is out of this range, there is a risk that the effectiveness of arginine decreases and the occurrence of side effects such as diarrhea increases. The reason is unknown, but it is presumed that glutamic acid or glutamine regulates arginine metabolism.
[0015]
By blending a nitrogen source according to the conditions as described above, the oral enteral nutrition composition of the present invention quickly resolves arginine deficiency in the body associated with increased protein metabolism for a wide range of disease patients, , Physiologic action of arginine, ie, immunostimulatory action, nitrogen saving action, stimulation of endocrine system in the state where side effects such as diarrhea and amino acid imbalance in the body do not occur The effects can be maximized.
[0016]
Nitrogen sources used in the oral enteral nutrition composition of the present invention include free crystalline amino acids and pharmacologically acceptable salts thereof, for example, metal salts such as sodium salts, mineral salts such as hydrochlorides, acetic acid An organic acid salt form such as a salt can be used. In addition, a part or all of the free crystalline amino acid may be used in the form of an N-acyl derivative, or a substance in which two kinds of amino acids are salt-bound, such as L-arginine-L-glutamate, L-lysine-L-aspartate and the like may be used. Furthermore, based on milk proteins such as casein and whey protein, egg proteins such as egg white, or hydrolysates thereof, free arginine, synthetic peptides containing arginine, or arginine such as protamine, a fish larva protein You may use what was correct | amended by the protein which contains highly, hydrolyzate thereof, etc. In particular, based on a nitrogen source consisting only of free crystalline amino acids, milk protein hydrolyzate or egg protein hydrolysate, free arginine or peptides corrected with peptides containing arginine and nitrogen sources mainly composed of free amino acids When used, the absorption from the intestinal tract is rapid, and it can be expected to obtain a better effect.
[0017]
The oral enteral nutrition composition of the present invention can be prepared by mixing the nitrogen source described above, but it contains nutrients such as carbohydrates, lipids, vitamins and minerals in an appropriate amount, that is, a nutrition supplemented with the necessary amount. It is practically preferable to use an agent.
[0018]
The preparation method of the oral enteral nutrition composition of the present invention is not substantially different from the usual preparation method of the oral enteral nutrition composition. For example, the raw material containing the above-mentioned ingredients is prepared by powder mixing. Or dissolved to prepare a liquid, or an appropriate emulsifier can be added to prepare an emulsified liquid. Furthermore, if necessary, a stabilizer such as erythorbic acid, a pH adjuster such as citric acid, malic acid, sodium carbonate, or other additives may be added. In addition, it is desirable that the liquid is sterilized by means such as heat sterilization or aseptic filtration. In addition, it is desirable that the powder be in a form that can be dissolved or suspended in water or warm water immediately before administration.
[0019]
The oral enteral nutrition composition of the present invention is preferably prepared and administered so as to be a solution having a nitrogen source concentration of 2 to 12% by weight. When energy sources such as carbohydrates and lipids are added, the ratio of the amount of calories derived from carbohydrates and lipids to the amount of nitrogen derived from nitrogen sources (Non-protein Cal / N ratio) should be within the range of 90-200. It is desirable to prepare and administer sugar and lipid concentrations within the range of 0.5 to 2 kcal / ml.
[0020]
The carbohydrate that can be blended in the oral enteral nutrition composition of the present invention is not particularly limited, and glucose, fructose, dextrin and the like may be used. In particular, when dextrin is used, the osmotic pressure of the oral enteral nutrition composition can be kept low, and the occurrence of diarrhea due to the high osmotic pressure at the time of administration can be reduced.
[0021]
The lipid that can be blended in the oral enteral nutrition composition of the present invention is not particularly limited, and soybean oil, safflower oil, corn oil, perilla oil, etc. may be used. In addition, since it is desirable that the lipid is a source of linoleic acid, which is an essential fatty acid, it is preferable to blend soybean oil or safflower oil containing linoleic acid. The blending amount is not particularly limited, but when 2 to 4 cal% linoleic acid is blended with respect to the total calories, essential fatty acids are not deficient. In addition, α-linolenic acid, which is an n-3 polyunsaturated fatty acid that has been confirmed to be another essential fatty acid in recent years, together with linoleic acid, preferably in an α-linolenic acid / linoleic acid ratio. The ratio should be about 1/5 to 1/3. That is, when α-linolenic acid is added, it is possible to prevent the occurrence of numbness, paralysis, muscle weakness, visual impairment and the like that are clinically recognized as deficiencies of n-3 polyunsaturated fatty acids.
