KR20170119871A - Zanthoxylum piperitum leaf extracts, fractions or compounds isolated therefrom with the effect of anti-inflammatory and analgesic - Google Patents
Zanthoxylum piperitum leaf extracts, fractions or compounds isolated therefrom with the effect of anti-inflammatory and analgesic Download PDFInfo
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- KR20170119871A KR20170119871A KR1020160048071A KR20160048071A KR20170119871A KR 20170119871 A KR20170119871 A KR 20170119871A KR 1020160048071 A KR1020160048071 A KR 1020160048071A KR 20160048071 A KR20160048071 A KR 20160048071A KR 20170119871 A KR20170119871 A KR 20170119871A
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- pain
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- arthritis
- ethyl acetate
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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- A61K36/758—Zanthoxylum, e.g. pricklyash
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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Abstract
본 발명은 초피 (Zanthoxylum piperitum)의 잎 추출물 또는 이로부터 분리된 화합물을 포함하는 관절염 치료 및 예방용 약학적 조성물에 관한 것으로서, 더욱 상세하게는 초피 잎에서 분리된 쿼세틴-3-O-알파-L-람노사이드 (쿼시트린, Quercitrin)와 캠퍼롤-3-O-알파-L-람노사이드 (아프젤린, Afzelin), 이들 화합물을 포함하는 초피 잎 추출물에서 중추성 및 말초성 통증억제 효과와 항염증 효과, 이를 기반으로 한 관절염 개선 효과를 확인하였다. 이에 본 발명은 통증과 염증 개선효과를 기반으로 한 관절염 치료 및 예방용 조성물로써 초피 잎 추출물 및 이로부터 분리된 화합물과 이 성분들을 최적의 조건으로 포함할 수 있는 공정방법에 관한 것이다.
즉, 본 발명에 따른 초피 잎 추출물 및 쿼시트린과 아프젤린은 통증 유도 동물모델과 염증 유도 모델, 관절염 유도 모델에서 통증과 염증, 관절염을 모두 억제하며, 이에 대한 분자적 지표에서도 매우 우수한 발현 및 억제 양상을 나타내어 통증 및 염증을 기반으로 하는 관절염 치료에 매우 유효한 약학 조성물로 사용할 수 있다.
The present invention relates to a pharmaceutical composition for treating and preventing arthritis, which comprises a leaf extract of Zanthoxylum piperitum or a compound isolated therefrom, and more particularly to a pharmaceutical composition for treating and preventing arthritis comprising quercetin-3-O-alpha-L - Central and peripheral pain suppression and antiinflammatory effects of Laminocide (Quercitrin) and camphorol-3-O-alpha-L-Laminoside (Afzelin) , And the improvement effect of arthritis based on this was confirmed. Accordingly, the present invention relates to a composition for treating and preventing arthritis based on the effect of improving pain and inflammation, a compound of papaya leaf extract and a compound isolated therefrom, and a process capable of including these components under optimal conditions.
In other words, the extracts of papaya leaf, aquaticin and afzelin according to the present invention suppress pain, inflammation and arthritis both in pain induction animal model, inflammation induction model and arthritis induction model, and excellent expression and inhibition And can be used as a pharmaceutical composition highly effective for the treatment of arthritis based on pain and inflammation.
Description
본 발명은 초피 (Zanthoxylum piperitum) 잎 추출물, 이의 분획물 또는 이로부터 분리된 화합물을 함유하는 항염증 및 진통에 유효한 조성물에 관한 것이다.
The present invention relates to an anti-inflammatory and analgesic composition comprising Zanthoxylum piperitum leaf extract, fractions thereof or compounds isolated therefrom.
통증은 자극에 대하여 즉각적인 반응을 보이는 1차 통증과 서서히 느끼는 2차 통증으로 나눌 수 있다. 이러한 통증은 피부나 조직에 분포되어 있는 수용체를 통하여 감지되는데, 주로 물리적인 자극이나 열에 의한 자극 및 화학물질에 의한 자극을 담당하는 수용체가 자극을 받아들이면 중추신경계로 전달되어 통증을 느끼게 된다. 이러한 통증은 다른 감각과는 달리 지속될수록 더 민감해지며, 약한 통증에도 감각반응은 더욱 높아진다. 통증을 치료하는 기존의 진통제는 크게 비마약성 진통제와 마약성 진통제로 분류되는데, 마약성 진통제로는 코데인, 모르핀, 펜타닐 등이 있으며, 비마약성 진통제로는 아세트아미노펜, 아스피린, 이부프로펜, 나프록센, 케토프로펜 등이 속해 있다. 비마약성 진통제는 주로 아라키돈산으로부터 프로스타글란딘이 생성되는 단계를 억제하며, 일반적인 통증과 관절염에 수반되는 통증, 해열 및 염증에 관한 치료 효과도 가지고 있어서 진통 및 소염제로 사용되고 있다. 주로 사용되고 있는 비마약성 진통제는 일반적으로 진통 및 해열 작용을 나타내는 아세트아미노펜과 프로스타글란딘을 억제하여 진통 및 해열, 소염 작용을 나타내는 비스테로이드성 소염진통제 (NSAIDs)로 분류된다. 아세트아미노펜과 같은 약물은 미국 류마티스 학회의 지침에서 위장에 대한 부작용이 적기 때문에 염증을 동반하지 않는 골관절염 환자에게 우선적으로 사용하도록 권장되고 있으며, 비스테로이드성 소염진통제는 소염작용이 있기 때문에 주로 염증을 동반한 관절염에 사용하도록 권고하고 있으나, 이러한 비스테로이드성 약물들은 위궤양 및 소화기관 출혈 등의 부작용을 나타낼 수 있기 때문에 주의해서 섭취해야 한다.Pain can be divided into primary pain with an immediate response to stimuli and secondary pain with a gradual feeling. This pain is detected through the receptors distributed in the skin or tissues. When receptors that are mainly responsible for physical stimulation, heat stimulation and chemical stimulation receive stimulation, they are transmitted to the central nervous system and feel pain. Unlike other senses, these pain become more sensitive as they persist, and the sensory response becomes even higher with weak pain. Existing analgesics that treat pain are classified as non-analgesic analgesics and narcotic analgesics. Drug analgesics include codeine, morphine, fentanyl, etc. Non-analgesic analgesics include acetaminophen, aspirin, ibuprofen, naproxen, Pen and so on. Non-analgesic analgesics inhibit the production of prostaglandins mainly from arachidonic acid, and have therapeutic effects on pain, arthritis, and pain associated with general pain and inflammation, and thus they are used as analgesic and anti-inflammatory agents. Most commonly used non-analgesic analgesics are classified as non-steroidal anti-inflammatory analgesics (NSAIDs), which exhibit analgesic, antipyretic, and anti-inflammatory effects by inhibiting acetaminophen and prostaglandins, which generally exhibit analgesic and antipyretic effects. Drugs such as acetaminophen are recommended to be used primarily in patients with osteoarthritis without inflammation because of the low side effects of gastrointestinal tracts in the guidelines of the American Rheumatology Society. Nonsteroidal anti-inflammatory analgesics are usually accompanied by inflammation Although it is recommended to use it in one arthritis, these nonsteroidal drugs should be taken with caution because they may cause side effects such as gastric ulcer and digestive tract hemorrhage.
염증반응은 감염성 물질, 허혈, 항원-항체 반응, 열 또는 상처 등과 같은 여러 가지 자극에 의해 발생하며, 홍반, 부종, 압통, 통증 등의 증상을 나타낸다. 이러한 염증반응은 손상된 조직을 회복시키기 위하여 일어나는 변화를 말하며, 각각의 다른 기전에 의해 매개되는 세 단계로 일어나게 된다. 첫째, 국소적인 혈관확장과 모세혈관 투과성 증가가 특징인 급성 단계, 둘째, 백혈구와 식세포성 세포의 침윤이 특징인 아급성 단계, 셋째, 조직변성과 섬유화가 일어나는 만성 단계가 이것이며, 그 외 많은 다른 기전들이 염증반응 과정에 수반된다. 생체내 염증 발생 원인으로는 다양한 생화학적인 현상이 관여하고 있다. 특히 일산화질소 (nitric oxide, NO)를 발생시키는 효소인 산화질소합성효소 (Nitric Oxide Synthase, NOS)와 프로스타글란딘의 생합성과 관련된 효소들은 염증 반응을 매개하는데 있어서 중요한 역할을 하고 있다. 염증에 사용될 수 있는 약물로는 염증세포 생성과 삼출을 억제할 수 있는 약물과 중간 염증매개물질의 분비를 감소시킬 수 있는 약물이다. 현재 염증에 사용되는 약물은 위에서 언급한 비스테로이드성 약물과 스테로이드성 약물로 나눌 수 있으며, 비스테로이드성 약물은 진통 및 소염제로 널리 사용되고 있다. 소염진통제로 많이 쓰이는 비스테로이드성 항염증제 (NSAIDs)는 생체 내에서 프로스타글란딘의 합성을 억제하여 항염의 효능을 나타내지만, 이의 작용점이 사이클로옥시게네이즈-1 (cyclooxygenase-1, COX-1)과 사이클로옥시게네이즈-2 (COX-2) 모두 해당되어 있어 이에 대한 부작용이 발생할 수 있다. 즉, COX-1은 각 조직에서 혈류의 유지, 세포분화, 점액과 중탄산염의 생성 등에 관여하는 프로스타글란딘의 양을 조절하는데, 이러한 COX-1의 활성을 NSAIDs가 저해함으로써 위장관과 신장의 부작용 및 항혈소판 작용을 나타낸다. 반면 COX-2는 뇌와 신장에서 주로 발견되며, 특히 염증부위에서 많이 유도되므로 이를 선택적으로 저해하는 항염증제 개발이 요구되고 있다.Inflammatory reactions are caused by various stimuli such as infectious substances, ischemia, antigen-antibody reactions, heat or scars, and symptoms such as erythema, edema, tenderness and pain. This inflammatory response is a change that occurs to restore damaged tissue, which occurs in three stages mediated by different mechanisms. First, acute stage characterized by local vasodilatation and increased capillary permeability. Second, subacute stage characterized by leukocyte and phagocytic cell infiltration. Third, chronic stage where tissue degeneration and fibrosis occur. Other mechanisms are involved in the inflammatory process. Various biochemical phenomena are involved in the cause of inflammation in vivo. In particular, enzymes involved in biosynthesis of prostaglandins and Nitric Oxide Synthase (NOS), an enzyme that generates nitric oxide (NO), play an important role in mediating the inflammatory response. Drugs that can be used for inflammation include drugs that can inhibit inflammatory cell formation and exudation, and medications that can reduce the secretion of mediators of inflammation. Currently, drugs used for inflammation can be divided into the above-mentioned nonsteroidal drugs and steroidal drugs, and nonsteroidal drugs are widely used as analgesic and antiinflammatory agents. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used as anti-inflammatory analgesics, inhibit the synthesis of prostaglandins in vivo and exhibit anti-inflammatory effects, but their action points are cyclooxygenase-1 (COX-1) and cyclooxygenase Genesis-2 (COX-2) is all that is involved and can cause side effects. In other words, COX-1 regulates the amount of prostaglandins involved in maintenance of blood flow, differentiation of cells, production of mucus and bicarbonate in each tissue, and inhibition of COX-1 activity by NSAIDs, resulting in adverse effects of gastrointestinal tract and kidney, Lt; / RTI > On the other hand, COX-2 is mainly found in the brain and kidney, and particularly in inflammatory sites, it is required to develop an anti-inflammatory agent that selectively inhibits COX-2.
관절염은 관절의 염증성 변화를 말하며, 관절염의 증상으로는 관절에 압통이 있고, 붓기가 있으며, 이에 따라 관절의 운동범위가 감소한다. 관절염은 크게 퇴행성 관절염과 류마티스 관절염으로 분류된다. 나이가 들어감에 따라 염증성의 변화없이 연골이 소실되고 관절이 변형되면서 퇴행성 변화가 나타나는 퇴행성 관절염과는 달리 류마티스 관절염은 만성 염증성 관절염 중 가장 흔한 질병으로 40대에 주로 발병하고, 심질환, 감염 및 암발병율을 높이며, 고령화 및 경제성장에 따른 사회적인 영향으로 발병률이 더욱 증가할 것으로 예상되는 질병이다. 류마티스 관절염은 주로 관절을 둘러싸고 있는 활막과 주위 연부조직에 만성 염증을 일으키는 전신적인 질환으로 성인 인구의 약 1%에서 나타나며, 발병원인은 아직 확실히 밝혀진 바 없다. Arthritis refers to the inflammatory changes of the joints. Symptoms of arthritis include tenderness in the joints, swelling, and thus the range of motion of the joints. Arthritis is largely classified into degenerative arthritis and rheumatoid arthritis. Unlike degenerative arthritis, where degenerative changes occur as cartilage disappeared as the age progresses, cartilage disappeared, and joint deformation was observed. Rheumatoid arthritis is the most common chronic inflammatory arthritis. It occurs mainly in the forties and causes heart disease, And it is expected that the incidence will increase further due to social impacts due to aging and economic growth. Rheumatoid arthritis is a systemic disease that causes chronic inflammation in the synovial membrane and surrounding soft tissues, which mainly surrounds the joints. It occurs in about 1% of the adult population, and the cause of the disease is not yet clear.
프로스타글란딘은 관절염에서 다양한 기능을 하는 염증 매개체이며, 현재 아스피린, NSAIDs 등이 프로스타글란딘의 생성을 억제하기 위하여 사용되고 있다. 위에서 언급한 것과 같이 아라키돈산은 사이클로옥시게네이즈에 의해 분해되어 프로스타글란딘으로 전환되며, COX-1과 COX-2의 두 가지 형태로 존재하는 사이클로옥시게네이즈는 여러 세포에 존재하지만 항상성 유지에 관여하는 COX-1에 비해서 COX-2는 염증성 세포에서만 발현된다. 이에 COX-2 억제 및 프로스타글란딘의 생성 억제는 소염진통 특히 이에 대한 관절염 치료제의 개발을 위해 중요하다.Prostaglandins are various inflammatory mediators in arthritis. Currently, aspirin, NSAIDs, etc. are used to inhibit the production of prostaglandins. As mentioned above, arachidonic acid is degraded by cyclooxygenase and converted to prostaglandin. Cyclooxygenase, which exists in two forms of COX-1 and COX-2, is present in various cells, but COX Compared to -1, COX-2 is expressed only in inflammatory cells. Therefore, inhibition of COX-2 and inhibition of the production of prostaglandins are important for the development of anti-inflammatory analgesics, particularly arthritis drugs.
한편, 초피 (Zanthoxylum piperitum)는 운향과의 낙엽관목으로서 대개 열매껍질 (과피)을 향신료와 약으로 쓰고 있으며, 씨앗이나 어린 잎, 나무, 줄기 또한 여러 용도로 사용되어진다. 초피 열매는 한방에서 해독, 구충, 진통제로 쓰이고 있으며, 주로 한국, 일본, 중국에 주로 분포하고 있다.On the other hand, Zanthoxylum piperitum is a deciduous shrub of hornblende, usually used as a spice and a medicine, and seeds, young leaves, trees and stems are also used for various purposes. Chowdhury fruit is used as a detox, insect repellent, and analgesic in oriental medicine. It is mainly distributed in Korea, Japan and China.
