TW201402130A - 包含蘿蔔硫素之組成物或包含一種蘿蔔硫素前驅物及鎂之組成物 - Google Patents
包含蘿蔔硫素之組成物或包含一種蘿蔔硫素前驅物及鎂之組成物 Download PDFInfo
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- TW201402130A TW201402130A TW102124064A TW102124064A TW201402130A TW 201402130 A TW201402130 A TW 201402130A TW 102124064 A TW102124064 A TW 102124064A TW 102124064 A TW102124064 A TW 102124064A TW 201402130 A TW201402130 A TW 201402130A
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- magnesium
- sulforaphane
- enzyme
- salt
- reducing
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Abstract
本發明係關於一種蘿蔔硫素前驅物、一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素、一種酵素增強劑,以及鎂或鎂之一種鹽類或複合物之組合。本發明亦與一種蘿蔔硫素或蘿蔔硫素之一種之衍生物,以及鎂或鎂之一種鹽類或複合物之組合有關。本發明亦與於一種青花菜萃取物或一種青花菜粉末,以及鎂或鎂之一種鹽類或複合物之組合有關。本發明提供與該些組合有關之組成物及方法。
Description
本申請案主張以下申請案之優先權,各該申請案之全部內容茲列為本申請案之參照:2012年7月5日申請之美國臨時專利申請案61/668,328號;2012年7月5日申請之美國臨時專利申請案61/668,342號;2012年7月5日申請之美國臨時專利申請案61/668,386號;2012年7月5日申請之美國臨時專利申請案61/668,396號;2012年7月5日申請之美國臨時專利申請案61/668,364號;2012年7月5日申請之美國臨時專利申請案61/668,374號;以及2013年3月15日申請之美國臨時專利申請案61/794,417號。
本發明係關於一種蘿蔔硫素前驅物、一種能夠將蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素、一種酵素增強劑(enzyme potentiator),以及鎂或鎂之一種鹽類或複合物之組合。本發明亦係關於一種蘿蔔硫素或一種蘿蔔硫素之衍生物,以及鎂或鎂之一種鹽類或複合物之組合。本發明亦係關於一種青花菜萃取物或一種青花菜粉末,以及鎂或鎂之一種鹽類或複合物之組合。本發明提供與上述組合有關之組成物及方法。
天然物於人類與動物伴侶間之使用日漸廣泛。有些天然物與膳食補充品及醫療用食品結合。本發明所屬技術領域對於可作為化學保護
劑及/或抗氧化劑之補充品有所需求。此外,對於可用在心血管相關疾病及失調之醫藥組成物及膳食補充品,本發明所屬技術領域亦有需求。
現今美國有超過三分之一(8,300萬)的成人患有一種或多種心血管疾病。在美國,心臟病與中風分別為主要致死原因之第一名與第三名,估計每年有935,000例心臟病與795,000例中風發生。將近有6,800萬成人患有高血壓,其中約有半數屬於控制不良高血壓之患者。此外,估計有7,100萬成人患有高膽固醇(即高水平之低密度脂蛋白膽固醇),估計其中有三分之二屬於控制不良高膽固醇之患者。該些健康問題是現今美國最普遍與費用最昂貴的慢性疾病之一,使用於醫療保健上的金錢大約每六美元中就有一美元係花費於此。心血管疾病之「核心」在於血管內皮功能障礙。內皮係由扁平細胞組成的一層薄膜,沿著所有血管排列,是人體最大的器官之一。血管內皮細胞在血液流動、血壓調節、凝血與抗凝血之活性,以及控制白血球細胞之選擇性黏附及組織遷移等方面,扮演至關重要的角色。在美國人口中,血管內皮功能障礙是動脈粥樣硬化、高血壓、血管發炎疾病之最大根本原因,該些疾病會導致許多致命性的心臟、循環、腎臟、神經之病變。總是導致重大心血管疾病之血管內皮功能障礙,經常是由長期發炎狀態所引起,而引起此種狀態之疾病包括糖尿病(第二型與胰島素依賴型糖尿病皆是)、免疫功能失調(例如狼瘡與類風濕性關節炎),以及其他許多慢性疾病。該些疾病與特定發炎指標(inflammatory marker)之水平升高有正向相關,這些指標包括C-反應蛋白(C-Reactive Protein,CRP)、介白素-8(Interleukin-8,IL-8),以及單核球趨化蛋白(Monocyte chemoattractant protein,MCP-1)。控制血管內皮功能障礙之建議包括調整生活習慣,例如
健康飲食、運動、減輕體重、避免抽菸及二手菸、降低膽固醇,以及控制糖尿病。
透過使用天然物獲得化學保護正發展成一種安全、有效、廉價、容易取得、並且實用的方式,用以預防或減少許多會影響人類與家庭動物之疾病的發生。目前已知,能在分子層級傷害細胞之致癌物,經常係以不具毒性的前驅物之型態被攝取及吸入。該些無毒前驅物進入體內後會轉換成致癌物質。化學保護劑,例如能夠活化解毒酵素或其輔助因子的天然物質,可以抵消致癌物之作用及使致癌物被清除。該些天然物質亦可增強其他現存之自然防禦機制,例如免疫系統。
動脈粥樣硬化係由多種不同的發炎串聯(inflammatory cascades)引起。證據顯示,由單核球衍生之巨噬細胞,是血管內皮發炎所涉關鍵細胞類型其中之一。介白素-8(IL-8)負責招引單核球與巨噬細胞,而單核球趨化蛋白(MCP-1)則在該些細胞之遷移與浸潤中發揮作用。目前已發現,在有動脈粥樣硬化的動脈壁上,IL-8與MCP-1之數量會顯著增加,更糟地是還會招引額外的發炎細胞,形成惡性循環。能夠同時抑制兩種生物標記(MCP-1及IL-8)之機制,可減少發炎以及之後的動脈粥樣硬化。Apostolakis等人在Cardiovasc Res,2009,84(3):353-360之文章中,以及Aukrust等人在Arterioscler Thromb Vasc Biol,2008,28:1909-1919之文章中,討論了IL-8在心血管疾病中之作用。Niu等人在Clin Sci(Lond),2009,117(3):95-109之文章中,以及Hoogeveen等人在Atherosclerosis,2005,183(2):301-307之文章中,討論了MCP-1在心血管疾病中之作用。MCP-1及IL-8與許多其他發炎性和血管之疾病及狀況有所相關。與MCP-1和IL-8有所關聯
之疾病與狀況實例包含,但不限於,動脈粥樣硬化、發炎性腸道疾病、發炎性肺部疾病、慢性肝臟疾病、發炎性風濕性疾病、牙齦炎、氣喘、牛皮癬、阿茲海默症、缺血性心臟疾病、急性冠狀動脈症候群、動脈損傷,以及動脈生成。
某些天然物具有抗氧化活性。在老化、神經退化性疾病之進程,以及例如局部缺血之生理創傷中,氧化壓力(Oxidative stress)扮演著主要角色。抗氧化劑可以減少或抑制重要生物分子之氧化,亦能在治療、預防,或減少氧化壓力相關疾病發生等方面發揮其作用。
蘿蔔硫素(sulforaphane)是被認為具化學保護及抗氧化特性的天然物之一實例。蘿蔔硫素係一有機硫化合物,又稱1-isothiocyanato-4-methylsulfinylbutane。蘿蔔硫素前驅物,即蘿蔔苷(glucoraphanin),可以從青花菜、抱子甘藍及甘藍等十字花科蔬菜中獲得。但要獲得產生化學保護所需的水平,必須食用非常大量之蔬菜。蘿蔔苷係由稱作芥子酵素(myrosinase)的一種硫代葡萄糖苷酵素(thioglucosidase enzyme)轉換成蘿蔔硫素,該轉換發生於各種外因性來源(例如十字花科蔬菜)及內因性之腸道菌相中。然而,並非所有動物都能在攝取蘿蔔苷之後將其轉換成蘿蔔硫素,原因很可能是微生物相及整體健康的變化。此外,在例如胃等酸性環境中,蘿蔔苷可能被轉換成惰性代謝物。活性代謝物蘿蔔硫素能夠誘發核轉錄因子nuclear factor erythroid-2-related factor(Nrf2),Nrf2會轉而上調(upregulate)第二階段去毒酵素(Phase II detoxification enzymes)及細胞保護酵素(cytoprotective enzymes)的產生,例如麩胺基硫轉移酵素(glutathione S-transferases)、氧化還原酵素NAD(P)H:quinine
