TW201601737A - 增強其他抗癌藥物效果之組合物 - Google Patents
增強其他抗癌藥物效果之組合物 Download PDFInfo
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Abstract
本發明係有關於來自中草藥、藥用植物及其萃取物之組合物，一種用於預防癌症及治療癌症及增強其他抗癌藥物效果之組合物。
更特定言之，本發明組合物係來自具人類長期消費史之各種中草藥或藥用植物。本發明組合物係經由特殊技術而得且於細胞毒殺試驗中顯示出對惡性黑色素瘤細胞、前列腺癌細胞、大腸癌細胞、肺癌細胞、胃癌細胞、乳癌細胞及肝癌細胞均具有良好的毒殺癌細胞活性。此外並可明顯地增強其他抗癌藥物效果。而癌症對醫藥團體提出了特殊之問題，其為本發明所專注的。
Description
本發明係有關於來自中草藥、藥用植物及其萃取物之組合物，一種用於預防癌症及治療癌症及增強其他抗癌藥物效果之組合物。更特定言之，本發明組合物係來自具人類長期消費史之各種中草藥或藥用植物。本發明組合物係經由特殊技術而得且於細胞毒殺試驗中顯示出對惡性黑色素瘤細胞、前列腺癌細胞、大腸癌細胞、肺癌細胞、胃癌細胞、乳癌細胞及肝癌細胞均具有良好的毒殺癌細胞活性。此外並可明顯地增強其他抗癌藥物效果。而癌症對醫藥團體提出了特殊之問題，其為本發明所專注的。
現代醫藥科學不斷地尋找新穎且更有效之藥劑以預防及治療癌症。人類每年花費數十億甚至數百億美元。每年由製藥公司花費巨額於鑑定、特性化及製造新抗癌藥物以對抗冒出之具抗藥性之癌細胞，其早已成為嚴重之問題。對預防癌症具可信賴之預防性處理亦為主要之關注。
本發明係有關於一種組合物，一種用於預防癌症及治療癌症及增強其他抗癌藥物之組合物。本發明組合物其中重量比大約為夏枯草(PRUNELLAE SPICA)：半枝蓮(SCUTELLARIAE BARBATAE HERBA)：
牛樟芝(ANTRODIA CAMPHORATA)：薑黃(CURCUMAE RHIZOMA)：牡丹皮(PAEONIAE SUFFRUTICOSAE CORTEX)：敗醬草(PATRINIAE HERBA)：小金英(IXERIS HERBA)：桑黃(PHELLINUS LINTEUS)=(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)。
癌症係位於十大死因之首，其特徵為惡性組織的不正常腫塊，起因於過度地細胞分裂。癌症細胞不具有正常細胞生長之限制，會不正常地侵入其他細胞的範圍。此處所指之癌症係包含所有種類之細胞不當增生或致癌過程或轉移。一般所謂的癌症包括腦癌、頭部與頸部的癌症、眼癌(例如視網膜母細胞瘤)、鼻咽癌、口腔癌、食道癌、肺癌、支氣管癌、間皮(Mesothelioma)、甲狀腺癌、乳癌、胃癌、肝癌、胰臟癌、膽管癌、腎臟癌、腎上腺皮質癌、嗜鉻細胞瘤、卵巢癌、子宮內膜癌、子宮頸癌、大腸直腸癌、膀胱癌、前列腺癌、陰莖癌、睪丸癌、陰道癌、血癌、肌肉癌(例如惡性肉瘤)、骨癌、關節癌、淋巴瘤、皮膚癌(例如惡性黑色素瘤)、神經癌(例如神經膠質瘤)、轉移癌與惡性肉瘤(Sarcoma)。
癌症治療的種類包括化學治療、手術治療、放射線治療、賀爾蒙療法、生物製劑療法、標靶治療以及這些治療的結合療法。化學治療一般使用一個或多個抑制癌細胞生長的化合物。
雖然目前已經發展了許多癌症化療藥物，但由於副作用、有限的療效及抗藥性等原因仍然需要更有效的化療藥物。此外更有人選擇以較為溫和之中醫療法進行癌症治療。中藥是民眾普遍認為對身體較溫和之治療藥物，並具
有較高之市場接受度。因此，若能發展出一種藥學組合物，其經實驗證明確實可毒殺癌細胞，必可對於癌症治療具有相當之助益。
本發明組合物，其係經口或經鼻或經皮膚或經注射或經肛門或經生殖器而給藥或經由吸入噴霧或藉由植入貯存器的方式或以手術等侵入性方式施用於內臟組織之患部而給藥或以針炙穴位經絡給藥。當本發明組合物經口給予時，係選自以下所組成之群之產品形式：糖果，甜點，凝膠，營養補充品，口香糖，醫藥及嬰兒營養品，飲料，優格，牛奶，再水合溶液及水溶液。
草藥及民間藥之使用於中國已有幾千年。此等草藥著手於治療無數疾病，從關節炎至病毒感染，以前被現代西方醫學視為無效且危險之疾病。於19世紀當中，許多含草藥之家庭醫療藥已申請專利及販賣。現代藥已代替那些家庭醫療藥，但許多現代藥含得自草藥之成分。例如，於1776年，英國植物學家及醫生William Withering學得一種由老農婦製造之草藥，有效於治療水腫，或組織中過剩之水，其由心臟不夠強無法打出血液所引起。其發現藥中之一種成分，其係由指頂花植物之葉製成，強化心臟打出能力。由指頂花植物製成之藥現稱為毛地黃。此外Monroe E.Wall及Mansukh C.Wani於1967年於美國國家癌症研究所，從太平洋紫杉(短葉豆杉)樹皮分離出化療藥物紫杉醇(taxol)。
民間藥對於西方而言為相對現代之用詞，而已意指透過各種草藥照護及治療疾病。近年來，民間藥已於西方科學醫藥界變得增加關注。
稱為夏枯草(PRUNELLAE SPICA)之中草藥，夏枯草之製備係自滁州夏枯草(Prunella vulgaris)或日本夏枯草(Prunella vulgaris subsp.asiatica)(亦稱為Prunella vulgaris vra.lilachina)之乾燥花穗或全草。兩植物皆屬唇形科。此草藥具苦味且為無毒性。治療劑量典型地供平均人類為每日4至110克。臨床上可治療高血壓，急性結膜炎，急性黃疸性肝炎，頸部淋巴炎、淋巴結核、單純性甲狀腺腫、扁桃腺炎與咽喉炎。亦可配合其他中草藥治療眼珠疼痛、流淚懼光、腹痛、瘡瘍與子宮出血。夏枯草可抑制痢疾桿菌、傷寒桿菌、霍亂弧菌、大腸桿菌、變形桿菌、綠膿桿菌、葡萄球菌與鏈球菌。Hozumi等揭示滁州夏枯草之花穗作為抗疱疹病毒劑供治療疱疹病毒感染。參見T.Hozumi等人，美國專利第5,411,733號，1995年5月2日公告。蔡修賢等人揭示夏枯草之水萃取物於2.5mg/ml濃度於試管試驗第三天可抑制100%愛滋病毒活性，而第四天仍可抑制100%愛滋病毒活性。參見蔡修賢等人，美國專利第5837257號，1998年11月17日公告。此外夏枯草亦可配合其他中草藥治療癌症：夏枯草與蒲公英併用治療以早期乳癌。參見張憲昌藥草(一)渡假出版社有限公司台北，台灣，第15頁(1997)。李健勇揭示一種由黨參、黃芪、薏苡仁、山佩蘭、橘皮、爵床、夏枯草、涼粉草、梔子、連翹、赤芍、大黃、蟅蟲、白花蛇舌草、扛板歸、山豆根、木槿皮、天南星、半邊蓮、白蘞、漏蘆、石葦、乳香、沒藥、蚤休、敗醬、白芷、射幹、蒲公英、螺厴草、皂莢、獨活、麻黃及升麻等組成中藥複方用於治療淋巴結關係型癌症，參見李健勇，台灣專利第I260226號，2006年08月21日公告。Y.Maimon揭示一種由黃芪、茯苓、白朮、枸杞、女貞子、白芍、北沙參、陳皮、麥冬、雞血藤、白花蛇舌草、半枝蓮及夏枯草所組成的組
