KR20210124035A - a composition comprising the extract of combined herbs comprising Longanae Arillus for the treatment or prevention of arthritis - Google Patents
a composition comprising the extract of combined herbs comprising Longanae Arillus for the treatment or prevention of arthritis Download PDFInfo
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- KR20210124035A KR20210124035A KR1020210032876A KR20210032876A KR20210124035A KR 20210124035 A KR20210124035 A KR 20210124035A KR 1020210032876 A KR1020210032876 A KR 1020210032876A KR 20210032876 A KR20210032876 A KR 20210032876A KR 20210124035 A KR20210124035 A KR 20210124035A
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Classifications
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A61K36/18—Magnoliophyta (angiosperms)
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
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Abstract
Description
본 발명은 용안육 포함 조합 생약 추출물을 유효성분으로 함유하는 관절염의 치료 또는 예방용 조성물 및 이의 용도에 관한 것이다. The present invention relates to a composition for the treatment or prevention of arthritis containing a combination herbal extract containing longan meat as an active ingredient, and to a use thereof.
[문헌1] Trengove NJ, Bielefeldt-Ohmann H, Stacey MC (2001) Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair and Regeneration. 8: 13-25.[Document 1] Trengove NJ, Bielefeldt-Ohmann H, Stacey MC (2001) Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair and Regeneration . 8: 13-25.
[문헌2] Armstrong DG, Jude EB (2002) The Role of Matrix Metalloproteinases in Wound Healing. Journal of the American Podiatric Medical Association. 92: 12-18.[Document 2] Armstrong DG, Jude EB (2002) The Role of Matrix Metalloproteinases in Wound Healing. Journal of the American Podiatric Medical Association . 92: 12-18.
[문헌3] Martins VL, Caley M, O' Toole EA (2013) Matrix metalloproteinases and epidermal wound repair. Cell and Tissue Research. 351: 255-268. [Document 3] Martins VL, Caley M, O' Toole EA (2013) Matrix metalloproteinases and epidermal wound repair. Cell and Tissue Research . 351: 255-268.
[문헌4] Jones JI, Nguyen TT, Peng Z, Chang M (2019) Targeting MMP-9 in Diabetic Foot Ulcers. Pharmaceuticals. 12: 79. [Document 4] Jones JI, Nguyen TT, Peng Z, Chang M (2019) Targeting MMP-9 in Diabetic Foot Ulcers. Pharmaceuticals . 12: 79.
[문헌5] Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery. 147: 295-302[Document 5] Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery . 147: 295-302
[문헌6] 정보섭, 도해향약대사전, 영림사, pp371-373, 1998[Document 6] Jeong Bo-seop, Dohaehyangyaksa Dictionary, Youngrimsa, pp371-373, 1998
[문헌7] 정보섭외 1인, 영림출판사, p428-429, 1998년[Document 7] One Information Recruiter, Younglim Publishing House, p428-429, 1998
[문헌8] 정보섭외 1인, 영림출판사, p798-799, 1998년[Document 8] One person for information recruitment, Younglim Publishing House, p798-799, 1998
[문헌9] Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832[Document 9] Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832
[문헌10] Jeong et al., 2019, J Invest Dermatol. 2019 May;139(5):1098-1109. doi: 10.1016/j.jid.2018.11.012. Epub 2018 Nov 29.[Document 10] Jeong et al., 2019, J Invest Dermatol. 2019 May;139(5):1098-1109. doi: 10.1016/j.jid.2018.11.012. Epub 2018 Nov 29.
[문헌11]Bulstra SK, Buurman WA, Walenkamp GH, Van der Linden AJ (1989) Metabolic characteristics of in vitro cultured human chondrocytes in relation to the histopathologic grade of osteoarthritis. Clin Orthop Relat Res: 294-302.[Document 11] Bulstra SK, Buurman WA, Walenkamp GH, Van der Linden AJ (1989) Metabolic characteristics of in vitro cultured human chondrocytes in relation to the histopathologic grade of osteoarthritis. Clin Orthop Relat Res: 294-302.
[문헌12] Osteoarthritis cartilage histopathology: grading and staging. OsteoArthritis and Cartilage (2006) 14, 13-29.[Document 12] Osteoarthritis cartilage histopathology: grading and staging. OsteoArthritis and Cartilage (2006) 14, 13-29.
일반적으로 염증 반응은 생체의 세포나 조직에 어떠한 기질적 변화를 가져오는 침습이 가해질 때 그 손상부위를 수복 재생하려고 하는 생체의 방어 반응과정이다. 따라서 이러한 일련의 반응에는 국소의 혈관, 체액의 각종 조직세포, 면역관여 세포 등이 포함된다. 최근 분자생물학의 발달과 더불어 염증성 질환이 사이토카인(cytokine)이라는 분자 수준에서의 이해가 시도되고 있으며, 이러한 질환에 영향을 주는 인자들도 하나씩 규명되고 있다.In general, the inflammatory reaction is a defense reaction process of the living body that tries to repair and regenerate the damaged area when an invasion that causes any organic change is applied to the cells or tissues of the living body. Therefore, this series of reactions includes local blood vessels, various tissue cells in body fluids, and immune-related cells. Recently, with the development of molecular biology, understanding of inflammatory diseases at the molecular level called cytokines is being attempted, and factors affecting these diseases are being identified one by one.
따라서 염증세포 활성화에 관여하는 IL-4, IL-5, IL-13 등 사이토카인 및 면역글로불린 E의 생산과 이들의 작용으로 호산구 등 염증세포에서 분비되는 시스테인 류코트리엔 생합성 등은 염증 및 알레르기 반응과 이로 인한 천식을 유발하는 주요 원인이므로 이들의 생산을 억제하기 위한 약물을 개발하고자 많은 연구가 진행되고 있다.Therefore, the production of cytokines such as IL-4, IL-5, IL-13, etc. and immunoglobulin E, which are involved in the activation of inflammatory cells, and the biosynthesis of cysteine leukotriene secreted from inflammatory cells such as eosinophils due to their action, can lead to inflammation and allergic reactions. Because it is a major cause of asthma, many studies are being conducted to develop drugs to inhibit their production.
염증 단계가 지속되면서 TNF-α, IL-1β, IL-6와 같은 전염증성 사이토카인(proinflammatory cytokines)과 MMPs (matrix metalloproteinases)과 발현되어 있는 반면에 PDGF, VEGF, IGF와 같은 성장인자들은 발현이 감소되어 있는 것으로 알려져 있다 (Trengove NJ, Bielefeldt-Ohmann H, Stacey MC (2001) Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair and Regeneration. 8: 13-25.; Armstrong DG, Jude EB (2002) The Role of Matrix Metalloproteinases in Wound Healing. Journal of the American Podiatric Medical Association. 92: 12-18.). 상처부위에서 MMPs(matrix metalloproteinases)는 활성저해제인 TIMPs (tissue inhibitors of metalloproteinases)에 의해 조절되고, 세포외기질을 분해하여 재상피화 (re-epithelialization)를 가능하게 한다 (Martins VL, Caley M, O' Toole EA (2013) Matrix metalloproteinases and epidermal wound repair. Cell and Tissue Research. 351: 255-268. ). 특히, MMPs 중에서도 MMP-9에 대한 연구가 가장 활발하게 진행되고 있으며, 만성 상처에서 가장 해로운 영향을 끼친다고 알려져 있다 (Jones JI, Nguyen TT, Peng Z, Chang M (2019) Targeting MMP-9 in Diabetic Foot Ulcers. Pharmaceuticals. 12: 79.; Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery. 147: 295-302.).As the inflammatory phase continues, proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 and matrix metalloproteinases (MMPs) are expressed, whereas growth factors such as PDGF, VEGF, and IGF are not expressed. known to be reduced (Trengove NJ, Bielefeldt-Ohmann H, Stacey MC (2001) Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair and Regeneration . 8: 13-25.; Armstrong DG, Jude EB (2002) The Role of Matrix Metalloproteinases in Wound Healing. Journal of the American Podiatric Medical Association . 92: 12-18.). At the wound site, matrix metalloproteinases (MMPs) are regulated by tissue inhibitors of metalloproteinases (TIMPs), which degrade the extracellular matrix to enable re-epithelialization (Martins VL, Caley M, O') Toole EA (2013) Matrix metalloproteinases and epidermal wound repair. Cell and Tissue Research . 351: 255-268.). In particular, among MMPs, MMP-9 is the most actively studied and known to have the most detrimental effect on chronic wounds (Jones JI, Nguyen TT, Peng Z, Chang M (2019) Targeting MMP-9 in Diabetic) Foot Ulcers. Pharmaceuticals . 12: 79.; Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL (2010) Matrix metalloproteinase-9 delays wound healing in a murine wound model. Surgery 147: 295-302 .).
지금까지 본 발명자들은 관절염에서 특징적으로 나타나는 다양한 종류의 치료제로써 여러 가지 자원, 특히 안전성 및 유효성이 이미 알려진 천연물 자원을 이용한 치료제 개발을 중점으로 하여 개발되어 오고 있어 온 바 있다.Until now, the present inventors have been developing with a focus on the development of therapeutic agents using various resources, particularly natural resources for which safety and efficacy are already known, as various types of therapeutic agents characteristic of arthritis.
용안육 (Dimocarpus longan Loureiro)은 무환자나무과(Sapindaceae)에 속하는 용안(Euphoria longan) 및 동속식물의 종피로서, 그 성분으로는 포도당, 서당, 단백질 등을 함유하고, 심장보호, 식욕촉진 등의 효능이 알려져 있다 (정보섭, 신민교, 도해향약대사전, 영림사, pp371-373, 1998).Longan meat (Dimocarpus longan Loureiro) is the seed coat of Euphoria longan and plants belonging to the Sapindaceae family. Yes (Bobo-Sup, Shin Min-Kyo, Dohae-Hyang Pharmacy Dictionary, Youngrimsa, pp371-373, 1998).
고본 (Ligusticum tenuissimum KITAG.)은 미나리과(Umbelliferae)에 속하는 다년생 초본으로서 그 근경 및 뿌리를 고본이라고 지칭하며, 크니딜리드 (cnidilide), 3-부틸(butyl) 프탈리드(phthalide) 등의 정유 성분을 함유하고 있으며, 항진균 작용 등의 효능을 지니고 있는 것으로 알려져 있다(정보섭외 1인, 영림출판사, p428-429, 1998년). Gobon (Ligusticum tenuissimum KITAG.) is a perennial herb belonging to the Umbelliferae family. It contains, and is known to have antifungal effects, etc. (Information Recruitment 1 person, Younglim Publishing House, p428-429, 1998).
원지 (Polygala tenuifolia WILLD.)는 원지과(Polygalaceae)에 속하는 다년생 초본으로서 그 뿌리를 원지(Polygalae Radix)라고 지칭하며, 다양한 사포닌 (saponin) 성분을 함유하고 있으며, 거담작용 및 항균작용 등의 효능을 지니고 있는 것으로 알려져 있다(정보섭외 1인, 영림출판사, p798-799, 1998년). Polygala tenuifolia WILLD. is a perennial herb belonging to the family Polygalaceae, and its root is called Polygalae Radix. It is known that there is (1 person in contact with information, Younglim Publishing House, p798-799, 1998).