oxidoreductase(NQO1),以及第一型血基質氧化酵素(heme-oxygenase-1,HO-1)。蘿蔔硫素已被認為能誘發該些酵素之產生而不會顯著地改變P450細胞色素酵素之合成。第二階段酵素的上調被認為在各種生物活性中均發揮了作用,包含保護腦部不受細胞毒性影響、保護肝臟不受脂肪蓄積之毒性作用影響,以及其他各種組織之去毒。
蘿蔔硫素其前驅物蘿蔔苷已受到廣泛的研究。Shapiro等人在Nutrition and Cancer,(2006),Vol.55(1),pp.53-62之文章中,討論了一項第一階段臨床試驗,該試驗係測定青花菜芽之硫代葡萄糖苷(glucosinolates)及異硫氰酸酯(isothiocyanates)之安全性、耐受性及代謝。Shapiro等人討論以含有硫代葡萄糖苷(例如蘿蔔苷)或異硫氰酸酯(例如蘿蔔硫素)之青花菜芽萃取物,對健康人類受試者所進行的一項有安慰劑控制組、雙盲、隨機之臨床試驗。該試驗發現,給受試者服用這些物質並不會導致系統的、有臨床顯著性之不良反應。Ye等人在(Clinica Chimica Acta,200,316:43-53)之文章中,討論了青花菜芽之異硫氰酸酯作用於人類時的藥物動力學。
鎂是一種對於身體許多系統,包含肌肉與神經系統,都相當重要的礦物質。鎂對於三酸苷磷酸(adenosine triphosphate,ATP)之代謝不可或缺,且對於蛋白質、脂肪、核酸之生成至關重要。適量水平的鎂對於高血壓的預防相當重要,而高血壓正是造成血管內皮功能障礙的主要原因。鎂對於鈣吸收、鈣調節,以及骨礦化等作用亦相當重要。雖然有許多種型態的鎂鹽可以添加在飲食裡藉此提高鎂攝取量,但其中螯合形態的鎂(螯合鎂,magnesium chelate)已被發現能夠增加鎂的生物利用率,同時降低副作用。舉例而言,與諸如硫酸鎂之鎂鹽類相比,螯合鎂已被發現能夠減
少腹瀉之副作用。
其他補充品亦已知為有益處,尤其在心血管健康方面。維生素K2,又稱甲萘醌類(Menaquinone),係一種脂溶性維生素,已知對身體之鈣調節作用不可或缺。甲萘醌類在自然界中有許多種分子形態,其特性因異戊二烯側鏈之數目(n)而異,並按異戊二烯側鏈之數目命名為甲萘醌-n(M enaquinone-n,MK-n)。MK-7十分容易在製作納豆時的黃豆發酵過程中獲得。低水平的維他命K2與血管鈣化有所關聯,血管鈣化包含動脈粥樣硬化斑塊之鈣化,以及骨質減少和骨質疏鬆等狀況。補充維他命K2可以減少膽固醇斑塊之鈣化、降低動脈剛度,並且促進骨礦化。Zhang等人在Proc.Natl.Acad.Sci.,(1994),Vol.91,pp.3147-3150之文章中,討論了一項對SD大鼠進行之試驗,以測定蘿蔔硫素及與其結構相關之合成降莰基異硫氰酸酯(norbornyl isothiocyanates)之抗致癌活性。該試驗測定出,給予服用蘿蔔硫素在阻斷乳腺腫瘤形成方面有效果。
Cornblatt等人在Carcinogenesis,(2007),Vol.38(7):pp.1485-1490之文章中,討論了一項對SD大鼠進行之試驗,以測定蘿蔔硫素在乳房中之化學預防效果。該試驗測定出,口服蘿蔔硫素會使乳腺上皮細胞中氧化還原酵素NAD(P)H:quinine oxidoreductase(NQO1)之酵素活性增加到三倍,及使第一型血基質氧化酵素(HO-1)之免疫染色提高到四倍。
歐洲專利申請案2 213 280號揭露了包含硫代葡萄糖苷(例如蘿蔔苷)及芥子酵素之配方,其中該配方係封入膠囊或以膜衣包覆。
本說明書所引用之一切參考資料,其全部內容茲以此述及方式納入本說明書。
發明提供一種組成物,該組成物包含:(i)一種蘿蔔硫素前驅物,較佳者為蘿蔔苷;(ii)一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素,較佳者為一種葡萄糖苷酵素,更佳者為一種硫代葡萄糖苷酵素,尤佳者為芥子酵素;(iii)一種酵素增強劑,較佳者為抗壞血酸;以及(iv)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於血管內皮及心血管系統相關疾病之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予該受試者服用:(i)一種蘿蔔硫素前驅物,(ii)一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素,(iii)一種酵素增強劑,以及(iv)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於降低一受試者體內介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)之水平或基因表現之方法,該方法包含給予該受試者服用:(i)一種蘿蔔硫素前驅物,(ii)一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素,(iii)一種酵素增強劑,以及(iv)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於一受試者體內介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)水平升高相關疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予該受試者服用:(i)一種蘿蔔硫素前驅物,(ii)一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素,(iii)一種酵素增強劑,以及(iv)鎂或鎂之一種鹽類或複合物。
本發明提供一種組成物,該組成物包含:(i)蘿蔔硫素或蘿蔔硫素之一種衍生物,以及(ii)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於一受試者體內血管內皮與心血管系統相關疾病之治療、預防、減少
發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予該受試者服用:(i)蘿蔔硫素或蘿蔔硫素之一種衍生物,以及(ii)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於降低一受試者體內之介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)之水平或基因表現之方法,該方法包含給予該受試者服用:(i)蘿蔔硫素或蘿蔔硫素之一種衍生物,以及(ii)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於一受試者體內介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)水平升高相關疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予該受試者服用:(i)蘿蔔硫素或蘿蔔硫素之一種衍生物,以及(ii)鎂或鎂之一種鹽類或複合物。