合物應用於減少與化療相關的副作用。參見Y.Maimon，美國專利第8,574,636號，2013年11月5日公告。
稱為半枝蓮(SCUTELLARIAE BARBATAE HERBA)之中草藥，係自半枝蓮(Scutellaria barbata)、半枝蓮(Scutellaria rivularis)或狗牙半枝蓮(Scutellaria dependens)製備，其屬於唇形科。此草藥具苦味且不應由貧血者服用。懷孕婦人應避免服此藥草。治療劑量典型地為每日4至300克。臨床上可治跌打損傷、驚風、肺炎、喉痛、腹痛與腸炎。蔡修賢等人揭示半枝蓮之水萃取物於2.5mg/ml濃度於試管試驗第三天可抑制92%愛滋病毒活性，而第四天可抑制94%愛滋病毒活性。參見蔡修賢等人，美國專利第5837257號，1998年11月17日公告。I.Cohen揭示以半枝蓮萃取物(未併用任何其他中草藥)治療晚期乳癌與轉移性乳癌。參見I.Cohen，美國專利第7700136號，2010年4月20日公告。此外半枝蓮亦可配合其他中草藥治療癌症：A.S.Sun揭示以白花蛇舌草、半枝蓮、綠豆與香菇改善惡性腫瘤。參見A.S.Sun，美國專利第5437866號，1995年8月1日公告。J.Dao等人揭示以靈芝、丹蔘與半枝蓮之乙酸乙酯萃取物治療癌症。參見J.Dao等人，美國專利第8173177號，2012年5月8日公告。Y.Maimon揭示一種由夏枯草、黃芪、茯苓、白朮、枸杞、女貞子、白芍、北沙參、陳皮、麥冬、雞血藤、白花蛇舌草及半枝蓮所組成的組合物應用於減少與化療相關的副作用。參見Y.Maimon，美國專利第8,574,636號，2013年11月5日公告。
稱為牛樟芝(ANTRODIA CAMPHORATA)之中草藥，牛樟芝係屬於非褶菌目(Aphyllophorales)多孔菌科(Polyporaceae)之多年生蕈菌類。牛樟芝之製備係自牛樟芝之子實體、菌絲體或二者之混合物。由牛樟
芝萃取之各種化合物有保護肝臟、抗氧化、抗炎與抗癌等各種不同之作用。G.Hsiao等人報告，牛樟芝萃取物能有效預防四氯化碳所誘導之肝毒性。參見G.Hsiao et al.,Antioxidative and hepatoprotective effects of Antrodia camphorate extract.J.Agric.Food Chem.,2003,51：3302-3308。W.C.Lin等人報告，由牛樟芝發酵之菌絲體能減緩四氯化碳所誘導大鼠肝纖維化的進展。參見W.C.Lin et al.Filtrate of fermented mycelia from Antrodia camphorata reduces liver fibrosis induced by carbon tetrachloride in rats World J Gastroenterol 2006 April；12(15)：2369-2374。S.Y.Liu等人揭示了牛樟芝的環己烯酮化合物能有效地抑制HBsAg(B型肝炎表面抗原)與HBeAg(B型肝炎e抗原)以達成抑制HBV(B型肝炎病毒)之目的。參見S.Y.Liu et al.，美國專利第7411003號，2008年8月12日公告。S.Y.Liu等人揭示牛樟芝的環己烯酮化合物減少肝臟損傷和自由基引起的氧化壓力，增強抗氧化能力，並達成保護肝臟之目的。參見S.Y.Liu et al.，美國專利第7456225號，2008年11月25日公告。C.H.HUANG等人報告，牛樟芝尤其於高劑量(0.1g/kg BW/day)時對被餵酒精的老鼠不只對高膽固醇起作用而且也減少肝臟的脂質。參見CH Huang et al.,Fruiting body of Niuchangchih(Antrodia camphorata)protects livers against chronic alcohol consumption damage.J Agric Food Chem.2010 Mar 24；58(6)：3859-66。T.Y.SONG等人報告，牛樟芝深層培養於不同溶劑萃取物中發酵濾液的乾物質(DMF)具有最強的抗氧化活性。參見T.Y.SONG et al.,Protective Effects of Fermented Filtrate from Antrodia camphorata in Submerged Culture against CCl4-Induced Hepatic Toxicity in Rats.J.Agric.Food Chem.2003, 51,1571-1577。Chuian-Fu KEN等人報告，重組之牛樟芝-過氧化氫酶(從牛樟芝所得之過氧化氫酶)可以起酵素作用地解毒．OH基。參見Chuian-Fu KEN et al.Biochemical characterization of a catalase from Antrodia camphorata：Expression in Escherichia coli and enzyme properties Botanical Studies(2008)49：119-125。Y.k.Rao等人報告，牛樟芝的氯仿和甲醇萃取物的抗炎作用，是由於抑制巨噬細胞介導的炎症介質。