그러나, 상기 문헌의 어디에도 용안육, 고본 및 원지로 구성된 조합 추출물을 유효성분으로 함유하는 관절염에 대한 치료효과가 개시되거나 교시된 바는 없다. However, none of the above documents discloses or teaches a therapeutic effect on arthritis containing a combination extract composed of longan meat, gobon, and raw paper as an active ingredient.
이에 본 발명자들은 본 발명의 조합 생약 추출물이 사람 피부 상피세포(HaCaT)를 이용한 사이토카인 발현 억제 효과 실험 (실험예 1), HT-29 세포와 THP-1 세포에서의 세포독성(cell viability) 평가 효과 시험 (실험예 2), 생약 혼합 추출물의 THP-1 세포에서의 항염증 효과 시험 (실험예 3), 생약 혼합 추출물의 면역 세포에서의 염증 인자 Beclin1과 LC3B-1 발현에 미치는 효과 시험 (실험예 4) 등의 시험관내 실험; 생약 혼합 추출물의 관절염 유도 래트 실험모델에서의 통증 역치 측정, 체중 부하(Weight bearing) 측정, 조직학적 분석 (Micro-CT) 실험, 조직 병리 분석 실험 등의 관절염 억제 효과 시험 (실험예 5) 등의 동물실험을 통하여 상기 시료가 강력한 항염증 효과 및 관절염 치료 및 개선 효과를 나타냄을 확인하여, 본 발명을 완성하였다. Therefore, the present inventors evaluated the effect of the combined herbal extract of the present invention on the inhibition of cytokine expression using human skin epithelial cells (HaCaT) (Experimental Example 1), cytotoxicity (cell viability) in HT-29 cells and THP-1 cells Effect test (Experimental Example 2), anti-inflammatory effect test on THP-1 cells of herbal mixture extract (Experimental Example 3), effect test on inflammatory factors Beclin1 and LC3B-1 expression in immune cells of herbal mixture extract (Experimental) Example 4) in vitro experiments such as; Arthritis inhibitory effect test (Experimental Example 5), such as pain threshold measurement, weight bearing measurement, histological analysis (Micro-CT) experiment, histopathological analysis experiment, etc. in an arthritis-induced rat experimental model of herbal mixture extract The present invention was completed by confirming that the sample exhibits a strong anti-inflammatory effect and an arthritis treatment and improvement effect through animal experiments.
본 발명의 목적은 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 치료 및 예방 효과를 갖는 경구용 약학 조성물을 제공하기 위한 것이다. It is an object of the present invention to provide an oral pharmaceutical composition comprising a combination herbal extract composed of longan meat, gobon and raw paper as an active ingredient, which has therapeutic and preventive effects for arthritis.
또한, 본 발명은 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 예방 및 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for the prevention and improvement of arthritis containing a combination herbal extract composed of longan meat, gobon and raw paper as an active ingredient.
상기의 목적을 달성하기 위한 하나의 양태로서, 본 발명은 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 예방 또는 치료 효과를 갖는 경구용 약학 조성물을 제공한다.As an aspect for achieving the above object, the present invention provides an oral pharmaceutical composition having an effect of preventing or treating arthritis, comprising as an active ingredient a combination herbal extract composed of longanyuk, gobon, and raw paper.
본원에서 정의되는 조합 생약 추출물은 바람직하게는, 용안육, 고본 및 원지의 중량 혼합비(w/w)가 0.01 - 100 : 0.01 - 100 : 0.01 - 100 중량부 (w/w), 보다 바람직하게는 0.5-50 : 0.5-50: 0.5-50 중량부 (w/w), 보다 더 바람직하게는 0.1-10 : 0.1-10: 0.1-10 중량부 (w/w), 보다 더 바람직하게는 1-5 : 1-5: 1-5 중량부 (w/w), 보다 더욱더 바람직하게는 1-3 : 1-3: 1-3 중량부 (w/w)로 배합된 배합물을 포함하는 것임을 특징으로 한다. The combination herbal extract as defined herein preferably has a weight mixing ratio (w/w) of longan meat, gobon, and raw paper of 0.01 - 100 : 0.01 - 100 : 0.01 - 100 parts by weight (w/w), more preferably 0.5 -50: 0.5-50: 0.5-50 parts by weight (w/w), even more preferably 0.1-10: 0.1-10: 0.1-10 parts by weight (w/w), even more preferably 1-5 : 1-5: 1-5 parts by weight (w/w), even more preferably 1-3: 1-3: 1-3 parts by weight (w/w) .
이하, 본 발명을 상세히 설명한다. 하기와 같은 통상의 추출과정을 통하여 조합 생약 추출물을 수득가능하다. Hereinafter, the present invention will be described in detail. A combination herbal extract can be obtained through a conventional extraction process as follows.
상기 단계에서 얻은 건조생약재료인 용안육, 고본 및 원지를 용안육, 고본 및 원지의 중량 혼합비(w/w)가 0.01 - 100 : 0.01 - 100 : 0.01 - 100 중량부 (w/w), 보다 바람직하게는 0.5-50 : 0.5-50: 0.5-50 중량부 (w/w), 보다 더 바람직하게는 0.1-10 : 0.1-10: 0.1-10 중량부 (w/w), 보다 더 바람직하게는 1-5 : 1-5: 1-5 중량부 (w/w), 보다 더욱더 바람직하게는 1-3 : 1-3: 1-3 중량부 (w/w)로 배합된 배합물을 제조하는 제 1단계; 상기 배합물을 세척하고 상기 배합물 시료의 1 내지 20배 (w/v) 중량, 바람직하게는 1 내지 10배 (w/v) 중량의 물, 에탄올, 메탄올, 프로판올, 부탄올, 아세톤, 에틸아세테이트, 헥산, 부틸렌글리콜, 프로필렌글리콜, 함수부틸렌글리콜, 함수프로필렌글리콜, 함수글리세린으로 구성된 그룹으로부터 선택된 하나 이상의 용매, 바람직하게는 물 또는 물 및 에탄올 혼합용매, 가장 바람직하게는 10% 내지 80% 에탄올로 50 내지 120℃, 바람직하게는 약 80-100℃에서 1시간 내지 24시간, 바람직하게는 2시간 내지 12시간 동안 열수 추출법, 냉침 추출법 또는 초음파 추출법, 바람직하게는 열수 추출법을 수행하여 추출액을 얻는 제 2단계; 상기 2단계의 추출공정을 2 내지 10회, 바람직하게는 3 내지 5회 반복하여 얻은 추출액을 회수하여 여과지로 여과하여 여과물을 수득하는 제 3단계; 상기 여과물을 동결건조, 상온건조 또는 열풍건조, 바람직하게는 동결건조를 수행하여 건조 상태의 조합 생약 추출물을 각각 수득하는 제 4단계 공정을 통하여 본 발명의 조합 생약 추출물을 제조가능하다. The weight mixing ratio (w/w) of the dried herbal material obtained in the above step, the longan meat, the old version, and the raw paper, is 0.01 - 100: 0.01 - 100: 0.01 - 100 parts by weight (w/w), more preferably 0.5-50: 0.5-50: 0.5-50 parts by weight (w/w), even more preferably 0.1-10: 0.1-10: 0.1-10 parts by weight (w/w), even more preferably 1 -5: 1-5: 1-5 parts by weight (w/w), even more preferably 1-3: 1-3: 1-3 parts by weight (w/w) step; The formulation is washed and 1 to 20 times (w/v) weight, preferably 1 to 10 times (w/v) weight of the formulation sample, water, ethanol, methanol, propanol, butanol, acetone, ethyl acetate, hexane , butylene glycol, propylene glycol, hydrous butylene glycol, hydrous propylene glycol, at least one solvent selected from the group consisting of hydrous glycerin, preferably water or a mixed solvent of water and ethanol, most preferably 10% to 80% ethanol An agent for obtaining an extract by performing hot water extraction, cold extraction or ultrasonic extraction, preferably hot water extraction, at 50 to 120° C., preferably about 80-100° C. for 1 hour to 24 hours, preferably 2 hours to 12 hours Step 2; a third step of recovering the extract obtained by repeating the extraction process of the second step 2 to 10 times, preferably 3 to 5 times, and filtering it with a filter paper to obtain a filtrate; The combined herbal extract of the present invention can be prepared through the fourth step process of lyophilizing the filtrate, drying at room temperature or drying with hot air, preferably freeze-drying to obtain the combined herbal extract in a dry state, respectively.
본 발명은 상기 제조방법 및 상기 제조방법으로 수득된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 치료 및 예방 효과를 갖는 경구용 약학조성물, 건강기능식품 또는 건강보조식품을 제공한다. The present invention provides an oral pharmaceutical composition, health functional food or health supplement having the therapeutic and preventive effects of arthritis, comprising the preparation method and the combined herbal extract obtained by the preparation method as an active ingredient.
본원에서 정의되는 "관절염"이란 강직성 척추염, 퇴행성 관절염, 골관절염, 류마티스 관절염, 건성 관절염, 통풍 또는 견관절주위염으로 이루어지는 군으로부터 선택되는 어느 하나일 수 있으며, 이에 한정되지 않는다."Arthritis" as defined herein may be any one selected from the group consisting of ankylosing spondylitis, degenerative arthritis, osteoarthritis, rheumatoid arthritis, spondyloarthritis, gout, or periarthritis, but is not limited thereto.
본원에서 정의되는 "추출물"은 상기 용안육, 고본, 및 원지들의 뿌리, 줄기 및 잎 부위를 추출재료의 추출물을 포함하며, 구체적으로는, 상기 추출재료의 물, 에탄올, 메탄올, 프로판올, 부탄올, 아세톤, 에틸아세테이트, 헥산, 부틸렌글리콜, 프로필렌글리콜, 함수부틸렌글리콜, 함수프로필렌글리콜, 함수글리세린으로 구성된 그룹으로부터 선택된 하나 이상의 용매, 바람직하게는 물 또는 물 및 메탄올, 에탄올의 혼합용매, 가장 바람직하게는 10% 내지 80% 메탄올 또는 에탄올 가용 추출물을 포함한다.The term "extract" as defined herein includes extracts of extracts from the roots, stems and leaf parts of the longan meat, gobon, and raw papers, specifically, water, ethanol, methanol, propanol, butanol, acetone of the extract material. , ethyl acetate, hexane, butylene glycol, propylene glycol, hydrous butylene glycol, hydrous propylene glycol, at least one solvent selected from the group consisting of hydrous glycerin, preferably water or a mixed solvent of water and methanol, ethanol, most preferably contains 10% to 80% methanol or ethanol soluble extract.
