KR101500485B1 - Compositions for Alleviating, Preventing or Treating Pain Comprising Ilex paraguayensis Extracts as Active Ingredients - Google Patents
Compositions for Alleviating, Preventing or Treating Pain Comprising Ilex paraguayensis Extracts as Active Ingredients Download PDFInfo
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- KR101500485B1 KR101500485B1 KR1020130044943A KR20130044943A KR101500485B1 KR 101500485 B1 KR101500485 B1 KR 101500485B1 KR 1020130044943 A KR1020130044943 A KR 1020130044943A KR 20130044943 A KR20130044943 A KR 20130044943A KR 101500485 B1 KR101500485 B1 KR 101500485B1
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Abstract
본 발명은 마테 추출물을 유효성분으로 포함하는 통증의 완화, 예방 또는 치료용 조성물을 제공한다. 본 발명의 조성물은 기 발생된 통증에 대해 완화 및 치료 효과를 가질 뿐 아니라 통증이 발생하기 이전에 대상에 투여하면 통증을 예방하는 효과를 나타낸다. 본 발명의 조성물은 정맥주사 또는 피부 도포 등의 방법이 아닌 경구 투여를 통해서도 현저한 통증 완화 효과를 나타내며, 이러한 특징을 갖는 본 발명의 조성물은 식품에 적용 가능성이 높다. The present invention provides a composition for alleviating, preventing or treating pain comprising Matte Extract as an active ingredient. The composition of the present invention not only alleviates and treats the pain generated, but also has an effect of preventing pain when administered to a subject before pain occurs. The composition of the present invention exhibits remarkable pain relieving effect not only by intravenous injection or skin application but also by oral administration, and the composition of the present invention having such characteristics is highly applicable to foods.
Description
본 발명은 마테 추출물을 유효성분으로 포함하는 통증의 완화, 예방 또는 치료용 조성물에 관한 것이다.
The present invention relates to a composition for alleviating, preventing or treating pain comprising a matte extract as an active ingredient.
현재, 진통제로는 아스피린이나 타이레놀 등의 소염진통제가 주류를 이루며, 심한 통증의 경우 모르핀 약물들이 대부분 사용되고 있다. 최근 새로운 통증 억제제를 개발하고 있는데, 통증 치료제 전문 개발사인 자벨린 파마슈티컬스(Javelin Pharmaceuticals)는 중증 수술 후 통증의 치료에 정맥주사 모르핀과 대등한 진통효과를 나타내는 뿌리는 마약성 진통제인 비강 내 모르핀 분무제 ‘릴로민’(Rylomine)을 개발하였다. 또한, 아일랜드 제약회사인 이랜(Elan)이 바다 달팽이독으로부터 개발한 진통제 ‘프라이얼트(Prialt)’가 영국에서 첫 시판되었다.Currently, analgesics such as aspirin and tylenol are the mainstream analgesics, and in the case of severe pain, most of the morphine drugs are used. Javelin Pharmaceuticals, a specialist in pain medicine, is developing a new pain-relieving drug, and its roots, which show analgesic effects equivalent to intravenous morphine for the treatment of pain after severe surgery, Rylomine was developed. In addition, the first painkiller "Prialt" developed by Elan, an Irish pharmaceutical company, was launched in the UK.
만성 악성 종양성 통증은 물론 사회가 고령화됨에 따라 퇴행성 관절염, 요통 관련 질환 환자는 매년 증가 추세에 있으나 모르핀과 같은 기존의 아편제제는 일반인에게 마약작용으로 인하여 사용에 제한이 있어 통증완화제의 수요는 향후 훨씬 더 늘 것으로 예상된다. 또한, 기존의 진통제에 반응하지 않는 통증에 대한 진통제 개발이 크게 요구되고 있고, 진통효과가 상대적으로 큰 것으로 알려진 기존의 아편유사제제 등의 마약성 및 심각한 부작용들로 인해 일반 환자가 편하게 사용할 수 없는 실정이므로 부작용이 없고 진통억제 효능을 갖는 천연자원의 개발이 필요하다.Chronic malignancies As well as benign pains and aging society, patients with degenerative arthritis and back pain-related diseases are on the rise every year. However, existing opioid preparations such as morphine have limited use due to drug action in the general population. Much more is expected. In addition, there is a great demand for the development of analgesics for pain that does not respond to existing analgesic drugs, and because of the narcotic and serious side effects of conventional opioids, which are known to have a relatively high analgesic effect, It is necessary to develop natural resources that have no side effects and have analgesic effect.
마테(Ilex paraguariensis, mate)는 감탕나무과의 상록 소교목으로 감탕나무과에 속하는 높이 6 m 정도의 식물로 남아메리카의 파라과이나 브라질 지역에 분포한다. 야생 상태에서는 본래 윗부분이 둥근 형태를 하고 있지만 재배할 경우에는 그 형태가 변형되어 줄기가 많은 관목이 되고 야생 상태보다 양질의 차잎을 재배할 수 있게 되며, 추수는 2년에 1번씩 한다. 마테의 꽃은 작고 잎겨드랑이에 달리며 4수이며 녹색이고, 열매는 적색 또는 적갈색이고 둥글며 지름 6 ㎜ 정도이다. 마테의 잎은 이미 수천년 전부터 남미 사람들의 음료로 애용되고 있으며, 차나무과(Thea sinensis L.)인 녹차와 비슷한 향을 갖는 차(tea)의 원료이다(Wikipedia, 2011). 잎에는 카페인 성분이 함유되어 있고(2% 내외) 향기가 좋으며, 잎은 따로 추수하고 말려서 물에 우려낸 차로 음용된다. Mate ( Ilex paraguariensis , mate) is an evergreen arboreal tree with a spruce tree. It is a plant of about 6 m in height and belongs to South America in Paraguay and Brazil. In the wild state, the upper part is originally round, but when cultivated, its shape will be transformed into a shrub with a lot of stem, and it will be possible to grow tea leaves of higher quality than the wild state, and the harvest is done once every two years. The flower of Matte is small, running on the axil, 4, green, and the fruit is red or reddish brown, round and about 6 ㎜ in diameter. Mate's leaves have already been used for thousands of years for beverages of South Americans and are a source of tea with an aroma similar to that of green tea (Thea sinensis L.) (Wikipedia, 2011). Leaves contain caffeine (about 2%), good fragrance, and leaves are harvested as a car that is harvested and dried separately.
