초록 ▼

1세부인 생물전환을 이용한 신한약제제 개발에서 한방처방의 생물전환 융합원천기술 개발 연구에서는 다빈도 한방처방 25종에 대하여 우수한 발효능을 나타내면서 원래 처방의 효능을 강화시키는 한약 발효에 특화된 유산균 30종을 선정하여 이에 대한 균주의 재검정과 대량생산 시 필요한 배양 조건의 표준화를 확립한 후 검증된 균주 보관 시설인 KCTC와 KCCM에 기탁하여 발효 균주 라이브러리를 구축하였음. 또한 한방처방 25종에 대한 다성분동시분석법을 확립하였으며, 한약재내 유효성분 증가를 위한 생물전환 효소도 발굴하였음.

효능강

1세부인 생물전환을 이용한 신한약제제 개발에서 한방처방의 생물전환 융합원천기술 개발 연구에서는 다빈도 한방처방 25종에 대하여 우수한 발효능을 나타내면서 원래 처방의 효능을 강화시키는 한약 발효에 특화된 유산균 30종을 선정하여 이에 대한 균주의 재검정과 대량생산 시 필요한 배양 조건의 표준화를 확립한 후 검증된 균주 보관 시설인 KCTC와 KCCM에 기탁하여 발효 균주 라이브러리를 구축하였음. 또한 한방처방 25종에 대한 다성분동시분석법을 확립하였으며, 한약재내 유효성분 증가를 위한 생물전환 효소도 발굴하였음.

효능강화검증을 통한 유효 및 선도물질 발굴 및 심화연구에서는 효능다면평가를 통해 항염, 항바이러스, 항암, 항골다공증, 혈행개선, 인지기능개선, 항소양증, 간보호, 항비만, 항균, 항산화, 주름개선, 상처치료 등 여러 질환에 대한 효능이 우수한 한약소재를 발굴하였음. 임상수요 중심 한약제제 발굴 및 과학적 효능검증연구에서는 실제 한의원에서 임상적으로 사용되고 있는 한약의 항암 및 혈행개선 효능을 과학적으로 검증하였음. 아토피 개선제, 항바이러스제, 혈행개선, 인지기능개선 등 후보물질 심화연구를 통해 후보물질 약리작용에 대한 기전을 규명하였으며, 후보물질 18건에 대한 약리활성성분을 분리, 동정, 구조를 규명하였음.

2세부인 후보물질 산업화연구에서 후보물질들의 대량생산기술을 개발하기 위하여 GMP 시설을 이용한 시제품 제작 9건을 완료하여 대량 생산에 필요한 기초 공정 자료를 확보하였음. 후보물질의 안전성을 확보하기 위하여 GLP시설에서 후보물질 15건에 대한 안전성 평가를 완료하였으며, 후보물질 5건에 대한 약물동태모델을 확립하였음.

본 과제를 통해 총 논문 290편, SCI(E) 논문 204편, SCI(E) 논문 중 인용지수 상위 20% 논문 63편, 특허 출원 75건(국내 46건, 국외 29건), 등록 70건(국내 52건, 국외 18건), 기술이전 16건 등 우수한 성과가 도출되었음. 특히 아토피치료제 KIOM-MA128은 피부개선 화장품으로 상용화되었으며, 발효십전대보탕은 “청명삼”, “동의현감”이라는 인지기능개선 제품으로 시판되고 있으며, 항바이러스제 KIOM-C는 “활력”이라는 제품으로 돼지사료첨가제로 상용되었음. 또한 안질환 개선제 KIOM-2015E는 연계 후속 과제를 진행 중에 있으며, 다른 후보물질도 연구결과를 바탕으로 한 후속 과제 기획에 활용할 계획임

( 출처: 보고서 초록 12p )

Abstract ▼

Ⅳ. Results
[ Part I ]
Performance goal 1.
Bioconversion technology development of herbal formulas

○ Identification and library establishment of bioconverted materials
- 16S rDNA analysis and identification of fermentation strain for industrialization and library construction of bi

Ⅳ. Results
[ Part I ]
Performance goal 1.
Bioconversion technology development of herbal formulas

○ Identification and library establishment of bioconverted materials
- 16S rDNA analysis and identification of fermentation strain for industrialization and library construction of bioconverted materials
- Establishment of library through strain deposition
(KFRI 127, 128, 129, 144, 145, 150, 161, 162, 164, 166, 217, 221,227, 228, 229, 231, 234, 239, 341, 347, 402, 425, 442, 481, 658,692, 693, 695, 733, 748)

○ Development of fermentation technology for increasing active compounds in herbal formular
- L-antri-derived -glucosidase was expressed, purified β and isolated in E. coli and used to turn geniposide into genipin in Gardenia jasm inoides and to convert polysaccharide to saponin in ginseng.

