표제지
제출문
보고서 요약서
요약문
Summary
Contents
목차
제1장 연구개발과제의 개요 18
제1절 연구개발의 필요성 18
1. 연구개발의 과학기술, 사회경제적 중요성 18
2. 지금까지의 연구개발 실적 19
3. 현기술 상태의 취약성 21
4. 앞으로의 전망 21
제2절 연구개발의 목표 및 내용 21
1. 연구개발의 최종목표 21
2. 연구개발의 내용 및 범위 22
가. 에너지부스팅 식품의약 개발 연구 22
나. 뇌기능개선용 식품의약 개발 연구(천연신소재 UG0402의 제품화) 24
다. 위기능장애개선 또는 혈당조절용 식품의약 개발 연구 25
라. 천연물의약 개발 연구: 동맥경화억제 및 치매치료용 소재 개발 26
마. 출시소재의 적용성 확대 연구 27
제2장 국내외 기술개발 현황 28
제1절 국외 동향 28
제2절 국내 동향 29
제3장 연구개발수행 내용 및 결과 32
제1절 연구개발 추진 전략 및 방법 32
1. 연구개발 추진 전략 32
2. 구체적 방법 33
가. 임상시험실시 33
나. 동물효능평가 방법 35
다. 제품화 자료의 확보 연구 43
라. 대량생산공정기술 개발 44
마. 출시제품의 적용성 확대연구 46
제2절 연구개발 결과 50
1. 에너지부스팅 식품의약 개발 연구 50
가. 동물 비교 효력실험을 통한 운동능력 효능확인 실험 50
나. 임상시험 준비 51
다. 임상시험 실시 51
라. 제품화 연구 52
마. 대량생산기술 연구 및 생산기술 개선연구 52
바. 출시준비 및 출시 54
사. 마케팅에 필요한 연구자료 확보 55
아. 제품 적용성 확대를 위한 연구 55
(1) 수용성 증대 55
(2) 제품 taste masking 연구 56
자. 표준품 확보 56
2. 뇌기능개선용 식품의약 개발 연구 57
가. 임상 시험 연구 57
나. 기전연구 59
3. 위기능장애개선 또는 혈당조절용 식품의약 개발 연구 61
가. 질환모델을 이용한 효능확인시험 61
(1) 위기능장애개선 식품의약 개발연구 61
(2) 혈당조절용 식품의약 개발 연구 62
나. 제품화 자료의 확보 64
(1) 기준 및 시험법 64
(2) 안정성시험 64
(3) 원물소싱 및 함량정보 축적 64
다. 대량생산공정기술 연구 65
4. 천연물의약 개발 연구 : 동맥경화억제 및 치매치료용 소재 개발 (천연신소재 UG0314,UG0404,UG0504의 제품화) 66
가. 동물효능 확인 검토 실험 66
(1) 동맥경화억제 효능 확인 66
(2) 치매치료 효능 확인 66
(3) 추가 후보소재의 효능 실험 67
나. 소재 평가 및 선정 68
(1) 적응증별 우수 효능소재 선정 68
다. 제품화 연구 68
(1) 안정성 시험 68
라. 대량생산을 위한 공정기술 연구 69
(1) 대량생산을 위한 최적화 연구 69
5. 출시소재의 적용성 확대 연구 71
가. 관절개선소재(UG0408)의 적용성 확대 연구 71
나. 혈액순환개선소재(UG0201)의 적용성 확대 연구 74
(1) 일반식품 제품화 연구 74
(2) 액상제품 제품화 연구 74
제4장 목표달성도 및 관련분야에의 기여도 76
제1절 연구개발 목표의 달성도 76
1. 1차년도 76
2. 2차년도 77
3. 3차년도 78
4. 4차년도 79
제2절 관련분야 기술발전에의 기여도 80
1. 연구개발결과의 파급효과 80
2. 연구개발결과에 대한 활용가능성 80
제5장 연구개발결과의 활용계획 81
제1절 연구개발성과 활용의 범위 및 내용 81
제2절 기대성과 및 활용방안 81
제3절 연구개발성과 활용 추진방법 및 일정계획 82
제4절 연구개발성과 활용 관련 산업재산권 목록 83
제6장 연구개발과정에서 수집한 해외과학기술정보 86
제7장 참고문헌 87
별첨 - 표와 그림 91
Table 1. Blood concentration of LDH, lactic acid, and corticosteroid in trained and non-trained rats 92
Table 2. Citrate synthase activities in rat skeletal muscle tissues 92
Table 3. Summary of Treatment emergent adverse events in the UG0712 human clinical trial in healthy adults under supervised exercise program. 94
Table 4. UG0712C1, UG0712C2, UG0712C3 and UG0712C4 contents of hydrolyzed ginseng leaf extract (UG0712). 100
Table 5. UG0712C1~UG0712C4 contents according to 7% acetic acid for 9 hr hydrolysis. 100
Table 6. UG0712C1~UG0712C4 contents according to 10% acetic acid for 9 hr hydrolysis. 100
Table 7. The content of UG0712C1~UG0712C4 according to the hydrolysis solvent recycling times. 101
Table 8. UG0712 blending validation results (UG0712-0801MP ~ UG0712-0803MP). 101
Table 9. Blood biochemical parameters of the male and female mice after 28 days repeated oral administration of UG0505. 114
Table 10. Relative organ weights (%) in the male and female mice after 28 days repeated oral administration of UG0505. 114
Table 11. The lesion scores and inhibition rates of UG0505 subfactions in the erosive gastritis damaged lesions induced by 100% ethanol (A) or 60% ethanol in the 150mM HCI (B). 118
Table 12. The lipid profiles in the high cholesterol diet induced atherosclerosis mice with or without treatment of UG0404 for 8-weeks. 122
Table 13. The contents of UG0404C1 in raw materials from several collection areas. 127
