TW201805014A - 含衍生自酵母菌之胞外囊胞之抗發炎組成物 - Google Patents
含衍生自酵母菌之胞外囊胞之抗發炎組成物 Download PDFInfo
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- TW201805014A TW201805014A TW106121540A TW106121540A TW201805014A TW 201805014 A TW201805014 A TW 201805014A TW 106121540 A TW106121540 A TW 106121540A TW 106121540 A TW106121540 A TW 106121540A TW 201805014 A TW201805014 A TW 201805014A
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Abstract
本說明書揭露一抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分;及一抗發炎組成物,其包括衍生自含酵母菌之食品之胞外囊胞作為活性成分。在一態樣中,該酵母菌可為啤酒酵母菌(Saccharomyces cerevisiae
)。該抗發炎組成物抑止或抑制發炎介質腫瘤壞死因子-α(TNF-α)或介白素-6(IL-6)之分泌。
Description
本說明書係關於一抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分。
多數動物細胞具有分泌不同大小及組分之細胞內源胞外囊胞之能力,而此等胞外囊胞可在所有生物流體中發現,其包含血液、尿液、唾液及細胞培養液(Loyer X, Vion AC, Tedgui A, Boulanger CM, Microvesicles as cell-cell messengers in cardiovascular diseases, Circ Res 2014; 114: 345-53, Ohno S, Ishikawa A, Kuroda M. Roles of exosomes and microvesicles in disease pathogenesis. Adv Drug Deliv Rev 2013; 65: 398-401)。
胞外囊胞係一具有約 20 nm至約2 μm直徑之膜囊胞,且 其大小及組成物非均一性。胞外囊胞係被分類成多種不同類型,其包含胞外體、核外粒體(ectosomes)、微囊胞(microvesicles)、微粒等。
不同類型之胞外囊胞係依其來源、直徑、蔗糖密度、形狀、沉降速率、脂質組成物、蛋白質標誌物(marker)或分泌方式(即藉由信號(觸發分泌)或自發(持續型分泌))區分。舉例而言,微囊胞係一約100至1,000 nm不規則形狀之膜囊胞。已知由細胞膜(細胞膜源)出芽且具有包含整聯蛋白(integrins)、選滯蛋白(selectins)及CD40配體之標誌物以及包含磷脂醯絲胺酸之脂質。另一方面,胞外體係最小之膜囊胞,其具有約30至100 nm(< 200 nm)之杯形。已知其由晚期胞內體(胞吞源(endocytic origin))向內出芽形成,且具有包含四穿膜蛋白(tetraspanins)CD63、CD9、TSG101及ESCRT之標誌物以及包含膽固醇、鞘磷脂、神經醯胺及含磷脂醯絲胺酸之脂質。
胞外囊胞反映出該分泌細胞(供體細胞)之狀態且根據該分泌細胞類型顯示出各種生物活性。其藉由在細胞間輸送遺傳物質及蛋白質而在細胞間相互作用中發揮重要作用。
亦已知原核或真核細胞會分泌胞外囊胞(Camussi, G., Deregibus, M. C., Bruno, S., Cantaluppi, V., & Biancone, L. (2010). Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney international, 78(9), 838-848, Bang, Claudia, and Thomas Thum. "Exosomes: New players in cell–cell communication." The international journal of biochemistry & cell biology 44.11 (2012): 2060-2064, Kim, D. K., Lee, J., Simpson, R. J., Lötvall, J., & Gho, Y. S. (2015, April), EVpedia: A community web resource for prokaryotic and eukaryotic extracellular vesicles research. In Seminars in cell & developmental biology(Vol. 40, pp. 4-7). Academic Press, Kim, J. H., Lee, J., Park, J., & Gho, Y. S. (2015, April). Gram-negative and Gram-positive bacterial extracellular vesicles. In Seminars in cell & developmental biology (Vol. 40, pp. 97-104). Academic Press)。
通常,胞外囊胞主要被用作生物標誌物。基於一胞外囊胞本身之作用使用該胞外囊胞作為特定用途之技術尚未被有效地開發出來。
