TW201410160A - 飲料及其製造方法 - Google Patents
飲料及其製造方法 Download PDFInfo
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- TW201410160A TW201410160A TW102126693A TW102126693A TW201410160A TW 201410160 A TW201410160 A TW 201410160A TW 102126693 A TW102126693 A TW 102126693A TW 102126693 A TW102126693 A TW 102126693A TW 201410160 A TW201410160 A TW 201410160A
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- Prior art keywords
- angiopoietin
- lactoperoxidase
- beverage
- decomposition product
- bone
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Classifications
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- A23C9/14—Milk preparations; Milk powder or milk powder preparations in which the chemical composition of the milk is modified by non-chemical treatment
- A23C9/146—Milk preparations; Milk powder or milk powder preparations in which the chemical composition of the milk is modified by non-chemical treatment by ion-exchange
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/15—Reconstituted or recombined milk products containing neither non-milk fat nor non-milk proteins
- A23C9/1512—Reconstituted or recombined milk products containing neither non-milk fat nor non-milk proteins containing isolated milk or whey proteins, caseinates or cheese; Enrichment of milk products with milk proteins in isolated or concentrated form, e.g. ultrafiltration retentate
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23C9/00—Milk preparations; Milk powder or milk powder preparations
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
本發明之課題為安全且藉由日常攝取，對於骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病之預防或治療為有用的新穎飲料。係一種飲料，其血管生成素及/或血管生成素分解物之含量超過0.8mg/100ml且為150mg/100ml以下，且乳過氧化酶及/或乳過氧化酶分解物之含量，相對於血管生成素及/或血管生成素分解物之質量比為0.3~23之範圍。藉由攝取如此的飲料，能夠強化骨骼，特別是對於骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病之預防及治療有效。
Description
本發明係關於新穎的飲料及其製造方法。本發明之飲料藉由含有特定的乳成分，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(remod eling))，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飲食品。
【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對於預防或治療骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病為有用的飲料。
本案發明人等發現：藉由攝取含有血管生成素及/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飲料，能獲得有效提高骨密度的作用，乃完
成本發明。
亦即，本發明係由以下構成者。
(1)一種飲料，其血管生成素及/或血管生成素分解物之含量為超過0.8mg/100ml且為150mg/100ml以下，且以相對於血管生成素及/或血管生成素分解物，質量比為0.3~23之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
(2)一種骨疾病之預防方法，係攝取如(1)之飲料200ml/日以上。
(3)一種如(1)之飲料之製造方法，包含以下步驟：將血管生成素及/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添加到飲料原料並且殺菌。
(4)一種如(1)之飲料之製造方法，包含以下步驟：於已殺菌之飲料原料中添加血管生成素及/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。
本發明之飲料，具有強化骨骼的作用，且對於預防、治療骨質疏鬆症、骨折、風濕病、關節炎等各種骨疾病為有用。
本發明之飲料之特徵為，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，且以特定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。
一般而言，在牛乳中，血管生成素及/或血管生成素分解物含量為約0.2~0.8mg/100ml，乳過氧化酶及/或乳過氧化酶分解物含量為約1.5~6.0mg/100ml。
相對於此，本發明之飲料，係添加血管生成素及/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，而使血管生成素及/或血管生成素分
