KR101920396B1 - Composition comprising extract of Camellia japonica for treating hyperuricemia - Google Patents
Composition comprising extract of Camellia japonica for treating hyperuricemia Download PDFInfo
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- KR101920396B1 KR101920396B1 KR1020170011171A KR20170011171A KR101920396B1 KR 101920396 B1 KR101920396 B1 KR 101920396B1 KR 1020170011171 A KR1020170011171 A KR 1020170011171A KR 20170011171 A KR20170011171 A KR 20170011171A KR 101920396 B1 KR101920396 B1 KR 101920396B1
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- KR
- South Korea
- Prior art keywords
- camellia
- extract
- hyperlipidemia
- uric acid
- present
- Prior art date
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Abstract
본 발명은 동백나무 잎 추출물을 유효성분으로 포함하는 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료용 조성물에 관한 것으로, 더욱 상세하게는 동물실험으로 혈중요산의 저하 효과를 나타내는 동백나무 잎 추출물을 유효성분으로 포함하는 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료용 조성물에 관한 것이다. 본 발명의 동백나무 잎 추출물은 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료용 기능성 식품, 약제학적 조성물 등에 유용하게 이용될 수 있다.The present invention relates to a composition for preventing and treating hyperlipidemia and hyperlipidemia-related metabolic disorders comprising an extract of Camelliaceae as an active ingredient, and more particularly to a composition for preventing and treating hyperlipidemia-related metabolic disorders, And a composition for preventing and treating hyperlipidemia-related metabolic disorders. The camellia officinal leaf extract of the present invention can be usefully used for functional foods and pharmaceutical compositions for the prevention and treatment of hyperlipidemia and hyperlipidemia-related metabolic disorders.
Description
본 발명은 동백나무 추출물을 유효성분으로 포함하는 고요산혈증 치료용 조성물에 관한 것이다.The present invention relates to a composition for treating hyperuricemia comprising an extract of Camellia sinensis as an active ingredient.
고요산혈증(Hyperuricemia)이란 혈액 내에 요산의 농도가 비정상적으로 증가되어 있는 것을 말한다. 이는 혈청에서 모노소디움 요산염의 농도가 제한된 용해도의 한계를 넘을 때 발생한다. 37℃에서 혈장의 요산 포화도는 약 7mg/dL이며, 이 농도를 넘으면 물리화학적으로 과포화 상태가 된다. 혈청 요산 농도는 정상인의 평균 혈청 요산 농도보다 +2 표준편차를 초과한 경우에 상대적으로 높은 것으로 알려져 있으며, 대부분의 역학 조사에서 남성의 상위 한계는 6.8 내지 7.0mg/dL, 여성은 6.0mg/dL이다. 이러한 이유 때문에 고요산혈증의 실질적인 상위 한계 수준은 7.0mg/dL 이상인 경우로 정의되고 있다. Hyperuricemia refers to an abnormally increased concentration of uric acid in the blood. This occurs when the concentration of monosodium iodate in the serum exceeds the limited solubility limit. At 37 캜, the uric acid saturation of plasma is about 7 mg / dL, and if it exceeds this concentration, it becomes physico-chemically supersaturated. The serum uric acid concentration is known to be relatively high when the serum uric acid concentration is higher than the normal serum uric acid concentration of normal persons by more than +2 standard deviation. In most epidemiological studies, the upper limit of the male is 6.8 to 7.0 mg / dL, to be. For this reason, the actual upper limit level of hyperlipidemia is defined as 7.0 mg / dL or more.
고요산혈증 및 고요산혈증 관련 대사 장애들은 미국에서 3백만 명 내지 5백만 명에게서 발생하고 있으며, 아프리카계 미국인은 백인보다 고요산혈증 관련 대사 장애를 가질 가능성이 2배이다. 또한, 고요산혈증은 중국, 일본, 폴리네시아 및 도시 사하라 이남 아프리카에서 만연하고 있다.Hyperlipidemia and hyperlipidemia-related metabolic disorders occur in 3 to 5 million people in the United States, and African Americans are twice as likely to have hypercalcemia-related metabolic disorders than white people. Hyperuricemia is also prevalent in China, Japan, Polynesia and sub-Saharan Africa.
고요산혈증을 위한 치료제는, 1) 크산틴 산화효소 억제제(알로퓨리놀, 페북소스타트), 2) 요산 배설 촉진제(설핀피라존, 벤즈브로마론, 프로베네시드), 3) 요산염 산화효소(페글로티카제, 푸리카제, 라스부리카제, 페길화 우리카제), 4) 요산염 저하제(페노피브레이트) 등이 있으며, 고요산혈증 관련 대사 장애를 위한 치료제는, 1) 비스테로이드성 항염증 약물(NSAID; 인도메타신, 이부프로펜), 2) 코르티코스테로이드, 3) 항염증제(콜히친) 등이 있다. 이러한 치료제들은 혈중 요산 농도를 저하시키는 기능을 하며, 치료제를 이용하여 혈중 요산 수준을 정상 범위로 회복시키면, 고요산혈증과 관련한 기타 대사 장애들을 예방할 수 있다.2) uric acid excretion promoters (sulfinpyrazone, benzbromarone, provenesid); 3) uric acid oxidase (such as pegllo or erythrocyte); (NSAIDs), such as NSAIDs, have been used for the treatment of hyperlipidemia-related metabolic disorders, including: 1) nonsteroidal antiinflammatory drugs (NSAIDs); 2) corticosteroids, and 3) anti-inflammatory drugs (colchicine). These treatments function to lower the uric acid level in the blood, and by using therapeutic agents, restoring the blood uric acid level to the normal range can prevent other metabolic disorders related to hyperuricemia.
그러나, 고요산혈증 또는 고요산혈증 관련 대사 장애에 이용하고 있는 치료제들 중의 다수는 여러 가지 부작용들이 알려져 있다. 예를 들면, 알로퓨리놀과 같은 크산틴 산화효소 억제제는 과민성 맥관염, 스티븐스-존슨 증후군, 탈락성 피부염, 재생불량성 빈혈 및 간 기능부전과 관련이 있다. 프로베네시드 및 벤즈브로마론과 같은 요산 배설 촉진제는 위장 장애, 요로 결석증 및 특이체질 환자에서의 전격성 간부전과 같은 부작용이 있다. 또한, 비스테로이드성 항염증 약물(NSAID)의 장기적 사용은 궤양성 천공 및 상부 위장관 출혈을 포함하는 부작용을 초래할 수 있다.However, many of the therapeutic agents used in hyperlipidemia or hyperlipidemia-related metabolic disorders are known to have various side effects. For example, xanthine oxidase inhibitors such as allophilinol are associated with hypersensitivity vasculitis, Stevens-Johnson syndrome, deciduous dermatitis, aplastic anemia and liver failure. Urinary excretion enhancers, such as probenecid and benzbromarone, have side effects such as gastrointestinal disorders, urinary tract necrosis, and fulminant hepatic insufficiency in patients with idiopathic hypertension. In addition, long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) can lead to side effects, including ulcerative perforation and upper gastrointestinal bleeding.
따라서, 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료를 위한 신규한 제제들의 개발이 여전히 요구되어지고 있으며, 그 중 천연물을 이용한 연구들이 진행되고 있다. 대한민국 공개특허 제10-2015-0135037호에는 고요산혈증 또는 통풍에 유효한 섬쑥부쟁이 추출물, 이의 분획물 및 이로부터 분리된 활성화합물이 개시되어 있으며, 대한민국 공개특허 제10-2010-0117979호에는 흑양파 추출물을 유효성분으로 포함하는 통풍 또는 고요산혈증 예방 및 치료용 조성물이 개시되어 있다.Therefore, the development of novel agents for the prevention and treatment of hyperlipidemia and hyperlipidemia-related metabolic disorders is still required, and studies using natural materials are underway. Korean Patent Laid-Open Publication No. 10-2015-0135037 discloses an extract of Mulberry japonica extract effective for hyperuricemia or gout, fractions thereof and active compounds isolated therefrom, and Korean Patent Publication No. 10-2010-0117979 discloses a black onion extract As an active ingredient, for the prevention and treatment of gout or hyperuricemia.