[0022]
The oral enteral nutrition composition of the present invention is administered orally or enterally, and its dosage may be the same as that of a normal oral enteral nutrition composition. The amount of nitrogen source per day may be 20 to 120 g. In addition, oral enteral nutritional compositions with any combination of carbohydrates, lipids, etc., prepared so that their amount is 1 kcal / ml, 200 to 2,400 ml as a guideline for patients to be administered What is necessary is just to increase / decrease suitably according to a disease state, nutritional state, age, weight, etc.
[0023]
EXAMPLES Hereinafter, an Example is shown and this invention is demonstrated in detail.
[Example 1]
According to the recipes in Table 3, Table 4 and Table 5, the nitrogen source having the amino acid composition shown in the column of Example 1 in Table 6 was dissolved and suspended together with other raw materials, and the pH was adjusted to near neutral with citric acid. Thereafter, the mixture was emulsified with a high-pressure homogenizer. Next, this emulsified liquid was filled into a synthetic resin bag, and the space portion was purged with nitrogen, then sealed, and heat-sterilized by a conventional method to produce the intended oral enteral nutrition composition.
[0024]
[Table 3]
[0025]
[Table 4]
────────────────────────────────
Monopotassium phosphate 64 (g / 100l)
Dipotassium phosphate 77
Sodium citrate monohydrate 382
Potassium chloride 137
Calcium chloride dihydrate 43
Calcium gluconate dihydrate 475
Magnesium sulfate heptahydrate 193
Manganese sulfate pentahydrate 0.6
Iron gluconate 6.5
Copper sulfate pentahydrate 0.5
Potassium iodide 0.008
────────────────────────────────
[0026]
[Table 5]
────────────────────────────────
Vitamin A oil 1.15 (g / 100l)
Vitamin D oil 0.13
Tocopherol 0.70
Phytonadione 0.06
Thiamine hydrochloride 0.60
Pyridoxine hydrochloride 0.50
Ascorbic acid 30.0
Riboflavin sodium phosphate 0.35
Nicotinamide 2.60
Calcium pantothenate 1.10
Cyanocobalamin 0.00032
Folic acid 0.042
Biotin 0.004
────────────────────────────────
[0027]
[Table 6]
[Comparative Example 1]
According to the recipes in Table 3, Table 4 and Table 5, the nitrogen source having the amino acid composition shown in the column of Comparative Example 1 in Table 6 was dissolved and suspended together with other raw materials, and the pH was adjusted to near neutral with citric acid. Thereafter, it was emulsified with a high-pressure homogenizer. Next, this emulsified solution was filled into a synthetic resin bag, and the space portion was purged with nitrogen, then sealed, and heat sterilized by a conventional method to produce the intended oral enteral nutrition composition.
This oral enteral nutrition composition is an example of a commonly used oral enteral nutrition composition. This oral enteral nutrition composition contains 7% by weight of arginine based on the total amino acid composition.
[0029]
[Comparative Example 2]
According to the recipes in Table 3, Table 4 and Table 5, the nitrogen source having the amino acid composition shown in the column of Comparative Example 2 in Table 6 was dissolved and suspended together with other raw materials, and the pH was adjusted to near neutral with citric acid. Thereafter, it was emulsified with a high-pressure homogenizer. Next, this emulsified solution was filled into a synthetic resin bag, and the space portion was purged with nitrogen, then sealed, and heat sterilized by a conventional method to produce the intended oral enteral nutrition composition.
In addition, this oral enteral nutrition composition was prepared according to the amino acid composition of an infusion solution [Japanese Patent Publication No. 5-79049] proposed as an amino acid preparation for cancer, and highly contains arginine. It is an example of an oral enteral nutrition composition having an immunostimulatory effect and an anticancer effect. This oral enteral nutrition composition contains 30% arginine in a weight ratio to the total amino acid composition.