○ Establishment of optimal fermentation system for herbal medicines (2009년 ∼ 2013년)
- Optimal fermentation condition for 25 frequently-described herbal medicines, Galgeuntang, Ssanghwatang, Bangpungtongsungsan,Ojeoksan, Yukmijihwangtang, Samultang, Gwibitang, Sipjeondaebotang,Hwangryundaedoktang, Insampaedoksan, Oyaksungisan, Bojungikkitang,Samsoeum, Ejungtang, Socheongryongtang, Soshihotang,Gumiganghwaltang, Oryeongsan, Jaeumganghwatang, Palmultang,Samchulgeonbitang, Pyungwisan, Banhabaekchulchonmatang,Sagunjatang, Yijintang

○ Simultaneous determination of compounds in bioconverted herbal medicine (2009년 ∼ 2012년)
- Simultaneous determination of compounds in 25 frequently-described herbal medicines, which are Galgeuntang, Ssanghwatang,Bangpungtongsungsan, Ojeoksan, Yukmijihwangtang, Samultang,Gwibitang, Sipjeondaebotang, Hwangryundaedoktang, Insampaedoksan,Oyaksungisan, Bojungikkitang, Samsoeum, Ejungtang, Socheongryongtang,Soshihotang, Gumiganghwaltang, Oryeongsan, Jaeumganghwatang, Palmultang, Samchulgeonbitang, Pyungwisan, Banhabaekchulchonmatang, Sagunjatang, Yijintang, before and after fermentation

Performance goal 2.
Discovery of hit and lead materials via efficacy test for target diseases

○ Discovery of hit and lead materials via efficacy test for target diseases
- Anti-inflammatory effect: OY (Oyaksungisan)-144, 442, SJ
(Sipjeondaebotang)-127, HR (Hwangryundaedoktang)-127, 227, SO
(Soshihotang), PM (Palmultang), OR (Oryeongsan), PW (Pyungwisan),W22, W15, W342, W108, E316, E301, E212, E115, E200
- Antiviral effect : W2, W12, W53, W147, W162, W172, W177, W192,W200, W205, W212, W217, W220, W249, W252, W263, W272,W277, W301, W308, W314, W359, and W364 (Influenza virus,vesicular stomatitis virus, new castle disease virus, herpes virus,enterovirus 71)
- Anticancer effect : SSE, ERR, JGT / fJGT, SRVF antitumor efficacy and mechanism studies, AE-BCT, ASF, WEH, EBGF, ELH :nti-metastasis efficacy and mechanism study, SO, WCUP : anti-cachexia efficacy and mechanism study
- Anti-osteoporosis effect : BPT, GGT, YMT, SMT, fHRT127, fHRT166,YJ, WESS, AMEE, WEAO, WEMC, OJWE, WEAO-2, WEMV, WEAC,WEUS, WEPM, WERC, WEAR, WEPP
- Hepatoprotection effect : E110, E149 non-alcoholic fatty liver improvement and liver protection efficacy
- Anti-thrombotic effect : S-A144, Kiom-18, W21, W13
- Wound treatment: Discovery of wound healing efficacy of W88,W99, W128
- cognitive function enhancer : E41, E188, W246
- Anti-allergy effect : F-AFE, LPE, VEE, DRE
- Anti-thrombotic effect : S-A144, Kiom-18, W21, W13
- Whitening effect : 25 ONOO-scavenging activity, 28 Tyrosinase Inhibitory activity, lead compound Swatiazaponin – (whitening effect)
- Wrinkle improvement effect : W39, W45, W313, W404, SJ. SPI
- Pancreatitis inhibition effect : 1- (2,4,5-Trihydroxy-3-methylphenyl)butan-1-one (OS), KIOM-2015E
- Promotion of muscle cell proliferation, differentiation : W3, W9,W12, W15, W78, W81, W114, W132
- Adipocyte proliferation, differentiation inhibition : W9, W32, W53,W78, W81, W109, W114, W121, W146, W121, W132, W199, W207
- Anti-hypertension effect : fGBT166, fOY744
- Antibacterial effect on MRSA : Fermented BPS, Fermented OJS,Fermented SJT, Fermented HRT, Fermented SA. Fermented SO,Fermented SCY, Fermented IS, Fermented GG Fermented OR,Fermented JGT

