TW201713225A - 調控激酶之方法 - Google Patents
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- TW201713225A TW201713225A TW105120604A TW105120604A TW201713225A TW 201713225 A TW201713225 A TW 201713225A TW 105120604 A TW105120604 A TW 105120604A TW 105120604 A TW105120604 A TW 105120604A TW 201713225 A TW201713225 A TW 201713225A
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Abstract
一種調控激酶的方法,其係藉由投予個體包含經高度水解之酪蛋白、經高度水解之酪蛋白分級物或彼等之組合的營養組成物。經調控之激酶可為調節發炎信號傳導、免疫耐受、代謝信號傳導、細胞週期及生長因子信號傳導之激酶。該營養組成物可劑量依賴地抑制某些絲胺酸激酶、蘇胺酸激酶及酪胺酸激酶。
Description
本發明關於藉由投予個體經高度水解之酪蛋白及/或其分級物(“eHC”)調控特異性激酶活性之方法。eHC可抑制抑制某些絲胺酸激酶、蘇胺酸激酶及酪胺酸激酶。該個體可為人,特別是人類嬰兒或兒童。
激酶為一種類型之催化磷酸化、磷酸基團轉移的酶。激酶調節許多複雜的過程且可調節並發揮重要的信號傳導作用(例如發炎信號傳導、免疫耐受性、代謝信號傳導、細胞週期及生長因子信號傳導)。因此,抑制激酶可減少或預防發炎、增加免疫耐受性且有利於代謝信號傳導、細胞週期和生長因子信號傳導。
因此,提供調控激酶之方法以減少或預防發炎、增加免疫耐受性將是有利的,且對代謝信號傳導、細胞週期和生長因子信號傳導是有利的。該方法可包括投予個體(特別是嬰兒或兒童)營養組成物。此外,該方法在動物,特別是人類嬰兒中應為功能上充分耐受且不應產生或
引起過量氣體、腹脹(abdominal distension)、胃氣脹(bloating)或腹瀉。
簡單地說,於一實施態樣中,本發明針對藉由投予個體包含經高度水解之酪蛋白、經高度水解之酪蛋白分級物或彼等之組合的營養組成物調控一種或多種激酶的方法。
於一實施態樣中,該調控為發炎信號傳導激酶之調控。該發炎信號傳導激酶可為IKKβ、IRAK4、ITK、JAK1、JAK3、JNK1(MAPK8)、JNK2、JNK3(MAPK10)、LCK、MAPKAPK2、p38α、SYK、COT(MAP3k8)、FYN同種型A、FYN同種型B、KIT、MAP3k2、SPHK1、SPHK2、FMS、BTK、Erk1(MAPK3)、Erk2(MAPk1)、Erk5(MAPk7)或彼等之一或多種組合。
於另一實施態樣中,該調控為代謝信號傳導激酶之調控。該代謝信號傳導激酶可為AKT1、AMPKα1/β1/γ1、p70S6K、PDK1、Erk2、SGK或彼等之一或多種組合。
再於另一實施態樣中,該調控為細胞週期激酶之調控。該細胞週期激酶可為AurA、CDK2/CycA2複合物、CHK1或彼等之一或多種組合。
於其他實施態樣中,該經調控之激酶為生長因子信號傳導激酶。該經調控之激酶可為IGF1R、MET、
PDGFRα、EGFR、EPHA2、EPHB4、FGFR1、FLT3、GSK3β、HGK、KDR、ABL、SRC、TIE2、TRKA、TYRO3之一或彼等之一或多種組合。
該方法亦可用於調控另外之激酶,諸如CAMK4、CK1ε、CSK、DAPK1、DYRK1B、MST1、NEK2、PAK2、PBK、PIm1、PKACα、PKCα、PKD2、PYK2、ROCK1、TSSK1或彼等之一或多種組合。
本發明之方法中的營養組成物可為嬰兒配方,且於一些實施態樣中,其可進一步包含脂肪、碳水化合物、益生菌、益生元或彼等之組合。益生元可包括聚葡萄糖及/或半乳寡糖。
現在參考本發明之實施態樣的詳細說明,下文中列舉其一或多個實例。所提供之各實例僅用於解釋本發明之營養組成物,而非限制。事實上,本技藝之技術熟習人士將清楚明白本發明之教示內容可在不偏離本發明之範圍下做各種修改及變化。例如,所說明或描述為一種實施態樣之一部分的特性可與另一實施態樣一起使用以產生更進一步之實施態樣。
因此,本發明意圖涵蓋該等在所附之申請專利範圍及其等效項之範圍內的修改和變化。本發明之其他目的、特性及態樣揭示於以下之詳細描述中或可從其中顯明。本技藝之一般技術人士將理解目前的討論僅用於描述
示例性實施態樣,而不欲限制本發明之更廣泛的態樣。
本發明大致上關於關於涉及適合投予兒科個體之營養組成物的方法。
“營養組成物”意指滿足至少一部分之個體營養需求的物質或調合物。在本發明之全文中,術語“營養”、“營養配方”、“腸內營養”及“營養補充劑”可作為營養組成物之非限制性實例。此外,“營養組成物”可指液體、粉劑、凝膠、糊劑、固體、濃縮物、懸浮液或即時使用形式之腸內配方、口服配方、嬰兒配方、兒科個體配方、兒童配方、成長乳及/或成人配方。
術語“腸內”意指可通過胃腸道或消化道或在胃腸道或消化道內投遞。“腸內投予”包括經口餵食、胃內餵食、經幽門投服或任何其他進入消化道之投予。“投予”較“腸內投予”廣義且包括腸胃道外投予或物質被攝入個體內所採取之任何其他投予途徑。
“兒科個體”意指不大於13歲的人。於一些實施態樣中,兒科個體係指在出生至8歲之間的人個體。於其他實施態樣中,兒科個體係指在1至6歲之間的人個體。再於進一步之實施態樣中,兒科個體係指在6至12歲之間的人個體。術語“兒科個體”可指如下述之嬰兒(早產或足月)及/或兒童。
“嬰兒”意指年齡在出生到不超過一歲之範圍內的人個體且包括0至12個月矯正年齡之嬰兒。“矯正年齡”一詞意指嬰兒之實足年齡減去嬰兒早產的時間量。因
此,嬰兒若足月出生則矯正年齡為嬰兒的年齡。術語嬰兒包括低出生體重嬰兒、非常低出生體重嬰兒、極低出生體重嬰兒及早產兒。“早產兒”意指在妊娠第37週結束前出生的嬰兒。“晚期早產兒”意指在妊娠第34週到第36週出生的嬰兒。“足月兒”意指在妊娠第37週結束後出生之嬰兒。“低出生體重嬰兒”意指出生體重小於2500克(約5磅8盎司)之嬰兒。“非常低出生體重嬰兒”意指出生體重小於1500克(約3磅4盎司)的嬰兒。“極低出生體重嬰兒”意指出生體重小於1000克(約2磅3盎司)之嬰兒。
“兒童”意指年齡在12個月至約13歲之範圍內的個體。於一些實施態樣中,兒童為年齡在1歲至12歲之間的個體。於其他實施態樣中,術語“兒童們”或“兒童”係指在1至約6歲之間或在約7至約12歲之間的個體。於其他實施態樣中,術語“兒童們”或“兒童”係指在12個月至約13歲之間的任何年齡範圍。
“兒童營養產品”係指滿足至少一部分之兒童營養需求的組成物。成長乳為兒童營養產品之一種實例。
術語“水解度”係指藉由水解方法打破肽鍵之程度。用於表徵營養組成物之水解蛋白質組分的蛋白質水解度可由配製技藝中之一般技術人士定量所選擇之調合物的蛋白質組分之胺基氮對總氮比(AN/TN)輕易地測定。該胺基氮組分係藉由用於測定胺基氮含量的USP滴定法定量,而總氮組分係藉由凱氏(Kjeldahl)定氮法測定,這些方法均為分析化學技藝中之一般技術人士所熟知的方法。
當藉由酶促水解將蛋白質中之肽鍵打破時,每一破裂之肽鍵釋出一個胺基團,造成胺基氮增加。應注意的是,即使是非水解蛋白質亦將含有一些裸露之胺基。水解蛋白亦將具有與形成彼等之非水解蛋白不同的分子量分佈。水解蛋白的功能和營養性能可能受不同尺寸之肽類影響。分子量分佈之給予通常係藉由列出特定範圍之分子量(以道耳吞計)分級物(例如2,000至5,000道耳吞,大於5,000道耳吞)的重量百分比。
當術語“莫耳質量分佈”之使用係與水解蛋白或蛋白質水解產物有關時,其係關於存在於蛋白質水解產物中之每種肽的莫耳質量有。例如,其莫耳質量分佈超過500道耳吞之蛋白質水解產物意指包含在該蛋白質水解產物中的每個肽具有至少500道耳吞之莫耳質量。為了產生其莫耳質量分佈超過500道耳吞的蛋白質水解產物,可將蛋白質水解產物進行某些過濾程序或本技藝中已知之任何用於除去莫耳質量小於500道耳吞之肽、胺基酸及/或其他蛋白性物質的其他程序。為了本發明之目的,可使用本技藝已知之任何方法來製造其莫耳質量分佈超過500道耳吞之蛋白質水解產物。
術語“蛋白質等效物”或“蛋白質等效來源”包括任何蛋白質來源,諸如大豆、蛋、乳清或酪蛋白,以及非蛋白質來源,諸如肽或胺基酸。此外,蛋白質等效來源可為本技藝中所使用之任何蛋白質等效來源,例如脫脂乳、乳清蛋白、酪蛋白、大豆蛋白、水解蛋白、胺基酸,等。
可用於實施本發明之牛乳蛋白來源包括,但不限於乳蛋白粉、乳蛋白濃縮物、乳蛋白分離物、脫脂乳固體、脫脂乳、脫脂奶粉、乳清蛋白、乳清蛋白分離物、乳清蛋白濃縮物、甜乳清、酸乳清、酪蛋白、酸性酪蛋白、酪蛋白酸鹽(例如酪蛋白酸鈉、酪蛋白酸鈉鈣、酪蛋白酸鈣)、大豆蛋白及彼等之任何組合。於一些實施態樣中,該蛋白質等效來源可包含水解蛋白,包括經部分水解之蛋白質和經高度水解之蛋白質。於一些實施態樣中,該蛋白質等效來源可包括完整蛋白質。
術語“蛋白質等效來源”亦包含游離胺基酸。於一些實施態樣中,該胺基酸可包含,但不限於組胺酸、異白胺酸、白胺酸、離胺酸、甲硫胺酸、半胱胺酸、苯丙胺酸、酪胺酸、蘇胺酸、色胺酸、纈胺酸、丙胺酸、精胺酸、天門冬醯胺、天門冬胺酸、麩胺酸、麩胺醯胺、甘胺酸、脯胺酸、絲胺酸、肉鹼、牛磺酸及彼等之混合物。於一些實施態樣中,該胺基酸可為支鏈胺基酸。於某些其他實施態樣中,小胺基酸肽可被包含在營養組成物中作為蛋白質組分。該等小胺基酸肽該夏可為天然發生或合成的胺基酸肽。
術語“部分水解”意指其水解度大於0%但小於約50%。
術語“經高度水解”意指其水解度大於或等於約50%。因此,“經高度水解之酪蛋白分級物”意指其水解度大於或等於約50%之酪蛋白。於一些實施態樣中,經高
度水解可包括大於約80%之水解度。於進一步之實施態樣中,經高度水解可包括大於約90%之水解度。“eHC”係指經高度水解之酪蛋白及/或其分級物。
術語“不含蛋白質”意指當藉由標準蛋白質檢測法(諸如十二烷基(月桂基)硫酸鈉-丙烯醯胺凝膠電泳法(SDS-PAGE)或尺寸排阻色層分析法)測量時不含有可測得之蛋白質量。於一些實施態樣中,該營養組成物實質上不含蛋白質,其中“實質上不含”之定義如下。
“嬰兒配方”意指滿足嬰兒之至少一部分營養需求的組成物。在美國,嬰兒配方之內容係由21 C.F.R.章節100、106及107中所載之聯邦法規規定。這些法規界定大量營養素、維生素、礦物質及其他成分之含量以努力模擬人類母乳之營養及其他性能。
術語“成長乳”係指欲作為多樣化膳食之一部分以支持年齡在約1至約6歲之間的兒童正常生長和發育的廣大類別之營養組成物。
“以乳為底質的”意指包含至少一種已從哺乳動物之乳腺提出或萃取出之組分。於一些實施態樣中,以乳為底質之營養組成物包含源自家養有蹄類動物、反芻動物或其他哺乳動物或彼等之任何組合的乳汁組分。再者,於一些實施態樣中,以乳為底質意指包含牛酪蛋白、乳清、乳糖或彼等之任何組合。此外,“以乳為底質之營養組成物”可指包含本技藝已知之任何源自乳品或以乳為底質之產品的任何組成物。
“乳汁”意指已從哺乳動物之乳腺抽取或萃取的組分。於一些實施態樣中,該營養組成物包含源自家養有蹄類動物、反芻動物或其他哺乳動物或彼等之任何組合的乳汁組分。
“分餾程序”包括其中將一定量之混合物分成許多稱為分級物的較小量的任何過程。該分級物在組成上可不同於混合物及其他分級物。分餾程序之實例包括,但不限於熔體分餾、溶劑分餾、超臨界流體分餾及/或彼等之組合。
“脂肪球”係指被磷脂及其他膜及/或血清蛋白包圍之脂肪小團塊,其中該脂肪本身可為任何植物或動物脂肪之組合。
“營養完整的”意指可作為唯一之營養來源的組成物,該組成物可實質上提供所有每日需要量之維生素、礦物質及/或微量元素,加上蛋白質、碳水化合物及脂質。確切地,“營養完整的”描述能提供支持個體正常生長和發育所需之足量的碳水化合物、脂質、必須脂肪酸、蛋白質、必須胺基酸、半必須胺基酸、維生素、礦物質及能源的營養組成物。
因此,根據定義,對早產兒而言為“營養完整”之營養組成物將定性且定量地提供早產兒生長所需之足量的碳水化合物、脂質、必須脂肪酸、蛋白質、必須胺基酸、半必須胺基酸、維生素、礦物質及能量。
根據定義,對足月兒而言為“營養完整”之營
養組成物將定性且定量地提供足月兒生長所需之足量的全部碳水化合物、脂質、必須脂肪酸、蛋白質、必須胺基酸、半必須胺基酸、維生素、礦物質及能量。
根據定義,對兒童而言為“營養完整”之營養組成物將定性且定量地提供兒童生長所需之足量的全部碳水化合物、脂質、必須脂肪酸、蛋白質、必須胺基酸、半必須胺基酸、維生素、礦物質及能量。
當應用於營養素時,術語“必須”係指身體無法合成足夠量以供正常生長及維持健康,因此必須由飲食供應的任何營養素。術語“半必須”當應用於營養素時意指當身體無法取得足量之先質化合物以發生內源性合成時,必須由膳食提供之營養素。
“益生菌”意指能對宿主健康發揮有益影響之具有低或無致病性的微生物。
術語“經滅活之益生菌”意指其中所指稱之益生菌的代謝活性或繁殖能力已被降低或破壞的益生菌。然而,該“經滅活之益生菌”確實仍然保留(在細胞層級)其細胞結構或與細胞相關之其他結構,例如外多醣及至少一部分其生物乙二醇-蛋白質和DNA/RNA結構。如本文所使用之術語“經滅活”與“非存活的”同義。
“益生元”意指經由選擇性地刺激消化道中可改善宿主健康之一種或有限數量之細菌生長及/或活性而有益地影響宿主的不易消化之食物成分。
“支鏈脂肪酸”(“BCFA”)意指含有從碳鏈分支之
碳組成部分的脂肪酸。通常,該支鏈為烷基支鏈,尤其是甲基團,但亦知有乙基和丙基支鏈。與相等之直鏈脂肪酸相比較,加入甲基支鏈可降低熔點。這包括在碳鏈中具有偶數個碳原子的支鏈型脂肪酸。這些支鏈型脂肪酸之實例可為十四烷酸、十六烷酸之異構體。
“奇數和支鏈脂肪酸”(“OBCFA”)為BCFA之子集,其具有奇數個碳原子且碳鏈中具有一或多個烷基支鏈。在牛乳中發現之主要的奇數與支鏈脂肪酸包括,但不限於十四烷酸、十五烷酸、十六烷酸及十七烷酸之異構體。在本發明之目的方面,術語“BCFA”包括支鏈脂肪酸及奇數與支鏈脂肪酸。