상기 용안육, 고본, 및 원지의 조합 추출물은The combined extract of longan meat, gobon, and raw paper is
(1) 용안육, 고본, 및 원지의 조합의 추출물, 또는(1) an extract of a combination of longan meat, gobon, and raw paper, or
(2) 개개 용안육 추출물, 고본 추출물, 및 원지 추출물들의 혼합물, 또는(2) a mixture of individual longan meat extracts, gobon extracts, and raw paper extracts, or
(3) 이들 조합을 포함한다.(3) including combinations of these.
일 구체예에서, 용안육, 고본, 및 원지의 혼합 추출물은 용안육, 고본, 및 원지의 혼합물의 추출물일 수 있다.In one embodiment, the mixed extract of longanyuk, gobon, and raw paper may be an extract of a mixture of longanyuk, gobon, and raw paper.
본 명세서에서, "추출물"은 생약에 추출 용매를 가하여 추출하여 얻어진 추출물뿐 아니라, 상기 추출물의 농축물 및 희석물, 및 상기 추출물, 농축물, 및 희석물의 건조물을 모두 포함하는 의미로, 특별한 언급이 없는 한, "추출물"은 생약에 추출 용매를 가하여 추출하여 얻어진 추출물, 상기 추출물의 건조물, 상기 추출물의 농축물 또는 희석물, 및 상기 농축물 또는 희석물의 건조물로 이루어진 군에서 선택된 1종 이상을 의미하는 것으로 해석될 수 있다. In the present specification, "extract" means not only extracts obtained by adding an extraction solvent to herbal medicines, but also concentrates and dilutions of the extracts, and dried products of the extracts, concentrates, and dilutions. Unless otherwise specified, "extract" means at least one selected from the group consisting of an extract obtained by adding an extraction solvent to a crude drug, a dried product of the extract, a concentrate or dilution of the extract, and a dried product of the concentrate or dilution. can be interpreted as meaning
본 발명자들은 본 발명의 조합 생약 추출물이 사람 피부 상피세포(HaCaT)를 이용한 사이토카인 발현 억제 효과 실험 (실험예 1), HT-29 세포와 THP-1 세포에서의 세포독성(cell viability) 평가 효과 시험 (실험예 2), 생약 혼합 추출물의 THP-1 세포에서의 항염증 효과 시험 (실험예 3), 생약 혼합 추출물의 면역 세포에서의 염증 인자 Beclin1과 LC3B-1 발현에 미치는 효과 시험 (실험예 4) 등의 시험관내 실험; 생약 혼합 추출물의 관절염 유도 래트 실험모델에서의 통증 역치 측정, 체중 부하(Weight bearing) 측정, 조직학적 분석 (Micro-CT) 실험, 조직 병리 분석 실험 등의 관절염 억제 효과 시험 (실험예 5) 등의 동물실험을 통하여 상기 시료가 강력한 항염증 효과 및 관절염 치료 및 개선 효과를 나타냄을 확인하여, 관절염의 예방 및 치료용 경구용 약학조성물, 건강기능식품 또는 건강보조식품으로 유용함을 확인하였다.The present inventors found that the combined herbal extract of the present invention was tested for the inhibitory effect of cytokine expression using human skin epithelial cells (HaCaT) (Experimental Example 1), cytotoxicity (cell viability) evaluation effect in HT-29 cells and THP-1 cells Test (Experimental Example 2), Anti-inflammatory effect test on THP-1 cells of mixed herbal extract (Experimental Example 3), Effect test on inflammatory factors Beclin1 and LC3B-1 expression in immune cells of mixed herbal extract (Experimental Example) 4) in vitro experiments such as; Arthritis inhibitory effect test (Experimental Example 5), such as pain threshold measurement, weight bearing measurement, histological analysis (Micro-CT) experiment, histopathological analysis experiment, etc. in an arthritis-induced rat experimental model of herbal mixture extract Through animal experiments, it was confirmed that the sample exhibits a strong anti-inflammatory effect and arthritis treatment and improvement effect, and it was confirmed that it is useful as an oral pharmaceutical composition for the prevention and treatment of arthritis, a health functional food, or a health supplement.
또한, 상기 생약들은 오랫동안 생약 및 식용으로 사용되어 오던 약재로서 이들로부터 추출된 본 발명의 추출물 역시 독성 및 부작용 등의 문제가 없이 장기간 사용 시에도 안심하고 사용할 수 있다.In addition, the herbal medicines have been used as herbal medicines and food for a long time, and the extracts of the present invention extracted therefrom also do not have problems such as toxicity and side effects, and can be used with confidence even when used for a long time.
본 발명에서 사용되는 용어, "예방"은 상기 추출물을 포함하는 조성물의 투여로 염증, 알레르기 또는 천식을 억제 또는 지연시키는 모든 행위를 의미한다. 또한, 본 발명에서 사용되는 용어, "치료"는 상기 추출물을 포함하는 조성물의 투여로 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term “prevention” refers to any action that suppresses or delays inflammation, allergy, or asthma by administration of a composition containing the extract. In addition, as used in the present invention, the term "treatment" refers to any action in which symptoms of a disease are improved or beneficially changed by administration of a composition containing the extract.
다른 하나의 양태로서, 본 발명에 따른 상기 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 관절염 환자에게 경구 투여함을 포함하는 관절염을 치료하기 위한 치료방법을 제공한다.As another aspect, there is provided a treatment method for treating arthritis, comprising orally administering to an arthritis patient the combination herbal extract composed of the longan meat, gobon, and raw paper according to the present invention.
다른 하나의 양태로서, 관절염 환자를 치료하기 위한 경구용 치료제 제조를 위한 용안육, 고본 및 원지로 구성된 조합 생약 추출물의 용도를 제공한다.As another aspect, there is provided the use of a combined herbal extract composed of longanyuk, gobon and raw paper for the manufacture of an oral therapeutic agent for treating arthritis patients.
본 발명에 따른 추출물을 포함하는 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 상기 추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화 할 경우에는 보통 사용하는 충진제, 중량제, 결합제, 습윤제, 봉해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물 및 분획물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다.The pharmaceutical composition comprising the extract according to the present invention is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. can be used in combination. Carriers, excipients and diluents that may be included in the composition comprising the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulating, it is prepared by using diluents or excipients such as fillers, weights, binders, wetting agents, sealants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract and fraction, for example, starch, calcium carbonate, sucrose (sucrose) or lactose (lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
상기한 제제에는 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤젤라틴 등이 사용될 수 있다.Non-aqueous solvents, suspending agents, propylene glycol (propylene glycol), polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate may be used in the above formulation. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol gelatin and the like can be used.
본 발명의 추출물을 포함하는 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 추출물을 포함하는 약학조성물은 1일 0.0001 내지 100 mg/kg으로, 바람직하게는 0.001 내지 100 mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The preferred dosage of the pharmaceutical composition comprising the extract of the present invention varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the pharmaceutical composition comprising the extract of the present invention is preferably administered at 0.0001 to 100 mg/kg per day, preferably at 0.001 to 100 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
본 발명의 추출물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내(Intracerebroventricular) 주사에 의해 투여될 수 있다.The extract of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명의 약학 조성물은, 조성물 총 중량에 대하여 상기 추출물을 0.1 내지 50 중량 %로 포함한다. The pharmaceutical composition of the present invention comprises 0.1 to 50% by weight of the extract based on the total weight of the composition.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리 에틸렌 글리콜 및 올리브 오일과 같은 식물성 기름 및 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지 및 글리 세로젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. Non-aqueous solvents and suspending agents include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, and glycerogelatin may be used.
본 발명의 추출물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 추출물은 0.0001 ~ 100 mg/kg으로, 바람직하게는 0.001 ~ 100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 조성물에서 본 발명의 추출물은 전체 조성물 총 중량에 대하여 0.0001 ~ 50 중량%의 함량으로 배합될 수 있다.The preferred dosage of the extract of the present invention varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the extract of the present invention may be administered in an amount of 0.0001 to 100 mg/kg, preferably 0.001 to 100 mg/kg, divided once or several times a day. In the composition, the extract of the present invention may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the total composition.
본 발명의 약학 조성물은 쥐, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 및 뇌혈관내 (intracere broventricular) 주사에 의해 투여될 수 있다. The pharmaceutical composition of the present invention may be administered to mammals such as mice, mice, livestock, and humans by various routes. All modes of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural and intracerebroventricular injections.
또한, 본 발명은 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 예방 및 개선용 건강기능 식품을 제공한다. In addition, the present invention provides a health functional food for the prevention and improvement of arthritis containing a combination herbal extract composed of longan meat, gobon and raw paper as an active ingredient.
본원에서 정의되는 "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다."Health functional food" as defined herein means a food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulating nutrients with respect to structure and function or physiological effects.
본 발명의 관절염의 예방 또는 개선을 위한 건강기능식품은, 조성물 총 중량에 대하여 상기 추출물을 0.01 내지 95%, 바람직하게는 1 내지 80% 중량백분율로 포함한다.The health functional food for the prevention or improvement of arthritis of the present invention contains the extract in an amount of 0.01 to 95%, preferably 1 to 80% by weight based on the total weight of the composition.
또한, 관절염의 예방 또는 개선을 위한 목적으로 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽 등의 약학 투여형태 또는 티백제, 침출차, 건강 음료 등의 형태인 건강기능식품으로 제조 및 가공이 가능하다.In addition, for the purpose of preventing or improving arthritis, pharmaceutical dosage forms such as powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups, etc. processing is possible.
또한, 본 발명은 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 예방 및 개선용 건강보조식품을 제공한다.In addition, the present invention provides a health supplement for the prevention and improvement of arthritis containing a combination herbal extract composed of longan meat, gobon and raw paper as an active ingredient.
또한, 본 발명은 용안육, 고본 및 원지로 구성된 조합 생약 추출물을 유효성분으로 함유하는 관절염의 예방 및 개선용 식품 또는 식품첨가물을 제공한다.In addition, the present invention provides a food or food additive for the prevention and improvement of arthritis containing a combination herbal extract composed of longan meat, gobon and raw paper as an active ingredient.
또한 상기 건강기능식품은 식품첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합여부는 다른 규정이 없는 한 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the health functional food may additionally contain food additives, and the suitability as a "food additive" is determined according to the general rules and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is judged according to the relevant standards and standards.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀롤로오스, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨 가알칼리제, 보존료제제, 타르색소제제 등의 혼합 제제류들을 들 수 있다.Items listed in the "Food Additives Codex", for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as depigmentation, licorice extract, crystalline cellulose, guar gum, L- Mixed preparations such as sodium glutamate preparations, noodles added alkali preparations, preservative preparations, and tar dye preparations may be mentioned.