[0030]
[Test Example 1]
An animal experiment was conducted using the oral enteral nutrition composition prepared in Example 1, Comparative Example 1, and Comparative Example 2.
Extensive small intestine excision of SD rats (12 rats per group) weighing 150-160g (the small intestine is excised from the 10cm anal side of the small intestine tritium ligament to the 5cm mouth side of the ileocecum, and the remaining intestine is sutured by end-to-end anastomosis) ) And duodenal catheter placement.
After the operation, the animals were fasted overnight, and each oral enteral nutritional composition was continuously administered for 10 days without restriction from a catheter placed in the duodenum from the next day. During the administration period, body weight and dose were measured every day, and the healing state of the sutured part and the stool properties were observed. In addition, stool and urine were collected for 3 days each in the early stage of administration (
[0031]
After the administration, the animals were fasted overnight for dissection, blood, femur skeletal muscle and thymus were collected, serum biochemical examination, analysis of plasma and skeletal muscle free amino acid composition, and measurement of thymus weight. Serum biochemical tests were performed using a Hitachi 7150 serum automatic analyzer. The analysis of free amino acid composition in plasma was performed using a Hitachi L-8500 type amino acid automatic analyzer after deproteinization treatment by adding an equal amount of 4% by weight sulfosalicylic acid solution to plasma. Furthermore, the analysis of the free amino acid composition in skeletal muscle was performed by homogenizing skeletal muscle, adding an equal amount of 4% by weight sulfosalicylic acid solution to deproteinize, and using Hitachi L-8500 type amino acid automatic analyzer. It was.
[0032]
FIG. 1 shows the calorie administration and body weight change rate of each group during the administration period. According to this, although there was no difference in the calorie administration of each group, about the weight change rate, the oral enteral nutrition composition administration group of Example 1 showed the high value from the administration early stage.
[0033]
FIG. 2 shows the nitrogen balance in the early stage of administration (2-4 days after administration) and in the latter period (day 8-10 of administration). According to this, the oral enteral nutrition composition administration group of Example 1 also showed a high value with respect to Comparative Examples 1 and 2 regarding the amount of nitrogen retained in the body.
[0034]
Table 7 shows the results of serum biochemical tests.
[Table 7]
In addition, the healthy rat group was a group (6 rats) that was fed in the same manner as the rats subjected to animal experiments, and was allowed to ingest normal rat chow CRF-1 (Oriental Yeast Co., Ltd.) freely. It was used as a reference value. The amount of serum albumin in the healthy rat group can be regarded as a normal value.
[0036]
From the above results, it was found that the oral enteral nutrition composition of the present invention exhibits an excellent nutritional effect.
[0037]
Table 8 shows the rate at which defective sutures (reopening of the wound) occurred during the operation during the administration period.
[Table 8]
[0038]
FIG. 3 shows changes in fecal properties over time during the administration period. According to this, the oral enteral nutrition composition administration group of Example 1 clearly showed the lowest value regarding the incidence of diarrhea and loose stool. In particular, the tendency was remarkable in the early postoperative period.
FIG. 4 shows the stool weight during the administration period. According to this, the oral enteral nutrition composition administration group of Example 1 showed the lowest value in both wet weight and dry weight in the early stage of administration (2-4 days after administration).
From the above results, it was found that the oral enteral nutrition composition of the present invention has a low incidence of diarrhea and a high nutrient absorption rate from the intestinal tract.
[0039]
Table 9 shows the measurement results of thymus weight.
[Table 9]
In addition, the healthy rat group was a group (6 rats) that was fed in the same manner as the rats subjected to animal experiments, and was allowed to ingest normal rat chow CRF-1 (Oriental Yeast Co., Ltd.) freely. It was used as a reference value. The thymus weight of a healthy rat group can be regarded as a normal value.
After the small intestine resection, rats fed with various nutrients showed thymus atrophy in all groups compared to healthy rats.
However, the average thymus weight ratio of each nutrient-administered group for healthy rats was 46% and 59% for Comparative Example 1 and Comparative Example 2 administration groups, respectively, compared with 68% for Example 1. In 1, the degree of thymic atrophy was most suppressed. From this result, it was found that the oral enteral nutrition composition of the present invention suppresses the decrease in immunity associated with thymus atrophy.