參見Y.k.Rao et al.,Evaluation of the anti-inflammatory and anti-proliferation tumoral cells activities of Antrodia camphorata,Cordyceps sinensis,and Cinnamomum osmophloeum bark extracts.Journal of Ethnopharmacology,2007 Oct 114(1),78-85。S.Y.Liu等人揭示牛樟芝的環己烯酮化合物促進在人體內磷酸肌酸激酶和血氨的代謝，有益他們的恢復，進一步達成延緩生理性疲勞之功能。參見S.Y.Liu et al.，美國專利第7468392號，2008年12月23日公告。S.Y.Liu等人揭示牛樟芝的環己烯酮化合物用以治療自身免疫性疾病。參見S.S.Y.Liu et al.，美國專利第7501454號，2009年3月10日公告.J.J.Liu等人報告，一種由牛樟芝菌絲體所得之獨特多醣體成份於體外與體內二模式均有明顯的抗腫瘤效果。參見J.J.Liu et al.,Antitumor effects of the partially purified polysaccharides from Antrodia camphorata and the mechanism of its action.Toxicol.Appl.Pharmacol,2004,201：186-193。C.Y.Lee揭示由白朮、當歸、韓信草、火炭母草、艾纳香、蒴藋、馬蘭、綠豆、甘蔗、大青根、半邊蓮、杏仁、牛樟芝、前胡、假茼蒿、茵陳蒿、牛樟芝(Nuzhenzi)、鬱金、枳實與半夏所組成藥品混合物用於肝癌與胰臟癌。參見C.Y.Lee.美國專利第6,998,141，號，2006年2月14日公告。Y.C.Lent等
人報告，牛樟芝二甲基氧化硫萃取物對人類骨肉瘤細胞MG 63之作用，於牛樟芝25~50微克/毫升之濃度時並不影響癌細胞存活率，而於牛樟芝100~200微克/毫升之濃度時則降低癌細胞存活率與誘導癌細胞自殺，以濃度依賴之方式降低癌細胞存活率與誘導癌細胞自殺。參見Y.C.Luet al.Effects of Antrodia camphorata on viability,apoptosis,[Ca2+],and MAPKs phosphorylation in MG63 human osteosarcoma cells.Drug Dev.Res.,2007,68：71-78。C.Y.Chang等人報告，牛樟芝乙醇萃取物當與抗腫瘤藥物併用時對人類肝癌細胞(體外)和植入腫瘤裸鼠異種移植細胞(體內)顯示出輔助抗細胞增殖之作用。參見C.Y.Chang et al.,The adjuvant effects of Antrodia camphorate extracts combined with anti-tumor agents on multidrug resistant human hepatoma cells.J.Ethnopharmacol.2008,118：387-395。S.Y.Liu等人揭示由牛樟芝而得之新穎化合物與用途尤其是Antroquinonol B and Antroquinonol C，能有效地抑制癌細胞的生長。參見S.Y.Liu et al.，美國專利第7,385,088號，2008年6月10日公告。S.L.Li等人報告，牛樟芝與甘草與大豆共同發酵之乙醇萃取物增強牛樟芝於人類肝癌細胞的抗腫瘤作用。參見S.L.Li et al.,The Augmented Anti-Tumor Effects of Antrodia camphorata Co-Fermented with Chinese Medicinal Herb in Human Hepatoma Cells,The American Journal of Chinese Medicine,2009,37,4,771-783。C.C.Huang等人報告，牛樟芝之二甲基氧化硫萃取物對OC2人類口腔癌細胞的功效，於牛樟芝25微克/毫升的濃度時顯著增加癌細胞存活率，而於牛樟芝100-200微克/毫升的濃度時則降低癌細胞存活率，以濃度依賴的方式降低癌細胞存活率。參見C.C.Huang et al.,Effects of Antrodia camphorata Extracts on the Viability,Apoptosis,|Ca2+|i,and MAPKs Phosphorylation of OC2 Human Oral Cancer Cells,Chinese Journal of Physiology,2009；52(3)：128-135。賴基銘等人揭示樂瓦司他汀(1ovastatin)(二羥甲戊酸徑(mevalonate pathway)抑制劑)可顯著增強牛樟芝(Antrodia camphorata)也稱為“Taiwanofungus camphoratus”萃取物於抑制癌症細胞生長的功效。參見賴基銘等人，台灣專利第I311912號，2009年07月21日公告。T.I.Chen等人報告，於90天之Sprague-Dawlly rats亞慢性毒性試驗，確認牛樟芝於無可見副作用之標準，其劑量大於每天每公斤體重3公克。參見T.I.Chen et al.,A 90-day subchronic toxicological assessment of Antrodia cinnamomea in Sprague-Dawley rats.Food and Chemical Toxicology 2011 Feb；49(2)：429-33。
稱為薑黃(CURCUMAE RHIZOMA)之中草藥，薑黃之製備係自薑黃、鬱金、黃根薑黃或莪术之乾燥根莖，這些植物皆屬薑科，其功能為活血、化瘀與止痛。治療劑量典型地供平均人類為每日3至12克。此外薑黃亦可與其他草藥或藥物併用以保護肝臟或治療癌症。N.KAORU等人揭示一種以薑黃與鯊烯或三十碳烷之混合物為主要成分之新穎含薑黃組成物，具有顯著之肝功能保護及改善效果。參見N.KAORU等人，台灣專利第I277422號，2007年04月01日公告。C.Y.Lee揭示由白朮、當歸、韓信草、火炭母草、艾纳香、蒴藋、馬蘭、綠豆、甘蔗、大青根、半邊蓮、杏仁、牛樟芝、前胡、假茼蒿、茵陳蒿、鬱金(Yujin)、枳實與半夏所組成藥品混合物用於肝癌與胰臟癌。C.Y.Lee.美國專利第6998141號，2006年2月14日公告。T.Newmark等人揭示一種由羅勒、姜、薑黃、黃芩、迷迭香、綠