동백나무는 우리나라를 비롯하여 중국과 일본에 자생하는 차나무과(Theaceae)에 속하는 약용식물로서 약 200여종이 알려져 있다. 이 중 약 70여종이 동백아속(亞屬), 즉 동백(Camellia japonica)과 애기동백(C. sasanqua)의 근연종이다. 한국에 자생하는 동백나무는 1종(Camellia japonica L.)으로 동백나무과(Theaceae), 동백속(Camelliae)의 교목이다. 동백나무의 잎은 건선, 인후통증, 화상에 효능이 있고, 가지와 열매는 머리비듬, 보혈, 비출혈(鼻出血), 어혈, 연골증, 월경이상, 이뇨, 인후통증, 장출혈, 종독(腫毒), 타박상, 토혈과 각혈, 행혈, 화상에 효과가 있다고 알려져 있다. 또한, 이전 연구에서는 동백나무 잎과 꽃에는 항균, 항산화, 및 항염증 활성을 갖는 트리테르펜(triterpene), 플라보노이드, 탄닌 및 지방산이 함유되어 있는 것으로 보고하였다. 이러한 동백나무는 오래 전부터 민간에서 출혈과 염증 등의 질환을 치료하는데 사용해왔다. 뿐만 아니라, 우리나라에서는 2004년 이후에 동백나무를 식품소재로 개발하여, 2007년에는“동백차”로 불리는 다류 식품으로 상품화하기도 하였다.Camellia is a medicinal plant belonging to the genus (Theaceae) which is native to China and Japan, including Korea. About 200 species are known. About 70 species are related to Camellia japonica , Camellia japonica and C. sasanqua . Camellia japonica L. is a species of Camellia japonica L. , which is a species of Camelliae and Camelliae. Leaves of Camellia have an effect on psoriasis, throat pain and burns. Branches and fruits are dandruff, blood, hemorrhoids, hemorrhoids, cartilage, menstrual disorders, diuresis, throat pain, intestinal bleeding, Poison), contusions, blood and blood, blood, and burns are known to be effective. In addition, previous studies reported that camellia leaves and flowers contain triterpene, flavonoids, tannins, and fatty acids with antimicrobial, antioxidant, and anti-inflammatory activities. These camellia have long been used to treat diseases such as bleeding and inflammation in the private sector. In addition, Korea has developed camellia as a food material after 2004, and commercialized it as a "tea of camellia" in 2007.
이에 본 발명자들은 혈중 요산 농도를 저하시키는 효과를 가지면서 인체 부작용이 적은 물질을 찾고자 예의 연구한 결과, 동백나무 추출물이 혈중 요산 농도를 저하시키는 기능을 가진다는 사실을 발견하였다. 그 결과 본 발명을 완성하게 되었다.Accordingly, the inventors of the present invention have found that a camellia extract has a function of lowering the uric acid concentration in blood as a result of studying a substance having a low uric acid concentration in the blood and a low human side effect. As a result, the present invention has been completed.
따라서, 본 발명의 목적은 동백나무 잎 추출물을 유효성분으로 포함하는 고요산혈증을 치료하기 위한 조성물을 제공하는 것이다. Accordingly, an object of the present invention is to provide a composition for treating hyperuricemia comprising an extract of Camelliaceae as an active ingredient.
본 발명의 다른 목적은 동백나무 잎 추출물을 유효성분으로 포함하는 고요산혈증의 예방 및 개선용 기능성 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a functional food composition for prevention and improvement of hyperlipidemia comprising an extract of Camelliaceae as an active ingredient.
본 발명의 또 다른 목적은 동백나무 잎 추출물을 유효성분으로 포함하는 고요산혈증을 치료하기 위한 약학 조성물을 제공하는 것이다.It is still another object of the present invention to provide a pharmaceutical composition for treating hyperlipidemia comprising an extract of Camelliaceae as an active ingredient.
하나의 양태로서, 본 발명은 동백나무 추출물을 유효성분으로 포함하는 고요산혈증을 예방 및 치료하기 위한 조성물을 제공한다.In one aspect, the present invention provides a composition for preventing and treating hyperuricemia, which comprises a camellia extract as an active ingredient.
본 발명에 있어서, 동백나무(Camellia japonica) 추출물은 동백나무의 잎, 줄기, 꽃, 뿌리, 열매, 종자, 및 이들의 혼합물로 이루어진 그룹으로부터 선택되는 하나 이상으로부터 추출한 추출물을 의미한다. 바람직하게는 동백나무 잎의 추출물을 의미한다. 또한, 상기 추출물은 통상의 방법에 의하여 동백나무로부터 추출한 추출액뿐만 아니라 이의 건조 분말 또는 이를 이용하여 제형화된 모든 형태를 말한다.In the present invention, the Camellia japonica extract means an extract extracted from at least one selected from the group consisting of camellia leaves, stem, flower, root, fruit, seed, and mixture thereof. Preferably an extract of camellia leaves. In addition, the above-mentioned extract refers not only to an extract extracted from a camellia tree by a conventional method but also to its dry powder or any form formulated using it.
특히 바람직하게, 본 발명의 동백나무 추출물은 물 또는 유기용매를 사용하여 추출할 수 있는데, 추출한 액은 액체 형태로 사용하거나 또는 농축 및/또는 건조하여 사용할 수 있다. 상기 유기 용매는 메탄올, 에탄올, 이소프로판올, 부탄올, 에틸렌, 아세톤, 헥산, 에테르, 클로로포름, 에틸아세테이트, 부틸아세테이트, 디클로로메탄, N,N-디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 1,3-부틸렌글리콜, 프로필렌글리콜 또는 이들의 혼합용매이며, 추출물의 유효성분이 파괴되지 않거나 최소화된 조건에서 실온 또는 가온하여 추출할 수 있다. 바람직하게 에탄올을 용매로 사용한 추출물의 경우, 다른 용매를 사용하여 추출한 추출물보다 유효성분의 함량이 높아 잔틴 산화효소 억제 효과, DPPH 자유 라디칼 소거 활성 효과, 환원력이 우수하다는 장점이 있다. 그러나, 추출 방법은 제한되지 않으며, 예를 들어, 냉침추출, 초음파 추출, 환류 냉각 추출 등이 있다.Particularly preferably, the camellia extract of the present invention can be extracted using water or an organic solvent, and the extracted liquid can be used in a liquid form or can be used by concentration and / or drying. The organic solvent may be selected from the group consisting of methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylformamide (DMF), dimethylsulfoxide , 3-butylene glycol, propylene glycol, or a mixed solvent thereof. The extract may be extracted at room temperature or with heating under conditions where the active ingredient of the extract is not destroyed or minimized. In the case of an extract using ethanol as a solvent, the content of the active ingredient is higher than that of the extract extracted with other solvents, which is advantageous in that it has an effect of inhibiting xanthine oxidase, DPPH free radical scavenging activity and reducing power. However, the extraction method is not limited, and examples thereof include cold extraction, ultrasonic extraction, and reflux cooling extraction.
본 발명의 동백나무 추출물은 추출, 분획, 또는 정제(분리, 분획)의 각 단계에서 얻어지는 모든 추출액, 분획, 정제물, 그들의 희석액, 농축액, 또는 건조물일 수 있다. The camellia extract of the present invention may be any extract, fraction, purified product, diluted solution, concentrate, or dried product obtained in each step of extraction, fractionation, or purification (separation, fractionation).
본 발명에 있어서, 상기 “유효성분”이란 단독으로 목적하는 활성을 나타내거나 또는 그 자체는 활성이 없는 담체와 함께 활성을 나타낼 수 있는 성분을 의미한다.In the present invention, the above-mentioned " active ingredient " means a component that exhibits the desired activity alone or can exhibit activity together with a carrier which is itself inactive.
하나의 구체적 실시에서, 상기 방법으로 추출한 동백나무 잎 추출물은 ICR 마우스에서 혈중 요산 저하 및 잔틴 산화효소 활성 감소 효과를 나타내었다.In one specific implementation, the extract of Camellia sinensis Leaf Extract, obtained by the method described above, showed an effect of lowering uric acid in serum and reducing the activity of xanthine oxidase in ICR mice.