發炎是一種針對細胞及組織損傷或感染之局部或全身防禦機制。發炎主要係源自一系列生物反應,其係藉由構成免疫系統之多種體液性介體之直接反應或藉由該體液性介體之局部或全身反應系統之刺激來誘導。參與此等發炎反應之介體包含諸如免疫細胞、巨噬細胞、嗜中性白血球、嗜酸性白血球及肥大細胞之發炎細胞、由此等細胞分泌之細胞激素等。
發炎疾病之特徵在於發炎細胞激素之分泌並造成組織損傷及癒合失衡。迄今已知之主要發炎細胞激素包含由巨噬細胞及單核白血球產生之TNF-α(腫瘤壞死因子-α)、IL-1(介白素-1)、IL-6、IL-8等。目前,正在進行各種研究來抑止該發炎細胞激素,從而治療由發炎細胞激素失衡引起之發炎疾病。關於抗發炎組成物之現有技術文獻包含韓國專利公開號10-2015-0053034。
引證表 專利文獻 專利文獻1:韓國專利公開號10-2015-0053034。
技術問題
在一態樣中,本說明書目的在於提供一抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分。
在另一態樣中,本說明書目的在於提供一抗發炎組成物,其包括衍生自含酵母菌之食品之胞外囊胞作為活性成分。
在又另一態樣中,本說明書目的在於提供一用於分離胞外囊胞之方法,其可以高產率分離出該胞外囊胞。 技術方案
在一態樣中,本說明書提供一抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分。
在另一態樣中,本說明書提供一抗發炎組成物,其包括衍生自含酵母菌之食品之胞外囊胞作為活性成分。
在一例示性具體實施例中,該酵母菌 可為啤酒酵母菌(Saccharomyces cerevisiae
)。
在一例示性具體實施例中,該胞外囊胞可具有20至200 nm之直徑。
在一例示性具體實施例中,該胞外囊胞可藉由密度梯度超高速離心分離。
在一例示性具體實施例中,該胞外囊胞 可具有在碘克沙醇(iodixanol)中1.08至1.19 g/mL之浮力密度。
在一例示性具體實施例中,該胞外囊胞可藉由粒徑篩析層析儀(size exclusion chromatography)分離。
在一例示性具體實施例中,該衍生自一含酵母菌食品之胞外囊胞可為一衍生自啤酒之胞外囊胞。
在一例示性具體實施例中,該抗發炎組成物可抑止或抑制該發炎介質腫瘤壞死因子-α(TNF-α)或介白素-6(IL-6)之分泌。
在一例示性具體實施例中,該抗發炎組成物可具有對發炎性皮膚病之抗發炎活性。
在一例示性具體實施例中,該發炎性皮膚病可為一或多選自於由痤瘡、接觸性皮膚炎、脂溢性皮膚炎、異位性皮膚炎及牛皮癬所組成之組群。
在一例示性具體實施例中,該抗發炎組成物可為一醫藥組成物、一美容組成物或一食品組成物。
在又另一態樣中,本說明書提供一用於產生一胞外囊胞之方法,其包括以下步驟:培養酵母菌;離心所得培養液以去除殘留物獲得一上清液及過濾該上清液;及超高速離心該濾液、收集沉澱物並使其經碘克沙醇密度梯度超高速離心。
在一例示性具體實施例中,該過濾可使用0.2至0.5 µm濾器進行過濾。
在一例示性具體實施例中,該超高速離心可於100,000 x g或其以上進行。
在一例示性具體實施例中,該胞外囊胞可在該碘克沙醇密度梯度超高速離心後由一級分獲得,其具有在碘克沙醇中1.08至1.19 g/mL之浮力密度。
本發明功效
在一態樣中,本說明書提供以下之效果:提供一抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分。
在另一態樣中,本說明書提供以下之效果:提供一抗發炎組成物,其包括衍生自一含酵母菌之食品之胞外囊胞作為活性成分。
在又另一態樣中,本說明書提供以下之效果:提供一用於分離胞外囊胞之方法,其允許以高產率分離出該胞外囊胞。
以下將對本發明詳細說明。
在一態樣中,本說明書提供一抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分。
在另一態樣中,本說明書提供一抗發炎組成物,其包括衍生自一含酵母菌之食品之胞外囊胞作為活性成分。
本文所使用之術語「活性成分」係指一成分,其自己本身或與不具有活性之載體等組合後可展現所需活性。
本文所使用之術語「抗發炎」係指防止、抑止、抑制、改善或治療發炎之效果。「發炎」包括症狀或跡象(signs),諸如由於組織細胞間體液增加引起之腫脹、由於血管擴張引起之充血、由於熱原(pyrogen)及血管擴張引起之發熱(fever)、花生四烯酸代謝物(arachidonic acid metabolites)引起之疼痛等。根據時間,發炎可被分類成急性、亞急性及慢性發炎疾病。根據病理狀況,還可分為感染性、過敏性、自身免疫性、中毒性、代謝性及創傷性發炎疾病。
在一例示性具體實施例中,該發炎可為選自於由以下所組成之組群,但不限於此:發炎性呼吸疾病,諸如鼻炎、鼻竇炎、中耳炎、鼻咽炎(nasopharyngitis)、喉炎、支氣管炎、哮喘、慢性阻塞性肺臟疾病、支氣管擴張、細支氣管炎、肺炎、肺纖維化等;發炎性胃腸道疾病,諸如口腔潰瘍、食管炎、胃炎、消化性潰瘍、腸躁症候群、發炎性腸症候群、膽囊炎、膽管炎、胰臟炎、肝炎等;發炎性皮膚病,諸如痤瘡、接觸性皮膚炎、脂溢性皮膚炎、異位性皮膚炎、牛皮癬等;發炎性心血管疾病,諸如心內膜炎、心肌炎、心包膜炎、血管炎、動脈硬化、敗血症等;發炎性內分泌疾病,諸如甲狀腺炎、腮腺炎(parathyroiditis)、糖尿病等;發炎性泌尿生殖疾病,諸如腎小球性腎炎、腎病、間質性腎病(interstitial renal disease)、睾丸炎、卵巢發炎、子宮內膜炎、陰道炎等;發炎性肌肉骨骼疾病,諸如風濕性關節炎、脊椎關節疾病、骨關節炎、痛風、全身性紅斑狼瘡、全身性硬化症、肌病變、薛格連氏症候群(Sjogren's syndrome)、貝賽特氏病(Behcet's disease)、抗磷脂質症候群;發炎性神經疾病,諸如血管性失智症、阿茲海默症、退化性腦部病變、憂鬱症、精神分裂症等。
