초록 ▼

○ 연구개발 목표 및 성과

골다공증은 가벼운 충격에도 골절이 일어나 삶의 질을 현저히 저하시켜, 급속한 노령화 시대에 골건강을 유지하기 위한 노력은 더욱 중요성이 커지고 있다. 현재까지 이루어진 골다공증 치료제의 대부분은 골분해(흡수) 억제제로 골다공증의 진행을 예방하는 수준이며, 골형성 촉진 기능을 갖는 파라티로이드호르몬(PTH) 제제의 경우는 호르몬이라는 한계가 있다. 이러한 이유로 본 과제에서는 현재 사용 중인 치료제의 여러 단점들을 극복하기 위하여, 골형성 촉진작용과 골소실 억제 기능성이 뛰어나며 안전성이 확보되

○ 연구개발 목표 및 성과

골다공증은 가벼운 충격에도 골절이 일어나 삶의 질을 현저히 저하시켜, 급속한 노령화 시대에 골건강을 유지하기 위한 노력은 더욱 중요성이 커지고 있다. 현재까지 이루어진 골다공증 치료제의 대부분은 골분해(흡수) 억제제로 골다공증의 진행을 예방하는 수준이며, 골형성 촉진 기능을 갖는 파라티로이드호르몬(PTH) 제제의 경우는 호르몬이라는 한계가 있다. 이러한 이유로 본 과제에서는 현재 사용 중인 치료제의 여러 단점들을 극복하기 위하여, 골형성 촉진작용과 골소실 억제 기능성이 뛰어나며 안전성이 확보되어 부작용이 최소화된 골 건강(골다공증) 개선 기능성 식품 소재를 개발하는 것을 목표로 다음과 같은 연구를 진행하였다. 동물 모델을 이용한 비임상 효력시험을 통해 최종 후보물질의 효능을 확인하였으며, 후보소재의 안전성을 평가하기 위한 다양한 독성시험에서 안전성을 확보하였다. 또한 개발 소재의 표준화 및 품질관리 기준을 설정하였으며 시제품의 제형을 결정하고 개발제품에 대한 안정성 시험을 진행하였다. 개발소재의 용도 특허출원/등록 및 학술지 투고를 통하여 과학적 근거자료를 마련하였다.

○ 연구내용 및 결과

1. 개발 소재의 품질관리설정 및 표준화 (물질특성, 효능평가 및 작용기전 연구 등)
- 생약원료 선정구매/ 탐색평가용 시료제조
- 시작품의 제품화 연구 및 활용기술개발
- in vitro 효능평가: 조골세포 분화 촉진, 파골세포 분화 억제 활성평가
- 조골세포분화 유도 작용기전 연구
- 파골세포분화 억제 작용기전 연구

2. 원재료 제조 및 기준 ‧ 규격 설정
- 최종 추출공정 확립
- 원료 기준 및 규격 확립
- 완제 제조 및 기준 ‧ 규격 설정

3. 비임상 효력시험 완료
- 난소절제 랫드모델을 이용한 골다공증 치료 효력시험
- 난소절제 랫드모델을 이용한 골다공증 예방 효력시험
- 제브라피쉬 모델을 이용한 골형성 효력시험

4. 허가자료 준비
- IRB 제출 자료 구비
- CMC 패키지 구축
- 원료 및 완제 안정성 평가
- 비임상 독성시험 안전성 평가(단회경구투여, 복귀돌연변이, 염색체이상시험, 제브라피쉬모델을 이용한 발생, 심장, 간, 신경독성)
- 임상시험 IRB 심사 접수(고려대학교 구로병원 IRB 심의 진행 중임)

5. 개발소재의 용도특허출원 및 학술지 발표(과학적 근거자료 마련)
- 발굴소재의 특허출원 2건 /등록 1건
- 학술지 게제 3건 완료

○ 연구성과 활용실적 및 계획

- 골건강 및 골다공증 개선 기능성 생약소재 추출물의 제조 및 효능평가 노하우 확보로 신제품 개발
- 고부가가치 기능성 핵심소재 원료/완제품의 국내외 사업화로 매출창출
- 골형성 증진 및 골흡수 억제의 이중작용기작으로 골관련 제품의 경쟁력 향상
- 의약품 등 타 산업분야로 응용확대
- 임상시험을 위한 신뢰성 있는 독성학적 기초자료를 확보함으로써, 의약외품 IND에 필요한 근거 자료 제공
- 국내산 고품질 식품생약조달 및 재배권장 자원의 실용화 사업으로 농민 소득증대 기여

(출처 : 연구개발보고서 초록 88p)

Abstract ▼

Purpose&Contents
Osteoporosis is one of the most frequently occurring bone diseases with increased risk of fracture leading to gait dysfunction and low quality of life.