本發明提供一種組成物,該組成物包含:(i)一種青花菜萃取物或一種青花菜粉末,以及(ii)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於一受試者體內血管內皮與心血管系統相關疾病之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予該受試者服用:(i)一種青花菜萃取物或一種青花菜粉末,以及(ii)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於降低一受試者體內之介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)之水平或基因表現之方法,該方法包含給予該受試者服用:(i)一種青花菜萃取物或一種青花菜粉末,以及(ii)鎂或鎂之一種鹽類或複合物。本發明亦提供一種用於一受試者體內介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)水平升高相關疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予該受試者服用:(i)一種青花菜萃取物或一種青花菜粉末,以及(ii)鎂
或鎂之一種鹽類或複合物。
圖1為一圖表,其呈現在38℃無抗壞血酸環境下蘿蔔苷之轉換,如實例4所述。
圖2為一圖表,其呈現蘿蔔苷在38℃下大約10分鐘內之轉換作為抗壞血酸濃度之函數,如實例4所述。
圖3為一圖表,其呈現在38℃及1mM抗壞血酸環境下,30分鐘內轉換成之蘿蔔硫素,如實例4所述。
圖4為一圖表,其呈現蘿蔔苷在模擬腸液中轉換成蘿蔔硫素,如實例5所述。
圖5為一圖表,其呈現實例6所述之實驗結果。
本發明係關於一種蘿蔔硫素前驅物、一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素、一種酵素增強劑,以及鎂或鎂之一種鹽類或複合物之組合。本發明亦係關於一種蘿蔔硫素或蘿蔔硫素之一種衍生物,以及鎂或鎂之一種鹽類或複合物之組合。本發明亦係關於一種青花菜萃取物或一種青花菜粉末,以及鎂或鎂之一種鹽類或複合物之組合。本發明亦係關於使用鎂或鎂之一種鹽類或複合物,並搭配由下列當中一項或多項所混合之物有關:蘿蔔硫素前驅物、蘿蔔硫素或蘿蔔硫素之一種衍生物,以及青花菜萃取物。本發明提供與該些組合有關之組成物。
本發明亦提供包含給予服用該些組合之方法。某些實施例中,可以給予一受試者服用該組合,以用於受試者之血管內皮與心血管系
統相關疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發。某些實施例中,可以給予一受試者服用該組合,以降低受試者體內介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)之水平或基因表現。某些實施例中,可以給予一受試者服用該組合,以用於受試者體內之介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)水平升高相關疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發。
蘿蔔硫素又稱為1-isothiocyanato-4-methylsulfinylbutane。蘿蔔硫素之衍生物包含但不限於蘿蔔硫素之次硫酸硫代氨基甲酸鹽類似物(sulfoxythiocarbamate analogues)、6-methylsulfinylhexyl isothiocyanate(6-HITC),以及包含蘿蔔硫素結構,但在異硫氰基(isothiocyanato group)及亞碸基(sulfoxide group)間有不同側鏈及/或不同間距基長度之化合物。蘿蔔硫素衍生物之範例包含以下參考資料所述者,各該參考資料之全部內容茲以此述及方式納入本說明書:Hu等人發表於Eur J Med Chem,2013,64:529-539之文章;Ahn等人發表於Proc Natl Acad Sci USA,2010,107(21):9590-9595之文章;Morimistu等人發表於J.Biol.Chem.2002,277:3456-3463之文章,以及Baird等人發表於Arch Toxicol,2011,85(4):241-272之文章。
某些實施例中,該組成物包含蘿蔔硫素或蘿蔔硫素之一種衍生物,較佳者為蘿蔔硫素,其份量為大約1μg至大約10g,較佳者為大約3μg至大約5g,較佳者為大約5μg至大約1000mg,較佳者為大約7μg至大約750mg,更佳者大約為10μg至大約500mg,尤佳者大約為100μg至大約100mg。某些實施例中,適合人類使用之組成物包含大約1mg至大約20mg。
某些實施例中,本發明之方法包含給予一受試者服用蘿蔔硫素或蘿蔔硫素之一種衍生物,較佳者為蘿蔔硫素,其份量為大約1μg至大約10g,較佳者為大約3μg至大約5g,較佳者為大約5μg至大約1000mg,較佳者為大約7μg至大約750mg,更佳者為大約10μg至大約500mg,尤佳者為大約100μg至100mg。在受試者為人類之某些實施例中,該方法包含給予受試者服用大約1mg至20mg。某些實施例中,本發明之方法包含給予一受試者服用蘿蔔硫素或蘿蔔硫素之一種衍生物,較佳者為蘿蔔硫素,其份量為大約0.01μg/kg至大約0.2g/kg,較佳者為大約0.05μg/kg至大約0.07g/kg,更佳者為大約0.07μg/kg至大約15mg/kg,更佳者為大約0.1μg/kg至大約11mg/kg,尤佳者為大約0.2μg/kg至大約7mg/kg。在受試者為人類之某些較佳實施例中,該方法包含給予受試者服用大約2μg/kg至大約2mg/kg之用量,更佳者為大約0.01mg/kg至大約0.3mg/kg之用量。上述該些用量可指每劑服用之量或每日總劑量。每日總劑量係指在24小時內給予一受試者服用之一種化合物或成分之總量。
某些實施例中,該方法包含給予服用一種蘿蔔硫素或蘿蔔硫素之一種衍生物當中不只一者。某些實施例中,該些組成物包含一種蘿蔔硫素或蘿蔔硫素之一種衍生物當中不只一者。舉例而言,該些方法或組成物可同時包含蘿蔔硫素與蘿蔔硫素之一種或多種衍生物,或是同時包含兩種或更多種蘿蔔硫素衍生物。某些實施例中,當該方法或組成物包含一種蘿蔔硫素或蘿蔔硫素之一種衍生物當中不只一者時,上述所提之量可指每種蘿蔔硫素或每種蘿蔔硫素衍生物各別之量,或是所使用的蘿蔔硫素與蘿蔔硫素衍生物之總量。
在本說明書中,「蘿蔔硫素前驅物」一詞係指可用於生產蘿蔔硫素之任何化合物、物質或原料。較佳實施例中,該蘿蔔硫素前驅物包含可被轉換或被代謝成蘿蔔硫素之一種化合物,較佳者為由一種酵素進行轉換或代謝。某些較佳之實施例中,該蘿蔔硫素前驅物包含蘿蔔苷。蘿蔔苷是一種硫代葡萄糖苷,亦稱4-methylsulfinylbutyl glucosinolate及1-S-[(1E)-5-(methylsulfinyl)-N-(sulfonatooxy)pentanimidoyl]-1-thio-β-D-glucopyranose。
某些實施例中,該組成物包含該蘿蔔硫素前驅物,較佳者為蘿蔔苷,其份量為大約1μg至大約10g;較佳者為大約250μg至大約5g;更佳者為大約500μg至大約2000mg;甚佳者為大約1mg至大約750mg,再甚佳者為大約1.5mg至大約250mg,更甚佳者為大約2mg至大約100mg;尤佳者為大約3mg至大約75mg。某些實施例中,適合人類之組成物包含大約3.5mg至大約50mg之蘿蔔素前驅物,較佳者為蘿蔔苷。
某些實施例中,該方法包含給予一受試者服用該蘿蔔硫素前驅物,較佳者為蘿蔔苷,其份量大約為1μg至大約10g,較佳者為大約250μg至大約5g,更佳者為大約500μg至大約2000mg,甚佳者為大約1mg至大約750mg,再甚佳者為大約1.5mg至大約250mg,更甚佳者為大約2mg至大約100mg,尤佳者為大約3mg至大約75mg。在受試者為人類之某些實施例中,該方法包含給予受試者服用大約3.5mg至50mg。某些實施例中,該方法包含給予一受試者服用一份量之蘿蔔硫素前驅物,其用量為大約1μg/kg至大約1000mg/kg,較佳者為大約5μg/kg至大約500mg/kg,更佳者為大約7.5μg/kg至大約100mg/kg,甚佳者為大約10μg/kg至25mg/kg,尤佳者為大