在一例示性具體實施例中,該抗發炎組成物可抑止或抑制該發炎介質 腫瘤壞死因子-α(TNF-α)或介白素-6(IL-6)之分泌。
在又另一態樣中,本說明書提供一用於防止、改善及/或治療發炎之方法,其包括施給需要之個體一有效量之該用於防止、改善及/或治療發炎之衍生自酵母菌之胞外囊胞。
在又另一態樣中,本說明書提供一用於防止、改善及/或治療發炎之方法,其包括施給需要之個體一有效量之用於防止、改善及/或治療發炎之該衍生自一含酵母菌食品之胞外囊胞。
在又另一態樣中,本說明書提供該衍生自酵母菌之胞外囊胞,其係用於防止、改善及/或治療個體之發炎。
在又另一態樣中,本說明書提供該衍生自一含酵母菌食品之胞外囊胞,其係用於防止、改善及/或治療個體之發炎。
在又另一態樣中,本說明書提供製備一用於防止、改善及/或治療個體之發炎之組成物之用途,其包括該衍生自酵母菌之胞外囊胞。
在又另一態樣中,本說明書提供製備一用於防止、改善及/或治療個體之發炎之組成物之用途,其包括該衍生自一含酵母菌食品之胞外囊胞。
在一例示性具體實施例中,該胞外囊胞可以一醫藥組成物、一美容組成物或一食品組成物施用或施給一個體。
在一例示性具體實施例中,該胞外囊胞可施用或施給至一個體之皮膚或頭皮。
在一例示性具體實施例中,該酵母菌可為啤酒酵母菌(Saccharomyces cerevisiae
)。
本文所使用之術語「胞外囊胞」係指一奈米大小之胞外囊胞,其係由一細胞分泌且被釋出至胞外空間中。可藉由細胞膜組分組成之一雙層脂質區分胞外囊胞之內側及外側。其含有細胞膜脂質、膜蛋白、細胞遺傳物質及細胞質組分,從而間接地表示該細胞之性質及狀態。此外,結合至其他細胞及組織之胞外囊胞會輸送膜組分、mRNAs、miRNAs、蛋白質(生長激素、細胞激素等)。其藉由將此等材料輸送到受體細胞作為胞外載體,用以介導細胞間之通訊。
在一例示性具體實施例中,該胞外囊胞 可為一胞外體。本文所使用之胞外體具有最廣意義,其不僅包括胞外體,還包括奈米大小囊狀結構相似之囊胞及一具該胞外體之組成物。
在一例示性具體實施例中,該胞外囊胞可具有20至200 nm之直徑。更具體地,該胞外囊胞可不小於20 nm、不小於22 nm、不小於24 nm、不小於26 nm、不小於28 nm、不小於30 nm、不小於32 nm、不小於34 nm、不小於36 nm、不小於38 nm、不小於40 nm、不小於42 nm、不小於44 nm、不小於46 nm、不小於48 nm、或 不小於50 nm 及不大於200 nm、不大於190 nm、不大於180 nm、不大於170 nm、不大於160 nm、不大於150 nm、不大於140 nm、不大於130 nm、不大於120 nm、不大於110 nm、不大於100 nm、不大於95 nm、不大於90 nm、不大於85 nm、不大於80 nm、不大於75 nm、或不大於70 nm。舉例而言,該胞外囊胞可具有20至150 nm、30至150 nm、30至100 nm或30至80 nm之直徑。
在一例示性具體實施例中,舉例而言,該胞外囊胞可具有一膜組分,其經化學或物理性改變用以有效率地在一標的細胞中表現所欲之功能。舉例而言,該胞外囊胞之膜組分可藉化學方法經以一硫醇基(-SH)或一胺基(-NH2
)來改變。或者,該胞外囊胞除該膜之組分外可進一步包括一組分,其藉由化學結合一標靶分子、一細胞膜融合體或一聚乙二醇。
在一例示性具體實施例中,該胞外囊胞可藉由使用一或多方法分離,其係選自於由超高速離心、差速離心、平衡密度離心、密度梯度、過濾、透析及自由流(free-flow)電泳所組成之組群。然而,用於分離該胞外囊胞之方法並不限於此。
密度梯度係一最常見用於分離不同密度物質之方法。本說明書之胞外囊胞係根據密度被分開因而可藉由密度梯度分離。舉例而言,此方法可使用密度梯度分隔材料來進行,諸如聚蔗糖(ficoll)、甘油、蔗糖、氯化銫、碘克沙醇(iodixanol)等,但不限於此。在一態樣中,該密度梯度可與超高速離心等組合使用。在另一態樣中,凝膠過濾或超微過濾可用於篩選胞外囊胞。 在又另一態樣中,透析可用以代替過濾以移除小分子。在另一態樣中,可使用自由流電泳。
在一例示性具體實施例中,該衍生自酵母菌之胞外囊胞可藉由密度梯度超高速離心分離。
在一例示性具體實施例中,該衍生自酵母菌之胞外囊胞具有在碘克沙醇中1.08-1.1 g/mL之浮力密度,更具體地為1.08 g/mL或以上、1.09 g/mL或以上、1.10 g/mL或以上、1.11 g/mL或以上、或1.12 g/mL或以上及1.19 g/mL或以下、1.18 g/mL或以下、1.17 g/mL或以下、1.16 g/mL或以下、或1.15 g/mL或以下。於此,該碘克沙醇係藉由混合等量之5%、10%、30%、40% 及50%碘克沙醇獲得。該浮力密度係指藉由密度梯度離心測量之密度。
在一例示性具體實施例中,衍生自一含酵母菌食品之胞外囊胞可藉由粒徑篩析層析儀(size exclusion chromatography)分離。
在一例示性具體實施例中,該含酵母菌之食品可為一或多選自由於麵包、啤酒、葡萄酒及濁酒(makgeolli)所組成之組群。。
在一例示性具體實施例中,該抗發炎組成物可為一凍乾製劑。該組成物可為即用型密封包裝或包裝容器中之凍乾製劑。
本說明書還提供一抗發炎套組,其包括含該胞外囊胞作為活性成分之凍乾製劑形式之組成物;及滅菌水或純化水。該套組可被包括在即型密封包裝或包裝容器中。
根據一例示性具體實施例,該組成物可為一醫藥組成物。
該醫藥組成物除該胞外囊胞外可進一步包含藥學佐劑,諸如防腐劑、穩定劑、水合劑或乳化促進劑,用於控制滲透壓之鹽及/或緩沖劑、及其它治療上有用之物質。根據常用方法可將其配製成用於口服或腸胃外給藥之各種製劑。