“反式脂肪酸”意指具有反式異構體之不飽和脂肪。反式脂肪可為單不飽和或多不飽和的。反式係指二個鍵結在參與雙鍵之碳原子的氫原子之排列方式。在反式排列中,該氫原子係位在鍵的相對二側。因此,反式脂肪酸為含有一或多個呈反式幾何構型之雙鍵的脂質分子。
“磷脂”意指含有一個二酸甘油酯、一個磷酸基團及一個單純有機分子的有機分子。磷脂之實例包括,但不限於磷脂酸、磷脂醯乙醇胺、磷脂醯膽鹼、磷脂醯絲胺酸、磷脂醯肌醇、磷酸磷脂醯肌醇、二磷酸磷脂醯肌醇及三磷酸磷脂醯肌醇、神經醯胺磷醯膽鹼、神經醯胺磷醯乙醇胺及神經醯胺磷醯甘油。此定義進一步包括神經鞘脂質、糖脂質及神經節苷脂。
“植物營養素”意指植物中天然產生之化學化合
物。植物營養素可能被包含在任何源自植物之物質或萃取物中。術語“植物營養素”包含數種由植物製造之廣大類別的化合物,諸如,例如多酚化合物、花青素、原花青素及黃烷-3-醇(即,兒茶素、表兒茶素),且可源自,例如果實、種子或茶萃取物。此外,術語植物營養素包括所有類胡蘿蔔素、植物固醇、硫醇及其他源自植物之化合物。再者,如熟習本技藝之人士將理解者,除了蛋白質之外,植物萃取物可包括植物營養素,諸如多酚、纖維或其他源自植物之組分。因此,例如除了其他源自植物之物質外,蘋果或葡萄籽萃取物可包含有益之植物營養素組分,諸如多酚類。
“β-葡聚醣”意指所有β-葡聚醣,包括特定類型之β-葡聚醣,諸如β-1,3-葡聚醣或β-1,3;1,6-葡聚醣。再者,β-1,3;1,6-葡聚醣為β-1,3-葡聚醣之一種類型。因此,術語“β-1,3-葡聚醣”包括β-1,3;1,6-葡聚醣。
“果膠”意指任何含有可在植物細胞壁中找到之半乳糖醛酸的天然產生之寡醣或多醣。本技藝中已知具有各種不同物理及化學性質之不同品種和等級的果膠。確切地說,植株之間、組織之間,甚至在單一細胞壁內的果膠結構可有明顯不同。一般而言,果膠係由帶負電荷之酸性糖類(半乳糖醛酸)所組成,且該酸性基團中有些為甲酯基團之形式。果膠之酯化度為連接半乳吡喃糖基糖醛酸單位之經甲醇酯化之羧基團的百分比測量值。
酯化度小於50%(即,少於50%之羧基團被
甲基化以形成甲酯基團)之果膠被歸類為低酯、低甲氧基或低甲基化(“LM”)之果膠,而那些酯化度為50%或更高(即,超過50%之羧基團被甲基化)之果膠被歸類為高酯、高甲氧基或高甲基化(“HM”)之果膠。非常低(“VL”)果膠(為低甲基化之果膠的子集)之酯化度小於約15%。
如本文所使用之“來自非人來源之乳鐵蛋白”意指從人乳汁以外之來源產生或取得的乳鐵蛋白。例如,用於本發明之乳鐵蛋白包括由經遺傳修飾之生物體製造之人乳鐵蛋白及非人乳鐵蛋白。本文所使用之術語“生物體”意指任何連續性生命系統,例如動物、植物、真菌或微生物。
如本文所使用之“非人乳鐵蛋白”意指具有不同於人乳鐵蛋白之胺基酸序列的胺基酸序列之乳鐵蛋白。
“病原體”意指引起疾病狀態或病理學症候群之生物體。病原體之實例可包括細菌、病毒、寄生蟲、真菌、微生物或彼等之組合。
“調控(modulate或modulating)”意指施加修飾、控制及/或調節影響。於一些實施態樣中,術語“調控”意指對特定組分之水準/量顯現增加或刺激作用。於其他實施態樣中,“調控”意指對特定組分之水準/量顯現降低或抑制作用。
除非另外具體指明,本文所使用之所有百分比、份數及比例係按總調和物之重量計。
被具體指定為“每日”投予的所有量可在24小時之期間內在一個單位劑量中、在單一服用量中或在二或多個劑量或服用量中投予。
本發明之營養組成物可能實質上不含任何本文所描述之可選擇或選定之成分,惟其該其餘之營養組成物仍含有所有本文所描述之必要成分或特性。在此背景下,除非另外具體指明,術語“實質上不含”意指該選定之組成物所含有之可選擇的成分可能少於該成分之功能量,通常少於該等可選擇或選定之成分的0.1重量%,且亦包括0重量%。
除非另外具體指明或明確暗示與所引用之背景相反,本發明中對單數特性或限制之所有引用應包括對應之複數特性或限制,反之亦然。
除非另外具體指明或明確暗示與所引用之組合的背景相反,本文所使用之方法或加工步驟的所有組合可以任何順序執行。
本發明之方法和組成物(包括其組分)可包含此處所描述之實施態樣的必須要素和限制,以及本文所描述或可用於營養組成物中之任何額外或可選擇之成分、組分或限制,由彼等所組成或實質上由彼等所組成。
如本文所使用之術語“約”應解釋為係指被具體指定為任何範圍之終點的二個數字。對範圍之任何引用應被認為係提供對該範圍內之任何子集的支持。
欲藉由本發明解決的問題之一係與激酶活性
有關且係藉由提供調節或調控一或多種激酶之方法來解決,該方法係藉由投予個體經高度水解之酪蛋白、經高度水解之酪蛋白分級物或彼等之組合。該經高度水解之酪蛋白可在營養組成物(特別是嬰兒配方)中投予個體。
eHC以劑量依賴方式抑制某些絲胺酸激酶、蘇胺酸激酶及酪胺酸激酶。相反地,胺基酸製劑未顯示出類似活性,這支持該激酶抑制活性可能由源自eHC之肽類介導的爭論。
受影響之激酶與,例如免疫耐受和發炎相關。經高度水解之酪蛋白可添加在營養組成物(諸如嬰兒配方)中以減少個體之發炎。
酪胺酸激酶絲胺酸激酶及蘇胺酸激酶(單獨地或為一個群組)可有助於導致獲得耐受性的免疫調控。例如,阻斷SYK先前已證明可防止過敏原致敏或在已建立過敏之小鼠中誘導脫敏。本文所鑑定之激酶的描述可在UniProt(Universal Protein Resource,可從uniprot.org進入)中找到。
該經調控之激酶可為發炎信號傳導激酶,包括KKβ、IRAK4、ITK、JAK1、JAK3、JNK1(MAPK8)、JNK2、JNK3(MAPK10)、LCK、MAPKAPK2、p38α、SYK、COT(MAP3k8)、FYN同種型A、FYN同種型B、KIT、MAP3k2、SPHK1、SPHK2、FMS、BTK、Erk1(MAPK3)、Erk2(MAPk1)、Erk5(MAPk7)或彼等之組合。
IKKβ為一種作為IκB激酶之蛋白質次單位的酶,其為參與觸發免疫反應之經細胞因子活化的胞內信號傳導通路的組分。IKK之活性引起轉錄因子NFκB活化,該轉錄因子NFκB在進入細胞核時活化涉及免疫反應的各種基因。
IRAK-4(介白素-1受體相關之激酶4)為一種蛋白激酶,其參與信號傳導從Toll樣受體開始之先天免疫反應。其亦支持從T細胞受體開始之信號傳導。沒有IRAK-4的動物對病毒和細菌更敏感,但對LPS挑戰可完全抵抗。JAK3(Janus激酶3)為屬於Janus族激酶之酪胺酸激酶。Janus族的其他成員包括JAK1、JAK2及TYK2。其為與細胞因子受體特異相關之胞質酪胺酸激酶。由於細胞因子受體蛋白缺乏酶活性,因此其倚賴JAK在與配體(例如細胞因子)結合時起始信號傳導。
JNK1(MAPK8)(c-Jun N-端激酶1/有絲分裂原(mitogen)活化之蛋白激酶8)為參與各種過程(諸如細胞增殖、分化、移行、轉化及程序性細胞死亡)的絲胺酸/蘇胺酸-蛋白激酶。胞外刺激(諸如促炎細胞因子或物理壓力)刺激該由壓力活化之蛋白激酶/c-Jun N-端激酶(SAP/JNK)信號傳導通路。在此級聯反應中,二種雙特異性激酶MAP2K4/MKK4及MAP2K7/MKK7磷酸化並活化JNK1。
JNK2(c-Jun N-端激酶2)活性調節數種重要的細胞功能,包括細胞生長、分化、存活及凋亡。多種壓力刺激可以活化JNK。
JNK3(MAPK10)(c-Jun N-端激酶3/有絲分裂原活化之蛋白激酶10)為參與各種過程(諸如神經元增殖、分化、移行及計劃性細胞死亡)之絲胺酸/蘇胺酸-蛋白激酶。胞外刺激(諸如促炎細胞因子或物理壓力)刺激該由壓力活化之蛋白激酶/c-Jun N-端激酶(SAP/JNK)信號傳導通路。
LCK(或淋巴細胞特異性蛋白酪胺酸激酶)為在淋巴細胞中發現的56kDa蛋白。LCK為一種酪胺酸激酶,其將參與胞內信號傳導之蛋白質的酪胺酸殘基磷酸化。LCK為酪胺酸激酶之SRC家族的成員且參與T淋巴細胞中之介白素2(IL-2)信號傳導。
MAPKAPK2(經有絲分裂原活化之蛋白激酶活化的蛋白激酶2)參與細胞過程,包括壓力、發炎反應、核輸出、基因表現及細胞增殖。
p38α有絲分裂原活化之蛋白激酶為有絲分裂原活化之蛋白激酶的一種類別。p38a有絲分裂原活化之蛋白激酶在回應發炎信號時被活化。此類別之激酶對壓力刺激(諸如細胞因子、紫外線照射、熱休克及滲透性休克)有反應且參與細胞分化、凋亡和自噬。
SYK(脾酪胺酸激酶)與ZAP70為酪胺酸激酶之SYK家族的成員。雖然SYK和ZAP-70主要表現在造血細胞中,但SYK亦表現在多種其他組織中。SYK和ZAP-70分別表現在B細胞或T細胞中,且分別傳遞來自B細胞受體或T細胞受體之信號。
ITK(介白素-2誘導型T細胞激酶)參與調節適
應性免疫反應。ITK調控T細胞及非傳統NKT細胞發育、功能及分化。
JAK1(Janus激酶1)為屬於janus族激酶之酪胺酸激酶。Janus族之其他成員包括JAK2、JAK3及TYK2。其為與細胞因子受體特異相關之胞質酪胺酸激酶。由於細胞因子受體蛋白缺乏酶催化活性,因此當與其配體(例如細胞因子)結合時,其依賴JAK啟動信號傳導。
JAK3(Janus激酶3)調節細胞生長、發育及分化。JAK3參與血液細胞組分之發育(造血作用)。
COT(MAP3k8)(有絲分裂原活化之蛋白激酶激酶激酶8)對由脂多醣(LPS)誘導的,TLR4介導之巨噬細胞中MAPK/ERK通路的活化而言是必要的,因此對於在免疫反應期間產生促炎細胞因子TNF-α(TNF)而言至關重要。參與調節T輔助細胞分化及T細胞中之IFNG表現。透過藉由負調節第I型干擾素(IFN)產生來參與介導宿主對細菌感染之抗性。在玻管內,以獨立於IRAK1之方式回應IL1來活化MAPK/ERK通路,導致IL8和CCL4上調。
FYN同種型A為表現在各種細胞類型中之酪胺酸激酶致癌基因族,其生物學功能有多樣且包括經由T細胞受體傳導信號、調節腦功能及由黏附介導之信號傳導。Fyn在適當之靶的組織中的量改變可導致對自體免疫疾病之較佳治療。
FYN同種型B為另一表現在各種細胞類型中之酪胺酸激酶致癌基因族,其生物學功能有多樣且包括經
由T細胞受體傳導信號、調節腦功能及由黏附介導之信號傳導。Fyn在適當之靶的組織中的量改變可導致對自體免疫疾病之較佳治療。
KIT(酪胺酸激酶受體KIT)為MGF(肥大細胞生長因子,亦稱為幹細胞因子)之第3型跨膜受體。此基因中之突變與胃腸道間質瘤及肥大細胞病有關。
MAP3K2(有絲分裂原活化之蛋白激酶激酶激酶2)為絲胺酸/蘇胺酸蛋白激酶族之成員,此激酶優先活化參與MAP激酶信號傳導通路的其他激酶。此激酶顯示出直接磷酸化及活化IκB激酶,從而參與NF-κB信號傳導通路。此激酶亦被發現結合並活化蛋白激酶C相關之激酶2,這表明其參與經調節之信號傳導過程。
SPHK1(鞘胺醇激酶1)催化鞘胺醇之磷酸化以形成鞘胺醇-1-磷酸鹽(S1P),此為同時具有細胞內和細胞外功能之脂質遞質。在細胞內,S1P調節增殖和存活,在細胞外,其為細胞表面G蛋白偶聯受體之配體。此蛋白質及其產物S1P在發炎、抗細胞凋亡及免疫過程中具有重要性的TNF-α信號傳導及NF-κ-B活化通路中具有關鍵性。
SPHK2(鞘胺醇激酶2)與SPHK1功能相似。
FMS(株落刺激因子1受體)為株落刺激因子1(一種控制巨噬細胞產生、分化及功能的細胞因子)之受體。此受體介導該細胞因子之大部分(若非全部)生物效應。配體結合會透過寡聚體化及轉磷酸化過程來活化受體激酶。該經編碼之蛋白質為酪胺酸激酶跨膜受體及酪胺酸
蛋白激酶之CSF1/PDGF受體家族的成員。
BTK(布魯頓(Bruton)丙種球蛋白血症(agammaglobulinemia)酪胺酸激酶)為一種非受體酪胺酸激酶且對B淋巴細胞發育、分化及信號傳導是不可缺少的。抗原與B細胞抗原受體(BCR)結合會觸發最終導致B細胞活化之信號傳導。BCR接合並在質膜活化後,PLCG2在數個位點磷酸化,透過鈣之動員激發下游信號傳導通路,隨後活化蛋白激酶C(PKC)家族成員。
Erk1(MAPK3)(有絲分裂原活化之蛋白激酶3)及Erk2(MAPK1)。MAPK3/ERK1和MAPK1/ERK2屬於絲胺酸/蘇胺酸激酶且為MAPK/ERK級聯反應中具有重要作用的二種MAPK。它們亦參與由經活化之KIT和KITLG/SCF起始的信號傳導級聯反應。根據細胞背景,該MAPK/ERK級聯反應透過調節轉錄、轉譯、細胞骨架重排來介導多種生物學功能,諸如細胞生長、黏附、存活及分化。MAPK/ERK級聯反應亦藉由磷酸化許多轉錄因子來參與起始和調節減數分裂、有絲分裂及經分化細胞之中的分裂後功能。
Erk5(MAPK7)(有絲分裂原活化之蛋白激酶7)為MAP激酶家族的成員。MAP激酶作為多種生化信號之整合點並參與許多種細胞過程,諸如增殖、分化、轉錄調節和發育。此激酶被有絲分裂原活化之蛋白激酶激酶5(MAP2K5/MEK5)特異地活化。其參與各種受體分子(包括受體型激酶及G蛋白偶聯受體)之下游信號傳導過程。在
回應胞外信號時,此激酶轉位至細胞核,其在此處藉由磷酸化調節基因表現並活化不同的轉錄因子。
該方法可調控代謝信號傳導激酶,包括AKT1、AMPK、p70S6K、PDK1、Erk2、SGK或彼等之組合。
AKT1(v-akt鼠胸腺瘤病毒致癌基因同源物1)激酶參與許多信號傳導通路,諸如細胞分化、細胞存活、細胞凋亡及神經系統形成和功能。
AMPK參與調節細胞能量,回應低ATP水準及調控脂肪酸氧化和自噬。AMPK包括AMPKα1、AMPKβ1和AMPKγ1。
p70S6K參與細胞信號傳導,包括細胞生長和G1細胞週期進程。
Erk2(亦稱為有絲分裂原活化之蛋白激酶1)為經胞外信號調節之激酶並參與細胞過程,諸如分化、發育、增殖及轉錄調節。
SGK(血清及糖皮質激素調節之激酶),包括SGK1,為離子通道調節劑,包括活化鉀、鈉和氯化物通道。
PDK(丙酮酸脫氫酶激酶)。丙酮酸脫氫酶為粒線體多酶複合物的一部分,其催化丙酮酸之氧化脫羧且為負責調節哺乳動物中之碳水化合物燃料的體內平衡的主要酶之一。酶催化活性係藉由磷酸化/去磷酸化循環調節。PDH被特異性PDK磷酸化會導致去活化。PDK包括
PDK1、PDK2、PDK3及PDK4。
於一實施態樣中,該調控為細胞週期激酶之調控。細胞週期激酶可為AurA、CDK2/CycA2複合物、CHK1或彼等之組合。
