TWI586362B - 新穎蛋白質素材 - Google Patents
新穎蛋白質素材 Download PDFInfo
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- TWI586362B TWI586362B TW102126685A TW102126685A TWI586362B TW I586362 B TWI586362 B TW I586362B TW 102126685 A TW102126685 A TW 102126685A TW 102126685 A TW102126685 A TW 102126685A TW I586362 B TWI586362 B TW I586362B
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- angiopoietin
- lactoperoxidase
- protein material
- decomposition product
- bone
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Description
本發明係關於新穎蛋白質素材及摻合了此蛋白質素材之對於骨疾病預防或治療為有用之醫藥品或飲食品、飼料。該素材促進成骨細胞之增殖,且具有抑制破骨細胞之分化及抑制破骨細胞所為之骨吸收的作用,對於骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病之預防或治療有用。
近年來,以世界性規模,伴隨高齡化等,骨質疏鬆症、骨折或腰痛等各種與骨相關的疾病已有增加,成為大的社會問題。其原因為鈣的攝取不足、鈣吸收能力下降、停經後的荷爾蒙失調等。為了預防骨質疏鬆症、骨折、腰痛等各種骨疾病,據認為:從年青時期開始促進成骨細胞所為之骨形成,使體內骨量儘可能增加,提高最大骨量、骨強度(骨密度+骨質)係為有效。又,骨質,係指骨的微細結構、代謝周轉、微小骨折、石灰化。又,作為預防骨質疏鬆症、骨折、腰痛等各種骨疾病的方法,也有人考慮抑制破骨細胞所為之骨吸收。骨會持續重複取得平衡的吸收與形成(再塑(remodeling)),但由於停經後荷爾蒙平衡性的變化等,會使得骨吸收多於骨形成,造成骨質疏鬆症、骨折、腰痛等各種骨疾病的原因。因此,可藉由抑制破骨細胞所為之骨吸收而保持骨強度為一定,結果能夠強化骨骼。
由如此的現狀,為了強化骨骼,有人會攝取將碳酸鈣、磷酸鈣、乳酸鈣等鈣鹽及乳清鈣、牛骨粉、蛋殼等天然鈣劑分別單獨地添加於醫藥品、飲食品、飼料等者。或有人會攝取將該等鈣劑與酪蛋白磷酸胜肽或寡糖等
有鈣吸收促進效果之物質一起添加於醫藥品、飲食品、飼料等者。但是據說:當攝取添加該等鈣鹽或天然鈣劑於飲食品者時,鈣之吸收率為50%以下,有許多鈣未能吸收而被排出到體外。又,即使是吸收到體內的鈣,取決於其形態或取決於同時攝取的其他營養成分的種類,對於骨的親和性不同,有時不一定會呈現骨代謝改善或骨骼強化的作用。此外,作為骨質疏鬆症治療、骨骼強化的醫藥,已知有女性荷爾蒙製劑、活性型維生素D3製劑、維生素K2製劑、雙膦酸鹽(bisphosphonate)製劑、降鈣素(calcitonin)製劑等,也正在進行抗RANKL抗體等新藥開發。但是使用該等醫藥品的情形,有時會伴隨耳鳴、頭痛、食慾不振等副作用。再者,該等物質,從安全性及成本等方面,處於目前尚不可添加於飲食品的狀況。另一方面,從骨質疏鬆症、骨折、腰痛等各種骨疾病之疾病之性質,希望能夠開發出可長期經口攝取,且作用為促進骨形成及抑制骨吸收而提高骨骼強度,並能期待其預防或治療效果的骨骼強化劑或飲食品、飼料。
目的為提高骨強度的食品素材,例如據報告乳來源的鹼性蛋白質或係其酵素分解物之胜肽組分有成骨細胞之增殖活性、破骨細胞之骨吸收抑制活性、及經由此等之骨骼強化作用(專利文獻1)。又,據報告:乳來源的鹼性蛋白質組分中含有的血管生成素、乳過氧化酶(lactoperoxide),分別單獨地具有改善骨代謝的作用(專利文獻2、3、4)。
【先前技術文獻】
【專利文獻】
【專利文獻1】日本特開平8-151331號公報
【專利文獻2】日本特開平10-7585號公報
【專利文獻3】日本特開2004-238320號公報
【專利文獻4】日本特開2005-60321號公報
