TWI639438B - 乳糜瀉和食物過敏之膳食管理 - Google Patents
乳糜瀉和食物過敏之膳食管理 Download PDFInfo
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- TWI639438B TWI639438B TW102119600A TW102119600A TWI639438B TW I639438 B TWI639438 B TW I639438B TW 102119600 A TW102119600 A TW 102119600A TW 102119600 A TW102119600 A TW 102119600A TW I639438 B TWI639438 B TW I639438B
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- celiac disease
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Abstract
本發明透過經腸投予有效量之至少一種水解蛋白及雷曼氏乳酸桿菌GG(LGG)提供膳食管理個體(如哺餵配方奶之嬰幼兒)之乳糜瀉及食物過敏的組成物及方法。本發明之營養組成物可包含除了有效量之LGG的益生菌成分以外,水解蛋白成分、脂質成分、碳水化合物成分、維生素成分、礦物質成分及益菌生成分。
Description
本發明關於透過經腸投予至少一種水解蛋白成分及包含雷曼氏乳酸桿菌(Lactobacillus rhamnosus)GG之益生菌成分,用於膳食管理人個體之乳糜瀉及食物過敏之方法及組成物。本揭示內容另關於包含該益生菌雷曼氏乳酸桿菌GG與至少一種完全水解蛋白成分之營養組成物(諸如嬰兒配方奶或營養補充劑),供管理、緩和或減輕乳糜瀉及/或乳蛋白過敏之症狀及供促進個體之健康腸道的生長及發育。
乳糜瀉(CD)是一種自體免疫媒介性腸道疾病,其發生於當具有遺傳傾向之個體攝取存在於小麥(麥膠蛋白)、黑麥(黑麥醇溶蛋白)、大麥(大麥醇溶蛋白)或彼等之任何雜交變異體中之醇溶蛋白時。(Rizello et al.,Appl Environ Microbiol.2007 Jul;73(14):4499-4507)。在乳糜瀉病患中,攝取醇溶蛋白通常誘發嚴重的腸道症狀,致使小腸黏膜損害,因為這些病患對於小麥麩質及/或相關
之醇溶蛋白不具口服耐受性。舉例來說,在大部分CD病患中,攝取麩質導致活化由Th1發炎前細胞激素主導之適應性免疫反應及由介白素15(IL-15)媒介之先天免疫反應。(Nadal et al.,J Med Microbiol.2007 Dec;56(Pt 12):1669-74)。在乳糜瀉的活性期,乳糜瀉也可能改變上皮通透性及緊密連接之完整性,藉以允許抗原接觸黏膜下層。
乳糜瀉為西方國家最常見的食物相關疾病之一,預估1至3%的歐洲及美國人口受到影響。疾病可在任何年齡出現,可能表現出各種臨床特徵。不過一般來說,在兒童早期即以小腸絨毛萎縮及吸收不良之徵候出現,可能導致兒童及/或嬰兒生長遲緩及/或嚴重營養不良。
CD的早期發生已被歸因於一些遺傳及環境因素。然而,在目前對該疾病的唯一有效治療為終生攝取嚴格的無麩質飲食。(Lindfors et al.,Clin Exp Immunol.2008 Jun;152(3):552-558)。
世界衛生組織的國際食品標準委員會(Codex Alimentarius Commission)以及聯合國糧農組織認定無麩質食物為該些由麩質含量<20ppm之成分組成的食物或麩質含量<200ppm之已被認定為無麩質之食物。(Rizello et al.,Appl.Environ.Microbiol.2007 Jul;73(14):4499-4507)。要達到「無麩質」狀態,在食物中的麩質可在攝取至消化道後被解毒,或可在攝取前的食物加工過程被水解。(Lindfors et al.)。
先前試驗指出,在麵團醱酵中使用益生菌可
在食物加工過程誘發麩質水解,因此有利於提供無麩質食物給乳糜瀉病患之製程(Lindfors et al.)。事實上,藉由使用選擇性麵團醱酵製程,利用CD病患可耐麵粉製作小麥及黑麥麵包或麵條,可能降低特定表位之毒性,但是這些食物中的麩質濃度通常仍超過6,000ppm。(Rizello et al.)。
最近也有發展不含乳糜瀉表位之小麥的研究
。同上。然而,發展不含毒性多肽序列之小麥品種被認為不可能,因為穀類蛋白家族之成員間存在高度序列同源性,因為穀類如小麥為六倍體。同上。因此,需要新的治療選擇。
另外,雖然CD病患遵守嚴格無麩質飲食,他
們還是有可能發展其他食物過敏。舉例來說,乳製品目前被允許作為終生無麩質飲食計畫之一部份。然而,當CD病患的腸道因為疾病影響而逐漸變得受損時,有些病患可能發展出某些程度之乳糖不耐。另外,某些CD病患發展出食物過敏,如牛奶過敏。
食物過敏為免疫媒介性臨床症候群,可能在攝食乳製品後發生。伴隨食物過敏之不良反應通常為立即免疫球蛋白E(IgE)媒介性反應,也稱為食物蛋白過敏。(Host,A.,et al.,Dietary Products Used in Infants for Treatment and Prevention of Food Allergy,Arch.Dis.Child 81:80-84(1999))。食物蛋白過敏之症狀包括血管性水腫、
蕁麻疹、濕疹、氣喘、鼻炎、結膜炎、嘔吐及/或過敏反應。
牛奶過敏是最常見於幼童的食物蛋白過敏,發生在約2%至3%的所有嬰兒。(Sampson,H.A.,Food Allergy.Part 1:Immunopathogenesis and Clinical Disorders,J Allergy Clin Immunol.103:717-728(1999))。大部分嬰兒配方中使用的牛奶蛋白被認為是外來蛋白。當嬰兒暴露於非母乳時,他們可發展出抗外來蛋白之抗體。研究顯示,在乳及黃豆配方中發現的重要食物過敏原在胃中維持長達60分鐘不被消化(相較於母乳蛋白在胃中15分鐘內即被消化)。外來蛋白接著通過胃完整抵達小腸,在該處接觸免疫系統造成過敏化。嬰兒的免疫系統接著「攻擊」外來蛋白,導致過敏反應之症狀。
嬰兒蛋白過敏如此盛行的一個可能解釋為,完整牛奶蛋白是嬰兒最早暴露且最常見的食物過敏原。