AurA(Aurora A)為有絲分裂絲胺酸/蘇胺酸激酶家族之成員。其牽涉有絲分裂和減數分裂(其適當功能為健康細胞增殖所不可或缺的)期間之重要過程。Aurora A在細胞週期中從G2期轉變到M期之期間被磷酸化活化。
CDK2/CycA2複合物(細胞週期蛋白依賴性激酶2複合物)控制細胞週期且對減數分裂是必要的。CDK2/CycA2複合物在人胚胎幹細胞中之細胞增殖、細胞死亡和DNA修復中具有作用。
CHK1/CHEK1(檢查點激酶1)屬於CAMKL激酶家族。CHK1調節細胞週期、細胞增殖及細胞死亡。
於其他實施態樣中,該經調控之激酶為生長因子信號傳導激酶。該經調控之生長因子信號傳導激酶可為IGF1R、MET、PDGFRα、EGFR、EPHA2、EPHB4、FGFR1、FLT3、GSK3β、HGK、KDR、ABL、SRC、TIE2、TRKA、TYRO3或彼等的組合之一。
IGF1R(胰島素樣生長因子1受體)介導細胞生長及細胞存活且可能在癌細胞的存活中具有作用。IGF1R介導胰島素樣生長因子1(IGF1)之活性。
MET(肝細胞生長因子受體;酪胺酸-蛋白激酶Met)轉導來自胞外基質之信號並調節細胞增殖、破壞、潰
散、形態發生、存活及細胞間連接。MET參與發育及傷口癒合期間之信號傳導、成人之器官再生和組織重塑。此外,MET之功能障礙可能為癌症的原因。
PDGFRα(血小板衍生之生長因子α)介導中樞神經系統(包括神經膠質細胞)之發育。PDGFRα作為PDGFA、PDGFB及PDGFC之細胞表面受體且在胚胎發育、細胞增殖、存活及趨化性之調節中具有重要作用。根據此背景,其可促進或抑制細胞增殖及細胞移行。其在源自骨髓之間質幹細胞的分化中具重要作用。其對正常的骨骼發育是必要的。
EGFR(ErbB-1或表皮生長因子受體)調節細胞分裂和細胞。EGFR活化數種信號傳導級聯反應以將細胞外線索轉化為適當之細胞反應。EGFR活化至少4種主要的下游信號傳導級聯反應,包括RAS-RAF-MEK-ERK、PI3激酶-AKT、PLC-γ-PKC及STATs模。EGFR亦可活化NF-κ=B信號傳導級聯反應。亦直接將其他蛋白質(如RGS16)磷酸化、活化其GTP酶活性並可能將EGF受體信號轉導與G蛋白偶聯受體信號傳導偶聯。EGFR可與癌細胞及神經變性疾病之發展有關。
EPHA2(肝細胞配體蛋白(ephrin)A2型)調節神經和血管系統的發育。EPHA2結合位於相鄰細胞上之膜結合肝細胞配體蛋白-A族配體,導致接觸依賴性雙向信號傳導至相鄰細胞中。EPHA2可參與由紫外線輻射誘導之細胞凋亡且在幾種胎兒問題的發展中具有功能。其參與
血管生成。
EPHB4(肝細胞配體蛋白B4型)調控神經系統之發育。EPHB4結合位於相鄰細胞上之跨膜肝細胞配體蛋白-B族配體,導致接觸依賴性雙向信號傳導至相鄰細胞中。EPHB4透過調節細胞黏附及細胞移行在心臟形態發生及血管生成中具有主要作用。由EPHB4介導之正向信號傳導控制細胞排斥及分離型EFNB2表現細胞。EPHB4參與出生後血管重塑、形態發生及滲透性,因此在腫瘤血管生成的背景下是重要的。
FGFR1(纖維母細胞生長因子受體1)調節細胞增殖、分化及移行。FGFR1作為纖維母細胞生長因子之細胞表面受體且與Pfeiffer症候群、Jackson-Weiss症候群、Antley-Bixler症候群及癌症相關。
HGK(肝細胞祖細胞激酶樣或生發中心激酶樣)調控細胞轉化、侵襲和黏附。
KDR(激酶插入結構域受體或血管內皮生長因子受體2)調節血管生成、血管發育及細胞分化。
ABL(酪胺酸-蛋白激酶ABL1;Abelson酪胺酸-蛋白激酶1)ABL在與細胞生長及存活相關的許多關鍵過程(諸如回應細胞外刺激之細胞骨架重塑、細胞運動和黏附、受體內吞作用、自噬、DNA損傷反應和凋亡)中具有作用。其透過控制細胞骨架動力學之蛋白質(像WASF3(參與分支形成);ANXA1(參與膜錨定);DBN1、DBNL、CTTN、RAPH1及ENAH(參與信號傳導);或MAPT和
PXN(微管結合蛋白))的酪胺酸磷酸化來協調肌動蛋白重塑。
SRC(原致癌基因(proto oncogene)酪胺酸-蛋白激酶Src)調節細胞分裂、運動、黏附和存活。SRC參與控制多種生物活性的信號傳導通路,包括基因轉錄、免疫反應、細胞黏附、細胞週期進程、凋亡、移行和轉化。
TIE2(血管生成素-1受體;蛋白受體酪胺酸激酶,上皮特異性)調節血管生成且作為ANGPT1、ANGPT2及ANGPT4之細胞表面受體,並調節血管生成、內皮細胞存活、增殖、移行、黏附和細胞擴散、肌動蛋白細胞骨架之重組,但亦維持血管靜止(vascular quiescence)。TIE2藉由防止促炎性血漿蛋白和白血球從血管滲漏而具有抗發炎效果。
TRKA(原肌球蛋白(tropomyosin)受體激酶A、高親和力神經生長因子受體、神經營養性酪胺酸激酶受體第1型或TRK1轉化酪胺酸激酶蛋白)調節細胞分化和神經系統發育。
TYRO3(TYRO3蛋白酪胺酸激酶)調節精子生成、免疫調節、吞噬作用及控制細胞存活和增殖。
GSK3β(肝醣合成酶激酶-3)為脯胺酸指導之絲胺酸-蘇胺酸激酶,其最初被鑑定為肝醣合成酶之磷酸化和去活化劑。GSK3β參與能量代謝、神經元細胞發育及身體特有形式之形成。
該方法亦可調控另外之激酶,諸如CAMK4、
CK1ε、CSK、DAPK1、DYRK1B、MST1、NEK2、PAK2、PBK、PIM1、PKACα、PKCα、PKD2、PYK2、ROCK1、TSSK1或彼等之組合。
CAMK4(鈣/鈣調蛋白依賴性蛋白激酶第IV型)調節淋巴細胞、神經元及雄性生殖細胞之轉錄。
CK1ε(酪蛋白激酶1ε)調節遺傳轉錄及轉譯。
CSK(c-src酪胺酸激酶)調節細胞生長、分化、移行及免疫反應。
DAPK1(死亡相關蛋白激酶1)調節細胞凋亡。
DYRK1B(雙特異性酪胺酸-(Y)-磷酸化調節之激酶1B)調節核細胞功能。
MST1(巨噬細胞刺激1)調節細胞凋亡、神經系統發育、器官生長及血管特有形式。
NEK2(絲胺酸/蘇胺酸-蛋白激酶Nek2)調節細胞減數分裂。
PAK2(p21活化之激酶)調節細胞凋亡。
PBK(起源於經淋巴因子活化之殺手T細胞的蛋白激酶)磷酸化MAP激酶p38且在淋巴樣細胞的活化中可能具有作用。
PIM1(原致癌基因絲胺酸/蘇胺酸-蛋白激酶)主要表現在脾、胸腺、骨髓、前列腺、口腔上皮、海馬迴及胎兒肝細胞中,PIM1亦被發現高度表現、於從人類腫瘤分離出之細胞培養物中。PIM1主要參與細胞週期進程凋亡和轉錄活化,以及更普遍之信號轉導通路。
PKACα(蛋白激酶A催化性次單位α)調節轉錄。
PKCα(蛋白激酶C-α)調節細胞黏附、細胞轉化、細胞週期檢查點及細胞體積控制。
PKD2(蛋白激酶D)調節細胞增殖、存活和免疫反應。
PYK2(富含脯胺酸之酪胺酸激酶)調節與血小板和免疫細胞相關之通路。
ROCK1(Rho相關,含有捲曲螺旋之蛋白激酶1)調節與纖維母細胞、血小板及免疫細胞相關之通路。
TSSK1(睾丸特異性絲胺酸激酶1)調節與精子生成相關之通路。
如所討論的,本發明關於藉由投予個體經高度水解之酪蛋白及/或其分級物來調控特異性激酶活性之方法。更特別地,於某些實施態樣中,eHC包括包含SEQ ID NO 4、SEQ ID NO 13、SEQ ID NO 17、SEQ ID NO 21、SEQ ID NO 24、SEQ ID NO 30、SEQ ID NO 31、SEQ ID NO:SEQ ID NO 32、SEQ ID NO 51、SEQ ID NO 57、SEQ ID NO 60及SEQ ID NO 63之肽組分。於一些實施態樣中,該肽組分可包含表1中所揭示之另外的肽類。例如,該組成物可包括至少10種表1中所揭示之另外的肽類。
於另一實施態樣中,該eHC進一步包括肽組分,該肽組分包含至少3種選自由下列所組成之群組的肽
類:SEQ ID NO 4、SEQ ID NO 13、SEQ ID NO 17、SEQ ID NO 21、SEQ ID NO 24、SEQ ID NO 30、SEQ ID NO 31、SEQ ID NO 32、SEQ ID NO 51、SEQ ID NO 57、SEQ ID NO 60和SEQ ID NO 63,以及至少5種選自表1之另外的肽類。
下列表1鑑別可包括在本發明之eHC中的特定胺基酸序列。
下列表2進一步鑑定來自表1之可包含於本發明之eHC中及/或包含本發明之eHC的胺基酸序列之子集。
營養組成物
如所述,該eHC可被納入或添加在營養組成物中,特別是嬰兒配方中。投予(例如餵養)個體該營養組成物包含用於調控個體之激酶的方法。
因此,本發明大致上關於包含蛋白質等效來源之營養組成物,其中至少1%之該蛋白質等效來源包含eHC且高達99%之該蛋白質等效來源包含完整蛋白質、經部分水解之蛋白質、胺基酸或彼等之組合。於實施態樣中,1%至80%之該蛋白質等效來源包含該eHC且20%至99%之該蛋白質等效來源包含完整蛋白質、經部分水解之蛋白質、胺基酸或彼等之組合。再於其他實施態樣中,40%至100%之該蛋白質等效來源包含該eHC且0至60%之該蛋白質等效來源包含完整蛋白質、經部分水解之蛋白質、胺基酸或彼等之組合。再於其他實施態樣中,40%至70%之該蛋白質等效來源包含該eHC且30%至60%之該蛋
白質等效來源包含完整蛋白質、經部分水解之蛋白質、胺基酸或彼等之組合。
於另一實施態樣中,20%至80%之該蛋白質等效來源包括肽組分,該肽組分包含至少3種選自由下列所組成之群組的肽類:SEQ ID NO 4、SEQ ID NO 13、SEQ ID NO 17、SEQ ID NO 21、SEQ ID NO 24、SEQ ID NO 30、SEQ ID NO 31、SEQ ID NO 32、SEQ ID NO 51、SEQ ID NO 57、SEQ ID NO 60和SEQ ID NO 63,及至少5種選自表1之另外的肽類。
於一些實施態樣中,該eHC在該營養組成物中之存在量可為約0.2g/100kcal至約5.6g/100kcal。於其他實施態樣中,該eHC在該營養組成物中之存在量可為約1g/100kcal至約4g/100kcal。再於其他實施態樣中,該eHC在該營養組成物中之存在量可為約2g/100kcal至約3g/100kcal。
本發明之蛋白質等效來源可與該營養組成物中之其他成分一起配製以提供該靶的個體適當之營養水準。於一些實施態樣中,該蛋白質等效來源係包含在適合支持正常生長之營養完整配方中。
於其他實施態樣中,該營養組成物可包含可添加在其他營養調合物(包括,但不限於食品及/或飲料)中之營養補充劑或添加劑。在本發明之目的方面,“營養補充劑”包括濃縮之營養來源,例如本文鑑定之肽類,或其他目的在於補充正常飲食之具有營養或生理效果之物質。
如所討論者,該eHC可以蛋白質等效來源之元素形式提供。於一些實施態樣中,表1和2中鑑定之肽類可藉由水解取得或者其可藉由本技藝之技術熟習人士已知之方法在玻管內合成。利用蛋白水解酶之水解方法的非限制性實例揭示於授讓予Rangavajla等人之美國專利案第7,618,669號中,其全文以引用方式併入本文,然而,可使用其他水解方法來實踐本發明。
於一些實施態樣中,該蛋白質等效來源包含水解蛋白質(諸如酪蛋白),該水解蛋白質包括經部分水解之蛋白質及經高度水解之蛋白質(即,eHC)。於一些實施態樣中,該eHC包含經高度水解之酪蛋白及/或其分級物,包括其莫耳質量分佈大於500道耳吞之肽類。於一些實施態樣中,該eHC包含其莫耳質量分佈在約500道耳吞至約1,500道耳吞之肽類。再者,於一些實施態樣中,該eHC可包含其莫耳質量分佈在約500道耳吞至約2,000道耳吞之肽類。
於一些實施態樣中,該蛋白質等效來源包含其水解度小於40%之經部分水解的蛋白質。再於其他實施態樣中,該蛋白質等效來源可包含其水解度小於25%或小於15%之經部分水解的蛋白質。
於一特定之實施態樣中,除了eHC之外,該營養組成物不含蛋白質而含有游離胺基酸作為蛋白質等效來源。於此實施態樣中,該胺基酸可包含,但不限於組胺酸、異白胺酸、白胺酸、離胺酸、蛋胺酸、半胱胺酸、苯
丙胺酸、酪胺酸、蘇胺酸、色胺酸、纈胺酸、丙胺酸、精胺酸、天門冬醯胺、天門冬胺酸、麩胺酸、麩胺醯胺、甘胺酸、脯胺酸、絲胺酸、肉鹼、牛磺酸及彼等之混合物。於一些實施態樣中,該胺基酸可為支鏈胺基酸。於其他實施態樣中,可包含小胺基酸肽類作為該營養組成物之蛋白質組分。這類小胺基酸肽類可為天然產生或合成的。在該營養組成物中之游離胺基酸的量可在約1至約5g/100kcal之間變化。於一實施態樣中,100%之該游離胺基酸的分子量小於500道耳吞。於此實施態樣中,該營養營養組成物可為低致敏性的。
於一實施態樣中,其中該蛋白質等效來源包含完整蛋白質,該完整蛋白質包含約40%至約85%之乳清蛋白及約15%至約60%之酪蛋白。
於一些實施態樣中,該營養組成物每100kcal包含約1g至約7g之蛋白質等效來源。於其他實施態樣中,該營養組成物每100kcal包含約3.5g至約4.5g之蛋白質等效來源。
包括eHC之本發明的營養組成物可每天在一或多個劑量中投予。本發明考量任何口服可接受之劑型。該等劑型之實例包括,但不限於丸劑、片劑、膠囊、軟凝膠、液體、液體濃縮物、粉末、酏劑、溶液、懸浮液、乳劑、含片、小珠、扁囊劑及彼等之組合。
於一些實施態樣中,該包含eHC之蛋白質等效來源可添加在更完整的營養產品中。於此實施態樣
中,該營養組成物可含有脂肪或脂質及碳水化合物來源或組分且可用於補充飲食或可作為唯一的營養來源。
於一些實施態樣中,該營養組成物包含至少一種碳水化合物。該碳水化合物源可為本技藝中所使用之任一者,例如乳糖、葡萄糖、果糖、玉米糖漿固體、麥芽糊精、蔗糖、澱粉、稻米糖漿固體,等。該營養組成物中之碳水化合物組分的量通常可在約5g/100kca至約25g/100kcal之間變化。於一些實施態樣中,該碳水化合物之量為約6g/100kcal至約22g/100kcal。於其他實施態樣中,該碳水化合物之量為約12g/100kcal至約14g/100kcal。於一些實施態樣中,玉米糖漿固體為較佳者。再者,該營養組成物中納入經水解、部分水解及/或高度水解之碳水化合物可能是有利的,因為它們容易消化。具體地說,經水解之碳水化合物較不可能含有過敏性表面結合部位。