本發明之課題為提供一種新穎蛋白質素材,其安全且以日常攝取,能有促進成骨細胞之增殖、抑制破骨細胞之分化及破骨細胞所為之骨吸收之作用,且能強化骨骼。又,本發明之課題在於提供利用經口攝取,對於骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病之預防、治療有用之骨骼強化用醫藥品或飲食品、飼料。
本案發明人等發現:藉由攝取以特定範圍之量含有血管生成素及/或血管生成素分解物,且相對於血管生成素及/或血管生成素分解物以特定範圍之質量比含有乳過氧化酶及/或乳過氧化酶分解物的蛋白質素材,能有效促進成骨細胞增殖,且可獲得抑制破骨細胞分化及抑制破骨細胞所為之骨吸收的作用,乃完成本發明。
亦即本發明係包含以下構成:
(1)一種蛋白質素材,其含有血管生成素及/或血管生成素分解物2~15mg/100mg,且相對於血管生成素及/或血管生成素分解物以質量比0.3~20之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
(2)一種飲食品或飼料,含有如(1)之蛋白質素材。
(3)一種骨骼強化劑,含有如(1)之蛋白質素材作為有效成分。
(4)一種骨骼強化方法,係攝取如(1)之蛋白質素材5mg/日以上。
(5)一種如(1)之蛋白質素材之製造方法,包含以下1)~3)之步驟;1)製備血管生成素及/或血管生成素分解物;2)製備乳過氧化酶及/或乳過氧化酶分解物;3)將上述2)之步驟製備之乳過氧化酶及/或乳過氧化酶分解物,以相對於上述1)之步驟製備之血管生成素及/或血管生成素分解物成為質量比0.3~20之方式摻合。
(6)一種如(1)之蛋白質素材之製造方法,包含以下步驟:從乳及/或乳原料,萃取含有血管生成素及/或血管生成素分解物與乳過氧化酶及/或乳過氧化酶分解物之組分,以使得乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比成為0.
3~20。
(7)如(6)之蛋白質素材之製造方法,更包含以下步驟:將含有血管生成素與乳過氧化酶之組分中之血管生成素及/或乳過氧化酶進行酵素分解。
本發明之蛋白質素材,藉由促進成骨細胞之增殖及抑制破骨細胞分化及抑制破骨細胞所為之骨吸收的作用,骨骼強化作用顯著。又,摻合了本發明之蛋白質素材的醫藥品或飲食品、飼料,對於強化骨骼,預防、治療骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病為有用。
本發明之蛋白質素材之特徵為,以特定之範圍之量含有血管生成素及/或血管生成素分解物,且相對於血管生成素及/或血管生成素分解物以特定範圍之質量比含有乳過氧化酶及/或乳過氧化酶分解物。
因此,本發明之蛋白質素材,可列舉:混合包含血管生成素及/或血管生成素分解物之組分與包含乳過氧化酶及/或乳過氧化酶分解物之組分使得成特定之範圍之質量比者、或從乳、或脫脂乳、乳清等乳源的乳原料直接、萃取以特定之範圍之質量比含有血管生成素及/或血管生成素分解物與乳過氧化酶及/或乳過氧化酶分解物的組分並製備者。又,本發明之蛋白質素材也包括使酵素等作用於此等,並將血管生成素及/或乳過氧化酶予以分解者。
當混合包含血管生成素及/或血管生成素分解物之組分與包含乳過氧化酶及/或乳過氧化酶分解物之組分而成為本發明之蛋白質素材的情形,作為包含血管生成素及/或血管生成素分解物之組分或包含乳過氧化酶及/或乳過氧化酶分解物之組分,可使用從人類、家牛、水牛、山羊、綿羊等
哺乳類乳汁製備的組分或以基因工程的方法生產的組分、從血液或臟器精製的組分等。又,也可使用經精製的市售的血管生成素或乳過氧化酶的試藥,也可藉由調整血管生成素及/或血管生成素分解物與乳過氧化酶及/或乳過氧化酶分解物的質量比,而製得本發明之蛋白質素材。
又,可將上述含有血管生成素之組分、血管生成素之試藥或含有乳過氧化酶之組分、乳過氧化酶之試藥等分別以1種以上的蛋白質分解酵素予以分解後,作為血管生成素分解物或乳過氧化酶分解物使用。