초피 (Zanthoxylum piperitum)와 관하여 다수의 특허가 공개되어 있다. (특허문헌 1 내지 4 참조) 종래발명에서는 주로 초피의 열매껍질, 뿌리, 목질부를 타겟으로 하여 연구가 진행되어 왔고, 이를 추출한 추출물이 항균, 항바이러스, 살충, 항암, 항염증, 동맥경화, 고지혈증, 당뇨, 골다공증, 피부미백에 유효한 활성을 나타내는 것으로 알려져 있다.A number of patents have been published concerning Zanthoxylum piperitum . (Refer to
하지만 현재까지 발표된 어떠한 문헌에서도 초피 (Zanthoxylum piperitum)의 잎 추출물이 진통 및 관절염 개선에 유효함이 개시된 바가 없다, However, none of the published literatures discloses that leaf extract of Zanthoxylum piperitum is effective in improving pain and arthritis,
특히 초피의 잎 추출물은 쿼세틴-3-O-알파-L-람노사이드와 캠퍼롤-3-O-알파-L-람노사이드가 지표물질겸 활성화합물로서 포함되어 있는데, 이 점만 살피더라도 종래의 초피 열매껍질, 뿌리, 목질부의 추출물과는 차이가 있다. 또한, 쿼세틴-3-O-알파-L-람노사이드 또는 캠퍼롤-3-O-알파-L-람노사이드가 진통 및 염증 개선에 유효함에 대해서는 어떤 문헌에도 개시된 바가 없다,
In particular, the leaf extract of Chamaecyparis obtusa contains quercetin-3-O-alpha-L-rhamnoside and camphorol-3-O-alpha-L-lumnoside as indicators and active compounds, It is different from the extracts of fruit skin, roots and woody parts. In addition, there is no disclosure in the literature that quercetin-3-O-alpha-L-rhamnoside or camphorol-3-O-alpha-L-lamboside is effective for improving analgesia and inflammation,
이에, 본 발명자들은 종래 알려진 소염진통 기반의 관절염 치료제들 보다 효과가 우수하면서 독성 및 부작용이 거의 없는 천연물질을 찾고자 연구를 거듭한 결과, 초피 잎 추출물, 이의 분획물 및 이로부터 분리한 활성화합물이 통증 유도 동물모델과 염증 유도 모델, 관절염 유도 모델에서 우수한 활성을 효과를 나타냄을 확인함으로써 본 발명을 완성하게 되었다. 특히, 초피 (Zanthoxylum piperitum)의 잎 추출물은 산초 (Zanthoxylum schinifolium) 추출물에 대비하여 함유성분의 차이가 극명하고, 또한 진통억제능이 탁월하게 우수하다는 것을 밝힘으로써 본 발명의 진보성을 확보하였다. [하기 실시예의 참고예 참조]Accordingly, the inventors of the present invention have searched for a natural substance which is more effective than conventional anti-inflammatory analgesic-based arthritic drugs and has little toxicity and side effects. As a result, it has been found that the extract of P. japonica, its fractions, The present inventors have completed the present invention by confirming that they exhibit excellent activity in an induction animal model, an inflammation induction model and an arthritis induction model. In particular, the leaf extract of Zanthoxylum piperitum has remarkable differences in contained components compared to Zanthoxylum schinifolium extract and has excellent antinociceptive ability, thus securing the inventive step of the present invention. [Reference example of the following examples]
따라서, 본 발명은 초피 잎 추출물, 이의 분획물 또는 이로부터 분리한 활성화합물을 유효성분으로 포함하는 염증 또는 통증 치료 및 예방용 약제 조성물을 제공하는데 그 목적이 있다.Accordingly, it is an object of the present invention to provide a pharmaceutical composition for treating or preventing inflammation or pain, comprising the extract of P. falciparum, fractions thereof, or an active compound isolated therefrom as an active ingredient.
또한, 본 발명은 초피 잎 추출물, 이의 분획물 또는 이로부터 분리한 활성화합물을 유효성분으로 포함하는 염증 또는 통증 개선용 건강식품 조성물을 제공하는데 그 목적이 있다.It is also an object of the present invention to provide a health food composition for improving inflammation or pain, comprising a papaya leaf extract, a fraction thereof or an active compound isolated therefrom as an active ingredient.
또한, 본 발명은 초피 잎으로부터 활성화합물을 분리하는 방법을 제공하는데 그 목적이 있다.
It is also an object of the present invention to provide a method for separating an active compound from a papaya leaf.
상기한 과제 해결을 위하여, 본 발명은 초피 (Zanthoxylum piperitum) 잎을 C1~4알콜 및 C1~4알콜 수용액으로부터 선택된 1종 이상의 용매로 추출하여 얻은 초피 추출물로, 하기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드 또는 하기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드 또는 이들의 혼합물이 활성성분으로 함유되어 있는 염증 또는 통증 치료 및 예방용 약제 조성물을 제공한다.In order to solve the above-mentioned problems, the present invention relates to a herbal extract which is obtained by extracting Zanthoxylum piperitum leaves with at least one solvent selected from the group consisting of C 1-4 alcohol and C 1-4 alcohol aqueous solution, -3-O-alpha-L-rhamnoside or camphorol-3-O-alpha-L-lamboside represented by the following
[화학식 1][Chemical Formula 1]
[화학식 2](2)
또한, 본 발명의 다른 태양은 상기한 초피 (Zanthoxylum piperitum) 추출물을 에틸아세테이트로 추출하여 얻은 에틸아세테이트 분획물을 함유하는 염증 또는 통증 치료 및 예방용 약제 조성물을 제공하는 것이다.Another aspect of the present invention is to provide a pharmaceutical composition for the treatment and prevention of inflammation or pain containing the ethyl acetate fraction obtained by extracting the above-mentioned Zanthoxylum piperitum extract with ethyl acetate.
또한, 본 발명의 다른 태양은 (A) 쿼세틴-3-O-알파-L-람노사이드, (B) 캠퍼롤-3-O-알파-L-람노사이드, (C) 4'-히드록시-아세토페논, (D) 2,4-디-tert-부틸페놀, 및 (E) 1,2-벤젠디카르복시산으로 이루어진 군으로부터 선택된 1종 이상의 화합물이 포함되어 있는 염증 또는 통증 치료 및 예방용 약제 조성물을 제공하는 것이다.Another aspect of the present invention is a pharmaceutical composition comprising (A) quercetin-3-O-alpha-L-lambsoside, (B) camperol-3-O- alpha-L-lambsoside, (C) 4'- (D) 2,4-di- tert -butylphenol, and (E) 1,2-benzene dicarboxylic acid is contained in the pharmaceutical composition for treating or preventing inflammation or pain .
또한, 본 발명의 다른 태양은 초피 (Zanthoxylum piperitum) 잎을 C1~4알콜 및 C1~4알콜 수용액으로부터 선택된 1종 이상의 용매로 추출하여 얻은 초피 추출물로, 상기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드 또는 상기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드 또는 이들의 혼합물이 활성성분으로 함유되어 있는 염증 또는 통증 개선용 건강식품 조성물을 제공한다.Another embodiment of the present invention is a papaya extract obtained by extracting Zanthoxylum piperitum leaves with at least one solvent selected from the group consisting of C 1-4 alcohol and C 1-4 alcohol aqueous solution. The extract of Quercetin-3 -O-alpha-L-rhamnoside or camphorol-3-O-alpha-L-lambsoside represented by the above formula (2) or a mixture thereof is contained as an active ingredient. do.
또한, 본 발명의 다른 태양은 상기한 초피 (Zanthoxylum piperitum) 추출물을 에틸아세테이트로 추출하여 얻은 에틸아세테이트 분획물을 함유하는 염증 또는 통증 개선용 건강식품 조성물을 제공한다.Another aspect of the present invention provides a health food composition for improving inflammation or pain containing an ethyl acetate fraction obtained by extracting Zanthoxylum piperitum extract with ethyl acetate.
또한, 본 발명의 다른 태양은 (A) 쿼세틴-3-O-알파-L-람노사이드, (B) 캠퍼롤-3-O-알파-L-람노사이드, (C) 4'-히드록시-아세토페논, (D) 2,4-디-tert-부틸페놀, 및 (E) 1,2-벤젠디카르복시산으로 이루어진 군으로부터 선택된 1종 이상의 화합물이 포함되어 있는 염증 또는 통증 개선용 건강식품 조성물을 제공한다.Another aspect of the present invention is a pharmaceutical composition comprising (A) quercetin-3-O-alpha-L-lambsoside, (B) camperol-3-O- alpha-L-lambsoside, (C) 4'- Acetophenone, (D) 2,4-di- tert -butylphenol, and (E) 1,2-benzenedicarboxylic acid. to provide.
또한, 본 발명의 다른 태양은 초피 (Zanthoxylum piperitum)로부터 활성화합물을 분리하는 방법으로서, Further, another aspect of the present invention is a method for separating an active compound from Zanthoxylum piperitum ,
ⅰ) 초피 (Zanthoxylum piperitum)의 잎을 C1~4알콜 및 C1~4알콜 수용액으로부터 선택된 1종 이상의 추출용매로 추출하여 알콜 추출물을 얻는 단계;I) extracting a leaf of Zanthoxylum piperitum with at least one extraction solvent selected from the group consisting of C 1-4 alcohol and C 1-4 alcohol aqueous solution to obtain an alcoholic extract;
ⅱ) 상기 알콜 추출물을 물로 현탁한 후, 노르말 헥산, 디클로로메탄, 에틸아세테이트로 및 노르말 부탄올의 차례로 분획하여, 에틸아세테이트 분획물을 얻는 단계; 및Ii) suspending the alcohol extract in water, and then fractionating the mixture with normal hexane, dichloromethane, ethyl acetate and normal butanol to obtain an ethyl acetate fraction; And
ⅲ) 상기 에틸아세테이트 분획물을 실리카겔 컬럼 크로마토그래피와 중압 크로마토그래피 (MPLC)를 수행하여 상기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드 또는 상기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드를 각각 수득하는 단계; 를 포함하는 공정을 수행하여 활성화합물을 분리하는 방법을 제공한다.Iii) The ethyl acetate fraction was subjected to silica gel column chromatography and medium pressure chromatography (MPLC) to obtain quercetin-3-O-alpha-L-rhamnoside represented by
본 발명이 제공하는 초피나무 (Zanthoxylum piperitum) 잎 추출물, 이의 분획물 또는 이로부터 분리한 활성화합물로서 쿼세틴-3-O-알파-L-람노사이드 및/또는 캠퍼롤-3-O-알파-L-람노사이드는 통증 유도 동물모델, 염증 유도 모델 또는 관절염 유도 모델 실험에서 우수한 치료 효능을 나타내었다. The present invention provides a Zanthoxylum piperitum leaf extract, a fraction thereof or an active compound isolated therefrom, wherein quercetin-3-O-alpha-L-lambsoside and / or camphorol-3-O- Lymphocytes exhibited excellent therapeutic efficacy in pain-induced animal models, inflammation-inducing models, or arthritis-inducing model experiments.
따라서, 초피나무 (Zanthoxylum piperitum) 잎 추출물, 이의 분획물 또는 이로부터 분리한 활성화합물은 염증 질환 또는 통증 질환의 치료, 예방 또는 개선을 위한 약제 또는 건강식품에 유효성성분으로 사용될 수 있다.Accordingly, Zanthoxylum piperitum leaf extract, its fractions or active compounds isolated therefrom can be used as an effective ingredient in medicines or health foods for the treatment, prevention or amelioration of inflammatory diseases or pain diseases.
도 1은 초피 잎 추출물로부터 용매 분획물 및 활성화합물을 수득하는 과정을 보여주는 공정도이다.
도 2는 (A)ZPE6A와 (B)ZPE6C 소분획물의 GC-MS 스펙트럼이다.
도 3은 ZPE6A 또는 ZPE6C 분획물로부터 분리된 4'-히드록시아세토페논, 2,4-디-tert-부틸페놀, 1,2-벤젠디카르복시산에 대하여 통증 억제효능을 확인한 그래프이다.
도 4는 (A)꼬리 회피반응 시험법, (B)열판시험법, (C) 포르말린시험법에 의해 초피 잎 추출물의 통증 억제효능을 확인한 그래프이다.
도 5는 초피 잎 추출물의 BV-2 미세교세포에서 측정된 BDNF 발현양상을 효소면역측정법을 이용하여 측정한 것이다.
도 6은 (A)역전사-PCR 분석법, (B)면역블롯법에 의하여 초피 잎 추출물에 대한 염증지표 인자 iNOS, COX-2, TNF-α, IL-1β, IL-6의 발현억제 효과를 확인한 그래프이다.
도 7은 아만성 귀부종 모델에서 초피 잎 추출물의 항염증 효과를 확인한 결과이다.
도 8은 콜라겐 유도 류마티스 관절염 모델(CIA)에서 확인된 초피 잎 추출물의 류마티스 관절염 치료효과를 확인한 3D로 이미지이다.
도 9는 콜라게나제 유도 골관절염 모델에서 확인된 초피 잎 추출물의 골관절염 치료효과를 확인한 H&E 염색 이미지이다.
도 10은 골관절염 모델에서 확인된 초피 잎 추출물, 쿼세틴-3-O-알파-L-람노사이드 및 캠퍼롤-3-O-알파-L-람노사이드 각각에 대하여 (A)MMP-2, (B)MMP-3, (C)TIMP-1 및 (D)TIMP-2의 생화학적 지표 변화를 확인한 그래프이다.
도 11은 BV-2 미세교세포에서 초피 잎 추출물, 쿼세틴-3-O-알파-L-람노사이드 또는 캠퍼롤-3-O-알파-L-람노사이드를 처치한 후에 K+ 개폐조절 단백질(KCNJ6)의 발현정도를 확인한 그래프이다.
도 12는 BV-2 미세교세포에서에서 포타슘(K+) 전류밀도를 측정한 그래프이다.
도 13은 콜라겐 유도 동물 모델(CIA)에서의 초피 잎 추출물, 쿼세틴-3-O-알파-L-람노사이드와 캠퍼롤-3-O-알파-L-람노사이드 처치 후에 NK세포에서 IFN-γ 발현량을 측정한 그래프이다.
도 14는 콜라겐 유도 동물 모델(CIA)에서의 초피 잎 추출물, 쿼세틴-3-O-알파-L-람노사이드와 캠퍼롤-3-O-알파-L-람노사이드 처치 후에 T세포 및 TH17 세포에서 염증 촉진성 사이토카인(A: IL-6, B: IL-17, C: IL-21 및 D: IL-22)의 발현량을 측정한 그래프이다.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a process drawing showing the process of obtaining a solvent fraction and an active compound from an extract of P. falciparum; FIG.
2 is a GC-MS spectrum of (A) ZPE6A and (B) ZPE6C fractions.
FIG. 3 is a graph showing a pain-inhibiting effect on 4'-hydroxyacetophenone, 2,4-di- tert -butylphenol and 1,2-benzenedicarboxylic acid isolated from ZPE6A or ZPE6C fractions.
Fig. 4 is a graph showing the pain-inhibiting effect of the extract of P. falciparum on the basis of (A) the Tail avoidance reaction test method, (B) the hot plate test method, and (C) the formalin test method.
FIG. 5 is a graph showing the BDNF expression pattern measured by BV-2 microsomal cells of P. japonicus leaf extract using enzyme immunoassay.
