TW201338786A - 預防及治療肝纖維化或非酒精性脂肪肝之醫藥組成物 - Google Patents
預防及治療肝纖維化或非酒精性脂肪肝之醫藥組成物 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A—HUMAN NECESSITIES
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
本發明係提供一種用於預防及治療肝纖維化或非酒精性脂肪肝之醫藥組成物,包含50至90重量%之冬蟲夏草菌絲體粉末及10至50重量%之濃縮黃耆粉。
Description
本發明係有關一種用於預防及治療肝纖維化或非酒精性脂肪肝之醫藥組成物,包含50至90重量%之冬蟲夏草菌絲體及10至50重量%之黃耆。
酒精、病毒或化學物質所引起之慢性肝損傷會使肝臟星狀細胞活化且分泌大量膠原蛋白等胞外基質,並使該等胞外基質過度沉積而造成肝纖維化。根據上述致病機制,治療肝纖維化之藥品開發主要係針對抑制胞外基質合成,或促進胞外基質降解等目標,但目前所發現之物質大多具有生物毒性,或會產生強烈的副作用,至今仍未發現在動物模式中有療效者。
非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)為沒有攝取過量酒精病患之肝脂肪含量超過肝臟重量之5%以上,這些患者臨床上常伴隨肥胖、糖尿病、高血脂等疾病,而可能引發肝纖維化及肝硬化。目前對於非酒精性脂肪肝之治療係以減重、血糖及血脂之控制,但並無任何藥物被證明可有效治療非酒精性脂肪肝且進一步預防其進展為肝纖維化及肝硬化。
本發明之目的在於提供一種以中草藥作為預防及治療肝纖維化或非酒精性脂肪肝之醫藥組成物。本發明之醫藥組成物主要係包含50至90重量%之冬蟲夏草菌絲體及10至50重量%之黃耆。
冬蟲夏草(Cordyceps sinensis)為一種傳統中藥材,具有抗菌、消炎、解熱、鎮靜、促進血管擴張、平喘、抗心律不整、促進新陳代謝、抗老化、抗腫瘤及刺激免疫活性等功效。由於野生冬蟲夏草產量稀少且價格昂貴,本發明所採用之冬蟲夏草係由冬蟲夏草分離純化而得之菌絲體,其包含下列各菌種:中國被毛孢(Hirsutella sinensis)、中國擬青黴(Paecilomyces sinensis)、中國金孢黴(Chrysosporium sinensis)、蟲生簇孢(Sporothrix insectorum)、葡萄穗黴屬(Stachybotrys sp.)、中國彎頸黴(Tolypocladium sinensis)、蝙蝠蛾擬青霉(Paecilomyces hepiali)及蝙蝠蛾被毛孢(Hirsutella hepiali)等。
根據本發明之一較佳具體例,該冬蟲夏草菌絲體係為蝙蝠蛾擬青霉菌絲體(Paecilomyces hepiali Chen et Dai mycelia)經分離培養及發酵,所得之菌絲體再經冷凍或烘乾乾燥以製成粉末,以作為本發明醫藥組成物中主要成分之一。
黃耆(Astragalus membranaceus)之藥用部分為其根部,具有增強細胞免疫之功能。本發明係採用選自蒙古黃耆(Astragalus membranaceus(Fisch.) Bge. Var. mongholicus(Bge.) Hsiao)或膜莢黃耆(Astragalus membranaceus(Fisch.) Bge.)的乾燥根所製成之濃縮黃耆粉,以作為本發明醫藥組成物中另一主要成分,任何其他種類黃耆亦屬於本發明範疇。
本發明醫藥組成物中可進一步包含大棗(Zizyphi Sativae)濃縮粉,及更進一步包含藥理學上可接受之賦形劑。該賦形劑係可選自磷酸鈣、葡萄糖酸鋅、硬脂酸鎂、二氧化矽及澱粉中之一或多者之組合。
本發明之另一目的為提供一種用於製作預防及治療肝纖維化或非酒精性脂肪肝藥劑或保健食品之醫藥組成物,且該藥劑或保健食品可為膠囊、錠劑或散劑等口服製劑形式。
以下將藉由本發明之一較佳具體例詳細說明其實施方式,及其用於預防及治療肝纖維化或非酒精性脂肪肝所達到之優異功效。