另一方面,從乳、或脫脂乳或乳清等乳源原料,直接、萃取以特定之範圍之質量比含有血管生成素及/或血管生成素分解物與乳過氧化酶及/或乳過氧化酶分解物的組分並製備的情形,例如使乳或乳原料與陽離子交換樹脂接觸之後,以0.1~2.0M之鹽濃度溶出吸附於此樹脂的乳源蛋白質,並利用逆滲透膜或電透析膜、超過濾膜、精密過濾膜等予以脫鹽、濃縮後,視需要以胰蛋白酶、胰酶、胰凝乳蛋白酶、胃蛋白酶、木瓜蛋白酶、激肽釋放酶、組織蛋白酶、嗜熱菌蛋白酶、V8蛋白酶等蛋白質分解酵素進行限制分解成為分子量為8,000以下,可藉此製備。又,以蛋白質分解酵素進行限制分解的情形,宜使分子量之下限為500以上。又,以如此的方式獲得之蛋白質素材,也可利用冷凍乾燥、噴霧乾燥等予以乾燥。
又,為了解析本發明之蛋白質素材之蛋白質組(proteome),依常法進行改性且於還原下以消化酵素進行限制分解後,以LC/MS/MS進行分析,結果:本發明之蛋白質素材,除了含有血管生成素及/或血管生成素分解物與乳過氧化酶及/或乳過氧化酶分解物以外,尚至少含有1種αs1酪蛋白、αs2酪蛋白、β酪蛋白、或κ酪蛋白中之任一種蛋白質及/或此等蛋白質的分解物。
本發明之蛋白質素材,含有血管生成素及/或血管生成素分解物2~15mg/100mg,且相對於血管生成素及/或血管生成素分解物以質量比為0.3~20之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
於後述試驗例所示,藉由使乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為0.3~20,比起分別單獨地
攝取,能獲得更為有效的骨骼強化作用。
又,作為參考,牛乳中之血管生成素及/或血管生成素分解物約0.001%,乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物的質量比為約20。又,在乳清蛋白質濃縮物(WPC)中,血管生成素及/或血管生成素分解物的含量約0.1%,乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為約30。
可藉由將本發明之蛋白質素材適當摻合作為有效成分而製劑為骨骼強化劑。又,本發明之蛋白質素材也可直接作為骨骼強化劑。又,製劑為骨骼強化劑的情形,除了係有效成分之本發明之蛋白質素材以外,也可混合糖類、脂質、蛋白質、維生素類、礦物質類、香料等其他的醫藥品,或飲食品、飼料中通常使用之原材料等,或進一步依常法製劑為粉末劑、顆粒劑、錠劑、膠囊劑、飲劑等。又,也可同時使用本發明之蛋白質素材與其他他顯示骨骼強化作用的成分,例如鈣、維生素D、維生素K、異黃酮等。
本發明之蛋白質素材,藉由於後述實驗動物的試驗中,體重每1kg經口攝取5mg以上,可強化骨骼。此實驗動物之攝取量,相當於血中藥物濃度,成人每人的攝取量(中島光好(1993),「第8卷藥效評價」,廣川書店,2-18頁),藉由通常成人每人每日攝取本發明之蛋白質素材5mg以上,可期待骨骼強化,尤其骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病之預防或治療之效果。所以,當摻合到骨骼強化劑等的情形,只要能確保此必要量即可。
本發明之蛋白質素材也可摻合於通常的飲食品,例如優格、飲料、威化餅、點心等。於此情形,取決於飲食品之形態,但宜飲食品每100g摻合本發明之蛋白質素材0.25~1000mg較佳,藉由為此摻合量,可期待骨骼強化作用。又,也可以摻合於飼料,例如家畜用飼料或寵物食品等,而製成骨骼強化用飼料。於此情形,飼料每100g宜摻合本發明之蛋白質素材0.25~1000mg較佳。
本發明之蛋白質素材製備為醫藥品、飲食品、飼料的形態使用時,係將本發明之蛋白質素材懸浮或溶解於去離子水並攪拌混合後使用。作為攪拌混合之條件,只要能將本發明之蛋白質素材均勻混合即可,亦可使用超分散器或TK均質混合器等進行攪拌混合。
又,該素材之溶液,視需要可以經逆滲透膜等進行脫鹽、濃縮、或冷凍乾燥後使用,以使得容易使用在醫藥品或飲食品、飼料。又,本發明之蛋白質素材,已確認即使進行了於醫藥品或飲食品、飼料之製造通常使用之殺菌處理也能維持關於骨骼強化之活性。該素材製成粉末狀時,也可進行乾熱殺菌。本發明之蛋白質素材,可使用於液狀、凝膠狀、粉末狀、顆粒狀等各種各樣形態之醫藥品或飲食品、飼料。
以下舉參考例、實施例及試驗例,針對本發明詳細說明,但此等僅為例示,並非限定本發明。
[參考例1]
(血管生成素組分之製備1)