마테는 칼슘과 철분 등 무기질이 많은 토양에서 자라기 때문에 철분 칼슘 마그네슘 등의 무기질이 많이 포함되어 있으며, 특히 철 함유량이 매우 높고, 녹차의 5배에 달하는 철 함유량을 가진다. 특히나 다른 차에는 철의 흡수를 방해하는 탄닌 성분이 들어있는데 반해 마테에는 탄닌이 거의 들어 있지 않다. 마테차는 마테의 잎을 말려서 부수어 만든 것으로서, 트리테르펜, 카페인및 카페인-유사 화합물을 함유한다. 마테차는 변비, 비만, 어깨 결림, 두통 등의 치료에 효과가 있다고 알려져 있으며, 이러한 마테의 약학 활성은 카페오일퀸산 및 카페인-유사 폴리페놀에 기인한다. 마테의 주요성분은 주로 클로로겐산, 루틴, 케르세틴 등과 같은 플라본이드 성분이 다량 함유되어 있고(SONIA CHANDRA et al., 2004), 항산화 및 항염증 작용, 혈관 이완 및 혈중 지질 억제 작용, 항암 작용, 혈당강하 작용, 체중 감소 효능 등과 같은 다양한 약리 효능이 알려져 있다(Bracesco et al., 2011).Mate is rich in minerals such as calcium, magnesium and magnesium because it grows in rich mineral soil such as calcium and iron. Especially iron content is very high and iron content is five times that of green tea. In particular, other cars contain tannins that interfere with iron absorption, while Mate has few tannins. Matéa is a dried and crumbled leaf of mate, containing triterpenes, caffeine and caffeine-like compounds. Marte is known to be effective in the treatment of constipation, obesity, shoulder stiffness, headache, and the like, and its pharmaceutical activity is attributed to caffeoylquinic acid and caffeine-like polyphenols. (SONIA CHANDRA et al., 2004), antioxidant and anti-inflammatory effects, vasodilatory and lipid-lowering effects, anti-cancer effects, hypoglycemic effects (Bracesco et al., 2011), which are known to be effective in the treatment of diabetes mellitus.
마테에 대한 종래 연구들은 크산틴(xanthine), 카페오일 유도체(caffeoylerivative), 플라보노이드(flavonoid) 및 트리테르페노이드 사포닌(triterpenoid saponin)과 같은 많은 생활성의 화합물의 존재를 발견하였다. 예르바 마테(Yerba mate, ilex paraguariensis)는 항산화 및 세포 보호작용(Filip et al., 2000; Gugliucci and Stahl, 1995), 항비만 및 발열작용(Martinet et al., 1999), 순환계 작용 및 콜레스테롤 저하효과(Gorgen et al., 2005) 및 담즙 촉진 작용(Gorzalczany et at., 2001) 등과 같은 다양한 생물학적 활성이 알려져 있다.
Previous studies on matte have found the presence of many bioactive compounds such as xanthine, caffeoylerivative, flavonoid and triterpenoid saponin. (Martinet et al., 1999), circulatory effects and cholesterol lowering effects (Yerba et al., 2000; Gugliucci and Stahl, 1995), antioxidant and cytoprotective actions (Yerba mate, ilex paraguariensis) (Gorgen et al., 2005) and bile-promoting action (Gorzalczany et al., 2001).
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
본 발명자들은 통증을 효과적으로 완화할 수 있는 인체에 안전한 물질, 특히 식물-유래 물질을 개발하고자 예의 연구 노력하였고, 그 결과 종래에 차의 원료로 사용되고 있는 마테가 통증을 완화, 예방 또는 치료하는데 매우 유효하다는 것을 규명함으로써, 본 발명을 완성하였다.The present inventors have made extensive efforts to develop a safe material for humans, particularly a plant-derived material, capable of effectively relieving pain, and as a result, it is very effective in alleviating, preventing or treating martes pain which is conventionally used as a raw material for tea The present invention has been completed.
따라서 본 발명의 목적은 통증의 완화, 예방 또는 치료용 조성물을 제공하는데 있다.Accordingly, an object of the present invention is to provide a composition for alleviating, preventing or treating pain.
본 발명의 다른 목적은 통증의 완화, 예방 또는 치료용 식품 조성물 및 약제학적 조성물을 제공하는데 있다.
Another object of the present invention is to provide a food composition and a pharmaceutical composition for alleviating, preventing or treating pain.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명 및 청구범위에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention and claims.
본 발명의 일 양태에 따르면, 본 발명은 마테(Ilex paraguayensis) 추출물을 유효성분으로 포함하는 통증의 완화, 예방 또는 치료용 조성물을 제공한다.
According to one aspect of the present invention, there is provided a composition for alleviating, preventing or treating pain comprising an extract of Mare ( Ilex paraguayensis ) as an active ingredient.
본 발명자들은 통증을 효과적으로 완화할 수 있는 인체에 안전한 물질, 특히 식물-유래 물질을 개발하고자 예의 연구 노력하였고, 그 결과 종래에 차의 원료로 사용되고 있는 마테가 통증을 완화, 예방 또는 치료하는데 매우 유효하다는 것을 규명하였다.The present inventors have made extensive efforts to develop a safe material for humans, particularly a plant-derived material, capable of effectively relieving pain, and as a result, it is very effective in alleviating, preventing or treating martes pain which is conventionally used as a raw material for tea .
본 발명의 조성물은 통증의 완화, 예방 또는 치료에 매우 효과적으로 작용한다. The composition of the present invention is very effective for alleviating, preventing or treating pain.
하기의 실시예에서 입증된 바와 같이, 피부 절개 수술에 앞서 본 발명의 조성물을 동물에 투여한 경우, 수술 부위의 통증 민감도가 감소하였으며 신경 분지 결찰 손상을 입은 동물에 본 발명의 조성물을 투여한 경우, 통증 민감도가 감소하였다. As demonstrated in the following examples, when the composition of the present invention was administered to an animal prior to the skin incision surgery, the pain sensitivity at the surgical site was decreased. When the composition of the present invention was administered to animals suffering from damage to the nerve branch ligation , And pain sensitivity decreased.
본 발명의 조성물은 정맥주사 또는 피부 도포 등의 방법이 아닌 경구 투여를 통해서도 현저한 통증 완화 효과를 나타낸다. 이러한 특징을 갖는 본 발명의 조성물은 식품에 잘 적용될 수 있다. The composition of the present invention exhibits remarkable pain relieving effect not only by intravenous injection or skin application but also by oral administration. The composition of the present invention having such characteristics can be applied to foods well.
본 발명의 조성물은 기 발생된 통증에 대해 완화 및 치료 효과를 가질 뿐 아니라 통증이 발생하기 이전에 대상에 투여하면 통증을 예방하는 효과를 나타낸다. The composition of the present invention not only alleviates and treats the pain generated, but also has an effect of preventing pain when administered to a subject before pain occurs.
본 발명의 조성물에서 유효성분으로 이용되는 마테(Ilex paraguayensis)는 감탕나무과의 상록 소교목으로 감탕나무과에 속하는 식물이다. Mate ( Ilex paraguayensis ), used as an active ingredient in the composition of the present invention, is an evergreen arboreous tree belonging to the broad-leaved tree family.