解物含量為超過0.8mg/100ml且為150mg/100ml以下，且相對於血管生成素及/或血管生成素分解物，以質量比為0.3~23之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
作為本發明之飲料含有之血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物，可使用從人類、家牛、水牛、山羊、綿羊等哺乳類乳汁製備的含有血管生成素及/或血管生成素分解物之組分、含有乳過氧化酶及/或乳過氧化酶分解物之組分、或以基因工程的方法生產的該等組分、從血液或臟器精製的血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物等。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。
又，也可含有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而得之血管生成素分解物或乳過氧化酶分解物。
另一方面，也可含有從乳、或脫脂乳或乳清等乳源原料，直接、萃取以含有血管生成素及/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而製備的蛋白質素材。如此之蛋白質素材，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，也可使飲料中含有已乾燥品。
本發明，係於飲料原料中添加上述血管生成素及/或血管生成素分解物、過氧化酶及/或過氧化酶分解物、含有此等之蛋白質素材，並且使血管生成素及/或血管生成素分解物含量為超過0.8mg/100ml且為150mg/100ml以
下，且相對於血管生成素及/或血管生成素分解物以質量比為0.3~23之範圍含有過氧化酶及/或過氧化酶分解物。
於後述試驗例所示，藉由如上述方式含有血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物，比起分別單獨地攝取，能獲得更為有效的骨骼強化作用。
本發明之飲料，除了以特定量含有血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物以外，無特別的限制，可依一般的方法製造。例如：於乳原料等飲料原料中摻合血管生成素及/或血管生成素分解物，使其成為特定量之範圍，並且添加乳過氧化酶及/或乳過氧化酶分解物，使相對於血管生成素及/或血管生成素分解物成為特定之範圍之質量比而製備。又，乳原料等飲料原料，包括牛乳、脫脂濃縮乳、脫脂奶粉、乳清、黃油(butter)、乳油(cream)、發酵乳、乳製品乳酸菌飲料、乳酸菌飲料等，此外，包括視需要混合此等而得之乳飲料、加工乳、成分調整牛乳、低脂肪牛乳、無脂肪牛乳等。
添加到乳原料等飲料原料的情形，血管生成素及/或血管生成素分解物或乳過氧化酶及/或乳過氧化酶分解物，可以添加到未殺菌的飲料原料，也可添加到已殺菌的飲料原料。當添加到未殺菌之飲料原料的情形，係實施添加後殺菌。殺菌宜以加熱殺菌進行較佳。例如：可將飲料原料本身、或將已添加血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物的飲料原料加溫到70℃，以均質機於15MPa之壓力進行均質，並於130℃進行2秒殺菌後冷卻至5℃以製備。當係將血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物添加到飲料原料後進行加熱殺菌的情形，宜於130℃殺菌2秒以下較佳。
又，本發明之飲料中，除了血管生成素及/或血管生成素分解物、乳過氧化酶及/或乳過氧化酶分解物以外，也可以摻合上述飲料原料以外之糖類、脂質、蛋白質、維生素類、礦物質類、香料等於飲食品通常使用之原材料等，也可摻合其他顯示骨強化作用之成分，例如鈣、維生素D、維生素K、異黃酮等。
本發明之飲料，藉由於後述實驗動物的試驗中，體重每1kg經口攝取200ml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飲料200ml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。
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。
將已填充係陽離子交換樹脂之碸化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。
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500L(pH6.7)。其次將此管柱以0.5M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5%之血管生成素組分18g。重複此等一連串的處理50次。
將已填充係陽離子交換樹脂之碸化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，對此管柱以流速25mL/min通入未殺菌脫脂乳360L(pH6.7)。通液後，將此管柱以去離子水充分洗滌後，以含有2.0M氯化鈉之0.02M碳酸緩衝液(pH7.0)進行溶出。然後，將含有乳過氧化酶之溶出組分以S-SepharoseFF管柱(Amersham Bioscience公司製)吸附，以去離子水充分洗滌，並以10mM的磷酸緩衝液(pH7.0)平衡化後，以0~2.0M的氯化鈉的直線梯度將已吸附的組分溶出，回收含有乳過氧化酶之組分。並且將此組分以使用HiLoad 16/60 Superdex75pg(Amersham Bioscience公司製)之凝膠過濾層析處理。將此溶出液以逆滲透膜脫鹽後，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。將此等一連串的處理重複進行25次。
飲料含有之血管生成素、血管生成素分解物及乳過氧化酶、乳過氧化酶分解物之測定，依改變日本特開2008-164511號公報的方法並實施。亦即，於超純水5ml中加入飲料106μl，並於其中添加1/1,000量之甲酸，作為試樣溶液。將此溶液10μl乾燥後，溶於含有8M尿素及1mM參(羧乙基)膦(TCEP)的0.1M重碳酸銨20μl，於56℃加溫30分鐘。回溫到室溫後，添加100mM碘乙醯胺溶液5μl，於遮光下反應30分鐘。於其中添加54μl超純水後，添加0.1μg/ml胰蛋白酶10μl及0.1μg/ml離胺醯肽鏈內切酶(lysyl endopeptidase)10μl，於37℃反應16小時。之後添加3μl甲酸，停止反應，作為測定試樣用胜肽溶液。將各試樣溶液以10fmol/μl之內部標準胜肽溶液(含0.1%甲酸、0.02%三氟乙酸(TFA)、2%乙腈)稀釋為6倍，將稀釋的溶液2.5μl以LC/MS/MS進行分析。
胜肽的分離，係使用HPLC系統進行梯度溶出。亦即，使用管柱附有5μl胜肽捕集器的MAGIC C18 0.2mmID×50mm，流速為2μl/min之MAGIC2002之HPLC系統。HPLC之溶劑，使用：A溶液：2%乙腈-0.05%甲酸與B溶液：90%乙腈-0.05%甲酸。溶出條件，為費時20分鐘使B溶液從2%至65%進行梯