將已填充係陽離子交換樹脂之磺化CHITO PEARL(富士紡公司製)30kg的管柱以去離子水充分洗滌後,對此管柱通入未殺菌脫脂乳1,000L(pH6.7)。然後,將此管柱以去離子水充分洗滌後,以0.1~2.0M氯化鈉之直線濃度梯度溶出。然後,將含有血管生成素之溶出組分以S-Sepharose陽離子交換層析(Amersham Bioscience公司製)分離,將獲得之含血管生成素之組分於90℃進行10分鐘加熱處理,進行離心分離,以去除沉澱。再者,將此含血管生成素之組分以Superose12凝膠過濾層析進行處理。將此溶出液以逆滲透膜予以脫鹽後,冷凍乾燥,獲得血管生成素之純度為90%之血管生成素組分16.5g。此等一連串的處理重複30次。
[參考例2]
(血管生成素組分之製備2)
將已填充肝素親和性SEPHAROSE(GE Healthcare公司製)10kg的管柱
以去離子水充分洗滌後,對此管柱通入未殺菌脫脂乳1000L(pH6.7)。其次將此管柱以0.6M氯化鈉溶液充分洗滌後,以1.5M之氯化鈉溶液溶出。然後將此溶出液以逆滲透膜脫鹽後,冷凍乾燥,獲得血管生成素之純度為2%之血管生成素組分32g。重複此等一連串的處理50次。
[參考例3]
(乳過氧化酶組分之製備)
將已填充係陽離子交換樹脂之磺化CHITOPEARL(富士紡製)600g的管柱(直徑5cm×高度30cm)以去離子水充分洗滌後,以流速25ml/min對此管柱通入未殺菌脫脂乳360L(pH6.7)。通液後,將管柱以去離子水充分洗滌,以含2.0M氯化鈉的0.02M碳酸緩衝液(pH7.0)進行溶出。然後使含有乳過氧化酶的溶出組分吸附於S-Sepharose FF管柱(Amersham Bioscience公司製),以去離子水充分洗滌,以10mM的磷酸緩衝液(pH7.0)平衡後,以0~2.0M的氯化鈉的線性梯度將已吸附的組分溶出,回收含有乳過氧化酶的組分。然後將此組分以使用HiLoad 16/60 Superdex75pg(Amersham Bioscience公司製)的凝膠過濾層析處理。將此溶出液以逆滲透膜脫鹽後,進行冷凍乾燥,獲得乳過氧化酶之純度為90%之乳過氧化酶組分27g。此等一連串的處理重複25次。
【實施例1】
將參考例1之血管生成素組分0.59mg與參考例2之血管生成素組分98.58mg與參考例3之乳過氧化酶組分0.83mg予以混合,製備成血管生成素及/或血管生成素分解物之含量為2.5mg/100mg且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為0.3的蛋白質素材(實施例品1)。
【實施例2】
將參考例1之血管生成素組分0.73mg與參考例2之血管生成素組分92.33mg與參考例3之乳過氧化酶組分6.94mg予以混合,製備成血管生成素及/或血管生成素分解物之含量為2.5mg/100mg且乳過氧化酶及/或乳過
氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為2.5的蛋白質素材(實施例品2)。
【實施例3】
將參考例1之血管生成素組分1.83mg與參考例2之血管生成素組分42.61mg與參考例3之乳過氧化酶組分55.56mg予以混合,製備成血管生成素及/或血管生成素分解物之含量為2.5mg/100mg且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為20之蛋白質素材(實施例品3)。
[比較例1]
將參考例1之血管生成素組分0.57mg與參考例2之血管生成素組分99.15mg與參考例3之乳過氧化酶組分0.28mg予以混合,製備成血管生成素及/或血管生成素分解物之含量為2.5mg/100mg且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為0.1之蛋白質素材(比較例品1)。
[比較例2]
將參考例1之血管生成素組分2.08mg與參考例2之血管生成素組分31.25mg與參考例3之乳過氧化酶組分66.67mg予以混合,製備成血管生成素及/或血管生成素分解物之含量為2.5mg/100mg且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為24之蛋白質素材(比較例品2)。
[試驗例1]
針對實施例品1~3及比較例品1、2,調查成骨細胞增殖效果、抑制破骨細胞所為之骨吸收之效果、及抑制破骨細胞之分化的效果。