본 발명의 추출물이 포함된 기능성 식품으로는 빵, 떡류, 건과류, 캔디류, 초콜릿류, 츄잉껌, 쨈류와 같은 과자류 아이스크림류, 빙과류, 아이스크림 분말류와 같은 아이스크림 제품류 우유류, 저지방 우유류, 유당분해우유, 가공유류, 산양유, 발효유류, 버터유류, 농축유류, 유크림류, 버터유, 자연치즈, 가공치즈, 분유류, 유청류와 같은 유가공품류 식육가공품, 알가공품, 햄버거와 같은 식육제품류 어묵, 햄, 소세지, 베이컨 등의 어육가공품과 같은 어육제품류 라면류, 건면류, 생면류, 유탕면류, 호화건먼류, 개량숙면류, 냉동면류, 파스타류와 같은 면류 과실음료, 채소류음료, 탄산음료, 두유류, 요구르트 등의 유산균음료, 혼합음료와 같은 음료 간장, 된장, 고추장, 춘장, 청국장, 혼합장, 식초, 소스류, 토마토케첩, 카레, 드레싱과 같은 조미식품 마가린, 쇼트닝 및 피자를 들 수 있으나, 이에 제한되는 것은 아니다.Functional foods containing the extract of the present invention include bread, rice cakes, dried fruits, candies, chocolates, chewing gum, confectionery products such as jams, ice cream products, ice cream products, ice cream products such as ice cream powder milk, low-fat milk, lactose-decomposed milk , Processed milk, goat milk, fermented milk, buttermilk, concentrated milk, milk cream, butter oil, natural cheese, processed cheese, milk powder, milk products such as whey Processed meat products, processed eggs, meat products such as hamburgers Fish cakes, ham Fish and meat products such as processed fish products such as , sausages and bacon Ramen, dried noodles, raw noodles, fried noodles, luxurious dried noodles, improved soft noodles, frozen noodles, pastas, etc. Fruit drinks, vegetable drinks, carbonated drinks, soy milk , lactic acid bacteria drinks such as yogurt, beverages such as mixed drinks soy sauce, soybean paste, gochujang, chunjang, cheonggukjang, mixed soy sauce, vinegar, sauces, tomato ketchup, curry, seasoning foods such as dressings, margarine, shortening and pizza. It is not limited.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 다른 기타 함유 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, (예를 들어, 포도당, 과당 등); 디사카라이드, (예를 들어 말토스, 슈크로스 등); 및 폴리사카라이드, (예를 들어 덱스트린, 시클로덱스트린 등)과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100㎖ 당 일반적으로 약 1~20g, 바람직하게는 약 5~12g 이다.The health functional beverage composition of the present invention is not particularly limited in other ingredients other than containing the extract as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional beverages. have. Examples of the aforementioned natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); disaccharides, (eg maltose, sucrose, etc.); and conventional sugars such as polysaccharides (eg, dextrin, cyclodextrin, etc.), and sugar alcohols such as xylitol, sorbitol, erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다. In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts. salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compositions of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination. The proportion of these additives is not critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
또한, 본 발명의 추출물은 목적 질환의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 추출 정제물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100㎖ 을 기준으로 0.02 내지 5g, 바람직하게는 0.3 내지 1g 의 비율로 가할 수 있다.In addition, the extract of the present invention may be added to food or beverage for the purpose of preventing the target disease. At this time, the amount of the extracted purified water in the food or beverage may be added in an amount of 0.01 to 15% by weight of the total food weight, and the health drink composition may be added in a ratio of 0.02 to 5g, preferably 0.3 to 1g based on 100ml. have.
상기 건강기능식품을 제조하는 과정에서 음료를 포함한 식품에 첨가되는 본 발명에 따른 추출물은 필요에 따라 그 함량을 적절히 가감할 수 있다. The extract according to the present invention, which is added to food including beverages in the process of manufacturing the health functional food, may appropriately increase or decrease its content as necessary.
본 발명에 따른 조합 생약 추출물은 사람 피부 상피세포(HaCaT)를 이용한 사이토카인 발현 억제 효과 실험 (실험예 1), HT-29 세포와 THP-1 세포에서의 세포독성(cell viability) 평가 효과 시험 (실험예 2), 생약 혼합 추출물의 THP-1 세포에서의 항염증 효과 시험 (실험예 3), 생약 혼합 추출물의 면역 세포에서의 염증 인자 Beclin1과 LC3B-1 발현에 미치는 효과 시험 (실험예 4) 등의 시험관내 실험; 생약 혼합 추출물의 관절염 유도 래트 실험모델에서의 통증 역치 측정, 체중 부하(Weight bearing) 측정, 조직학적 분석 (Micro-CT) 실험, 조직 병리 분석 실험 등의 관절염 억제 효과 시험 (실험예 5) 등의 동물실험을 통하여 상기 시료가 강력한 항염증 효과 및 관절염 치료 및 개선 효과를 나타냄을 확인하여, 관절염의 예방 또는 치료제로 널리 활용될 수 있다. The combination herbal extract according to the present invention was tested for the effect of inhibiting cytokine expression using human skin epithelial cells (HaCaT) (Experimental Example 1), cytotoxicity (cell viability) evaluation effect test in HT-29 cells and THP-1 cells ( Experimental Example 2), anti-inflammatory effect test on THP-1 cells of herbal mixture extract (Experimental Example 3), effect test on inflammatory factors Beclin1 and LC3B-1 expression of herbal mixture extract on immune cells (Experimental Example 4) in vitro experiments such as; Arthritis inhibitory effect test (Experimental Example 5), such as pain threshold measurement, weight bearing measurement, histological analysis (Micro-CT) experiment, histopathological analysis experiment, etc. in an arthritis-induced rat experimental model of herbal mixture extract By confirming that the sample exhibits a strong anti-inflammatory effect and an arthritis treatment and improvement effect through animal experiments, it can be widely used as a preventive or therapeutic agent for arthritis.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 더욱 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의하여 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the content of the present invention is not limited by the examples.
실시예 1. Example 1. 조합 생약추출물의 제조Preparation of Combination Herbal Extracts
건조 상태의 용안육 (부영약업사) 20g, 원지 (부영약업사) 20g, 고본 (부영약업사) 20g을 깨끗이 세척하고 잘게 절단한 후, 6배 부피 (v/w)의 20% (v/v) 에탄올/물 용매를 가하여 옹기 약탕기에서 90±5°C에서 3시간 환류추출한 후 여과 (10μm 이하)하고 남은 고형분에 다시 4배 부피 (v/w)의 20% (v/v) 에탄올/물 용매를 추가하여 상기와 동일한 조건에 따라 2차 추출한 후 여과(10μm 이하)하였다.After washing and cutting 20 g of dried longan meat (Buyeong Pharm), 20 g of raw paper (Buyeong Pharm), and 20 g of Gobon (Buyeong Pharm), 20% (v/v) ethanol/ Add water solvent and extract under reflux at 90±5°C for 3 hours in an Onggi yaktanggi, then filter (10 μm or less) and add 4 times the volume (v/w) of 20% (v/v) ethanol/water solvent to the remaining solid content. After secondary extraction under the same conditions as above, it was filtered (10 μm or less).
상기 3가지 추출액을 혼합 후 감압농축 (16~21 brix) 후 농축액을 살균 (80~90°C) 후에 냉각하였다. 동결건조 후 용안육, 원지 및 고본의 혼합 에탄올 추출분말을 파쇄 (50 mesh 이하)하여 실험예 시료로 사용하였다 (이하, "WIN-1001X"로 명명).The three extracts were mixed, concentrated under reduced pressure (16-21 brix), and the concentrate was sterilized (80-90°C) and then cooled. After freeze-drying, the mixed ethanol extract powder of longan meat, raw paper and gobon was crushed (50 mesh or less) and used as an experimental sample (hereinafter, named "WIN-1001X").
실시예 2-6. Example 2-6. 조합 생약추출물의 제조Preparation of Combination Herbal Extracts
건조 상태의 용안육 (부영약업사), 원지 (부영약업사) 및 고본의 건조중량을 기준으로 하기 표 1의 조성으로 배합비 및 추출용매를 달리하는 것만을 제외하고 실시예 시료 2-6를 각각 제조하여 하기 실험예 시료로 사용하였다.Based on the dry weight of the dry longan meat (Buyeong Pharmaceutical Company), the base paper (Buyeong Pharmaceutical Company) and the old book, Example Samples 2-6 were prepared respectively with the composition shown in Table 1 below, except that the mixing ratio and the extraction solvent were different Experimental Example was used as a sample.
실험예 1. 생약 혼합 추출물의 사이토카인 발현 억제 효과 시험 (in vitro)Experimental Example 1. Cytokine expression inhibition effect test of herbal mixture extract (in vitro)
상기 실시예 시료의 사이토카인 발현에 대한 억제 효과를 확인하기 위하여 기존 문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다. (Jeong et al., 2019, J Invest Dermatol. 2019 May;139(5):1098-1109. doi: 10.1016/j.jid.2018.11.012. Epub 2018 Nov 29.) In order to confirm the inhibitory effect on the cytokine expression of the sample of the above example, an experiment was performed as follows by applying the method described in the existing literature. (Jeong et al., 2019, J Invest Dermatol. 2019 May;139(5):1098-1109. doi: 10.1016/j.jid.2018.11.012. Epub 2018 Nov 29.)
인체 피부상피세포(HaCaT, 300493, CLS)를 10% fetal bovine serum (FBS) 와 100units/ml 페니실린, 100μg/ml 스트렙토마이신이 포함된 DMEM 배지(D6429, Sigma-Aldrich)에 적정 습도(85-95%)와 5% CO2가 유지되는 37℃ 배양기(HERA cell 150i, Thermo Fisher Scientific)에서 배양하였다.Human skin epithelial cells (HaCaT, 300493, CLS) were placed in DMEM medium (D6429, Sigma-Aldrich) containing 10% fetal bovine serum (FBS), 100 units/ml penicillin, and 100 μg/ml streptomycin at an appropriate humidity (85-95). %) and 5% CO 2 were maintained in a 37° C. incubator (HERA cell 150i, Thermo Fisher Scientific).
유전자 발현 조사를 위해 상기 세포를 12개의 웰에 계대하여 TNFα (RC214-12, Biobasic) 50ng/ml을 1시간 동안 처리하여 염증반응을 유발하였다. For gene expression investigation, the cells were passaged into 12 wells and treated with TNFα (RC214-12, Biobasic) 50ng/ml for 1 hour to induce an inflammatory response.
염증 유발 1시간 후에 동일 배지에 생약 혼합 추출물을 각 1μg/ml 농도로 처리하고 추가로 1시간 배양하였다.One hour after induction of inflammation, the herbal mixture extract was treated at a concentration of 1 μg/ml each in the same medium and cultured for an additional hour.
비교군으로 덱사메타손 (200nM; 양성대조군; DEX로 표시; D4902, Sigma-Aldrich) 또는 DIW (탈이온수; 음성대조군)를 각각 사용하였다. As a comparison group, dexamethasone (200 nM; positive control; denoted by DEX; D4902, Sigma-Aldrich) or DIW (deionized water; negative control) was used, respectively.