適合用於本發明之碳水化合物物質的非限制性實例包括經水解的或完整的、天然或經化學修飾之來自玉米、木薯、稻米或馬鈴薯之糯和非糯形式的澱粉。合適之碳水化合物的非限制性實例包括各種特徵為經水解之玉米澱粉、麥芽糊精、麥芽糖、玉米糖漿、右旋糖、玉米糖漿固體、葡萄糖及各種其他葡萄糖聚合物的水解澱粉及彼等之組合。其他合適之碳水化合物的非限制性實例包括那些常稱為蔗糖、乳糖、果糖、高果糖玉米糖漿、不可消化之寡醣(諸如果寡醣)者及彼等之組合。
於一特定之實施態樣中,該營養組成物之碳水化合物組分係由100%之乳糖所組成。於另一實施態樣中,該額外之碳水化合物組分包含約0%至60%之乳糖。於另一實施態樣中,該額外之碳水化合物組分包含約15%至55%之乳糖。再於另一實施態樣中,該碳水化合物組分包含約20%至30%之乳糖。於這些實施態樣中,該碳水化合物之其餘來源可為本技藝中已知之任何碳水化合物。於一實施態樣中,該碳水化合物組分包含約25%之乳糖及約75%之玉米糖漿固體。
於一些實施態樣中,該碳水化合物可包含至少一種澱粉或澱粉組分。澱粉為由二種不同之聚合物分級物(直鏈澱粉及支鏈澱粉)所組成的碳水化合物。直鏈澱粉為由α-1,4鏈接之葡萄糖單位所組成的直鏈型分級物。支鏈澱粉具有與直鏈澱粉相同的結構,但有些葡萄糖單位係以α-1.6鍵聯組合在一起而產生支鏈結構。澱粉一般含有17-24%之直鏈澱粉及76-83%之支鏈澱粉。而可產生具有不尋常之直鏈澱粉對支鏈澱粉比的特殊植物遺傳變種已研發出。有些植物產生不含直鏈澱粉之澱粉。這些突變種在胚乳及花粉中產生澱粉顆粒,該澱粉顆粒以碘染色時會變成紅色且含有接近100%之支鏈澱粉。該等支鏈澱粉製造植物中主要為糯玉米、糯高粱及糯稻米澱粉。
澱粉在熱、剪切及酸之條件下的性能可藉由化學修飾來修飾或改善。修飾通常係藉由引入化學取代基來達成。例如,在高溫或高剪切下可藉由與雙官能或多官
能試劑(諸如磷醯氯)交聯來增加或穩定黏度。
在一些情況下,本發明之營養組成物包含至少一種經膠化及/或預膠化之澱粉。如本技藝所已知者,膠化係當聚合物分子在其一部分長度上交互作用以形成捕捉溶劑及/或溶質分子之網路時發生。再者,凝膠係當果膠分子因為共溶質分子競爭水化而失去一些水化的水時形成。影響膠化發生之因子包括pH值、共溶質之濃度、陽離子之濃度和類型、溫度及果膠濃度。值得注意的是,LM果膠僅在二價陽離子(諸如鈣離子)存在時膠凝。在LM果膠之中,那些酯化度最低之果膠具有最高之膠凝溫度且對用於交叉橋聯之二價陽離子的需求最大。
同時,澱粉預膠化為預煮澱粉以產生在冷水中水化及膨脹之物質的過程。然後,將該預煮之澱粉乾燥,例如藉由轉鼓式乾燥或噴霧乾燥。再者,本發明之澱粉可經化學修飾以進一步擴展其成品性能之範圍。本發明之營養組成物可包含至少一種預膠化之澱粉。
天然澱粉顆粒不溶於水,但是當在水中加熱時,當存有足夠克服澱粉分子之結合力的熱能時,天然澱粉顆粒開始膨脹。藉由持續加熱,顆粒膨脹成其原始體積之數倍。這些膨脹的顆粒之間的摩擦為促成澱粉糊黏性的主要因素。
本發明之營養組成物可包含天然或經修飾之澱粉,諸如,例如糯玉米澱粉、糯稻米澱粉、玉米澱粉、稻米澱粉、馬鈴薯澱粉、木薯澱粉、小麥澱粉或彼等之任
何混合物。一般而言,尋常之玉米澱粉包含約25%之直鏈澱粉,而糯玉米澱粉幾乎全部由支鏈澱粉所組成。同時,馬鈴薯澱粉通常包含約20%之直鏈澱粉,稻米澱粉包含比例為約20:80之直鏈澱粉:支鏈澱粉,而糯稻米澱粉僅包含約2%之直鏈澱粉。此外,木薯澱粉通常包含約15%至約18%之直鏈澱粉,而小麥澱粉之直鏈澱粉含量為約25%。
於一些實施態樣中,該營養組成物包含膠化及/或預膠化之糯玉米澱粉。於其他實施態樣中,該營養組成物包含膠化及/或預膠化之木薯澱粉。亦可使用其他膠化或預膠化之澱粉,諸如稻米澱粉或馬鈴薯澱粉。
用於本發明之營養組成物的合適脂肪或脂質可為本技藝中所已知或使用之任一者,包括,但不限於動物來源,例如乳脂肪、奶油、奶油脂肪、蛋黃脂質;海洋來源,諸如魚油、海洋生物油、單細胞油;蔬菜和植物油,諸如玉米油、芥花油、葵花油、大豆油、棕櫚油、椰子油、高油酸葵花油、月見草油、菜籽油、橄欖油、亞麻仁(亞麻籽)油、棉籽油、高油酸紅花油、棕櫚油硬脂、棕櫚仁油、小麥胚芽油;中鏈三酸甘油脂油類和乳劑及脂肪酸之酯類;以及彼等之任何組合。
於一實施態樣中,該脂質或脂肪的量不多於約7g/100kcal;於一些實施態樣中,該脂質或脂肪之存在量為約2至約7g/100kcal。
於某些實施態樣中,該營養組成物亦可含有
一或多種益生元(亦稱為益生元組分)。益生元發揮健康利益,這些健康利益可包括,但不限於選擇性刺激一種或有限數量之有益的腸道細菌生長及/或活性、刺激攝入之益生菌微生物生長及/或活性、選擇性減少腸道病原體及有利地影響腸道短鏈脂肪酸之變化形廓。該等益生元可為天然產生的、合成的或透過有機體及/或植物之遺傳工程操作來發展,無論這類新來源為現在已知的或稍後研發的。可用於本發明中之益生元可包括寡醣、多醣及其他含有果糖、木糖、大豆、半乳糖、葡萄糖及甘露糖之益生元。
更具體地說,用於本發明之益生元可包括聚右旋糖(PDX)、聚右旋糖粉、乳果糖、乳果寡醣、棉籽糖、葡萄寡醣、菊糖、果寡醣(FOS)、異麥芽寡醣、大豆寡醣、乳果糖、木寡醣(XOS)、殼寡醣、甘露寡醣、阿拉伯寡醣、唾液酸寡醣、岩藻寡醣、半乳寡醣(GOS)及龍膽寡醣。
於一實施態樣中,存在於該營養組成物中之益生元的總量可為每升組成物約1.0g至約10.0g。更佳地,存在於該營養組成物中之益生元的總量可為每升組成物約2.0g至約8.0g。於一些實施態樣中,存在於該營養組成物中之益生元的總量可為每100kcal約0.01g至約1.5g。於某些實施態樣中,存在於該營養組成物中之益生元的總量可為每100kcal約0.15g至約1.5g。再者,該營養組成物可包含含有PDX之益生元組分。於一些實施
態樣中,該益生元組分包含至少20% w/w之PDX、GOS或彼等之混合物。
於一實施態樣中,該營養組成物中之PDX的量可在約0.015g/100kcal至約1.5g/100kcal之範圍內。於另一實施態樣中,該聚右旋糖的量係在約0.2g/100kcal至約0.6g/100kcal之範圍內。於一些實施態樣中,包含在該營養組成物中之PDX的量可足以提供約1.0g/L至10.0g/L之PDX。於另一實施態樣中,該營養組成物含有之PDX的量為約2.0g/L至8.0g/L。再於其他實施態樣中,該營養組成物中之PDX的量可為約0.05g/100kcal至約1.5g/100kcal。
於一些實施態樣中,該益生元組分亦包含GOS。於一實施態樣中,該營養組成物中之GOS的量可為約0.015g/100kcal至約1.0g/100kcal。於另一實施態樣中,該營養組成物中之GOS的量可為約0.2g/100kcal至約0.5g/100kcal。
於本發明之一特定實施態樣中,PDX係與GOS一起投予。
於一特定之實施態樣中,該營養組成物中係補充總量為至少約0.015g/100kcal或約0.015g/100kcal至約1.5mg/100kcal之GOS和PDX。於一些實施態樣中,該營養組成物可包含總量為約0.1至約1.0mg/100kcal之GOS及PDX。
於本發明之營養組成物的一些實施態樣中亦
可包含乳鐵蛋白。根據物種,乳鐵蛋白為含有1-4個聚醣之約80kD的單鏈多肽。不同物種之乳鐵蛋白的3-D結構非常相似,但不完全相同。每一乳鐵蛋白各包含二個同源小葉,稱為N-和C-小葉,其分別指該分子之N-端和C-端部分。每一小葉進一步由二個形成裂縫之子葉或結構域組成,在該裂縫中三價鐵離子(Fe3+)與碳酸(氫)根陰離子協同合作緊密地結合。這些結構域分別稱為N1、N2、C1及C2。乳鐵蛋白之N端具有負責一些重要的結合特性之強力陽離子肽區。乳鐵蛋白具有非常高之等電點(~pI9)且其陽離子性質在其防禦細菌、病毒及真菌病原體的能力中具有主要功能。在乳鐵蛋白之N-端區內有幾個陽離子性胺基酸殘基簇,其介導該乳鐵蛋白對抗多種微生物之生物活性。例如,人乳鐵蛋白之N-端殘基1-47(牛乳鐵蛋白之1-48)對乳鐵蛋白之與鐵無關的生物活性至關重要。在人乳鐵蛋白中,殘基2至5(RRRR)及28至31(RKVR)為N-端中富含精胺酸之陽離子結構域,其對乳鐵蛋白之抗菌活性而言特別重要。牛乳鐵蛋白被發現在N-端有類似之區域(殘基17至42;FKCRRWQWRMKKLGAPSITCVRRAFA)。
來自不同宿主物種之乳鐵蛋白的胺基酸序列可能不同,雖然其共通擁有相當高之等電點,在內葉之終端區具有帶正電荷之胺基酸。用於本發明之合適的非人乳鐵蛋白包括,但不限於那些與人乳鐵蛋白之胺基酸序列具有至少48%之同源性者。例如,牛乳鐵蛋白(“bLF”)之胺
基酸組成與人乳鐵蛋白之胺基酸組成具有約70%之序列同源性。於一些實施態樣中,該非人乳鐵蛋白與人乳鐵蛋白具有至少55%之同源性且於一些實施態樣中,具有至少65%之同源性。可被接受用於本發明之非人乳鐵蛋白包括,但不限於牛乳鐵蛋白、豬乳鐵蛋白、馬乳鐵蛋白、水牛乳鐵蛋白、山羊乳鐵蛋白、鼠乳鐵蛋白及駱駝乳鐵蛋白。
於一實施態樣中,該營養組成物中之乳鐵蛋白的存在量為至少約15mg/100kCal。於某些實施態樣中,該營養組成物每100kCal可包含約15至約300mg之乳鐵蛋白。於另一其中該營養組成物為嬰兒配方之實施態樣中,該營養組成物每100kCal可包含約60mg至約150mg之乳鐵蛋白;再於另一實施態樣中,該營養組成物每100kCal可包含約60mg至約100mg之乳鐵蛋白。
於一些實施態樣中,該營養組成物之每毫升配方中可包含之乳鐵蛋白量為約0.5mg至約1.5mg。於取代人乳之營養組成物中,每毫升配方中之乳鐵蛋白的存在量可為約0.6mg至約1.3mg。於某些實施態樣中,該營養組成物每升可包含約0.1至約2克之乳鐵蛋白。於一些實施態樣中,該營養組成物之每升配方中可包含約0.6至約1.5克之乳鐵蛋白。
於某些實施態樣中,所使用之bLF可為從全脂乳分離及/或具有低體細胞計數之任何bLF,其中“低體細胞計數”意指體細胞計數小於200,000個細胞/mL。舉例
而言,合適之bLF可從紐西蘭Morrinsville之Tatua Co-operative Dairy Co.Ltd、荷蘭Amersfoort之FrieslandCampina Domo或紐西蘭奧克蘭之Fonterra Co-Operative Group Limited取得。
用於本發明之乳鐵蛋白可,例如從非人動物之乳汁中分離出或由經遺傳工程修改之生物體產生。例如,在美國專利案第4,791,193號(其全文以引用方式併入本文中作為參考)中,Okonogi等人揭示用於製造高純度牛乳鐵蛋白之方法。一般而言,所揭示之方法包括三個步驟。首先將乳汁原料與弱酸性陽離子交換劑接觸以吸收乳鐵蛋白,然後進行第二步驟,在第二步驟中進行洗滌以除去未被吸附之物質。接著為解吸附步驟,其中移除乳鐵蛋白以製造純化之牛乳鐵蛋白。其他方法可包括,如美國專利案第7,368,141、5,849,885、5,919,913及5,861,491號(其揭示內容全文以引用併入本文)中所描述之步驟。
於某些實施態樣中,本發明中使用之乳鐵蛋白可藉由用於從乳汁來源分離蛋白質之膨脹床(expanded bed)吸附(“EBA”)方法提供。EBA(有時亦稱為穩定化之流化床吸附)為從乳汁來源分離出乳蛋白(諸如乳鐵蛋白)的方法,其包含建立包含顆粒基質之膨脹床吸附柱,將乳汁來源施放於該基質,並以包含約0.3M至約2.0M氯化鈉之洗提緩衝液從基質中洗提出乳鐵蛋白。本發明之方法中可使用任何哺乳動物乳汁來源,雖然在特定之實施態樣中,該乳汁來源為牛乳來源。於一些實施態樣中,該乳汁來源
包括全脂乳、低脂乳、脫脂乳、乳清、酪蛋白或彼等之混合物。
於特定之實施態樣中,該靶蛋白為乳鐵蛋白,雖然亦可分離出其他乳蛋白,諸如乳過氧化物酶或乳白蛋白。於一些實施態樣中,該方法包含下列步驟:建立包含顆粒基質之膨脹床吸附柱,將乳汁來源施放於該基質,並以約0.3M至約2.0M之氯化鈉從基質中洗提出乳鐵蛋白。於其他實施態樣中,以約0.5M至約1.0M之氯化鈉洗提該乳鐵蛋白,而於進一步之實施態樣中,以約0.7M至約0.9M之氯化鈉洗提該乳鐵蛋白。
膨脹床吸附柱可為本技藝中已知之任一者,諸如美國專利案第7,812,138、6,620,326及6,977,046號(其揭示內容以引用方式併入本文)中所描述者。於一些實施態樣中係將該乳汁來源施放於膨脹模式之管柱並以膨脹或包裝模式進行洗提。於特定之實施態樣中,洗提係以膨脹模式進行。例如,膨脹模式中之膨脹比可為約1至約3,或約1.3至約1.7。EBA技術進一步描述於國際發表之申請案第WO 92/00799、WO 02/18237、WO 97/17132號(其全部內容以引用方式併入本文)中。
乳鐵蛋白之等電點為約8.9。先前分離乳鐵蛋白之EBA方法係使用200mM氫氧化鈉作為洗提緩衝液。因此,系統之pH上升至超過12,該乳鐵蛋白之結構和生物活性可能包含不可逆之結構變化。現已發現,氯化鈉溶液可作為從EBA基質中分離出乳鐵蛋白的洗提緩衝液。
於某些實施態樣中,該氯化鈉之濃度為約0.3M至約2.0M。於其他實施態樣中,該乳鐵蛋白洗提緩衝液之氯化鈉濃度為約0.3M至約1.5M,或約0.5m至約1.0M。
於某些實施態樣中,本發明之營養組成物亦可含有LCPUFA之來源;尤其是包含DHA的LCPUFA來源。其他合適之LCPUFA包括,但不限於α-亞油酸、γ-亞油酸、亞油酸、亞麻仁油酸、二十碳五烯酸(EPA)及ARA。確切地,DHA及/或ARA可與肌醇協同作用以進一步改善神經健康和發育。
於一實施態樣中,尤其是若該營養組成物為嬰兒配方,該營養組成物係同時輔以DHA和ARA。於此實施態樣中,ARA:DHA之重量比可在約1:3至約9:1之間。於一特定之實施態樣中,ARA:DHA之比為約1:2至約4:1。
該營養組成物中之長鏈多不飽和脂肪酸的量較有利為至少約5mg/100kcal,且可在約5mg/100kcal至約100mg/100kcal之間變化,更佳為約10mg/100kcal至約50mg/100kcal。
該營養組成物可使用本技藝中已知之標準技術輔以含有DHA及/或ARA之油。例如,可經由取代等量之通常存在於該組成物中的油(諸如高油酸葵花油)來將DHA及ARA添加在該組成物中。另一實例為可經由取代等量之通常存在於該不含DHA和ARA的組成物中之總脂肪摻合物之其餘部分來將該含有DHA和ARA之油添加到
組成物中。