本發明之一較佳具體例所採用之冬蟲夏草菌絲體係為蝙蝠蛾擬青霉菌絲體粉末。該蝙蝠蛾擬青霉菌絲體粉末之製備係參照圖1之流程圖,該蝙蝠蛾擬青霉菌株係經培養及發酵,所得菌絲體再經冷凍或烘乾乾燥、研磨及過篩以製成粉末。另,黃耆係採用選自蒙古黃耆或膜莢黃耆的乾燥根所製成之市售黃耆濃縮粉末。此外,本發明之醫藥組成物更進一步包含大棗濃縮粉及藥理學上可接受之賦形劑,該賦形劑係可選自磷酸鈣、葡萄糖酸鋅、硬脂酸鎂、二氧化矽及澱粉中之一或多者之組合。上述組成物較佳係製成膠囊形式,其中所包含各成分及含量如下述:
本發明組成物之人體劑量(70公斤)係為3120毫克/日;大鼠口服劑量依據實驗動物與人體表面積比等效劑量換算比率計算,大鼠200公克與70公斤人體表面積比值為0.018,換算200公克大鼠劑量為56.16毫克/日。以下將以本發明組成物檢測對於預防及治療肝纖維化或非酒精性脂肪肝之功效。
將5週齡雄性Wistar大鼠分成四組,分別處理如下:
TAA係以每星期三次注射100毫克/公斤,以誘發大鼠之肝纖維化症狀;及以每星期六次分別管灌各組之去離子水、一倍或五倍劑量之本發明組成物,持續八週。
八週後採集血液測定各組大鼠血清中與肝傷害相關之生化指數與血脂,及測定肝組織之脂質含量、細胞激素、膠原蛋白、抗氧化酵素活性及過氧化代謝產物。結果分述如下:
1. 血液生化值與肝臟脂質含量之影響
如圖2A及圖2B所示,TAA處理會導致血脂(三酸甘油酯(TG)及膽固醇(TC))下降,而補充本發明組成物之個體血清中,TG及TC都顯著高於只以TAA處理之個體,TC甚至可恢復至控制組的水準;而肝臟脂質分析結果則顯示補充本發明組成物可有效減少肝臟脂肪之堆積(如表1所示)。
2. 肝臟抗氧化能力之影響
測定各組之抗氧化成分與酵素活性,結果如表2所示。
結果顯示補充本發明組成物有顯著降低脂質過氧化產物丙二醛(melondialdehyde,MDA)、提高總抗氧化能力(trolox equivalent antioxidant capacity,TEAC)、及提高抗氧化酵素SOD、CAT、GPx之活性。
3. 肝臟受損情形之影響
丙胺酸轉胺酶(alanine transaminase,ALT)及天冬胺酸轉胺酶(aspartate transaminase,AST)係可作為肝臟損傷之指標,結果顯示補充本發明組成物可有效降低血液中ALT及AST(如圖2C及圖2D所示),且低劑量之組成物即展現降低ALT及AST之能力。
腫瘤壞死因子-α(TNFα)及介白素-1β(IL1-β)係受損肝臟細胞分泌之細胞激素,會加劇細胞之傷害,引發強烈發炎反應。檢測結果如表3所示,顯示補充本發明組成物可有效降低TNFα與IL1-β之含量,表示減緩了肝臟損傷程度。此外,分析肝臟中膠原蛋白,補充本發明組成物亦可顯著降低肝臟中膠原蛋白之含量(表3)。
由上述以TAA誘導大鼠肝纖維化之模式中,證明本案之醫藥組成物可藉由改善肝臟中脂質代謝、減少脂肪堆積、提高抗氧化能力及減緩因TAA造成之肝損傷,且使用低劑量(正常試驗組)即可達到預期效果。
將Spraque-Dawley大鼠分為五組,分別處理如下:
以口服方式投藥六週,以每星期三次管餵1毫升/公斤之40%溶於橄欖油之四氯化碳;及每日管餵各組去離子水、一倍或十倍劑量之本發明組成物及水飛薊素。
1. 血液生化值及分析
六週後採血檢驗下列表4中各項肝臟功能。結果顯示投予本發明組成物可降低AST、ALT及膽紅素,且增加血清白蛋白含量。
2. 抗氧化酵素與蛋白質濃度
檢測肝臟組織中抗氧化分子麩胺基硫(GSH)、麩胺基硫過氧化酶(GSH-Px)、麩胺基硫還原酶(GSH-Rd)、超氧化歧化酶(SOD)及過氧化氫酶(Catalase)之活性。結果如表5所示。
結果顯示投予本發明組成物後測得GSH及GSH-Px增加至與正常對照組接近,Catalase及SOD甚至較投予水飛薊素之正對照組為高,蛋白質濃度亦為此相同趨勢。
3. 病理切片
四氯化碳造成之肝損傷由病理切片中可發現肝臟表面粗糙,但投予本發明組成物之大鼠肝組織顯示纖維化的現象輕微,肝小葉變形機率下降。
以Sirius red組織染色觀察膠原蛋白在肝組織之分布,以四氯化碳處理之負對照組於肝組織切片顯示膠原蛋白面積增加,且肝小葉有嚴重的肝纖維化。經定量分析結果如表6所示,顯示本發明組成物兩種劑量均使肝臟中膠原蛋白減少,具有保護肝臟之作用。