約25μg/kg至大約10mg/kg。在受試者為人類之某些實施例中,該方法包含給予受試者服用大約50μg/kg至大約800μg/kg。上述該些用量可指每劑服用之量或指每日總劑量。
某些實施例中,該方法包含給予服用不只一種蘿蔔硫素前驅物。某些實施例中,該組成物包含不只一種蘿蔔硫素前驅物。某些實施例中,當該方法或該組成物包含不只一種蘿蔔硫素前驅物時,上述該些用量可指每一種蘿蔔硫素前驅物之量,或指該些蘿蔔硫素前驅物之總量。
該蘿蔔硫素前驅物可被轉換或被代謝成蘿蔔硫素。某些實施例中,該蘿蔔硫素前驅物係由一種酵素轉換成蘿蔔硫素。某些實施例中,能夠將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素包含一種葡萄糖苷酵素(glucosidase enzyme),較佳者為一種硫代葡萄糖苷酵素(thioglucosidase enzyme),更佳者為芥子酵素。芥子酵素亦稱硫代葡萄糖苷醣類水解酵素(thioglucoside glucohydrolase)。
某些實施例中,該組成物所包含該酵素之量為大約1pg至大約1μg,較佳者為大約為50pg至大約500ng,尤佳者為大約1ng至大約150ng。某些實施例中,適合人類使用之組成物包含之該酵素為大約5ng至大約75ng。
某些實施例中,該方法包含給予服用該酵素,較佳者為芥子酵素,份量為大約1pg至大約1μg,較佳者為大約50pg至大約500ng,尤佳者為大約1ng至大約150ng。在受試者為人類之某些實施例中,該方法包含給予受試者服用該酵素大約5ng至大約75ng。某些實施例中,該方法包含給予一受試者服用該酵素,用量為大約0.02pg/kg至大約0.02μg/kg,較佳者
為大約0.7pg/kg至大約7ng/kg,尤佳者為大約0.02ng/kg至大約2ng/kg。在受試者為人類之某些較佳實施例中,該方法包含以大約0.1ng/kg至大約1ng/kg之量給予服用。上述該些用量可指每劑服用之量或每日總劑量。
某些實施例中,該方法包含給予服用不只一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素。某些實施例中,該組成物包含不只一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素。某些實施例中,當該些方法或該些組成物包含不只一種酵素時,上述該些用量可指每一種酵素之量,或指該些酵素之總量。
本發明亦提供一種青花菜萃取物及/或一種青花菜粉末之使用,包含但不限於青花菜種子及青花菜芽之萃取物及粉末。本發明提供給與服用青花菜萃取物及/或青花菜粉末之方法,以及包含青花菜萃取物及/或青花菜粉末之組成物。某些實施例中,該青花菜萃取物或青花菜粉末經過標準化處理,使之包含大約1%至大約75% w/w,更佳者為大約2.5%至大約50%,甚佳者為大約5%至大約25%,尤佳者為大約10%至大約20%之一種蘿蔔硫素前驅物,較佳者為蘿蔔苷。青花菜萃取物與青花菜粉末之範例,包含但不限於美國專利5,411,986號;5,725,895號;5,968,505號;5,968,567號;6,177,122號;6,242,018號;6,521,818號;7,303,770號及8,124,135號所述者,各該專利之全部內容茲以此述及方式納入本說明書。青花菜粉末可以經由將青花菜,較佳者為青花菜芽,舉例而言,風乾、冷凍乾燥、滾筒乾燥、噴霧乾燥、加熱乾燥及/或部分真空乾燥而獲得。某些實施例中,該些組成物以及方法包含使用該青花菜萃取物大約1μg至大約10g,更佳者為大約250μg至大約5g,佳者為大約500μg至大約1g,再甚佳者為大約600
μg至大約500mg,更甚佳者為大約750μg至大約400mg,尤佳者為大約1mg至大約300mg。某些實施例中,該青花菜萃取物或青花菜粉末係存在於一組成物中,或係以足夠提供上述該些份量之一種蘿蔔硫素前驅物或蘿蔔硫素之量,而給予一受試者服用。某些實施例中,該組成物可更包含一種酵素增強劑,較佳者為抗壞血酸。某些實施例中,該方法可更包含給予服用一種酵素增強劑,較佳者為抗壞血酸。
該蘿蔔硫素或蘿蔔硫素之一種衍生物,該蘿蔔硫素前驅物,及/或能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素,可取自任何來源,包含但不限於一種或多種之十字花科(亦稱蕓薹科)植物。十字花科植物之範例包含但不限於以下所列者:青花菜、抱子甘藍、花椰菜、甘藍、辣根、歐洲防風草、蘿蔔、山葵、水田芥,以及白芥菜。某些較佳之實施例中,蘿蔔硫素前驅物,較佳者為蘿蔔苷,以及該酵素,較佳者為芥子酵素,係取自青花菜、青花菜芽或青花菜種子。該蘿蔔硫素前驅物及該酵素可由相同的或是不同的來源獲得。某些實施例中,該蘿蔔硫素前驅物與該酵素可皆取自該些植物之一種萃取物或粉末,較佳者為青花菜種子或青花菜芽之一種萃取物或粉末。
本發明提供一種酵素增強劑之使用。酵素增強劑可用來增強能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素的活性。某些實施例中,該酵素增強劑包含一種酵素輔助因子,較佳者為抗壞血酸。抗壞血酸,又稱抗壞血酸鹽或維生素C,能夠激活芥子酵素之活性。某些實施例中,當沒有諸如抗壞血酸之酵素增強劑存在時,轉換成蘿蔔硫素之反應可能會太慢,以致無法在最大吸收(peak absorption)所需之位置發生。該酵素增強
劑可取自一天然來源或以合成方式生產。
某些實施例中,該些組成物可包含該酵素增強劑大約1mg至大約500mg,較佳者為大約1mg至250mg,尤佳者為大約1mg至大約125mg。某些較佳之實施例中,適合人類使用之組成物包含該酵素增強劑大約1mg至大約50mg。
某些實施例中,本發明之該方法包含給予服用一種酵素增強劑,較佳者為抗壞血酸,其份量為大約1mg至大約500mg,較佳者為大約1mg至250mg,尤佳者為大約1mg至大約125mg。在受試者為人類之某些較佳實施例中,該方法包含給予服用大約1mg至50mg。某些實施例中,本發明之該方法包含給予服用該酵素增強劑,較佳者為抗壞血酸,用量為大約0.01mg/kg至大約3mg/kg,尤佳者為大約0.02mg/kg至大約2mg/kg。在受試者為人類之某些較佳實施例中,該方法包含以大約0.02mg/kg至0.7mg/kg之量給予服用該酵素增強劑。上述該些用量可指每劑服用之量或每日總劑量。
某些實施例中,該方法包含給予服用不只一種酵素增強劑。某些實施例中,該組成物包含不只一種酵素增強劑。某些實施例中,當該方法或該組成物包含使用不只一種酵素增強劑時,上述該些用量可指每一種酵素增強劑之量,或指該些酵素增強劑之總量。
本發明更包含鎂或鎂之一種鹽類或複合物。本發明提供任何含有鎂之化合物的使用,例如鎂油。鎂鹽類包含但不限於:硫酸鎂、氧化鎂、檸檬酸鎂、麩氨酸鎂(magnesium glutamate)、葡萄糖酸鎂(magnesium gluconate)、甘氨酸鎂(magnesium glycinate)、溴化鎂、碳酸鎂、化鎂、氟化鎂、碘化鎂、硝酸鎂、過酸鎂、過錳酸鎂、磷酸鎂、乳清酸鎂(magnesium
orotate)、蘋果酸鎂、門冬氨酸鉀鎂(magnesium aspartate),以及蘋果酸二鎂(dimagnesium malate)。鎂之複合物包含但不限於螯合鎂,例如雙甘氨酸螯合鎂(magnesium bisglycinate chelate)、賴氨酸甘氨酸螯合鎂(magnesium lysinate glycinate chelate)、甘氨酸谷氨酸螯合鎂(magnesium glycinate glutamine chelate)。某些較佳之實施例中,該鎂或鎂之一種鹽類或複合物包含硫酸鎂、氧化鎂、檸檬酸鎂、蘋果酸鎂、甘氨酸鎂、蘋果酸二鎂,或雙甘氨酸螯合鎂。某些實施例中,本發明之該些組成物及/或方法包含蘋果酸鎂,或雙甘氨酸螯合鎂,其為一種生物可利用之鎂的型態,具有低不良副作用、低度藥物交互作用,以及高吸收率。某些實施例中,該些組成物及/或方法包含使用不只一種之鎂或鎂之一種鹽類或複合物。