Table 14. Extraction conditions and relative yields obtained from the process development of UG0404 in Lab scale. 127
Table 15. Extraction conditions and relative yields obtained from the pilot-scale(50L) for production of UG0404. 128
Table 16. Result of prototype production (1ton) by optimized production process. 128
Table 17. A two tailed t-test analysis. 129
Table 18. A two tailed t-test analysis. 130
Table 19. Mean quantitative measurement of functional observational battery. Values represent the total mean of the individual mean of each animal observed. 130
Table 20. Hematology results for male. 131
Table 21. Hematology results for females. 133
Table 22. Coagulation test results: All animals were fasted overnight prior to each blood collection. 133
Table 23. Clinical chemistry results for both males and females. 135
Table 24. Urine analysis results. 136
Table 25. Sperm Count Results. 137
Table 26. Estrus cycle staging results. 137
Table 27. Organ-to-body weight ratios. 138
Table 28. Change in body weights of female rats after repeat treatment(GD6~GD15) with UG0408. 139
Table 29. Change in feed consumption of female rats after repeat treatment(GD6~GD15) with UG0408. 140
Table 30. Change in absolute organ weight of female rats after repeat treatment(GD6~GD15) with UG0408. 140
Table 31. Change in relative organ weight of female rats after repeat treatment(GD6~GD15) with UG0408. 141
Table 32. Reproductive performance of dams orally exposed to UG0408 from GD6~15. 142
Table 33. Skeletal observations of fetuses of dams orally exposed to UG0408 from GD6~GD15. 142
Table 34. Water solubility UG0201. 149
Table 35. Contents of tricin, p-coumaric acid according to extraction solvent. 149
Fig. 1. Treadmill test of UG0712 (exercise(excercise) rat group). Maximal running distance at 2 weeks (A) and 8 weeks (B) in regular exercise rats with 25 mg/kg UG0712 oral administration. 91
Fig. 2. Treadmill test of UG0712 (non-exercise(excercise) rat group). Maximal running distance at 6 weeks (A) and 9 weeks (B) in non-exercise rats with 25 mg/kg UG0712 oral administration. 92
Fig. 3. Change in VO2 max from baseline in the UG0712 human clinical trial on the improvement of exercise performance in healthy adults under supervised exercise program 93
Fig. 4. Change in anaerobic threshold (AT) from baseline in the UG0712 human clinical trial on the improvement of exercise performance in healthy adults under supervised exercise program. 94
Fig. 5. The HPLC chromatogram of standard mixture of UG0402C1, UG0402C2, UG0402C3 and UG0402C4 94
Fig. 6. The HPLC chromatogram of UG0402. 95
Fig. 7. The changes of UG0402C1 content in UG0402 for 6-months 95
Fig. 8. The changes of UG0402C2 content in UG0402 for 6-months. 96
Fig. 9. The changes of UG0402C3 content in UG0402 for 6-months. 96
Fig. 10. The changes of UG0402C4 content in UG0402 for 6-months. 97
Fig. 11. The changes of UG0402C1 content in UG0402 for 24-months. 97
Fig. 12. The changes of UG0402C2 content in UG0402 for 24-months 98
Fig. 13. The changes of UG0402C3 content in UG0402 for 24-months 98
Fig. 14. The changes of UG0402C4 content in UG0402 for 24-months 98