본 발명의 고요산혈증(고요산혈증 관련 대사 장애 포함) 예방 및 치료용 조성물은 유효성분으로서 동백나무 추출물을 용도, 제형, 배합 목적 등에 따라 임의의 양(유효량)으로 포함할 수 있는데, 통상적인 유효량은 조성물 전체 중량을 기준으로 할 때 0.001 중량% 내지 70 중량% 범위 내에서 결정될 수 있다. 여기서 “유효량”이란 고요산혈증 및 고요산혈증 관련 대사 장애의 예방, 개선, 치료, 또는 그 증상의 발현 지연을 유도할 수 있는 유효성분의 양을 말한다. 이러한 유효량은 당업자의 통상의 능력 범위 내에서 실험적으로 결정될 수 있다. 바람직하게는 0.01 중량% 내지 50 중량%, 보다 바람직하게는 0.01 내지 30 중량%의 함량으로 포함될 수 있다. 상기 동백나무 추출물의 함량이 0.001 중량% 미만일 경우 고요산혈증 및 고요산혈증 관련 대사 장애 개선 효과가 미약하고, 70 중량%를 초과하는 경우 함량 증가에 따른 효과 증가가 비례적이지 않아 비효율적일 수 있으며, 제형상의 안정성이 확보되지 않는 문제가 있다.The composition for preventing and treating hyperuricemia (including hyperuricemia-related metabolic disorders) of the present invention may contain an effective amount of Camellia sinensis extract as an effective ingredient in an arbitrary amount (effective amount) depending on the purpose of use, formulation, compounding purpose and the like. Can be determined within the range of 0.001 wt% to 70 wt% based on the total weight of the composition. Herein, the term " effective amount " refers to the amount of active ingredient capable of preventing, ameliorating, treating, or delaying the onset of symptoms of hyperlipidemia and hyperlipidemia-related metabolic disorders. Such effective amounts can be determined experimentally within the ordinary skill of those skilled in the art. By weight, preferably 0.01% by weight to 50% by weight, and more preferably 0.01% by weight to 30% by weight. If the content of the extract is less than 0.001% by weight, the effect of improving hyperlipidemia and hyperlipidemia-related metabolic disorders is insignificant. If the content of the extract is more than 70% by weight, There is a problem that stability of the shape is not ensured.
본 발명에 있어서, 상기 고요산혈증 및 고요산혈증 관련 대사 장애는 요산이 정상 수치보다 많아져서 신장이 요산을 배설시키는 능력이 저하될 경우 혈액 중에 여분의 요산이 남아있게 되고 혈중요산치가 높아져 발생되는 질환이나 질병을 말한다.In the present invention, the hyperlipidemia and hyperlipidemia-related metabolic disorders are caused by the fact that the uric acid is higher than the normal level and thus the ability of the kidney to excrete uric acid is lowered, the extra uric acid remains in the blood, Disease.
상기 고요산혈증 관련 대사 장애에는 통풍, 요산 결정, 관절내 요산염 결정의 침착, 요산염 결정의 침착으로 인한 급성 관절성 관절염, 단일 관절성 관절염, 염증성 관절염의 통증 발작, 요로 결석증, 신결석증 및 통풍성 신병증이 포함된다. 장기적인 신결석증 및 통풍성 신병증은 신장 손상 및 신부전의 위험을 증가시키는 것으로 알려져 있다. The hyperlipidemia-related metabolic disorders include acute arthritic arthritis, arthritic arthritis, painful seizures of inflammatory arthritis, urinary incontinence, nephrolithiasis, and gout, due to gout, uric acid crystals, deposition of urate crystals in the joints, Includes nephropathy. Long-term nephrolithiasis and gouty nephropathy are known to increase the risk of kidney damage and renal failure.
상기 통풍은 통상적으로 급성 염증성 관절염의 재발성 발작을 특징으로 하는 의학적 상태이며, 엄지 발가락 기저부의 중족-지골 관절에서 흔하게 발생한다. 또한, 통풍은 관절, 힘줄 및 주변 조직들 내에서 결정화되고 침착되는 혈중 요산에 의해 유발되며, 통풍 결절, 신장 결석 또는 요산염 신병증으로서 존재할 수도 있다.The gout is usually a medical condition characterized by a recurrent seizure of acute inflammatory arthritis and is common in the mid-phalangeal joints of the base of the big toe. In addition, gout is caused by blood uric acid crystallized and deposited in the joints, tendons and surrounding tissues, and may be present as gout, kidney stones, or urate nephropathy.
페놀류(phenolics)는 항산화 활성과 잔틴 산화효소 저해 활성을 가지며 혈청 중 요산의 농도를 감소시키는 것으로 알려져 있다. GC-MS 분석에 따르면, 동백나무 잎 추출물은 다양한, 페놀류, 예컨대 비타민 E(vitamin E, 25.35%), n-에이코산(eicosane, 10.2%), 네오피타디엔(neophytadiene, 0.91%), 트랜스-스쿠알렌 (3.32%), n-옥타코산(2.65%), 6,9-펜타데카디엔-1-올 (1.51%), α-리놀렌산 (1.41%), 및 n-헥사데칸산(0.61%) 등을 함유한다. 도 2 내지 4에서 보이는 바와 같이, 본 발명에 따른 동백나무 잎 추출물은 강제로 유발된 고요산혈증 동물에서 혈청 내 요산의 농도를 감소시키고, 간과 혈청 XO 활성을 저해하였다. 이러한 결과는 ECJL의 투여가 실험동물의 고요산혈증 상태를 현저하게 개선할 수 있음을 보여준다.Phenolics have antioxidant activity and xanthine oxidase inhibitory activity and are known to reduce the concentration of uric acid in the serum. According to GC-MS analysis, Camellia sinensis leaf extract contained various phenols such as vitamin E (25.35%), eicosane (10.2%), neophytadiene (0.91% (1.41%), n-hexadecanoic acid (0.61%), and the like were used as the starting materials. Lt; / RTI > As shown in FIGS. 2 to 4, the extract of Camellia sinensis according to the present invention decreased the concentration of uric acid in the serum and inhibited hepatic and serum XO activity in the forced-induced hypolipidemic animals. These results show that administration of ECJL can significantly improve the hyperuricemic state of experimental animals.
알로퓨리놀(allopurinol)은 고요산혈증을 치료 및 조절하기 위해 사용된다. 그러나, 알로퓨리놀의 사용은 환자에게 부작용을 유발할 수 있으며, 이러한 부작용은 고요산혈증 치료를 포기하는 주된 원인으로 보고되었다. 본 발명에서는 ECJL의 항-고요산혈증 활성을 평가하고 생체 내 최적 용량을 측정하였다. 그 결과, ECJL은 요산 농도를 감소시키고 간/혈청 XO 활성을 저해하는데 효과적이었다. 이는 ECJL이 알로퓨리놀을 대체하는 고요산혈증 치료제로서 사용될 수 있음을 시사한다.Allopurinol is used to treat and control hyperuricemia. However, the use of alopyrinol can cause side effects in patients, and these side effects have been reported as the main reason for abstaining from hyperuricemic treatment. In the present invention, the anti-hyperlipidemic activity of ECJL was evaluated and the optimal dose in vivo was measured. As a result, ECJL was effective in reducing uric acid concentration and inhibiting liver / serum XO activity. This suggests that ECJL can be used as a therapeutic agent for hyperlipemia, which replaces allrogenol.
본 발명에서 사용되는 용어 “예방”은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸리기 쉬운 경향이 있는 개체에서 질환 또는 질병의 발생을 억제하는 것을 의미한다. The term " prevention ", as used herein, refers to inhibiting the occurrence of a disease or disease in an individual who has never been diagnosed as having a disease or disease, but has a tendency to become susceptible to such disease or disease.
본 발명에서 사용되는 용어 “치료” 또는 “개선”은 개체에서 (a) 질환 또는 질병의 발전의 억제 (b) 질환 또는 질병의 경감 및 (c) 질환 또는 질병의 제거를 의미한다. The term " treatment " or " improvement ", as used herein, refers to (a) inhibiting the development of a disease or disease, (b) relieving the disease or disorder and (c) eliminating the disease or disorder.
본 명세서에서 사용되는 용어 “개체”는 본 발명의 상기 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간을 포함한 원숭이, 소, 말, 돼지, 양, 개, 고양이, 랫트, 마우스, 침팬지 등의 포유동물을 의미한다. The term " individual " as used herein means a mammal such as a monkey, a cow, a horse, a pig, a sheep, a dog, a cat, a rat, a mouse or a chimpanzee including a human having a disease Of mammals.
본 발명은 동백나무 추출물을 유효성분으로 포함하는 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 개선용 기능성 식품 조성물을 제공한다.The present invention provides a functional food composition for preventing and ameliorating hyperlipidemia and hyperlipidemia-related metabolic disorders comprising a camellia extract as an active ingredient.
본 발명의 동백나무 추출물이 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 개선용 기능성 식품 조성물의 유효성분으로 사용되는 경우, 유효성분으로서 동백나무 추출물 이외에 식품 제조 시에 통상적으로 첨가되는 식품보조 첨가제, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 추가로 포함할 수 있다.When the camellia extract of the present invention is used as an active ingredient of a functional food composition for preventing and ameliorating hyperlipidemia and hyperlipidemia-related metabolic disorders, it is possible to use, as an active ingredient, a food-aid additive usually added in the manufacture of food, For example, proteins, carbohydrates, fats, nutrients, flavoring agents and flavoring agents.