본 발명의 조성물에서 이용되는 마테 추출물을 마테에 추출용매를 처리하여 수득하는 경우에는, 다양한 추출용매가 이용될 수 있다. 본 발명에 따르면, 극성 용매 또는 비극성 용매를 이용할 수 있다. 극성 용매로서 적합한 것은, (i) 물, (ii) 알코올(바람직하게는, 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올, 노말-부탄올, 1-펜탄올, 2-부톡시에탄올 또는 에틸렌글리콜), (iii) 아세트산, (iv) DMFO(dimethyl-formamide) 및 (v) DMSO(dimethyl sulfoxide)를 포함한다. 비극성 용매로서 적합한 것은, 아세톤, 아세토나이트릴, 에틸 아세테이트, 메틸 아세테이트, 플루오로알칸, 펜탄, 헥산, 2,2,4-트리메틸펜탄, 데칸, 사이클로헥산, 사이클로펜탄, 디이소부틸렌, 1-펜텐, 1-클로로부탄, 1-클로로펜탄, o-자일렌, 디이소프로필 에테르, 2-클로로프로판, 톨루엔, 1-클로로프로판, 클로로벤젠, 벤젠, 디에틸 에테르, 디에틸 설파이드, 클로로포름, 디클로로메탄, 1,2-디클로로에탄, 어닐린, 디에틸아민, 에테르, 사염화탄소 및 THF를 포함한다.When the matte extract used in the composition of the present invention is obtained by treating the matte extracting solvent, various extracting solvents can be used. According to the present invention, a polar solvent or a non-polar solvent can be used. Suitable polar solvents are (i) water, (ii) alcohols (preferably methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, Or ethylene glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMFO) and (v) dimethyl sulfoxide (DMSO). Suitable nonpolar solvents are acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1- But are not limited to, pentane, 1-chlorobutane, 1-chloropentane, o -xylene, diisopropyl ether, 2- chloropropane, toluene, 1- chloropropane, chlorobenzene, benzene, diethyl ether, diethylsulfide, Methane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride, and THF.
본 발명의 일 구현예에 따르면, 본 발명에서 이용되는 추출용매는 (a) 물, (b) 탄소수 1-4의 무수 또는 함수 저급 알코올(메탄올, 에탄올, 프로판올, 부탄올 등), (c) 상기 저급 알코올과 물과의 혼합용매, (d) 아세톤, (e) 에틸 아세테이트, (f) 클로로포름, (g) 부틸아세테이트, (h) 1,3-부틸렌글리콜, (i) 헥산 및 (j) 디에틸에테르를 포함한다. 본 발명의 다른 구현예에, 본 발명에서 이용되는 추출용매는 물, 에탄올 또는 이의 조합이다. 본 발명의 특정 구현예에 따르면, 본 발명에서 이용되는 추출용매는 40-80 vol% 주정(grain alcohol)이다.According to an embodiment of the present invention, the extraction solvent used in the present invention may be selected from the group consisting of (a) water, (b) an anhydrous or hydrated lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, propanol, butanol, (E) ethyl acetate, (f) chloroform, (g) butyl acetate, (h) 1,3-butylene glycol, (i) hexane, and (j) Diethyl ether. In another embodiment of the present invention, the extraction solvent used in the present invention is water, ethanol or a combination thereof. According to a specific embodiment of the present invention, the extraction solvent used in the present invention is 40-80 vol% grain alcohol.
본 발명의 일 구현예에 따르면, 본 발명의 마테 추출물은 마테잎에 주정을 가하여 추출한 다음, 여과하여 감압 농축 한 후 동결건조하여 수득한다. According to one embodiment of the present invention, the matte extract of the present invention is obtained by extracting the matte with the addition of alcohol to the matte, followed by filtration, concentration under reduced pressure, and lyophilization.
본 발명에서 이용되는 마테 추출물은 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말 상태로 제조될 수 있다.The matte extract used in the present invention may be prepared in powder form by an additional process such as vacuum distillation and freeze drying or spray drying.
본 명세서에서 사용되는 용어 ‘추출물’은 상술한 바와 같이 당업계에서 조추출물(crude extract)로 통용되는 의미를 갖지만, 광의적으로는 추출물을 추가적으로 분획(fractionation)한 분획물도 포함한다. 즉, 마테 추출물은 상술한 추출용매를 이용하여 얻은 것뿐만 아니라, 여기에 정제과정을 추가적으로 적용하여 얻은 것도 포함한다. 예컨대, 상기 추출물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피 (크기, 전하, 소수성 또는 친화성에 따른 분리를 위해 제작된 것)에 의한 분리 등, 추가적으로 실시된 다양한 정제 방법을 통해 얻어진 분획도 본 발명의 마테 추출물에 포함되는 것이다.As used herein, the term " extract " means that it is used in the art as a crude extract as described above, but broadly includes fractions obtained by further fractionating the extract. That is, the matte extract includes not only those obtained by using the above-described extraction solvent but also those obtained by further applying a purification process thereto. For example, a fraction obtained by passing the above extract through an ultrafiltration membrane having a constant molecular weight cut-off value, and a separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity) The fraction obtained through the purification method is also included in the matte extract of the present invention.
본 명세서에서 용어 ‘유효성분으로 포함하는’이란 하기의 마테 추출물의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 본 발명은 조성물은 천연식물재료인 마테로부터 수득한 추출물을 포함하는 것으로서 과량 투여하여도 인체에 부작용이 없으므로 마테 추출물이 본 발명의 조성물에 포함된 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.As used herein, the term " comprising as an active ingredient " is meant to include an amount sufficient to achieve efficacy or activity of the following Mart extract. Since the composition of the present invention contains an extract obtained from Matte which is a natural plant material, there is no adverse effect on the human body even when it is administered in an excessive amount. Therefore, the quantitative upper limit of the amount of the extract of Matte extract contained in the composition of the present invention is selected by a person skilled in the art .
본 발명에서 용어 “통증(pain)”은 넓은 의미로 사용되며, 통각수용성 통증과 같은 급성 및 만성 통증, 예컨대 체성 통증(somatic pain) 및 내장성 통증(visceral pain); 염증성 통증, 기능장애 통증, 특발성 통증, 표면성 통증(superficial pain), 심부 통증(deep pain), 가려움, 신경병증성 통증, 예컨대, 중추발생성 통증(centrally generated pain) 및 말초발생성 통증(peripherally generated pain), 편두통 및 암 통증을 포함하는 모든 타입의 통증을 의미한다. The term " pain " is used in the present invention in its broadest sense and includes acute and chronic pain such as pain ache and pain, such as somatic pain and visceral pain; Pain, pain, inflammatory pain, dysfunctional pain, idiopathic pain, superficial pain, deep pain, itching, neuropathic pain such as centrally generated pain and peripherally generated pain, migraine, and cancer pain.