某些實施例中,可使用鎂或鎂之一種鹽類或複合物。某些實施例中,本發明之組成物包含大約1mg至大約1000mg,較佳者為大約5mg至大約750mg,更佳者為大約10mg至大約500mg,尤佳者為大約15mg至大約350mg。在該組成物適合人類使用之某些較佳實施例中,該組成物包含大約20mg至大約200mg之元素鎂(elemental magnesium)。
某些實施例中,本發明之方法包含給予服用大約1mg至大約1000mg,較佳者為大約5mg至大約750mg,更佳者為大約10mg至大約500mg,尤佳者為大約15mg至大約350mg之元素鎂。在受試者為人類之某些較佳實施例中,該方法包含給予服用大約20mg至大約200mg之元素鎂。某些實施例中,本發明之方法包含以大約0.1mg/kg至大約15mg/kg,較佳者為大約0.15mg/kg至大約10mg/kg,更佳者為大約0.2mg/kg至大約7.5mg/kg,甚佳者為大約0.3mg/kg至大約5mg/kg,尤佳者為大約0.3mg/kg至大約4mg/kg
之用量給予服用元素鎂。在受試者為人類之某些較佳實施例中,該方法包含以大約0.3mg/kg至大約3mg/kg之用量給予服用元素鎂。上述該些用量可指每劑服用之量或每日總劑量。
某些實施例中,該方法包含給予服用不只一種之鎂或鎂之一種鹽類或複合物。某些實施例中,該組成物包含不只一種之鎂或鎂之一種鹽類或複合物。某些實施例中,當該方法或該組成物包含不只一種之鎂或鎂之一種鹽類或複合物時,上述該些用量可指每一種鎂或鎂之一種鹽類或複合物之量,或指該些鎂或鎂之一種鹽類或複合物之總量。
某些實施例中,可更使用一種維生素K2。該選擇性添加之維生素K2可提供協同作用。維生素K2,又稱甲萘醌類(menaquinone),能夠以甲萘醌-4(MK-4)、甲萘醌-5(MK-5)、甲萘醌-6(MK-6)、甲萘醌-7(MK-7)、甲萘醌-8(MK-8)、甲萘醌-9(MK-9)、甲萘醌-10(MK-10)、甲萘醌11(MK-11),以及葉醌(phylloquinone)之形態提供。葉醌可以取自諸如綠色葉菜等植物來源,葉醌在血漿中的半衰期很短,但可以由內皮細胞、睪丸及胰臟轉換成甲萘醌-4(MK-4)。葉醌可由腸道細菌合成,亦可存在於乳酪中。某些較佳之實施例中,維生素K2係由甲萘醌-7(MK-7)提供。
某些實施例中,該組成物包含甲萘醌-7(MK-7)大約10μg至大約500μg,較佳者為大約20μg至大約400μg,更佳者為大約為40μg至大約300μg,尤佳者為大約50μg至大約250μg。在該組成物適合人類使用之某些較佳實施例中,該組成物包含甲萘醌-7(MK-7)大約75μg至大約250μg。
某些實施例中,該方法包含給予服用甲萘醌-7(MK-7)大約10μg至大約500μg,較佳者為大約為20μg至大約400μg,更佳者為大約為40μg
至大約300μg,尤佳者為大約為50μg至大約250μg。在受試者為人類之某些較佳實施例中,該方法包含給予一受試者服用甲萘醌-7(MK-7)大約75μg至大約250μg。某些實施例中,該方法包含以大約0.1μg/kg至大約8μg/kg,較佳者為大約0.3μg/kg至大約5μg/kg,更佳者為大約0.5μg/kg至大約4.5μg/kg,尤佳者為大約0.75μg/kg至大約3.5μg/kg之量,給予一受試者服用甲萘醌-7(MK-7)。在受試者為人類之某些較佳實施例中,該方法包含以大約1μg/kg至大約3μg/kg之量,給予一受試者服用甲萘醌-7(MK-7)。上述該些用量可指每劑服用之量或每日總劑量。
本發明之該些組成物與方法所含之每一種成份,例如,該蘿蔔硫素前驅物、能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素、該酵素增強劑,以及鎂或鎂之一種鹽類或複合物,可取自一天然來源或以合成方式生產。
本發明之方法可更包含給予服用一種或多種額外成分。本發明之組成物可更包含一種或多種額外成分。該些額外成分可包含有效藥劑成分、營養補充劑及營養萃取物。額外成分之範例包含,但不限於,葡聚醣、熊果酸、槲皮素或槲皮素之一種衍生物、一種胺基糖類,例如葡萄糖胺、一種葡萄胺聚糖,例如軟骨素、鱷梨/大豆之不皂化物、維生素,例如維生素K2、咖啡果實、鎂、熊果酸、原花青素、α-及β-葡聚醣、薑黃素、植物固醇、植物固烷醇,以及S-腺苷甲硫胺酸(SAMe)。該些額外成分可存在於乳薊(Silybum marianum)之萃取物(水飛薊素)、蔓越橘(Vaccinium macrocarpon)之萃取物(原花青素、槲皮素及熊果酸)、薑黃(Curcuma longa)、藥用蕈菇(例如舞菇或靈芝)中。
某些實施例中,鎂或鎂之一種鹽類或複合物對蘿蔔硫素或蘿蔔硫素之一種衍生物之比為大約1:1至大約50:1,較佳者為大約1.5:1至大約20:1,更佳者為大約1.75:1至大約15:1,甚佳者為大約2:1至大約11:1,尤佳者為大約2:1至8:1。某些實施例中,鎂或鎂之一種鹽類或複合物對蘿蔔硫素前驅物之比為大約1:1至大約25:1,較佳者為大約2:1至大約10:1,更佳者為大約3:1至大約8:1,甚佳者為大約4:1至大約7:1,尤佳者為大約4:1至大約6:1。
某些實施例中,該組成物包含一種單位劑量形式,其包含但不限於適合口服、直腸給藥、靜脈注射、皮下注射、肌肉注射、經皮吸收、經黏膜吸收,以及局部給藥之醫藥劑量形式。某些較佳之實施例中,該組成物包含一種口服劑型或一種直腸給藥劑型。口服劑型之範例包含,但不限於藥錠、膠囊、可分散於飲料中之粉末、一種液體,例如溶液、懸浮液、或乳劑、一種軟膏/咀嚼膠囊、一種咀嚼棒,或本發明所屬技術領域中已知之其他合適劑型。某些較佳之實施例中,該組成物包含一種藥錠、膠囊或柔軟之咀嚼點心。該些口服劑型可製備成立即釋放、持續釋放或延遲釋放。
某些實施例中,用於提供至少該蘿蔔硫素前驅物、該酵素,以及該酵素增強劑之一劑型,係能夠在消化道中pH值至少為4之一區域,較佳者為pH值至少為5之一區域釋放者,例如小腸,較佳者為十二指腸。某些實施例中,用於提供至少該蘿蔔硫素或蘿蔔硫素衍生物及/或該青花菜萃取物或青花菜粉末之一劑型,係能夠在消化道中pH值至少為4之一區域,較佳者為pH值至少為5之一區域釋放者,例如小腸,較佳者為十二指腸。某些實施例中,該鎂或鎂之一種鹽類或複合物及/或任何選擇性額外成分,亦釋放
於消化道中pH值至少為4之一區域,較佳者為pH值至少為5之一區域,例如小腸,較佳者為十二指腸。前文所述之小腸包含十二指腸、空腸及迴腸。
某些實施例中,每一種成分(亦即蘿蔔硫素前驅物、酵素、酵素增強劑、蘿蔔硫素或蘿蔔硫素之一種衍生物、青花菜萃取物或青花菜粉末、鎂或鎂之一種鹽類或複合物,及/或額外成分)係同時釋放或相伴釋放(亦即在一短時間內彼此伴隨釋放)。這種方式優於被製備成在消化道中具有pH值低於4之一區域,例如胃,釋放之含蘿蔔苷之組成物。因在此種低pH值環境下,其酸性環境會將蘿蔔硫素前驅物改而轉換成生理上非活性之其他最終產物,例如蘿蔔硫腈(sulforaphane nitrile)及環硫腈(epithionitrile)。
某些實施例中,該些組成物可包括含有胃腸保護配方之口服組成物,其包含腸溶膜衣劑型或在pH值小於4之消化道區域中,例如胃,耐降解之任何劑型。舉例而言,該口服組成物可包括含腸溶膜衣之一藥錠或膠囊。該腸溶膜衣所包括之材料可包括,但不限於乙醯醋酸纖維素(cellulose acetate phthalate)、鄰苯二甲酸羥丙基甲基纖維素(hydroxypropyl methylcellulose phthalate)、聚乙烯鄰苯二甲酸乙酸(polyvinyl acetate phthalate)、甲基丙烯酸共聚物(methacrylic acid copolymer)、甲基丙烯酸:丙烯酸酯共聚物(methacrylic acid:acrylic ester copolymer)、羥丙基甲基纖維素琥珀酸醋酸鹽(hydroxypropyl methylcellulose acetate succinate)、羥丙基甲基纖維素偏苯三甲酸酯(hydroxypropyl methylcellulose trimellitate)、蟲膠(shellac)、乙酸偏苯三甲酸酯纖維素(cellulose acetate trimellitate)、羧甲基乙基纖維素(carboxymethylethylcellulose),以及各項之混合物。該腸溶膜衣可包含本發明所屬技術領域中已知之任何合適之腸溶性聚合物。某些實施