茶、虎杖、中國黃連與伏牛花的水醇萃取物所組成之組合物，用於治療前列腺癌。參見T.Newmark等人，美國專利第7,470,440號，2008年11月30日公告。T.Newmark等人揭示一種由羅勒、姜、薑黃、黃芩、迷迭香、綠茶、虎杖、中國黃連與伏牛花的水醇萃取物所組成之組合物，用於治療膠質母細胞瘤。參見T.Newmark等人，美國專利第7,622,142號，2009年11月24日公告。T.Newmark，等人揭示一種由羅勒、姜、薑黃、黃芩、迷迭香、綠茶、虎杖、中國黃連與伏牛花的水醇萃取物所組成之組合物，用於治療前列腺癌。參見T.Newmark等人，美國專利第7,470,440號，2008年11月30日公告。薑黃素為薑黃之主成份，被用為預防癌症與抗氧化之保健食品。李政育等人揭示一種由牛黃、鬱金、水牛角、黃芩、黃連、雄黃、生梔子、朱砂、龍腦、麝香、真珠與金箔所組成之組合物，用於預防腦缺血後再灌注之病變。參見李政育等人，台灣專利第I353846號，2011年12月11日公告。
稱為牡丹皮(PAEONIAE SUFFRUTICOSAE CORTEX)之中草藥，牡丹皮之製備係自牡丹(Paeonia suffruticosa)、矮牡丹(Paeonia suffruticosa var.spontanea)、紫斑牡丹(Paeonia papaveracea)、川牡丹(Paeonia szechuanica)、黃牡丹(Paeonia lutea)、野牡丹(Paeonia delavayi)、保氏牡丹(Paeonia potanini)、茂紋牡丹(Paeonia thalictrumifolia)與雲南牡丹(Paeonia yunnanonsis)之乾燥根皮。此九種植物均為毛茸科。臨床上用以治療發斑、驚癇、吐血、屻血、便血、經閉。腫瘤、瘡瘍與細菌感染、月經過多。孕婦。腹瀉與多汗者均不宜用。治療劑量典型地為每日7至12克。謝秀梅等人揭示一種由黃蓮、升麻、當歸、生地黃與牡丹皮所組成之組合物，用於以抑制肺癌幹細胞生長。參見謝秀梅等人，台灣專利第I413525
號，2013年11月1日公告。
稱為敗醬草(PATRINIA HERBA)之中草藥，敗醬草之製備係自黃花敗醬草(Patrinia scabiosaefolia)或白花敗醬草(Patrinia villosa)乾燥全草。治療劑量典型地為每日10至20克。臨床上可治療感染性疾病：流行性感冒、腮腺炎、結膜炎、扁桃腺炎、急性胰臟炎、肺炎、肝膿瘍、腸胃炎、吐血、流鼻血與神經衰弱。李健勇揭示一種由黨參、黃芪、薏苡仁、山佩蘭、橘皮、爵床、夏枯草、涼粉草、梔子、連翹、赤芍、大黃、蟅蟲、白花蛇舌草、扛板歸、山豆根、木槿皮、天南星、半邊蓮、白蘞、漏蘆、石葦、乳香、沒藥、蚤休、敗醬草、白芷、射幹、蒲公英、螺厴草、皂莢、獨活、麻黃及升麻等組成中藥複方用於治療淋巴結關係型癌症，參見李健勇，台灣專利第I260226號，2006年08月21日公告。
稱為小金英(IXERIS HERBA)之中草藥，小金英之製備係自小金英(Ixeris chinensis)乾燥全草。治療劑量典型地為每日10至40克。臨床上可治療肺炎、咽喉痛、白喉、腸炎、膀胱炎、痔瘡與尿路結石。此外小金英可與其他中草藥併用，以當女性成長養生品。參見蔡宗義，台灣專利第M376295號，2010年03月21日公告。
稱為桑黃(PHELLINUS LINTEUS)之中草藥，桑黃之製備可取桑黃子實體、菌絲體或二者之混合物。桑黃為屬於刺革菌科之蕈菌類。在日本、韓國與中國桑黃已廣泛地被使用。桑黃對於各種疾病有效，像改善血液循環、促進解毒、保護人體肝臟、防治過敏與糖尿病、治癒口腔潰瘍與減輕胃腸障礙或淋巴疾病。桑黃萃取物被報告擁有免疫調節與抗癌作用。桑黃為抗氧化劑與肝臟保護劑之優良中草藥源。參見T.Zhu等人，A Medicinal Mushroom：Phellinus linteus,Current Medicinal Chemistry 2008,15：1330~1335。
本發明係有關於一種組合物，一種用於預防癌症及治療癌症及增強其他抗癌藥物之組合物。本發明組合物其中重量比大約為夏枯草(PRUNELLAE SPICA)：半枝蓮(SCUTELLARIAE BARBATAE HERBA)：牛樟芝(ANTRODIA CAMPHORATA)：薑黃(CURCUMAE RHIZOMA)：牡丹皮(PAEONIAE SUFFRUTICOSAE CORTEX)：敗醬草(PATRINIAE HERBA)：小金英(IXERIS HERBA)：桑黃(PHELLINUS LINTEUS)=(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)。本發明之組合物，其劑量對於須治療之哺乳類範圍可由每天0.4克至120克。精於此道者要了解的是依個人之體重及病情而定。精於此道者對於指定之個人可增減各劑量比例而無不當之經驗。更特定言之，對於指定之組合物之劑量，範圍可由每天0.4克至100克，更佳地每天10克至25克。較佳地，此等組合物至少每天投予3次，然而，大丸劑投藥有效。應了解的是本文所述劑量係對於以乾燥形式之草藥(萃取物附著於研磨之植物或吸附劑上)。另外，本發明組合物之萃取物會增加活性物之濃度，因此要明白降低劑量。低至對於本發明組合物所述者之10%之劑量涵蓋在內。
本發明組合物較好以口或腸內給藥，然而，靜脈內(I.V.)及/或肌肉內(I.M.)給藥，亦涵蓋於本文。精於此道者要了解如何製備I.V.及I.M.調配物，及如何可得有效劑量。
用為本發明之起始物質之藥草可得自商業基源，為單藥草草藥，
可將其混合或萃取及濃縮，並置於組合物中以供投予人類。植物萃取物，一旦自植物材分離，可濃縮再置於可適當投予人類之形式(亦即丸劑、膠囊及錠劑)中。
亦揭示者為藉由包含下列步驟之方法製造之醫藥產品：(a)將粉碎之植物材料混合物與水接觸形成水分散液；(b)加熱水分散液至約100℃並維持於該溫約0.5小時至約3小時；(c)自水相分離不溶之植物材料；及(d)將含於水相中之溶質濃縮。濃縮之溶質經由冷凍乾燥、噴霧乾燥、蒸發或超濾而得。