Fig. 15. The content of UG0402C1, UG0402C2, UG0402C3 and UG0402C4 in raw materials according to the manufacturers 99
Fig. 16. The content of UG0402C1, UG0402C2, UG0402C3 and UG0402C4 in raw materials according to the nation 99
Fig. 17. The content of UG0402C1, UG0402C2, UG0402C3 and UG0402c4 in raw materials according to the part 99
Fig. 18. The content of UG0402C1, UG0402C2, UG0402C3 and UG0402C4 in raw materials according to the extraction solvent. 100
Fig. 19. UG0712 tablet and soft capsule sample 102
Fig. 20. HPLC chromatogram of fermented ginseng leaf extract. 102
Fig. 21. Ginsenoside content of fermented ginseng leaf extract(UG0407) 102
Fig. 22. UG0712, A Novel Ginsenoside Composition Enhances the Endurance Exercise Capacity and Fatigue Recovery., Lab. Anim. Res. 2009: 25(3), 207-212 103
Fig. 23. Effect of endothelial denudation and an inhibitor of endothelial nitric oxide synthase on the UG0712-induced vasorelaxation in the aortic ring of rats. Endothelial denudation was confirmed by the loss of acetylcholine-induced relaxation, and... 104
Fig. 24. Vasorelaxing effect of UG0712 (0.01 ~ 0.1 mg/ml) on phenyl -ephrine-induced contraction in the aortic ring of rats. The contraction was evoked by the treatment of 300 nM phenylephrine. 104
Fig. 25. Effect of L-nitroarginine methyl ester (L-NAME, 0.1 mM), an inhibitor of nitric oxide synthase inhibitor, on the UG0712-induced vasorelaxation on the phenylephrine-induced contraction in the thoracic aortic rings of rats. Each symbol is... 105
Fig. 26. Effects of UG0712 on swimming exercise in mice. The mice were given vehicle (1% tween 80), Guarana, Red ginseng, UG0712 and Formulated UG0712(100mg/kg) respectively. The mice swam with weights attached to their tails... 105
Fig. 27. UG0712 solubility test results 106
Fig. 28. Photo of UG0712 and UG0712/β-CD complex water solution 106
Fig. 29. Photo of UG0712 and UG0712/β-CD complex powder 106
Fig. 30. Recycling prep-HPLC chromatogram of UG0712C1/C2. 107
Fig. 31. Learning & memory effects of UG0402 (UG3) on the total correct score of verbal learning test in normal adults. 107
Fig. 32. Fig.2. Executive function effects of UG0402 (UG3) on the Wisconsin card sorting test in normal adults. Wisconsin card sorting test is cognitive function test about executive function. 108
Fig. 33. Attention effects of UG0402 (UG3) on the total error of auditory controlled continuous performance in normal adults. Total error in sum of various kind of errors. 108
Fig. 34. Morris water maze tests and carried out in the 18-months old aged rat for assessment of learning and memory function decline. UG0402 (50 and 100 mg/kg) showed dose dependent enhancement of hippocampal memory function (Left... 109
Fig. 35. A) AchR-β1 immunoreactivity in the hippocampal CA1 region of control(a) and UG0402 treated group (b) of the 21 months aged rats. Note that the AchRβ1 immunoreactivity is significantly increased in the UG0402 treated group compared... 109
Fig. 36. A) Age-related changes of choline acetyltransferase (ChAT) immunoreactive neurons in the medial septum (upper line) and diagonal band (under line) at 22 months(A,D), 25 months(B,E), and UG0402-treated 25... 110