口服劑型包含,舉例而言,片劑(tablet)、丸劑(pill)、硬及軟膠囊、液體、懸浮液、乳劑、糖漿、粉末(powder)、粉劑(dust)、顆粒劑(granule)、團粒(pellet)等。此等劑型除該活性成分外可包括:表面活性劑,稀釋劑(例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纖維素及甘胺酸)及潤滑物(例如二氧化矽、滑石、硬脂酸及其鎂鹽或鈣鹽及聚乙二醇)。該片劑可包括成型劑(binder),諸如矽酸鎂鋁、澱粉糊、明膠、黃蓍膠(tragacanth)、甲基纖維素、羧甲基纖維素鈉鹽及聚乙烯吡咯烷酮;及可擇地一醫藥添加物,諸如崩解劑(例如澱粉、瓊脂、海藻酸或其鈉鹽)、吸收劑、著色劑、調味劑、甜味劑等。該片劑可根據常見混合、造粒或塗覆方法製備。
腸胃外給藥之劑型可為透皮劑型,舉例而言,注射劑、滴劑、軟膏劑、洗劑、凝膠劑、霜劑、噴霧劑、懸浮劑、乳劑、栓劑、貼劑等,但不限於此。
該活性成分劑量之確定屬於本領域技術人員之知識。藥物之每日劑量將根據各種因素而變化,諸如疾病進展及發病時間、年齡及受試者健康狀況、併發症等。然而,在一態樣中,成人劑量可為每日1至3分組劑量之1 µg/kg至200 mg/kg組成物。在另一態樣中,其可為每日1至3分組劑量50 μg/kg至50 mg/kg組成物。該劑量未以任何方式限制本說明書範圍。
該醫藥組成物可為用於皮膚外用之製備物。該皮膚外用之製備物包括施用在皮膚上之任何物質且可包括各種製劑形式之藥物。
根據一例示性實施例,該組成物可為一美容組成物。
該美容組成物除胞外囊胞外,可進一步包含一功能性添加物及包含在通常美容組成物中之成分。該功能性添加物可為選自於由水溶性維生素、油溶性維生素、多肽、多醣、神經鞘脂及海藻提取物所組成之組群之任一者。可能包含在該組成物中之其他成分包含油及脂肪、保濕劑、潤滑劑、表面活性劑、有機或無機顏料、有機粉末、紫外線吸收劑、防腐劑、滅菌劑、抗氧化劑、植物提取物、pH調節劑、酒精、著色劑、香料、血液循環興奮劑、冷卻劑、止汗劑、純化水等。
該美容組成物之製劑沒有特別限制,可根據目的適當選擇。舉例而言,其可被配製成一或多選自於由以下所組成之組群,但不限於此:潤膚露(skin lotions),柔膚液(skin softeners),爽膚水(skin toners),收斂水(astringents),化妝水(lotions),潤膚乳(milk lotions),保濕露(moisturizing lotions),滋養露(nourishing lotions),按摩霜(massage creams),滋養霜(nourishing creams),保濕霜(moisturizing creams),護手霜(hand creams),底霜(foundations),精華液(essences),滋養精華液(nourishing essences), 面膜(packs),肥皂(soaps),清潔泡沫(cleansing foams),清潔露(cleansing lotions),清潔霜(cleansing creams),身體乳液(body lotions)及身體清潔劑(body cleansers)。
當本發明之製劑為漿劑(paste)、霜劑或凝膠劑,可使用動物纖維、植物纖維、蠟、石蠟、澱粉、黃蓍膠、纖維素衍生物、聚乙二醇、矽酮、膨潤土、二氧化矽、滑石或氧化鋅等作為載體。
當本發明之製劑為粉劑或噴霧劑,可使用乳糖、滑石、二氧化矽、氫氧化鋁、矽酸鈣或聚胺粉末作為載體。特別地,當該製劑為噴霧劑,其可進一步包括一推進劑,諸如氯氟烴(chlorofluorohydrocarbon)、丙烷/丁烷或二甲醚。
當本發明之製劑為溶液或乳劑,可使用溶劑、溶解劑或乳化劑作為載體。其實施例包含水、乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸芐酯、丙二醇、1,3-丁二醇油、甘油脂族酯(glycerol aliphatic ester)、去水山梨醇之聚乙二醇或脂肪酸酯。
當本發明之製劑為懸浮液,可使用液態稀釋劑(諸如水、乙醇或丙二醇)、懸浮劑(諸如乙氧基化異硬脂醇(ethoxylated isostearyl alcohol)、聚氧乙烯山梨醇酯(polyoxyethylene sorbitol ester)及聚氧乙烯去水山梨醇酯(polyoxyethylene sorbitan ester))、微晶型纖維素、偏氫氧化鋁(aluminum metahydroxide)、膨潤土、瓊脂或黃蓍膠等作為載體。
當本發明之製劑為含表面活性劑之清潔劑,可使用脂肪醇硫酸酯(aliphatic alcohol sulfate)、脂肪醇醚硫酸酯(aliphatic alcohol ether sulfate)、磺基琥珀酸單酯(sulfosuccinic acid monoester)、羥乙基磺酸鹽(isethionate)、咪唑衍生物(imidazolium derivative)、甲基牛磺酸鹽(methyltaurate)、肌氨酸鹽(sarcosinate)、脂肪酸醯胺醚硫酸鹽(fatty acid amide ether sulfate)、烷基醯胺甜菜鹼(alkylamido betaine)、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇醯胺(fatty acid diethanolamide)、植物油、亞麻油酸酯衍生物或乙氧基化甘油脂肪酸酯(ethoxylated glycerol fatty acid ester)作為載體。
根據一例示性實施例,該組成物可為一食品組成物。
該食品組成物可為液態或固態劑型。舉例而言,其可為各種食品、飲料、口香糖、茶葉、維生素複合物、保健補充品等之形式。其可為粉末、顆粒、片劑、膠囊或飲料之形式。各劑型形式之該食品組成物除活性成分外可進一步包含相關領域常用之成分。根據所欲劑型或目的,本領域技術人員可以毫無困難地選擇及添加成分。添加其他成分可能會產生協同效應。