上述之中草藥及藥草之特殊說明可於下面參考中找到：(1)甘偉松：藥用植物學，中國醫藥研究所，台北，台灣1973：271,485,532,641,642,643。(2)林景彬：常用中藥藥理與應用(一)，中國醫藥學院，台中，台灣1985；201~207,236~246(1985)。(3)邱年永與張光雄：原色台灣藥用植物圖鑑(1)，南天書局，台北，台灣1995；186,188。(4)邱年永與張光雄：原色台灣藥用植物圖鑑(2)，南天書局，台北，台灣1995；245。(5)邱年永與張光雄：原色台灣藥用植物圖鑑(4)，南天書局，台北，台灣1995；81。(6)張憲昌：藥草(一)，渡假出版社有限公司，台北，台灣1997：15。(7)張憲昌：藥草(二)，渡假出版社有限公司，台北，台灣1997：15。(8)李沐勳與李威著：常用中草藥手冊，中國醫藥研究所，台北，台灣2001：30,44,62,85,98,103,133,142
要注意的是於傳統中藥實務中，草藥用來治療患者之症狀，而非疾病或病原物本身，且因此已知並非對特別疾病有特異性。草藥依個別患者之症狀而處方。草藥之組合物亦隨病例而異，且甚至於治療過程中，依
各治療結果，對個別患者加以改變。因此很難從先前技藝中處方出一種適宜特殊疾病之特別之藥草組合物。本發明之治療癌症之藥草組合物為得自個別藥草、藥草組合物及商業上可得之中草藥。此等新穎之藥草組合物及其萃取物於本文證明具有毒殺各種癌細胞之活性，並且可明顯地增強其他抗癌藥物效果。
本申請案敘述於本發明可利用之數據，及完全描述物質之組合物、彼等之製備、臨床之應用及用於將各種活性組成份特定化之分析工具。本發明之這些及其他方面，由下面之實例將顯然於精於此道者，而下面實例意欲說明而非限制本發明。
細胞培養基：
C1-A‧‧‧含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的DMEM
C1-B‧‧‧含有10% FBS (fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的RPMI 1640
C1-C‧‧‧含有10% FBS(fetal bovine serum胎
牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的MEM
C1-D‧‧‧含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的F-12K。陰性對照組：只有培養基而不加藥。陽性對照組：Triton X100(1%)，標示為C2。Triton X100是一種清潔劑能殺死90%以上之細胞
S1‧‧‧本藥草組合物5mg/ml
S2‧‧‧5-FU 5ug/ml
S3‧‧‧Oxaliplatin 10ug/ml
S4‧‧‧Irinotecan5 ug/ml
S5‧‧‧(本藥草組合物5mg/ml與5-FU 5ug/ml)
S6‧‧‧(本藥草組合物5mg/ml與Oxaliplatin 10ug/ml)
S7‧‧‧(本藥草組合物5mg/ml與Irinotecan 5ug/ml)
S8‧‧‧(本藥草組合物5 mg/ml與5-FU 5ug/ml與Oxaliplatin 10ug/ml)
S9‧‧‧(本藥草組合物5mg /ml與5-FU 5ug/ml與Irinotecan 5ug/ml)
S10‧‧‧ (5-FU 5ug/ml與Oxaliplatin 10ug/ml)
S11‧‧‧(5-FU 5ug/ml與Irinotecan 5ug/ml)
圖1顯示以0.5mg/ml,1mg/ml,5mg/ml及10mg/ml之藥草組合物萃取物處理後，黑色素瘤細胞A375之存活率。圖2顯示以0.5mg/ml,1mg/ml,5mg/ml及10mg/ml之藥草組合物萃取物處理後，前列腺癌細胞PC3之存活率。圖3顯示以0.5mg/ml,1mg/ml,5mg/ml及10mg/ml之藥草組合物萃取物處理後，大腸癌細胞HT29之存活率。圖4顯示以0.5mg/ml,1mg/ml,5mg/ml及10mg/ml之藥草組合物萃取物處理後，肺癌細胞A549之存活率。圖5顯示以0.22mg/ml,0.44mg/ml,0.87mg/ml,1.75mg/ml,3.50mg/ml及7.00mg/ml之藥草組合物萃取物處理後，胃癌細胞AGS之存活率。圖6顯示以0.24mg/ml,0.48mg/ml,0.95mg/ml,1.90mg/ml,3.80mg/ml及7.60mg/ml之藥草組合物萃取物處理後，乳癌細胞MCF-7之存活率。圖7顯示以0.25mg/ml,0.51mg/ml,1.01mg/ml,2.02mg/ml,4.05mg/ml及8.09mg/ml之藥草組合物萃取物處理後，肝癌細胞
Huh7之存活率。圖8顯示以5mg/ml之中草藥組合物萃取物(有/無)併用不同化療藥物處理後，多重抗藥性大腸癌細胞HT29之存活率。
進行本發明之最佳方式：為使精於此道者了解本發明之原理，提出下面實例，欲提供例證而非限制。
實例1：藥草組合物之製備-於製備根據本發明之藥草組合物中，自商業來源以粉末形式之單藥草型中草藥。將個別之單藥草草藥以相同重量混合製備本藥草組合物。要揭示的是，個別自單藥草草藥之來源植物製備之煎劑混合物或自各藥草混合物之單藥草組成份之預先混合之來源植物製備之煎劑，於本發明範圍內。
實例2：單藥草草藥之製備-得各單藥草草藥之植物來源列示於本申請案之先前技藝及概要之節中。應了解的是多於一個種或屬之藥用植物可用來製備相同之草藥。例如夏枯草(PRUNELLAE SPICA)之製備可自滁州夏枯草(Prunella vulgaris)或日本夏枯草(Prunella vulgaris subsp.asiatica)(亦稱為Prunella vulgaris vra.lilachina)。半枝蓮(SCUTELLARIAE BARBATAE HERBA)之製備，可自半枝蓮(Scutellaria barbata)、半枝蓮(Scutellaria rivularis)或狗牙半枝蓮(Scutellaria dependens)製備。牡丹皮(PAEONIAE SUFFRUTICOSAE CORTEX)之製備可自牡丹(Paeonia suffruticosa)、矮牡丹(Paeonia suffruticosa var.spontanea)、紫斑牡丹(Paeonia papaveracea)、川牡丹(Paeonia szechuanica)、黃牡丹(Paeonia lutea)、野牡丹(Paeonia delavayi)、保氏牡丹(Paeonia potanini)、茂紋牡丹(Paeonia thalictrumifolia)與雲南牡丹(Paeonia yunnanonsis)。草藥係自其