因此,需要能被乳糜瀉及/或食物過敏(如牛奶過敏)病患良好耐受之營養組成物(如嬰兒配方),以最小化所包含之免疫誘發表位。
發明簡單說明
因此簡言之,本發明關於經由投予營養組成物供乳糜瀉及/或食物過敏(如牛奶蛋白過敏)之膳食管理的方法及組成物,該營養組成物包括有效量之雷曼氏乳
酸桿菌(Lactobacillus rhamnosus)GG與水解蛋白成分。
在一實施態樣中,本揭示內容關於一種緩和個體之乳糜瀉症狀之方法。該方法包括對個體投予有效量之雷曼氏乳酸桿菌(Lactobacillus rhamnosus)GG。
在另一實施態樣中,本揭示內容關於一種促進乳糜瀉個體之健康腸道發育之方法。該方法包括對該個體投予包含完全水解蛋白與至少一種益生菌之營養組成物,該至少一種益生菌包括雷曼氏乳酸桿菌GG。在另一實施態樣中,本揭示內容關於一種藉由對餵配方之個體投予營養組成物以提供該個體營養支持之方法,該營養組成物包含完全水解蛋白及至少一種益生菌,其中該至少一種益生菌包含雷曼氏乳酸桿菌GG。
在又一實施態樣中,本揭示內容關於一種提供營養支持給罹患乳糜瀉之餵配方嬰兒之方法。該方法包括對該嬰兒經腸投予營養組成物之步驟,該營養組成物包括完全水解蛋白、脂質成分及包括有效量之雷曼氏乳酸桿菌GG之益生菌成分。
應了解的是,前述一般說明及以下之詳細說明皆描述本發明之實施態樣,其意欲提供概述或架構,以供了解本發明所主張之權利範圍的性質及特徵。該說明係用來解釋該主張之專利標的之原則及操作。本發明之其他特徵及優點,在該領域之技藝人士閱讀下列揭示之後將顯而易見。
發明詳細說明
現在將開始詳細說明本發明之實施態樣,以下闡述本發明之一或多個實施例。各實施例係用於解釋,非作為限制之用。事實上,該領域之技藝人士將顯而易見的是,可對本發明之揭示內容進行各種修飾及變化。舉例來說,經示範或描述為一實施態樣之部分的特徵可與另一實施態樣一起使用以產生又一實施態樣。因此,本發明意欲涵蓋屬於該隨附之權利要求及其相等物之範圍內的該等修飾及變化。
定義
以下所稱之「經腸投予」包括但不限於經由鼻胃管餵食、口胃管餵食、胃管餵食、幽門管投予、經口投予及/或經直腸投予。「經腸投予」也可能包括該領域已知之用於導入營養組成物至消化道之任何其他方法。
用語「營養組成物」包括營養補充劑、嬰兒配方、兒童奶粉配方、成長配方、母乳強化劑、嬰兒配方強化劑及類似物,但不限於相同物。本發明之營養組成物可能適用於經腸投予。
用語「嬰兒」係指自出生至不超過約一歲之人個體,包括0至約12個月校正年齡之嬰兒。用語「校正年齡」係指嬰兒的實際年齡減去提早出生的週數。因此,足月出生嬰兒的校正年齡即為實際年齡。用語嬰兒包括低出生體重兒、極低出生體重兒、超低出生體重兒及早產
兒。
用語「兒童」係指年齡約1至12歲的人。在某些實施態樣中,兒童介於約1至6歲。在其他實施態樣中,兒童介於約7至12歲。
用語「水解程度」係指肽鍵藉由水解方法被打斷之程度。
用語「部分水解」係指具有高於0%但低於約50%之水解程度。
用語「完全水解」係指具有高於或等於約50%之水解程度。
用語「不含蛋白」係指以標準蛋白檢測方法如十二基(月桂基)硫酸鈉-聚丙醯胺膠體電泳(SDS-PAGE)或大小排除層析測量時,不含可測量之量的蛋白。
用語「益生菌」係指對宿主健康具有益效應之活微生物。
用語「不活化益生菌」或「不活化LGG」係指該指涉之益生菌或LGG有機體的代謝活性或生殖能力被減少或破壞的益生菌。然而,該「不活化益生菌」或「不活化LGG」在細胞層面仍保留至少部分之生物性醣蛋白及DNA/RNA結構。此處使用之用語「不活化」係與「非活的(non-viable)」同義。
此處使用之所有百分比、部分及比率係根據總組成物之重量計算,除非另外指明。
本發明之營養組成物亦可能實質上不含此處
所述之任何可任選或選擇性成分,惟其該其餘營養組成物仍包含此處所述之所有必要成分或特徵。在此上下文中除非另外說明,用語「實質上不含」係指該選定之組成物包含少於功能性量之該可任選之成分(通常少於0.1重量%),也包括零重量百分比之該可任選或選定之成分。
本發明中指涉之所有單數特徵或限制應包括
該對應之複數特徵或限制,反之亦然,除非在該指涉之上下文中另外特別指明或清楚示意為相反。
本發明所使用之方法或程序步驟之所有組合
可以任何順序進行,除非在該指涉之組合的上下文中另外特別指明或清楚示意為相反。
本發明之方法及組成物(包括彼之成分)可
包含下列、由下列組成或實質上由下列組成:此處所述之本發明之實施態樣的必要元件及限制,以及此處所述或以其他方式用於營養組成物之任何額外或可任選之成分、組分或限制。
此處所使用之用語「約」應被視為指涉任何
範圍所指明之兩個數字。對於一範圍之任何指涉應被視為同樣指涉該範圍內之任何亞群。
實施態樣
本發明提供經由投予包含雷曼氏乳酸桿菌(Lactobacillus rhamnosus)GG(LGG)之益生菌成分以膳食管理乳糜瀉及/或食物過敏之症狀的營養組成物及方法。
該LGG可於健康促進營養組成物中投予,藉由提供包含極少過敏原表位之營養組成物以緩和乳糜瀉及/或食物過敏之症狀。本發明另提供用於提供罹患乳糜瀉及/或食物過敏之個體(如嬰兒)營養支持之方法。本申請專利之發明的完整及可行之揭露,包括與該領域之一般技藝有關之最佳模式係闡述於下。
已知嬰兒腸道的微生物叢發育遠不及成人。
成人的微生物叢係由超過1013微生物及將近500種微生物組成,有些具有害處,有些具有益處,但是嬰兒的微生物叢僅包含該些微生物的一部分,不論在數量或種類變化性上皆然。嬰兒出生時的腸道為無菌狀態,但嬰兒經由產道、環境及攝取的食物獲得腸道菌叢。由於腸道微生物叢族群在新生兒時期相當不穩定,嬰兒的腸道通常很難維持有害及有益細菌之間的微妙平衡,因此降低免疫系統正常作用之能力。
餵配方乳的嬰兒特別難以維持這個平衡,因
為餵配方乳與餵母乳的嬰兒之間的腸道細菌種類有所差異。餵母乳嬰兒的糞便主要包含雙叉乳酸桿菌(Bifidobacterium),鏈球菌(Streptococcus)及乳酸菌(Lactobacillus)則較為少見。相反地,餵配方乳之嬰兒的微生物叢比餵母乳嬰兒的菌叢多變,包含雙叉乳酸桿菌(Bifidobacterium)及桿菌(Bacteroides)以及較具致病性之菌種葡萄球菌(Staphylococcus)、大腸桿菌(Escherichia coli)及梭菌(Clostridia)。餵母乳與餵配方乳嬰兒的糞