상기 용어 “통각수용성 통증(nociceptive pain)”은 신체 조직들을 손상시킬 우려가 있거나 또는 실제로 손상시키는 유해한 자극에 의해 유발되는 모든 통증을 포함하는데 사용되며, 벤 상처(cut), 타박상(bruise), 골절(bone fracture), 압궤손상(crush injury), 화상(burn) 및 이와 유사한 상처에 의한 통증을 제한 없이 포함한다. 조직 손상에 대한 통증 수용체(통각수용기, nociceptors)는 대부분 피부, 근골격계 또는 내부장기(internal organs)에 위치하고 있다. The term " nociceptive pain " is used to include all pain caused by noxious stimuli that may or may damage nervous tissues and may include ben, cut, bruise, fracture, bone pain, bone fracture, crush injury, burn, and similar wounds. Pain receptors for tissue damage (nociceptors) are mostly located in the skin, musculoskeletal or internal organs.
상기 용어 “체성 통증(somatic pain)”은 뼈, 관절, 근육, 피부 또는 결합조직(connective tissue)에서 일어나는 통증을 나타내는데 사용된다. 이러한 타입의 통증은 전형적으로 매우 국부적이다.The term " somatic pain " is used to indicate pain that occurs in bones, joints, muscles, skin or connective tissue. This type of pain is typically very localized.
상기 용어 “내장성 통증(visceral pain)”은 본 명세서에서 호흡기(respiratory), 위장기관(gastrointestinal tract) 및 췌장(pancreas)과 같은 내장장기들, 요로(urinary tract) 및 생식기관(reproductive organs)에서 일어나는 통증을 나타내는데 사용된다. 내장성 통증은 장기피막(organ capsule)의 종양 침범(tumor involvement)에 의해 유도되는 통증을 포함한다. 다른 타입의 내장성 통증은 전형적으로 유강장기(hollow viscus)의 폐색에 의해 유발되며, 간헐적 경련(intermittent cramping) 및 심한 국부 통증이 특징이다. 내장성 통증은 방광염(cystitis) 또는 역류성 식도염(reflux esophagitis)의 경우에서와 같이 염증과 관련될 수 있다.The term " visceral pain " is used herein to refer to any or all of the organs such as respiratory, gastrointestinal tract and pancreas, urinary tract and reproductive organs, Used to indicate pain that occurs. Embolic pain includes pain induced by tumor involvement of the organ capsule. Other types of visceral pain are typically caused by occlusion of the hollow viscus, characterized by intermittent cramping and severe local pain. Embolic pain may be associated with inflammation, as in the case of cystitis or reflux esophagitis.
상기 용어 “염증성 통증”은 외상(trauma), 외과수술, 감염 및 자가면역 질환 등에 의해 유발될 수 있는 활동성 염증(active inflammation)과 관련이 있는 통증을 포함한다.The term " inflammatory pain " includes pain associated with active inflammation, which may be caused by trauma, surgery, infection, and autoimmune diseases.
상기 용어 “표면성 통증(superficial pain)"은 배근(dorsal root)의 신경이 분포된 피부 분절에 따라 느껴지는 통증을 말하며, 자극을 느낀 지점에서 통증을 느끼는 직접적인 통증이다. The term " superficial pain "refers to the pain sensed by the skin segments of the nerves of the dorsal root, and is a direct pain to feel the pain at the point of stimulation.
상기 용어 “심부통증(deep pain)"은 심부 기관에서 유래되는 통증으로 조직의 성격에 따라 통증의 특징과 정도가 다르다. 통각이 특히 예민한 부분은 건(tendon), 심부근만, 인대, 관절, 골막, 혈관 및 신경이다. 일반적으로 심부통증은 감각이 둔하고 주위로 퍼지며 느껴지는 부위가 넓다. 심부나 내장 등의 통증은 그 기전이 복잡하여 표면성 통증보다 통증의 위치를 찾기 어렵고, 오심, 발한, 혈압 상승 등의 문제도 함께 나타난다. The term " deep pain "refers to pain originating from the deep organs, which varies in character and degree depending on the nature of the tissue. Particularly sensitive areas of pain include tendons, In general, deep pain is a dull feeling, spreads to the surrounding area, and the area to be felt is wide. The pain of the deep part or the internal organs is complex, and it is difficult to locate the pain rather than the surface pain, And problems such as an increase in blood pressure also occur.
상기 용어 “신경병증성 통증(neuropathic pain)”은 본 명세서에서 말초 또는 중추신경계의 장애의 결과로 생기는 말초 또는 중추신경계에 의한 비정상적 과정(abnormal processing)의 감각 입력에서 비롯된 통증을 나타내는데 사용된다.The term " neuropathic pain " is used herein to denote pain resulting from sensory input of abnormal processing by the peripheral or central nervous system resulting from disturbance of the peripheral or central nervous system.
상기 용어 “시술 통증(procedural pain)”은 내과, 치과 또는 외과 시술에서 일어나는 통증을 나타내며 상기 시술은 보통 예정되어 있거나 또는 급성 외상과 관련되어 있다.The term " procedural pain " refers to pain that occurs in internal medicine, dentistry, or surgery, and the procedure is usually scheduled or associated with acute trauma.
상기 용어 “가려움(itch)”은 본 명세서에서 넓은 의미로 사용되며, 국부에 제한하여 일반적으로 설명될 수 있는 급성 간헐성 및 지속성의, 모든 타입의 가렵고 찌르는 듯한 감각들을 의미한다. 상기 가려움은 특발성, 알러지성, 대사성, 감염성, 약물-유도성, 간, 신장 질환에 기인하거나 또는 암에 의한 것일 수 있다. “소양증(Pruritus)”은 중증 가려움증(severe itching)이다.The term " itch " is used herein in its broadest sense and refers to all types of itchy, stinging sensations of acute intermittency and persistence that can be generally described by limiting to local. The itch may be due to idiopathic, allergic, metabolic, infectious, drug-induced, liver, kidney disease or by cancer. "Pruritus" is severe itching.
“환자”라 함은 임의의 동물을 의미한다. 본 발명의 일 구현예에서, 상기 환자는 인간이다. 본 발명의 조성물을 이용하여 치료될 수 있는 다른 동물들은 비-인간 영장류들(예컨대, 원숭이, 고릴라, 침팬지), 가축(예컨대, 말, 돼지, 염소, 토끼, 양, 소, 라마), 및 반려동물(예컨대, 기니피그, 래트(rats), 마우스(mice), 도마뱀, 뱀, 개, 고양이, 관상어, 햄스터 및 새)을 포함하나 이에 한정되지는 않는다.&Quot; Patient " means any animal. In one embodiment of the invention, the patient is a human. Other animals that may be treated using the composition of the invention include non-human primates (e.g., monkeys, gorillas, chimpanzees), livestock (e.g., horses, pigs, goats, rabbits, sheep, cows, llamas) But are not limited to, animals (such as guinea pigs, rats, mice, lizards, snakes, dogs, cats, ornamental fish, hamsters and birds).
