JP6077857B2 - β−ヒドロキシ−β−メチル酪酸塩(HMB)の改善された投与方法 - Google Patents
β−ヒドロキシ−β−メチル酪酸塩(HMB)の改善された投与方法 Download PDFInfo
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Description
[0001]本出願は、2009年12月18日に出願した米国特許出願第61/287,857号の優先権を主張し、その全文は参照により本明細書に組み込まれる。
本発明は、下記の態様を包含する。
(1) β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMB酸を約0.5グラム〜約30グラム含み、該組成物の効果が等量のHMB組成物のカルシウム塩を投与するよりも高くなる、上記組成物。
(2) 該組成物によって生じる高くなる効果が、窒素保持の向上、タンパク質節約の向上、除脂肪体重の増加、筋肉機能の向上、筋肉性能の向上、ストレスに曝された筋肉での筋肉損傷の低減、傷つけられた筋肉での筋肉損傷の低減、ヒトの免疫反応の向上、疾患に関連する衰弱の減少、ヒトの脂質プロファイルの向上、及びヒトの心の状態の改善から成る群より選択される、(1)に記載の組成物。
(3) 該HMB酸をゲルとして投与する、(1)に記載の組成物。
(4) 舌下に投与するための、(1)に記載の組成物。
(5) 嚥下するための、(1)に記載の組成物。
(6) 24時間当たり1回投与するための、(1)に記載の組成物。
(7) β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMB酸を約0.5グラム〜約30グラム含み、HMBの効果が等量のHMB組成物のカルシウム塩を投与するよりも少なくとも10%上昇する、上記組成物。
(8) 該組成物によってもたらされる効果の向上が、窒素保持の向上、タンパク質節約の向上、除脂肪体重の増加、筋肉機能の向上、筋肉性能の向上、ストレスに曝された筋肉での筋肉損傷の低減、傷つけられた筋肉での筋肉損傷の低減、ヒトの免疫反応の向上、疾患に関連する衰弱の減少、ヒトの脂質プロファイルの向上、及びヒトの心の状態の改善から成る群より選択される、(7)に記載の組成物。
(9) β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMB酸を約0.5グラム〜約30グラム含み、HMBの血漿濃度が等量のHMB組成物のカルシウム塩を投与するよりも大幅に上昇する、上記組成物。
(10) β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMB酸を約0.5グラム〜約30グラム含み、HMBの最大血漿濃度到達時間が、等量のHMB組成物のカルシウム塩を投与するよりも短縮される、上記組成物。
(11) β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMB酸を含み、HMBの効果を向上させる上記組成物。
(12) HMB酸によってもたらされるHMBの効果の向上が、窒素保持の向上、タンパク質節約の向上、除脂肪体重の増加、筋肉機能の向上、筋肉性能の向上、ストレスに曝された筋肉での筋肉損傷の低減、傷つけられた筋肉での筋肉損傷の低減、ヒトの免疫反応の向上、疾患に関連する衰弱の減少、ヒトの脂質プロファイルの向上、及びヒトの心の状態の改善から成る群より選択される、(11)に記載の組成物。
(13) HMB酸によってもたらされるHMBの効果の向上が、HMBの血漿濃度の大幅な上昇及びHMBの最大血漿濃度到達時間の短縮から成る群より選択される、(11)記載の組成物。
(14) β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMB酸を基準として、体重1キログラムにつき24時間当たりの量が、0.01〜0.02グラムの範囲のHMBを含み、該組成物の効果が等量のHMB組成物のカルシウム塩を投与するよりも向上する、上記組成物。
(15) 組織によるβ−ヒドロキシ−β−メチル酪酸(HMB)の利用を向上させる組成物であって、HMB酸を約0.5グラム〜約30グラム含み、組織によるHMBの利用が向上する結果、等量のカルシウム塩HMB組成物を投与するよりも代謝効果の改善が生じる、上記組成物。
実施例1:HMB酸ゲルとカプセル形態のCaHMBの吸収の比較
材料及び方法
[00046](ヒト対象) 試験1では、大学生の年齢の、4人の男性及び4人の女性を対象として試験した。試験2では、大学生の年齢の、別の4人の男性及び4人の女性を試験した。両試験のプロトコールはアイオワ州立大学(Iowa State University)IRBで認可され、そして各対象は試験に参加するためのインフォームドコンセントを提出した。治療の特性により、患者だけでなく研究者らに対しても盲検でなくてもよい。
[00051](計算及び統計) 基準より上の面積を合計する台形法により(文献51)、それぞれの対象について、曲線下面積を計算した。試験2では血漿HMBの半減期を計算した。以下の式を用いた。
t1/2=0.693/k
[00052]各対象の最高血漿濃度をCpeakに用いた。720分での血漿濃度が基準と有意な差がなかったため、トラフ濃度、すなわちCtroughは720分で測定した濃度である。TpeakはCpeakが測定された時間であり、TintervalはTpeakからCtrough(720分)時点までの時間である。細胞外液分画は体重の20%と仮定し、以下の式3を用いて計算した(文献1)。その後、HMBの血漿クリアランスを、式4に示したように、細胞外液分画であるVdと排泄定数であるKelとを乗算することにより計算した{Thalhammer, 1998 9588/同上}。