상기 세포에 생약 혼합 추출물을 1시간 동안 처리 후 RNA를 추출하고 (FATRR-001, Favorgen), cDNA synthesis kit (RR036A, ,TAKARA)을 이용하여 상기 추출한 RNA로부터 cDNA를 합성하였다. After treating the cells with the herbal mixture extract for 1 hour, RNA was extracted (FATRR-001, Favorgen), and cDNA was synthesized from the extracted RNA using a cDNA synthesis kit (RR036A, ,TAKARA).
합성된 cDNA와 Sybrgreen kit (RT500M, Enzynomics)를 이용하여 중합반응을 수행하고, 피부염증과 관련된 사이토카인 (TSLP, GM-CSF 및 IL-1β)에 대한 프라이머(primer)를 사용하여 Real-time PCR을 수행하였다. 상기 PCR에 사용된 프라이머는 표 2와 같다. Polymerization was performed using synthesized cDNA and Sybrgreen kit (RT500M, Enzynomics), and Real-time PCR using primers for cytokines related to skin inflammation (TSLP, GM-CSF and IL-1β) was performed. The primers used in the PCR are shown in Table 2.
상기 프라이머를 이용하여 Real-time PCR로 정량한 결과를 표 3에 나타내었다. 표 3에 나타난 바와 같이, 실시예 1의 추출물이 처리된 시험군은 DIW가 처리된 음성대조군과 비교하여 피부염증 관련 사이토카인들의 발현 정도가 현저히 감소하였으며, 그 감소 정도는 덱사메타손(DEX)이 처리된 양성대조군과 동등한 것으로 확인되었다.(표 3)Table 3 shows the results of quantification by real-time PCR using the primers. As shown in Table 3, the test group treated with the extract of Example 1 significantly reduced the expression level of skin inflammation-related cytokines compared to the DIW-treated negative control group, and the degree of decrease was treated with dexamethasone (DEX) It was confirmed that it was equivalent to the positive control group used (Table 3).
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DIWTNFα
DIW
WIN-1001XTNFα
WIN-1001X
WIN-1002XTNFα
WIN-1002X
WIN-1003XTNFα
WIN-1003X
WIN-1005XTNFα
WIN-1005X
DexTNFα
Dex
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DIWTNFα
DIW
WIN-1001XTNFα
WIN-1001X
WIN-1002XTNFα
WIN-1002X
WIN-1003XTNFα
WIN-1003X
WIN-1005XTNFα
WIN-1005X
DexTNFα
Dex
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DIWTNFα
DIW
WIN-1001XTNFα
WIN-1001X
WIN-1002XTNFα
WIN-1002X
WIN-1003XTNFα
WIN-1003X
WIN-1005XTNFα
WIN-1005X
DexTNFα
Dex
통계처리Statistical processing
실험 결과는 3회 반복 측정 후 평균 ± SD로 나타내었다. 통계분석은 SAS program (SAS Institue, Cary, NC, USA)을 이용하여 분석한 후 Duncan의 다중검정을 실시하였으며, 상관관계를 분석하였다. Experimental results are expressed as mean ± SD after three repeated measurements. Statistical analysis was performed using SAS program (SAS Institute, Cary, NC, USA), and then Duncan's multiple test was performed, and correlation was analyzed.
실험예 2. 생약 혼합 추출물의 HT-29 세포와 THP-1 세포에서의 세포독성(cell viability) 평가 효과 시험 (in vitro)Experimental Example 2. Evaluation of cell viability in HT-29 cells and THP-1 cells of herbal mixture extract (in vitro)
상기 실시예 시료의 HT-29 세포와 THP-1 세포에서의 세포독성(cell viability)을 확인하기 위하여 하기와 같이 실험하였다. In order to confirm the cytotoxicity (cell viability) in the HT-29 cells and THP-1 cells of the sample of the above example, the experiment was carried out as follows.
2-1.실험 과정2-1.Experimental process
human colon epithelial cell (HT-29 세포, 한국세포주 은행)와 human monocyte 세포주(THP-1 세포, 한국세포주 은행)를 배양하였다. HT-29 세포는 DMEM 배양배지(Dulbecco's modified Eagle Medium, 10% fetal bovine serum, 1% penicillin-streptomycin solution첨가)에서 배양하였고, THP-1세포는 배양 배지 (RPMI 1640 medium, 10% fetal bovine serum, 1% penicillin-streptomycin solution)에서 배양하였다.Human colon epithelial cells (HT-29 cells, Korea Cell Line Bank) and human monocyte cell lines (THP-1 cells, Korea Cell Line Bank) were cultured. HT-29 cells were cultured in DMEM culture medium (Dulbecco's modified Eagle Medium, 10% fetal bovine serum, 1% penicillin-streptomycin solution added), and THP-1 cells were cultured in culture medium (RPMI 1640 medium, 10% fetal bovine serum, 1% penicillin-streptomycin solution).
HT-29 세포와 THP-1 세포에 25, 50, 100, 250, 500, 1000 ㎍/mL 실시예 시료를 처리하여 배양 24시간 후에 CCK-8 (Cell Counting Kit-8, Dojindo Molecular Technologies, Inc.) 을 처리하여 450 nM에서 OD (optical density)를 측정함으로써 세포 생존율을 평가하였다.HT-29 cells and THP-1 cells were treated with 25, 50, 100, 250, 500, and 1000 μg/mL Example samples, and after 24 hours of incubation, CCK-8 (Cell Counting Kit-8, Dojindo Molecular Technologies, Inc.) ) was treated and cell viability was evaluated by measuring OD (optical density) at 450 nM.
2-2.실험 결과2-2.Experiment result
상기 실험 결과, HT-29 세포에서는 25-1000 ㎍/mL의 시료 처리시에 배지만 처리한 그룹 (대조군) 의 세포생존율과 차이가 없었으며 THP-1 세포에서는 500, 1000 ug/mL 시료 처리시 90.5%, 26.5%의 세포생존율을 각각 보여 대조군(control)의 세포생존율과 유의적인 차이가 있었다 (표 4). 이에 따라 THP-1 세포에서는 500 μg/mL 이하 농도의 시료를 처리하기로 하였다.As a result of the above experiment, in HT-29 cells, there was no difference from the cell viability of the group treated with medium only (control) when the sample was treated at 25-1000 μg/mL, and in THP-1 cells, when the sample was treated at 500 and 1000 ug/mL, it was 90.5 % and 26.5% cell viability, respectively, was significantly different from the cell viability of the control group (Table 4). Accordingly, it was decided to process the sample with a concentration of 500 μg/mL or less in THP-1 cells.
㎍/mLWIN1001X
μg/mL
실험예 3. 생약 혼합 추출물의 THP-1 세포에서의 항염증 효과 시험 (in vitro)Experimental Example 3. Anti-inflammatory effect test in THP-1 cells of herbal medicine mixture extract (in vitro)
상기 실시예 시료의 THP-1 세포에서의 항염증 효과를 확인하기 위하여 하기와 같이 실험하였다. In order to confirm the anti-inflammatory effect in the THP-1 cells of the sample of the above example, an experiment was performed as follows.
3-1.실험 과정 3-1.Experimental process (IL-1β 수준 측정)(Measurement of IL-1β levels)
human monocyte 세포주(THP-1 세포, 한국세포주 은행)에 염증 유발 물질인 LPS (lipopolysaccharide, Sigma)를 10, 20, 50, 100, 500 ㎍/mL 처리하여 염증모델을 준비하였다.Inflammation models were prepared by treating human monocyte cell lines (THP-1 cells, Korea Cell Line Bank) with 10, 20, 50, 100, and 500 μg/mL of LPS (lipopolysaccharide, Sigma), an inflammatory substance.
LPS 처리 24시간 후에 세포상층액을 모아 염증성 사이토카인인 IL-1β 수준을 측정하였다. 또한 실시예 시료의 항염증 효과를 확인하기 위하여 THP-1 세포에 10, 25, 50, 100 ㎍/mL 시료를 4시간 처리하고, LPS를 처리하였다. LPS 처리 24시간 후에 세포상층액을 모아 염증성 사이토카인(pro-inflammatory cytokine)인 IL-1β의 수준을 ELISA (IL-1 beta/IL-1F2 Duo set ELISA, R&D Systems)를 이용하여 측정하였다. After 24 hours of LPS treatment, the cell supernatant was collected and the level of IL-1β, an inflammatory cytokine, was measured. In addition, in order to confirm the anti-inflammatory effect of the sample sample, THP-1 cells were treated with 10, 25, 50, and 100 μg/mL samples for 4 hours, followed by LPS treatment. After 24 hours of LPS treatment, the cell supernatant was collected and the level of IL-1β, a pro-inflammatory cytokine, was measured using ELISA (IL-1 beta/IL-1F2 Duo set ELISA, R&D Systems).
3-1.실험 결과3-1.Experiment result (IL-1β 수준 측정) (Measurement of IL-1β levels)
상기 실험 결과, 표 5에 표시된 바와 같이, LPS 농도 의존적으로 염증성 사이토카인 IL-1β 수준이 증가하고 WIN1001X 처리를 함으로써 IL-1β 가 감소하는 것을 확인하였다. 20 ㎍/mL LPS를 처리한 세포에서는 10, 25, 50 ㎍/mL 농도의 시료에서 IL-1β가 유의적으로 감소하였고, 50 ㎍/mL LPS를 처리한 세포에서는 25, 50, 100 ㎍/mL 농도의 시료에서 IL-1β가 유의적으로 감소하였다. 100 ㎍/mL LPS를 처리한 세포에서는 10, 25, 50, 100 ㎍/mL 농도의 시료에서 IL-1β가 유의적으로 감소하였고, 500 ㎍/mL LPS를 처리한 세포에서는 25, 50 ㎍/mL 농도의 시료에서 IL-1β가 유의적으로 감소하였다. 결론적으로 실시예 시료의 농도에 따라 IL-1β 분비가 저해되어 실시예 시료에 의한 강력한 항염증 효과를 확인할 수 있었다. As a result of the above experiment, as shown in Table 5, it was confirmed that the LPS concentration-dependent inflammatory cytokine IL-1β level increased and IL-1β decreased by WIN1001X treatment. In cells treated with 20 μg/mL LPS, IL-1β was significantly decreased in the samples at concentrations of 10, 25, and 50 μg/mL, and in cells treated with 50 μg/mL LPS, 25, 50, and 100 μg/mL IL-1β was significantly decreased in the samples at concentrations. In cells treated with 100 μg/mL LPS, IL-1β was significantly reduced in samples at concentrations of 10, 25, 50, and 100 μg/mL, and in cells treated with 500 μg/mL LPS, 25, 50 μg/mL IL-1β was significantly decreased in the samples at concentrations. In conclusion, IL-1β secretion was inhibited depending on the concentration of the sample sample, thereby confirming the strong anti-inflammatory effect of the sample sample.