便中的雙叉乳酸桿菌(Bifidobacterium)也有所不同。許多因素被提出以解釋餵母乳及餵配方乳嬰兒之間糞便菌叢不同的原因,包括母乳中的蛋白含量較低及組成不同、母乳中的磷含量較低、母乳中寡糖種類繁多及母乳中多種體液性及細胞性免疫功能媒介物。(Agostoni,et al.,Probiotic Bacteria in Dietetic Products for Infants.A Commentary by the ESPGHAN Committee on Nutrition,J.Pediatr.Gastro.Nutr.38:365-374(April 2004))。
由於餵配方乳嬰兒的微生物叢非常不穩定,
他們的腸道微生物叢大部分參與刺激腸道免疫性,餵配方乳之嬰兒很可能發生疾病。因此,研究顯示餵配方乳嬰兒可能比餵母乳嬰兒更早出現乳糜瀉。乳糜瀉對小腸造成損害,導致只會進一步複雜化餵配方乳嬰兒的健康問題之營養吸收問題。
另外,乳糜瀉兒童與年齡相符之對照的總糞
便微生物相之多變性以及乳酸細菌和雙叉乳酸桿菌之菌種組成之間具有顯著差異。(Sanz et al.FEMS Immunol.Med.Micobiol.2007 Dec;51(3):562-8)。事實上,研究顯示活動性乳糜瀉病患的總細菌及革蘭氏陰性細菌的比例顯著較高。(Nadal et al.J Med Microbiol.2007 Dec;56(Pt 12):1669-74)。整體來說,乳糜瀉兒童之十二指腸微生物相的較高革蘭氏陰性及可能的發炎前細菌發生率已被發現與疾病之症狀表現有關且可能促成疾病之病理學過程。(Nadal et al.J Med Microbiol.2007 Dec;56(Pt 12):1669-
74)。
然而,某些益生菌株可能對麩質/麥膠蛋白具
有保護作用,因此改善嬰兒及兒童的乳糜瀉症狀。事實上,益生菌可能保留緊密連接之外表,誘發上皮細胞之黏液分泌或中和由麥膠蛋白誘發之大型膜波緣之形成。
不同的益生菌細菌株具有各自特殊的肽酶,彼此之間可能非常不同,具有不同的受質特異性。(Lindfors et al.Clin Exp Immunol.2008 Jun;152(3):552-558)。舉例來說,一菌株的肽酶貯庫可能只是比另一菌株能更有效地將麥膠蛋白分解成小型無害之肽產物。同上。然而,調節上皮對益生菌之反應的機轉相當複雜且大多未知。
特定乳酸桿菌菌株在人疾病之角色的直接證據過去尚未被提供。(Sanz et al.FEMS Immunol.Med.Micobiol.2007 Dec;51(3):562-8)。然而,本發明之發明人發現,當經腸投予時,特定雷曼氏乳酸桿菌(Lactobacillus rhamnosus)GG(LGG)菌株可緩和乳糜瀉之症狀及促進腸道健康。在一些實施態樣中,LGG可促進上皮細胞之黏液分泌。在其他實施態樣中,LGG可保留緊密連接之形成。在又其他實施態樣中,LGG可中和大型膜波緣之形成。事實上,本發明關於投予有效量之LGG以緩和乳糜瀉及/或食物過敏之症狀,及促進健康腸道發育及生長之方法及營養組成物。
LGG為自健康人腸道菌叢分離之益生菌株。
其係於美國專利第5,032,399號(Gorbach,et al.)中揭示,該專利在此處藉由參照以整體納入。LGG對大多數抗生素具抗藥性,在酸及膽汁存在時維持穩定,且能牢固地附著在人腸道之黏膜細胞。其在大多數個體存活1至3天,在30%的人存活長達7天。除了其定殖能力之外,LGG也有益地影響黏膜免疫反應。LGG以編號ATCC 53103寄存於美國菌種保存中心(ATCC)。
所欲對個體投予之LGG的量為足以提供或遞
送該所欲之將改善如上所述之乳糜瀉及/或食物過敏之症狀的益生菌效應之量。足夠量之LGG可能有廣泛的相異範圍,取決於例如LGG細胞之總量、所需之每日總劑量及本發明之營養組成物的任何實施態樣之其他性質及成分。舉例來說,該營養組成物之一些實施態樣可能包含每克LGG調製劑約104至1012集落形成單位(cfu)。在另一實施態樣中,該營養組成物之每日劑量可能包含每克LGG組成物約107至約1010cfu。在又一實施態樣中,本發明之營養組成物的每日劑量可包含每克LGG組成物約108至約1011cfu。在一特定實施態樣中,本發明之營養組成物的每日劑量可包含每克LGG組成物約109cfu。
另外,在本發明之方法及組成物的一些實施
態樣中,有效量之LGG可能對應約1×104至1×1012cfu/L/kg/day。在另一實施態樣中,有效量之LGG包含投予約1×108至1×109cfu/L/kg/day LGG。在又一實施態樣中,該營養組成物包含投予約1×108
cfu/L/kg/day LGG。
在本發明之方法及組成物中投予LGG之形
式並不重要,只要投予治療有效量即可。事實上,在一些實施態樣中,LGG可被包封於糖、脂質或多醣基材以進一步增加細菌存活之機率。本發明之組成物亦可以適合攝取之形式提供,該形式選自飲料、乳、優格、果汁、水果基底飲料、口嚼錠、甜餅乾、鹹餅乾或彼等之組合。
若個體在出生的第一年吃母乳,則LGG可
經由母親的母乳投予。在此實施態樣中,母親可在餵母乳期間補充LGG,藉此經由母乳轉移有效量之LGG給她的小孩。
若個體在出生的第一年吃配方乳,或個體在
吃母乳之外還補充配方乳,則可補充LGG於嬰兒配方以餵食給該個體。
在一實施態樣中,投予LGG持續至少3個
月。在另一實施態樣中,投予LGG持續至少6個月。在又一實施態樣中,投予LGG持續至少12個月。在特定實施態樣中,產後投予LGG持續不限期。
在本發明之某些實施態樣中,該營養組成物
可能包含一或多種額外之益生菌與LGG。任何該領域已知之益生菌只要達到該所欲之結果即可用於此實施態樣。在特定實施態樣中,該益生菌可選自任何乳酸桿菌(Lactobacillus)菌種或任何雙叉乳酸桿菌(Bifidobacterium)菌種,如龍根雙叉乳酸桿菌(Bifidobacterium longum)及動
物雙叉乳酸桿菌(Bifidobacterium animalis)乳酸亞種BB-12(DSM No.10140)或彼等之組合。
在一實施態樣中,本發明之益生菌可能為活
的或非活的。此處之用語「活的」係指活的微生物。用語「非活的」或「非活的益生菌」係指不是活的益生菌微生物、彼等之細胞成分及/或代謝物。該等非活的益生菌可能經熱殺滅或以其他方式去活,但它們維持有利影響宿主健康之能力。用於本發明之益生菌可能為天然發生、合成或經由基因操作有機體發展,不論該新來源為現在已知或之後發展。