신경병증성(Neuropathic), 염증성(inflammatory) 및 통각수용성(nociceptive) 통증은 병인학(etiology), 병리생리학(pathophysiology), 진단 및 처치에 있어서 차이가 있다. 통각수용성 통증은 말초감각신경(peripheral sensory neurons)의 특이적 부분(specific subset), 즉 강렬한 또는 유해한 자극에 의해 통각수용기들의 활성화에 반응하여 일어난다. 통각수용성 통증은 일반적으로 민감하고, 자기제한적(self-limiting)이며 잠재적 또는 진행 중인 조직 손상의 경고로 작용함으로서 보호의 생물학적 기능을 제공한다. 통각수용성 통증은 전형적으로 국부에 매우 제한된다. 통각수용성 통증의 예들은, 외상성(traumatic) 또는 외과수술성(surgical) 통증, 분만 진통(labor pain), 염좌(sprains), 골절(bone fractures), 화상(burns), 충돌(bumps), 타박상(bruises), 주사(injections), 치과시술(dental procedures), 피부검사(skin biopsies) 및 폐색(obstructions)을 포함하나 이에 한정되지는 않는다.Neuropathic, inflammatory, and nociceptive pain are different in etiology, pathophysiology, diagnosis and treatment. Acupuncture pain occurs in response to activation of nociceptors by a specific subset of peripheral sensory neurons, that is, intense or harmful stimuli. Acute water-soluble pain is a generally sensitive, self-limiting, and provides a biological function of protection by acting as a warning of potential or ongoing tissue damage. Pain Acceptable pain is typically very limited to locality. Examples of painful painful pain include, but are not limited to, traumatic or surgical pain, labor pain, sprains, bone fractures, burns, bumps, but are not limited to, bruises, injections, dental procedures, skin biopsies and obstructions.
염증성 통증은 수술 후(postoperative), 외상 후(post-traumatic) 통증, 관절염(류마티스성(rheumatoid) 또는 골관절염(osteoarthritis)) 통증, 및 축성 하부요통(axial low back pain)의 경우와 같이 관절(joints), 근육 및 힘줄(tendons)의 손상과 관련된 통증을 포함하는 조직 손상 또는 염증이 있는 경우에 발생하는 통증이다.Inflammatory pain is associated with joints such as postoperative, post-traumatic pain, arthritis (rheumatoid or osteoarthritis) pain, and axial low back pain. ), Pain associated with damage to muscles and tendons, or pain when there is a tissue injury or inflammation.
통각수용성 통증과 대조적으로, 신경병증성 통증은 실제 “타는 듯한(burning),” “감전된 듯한(electric),” “얼얼하거나 저린(tingling),” 또는 “쿡쿡 쑤시는(shooting)” 것으로 묘사된다. 신경병증성 통증은 종종 만성 이질통(chronic allodynia)(가벼운 터치와 같은, 보통 통증반응을 유발하지 않는 자극으로 인한 통증으로 정의된다) 및 감각과민(hyperalgesia)(정상적인 통증자극에 대한 높은 감수성으로 정의된다)에 의해 설명되며, 어떤 손상된 조직의 외관상 치료(apparent healing) 후 수개월 또는 수년 동안 지속될 수 있다.Pain In contrast to water-soluble pain, neuropathic pain is depicted as actual "burning," "electric," "tingling," or "shooting" do. Neuropathic pain is often defined as chronic allodynia (defined as pain due to stimuli that do not cause a normal pain response, such as a mild touch) and hyperalgesia (a high susceptibility to normal pain stimuli ) And may last for months or years after apparent healing of any damaged tissue.
본 발명의 일 구현예에 따르면, 본 발명의 조성물은 지속적 말초 신경병증성 통증(persistent peripheral neuropathic pain)의 완화, 예방 또는 치료에 매우 효과적으로 작용한다.
According to one embodiment of the present invention, the composition of the present invention is very effective in relieving, preventing or treating persistent peripheral neuropathic pain.
본 발명의 조성물은 식품 조성물로 제공될 수 있다.The composition of the present invention can be provided as a food composition.
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 마테 추출물뿐 만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 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. When the composition of the present invention is prepared with a food composition, it includes not only mate extract as an active ingredient, but also components which are ordinarily added in food production, for example, proteins, carbohydrates, fats, nutrients, . Examples of the above-mentioned 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 flavors (tau martin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be used as flavorings.
예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 마테 추출물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다.For example, when the food composition of the present invention is prepared as a drink, it may further include citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract, have.
본 발명의 조성물은 약제학적 조성물로 제공될 수 있다.The composition of the present invention may be provided as a pharmaceutical composition.
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 유효성분으로서 마테 추출물뿐 만 아니라, 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is manufactured from a pharmaceutical composition, it includes not only Mate extract as an active ingredient, but also a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, the composition can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, or the like.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. 본 발명의 바람직한 구현예에 따르면, 본 발명의 약제학적 조성물의 1일 투여량은 0.001-100 ㎎/㎏이다.The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate and responsiveness of the patient, Usually, a skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis. According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-100 mg / kg.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.
The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
본 발명의 특징 및 이점을 요약하면 다음과 같다: The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 마테 추출물을 유효성분으로 포함하는 통증의 완화, 예방 또는 치료용 조성물을 제공한다.(a) The present invention provides a composition for alleviating, preventing or treating pain comprising Mart extract as an active ingredient.
(b) 본 발명의 조성물은 기 발생된 통증에 대해 완화 및 치료 효과를 가질 뿐 아니라 통증이 발생하기 이전에 대상에 투여하면 통증을 예방하는 효과를 나타낸다. (b) The composition of the present invention not only alleviates and treats the pain generated, but also has the effect of preventing pain when administered to a subject before pain occurs.
(c) 본 발명의 조성물은 정맥주사 또는 피부 도포 등의 방법이 아닌 경구 투여를 통해서도 현저한 통증 완화 효과를 나타내며, 이러한 특징을 갖는 본 발명의 조성물은 식품에 적용 가능성이 높다.
(c) The composition of the present invention exhibits remarkable pain relieving effect not only by intravenous injection or skin application but also by oral administration, and the composition of the present invention having such characteristics is highly applicable to food.
도 1은 실험동물에 마테 추출물을 경구 투여한 다음, 피부 절개 수술을 실시하고 5시간 후 수술 부위의 통증 민감도를 기계적 이질통 평가를 통해 측정한 결과이다.
대조군(n=10), 마테 추출물(300 mg/kg) 투여군(n=10), * p<0.05
도 2는 실험동물에 마테 추출물을 경구 투여한 다음, 피부 절개 수술을 실시하고 6시간 후 실험동물이 22-27 kHz 음력대의 초음파를 발생시키는 횟수를 측정한 결과이다.