㎍/mLWIN1001X
μg/mL
3-3.실험 과정 ( IL-10 수준 측정)3-3.Experimental process (IL-10 level measurement)
human monocyte 세포주(THP-1 세포, 한국세포주 은행)에 염증 유발 물질인 LPS 를 10, 20, 50, 100, 500 ㎍/mL 처리하여 염증모델을 준비하였다.An inflammation model was prepared by treating human monocyte cell lines (THP-1 cells, Korea Cell Line Bank) with 10, 20, 50, 100, and 500 μg/mL of LPS, an inflammatory substance.
LPS 처리 24시간 후에 세포상층액을 모아 항염증성 사이토카인인 IL-10 수준을 ELISA (IL-10 DuoSet ELISA, R&D Systems) 를 사용하여 측정하였다. 시료의 항염증 효과를 확인하기 위하여 THP-1 세포에 10, 25, 50, 100 ㎍/mL 시료를 4시간 처리하고, LPS를 처리하였다. LPS 처리 24시간 후에 세포상층액을 모아 항염증성 사이토카인(anti-inflammatory cytokine)인 IL-10의 수준을 측정하였다. After 24 hours of LPS treatment, the cell supernatant was collected and the level of IL-10, an anti-inflammatory cytokine, was measured using ELISA (IL-10 DuoSet ELISA, R&D Systems). In order to confirm the anti-inflammatory effect of the sample, 10, 25, 50, 100 μg/mL samples were treated in THP-1 cells for 4 hours, followed by LPS treatment. After 24 hours of LPS treatment, the cell supernatant was collected and the level of IL-10, an anti-inflammatory cytokine, was measured.
3-4.실험 결과( IL-10 수준 측정)3-4.Experiment result (IL-10 level measurement)
상기 실험 결과, LPS 농도 의존적으로 100 ㎍/mL 실시예 시료를 처리한 세포에서 IL-10 수준이 증가함을 확인하였다.(표 6)As a result of the above experiment, it was confirmed that the IL-10 level was increased in the cells treated with the 100 μg/mL Example sample in a LPS concentration-dependent manner. (Table 6)
실험예 4: 생약 혼합 추출물의 면역 세포에서의 오토파지 활성에 미치는 효과 시험 (in vitro)Experimental Example 4: Effect of herbal mixture extract on autophagy activity in immune cells (in vitro)
상기 실시예 시료의 면역 세포에서의 염증 인자 발현에 미치는 효과를 확인하기 위하여 하기와 같이 실험하였다. In order to confirm the effect of the sample of the Example on the expression of inflammatory factors in immune cells, an experiment was performed as follows.
4-1. 실험 과정 (오토파지 활성 인자 LC3B-1의 발현 효과 측정)4-1. Experimental procedure (measurement of the expression effect of autophagy activator LC3B-1)
항염증과 autophagy pathway의 상관성을 확인하기 위하여 human monocyte 세포주(THP-1 세포, 한국세포주 은행)에 염증 유발 물질인 LPS를 10, 20, 50, 100, 500 ㎍/mL 처리하여 염증모델을 준비하였다. In order to confirm the correlation between anti-inflammatory and autophagy pathways, an inflammation model was prepared by treating human monocyte cell lines (THP-1 cells, Korea Cell Line Bank) with 10, 20, 50, 100, and 500 μg/mL of LPS, an inflammatory substance. .
10, 25, 50, 100 ㎍/mL 실시예 시료를 처리한 후, 20, 100 ㎍/mL의 LPS를 처리하여 오토파지 마커 (autophagy marker)인 Beclin1, LC3B의 발현을 각각 anti-Beclin 1 antibody (Abcam)과 LC3B-antibody (Cell Signaling)를 사용한 immuno-blotting을 통해 확인하고, ChemiDocTMMPImagingSystem (Biorad)를 사용하여 감광된 필름을 스캔 (Image Lab 6.0.1, Biorad)함으로써 정량하였다. 10, 25, 50, and 100 μg/mL Example samples were treated, and then 20 and 100 μg/mL LPS were treated to inhibit the expression of autophagy markers, Beclin1 and LC3B, respectively, with anti-Beclin 1 antibody ( Abcam) and LC3B-antibody (Cell Signaling) were confirmed by immuno-blotting, and quantified by scanning the photosensitized film (Image Lab 6.0.1, Biorad) using ChemiDoc TM MPImagingSystem (Biorad).
4-2. 실험 결과 (오토파지 활성 인자 Beclin1과 LC3B-1의4-2. Experimental results (autophagy activators Beclin1 and LC3B-1 발현 효과 측정)expression effect measurement)
표 7에서와 같이 20 ㎍/mL의 LPS를 처리한 THP-1에서 LC3B-1의 발현양은 50, 100 ㎍/mL 수준의 실시예 시료를 처리한 군에서 증가하였고 100 ㎍/mL의 LPS를 처리한 THP-1에서 LC3B-1의 발현양은 시료농도에 농도 의존적으로 증가하였고, Beclin1은 50 ㎍/mL 시료 처리시 약간 증가하는 경향을 나타냈다.As shown in Table 7, the expression level of LC3B-1 in THP-1 treated with 20 μg/mL of LPS was increased in the group treated with the Example samples at 50 and 100 μg/mL, and LPS of 100 μg/mL was increased. In one THP-1, the expression level of LC3B-1 increased in a concentration-dependent manner with the sample concentration, and Beclin1 showed a tendency to slightly increase when the 50 μg/mL sample was treated.
Beclin/β-actinratio
Beclin/β-actin
LC3/β-actinratio
LC3/β-actin
Beclin/β-actinratio
Beclin/β-actin
LC3/β-actinratio
LC3/β-actin
실험예 5: 생약 혼합 추출물의 관절염 유도 래트 실험모델에서의 관절염 억제 효과 시험 (animal model test)Experimental Example 5: Arthritis inhibitory effect test in an arthritis-induced rat experimental model of herbal mixture extract (animal model test)
상기 실시예 시료의 관절염 유도 래트 실험모델에서의 관절염 억제 효과를 확인하기 위하여 실험하였다.An experiment was conducted to confirm the arthritis inhibitory effect of the sample of the above example in an arthritis-induced rat experimental model.
5-1. 실험 과정 5-1. experimental process
Monosodium iodoacetate(MIA)로 유도된 골관절염 래트 모델에서 실시예 시료의 효능을 비교 평가하기 위하여, 카톨릭 대학교 관절 면역 질환 T2B 구축 센터(박성환 MD, PhD, 서울 성모 병원 류마티스 내과, 서울특별시 서초구 반포대로 222 의생명산업연구원 5017호)에서 실험을 수행하였다.In order to compare and evaluate the efficacy of the sample samples in a rat model of monosodium iodoacetate (MIA) induced osteoarthritis, the Catholic University of Korea Joint Immune Disease T2B Construction Center (Sunghwan Park MD, PhD, Department of Rheumatology, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul, Korea) The experiment was conducted at the Institute of Biotechnology and Biotechnology No. 5017).
5-1-1. 시험 구성5-1-1. test configuration
5-1-1-1. 동물 실험 계획5-1-1-1. animal test plan
(1) 시험 동물: 래트 (Male Wistar rats, Central Lab. animal, Seoul, Korea)-7 ~ 8주령, 200 ~ 250g)를 구입하여 사육실의 환경을 항온 (21 ± 2℃), 항습 (50 ± 20%), 12시간 간격 (08:00 ~ 20:00)의 광주기로 일정한 조건을 유지하고 시험기간 동안 polysulfone cage에 2마리 또는 3마리의 사육밀도로 수용하여 관리하였다.(1) Test animals: Purchase rats (Male Wistar rats, Central Lab. animal, Seoul, Korea) - 7 to 8 weeks old, 200 - 250 g) and set the environment in the breeding room at constant temperature (21 ± 2 °C), constant humidity (50 ± 20%), a photoperiod of 12 hours (08:00 ~ 20:00) was maintained under constant conditions, and during the test period, 2 or 3 animals were housed in polysulfone cages and managed.
(2) 시험 방법: 3 ㎎/㎏의 Monosodium iodoacetate(MIA, I2512, Sigma, Poole, UK) 약물을 주사용 saline에 60 ㎎/㎖ 농도로 용해하여 실험개시 당일(day 0) 조제하였고, 군 분리 후 실험 개시일에 동물은 마취 챔버에 놓고, diethly ether를 이용하여 마취한 후에, MIA를 26.5 gauge 1cc 주사기를 사용하여 우측 슬관절 내로 무릎 관절의 슬개건 (infrapatellar ligament)을 경유하여 50μL(MIA 3 mg/body)를 주사하여 골관절염을 유도시켜 실험을 수행하였다.(2) Test method: 3 mg/kg of Monosodium iodoacetate (MIA, I2512, Sigma, Poole, UK) was dissolved in saline for injection at a concentration of 60 mg/ml, prepared on the day of the start of the experiment (day 0), and group separation On the day of the start of the experiment, the animals were placed in an anesthesia chamber, anesthetized using diethly ether, and then MIA was injected into the right knee joint using a 26.5 gauge 1cc syringe via the infrapatellar ligament of the knee joint 50 μL (MIA 3 mg/ body) was injected to induce osteoarthritis, and the experiment was performed.
(3) 투여 물질: 실시예 시료(3) Administrative substance: Example sample
(4) 양성 대조군 약물: Celecoxib (Hanlim Pharmaceutical Company, Seoul, Korea) (4) Positive control drug: Celecoxib (Hanlim Pharmaceutical Company, Seoul, Korea)
(5) 투여방법: 골관절염 유도 3일 후를 기점으로 1일 1회 경구 투여(5) Administration method: Oral administration once a day starting 3 days after osteoarthritis induction
(6) 시험군 구성 (표 8 참조): 실험군은 표 8에 표시하였다.(6) Test group composition (see Table 8): The test group is shown in Table 8.
5-1-1-2. 투여방법 및 시험기간5-1-1-2. Administration method and test period
(1) 투여방법(1) Administration method
MIA로 골관절염을 유발시킨 후, 시험물질 투여군(G2, G3)은 시험물질을 정해진 용량에 따라 vehicle(saline)에 균질화한 후 1 mL을 1일 1회 경구 투여를 실시하였다. After osteoarthritis was induced by MIA, the test substance administration group (G2, G3) was orally administered with 1 mL once a day after homogenizing the test substance in a vehicle (saline) according to a predetermined dose.
부형제 대조군(G1)은 동량의 vehicle만을 시험물질 투여와 동일한 일정으로 1일 1회 경구 투여를 실시하였다. 양성대조군(G4)은 정해진 용량에 따라 vehicle에 균질화한 후 1일 1회 경구 투여를 실시하였다. For the excipient control group (G1), only the same amount of vehicle was orally administered once a day on the same schedule as the test substance administration. The positive control group (G4) was orally administered once a day after homogenization in the vehicle according to the prescribed dose.
(2) 시험기간(2) Test period
래트 수는 각 군당 6마리로 총 24마리이며, 각각의 시험물질과 양성대조물질은 정해진 시간에 맞추어 경구 투여하였다.The number of rats was 6 in each group, totaling 24, and each test substance and positive control substance was orally administered at a predetermined time.