針對成骨細胞增殖效果,如以下方式調查。將成骨細胞株(MC3T3-E1)接種於96孔平板細胞培養板,使成為2×103cells/well,以含10%胎牛血清之α-MEM培養基培養24小時。將培養基全部去除後,各添加不含胎牛血清之
α-MEM培養基90μl,並各添加10μl已溶有實施例品1~3及比較例品1、2之溶液,再繼續培養24小時。添加Cell Proliferation kit(GE Healthcare公司製)附帶的溴去氧尿嘧啶(BrdU),培養2小時後,使與過氧化酶標記抗BrdU抗體反應,並添加基質3,3',5,5'-四甲基聯苯胺,測定於450nm之吸光度,以測定納入到細胞內之BrdU量,藉此求取成骨細胞增殖活性。相對於在培養基中未添加實施例品1~3及比較例品1、2的群(對照)於450nm之吸光度,當有添加之群之吸光度顯著較高的情形,定成骨細胞增殖活性為陽性。
針對抑制破骨細胞所為之骨吸收之效果,以如下方式調查。摘取5日大的兔的脛骨及大腿骨,去除軟組織後,將在含5%FBS之α-MEM培養基中以機械性切碎的含破骨細胞之全骨髓細胞撒播於結晶性磷酸鈣板(Cornig公司製)之井上,使成為1×106cells/well並培養。培養2小時後,將培養基全部去除,之後各添加含5%FBS之α-MEM培養基180μl,並各添加溶有實施例品1~3及比較例品1、2之溶液20μl,培養72小時。然後,添加5%次亞氯酸鈉溶液以去除細胞後,於實體顯微鏡下拍攝在磷酸鈣板之井上出現的骨吸收窩(凹坑(pit)),以圖像解析測定其面積,以調查抑制破骨細胞所為之骨吸收之效果(瀬野悍二等人,研究主題別動物培養細胞手冊,pp.199-200,1993)。當相對於在培養基未添加實施例品1~3及比較例品1、2之群(對照)之凹坑面積,有添加之群之凹坑面積顯著較小時,定破骨細胞骨吸收抑制活性為陽性。
針對抑制破骨細胞之分化的效果,以如下方式調查。將從ddy小鼠(7或8週大、雄性)之大腿骨採取的骨髓細胞播種於96井板,使其成為4×104cells/well,以含有25ng/ml M-CSF之含10%FBS之α-MEM培養基(GIBCO公司製)200μl,於37℃、5%CO2之條件培養。培養2日後將培養液除去,添加含有5ng/mlRANKL及25ng/mlM-CSF之含10%FBS之α-MEM培養基180μl/well,並各添加溶有實施例品1~3及比較例品1、2之溶液20μl,於37℃、5%CO2之條件培養2日後,更換培養基,再培養1日。培養結束後,將培養液除去,以PBS洗滌,以丙酮-乙醇(1:1)溶液處理1分鐘進行固定後,添加1.5mg/ml之對硝基苯基磷酸二鈉-20mM酒石酸鈉-50mM檸檬
酸緩衝液(pH4.5)100μl/well,於室溫進行30分鐘反應。添加1M氫氧化鈉溶液50μl/well而停止反應後,測定405nm之吸光度,作為破骨細胞分化成熟之指標。當相對於在培養基未添加實施例品1~3及比較例品1、2之群(對照)於405nm之吸光度,有添加之群之吸光度顯著較低時,定破骨細胞分化抑制活性為陽性。該等結果如表1。
由表1之結果,本發明之蛋白質素材實施例品1~3,在所有細胞試驗的活性均為陽性。相對於此,比較例品1、2,在部分的細胞試驗的活性為陽性,但也存在陰性之細胞試驗。
【實施例4】
將已填充陽離子交換樹脂之磺化CHITO PEARL(富士紡公司製)600g的管柱(直徑5cm×高度30cm)以去離子水充分洗滌後,於此管柱以流速25ml/min通入未殺菌脫脂乳(pH6.7)40L。通液後將此管柱以去離子水充分洗滌,以含0.78M氯化鈉之0.02M碳酸緩衝液(pH7.0)使吸附於樹脂之蛋白質溶出。然後,將此溶出液以逆滲透膜脫鹽後,進行冷凍乾燥,獲得粉末狀之蛋白質素材18g(實施例品4)。此蛋白質素材的血管生成素及/或血管生成素分解物之含量為2mg/100mg,且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為18,可以直接作為骨骼強化劑、或作為骨骼強化劑之有效成分使用。又,蛋白質組解析之結
果,此蛋白質素材中含有β酪蛋白與κ酪蛋白之分解物。
【實施例5】
