TRENS IN MEDICINAL PLANT RESEARCH.ppt

TRENSINMEDICINALPLANTRESEARCH,工研院生醫所報告人李連滋中華民國九十六年十二月二十六日,CostandTimeperDrugtoMarket,PhaseI,PhaseII,PhaseIII,Exploratory,LeadOptimization,DevelopmentCandidate,Pre-clinical&PhaseIDevelopment,DemonstrateSafetyandEfficacyinPatientsPhasell&lllClinicalTrial,DrugDiscovery&DevelopmentProcess,Discovery,PreclinicalTesting,PhaseI,PhaseII,PhaseIII,NDA&Approval,Post-Marketing,(Efficacy,Safety,DMPK,Tox),(20-80volunteersforsafetyanddosage),(100-300patientforefficacyandsideeffects),(1,000-5,000patientforadversereactionsandefficacy),(Additionaltestingforotherindicationsand/orlong-termsafetymonitoring),10-15Years($800M),SuccessRate,10,000Screened200enterpreclinicaltest3-5enterclinicaltest1approvedbyFDA,60%,60%*inlatestage,*survivalrate,50%,80%,90%,(HTS,Selectivity,Potency),FromDrugDiscoverytoMarket,PhRMA,1998,Toxicity17%,AdverseEffects16%,Commercial7%,Efficacy46%,Miscellaneous7%,Pharmacokinetics17%,CausesofNewDrugFailure,TargetIdentificationValidation,LeadOptimization,LeadPrioritization,PreclinicalDevelopment,ClinicalDevelopment,PostApproval,ALINEARPROCESSDiscoveryTechnologies/DevelopmentServices,PartnershipsandCollaborations,NEWDRUGDISCOVERY&DEVELOPMENTPORCESS,B:生技藥物N:天然物成分.ND天然物成分衍生物:S:純合成化合物.S*:由天然物成分發展之合成化合物.,資料來源：TRENDSINMEDICINALPLANTRESEARCH:SCREENING,BIOTECHNOLOGYANDRATIONALPHYTOTHERAPY,處方藥之來源,Materiamedica,extraction&separation,biologicalactivity,Preclinical,Clinicaltest,identifiedwithgenepattern,newresource,extraction,Membraneseparation,Invitrotest,Invivotest,Enzymeactivitysignaltransductionproteinexpression,biochemicalassay,Acuteresponse,CellmembranevoltageintracellCa2+changesignaltransduction,cell-basedphysiologicalresponseassay,mRNA,cDNAvariation,PCRproliferateDNA,DNAArraysSurveyDisplaygene,Analysisgenepattern&comparewithactivecomponents,Acuteresponse,Chronicresponse,Acuteresponse,RAPDAFLPSSLPRFLP,Affinitymembraneartificialmembraneultrafiltration,SupercriticalextractionTwophaseaquousextrationReversedmicellarextractionaffinityextraction,Pathology,TransgeneanimalAnimalmodel,BioavailabilityPharmacokineticsToxicology,PhaseIphaseIIphaseIII,BioreactorsuspensionculturesembryogenicculturesHRCs,中藥新藥開發新技術（開發現代化中藥之價值鏈）,HerbalExtractionSeparationPurificationCompound1,2,NInvitroscreening,BotanicallibraryCrudeextract1,2,3,nHTSscreeningActiveextractActivity-guidedseparationActivecompound,BotanicallibraryCrudeextract1,2,3,nHPLC/FCprefractionationFr1,2,3,.nuHTSscreeningActivefractionActivityguidedseparationActivecompound,Activecompound,Traditionally,Recently,Newapproach,Plantmaterialssource:endemicornativeRichresourcesBiodiversity,Botanicallibrarycollection,FractionationFC/HPLC,uHTSscreening,Over20screeningmodels1millioncompounds/day,中藥新藥之目標市場,傳統中藥市場中醫師用藥市場西醫市場新用途開發,科學化中藥,中醫用藥,市場,西醫市場,新用途開發,劑型改善,品管,藥效驗證,臨床試驗,中藥新產業成功關鍵因素,科學和臨床之驗證法規審核之通過專利保護全球市場之經營,中藥申請專利項目,1.