除本文揭露之活性成分外,對於可被包含之液態成分沒有特別限制。其可包括各種調味劑或天然碳水化合物作為額外成分,常見飲料也是如此。天然碳水化合物之實例為習用之糖,諸如單醣、雙醣 (諸如葡萄糖及果糖)、多醣(諸如麥芽糖及蔗糖)、糊精、環糊精等及糖醇(諸如木糖醇、山梨糖醇、赤蘚醇等)。此外,可有利地使用天然調味劑(索馬甜、甜菊萃取物(如萊鮑迪苷A、甘草素等))及合成調味劑(例如糖精、阿斯巴甜等)作為調味劑。通常,在本文揭露之組成物中可包含約1至20g量之天然碳水化合物,及在一態樣中每100ml約5至12g。
在一態樣中,該食品組成物可包括各種營養素、維生素、礦物質(電解質)、調味劑(諸如合成調味劑及天然調味劑)、著色劑及改善劑(乾酪、巧克力等)、果膠酸或其鹽類、海藻酸或其鹽類、有機酸、保護性膠體增稠劑、pH調控劑、穩定劑、防腐劑、甘油、酒精、碳酸飲料中使用之碳酸化劑等。 在另一態樣中,其可包括用於生產天然果汁及蔬菜飲料之果肉。此等成分可單獨使用或作為其混合物使用。該添加物之量可改變。然而,通常為相對於本文揭露組成物100重量份之0.001至約20重量份。
在又另一態樣中,本說明書提供一用於產生衍生自酵母菌之胞外囊胞之方法,其包括以下步驟:培養酵母菌;離心所得培養液以去除殘留物獲得一上清液及過濾該上清液;及超高速離心該濾液、收集沉澱物及使其再次懸浮在一緩衝液中,使其經碘克沙醇密度梯度超高速離心。
在一例示性具體實施例中,該過濾藉使用0.2至0.5 µm 濾器進行。或者,該過濾可使用0.2至0.4 µm 濾器、0.3至0.5 µm 濾器或0.4至0.5 µm 濾器進行。
在一例示性具體實施例中,該超高速離心可於100,000 x g或其以上進行。具體地,其可於100,000至200,000 x g或100,000至150,000 x g或150,000至200,000 x g進行。
在一例示性具體實施例中,該胞外囊胞可在碘克沙醇 密度梯度超高速離心後由一級分獲得,其具有在碘克沙醇中1.08至1.19 g/mL之浮力密度,更具體為1.08 g/mL或以上、1.09 g/mL或以上、1.10 g/mL或以上、1.11 g/mL或以上或1.12 g/mL或其以上及1.19 g/mL或以下、1.18 g/mL或以下、1.17 g/mL或以下、1.16 g/mL或以下或1.15 g/mL或以下。
在又另一態樣中,本說明書提供一用於產生衍生自含酵母菌食品之胞外囊胞之方法,其包括以下步驟:離心液態形式之食品以去除殘餘物,過濾所得之上清液,超高速離心該濾液,及使所得物經粒徑篩析層析儀以獲得一胞外囊胞。
在一例示性具體實施例中,該過濾可藉由使用0.1至0.4 µm 濾器進行。或者,該過濾可藉由使用0.2至0.4 µm 濾器、0.3至0.4 µm 濾器、0.1至0.3 µm 濾器或0.1至0.2 µm 濾器進行。
在一例示性具體實施例中,該超高速離心可於100,000 x g或其以上進行。具體地,其可於100,000至200,000 x g或100,000至150,000 x g或150,000至200,000 x g進行。
本文以下將藉由實施例對本發明進行詳細說明。本領域技術人員顯然可知曉此等實施例僅用於說明目的,且本發明範圍不應被解釋為受限於此等實施例。
測試實施例 1 :細胞培養
(1)巨噬細胞
在DMEM (Dulbecco's Modified Eagle Medium)中培養小鼠巨噬細胞 J774A.1細胞。添加10% FBS及1%抗生素-抗黴劑(Invitrogen)至該培養基中。所有細胞系皆為未感染黴漿菌之細胞系,使用e-MyCoTM Mycoplasma PCR Detection Kit (iNtRON Biotechnology, Inc., Seoul, Korea)確認。 (2)角質細胞
將人類初生表皮角質細胞(human primary epidermal keratinocytes) (ScienCell)置於一預塗聚-L-離氨酸(PLL)盤及在角質細胞培養基(ScienCell)中培養。
測試實施例 2 :分離胞外體
(1)衍生自酵母菌之胞外體
由用於發酵麵包、啤酒等之酵母菌細胞分離出呈胞外囊胞之胞外體。具體地,在合成之完全培養基(其為化學成分確定之培養基)中於30˚C搖動及培養啤酒酵母菌(Saccharomyces cerevisiae
) BY4741野生型細胞24小時。然後,於4,000 × g沉澱(pelletized)該啤酒酵母菌(S. cerevisiae
)培養基15分鐘二次以去除酵母菌細胞。使用0.45 µm真空濾器過濾所得之上清液係,使用MinimateTM
tangential-flow filter (TFF) capsule (Pall Corporation, East Hills, NY)藉超過濾進一步濃縮。此外,以0.45 µm注射濾器過濾該經濃縮之上清液以去除聚集物,於4˚C下100,000 x g超高速離心2小時該殘留物。所得之沉澱物被再次懸浮在HEPES-鹽緩衝液(HBS)中,及將該樣品加入到管之頂部,其各含有2 mL之5、15、30、40、50%碘克沙醇 (Axis-Shield PoC AS, Nycomed, Oslo Norway)。於4˚C 經200,000 x g超高速離心15小時後,由該密度梯度之頂部收集十份等體積之級分(1 mL)。使用Bradford蛋白測定法(Bio-Rad, Munich, Germany)及奈米顆粒分析(Malvern Instruments Ltd.)測定各級分之蛋白質及顆粒含量。 (2)衍生自實驗室啤酒 (Lab-beer)(L- 啤酒 ) 之胞外體