在一些實施態樣中,失活之LGG被用於本發
明之營養組成物。失活可能經由該領域目前已知之任何方法發生。失活可能經由例如熱處理、冷凍乾燥、紫外線、伽瑪輻射、壓力、化學破壞或機械破壞完成。
在本發明之方法及組成物中投予LGG(活化及/或非活化)之形式並不重要,只要投予有效量即可。在一些實施態樣中,該LGG係經由營養組成物投予至個體。在一些實施態樣中,該活化及/或非活化之LGG係以錠劑、丸劑、包封劑、橢圓形錠劑、膠囊錠、膠囊、油滴或小袋形式投予至個體。
在一實施態樣中,非活化之LGG可與一或多種額外之活的及/或非活化之益生菌組合,以緩和個體(如餵配方乳之嬰兒)的乳糜瀉及/或食物過敏之症狀。任何該領域已知之活的或不活化之益生菌只要達到該所欲之
結果即可用於此實施態樣。在特定實施態樣中,該活的及/或不活化之益生菌係選自乳酸桿菌及雙叉乳酸桿菌。
若活的益生菌係與不活化之益生菌組合投予,該活的益生菌之量可能對應每天每公斤體重約1×104至1×1012集落形成單位(cfu)。在另一實施態樣中,該活的益生菌可能包含每天每公斤體重約1×106至1×109cfu。在又一實施態樣中,該活的益生菌可能包含每天每公斤體重約1×108cfu。
此外,在一些實施態樣中,活的及不活化之LGG可彼此組合投予。活的LGG與不活化之LGG的組合被認為可提供在含有這些劑的調製劑之抗發炎性質方面有益或協同效應。雖然不希望受到此理論或任何其他理論之束縛,活的益生菌如LGG被認為部分經由與特定免疫細胞表面上稱為類鐸受器(TLR)之特定受體交互作用以授予抗發炎效應。活LGG與這些受體之間直接或間接的交互作用啟動細胞內信號傳導級聯,導致改變這些標靶細胞中之基因表現。這種特定交互作用及其所導致之基因表現改變與其他細胞效應,被認為與發炎之調節有關。因此,由於活的LGG及不活化之LGG被認為經由不同機轉作用,一般相信組合這些成分提供有益或協同之抗發炎效應。
另外,本發明提供可用於促進個體的健康腸道生長及發育之方法及營養組成物。事實上,除了包含LGG之益生菌成分之外,本發明之營養組成物可提供將促進個體(如兒童或嬰兒)健康發育之有效量的營養。
特別是,本發明之營養組成物可提供給個體
否則可能因為各種原因如乳糜瀉影響所致之營養不良而缺乏之有益營養。該等營養包括但不限於脂質成分、蛋白成分、碳水化合物成分及/或益菌生成分。
另外,該營養組成物可每天投予一至二次或
遵照醫學專業人員指示之更常投予。投予可在出生後立即開始,且可持續在個體有營養需求時投予。
本發明之營養組成物可能包含營養補充劑、
嬰兒配方、兒童配方、成長奶粉或任何其他可食之營養產品。另外,該揭示之營養組成物可能以該領域已知之任何形式提供,如粉、膠、懸浮液、糊料、固體、液體、液體濃縮劑、可重構之奶粉取代物或立即可用之產品。在一些實施態樣中,營養組成物為適合用於經腸投予之液體營養補充劑。在其他實施態樣中,該營養組成物為可用水重構之粉末調製劑。在其他實施態樣中,該營養組成物為可輕易地與母乳或嬰兒配方混合之液體強化劑。
該營養組成物包含含有脂肪或脂肪之組合的
脂質成分,以遞送所欲之脂肪酸混合物給個體。用於實施本發明之適當的脂肪或脂質來源可能包含該領域已知之任何脂質來源,包括但不限於動物來源(如乳脂肪、奶油、奶油脂肪、蛋黃脂質)、海洋來源(如魚油、海洋生物油、單細胞油)、蔬菜及植物油(如玉米油、芥花籽油、葵花油、大豆油、棕櫚油、椰子油、高油酸葵花油、月見草油、油菜籽油、橄欖油、亞麻籽(亞麻仁)油、棉籽油、
高油酸紅花油、棕櫚硬脂、大豆卵磷脂、棕櫚仁油、小麥胚芽油、中鏈三酸甘油酯油)。
另外,所有或部分之脂質成分可能包含脂質乳液。在某些實施態樣中,該脂質成分可能每100mL之營養組成物包含約2.5至約5g。在一些實施態樣中,該營養組成物可能包含約5至約20% w/w之脂質成分。
在一些實施態樣中,該營養組成物包括含有至少一種脂肪酸之脂肪酸成分,如長鏈多不飽和脂肪酸(LCPUFA)或LCPUFA之組合。LCPUFA通常具有至少18之碳鏈長度。用於包含在該營養組成物中之適當LCPUFA包括但不限於花生油酸(ARA)及二十二碳六烯酸(DHA)。在一實施態樣中,該脂質成分包含DHA。在另一實施態樣中,該脂質成分包含ARA。在其他實施態樣中,該營養組成物之脂質成分包含DHA及ARA。包含於該營養組成物中之較佳形式之DHA及ARA為游離、非酯化之DHA及ARA。
在一些實施態樣中,該營養組成物可能包含約0.3%至約5% w/w之DHA。在一些實施態樣中,該營養組成物包括足以遞送每天每公斤體重約3mg至每天每公斤體重約150mg之DHA至個體之量的DHA。在一實施態樣中,該量係每天每公斤體重約6mg至每天每公斤體重約100mg。在另一實施態樣中,該量係每天每公斤體重約10mg至每天每公斤體重約60mg。在又一實施態樣中,該量係每天每公斤體重約15mg至每天每公斤體重
約30mg。
該DHA之來源可能為該領域任何已知來源,如海洋生物油、魚油、單細胞油、蛋黃脂質及腦脂質。DHA可為天然或精製形式。另外,在一實施態樣中,該營養組成物包含含有DHASCO®及/或真菌油混合物之DHA來源。
類似地,在一些實施態樣中,該營養組成物可能經調製以遞送至少約25mg/kg/day之二十二碳六烯酸至該個體。在一些實施態樣中,該營養組成物可能經調製以遞送至少約50mg/kg/day DHA。在其他實施態樣中,該營養組成物可能遞送至少約60mg/kg/day之DHA至該個體。且在一些實施態樣中,該營養組成物可能經調製以遞送至少約75mg/kg/day之二十二碳六烯酸至該個體。在其他實施態樣中,該營養組成物經調製以遞送至少約100mg/kg/day DHA。在一些實施態樣中,用於該營養組成物中之DHA的量為約5mg/100kcal至約80mg/100kcal不等。在一實施態樣中,該量為約10mg/100kcal至約50mg/100kcal不等;且在另一實施態樣中約15mg/100kcal至約20mg/100kcal。在本發明之特定實施態樣中,DHA之量為約17mg/100kcal。在一些實施態樣中,該營養組成物將包含每100mL約12至約200mg之DHA。
該營養組成物可能包含約0.5%至約5% w/w之ARA。在一些實施態樣中,該營養組成物中ARA之量係每天每公斤體重約5mg至每天每公斤體重約150mg。