대조군(n=10), 마테 추출물(300 mg/kg) 투여군(n=10), * p<0.05
도 3은 신경 분지 결찰 손상 수술 전 실험동물의 통증 역치값을 측정한 결과이다.
대조군(n=10), 마테 추출물(300 mg/kg) 투여군(n=10)
도 4는 신경 분지 결찰 손상 수술 후 실험동물에 마테 추출물을 14일간 경구투여한 후 통증 역치값을 측정한 결과이다.
대조군(n=10), 마테 추출물(300 mg/kg) 투여군(n=10), * p<0.05FIG. 1 is a result of measuring the pain sensitivity of the
Control group (n = 10), mate extract (300 mg / kg) group (n = 10), p <0.05
FIG. 2 shows the results of measurement of the number of times that the animals were exposed to 22-27 kHz ultrasonic waves after oral administration of mote extract to an experimental animal and after 6 hours of skin incision operation.
Control group (n = 10), mate extract (300 mg / kg) group (n = 10), p <0.05
FIG. 3 shows the result of measuring the pain threshold value in the experimental animals before the nerve branch ligation injury.
Control group (n = 10), matte extract (300 mg / kg) group (n = 10)
FIG. 4 shows the result of measuring the pain threshold value after oral administration of Mart extract to the experimental animals after 14 days of nerve branch ligation injury surgery.
Control group (n = 10), mate extract (300 mg / kg) group (n = 10), p <0.05
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 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 Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예Example
실험방법Experimental Method
1. 마테 추출1. Matte Extract
천연물 추출물 시료는 경동시장 내에 있는 ㈜약수당(한국)에서 건조된 마테잎을 원물로 구입하였으며, 추출 전 세절하여 추출하였다. 마테 원물 100 g당 70 vol% 주정을 10배 첨가하여 80℃에서 4시간 동안 추출한 후 여액 및 잔사 추출액을 합하여 여과 후 감압 농축하였다. 모든 추출물은 여과 및 감압농축을 거쳐 동결건조한 후 분말화하여 실험에 사용하였다.
Natural extract extracts were purchased from Kangdong Market (Korea), located in Kyungdong Market, and were extracted as raw materials before extraction. After adding 70 vol% alcohol per 100 g of matrix
2. 실험동물2. Experimental animals
Sprague-Dawley(SD) 랫트(200-250 g, 웅성)는 (주)Samtako에서 분양받아 실험동물용 사육상자에 일주일간 적응시킨 후 실험에 사용하였다. 동물의 사육은 온도 22±1℃, 습도 55± 5%, 밤낮주기(12 시간 낮/ 12 시간 밤), 조도 300 Lux의 조건하에 이루어졌으며, 사료 및 음수는 자유 급여하였다. 모든 동물들은 KFRI-IACUC(Korea Food Research Institute, Institutional Animal Care and Use Committee)의 실험동물 사용지침에 의해 관리되었다.
Sprague-Dawley (SD) rats (200-250 g, male) were purchased from Samtako Co., Ltd. and used for experiments for one week in an experimental animal breeding box. The animals were fed under the conditions of temperature 22 ± 1 ℃, humidity 55 ± 5%, day and night cycle (12 hours day / 12 hours night), illumination 300 lux, feed and water free. All animals were managed by the KFRI-IACUC (National Food Research Institute, Laboratory Animal Care and Use Committee) guidelines.
3. 시료조제 및 투여3. Sample Preparation and Administration
적응 후 정상으로 판단된 동물에 대하여 체중을 측정하고 무작위적으로 실험군을 분리하였으며, 실험동물의 개체식별은 피모색소표시법을 이용 실시하였다. 마테 70% 주정 추출물 시료는 2차 증류수에 적정 농도로 용해 및 현탁시켜 제조하였다. 제조된 시료는 수술 30분 전 300 mg/kg/5 ml의 용량으로 경구투여 하였으며, 대조군은 동량의 2차 증류수를 수술 30분 전 경구투여 하였다.
Body weight was measured for normal animals after the adaptation, and the experimental group was randomly selected. The animal identification of the experimental animals was carried out using the pigment coloring method.
4. 통증 동물모델 제작4. Pain modeling
4-1. 피부 절개 모델(skin incision model)4-1. Skin incision model
랫트 피부 절개모델은 Brennan에 의해 제안되었다(Brennan, 1996). 일반적으로 수술 후 통증은 급성통증의 한 형태로 생각되고 있으며, 랫트의 절개모델은 인간의 수술 후 통증 상태와 유사하다고 생각되고 있다. 펜토바르피탈을 이용하여 SD 웅성 랫트(200-250 g)를 전신마취 하고 왼쪽 발바닥을 10% 포비돈액으로 소독 후 발 뒤꿈치 끝부분 0.5 cm 떨어진 부분에서 시작하여 세로방향으로 1 cm 길이의 피부와 근막을 11번 수술용 칼로 절개하였다. 절개한 부분의 발바닥 근육(족저근)을 포셉으로 들어 올려 1 cm 길이를 분리하였다. 세로방향의 양쪽 끝부분은 발바닥 근육이 떨어지지 않게 조심해서 들어 올려 분리하고 절개된 부분을 부드럽게 압박하여 지혈하였다. 지혈된 절개부위의 근막과 피부는 나일론 4-0 봉합사로 봉합 후 10% 포비돈액으로 소독하였다. 수술 후 감염방지를 위해 항생제 연고를 도포하고, 사육케이지에 옮겨 회복시켰다. 관찰기간 중 감열이 발생하거나, 봉합부위가 터진 동물과 부종이 생긴 동물은 실험에서 제외시켰다.
A rat skin incision model was proposed by Brennan (Brennan, 1996). Generally, postoperative pain is thought to be a form of acute pain, and the incision model of the rat is thought to be similar to the postoperative pain state in humans. SD male rats (200-250 g) were anesthetized using pentobarbital and the left footpad was disinfected with 10% povidone solution and then started at a distance of 0.5 cm from the tip of the heel. The skin and fascia Were incised with a No. 11 surgical knife. The plantar muscle (plantar muscle) of the incision was lifted with a forceps to separate a length of 1 cm. At both ends of the vertical direction, the foot muscles were lifted carefully to avoid falling, and the bleeding was performed by gently pressing the incision. The fascia and skin of the bleeding incision site were closed with nylon 4-0 suture and disinfected with 10% povidone solution. After surgery, antibiotic ointment was applied to prevent infection and transferred to a cage for restoration. Animals that developed fever during the observation period, or sutures and edema were excluded from the study.