상기 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등)] 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.Examples of such carbohydrates are monosaccharides, such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavors (saccharin, aspartame, etc.) may be used as flavorings.
상기 식품의 종류에는 특별한 제한이 없다. 본 발명의 동백나무 추출물을 첨가할 수 있는 식품의 예로는 가공육류, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강 기능성 식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of foods to which the camellia extract of the present invention can be added include processed meats, breads, chocolates, candies, snacks, confectionery, pizza, ramen noodles, other noodles, gums, dairy products including ice cream, various soups, , A drink, an alcoholic beverage, and a vitamin complex, all of which include health functional foods in a conventional sense.
본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 유효성분인 동백나무 추출물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙 등을 추가로 포함시킬 수 있다.When the food composition of the present invention is prepared as a drink, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, and the like may be further added in addition to the camellia extract as an active ingredient of the present invention.
또한, 상기 식품 조성물은 상술한 성분 외에 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 식품 조성물은 천연 과일쥬스, 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.In addition, the food composition may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin , Alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the food composition of the present invention may contain flesh for the production of natural fruit juices, beverages and vegetable drinks. These components may be used independently or in combination.
본 발명은 동백나무 추출물을 유효성분으로 포함하는 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing and treating hyperlipidemia and hyperlipidemia-related metabolic disorders comprising a camellia extract as an active ingredient.
본 발명의 동백나무 추출물이 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료용 약제학적 조성물의 유효성분으로 사용되는 경우, 유효성분으로서 동백나무 추출물 이외에 약학적으로 허용가능한 담체를 추가로 포함할 수 있다. When the camellia extract of the present invention is used as an active ingredient of a pharmaceutical composition for the prevention and treatment of hyperlipidemia and hyperlipidemia-related metabolic disorders, a pharmaceutically acceptable carrier other than the camellia extract may be further included as an active ingredient .
본 발명의 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 탄수화물류 화합물(예: 락토스, 아밀로스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 셀룰로스 등), 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 염 용액, 알코올, 아라비아 고무, 식물성 기름(예: 옥수수 기름, 목화 종자유, 두유, 올리브유, 코코넛유), 폴리에틸렌 글리콜, 메틸 셀룰로스, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. The pharmaceutically acceptable carriers of the present invention are those conventionally used in the present invention and include carbohydrate compounds such as lactose, amylose, dextrose, sucrose, sorbitol, mannitol, starch, cellulose and the like, acacia rubber, calcium phosphate , Alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, salt solution, alcohol, gum arabic, vegetable oil such as corn oil, cottonseed oil, soybean oil, But are not limited to, polyethylene glycol, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
본 발명의 약학적으로 허용되는 담체는 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있으며, 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.The pharmaceutically acceptable carriers of the present invention may further comprise lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, preservatives and the like in addition to the above-mentioned components. Suitable pharmaceutically acceptable carriers and preparations are Remington's Pharmaceutical Sciences (19th ed., 1995).
상기 약학 조성물은 통상의 방법에 따라 산제, 과립제, 캡슐제, 현탁액, 에멀젼, 시럽제, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액 등의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition may be formulated in the form of powders, granules, capsules, suspensions, emulsions, oral preparations such as aerosols, external preparations, suppositories and sterilized injection solutions according to a conventional method.
상기 약학 조성물은 고요산혈증 및 고요산혈증 관련 대사 장애를 예방 및 치료할 수 있는데, 치료방법은 상기 약학 조성물을 약제학적 유효량으로 쥐, 생쥐, 가축, 인간 등의 포유동물 내에 다양한 경로로 투여하는 것을 포함한다. 상기 투여방법은 모든 방식으로 이루어질 수 있는데, 예를 들어, 경구, 직장 또는 정맥 내 주입, 복강 내 투여, 근육 내 투여, 또는 피하 투여 등으로 투여될 수 있다.The pharmaceutical composition may prevent or treat hyperlipidemia and hyperuricemia-related metabolic disorders. The therapeutic method includes administering the pharmaceutical composition in a pharmaceutically effective amount in various routes in a mammal such as a mouse, a mouse, a domestic animal, or a human . The administration method can be carried out in any manner, for example, by oral, rectal or intravenous infusion, intraperitoneal administration, intramuscular administration, or subcutaneous administration.
본 발명의 약학 조성물의 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성별, 병적 상태 등의 요인에 따라 달라질 수 있다. 본 발명의 약학 조성물의 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다. 다만, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것이 아니다.The dosage of the pharmaceutical composition of the present invention may be varied depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition and the like of the patient. The dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg / kg on an adult basis. However, the dose is not limited in any way to the scope of the present invention.
다른 하나의 양태로서, 본 발명의 상술한 동백나무 잎 추출물을 유효성분으로 포함하는 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료용 조성물을 개체에 투여하여 고요산혈증 및/또는 고요산혈증 관련 대사 장애를 치료, 예방, 또는 개선하는 방법을 제공한다.In another embodiment, a composition for preventing and treating hyperlipidemia and hyperlipidemia-related metabolic disorders comprising the above-mentioned camellia leaf extract of the present invention as an active ingredient is administered to a subject to prevent hyperlipidemia and / or hyperlipidemia-related metabolic disorders Prevent, or ameliorate a disease or condition.
본 발명에 따른 고요산혈증 및/또는 고요산혈증 관련 대사 장애의 치료에 있어서, 상기 개체는 인간을 포함한 원숭이, 소, 말, 돼지, 양, 개, 고양이, 랫트, 마우스, 침팬지 등의 포유동물을 의미한다.In the treatment of hyperalgesia and / or hyperlipidemia-related metabolic disorders according to the present invention, said subject means a mammal such as a monkey, a cow, a horse, a pig, a sheep, a cat, a rat, a mouse or a chimpanzee including a human being do.
본 발명에 따른 동백나무 잎 추출물은 혈중 요산의 농도를 저하시키는데 탁월한 효과를 나타낸다. 따라서 본 발명에 따른 동백나무 추출물은 고요산혈증 및 고요산혈증 관련 대사 장애 예방 및 치료를 위한 약제학적 조성물, 기능성 식품 조성물 등의 제조를 위한 활성성분으로 유용하게 이용될 수 있다. The camelliace leaf extract according to the present invention exhibits an excellent effect in lowering the concentration of uric acid in the blood. Therefore, the camellia extract according to the present invention can be effectively used as an active ingredient for the production of a pharmaceutical composition, a functional food composition and the like for the prevention and treatment of hyperlipidemia and hyperlipidemia-related metabolic disorders.
도 1은 본 발명에 따른 동백나무 잎 추출물(ECJL 2mg/ml)과 알로퓨리놀(allopurinol, 30ug/ml)의 시험관 내 잔틴 산화효소 억제 활성을 비교한 그래프이다. 각각의 시험값은 3회의 별도 실험의 평균 ± SD이다(n=5).
도 2는 정상 대조군(Normal control), 고요산혈증 대조군(Model control, HU), 알로퓨리놀 투여군(Positive control, HU+10 mg/kg ALP), 동백나무 잎 추출물 투여군(HU+ECJL30, HU+ECJL100, HU+ECJL300)의 혈중 요산 농도를 나타낸 그래프이다. 직사각형 막대와 그의 오차 막대는 각각 평균과 표준편차를 나타낸다(n=5). *: 다른 그룹과 비교하여 상당히 다른 값(p<0.05, ANOVA posteriori Tukey's multiple range test)
도 3은 정상 대조군(Normal control), 고요산혈증 대조군(Model control, HU), 알로퓨리놀 투여군(Positive control, HU+10 mg/kg ALP), 동백나무 잎 추출물 투여군(HU+ECJL30, HU+ECJL100, HU+ECJL300)의 간에서의 잔틴 산화효소 활성을 나타낸 그래프이다. 직사각형 막대와 그의 오차 막대는 각각 평균과 표준편차를 나타낸다(n=5). *: 다른 그룹과 비교하여 상당히 다른 값(p<0.05, ANOVA posteriori Tukey's multiple range test)
도 4는 정상 대조군(Normal control), 고요산혈증 대조군(Model control, HU), 알로퓨리놀 투여군(Positive control, HU+10 mg/kg ALP), 동백나무 잎 추출물 투여군(HU+ECJL30, HU+ECJL100, HU+ECJL300)의 혈중 잔틴 산화효소 활성을 나타낸 그래프이다. 직사각형 막대와 그의 오차 막대는 각각 평균과 표준편차를 나타낸다(n=5). *: 다른 그룹과 비교하여 상당히 다른 값(p<0.05, ANOVA posteriori Tukey's multiple range test)
도 5는 본 발명에 따른 동백나무 잎 추출물의 활성 성분을 분석한 GC-MS 크로마토그램을 나타낸 그래프이다.