FIG. 6 shows the inhibitory effect of the inflammatory index factors iNOS, COX-2, TNF-α, IL-1β and IL-6 on the extract of P. japonica leaf by the reverse transcription-PCR method and the immunoblotting method (A) Graph.
FIG. 7 shows the anti-inflammatory effect of the extract of P. falciparum in the subchronic ear edema model.
FIG. 8 is a 3D image showing the effect of treating the rheumatoid arthritis of the extract of P. haploi obtained in the collagen-induced rheumatoid arthritis model (CIA).
FIG. 9 is a H & E staining image showing the effect of treating the osteoarthritis of the extract of P. hawk extract in a collagenase-induced osteoarthritis model.
10 shows the results of (A) MMP-2, (B), (B) and (B) for each of the extracts of quercetin-3-O-alpha-L-lambsoside and camphorol- ) MMP-3, (C) TIMP-1 and (D) TIMP-2.
11 is a graph showing the effect of K + opening and closing control protein (KCNJ6) after treating papaya leaf extract, quercetin-3-O-alpha-L-lamboside or camphorol-3-O- Of the present invention.
12 is a graph showing the measurement of potassium (K + ) current density in BV-2 microcyst cells.
Figure 13 shows the effect of IFN-y on NK cells after collagen-induced animal model (CIA) papaya leaf extract, quercetin-3-O-alpha-L-lambsoside and camphorol-3-O- And the amount of expression was measured.
14 is a graph showing the effect of the extracts of papaya leaf in collagen-induced animal model (CIA), quercetin-3-O-alpha-L-lambsoside and camphorol-3-O-alpha-L- (A: IL-6, B: IL-17, C: IL-21 and D: IL-22).
이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.
본 발명은 초피 (Zanthoxylum piperitum) 잎 추출물, 상기 추출물을 유기용매로 추출한 용매 분획물 및 이로부터 분리된 쿼세틴-3-O-알파-L-람노사이드와 캠퍼롤-3-O-알파-L-람노사이드를 유효성분으로 함유하는 염증 또는 통증을 개선, 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition comprising Zanthoxylum piperitum leaf extract, a solvent fraction obtained by extracting the extract with an organic solvent, quercetin-3-O-alpha-L-lambsoside isolated therefrom and camphorol-3-O- Prevention, and treatment of inflammation or pain containing the active ingredient as an active ingredient.
또한, 본 발명은 초피 (Zanthoxylum piperitum)로부터 추출물, 분획물 및 활성화합물을 분리하기 위한 일련의 방법을 특징으로 하며, 구체적으로 하기의 단계를 포함한다 : In addition, the present invention features a series of methods for separating extracts, fractions and active compounds from Zanthoxylum piperitum , and specifically includes the following steps:
ⅰ) 초피 (Zanthoxylum piperitum)의 잎을 C1~4알콜 및 C1~4알콜 수용액으로부터 선택된 1종 이상의 추출용매로 추출하여 알콜 추출물을 얻는 단계;I) extracting a leaf of Zanthoxylum piperitum with at least one extraction solvent selected from the group consisting of C 1-4 alcohol and C 1-4 alcohol aqueous solution to obtain an alcoholic extract;
ⅱ) 상기 알콜 추출물을 물로 현탁한 후, 노르말 헥산, 디클로로메탄, 에틸아세테이트로 및 노르말 부탄올의 차례로 분획하여, 에틸아세테이트 분획물을 얻는 단계; 및Ii) suspending the alcohol extract in water, and then fractionating the mixture with normal hexane, dichloromethane, ethyl acetate and normal butanol to obtain an ethyl acetate fraction; And
ⅲ) 상기 에틸아세테이트 분획물을 실리카겔 컬럼 크로마토그래피와 중압 크로마토그래피 (MPLC)를 수행하여 하기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드 또는 하기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드를 각각 수득하는 단계.
Iii) The ethyl acetate fraction was subjected to silica gel column chromatography and medium pressure chromatography (MPLC) to obtain quercetin-3-O-alpha-L-rhamnoside represented by the following
도 1의 공정도를 참조하여, 초피 잎으로부터 추출물, 용매분획물 또는 활성화합물의 분리방법을 보다 구체적으로 설명하면 하기와 같다.The method for separating the extract, the solvent fraction or the active compound from the papaya leaf will be described in more detail with reference to the process drawing of FIG.
ⅰ)단계는, 초피 (Zanthoxylum piperitum) 잎 추출물을 수득하는 단계이다.Step i) is a step of obtaining a Zanthoxylum piperitum leaf extract.
초피는 잎, 줄기, 가지, 뿌리 등 식물 전체를 이용할 수도 있다. 본 발명자들의 실험결과에 의하면 초피의 부위별로 통증 억제능에서 현격한 차이를 나타내었는데, 초피 잎 추출물은 뿌리 추출물에 대비하여 대략 700% 정도의 통증억제율이 우수하였고, 열매 추출물에 대비하여서도 대략 26% 통증억제율이 우수하다는 것으로 확인하였다. [하기 실시예 1 참조] 이에, 본 발명에서는 초피 식물의 여러 부위 중에서도 잎(leaf) 부위를 선택 사용하는 것을 특징으로 한다.Chamaecypally also can utilize whole plants such as leaves, stems, branches, roots. According to the results of the present inventors' experiments, there was a remarkable difference in pain control ability at each part of the plant. The extract of Pepper leaf showed excellent inhibition of pain by about 700% compared to root extract, and about 26% And it was confirmed that the pain suppression rate was excellent. [0052] [52] [52] [52] Hereinafter, the present invention will be described in detail.
초피의 잎은 물로 깨끗이 세척하고 건조시킨 후 음건 세절하였다. 그리고 C1~4알콜 및 C1~4알콜 수용액으로부터 선택된 1종 이상의 추출용매에 침지시켜 추출한다. 상기 추출용매는 메탄올, 에탄올, 이소프로판올, 프로판올, 부탄올 및 이들의 수용액으로부터 선택될 수 있으며, 바람직하기로는 에탄올 또는 에탄올 수용액을 사용하는 것이며, 보다 바람직하기로는 90 ~ 95% 농도의 에탄올 수용액을 사용하는 것이다. 상기 추출용매의 양은 초피 잎의 건조 중량 대비하여 1: 1 ~ 30 중량배로 사용함이 바람직하고, 보다 바람직하기로는 1: 10 ~ 20 중량배로 사용하는 것이며, 본 발명이 추출용매의 사용량을 한정하는 것은 아니다. 추출시 온도는 상온 내지 추출용매의 환류온도 범위일 수 있으며, 구체적으로는 20 ~ 80℃ 온도 조건에서 추출할 수 있다. 상기 추출 시간은 1 내지 10일인 것이 바람직하나 이에 한정되지 않는다. 또한, 추출 횟수는 1회 이상 실시할 수 있으나, 추출이 계속될수록 활성성분의 수득량이 현저히 감소되므로 5회 이상 반복 실시하는 것은 경제적이지 않을 수 있으므로, 추출은 2 ~ 5회 반복 실시하는 것이 바람직하다. The leaves of the mulberry leaves were cleaned with water, dried and shrunk. And extracted by immersing in at least one extraction solvent selected from the group consisting of C 1-4 alcohol and C 1-4 alcohol aqueous solution. The extraction solvent may be selected from methanol, ethanol, isopropanol, propanol, butanol and aqueous solutions thereof. Preferably, ethanol or ethanol aqueous solution is used. More preferably, ethanol aqueous solution having a concentration of 90 to 95% will be. The amount of the extraction solvent is preferably 1: 1 to 30 times by weight, more preferably 1:10 to 20 times by weight, based on the dry weight of the papaya leaf, and the amount of the extraction solvent is limited by the present invention no. The extraction temperature may be in the range of from room temperature to the reflux temperature of the extraction solvent, and specifically, it may be extracted at a temperature of 20 to 80 ° C. The extraction time is preferably 1 to 10 days, but is not limited thereto. The number of times of extraction may be one or more times, but since the yield of the active ingredient is remarkably reduced as the extraction continues, it may not be economical to repeat the extraction more than 5 times. Therefore, the extraction is preferably repeated two to five times Do.
상기 추출방법은 당업계에서 통상적으로 알려진 방법으로, 예를 들면 초임계추출, 아임계추출, 고온추출, 고압추출 또는 초음파추출법 등의 추출장치를 이용한 방법 또는 XAD 및 HP-20을 포함한 흡착 수지를 이용하는 방법 등을 이용할 수 있다. The extraction method is a method commonly known in the art, for example, a method using an extraction device such as a supercritical extraction, a subcritical extraction, a high-temperature extraction, a high-pressure extraction or an ultrasonic extraction, or a method using an adsorption resin containing XAD and HP- And the like can be used.
또한, 추출액은 진공회전증발기 등을 이용하여 감압 농축하여 엑기스를 얻는다. 또한, 얻어진 엑기는 필요에 따라 감압건조, 진공건조, 비등건조, 분무건조, 상온건조 또는 동결건조 등을 실시할 수도 있다.
The extract is concentrated under reduced pressure using a vacuum rotary evaporator or the like to obtain an extract. The resulting extract may also be subjected to vacuum drying, vacuum drying, boiling drying, spray drying, room temperature drying, freeze drying, and the like, if necessary.
ⅱ)단계는, 초피 추출물을 유기용매로 추출하여 에틸아세테이트 분획물을 얻는 단계이다.Step ii) is a step of extracting the herbal extract with an organic solvent to obtain an ethyl acetate fraction.
구체적으로, 상기 ⅰ)단계에서 수득한 초피 잎의 에탄올 추출물을 물에 현탁시킨 후에, 노르말 헥산, 디클로로메탄, 에틸아세테이트 및 노르말 부탄올로 순차적으로 계통 분획하여 얻은 분획물 중에서, 가장 활성이 우수한 에틸아세테이트 분획물을 수득한다. 상기 분획은 1회 내지 5회, 바람직하게는 3회 반복하여 수득할 수 있고, 분획 후 감압 농축 및 건조할 수 있으며 본 발명은 이에 한정하지 않는다.
Specifically, among the fractions obtained by suspending the ethanolic extract of the chickpea leaves obtained in the step (i) in water and sequentially fractionating the fractions with normal hexane, dichloromethane, ethyl acetate and normal butanol, the ethyl acetate fraction having the highest activity ≪ / RTI > The above fraction can be obtained by repeating from 1 to 5 times, preferably 3 times, followed by fractionation and concentration under reduced pressure and drying, but the present invention is not limited thereto.
ⅲ)단계는, 상기 에틸아세테이트 분획물을 실리카겔 컬럼 크로마토그래피와 중압 크로마토그래피 (MPLC)를 수행하여 활성화합물을 분리 수득하는 단계이다.Step iii) is a step of isolating the active compound by subjecting the ethyl acetate fraction to silica gel column chromatography and medium pressure chromatography (MPLC).
구체적으로, 상기 ⅱ)단계에서 수득한 에틸아세테이트 분획물을 실리카 비드(Silica beads)가 충진된 유리컬럼 (5 × 50 cm)에 충진시켜 실리카겔 컬럼 크로마토그래피를 실시한다. 이때, 용출액으로는 에틸아세테이트와 메탄올의 혼합용액을 사용하였으며, 에틸아세테이트/메탄올의 부피비를 90/10로부터 60/40까지 변화시키면서 용출한다. 상기 실리카겔 컬럼 크로마토그래피를 수행한 결과 7개의 분획을 얻었으며, 얻어진 분획물은 ZPE1, ZPE2, ZPE3, ZPE4, ZPE5, ZPE6, ZPE7로 명명하였다. 상기 실리카겔 컬럼 크로마토그래피를 수행하여 얻은 7개의 분획 중에서도 ZPE6가 가장 우수한 활성을 보였으며, 분획 ZPE6을 선택하여 중압 크로마토그래피 (MPLC)를 이후에 실시하였다.Specifically, the ethyl acetate fraction obtained in the step (ii) is loaded on a glass column (5 x 50 cm) filled with silica beads, and subjected to silica gel column chromatography. At this time, a mixed solution of ethyl acetate and methanol was used as an eluent, and elution was carried out by changing the volume ratio of ethyl acetate / methanol from 90/10 to 60/40. Seven fractions were obtained by the above silica gel column chromatography. The obtained fractions were named ZPE1, ZPE2, ZPE3, ZPE4, ZPE5, ZPE6 and ZPE7. Among the seven fractions obtained by performing the above silica gel column chromatography, ZPE6 showed the most excellent activity, and the fraction ZPE6 was selected and then subjected to MPLC (medium pressure chromatography).
선택된 분획 ZPE6는 sephadex LH-20 컬럼에 충진시켜 중압 크로마토그래피 (MPLC)를 실시한다. 이때, 용출액으로는 메탄올 단독용액을 사용하여 용출한다. 상기 중압 크로마토그래피 (MPLC)를 수행한 결과 3개의 소분획을 얻었으며, 얻어진 소분획물은 ZPE6A, ZPE6B, ZPE6C로 명명하였다. 상기 중압 크로마토그래피 (MPLC)를 실시하여 얻은 3개의 소분획 중에서도 ZPE6B가 가장 우수한 활성을 보였으며, 소분획 ZPE6B를 선택하여 활성화합물을 분리한다. The selected fraction ZPE6 is loaded on a sephadex LH-20 column and subjected to medium pressure chromatography (MPLC). At this time, the eluent is eluted with methanol alone solution. As a result of the MPLC, three small fractions were obtained. The obtained fractions were named ZPE6A, ZPE6B and ZPE6C. Among the three small fractions obtained by the above-mentioned MPLC, ZPE6B exhibited the most excellent activity, and the active compound was isolated by selecting the small fraction ZPE6B.
소분획 ZPE6B로부터 활성화합물을 분리하기 위하여, 옥타데실화 실리카가 충진된 역상컬럼을 이용하는 고속액체크로마트그래피 (HPLC)를 수행한다. 이때, 용출액으로는 메탄올과 물의 혼합용액을 사용하며, 바람직하기로는 메탄올과 물이 동등량으로 포함된 50% 메탄올 수용액을 사용하는 것이다.To separate the active compound from the small fraction ZPE6B, high performance liquid chromatography (HPLC) is carried out using a reversed phase column packed with octadecylated silica. At this time, a mixed solution of methanol and water is used as the eluent, and a 50% methanol aqueous solution containing an equal amount of methanol and water is preferably used.
상기 HPLC를 통해 분리된 활성화합물은 핵자기 공명 분광 분석을 통하여, 하기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드 (쿼시트린, Quercitrin)와 하기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드 (아프젤린, Afzelin)로 확인되었다. The active compound separated through HPLC was analyzed by nuclear magnetic resonance spectroscopy to determine the presence of quercetin-3-O-alpha-L-luramnoside (quercitrin) represented by the following formula (1) -3-O-alpha-L-lamboside (Afzelin).
상기에서 분리한 활성성분 1과 활성성분 2는 각각 핵자기 공명 분광 분석을 통해 화학구조를 규명하였다. The
[화학식 1][Chemical Formula 1]
[화학식 2](2)
이상의 분리방법을 통해 수득되는 초피 (Zanthoxylum piperitum) 잎 추출물, 상기 추출물을 유기용매로 추출한 용매 분획물 및 이로부터 분리된 쿼세틴-3-O-알파-L-람노사이드 (화학식 1)와 캠퍼롤-3-O-알파-L-람노사이드 (화학식 2)는 통증 유도 동물모델, 염증 유도 동물모델 및 관절염 유도 동물모델에서 유의성 있는 결과를 보이고 있음을 확인할 수 있었다. 따라서, 초피 잎 추출물, 이의 분획물 및/또는 이로부터 분리된 활성화합물로서 화학식 1 또는 2로 표시되는 화합물은 통증 질환 및 염증 질환의 개선, 예방, 치료를 목적하는 약제 조성물 또는 건강식품 조성물에 유효성분으로 포함될 수 있다.