將已填充陽離子交換樹脂之SP TOYO PEARL(東曹(股)公司製)30kg之管柱(直徑20cm×高度100cm)以去離子水充分洗滌後,對此管柱以流速10L/min通入經於75℃進行了15秒加熱殺菌的乳清3t(pH6.2)。通液後將此管柱以去離子水充分洗滌,以含0.68M氯化鈉之0.1M檸檬酸緩衝液(pH5.7)將吸附於樹脂之蛋白質溶出。然後,將此溶出液以電透析膜脫鹽後,進行冷凍乾燥。重複此一連串操作20次,獲得粉末狀之蛋白質素材3.3kg(實施例品5)。此蛋白質素材之血管生成素及/或血管生成素分解物之含量為15mg/100mg,且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為0.8,可直接作為骨骼強化劑、或作為骨骼強化劑之有效成分使用。又,蛋白質組解析之結果,於此蛋白質素材中含有αs1酪蛋白與κ酪蛋白之分解物。
【實施例6】
將實施例品4之蛋白質素材4g溶於水800ml,並加入係蛋白質分解酵素之胰酶(Sigma公司製),使得最終濃度成為0.02重量%,於37℃進行8小時酵素處理。然後,於90℃進行5分鐘加熱處理使酵素失活後,進行冷凍乾燥,獲得蛋白質素材3.2g(實施例品6)。又,以此方式獲得之蛋白質素材之血管生成素分解物含量為2.0mg/100mg,且乳過氧化酶分解物相對於血管生成素分解物之質量比為16,分子量為8,000以下,可以直接作為骨骼強化劑、或作為骨骼強化劑之有效成分使用。又,蛋白質組解析之結果,於此蛋白質素材中含有β酪蛋白與κ酪蛋白之分解物。
【實施例7】
將實施例品5之蛋白質素材4g溶於水800ml,並添加蛋白質分解酵素胰蛋白酶(Sigma公司製)使得最終濃度成為0.03重量%,於37℃進行8小時酵素處理。然後,於90℃進行5分鐘加熱處理使酵素失活後,冷凍乾燥,獲得蛋白質素材3.0g(實施例品7)。又,以此方式獲得之蛋白質素材之血管生
成素分解物含量為14mg/100mg,且乳過氧化酶分解物相對於血管生成素分解物之質量比為0.7,分子量為8,000以下,故可直接作為骨骼強化劑、或作為骨骼強化劑之有效成分使用。又,蛋白質組解析之結果,於此蛋白質素材中含有αs1酪蛋白與κ酪蛋白之分解物。
[比較例3]
將參考例3之乳過氧化酶組分10mg與實施例品4之蛋白質素材100mg予以混合,製備為血管生成素及/或血管生成素分解物之含量為1.8mg/100mg且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為22.5之蛋白質素材(比較例品3)。
[比較例4]
將參考例1之血管生成素組分1g與實施例品5之蛋白質素材2g予以混合,並溶於水800ml,添加蛋白質分解酵素胰蛋白酶(Sigma公司製)使得最終濃度成為0.02重量%,於37℃進行12小時酵素處理。然後,於90℃進行5分鐘加熱處理使酵素失活後,冷凍乾燥,獲得蛋白質素材2.8g(比較例品4)。以此方式獲得之蛋白質素材之血管生成素分解物含量為39mg/100mg,且乳過氧化酶分解物相對於血管生成素分解物之質量比為0.2。
[比較例5]
將已填充陽離子交換樹脂之CMSEPHAROSEFF(GE Healthcare公司製)100g之管柱(直徑5cm×高度5cm)以去離子水充分洗滌後,於此管柱以流速40ml/min通入未殺菌脫脂乳(pH6.7)40L。通液後將此管柱以去離子水充分洗滌,以含0.98M氯化鈉之0.02M碳酸緩衝液(pH6.8)將吸附於樹脂之蛋白質溶出。然後,將此溶出液以逆滲透膜脫鹽後,冷凍乾燥,獲得粉末狀之蛋白質素材20g(比較例品5)。此蛋白質素材之血管生成素及/或血管生成素分解物之含量為1.5mg/100mg,且乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比為30。
[試驗例2]
針對實施例品4、5及比較例品3、5之骨骼強化作用,以動物實驗進行調查。實驗使用5週大的C3H/HeJ系雄小鼠。於1週預備飼養後,將小鼠以6隻為1群,分成5群,將實施例品4、5及比較例品3、5,以就小鼠體重每1kg各為5mg,每日1次以胃管經口投予,飼養4週。又,將未投予實施例品4、5及比較例品3、5者作為對照群。投予結束後(第4週),以MICRO CT(RIGAKU(股)製)測定小鼠之右脛骨之骨密度。其結果如表2。
如表2所示,經口投予了4週係本發明蛋白質素材之實施例品4、5的群,比起對照群或投予比較例品3、5,骨密度顯著上升。