由上述以四氯化碳誘導大鼠肝損傷之模式中,證明本案之醫藥組成物可降低四氯化碳對大鼠肝指數之損傷、增加抗氧化酵素活性與蛋白質濃度,於病理切片及膠原蛋白含量上亦說明可降低肝臟纖維化之現象。
以含60%以上熱量為油脂之高油飼料(D12492,Research Diets,USA)飼養6週齡之C57BL/6小鼠共18週,誘發小鼠肥胖;及以含10%熱量為油脂之正常飼料(D12450B,Research Diets,USA)飼養同週齡之C57BL/6小鼠作為對照組。
各組分別以每星期五次口服投予無菌水(10毫升/公斤)或本發明組成物(557毫克/公斤或2786毫克/公斤),連續十週。每週測量體重,十週後,採集血液測量血清AST、ALT及胰島素,並取下肝臟秤重。
餵食正常飼料之空白組的小鼠體重於整個實驗過程中無明顯的變化;餵食高油飼料之對照組的小鼠體重統計上明顯高於空白組。本發明組成物557毫克/公斤劑量相較於對照組,並無明顯差異;而以高劑量2786毫克/公斤劑量口服的小鼠體重從第22天開始下降;第36天至57天可明顯觀察到小鼠之體重減輕(圖3)。
本發明組成物以高劑量2786毫克/公斤口服八週後,相較於對照組(174±46.7 U/L)係降低血清AST值(73±6.6 U/L)約58%,尤其是明顯降低血清ALT值(9±3.7 U/L)約84%(對照組為56±13.2 U/L,p<0.05)(圖4A及圖4B),具有統計上的差異。
餵食高油飼料小鼠之胰島素(9.69±2.04 ng/ml)係高於餵食正常飼料(3.55±0.65 ng/ml)2.7倍,然,以本發明組成物557毫克/公斤或2786毫克/公斤兩種劑量口服,相較於對照組(9.69±2.04 ng/dl),可分別增加24%及36%胰島素含量(12.00±1.83 ng/dl及13.17±2.31 ng/dl)(圖5)。根據文獻記載,分泌胰島素係有助於肝臟功能的保護作用。
餵食高油飼料之小鼠肝臟濕重係高於空白組。本發明組成物557毫克/公斤劑量口服十週後,小鼠的肝臟濕重相較於對照組,在統計上無明顯的差異。然而,以本發明組成物2786毫克/公斤劑量口服8週,小鼠的肝臟濕重相較於對照組約減少29%(1.16±0.1克vs.對照組1.64±0.1克)(圖6)。
本發明係參照較佳具體例及圖式說明如上,其並非用於限制本發明。熟悉本技藝者對上述具體例之內容所作各種修改、省略及變化均屬本發明之範圍。
圖1為製備本發明蝙蝠蛾擬青霉菌絲體粉末之流程圖。
圖2為TAA誘導肝纖維化試驗中於四種處理下所測得(A)三酸甘油酯、(B)膽固醇、(C)AST及(D)ALT含量,表中數據為平均值±SEM(n=12),標示不同字母表示差異顯著(p<0.05)。
圖3為高油飼料誘導脂肪肝試驗中對照組與兩種劑量(557及2786毫克/公斤)處理下所測得小鼠體重變化。
圖4為高油飼料誘導脂肪肝試驗中於四種處理下所測得(A)AST及(B)ALT含量。
圖5為高油飼料誘導脂肪肝試驗中於四種處理下所測得胰島素含量。
圖6為高油飼料誘導脂肪肝試驗中於四種處理下所測得肝臟濕重。
Claims (12)
- 一種用於預防及治療肝纖維化之醫藥組成物,包含50至90重量%之冬蟲夏草菌絲體及10至50重量%之黃耆。
- 如申請專利範圍第1項之醫藥組成物,其中,該冬蟲夏草菌絲體係為蝙蝠蛾擬青霉菌絲體(Paecilomyces hepiali Chen et Dai mycelia)。
- 如申請專利範圍第1項之醫藥組成物,其中,該冬蟲夏草菌絲體係為乾燥粉末形式。
- 如申請專利範圍第1項之醫藥組成物,其中,該黃耆係選自蒙古黃耆(Astragalus membranaceus(Fisch.) Bge. Var. mongholicus(Bge.) Hsiao)或膜莢黃耆(Astragalus membranaceus(Fisch.) Bge.)的乾燥根所製成之濃縮黃耆粉。
- 如申請專利範圍第1項之醫藥組成物,其係用於製作藥劑或保健食品。
- 如申請專利範圍第5項之醫藥組成物,其中,該藥劑或保健食品係為膠囊、錠劑或散劑之口服製劑。