(1) a Zanthoxylum piperitum leaf extract obtained through the above separation method, a solvent fraction obtained by extracting the extract with an organic solvent, quercetin-3-O-alpha-L-lamboside -O-alpha-L-lamboside (Formula 2) showed significant results in the pain-induced animal model, the inflammation-inducing animal model, and the arthritis-induced animal model. Accordingly, the compound represented by the general formula (1) or (2) as an active compound isolated from a papaya leaf extract, a fraction thereof and / or an active ingredient thereof can be used as a pharmaceutical composition or a health food composition for the purpose of improving, ≪ / RTI >
본 발명에 따른 약제 조성물은 초피 잎 추출물, 이의 분획물 및/또는 이로부터 분리된 활성화합물을 유효성분으로 포함하며, 조성물 총 중량에 대하여 상기 유효성분은 0.1 내지 50 중량%로 포함될 수 있으며, 본 발명이 이에 한정되지 않는다.The pharmaceutical composition according to the present invention may comprise as an active ingredient an extract of P. falciparum, a fraction thereof and / or an active compound isolated therefrom, and the effective ingredient may be contained in an amount of 0.1 to 50% by weight based on the total weight of the composition, The present invention is not limited thereto.
본 발명의 약제 조성물은 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화 하여 사용될 수 있다. 따라서 본 발명의 약제 조성물은 약제의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method. Accordingly, the pharmaceutical composition of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of medicaments.
본 발명의 약제 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 히드록시메틸셀룰로오스, 미결정셀룰로스, 규소화미결정셀룰로오스, 포비돈, 크로스포비돈, 크로스카멜로오스나트륨, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 노이시린, 콜로이드실리콘디옥사이드, 유당, 탈크, 스테아르산마그네슘, 콜로이드 스테아릴마그네슘, 및 광물유 등으로부터 선택된 1종 이상이 포함될 수 있다.Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methylcellulose, hydroxymethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose, povidone, crospovidone, croscarmellose sodium, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, Colloidal silicon dioxide, lactose, talc, magnesium stearate, colloidal stearyl magnesium, mineral oil, and the like.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 트로키제, 로진지, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 조성물에 적어도 하나 이상의 부형제 예를 들면, 락토오스, 사카로오스, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스, 탄산칼슘, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 엘릭실제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세롤젤라틴 등이 사용될 수 있다. 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 주입방식이 일반적일 수 있다. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, troches, rosin, capsules and the like, which may contain at least one excipient such as lactose, saccharose, sorbitol , Mannitol, starch, amylopectin, cellulose, calcium carbonate, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, elixirs, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are used in addition to water and liquid paraffin, May be included. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol gelatin and the like can be used. Parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection or intra-thoracic injection.
본 발명의 약제 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여법이라면 어느 것이나 사용 가능하고, 전신 투여 또는 국소 투여가 가능하나, 전신 투여가 더 바람직하며, 정맥 내 투여가 가장 바람직하다.The pharmaceutical composition of the present invention can be administered orally or parenterally. Any parenteral administration method can be used, and systemic administration or local administration is possible, but systemic administration is more preferable, and intravenous administration is most preferable.
본 발명의 약제 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 약제 조성물은 1일 0.0001 내지 1000 ㎎/㎏으로, 바람직하게는 10 내지 300 ㎎/㎏(몸무게)으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.
The preferred dosage of the pharmaceutical composition of the present invention varies depending on the condition and body weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the pharmaceutical composition of the present invention is preferably administered at a daily dose of 0.0001 to 1000 mg / kg, preferably 10 to 300 mg / kg (body weight). The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
또한, 본 발명에 따른 건강식품 조성물은 초피 잎 추출물, 이의 분획물 및/또는 이로부터 분리된 활성화합물을 유효성분으로 포함하며, 식품, 음료 등의 건강보조 식품에 첨가할 수 있다.In addition, the health food composition according to the present invention contains the extract of P. japonica, fractions thereof and / or active compounds isolated therefrom as an active ingredient, and may be added to health supplements such as food, beverage, and the like.
상기 식품의 종류에는 특별한 제한은 없다. 상기 유효성분을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알콜 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다. 상기 유효성분은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 함유량은 그의 사용 목적 (예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 조성물 중에 유효성분은 0.1 내지 90 중량% 포함될 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.There is no particular limitation on the kind of the food. Examples of foods to which the active ingredient can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolates, snacks, confectionery, pizza, ramen noodles, other noodles, gums, ice cream, , Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense. The active ingredient may be added directly to the food or may be used together with other food or food ingredients, and may be suitably used according to conventional methods. The content of the active ingredient can be suitably determined according to its use purpose (for prevention or improvement). Generally, the active ingredient in the health food composition may be contained in an amount of 0.1 to 90% by weight. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
본 발명의 건강식품 조성물을 이용하여 음료로 제조할 수 있다. 음료에 포함되는 성분으로서 유효성분 이외에 다른 성분의 선택에 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제 (타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The beverage can be prepared using the health food composition of the present invention. There are no particular restrictions on the selection of other ingredients other than the active ingredient as a component to be contained in the beverage, and it may contain various flavors or natural carbohydrates as additional ingredients such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
또한, 본 발명의 건강식품 조성물은 유효성분 이외에도 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 첨가제로 함유할 수 있다. 그 밖에도 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 건강식품 조성물 중에 0.1 내지 20 중량%의 범위에서 선택되는 것이 일반적이다.
In addition, the health food composition of the present invention may contain various additives such as various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and aging agents (cheese, chocolate, etc.) Salts, 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. It can also contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so important, but is generally selected in the range of 0.1 to 20% by weight in the health food composition of the present invention.
이상에서 설명한 바와 같은 본 발명은 다음 실시예에 의거하여 더욱 상세히 설명하겠는바, 본 발명이 이에 한정되는 것은 아니다.
The present invention as described above is explained in more detail based on the following examples, but the present invention is not limited thereto.
[실시예]
[Example]
[통증억제 효능 및 항염증 효능 측정방법][Pain-inhibiting efficacy and anti-inflammatory efficacy measurement method]
본 발명에서 수득한 초피 잎 추출물, 분획물 또는 활성화합물의 통증억제 효능 및 항염증 효능은 하기의 방법으로 측정하였다.
The anti-pain and anti-inflammatory effects of the extracts, fractions or active compounds of the extracts of the present invention were measured by the following methods.
1. 통증억제 효능 확인방법1. Method to confirm pain relieving efficacy
(1) 아세트산 유도 통증모델에 의한 진통효과 (1) analgesic effect by acetic acid induced pain model
아세트산 유도 통증모델 (Acetic acid-induced writhing syndrome test)은 진통효과를 알아보기 위한 동물모델로서, 말초신경계에 작용하는 진통제의 효력시험에 주로 사용된다. 실험동물은 5주령 ICR 마우스 (중앙실험동물, 서울)를 구입하여 1주간 습도 50%, 온도 24~26℃로 유지되는 사육장에서 순화시켰으며, 사료 및 물은 자유롭게 섭취할 수 있도록 공급하였다. 자극물 (irritants)로서 1.5% 아세트산을 마우스의 복강에 주입하면, 이에 의해 복강 내에서 통증을 유발하여 몸을 뒤틀거나, 뒷다리를 쭉 뻗는 동작 등의 라이딩 신드롬 (writhing syndrome) 반응을 보이게 된다. 이에 실험물질을 통증 유발 60분 전에 미리 경구 투여하여 진통효과 정도를 측정하였다.
Acetic acid-induced writhing syndrome test is an animal model for analgesic effects and is mainly used to test the efficacy of painkillers acting on the peripheral nervous system. Five-week-old ICR mice (Central Experimental Animals, Seoul) were purchased from the experimental animals. The animals were kept in a habitat maintained at 50% humidity and 24 ~ 26 ℃ for 1 week. Feed and water were supplied for free consumption. When 1.5% acetic acid is injected into the abdominal cavity of the mouse as irritants, it causes pain in the abdominal cavity and causes a writhing syndrome reaction such as twisting the body or stretching the hind legs. The analgesic effect was measured by oral administration of the
(2) 꼬리 회피반응 시험법에 의한 진통효과(2) Analgesic effect by tail avoidance test
꼬리 회피반응 시험법 (Tail-flick test)은 급성 통증 모델을 이용하여 중 중추신경계에 작용하는 진통제의 효력시험에 주로 사용된다. 실험물질을 통증 유발 30분과 60분 전에 경구투여한 후 열판위에 마우스 꼬리를 올려놓고 꼬리의 회피반응을 측정하였다.
Tail-flick test is mainly used to test the efficacy of analgesics acting on the central nervous system using acute pain models. The experimental materials were orally administered 30 minutes and 60 minutes before the pain, and the mice 'tail was placed on the hot plate and the tail evasion reaction was measured.
(3) 열판시험법에 의한 진통효과(3) Analgesic effect by hot plate test method
열판시험법 (Hot plate test)은 중추신경계에 작용하는 진통제를 검색할 때 사용하는 방법으로, 마우스의 발바닥이 열에 매우 민감하므로 참을 수 없을 정도의 열이 감지되면 마우스사 뛰거나, 발바닥을 움츠리거나, 또는 핥는 행위를 한다. 실험물질을 통증 유발 60분 전에 경구투여 한 후, 열판에 접촉할 때부터 뒷발을 털거나 핥을 때까지의 시간 (sec)을 측정하였다.
Hot plate test is a method used to search for painkillers acting on the central nervous system. Since the soles of the mouse are very sensitive to heat, when an unbearable heat is detected, the mouse is run, the soles are shrunk , Or licking. The test substance was orally administered 60 minutes before the pain, and the time (sec) from the time of contact with the hot plate to the time of shaving or licking the rear foot was measured.
(4) 포르말린 시험법에 의한 진통효과(4) Analgesic effect by the formalin test method
포르말린 시험법은 통증자극과 반응이 일시적이지 않고 지속으로 있는 만성통증 모델을 대상으로 약물의 진통작용을 측정하는데 주로 이용된다. 포르말린에 의해 유도된 통증반응은 1, 2상 단계를 거치며, 이 두 단계는 약물학적으로 구별될 수 있다. 실험물질과 양성대조군인 아세트아미노펜 또는 아스피린을 통증 유발 60분 전에 경구투여한 후 랫트의 뒷발에 10% 포르말린을 피하 주사하고, 3분 단위로 통증에 대한 행동 수를 측정하였다. 통증에 대한 행동은 1상 (0~12분)과 2상 (24~39분)으로 나누어 측정하였다.
The formalin test is mainly used to measure the analgesic effects of drugs on chronic pain models in which pain stimuli and responses are temporarily and persistently present. Formalin-induced pain responses undergo a one- and two-phase steps, which can be pharmacologically distinguishable. The experimental material and acetaminophen or aspirin, which is a positive control, were orally administered 60 minutes before the pain, 10% formalin was subcutaneously injected into the hind paw of the rats, and the number of behaviors for pain was measured every 3 minutes. The behavior of pain was divided into 1 phase (0 ~ 12 min) and 2 phase (24 ~ 39 min).
2. 항염증 효능 확인방법2. Anti-inflammatory efficacy confirmation method
(1) 효소면역측정법 (Enzyme-Linked ImmunoSorbent Assay)(1) Enzyme-Linked ImmunoSorbent Assay
BDNF (brain derivated neurotrophic factor)는 주로 뇌에 존재하는 신경영양인자로서, 트로포마이신-관련 키나제B (TrkB) 및 p75 등의 수용체와 결합하고, 이들과의 상호작용을 통해 통증을 유발한다. 실험물질에 의한 BDNF 발현양상을 측정하기 위해, ELISA 키트 (Uscn, china)를 사용하여 BV-2 미세교 세포에서의 BDNF 발현량을 조사하였다.
BDNF (brain derived neurotrophic factor) is a neurotrophic factor mainly present in the brain. It binds to receptors such as tropomycin-related kinase B (TrkB) and p75, and causes pain through interaction with them. In order to measure the expression pattern of BDNF by the test substance, the amount of BDNF expression in BV-2 microdissociated cells was examined using an ELISA kit (Uscn, china).
(2) 역전사-PCR 분석법(2) reverse transcription-PCR method
RNA는 제조사의 지시에 따라 TRIzol Reagent kit (Gibco BRL)를 사용하여 용해시켰다. RNA 1 μg을 10,000 U의 역전사 효소와 0.5 g/L oli-(dT)15 프라이머와 함께 역전사시켰다. 합성된 cDNA 1 μL는 iNOS, COX-2, TNF-α, IL-1β, IL-6 프라이머를 사용하여 PCR을 통해 증폭시켰다. PCR 생성물은 1 % 아가로스 겔 상에서 분리하였고, UV와 함께 시각화하였다.
The RNA was lysed using the TRIzol Reagent kit (Gibco BRL) according to the manufacturer's instructions. 1 μg of RNA was reverse transcribed with 10,000 U of reverse transcriptase and 0.5 g / L oli- (dT) 15 primer. 1 μL of the synthesized cDNA was amplified by PCR using iNOS, COX-2, TNF-α, IL-1β and IL-6 primers. The PCR product was isolated on 1% agarose gel and visualized with UV.
(2) 면역블롯법 (Immunoblot analysis)(2) Immunoblot analysis
세포 용해물을 버퍼용액 40 μL에 넣고 4℃에서 30분간 보관한 후에, 단백질 30 μg을 10% SDS-폴리아크릴아미드 겔 상에서 전기 영동법으로 분류하였다. 그런 다음 단백질을 니트로셀룰로오즈 세포막으로 옮겨지고, 1시간 동안 탈지분유로 차단하였다. TBST 완충용액으로 10분씩 3번 씻어준 후, 1차 항체를 처리하였다. 세포막은 HRP (horseradish peroxidase)에 결합된 2차 항체와 함께 보관하였다. 면역반응성 밴드는 제조사의 지시에 따라 ECL 형광 (enhanced chemiluminescence) 시약에 의해 검출하였다.
The cell lysate was placed in 40 μL of buffer solution and stored at 4 ° C. for 30 minutes. Then, 30 μg of protein was classified by electrophoresis on 10% SDS-polyacrylamide gel. The protein was then transferred to the nitrocellulose membrane and blocked with skim milk for 1 hour. After washing three times for 10 minutes with TBST buffer solution, the primary antibody was treated. Cell membranes were stored with secondary antibody conjugated to HRP (horseradish peroxidase). Immunoreactive bands were detected by ECL fluorescence (enhanced chemiluminescence) reagents according to the manufacturer's instructions.
(4) 아만성 귀부종 모델에서의 항염증 효과(4) Anti-inflammatory effect in subchronic ear edema model
12-O-테트라데카노일-13-포르볼 아세테이트 (TPA)에 의해 귀부종이 유발된 마우스 귀부종 모델에서 측정하였다. 1주일 순화과정을 거친 5주령 ICR 마우스에 실험물질을 경구투여하고, 1 시간 후에 TPA 1μg/ear를 오른쪽 귀에 도포하였다. 이와 같은 과정을 3일 동안 반복 한 뒤 4일째 마우스 귀의 두께를 측정하고, 귀 조직의 면적당 무게를 측정하였다.