例中,該組成物之一種或多種成分可嵌入腸溶性聚合物之一基質。某些實施例中,該些口服組成物包含會在胃酸中緩慢溶解並移動至小腸之一種耐酸膠囊,例如CAPSUGEL®所銷售之DRCAPSTM耐酸膠囊,或其他任何耐酸膠囊。
在最佳形式下,該口服組成物係由一膜衣包圍,該膜衣只會在周圍介質之pH值至少為4,更佳者為pH值至少為5,時才會溶解。作為一替代方案,可採用一種由時間而非pH值來控制釋放之膜衣,其釋放速率被調整至只有在消化道之pH值上升到至少為4,更佳者為上升到至少為5,該些成分才會被釋放。因此,一種依時間釋放之配方可用於防止該蘿蔔硫素前驅物、能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素及該酵素增強劑,或是防止該蘿蔔硫素,於胃部釋放。該(些)膜衣層可以標準包覆技術應用於口服組成物。該些腸溶膜衣之材料能溶解或分散於有機溶劑或水溶劑中。使該腸溶膜衣開始溶解之pH值,可經由具選定之側鏈基及/或側鏈基比率之一種聚合物或多種聚合物之組合加以控制。舉例而言,該聚合物膜之溶解特性可以透過游離羧基對酯基之比例變化而改變。腸溶膜衣層亦含有醫藥上可接受之塑化劑,例如檸檬酸三乙酯(triethyl citrate)、鄰苯二甲酸二丁酯(dibutyl phthalate)、三醋汀(triacetin)、聚乙二醇(polyethylene glycols)、聚山梨醇酯(polysorbates)或其他塑化劑。添加物亦可包含在內,例如分散劑、著色劑、抗黏著劑及抗發泡劑。
該些組成物可包含一種或多種非有效藥劑成分(通常亦稱「賦形劑」)。非有效成分,舉例而言,有助於溶解、懸浮、稠化、稀釋、乳化、穩定、保存、保護、著色、調味,以及塑造該些有效成分,使其成
為可適用及有效之一種製劑,該製劑是安全、方便並在其他方面可以使用的。該些賦形劑最好為醫藥上可接受之賦形劑。醫藥上可接受之賦形劑類別之範例包含潤滑劑、緩衝劑、穩定劑、起泡劑、色素、著色劑、調味劑、充填劑、增積劑、香水、釋出修飾劑(release modifiers)、佐劑、塑化劑、流加速劑(flow accelerators)、離型劑、多元醇、造粒劑(granulating agents)、稀釋劑、黏合劑、緩衝劑、吸收劑、滑動劑、黏合劑、抗黏劑、酸化劑、軟化劑、樹酯、緩和劑、溶劑、表面活性劑、乳化劑、彈性體,以及各項之混合物。
某些實施例中,(i)一種蘿蔔硫素前驅物,較佳者為蘿蔔苷,(ii)一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素,較佳者為一種葡萄糖苷酵素,更佳者為一種硫代葡萄糖苷酵素,尤佳者為芥子酵素,(iii)一種酵素增強劑,較佳者為一種酵素輔助因子,更佳者為抗壞血酸,以及(iv)鎂或鎂之一種鹽類或複合物之組合,表現出協同作用。某些實施例中,蘿蔔硫素(或一種蘿蔔硫素前驅物)與鎂或鎂之一種鹽類或複合物之組合表現出協同作用。協同作用係指兩種或多種成分之組合所提供之效果,大於該些作用物單獨使用時所產生效果之總和。某些較佳之實施例中,該協同作用大於累加作用。某些實施例中,一種蘿蔔硫素前驅物、一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素、一種酵素增強劑,以及鎂或鎂之一種鹽類或複合物之組合,相較於下列情況而有統計顯著性之較大效果:(i)僅有各單獨成分,(ii)僅有該蘿蔔硫素前驅物及該酵素之組合;及/或(iii)僅有該蘿蔔硫素前驅物、該酵素及該酵素增強劑之組合。
較佳實施例中,該蘿蔔硫素前驅物、該酵素、該酵素增強劑,
以及鎂或鎂之一種鹽類或複合物之組合,因相較於僅有該蘿蔔硫素前驅物及僅有鎂或鎂之一種鹽類或複合物之情況,顯示出有統計顯著性及/或大於累加之效應,而證實其協同作用。某些實施例中,相較於僅有蘿蔔苷、芥子酵素、抗壞血酸之組合,以及相較於僅有鎂之情況,蘿蔔苷、芥子酵素、抗壞血酸,以及鎂或鎂之一種鹽類或複合物之組合,具有協同作用。
某些實施例中,一種蘿蔔硫素(或蘿蔔硫素之一種衍生物)及鎂或鎂之一種鹽類或複合物之組合,較下列情況有統計顯著性及/或大於累加之效應:(i)僅有蘿蔔硫素(或蘿蔔硫素之一種衍生物),及/或(ii)僅有鎂或鎂之一種鹽類或複合物。某些實施例中,相較於僅有蘿蔔硫素及僅有葡聚醣之情況,蘿蔔硫素及葡聚醣之組合具有協同作用。
某些實施例中,青花菜萃取物或青花菜粉末及鎂或鎂之一種鹽類或複合物之組合,較下列情況有統計顯著性及/或大於累加之效應:(i)僅有青花菜萃取物或青花菜粉末,及/或(ii)僅有鎂或鎂之一種鹽類或複合物。某些實施例中,相較於僅有青花菜萃取物或青花菜粉末及僅有鎂之情況,青花菜萃取物或青花菜粉末及MK-7之組合具有協同作用。
本發明提供使用之方法,其包含給予有需要之一受試者服用之方法。某些實施例中,該方法包含給予服用一種蘿蔔硫素前驅物、一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素、一種酵素增強劑,以及鎂或鎂之一種鹽類或複合物之組合。某些實施例中,該方法包含給予服用一種蘿蔔硫素或蘿蔔硫素之一種衍生物,以及鎂或鎂之一種鹽類或複合物之組合。某些實施例中,該方法包含給予服用一種青花菜萃取物或青花菜粉末,以及鎂或鎂之一種鹽類或複合物之組合。
某些實施例中,該些方法係關於一受試者之疾病或狀況,例如血管內皮及心血管系統相關疾病或狀況,之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發。某些較佳之實施例中,該些疾病及狀況包含動脈粥樣硬化、缺血性心臟疾病、急性冠狀動脈症候群,或動脈損傷。該些方法亦可與降低血管內皮之C-反應蛋白以減少血管發炎、增加血管內皮之一氧化氮以促使血管擴張改善血流量、減少動脈粥樣硬化斑之鈣化、減少血管損傷或剛度,以及/或增加骨礦物質密度有關。
某些實施例中,該組合可給予一受試者服用,以降低其體內介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)之水平或基因表現。某些實施例中,該組合可給予一受試者服用,以用於其體內與介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1)水平升高相關疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發。
在本說明書中,疾病與狀況之範例包含,但不限於:動脈粥樣硬化、發炎性腸道疾病、發炎性肺部疾病、慢性肝臟疾病,例如肝硬化、發炎性風濕性疾病、骨關節炎、牙齦炎、氣喘、牛皮癬、阿茲海默症、缺血性心臟疾病、急性冠狀動脈症候群、動脈損傷、動脈生成、憂鬱症、第二型糖尿病、代謝症候群、大腸癌、偏頭痛、氣喘、腎臟疾病、骨質疏鬆症、萊姆病、缺血性失調、神經病變、消化道疾病,以及專門發生於動物身上之疾病,例如蹄葉炎(例如,發生於馬身上者),以及心絲蟲治療(例如,發生於犬貓身上者)後之症狀。該些組成物亦能在手術後給予服用。
某些實施例中,該些方法係關於為生物標記提供有益之影響,以及該些生物標記之異常水平之治療、預防、減少發生、減輕相關症