クリアランス=Vd(Kel)(50)
[00053]データを、SAS中のProc GLMを用いて、クロスオーバー法により解析した(文献45)。各時点で測定した血漿HMBについては、反復測定多項式モデルを用いた。このモデルには、対象、順序、並びに必要に応じて、治療の相互作用による治療の主要効果及び時間を含めた。その他の指標についてもまた、対象、順序、治療の主要効果及び治療の主要効果について報告されたp値を含むProc GLMを使用した。p<0.05の場合に統計的な有意差があると見なし、0.05<p<0.10の場合に傾向があると見なした。
[00055]試験結果を図1〜7に示す。図1は、一連の激しい運動を行った後のCPK及びLDHの血漿レベルを示している。図2は、一連の激しい運動を行った後の筋肉強度及び主観的な痛みを示している。図3は、試験1での血漿HMBレベルを示している。値は平均±SEMであり、n=男性4人と女性4人である。遊離酸での治療対CaHMBカプセルについて、*=p、0.05、+=p、0.001、+p、0.0001である。図4は、試験1での、CaHMB、HMB酸ゲルの嚥下(FASW)、又はHMB酸ゲルを舌下で維持し、その後嚥下する(FASL)のいずれかを単回投与した後の、最高血漿HMB濃度と、最高濃度到達時間を示している。**=p、0.0002。図5は、試験2の血漿HMBレベルを示している。値は平均±SEMであり、n=男性4人と女性4人である。*=p、0.05、+=p、0.01、++p、0.0001。図6は、試験2で、CaHMB、HMB酸ゲルの嚥下(FASW)、又はHMB酸ゲルを舌下で維持し、その後嚥下する(FASL)のいずれかを単回投与した後の、最高血漿HMB濃度と、最高濃度到達時間を示している。**は、濃度についてはp<0.0002であり、時間についてはp<0.0001である。図7は、摂取後24時間で、尿中に排出されたHMBの量の割合と、保持された量の相対的な割合を示している。*=p<0.002。
[00064]本試験から、遊離酸ゲル形態のHMBの経口又は舌下投与が、硬ゼラチンカプセル中に入れカルシウム塩として投与したHMB(CaHMB)と比較して、血漿HMBのより迅速な上昇と上昇の維持をもたらすことは明かである。HMBの遊離酸ゲルの投与は、血漿中HMBの半減期又は尿中排泄の大きな変化を伴うことなく、血漿HMBのAUCを有意に上昇させた(平均+14.8%)。合わせてこれは、HMBのクリアランス及び組織による利用を有意に上昇させ、組織による利用はCaHMB形態の利用よりも25%高かった。このデータは、HMBをこの形態で送達することによる効果の向上を示している。
[00068]この実施例では、一連の激しい運動を行った後の筋肉損傷におよぼすHMB酸ゲルの投与の効果を、カルシウムHMBの効果と比較した。実施例1に示したように、HMB遊離酸を投与すると、CaHMBと比較して、HMBの最高血漿濃度とHMBのクリアランス率が上昇した(文献13)。この実施例は、一連の激しい運動の前後に遊離酸ゲルとして投与したHMBのより迅速な反応が、HMBをカルシウムHMB塩として投与するよりも、筋肉損傷に対してより保護的であること示している。
[00071]対象: アイオワ州立大学ヘルスアンドヒューマンパフォーマンス研究室(Iowa State University Health and Human Performance Laboratory)で試験を実施した。この試験はアイオワ州立大学の施設内治験審査委員会(Iowa State University Institutional Review Board)で認可され、ClinicalTrials.gov(NCTOl 150526)に登録された。アイオワ州立大学の共同体と周辺地域から、年齢が20才から36才の間の、12人の男性と13人の女性に試験に参加してもらった。
・治療1: 偽薬。この群は、各回の投与で偽薬カプセルと偽薬のシリンジ投与を受けた。
・治療2: CaHMB、運動前。この群は、一連の激しい運動の30分前に、CaHMBカプセルと偽薬のシリンジ投与を受けた。試験期間中の残りの投与では、偽薬カプセル1錠と、偽薬のシリンジ投与1回を受けた。
・治療3: HMB酸ゲル、運動前。この群は、一連の激しい運動の30分前に、偽薬カプセルとHMB酸ゲルのシリンジ投与を受けた。試験期間中の残りの投与では、偽薬カプセル1錠と、偽薬のシリンジ投与1回を受けた。
・治療4: CaHMB、運動前後。この群は、試験期間中の全ての投与時間に、CaHMBカプセルと偽薬のシリンジ投与を受けた。
・治療5: HMB酸ゲル、運動前後。この群は、試験期間中の全ての投与時間に、HMB酸ゲルのシリンジ投与と偽薬カプセル1錠を受けた。
(治療1): 偽薬カプセル及び偽薬のシリンジ投与
(治療2): 運動前にカルシウムHMBカプセルと偽薬のシリンジ投与、及び運動後に偽薬カプセルと偽薬のシリンジ投与
(治療3): 運動前に偽薬カプセルとHMB酸ゲルのシリンジ投与及び運動後に偽薬カプセルと偽薬のシリンジ投与
(治療4): 運動前後にカルシウムHMBカプセルと偽薬のシリンジ投与
(治療5): 運動前後に偽薬カプセルとHMB酸ゲルのシリンジ投与
治療を1日3回、朝の試験の30分前、その後、およそ正午と午後6時に投与した。
