JP2022550029A - 乳清タンパク加水分解物を有効成分として含有する筋減少症の改善、予防又は治療用組成物 - Google Patents
乳清タンパク加水分解物を有効成分として含有する筋減少症の改善、予防又は治療用組成物 Download PDFInfo
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Abstract
Description
本発明は、筋減少を抑制させて筋肉の大きさ及び筋力を増加させる、乳清タンパク加水分解物を有効成分として含有する、筋減少症の改善、予防又は治療用組成物に関する。
以下、本発明の理解を助けるために好ましい実施例を提示するが、下記の実施例は、本発明を例示するものに過ぎず、本発明の範囲及び技術思想の範囲内で様々な変更及び修正が可能であることは、当業者にとって明白であり、このような変形及び修正が添付する特許請求の範囲に属することも当然であろう。
乳清タンパク(WPC)と50℃の水を1:5の重量比で混合した後、重曹を用いてpHを7.0~7.5に調節して前記乳清タンパクを溶解させた後、該溶解された乳清タンパク溶解物100重量部に混合酵素(アルカラーゼ(Alcalase2.4L FG,Novo Nordisk社):プロタメックス(Protamax,Novo Nordisk社)=1:1の重量比)を0.4重量部で投入し、50℃で4時間1次加水分解を行った。ここで、1次加水分解反応終了時のpHは。6.0~7.0である。
前記実施例1と同一に実施するが、2次加水分解された分解物をハウジングフィルターで濾過せずにそのまま使用し、水溶性でない乳清タンパク加水分解物を得た。
前記実施例1と同一に実施するが、乳清タンパクの代わりに酸性乳清タンパクを用いて水溶性酸性乳清タンパク加水分解物を得た。
前記比較例1と同一に実施するが、2次加水分解された分解物をハウジングフィルターで濾過せずにそのまま使用し、水溶性でない酸性乳清タンパク加水分解物を得た。
実験動物
マウスの後肢固定(hindlimb immobilization,IM)を実施する筋肉萎縮動物モデルを用いて筋肉萎縮を形成させた後、実施例及び比較例で製造された加水分解物を投与し、筋肉萎縮が回復するかを調べようとした。
正常群(Normal):筋肉萎縮を形成していない群。
対照群(IM):筋肉萎縮後に加水分解物の代わりに飲料水投与。
実施例1(WP-S):筋肉萎縮後に加水分解物(WP-S)800mg/kg/day投与。
実施例2(WP-H):筋肉萎縮後に加水分解物(WP-H)800mg/kg/day投与。
比較例1(AW-S):筋肉萎縮後に加水分解物(AW-S)800mg/kg/day投与。
比較例2(AW-H):筋肉萎縮後に加水分解物(AW-H)800mg/kg/day投与。
図1は、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群に供給されたタンパク質の含有量を示すグラフである。
図2は、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群において時間の経過による握力変化を示すグラフである(#P<0.05、##P<0.01、###P<0.001)。
図3Aは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの大腿四頭筋(quadriceps)の重さを測定したグラフであり、図3Bは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの腓腹筋(Gastrocnemius)の重さを測定したグラフであり、図3Cは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスのヒラメ筋(Soleus)の重さを測定したグラフである(#P<0.05、##P<0.01、###P<0.001)。
図4は、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの筋線維断面積を染色した写真であり、図5Aは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの筋線維断面積を定量化したグラフであり、図5Bは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの筋肉において筋線維CSAの分布を示すグラフである(#P<0.05、##P<0.01、###P<0.001)。
図6Aは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの筋肉分解関連因子の発現を示すウェスタンブロットであり、図6B~図6Gはそれぞれ、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスのp-Foxo3a、Atrogin-1タンパク質、MuRF-1タンパク質、Atrogin-1 mRNA、MuRF-1 mRNA及びBnip3 mRNA因子それぞれの発現程度を示すグラフである(#P<0.05、##P<0.01、###P<0.001)。
図7Aは、本発明の正常群、対照群、実施例1の投与群、実施例2の投与群、比較例1の投与群及び比較例2の投与群マウスの筋肉合成関連因子の発現を示すウェスタンブロットであり、図7B~図7Eは、筋肉合成関連因子のリン酸化比率を示すグラフである(#P<0.05、##P<0.01、###P<0.001)。
前記実施例1の水溶性乳清タンパク加水分解物を利用した。
アーラ乳清タンパク加水分解物(Arla Foods Ingredients,Arla SP-8011、アーラウェイプロテイン)を利用した。
ヒルマ乳清タンパク加水分解物(Hilmar Ingredients,Hilmar8010)を利用した。
マリー ゴールバーン乳清タンパク加水分解物(韓国登録特許第1311318号公報の実施例2)を利用した。
試験例7.構成アミノ酸測定。