各別之植物源製備如下：得適宜部分或全草，以冷水洗，乾燥及粉碎。植物材料再以沸水萃取，基於1份重量之植物材料對約5份至10份重量之水。所用水量至少蓋住萃取容器中之植物材料。將樣品煮沸0.5小時至1小時，但不超過3小時，以令有效地萃取所須組成份。以較短或較長之加熱實質上不影響萃取，除了產量及費用外。以過濾自植物材料分離水溶液。水溶液可冷凍乾燥或噴霧乾燥，或藉加熱，有或無應用真空下降低體積。可將濃縮物再噴霧乾燥或冷凍乾燥或吸收於相同植物材料，澱粉或其他吸收劑之粉末形式上。因此製備單藥草草藥。煎劑為植物材料之水溶液，其藉由將植物材料於水中如上述煮沸約0.5小時至1小時而製備。煎劑於製備及冷卻至溫的或周溫後可直接服用或以適當滅菌保存供後來服用。滅菌可藉微過濾或加熱完成。
藥草組合物之水萃取物對癌細胞之毒殺試驗-癌細胞之毒殺試驗是用MTT assay。MTT assay：常被用於分析細胞存活率(percent of viable cells)及細胞毒性(cytotoxicity)之方法。MTT是一種terazolium salt，全名為(3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide)，為黃色染劑，可被活細胞吸收並被粒腺體中的琥珀酸四唑還原酶(succinate tetrazolium reductase)還原成藍紫色的formazan結晶體，藉由formazan形成，即可計算細胞之存活率。細胞存活率(%)=(Nt/Nc)X 100。Nt是加藥組之吸光值，而Nc是未加藥組(陰性對照組)之吸光值。陰性對照組：只用細胞培養基者，其細胞存活率定為100%。以不同濃度的藥物為橫軸且以細胞存活率為縱軸而繪製柱狀圖。細胞培養基：C1-A：含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的DMEM。C1-B：
含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的RPMI 1640。C1-C：含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的MEM。C1-D：含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的F-12K。
MTT assay-A：將癌細胞於培養基中培養2天後，於96孔盤培養皿中每孔殖入10,000個癌細胞，培養24小時後，分別以各種不同濃度的本藥草混合物處理。處理之後，在無血清之培養基內細胞與100μl of MTT(0.5mg/ml)共同培養4小時，之後由存活細胞所產生之formazan結晶體以100μl solubilisation buffer(10%(v/v)Triton X-100與0.1N HCl in isopropanol)處理1小時而溶解。於波長570nm以Beckmann Coulter Elisa plate reader(Bio Tek Power Wave XS)測量溶液之光密度，樣品經三次分析且以上述之公式計算細胞相對於陰性對照組(未加藥組)之存活率(%)。只有培養基而不加藥的培養皿當陰性對照組。Triton X100是一種清潔劑能殺死90%以上之細胞，Triton X100(1%)當陽性對照組，標示為C2。
MTT assay-B：MTT assay-B與MTT assay-A所利用之原理是相同的且其方法是相似的。但是MTT assay-B以Spectra Max M5 Microplate Reader(Molecular Devices)測量溶液之光密度。此外本assay無陽性對照組。陰性對照組：只用細胞培養基者，其細胞存活率定為100%，未標示於圖中。
實例3：藥草組合物之水萃取物對人類惡性黑色素腫瘤細胞A375之毒殺試驗。人類惡性黑色素腫瘤細胞A375之細胞培養基：C1-A。將人類惡
性黑色素腫瘤細胞A375分別以0.5mg/ml、1mg/ml、5mg/ml及10mg/ml實施例1之組合物處理後，以MTT assay-A來測定細胞之存活率。陰性對照組：C1-A，陽性對照組：C2。實驗結果如圖1所示以濃度依賴之狀態，隨着本發明組合物之濃度遞增其毒殺癌細胞之活性亦遞增。且依照實驗結果計算其IC 50為3.20mg/ml。
實例4：藥草組合物之水萃取物對人類前列腺癌細胞PC3之毒殺試驗。人類前列腺癌細胞PC3之細胞培養基：C1-A。將人類前列腺癌細胞PC3分別以0.5mg/ml、1mg/ml、5mg/ml及10mg/ml實施例1之組合物處理後，以MTT assay-A來測定細胞存活率。陰性對照組：C1-A，陽性對照組：C2。實驗結果如圖2所示於本發明組合物之濃度1mg/ml~10mg/ml時，以濃度依賴之狀態隨着本發明組合物之濃度遞增其毒殺癌細胞之活性亦遞增。且依照實驗結果計算其IC 50為8.36mg/ml。
實例5：藥草組合物之水萃取物對人類大腸癌細胞HT29之毒殺試驗。人類大腸癌細胞HT29之細胞培養基：C1-B。將人類大腸癌細胞HT29分別以0.5mg/ml、1mg/ml、5mg/ml及10mg/ml實施例1之組合物處理後，以MTT assay-A來測定細胞存活率。陰性對照組：C1-B，陽性對照組：C2。實驗結果如圖3所示於本發明組合物之濃度1mg/ml~10mg/ml時，以濃度依賴之狀態隨着本發明組合物之濃度遞增其毒殺癌細胞之活性亦遞增。且依照實驗結果計算其IC 50為3.47mg/ml。