狀。此等生物標記之範例包含,但不限於NADPH依賴性酵素(NADPH-dependent enzymes)、硫氧化還原蛋白(thioredoxin,TXN)、硫氧化還原蛋白還原酵素(thioredoxin reductase-1,Txnrd-1)、麩胺酸-半胱胺酸接合酵素次單位(glutamate-cysteine ligase subunit,GCLC)、亞硫酸基轉移酵素1A1(sulfotransferase 1A1,SULT1A1)、第一型血基質氧化酵素(heme oxygenase-1,HMOX1)、麩胺基硫過氧化酶-3(glutathione peroxidase-3,GPx-3)、麩胺基硫轉移酵素theta 2(glutathione S-transferse theta 2,GSTT2)、微粒體麩胺基硫轉移酵素1(microsomal glutathione S-transferase 1,MGST1)、醛氧化酵素(aldehyde oxidase,AOX1)、醛酮還原酵素1B8(aldo-keto reductase 1B8,Akr1b8)、含黃素之單氧酵素2(flavin-containing monooxygenase 2,FMO2)、Fc受體區域受體III(Fc receptor region receptor III,Fcgr3)、類胰蛋白酵素beta 1(tryptase beta 1,TPSB1)、肥大細胞蛋白分解酵素-6(mast cell protease-6,Mcpt6)、神經細胞表面蛋白-1-alpha(neurexin-1-alpha,NRXN-1)、小眼症相關轉錄因子(microphthalmia-associated transcription factor,MITF)、第二型碘化甲狀腺素脫碘酵素(type II iodothyronine deiodinase,DIO2)、血管生成素-14(angiopoietin-14,Angpt14)、細胞膜表面抗原分化群36(cluster of differentiation,CD36),以及Ntel。與該些生物標記之高水平或異常水平相關之疾病或狀況包含,但不限於癌症、肺結核與中樞神經系統結核、多發性硬化症、局部性迴腸炎、動脈粥樣硬化、骨關節炎、氣喘、中風、肺氣腫、糖尿病性腎病變、胎盤之慢性組織細胞絨毛炎、高血壓、腹主動脈瘤、發炎性腸道疾病、慢性鼻竇炎、冠狀動脈疾病,以及腎臟疾病。
某些實施例中,該方法包含給予一有需要之受試者服用蘿蔔硫素及鎂或鎂之一種鹽類或複合物之組合。某些實施例中,該方法包含給予一有需要之受試者服用青花菜萃取物或青花菜粉末及鎂或鎂之一種鹽類或複合物之組合。某些較佳之實施例中,該方法包含給予該受試者服用蘿蔔苷、芥子酵素、抗壞血酸,以及鎂或鎂之一種鹽類或複合物之組合。在較佳之實施例中,該些組合在本發明之該些方法中表現出協同作用。
在較佳之實施例中,該些組合之一種或多種成份(例如,該蘿蔔硫素前驅物、能將蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素、該酵素增強劑、該鎂或鎂之一種鹽類或複合物;或是該蘿蔔硫素或其衍生物以及該鎂或鎂之一種鹽類或複合物;或是該青花菜萃取物或青花菜粉末以及該鎂或鎂之一種鹽類或複合物),係以單一組成物或單一劑型之方式一起服用,或者係分開服用,較佳者為在該些成分之治療性質互相重疊之一段時間內服用。某些實施例中,該些組合之成份可以兩個或更多個口服組成物或劑型之方式服用。舉例而言,某些實施例中,該蘿蔔硫素前驅物、能將蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素,係以單一口服劑型之方式服用,而該鎂或鎂之一種鹽類或複合物則以分開或額外之一個或多個口服劑型之方式服用。在較佳之實施例中,該組合之該些成份係以單一劑型之方式服用。
某些實施例中,該組合可以每日一次至十次之頻率服用,較佳者為每日一次至五次,更佳者為每日一次至三次,尤佳者為每日一次。
於本申請案揭露之該些劑量係泛指適用於人類之劑量。劑量之計算,可由熟悉本發明所屬技術領域者進行體重、表面積、代謝率,以
及物種差異之評估後加以判定。
在本說明書中,「受試者」一詞係指任何動物,包含哺乳類與鳥類。哺乳動物包含,但不限於人類、狗、貓、馬、牛、駱駝、象、獅、虎、熊、海豹,以及兔。在較佳之實施例中,該些受試者包含非供食用之哺乳動物,例如人類、貓及狗。
以下為一示範性配方:
含蘿蔔苷之青花菜種子萃取物(濃度大約12%w/w),50mg至5g
含芥子酵素之冷凍乾燥青花菜芽粉末,25mg至500mg
抗壞血酸,5mg至500mg
蘋果酸鎂,其提供20mg至200mg之元素鎂。
一種疏水性交互作用層析(hydrophobic interaction chromatographic,HILIC)法已研究出來,該方法包含以下條件:
層析管柱:沃特斯公司(Waters Corp.)之BEH(ethylene bridged hybrid)
醯胺,粒徑1.7-μm;內徑2.1mm x 100mm
流動相溶液:20% 10mM之醋酸胺,pH 5.0;80%之乙腈
分離方式:等位(isocratic)
管柱溫度:70℃
流率:0.7mL/min
以上之條件允許分離五種典型的十字花科硫代葡萄糖苷,包含蘿蔔硫素前
驅物,蘿蔔苷。
蘿蔔苷消耗量作為抗壞血酸濃度之函數。
在有可變濃度之抗壞血酸(範圍由0至600μmoles/Liter)環境
下,以取自青花菜芽之固定濃度之芥子酵素,將含有約12%(w/w)蘿蔔苷之大約250mg青花菜種子萃取物加以水解。使該些反應混合物保持在38℃之恆溫下計60分鐘,每過15分鐘取出等份量(aliquots)之實驗試樣,並以層析法測定蘿蔔苷之濃度。蘿蔔苷之消耗速率解釋為其轉換成蘿蔔硫素之速率。將蘿蔔苷含量減少作為抗壞血酸濃度增加之函數以圖表呈現時產生了一系列之線性圖;該些線性迴歸線之斜率,單位為μmoles/minute,反映了蘿蔔苷消耗之速率。顯然地,在有濃度600μmoles/Liter之抗壞血酸存在下,其反應速率較缺少抗壞血酸之調節作用時之反應速率增加到13倍
蘿蔔苷等莫耳轉換成蘿蔔硫素。
進行一項由兩部分組成之實驗以進一步闡釋抗壞血酸調節芥子酵素活性之功效。所有溶液皆用20mM TBS緩衝液(Tris-buffered saline)製備,pH值為7.5,該pH值之前已被指為最適於芥子酵素之活性;每一取樣管被裝有精確秤重之100mg冷凍乾燥青花菜粉末,作為芥子酵素之來源。該實驗在38℃下進行2小時,每隔30分鐘移除等分之試樣,且蘿蔔苷及蘿蔔硫素之含量皆以HPLC法測定。一種強酸性之反應停止液被用於即刻抑制移除之樣本內的芥子酵素之進一步活性。一控制組樣本不含抗壞血酸,且未以輔助因子協助酵素轉換之進行。
第一部分。在濃度固定為1mmol/Liter之抗壞血酸的環境中,加入青花菜種子萃取物(含大約12% w/w之蘿蔔苷),份量由250mg增加至500mg。
第二部分。將青花菜種子萃取物之量固定為250mg,改變環境中抗壞血酸之濃度,範圍由0.4mmol/Liter變化至3.8mmol/Liter。
下表將蘿蔔苷(GR)及蘿蔔硫素以μmole為單位表示。明顯地,幾乎全部的反應混合物中,蘿蔔苷轉換成蘿蔔硫素在前30分鐘內便告完成。然而,控制樣本在沒有抗壞血酸(AA)之刺激作用下所發生之酵素轉換經仔細檢驗後顯示,蘿蔔苷等莫耳轉換成蘿蔔硫素,亦即該蘿蔔苷所消耗之量相當於蘿蔔硫素所生成之量。
在實驗之第二部分評定了濃度漸增之抗壞血酸對芥子酵素活性之調節作用。可觀察到,在芥子酵素之促進下,蘿蔔苷轉換成蘿蔔硫素一開始明顯呈線性,直到抗壞血酸濃度達2mmol/L,之後便顯著趨於平穩。
最後,檢驗實驗第一部分中30分鐘之後的蘿蔔硫素產量,其顯示在1mmol/Liter抗壞血酸之環境下,100mg冷凍乾燥青花菜芽粉末中所含固定份量之芥子酵素,能夠以可預測之線性方式產生至少200μmole之蘿蔔硫素。圖1、圖2、圖3與圖4呈現了本實驗之結果。
蘿蔔苷在模擬腸液之環境下轉換成蘿蔔硫素。
本實驗使用之模擬腸液(SIF)粉末,係一種市售之濃縮物,在組成、pH值及離子強度方面十分接近人類之腸內容物。本實驗使用美國藥典(USP)溶離試驗儀2(Dissolution Apparatus 2(槳形)),有500mL之模擬腸液分配至該試驗儀之六個溶解容器,並以150mg之冷凍乾燥青花菜芽粉末作為芥子酵素(MYR)之來源。在容器1~4中,抗壞血酸(Ascorbate)之濃度從0.25mmol/Liter至1.00mmol/Liter不等;在容器5中,除濃度1mmol/Liter之抗壞血酸外,還懸浮有3.125g之胰酵素(Pancreatin)(8x USP);在容器6中,除濃度1mmol/Liter之抗壞血酸及3.125g之胰酵素(8x USP)外,還加有雙倍份量之冷凍乾燥青花菜芽粉末(300mg)。在該些容器溫度達到38℃後,各加入250mg富含蘿蔔苷(8% w/w)之青花菜種子萃取物,並將以此得到之懸浮液以75RPM之轉速攪動2小時。每隔15分鐘抽取等份之樣本,並測定蘿蔔硫素之含量。圖4呈現蘿蔔硫素之較大產出與抗壞血酸之較高濃度間之直接相關,尤其是在該實驗之前期階段。