12-O-tetradecanoyl-13-phorbol acetate (TPA). The experimental material was orally administered to a 5-week-old ICR mouse that had been subjected to a one-week purification process, and 1 μg / ear of TPA was applied to the right ear after 1 hour. This process was repeated for 3 days, and the thickness of the mouse ear was measured on the fourth day, and the weight per area of the ear tissue was measured.
[제조예]
[Manufacturing Example]
제조예 1. 초피 잎의 추출물, 분획물 및 활성화합물의 분리Production Example 1. Isolation of Extracts, Fractions and Active Compounds of Pepsi Leaf
도 1에 나타낸 공정도에 의거하여, 초피 잎으로부터 추출물, 분획물 및 활성화합물을 분리하는 과정을 설명하면 하기와 같다.The process of separating the extract, fraction and active compound from the leaf of a papaya leaf according to the process chart shown in Fig. 1 will be described below.
초피 (Zanthoxylum piperitum)는 우리나라 남부지방에서 채취한 국내산 초피를 입수하였다. 초피의 잎을 세척 및 건조시킨 후 음건 세절하였다. 초피의 잎을 90% 에탄올 수용액에 침지하고, 실온에서 2 ~ 5회 반복 추출하였다. 추출액을 감압 증류하여 초피 잎의 에탄올 추출물을 얻었다. Zanthoxylum piperitum was obtained from the southern region of Korea. The leaves of the chestnut were washed, dried and shrunk. The leaves of the mulberry leaves were immersed in a 90% ethanol aqueous solution and extracted 2 to 5 times at room temperature. The extract was subjected to vacuum distillation to obtain an ethanol extract of papaya leaf.
초피 잎의 에탄올 추출물 68.8 g을 증류수 2 L에 현탁한 후, 동등량의 노르말 헥산, 디클로로메탄, 에틸아세테이트, 노르말 부탄올 및 물로 차례로 분획한 다음 감압 농축하여 각 용매 분획물을 얻었다. 얻어진 각 용매 분획물 각각에 대해 항염증 및 통증억제 효능을 확인하여, 그 중에서 가장 우수한 활성을 보이는 에틸아세테이트 분획물을 선택하였다.68.8 g of ethanol extract of P. chinensis was suspended in 2 L of distilled water, and then fractionated with an equal amount of normal hexane, dichloromethane, ethyl acetate, normal butanol and water, and concentrated under reduced pressure to obtain respective solvent fractions. Each of the obtained solvent fractions was tested for anti-inflammatory and pain-inhibiting activity, and the ethyl acetate fraction showing the most excellent activity was selected.
에틸아세테이트 분획물은 실리카 비드 (Silica beads)가 충진된 유리컬럼 (5 × 50 cm)에 충진시켜 실리카겔 컬럼 크로마토그래피를 실시하였다. 이때, 용출액으로는 에틸아세테이트와 메탄올의 혼합용액을 사용하였으며, 에틸아세테이트/메탄올의 부피비를 90/10로부터 60/40까지 변화시키면서 용출하였다. 상기 실리카겔 컬럼 크로마토그래피를 수행하여, 7개의 분획 (분획 ZPE1, 2.86 g; 분획 ZPE2, 0.32 g; 분획 ZPE3, 0.30 g; 분획 ZPE41, 1.13 g; 분획 ZPE5, 0.54 g; 분획 ZPE6, 1.90 g; 분획 ZPE7, 1.90 g)을 얻었다. 상기 7개의 분획 각각에 대해 항염증 및 통증억제 효능을 확인하여, 그 중에서 가장 우수한 활성을 보이는 분획 ZPE6을 선택하였다. The ethyl acetate fraction was loaded on a glass column (5 x 50 cm) filled with silica beads (silica beads) and subjected to silica gel column chromatography. At this time, a mixed solution of ethyl acetate and methanol was used as an eluent, and elution was carried out by changing the volume ratio of ethyl acetate / methanol from 90/10 to 60/40. Fraction ZPE6, 1.90 g; Fraction ZPE2, 0.32 g Fraction ZPE2, 0.30 g Fraction ZPE41, 1.13 g Fraction ZPE5, 0.54 g Fraction ZPE6, 1.90 g Fraction ZPE7, 1.90 g). The anti-inflammatory and pain-inhibiting effects of each of the seven fractions were confirmed, and the fraction ZPE6 showing the most excellent activity was selected.
분획 ZPE6을 감압 농축하고, 완전히 건조시킨 후에 sephadex LH-20 컬럼에 충진시켜 중압 크로마토그래피 (MPLC)를 실시하였다. 이때, 용출액으로는 메탄올 단독용액을 사용하여 용출하였다. 상기 중압 크로마토그래피 (MPLC)를 실시하여 3개의 소분획 (분획 ZPE6A, 24.7 ㎎; 분획 ZPE6B, 416 ㎎; 분획 ZPE6C, 85.4 ㎎)을 얻었다. 상기 3개의 소분획 각각에 대해 항염증 및 통증억제 효능을 확인하여, 그 중에서 가장 우수한 활성을 보이는 소분획 ZPE6B를 선택하였다. The fraction ZPE6 was concentrated under reduced pressure, completely dried, and packed in a column of sephadex LH-20, and subjected to medium pressure chromatography (MPLC). At this time, the eluent was eluted with methanol alone solution. Three fractions (fraction ZPE6A, 24.7 mg; fraction ZPE6B, 416 mg; fraction ZPE6C, 85.4 mg) were obtained by performing the above intermediate pressure chromatography (MPLC). The anti-inflammatory and anti-inflammatory effects of each of the three small fractions were confirmed, and a small fraction of ZPE6B exhibiting the best activity was selected.
소분획 ZPE6B는 옥타데실화 실리카가 충진된 역상컬럼을 이용하는 HPLC (용출액: 메탄올/물 = 50/50)를 실시하여, 활성성분 1과 활성성분 2를 분류하였다.The small fraction ZPE6B was subjected to HPLC (eluent: methanol / water = 50/50) using a reversed phase column packed with octadecylsilica to classify
상기에서 분리한 활성성분 1과 활성성분 2는 각각 핵자기 공명 분광 분석을 통해 화학구조를 규명하였다. The
활성성분 1 : Active ingredient 1 :
1H-NMR (300 MHz, DMSO-d 6) δ 0.9 (d, J = 6 Hz, CH3), 5.2 (d, J = 1.5 Hz, H-1"), 6.15 (d, J = 2.2 Hz, H-6), 6.36 (d, J = 2.2 Hz, H-8), 6.95 (d, J = 8.2 Hz, H-5'), 7.25 (dd, J = 2.2 Hz and J = 8.2 Hz, H-6'), 7.35 (d, J = 2.2 Hz, H-2'); 13C-NMR (75 MHz, DMSO-d 6) δ 17.5 (C-6"), 70.0 (C-5"), 70.2 (C-3"), 70.5 (C-2"), 71.1 (C-4"), 93.6 (C-8), 98.6 (C-6), 101.8 (C-1"), 104.0 (C-10), 115.4 (C-2'), 115.6 (C-5'), 120.7 (C-6'), 121.1 (C-1'), 134.2 (C-3), 145.1 (C-3'), 148.3 (C-4'), 156.4 (C-2), 157.2 (C-9), 161.3 (C-5), 164.2 (C-7), 177.7 (C-4) 1 H-NMR (300 MHz, DMSO- d 6) δ 0.9 (d, J = 6 Hz, CH 3), 5.2 (d, J = 1.5 Hz, H-1 "), 6.15 (d, J = 2.2 Hz , H-6), 6.36 ( d, J = 2.2 Hz, H-8), 6.95 (d, J = 8.2 Hz, H-5 '), 7.25 (dd, J = 2.2 Hz and J = 8.2 Hz, H -6 '), 7.35 (d, J = 2.2 Hz, H-2'); 13 C-NMR (75 MHz, DMSO- d 6) δ 17.5 (C-6 "), 70.0 (C-5"), (C-2), 71.1 (C-4), 93.6 (C-8), 98.6 (C-3 '), 115.1 (C-2'), 115.6 (C-5 '), 120.7 148.3 (C-4 '), 156.4 (C-2), 157.2 (C-9), 161.3 (C-
이상의 분광 분석한 결과를 토대로, 활성성분 1은 하기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드로 확인되었다. 활성성분 1의 분광 분석한 결과는 쿼세틴-3-O-알파-L-람노사이드 (쿼시트린, Quercitrin)의 문헌값과 잘 일치하였다.Based on the results of the above spectroscopic analysis, the
[화학식 1][Chemical Formula 1]
활성성분 2 : Active Ingredient 2 :
1H-NMR (300 MHz, DMSO-d 6) δ 0.9 (d, J = 6 Hz, CH3), 5.29 (1H, d, J = 1.5 Hz, H-1"), 6.21 (1H, d, J = 2.5 Hz, H-6), 6.42 (1H, d, J = 2.5 Hz, H-1"), 6.21 (1H, d, J = 2.5 Hz, H-6), 6.42 (1H, d, J = 2.5 Hz, H-8), 6.91 (2H, d, J = 8.4 Hz, H-3' and H-5'), 7.74 (2H, d, J = 8.4 Hz, H-2' and H-6'); 13C-NMR (75 MHz, DMSO-d 6) δ 17.4 (C-6"), 70.0 (C-5"), 70.2 (C-2"), 70.6 (C-3"), 71.0 (C-4"), 93.7 (C-8), 98.7 (C-6), 101.7 (C-1"), 104.0 (C-10), 115.3 (C-3', C-5'), 120.5 (C-1), 130.6 (C-2', C-6'), 134.2 (C-3), 156.5 (C-9), 157.2 (C-2), 159.9 (C-4'), 161.2 (C-5), 164.3 (C-4), 177.7 (C-7) 1 H-NMR (300 MHz, DMSO- d 6) δ 0.9 (d, J = 6 Hz, CH 3), 5.29 (1H, d, J = 1.5 Hz, H-1 "), 6.21 (1H, d, J = 2.5 Hz, H-6 ), 6.42 (1H, d, J = 2.5 Hz, H-1 "), 6.21 (1H, d, J = 2.5 Hz, H-6), 6.42 (1H, d, J = 2.5 Hz, H-8) , 6.91 (2H, d, J = 8.4 Hz, H-3 'and H-5'), 7.74 (2H, d, J = 8.4 Hz, H-2 'and H-6 '); 13 C-NMR (75 MHz, DMSO- d 6) δ 17.4 (C-6 "), 70.0 (C-5"), 70.2 (C-2 "), 70.6 (C-3"), 71.0 (C- (C-10), 115.3 (C-3 ', C-5'), 120.5 (C- 1), 130.6 (C-2 ', C-6'), 134.2 (C-3), 156.5 (C-9), 157.2 ), 164.3 (C-4), 177.7 (C-7)
이상의 분광 분석한 결과를 토대로, 활성성분 2는 하기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드로 확인되었다. 활성성분 2의 분광 분석한 결과는 캠퍼롤-3-O-알파-L-람노사이드 (아프젤린, Afzelin)의 문헌값과 잘 일치하였다.Based on the results of the above spectroscopic analysis, the
[화학식 2](2)
실시예 1. 초피 부위별 통증억제 효능 대비Example 1: Preparation of pain-inhibiting effect of each region
초피 잎, 어린가지, 열매, 줄기, 뿌리의 부위별로 추출물의 통증억제 효능을 대비하기 위하여, 상기 제조예 1에 따른 추출방법으로 실시하여 90% 에탄올 추출물을 각각 얻었다. 각 추출물에 대해서는 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 하기 표 1에 나타내었다.The extracts according to Preparation Example 1 were used to prepare 90% ethanol extracts to prepare the extracts for inhibiting the pain of each of the leaves, young leaves, fruits, stems and roots. The pain relief efficacy of each extract was measured using acetic acid induced pain model, and the results are shown in Table 1 below.
(100 mg/kg, po)Pain inhibition (%)
(100 mg / kg, po)
상기 표 1의 결과에 의하면, 초피 부위별로 통증 억제효능에서 현격한 차이를 나타내고 있으며, 잎 추출물의 효능이 가장 탁월하였다. 잎 추출물의 경우 열매 추출물에 대비하여 통증억제율이 약 25.8% 더 우수하다는 것을 알 수 있다.
According to the results shown in Table 1, there was a remarkable difference in the pain-suppressing effect of each part of the dandruff, and the efficacy of the leaf extract was the most excellent. Leaf extracts showed about 25.8% better inhibition of pain than fruit extracts.
실시예 2. 에탄올 수용액의 농도별 통증억제 효능 대비Example 2. Preparation of pain-inhibiting effect by concentration of aqueous ethanol solution
추출용액의 농도에 따른 초피 잎 추출물의 통증억제 효능을 대비하였다. 즉, 0 ~ 100% 농도의 에탄올 수용액을 사용하여 상기 제조예 1에 따른 추출방법으로 실시하여 초피 잎의 에탄올 추출물을 각각 얻었다. 그리고 각 추출물에 대해서는 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 하기 표 2에 나타내었다.The antioxidant activity of the extracts of P. falciparum was determined by the concentration of extract solution. That is, ethanol extracts of papaya leaf were obtained by the extraction method according to Preparation Example 1 using an ethanol aqueous solution having a concentration of 0 to 100%. For each extract, acetic acid-induced pain model was used to measure the pain-inhibiting effect, and the results are shown in Table 2 below.
(100 mg/kg, po)Pain inhibition (%)
(100 mg / kg, po)
상기 표 2의 결과에 의하면, 추출에 사용된 에탄올 수용액의 농도가 증가될수록 초피 잎 추출물의 통증억제율이 증가되는 경향을 보였다. 통증억제 효능 면에서 볼 때, 에탄올 수용액의 농도는 50% 이상인 것이 바람직하고, 보다 바람직하기로는 90% 이상의 에탄올 수용액을 사용하는 것이다.
According to the results shown in Table 2 above, as the concentration of aqueous ethanol solution used for extraction was increased, the inhibition rate of the papaya leaf extract was increased. From the viewpoint of the pain-inhibiting effect, the concentration of the aqueous ethanol solution is preferably 50% or more, more preferably 90% or more of the aqueous ethanol solution.
실시예 3. 초피 잎 분획물의 통증억제 효능 대비Example 3: Pain-inhibiting effect of fractions of Leaf leaf
상기 제조예 1에 따라 초피 잎 에탄올 추출물을 용매분획하여 수득한 각 용매분획물에 대하여 통증억제 효능을 대비하였다. 즉, 90% 에탄올 추출물을 노르말 헥산, 디클로로메탄, 에틸아세테이트, 노르말 부탄올 및 물로 차례로 분획하여 얻은 각 분획물에 대하여 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 하기 표 3에 나타내었다.The solvent fractions obtained by fractionating the ethanol extract of P. chinensis according to Preparation Example 1 were prepared for the pain-inhibiting effect. That is, the fractions obtained by successively fractionating the 90% ethanol extract with normal hexane, dichloromethane, ethyl acetate, normal butanol and water were measured for the pain-inhibiting effect using the acetic acid-induced pain model. The results are shown in Table 3 .
(50 mg/kg, po)Pain inhibition (%)
(50 mg / kg, po)
상기 표 3에 의하면, 에틸아세테이트 분획물에서 가장 우수한 통증억제 효과를 보였다.