- 一種用於預防及治療非酒精性脂肪肝之醫藥組成物,包含50至90重量%之冬蟲夏草菌絲體及10至50重量%之黃耆。
- 如申請專利範圍第7項之醫藥組成物,其中,該冬蟲夏草菌絲體係為蝙蝠蛾擬青霉菌絲體(Paecilomyces hepiali Chen et Dai mycelia)。
- 如申請專利範圍第7項之醫藥組成物,其中,該冬蟲夏草菌絲體係為乾燥粉末形式。
- 如申請專利範圍第7項之醫藥組成物,其中,該黃耆係選自蒙古黃耆(Astragalus membranaceus(Fisch.) Bge. Var. mongholicus(Bge.) Hsiao)或膜莢黃耆(Astragalus membranaceus(Fisch.) Bge.)的乾燥根所製成之濃縮黃耆粉。
- 如申請專利範圍第7項之醫藥組成物,其係用於製作藥劑或保健食品。
- 如申請專利範圍第11項之醫藥組成物,其中,該藥劑或保健食品係為膠囊、錠劑或散劑之口服製劑。
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US8986756B2 (en) * | 2006-12-20 | 2015-03-24 | Jung Sik Lee | Composition comprising the extract of combined herbs for preventing and treating liver disease |
JP2008201749A (ja) * | 2007-02-21 | 2008-09-04 | Okayama Univ | 肝細胞増殖因子産生誘導剤及びその医薬品組成物 |
CN101574388A (zh) * | 2009-03-26 | 2009-11-11 | 杨毅 | 虫草口服液及其制备方法 |
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2012
- 2012-03-28 TW TW101110713A patent/TWI554277B/zh active
- 2012-09-19 EP EP12184990.5A patent/EP2644201B1/en active Active
- 2012-09-26 CN CN2012103636397A patent/CN103356732A/zh active Pending
- 2012-09-26 CN CN201410673517.7A patent/CN104382985A/zh active Pending
- 2012-10-31 US US13/664,550 patent/US8658181B2/en active Active
- 2012-11-22 JP JP2012255844A patent/JP6050099B2/ja active Active
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JP2013203739A (ja) | 2013-10-07 |
US8658181B2 (en) | 2014-02-25 |
TWI554277B (zh) | 2016-10-21 |
EP2644201B1 (en) | 2018-12-26 |
JP6050099B2 (ja) | 2016-12-21 |
US20140127256A1 (en) | 2014-05-08 |
CN104382985A (zh) | 2015-03-04 |
US8858954B2 (en) | 2014-10-14 |
CN103356732A (zh) | 2013-10-23 |
EP2644201A1 (en) | 2013-10-02 |
US20130259894A1 (en) | 2013-10-03 |
JP2017031171A (ja) | 2017-02-09 |
JP6355689B2 (ja) | 2018-07-11 |
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