若使用DHA及/或ARA時,該DHA及/或ARA之來源可為本技藝中已知之任何來源,諸如海洋油、魚油、單細胞油、蛋黃脂質及腦脂質。於一些實施態樣中,該DHA和ARA係源自單細胞Martek油、DHASCO®及ARASCO®,或彼等之變化。該DHA和ARA可為天然形式,惟該LCPUFA來源的其餘部分不會對嬰兒造成任何實質有害的影響。或者,可使用精製形式之DHA和ARA。
於一實施態樣中,該DHA和ARA之來源為如美國專利案第5,374,657;5,550,156;及5,397,591號(其全部揭示內容以引用方式併入本文)中所教示之單細胞油。然而,本發明並不僅限於該等油。
於一些實施態樣中,該營養組成物可包括源自乳汁之富集脂質的分級物。該源自乳汁之富集脂質的分級物可藉由任何數量之分餾技術產生。這些技術包括,但不限於熔點分餾、有機溶劑分餾、超臨界流體分餾及彼等之任何變體和組合。於一些實施態樣中,該營養組成物可包括含有乳脂肪球之源自乳汁的富集脂質的分級物。
於某些實施態樣中,添加富集脂質之分級物或包括乳脂肪球之富集脂質的分級物可提供該營養組成物飽和脂肪酸、反式脂肪酸、單不飽和脂肪酸、多不飽和脂肪酸、奇數和支鏈脂肪酸(OBCFA)、支鏈脂肪酸(BCFA)、(共軛之亞油酸)CLA、膽固醇、磷脂及/或乳脂肪球膜
(MFGM),以及MFGM蛋白之來源。
該乳脂肪球之平均直徑(體積-表面積平均直徑)為至少約2μm。於一些實施態樣中,該平均直徑為約2μm至約13μm。於其他實施態樣中,該乳脂肪球之平均直徑為約2.5μm至約10μm。再於其他實施態樣中,該乳脂肪球之平均直徑可為約3μm至約6μm。於某些實施態樣中,該乳脂肪球之比表面積小於3.5m2/g,且於其他實施態樣中為約0.9m2/g至約3m2/g。不受任何特定理論的約束,咸信,具有前述尺寸之乳脂肪球更易接近脂肪酶,因而導致更好的脂肪消化。
於一些實施態樣中,該富集脂質之分級物及/或乳脂肪球含有飽和脂肪酸。該飽和脂肪酸之存在濃度可為約0.1g/100kcal至約8.0g/100kcal。於某些實施態樣中,該飽和脂肪酸之存在濃度可為約0.5g/100kcal至約2.0g/100kcal。再於其他實施態樣中,該飽和脂肪酸之存在濃度可為約3.5g/100kcal至約6.9g/100kcal。
適合包含之飽和脂肪酸的實例包括,但不限於丁酸、戊酸、己酸、辛酸、癸酸、月桂酸、肉荳蔻酸、棕櫚酸、硬脂酸、花生酸、山萮酸、二十四烷酸、十四烷酸、十六烷酸、棕櫚酸和十八烷酸及/或彼等之組合和混合物。
此外,於一些實施態樣中,該富集脂質之分級物及/或乳脂肪球可包含月桂酸。月桂酸(亦稱為十二烷酸)為帶有一具有12個碳原子之鏈的飽和脂肪酸,咸信其
為目前在人類母乳中所發現之主要的抗病毒和抗菌物質之一。該乳脂肪球可能富集三酸甘油酯,該三酸甘油酯在Sn-1、Sn-2及/或Sn-3位置任一處含有月桂酸。不欲受限於任何特定理論,咸信,當攝入該富集脂質之分級物時,嘴巴之舌脂肪酶及胰脂肪酶會將三酸甘油酯水解成包括單月桂酸及游離月桂酸之甘油酯的混合物。
小球中之月桂酸的濃度可在80mg/100ml至800mg/100ml之間變化。小球中之單月桂基的濃度可為每100ml餵料20mg至300mg。於一些實施態樣中,該單月桂基的濃度範圍為60mg/100ml至130mg/100ml。
於某些實施態樣中,該富集脂質之分級物及/或乳脂肪球可含有反式脂肪酸。包含在該乳脂肪球中之反式脂肪酸可為單不飽和或多不飽和反式脂肪酸。於一些實施例中,該反式脂肪酸之存在量可為約0.2g/100kcal至約7.0g/100kcal。於其他實施態樣中,該反式脂肪酸之存在量可為約3.4g/100kcal至約5.2g/100kcal。再於其他實施態樣中,該反式脂肪酸之存在量可為約1.2g/100kcal至約4.3g/100kcal。
用於包含在內之反式脂肪酸的實例包括,但不限於異油酸(vaccenic acid)或反油酸(elaidic acid),及彼等之混合物。再者,當食用時,哺乳動物將異油酸轉換成瘤胃酸(其為一種顯現抗致癌性能之共軛亞油酸)。此外,富含異油酸之飲食可能有助於降低總膽固醇、LDL膽固醇及三酸甘油酯含量。
於一些實施態樣中,該富集脂質之分級物及/或乳脂肪球可含有OBCFA。於某些實施態樣中,該OBCFA之存在量可為約0.3g/100kcal至約6.1g/100kcal。於其他實施態樣中,OBCFA之存在量可為約2.2g/100kcal至約4.3g/100kcal。再於另一實施態樣中,OBCFA之存在量可為約3.5g/100kcal至約5.7g/100kcal。於其他實施態樣中,該乳脂肪球包含至少一種OBCFA。
通常,嬰兒還在子宮內時可吸收OBCFA,並可從哺乳母親之乳汁吸收OBCFA。因此,在人乳中所鑑定出之OBCFA為用於納入該營養組成物之乳脂肪球中的較佳OBCFA。在嬰兒或兒童配方中添加OBCFA令該等配方可反映人乳之組成及功能性,並促進整體健康及福祉。
於一些實施態樣中,該富集脂質之分級物及/或乳脂肪球可包含BCFA。於一些實施態樣中,該BCFA之存在濃度為約0.2g/100kcal至約5.82g/100kcal。於另一實施態樣中,該BCFA之存在量為約2.3g/100kcal至約4.2g/100kcal。而於另一實施態樣中,該BCFA之存在濃度為約4.2g/100kcal至約5.82g/100kcal。再於其他實施態樣中,該乳脂肪球包含至少一種BCFA。
用於納入該營養組成物中之較佳BCFA為在人乳中所鑑定出者。在嬰兒或兒童配方中添加BCFA令該等配方可反映人乳之組成及功能性,並促進整體健康及福祉。
於某些實施態樣中,該富集脂質之分級物及/
或乳脂肪球可包含CLA。於一些實施態樣中,CLA之存在濃度可為約0.4g/100kcal至約2.5g/100kcal。於其他實施態樣中,CLA之存在濃度可為約0.8g/100kcal至約1.2g/100kcal。再於其他實施態樣中,CLA之存在濃度可為約1.2g/100kcal至約2.3g/100kcal。再於其他實施態樣中,該乳脂肪球包含至少一種CLA。
用於納入該營養組成物中之較佳CLA為在人乳中所鑑定出者。通常,嬰兒係從哺乳母親之人乳中吸收CLA。在嬰兒或兒童配方中添加CLA令該等配方可反映人乳之組成及功能性,並促進整體健康及福祉。
在乳脂肪球中所發現之用於該營養組成物的CLA之實例包括,但不限於順式-9,反式-11 CLA、反式-10,順式-12 CLA、順式-9,反式-12十八碳二烯酸及彼等之混合物。
於一些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球包含單不飽和脂肪酸。該富集脂質之分級物及/或乳脂肪球可配製成包含約0.8g/100kcal至約2.5g/100kcal之單不飽和脂肪酸。於其他實施態樣中,該乳脂肪球可包括約1.2g/100kcal至約1.8g/100kcal之單不飽和脂肪酸。
適合之單不飽和脂肪酸的實例包括,但不限於棕櫚油酸、順式-異油酸、油酸及彼等之混合物。
於某些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球包含約2.3g/100kcal至約4.4
g/100kcal之多不飽和脂肪酸。於其他實施態樣中,該多不飽和脂肪酸之存在濃度為約2.7g/100kcal至約3.5g/100kcal。再於另一實施態樣中,,該多不飽和脂肪酸之存在濃度為約2.4g/100kcal至約3.3g/100kcal。
於一些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球包含多不飽和脂肪酸,諸如,例如亞油酸、亞麻仁油酸、十八碳三烯酸、花生四烯酸(ARA)、二十碳四烯酸、二十碳五烯酸(EPA)、二十二碳五烯酸(DPA)及二十碳六烯酸(DHA)。多不飽和脂肪酸為前列腺素及類二十烷酸(eicosanoid)(已知其可提供大量之健康益處,包括抗發炎反應、吸收膽固醇及增加支氣管功能)之先質。
於一些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球亦可包含約100mg/100kcal至約400mg/100kcal之量的膽固醇。於另一實施態樣中,膽固醇之存在濃度為約200mg/100kcal至約300mg/100kcal。類似於人乳及牛乳,包含在乳脂肪球中之膽固醇可存在於乳脂肪球之外雙層膜中,以提供該球形膜穩定性。
於一些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球包含約50mg/100kcal至約200mg/100kcal之磷脂。於其他實施態樣中,該磷脂之存在濃度為約75mg/100kcal至約150mg/100kcal。再於其他實施態樣中,該磷脂之存在濃度為約100mg/100kcal至約250mg/100kcal。
於某些實施態樣中,可將磷脂納入乳脂肪球中以藉由提供磷脂膜或雙層磷脂膜來穩定該乳脂肪球。因此,於一些實施態樣中,該乳脂肪球可被配製成較人乳中所發現者具有更多量之磷脂。
人乳脂質之磷脂質組成(以總磷脂質之重量百分比表示)的測量值為磷脂醯膽鹼(“PC”)24.9%、磷脂醯乙醇胺(“PE”)27.7%、磷脂醯絲胺酸(“PS”)9.3%、磷脂醯肌醇(“PI”)5.4%及鞘磷脂(“SPGM”)32.4%(Harzer,G.et al.,Am.J.Clin.Nutr.,Vol.37,pp.612-621(1983))。因此,於一實施態樣中,該乳脂肪球包含一或多種之PC、PE、PS、PI、SPGM及彼等之混合物。此外,包含在該乳脂肪球中之磷脂組成物可藉由納入所需之磷脂而配製成提供某些健康益處。
於某些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球包含乳脂肪球膜蛋白。於一些實施態樣中,該乳脂肪球膜蛋白之存在量為約50mg/100kcal至約500mg/100kcal。
於一些實施態樣中,本發明之富集脂質之分級物及/或乳脂肪球中可包含半乳醣脂。在本發明之目的方面,“半乳醣脂”係指其糖基為半乳糖的任何醣脂。更具體地,半乳醣脂與鞘醣脂之不同處在於其組成中不具有氮。半乳醣脂在支持大腦發育及整體神經元健康中具有重要作用。此外,半乳醣脂、半乳糖腦苷脂及硫苷脂分別構成總髓鞘脂質含量之約23%及4%,因此,於一些實施態
樣中,可將其納入乳脂肪球中。
此外,本發明之營養組成物包含至少一種果膠來源。該果膠來源可包含本技藝中已知之任何種類或等級的果膠。於一些實施態樣中,該果膠之酯化度小於50%且被歸類為低甲基化(“LM”)果膠。於一些實施態樣中,該果膠之酯化度高於或等於50%且被歸類為高酯或高甲基化(HM”)果膠。再於其他實施態樣中,該果膠為非常低(“VL”)果膠,其酯化度低於約15%。再者,本發明之營養組成物可包含LM果膠、HM果膠、VL果膠或彼等之任何混合物。該營養組成物可包括可溶於水之果膠。且,如本技藝中所已知,果膠溶液之溶解度和黏度與該果膠製品之分子量、酯化度、濃度和pH以及抗衡離子之存在有關。
再者,果膠具有形成凝膠之獨特能力。一般而言,在類似條件下,果膠之膠化程度、膠化溫度和凝膠強度彼此成比例,且一般而言,各自與果膠的分子量成正比,而與酯化度成反比。例如,當果膠溶液之pH值降低時,該羧酸鹽基團之離子化被抑制,且由於失去其電荷,醣分子在其整個長度內之不會彼此排斥。因此,該多醣分子之一部分長度可聯結以形成凝膠。而甲基化程度增加之果膠在稍高之pH值下將凝膠化,因為其在任何指定之pH值下會具有較少之羧酸鹽陰離子。(J.N.Bemiller,An Introduction to Pectins:Structure and Properties,Chemistry and Function of Pectins;Chapter 1;1986.)。
該營養組成物可包含膠化及/或預膠化之澱粉與果膠及/或膠化之果膠。雖然不欲受限於任何理論,咸信,使用果膠(諸如LM果膠,其為具有大分子量之水膠體)加上澱粉顆粒可在流體基質內提供增加分子內摩擦的協同效果。果膠之羧酸基團亦可與存在於該營養組成物中之鈣離子相互作用,從而導致黏度增加,因為該果膠之羧酸基團與鈣離子以及存在於該營養組成物中之肽形成弱凝膠結構。於一些實施態樣中,該營養組成物包含之澱粉對果膠的比例分別介於約12:1至20:1之間。於其他實施態樣中,該澱粉對果膠之比例為約17:1。於一些實施態樣中,該營養組成物可包含約0.05至約2.0%w/w之果膠。於一特殊之實施態樣中,該營養組成物可包含約0.5%w/w之果膠。
本發明所使用之果膠之峰值分子量通常為8000道耳吞或更大。本發明之果膠之較佳峰值分子量為8000至約500,000道耳吞,更佳為約10,000至約200,000道耳吞,最佳為約15,000至約100,000道耳吞。於一些實施態樣中,本發明之果膠可為分子量小於完整或未經修飾之果膠的經水解果膠。本發明之經水解的果膠可藉由本技藝中已知之任何用於降低分子量之方法製備。實例包括化學水解、酶促水解及機械剪切。降低分子量之較佳方法為在提高之溫度下藉由鹼性或中性水解進行。於一些實施態樣中,該營養組成物包含經部分水解之果膠。於某些實施態樣中,該經部分水解之果膠的分子量小於完整或未經修
飾之果膠,但超過3,300道耳吞。
該營養組成物可含有至少一種酸性多醣。酸性多醣(諸如帶負電荷之果膠)可在個體之胃腸道中引起對病原體之抗黏附作用。確切地,源自果膠之非人乳酸性寡醣能夠與上皮表面交互作用且已知可抑制病原體黏附在上皮表面。
於一些實施態樣中,該營養組成物包含至少一種源自果膠之酸性寡醣。源自果膠之酸性寡醣(pAOS)係從酶促果膠分解產生,且pAOS之大小係取決於所使用之酶及反應持續時間。於該等實施態樣中,pAOS可有利地影響個體之糞便黏度、排便頻率、糞便pH值及/或餵食耐受性。本發明之營養組成物可在每升營養組成物中包含約1g pAOS至約6g pAOS。
於一些實施態樣中,該營養組成物包含高達約20%w/w之澱粉與果膠的混合物。於一些實施態樣中,該營養組成物包含高達約19%之澱粉及高達約1%之果膠。於其他實施態樣中,該營養組成物包含高達約15%之澱粉及高達約5%之果膠。再於其他實施態樣中,該營養組成物包含高達約18%之澱粉及高達約2%之果膠。於一些實施態樣中,該營養組成物包含約0.05%w/w至約20%w/w之澱粉與果膠的混合物。其他實施態樣包含約0.05%至約19%w/w之澱粉及約0.05%w/w至約1%w/w之果膠。此外,該營養組成物可包含約0.05%w/w至約15%w/w之澱粉及約0.05%w/w至約5%w/w之果膠。