在一實施態樣中,該量係每天每公斤體重約10mg至每天每公斤體重約120mg不等。在另一實施態樣中,該量係每天每公斤體重約15mg至每天每公斤體重約90mg不等。在又一實施態樣中,該量係每天每公斤體重約20mg至每天每公斤體重約60mg不等。
另外,在一些實施態樣中,該營養組成物可
能經調製以遞送至少約25mg/kg/day之花生油酸至該個體。在一些實施態樣中,該營養組成物可能經調製以遞送至少約40mg/kg/day ARA。在其他實施態樣中,該營養組成物可能遞送至少約50mg/kg/day之ARA至該個體。且在一些實施態樣中,該營養組成物可能經調製以遞送至少約60mg/kg/day之ARA至該個體。
在一些實施態樣中,用於該營養組成物中之
ARA的量為約10mg/100kcal至約100mg/100kcal不等。在一實施態樣中,ARA的量為約15mg/100kcal至約70mg/100kcal不等。在另一實施態樣中,ARA的量為約20mg/100kcal至約40mg/100kcal不等。在本發明之特定實施態樣中,ARA之量為約34mg/100kcal。
ARA來源可為該領域已知之任何ARA來源。
在一些實施態樣中,該營養組成物包含含有ARASCO®及/或真菌油混合物之ARA來源。在一些實施態樣中,該營養添加劑之ARA成分包含約30%之真菌油混合物。
該營養組成物可能添加DHA及ARA作為部分之脂質成分。在一些實施態樣中,該DHA:ARA比率係
約1:6至約6:1。在其他實施態樣中,該DHA:ARA比率係約1:2至約2:1。在又其他實施態樣中,該DHA:ARA比率係約1:1。在仍其他實施態樣中,該DHA:ARA比率可能為約3:1至約1:9。
在一些實施態樣中,該營養組成物另包含蛋
白成分。該蛋白成分可能包含但不限於乳蛋白粉、乳蛋白濃縮物、乳蛋白分離物、脫脂乳固形物、脫脂乳、脫脂乳粉、乳清蛋白、乳清蛋白分離物、乳清蛋白濃縮物、甜乳清、酸乳清、乳酪素、酸乳酪素、酪蛋白鹽(如酪蛋白鈉、酪蛋白鈣鈉、酪蛋白鈣)及彼等之任何組合。
在一實施態樣中,該營養組成物之蛋白成分
可能包含完整蛋白。在其他實施態樣中,該蛋白成分為完整蛋白及部分水解蛋白兩者之組合,該水解程度介於約4%至10%。在其他實施態樣中,該蛋白的水解較為完全。在其他實施態樣中,該蛋白成分包含部分水解蛋白。在另一實施態樣中,該蛋白成分包含完全水解蛋白。在另一實施態樣中,該營養組成物之蛋白成分實質上由完全水解蛋白組成,以最小化食物過敏之發生。在另一實施態樣中,該蛋白來源可能包含含麩醯胺酸之肽。
有些人會對完整蛋白(即全蛋白)過敏或敏
感,如在完整牛奶蛋白或完整大豆蛋白分離物基底配方中之蛋白。這些對蛋白過敏或敏感的人當中,許多能耐受水解蛋白。水解蛋白配方(又稱為半元素配方)包含已經水解或分解成短肽片段及胺基酸之蛋白,因此更容易消化。
在對蛋白敏感或過敏的人當中,免疫系統相關性過敏或敏感通常導致皮膚、呼吸或消化道症狀如嘔吐及下痢。對完整蛋白配方有反應的人通常不會對水解蛋白配方有反應,因為他們的免疫系統不會將該水解蛋白辨識為引起症狀之完整蛋白。
另外,最近研究顯示有些乳糜瀉病患對完整蛋白(特別是牛酪蛋白)之反應係經由血清IgA活性。(Cabrera-Chavez et al.,Nutrition.2009 Jun;25(6):715-716)。研究指出來自牛酪蛋白之表位可能是引發乳糜瀉症狀之原因。同上。
因此,有些麥膠蛋白及牛酪蛋白可能具有被抗麥膠蛋白IgA抗體辨識之相同表位。因此,本發明之營養組成物藉由提供包含水解蛋白之蛋白成分,減少食物過敏(例如蛋白過敏)之發生率,以及CD病患對蛋白如牛酪蛋白之免疫反應。水解蛋白成分相較於完整蛋白成分包含較少之過敏原性表位。
因此,在一些實施態樣中,該營養組成物之蛋白成分包含部分或完全水解之蛋白,如來自牛奶之蛋白。該水解蛋白可能經酶處理以分解造成不良症狀之一些或大部分蛋白,目標為減少過敏反應、不耐及敏感性。另外,該等蛋白可經該領域中習知之任何方法水解。
由於有些麥膠蛋白及牛酪蛋白可能具有引發CD病患之免疫反應的相同表位,因此本發明之營養組成物藉由提供比較不可能引發免疫反應之水解蛋白成分(因
為其經蛋白水解而包含較少過敏原性表位),以緩和、治療或預防CD之症狀。
用於本發明之方法及組成物的水解蛋白(蛋白水解物),是已經水解及分解成較短肽片段及胺基酸之蛋白,其中該導致之水解程度係至少約20%,較佳約20%至約80%。此處使用之用語「水解」係指具有最小水解程度至少約20%之蛋白水解物,其較佳水解範圍如上所述。以最廣義來說,當一或多個醯胺鍵斷裂,蛋白即被水解。醯胺鍵斷裂可能在製造期間非故意或順帶發生,例如由於加熱或剪斷,但就本發明之方法及組成物的目的而言,用語「水解蛋白」僅代表以意圖斷裂醯胺鍵之方式加工或處理之蛋白。意圖水解可能藉由例如用酶或酸處理完整蛋白而起作用。
用語「蛋白水解物」或「水解蛋白」在此處可交換使用,係指經水解之蛋白,其中該水解程度係至少約20%,較佳約20%至約80%,更佳約30%至約80%,甚至更佳約40%至約60%。水解程度為肽鍵藉由水解方法被打斷之程度。就特徵化該營養組成物之水解蛋白成分之目的而言,蛋白水解之程度可輕易地由調製劑領域之一般技藝人士藉由量化該選定調製劑之蛋白成分的胺基氮對總氮比(AN/TN)加以測定。胺基氮成分藉由測定胺基氮含量之USP滴定法測定,而總氮成分藉由Tecator Kjeldahl方法測定,這些方法都是分析化學領域中之一般技藝人士所廣為周知之方法。
當蛋白中之肽鍵被酶水解作用打斷時,每個斷裂之肽鍵會釋出一個胺基,導致胺基氮增加。應注意的是,即使非水解蛋白仍包含一些暴露胺基,具有大於零百分比之AN/TN比。水解蛋白也將與其來源之非水解蛋白具有不同的分子量分布。水解蛋白之功能及營養特性可受到不同大小肽之影響。分子量資料通常以特定範圍之分子量(道爾頓)部分(例如2000至5000道爾頓、大於5000道爾頓)的百分比列示。如前所述,對全蛋白或完整蛋白敏感之人可受益於攝取包含水解蛋白之營養配方。該敏感個體可能特別受益於攝取低過敏配方。
在一些實施態樣中,本發明之營養組成物實質上不含完整蛋白。在此上下文中,用語「實質上不含」係指此處之較佳實施態樣包含足夠低濃度之完整蛋白,因此使該配方為低過敏性。本發明之營養組成物實質上不含完整蛋白,因此為低過敏性之程度,係由美國小兒科學會於2000年8月的政策聲明制定,其中低過敏配方被定義為經適當臨床試驗證明,當該配方在前瞻性隨機雙盲安慰劑對照試驗給予時,其不會在90%經證實對牛奶過敏的嬰兒或兒童中引起過敏反應,具有95%信賴區間。