5-2. 평가항목5-2. Evaluation items
5-2-1. 통증 역치 측정5-2-1. pain threshold measurement
동물 (Male Wistar rats)의 발에 가해지는 힘이 일정한 시간에 걸쳐 서서히 증가하는 장치인 dynamic plantar aesthesiometer(Ugo Basile, 37400, Comerio, Italy)를 이용하여 통증 역치 (nociceptive latency threshold) 측정을 Von Frey hair 평가 방법을 이용하여 실험을 수행하였다 (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832). The nociceptive latency threshold was measured using a dynamic plantar aesthesiometer (Ugo Basile, 37400, Comerio, Italy), which is a device in which the force applied to the paw of an animal (Male Wistar rats) is gradually increased over a certain period of time by Von Frey hair. An experiment was performed using the evaluation method (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832).
측정 전 동물은 하부가 wire mesh bench로 이루어진 아크릴 박스 안에 두고 5분간 적응시켰다.Before measurement, the animals were placed in an acrylic box with the lower part of a wire mesh bench and acclimatized for 5 minutes.
동통 역치는 각 동물의 우측 뒷발바닥 중심부에 metal filament를 이용하여 10초에 걸쳐 0에서 50 g까지 서서히 힘을 가하여 동물이 발을 회피하는 하는 반응(paw withdrawal behavior)을 나타내는 무게를 측정하였다.For the pain threshold, the weight indicating the paw withdrawal behavior of the animal was measured by gradually applying a force from 0 to 50 g over 10 seconds using a metal filament in the center of the right hind paw of each animal.
조직 손상을 피하기 위하여 cut-off threshold는 50 g으로 설정하였으며 측정 시기는 정상 대조군(G1), 실험군(G2, G3), 양성대조군(G4)에서 MIA 투여 후 관절염이 유발되기 전(day 0)에 측정하여 기저(baseline)값을 구하였고, 시험물질 투여 전 (day3)에도 동일하게 값을 측정하였으며, 이후 관절강 내 시험물질 투여하여 매주 1회 일정시각에 값을 측정하였다.To avoid tissue damage, the cut-off threshold was set to 50 g, and the measurement period was before arthritis (day 0) after MIA administration in the normal control group (G1), experimental group (G2, G3), and positive control group (G4). The baseline value was obtained by measuring, and the same value was measured before the test substance administration (day3), and then the test substance was administered intra-articularly and the value was measured once a week at a certain time.
동통 역치에 대한 결과는 족부회피에 걸리는 시간(paw withdrawal latency, sec)와 족부회피 역치 (paw withdrawal threshold, g)으로 산출하였다. Results for the pain threshold were calculated as the paw withdrawal latency (sec) and the paw withdrawal threshold (g).
5-2-2. 통증 측정 결과5-2-2. Pain measurement results
통증의 측정결과, 실시예 시료는 100, 150 mg/kg 투여군에서 담체(Vehicle) 대비 통증이 억제되는 효력을 보였으며, 용량 의존 경향(Dose dependency)도 확인하였다.(표 9-10)As a result of the measurement of pain, the Example sample showed the effect of inhibiting pain compared to the carrier in the 100 and 150 mg/kg administration groups, and also confirmed the dose dependency. (Table 9-10)
100 ㎎/㎏ (s)WIN1001X
100 mg/kg (s)
150 ㎎/㎏ (s)WIN1001X
150 mg/kg (s)
30 ㎎/㎏ (s)Celecoxib
30 mg/kg (s)
100 ㎎/㎏ (g)WIN1001X
100 mg/kg (g)
150 ㎎/㎏ (g)WIN1001X
150 mg/kg (g)
30 ㎎/㎏ (g)Celecoxib
30 mg/kg (g)
5-2-2. 체중 부하(Weight bearing) 측정5-2-2. Weight bearing measurement
5-2-2-1. 체중 부하 측정시험5-2-2-1. weight bearing test
편측으로 관절염이 유발된 뒷다리 무릎의 동통에 의해 발생하는 정상 뒷다리(좌측)와 관절염 유발 뒷다리(우측) 사이의 체중 부하(또는 체중 분포) 변화를 측정하는 실험으로서, 체중부하를 측정하는 장치인 incapacitance meter(Model 600, IITC, USA)를 이용하여 양쪽 뒷발의 하중을 각각 문헌에 기재된 방법에 따라 측정하였다 (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832).This is an experiment to measure the change in weight bearing (or weight distribution) between the normal hindlimb (left) and the arthritis-induced hindlimb (right) caused by pain in the knee of the hindlimb induced by unilateral arthritis. Incapacitance, a device for measuring weight bearing Using a meter (Model 600, IITC, USA), the load on both hind paws was measured according to the method described in the literature (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832).
동물의 발을 딛는 자세에 따라서 하중이 변화할 수 있기 때문에 동물이 홀더 내에 정확하게 위치하여 양발을 대칭으로 디딜 수 있도록 고정시키고, 이에 고정 담당자는 1인으로 정하여 최대한으로 오차를 줄이도록 하였다.Since the load can change depending on the animal's foot posture, the animal is accurately positioned in the holder and fixed so that both feet can step symmetrically.
각 동물이 홀더 내에 정확히 위치했을 때 기계를 작동하되 측정시간은 5초로 총 2회씩 측정하였다. 이 값에 대한 평균값은 각 발의 weight bearing(g) 수치로 하였다.When each animal was correctly positioned in the holder, the machine was operated, but the measurement time was 5 seconds, and measurements were made twice in total. The average value of this value was set as the weight bearing (g) value of each foot.
측정 시기는 정상 대조군(G1), 실험군(G2, G3), 양성대조군(G4)에서 MIA 투여에 의한 관절염 유발 전(day 0)에 측정하여 기저(baseline) 값을 구한 후, 시험물질 투여 전(day3)에 측정하여 군 분리 후 주 2회 일정 시각에 측정하였다.The measurement period was measured before the induction of arthritis by MIA administration (day 0) in the normal control group (G1), experimental group (G2, G3), and positive control group (G4) to obtain a baseline value, and then before administration of the test substance ( Day 3) was measured twice a week at a fixed time after group separation.
체중 부하 측정시험의 결과를 하기 수학식 1의 계산식을 이용하여 weight bearing ratio로 전환하여 분석을 실시하였다. The result of the weight bearing measurement test was converted into a weight bearing ratio using the formula of Equation 1 below and analyzed.
5-2-2-2. 체중 부하 측정 실험 결과5-2-2-2-2. Weight bearing test results
상기 체중 부하(Weight bearing) 측정실험 결과, Vehicle 대비 전체 약물 투여군에서 양발의 균형능력(balance) 개선이 일어남을 확인하였다.(표 11)As a result of the weight bearing measurement experiment, it was confirmed that the balance ability of both feet was improved in the total drug administration group compared to the vehicle. (Table 11)
100 ㎎/㎏ (%)WIN1001X
100 mg/kg (%)
150 ㎎/㎏ (%)WIN1001X
150 mg/kg (%)
30 ㎎/㎏ (%)Celecoxib
30 mg/kg (%)
5-2-3. 조직학적 분석 (Micro-CT) 실험5-2-3. Histological analysis (Micro-CT) experiments
골관절염 골 손상 억제 효과 분석을 위해 조직학적 분석 (Micro-CT) 실험을 문헌에 기재된 방법을 이용하여 실험을 수행하였다 (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832 ).Histological analysis (Micro-CT) experiment was performed to analyze the inhibitory effect on osteoarthritis bone damage. Experiments were performed using the method described in the literature (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832).
5-2-3-1. 골관절염 골 손상 억제 효과시험5-2-3-1. Osteoarthritis Bone Damage Inhibition Effect Test
동물 (Male Wistar rats)을 희생 후 MIA 및 시험물질을 투여한 랫트의 오른쪽 슬관절을 포르말린으로 고정한 후에 animal scanner (SKYSCAN1272 ex-vivo micro-CT, Bruker micro CT, Belgium) 로 X-ray source (70kV, 142uA, Al 0.5mm 필터사용, rotation step 0.6°)를 사용하여 Pixel resolution 15μm에서 micro-CT 촬영을 진행하였다. 단면생성(NRecon), 단면회전(DataViewer), 분석(CTAn), Volumerendering생성(CTVox), surface rendering (CTAn+CTVol)을 측정했다. After sacrificing the animals (Male Wistar rats), the right knee joint of the rats administered MIA and the test substance was fixed with formalin, and then X-ray source (70kV, Micro-CT imaging was performed at a pixel resolution of 15 μm using 142uA, Al 0.5mm filter, rotation step 0.6°). Section creation (NRecon), section rotation (DataViewer), analysis (CTAn), volumerendering generation (CTVox), and surface rendering (CTAn+CTVol) were measured.
슬관절의 femur 부위를 중심으로 골표면 손상 정도를 분석하였으며, 군당 3수씩 촬영하였다. The degree of bone surface damage was analyzed focusing on the femur area of the knee joint, and three shots were taken per group.
5-2-3-2. 골관절염 골 손상 억제 효과 결과5-2-3-2. Osteoarthritis Bone Damage Inhibitory Effect Results
상기 실험결과, Micro-CT 촬영결과에서 담체군(Vehicle group) 대비 실시예 시료(WIN1001X ) 100 mg/kg 과 150 mg/kg 군에서 골 표면 손상이 효과적으로 억제되었음을 확인하였다.(표 12)As a result of the above experiment, it was confirmed that the bone surface damage was effectively inhibited in the 100 mg/kg and 150 mg/kg groups of the Example sample (WIN1001X) compared to the carrier group in the Micro-CT imaging results. (Table 12)
100 ㎎/㎏ WIN1001X
100 mg/kg
150 ㎎/㎏ WIN1001X
150 mg/kg
30 ㎎/㎏ Celecoxib
30 mg/kg
5-2-4. 조직 병리 분석 실험5-2-4. histopathology assay
조직 병리 분석 실험을 문헌에 기재된 방법을 이용하여 실험을 수행하였다 (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832 ).Histopathology analysis experiments were performed using methods described in the literature (Kwon JY et al., Sci Rep. 2018 Sep 14;8(1):13832).
5-2-4-1. 조직 병리 분석5-2-4-1. histopathology analysis 시험exam
동물(Male Wistar rats) 을 희생 후 MIA 및 시험물질을 투여한 랫트의 오른쪽 슬관절을 탈회하고 만든 절편으로 safranin O 염색을 진행하였다. After sacrificing animals (Male Wistar rats), safranin O staining was performed with the sections made by decalcifying the right knee joint of the rats administered with MIA and the test substance.
슬관절의 femur부위를 중심으로 현미경으로 200배율 촬영을 진행하였으며(표 11), 기존 문헌에 기재된 Total Mankin score (Bulstra SK et al., 1989, Clin Orthop Relat Res: 294-302.) 및 OARSI score (Pritzker K.P.H. et al., 2006, Osteoarthritis Cartilage 14:13-29) 를 수치화하여 평가하였다.(표 13)200x magnification was taken under a microscope focusing on the femur of the knee joint (Table 11), and the Total Mankin score (Bulstra SK et al., 1989, Clin Orthop Relat Res: 294-302.) and OARSI score ( Pritzker KPH et al., 2006, Osteoarthritis Cartilage 14:13-29) were evaluated numerically (Table 13).