於一些實施態樣中,該營養組成物包含唾液酸。唾液酸為具有超過50個9碳糖成員的家族,所有這些均為神經胺酸衍生物。人體中所發現之主要唾液酸家族係來自N-乙醯神經胺酸子家族。唾液酸係乳汁(例如牛乳和山羊乳)中找到。在哺乳動物中,與其他體細胞膜相比較,神經元細胞膜具有最高之唾液酸濃度。唾液酸殘基亦為神經節苷脂(ganglioside)的組分。
若唾液酸被包含在營養組成物中,其存在量可為約0.5mg/100kcal至約45mg/100kcal。於一些實施態樣中,唾液酸之存在量可為約5mg/100kcal至約30mg/100kcal。再於其他實施態樣中,唾液酸之存在量可為約10mg/100kcal至約25mg/100kcal。
於一實施態樣中,該營養組成物可含有一或多種益生菌。本技藝中已知之任何益生菌均可被本實施態樣接受。於特殊之實施態樣中,該益生菌可選自任一乳酸桿菌種(Lactobacillus species),諸如鼠李糖乳桿菌GG(Lactobacillus rhamnosus GG)(ATCC編號53103)、雙岐桿菌種(Bifidobacterium species),諸如長雙岐桿菌BB536(Bifidobacterium longum BB536)(BL999,ATCC:BAA-999)、長雙岐桿菌AH1206(NCIMB:41382)、短雙岐桿菌AH1205(Bifidobacterium breve AH1205)(NCIMB:41387)、嬰兒雙岐桿菌35624(Bifidobacterium infantis 35624)(NCIMB:41003)及動物雙歧桿菌乳亞種BB-12(Bifidobacterium animalis subsp.lactis BB-12)(DSM編
號10140)或彼等之任何組合。
若包含在組成物中,該益生菌之量可在每100kcal約1×104至約1.5×1012菌落形成單位(cfu)之間變化。於一些實施態樣中,該益生菌之量可為每100kcal約1×106至約1×109cfu。於某些其他實施態樣中,該益生菌之量可在每100kcal約1×107cfu至約1×108cfu之間變化。
於一實施態樣中,該益生菌可為可存活的或不能存活的。如本文所使用之術語“可存活的”係指活的微生物。術語“不能存活的”或“不能存活的益生菌”係指非存活之益生菌微生物、彼等之細胞組分及/或彼等之代謝物。該等不能存活之益生菌可能已經過熱滅殺或以其他方式滅活,但其保留能有利地影響宿主健康的能力。可用於本發明中之益生菌可為天然產生的、合成的或透過遺傳工程操作有機體而發展的,無論該等來源為現在已知的或稍後研發的。
於一些實施態樣中,該營養組成物可包括含有益生菌細胞等效物的來源,此係指相當於相等數量之活細胞的不能存活、非複製之益生菌的量。術語“非複製”應被理解為從相同量之複製細菌取得之非複製微生物的量(cfu/g),包括經滅活之益生菌、DNA片段、細胞壁或細胞質化合物。換言之,非存活、非複製有機體之量係以cfu表示,彷彿所有微生物都存活,無論它們是否為死亡、非複製、經滅活、片段化,等。在營養組成物中包含不能存
活之益生菌時,該益生菌細胞等效物之量可在每100kcal約1×104至約1.5×1010個益生菌細胞等效物之間變化。於一些實施態樣中,該益生菌細胞等效物之量可為每100kcal營養組成物約1×106至約1×109個益生菌細胞等效物。於某些其他實施態樣中,該益生菌細胞等效物之量可在每100kcal營養組成物約1×107至約1×108個益生菌細胞等效物之間變化。
於一些實施態樣中,該納入營養組成物中之益生菌來源可同時包含存活之菌落形成單位及不能存活之細胞等效物。
於一些實施態樣中,該營養組成物包含來自益生菌批式培養過程之末期指數生長期的培養上清液。不欲受理論之束縛,咸信,該培養上清液之活性可歸因於該被發現在益生菌之批式培養的末期指數期(或“log”)釋入培養基中之組分的混合物(包括蛋白質性物質且可能包括(胞外)多醣物質)。如本文所使用之術語“培養上清液”包括在培養基中所發現之組分的混合物。細菌之批式培養中所識別之階段為熟習本技藝之人士所已知。這些階段為“滯後(lag)”、“對數(log)”(“對數(logarithmic)”或“指數(exponential)”)、“靜止(stationary)”及“死亡(death)”(或“對數下降(logarithmic decline)”)期。在其中存有活菌的所有期中,該細菌代謝來自培養基之營養素並分泌(施加、釋出)物質入該培養基中。在生長階段之指定時點所分泌出之物質的組成通常是無法預測的。
於一實施態樣中,該培養上清液可藉由包含下列步驟之過程取得:(a)使用批式過程將益生菌(諸如LGG)培養在合適之培養基中;(b)在該培養步驟之末期指數生長期收穫培養上清液,該末期指數生長期之定義係參考介於該批式培養過程之滯後期和靜止期之間的後半段時間;(c)視需要地從該上清液除去低分子量組成成分,從而保留分子量大於5至6千道耳吞(kDa)之組成成分;(d)從該培養上清液去除液體內容物,從而取得該組成物。
該培養上清液可包含從末期指數期收穫之分泌物質。末期指數期係發生在中期指數期後之時間(中期指數期為指數期持續期間之一半時間,因此,對末期指數期之引用係指介於滯後期和靜止期之間的後半段時間)。尤其是,本文所使用之術語“末期指數期”係指介於LGG批式培養過程之滯後期和靜止期之間的後四分之一時間部分。於一些實施態樣中,該培養上清液係在指數期持續期間之75%至85%的時間點收穫,且可在指數期約經過六分之五的時間收穫。
如所指出者,本發明之營養組成物可包含β-葡聚醣之來源。葡聚醣為多醣類,具體地說為葡萄糖之聚合物,其為天然產生且可在細菌、酵母菌、真菌及植物之細胞壁中找到。乙型葡聚醣(β-葡聚醣)本身為葡萄糖聚合物的不同子集,其係由經由β型糖苷鍵鏈接在一起以形成複合碳水化合物的葡萄糖單體鏈組成。
β-1,3-葡聚醣為從,例如酵母菌、蘑菇、細菌、藻類或穀物純化之碳水化合物聚合物。β-1,3-葡聚醣之化學結構取決於該β-1,3-葡聚醣之來源。再者,各種理化參數(諸如溶解度、一級結構、分子量及分支)在β-1,3-葡聚醣之生物活性中具有作用。
β-1,3-葡聚醣為帶有或不帶有β-1,6-葡萄糖側鏈之天然多醣,其可在各種植物、酵母菌、真菌及細菌之細胞壁中找到。β-1,3;1,6-葡聚醣為含有以(1,3)方式鏈接之葡萄糖單位的聚醣且其側鏈係連接在位置(1,6)處。β-1,3;1,6-葡聚醣為一群分享結構共性的異質性葡萄糖聚合物(其包括藉由β-1,3鍵鏈接之直鏈葡萄糖單位骨幹,帶有從此骨幹延伸之以β-1,6方式鏈接的葡萄糖分支)。雖然這是目前描述之β-葡聚醣類別的基本結構,其中可能存有一些變化。例如,某些酵母菌β-葡聚醣具有從β(1,6)分支延伸之另外的β(1,3)分支區,這進一步為其各別結構添加複雜性。
源自麵包酵母(釀酒酵母(Saccharomyces cerevisiae))之β-葡聚醣係由連接在位置1和3之D-葡萄糖分子鏈所組成,其具有連接在位置1和6之葡萄糖側鏈。源自酵母菌之β-葡聚醣為不溶性、纖維狀複糖,其具有直鏈葡萄糖單位之一般結構,帶有β-1,3骨幹,其間穿插長度通常為6至8個葡萄糖單位之β-1,6側鏈。更具體地說,源自麵包酵母之β-葡聚醣為聚-(1,6)-β-D-吡喃葡萄糖基-(1,3)-6-D-吡喃葡萄糖。
此外,β-葡聚醣之耐受性良好且不會在兒科個體內產生或引起過量氣體、腹脹(abdominal distension)、脹氣(bloating)或腹瀉。在用於兒科個體之營養組成物(諸如嬰兒配方、成長乳或其他兒童營養產品)中添加β-葡聚醣將可經由增加對抗入侵病原體的抗性來改善個體之免疫反應,從而維持或改善整體健康。
於一些實施態樣中,該組成物中之β-葡聚醣的存在量為每100g組成物約0.010至約0.080g。於其他實施態樣中,該營養組成物之每份服用量包含約10至約30mg之β-葡聚醣。於另一實施態樣中,該營養組成物之每份8fl.Oz.(236.6ml)服用量包含約5至約30mg之β-葡聚醣。於其他實施態樣中,該營養組成物包含之β-葡聚醣量足以提供每天約15mg至約90mg之β-葡聚醣。該營養組成物可以在數個劑量內投遞以達成在一整天內將目標量之β-葡聚醣投遞予個體。
於一些實施態樣中,該營養組成物中之β-葡聚醣的量為每100kcal約3mg至約17mg。於另一實施態樣中,該β-葡聚醣的量為每100kcal約6mg至約17mg。
該營養組成物中亦可添加一或多種維生素及/或礦物質,其含量足以供應個體之每日營養需求。本技藝之一般技術人士能夠理解維生素及礦物質之需求將根據,例如兒童的年齡而有所不同。例如,嬰兒之維生素和礦物質需求可能與年齡在1至13歲之間的兒童不同。因此,本實施態樣並不欲將該營養組成物限制在特定之年齡組,
而是提供可接受之維生素和礦物質組分的範圍。
該營養組成物可視需要地包括,但不限於一或多種下列維生素或彼等之衍生物:維生素B1(硫胺素(thiamin)、焦磷酸硫胺素、TPP、三磷酸硫胺素、TTP、鹽酸硫胺素、單硝酸硫胺素)、維生素B2(核黃素(riboflavin)、黃素單核苷酸、FMN、黃素腺嘌呤二核苷酸、FAD、核黃素(lactoflavin)、卵黃素(ovoflavin))、維生素B3(菸鹼酸(niacin)、菸鹼酸(nicotinic acid)、菸醯胺(nicotinamide)、菸鹼醯胺(niacinamide)、菸醯胺腺嘌呤二核苷酸、NAD、菸鹼酸單核苷酸、NicMN、吡啶-3-羧酸)、維生素B3先質色胺酸、維生素B6(吡哆醇(pyridoxine)、吡哆醛(pyridoxal)、吡哆胺(pyridoxamine)、鹽酸吡哆醇)、泛酸(泛酸鹽、泛醇(panthenol))、葉酸鹽(葉酸、葉酸(folacin)、蝶醯麩胺酸(pteroylglutamic acid))、維生素B12(鈷胺素(cobalamin)、甲鈷胺素、脫氧腺苷鈷胺素、氰鈷胺素、羥鈷胺素、腺苷鈷胺素)、生物素、維生素C(抗壞血酸)、維生素A(視黃醇(retinol)、醋酸視黃酯(retinyl acetate)、棕櫚酸視黃酯(retinyl palmitate)、具其他長鏈脂肪酸之視黃酯、視黃醛(retinal)、視黃酸(retinoic acid)、視黃醇酯)、維生素D(骨化醇(calciferol)、膽骨化醇(cholecalciferol)、維生素D3、1,25-二羥基維生素D)、維生素E(α-生育酚(α-tocopherol)、醋酸α-生育酚、琥珀酸α-生育酚、菸鹼酸α-生育酚、α-生育酚)、維生素K(維生素K1、葉綠醌(phylloquinone)、萘醌
(naphthoquinone)、維生素K2、甲萘醌(menaquinone)-7、維生素K3、甲萘醌-4、甲萘醌(menadione)、甲萘醌-8、甲萘醌-8H、甲萘醌-9、甲萘醌-9H、甲萘醌-10、甲萘醌-11、甲萘醌-12、甲萘醌-13)、膽鹼、肌醇、β-胡蘿蔔素及彼等之任何組合。
此外,該營養組成物可視需要地包括,但不限於一或多種下列礦物質或彼等之衍生物:硼、鈣、醋酸鈣、葡萄糖酸鈣、氯化鈣、乳酸鈣、磷酸鈣、硫酸鈣、氯化物、鉻、氯化鉻、吡啶甲酸鉻(chromium picolonate)、銅、硫酸銅(copper sulfate)、葡萄糖酸銅、硫酸銅(cupric sulfate)、氟化物、鐵、羰基鐵、三價鐵、富馬酸亞鐵、正磷酸鐵、研磨鐵、多醣鐵、碘化物、碘、鎂、碳酸鎂、氫氧化鎂、氧化鎂、硬脂酸鎂、硫酸鎂、錳、鉬、磷、鉀、磷酸鉀、碘化鉀、氯化鉀、醋酸鉀、硒、硫、鈉、多庫酯鈉(docusate sodium)、氯化鈉、硒酸鈉、鉬酸鈉、鋅、氧化鋅、硫酸鋅及彼等之混合物。礦物質化合物之非限制性示例性衍生物包括任何礦物質化合物之鹽、鹼鹽、酯及螯合物。
礦物質可以鹽之形式添加在營養組成物中,諸如為磷酸鈣、甘油磷酸鈣、檸檬酸鈉、氯化鉀、磷酸鉀、磷酸鎂、硫酸亞鐵、硫酸鋅、硫酸銅、硫酸錳及亞硒酸鈉之形式。另外之維生素和礦物質可依本技藝所知者添加。
於一實施態樣中,該營養組成物之每一服用
量中之維生素A、C和E、鋅、鐵、碘、硒及膽鹼的量可為任一指定國家之最大飲食建議量的約10至約50%,或國家群組之平均飲食建議量的約10至約50%。於另一實施態樣中,兒童營養組成物之每一服用量可供應之維生素B量可為任一指定國家之最大飲食建議量的約10至30%,或國家群組之平均飲食建議量的約10至30%。再於另一實施態樣中,兒童營養產品中之維生素D、鈣、鎂、磷及鉀的含量可相當於乳品中所發現者之平均含量。於其他實施態樣中,該兒童營養組成物之每一份服用量中之其他營養素的存在量可為任何指定國家的最大飲食建議量之約20%,或國家群組之平均飲食建議量的約20%。
本發明之營養組成物可視需要地包括一或多種下列調味劑,包括,但不限於調味之萃取物、揮發油、可可亞或巧克力調味劑、花生醬調味劑、餅乾碎片、香草或任何市售之調味劑。有用之調味劑的實例包括,但不限於純茴香萃取物、仿香蕉萃取物、仿櫻桃萃取物、巧克力萃取物、純檸檬萃取物、純柳橙萃取物、純薄荷萃取物、蜂蜜、仿鳳梨萃取物、仿蘭姆酒萃取物、仿草莓萃取物或香草萃取物;或揮發油,諸如香蜂花油(balm oil)、月桂油、佛手柑油(bergamot oil)、柏木油(cedarwood oil)、櫻花油、肉桂油、丁香油或薄荷油;花生醬、巧克力調味劑、香草餅乾碎片、奶油糖果、太妃糖及彼等之混合物。調味劑的量可根據所使用之調味劑而有很大的變化。調味劑之類型和量可依本技藝所已知者選擇。
本發明之營養組成物可視需要地包括一或多種添加在其中以用來穩定最終產品之乳化劑。合適之乳化劑的實例包括,但不限於卵磷脂(例如來自卵或大豆)、α-乳白蛋白及/或單酸甘油酯和二酸甘油酯,及彼等之混合物。其他乳化劑對熟習本技藝之人士而言是顯而易見的且合適之乳化劑的選擇將部分取決於該調合物及最終產品。
本發明之營養組成物可視需要地包含一或多種亦可添加在其中以延長產品之貨架期的防腐劑。合適之防腐劑包括,但不限於山梨酸鉀、山梨酸鈉、苯甲酸鉀、苯甲酸鈉、EDTA二鈉鈣及彼等之混合物。