食物過敏及/或乳蛋白過敏之個體(如嬰兒)的另一種替代性選擇為不含蛋白之以胺基酸為基礎之營養組成物。胺基酸為蛋白質之基本結構建造單位。藉由完整預消化蛋白以將蛋白分解成基本的化學結構,使得以胺基酸為基礎之配方為可獲得之最低過敏性配方。
在特定實施態樣中,該營養組成物不含蛋白
且包含作為蛋白相等來源之游離胺基酸。在此實施態樣中,胺基酸可能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、天冬醯胺酸、天冬胺酸、麩胺酸、麩醯胺酸、甘胺酸、脯胺酸、絲胺酸、肉鹼、牛磺酸及彼等之混合物。在一些實施態樣中,該等胺基酸可能為支鏈胺基酸。在其他實施態樣中,小胺基酸肽可能被包含以作為該營養組成物之蛋白成分。該等小胺基酸肽可能為天然發生或合成。在該營養組成物中之游離胺基酸的量可能為約1至約5g/100kcal不等。在一實施態樣中,100%之游離胺基酸具有少於500道爾頓之分子量。在此實施態樣中,該營養調製劑可能為低過敏性。
在一些實施態樣中,該營養組成物包含碳水
化合物成分。該營養組成物所使用之碳水化合物可能依用途而定為任何可消化之碳水化合物,如乳糖、葡萄糖、果糖、蔗糖、麥芽糖、麥芽糊精、玉米糖漿固體或彼等之混合物。在一些實施態樣中,玉米糖漿固體為較佳。另外,水解、部分水解及/或完全水解之碳水化合物可能適合被包含於該營養組成物,因為彼等易於消化及減輕CD影響之能力。特別是,經水解之碳水化合物比較不可能包含引發CD症狀或使之惡化之過敏性表位。
適合用於此處之碳水化合物材料的非限制性
實例包括源自糯性(waxy)或非糯性形式之玉米、樹薯、米
或馬鈴薯的水解或完整、天然或經化學修飾之澱粉。適當碳水化合物之非限制性實例包括各種水解澱粉,其特徵為水解玉米澱粉、麥芽糊精、麥芽糖、玉米糖漿、葡萄糖、玉米糖漿固體、葡萄糖及各種其他葡萄糖聚合物與彼等之組合。其他適當碳水化合物之非限制性實例包括該些通常被稱為蔗糖、乳糖、果糖、高果糖玉米糖漿、不消化性寡醣如寡果醣及彼等之組合。
在特定實施態樣中,該營養組成物之碳水化
合物成分包含100%乳糖。在另一實施態樣中,該碳水化合物成分包含約0%至60%乳糖。在另一實施態樣中,該碳水化合物成分不含乳糖,其中其包含0%乳糖。在一些實施態樣中,該碳水化合物成分不含半乳糖及/或不含蔗糖,其中其分別包含0%半乳糖及/或蔗糖。在另一實施態樣中,該碳水化合物成分包含約15%至55%乳糖。在另一實施態樣中,該碳水化合物成分包含約20%至30%乳糖。
在這些實施態樣中,碳水化合物之其餘來源可能為該領域已知之任何碳水化合物。在一實施態樣中,該碳水化合物成分包含約25%乳糖及約75%玉米糖漿固體。
該營養組成物可能包括維生素及礦物質成分
。該維生素及礦物質成分可任意選擇地包括但不限於一或多種下列礦物質或其衍生物: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、銅、硫酸銅、葡萄糖酸銅、硫酸銅、氟化物、鐵、羰基鐵、三價鐵離子、反丁烯二酸亞鐵、正
磷酸鐵、研磨鐵、多糖鐵、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、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範性衍生物包括任何礦物質化合物之鹽、鹼式鹽、酯及螯合物。
礦物質可以鹽之形式被添加至該營養產品,如磷酸鈣、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。其他維生素及礦物質可如該領域所知被添加。
該營養組成物之維生素成分可任意選擇地包括但不限於一或多種下列維生素或彼之衍生物:維生素B1(硫胺、焦磷酸噻胺、TPP、三磷酸硫胺素、TTP、鹽酸硫胺、噻胺硝酸鹽)、維生素B2(核黃素、黃素單核苷酸、FMN、黃素腺二核苷酸、FAD、乳黃素、卵核黃素)、維生素B3(菸鹼酸(niacin,nicotinic acid)、菸鹼醯胺(nicotinamide,niacinamide)、菸鹼醯胺腺二核苷酸、NAD、菸鹼酸一核苷酸、NicMN、吡啶-3-羧酸)、維生素B3先驅物色胺酸、維生素B6(吡哆醇、吡哆醛、吡哆胺、鹽酸吡哆醇)、泛酸(泛酸酯、泛酸醇)、葉酸(葉酸(folic acid)、葉酸素(folacin)、喋醯麩胺酸)、維生素B12(鈷胺、甲基鈷胺素、去氧腺嘌呤鈷胺素、氰鈷胺、羥基鈷胺、腺苷鈷胺)、生物素、維生素C(抗壞血酸)、維生素A(視網醇、乙酸視網酯、軟脂酸視網酯、具其他長
鏈脂肪酸之視網酯、視網醛、視網酸、視網醇酯)、維生素D(鈣化醇、膽鈣化醇、維生素D3、1,25,-二羥基維生素D)、維生素E(α-生育酚、α-生育酚醋酸酯、α-生育酚琥珀酸酯、α-生育酚菸鹼酸酯、γ-生育酚)、維生素K(維生素K1、葉醌、萘醌、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。
在某些實施態樣中,本發明之營養組成物可
能包含至少一種益菌生。在此實施態樣中,可能包含該領域已知之任何益菌生。在特定實施態樣中,該益菌生可選自寡果醣、葡萄寡糖、半乳糖寡糖、異麥芽寡糖、木寡糖、乳酮糖、聚葡萄糖及彼等之任何組合。
在一些實施態樣中,聚葡萄糖(PDX)可能以足
以提供約1.0g/L至10.0g/L之量被包含於該營養組成物中。在另一實施態樣中,該營養組成物包含約2.0g/L至8.0g/L之量的PDX。
在本發明之特定實施態樣中,PDX係與半乳
糖寡糖(GOS)組合投予。在此實施態樣中,PDX與GOS可以介於約9:1至1:9之PDX:GOS比例投予。在另一實施態樣中,該PDX:GOS比率可為約5:1至1:5。在又一實施態樣中,該PDX:GOS比率可為約1:3至3:1。在特定實施態樣中,PDX與GOS之比率可為約5:5。在另一特定實施
態樣中,PDX與GOS之比率可為約8:2。
該營養組成物中PDX:GOS組合之量可為約
1.0g/L至10.0g/L。在另一實施態樣中,該PDX:GOS組合之量可為約2.0g/L至8.0g/L。在特定實施態樣中,該PDX:GOS組合之量可為約2g/L之PDX與2g/L之GOS。