尿中クレアチニン比を表9に示す。基準値(0時間)と差は無かった。激しい運動によって血清CPKが4倍まで上昇したことは筋肉膜の損傷を示している。しかしながら、運動前と運動後の両方でHMB酸ゲルを投与すると(治療5)、この上昇は、運動後24時間では64%(P<0.03)、そして運動後48時間では86%(P<0.005)抑えられた。72時間まで継続すると、HMB酸ゲル治療を行ってもCPKの上昇はほとんど認められなかった。図9は、この試験の時間経過に伴うCPK値の上昇と減少を示している。表2でもまた、筋肉でのタンパク質分解の指標である、3MH:クレアチニン比に及ぼす治療の効果を示している。これらのデータは傾向を表しているだけではあるが、運動前後にHMB酸ゲルで治療すると、タンパク質分解が上昇せずに減少さえすることを示している。これは、タンパク質分解の減少が、筋内でのより適したタンパク質代謝及びタンパク質沈着をもたらしていることを示していると考えられる。
[00080]実施例1での観察に基づき、HMB遊離酸を投与した場合、筋肉組織はかなり高い濃度の血清HMBに曝された。加えて実施例1では、HMB酸を投与した場合には、CaHMB投与と比較して、HMBの血清から筋肉及び組織へのクリアランスがかなり上昇したことが分かった。従って実施例2からは、筋肉による遊離酸形態のHMBのこの利用の増加が、カルシウム形態のHMBを投与した場合よりも、一連の激しい運動を行った後の筋肉組織に対してより保護的であることが分かった。
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Claims (7)
- β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMBの遊離酸を0.5グラム〜30グラム含み、筋肉機能の向上、筋肉性能の向上、ストレスに曝された筋肉での筋肉損傷の低減、傷つけられた筋肉での筋肉損傷の低減のために使用される、上記組成物。
- 該HMBの遊離酸をゲルとして投与する、請求項1に記載の組成物。
- 舌下に投与するための、請求項1に記載の組成物。
- 嚥下するための、請求項1に記載の組成物。
- 24時間当たり1回投与するための、請求項1に記載の組成物。
- β−ヒドロキシ−β−メチル酪酸(HMB)を投与するための組成物であって、HMBの遊離酸を含み、筋肉機能の向上、筋肉性能の向上、ストレスに曝された筋肉での筋肉損傷の低減、傷つけられた筋肉での筋肉損傷の低減のために使用される、上記組成物。
- 該HMBの遊離酸がゲルとして、舌下または嚥下によって投与される、請求項1〜6のいずれかに記載の組成物。
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US20040220266A1 (en) * | 2002-09-09 | 2004-11-04 | Wiley David B. | Composition and method for enhancing the bioavailability of calcium and magnesium in dietary supplements and food additives |
EP1750527A1 (en) * | 2004-03-11 | 2007-02-14 | Wiley Organics, Inc. | Compositions and method for enhancing the bioavailability of calcium and magnesium in dietary supplements and food additives |
US20050215640A1 (en) * | 2004-03-26 | 2005-09-29 | Baxter Jeffrey H | HMB compositions and uses thereof |
WO2007056176A2 (en) * | 2005-11-03 | 2007-05-18 | Southwest Immunology, Inc. | Compositions for preventing and reducing delayed onset muscle soreness |
HUE039841T2 (hu) * | 2008-12-09 | 2019-02-28 | Metabolic Tech Inc | Táplálkozási beavatkozás izomfunkció és erõ növeléséhez |
JP2009155336A (ja) * | 2009-03-31 | 2009-07-16 | Tsujido Chemical Corp | 治療剤 |
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EP2512236A4 (en) | 2013-06-19 |
US20120053240A1 (en) | 2012-03-01 |
PL2512236T3 (pl) | 2017-06-30 |
CN102762097B (zh) | 2015-06-17 |
HUE032486T2 (en) | 2018-05-02 |
JP2016026181A (ja) | 2016-02-12 |
JP2013515009A (ja) | 2013-05-02 |
EP2512236A1 (en) | 2012-10-24 |
CA2784836C (en) | 2019-08-20 |
DK2512236T3 (en) | 2017-01-16 |
ES2608483T3 (es) | 2017-04-11 |
WO2011075741A1 (en) | 2011-06-23 |
CN102762097A (zh) | 2012-10-31 |
EP2512236B1 (en) | 2016-10-19 |
PT2512236T (pt) | 2016-12-29 |
CA2784836A1 (en) | 2011-06-23 |
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