由與前文用相同之酵母菌發酵之啤酒分離出呈胞外囊胞之胞外體。具體地,在印度淡色艾爾(Indian pale ale)(IPA)中於室溫不搖動下培養啤酒酵母菌(Saccharomyces cerevisiae
) BY4741野生型細胞2星期。使IPA中之啤酒酵母菌(S. cerevisiae
)培養基依序經4,000 × g沉澱15分鐘及經10,000 × g沉澱30分鐘。使用0.22 µm真空濾器過濾所得之上清液,及於4˚C下以150,000 × g超高速離心3小時。在HEPES-鹽緩衝液(HBS)中再次懸浮所得之沉澱物,使該樣品經粒徑篩析層析儀Sepakril S-500管柱以分離出胞外體。 (3)胞外體 ( 其係 ) 衍生自海尼根啤酒 (H- 啤酒 )
由市售海尼根啤酒分離出呈胞外囊胞之胞外體。具體地,使海尼根啤酒依序經4,000 × g沉澱15分鐘及經10,000 × g沉澱30分鐘。使用0.22 µm真空濾器過濾所得之上清液,及於4˚C下以150,000 × g超高速離心3小時。在HEPES-鹽緩衝液(HBS)中再次懸浮所得之沉澱物,使該樣品經粒徑篩析層析儀Sepakril S-500管柱以分離出胞外體。
測試實施例 3 :胞外體分析
(1)奈米顆粒追蹤分析 (NTA)
該樣品被置於Nanosight LM10 (Malvern Instruments Ltd.)之腔室中,並使用奈米顆粒追蹤分析軟體計算胞外體數目。 (2)動態光散射 (DLS)
NVs(奈米囊胞)之大小分佈係經以Zetasizer Nano ZS (Malvern Instrument Ltd., Malvern, U.K.)測量。基於相對頻率之大小分佈係於散射強度10×30s以紅外線(633nm波長)穿透該樣品來測量。 (3)穿透式電子顯微 (TEM)
經純化之胞外體係被加入至輝光放電(glow-discharged) 碳披覆銅網格(grid)(Electron Microscopy Sciences, Fort Washington, PA)。使NVs被吸收入該網格1小時。然後,該網格經以4%多聚甲醛固定10分鐘、以去離子水水滴洗滌然後以2%醋酸鈾醯負染(Ted Pella, Redding, CA)。用JEM 1011顯微鏡(JEOL, Tokyo, Japan)在100kV加速電壓下記錄該電子顯微照片。
測試實施例 4 :胞外體效果之體外分析
(1)細胞存活分析 (WST-1)
小鼠巨噬細胞 J774A.1細胞(2 x 104
細胞/井)被覆在96-井盤上。 隔夜培養後,加入1 ng/mL DMEM中LPS(其含有0.5% FBS)及各種濃度(10-1000 ng/mL)之S. cerevisiae
胞外體至該細胞中培養12小時。加入2 µl WST-1試劑至各井中,進行培養1小時。使用微盤分析儀於440 nm波長測量經轉化染料之吸收度,於690 nm減去背景。在此分析中,由經以含0.5% FBS之DMEM處理之細胞獲得之數值被認定為100%存活。 (2)細胞激素 ELISA
小鼠巨噬細胞J774A.1細胞(2 x 104
細胞/井)被覆於一96井盤中。在共處理之情況下,加入含0.5% FBS之1 ng/mL之DMEM中LPS及各種濃度(1-1000 ng/mL)之 釀酒酵母(S. cerevisiae)
胞外體至該細胞並培養12小時。在後處理之情況下,加入含0.5% FBS之1 ng/mL之DMEM中LPS至該細胞。一小時後,以各種濃度(1-1000 ng/mL)之S. cerevisiae
胞外體處理該細胞,並培養15小時。在啤酒胞外體之情況下,以在含0.5% FBS之DMEM中各種濃度(5-500 ng/mL)實驗室啤酒或海尼根啤酒胞外體預處理該細胞12小時。然後使其經以1 ng/mL之LPS處理,並培養另外12小時。收集各細胞培養上清液用於ELISA。根據製造商之操作手冊使用DuoSet ELISA kit(R&D Systems)來量化人類IL-8、CXCL10、IL-6蛋白質或小鼠TNF-α及IL-6蛋白質。 人類角質細胞(1 x 105
細胞/井,第3代)被覆在一12井盤中,加入在角質細胞基礎培養基底(keratinocyte media-basal)(ScienCell)中不同濃度(500、1000、2000 ng/mL)之S. cerevisiae
胞外體至該細胞。12小時後,該角質細胞基礎培養基底係經以10 ng/mL之TNF-α/IFN-γ處理,並培養另外12小時。收集各細胞培養上清液用於ELISA。根據製造商之操作手冊使用DuoSet ELISA kit(R&D Systems)來量化人類IL-8、CXCL10、IL-6蛋白質或小鼠TNF-α及IL-6蛋白質(見圖8A及圖8B)。
測試實施例 5 :統計分析
使用GraphPad Prism software (GraphPad Software)進行統計分析。以平均值±表現數據。使用未成對雙尾學生t檢驗(unpaired two-tailed Student's t-test)計算P值,P<0.05時判定為顯著(*:P<0.05
, **:P<0.01
, ***:P<0.001
)。
測試結果 1. 分離胞外體及其特徵分析
大多數常規已知用於分離衍生自酵母菌之胞外囊胞之細胞之方法係超高速離心(Sci Rep., 14(5):7763, 2015, PLoS One., 5(6): e11113, 2010)。然而,問題係在於單單超高速離心無法有效地從胞外囊胞分離出諸如蛋白質聚集物等污染物。 相比之下,根據測試實施例使用密度梯度超高速離心或粒徑篩析層析儀分離胞外囊胞時,可純粹地分離出並純化該胞外囊胞。 在一合成之完全培養基(SC medium)(其為化學成分確定之培養基)中培養酵母菌細胞,然後藉由超高速離心及碘克沙醇密度梯度離心以高產率分離及純化出衍生自酵母菌之胞外體細胞(見圖1及圖2)。如圖3A及圖3B所示,以穿透式電子顯微鏡及動態光散射確認胞外體之形狀及胞外體約25至150 nm之直徑。此外,該由測試實施例獲得之衍生自酵母菌之胞外體之產率係被計算,其為每100 mL約12 μg蛋白質及1.3 × 1010