[試驗例3]
針對實施例品6、7及比較例品4、5之骨骼強化作用,以動物實驗進行調查。實驗使用51週大的SD系雌大鼠48隻。將大鼠8隻為1群,分成6群,其中5群實施卵巢摘除手術,其餘的1群實施虛擬手術。設置4週回復期間,對於已實施卵巢摘除手術之大鼠,將實施例品6、7及比較例品4、5,就大鼠體重每1kg各為5mg,每日1次以胃管經口投予,飼養16週。將未投予實施例品6、7及比較例品4、5者作為對照群。又,4週回復期間後,將已實施虛擬手術的大鼠也和對照群同樣飼養16週。投予結束後(第16週),以MICRO CT(RIGAKU(股)製)測定大鼠之右大腿骨骨密度。其結果如表3。
如表3,經口投予了16週係本發明蛋白質素材之實施例品6、7的群,比起對照群或投予比較例品4、5之群,骨密度顯著上升,且其值接近虛擬手術群的水平。
【實施例8】
(骨骼強化用液狀營養組成物之製備)
將實施例品4之蛋白質素材5g溶於4995g之去離子水,以TK均質混合機(TK ROBO MICS;特殊機化工業公司製),於6000rpm進行30分鐘攪拌混合,獲得含有100mg/100g之實施例品4的溶液。於此溶液5.0kg中,摻合酪蛋白4.0kg、大豆蛋白質5.0kg、魚油1.0kg、紫蘇油3.0kg、糊精18.0kg、礦物質混合物6.0kg、維生素混合物1.95kg、乳化劑2.0kg、安定劑4.0kg、香料0.05kg,填充在200ml的殺菌軟袋,以加壓加熱殺菌機(第1種壓力容器、TYPE:RCS-4CRTGN、日阪製作所公司製)於121℃進行20分鐘殺菌,製造骨骼強化用液狀營養組成物50kg。於以此方式獲得之骨骼強化用液狀營養組成物中,未認為有沉澱等,也未感到風味有異常。
【實施例9】
(骨骼強化用凝膠狀食品之製備)
將實施例品5之蛋白質素材2g溶於708g之去離子水,以超分散器
(ULTRA-TURRAX T-25;IKA JAPAN公司製),以9500rpm進行30分鐘攪拌混合。於此溶液添加山梨醇40g、酸味料2g、香料2g、果膠5g、乳清蛋白質濃縮物5g、乳酸鈣1g、去離子水235g,並攪拌混合後,填充於200ml之附瓶蓋鋁箔便利包(cheer pack),於85℃進行20分鐘殺菌後蓋緊,製備為骨骼強化用凝膠狀食品5袋(內容量200g)。於以此方式獲得之骨骼強化用凝膠狀食品中,未認為有沉澱等,風味未感到有異常。
【實施例10】
(骨骼強化用飲料之製備)
將酸味料2g溶解於706g之去離子水後,溶解實施例品6之蛋白質素材4g,以超分散器(ULTRA-TURRAX T-25;IKA JAPAN公司製),於9500rpm進行30分鐘攪拌混合。添加麥芽糖醇100g、還原水飴20g、香料2g、去離子水166g後,填充於100ml之玻璃瓶,於95℃殺菌15秒後蓋緊,製備為10瓶骨骼強化用飲料(內容量100ml)。以此方式獲得之骨骼強化用飲料,未認為有沉澱等,風味未感覺有異常。
【實施例11】
(骨骼強化用飼料之製備)
將實施例品7之蛋白質素材2kg溶於98kg之去離子水,以TK均質混合機(MARKII 160型;特殊機化工業公司製),以3600rpm進行40分鐘攪拌混合,獲得含有實施例品7之蛋白質素材2g/100g的溶液。於此溶液10kg摻合黃豆粕12kg、脫脂奶粉14kg、大豆油4kg、玉米油2kg、棕櫚油23.2kg、玉米澱粉14kg、麵粉9kg、麩2kg、維生素混合物5kg、纖維素2.8kg、礦物質混合物2kg,於120℃殺菌4分鐘,製造骨骼強化用犬飼養飼料100kg。
【實施例12】
(骨骼強化劑(錠劑)之製備)
以表4所示之配比混合原料後,依常法成型、打錠為1g,製造骨骼強化劑。
Claims (9)
- 一種蛋白質素材,其含有血管生成素及/或血管生成素分解物2~15mg/100mg,且相對於血管生成素及/或血管生成素分解物以質量比0.3~20之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
- 一種飲食品,含有如申請專利範圍第1項之蛋白質素材。
- 一種飼料,含有如申請專利範圍第1項之蛋白質素材。
- 一種骨骼強化劑,含有如申請專利範圍第1項之蛋白質素材作為有效成分。