4-2. 신경 분지 결찰 손상(Spared nerve injury, SNI) 4-2. Spinal nerve injury (SNI)
신경 분지 결찰 손상 동물모델은 Decosterd 및 Woolf에 의해 제안되었다(Decosterd & Woolf, 2000). 펜토바르피탈을 이용하여 SD 웅성 랫트(200-250 g)를 전신마취 하였다. 전신마취 하에서 랫트의 좌측 넓적다리의 측면 피부를 면도하고 절개하고 대퇴이둔근(biceps femoris)을 분리한 후 좌골신경의 세 말단분지를 노출시켰다. 좌골신경은 비복신경(sural nerve), 총비골신경(common peroneal never), 경골신경(tibial nerve)의 세 가닥의 신경으로 이루어져있다. 이중 비복신경은 손상을 가하지 않고 온전히 유지해야하는데 좌측다리 기준에서 관찰시 오른쪽으로 분기해 있으며, 가장 작은 신경이다. 총비골신경, 경골신경은 다리 방향으로 근육을 따라 분기해 있으며, 각각 분리하여, 나일론 4-0 봉합사를 이용하여 단단히 결찰한 후, 포셉과 가위를 이용하여 2-4 mm 길이를 절단하여 제거하였다. 신경절단을 마무리 한 후, 근육층을 봉합사로 봉합한 다음, 피부 절개부위를 다시 봉합하여 실험동물을 사육케이지로 옮겨 회복시켰다.
The nerve branch ligation impaired animal model was proposed by Decosterd and Woolf (Decosterd & Woolf, 2000). SD male rats (200-250 g) were anesthetized with pentobarbital. Under general anesthesia, the lateral skin of the left thigh of the rat was shaved, incised, and the biceps femoris separated and exposed to the three terminal branches of the sciatic nerve. The sciatic nerve consists of three nerves of the sural nerve, the common peroneal nerve, and the tibial nerve. The double sympathetic nerve should remain intact without damage, branching to the right when viewed from the left leg reference, and the smallest nerve. The total peroneal nerve and tibial nerve branches along the muscles in the direction of the leg. They were separated and ligated firmly using nylon 4-0 suture, and then cut by 2-4 mm length using forceps and scissors . After finishing the nerve cutting, the muscle layer was sutured with a suture, and the skin incision site was closed again, and the experimental animals were transferred to a breeding cage to recover.
5. 평가방법5. Evaluation Method
5-1. 기계적 이질통 평가(von frey filament test)5-1. Von frey filament test
동물통증모델 제작 후 기계적 이질통의 정도를 측정하기 위한 방법으로 Chaplan 등에 의해 기술되었다(Chaplan et. al, 1994). 랫트를 그물눈의 크기가 2×2 mm 인 철망 실험대 위에 설치된 아크릴 상자에 넣고 15분 이상 적응시킨 뒤, 쥐의 움직임 등이 조용해지면 연속된 굵기의 본 프레이 필라멘트(Stoelting, 미국)를 사용하여 통증 역치(g) 값을 평가하였다. 필라멘트를 좌측 환부 발바닥에 수직으로 접촉시키고 5-6초간 유지시켜 랫트가 신속한 회피반응을 보이거나 또는 hairs를 떼면서 즉시 움찔하거나 발바닥을 핥으면 양성반응을 보인 것으로 간주한다. 중앙부의 본 프레이 필라멘트부터 자극하여 양성반응을 보이면 약한 필라멘트로 자극하고, 양성반응이 없으면 강한 필라멘트로 자극하며 진행한다. 양성반응을 나타내는 최소의 자극 크기를 역치로 하며, 15 g 이상에서도 반응이 없을 때를 상한선으로 하여 더 이상 적용하지 않는다.
A method for measuring the degree of mechanical allodynia after animal pain modeling has been described by Chaplan et al. (Chaplan et al., 1994). The rats were placed in an acrylic box placed on a wire mesh test bench with a mesh size of 2 x 2 mm and adapted for at least 15 minutes. When the movement of the mice became quiet, the continuous whitening prefilament (Stoelting, USA) (g) were evaluated. The filament is contacted vertically on the left footpad and maintained for 5-6 seconds, and the rat is regarded as showing a positive avoidance reaction or showing a positive response if it immediately flaps or licks the foot as the hairs are released. Stimulate with weak filaments when stimulating positive filaments from central filaments, stimulating with weak filaments, and stimulating with strong filaments. The minimum stimulation size for positive reactions should be considered as a threshold, and the upper limit should not be applied when there is no reaction even at 15 g or more.
5-2. 초음파 발성음(ultrasound vocalization calls)5-2. Ultrasound vocalization calls
랫트는 통증, 고통, 위축, 스트레스 상태에 있을 때 초음파를 발생시키며, 그 초음파 범위는 22-27 KHz 로 보고되고 있다(Portfors, 2007). 수술 후 3.5 시간, 6 시간 및 24 시간의 통증 정도를 알아보기 위하여 각 10분 동안 USV 측정 시스템(Sonotrack, ver 1.5.0, Metris, 네덜란드) 장비를 이용하여 통증을 느낄 때 랫트가 내는 초음파(22-27 KHz) 발성음을 측정하였다. 초음파를 측정할 수 있는 아크릴 상자에 랫트를 넣어두고 15분 동안 안정화 시킨 후 10분 동안 초음파 측정 실험을 진행하였다.
Rats produce ultrasound when they are in pain, distress, atrophy or stress, and their ultrasound range is reported to be 22-27 KHz (Portfors, 2007). To assess the degree of pain at the 3.5, 6, and 24 hours postoperatively, USV measurement system (Sonotrack, ver 1.5.0, Metris, Netherlands) was used for 10 minutes each. Ultrasound -27 KHz). The rats were placed in an acrylic box capable of measuring ultrasound, stabilized for 15 minutes, and ultrasonic measurement was conducted for 10 minutes.
실험결과Experiment result
기계적 이질통 평가를 통한 마테의 통증 완화 효과 확인Assessment of Mate's pain relief through mechanical allodynia evaluation
피부 절개 수술 5시간 후에 수술 부위의 통증 민감도를 측정하기 위하여 기계적 이질통 평가를 하였다. 그 결과, 대조군의 통증 역치(g) 값이 0.279±0.058 (g)인데 비하여 마테 300 mg/kg 군은 1.112±0.375(g)로 통증을 느끼는 힘의 크기가 유의적(p<0.05)으로 증가함을 확인하였다. 또한, 수술 후 1일(POD1) 통증 역치 결과는 통계적 유의성은 나타나지 않았지만 여전히 마테 300 mg/kg 군에서 통증 역치(g) 값이 증가하는 경향을 확인하였다.
After 5 hours of skin incision, mechanical allodynia was evaluated to determine the pain sensitivity at the surgical site. As a result, the pain threshold value (g) of the control group was 0.279 ± 0.058 (g), whereas that of the matte 300 mg / kg group was 1.112 ± 0.375 (g) Respectively. In addition, there was no statistical significance in the results of POD1 pain (POD1), but the pain threshold (g) tended to increase in the 300 mg / kg group.