構成アミノ酸組成は、乳清タンパク質加水分解物を酸加水分解法で分解した後、アミノ酸自動分析機で組成を測定した。すなわち、乳清タンパク質加水分解物25mgをキャップチューブ(cap tube)に正確に称量して入れた後、2.5mLの6N HClを加え、110℃で24時間加水分解した。3G-4ガラスフィルターで未加水分解物質を除去した濾液は、回転真空蒸発器(N-1110,EYELA,Tokyo,Japan)を用いて、50℃で完全に溶媒を揮発させた後、0.01N HClを用いて25mLに定溶し、アミノ酸分析用試料として使用した。アミノ酸分析は、試料溶液40uLを注入してアミノ酸自動分析機(Biochrom 30,Cambridge,UK)で分析した。
図8は、本発明の実施例1によって製造された加水分解物の分子量を測定したグラフである。
指標ペプチド合成。
アミノ酸配列分析によって確認した指標ペプチドLeu-Asp-Ile-Gln-Lys(LDIQK)は、一般固相合成法によってアブクロン社(ソウル,韓国)で合成し、合成ペプチドLDIQKの分子量と純度はそれぞれ、615.73Daと95.05%であった。
指標ペプチドの定量は、Watchers 120 ODS-BP(.6×250mm,5um)を装着したAgilent 1260 infinity HPLCシステム(Santa Clara,CA,USA)とShimdzu HPLC prominenceシステムで実施した。分析装備以外の分析条件は同一に適用した。実施例1の試料は、別の前処理をせず、実施例1の試料粉末0.5gをHPLC級蒸留水に完全に溶かして10mLに定溶した後、遠心分離(7,500xg、20分)して得た上清液を0.20umシリンジフィルターで濾過し、分析用試料として使用した。タンパク質濃度確認のためにビウレット(Biuret)法で可溶性タンパク質の濃度を測定した。それぞれのHPLCシステムにおいて指標ペプチド定量のための分析条件は表3の通りであり、指標ペプチド(LDIQK)の含有量は表4に示した。
図9A~図9Dは、実施例1及び比較例3~5の各乳清タンパク質加水分解物に対する細胞毒性を示すグラフである。
図10は、対照群(無処理)、デキサメタゾン処理群、実施例1及び比較例3~5で処理時の筋管細胞の厚さを顕微鏡で測定した写真である。
図12は、対照群(無処理)、デキサメタゾン処理群、実施例1及び比較例3~5で処理時の筋管細胞の厚さを顕微鏡で測定した写真である。
実施例1で得た水溶性乳清タンパク加水分解物500mg。
乳糖100mg。
タルク10mg。
前記の成分を混合して気密布に充填して散剤を製造する。
実施例1で得た水溶性乳清タンパク加水分解物300mg。
とうもろこし澱粉100mg。
乳糖100mg。
ステアリン酸マグネシウム2mg。
前記の成分を混合した後、通常の錠剤の製造方法によって打錠して錠剤を製造する。
実施例1で得た水溶性乳清タンパク加水分解物200mg。
結晶性セルロ-ス3mg。
ラクトース14.8mg。
ステアリン酸マグネシウム0.2mg。
通常のカプセル剤の製造方法によって前記の成分を混合し、ゼラチンカプセルに充填してカプセル剤を製造する。
実施例1で得た水溶性乳清タンパク加水分解物600mg。
マンニトール180mg。
注射用滅菌蒸留水2974mg。
Na2HPO4、12H2O 26mg。
通常の注射剤の製造方法によって1アンプル当たりに前記の成分含有量で製造する。
実施例1で得た水溶性乳清タンパク加水分解物4g。
異性化糖10g。
マンニトール5g。
精製水 適量。
通常の液剤の製造方法によって精製水にそれぞれの成分を加えて溶解させ、レモン香を適量加えた後、前記の成分を混合後に精製水を加え、全体に精製水を加えて全体100gに調節した後、褐色瓶に充填後に滅菌させ、液剤を製造する。
実施例1で得た水溶性乳清タンパク加水分解物1,000mg。
ビタミン混合物 適量。
ビタミンAアセテート70μg。
ビタミンE 1.0mg。
ビタミンB 10.13mg。
ビタミンB 20.15mg。
ビタミンB 60.5mg。
ビタミンB 120.2μg。
ビタミンC 10mg。
ビオチン10μg。
ニコチン酸アミド1.7mg。
葉酸50μg。
パントテン酸カルシウム0.5mg。
無機質混合物 適量。
硫酸第一鉄1.75mg。
酸化亜鉛0.82mg。
炭酸マグネシウム25.3mg。
第1リン酸カリウム15mg。
第2リン酸カルシウム55mg。
クエン酸カリウム90mg。
炭酸カルシウム100mg。
塩化マグネシウム24.8mg。
上記のビタミン及びミネラル混合物の組成比は、比較的顆粒剤に適合した成分を好ましい実施例で混合組成したが、その配合比を任意に変形実施しても構わなく、通常の顆粒剤製造方法によって上記の成分を混合した後、顆粒を製造し、通常の方法によって健康機能食品組成物の製造に使用することができる。
実施例1で得た水溶性乳清タンパク加水分解物1,000mg。
クエン酸1,000mg。
オリゴ糖100g。
梅の実濃縮液2g。
タウリン1g。
精製水を加えて全体900mL。
通常の健康飲料の製造方法によって上記の成分を混合した後、約1時間85℃で撹拌加熱した後、作られた溶液を濾過し、滅菌された2L容器に取って密封滅菌した後に冷蔵保管し、本発明の機能性飲料組成物の製造に使用する。
Claims (20)
- 乳清タンパクをバチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)で1次加水分解し、アスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)で2次加水分解したことを特徴とする乳清タンパク加水分解物。