According to the above Table 3, the ethyl acetate fraction showed the most excellent pain suppressing effect.
실시예 4. 에틸아세테이트 소분획물의 통증억제 효능 대비Example 4. Anti-pain control effect of ethyl acetate small fraction
상기 제조예 1에 따라 에틸아세테이트 분획물을 실리카겔 컬럼 크로마토그래피하여 수득한 7개의 소분획에 대하여 통증억제 효능을 대비하였다. 즉, ZPE1, ZPE2, ZPE3, ZPE4, ZPE5, ZPE6, ZPE7로 분류된 소분획에 대해서는 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 하기 표 4에 나타내었다.The seven fractions obtained by silica gel column chromatography on ethyl acetate fractions according to Preparation Example 1 were prepared for pain control efficacy. That is, the pain-inhibiting effect was measured using an acetic acid-induced pain model for small fractions classified as ZPE1, ZPE2, ZPE3, ZPE4, ZPE5, ZPE6 and ZPE7, and the results are shown in Table 4 below.
(100 mg/kg, po)Pain inhibition (%)
(100 mg / kg, po)
상기 표 4에 의하면, 에틸아세테이트 소분획물 중에서도 6번째 소분획물(ZPE6)이 가장 우수한 통증억제 효과를 보였다.
According to Table 4, the sixth small fraction (ZPE6) among the ethyl acetate small fractions showed the most excellent pain suppressing effect.
실시예 5. ZPE6 소분획물의 통증억제 효능 대비Example 5: Anti-pain effect of ZPE6 small fraction
상기 제조예 1에서 수득한 ZPE6 분획을 중압 크로마토그래피(MPLC)로 분리하여 수득한 3개의 소분획물에 대하여 통증억제 효능을 대비하였다. 즉, ZPE6A, ZPE6B, ZPE6C로 분류된 소분획에 대해서는 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 하기 표 5에 나타내었다.The three sub-fractions obtained by separating the ZPE6 fraction obtained in Preparation Example 1 by medium pressure chromatography (MPLC) were prepared for pain control efficacy. That is, for the small fractions classified as ZPE6A, ZPE6B, and ZPE6C, the pain-inhibiting effect was measured using an acetic acid-induced pain model, and the results are shown in Table 5 below.
(100 mg/kg, po)Pain inhibition (%)
(100 mg / kg, po)
상기 표 5에 의하면, ZPE6의 소분획물 중에서도 2번째 소분획물(ZPE6B)이 가장 우수한 통증억제 효과를 보였다.
According to the above Table 5, the second small fraction (ZPE6B) among the small fractions of ZPE6 showed the most excellent pain suppressing effect.
실시예 6. ZPE6B 소분획물에서 분리한 유효성분의 통증억제 효능 대비Example 6: Pain inhibiting effect of active ingredient isolated from ZPE6B small fraction
상기 제조예 1에서 수득한 ZPE6B 분획에서 화학식 1과 2로 표시되는 2개의 활성성분 쿼세틴-3-O-알파-L-람노사이드 (쿼시트린, Quercitrin)와 캠퍼롤-3-O-알파-L-람노사이드 (아프젤린, Afzelin)를 분리하였으며, 이에 대하여 통증억제 효능을 대비하였다. 즉, 쿼세틴-3-O-알파-L-람노사이드 (쿼시트린, Quercitrin)와 캠퍼롤-3-O-알파-L-람노사이드 (아프젤린, Afzelin)에 대하여 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 하기 표 6에 나타내었다.In the ZPE6B fraction obtained in Preparation Example 1, the two active ingredients quercetin-3-O-alpha-L-quercitrin and camphorol-3-O-alpha-L - Laminocyte (Afzelin) was isolated, and the pain control effect was prepared. That is, the acetic acid-induced pain model was applied to quercetin-3-O-alpha-L-lumnoside (quercitrin) and camphorol-3-O- alpha-L-lamboside (afzelin) The inhibition efficacy was measured and the results are shown in Table 6 below.
(50 mg/kg, po)Pain inhibition (%)
(50 mg / kg, po)
상기 표 6에 의하면, 화학식 1과 2로 표시되는 활성성분인 쿼세틴-3-O-알파-L-람노사이드 (쿼시트린, Quercitrin)와 캠퍼롤-3-O-알파-L-람노사이드 (아프젤린, Afzelin)는 모두 아세트산 유도 통증모델에서 우수한 통증억제율을 나타내었다. 특히, 소분획물 ZPE6B로부터 분리된 아프젤린은 통증억제율이 탁월하게 우수하였다.According to the above Table 6, the active ingredient quercetin-3-O-alpha-L-lumnoside (quercitrin) and camphorol-3-O-alpha-L- Jelin, and Afzelin) showed excellent pain suppression rates in the acetic acid-induced pain model. In particular, afzelin isolated from the small fraction, ZPE6B, excellently superior in pain inhibition.
상기 표 6의 결과에 의하면, 상기 제조예 1에서 중압 크로마토그래피(MPLC)로 분리한 3개의 소분획물 중 ZPE6B가 진통효과가 우수하였는데, ZPE6B에는 아프젤린 등의 통증억제 활성이 우수한 화합물이 다량 포함되어 있는데 그 이유가 있는 것으로 판단된다.
According to the results shown in Table 6 above, ZPE6B was superior in analgesic effect among the three small fractions separated by the medium pressure chromatography (MPLC) in Production Example 1, and ZPE6B contained a large amount of compounds having excellent pain inhibiting activity such as afzelin It seems that there is a reason.
실시예 7. ZPE6A 및 ZPE6C 소분획물의 GC-MS 분석 대비Example 7. GC-MS analysis of small fractions of ZPE6A and ZPE6C
상기 제조예 1에서 분리한 3개의 소분획물 중 ZPE6A와 ZPE6C의 경우는 ZPE6B보다 진통 효과가 낮게 나타났지만, 다른 분획물 또는 대조군과 비교하였을 때 진통효능이 우수한 것으로 판단된다. 하기 표 7에는 소분획 ZPE6A 및 ZPE6C에 포함된 활성성분을 분석하기 위하여, GC-MS 분석한 결과를 나타내었다. ZPE6A and ZPE6C showed lower analgesic effect than ZPE6B among the three small fractions isolated in Preparation Example 1, but the analgesic activity was superior to the other fractions or the control group. Table 7 below shows the results of GC-MS analysis for analyzing the active components contained in the small fractions ZPE6A and ZPE6C.
번호peak
number
(%)Area
(%)
(%)Area
(%)
상기 표 7의 GC-MS 분석 결과에 의하면, ZPE6A 또는 ZPE6C 분획물 중에는 하기 화학식 3으로 표시되는 4'-히드록시아세토페논, 하기 화학식 4로 표시되는 2,4-디-tert-부틸페놀, 하기 화학식 5로 표시되는 1,2-벤젠디카르복시산이 함유되어 있는 것으로 확인된다. According to the results of the GC-MS analysis of Table 7, among the ZPE6A or ZPE6C fractions, 4'-hydroxyacetophenone represented by the following
또한, ZPE6A 또는 ZPE6C 분획물로부터 분리한 4'-히드록시아세토페논, 2,4-디-tert-부틸페놀, 1,2-벤젠디카르복시산에 대하여 아세트산 유도 통증모델을 이용하여 통증 억제효능을 측정하였으며, 그 결과는 도 3에 나타내었다. In addition, pain relieving efficacy was measured using 4'-hydroxyacetophenone, 2,4-di- tert -butylphenol and 1,2-benzenedicarboxylic acid isolated from the ZPE6A or ZPE6C fractions using acetic acid induced pain model , And the results are shown in Fig.
도 3에 의하면, 4'-히드록시아세토페논, 2,4-디-tert-부틸페놀 및 1,2-벤젠디카르복시산 역시 통증 억제효능이 우수하다는 것을 확인할 수 있고, 그 중에서도 4'-히드록시아세토페논은 통증 억제효능이 탁월하게 우수하다는 것을 확인할 수 있다.
3 shows that 4'-hydroxyacetophenone, 2,4-di- tert -butylphenol and 1,2-benzene dicarboxylic acid are also excellent in pain control effect. Among them, 4'- Acetophenone can be confirmed to be excellent in pain control efficacy.
실시예 8. 추출조건에 따른 활성화합물의 함량 대비Example 8: Comparison of the content of active compound with extraction conditions
상기 제조예 1에 따른 초피 잎의 추출물을 수득하는 과정에서, 추출용매와 온도조건을 변화시키면서 각각의 추출물을 얻었다. 그리고, 각 추출물에 대해서는 활성화합물(쿼시트린, 아프젤린)의 함량을 HPLC로 분석하였고, 그리고 아세트산 유도 통증모델을 이용하여 통증억제율을 측정하였으며, 그 결과는 하기 표 8에 나타내었다.In the process of obtaining the extract of P. japonicus according to Preparation Example 1, each extract was obtained while changing the extraction solvent and temperature conditions. For each extract, the content of active compounds (aquitinel, arthritis) was analyzed by HPLC, and the pain inhibition rate was measured using an acetic acid-induced pain model. The results are shown in Table 8 below.
[추출조건][Extraction condition]
조건1) 90% 에탄올 추출물 (비가열), Condition 1) 90% ethanol extract (unheated),
조건2) 90% 에탄올 추출물 (가열), Condition 2) 90% ethanol extract (heating),
조건3) 가열 방식을 이용한 90% 에탄올 추출물을 원심분리하여 에멀전을 제거한 물질.Condition 3) A substance obtained by centrifuging a 90% ethanol extract using a heating method to remove the emulsion.
조건4) 90% 에탄올 추출물을 디클로로메탄으로 분획한 분획물,Condition 4) A fraction obtained by fractionating 90% ethanol extract with dichloromethane,
조건5) 90% 에탄올 추출물을 디클로로메탄으로 분획한 분획물을 제외한 잔류물, Condition 5) The residue except for the fraction obtained by fractionating the 90% ethanol extract with dichloromethane,
조건6) 노르말 헥산 추출물, Condition 6) Normal hexane extract,
조건7) 노르말 헥산 추출물을 90% 에탄올으로 추출한 에탄올 추출물, Condition 7) The ethanol extract obtained by extracting the normal hexane extract with 90% ethanol,
조건8) 디클로로메탄 추출물, Conditions 8) Dichloromethane extract,
조건9) 디클로로메탄 추출물을 90% 에탄올으로 추출한 에탄올 추출물.Conditions 9) Dichloromethane Extracts were extracted with 90% ethanol.
조건extraction
Condition
(%)yield
(%)
(50 mg/kg, po)Pain inhibition (%)
(50 mg / kg, po)
CH2Cl2 분획물Ethanol extract
CH 2 Cl 2 fractions
상기 표 8에 의하면, 추출조건에 의해서는 활성화합물의 함량이 달라질 수 있음을 알 수 있다. 본 발명이 제안하는 바대로 조건 1, 2, 3에 의해 추출하여 얻은 알코올 추출물은 활성화합물의 함량이 매우 높고 통증억제율도 효과적으로 억제하였다.
According to the above Table 8, it can be seen that the content of the active compound may be varied depending on the extraction conditions. As suggested by the present invention, the alcohol extract obtained by the
실시예 9. 초피 잎 추출물의 진통효과Example 9. Analgesic effect of the leaf extract
상기 제조예 1에서 수득한 초피 잎의 90% 에탄올 추출물에 대하여, 여러 동물모델을 이용하여 진통효능을 측정하였다.The analgesic efficacy of the 90% ethanol extract of the chickpea leaf obtained in Preparation Example 1 was measured using various animal models.
도 4에는 (A)꼬리 회피반응 시험법, (B)열판시험법, (C)포르말린 시험법에 의해 초피 잎 추출물의 진통효과를 측정한 결과가 도시되어 있다. 도 4에 의하면, 본 발명에 따른 초피 잎 추출물은 진통억제 효능이 우수하다는 것을 알 수 있다.
Fig. 4 shows the results of measuring the analgesic effect of the papaya leaf extract by (A) the Tail Avoidance Test, (B) the Hot Plate Test, and (C) the formalin test. 4, it can be seen that the extract of P. falciparum according to the present invention is excellent in anti-analgesic effect.
실시예 10. 초피 잎 추출물의 항염증효과Example 10 Anti-inflammatory Effect
상기 제조예 1에서 수득한 초피 잎의 95% 에탄올 추출물에 대하여, 효소면역측정법, 역전사-PCR 분석법, 면역블롯법을 이용하여 항염증효능을 측정하였다.The anti-inflammatory activity of the 95% ethanol extract of P. japonicus leaf obtained in Preparation Example 1 was measured by enzyme immunoassay, reverse transcription-PCR, and immunoblotting.
도 5에는 면역측정법에 의해 초피 잎 추출물의 처치량 0, 25, 50, 100 ㎍/mL에서 BDNF 발현량을 조사한 결과가 도시되어 있다. 초피 잎 추출물의 처리량이 증가할 수록 BDNF 발현량이 감소되는 경향을 보였으며, 그 결과 초피 잎 추출물 100 ㎍/mL에서 최고의 항염증 활성을 나타냄을 확인할 수 있었다.FIG. 5 shows the results of an examination of the amount of BDNF expression at 0, 25, 50, and 100 占 퐂 / mL of the extract of P. japonicus by immunoassay. The amount of BDNF expression decreased with increasing the throughput of the leaf extract. As a result, it was confirmed that the extract showed the highest anti - inflammatory activity at 100 ㎍ / mL.
도 6에는 (A)역전사-PCR 분석법과 (B)면역블롯법을 이용하여 측정한 염증지표인자의 발현억제 효과를 측정한 결과가 도시되어 있다. 도 6에 의하면, 초피 잎 추출물을 처리한 군에서는 리포다당류 (LPS)에 의해 과발현 된 iNOS, COX-2, TNF-α, IL-1β, IL-6의 염증지표인자의 발현억제가 효과적으로 이루어졌다는 것을 알 수 있다.
Fig. 6 shows the results of measuring the inhibitory effect of the inflammatory index factors measured by (A) reverse transcription-PCR and (B) immunoblotting. FIG. 6 shows that the inhibition of the expression of inflammatory markers of iNOS, COX-2, TNF-α, IL-1β and IL-6 overexpressed by lipopolysaccharide (LPS) .
실시예 11. 초피 잎 추출물의 아만성 귀부종 모델에서의 항염증 효과Example 11 Anti-Inflammatory Effect of Chow Leaf Extract on Subchronic Ear Edema Model
TPA에 의해 귀부종이 유도된 마우스 모델에서 초피 잎 추출물을 25, 50, 100 mg/kg 농도로 경구투여한 후에 항염증 효능을 측정한 결과가 도 7에 도시되어 있다. FIG. 7 shows the result of measuring the anti-inflammatory effect after orally administered at 25, 50, and 100 mg / kg of P. japonicus leaf extract in a mouse model induced by TPA.
TPA에 의하여 귀의 두께와 무게가 모두 확연하게 증가하였고, 초피 잎 추출물을 경구투여함으로써 귀부종의 두께와 무게가 효과적으로 감소되었음을 확인할 수 있었다. 이러한 항염증 효과는 초피 잎 추출물의 처리량이 증가할 수록 그 효능도 증가하는 경향을 보였다. 면역화학염색 (immunohistochemistry)을 통한 조직 면역학적 분석 결과를 살폈을 때, 초피 잎 추출물은 면역 세포들의 조직 내로의 침투를 효과적으로 억제하는 것을 확인할 수 있다.