도 6은 본 발명에 따른 동백나무 잎 추출물의 활성 성분을 분석한 HPLC 크로마토그램을 나타낸 그래프이다.1 is a graph comparing the inhibitory activity of camphor tree leaf extract (
FIG. 2 is a graph showing the results of a control (HU + ECJL100, HU + ECJL100, HU + ECL100, HU + 10 mg / kg ALP) + ECJL300). ≪ / RTI > Rectangular bars and their error bars represent mean and standard deviation, respectively (n = 5). *: Significantly different values compared to other groups (p <0.05, ANOVA posteriori Tukey's multiple range test)
FIG. 3 is a graph showing the results of normal control, model control (HU), allopurinol (Positive control, HU + 10 mg / kg ALP) + ECJL300) in the liver. Rectangular bars and their error bars represent mean and standard deviation, respectively (n = 5). *: Significantly different values compared to other groups (p <0.05, ANOVA posteriori Tukey's multiple range test)
FIG. 4 is a graph showing the results of a normal control, a model control (HU), a positive control (HU + 10 mg / kg ALP), a camellia leaf extract administration group (HU + ECJL30, HU + ECJL100, HU + ECJL300). ≪ / RTI > Rectangular bars and their error bars represent mean and standard deviation, respectively (n = 5). *: Significantly different values compared to other groups (p <0.05, ANOVA posteriori Tukey's multiple range test)
FIG. 5 is a graph showing a GC-MS chromatogram of an active ingredient of a camellia sinica leaf extract according to the present invention.
FIG. 6 is a graph showing an HPLC chromatogram of an active ingredient of a camellia sinica leaf extract according to the present invention.
이하, 제조예 및 실험예 등을 통하여 본 발명을 더욱 상세히 설명하였다. 이들 제조예 및 실험예 등은 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 제조예 및 실험예 등에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Production Examples and Experimental Examples. These production examples and experimental examples are intended to explain the present invention more specifically, and it should be apparent to those skilled in the art that the scope of the present invention is not limited by these production examples and experimental examples. will be.
모든 데이터는 평균±표준 편차로 표현하였고, 반올림하여 나타내었다. 두 평균 사이의 차이는 t-테스트를 수행하였고, 세 개 이상의 평균 사이의 차이는 사후 검증 (Tukey's multiple range test) 변화량 분석을 수행하였으며, p-값<0.05 수준에서 유의차를 검정하였다.All data are expressed as mean ± SD and rounded. The difference between the two averages was tested by t-test, and the difference between three or more averages was analyzed by Tukey's multiple range test. The significance was tested at p-value <0.05.
제조예 1: 동백나무 잎 추출물(ECJL)의 제조Production Example 1: Preparation of Camellia sinica leaf extract (ECJL)
대한민국 전라남도 완도 수목원으로부터 제공된 동백나무(Camellia japonica, CJ)에서 잎을 채집하여 건조한 다음 마쇄기로 분쇄하여 미세분말을 준비하였다. 동백나무 잎의 채집 표본 (MNUCSS-CJ-01)은 대한민국 무안의 목포 국립 대학교에 보관하였다.Leaves were collected from camellia japonica ( CJ) supplied from Wando Arboretum, Jeollanam-do, Korea , and then dried and pulverized by a grinder to prepare a fine powder. The collected sample of camellia leaves (MNUCSS-CJ-01) was stored at Mokpo National University, Muan, Korea.
분쇄한 동백나무의 잎 분말 10g을 상온에서 3일 동안 에탄올 100mL로 2회 추출하였다. 이후, 얻어진 에탄올 용액을 증발시키고 건조하여 -50℃에 보관하였다. 샘플을 활성성분의 시험관내 및/또는 생체내 실험과 분석에 사용하였다. 10 g of crushed camellia leaves were extracted twice with 100 mL of ethanol for 3 days at room temperature. Then, the obtained ethanol solution was evaporated, dried and stored at -50 캜. Samples were used for in vitro and / or in vivo experiments and analysis of active ingredients.
실험예 1: 동백나무 잎 추출물(ECJL)의 항산화 활성 측정Experimental Example 1: Antioxidant activity measurement of Camellia sinica leaf extract (ECJL)
1) DPPH 라디칼(radical) 소거 활성 분석1) DPPH radical scavenging activity analysis
동백나무 잎 추출물(ECJL)의 항산화 활성은 517nm에서 항산화 화합물에 의해 2,2-디페닐-1-피크릴하이드라질(picrylhydrazyl)(DPPH) 라디칼의 양이 줄어들어 최대 흡광도(A)가 사라지는 DPPH 라디칼 소거 활성 분석을 통해 측정하였다. 흡광도(A)는 마이크로플레이트 리더(Perkin Elmer, Waltham, MA, USA)를 이용해 측정하였으며, DPPH 라디칼 소거 활성(%)은 하기 수학식 1을 이용하여 계산하였다. The antioxidative activity of camellia japonica leaf extract (ECJL) was determined by the antioxidant compound at 517 nm, and the amount of 2,2-diphenyl-1-picrylhydrazyl (DPPH) Were measured by scavenging activity assay. The absorbance (A) was measured using a microplate reader (Perkin Elmer, Waltham, MA, USA) and the DPPH radical scavenging activity (%) was calculated using the following equation.
구체적으로, 동백나무 잎 추출물(ECJL) 1mL에 0.4mM의 DPPH 1mL를 넣고 혼합하여 어두운 상온에서 10분 동안 반응시킨 후, 517nm에서 흡광도를 측정하였다. 그 결과를 하기 표 1에 나타내었으며, 동백나무 잎 추출물의 DPPH 자유 라디칼 소거 활성의 IC50 농도는 38.53±0.72μg/mL의 비교적 낮은 값으로 나타났다. 낮은 IC50 농도는 강력한 항산화활성을 나타낸다.Specifically, 1 ml of 0.4 mM DPPH was added to 1 ml of Camellia sinensis leaf extract (ECJL), mixed and reacted at a dark room temperature for 10 minutes, and absorbance was measured at 517 nm. The results are shown in Table 1, and IC 50 concentration of DPPH free radical scavenging activity of Camellia sinica leaf extract was 38.53 ± 0.72 μg / mL. Low IC 50 concentrations indicate potent antioxidant activity.
2) 라디칼 환원력 분석2) Analysis of the radical reduction power
동백나무 잎 추출물(ECJL)의 라디칼 환원력은 문헌 [Kim, Y. H. (2015), “The antioxidant activity and their major antioxidant compounds from Acanthopanax senticosus and A. koreanum.” Molecules, 20: 13281-13295]에 개시된 방법을 수정한 환원력 분석 방법을 통해 계산하였다. The radical reducing power of the camellia leaf extract (ECJL) can be determined by the method disclosed in Kim, YH (2015), " The antioxidant activity and their major antioxidant compounds from Acanthopanax senticosus and A. koreanum. &Quot; Molecules , 20 : 13281-13295 And calculated by the modified power analysis method.
구체적으로, 동백나무 잎 추출액 0.1mL, 0.2M 인산나트륨 완충용액(sodium phosphate) 0.5mL 및 1% 포타슘 페리시아나이드(potassium ferricyanide) 0.5mL를 혼합하고, 50℃에서 20분 동안 반응하였다. 그 다음, 10% 삼염화아세트산(trichloroacetic acid) 수용액 0.5mL를 반응 혼합물에 첨가하고, 12,000rpm에서 10분 동안 원심 분리하였다. 그 다음, 원심 분리하여 얻은 상청액과 증류수 0.5mL 및 0.1% 염화 제3철(iron(III) chloride) 수용액 0.1mL를 혼합하고, 700nm에서 흡광도를 측정하였다. 라디칼 환원력 분석 실험의 양성 대조군으로 아스코르브산(Ascorbic acid)를 사용하였으며, Fe3 +에서 Fe2 +로의 환원력은 아스코르브산(Ascorbic acid) eq. μg/50 μg ext.로 나타내었다. 그 결과를 하기 표 1에 나타내었으며, 50μg 동백나무 추출물(ECJL)의 환원력은 13.34±1.7μg이었다.Specifically, 0.1 ml of the camellia leaf extract, 0.5 ml of 0.2 M sodium phosphate buffer and 0.5 ml of 1% potassium ferricyanide were mixed and reacted at 50 ° C for 20 minutes. Then 0.5 mL of 10% aqueous trichloroacetic acid solution was added to the reaction mixture and centrifuged at 12,000 rpm for 10 minutes. Then, the supernatant obtained by centrifugation, 0.5 mL of distilled water, and 0.1 mL of 0.1% aqueous solution of iron (III) chloride were mixed and the absorbance was measured at 700 nm. Ascorbic acid was used as a positive control in the analysis of the radical reduction power, and the reducing power from Fe 3 + to Fe 2 + was ascorbic acid eq. μg / 50 μg ext. The results are shown in Table 1, and the reducing power of 50 μg of Camellia sinensis extract (ECJL) was 13.34 ± 1.7 μg.