Also, constant effort on bone health maintenance is critical as it becomes more common with age, and the average age of t

Purpose&Contents
Osteoporosis is one of the most frequently occurring bone diseases with increased risk of fracture leading to gait dysfunction and low quality of life.

Also, constant effort on bone health maintenance is critical as it becomes more common with age, and the average age of the population is growing older. Most of the osteoporosis treatments currently available are only capable of preventing the progression of osteoporosis with the inhibition of resorption, and parathyroid hormone treatment with bone formation stimulating effect provides limited use due to its hormonal properties.

Therefore, the purpose of this study is to select candidate ingredients and develop safe health functional food for bone health products with bone formation activation and bone resorption inhibition with minimum side effects, and also overcoming the current disadvantages of current treatments.

□ Study on new herbal medicine ingredient of bone formation induction activity and bone resorption inhibition activity
□ Development of new functional food materials extract on bone health and osteoporosis improvement
□ Utility patent and journal publication (for scientific evidence) of the developed product
□ Establishment of quality control standards and standardization (research on material property) of the developed product
□ Efficacy evaluation, formulation selection, and stability data (for regulatory documents) of sample product
□ Non-clinical efficacy and toxicity studies (sufficient preliminary data for future clinical efficacy studies)
□ Clinical efficacy studies - Guidelines for the individual recognition (IRB approved)

Results
1. Establishment of quality control standards and standardization
(1) Selection of herbal medicine ingredient / sample preparation for in vitro efficacy evaluation
- Screening and selection of herbal medicine ingredients based on the ingredients allowed to be used as food and other quasi-drugs for anti-inflammation.

- Establishment and evaluation of ALP stimulation activity of osteoblast differentiation
- Establishment and evaluation of TRAP inhibition activity of osteoclast differentiation

- Selection of 3 herbal medicine ingredients with high potential for development (Dimocarpus longan, Mori Ramulus and Alpinia officinarum)

- Final selection of Dimocarpus longan for production of sample products after evaluating the extracts and fractions of 3 herbal medicine ingredients by in vitro and in vivo studies

(2) Study of mode of action (MoA) of osteoblast differentiation activation
- Evaluation of Osteoblast maker gene expression (ALP, Runx2, OCN)
- Evaluation of Wnt/b-catenin signaling activity stimulation
- Evaluation of Erk1/2 signaling activity stimulation
- Evaluation of p38, JNK signaling activity stimulation

(3) Study of mode of action (MoA) of osteoclast differentiation inhibition
- Evaluation of NF-kB signaling activity inhibition (IkB-a)
- Evaluation of Osteoclast maker gene expression (Trap)
- Evaluation of Osteoclast maker protein expression (NFATc1, NF-kB)

2. Production of raw material and establishment of standards and specifications
(1) Optimization of extraction condition
- Selection of extraction solvent, time and temperature condition
- Evaluation of ALP activity and gene expression for condition
- Selection of extraction volume and frequency

(2) Establishment of standards and specifications for materials
- Selection of quality control standards and development of method of analysis
- Verification of method of analysis (specificity, linearity, accuracy, precision)
- Production of pilot scale

(3) Establishment of standards and specifications for products
- Evaluation of hygroscopic property and solubility
- Study on the prescription / formulation
- Establishment of standards and specifications
- Verification of method of analysis (specificity, linearity, accuracy, precision)

3. Completion of non-clinical efficacy studies
(1) Efficacy study for osteoporosis on ovariectomized rat model
- Evaluation of efficacy test on animals (rodents OVX rat) with individual extracts of Dimocarpus longan, Mori Ramulus and Alpinia officinarum
- Selection of final ingredients of Dimocarpus longan and Mori Ramulus with highest efficacy on BMD and CTx efficacy testing

(2) Efficacy study for osteoporosis on pretreat-ovariectomized rat model
- Evaluation of efficacy test on animals (rodents OVX rat) with individual or mixed extracts of Dimocarpus longan and Mori Ramulus before ovariectomy.
- Selection of final ingredients of Dimocarpus longan with highest efficacy on bone formation (BMD) from rodent OVX rat model

(3) Efficacy study for bone formation on zebrafish model
- Evaluation of bone formation efficacy test on animals (zebrafish embryo) with final ingredients of Dimocarpus longan extracts
- Selection of final ingredients of Dimocarpus longan with highest efficacy on bone formation and segmentation from non-rodent zebra fish model
- Verification of bone formation increase on bone growth and somite efficacy testing in no rodents zebrafish models