奈米顆粒。 此外,由實驗室啤酒及海尼根啤酒分離出及純化衍生自啤酒之胞外體,藉由超高速離心及尺寸篩除膠過濾(見圖4)。使用穿透式電子顯微鏡、動態光散射及奈米顆粒追蹤分析觀察該胞外體之形狀及大小。結果如圖5A、5B及5C所示,其被發現具有30至100 nm之直徑。並計算該由測試實施例獲得之衍生自啤酒之胞外體之產率。結果,發現每100 mL實驗室啤酒可獲得約33 μg蛋白質及13 × 1010
奈米顆粒,每100 mL海尼根啤酒可獲得約66 μg蛋白質及12 × 1010
奈米顆粒。
測試結果 2. 分析胞外體抗發炎效果
(1)衍生自酵母菌之胞外體
當小鼠巨噬細胞(J774A.1 cells)係經以衍生自酵母菌之胞外體處理24小時,其於高達1000 ng/mL之濃度仍不會誘導腫瘤壞死因子-α(TNF-α)及介白素-6之分泌,其係代表性促發炎細胞激素(見圖6A)。 此外,在發炎反應係經以脂多醣(LPS)(一種發炎反應刺激物)處理來誘導之小鼠巨噬細胞模式中,證實同時以衍生自酵母菌之胞外體與LPS一起處理該細胞時,其抑止IL-6及 TNF-α之分泌(其係代表性促發炎細胞激素(proinflammatory cytokines))。100 ng/mL之衍生自酵母菌之胞外體抑止40%之IL-6分泌及50%之TNF-α分泌 (見圖6B)。當小鼠巨噬細胞經以LPS預處理以誘導發反應然後施用衍生自酵母菌之胞外體,其也抑止IL-6及TNF-α分泌(其係代表性促發炎細胞激素)。1000 ng/mL之衍生自酵母菌之胞外體抑制42%之IL-6分泌及45%之TNF-α分泌(見圖6C)。 總之,衍生自酵母菌胞外體其本身在小鼠巨噬細胞中不會誘導發炎反應。當小鼠巨噬細胞用LPS及該胞外體共處理或用該胞外體後處理時,其以濃度依賴型方式表現出抗發炎效果。在共處理之情況下半抑制濃度估計為約100 ng/mL而在後處理情況下為<1000 ng/ mL。 (2)衍生自啤酒之胞外體
當小鼠巨噬細胞(J774A.1 cells)經以衍生自啤酒之胞外體處理24小時,其於高達500 ng/mL之濃度仍不會誘導促發炎細胞激素IL-6分泌(見圖7A)。 當小鼠巨噬細胞(J774A.1 cells)經以衍生自啤酒之胞外體預處理然後經以LPS(一發炎反應刺激物)處理,二類型之衍生自啤酒之胞外體 皆於5 ng/mL之濃度抑制20%之IL-6分泌。其還會於500 ng/mL之濃度抑制50%或其以上之IL-6 分泌(見圖7B). 總之,衍生自啤酒之胞外體其本身不會誘導小鼠巨噬細胞之發炎反應。且,當以其預處理小鼠巨噬細胞,其表現出濃度依賴型方式之抗發炎效果。其半抑制濃度估計約為300至500 ng/mL。
本發明一態樣之組成物製劑實施例係如下所述,但其他製劑也可被使用。該製劑實施例僅用於說明目的,並非有意限制本發明範圍。
[ 製劑實施例 1] 軟膠囊
混合50 mg該胞外體、80-140 mg L-肉鹼、180 mg大豆油、2 mg棕櫚油、8 mg氫化植物油、4 mg黃蠟及6 mg卵磷脂。然後,每一膠囊裝入400 mg該混合物來製備軟膠囊。
[ 劑型實施例 2] 片劑
混合50 mg該胞外體、200 mg半乳寡醣、60 mg乳糖及140 mg麥芽糖並使用流體化床乾燥機(fluidized bed dryer)形成顆粒。然後,在加入6 mg糖酯後,將該混合物用壓片機壓片以製成片劑。
[ 劑型實施例 3] 顆粒
混合50 mg該胞外體、250 mg無水結晶葡萄糖及550 mg澱粉並使用流體化床乾燥機形成顆粒。將所得顆粒裝入小袋(pouch)中。
[ 劑型實施例 4] 飲料
混合50 mg該胞外體、10 g葡萄糖、0.6 g 檸檬酸及25 g液態寡糖並加入300 ml純化水。將200 mL 該混合物裝入瓶中並在130°C 滅菌4-5秒以製成飲料。
[ 劑型實施例 5] 洗劑 (lotion)
根據常用方法用下表1所述之組成物製成洗劑。 表1
[ 劑型實施例 6] 霜劑
根據常用方法用下表2 所述之組成物製成霜劑。 表2
[ 劑型實施例 7] 面膜
根據常用方法用下表3 所述之組成物製成面膜。 表3
儘管前文詳細描述了本發明之特定具體實施例,但是對於本領域技術人員而言顯而易見該具體描述僅為所欲之具體實施例,而不應被解釋為限制本發明之範圍。因此,本發明之實質範圍係由所附之申請專利範圍及其均等物界定。
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圖1顯示根據本說明書一測試實施例之一衍生自酵母菌之胞外體之分離過程。 圖2顯示根據本說明書一測試實施例之一用於分離衍生自酵母菌之胞外體之方法,及在該被分級之級分中之蛋白質含量及奈米顆粒數目。 圖3顯示根據本說明書一測試實施例之對衍生自酵母菌之胞外體之分析結果。圖3A顯示衍生自酵母菌之胞外體之形狀,而圖3B說明衍生自酵母菌之胞外體大小。 圖4顯示根據本說明書一測試實施例之用於分離衍生自啤酒之胞外體之過程。 圖5顯示根據本說明書一測試實施例分離之衍生自啤酒之胞外體之分析結果。圖5A顯示衍生自海尼根(Heineken)啤酒之胞外體(加框區)之層析圖,圖5B顯示衍生自海尼根啤酒之胞外體之形狀,圖5C顯示衍生自海尼根啤酒之胞外體之大小。 圖6係根據本說明書一測試實施例之衍生自酵母菌之胞外體作用之體外分析結果。圖6A顯示衍生自酵母菌之胞外體對TNF-α及IL-6分泌之作用,圖6B顯示以衍生自酵母菌之胞外體及LPS共處理之結果,圖6C顯示LPS誘導發炎反應後以衍生自酵母菌之胞外體後處理之結果。 圖7顯示根據本說明書一測試實施例分離之衍生自啤酒之胞外體作用之體外分析結果。圖7A顯示衍生自啤酒之胞外體對IL-6分泌之作用,圖7B顯示以衍生自啤酒之胞外體預處理後LPS誘導之發炎反應之結果。 圖8A及8B顯示在人類角質細胞中根據本說明書一測試實施例分離之衍生自酵母菌之胞外體作用之體外分析結果。