- 前記乳清タンパクが、チーズ乳清由来であることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 前記乳清タンパクが、一般乳清粉末(Normal whey powder)、脱塩乳清粉末(Demineralized whey powder)、乳清タンパク濃縮物(Whey protein concentrate)又は乳清タンパク分離物(Whey protein isolate)であることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 不溶性物質が除去された水溶性乳清タンパク加水分解物であることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 前記バチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)は、アルカラーゼ(Alcalase)、プロタメックス(Protamax)又はそれらの混合酵素であり、前記アスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)は、フラボザイム(Flavourzyme)であることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 前記混合酵素が、アルカラーゼ(Alcalase)とプロタメックス(Protamax)とが1:0.5~2の重量比で混合されたことを特徴とする、請求項5に記載の乳清タンパク加水分解物。
- Cys 9~11mg/g、Tyr 19~22mg/g、Arg 18~19mg/g、Ala 37~39mg/g、Pro 43~45mg/g、Lys 68~72mg/g、His 13.5~14mg/g、Ile 40~41mg/g、Leu 77~80mg/g、Met 15~17mg/g、Phe 24~25mg/g、Val 36~37mg/g、Glu 120~130mg/g、Asp 80~82mg/g、Ser 35~41mg/g、Gly 14.5~15mg/g、Thr 54~55mg/g及びTrp 10~11mg/gのアミノ酸からなることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 全アミノ酸中に遊離アミノ酸が1~5重量%含まれていることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- BCAAアミノ酸が155~180mg/g含まれていることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 指標ペプチドの含有量が、10~40mg/gであることを特徴とする、請求項1に記載の乳清タンパク加水分解物。
- 乳清タンパクを、バチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)で1次加水分解し、アスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)で2次加水分解した乳清タンパク加水分解物を有効成分として含有する筋機能改善用食品組成物。
- 乳清タンパクをバチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)で1次加水分解し、アスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)で2次加水分解した乳清タンパク加水分解物を有効成分として含有する筋減少症の改善又は予防用食品組成物。
- 前記筋減少症が、筋萎縮症、筋無力症、筋異栄養症、筋強直症、筋緊張低下、筋力弱化、筋肉退行萎縮、筋萎縮性側索硬化症又は重症筋無力症であることを特徴とする、請求項12に記載の食品組成物。
- 乳清タンパクをバチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)で1次加水分解し、アスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)で2次加水分解した乳清タンパク加水分解物を有効成分として含有する筋減少症の予防又は治療用薬学組成物。
- 前記組成物が、筋肉の大きさを増加させることを特徴とする、請求項14に記載の薬学組成物。
- 前記筋減少症が、筋萎縮症、筋無力症、筋異栄養症、筋強直症、筋緊張低下、筋力弱化、筋肉退行萎縮、筋萎縮性側索硬化症又は重症筋無力症であることを特徴とする、請求項14に記載の薬学組成物。
- (A)乳清タンパクと水を1:3~10の重量比で混合して前記乳清タンパクを溶解させる段階と、
(B)前記溶解された乳清タンパク溶解物100重量部に、バチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)を0.1~1の重量部で投入して1次加水分解を行う段階と、
(C)前記1次加水分解された分解物にアスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)を0.1~1の重量部で投入して2次加水分解を行う段階と、
(D)前記2次加水分解された分解物を濾過させて不溶性物質を除去することで、水溶性乳清タンパク加水分解物を得る段階と、を含むことを特徴とする水溶性乳清タンパク加水分解物の製造方法。 - 前記(D)段階後に、
(E)前記得られた水溶性乳清タンパク加水分解物を殺菌後に室温で冷却させる段階と
(F)前記殺菌及び冷却された水溶性乳清タンパク加水分解物を乾燥させて濾過する段階と、をさらに含むことを特徴とする、請求項17に記載の水溶性乳清タンパク加水分解物の製造方法。 - 前記バチルス・リケニフォルミス(Bacillus licheniformis)由来エンドプロテアーゼ(Endo protease)が、アルカラーゼ(Alcalase)、プロタメックス(Protamax)又はそれらの混合酵素であることを特徴とする、請求項17に記載の水溶性乳清タンパク加水分解物の製造方法。
- 前記アスペルギルス・オリゼー(Aspergillus oryzae)由来エキソプロテアーゼ(Exo protease)が、フラボザイム(Flavourzyme)であることを特徴とする、請求項17に記載の水溶性乳清タンパク加水分解物の製造方法。
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