本發明之營養組成物亦可包含乳化劑。該乳
化劑可能包含微膠囊、表面活性劑、乳化穩定劑或彼等之組合。在一些實施態樣中,該乳化劑可能包含例如卵磷脂、一甘油酯或二甘油酯。在一些實施態樣中,該營養組成物之脂質成分提供呈穩定乳劑形式之脂肪酸。在其他實施態樣中,該營養組成物可能包含安定劑,如鹿角菜膠,以取代乳化劑或在乳化劑以外另包含之。
另外,該營養組成物之一些實施態樣可能模
擬母乳之某些特徵。然而,為了達成某些個體之特殊營養需求,該營養組成物的一些營養成分之含量可能比母乳更高。舉例來說,該營養組成物可能包含比母乳更高量之DHA。該營養組成物增加之DHA的量補償任何已存在之營養性DHA缺乏。
另外,在一些實施態樣中,該營養組成物具
有完整營養,包含能作為個體之單獨營養來源之適當種類及量的脂質、碳水化合物、蛋白質、維生素及礦物質。事實上,該營養組成物可任意選擇地包括任何數量之蛋白質、肽、胺基酸、脂肪酸、益生菌及/或彼等之代謝副產物、益菌生、碳水化合物及任何其他營養或可提供許多營養
及生理好處給個體之其他化合物。另外,本發明之營養組成物之可能包含香料、調味增強劑、甜味劑、色素、維生素、礦物質、治療性成分、功能性食物成分、食物成分、加工成分或彼等之組合。
本發明另提供一種用於提供營養支持給個體
之方法。該方法包括投予有效量之本發明之營養組成物至該個體。
該營養組成物可直接灌入個體之腸道。在一
些實施態樣中,該營養組成物被直接灌入小腸。在一些實施態樣中,該組成物可能經調製以在醫師之監督下經腸攝取或投予,且可能意圖用於疾病或病況之特定膳食管理,如乳糜瀉及/或食物過敏,其中根據已知科學原則之特殊營養需求係經由醫學評估建立。
本發明之營養組成物不限於包含此處特別列
示之營養之組成物。任何營養皆可作為該組成物之部分遞送,以符合營養需求之目的及/或最佳化個體之營養狀態。
在一些實施態樣中,該營養組成物可能自嬰
兒出生開始遞送直到足月。在一些實施態樣中,該營養組成物可能遞送至嬰兒至少約三個月校正年齡。在另一實施態樣中,只要有校正營養缺乏之需求,即可遞送該營養組成物至個體。在又一實施態樣中,該營養組成物可能自嬰兒出生開始遞送直到至少約六個月校正年齡。在又一實施態樣中,該營養組成物可能自嬰兒出生開始遞送直到至少約一歲校正年齡。
本發明之營養組成物可經標準化為特定熱量
含量,其可提供為立即可用之產品,或可提供為濃縮形式。
本發明提供下列實例以示範該營養組成物的
實施態樣,但不應被解讀為對本發明之限制。該等實例示範含LGG之嬰兒配方奶粉。在這些實例中,嬰兒配方中之三種主要成分係互相混合:粉基底、玉米糖漿固體及蛋白水解物。嬰兒配方之一實施態樣的粉基底成分如表1所示。
將一初始量之LGG添加至表1之粉基底、玉米糖漿固形物及蛋白質水解混合物以製備包含6.25×108cfu/g產品之產品。
表2顯示該粉基底之另一實施態樣。將一初
始量之LGG添加至表2之粉基底,以製備包含5.7×107cfu/g產品之產品。
所有在此申請案中引述之參考資料,包括但
不限於所有文獻、公開資料、專利、專利申請案、口頭報告、文字、報告、手稿、文宣小冊、書籍、網路帖子、期刊文章、期刊及類似物,在此以參照方式整體納入本申請案中。此處之文獻討論僅意圖摘述這些文獻作者作出之結論,並非承認任何參考資料構成現有技術。申請人保留質疑引述文獻之正確性及適當性之權利。
雖然本發明之較佳實施態樣已利用特定用語、方式及方法說明,但該等說明僅供示範之目的。所使用之文字為說明之文字而非限制之文字。應了解的是,該領域之一般技藝人士可進行改變及變化,而不背離本發明於下面申請專利範圍中所闡述之精神或範圍。此外,應了解的是,各種實施態樣之不同態樣可完整或部分互換。舉例來說,雖然已示範說明用於產製該所述之供販售無菌液體營養補充劑之方法,但仍可考慮其他用途。因此,隨附之權利要求的精神與範圍不應被限制於其中包含之較佳版本之說明。
Claims (6)
- 一種營養組成物於製備供緩和乳糜瀉嬰兒或兒童之乳糜瀉症狀並促進乳糜瀉嬰兒或兒童之健康腸道發育的藥物之用途,其中該營養組成物包含完全水解蛋白及含量為107至1010集落形成單位(cfu)/g該營養組成物之雷曼氏乳酸桿菌(Lactobacillus rhamnosus)GG,其中該藥物係經腸投予。
- 如申請專利範圍第1項之用途,其中該營養組成物另包含至少一種長鏈多不飽和脂肪酸。
- 如申請專利範圍第2項之用途,其中該至少一種長鏈多不飽和脂肪酸包含二十二碳六烯酸。
- 如申請專利範圍第2項之用途,其中該至少一種長鏈多不飽和脂肪酸包含二十二碳六烯酸及花生油酸。
- 如申請專利範圍第1項之用途,其中該營養組成物另包含至少一種益菌生(prebiotic)。
- 如申請專利範圍第1至5項中任一項之用途,用於進一步提供乳糜瀉嬰兒或兒童之營養支持。
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US13/528,818 US20130344042A1 (en) | 2012-06-20 | 2012-06-20 | Dietary management of celiac disease and food allergy |
US13/528,818 | 2012-06-20 |
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EP (1) | EP2863761B1 (zh) |
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AR (1) | AR094624A1 (zh) |
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CA (1) | CA2877308C (zh) |
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SG (1) | SG11201407038XA (zh) |
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CN104780932A (zh) | 2012-02-29 | 2015-07-15 | 伊西康内外科公司 | 微生物区系的组合物及与其相关的方法 |