Claims (16)
- 一種抗發炎組成物,其包括衍生自酵母菌之胞外囊胞作為活性成分。
- 一種抗發炎組成物,其包括衍生自含酵母菌之食品之胞外囊胞作為活性成分。
- 如請求項1或2所述之抗發炎組成物, 其中該酵母菌係啤酒酵母菌(Saccharomyces cerevisiae )。
- 如請求項1或2所述之抗發炎組成物, 其中該胞外囊胞具有20至200 nm之直徑。
- 如請求項1所述之抗發炎組成物, 其中該胞外囊胞係藉由密度梯度超高速離心分離。
- 如請求項1所述之抗發炎組成物, 其中該胞外囊胞具有在碘克沙醇中1.08至1.19 g/mL之浮力密度。
- 如請求項2所述之抗發炎組成物, 其中該胞外囊胞係藉由粒徑篩析層析儀分離。
- 如請求項2所述之抗發炎組成物, 其中該衍生自一含酵母菌食品之胞外囊胞係一衍生自啤酒之胞外囊胞。
- 如請求項1或2所述之抗發炎組成物, 其中該抗發炎組成物抑止或抑制該發炎介質腫瘤壞死因子-α(TNF-α)或介白素-6(IL-6)之分泌。
- 如請求項1或2所述之抗發炎組成物, 其中該抗發炎組成物具有對發炎性皮膚病之抗發炎活性。
- 如請求項10所述之抗發炎組成物, 其中該發炎性皮膚病係一或多選自於由痤瘡、接觸性皮膚炎、脂溢性皮膚炎、異位性皮膚炎及牛皮癬所組成之組群。
- 如請求項1或2所述之抗發炎組成物, 其中該抗發炎組成物係一醫藥組成物、一美容組成物或一食品組成物。
- 一種用於產生如請求項1所述之胞外囊胞之方法,其包括以下步驟: 培養酵母菌; 離心所得培養液以去除殘留物獲得一上清液及過濾該上清液;及 超高速離心該濾液、收集沉澱物並使其經碘克沙醇密度梯度超高速離心。
- 如請求項13所述之用於產生胞外囊胞之方法, 其中該過濾係使用0.2至0.5 µm濾器進行過濾。
- 如請求項13所述之用於產生胞外囊胞之方法, 其中該超高速離心係於100,000 x g或其以上進行。
- 如請求項13所述之用於產生胞外囊胞之方法, 其中該胞外囊胞係在該碘克沙醇密度梯度超高速離心後由一級分獲得,其具有在碘克沙醇中1.08至1.19 g/mL之浮力密度。
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CN113382773A (zh) * | 2019-02-01 | 2021-09-10 | 达芬奇环球有限公司 | 控制生物功能的新成分 |
WO2020166868A1 (ko) * | 2019-02-14 | 2020-08-20 | 주식회사 엠디헬스케어 | 로치아 속 세균 유래 나노소포 및 이의 용도 |
WO2021167310A1 (ko) * | 2020-02-18 | 2021-08-26 | 주식회사 피코엔텍 | 알데히드탈수소 효소를 함유하는 아토피 억제 조성물 |
WO2021167309A1 (ko) * | 2020-02-18 | 2021-08-26 | 주식회사 피코엔텍 | 알데히드탈수소 효소를 함유하는 천식 억제용 조성물 |
KR102460570B1 (ko) * | 2020-02-18 | 2022-10-28 | 주식회사 피코엔텍 | 신규한 돌연변이 효모를 함유하는 아토피 억제 조성물 |
KR102522167B1 (ko) * | 2020-10-23 | 2023-04-14 | 포항공과대학교 산학협력단 | 인공 마이크로베시클 제조방법 |
KR20230008997A (ko) * | 2021-07-08 | 2023-01-17 | 주식회사 래디안 | 효모유래 세포외소포 및 용해물을 함유하는 화장료 조성물 |
WO2023062422A1 (en) * | 2021-10-11 | 2023-04-20 | Vastu Vihar Biotech Private Limited | An anti-inflammatory composition and a method of obtaining the same |
CN118510528A (zh) * | 2021-10-13 | 2024-08-16 | 达芬奇环球有限公司 | 包含源自曲的细胞外囊泡或源自发酵酒酵母的细胞外囊泡的冠状病毒传染病用组合物 |
KR20240023949A (ko) | 2022-08-16 | 2024-02-23 | 주식회사에이치엔비랩스 | 초고압 나노균질기를 이용하여 수율이 향상된 엑소좀의 제조방법 |
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GB201108560D0 (en) * | 2011-05-20 | 2011-07-06 | 3 Ch Ltd | Use of fermented wheat germ in the treatment of inflammatory bowel disease |
EP2687219A1 (en) * | 2012-07-18 | 2014-01-22 | Universität Duisburg-Essen | Use of preparations comprising exosomes derived from mesenchymal stem cells (MSCs) in the prevention and therapy of inflammatory conditions |
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