[0041]
Table 10 shows the arginine, proline, ornithine and lysine concentrations in the free amino acid composition of skeletal muscle.
[Table 10]
In addition, the healthy rat group was a group (6 rats) that was fed in the same manner as the rats subjected to animal experiments, and was allowed to ingest normal rat chow CRF-1 (Oriental Yeast Co., Ltd.) freely. The amino acid concentration of the healthy rat group can be regarded as a normal value. In addition, the amino acid concentrations other than arginine, proline, ornithine and lysine were not significantly different between any groups.
[0042]
As is clear from Table 10, the arginine, proline, ornithine, and lysine concentrations in skeletal muscle showed the lowest values in Comparative Example 1 and the highest values in Comparative Example 2. Among them, the concentration of each amino acid in Example 1 showed the closest value to the normal value (healthy rat group), and the composition ratio of each amino acid was also the value that Example 1 was closest to the normal value.
From this result, the oral enteral nutrition composition of the present invention varies the amino acid composition in skeletal muscle, which is the main amino acid storage pool in the body, compared to existing products (Comparative Examples 1 and 2) in postoperative nutritional management. There are few things. In particular, it was found that the excess and deficiency of arginine, proline, ornithine and lysine was the smallest in Example 1 and the amino acid balance was excellent.
[0043]
[Test Example 2]
Using the oral enteral nutrition composition prepared in Example 1, Comparative Example 1, and Comparative Example 2, an animal experiment as a control for Test Example 1 was performed.
That is, the experiment was performed in the same procedure as in Test Example 1 except that the large intestine resection was not performed. Moreover, the administration method and dose of the nutrient were also the same as in Test Example 1. Since the rat bred in Test Example 2 is not subjected to extensive excision of the small intestine, it can be regarded as a healthy rat that has hardly undergone invasion of gastrointestinal surgery.
FIG. 5 shows the calorie intake and weight change rate during 10 days of breeding in Test Example 2. Although there is no difference in calorie administration in each group, and there is no difference with Test Example 1, the weight change rate is different from the result of Test Example 1 in both Example 1, Comparative Example 1 and Comparative Example 2 from the early administration period. Throughout the same period, there was no difference.
On the other hand, with respect to nitrogen balance, Example 1 showed a high value from the early administration compared to Comparative Example 1, but no difference was observed between Comparative Example 2 and Comparative Example 2.
From these results, it was found that the oral enteral nutrition composition of Example 1 exerts a remarkable effect in nutritional management in the invasive phase such as after gastrointestinal surgery.
[0044]
【The invention's effect】
The oral enteral nutrition composition of the present invention is suitable for patients with malnutrition that occurs in invasive periods such as after surgery or in various pathological stages such as intestinal diseases or intestinal disorders, such as nitrogen sources, carbohydrates and lipids. The absorption rate and in-vivo utilization rate of various nutrients from the intestinal tract can be increased, and it is useful as a nutritional composition for the purpose of promoting early healing and recovery of medical conditions as an immediate-acting nutritional therapy.
[Brief description of the drawings]
1 shows calorie intake and body weight change rate during 10 days after surgery in Test Example 1. FIG.
[Explanation of symbols]
* Significantly different from the examples with a risk factor of 0.05
FIG. 2 shows nitrogen balance during each administration period in Test Example 1.
[Explanation of symbols]
* Significantly different
A Comparative Example 1
B Example 1
C Comparative Example 2
FIG. 3 shows changes in fecal properties over time in Test Example 1.
4 shows the stool wet weight and dry weight in Test Example 1. FIG.
[Explanation of symbols]
* Significantly different
A Comparative Example 1
B Example 1
C Comparative Example 2
FIG. 5 shows calorie intake and weight change rate in Test Example 2.