Fig. 37. A) Age-related changes of AchR-α7 in the hippocampal CA1 region at 22 months (A), 25 months (B) and UG0402 treated-25 months (C) (100mg/kg, 12 weeks) group. Note that the number of AchR-α7 positive neurons are decreased... 110
Fig. 38. Representative pictures of ethanol induced erosive gastritis damaged lesions. Absolute or 60% ethanol in HCI were injected by per oral administration (0.5 ml/100g of body weight) after 24 hours fasting and depriving of water. 111
Fig. 39. Gross lesion scores of ethanol induced erosive gastritis lesions with or without treatment of UG0505. The gastric damage scores of control, positive control, and UG0505 treated rats were 3.33±1.15, 1.01±0.32, and 1.23±0.54, respectively. 111
Fig. 40. Maintenance and spontaneous recovery patterns of the ethanol induced erosive gastritis lesions. Lesion index were measured by computer-assisted area measurement program, analySISTM Lifescience Research (Soft Imaging System,... 111
Fig. 41. The changes of body weight (A, male; B, female) in mice treated with single acute oral administration of UG0505. 113
Fig. 42. The changes of body weight (A, male; B, female) in mice treated with 28-day repeated oral dose of UG0505. 114
Fig. 43. The oral glucose(gluose) tolerance test in C57BLKS/J- ob/ob mice with or without treatment of UG0506 for 8-weeks. 115
Fig. 44. The HbA1c levels in C57BLKS/J- db/db mice with or without treatment of UG0506 for 12-weeks. 116
Fig. 45. The oral glucose(gluose) tolerance test in streptozotocin and nicotinamide induced pancreatic β-cell reduction animal model. Note that fasting blood glucose level of induced rats is increased compared as control rats (243.5±27.6 vs 96.3±2.5 mg/dl, respectively)... 116
Fig. 46. The changes of fasting (A) and non-fasting (B) blood glucose in the diabetic C57BLK/KsJ-db/db mice treated with or without UG0506 at the dose of 100mg/kg/day for 12 weeks. 117
Fig. 47. Changes of blood glucose in oral glucose tolerance test (OGTT) in C57BLKS/J-db/db mice with or without treatment of UG0506 for 12-weeks. 117
Fig. 48. Changes of HbA1c value in C57BLKS/J-db/db mice with or without treatment of UG0506 for 12-weeks. 118
Fig. 49. Effects of test articles on acidified ethanol-induced gastric lesions (mm) in rats. Data are expressed as Mean ±S.E. The results were statistically analyzed by student''s t-test. G1: control, n＝40; G2: treatment of 100 mg/kg of UG0505-1... 119
Fig. 50. The HPLC chromatogram of standard mixture of UG0506C1, UG0506C2, UG0506C3 and UG0506 sample. 119
Fig. 51. The changes of UG0506C1 content in UG0506 for 6-months 120
Fig. 52. The changes of UG0506C2 content in UG0506 for 6-months 121
Fig. 53. The changes of UG0506C3 content in UG0506 for 6-months 121
Fig. 54. The content variation of UG0506C1, UG0506C2 and UG0506C3 in raw materials according to the manufacturers. 122
Fig. 55. Changes of body weight in the high cholesterol diet induced atherosclerosis mice with or without treatment of UG0404. for 8-weeks. 122
Fig. 56. Morphometry of Oil red O stained of frozen sections of aortic valve lesion areas by computer-associated image analysis in the high cholesterol diet induced atherosclerosis mice with or without treatment of UG0404 for 8-weeks. 123