- 一種如申請專利範圍第1項之蛋白質素材之製造方法,包含以下1)~3)之步驟;1)製備血管生成素及/或血管生成素分解物;2)製備乳過氧化酶及/或乳過氧化酶分解物;3)將上述2)之步驟製備之乳過氧化酶及/或乳過氧化酶分解物,對於上述1)之步驟製備之血管生成素及/或血管生成素分解物以成為質量比0.3~20之方式摻合。
- 一種如申請專利範圍第1項之蛋白質素材之製造方法,包含以下步驟:從乳及/或乳原料,萃取含有血管生成素及/或血管生成素分解物與乳過氧化酶及/或乳過氧化酶分解物之組分,以使得乳過氧化酶及/或乳過氧化酶分解物相對於血管生成素及/或血管生成素分解物之質量比成為0.3~20。
- 如申請專利範圍第6項之蛋白質素材之製造方法,更包含以下步驟:將含有血管生成素與乳過氧化酶之組分中之血管生成素及/或乳過氧化酶進行酵素分解。
- 一種蛋白質素材的用途,係用於製造骨強化之藥劑,該蛋白質素材含有血管生成素及/或血管生成素分解物2~15mg/100mg,且相對於血管生成素及/或血管生成素分解物以質量比0.3~20之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
- 如申請專利範圍第8項之蛋白質素材的用途,其中,該蛋白質素材係攝取5mg/日以上。
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MY167578A (en) | 2012-07-31 | 2018-09-20 | Megmilk Snow Brand Co Ltd | Novel cheese and method for producing the same |
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CA2879992C (en) | 2012-07-31 | 2020-08-25 | Megmilk Snow Brand Co., Ltd. | Novel fermented milk product and method for producing the same |
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AU2012386759B2 (en) | 2016-05-19 |
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CA2879948C (en) | 2017-03-14 |
BR112015002045A2 (pt) | 2017-08-01 |
CN104507334A (zh) | 2015-04-08 |
KR20200011584A (ko) | 2020-02-03 |
JP6203724B2 (ja) | 2017-09-27 |
CN104507334B (zh) | 2016-11-16 |
MX2015001339A (es) | 2015-09-04 |
HK1207259A1 (zh) | 2016-01-29 |
WO2014020676A1 (ja) | 2014-02-06 |
US20170348399A1 (en) | 2017-12-07 |
JPWO2014020676A1 (ja) | 2016-07-11 |
KR102277775B1 (ko) | 2021-07-15 |
NZ704911A (en) | 2016-01-29 |
PH12015500049A1 (en) | 2015-03-02 |
TW201410254A (zh) | 2014-03-16 |
CA2879948A1 (en) | 2014-02-06 |
AU2012386759A1 (en) | 2015-03-05 |
SG11201500457RA (en) | 2015-03-30 |
US20150297690A1 (en) | 2015-10-22 |
KR20190060895A (ko) | 2019-06-03 |
KR20180085063A (ko) | 2018-07-25 |
EP2880995A1 (en) | 2015-06-10 |
US9861687B2 (en) | 2018-01-09 |
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