EP3082842B1 (en) * | 2013-12-16 | 2022-04-13 | Société des Produits Nestlé S.A. | Newly identified peptides for use in the induction of oral tolerance |
FR3020949B1 (fr) * | 2014-05-16 | 2018-02-09 | Ecole Normale Superieure De Lyon | Composition permettant de favoriser la croissance juvenile humaine et animale en cas de malnutrition |
FI127483B (en) * | 2014-06-11 | 2018-07-13 | Gut Guide Oy | Microbial marker for celiac disease and related product |
US20160095339A1 (en) * | 2014-10-01 | 2016-04-07 | Mead Johnson Nutrition Company | Nutritional composition for gastrointestinal environment to provide improved microbiome and metabolic profile |
EP3212001A4 (en) | 2014-10-31 | 2018-04-25 | Whole Biome Inc. | Methods and compositions relating to microbial treatment and diagnosis of disorders |
CN106520603B (zh) * | 2016-10-27 | 2020-01-21 | 江南大学 | 一种在细胞水平筛选具有增强肠道细胞紧密连接功能益生菌的方法 |
WO2018227146A1 (en) * | 2017-06-08 | 2018-12-13 | Allergyintellect, Inc | Vitamin d compounds and methods of using the same |
CN111372596A (zh) | 2017-08-30 | 2020-07-03 | 潘德勒姆治疗公司 | 用于治疗微生物组相关病症的方法和组合物 |
US11392854B2 (en) | 2019-04-29 | 2022-07-19 | Kpn Innovations, Llc. | Systems and methods for implementing generated alimentary instruction sets based on vibrant constitutional guidance |
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- 2013-05-22 AU AU2013277652A patent/AU2013277652B2/en active Active
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- 2013-05-22 WO PCT/US2013/042133 patent/WO2013191845A1/en active Application Filing
- 2013-05-22 CA CA2877308A patent/CA2877308C/en not_active Expired - Fee Related
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- 2013-05-22 RU RU2014150662A patent/RU2014150662A/ru not_active Application Discontinuation
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US20130344042A1 (en) | 2013-12-26 |
RU2014150662A (ru) | 2016-08-10 |
WO2013191845A1 (en) | 2013-12-27 |
NZ701398A (en) | 2016-10-28 |
CA2877308C (en) | 2020-04-14 |
CA2877308A1 (en) | 2013-12-27 |
ES2682285T3 (es) | 2018-09-19 |
PH12014502811A1 (en) | 2015-03-02 |
SG11201407038XA (en) | 2014-11-27 |
MY169755A (en) | 2019-05-15 |
AU2013277652B2 (en) | 2016-07-21 |
BR112014027820A2 (pt) | 2017-06-27 |
CN112237280A (zh) | 2021-01-19 |
EP2863761A1 (en) | 2015-04-29 |
EP2863761B1 (en) | 2018-06-27 |
CN104394714A (zh) | 2015-03-04 |
PL2863761T3 (pl) | 2019-03-29 |
TW201410251A (zh) | 2014-03-16 |
ECSP15001892A (es) | 2015-09-30 |
PE20150359A1 (es) | 2015-04-06 |
AR094624A1 (es) | 2015-08-19 |
AU2013277652A1 (en) | 2014-11-13 |
PH12014502811B1 (en) | 2015-03-02 |
HK1207798A1 (zh) | 2016-02-12 |
MX356300B (es) | 2018-05-23 |
MX2014013845A (es) | 2015-02-12 |
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