○ Discovery of clinical demand-oriented herbal medicine and scientific efficacy verification
- Anticancer efficacy of clinical herbal medicine NH
- Anti-thrombosis efficacy of clinical herbal medicine NH

Performance goal 3.
In-depth study on candidate materials
○ Identification of action mechanism of candidates
- KIOM-MA128 : Completion of anti-atopic dermatitic efficacy and underlying mechanism study in vitro/in vivo, Development of efficacy optimized candidate, F-PASA from KIOM-MA128, in vitro/in vivo asthma efficacy of KIOM-MA128, Performance of researcher clinical trial of KIOM-MA128 on atopic dermatitis patients in hospitals
- KIOM-2015E : Completion of efficacy and underlying mechanism study on dry eye syndrome and Ischemic retinal disease In vitro/in vivo
- fHRT, S-164, WEAT : Completion of anti-osteoporosis efficacy and underlying mechanism study in vitro/in vivo
- KIOM-C, KIOM-MA128 : Completion of in vitro/in vivo anti-tumor and anti-metastasis efficacy and underlying mechanism study
- WCUP : Completion of in vitro/in vivo cachexia improvement efficacy and underlying mechanism study
- fSJ-164 : Completion of cognitive function improvement and brain neuroprotection efficacy and underlying mechanism study in vitro/in vivo.
- Compound 1, W10 : Completion of blood circulation efficacy and underlying mechanism study in vitro/in vivo. (anti-thrombosis, anti-proliferation of blood vessel)
- KIOM-2012H : Completion of liver protection efficacy and underlying mechanism study in vitro/in vivo

○ Purification and identification of active compounds in candidates
- Anti-atopic dermatitis candidate KIOM-MA128 : 20 kinds of single compound isolation and structure identification
- Antiviral candidate KIOM-C : 47 kinds of single compound isolation and structure identification
- Antiviral candidate EYK : 15 kinds of single compound isolation and structure identification
- Cognitive function improvement candidate Ulmi Cortex : 19 kinds of single compound isolation and structure identification
- Antiviral candidate Asteris Radix : 32 kinds of single compound isolation and structure identification
- Antiviral candidate Foeniculi Fructus : 15 kinds of single compound isolation and structure identification
- Antiviral candidate Hoveniae Semen Cum Fructus : 21 kinds of single compound isolation and structure identification
- Antiviral candidate Mori Radicis Cortex : 18 kinds of single compound isolation and structure identification
- Antiviral candidate Schizonepetae Spica : 5 kinds of single compound isolation and structure identification
- Anti-cachexia candidate CUP : 7 kinds of single compound isolation and structure identification
- Bloood circulation enhancer candidate Platycodi Radix : 45 kinds of single compound isolation and structure identification
- Anti-osteoporosis candidate Alpiniae Officinari Rhizoma : 20 kinds of single compound isolation and structure identification
- Wound healing candidate Massa Medicata Fermentata : 9 kinds of single compound isolation and structure identification
- Eye disease treatment candidate KIOM-2015E: 24 kinds of single compound isolation and structure identification
- Anti-inflammation candidate Forsythiae Fructus : 24 kinds of single compound isolation and structure identification
- Anti-atopic dermatitis candidate Sanguisorbae Radix : 33 kinds of single compound isolation and structure identification
- Anti-obesity candidate Polygalae Radix : 9 kinds of single compound isolation and structure identification
- Anti-obesity candidate Albizziae Cortex : 21 kinds of single compound isolation and structure identification