4. Regulatory documents
(1) Preparation of IRB documents
- Preparation of documents for safety and efficacy evaluation based on ‘Regulation on registration, evaluation, and approval of quasi-drug product’

- Preparation of documents for ingredient and finished product about physicochemistry, manufacturing documents, establishment of specifications and safety control

(2) Preparation of CMC documents for product development
- Establishment of quality control standards and safety of the ingredient and finished product
- Establishment of manufacturing process, selection of marker compounds, verification of method of analysis, standards and specifications, and stability evaluation of the ingredient and finished product

(3) Stability study of ingredient and finished product
- Stability test of real-time condition (25±5℃, 60±5% RH) and accelerated condition (40±5℃, 75±5% RH)
- No significant change in marker compounds in the ingredient (up to 15 months) and the finished product (up to 2 months)

(4) Non-clinical toxicity study
- Completion of single-dose toxicity study with oral administration on SD-Rat
- Completion of bacterial reverse mutation test
- Completion of chromosomal aberration test on mammalian cultured cells
- Completion of teratotoxicity, cardiotoxicity, hepatotoxicity, and neurotoxicity in zebrafish models

5. Utility patent application and journal publication of developed material
- Patent: 2 applications, 1 registration
- Publication: 3 publications completed
- Academic conference: 7 presentations at conferences
- Advertisement: 2 presentations at conferences

Expected Contribution
[Application plan]
- Manufacture and efficacy study of non-toxic (low toxic) functional herbal medicine extract for new product development, mass production, and efficacy and toxicity data

- Commercialization of functional ingredient for improvement of bone health (osteoporosis)
- Increased sales from high added value functional ingredient and its finished product
- Acquisition of new health functional food ingredient from MFDS
- Establishment of library of new treatment for the age-related metabolic disease through development of natural herbal extract based on the osteoblast differentiation induction mechanism

- Expanded usage in global nutraceuticals products and natural pharmaceutical industry
- Synergy effect of natural functional ingredient, micro-calcium and vitamin D complex herbal medication
- Improvement of osteoporosis drugs based on the dual mechanism of bone formation induction and bone resorption inhibition activity

[Expected outcome]
1. Technological outcome
- Core technological development based on natural herbal extract through osteoblast differentiation induction and osteoclast differentiation inhibition activity

- Establishment of extraction process and standardized technology on new functional herbal extract
- Development of safe functional materials for improvement of bone health (osteoporosis) solving the problem of existing treatments.

- Increased possibility of new treatment for the age-related metabolic diseases through development of natural herbal extract based on the dual mechanism of bone health

- Expanded usage in pharmaceutical industry

2. Economic and Industrial outcome
- Establishment of converging technology of nutraceuticals and drugs based on the functional food industry

Expected Contribution
- Increased agricultural income for high quality herbal medicine supply and cultivation
- High value added product and foreign currency profit model through USA market
- Reducing social costs that may occur from osteoporosis.

(출처 : SUMMARY 8p)

목차 Contents

• 표지 ... 1
• 제 출 문 ... 2
• 보고서 요약서 ... 3
• 국문 요약문 ... 4
• SUMMARY ... 8
• Contents ... 13
• 목차 ... 14
• 1. 연구개발과제의 개요 ... 15
• 1-1. 연구개발 목적 ... 15
• 1-2. 연구개발의 필요성 ... 15
• 1-3. 연구개발 범위 ... 22
• 2. 국내외 기술개발 현황 ... 24
• 2-1. 국내 제품생산 및 시장현황 ... 24
• 2-2. 국외 제품생산 및 시장현황 ... 26
• 3. 연구수행 내용 및 결과 ... 29
• 3.1. 후보 소재 선정 및 최종 후보군(원료 및 완제) 도출 ... 29
• 3.2. 비임상시험 및 허가자료 구비 ... 67
• 4. 목표달성도 및 관련분야 기여도 ... 82
• 4-1. 목표 달성도 ... 82
• 4-2. 관련분야 기여도 ... 82
• 5. 연구결과의 활용계획 ... 84
• 6. 연구과정에서 수집한 해외과학기술정보 ... 84
• 7. 연구개발결과의 보안등급 ... 84
• 8. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 84
• 9. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 85
• 10. 연구개발과제의 대표적 연구실적 ... 86
• 11. 기타사항 ... 86
• 12. 참고문헌 ... 87
• [별첨 1] 연구개발보고서 초록 ... 88
• 끝페이지 ... 90