既存中草藥之新用途2.中草藥製備之新製程3.中草藥新組合而有特殊用途4.新有效成份之分離,H,單離有效成份,風險,技術層次,中草藥產業/技術現況,傳統方劑,植物抽取新藥（單、複方）,例；六味地黃丸、小柴胡湯、四物湯,例：銀杏葉抽取物,例：青蒿素,非傳統方劑,例：冠心1號、冠心2號,資料來源:中草藥產業技術發展五年計畫,3050傳統方劑及健康食品IND,15植物抽取新藥IND,中西醫學之比較,治療對象治療方法理論治病方針治療手段藥品,西醫疾病病因除去法解剖、病理、生理（實証科學)對症下藥內科、外科有機化學品,中醫人體質改善論陰陽五行、經絡（玄學）對證下藥方劑、針灸本草,中藥進入西方醫療體系之問題,藥材之均一性多成份、多功能、多基因（因素）中西醫學之接軌,Ps:PolysaccharideSp:solubleproteinSol:shogaolgol:gingerolep:ephedrinesa,sd:saikosaponina,def:ethy1-D-fructofuranosideg1:glycyrrhitinga:glycyrrhetinicacidil:isoliquiritigeninbi:baicalinbe:baicalein,材料湯煎湯液凍結乾燥粉末EtOH沈殿,沈殿(Ep),上清(Es),多糖體分畫,*洋蔥；紅蘿蔔；牛蔘；蘿蔔；波菜；包心菜；小黃瓜；蕃茄；茄子；一各30g,中草藥現代化開發方向,中草藥單方現代化治療藥銀杏.健康食品紅麴中藥方劑現代化治療藥數種進入臨床但尚無成功實例由中草藥發現新化學單體治療藥麻黃鹼,TAXOL,青蒿素,生醫工程中心(BMEC)中草藥開發過去成果簡介,hesperidinamygdalinglyhrrizinsolanesolinositoltocopheroltaxolmorphinepapaverinecodeinenoscarpine,植物組織培養金線蓮日日春紅豆杉醱酵技術冬蟲夏草,山防風巴豆燈籠草,高濃縮粒劑微膠囊劑型口服液劑速溶粒劑,天然藥物提煉,藥材生產技術開發,新藥開發,新劑型,植物組織培養金線蓮日日春紅豆杉藥材成分生產Taxol、Shikonin、Tripterine及其衍生物醱酵技術冬蟲夏草,1.藥材生產及培養技術,台灣紅豆杉(枝條、葉片),癒合組織誘導,細胞懸浮培養,反應器大量培養,產品回收純化,紅豆杉醇,紅豆杉醇原料藥,針劑調製,醫界使用,紅豆杉醇生產,hesperidinamygdalinglyhrrizinsolanesolinositoltocopheroltaxolmorphinepapaverinecodeinenoscarpine,萃取溶劑吸附劑離子交換超臨界流體雙水相萃取薄膜分離結晶薄膜蒸餾HPLC,2.萃取、提煉、分離、純化技術,技術,研製項目,傳統製程,BMEC製程,心腦循環改善藥中間體solanesol之提煉,3.劑型設計開發技術,高濃縮粒劑歸脾湯、補中益氣湯、麥門冬湯、大黃、六味地黃散、甘露飲、四君子湯微膠囊劑型麥門冬、四物湯、天王補心丹口服液劑葛根湯、人參養榮湯速溶粒劑刺五加、補中益氣湯、平胃散、六君子湯貼片劑型紫雲膏,藥材,萃取工程,分離純化工程,濃縮,粉末造粒,過篩整粒,充填,膠囊,中藥膠囊新劑型製程開發,山防風巴豆燈籠草,Polythiophene衍生物28項專利228化合物合作單位：NCI、普渡、台大、陽明,腫瘤生長情形，對照組腫瘤肉眼明顯可見，治療組則肉眼看不到且觸摸不到腫瘤,對照組腫瘤肉眼明顯可見，治療組則無肉眼可見的腫瘤存在,多塞吩化合物(Polythiophene),天然菊科中草藥山防風為多年驗證具奇特廣效性之家傳偏方多塞吩抗癌藥物為山防風之活性成分之衍生物活性測試具有抗癌、抗炎以及免疫調節之功效,4.中藥發展NCE新藥,藥材管控技術,標準藥材採集,藥材檢測系統,藥材鑑定/功能基因應用開發,基原鑑別,理化鑑別,顯微鑑別,藥材來源規範,性狀鑑別,色譜法,DNA指紋圖譜鑑定法,光譜法,X衍射分析法(XRO),差熱分析法(DAT),分生技術遺傳基因鑑別,計算機圖像分析技術(CIA),電泳法,電分析法,X射線螢光光譜分析法(XRF),多元回歸分析法,rRNA分子標記,TLC,TLCS,HPLC,GC,GC/MS,LC/MS,示波極譜法,等電法,BioChip,PCR-SSCP,RELP,SEM,PCR-RFLP,MASA-PCR,ITS,Internaltranscribedspacer,RAPD,RanodmAmplifiedPolymorphicDNA,AFLP,Amplifiedlengthpolymorphism,UV,DS,IR,FP,MS,MS/MS,NMR,LC/MNR,PAGE,2D-PAGE,毛細管電泳法(CE),CMC規範,微生物檢測,農藥殘留檢測,重金屬殘留檢測,GAP規範,藥材保存/運輸,炮製方法及規格,放射線物質檢測,成分檢測,AA,ICP-MS,GC/SCD,生菌數測定,病原菌偵測,PCR檢測技術,E.Coli,Listeriamonocytogenes,SalmonellaShigellaCampylobacterjeuni,BacilluscereusAspergillusflavus,A.parasiticus,Penicillus,Pb,Cd,Hg,AS,Cu,A-BHCB-BHCR-BHCD-BHC24-DDE44-DDE24-DDT44-DDTAldrinDieldrinEndrinPCNBHeptachlor,指標/活性成分資料庫,組織切片鑑別技術粉沫鏡檢技術偏光顯微鏡鑑別技術,營養成分分析技術,中草藥藥材-管控技術(圖二),資料來源經濟部中草藥辦公室,RAPD鑑定原理,以10個核甘酸的引子由聚合鏈反應逢機複製中藥染色體DNA，所複製DNA片段的差異可鑑定中藥材的基源,RAPD:逢機複製多樣性DNA,ITS鑑定原理,18SrDNA,5.8SrDNA,28SrDNA,ITS:核糖體基因間序列差異區,以聚合鏈反應複製、限制分析或由序列比對中藥材核糖體基因間的序列差異可鑑定中藥材的基源,核糖體基因間序列相同區,中草藥藥材-資源開發(圖五),中草藥(藥用植物),植物組織培養,大量培養,生藥材生產,純化物生產,化合物單離,乾燥,抽出製品化,最適化,分化組織培養,遺傳物質,基因導入