實例6：藥草組合物之水萃取物對人類肺癌細胞A549之毒殺試驗。人類肺癌細胞A549之細胞培養基：C1-C。將人類肺癌細胞A549分別以0.5mg/ml、1mg/ml、5mg/ml及10mg/ml實施例1之組合物處理後，以
MTT assay-A來測定細胞存活率。陰性對照組：C1-C，陽性對照組：C2。實驗結果如圖4所示以濃度依賴之狀態，隨着本發明組合物之濃度遞增其毒殺癌細胞之活性亦遞增。雖然在5mg/ml之濃度時肺癌細胞A549之存活率只剩34%，然而依照實驗結果計算其IC 50為5.04mg/ml。
實例7：藥草組合物之水萃取物對人類胃癌細胞AGS之毒殺試驗。人類胃癌細胞AGS之細胞培養基：C1-D。將人類胃癌細胞AGS分別以0.22mg/ml、0.44mg/ml、0.87mg/ml、1.75mg/ml、3.50mg/ml及7.00mg/ml實施例1之組合物處理後，以MTT assay-B來測定細胞之存活率。實驗結果如圖5所示以濃度依賴之狀態，隨着本發明組合物之濃度遞增其毒殺癌細胞之活性亦遞增。且依照實驗結果計算其IC 50為3.19mg/ml。
實例8：藥草組合物之水萃取物對人類乳癌細胞MCF-7之毒殺試驗。人類乳癌細胞MCF-7之細胞培養基：C1-C。將人類乳癌細胞MCF-7分別以0.24mg/ml、0.48mg/ml、0.95mg/ml、1.90mg/ml、3.80mg/ml及7.60mg/ml實施例1所陳述之組合物處理後，以MTT assay-B來測定該細胞之存活率。實驗結果如圖6所示於本發明組合物之濃度0.95mg/ml~7.60mg/ml時，以濃度依賴之狀態隨着本發明組合物之濃度遞增其毒殺癌細胞之活性亦遞增。且依照實驗結果計算其IC 50為4.38mg/ml。
實例9；藥草組合物之水萃取物對人類肝癌細胞Huh7之毒殺試驗。人類肝癌細胞Huh7之細胞培養基：C1-A。將人類肝癌細胞Huh7分別以0.25mg/ml、0.51mg/ml、1.01mg/ml、2.02mg/ml、4.05mg/ml及8.09mg/ml實施例1之組合物處理後，以MTT assay-B來測定細胞存活率。實驗結果如圖7所示以濃度依賴之狀態，隨着本發明組合物之濃度遞增其毒殺癌細
胞之活性亦遞增。且依照實驗結果計算其IC 50為1.50mg/ml。
實例10：藥草組合物之水萃取物與其他化療療物併用對大腸癌細胞HT29之毒殺試驗。5-FU(5-fluorouracil)購自Celon Lab，Irinotecan購自Dr.Reddy Lab及Oxaliplatin購自Panacea Biotech。人類大腸癌細胞HT29之細胞培養基：C1-B。將人類大腸癌細胞HT29分別以S1：本藥草組合物5mg/ml、S2：5-FU 5ug/ml、S3：Oxaliplatin 10ug/ml、S4：Irinotecan5ug/ml、S5：(本藥草組合物5mg/ml與5-FU 5ug/ml)、S6：(本藥草組合物5mg/ml與Oxaliplatin 10ug/ml)、S7；(本藥草組合物5mg/ml與Irinotecan 5ug/ml)、S8：(本藥草組合物5mg/ml與5-FU 5ug/ml與Oxaliplatin 10ug/ml)、S9：(本藥草組合物5mg/ml與5-FU 5ug/ml與Irinotecan 5ug/ml)、S10：(5-FU 5ug/ml與Oxaliplatin 10ug/ml)及S11：(5-FU 5ug/ml與Irinotecan 5ug/ml)處理後，以MTT assay-A來測定細胞存活率。陰性對照組：C1-B，陽性對照組：C2。由圖8所示本發明藥草組合物確實有很好的毒殺癌細胞活性，並能與其他抗癌藥物產生明顯之協同作用，因此，本發明的組合物確實可當作癌症治療之輔佐劑以增強其他抗癌藥物之效果。
本文所述之治療作用可經由投予"照原樣"之草藥，或以茶、煎藥、飲料、糖果或其他糖膏劑、腸內液體營養產品如嬰兒配方及成人營養產品、藥用食物、營養補充品或營養品。對於藥品藥物，可以單位劑型如膠囊、小包或錠劑(有或無控制釋放塗膜)投藥。本發明是針對於一部分，這樣的發現，即特定的藥用植物或草藥或它們的混合物具有令人驚訝的抗癌活性。更具體地，本發明的組合物是由具有人類消費的悠久歷史的各種中國草藥或藥用植物衍生的。它們是GRAS(通常認為是安全的)。
工業上應用性：化療的副作用很多諸如疲勞、反胃、便秘與腹瀉、口腔潰爛、頭皮與脫髮、皮膚痕癢剝落、神經和肌肉痲痹、聽覺改變、血液出現問題以及生育能力下降。放療的副作用也很多諸如疲勞、血液改變、口腔疼痛、味覺改變、吞嚥困難、噁心和嘔吐、食慾不振、體重下降、聲音轉變、便秘或腹瀉、毛髮脫落、皮膚痕癢剝落以及生育能力下降。上述諸副作用經常困擾著癌症患者且使其痛苦不堪。此外因化療或放療而被殺之正常細胞會產生WNT16B，該WNT16B會促進存活之癌細胞成長，轉移與抵抗治療。參見Yu Sun et.,Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B,Sep 2012；18(9)：1359~1368。而本發明組合物其8個單方中草藥之中有5個(夏枯草、牛樟芝、薑黃、小金英及桑黃)被台灣衛生主管機關認定可做為食品原料，另外3個單方中草藥(半枝蓮、牡丹皮及敗醬草)則為自古以來中醫師常用之藥，故其安全性乃不言可喻。
依照Eur.J.Cancer報導，Professor Jean-Francois MD說：”於大腸癌手術前不論有無併用化療之放射療法，其後以5-Fu為輔助化療並不能影響其無病存活率或整體存活率。我們的試驗並不支持手術前不論有無併用化療之放射療法其後輔助化療的現行做法。結合新輔助化療的新的治療策略是必需的。”參見Prof Jean-François Bosset MD et al.,Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer：long-term results of the EORTC 2292 randomised study,The Lancet Oncology,Feb 2014；15(2)；184~190。而本發明組合物顯示出可明顯地增強其他抗癌藥物效果，將能滿足其需求成為新的化療輔助劑。