度溶出。
乳過氧化酶之測定對象離子，係以母離子為NH2-IHGFDLAAINLQR-COOH且m/z 734.4，MS/MS標靶離子為NH2-IHGFDLA-COOH且m/z 754.4，血管生成素之測定對象離子，係母離子為NH2-YIHFLTQHYDAK-COOH且m/z 768.8，MS/MS標靶離子為NH2-FLTQHYDAK-COOH且m/z 1122.8進行測定。內部標準胜肽，係以母離子為NH2-ETTVFENLPEK-COOH(惟P之碳經C13、氮經N15標定)且m/z 656.9，MS/MS之標靶離子為NH2-FENLPEK-COOH(惟P之碳以C13、氮以N15標定)且m/z 882.4進行。
MS使用LCQ Advantage。從獲得的層析圖求取各蛋白質的峰部面積，並從與內部標準胜肽的比求出濃度。
於牛乳200ml中混合參考例1之血管生成素組分330mg與參考例3之乳過氧化酶組分90mg，於130℃進行2秒加熱殺菌後，冷卻至10℃，獲得飲料(實施例品1)。獲得之飲料中含有血管生成素及/或血管生成素分解物150mg/100ml，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。
於牛乳200ml中混合參考例2之血管生成素組分24mg與參考例3之乳過氧化酶組分30mg，於130℃進行2秒加熱殺菌後，冷卻至10℃，獲得飲料(實施例品2)。獲得之飲料中含有血管生成素及/或血管生成素分解物0.81mg/100ml，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23。
於牛乳200ml中混合參考例1之血管生成素組分24mg與參考例3之乳過氧化酶組分30mg，於130℃進行2秒加熱殺菌後，冷卻至10℃，獲得飲料(實施例品3)。獲得之飲料中含有血管生成素及/或血管生成素分解物11mg/100ml，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1.7。
於牛乳200ml中混合參考例2之血管生成素組分20mg與參考例3之乳過氧化酶組分34mg，於130℃進行2秒加熱殺菌後，冷卻至10℃，獲得飲料(比較例品1)。獲得之飲料中含有血管生成素及/或血管生成素分解物0.7mg/100ml，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29。
於牛乳200ml中混合參考例1之血管生成素組分360mg與參考例3之乳過氧化酶組分60mg，於130℃進行2秒加熱殺菌後，冷卻至10℃，獲得飲料(比較例品2)。獲得之飲料中含有血管生成素及/或血管生成素分解物162mg/100ml，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0.19。
實施例品1~3及比較例品1、2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週的預備飼育後，將小鼠10隻為1群，分成6群，將實施例品1~3及比較例品1、2，以就小鼠體重每1kg每日各為200ml，每日2次以胃管經口投予，飼養2週。又，將未投予實施例品1~3及比較例品1、2者作為對照群。投予結束後(第2週)，以MICRO CT(RIGAKU(股)製)測定小鼠之右脛骨之骨密度。其結果如表1。如表1所示，經口投予了2週實施例品1~3的群，比起對照群或投予了比較例品1、2的群，骨密度顯著上升。
【表1】
將已填充陽離子交換樹脂之碸化CHITO PEARL(富士紡公司製)400g的管柱(直徑4cm×高度30cm)以去離子水充分洗滌後，對此管柱以流速25ml/min通入未殺菌脫脂乳40L(pH6.7)。通液後，將此管柱以去離子水充分洗滌後，以含0.78M氯化鈉之0.02M碳酸緩衝液(pH7.0)將吸附於樹脂的蛋白質溶出。然後，將此溶出液以逆滲透膜予以脫鹽後，冷凍乾燥，獲得粉末狀之蛋白質素材18g(參考例品4)。
將參考例品4之蛋白質素材4g溶於水800ml，加入係蛋白質分解酵素之胰蛋白酶(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，獲得粉末狀之蛋白質素材3.0g(參考例品5)。
於經殺菌之牛乳200ml中混合40mg的參考例品4，獲得飲料(實施例品4)。獲得的飲料中含有血管生成素及/或血管生成素分解物1.2mg/100ml，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的質量比為7.5。
於經殺菌之牛乳200ml中混合40mg的參考例品5，獲得飲料(實施例品
5)。獲得之飲料中含有血管生成素及/或血管生成素分解物1.15mg/100ml，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7.4。
於經殺菌之牛乳200ml中混合15mg之參考例品4與參考例3之乳過氧化酶組分25mg，獲得飲料(比較例品3)。獲得之飲料中含有血管生成素及/或血管生成素分解物0.7mg/100ml，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25.4。
針對實施例品4、5及比較例品3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40隻。將大鼠8隻為1群，分成5群，其中4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4、5及比較例品3，就大鼠體重每1kg每日各為200ml，每日6次以胃管經口投予，飼養16週。將未投予實施例品4、5及比較例品3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2。如表2所示，經口投予了16週實施例品4、5的群，比起對照群或投予比較例品3之群，骨密度顯著上升，且其值接近虛擬手術群的水平。
Claims (4)
- 一種飲料，其血管生成素及/或血管生成素分解物之含量為超過0.8mg/100ml且為150mg/100ml以下，且以相對於血管生成素及/或血管生成素分解物之質量比為0.3~23之範圍含有乳過氧化酶及/或乳過氧化酶分解物。
- 一種骨疾病之預防方法，係攝取如申請專利範圍第1項之飲料200ml/日以上。
- 一種如申請專利範圍第1項之飲料之製造方法，包含以下步驟：將血管生成素及/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添加到飲料原料並且殺菌。
- 一種如申請專利範圍第1項之飲料之製造方法，包含以下步驟：於已殺菌之飲料原料中添加血管生成素及/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。
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