本發明之營養組成物可視需要地包括一或多種穩定劑。用於實行本發明之營養組成物的合適穩定劑包括,但不限於阿拉伯膠、印度樹膠(gum ghatti)、刺梧桐樹膠(gum karaya)、黃蓍膠(gum tragacanth)、瓊脂、紅藻膠(furcellaran)、果阿膠(guar gum)、結冷膠(gellan gum)、刺槐豆膠(locust bean gum)、果膠(pectin)、低甲氧基果膠、明膠、微晶型纖維素、CMC(羧甲基纖維素鈉)、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、DATEM(單酸甘油酯及二酸甘油酯之二乙醯基酒石酸酯)、右旋糖苷、角叉菜膠(carrageenan)及彼等之混合物。
所揭示之營養組成物可以本技藝已知之任何形式提供,諸如粉劑、凝膠、懸浮液、糊劑、固體、液體、液體濃縮物、可重構成之奶粉替代品或即時使用之產品。於某些實施態樣中,該營養組成物可包含營養補充
劑、兒童營養產品、嬰兒配方、人乳強化劑、成長乳或任何其他經過設計以用於嬰兒或小兒個體之營養組成物。本發明之營養組成物包括,例如經口食入,促進健康之物質,包括,例如食品、飲料、片劑、膠囊和粉劑。再者,本發明之營養組成物可經標準化成特定之卡路里含量,其可以即時使用之產品形式提供,或可以濃縮形式提供。於一些實施態樣中,該營養組成物為粉劑形式,其粒徑在5μm至1500μm之範圍內,更佳為在10μm至300μm之範圍內。
若該營養組成物為即時使用之產品的形式,該營養組成物之滲透壓濃度可為每公斤水約100至約1100mOsm,更常為每公斤水約200至約700mOsm。
本發明之營養組成物可進一步包括至少一種額外之植物營養素,亦即,除了上述之果膠及/或澱粉組分外,包括另一種植物營養素組分。在人類母乳中所鑑定出之植物營養素或其衍生物(共軛形式或先質)為包含在該營養組成物中之較佳形式。通常,哺乳之母親吸收膳食來源中之類胡蘿蔔素及多酚類並將其保留在母乳中,使其可被接受哺乳之嬰兒利用。在嬰兒或兒童配方中添加這些植物營養素可允許該等配方反映人類母乳之組成和功能,並促進整體健康和福祉。
例如,於一些實施態樣中,本發明之營養組成物可在8液盎司(236.6毫升)之服用量中包含約80至約300mg之花青素、約100至約600mg之原花青素、約50
至約500mg之黃烷-3-醇或彼等之任何組合物或混合物。於其他實施態樣中,該營養組成物包含蘋果萃取物、葡萄籽萃取物或彼等之組合物或混合物。此外,該營養組成物之至少一種植物營養素可源自任何單一水果、葡萄籽及/或蘋果或茶萃取物或彼等之摻合物。
在本發明之目的方面,該額外之植物營養素可以天然、經純化、經包封在膠囊及/或經化學或酶修飾之形式添加在營養組成物中,從而投遞所需之感官和穩定性能。在包封在膠囊的情況中,該包封在膠囊中之植物營養素最好能抵抗水之溶解力,但在到達小腸時釋出。此可經由應用腸衣(諸如交聯藻酸鹽,等)來實現。
適合用於營養組成物之額外的植物營養素的實例包括,但不限於純化或天然形式之花青素、原花青素、黃烷-3-醇(即,兒茶素、表兒茶素,等)、黃烷酮、類黃酮、異類黃酮、類二苯乙烯化合物(stilbenoids)(即,白藜蘆醇(resveratrol),等)、原花青素、花青素、白藜蘆醇、槲皮素(quercetin)、薑黃素(curcumin)和/或彼等之任何混合物,以及植物營養素之任何可能的組合物。該營養組成物之某些組分(尤其是以植物為底質之組分)可提供植物營養素之來源。
常用來製作用於兒科個體之營養組成物的已知成分(諸如天然油類)中可能先天存在一些量之植物營養素。這些先天存在之植物營養素可能,但不一定被視為是本發明所描述之植物營養素組分的一部分。於一些實施態
樣中,本文所描述之植物營養素的濃度和比率係根據所添加及先天存在之植物營養素來源計算。於其他實施態樣中,本文所描述之植物營養素的濃度和比率係根據添加之植物營養素來源計算。
於一些實施態樣中,該營養組成物包含花青素,諸如,例如花色素苷(aurantinidin)、矢車菊素(cyanidin)、飛燕草素(delphinidin)、歐林苷(europinidin)、木樨黄定(luteolinidin)、天竺葵素(pelargonidin)、錦葵素(malvidin)、芍藥素(peonidin)、矮牽牛花苷(petunidin)及薔薇素(rosinidin)之葡糖苷。這些及其他適合用於營養組成物中之花青素可在各種植物來源中找到。花青素可能源自單一植物來源或植物來源之組合。富含適合用於本發明組成物之花青素的植物之非限制性實例包括:漿果(巴西莓、葡萄、山桑子、藍莓、紅豆、黑加侖、阿龍尼亞苦味果(chokeberry)、黑莓、覆盆子、櫻桃、紅醋栗、蔓越莓、岩高蘭、黃莓、越橘、花楸漿果(rowanberry))、紫玉米、紫薯、紫胡蘿蔔、紅甜薯、紅甘藍、茄子。
於一些實施態樣中,本發明之營養組成物包含原花青素,該原花青素包括,但不限於黃烷-3-醇及聚合度為2至11之黃烷-3-醇(例如兒茶素、表兒茶素)聚合物。該等化合物可能源自單一植物來源或植物來源之組合。適合用於本發明之營養組成物的富含原花青素之植物來源的非限制性實例包括:葡萄、葡萄皮、葡萄籽、綠
茶、紅茶、蘋果、松樹皮、肉桂、可可、山桑子、蔓越莓、黑加侖、阿龍尼亞苦味果。
適合用於本發明之營養組成物的黃烷-3-醇之非限制性實例包括兒茶素、表兒茶素、沒食子兒茶素、表沒食子兒茶素、表兒茶素沒食子酸酯、表兒茶素-3-沒食子酸酯、表沒食子兒茶素及沒食子酸酯。富含合適之黃烷-3-醇的植物包括,但不限於茶、紅葡萄、可可、綠茶、杏及蘋果。
某些多酚化合物,尤其是黃烷-3-醇,可能經由增加大腦的血流(此與腦能量/營養輸送之增加和持續以及形成新的神經元有關)來改善人個體之學習和記憶。多酚亦可提供神經保護作用並可同時增加大腦突觸生成及抗氧化能力,從而支持年幼的兒童最佳的大腦發育。
用於營養組成物之較佳的黃烷-3-醇來源包括至少一種蘋果萃取物、至少一種葡萄籽萃取物或彼等之混合物。在蘋果萃取物方面,4%至20%之黃烷-3-醇被分解成單體,80%至96%被分解成聚合物。在葡萄籽萃取物方面,黃烷-3-醇被分解成單體(約總黃烷-3-醇及總多酚含量之46%)及聚合物(約總黃烷-3-醇及總多酚含量之54%)。聚合性黃烷-3-醇之較佳聚合度為約2至11。此外,蘋果和葡萄籽萃取物可含有兒茶素、表兒茶素、表沒食子兒茶素、表兒茶素沒食子酸酯、表沒食子兒茶素沒食子酸酯、聚合性原花青素、類二苯乙烯化合物(即,白藜蘆醇)、黃酮醇類(即,槲皮素、楊梅素),或彼等之任
何混合物。富含黃烷-3-醇之植物來源包括,但不限於蘋果、葡萄籽、葡萄、葡萄皮、茶(綠茶或黑茶)、松樹皮、肉桂、可可、山桑子、小紅莓、黑醋栗、阿龍尼亞苦味果。
若該營養組成物係投予兒科個體,黃烷-3-醇(包括單體之黃烷-3-醇、聚合性黃烷-3-醇或彼等之組合物)之投予量可為每天約0.01mg至約450mg。於一些情況中,用於投予嬰兒或兒童之黃烷-3-醇的量可為每天約0.01mg至約170mg、每天約50mg至約450mg,或每天約100mg至約300mg。
於本發明之一實施態樣中,該營養組成物中中之黃烷-3-醇的存在量為每克營養組成物約0.4至約3.8mg(約9至約90mg/100kcal)。於另一實施態樣中,該黃烷-3-醇之存在量為每克營養組成物約0.8至約2.5mg(約20至約60mg/100kcal)。
於一些實施態樣中,本發明之營養組成物包含黃烷酮。合適之黃烷酮的非限制性實例包括紫鉚黄銅(butin)、聖草酚(eriodictyol)、橙皮素(hesperetin)、橙皮苷(hesperidin)、高聖草素(homeriodictyol)、異櫻花素(isosakuranetin)、柚皮素(naringenin)、柚皮苷(naringin)、松屬素(pinocembrin)、枸橘苷(poncirin)、櫻花素(sakuranetin)、櫻花苷(sakuranin)、steurbin。富含黃烷酮之植物來源包括,但不限於橙、柑、葡萄柚、檸檬、酸橙。該營養組成物可經配製以每天投遞約0.01至約
150mg之黃烷酮。
此外,該營養組成物亦可包含黃酮醇。可使用來自植物或海藻萃取物之黃酮醇。可包含在該營養組成物中之黃酮醇(諸如異鼠李素(isorhamnetin)、山柰酚(kaempferol)、槲皮素(myricetin)、槲黃素(quercetin))的量為足以每天投遞給個體約0.01至150mg之黃酮醇。
該營養組成物之植物營養素組分亦可包含已在人類母乳中鑑定出之植物營養素,包括,但不限於柚皮素、橙皮素、花青素、槲黃素、山奈酚、表兒茶素、表沒食子兒茶素、表兒茶素沒食子酸酯、表沒食子兒茶素-沒食子酸酯或彼等之任何組合。於某些實施態樣中,該營養組成物包含約50至約2000nmol/L之表兒茶素、約40至約2000nmol/L之表兒茶素沒食子酸酯、約100至約4000nmol/L之表沒食子兒茶素沒食子酸酯、約50至約2000nmol/L之柚皮素、約5至約500nmol/L之山奈酚、約40至約4000nmol/L之橙皮素、約25至約2000nmol/L之花青素、約25至約500nmol/L之槲皮素或彼等之混合物。此外,該營養組成物可包含植物營養素或其母化合物之代謝物,或者該營養組成物可包含其他類別之膳食植物營養素,諸如硫代葡萄糖苷或蘿蔔硫素。
於某些實施態樣中,該營養組成物包含類胡蘿蔔素,諸如葉黃素(lutein)、黍黃素(zeaxanthin)、蝦青素(astaxanthin)、番茄紅素(lycopene)、β-胡蘿蔔素、α-胡蘿蔔素、γ-胡蘿蔔素及/或β-玉米黃質。富含類胡蘿蔔素
之植物來源包括,但不限於奇異果、葡萄、柑橘、番茄、西瓜、木瓜及其他紅色水果,或深綠色蔬菜,諸如甘藍、菠菜、蘿蔔青菜、羽衣甘藍、西生菜、花椰菜、西葫蘆、豌豆及抱子甘藍、菠菜、胡蘿蔔。
人類無法合成類胡蘿蔔素,但在人類母乳中已鑑定出超過34種類胡蘿蔔素,包括某些類胡蘿蔔素之異構物和代謝物。除了存在於母乳外,膳食類胡蘿蔔素(諸如α和β-胡蘿蔔素、番茄紅素、葉黃素、黍黃素、蝦青素及玉米黃質)還存在於哺乳期婦女和由母乳喂養之嬰兒的血清中。一般而言,類胡蘿蔔素據報導可改善細胞-至-細胞之聯繫、促進免疫功能、支持健康之呼吸道健康、保護皮膚免受紫外線光損傷且與某些類型之癌症風險及所有原因之死亡率降低有關。此外,類胡蘿蔔素和/或多酚之膳食來源被人類個體吸收,累積並保留在母乳中,使其可被襁褓中的嬰兒利用。因此,在嬰兒配方或兒童產品中添加植物營養素將使該配方在組成和功能上更接近人類母乳。
整體而言,該營養組成物中亦可包含類黃酮化合物,因為人類無法合成類黃酮化合物。此外,來自植物或藻類萃取物之類黃酮化合物可能以單體、二聚體和/或聚合物形式使用。於一些實施態樣中,該營養組成物包含之單體形式之類黃酮化合物的量類似於哺乳期前三個月期間人類母乳中所包含者。雖然人類母乳樣本中已鑑定出黃酮苷元(flavonoid aglycone)單體),該營養組成物中亦
可使用共軛形式之類黃酮化合物和/或其代謝物。類黃酮化合物可以下列形式添加在營養組成物中:游離、葡萄糖醛酸、甲基葡萄糖醛酸、硫酸鹽及甲基硫酸鹽。
該營養組成物亦可包含異類黃酮化合物及/或異黃酮。實例包括,但不限於染料木素(genistein)(染料木黃酮(genistin))、黃豆苷原(daidzein)(大豆苷(daidzin))、黃豆黃素(glycitein)、鷹嘴豆芽素A(biochanin A)、芒柄花黃素(formononetin)、香豆雌酚(coumestrol)、德鳶尾素(irilone)、二羥四氫黄酮(orobol)、假靛黄素(pseudobaptigenin)、anagyroidisoflavone A及B、毛蕊異黃酮(calycosin)、大豆黃素(glycitein)、鳶尾苷元(irigenin)、5-O-甲基染料木素、紅車軸草異黃酮(pratensein)、櫻黃素(prunetin)、psi-鳶尾黃素(psi-tectorigenin)、瑞士黃酮(retusin)、鳶尾黃素(tectorigenin)、野鳶尾苷(iridin)、芒柄花苷(ononin)、葛根(puerarin)、鳶尾黃酮苷(tectoridin)、derrubone、黃羽扇豆酮(luteone)、異戊烯基異黄酮懷特酮(wighteone)、高山金蓮花素(alpinumisoflavone)、吡喃異黄酮(barbigerone)、二-O-甲基高山金蓮花素(di-O-methylalpinumisoflavone)及4’-甲基-高山金蓮花素(4’-methyl-alpinumisoflavone)。富含異黃酮之植物來源包括,但不限於大豆、補骨脂(psoralea)、葛根、扁豆、蠶豆、鷹嘴豆、苜蓿、豆莢及花生。該營養組成物可經配製以每無投遞約0.01至約150mg之異黃酮和/或異類黃酮化合物。
於一實施態樣中,本發明之營養組成物包含有效量之膽鹼。膽鹼為細胞之正常功能的必要營養。其為膜磷脂質之先質,且其加速乙醯膽鹼(一種涉及記憶儲存的神經遞質)之合成和釋出。此外,儘管不欲受限於此學理或任何其他學理,咸信膳食膽鹼與二十二碳六烯酸(DHA)協同作用以促進生物合成磷脂醯膽鹼,從而協助促進人類個體中之突觸生成。此外,膽鹼和DHA可顯現促進樹突脊形成(其對維持已建立之突觸連接很重要)之協同作用。於某些實施態樣中,本發明之營養組成物包括有效量之膽鹼,該有效量為每8液盎司(236.6mL)服用量約20mg膽鹼至每8液盎司(236.6mL)服用量約100mg膽鹼。
再者,於一些實施態樣中,該營養組成物為營養完整的,其含有作為個體唯一之營養來源的合適類型及量之脂質、碳水化合物、蛋白質、維生素及礦物質。確切地說,該營養組成物可視需要地包含任意數量之蛋白質、肽、胺基酸、脂肪酸、益生菌及/或彼等之代謝副產物、益生元、碳水化合物及可提供個體許多營養和生理助益之任何其他營養素或其他化合物。此外,本發明之營養組成物可包含調味劑、增味劑、甜味劑、色素、維生素、礦物質、治療成分、功能性食品成分、食品成分、加工成分或彼等之組合。
下列實施例描述本發明之實施態樣。熟習本技藝之人士從考量本專利說明書或實行本文所揭示之方法
可清楚明白在本文之申請專利範圍內的其他實施態樣。本專利說明書,連同實施例僅意圖用於示例,本發明之範圍和精神係由接續在實施例後之申請專利範圍所指定。在實施例中,除非另有說明,所有百分比均按重量計。