依照世界衛生組織2014年世界癌症報告，癌症在未來20年將成為全球健康照護很大的負擔，其發生率將增加57%，且其死亡率將增加63%。全球對抗癌症之戰，不能只用治療贏得勝利。迫切需要有效的預防方法來預防癌症危機。參見Stewart BW,Wild CP,editors(2014).World Cancer Report 2014。而本發明組合物既安全又有明顯的毒殺癌細胞作用，所以既可預防癌症又可治療癌症，正能滿足如此之迫切需求，所以本發明組合物之工業上應用性很明顯。
醫藥研究團體經常需要研究可以預防癌症或治療癌症或輔助治療癌症的方法及產品。根據本發明的萃取物的產品及萃取物將很容易地為醫藥團體接受作為預防癌症或治療癌症或癌症治療輔助劑的另一選擇。尤其是，本發明組合物顯示出可明顯地增強其他抗癌藥物效果。此外越來越多的人喜歡更溫和的中國傳統醫學對癌症的治療。
雖然本發明的較佳具體實例已經發明，對那些熟悉此技術的人很明顯地可在其中做各種改變及修飾但仍不會偏離本發明範圍的精神符號說明。
C1-B‧‧‧一種細胞培養基含有10% FBS(fetal bovine serum胎牛血清)，100units/ml Penicillin及100ug/ml Streptomycin的RPMI 1640。陰性對照組：只有培養基而不加藥，於本試驗為C1-B。陽性對照組：Triton X100(1%)，標示為C2。
Triton X100是一種清潔劑能殺死90%以上之細胞
S1‧‧‧本藥草組合物5 mg/ml
S2‧‧‧5-FU 5ug/ml
S3‧‧‧Oxaliplatin 10ug/ml
S4‧‧‧Irinotecan5 ug/ml
S5‧‧‧(本藥
草組合物5mg/ml與5-FU 5ug/ml)
S6‧‧‧ (本藥草組合物5mg/ml與Oxaliplatin 10ug/ml)
S7‧‧‧(本藥草組合物5mg/ml
與Irinotecan 5ug/ml)
S8‧‧‧(本藥草組合物5mg/ml與5-FU 5ug/ml與
Oxaliplatin 10ug/ml)
S9‧‧‧(本藥草組合物5mg/ml與5-FU 5ug/ml與
Irinotecan 5ug/ml)
S10‧‧‧(5-FU 5ug/ml與Oxaliplatin 10ug/ml)
S11‧‧‧(5-FU 5ug/ml與Irinotecan 5ug/ml)
Claims (5)
- 一種用於增強其他抗癌藥物效果之組合物，係由夏枯草(PRUNELLAE SPICA)、半枝蓮(SCUTELLARIAE BARBATAE HERBA)、牛樟芝(ANTRODIA CAMPHORATA)、薑黃(CURCUMAE RHIZOMA)、牡丹皮(PAEONIAE SUFFRUTICOSAE CORTEX)、敗醬草(PATRINIAE HERBA)、小金英(IXERIS HERBA)及桑黃(PHELLINUS LINTEUS)之萃取物所組成一種植物之水性萃取物。
- 根據申請專利範圍第1項的組合物，其中重量比大約為夏枯草(PRUNELLAE SPICA)：半枝蓮(SCUTELLARIAE BARBATAE HERBA)：牛樟芝(ANTRODIA CAMPHORATA)：薑黃(CURCUMAE RHIZOMA)：牡丹皮(PAEONIAE SUFFRUTICOSAE CORTEX)：敗醬草(PATRINIAE HERBA)：小金英(IXERIS HERBA)：桑黃(PHELLINUS LINTEUS)=(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)：(0.5~1.5)
- 根據申請專利範圍第1項的組合物，其中該萃取物之有效量為每天0.4~120克。
- 根據申請專利範圍第1項的組合物，其係經口或經鼻或經眼或經耳或經皮膚或經注射或經肛門或經生殖器而給藥或經由吸入噴霧或藉由植入貯存器的方式或以手術等侵入性方式施用於內臟組織之患部而給藥或以針炙穴位經絡給藥。
- 根據申請專利範圍第1項的該組合物，其進一步包括選自以下所組成之群之添加物：糖果、甜點、凝膠、營養補充品、口香糖、醫藥及嬰兒營養品、飲料、優格、牛奶、再水合溶液及水溶液。
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| US11944659B2 (en) | 2020-10-19 | 2024-04-02 | Grape King Bio Ltd | Method for improving sarcopenia by using Phellinus linteus |
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| KR101895850B1 (ko) * | 2017-05-18 | 2018-09-07 | 충남대학교 산학협력단 | 벌씀바귀 추출물을 유효성분으로 함유하는 전립선 질환의 예방, 개선 또는 치료용 조성물 |
| CN107468871A (zh) * | 2017-09-27 | 2017-12-15 | 张存法 | 一种治疗肿瘤的中药组合物及其制备方法 |
| TW202116342A (zh) * | 2019-07-08 | 2021-05-01 | 薩摩亞商吉亞生技控股股份有限公司 | 改善或抑制胃腸道不適的組合物及方法 |
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| US11944659B2 (en) | 2020-10-19 | 2024-04-02 | Grape King Bio Ltd | Method for improving sarcopenia by using Phellinus linteus |
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| TWI611807B (zh) | 2018-01-21 |
| TW201601736A (zh) | 2016-01-16 |
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