100 ㎎/㎏ WIN1001X
100 mg/kg
150 ㎎/㎏ WIN1001X
150 mg/kg
30 ㎎/㎏ Celecoxib
30 mg/kg
5-2-4-2. 조직 병리 분석5-2-4-2. histopathology analysis 시험 결과Test result
표 14에 표시된 바와 같이, Total Mankin score와 OARSI score 모두 부형제 대조군 대비 WIN-1001X 100 mg/kg 군에서 가장 큰 감소가 확인되었으며, WIN-1001X 100, 150 mg/kg, Celecoxib 30 mg/kg 군에서 통계적으로 유의하게 감소하였다 (표 14; 부형제 대조군 대비 *P <0.05, **P <0.01, ***P <0.005).As shown in Table 14, both the Total Mankin score and the OARSI score showed the greatest reduction in the WIN-1001X 100 mg/kg group compared to the excipient control group, and in the WIN-1001X 100, 150 mg/kg, and Celecoxib 30 mg/kg group. There was a statistically significant decrease (Table 14; * P <0.05, ** P <0.01, *** P <0.005 vs. excipient control).
또한 Safranin O 결과에서 Vehicle group 대비 시료(WIN1001X) 100 mg/kg, 150 mg/kg 투여군에서 OARSI score 및 Mankin score의 감소를 보였다.(표 14)In addition, Safranin O results showed a decrease in OARSI score and Mankin score in the sample (WIN1001X) 100 mg/kg, 150 mg/kg administration group compared to the Vehicle group (Table 14).
100 ㎎/㎏ WIN1001X
100 mg/kg
150 ㎎/㎏ WIN1001X
150 mg/kg
30 ㎎/㎏ Celecoxib
30 mg/kg
이상의 결과로 보아 이번 시험에서 실시예 시험물질 ("WIN-1001X")은 퇴행성질환 가운데 대표적인 골관절염 질환 동물모델에서 부형제 대조군 대비 실시예 시험물질 ("WIN-1001X") 100, 150 mg/kg 군에서 통증 역치 및 체중 부하의 개선을 보였으며, 그와 일치하게 micro-CT에서 골표면 손상 억제 및 조직병리에서도 부형제 대조군 대비 연골보호 효과를 확인하였다. Based on the above results, the Example test substance ("WIN-1001X") in this test was compared to the excipient control group in an animal model of osteoarthritis, a representative degenerative disease, in the 100 and 150 mg/kg group. The pain threshold and weight bearing were improved. Consistent with this, micro-CT showed chondroprotective effects compared to the excipient control group in the inhibition of bone surface damage and histopathology.
5-3. 통계처리5-3. Statistical processing
모든 데이터는 평균과 표준편차(mean±SD)로 표시하였으며, 통계학적 유의성 검증은 GraphPad PRISM Version 5.0 (GraphPad Software, USA) 분석프로그램의 two-way ANOVA, one-way ANOVA를 이용하며, P < 0.05 이하인 경우 유의성 있는 것으로 판정하였음.All data were expressed as mean and standard deviation (mean±SD), and statistical significance was verified using two-way ANOVA and one-way ANOVA of GraphPad PRISM Version 5.0 (GraphPad Software, USA) analysis program, P < 0.05 The following cases were judged to be significant.
하기에 본 발명의 추출물을 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, a formulation example of a composition containing the extract of the present invention will be described, but the present invention is not intended to be limited thereto, but only to be described in detail.
제제예 1. 산제의 제조Formulation Example 1. Preparation of powder
WIN-1001X 20 mg WIN-1001X 20 mg
유당 100 mgLactose 100 mg
탈크 10 mgtalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다. The above ingredients are mixed and filled in an airtight bag to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2. Preparation of tablets
WIN-1002X 10 mgWIN-1002X 10 mg
옥수수전분 100 mg100 mg cornstarch
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.
제제예 3. 캡슐제의 제조 Formulation Example 3. Preparation of capsules
WIN-1003X 10 mgWIN-1003X 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mg0.2 mg magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
제제예 4. 주사제의 제조Formulation Example 4. Preparation of injection
WIN-1004X 10 mgWIN-1004X 10 mg
만니톨 180 mgmannitol 180 mg
주사용 멸균 증류수 2974 mg2974 mg of sterile distilled water for injection
Na2HPO4,12H2O 26 mgNa 2 HPO 4 ,12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2㎖) 상기의 성분 함량으로 제조한다.According to a conventional method for preparing injections, the content of the above ingredients per 1 ampoule (2 ml) is prepared.
제제예 5. 액제의 제조Formulation Example 5. Preparation of liquid formulation
WIN-1005X 20 mgWIN-1005X 20 mg
이성화당 10 g10 g isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water appropriate amount
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.According to a conventional liquid preparation method, each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 ml by adding purified water, and then filled in a brown bottle. Sterilize to prepare a solution.
제제예 6. 건강 식품의 제조Formulation Example 6. Preparation of health food
WIN-1006X 1000 ㎎WIN-1006X 1000 mg
비타민 혼합물 적량appropriate amount of vitamin mixture
비타민 A 아세테이트 70 ㎍70 μg vitamin A acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 ㎎Vitamin C 10 mg
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 ㎎Nicotinamide 1.7 mg
엽산 50 ㎍50 μg folic acid
판토텐산 칼슘 0.5 ㎎Calcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture appropriate amount
황산제1철 1.75 ㎎Ferrous sulfate 1.75 mg
산화아연 0.82 ㎎Zinc oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎Dibasic calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium citrate 90 mg
탄산칼슘 100 ㎎Calcium carbonate 100 mg
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.The composition ratio of the above vitamin and mineral mixture is a composition that is relatively suitable for health food in a preferred embodiment, but the mixing ratio may be arbitrarily modified. , to prepare granules, and can be used for preparing health food compositions according to a conventional method.
제제예 7. 건강 음료의 제조Formulation Example 7. Preparation of a health drink
WIN-1001X 1000 ㎎WIN-1001X 1000 mg
구연산 1000 ㎎citric acid 1000 mg
올리고당 100 g100 g of oligosaccharides
매실농축액 2 g2 g of plum concentrate
타우린 1 g1 g taurine
정제수를 가하여 전체 900 ㎖Total 900 ml with purified water
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above ingredients according to a conventional health drink manufacturing method, stirring and heating at 85° C. for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2L container, sealed and sterilized, and then refrigerated. used in the manufacture of health beverage compositions of
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용 용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demand class, demanding country, and use.
<110> PARK, Ok Nam MEDI HELP LINE Co., LTD. <120> a composition comprising the extract of combined herbs comprising Longanae Arillus for the treatment or prevention of arthritis <130> DIF/2021-02-006/EK <150> KR 10-2020-0040950 <151> 2020-04-03 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 19 <212> DNA <213> Homo sapiens <400> 1 agcccagaac actggtctc 19 <210> 2 <211> 21 <212> DNA <213> Homo sapiens <400> 2 actcaggatt tcaatggtgc c 21 <210> 3 <211> 23 <212> DNA <213> Homo sapiens <400> 3 tatgagtggg accaaaagta ccg 23 <210> 4 <211> 22 <212> DNA <213> Homo sapiens <400> 4 gggattgaag gttaggctct gg 22 <210> 5 <211> 22 <212> DNA <213> Homo sapiens <400> 5 tcctgaacct gagtagagac ac 22 <210> 6 <211> 19 <212> DNA <213> Homo sapiens <400> 6 tgctgcttgt agtggctgg 19 <210> 7 <211> 20 <212> DNA <213> Homo sapiens <400> 7 ctccagggac aggatatgga 20 <210> 8 <211> 20 <212> DNA <213> Homo sapiens <400> 8 tctttcaaca cgcaggacag 20 <110> PARK, Ok Nam MEDI HELP LINE Co., LTD. <120> a composition comprising the extract of combined herbs comprising Longanae Arillus for the treatment or prevention of arthritis <130> DIF/2021-02-006/EK <150> KR 10-2020-0040950 <151> 2020-04-03 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 19 <212> DNA <213> Homo sapiens <400> 1 agcccagaac actggtctc 19 <210> 2 <211> 21 <212> DNA <213> Homo sapiens <400> 2 actcaggatt tcaatggtgc c 21 <210> 3 <211> 23 <212> DNA <213> Homo sapiens <400> 3 tatgagtggg accaaaagta ccg 23 <210> 4 <211> 22 <212> DNA <213> Homo sapiens <400> 4 gggattgaag gttaggctct gg 22 <210> 5 <211> 22 <212> DNA <213> Homo sapiens <400> 5 tcctgaacct gagtagagac ac 22 <210> 6 <211> 19 <212> DNA <213> Homo sapiens <400> 6 tgctgcttgt agtggctgg 19 <210> 7 <211> 20 <212> DNA <213> Homo sapiens <400> 7 ctccagggac aggatatgga 20 <210> 8 <211> 20 <212> DNA <213> Homo sapiens <400> 8 tctttcaaca cgcaggacag 20
Claims (9)
상기 건강기능식품은 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽제, 티백제, 침출차, 또는 건강 음료 형태인 건강기능식품.6. The method of claim 5,
The health functional food is a health functional food in the form of powder, granule, tablet, capsule, pill, suspension, emulsion, syrup, tea bag, leached tea, or health drink.
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KR20150115638A (en) * | 2014-04-04 | 2015-10-14 | (주)내츄럴엔도텍 | Compositions Comprising Extracts of Longan Arillus as Active Ingredients for Preventing or Treating an Osteoporosis |
KR20160054681A (en) * | 2014-11-06 | 2016-05-17 | 주식회사 엘지생활건강 | Composition for promoting synthesis of hyaluronic acid comprising Polygala tenuifolia Willd extracts and the use thereof |
KR20190100880A (en) * | 2018-02-21 | 2019-08-29 | 경북대학교 산학협력단 | Composition for preventing, treating or improving obesity or obesity-related disease comprising extracts of Angelica tenuissima |
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KR20150115638A (en) * | 2014-04-04 | 2015-10-14 | (주)내츄럴엔도텍 | Compositions Comprising Extracts of Longan Arillus as Active Ingredients for Preventing or Treating an Osteoporosis |
KR20160054681A (en) * | 2014-11-06 | 2016-05-17 | 주식회사 엘지생활건강 | Composition for promoting synthesis of hyaluronic acid comprising Polygala tenuifolia Willd extracts and the use thereof |
KR20190100880A (en) * | 2018-02-21 | 2019-08-29 | 경북대학교 산학협력단 | Composition for preventing, treating or improving obesity or obesity-related disease comprising extracts of Angelica tenuissima |
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