測試在三種不同濃度下之二種水解產物和一種胺基酸混合物-經高度水解之酪蛋白(eHC)、>500Da之經高度水解之酪蛋白分級物(eHC>500Da)及胺基酸製品AA),該濃度係在50至5000μg/ml之範圍內。
將樣本溶解在含有20mM之4-(2-羥乙基)-1-六氫吡乙磺酸(HEPES)、0.01%之辛基酚乙氧基化物(triton X-100)和2mM二硫蘇糖醇(DTT),輔以4%之二甲亞碸(DMSO)的pH=7.5緩衝液中,使成為2%(20mg/mL)儲存溶液。在三種濃度:50μg/mL、500μg/mL及5000μg/mL下,藉由酶聯免疫吸附分析(ELISA)、基於固定化金屬離子親和力的螢光偏振(IMAP)或在KmATP之移行率分析(MSA)測定激酶活性。
激酶數據係以抑制熱圖(heat map)表現,包括與“+激酶”(100%)和“無激酶”(0%)相比較之抑制百分比。使用下式計算抑制百分比:(1-(實驗值-“無激酶”值)/(“+激酶”值-“無激酶”值))* 100。在熱圖中,負值設為零(無抑制)。
從表3和4可以看出下列趨勢:AA顯示低活
性-eHC顯示對特異性激酶之活性,eHC>500Da較eHC更有活性,表明eHC中較長之序列最可能介導激酶抑制。
在激酶變化形廓中有明顯的趨勢。此趨勢為劑量相關的且影響大多數測試之激酶。SYK和GSK3β為受到最強抑制的激酶。
AA顯示出在50μg/ml和500μg/ml下無活性。在5000μg/ml下可觀察到對大多數激酶具中度活性(可能有非特異性抑制)。
在eHC和>500Da eHC方面,在50μg/ml下,SYK和GSK3β遵循趨勢。在500μg/ml下,PIM1、IKKβ、SYK、GSKβ、PDK1和AurA遵循趨勢。在5000μg/ml下,遵循趨勢的有:生長因子受體激酶,尤其是PDGFRα、EGFR、EPHA2、EPHB4、FLT3、HGK、KDR、SRC、TIE2及TRKA;發炎信號傳導激酶,特別是IKKβ、IRAK4、JAK3、JNK2、LCK、p38α、SYK;代謝信號傳導激酶,特別是GSK3β、PDK1、Erk2、SGK、細胞週期激酶AurA;及PIM1、PYK2、TSSK1。
在>500Da之eHC和eHC方面,在50μg/ml下,SYK和GSK3β受抑制。
在測試之濃度下,TYRO3、CK1ε、DYRK1B、PKACα、PDK2及ROCK1不會被該水解產物抑制。
eHC>500Da較eHC更具活性,這說明eHC之分級以劑量依賴方式增加活性。
表5提供根據本發明之營養組成物的示例性實施態樣,並描述每100kcal服用量所包含之各成分的量。
雖然本發明之較佳實施態樣已使用特定術語、裝置及方法描述,該等描述僅用於說明。所使用之文字係用於描述,而非限制。需理解的是,本技藝之一般技術人士可在不背離本發明之精神和範圍(其陳述於接續之申請專利範圍中)的情況下作出各種改變和變化。此外,應理解的是,各種實施態樣之態樣可以全部或部分互換。因此,所附之申請專利範圍的精神和範圍不應只限於其中所包含之版本的描述。
本專利說明書中所引用之所有參考資料,包括,但不限於所有論文、出版物、專利案、專利申請案、演示、文本、報告、手稿、手冊、書籍、網路貼文、雜誌文章、期刊,等的全部內容在此以引用方式納入本專利說明書中。本文中參考文獻之討論只是為了概述由其作者所下之斷言,並非承認任何參考文獻構成先前技藝。本申請者保留質疑所引用之參考文獻的準確性和相關性之權利。
<110> Mead Johnson營養公司
<120> 調控激酶之方法
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Claims (13)
- 一種經高度水解之酪蛋白、經高度水解之酪蛋白分級物或彼等之組合於製備用於調控個體之激酶的營養組成物之用途,其中該經高度水解之酪蛋白、經高度水解之酪蛋白分級物或彼等之組合具有大於500道耳吞之莫耳質量分佈。
- 如申請專利範圍第1項之用途,其中該營養組成物包含蛋白質等效來源,其中至少1%之該蛋白質等效來源包含經高度水解之酪蛋白、經高度水解之酪蛋白分級物或彼等之組合,使得至少1%至80%之該蛋白質等效物包含下列個別肽類:SEQ ID NO 4、SEQ ID NO 13、SEQ ID NO 17、SEQ ID NO 21、SEQ ID NO 24、SEQ ID NO 30、SEQ ID NO 31、SEQ ID NO 32、SEQ ID NO 51、SEQ ID NO 57、SEQ ID NO 60、及SEQ ID NO 63。
- 如申請專利範圍第2項之用途,其中該蛋白質等效來源之存在量為該營養組成物之約0.2g/100kcal至約5.6g/100kcal。
- 如申請專利範圍第2項之用途,其中該蛋白質等效來源進一步包含至少10種選自由下列組成之群組的個別肽類:SEQ ID NO 1、SEQ ID NO 2、SEQ ID NO 3、SEQ ID NO 5、SEQ ID NO 6、SEQ ID NO 7、SEQ ID NO 8、SEQ ID NO 9、SEQ ID NO 10、SEQ ID NO 11、SEQ ID NO 12、SEQ ID NO 14、SEQ ID NO 15、SEQ ID NO 16、SEQ ID NO 18、SEQ ID NO 19、SEQ ID NO 20、SEQ ID NO 22、SEQ ID NO 23、SEQ ID NO 25、SEQ ID NO 26、SEQ ID NO 27、SEQ ID NO 28、SEQ ID NO 29、SEQ ID NO 33、SEQ ID NO 34、SEQ ID NO 35、SEQ ID NO 36、SEQ ID NO 37、SEQ ID NO 38、SEQ ID NO 39、SEQ ID NO 40、SEQ ID NO 41、SEQ ID NO 42、SEQ ID NO 43、SEQ ID NO 44、SEQ ID NO 45、SEQ ID NO 46、SEQ ID NO 47、SEQ ID NO 48、SEQ ID NO 49、SEQ ID NO 50、SEQ ID NO 52、SEQ ID NO 53、SEQ ID NO 54、SEQ ID NO 55、SEQ ID NO 56、SEQ ID NO 58、SEQ ID NO 59、SEQ ID NO 61、SEQ ID NO 62、SEQ ID NO 64及彼等之組合。
- 如申請專利範圍第1項之用途,其中該營養組成物進一步包含至少一種長鏈多不飽和脂肪酸。
- 如申請專利範圍第5項之用途,其中該至少一種長鏈多不飽和脂肪酸係選自由下列組成之群組:二十二碳六烯酸(docosahexaenoic acid)及花生四烯酸(arachidonic acid)。
- 如申請專利範圍第1項之用途,該營養組成物進一步包含益生菌批式培養過程之末期指數生長期的培養上清液。
- 如申請專利範圍第1項之用途,該營養組成物進一步包含益生菌。
- 如申請專利範圍第1項之用途,該營養組成物進一步包含益生元(prebiotic)。
- 如申請專利範圍第9項之用途,其中該益生元包含聚葡萄糖。
- 如申請專利範圍第10項之用途,其中該益生元進一步包含半乳寡糖。
- 如申請專利範圍第1項之用途,其中該營養組成物進一步包含脂肪來源及碳水化合物來源。
- 如申請專利範圍第1項之用途,其中該營養組成物為嬰兒配方。
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CN110204595A (zh) * | 2019-06-04 | 2019-09-06 | 海普诺凯营养品有限公司 | 一种具有调节b淋巴细胞活性的羊乳酪蛋白水解肽及其制备方法 |
CN110564643B (zh) * | 2019-09-16 | 2021-07-09 | 泰安大凡神农生物有限公司 | 一株具有促骨髓间充质干细胞增殖作用的动物双歧杆菌及其应用 |
CN112753773A (zh) * | 2019-11-11 | 2021-05-07 | 东北农业大学 | 一种降血压牛乳配方奶粉及其制备方法 |
WO2023159125A2 (en) * | 2022-02-17 | 2023-08-24 | Metabico, Inc. | Peptide regulators of metabolism |
CN115536466B (zh) * | 2022-10-09 | 2023-08-25 | 北京中医药大学 | 一种甘草的根瘤菌肥及其制备方法 |
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ZA92452B (en) | 1991-01-24 | 1992-10-28 | Martek Corp | Microbial oil mixtures and uses thereof |
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AU2001258238B2 (en) | 2000-05-12 | 2005-06-23 | Upfront Chromatography A/S | A bed adsorption system |
US6332533B1 (en) | 2000-08-29 | 2001-12-25 | H.H.H. Incorprorated | Media holder mouse pad |
DK1401289T3 (da) | 2001-06-01 | 2005-07-18 | Upfront Chromatography As | Fraktionering af proteinholdige blandinger |
US7368141B2 (en) | 2002-03-07 | 2008-05-06 | Upfront Chromatography A/S | Process of isolating lactoferrin |
US7618669B2 (en) | 2005-06-01 | 2009-11-17 | Mead Johnson Nutrition Company | Low-lactose partially hydrolyzed infant formula |
SG183849A1 (en) * | 2010-05-28 | 2012-10-30 | Mead Johnson Nutrition Co | Nutritional compositions |
US9289461B2 (en) * | 2013-03-15 | 2016-03-22 | Mead Johnson Nutrition Company | Reducing the risk of autoimmune disease |
US9352020B2 (en) * | 2013-03-15 | 2016-05-31 | Mead Johnson Nutrition Company | Reducing proinflammatory response |
US8889633B2 (en) * | 2013-03-15 | 2014-11-18 | Mead Johnson Nutrition Company | Nutritional compositions containing a peptide component with anti-inflammatory properties and uses thereof |
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2015
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2016
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- 2016-06-14 WO PCT/US2016/037330 patent/WO2017014865A1/en active Application Filing
- 2016-06-14 BR BR112018000594A patent/BR112018000594A2/pt not_active Application Discontinuation
- 2016-06-14 MX MX2018000600A patent/MX2018000600A/es unknown
- 2016-06-14 EP EP16732437.5A patent/EP3324991A1/en not_active Withdrawn
- 2016-06-14 CA CA2993294A patent/CA2993294A1/en not_active Abandoned
- 2016-06-14 AU AU2016296111A patent/AU2016296111A1/en not_active Abandoned
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2018
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US20170020950A1 (en) | 2017-01-26 |
PH12018500089A1 (en) | 2018-07-09 |
WO2017014865A1 (en) | 2017-01-26 |
AR105427A1 (es) | 2017-10-04 |
AU2016296111A1 (en) | 2018-01-25 |
CA2993294A1 (en) | 2017-01-26 |
HK1252644A1 (zh) | 2019-05-31 |
MX2018000600A (es) | 2018-06-06 |
EP3324991A1 (en) | 2018-05-30 |
BR112018000594A2 (pt) | 2018-09-11 |
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