Claims (5)
（１）全アミノ酸に対する必須アミノ酸の割合（重量％）は以下の通りである。
L-イソロイシン 4.0 〜 8.0
L-ロイシン 7.0 〜 14.0
L-リジン 5.0 〜 10.0
L-メチオニン及びL-シスチン 3.0 〜 6.0
L-フェニルアラニン及びL-チロシン 6.0 〜 9.0
L-スレオニン 4.0 〜 6.0
L-トリプトファン 1.0 〜 2.0
L-バリン 5.0 〜 10.0
L-ヒスチジン 2.0 〜 4.0
（２）全アミノ酸に対するL-アルギニンの割合は10〜30重量％である。
（３）L-リジンに対するL-アルギニンの割合は重量比で１〜４である。
（４）全アミノ酸に対するL-アルギニンを除く非必須アミノ酸の割合（重量％）は以下の通りである。
L-アラニン 2.5 〜 10.0
L-アスパラギン酸及びL-アスパラギン 6.0 〜 11.0
L-グルタミン酸及びL-グルタミン 7.0 〜 21.0
グリシン 1.0 〜 8.0
L-プロリン 3.0 〜 11.0
L-セリン 2.0 〜 7.0
（５） L- グルタミン酸及び L- グルタミンに対する L- アルギニンの割合は重量比で１〜３である。 An oral enteral nutrition composition comprising an amino acid composition as a nitrogen source so as to satisfy the following conditions (1) to ( 5 ):
(1) The ratio (% by weight) of essential amino acids to all amino acids is as follows.
L-isoleucine 4.0-8.0
L-Leucine 7.0 to 14.0
L-Lysine 5.0 to 10.0
L-methionine and L-cystine 3.0-6.0
L-Phenylalanine and L-Tyrosine 6.0-9.0
L-threonine 4.0-6.0
L-tryptophan 1.0-2.0
L-Valine 5.0 to 10.0
L-Histidine 2.0-4.0
(2) The ratio of L-arginine to all amino acids is 10 to 30% by weight.
(3) The ratio of L-arginine to L-lysine is 1 to 4 by weight.
(4) The ratio (% by weight) of non-essential amino acids excluding L-arginine relative to all amino acids is as follows.
L-alanine 2.5 to 10.0
L-aspartic acid and L-asparagine 6.0 to 11.0
L-glutamic acid and L-glutamine 7.0 to 21.0
Glycine 1.0-8.0
L-proline 3.0 to 11.0
L-Serine 2.0-7.0
(5) The ratio of L- arginine to L - glutamic acid and L- glutamine is 1 to 3 by weight.
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| JP2001316278A (en) * | 2000-05-10 | 2001-11-13 | Sanwa Kagaku Kenkyusho Co Ltd | Liquid enteral nutrition composition |
| DE10057290B4 (en) * | 2000-11-17 | 2004-01-08 | Fresenius Kabi Deutschland Gmbh | Enteral supplement for parenteral nutrition or partial enteral / oral nutrition for critically ill, chronically ill and malnourished |
| JP2007500208A (en) * | 2003-05-22 | 2007-01-11 | エヌ．ブイ．・ヌートリシア | Method for treating or preventing chronic wounds and a complete nutritional composition comprising glycine and / or leucine for use therein |
| JP4512948B2 (en) * | 2005-04-04 | 2010-07-28 | コスモ食品株式会社 | Useful amino acid composition, food or food compounding agent containing the same, and method for producing the same |
| CN101267818B (en) * | 2005-09-20 | 2011-04-27 | 西北大学 | Uses of amino acid and amino acid supplements thereof |
| JP2011121888A (en) * | 2009-12-09 | 2011-06-23 | En Otsuka Pharmaceutical Co Ltd | Amino acid composition for inflammatory bowel disease |
| JP2011144116A (en) * | 2010-01-12 | 2011-07-28 | En Otsuka Pharmaceutical Co Ltd | Additive for inflammatory bowel disease |
| MX350541B (en) | 2010-09-24 | 2017-09-08 | Univ Florida | MATERIALS AND METHODS TO IMPROVE GASTROINTESTINAL FUNCTION. |
| EP2968241B1 (en) | 2013-03-11 | 2018-10-31 | University of Florida Research Foundation, Inc. | Materials and methods for improving lung function and for prevention and/or treatment of radiation-induced lung complications |
| JP2019058140A (en) * | 2017-09-27 | 2019-04-18 | 味の素株式会社 | Nutritional composition |
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