실험예 2: 동백나무 잎 추출물(ECJL)의 총 페놀 및 플라보노이드 함량 측정Experimental Example 2: Determination of total phenol and flavonoid content of Camellia sinica leaf extract (ECJL)
일부 페놀과 플라보노이드 화합물은 항산화 활성 및 혈청 요산 수치를 감소시킬 수 있는 잔틴 산화효소 억제 활성을 가진다. 따라서, 본 발명의 동백나무 추출물을 대상으로 총 페놀의 함량을 측정하여 비교하였다.Some phenol and flavonoid compounds have antioxidant activity and xanthine oxidase inhibitory activity which can reduce serum uric acid levels. Therefore, the content of total phenol was measured and compared with the camellia extract of the present invention.
페놀 함량은 몰리브데늄 염의 색변화를 이용하는 페놀 분석법으로 가장 널리 사용되는 Folin-Ciocalteu 분석법을 이용하여 측정하였다. Phenol content was measured by the Folin-Ciocalteu method, which is the most widely used phenol method using color change of molybdenum salt.
구체적으로, 동백나무 잎 추출물(ECJL) 5mg을 물 1mL에 녹인 다음 2% 탄산나트륨(sodium carbonate) 수용액 1mL와 10% Folin-Ciocalteu's 페놀 시약 1mL와 혼합하였다. 그 다음, 혼합액을 상온에서 10분 동안 배양하고, 마이크로플레이트 리더(Perkin Elmer)를 사용하여 750nm에서 흡광도를 측정하였다. 표준물질은 갈릭산(gallic acid)을 이용하였다. 총 폴리페놀 함량은 갈릭산(gallic acid)을 표준용액으로 하여 작성한 표준곡선(식: y= 0.023x + 0.124, r2= 0.999)와 대비하여 구하였으며, mg/g eq. 갈릭산으로 나타내었다. 그 결과를 상기 표 1에 나타내었으며, 총 폴리페놀 함량은 46.6±1.6 mg/g eq. 갈릭산으로 나타났다.Specifically, 5 mg of camellia japonica leaf extract (ECJL) was dissolved in 1 mL of water and then mixed with 1 mL of 2% sodium carbonate aqueous solution and 1 mL of 10% Folin-Ciocalteu's phenol reagent. Then, the mixed solution was incubated at room temperature for 10 minutes, and the absorbance was measured at 750 nm using a microplate reader (Perkin Elmer). Gallic acid was used as a reference material. The total polyphenol content was determined in comparison with a standard curve (formula: y = 0.023x + 0.124, r 2 = 0.999) prepared with gallic acid as a standard solution, and mg / g eq. Gallic acid. The results are shown in Table 1, and the total polyphenol content was 46.6 ± 1.6 mg / g eq. Garlic mountain.
실험예 3: 잔틴 산화효소 억제(Xanthine Oxidase Inhibition) 시험관 내 실험Experimental Example 3: Xanthine Oxidase Inhibition In vitro test
잔틴 산화효소(XO)의 반응으로 잔틴이 산화되면서 요산이 생성되는데, 본 실험에서는 동백나무 잎 추출물(ECJL)의 요산 생성 억제 효능을 확인하기 위하여 문헌 [Arimboor, R. (2011), “Tetrahydroamentoflavone(THA) from Semecarpus anacardium as a pootent inhibitor of xanthine oxidase.” J Ethnopharmacol, 133: 1117-1120]에 개시된 방법에 따라 잔틴 산화효소(XO) 시스템에서 요산 생성을 측정하였다.In order to confirm the efficacy of ECJL on the inhibition of uricoxylation, Arimboor, R. (2011), " Tetrahydroamentoflavone < (R) > The production of uric acid was measured in a xanthine oxidase (XO) system according to the method described in J. Ethnopharmacol ., 133 : 1117-1120.
구체적으로 100mM 인산완충용액(pH 7.4) 0.6mL에 0.1mL 동백나무 잎 추출물(ECJL), 잔틴 산화효소(농도 0.2 U/mL) 0.1mL 및 잔틴 0.2mL (1mM; dissolved in 0.1N NaOH)로 구성된 시스템에 촉매와 억제제 또는 촉매만을 첨가하여 반응을 개시하고, 15분 동안 혼합물의 흡광도 변화를 290nm에서 대조군의 흡광도와 비교하였다. 그 다음, 1N 염화수소(HCl) 0.2mL를 넣어 효소 작용을 중지시켰다. Specifically, 0.6 mL of a 100 mM phosphate buffer solution (pH 7.4) was charged with 0.1 mL of Camellia sinensis leaf extract (ECJL), 0.1 mL of xanthine oxidase (concentration 0.2 U / mL) and 0.2 mL of dissolved xanthine (1 mM; dissolved in 0.1 N NaOH) The reaction was initiated by adding only catalyst and inhibitor or catalyst to the system and the change in absorbance of the mixture for 15 minutes was compared to the absorbance of the control at 290 nm. Then, 0.2 mL of 1 N hydrogen chloride (HCl) was added to stop the enzyme action.
양성 대조군으로는 잔틴 산화효소 저해제로서 잘 알려져 있으며, 농도 30μg/mL일 때, 64.6±3.4%의 잔틴 산화효소 억제율(35.4±3.4%의 요산 생성물 발생률)을 나타내는 알로퓨리놀(allopurinol)을 사용하였다. As a positive control, allopurinol, which is well known as a xanthine oxidase inhibitor, exhibits 64.6 ± 3.4% of xanthine oxidase inhibition (35.4 ± 3.4% uric acid production rate) at a concentration of 30 μg / mL.
동백나무 잎 추출물(ECJL)의 잔틴 산화효소 억제율은 요산(uric acid) 생성물 억제 비율로 나타내었으며, 그 결과를 도 1에 나타내었다. 그 결과, 동백나무 잎 추출물(ECJL) 투여량을 증가시킬수록 잔틴 산화효소 억제율이 증가되는 것을 알 수 있었으며, 동백나무 잎 추출물(ECJL) 농도가 2mg/ml일 때, 41.3±5.5%의 잔틴 산화효소 억제율(58.7±5.5%의 요산 생성물 발생률)을 나타냈다. The inhibition rate of xanthine oxidase of Camellia japonica leaf extract (ECJL) was indicated by the uric acid product inhibition ratio, and the results are shown in Fig. As a result, it was found that the inhibition rate of xanthine oxidase was increased as the ECJL dose was increased. When ECJL concentration was 2 mg / ml, 41.3 ± 5.5% of xanthine oxidase The rate of enzyme inhibition was 58.7 ± 5.5%.
실험예 4: 고요산혈증 유발 동물 모델에서의 혈중 요산 감소 실험Experimental Example 4: Reduction of serum uric acid in an animal model inducing hypercalcemia
본 발명의 동백나무 잎 추출물(ECJL)의 혈중 요산 감소 효능을 확인하기 위하여 요산 분해 효소 저해제인 칼륨 옥소네이트(potassium oxonate)를 투여하여 고요산혈증을 유도한 후, 동백나무 잎 추출물(ECJL)의 혈중 요산 감소효과에 대한 실험을 수행하였다. 양성 대조군에는 요산 합성 저해제인 알로퓨리놀(allopurinol)을 투여하여 비교 실험을 수행하였다.In order to confirm the efficacy of the camellia japonica leaf extract (ECJL) of the present invention for reducing uric acid in blood, potassium oxonate, a uricase inhibitor, was administered to induce hyperuricemia, Experiments were conducted on the effect of uric acid reduction. A comparative experiment was conducted by administering allopurinol, a uricosynthesis inhibitor, to the positive control group.