초음파 발성음 측정을 통한 마테의 완화 효과 확인Determination of Mate's Relaxation Effect by Ultrasonic Speech Sound Measurement
피부 절개 수술 후 3.5 시간, 6 시간, 24 시간(POD1)의 시간대 별로 실험동물이 통증을 느낄 때 유발하는 초음파 음력대(22-27 kHz)를 측정 후, 그 횟수를 정량화하여 마테의 통증 완화 효과를 확인하였다. 수술 6 시간 후, 초음파 발성음 측정값에서 대조군이 10.4±1.869(calls)인데 비하여 마테 300 mg/kg 군은 5.1±1.233(calls)을 기록하여 유의적(p<0.05)으로 감소함을 확인하였다. 다른 시간대인 3.5 시간, POD1에서도 대조군에 비하여 마테 300 mg/kg 군의 22-27 kHz 초음파 측정 기록이 감소하였다.
(22-27 kHz), which is caused when the animals feel pain in the time period of 3.5 hours, 6 hours, 24 hours (POD1) after the skin incision operation, is quantified and quantified, Respectively. At 6 hours after surgery, the ultrasonic sound level was 10.4 ± 1.869 (calls) in the control group, whereas it was significantly decreased (p <0.05) by recording 5.1 ± 1.233 (calls) in the maternal 300 mg / kg group . At other times of the day, 3.5 hours, POD1 showed a 22-27 kHz ultrasound measurement record of 300 mg / kg of Matte compared to the control group.
기계적 이질통 평가를 통한 마테의 통증 완화 효과 확인Assessment of Mate's pain relief through mechanical allodynia evaluation
신경 분지 결찰 손상 수술 후 14일 동안 장기적으로 마테를 경구투여하며 통증 민감도를 측정하기 위하여 기계적 이질통 평가를 하였다. 그 결과, 대조군의 통증 역치(g) 값이 0.429±0.123(g)인데 비하여 마테 300 mg/kg 군은 2.88±1.079(g)로 통증을 느끼는 힘의 크기가 유의적(p<0.05)으로 증가함을 확인하였다. 이 결과, 마테의 통증완화 효과는 단기모델 뿐 만 아니라 장기모델에서도 확인되었다. 신경 분지 결찰 손상 수술 전 두 군간의 통증에 대한 베이스라인을 확인하기 위하여 기계적 이질통 평가를 실시하였다. 그 결과, 두 실험군 사이의 수술 전 통증 역치(g) 값은 동일하였음을 확인 하였다.
Nerve branch ligation injury For 14 days after surgery, mate was orally administered in the long term and mechanical allodynia was evaluated to determine pain sensitivity. As a result, the pain threshold value (g) of the control group was 0.429 ± 0.123 (g), while that of the maté 300 mg / kg group was 2.88 ± 1.079 (g) Respectively. As a result, the pain relief effect of Mate was confirmed not only in the short - term model but also in the long - term model. Nerve branch ligation injury To assess the baseline pain between the two groups, mechanical allodynia evaluation was performed. As a result, it was confirmed that the preoperative pain threshold value (g) was the same between the two experimental groups.
결론conclusion
본 발명인 마테(Ilex paraguayensis) 추출물은 통증 동물모델인 피부 절개 모델과 신경 분지 결찰 손상 모델에서 모두 통증을 완화시키는 효과를 확인하였으며, 특히 단기효과 뿐 만 아니라 장기효과도 확인할 수 있었다. 따라서, 본 발명의 마테 추출물을 유효성분으로 포함하는 조성물을 이용하여 통증 예방, 완화 또는 치료하는 효과를 나타낸다.
The extract of Ilex paraguayensis of the present invention confirmed the pain relieving effect both in the pain model animal, the skin incision model and the nerve branch ligation damage model, and in particular, the short-term effect as well as the long-term effect. Accordingly, the present invention provides a method for preventing, alleviating, or treating pain using a composition comprising the matte extract of the present invention as an active ingredient.
참고문헌references
1. Polyphenolic Compounds, Antioxidant Capacity, and Quinone Reductase Activity of an Aqueous Extract of Ardisia compressa in Comparison to Mate (Ilex paraguariensis) and Green (Camellia sinensis) Teas, J. Agric. Food Chem. 52, 3583-3589(2004).1. Polyphenolic Compounds, Antioxidant Capacity, and Quinone Reductase Activity of an Aqueous Extract of Ardisia compressa in Comparison with Mate (Ilex paraguariensis) and Green (Camellia sinensis) Teas, J. Agric. Food Chem . 52, 3583-3589 (2004).
2. Recent advances on Ilex paraguariensis research: Minireview, Journal of Ethnopharmacology, 136:378384(2011).2. Recent advances on Ilex paraguariensis research: Minireview, Journal of Ethnopharmacology , 136: 378384 (2011).
3. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 64:493-501(1996).3. Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 64: 493-501 (1996).
4. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149-58(2000).4. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87: 149-58 (2000).
5. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55-63(1994).5. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53: 55-63 (1994).
6. Portfors CV. Types and functions of ultrasonic vocalizations in laboratory rats and mice. J Am Assoc Lab Anim Sci. 46(1):28-34(2007).
6. Portfors CV. Types and functions of ultrasonic vocalizations in laboratory rats and mice. J Am Assoc Lab Anim Sci . 46 (1): 28-34 (2007).
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (7)
A pharmaceutical composition for alleviating, preventing or treating neuropathic pain or post-surgical pain comprising an alcohol extract of Mate ( Ilex paraguayensis ) as an active ingredient.
The composition of claim 1, wherein the composition is a composition for preventing pain.
2. The composition of claim 1, wherein the neuropathic pain is persistent peripheral neuropathic pain.
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| US11918014B2 (en) | 2019-04-06 | 2024-03-05 | Cargill, Incorporated | Sensory modifiers |
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| US11351214B2 (en) | 2017-10-06 | 2022-06-07 | Cargill, Incorporated | Methods for making yerba mate extract composition |
| US11701400B2 (en) | 2017-10-06 | 2023-07-18 | Cargill, Incorporated | Steviol glycoside compositions with reduced surface tension |
| US11717549B2 (en) | 2017-10-06 | 2023-08-08 | Cargill, Incorporated | Steviol glycoside solubility enhancers |
| US11344596B2 (en) | 2019-04-06 | 2022-05-31 | Cargill, Incorporated | Methods for making botanical extract composition |
| US11918014B2 (en) | 2019-04-06 | 2024-03-05 | Cargill, Incorporated | Sensory modifiers |
| US11931391B2 (en) | 2019-04-06 | 2024-03-19 | Cargill, Incorporated | Methods for making botanical extract composition |
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