Performance goal 4.
Study on leads and candidates effective for viral diseases
○ Identification of mechanism study and active compounds on antivir al candidates
- KIOM-C : Anti-H1N1, H5N2, H7N3, H9N2 influenza efficacy and underlying mechanism study in vitro/in vivo, innate immune stimulation mechanism study in vitro, antiviral efficacy against vesticular stomatitis virus, new castle disease virus, herpes virus, enterovirus 71 in vitro
- EYK : Anti-H1N1, H5N2, H7N3, H9N2 influenza efficacy and underlying mechanism study in vitro/in vivo, innate immune stimulation mechanism study in vitro, antiviral efficacy against vesticular stomatitis virus, new castle disease virus, herpes virus, enterovirus 71, rhino virus in vitro
- WPS : Anti-H1N1 influenza efficacy and underlying mechanism study in vitro/in vivo, innate immune stimulation mechanism study in vitro, antiviral efficacy against vesticular stomatitis virus, new castle disease virus, herpes virus, enterovirus 71 in vitro
- EMF : Anti-H1N1 influenza efficacy and underlying mechanism study in vitro/in vivo, antiviral efficacy against vesticular stomatitis virus, new castle disease virus, herpes virus, enterovirus 71 in vitro
- PNR : Anti-H1N1 influenza efficacy and underlying mechanism study in vitro/in vivo, innate immune stimulation mechanism study in vitro
- Anti-viral efficacy of single compounds, Paeoniflorin, Marmesinin, Baicalein, Chrysophanol 8-0-beta-D-glucopyranoside derived from KIOM-C
- Anti-viral efficacy of single compounds, EYK-derived quercetin
- Anti-viral efficacy of single compounds, Quercetin, Quercitrin,

Psoralen derived from WEF
[ Part II ] : Starting from year 2016 until year 2017
Performance goal 1.
Development of mass production technology of candidates
(until 2015 : total, from 2016 to 2017 : part II)
○ Industrialization system establishment for bioconversion fusion technology
- Establishment of mass production condition and completion of process standardization in GMP facility on candidates (KIOM-MA128, KIOM-2012H, EYK, fSJ164, KIOM-C, CUP)
- Completion of 6 new formula prototypes on candidates (KIOM-MA128,KIOM-2012H, EYK, fSJ164, KIOM-C, CUP)

○ Formulation study of candidates (from 2011 to 2012)
- KIOM-MA128, KIOM-C, S164 nano-formula study

Performance goal 2. Safety evaluation of candidates
( until 2015 : total, from 2016 to 2017 : part II)
○ Safety evaluation of candidates (GLP system)
- Completion of acute toxicity (Rodent/Beagle dog), genetic toxicity, repeated toxicity on KIOM-MA128, S164, G144, KIOM-2100, GB166, HR166, OY744, KIOM-2012OS1, KIOM-2012OS2, KBH-1, KIOM-2012H, EYK, fSJ164, KIOM-C, CUP, KIOM-2015E

Performance goal 3. Pharmacokinetics of candidates
○ Establishment of pharmacokinetics model of candidates
- Completion of pharmacokinetics on KIOM-MA128, CUP, KIOM-2012H, fSJ-164, fPASA, KIOM-2015E
○ Assessment of herbal drug interaction (from 2011 to 2014)
- Completion of drug interaction study via cytochrome P450 inhibition assay on fermented SST, fermented GGT, KIOM-MA128, KIOM-C, fermented HRT, KBH-1

( 출처 : SUMMARY 28p )

목차 Contents

• 표지 ... 1
• 제 출 문 ... 7
• 보고서 초록 ... 11
• 요 약 문 ... 13
• Ⅰ. 제 목 ... 13
• Ⅱ. 연구개발의 목적 및 필요성 ... 13
• Ⅲ. 연구개발의 내용 및 범위 ... 14
• Ⅳ. 연구개발결과 ... 17
• Ⅴ. 연구개발결과의 활용계획 ... 22
• SUMMARY ... 24
• Contents ... 37
• 목차 ... 43
• 제1장 제 목 ... 47
• 제2장 연구개발의 목적 및 필요성 ... 49
• 제3장 연구개발의 내용 및 범위 ... 63
• [ 1 세부 ] ... 66
• 성과목표 1 한방처방의 생물전환 융합 원천 기술 개발 ... 66
• 성과목표 2 효능 검증을 통한 유효·선도물질 발굴 및 심화연구 ... 89
• 성과목표 3 후보물질 심화연구 ... 201
• 세부목표 4 항바이러스 선도물질 및 후보물질 심화연구 ... 255
• [ 2 세부 ] ... 266
• 성과목표 1 후보물질 대량생산 개발 ... 266
• 성과목표 2 후보물질 안전성 확보 ... 269
• 성과목표 3 후보물질 약물동태학적 평가 ... 281
• 제4장 연구개발결과 ... 313
• [ 1 세부 ] ... 315
• 성과목표 1 한방처방의 생물전환 융합 원천 기술 개발 ... 315
• 성과목표 2 효능 검증을 통한 유효·선도물질 발굴 및 심화연구 ... 613
• 끝페이지 ... 816