Fig. 57. Morphometry of Oil red O stained aortic valve lesion areas by computer-associated image analysis in the high cholesterol diet induced atherosclerosis mice with or without treatment of UG0404 for 8-weeks. 124
Fig. 58. Efficacy screening for anti-Alzheimer''s disease; A) Inhibitory activity of UG0504 and their fractions on Aβ aggregation assay. All samples were treated with 10ug/ml. B) Inhibitory activity of UG0504 against aggregated Aβ induced... 124
Fig. 59. Efficacy screening for anti-Alzheimer''s disease; A) Inhibitory activity of UG0314 (10ug/ml) on Aβ aggregation assay. B) Inhibitory activity of UG0314 against aggregated Aβ induced cytotoxicity with HT22 cells. 25uM of recombinant... 125
Fig. 60. Cytotoxicity of UG0402P on human smooth muscle cells. 125
Fig. 61. Inhibitory effect of vascular aortic smooth muscle cell proliferation by UG0402P. 126
Fig. 62. The HPLC chromatogram of UG0404C1 standard and UG0404 sample. 126
Fig. 63. The changes of UG0404C1 content in UG0404 for 6-months 127
Fig. 64. Development of manufacturing process of UG0404 129
Fig. 65. Formalin test; CD-1 mice (n＝6) were treated with Ibuprofen (positive drug), UG0406 and commercial herbal medicine at the dose of 100mg/kg p.o an half hour before intraplantar inoculation of 2.5% formalin at the right hind paw.... 129
Fig. 66. Writhing test; CD-1 mice (n＝6) were treated with Ibuprofen (positive drug), UG0408 and commercial herbal medicine at the dose of 100mg/kg p.o an half hour before IP administration of 0.6% acetic acid. Data reported as mean ± SD. 130
Fig. 67. Mean total Measurements; Motor activity (MA) was evaluated near the end of the study on all males (Day 90) and females (Day 91) of the control and high dose groups. Each animal was placed into a polycarbonate solid bottom cage 131
Fig. 68. Individual in body weights were recorded twice during the acclimation period, on Day 1 (the day of study start) and approximately weekly thereafter (7 day intervals ± 1) for 13 weeks for both males and females. Data expressed as mean ± SD. 134
Fig. 69. Individual food consumption was measured and recorded weekly adjusting for spillage. Mean daily food consumption was calculated for each sex/dose level during each weekly interval and overall (Days 1-91) testing for both males... 135
Fig. 70. Change in body weights of female rats after repeat treatment (GD6~GD15) with UG0408. ●, No treatment; □, Saline; △, 250mg/kg; ◇, 500mg/kg; ▼, 1000mg/kg UG0408. 138
Fig. 71. Change in feed consumption of female rats after repeat treatment (GD6~GD15) with UG0408. ●, No treatment; □, Saline; △, 250mg/kg; ◇, 500mg/kg; ▼, 1000mg/kg UG0408. Significant differences as compared with No treatment; 140
Fig. 72. Photo of Univestin-K pills. 143
Fig. 73. The product declaration of Dietary supplement for Univestin-K pills.(그림없음) 143
Fig. 74. HPLC chromatogram of catechin 145
Fig. 75. HPLC chromatogram of baicalin 145
Fig. 76. Water solubility of UG0408 & UG0408S. 145
Fig. 77. IR spectrum of UG0408 & UG0408S 146
Fig. 78. Comparison of physical appearance in pastry containing UG0201 147
Fig. 79. Question and answer after taste test of pastry containing UG0201 148
Fig. 80. Product launching of UniBEX-S (UG0201-Taiwan version) 149
Fig. 81. Stability test of UG0201 liquid formulation 150