실험동물은 생후 4주 정도의 ICR 마우스(Orient Bio, Co., 대한민국)를 구입하여 사용하였다. 사육환경은 온도 20~23℃, 상대습도 50±5%이며, 조명 시간 12시간(오전 7시 점등~오후 7시 소등)으로 설정한 무균 처리된 환기되는 케이지(Tecniplast USA, Inc.)에서 사육하였으며, 사료(Agribrands Purina Korea, InC.)와 물은 더 이상 먹지 않고 남을 때까지 충분히 공급하였다. 모든 동물 실험은 대한민국 나주의 AIC-JBF(Animal Investigation Committee of Jeonnam Bioindustry Foundation)의 승인번호 JINR 1517 지침에 준하여 수행하였다. ICR mice (Orient Bio, Co., Korea) were used for about 4 weeks. The breeding environment was maintained in a sterilized ventilated cage (Tecniplast USA, Inc.) set at a temperature of 20 to 23 ° C, a relative humidity of 50 ± 5%, and a lighting time of 12 hours (7 o'clock to 7 o'clock off) And feed (Agribrands Purina Korea, InC.) And water were fed until they were no longer eaten. All animal experiments were carried out in accordance with the JINR 1517 Guidance for Approval of the AIC-JBF (Animal Investigation Committee of Jeonnam Bioindustry Foundation) in Naju, Korea.
본 실험에서는 요산 분해 효소 저해제인 칼륨 옥소네이트(potassium oxonate) 250mg/kg을 시료 투여 1시간 전에 복강 내에 투여하여 고요산혈증을 유도하였다. 칼륨 옥소네이트를 투여하고 1시간 후, 고요산혈증의 유도 여부를 확인하기 위해 혈중 요산 농도를 측정하였으며, 그 결과 정상 대조군에 비하여 높은 혈중 요산 농도를 나타내어 고요산혈증이 유도된 것을 확인하였다. In this experiment, potassium oxonate (uricolytic enzyme inhibitor) 250 mg / kg was administered intraperitoneally 1 hour before the administration of the sample to induce hyperuricemia. One hour after the administration of potassium oxonate, the uric acid concentration in the blood was measured to confirm the induction of hyperuricemia. As a result, it was confirmed that hyperuricemia was induced due to high uric acid concentration in the blood compared with the normal control group.
실험동물은 정상 대조군(Normal control), 고요산혈증 대조군(Model control, HU), 알로퓨리놀 투여군(Positive control, HU+ALP), 동백나무 잎 추출물 투여군(HU+CJ30, HU+CJ100, HU+CJ300)으로 각 그룹당 5마리씩 다섯 그룹으로 나누어 실험하였다.HU + CJ300, HU + CJ100, and HU + CJ300) were administered to the control group, normal control, model control (HU), allopurinol (Positive control, HU + ALP) Five groups were tested in each group.
동백나무 잎 추출물 투여군은 ECJL 30mg/kg, 100mg/kg 및 250mg/kg을, 알로퓨리놀 투여군은 알로퓨리놀 10mg/kg을 각각 0.3% 카르복시메틸셀루로오스나트륨 (CMC-Na) 수용액에 녹여 7일 동안 1회/1일 경구 투여를 실시하였으며, 약 투여하기 1.5시간 전에는 물을 제외한 음식물을 주지 않았다.In the alfurinol group, 10 mg / kg of alopulinol was dissolved in a 0.3% aqueous solution of carboxymethylcellulose sodium (CMC-Na) for 1 day for 7 days, / Day for oral administration, and no food except water was given 1.5 hours before drug administration.
약물 투여 마지막 날(7일째), 마지막 약 투여 1시간 전에 칼륨 옥소네이트(potassium oxonate) 300mg/kg을 복강 내에 투여하여 고요산혈증을 유도하고, 1시간 후 마지막 약물을 경구 투여하였다. 약물 투여 1시간 후, 실험동물의 꼬리 혈관에서 혈액 샘플을 채취하여 상온에서 1시간 동안 응고시켰다. 응고된 혈액으로부터 혈청을 얻기 위해서 혈액 샘플을 10,000rpm에서 15분 동안 원심분리 하였으며, 얻어진 혈청 샘플은 -80℃에 보관하였다. 혈청 요산 농도는 요산 분석 키트(Abcam, Cambridge, UK)를 사용하여 3회씩 반복하여 분석하였다. 실험 모델에서는 300mg/kg의 칼륨 옥소네이트의 복강경 주사에 의해 혈청 요산 농도가 효과적으로 증가하였다(14.19±1.62uM).On the last day of the drug administration (day 7),
그 결과를 도 2에 나타내었으며, 동백나무 잎 추출물의 투여로 인하여 동백나무 잎 추출물 투여군(HU+CJ30, HU+CJ100, HU+CJ300)과 알로퓨리놀군의 혈청에서의 요산 농도는 각각 6.64±0.74μM, 12.89±1.13μM, 8.89±1.17μM 및 7.23±1.63μM를 나타냈다. The results are shown in FIG. 2. The uric acid concentrations in the serum of the camellia leaf extract-treated group (HU + CJ30, HU + CJ100, HU + CJ300) and the allophrenol group were 6.64 ± 0.74 μM , 12.89 ± 1.13 μM, 8.89 ± 1.17 μM and 7.23 ± 1.63 μM, respectively.
10mg/kg의 알로퓨리놀은 53%까지 혈청 요산을 억제하였고, 300mg/kg의 ECJL이 49.1%까지 혈청 요산을 저해하였다. 즉, 알로퓨리놀 투여군(Positive control, HU+ALP)에 비교하여 ECJL 투여군의 요산 감소능력이 다소 떨어지는 경향을 보이지만, 동백나무 잎 추출물이 식물에서 추출한 안전한 천연물임을 감안하면 다양한 부작용을 나타내는 알로퓨리놀의 대체 약물로 유용하다는 것을 확인할 수 있었다. Allofurinol at 10 mg / kg inhibited serum uric acid up to 53% and ECJL at 300 mg / kg inhibited serum uric acid up to 49.1%. Compared with positive control (HU + ALP), the ECJL-treated group showed a slightly decreased ability to reduce uric acid. However, considering that Camellia sinica leaf extract is a safe natural product extracted from plants, it is an alternative drug to alopurinol It was confirmed that it was useful.
실험예Experimental Example 5: 간(Hepatic)과 혈청에서의 5: Hepatic and Serum 잔틴Xanthine 산화효소 활성 실험 Oxidase activity test
고요산혈증이 유도된 실험동물의 간과 혈청에서의 잔틴 산화효소 잔여 활성을 측정하기 위해서 잔틴으로부터 요산이 형성되는 것을 모니터링하여 분광 광도법으로 측정하였다.In order to measure the residual activity of xanthine oxidase in hepatic and serum of laboratory animals induced hyperuricemia, the formation of uric acid from xanthine was monitored and measured by spectrophotometric method.
고요산혈증이 유도된 실험동물의 간 0.5g을 50mM 인산나트륨완충용액(pH 7.4) 1mL에 균질화하고, 균질화된 간을 4℃, 3,000rpm에서 10분 동안 원심분리 하였다. 그 다음, 액상을 제거하고, 상청액을 4℃, 10,000rpm에서 60분 동안 원심분리 하여 잔틴 산화효소의 잔여 활성과 총 단백질 농도를 측정하였다.0.5 g of liver of laboratory animals in which hyperuricemia was induced was homogenized in 1 mL of 50 mM sodium phosphate buffer (pH 7.4), and the homogenized liver was centrifuged at 3,000 rpm for 10 minutes at 4 ° C. Then, the liquid phase was removed, and the supernatant was centrifuged at 4 DEG C and 10,000 rpm for 60 minutes to measure the residual activity of xanthine oxidase and the total protein concentration.