以下所進行之試驗係為了測定蘿蔔硫素及硫酸鎂(MgSO4)之組合,對一種發炎介質單核球趨化蛋白(MCP-1)表現之作用。MCP-1係一種會將單核球、巨噬細胞,以及淋巴細胞吸引至發炎區域之趨化激素。MCP-1的減少有益於組成心血管系統的內皮細胞之健康。
在該試驗中,將小鼠巨噬細胞(RAW cells)以1μg/mL之脂多醣(lipopolysaccharide,LPS)活化30分鐘,以刺激能引起MCP-1基因表現的誘導作用。在LPS處理後,接著將該些細胞以下列其中之一加以處理:(i)二甲亞碸(DMSO,其為載體控制組(vehicle control))、(ii)0.5μM蘿蔔
硫素(SFN)、(iii)2.5mM硫酸鎂(MgSO4),或(iv)0.5μM蘿蔔硫素(SFN)及2.5mM硫酸鎂(MgSO4)之組合。在處理24小時後,以定量RT-PCR法測定MCP-1的水平。
如圖5所示之實驗結果顯示,相較於僅有蘿蔔硫素或僅有硫酸鎂之情況,蘿蔔硫素及硫酸鎂之組合具有協同作用(大於累加作用)。下列數據顯示MCP-1水平降低之情形:僅以硫酸鎂處理時降低大約16%,僅以蘿蔔硫素處理時降低大約29%,以蘿蔔硫素及硫酸鎂之組合處理時降低大約53%。此結果顯示該組合對於降低MCP-1水平有一大於累加作用之效果。
患有動脈粥樣硬化之一受試者經歷之症狀包括動脈損傷及胸痛。給予該受試者服用含有蘿蔔苷、芥子酵素、抗壞血酸以及蘋果酸鎂之一藥錠。該藥錠為一種腸溶膜衣配方,會將該些內容物在小腸中釋放。每日服用該藥錠一個月後,該受試者感到多種替代性生物標記(surrogate biomarkers),包含與症狀改善相關之介白素-8(IL-8)及/或單核球趨化蛋白(MCP-1),均獲得調節。
Claims (29)
- 一種可口服組成物,其包含:一種蘿蔔硫素前驅物;一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素;一種酵素增強劑;以及鎂或鎂之一種鹽類或複合物。
- 如申請專利範圍第1項之可口服組成物,其中該蘿蔔硫素前驅物包含蘿蔔苷。
- 如申請專利範圍第1項之可口服組成物,其中能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素包含芥子酵素。
- 如申請專利範圍第1項之可口服組成物,其中該酵素增強劑包含抗壞血酸。
- 如申請專利範圍第1項之可口服組成物,其中該組成物包含一種腸溶膜衣劑型。
- 如申請專利範圍第1項之可口服組成物,其中該組成物更包含自:維生素K2、槲皮素、一種胺基糖(aminosugar)、一種葡萄胺聚醣(glycosaminoglycan)、鱷梨/大豆之不皂化物、一種維生素、咖啡果實、水飛薊素、原花青素、熊果酸、薑黃素、植物固醇,以及植物固烷醇所組成之群體中選定之一種或多種額外成分。
- 如申請專利範圍第1項之可口服組成物,其包含蘿蔔苷、芥子酵素、抗壞血酸,以及一種鎂鹽。
- 如申請專利範圍第1項之可口服組成物,其中該組成物包含青花菜萃取物或青花菜粉末。
- 一種用於心血管之一種疾病或障礙之治療、預防、減少發生、減輕相關症狀,以及減少二次復發之方法,該方法包含給予有需要之一受試者服用一種蘿蔔硫素前驅物;一種能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之酵素;一種酵素增強劑;以及鎂或鎂之一種鹽類或複合物。
- 如申請專利範圍第10項之方法,其中該蘿蔔硫素前驅物包含蘿蔔苷。
- 如申請專利範圍第10項之方法,其中能將該蘿蔔硫素前驅物轉換成蘿蔔硫素之該酵素包含芥子酵素。
- 如申請專利範圍第10項之方法,其中該酵素增強劑包含抗壞血酸。
- 如申請專利範圍第10項之方法,其包含給予服用蘿蔔苷、芥子酵素、抗壞血酸,以及一種鎂鹽。
- 如申請專利範圍第10項之方法,其包含給予服用一種腸溶膜衣劑型。
- 一種可口服組成物,其包含一種青花菜萃取物或一種青花菜粉末,以及鎂或鎂之一種鹽類或複合物。
- 如申請專利範圍第16項之可口服組成物,其中該青花菜萃取物或青花菜粉末包含大約1% w/w至大約75% w/w之蘿蔔苷。
- 如申請專利範圍第16項之可口服組成物,其中該青花菜萃取物或青花菜粉末包含芥子酵素。
- 如申請專利範圍第16項之可口服組成物,其更包含一種酵素增強劑。
- 如申請專利範圍第16項之可口服組成物,其中該酵素增強劑包含抗壞血酸。
- 如申請專利範圍第16項之可口服組成物,其中該組成物包含一種腸溶膜衣劑型。
- 如申請專利範圍第16項之可口服組成物,其更包含自:維生素K2、槲皮素、一種胺基糖(aminosugar)、一種葡萄胺聚醣(glycosaminoglycan)、鱷梨/大豆之不皂化物、咖啡果實、鎂、水飛薊素、原花青素、熊果酸、薑黃素、植物固醇、植物固烷醇,以及舞菇、香菇及/或靈芝所組成之群體中選定之一種或多種額外成分。
- 一種用於血管內皮或心血管系統相關之一種疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及減少二次復發之方法,該方法包含給予有前揭需要之一受試者服用青花菜萃取物或青花菜粉末,以及鎂或鎂之一種鹽類或複合物。
- 一種用於降低一受試者體內之介白素-8(interleukin-8,IL-8)及/或單核球趨化蛋白(monocyte chemoattractant protein-1,MCP-1)之水平或基因表現之方法,該方法包含給予有前揭需要之該受試者服用青花菜萃取物或青花菜粉末,以及鎂或鎂之一種鹽類或複合物。
- 一種用於一受試者體內介白素-8(interleukin-8,IL-8)及/或單核球趨化蛋白(monocyte chemoattractant protein-1,MCP-1)水平升高相關之一種疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予有前揭需要之該受試者服用青花菜萃取物或青花菜粉末,以及鎂或鎂之一種鹽類或複合物。
- 一種可口服組成物,其包含蘿蔔硫素或蘿蔔硫素之一種衍生物,以及鎂或鎂之一種鹽類或複合物。
- 如申請專利範圍第26項之可口服組成物,其更包含自:維生素K2、槲皮素、一種胺基糖(aminosugar)、一種葡萄胺聚醣(glycosaminoglycan)、鱷梨/大豆之不皂化物、咖啡果實、鎂、水飛薊素、原花青素、熊果酸、薑黃素、植物固醇、植物固烷醇,以及舞菇、香菇及/或靈芝所組成之群體中選定之一種或多種額外成分。
- 一種用於血管內皮或心血管系統相關之一種疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及減少二次復發之方法,該方法包含給予有前揭需要之一受試者服用蘿蔔硫素或蘿蔔硫素之一種衍生物,以及鎂或鎂之一種鹽類或複合物。
- 一種用於降低一受試者體內之介白素-8(interleukin-8,IL-8)及/或單核球趨化蛋白(monocyte chemoattractant protein-1,MCP-1)之水平或基因表現之方法,該方法包含給予有前揭需要之該受試者服用蘿蔔硫素或蘿蔔硫素之一種衍生物,以及鎂或鎂之一種鹽類或複合物。
- 一種用於一受試者體內介白素-8(interleukin-8,IL-8)及/或單核球趨化蛋白(monocyte chemoattractant protein-1,MCP-1)水平升高相關之一種疾病或狀況之治療、預防、減少發生、減輕相關症狀,以及/或減少二次復發之方法,該方法包含給予有前揭需要之該受試者服用蘿蔔硫素或蘿蔔硫素之一種衍生物,以及鎂或鎂之一種鹽類或複合物。
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