The thickness and weight of ears were significantly increased by TPA, and it was confirmed that the thickness and weight of ear edema were effectively reduced by oral administration of papaya leaf extract. The anti - inflammatory effect tended to increase as the throughput of the extract was increased. When the results of immunohistochemical analysis of immunohistochemistry were examined, it can be confirmed that the papaya leaf extract effectively inhibited the infiltration of immune cells into tissues.
실시예 12 : 초피 잎 추출물의 류마티스 관절염 치료 효과Example 12: Treatment effect of raspberry leaf extract on rheumatoid arthritis
류마티스 관절염 치료 효능을 알아보기 위한 방법의 하나로 콜라겐으로 유도된 관절염 동물모델에서 각 시험물질의 항류마티스 효능을 측정하였다. 실험동물은 5주령 DBA/1J 마우스 (중앙실험동물, 서울)를 구입하여 1주간 습도 50%, 온도 24~26℃로 유지되는 사육장에서 순화시켰으며, 사료 및 물은 자유롭게 섭취할 수 있도록 공급하였다. 관절염을 유도하기 위해 제 2형 콜라겐과 CFA(complete Freund's adjuvant)를 혼합하여 유상액을 얻었다. DBA/1J 마우스의 몸통으로부터 2~3cm 떨어진 꼬리의 아랫 부분에 200 μL의 유상액을 피하(id) 주사하였으며, 1차 항원 노출 21일 뒤 동량의 유상액을 처음 주사와 동일한 방법으로 꼬리의 아랫부분에 150 μL의 2차 주사를 실시하였다. 최초 항원 노출 22일부터 양성대조군은 덱사메타손 (Dexamethasone)을 1 mg/kg 용량으로 경구투여하고, 초피 잎 추출물 투여군은 100 mg/kg로 3주간 경구 투여 후 류마티스 관절염 병변을 육안 관찰하여 등급화하였으며, 이에 대한 관절염 개선 효능을 임상 점수(Clinical score)로 측정하였다.The anti-rheumatic efficacy of each test substance was measured in an animal model of arthritis induced by collagen as one of the methods for evaluating the efficacy of rheumatoid arthritis treatment. Five-week-old DBA / 1J mice (Central Experimental Animals, Seoul) were purchased and cultivated in a farm maintained at 50% humidity and 24-26 ℃ for 1 week. Feed and water were fed for free consumption . To induce arthritis, type II collagen and complete Freund's adjuvant (CFA) were mixed to obtain an emulsion. 200 μL of emulsion was injected subcutaneously to the lower part of the
상기 방법으로 측정한 육안 임상 점수는 하기 표 9에 나타내었다.The visual clinical scores measured by the above method are shown in Table 9 below.
상기 표 9에 나타난 바와 같이, 대조군의 평균점수가 11.8인데 반하여 초피 잎 추출물 투여군의 평균점수는 8점으로서 매우 낮다는 것을 알 수 있다. 양성대조군인 덱사메타손 투여군의 평균점수가 6.3점인 점을 감안하면 초피 잎 추출물은 류마티스 관절염 치료제로서 유효함을 알 수 있다.
As shown in Table 9, the average score of the control group was 11.8, whereas the average score of the group treated with the extract of P. japonicus was 8, which is very low. Considering that the average score of the dexamethasone-treated group, which is a positive control, is 6.3, the extract of P. japonica is effective as a treatment for rheumatoid arthritis.
또한, 도 8에는 마이크로-CT를 이용하여 뒷발의 발목관절을 3D 이미지 상에서 분석한 결과가 도시되어 있다. 대조군은 관절에서의 뼈 모양이 불규칙하게 변하여 염증에 의한 뼈의 파괴가 상당히 진행되어 있음을 확인할 수 있다. 이에 반하여, 초피 잎 추출물 투여군은 뼈의 파괴나 변형이 현저히 감소한 것을 3D 이미지 상에서 관찰할 수 있었으며, 덱사메타손 투여군에 대비하여서도 관절염 치료 효능이 거의 동일함을 확인할 수 있다.
8 shows the result of analyzing an ankle joint of a hind leg on a 3D image using a micro-CT. In the control group, the shape of the bone in the joints changes irregularly, indicating that bone destruction due to inflammation is progressing considerably. On the contrary, it was observed that the bone destruction or deformation was remarkably decreased in the 3D-image of the group treated with the extract of P. falciparum, and the efficacy of treating arthritis was almost the same even in the dexamethasone group.
실시예 13. 골관절염 유도된 동물 모델에서의 치료 효과Example 13. Therapeutic effect in osteoarthritis-induced animal models
골관절염 치료 효능을 알아보기 위한 방법의 하나로 콜라게네이즈로 유도된 관절염에 대한 시험물질의 개선 효능을 측정하였다. 실험동물은 5주령 SD 랫 (중앙실험동물, 서울)을 구입하여 1주간 습도 50%, 온도 24~26℃로 유지되는 사육장에서 순화시켰으며, 사료 및 물은 자유롭게 섭취할 수 있도록 공급하였다. 관절염을 유도하기 위해 4 mg/mL의 제 2형 콜라게네이즈를 랫의 오른쪽 관절의 관절낭에 0.05 mL 주사하고 (0 day) 4 일 후 시작하였다. 콜라게네이즈 주사 후 증류수를 투여한 정상 대조군과 골관절염 유도 대조군, 양성대조군으로 셀레콕시브(10 mg/kg), 초피 잎 추출물(300 mg/kg)을 매일 1 회 경구투여하였다. 7주 후 관절 부분을 조직 병리하여 관찰한 결과는 도 9에 나타내었다.One of the methods for evaluating the efficacy of osteoarthritis treatment was to measure the improving effect of test substances on collagenase-induced arthritis. Five-week-old SD rats (Central laboratory animals, Seoul) were purchased from the experimental animals. The animals were kept in a habitat maintained at 50% humidity and 24 ~ 26 ℃ for 1 week. Feed and water were supplied for free consumption. To induce arthritis, 4 mg /
도 9에 의하면 초피 잎 추출물 투여군은 7주 후에 염증 부위가 현격하게 감소되었으며, 셀레콕시브 투여군에 대비하여 그 효과가 탁월하다는 것을 확인할 수 있다.
According to FIG. 9, the area of inflammation was significantly reduced after 7 weeks in the extract of P. falciparum extract, and it was confirmed that the effect was excellent in comparison with the group treated with celecoxib.
실시예 14. 골관절염 유도된 동물 모델에서의 치료 효과Example 14. Therapeutic effect in osteoarthritis-induced animal models
골관절염은 연골세포의 대사 이상으로 발생하며, 연골손상에 관여하는 효소는 대표적으로 메트릭스 메탈로프로테이네이즈(matrix metalloproteinases; MMPs), 메탈로프로테이나제 조직 저해제(tissue inhibitor of metalloproteinases; TIMPs)가 있다. MIA(Monosodium Iodoacetate) 투여에 의해 유발된 골관절염 동물 모델은 연골세포의 대사를 방해하여 무릎관절의 연골 손상을 유도한 것으로, 골관절염과 유사한 증상이 나타난다. Osteoarthritis occurs as an abnormality in cartilage cell metabolism, and the enzymes involved in cartilage damage are typically matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) . An animal model of osteoarthritis induced by the administration of MIA (Monosodium Iodoacetate) induces cartilage damage of the knee joint by interfering with the metabolism of chondrocytes, and symptoms similar to osteoarthritis appear.
도 10에는 MIA에 의해 유발된 골관절염 동물 모델에서 MMP-2, MMP-3, TIMP-1 및 TIMP-2의 생화학적 지표 변화를 확인한 결과가 도시되어 있다. 도 10에 의하면, 초피 잎 추출물과 활성화합물(쿼시트린, 아프젤린)은 골관절염 치료효과가 우수하였음을 알 수 있고, 특히 아프젤린은 골관절염 치료 효과가 탁월하다는 것을 확인할 수 있다.
FIG. 10 shows the results of biochemical markers changes of MMP-2, MMP-3, TIMP-1 and TIMP-2 in an animal model of osteoarthritis induced by MIA. According to FIG. 10, it can be seen that the extract of P. japonica and the active compounds (quasitrin, arthritis) have excellent therapeutic effect on osteoarthritis, and in particular, afzelin has excellent therapeutic effect on osteoarthritis.
실시예 15. 초피 잎 추출물과 활성 물질의 통증억제 작용기전 규명Example 15. Identification of the mechanism of action of pain suppressant extracts and active substances
관절염 등 각종 염증 및 통증억제 작용기전을 규명하기 위하여 뇌 미세교세포인 BV-2 세포를 이용하여 PCR 배열을 관찰하였다. 실험군은 초피 잎 추출물과 활성화합물인 퀘르시트린(quercitrin), 아프제린(afzelin)으로 나누어 실시하였다. In order to investigate the mechanism of inflammation and pain suppression such as arthritis, the PCR arrangement was observed using BV-2 cells, a brain microsoprotein. Experimental groups were divided into chestnut leaf extract and active compounds quercitrin and afzelin.
도 11에는 뇌 미세교세포인 BV-2세포에서 초피 잎 추출물, 퀘르시트린(quercitrin) 및 아프제린(afzelin)으로 처리한 후에, 단백질 KCNJ6의 발현 정도를 확인한 그래프가 도시되어 있다. 또한, 도 12에는 뇌 미세교세포인 BV-2세포에서 포타슘(K+) 전류밀도를 측정한 그래프가 도시되어 있다.FIG. 11 is a graph showing the degree of expression of the protein KCNJ6 after treatment with papaya leaf extract, quercitrin, and afzelin in brain microsoprotein BV-2 cells. 12 is a graph showing the measurement of potassium (K + ) current density in BV-2 cells as brain microsoprobes.
상기 도 11과 도 12의 결과에 의하면, K+ 개폐조절 단백질인 KCNJ6의 발현 정도가 증가함에 따라 K+ 전류밀도도 증가하는 경향을 보인다는 것을 확인할 수 있다. 즉, 포타슘(K+) 전류밀도를 감소시켜 유발된 통증 질환은 초피 잎 추출물, 퀘르시트린(quercitrin) 또는 아프제린(afzelin)을 처리하여 포타슘(K+) 전류밀도가 증가됨으로 인하여 통증 질환이 치료됨을 확인할 수 있다.
The results of FIGS. 11 and 12 show that the K + current density tends to increase as the degree of expression of the K + regulatory protein KCNJ6 increases. That is, potassium (K +) a reduced current density to cause pain disorders Chopi leaf extract, quercitrin (quercitrin) or aching pain diseases potassium (K +) current density processes the jerin (afzelin) due to the increased .
실시예 16. 콜라겐 유도 동물 모델(CIA)에서의 류마티스 관절염 개선 효과Example 16. Improvement of rheumatoid arthritis in collagen-induced animal model (CIA)
콜라겐 유도 동물 모델(CIA)에서 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처치한 후에 NK세포(자연살해세포)를 분리하여 IFN-γ 세포의 발현량을 측정하여 류마티스 관절염의 치료효과를 확인하였다.After treating collagen-derived animal models (CIA) with extracts of papaya leaves or active compounds (quatitrin, arthritis), NK cells (natural killer cells) were isolated to measure the expression level of IFN-y cells and the therapeutic effect of rheumatoid arthritis Respectively.
IFN-γ는 면역자극에 의해 T세포 또는 NK세포에서 생성되는 사이토카인으로, 콜라겐 유도 동물은 IFN-γ 세포의 발현이 증가되는 경향을 보인다. 도 13은 콜라겐 유도 동물 모델(CIA)에 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처치한 후에 측정된 NK세포에서의 IFN-γ 생성량을 도시한 그래프이다. 도 13에 의하면 콜라겐 유도 동물 모델(CIA)에 대비하여, 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처치된 실험군은 NK세포의 IFN-γ의 발현량이 현저하게 감소되었음을 확인할 수 있다.
IFN-y is a cytokine produced by T cells or NK cells by immunostimulation, and collagen-induced animals show a tendency to increase the expression of IFN-y cells. Fig. 13 is a graph showing the amount of IFN-y production in NK cells measured after treating a collagen-derived animal model (CIA) with a papaya leaf extract or an active compound (aquatitin, afzelin). According to FIG. 13, it can be confirmed that the expression level of IFN-y in NK cells was significantly reduced in the experimental group treated with extracts of papaya leaf or active compounds (aquatitin, arthritis) in contrast to the collagen-induced animal model (CIA).
실시예 17. 콜라겐 유도 동물 모델(CIA)에서의 류마티스 관절염 개선 효과Example 17. Improvement of rheumatoid arthritis in collagen-induced animal model (CIA)
콜라겐 유도 동물 모델(CIA)에서 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처치한 후에 T세포의 IL-6, TH17세포의 IL-17, IL-21 및 IL-22의 발현량을 측정하여 류마티스 관절염의 치료효과를 확인하였다.IL-17, IL-21 and IL-22 expression levels of T-cell IL-6 and TH17 cells after treatment with extracts of papaya leaf or active compounds (quasitrin, arthritis) in collagen-induced animal model (CIA) And the treatment effect of rheumatoid arthritis was confirmed.
류마티스 관절염은 인체의 여러 관절에서 심한 통증이 수반되는 염증성 질환으로 류마티스 관절염 환자들의 관절 부위에는 염증 촉진성 사이토카인(IL-6, IL-17, IL-21 및 IL-22)이 다량 존재한다. 도 14은 콜라겐 유도 동물 모델(CIA)에 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처치한 후에 측정된 염증 촉진성 사이토카인(IL-6, IL-17, IL-21 및 IL-22)의 발현량을 도시한 그래프이다. 도 14에 의하면 콜라겐 유도 동물 모델(CIA)에 대비하여, 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처치된 실험군은 T세포에서 분비되는 IL-6의 발현량이 감소되며, TH17세포에서 분비되는 IL-17, IL-21 및 IL-22 의 발현량이 현저하게 감소되었음을 확인할 수 있다.
Rheumatoid arthritis is an inflammatory disease involving severe pain in various joints of the human body. There are abundant inflammatory cytokines (IL-6, IL-17, IL-21 and IL-22) in joints of rheumatoid arthritis patients. FIG. 14 is a graph showing the effect of the inflammatory-promoting cytokines (IL-6, IL-17, IL-21 and IL-21) measured after treating the collagen-derived animal model (CIA) 22) expressed in the culture medium. FIG. 14 shows that the experimental group treated with the extract of P. japonicus or the active compound (quasitrin, arthritis) compared to the collagen-induced animal model (CIA) decreased the expression level of IL-6 secreted from T cells, It was confirmed that the expression levels of IL-17, IL-21 and IL-22 secreted were remarkably reduced.
실시예 18. 자가면역 치료 효과Example 18. Effect of autoimmune therapy
염증 촉진성 사이토카인을 억제할 경우, 아토피 등 자가면역질환이 억제되는 것으로 보고되어 있다. 이에, 본 실시예에서는 비만세포 RBL-2H3를 대상으로 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)을 처리하여 β-헥소사미니다제 (β- hexosaminidase)의 분비 억제능을 확인하였다. 즉, 초피 잎 추출물 또는 활성화합물(쿼시트린, 아프젤린)에 대하여 비만세포 탈과립화 억제 효능을 확인하였다. 그 결과는 하기 표 10에 나타내었다.