구체적으로, 50mM 인산나트륨완충용액(pH 7.4)에 10μL의 균질화된 간과 1mM 포타슘 옥소네이트(potassium oxonate) 용액 0.54mL를 넣고 35℃에서 15분 동안 배양한 시험관에 250mM 잔틴 용액 0.12mL을 넣어 반응시키고, 반응 0 내지 30분 후, 0.6M 염화수소(HCl)를 0.1mL 넣어 반응을 중단시켰다. 그 다음, 시험관을 3,000rpm에서 5분 동안 원심분리하고, UV/VIS 스펙트로미터를 이용하여 295nm에서 상청액의 흡광도를 측정하였다. 총 단백질 농도는 브래드포드(Bradford) 방법에 따라 분광광도법에 의해 측정하였고 XO 활성은 단백질 1mg에 대하여 분 당 형성된 요산의 uM로 표시하였으며, 그 결과를 도 3 및 도 4에 나타내었다.Specifically, 0.54 mL of homogenized liver and 1 mM potassium oxonate solution was added to 50 mM sodium phosphate buffer (pH 7.4), and 0.12 mL of 250 mM xanthine solution was added to a test tube cultured at 35 ° C for 15 minutes to react After 0 to 30 minutes of reaction, 0.1 mL of 0.6 M hydrogen chloride (HCl) was added to stop the reaction. The test tube was then centrifuged at 3,000 rpm for 5 minutes and the absorbance of the supernatant was measured at 295 nm using a UV / VIS spectrometer. The total protein concentration was measured by the spectrophotometric method according to the Bradford method and the XO activity was expressed as uM of uric acid formed per minute per 1 mg of protein. The results are shown in FIG. 3 and FIG.
도 3과 4에 나타낸 바와 같이, 칼륨 옥소네이트로 유발된 고요산혈증 실험동물의 간에서의 잔틴 산화효소 활성은 일주일 동안 동백나무 잎 추출물 100mg/kg과 300mg/kg 및 알로퓨리놀을 경구 투여하였을 때 각각 55.2, 64.7, 및 66.1%로 상당히 감소하였다. 또한, 칼륨 옥소네이트로 유발된 고요산혈증 실험동물의 혈장에서의 잔틴 산화효소 활성은 일주일 동안 동백나무 잎 추출물 100mg/kg과 300mg/kg 및 알로퓨리놀을 경구 투여하였을 때 각각 45.2, 59.3, 및 65%로 상당히 감소하였다.As shown in FIGS. 3 and 4, the activity of xanthine oxidase in the liver of potassium oxonate-induced hypolipidemic test animals was 55.2 mg / kg orally when oral administration of 100 mg / kg and 300 mg / kg of camellia sinensis leaf extract and alopyrinol for 1 week , 64.7, and 66.1%, respectively. In addition, the activity of xanthine oxidase in the plasma of potassium oxonate-induced hyperlipidemia was 45.2, 59.3, and 65%, respectively, when oral administration of 100 mg / kg and 300 mg / kg of camellia sinensis leaf extract and alopyrinol were performed for one week Respectively.
그러나, 정상 및 고요산혈증 대조군 사이에서 간과 혈장 잔틴 산화효소 활성의 유의한 차이는 없는 것을 고려하면, 300mg/kg의 ECJL이 10mg/kg의 알로퓨리놀과 유사한 잔틴 산화효소 억제 활성을 가지는 것을 알 수 있었다.However, considering that there is no significant difference in liver and plasma xanthine oxidase activity between normal and hyperlipidemic control group, it was found that ECJL of 300 mg / kg has an inhibitory activity of xanthine oxidase similar to allophilinol of 10 mg / kg.
실험예 6: 동백나무 잎 추출물(ECJL)의 활성 성분 분석Experimental Example 6: Analysis of active ingredients of Camellia sinica leaf extract (ECJL)
항산화 및 잔틴 산화효소 억제 활성을 가지는 동백나무 잎 추출물(ECJL)의 활성 성분을 확인하기 위해 GC-MS 및 HPLC 분석을 수행하였다. GC-MS and HPLC analyzes were performed to identify the active ingredients of Camellia sinica leaf extract (ECJL) with antioxidant and xanthine oxidase inhibitory activity.
GC-MS 분석은 문헌 [Bae, M. S. (2014), “Long-range transport of biomass burning emissions based on organic molecular markers and carbonaceous thermal distribution”, Sci Total Environ, 56-66: 466-467]에 보고된 방법을 수정하여 수행하였다.The GC-MS analysis was carried out according to the method reported in Bae, MS (2014), "Long-range transport of biomass burning emissions based on organic molecular markers and carbonaceous thermal distribution", Sci Total Environ , 56-66 : 466-467 .
유기화합물의 분석은 Agilent HP-5MS 용융 실리카 모세관 컬럼 (30mm l. x 0.25mm i.d., 0.25-μm 필름 두께)을 갖춘 사극자 Agilent 5975C 전자 이온화(70 eV) 질량 분광분석 검출기(Agilent Technologies, Palo alto, CA, USA)와 연결된 가스 크로마토그래피 시스템(Agilent 7890)으로 수행하였다.Analysis of the organic compounds was carried out using a quadrupole Agilent 5975C electron ionization (70 eV) mass spectrometry detector (Agilent Technologies, Palo alto, Calif.) With Agilent HP-5MS fused silica capillary columns (30 mm l x 0.25 mm id, , CA, USA) with a gas chromatography system (Agilent 7890).
GC-MS의 작동 파라미터는 하기 표 2에 나타내었다. GC-MS는 전자 이온화(EI) 질량 프래그먼트가 69.0, 219.0, 502.0m/z인 PFTBA (perfluorotributylamine)을 사용하여 조정하였으며, 오븐은 운반기체로 Helium(He)을 300/10min로 흘려주며, 10분 동안 65℃ 등온조건으로 가열하였다. 트랜스퍼 라인은 300℃로 가열하였으며, 질량 스펙트로미터의 스캔모드는 50-550amu로 하였다. 모든 질량 스펙트럼은 데이터 시스템 라이브러리(NIST 2008)와 대비하여 분석하였다. The operating parameters of GC-MS are shown in Table 2 below. GC-MS was adjusted using PFTBA (perfluorotributylamine) with electron ionization (EI) mass fractions of 69.0, 219.0, and 502.0 m / z. The oven was fed with Helium (He) as carrier gas for 300 / Lt; RTI ID = 0.0 > 65 C < / RTI > The transfer line was heated to 300 ° C and the mass spectrometer was set to a scan mode of 50-550 amu. All mass spectra were analyzed against the data system library (NIST 2008).
HPLC 분석은 포토다이오드 어레이(photodiode array) 검출기를 갖춘 Alliance 2695 HPLC system(Waters; Millford, MA, USA)으로 수행하였다.HPLC analysis was performed on an Alliance 2695 HPLC system (Waters; Millford, Mass., USA) equipped with a photodiode array detector.
하기 표 3에 나타낸 바와 같이, Agilent Zorbax extended C18(5μm, 150mm l. x 5mm i.d.) 컬럼과 용매 A(아세토니트릴) 및 B(0.2% 인산을 함유하는 물)로 구성된 이동상을 사용하였으며, 용매의 구배 용리(10/90 ~ 100/0, v/v)는 유속 1.0mL/min으로 수행하였다. 컬럼 온도는 25℃를 유지하여 수행하였으며, 검출 파장은 루틴(rutin)에 대한 270nm에서 수행하였다. 용매는 0.22μm 필터로 필터하고, 가스를 제거하여 사용하였으며, 샘플 주입량은 10μL로 수행하였다.As shown in Table 3 below, a mobile phase consisting of a column of Agilent Zorbax extended C18 (5 μm, 150 mm 1 × 5 mm id), solvent A (acetonitrile) and B (water containing 0.2% phosphoric acid) The gradient elution (10/90 to 100/0, v / v) was carried out at a flow rate of 1.0 mL / min. The column temperature was maintained at 25 캜, and the detection wavelength was performed at 270 nm for rutin. The solvent was filtered with a 0.22 μm filter, and the gas was removed. The sample injection volume was 10 μL.
GC-MS 및 HPLC 분석을 통해 동백나무 잎 추출물(ECJL)의 활성 성분을 확인한 결과는 도 5 및 도 6에 나타내었다. 액체 크로마토그래피에 의해 XO 저해제, 예컨대 루틴을 확인하였다. 또한 GC-MS에 의해 비타민 E(vitamin E, 25.35%), n-에이코산(eicosane, 10.2%), 네오피타디엔(neophytadiene, 0.91%), 트랜스-스쿠알렌 (3.32%), n-옥타코산(2.65%), 6,9-펜타데카디엔-1-올 (1.51%), α-리놀렌산 (1.41%), 및 n-헥사데칸산(0.61%)의 8가지 활성 성분을 확인하였다.The results of GC-MS and HPLC analysis of the active ingredients of Camellia sinica leaf extract (ECJL) are shown in FIG. 5 and FIG. XO inhibitors, such as routines, were identified by liquid chromatography. In addition, by GC-MS, vitamin E (25.35%), eicosane (10.2%), neophytadiene (0.91%), trans-squalene (3.32% 8.65%), 6,9-pentadecadien-1-ol (1.51%), alpha -linolenic acid (1.41%) and n-hexadecanoic acid (0.61%).
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