Inhibition of inflammatory-promoting cytokines has been reported to inhibit autoimmune diseases such as atopy. Thus, in this Example, mast cell RBL-2H3 was treated with extracts of papaya leaf or active compounds (quasitrin, arthritis) to confirm secretion inhibition ability of? -Hexosaminidase. In other words, the extract of papaya leaf or the active compounds (quasitrin, arthritis) inhibited the degranulation of mast cells. The results are shown in Table 10 below.
(μg/mL)Treatment amount
(μg / mL)
상기 표 10에 의하면, 항히스타민제로 알려진 케토티펜(ketotifen) 약물에 대비하여 RBL-2H3 세포에 대한 탈과립 억제효과가 우수함을 알 수 있다. 처치용량 100 μg/mL에서 케토티펜 약물에 대비하여 초피 잎 추출물은 약 70%, 퀘시트린은 약 50%, 아프젤린은 93% 탈과립화 억제능을 보였다. 그리고, 처치용량 25 μg/mL에서 케토티펜 약물에 대비하여 초피 잎 추출물은 약 63%, 퀘시트린은 약 70%, 아프젤린은 195% 탈과립화 억제능을 보였다.Table 10 shows that the detergent inhibitory effect on RBL-2H3 cells is superior to that of ketotifen drugs known as antihistamines. Compared to the ketotifen drug, the extracts showed about 70% inhibition of decarburization, about 50% inhibition of quercitin and 93% inhibition of afzelinen at 100 μg / mL of treatment capacity. Compared with the ketotifen drug, about 63% of the extract of Chrysanthemum japonica extract, about 70% of quercitin, and 195% of 195% of desazurin inhibited the treatment capacity at 25 μg / mL.
[참고예][Reference Example]
본 발명은 초피(Zanthoxylum piperitum) 잎 추출물의 통증억제 및 항염증 효능을 기반으로 하는 약제조성물 또는 건강식품 조성물을 특징으로 하는 발명이다. 또한, 종래 발명으로 한국등록특허 10-1363311호에는 산초(Zanthoxylum schinifolium) 추출물의 궤양성 대장염의 치료 및 예방 효능이 개시되어 있다.The present invention is an invention characterized by a pharmaceutical composition or a health food composition based on the pain suppression and anti-inflammatory effect of Zanthoxylum piperitum leaf extract. Korean Patent No. 10-1363311 discloses a therapeutic and preventive effect of ulcerative colitis of Zanthoxylum schinifolium extract.
초피나무와 산초나무는 초피 속(Zanthoxylum sp.)에 속하는 식물으로 동일 내지 유사한 식물로 취급될 수도 있다고 판단된다. 이에, 본 참고예에서는 초피나무(Zanthoxylum piperitum)의 잎 추출물과 산초나무(Zanthoxylum schinifolium)의 열매 추출물이 실질적으로 함유성분이 극명하게 차이가 있는 별개의 추출물임을 여러 분석 결과를 토대로 입증하기로 한다.
It is judged that the first and second trees are belonging to Zanthoxylum sp. And can be treated as the same or similar plants. In this reference example, it is verified from the results of various analyzes that the leaf extract of Zanthoxylum piperitum and the fruit extract of Zanthoxylum schinifolium are distinct extracts having substantially different contents.
(1) 초피나무의 잎 추출물과 산초나무의 열매 추출물의 GC-MS 분석 대비(1) GC-MS analysis of the leaf extracts and the fruit extracts of Sancho
초피(Zanthoxylum piperitum)의 잎과 산초(Zanthoxylum schinifolium)의 열매를 90% 에탄올 수용액으로 추출하였고, 얻어진 각 추출물에 대해서는 GC-MS 분석하였다. 하기 표 11에는 초피의 잎 추출물과 산초 열매 추출물에 대해 GC-MS 분석한 결과를 정리하여 나타내었다.
The extracts of Zanthoxylum piperitum and Zanthoxylum schinifolium were extracted with a 90% aqueous ethanol solution. The extracts were analyzed by GC-MS. In Table 11, GC-MS analysis of the leaf extract and anthocyanin extract of chinese cabbage is summarized.
상기 표 11에 나타낸 바와 같이, 초피(Zanthoxylum piperitum)의 잎 추출물과 산초(Zanthoxylum schinifolium)의 열매 추출물은 공통된 함유성분이 거의 없으며, 함유성분의 구성이 극명하게 차이가 있다는 것을 확인할 수 있다.
As shown in Table 11 above, leaf extract of Zanthoxylum piperitum and Zanthoxylum schinifolium ) have almost no common components, and it can be confirmed that the compositions of the components contained therein are remarkably different.
또한, 초피(Zanthoxylum piperitum)의 잎 추출물, 열매 추출물과 산초(Zanthoxylum schinifolium)의 열매 추출물에 대하여 말초신경계와 중추신경계의 진통효과를 동시에 알아보기 위하여, 포르말린 시험법으로 진통효능을 측정하였으며, 그 결과는 하기 표 12에 나타내었다.In order to examine the analgesic effect of peripheral nervous system and central nervous system simultaneously on leaf extract, fruit extract and zanthoxylum schinifolium fruit extract of Zanthoxylum piperitum , analgesic efficacy was measured by the formalin test method, Are shown in Table 12 below.
하기 표 12에 의하면 초피 잎 추출물은 초피 열매 추출물 또는 산초 열매 추출물보다 그 효과가 극명하게 우수함을 확인할 수 있다.
According to the following Table 12, it can be confirmed that the extract of Peppermint Leaf is remarkably superior to the extract of Peppermint Fruit or Peppermint Fruit Extract.
[제제예][Formulation Example]
하기 제제예에서는 본 발명의 추출물, 분획물 또는 활성화합물(퀘르시트린(quercitrin)과 아프젤린(afzelin) 또는 이의 혼합물)을 유효성분으로 포함하는 약학적 조성물 또는 건강식품 조성물의 제조예를 설명하였다. 하기 제제예는 본 발명을 구체적으로 설명하기 위한 것이고, 이에 의해 본 발명이 한정되는 것은 아니다.
Examples of the preparation of a pharmaceutical composition or a health food composition containing the extract, fraction or active compound (quercitrin and afzelin or a mixture thereof) of the present invention as an active ingredient were described in the following formulation examples. The following Preparation Examples are intended to illustrate the present invention in detail, but the present invention is not limited thereto.
제제예 1. 약학적 조성물의 제조Formulation Example 1. Preparation of a pharmaceutical composition
(1) 정제의 제조(1) Preparation of tablets
에탄올 50 g에 포비돈 10 g을 녹여 결합액을 조제한 후 유효성분 150 g을 결합액에 넣어 균질하게 교반하였다. 규소화미결정셀룰로오스 130 g, 크로스카멜로오스나트륨 15 g, 콜로이드실리콘디옥사이드 20 g을 혼합한 후 유효성분과 균질하게 교반시킨 결합액을 투입하여 과립공정을 진행 후 과립물을 건조 및 정립하였다. 제조된 과립물에 크로스포비돈 15 g을 넣고 혼합하고, 콜로이드실리콘디옥사이드 3.5 g과 스테아르산마그네슘 6.5 g을 넣고 활택공정을 진행 후 정제로 만들었다.
After dissolving 10 g of povidone in 50 g of ethanol to prepare a binding solution, 150 g of the active ingredient was added to the binding solution and homogeneously stirred. 130 g of silicified microcrystalline cellulose, 15 g of croscarmellose sodium, and 20 g of colloidal silicon dioxide were mixed, and then a binding solution homogeneously stirred with the active ingredient was added thereto, followed by granulation, followed by drying and sizing of the granules. 15 g of crospovidone was added to the prepared granules, and the mixture was mixed. 3.5 g of colloidal silicon dioxide and 6.5 g of magnesium stearate were added thereto, and the mixture was subjected to a filtration step, followed by purification.
(2) 정제의 제조(2) Production of tablets
에탄올 50 g에 포비돈 19 g을 녹여 결합액을 조제한 후, 유효성분 150 g을 결합액에 넣어 균질하게 교반하였다. 규소화미결정셀룰로오스 143 g, 크로스카멜로오스나트륨 15 g, 노이시린 20 g을 혼합한 후 유효성분과 균질하게 교반시킨 결합액을 투입하여 과립공정을 진행 후 과립물을 건조 및 정립하였다. 제조된 과립물에 크로스포비돈 15 g을 넣고 혼합하고, 콜로이드실리콘디옥사이드 5 g과 스테아르산마그네슘 8 g을 넣고 활택공정을 진행 후 정제로 만들었다.
After dissolving 19 g of povidone in 50 g of ethanol to prepare a binding solution, 150 g of the active ingredient was added to the binding solution and homogeneously stirred. 143 g of microcrystalline cellulose, 15 g of croscarmellose sodium, and 20 g of neosilane were mixed and then stirred to homogeneously mix with the active ingredient. The mixture was granulated and dried and dried. 15 g of crospovidone was added to the granules and mixed. 5 g of colloidal silicon dioxide and 8 g of magnesium stearate were added, and the mixture was subjected to a filtration process to form tablets.
(3) 정제의 제조(3) Preparation of tablets
에탄올 50 g에 포비돈 12.5 g을 녹여 결합액을 조제한 후 유효성분 150 g을 결합액에 넣어 균질하게 교반하였다. 규소화미결정셀룰로오스 62.5 g, 유당수화물 65 g, 크로스카멜로오스나트륨 15 g, 콜로이드실리콘디옥사이드 20 g을 혼합한 후 유효성분과 균질하게 교반시킨 결합액을 투입하여 과립공정을 진행 후 과립물을 건조 및 정립하였다. 제조된 과립물에 크로스포비돈 15 g을 넣고 혼합하고, 콜로이드실리콘디옥사이드 3.5 g과 스테아르산마그네슘 6.5 g을 넣고 활택공정을 진행 후 정제로 만들었다.
After dissolving 12.5 g of povidone in 50 g of ethanol to prepare a binding solution, 150 g of the active ingredient was added to the binding solution and homogeneously stirred. 62.5 g of silicified microcrystalline cellulose, 65 g of lactose hydrate, 15 g of croscarmellose sodium, and 20 g of colloidal silicon dioxide were mixed and the mixture was homogenously mixed with the active ingredient to give a granulation process, followed by drying and sizing of the granules Respectively. 15 g of crospovidone was added to the prepared granules, and the mixture was mixed. 3.5 g of colloidal silicon dioxide and 6.5 g of magnesium stearate were added thereto, and the mixture was subjected to a filtration step, followed by purification.
(4) 정제의 제조(4) Preparation of tablets
에탄올 33.5 g에 포비돈 19g을 녹여 결합액을 조제한 후 유효성분 150 g을 결합액에 넣어 균질하게 교반하였다. 규소화미결정셀룰로오스 105 g(주성분이 함유하고 있는 에탄올의 양 만큼 규소화미결정셀룰로오스의 양을 추가한다.), 크로스카멜로오스나트륨 17.5 g, 노이시린 20 g을 혼합한 후 유효성분과 균질하게 교반시킨 결합액을 투입하여 과립공정을 진행 후 과립물을 건조 및 정립하였다. 제조된 과립물에 크로스포비돈 17.5 g과 규소화미결정셀룰로오스 33 g을 넣고 혼합하고, 콜로이드실리콘디옥사이드 7.5 g과 스테아르산마그네슘 8 g을 넣고 활택공정을 진행 후 정제로 만들었다.
After 19 g of povidone was dissolved in 33.5 g of ethanol to prepare a binding solution, 150 g of the active ingredient was added to the binding solution and stirred homogeneously. 105 g of silicified microcrystalline cellulose (amount of silicified microcrystalline cellulose is added by the amount of ethanol contained in the main component), 17.5 g of croscarmellose sodium and 20 g of neohelin are mixed and homogeneously stirred with the active ingredient After the granulation process was carried out, the granules were dried and set. 17.5 g of crospovidone and 33 g of silicified microcrystalline cellulose were added to the prepared granules, and 7.5 g of colloidal silicon dioxide and 8 g of magnesium stearate were added thereto, followed by filtration and purification.
(5) 코팅정의 제조(5) Manufacture of coating definition
상기 제제예 1 내지 4에서 제조한 정제 755 mg(유효성분 300 mg 포함)을 통상적인 펜 코팅 시스템(Opadryㄾ, Opadry200ㄾ 또는 Opaglosㄾ)을 이용하여 코팅정을 제조하였다
755 mg of the tablets prepared in Preparation Examples 1 to 4 (including 300 mg of the active ingredient) were coated with a conventional pen coating system ( Opadry® , Opadry 200® or Opaglos® )
제제예 2. 건강식품의 제조Preparation Example 2. Preparation of health food
(1) 음료의 제조(1) Production of beverages
유효성분 1000 ㎎, 구연산 1000 ㎎, 올리고당 100 g, 타우린 1 g을 혼합하여, 여기에 정제수를 가하여 전체 부피가 900 ㎖가 되도록 하였다. 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 담아서 밀봉 멸균하여 음료를 제조하였다.
1000 mg of active ingredient, 1000 mg of citric acid, 100 g of oligosaccharide and 1 g of taurine were mixed, and purified water was added thereto to make the total volume 900 ml. After stirring and heating at 85 DEG C for about 1 hour, the solution was filtered and sterilized by sealing in a sterilized 2 liter container to prepare a beverage.
[실험예]
[Experimental Example]
실험예 1. 정제의 붕해도 측정Experimental Example 1. Determination of the Disintegration of Tablets
상기 제제예 5에서 제조한 정제 755 mg(유효성분 300 mg 포함)을 12개 준비하였다. 약전 붕해시험법에 따라 시험하여 5분 간격으로 붕해된 정제의 개수를 확인하여 하기 표 13에 나타내었다. 12개의 정제가 완전히 붕해될 때까지 시험을 실시하였다.Twelve of 755 mg tablets (containing 300 mg of active ingredient) prepared in Preparation Example 5 were prepared. The test was conducted according to the pharmacodynamic disintegration test method to confirm the number of disintegrated tablets at intervals of 5 minutes, and the results are shown in Table 13 below. The test was run until the 12 tablets were completely disintegrated.
실험예 2. 타정의 마손도 측정Experimental Example 2 Measurement of wear on the pad
상기 제제예 5에서 제조한 정제 755 mg(유효성분 300 mg 포함)을 경도 10~12 kp, 12~14 kp, 14 kp 이상으로 나누어 타정하였다. 타정의 마손도를 측정한 결과, 10 kp 이상의 경도에서 마손도 0.1% 이하의 수치를 나타내었다.
755 mg tablets (containing 300 mg of the active ingredient) prepared in Preparation Example 5 were divided into tablets having a hardness of 10 to 12 kp, 12 to 14 kp, and 14 kp or more. As a result of measuring the degree of grindability of the tablets, the degree of grindability was 0.1% or less at a hardness of 10 kp or more.
실험예 3. 정제의 물성 측정Experimental Example 3 Measurement of Physical Properties of Tablets
상기 제제예 5에서 제조한 정제 755 mg(유효성분 300 mg 포함)의 유동성을 확인하기 위하여, 부피밀도 (bulk density), 탭밀도 (Tapped density), 하우스너비 (Hausner ratio), 압축지수 (Compressibility index), 인식각 (Angle of repose)를 각각 측정하였다. 그 결과는 하기 표 14에 나타내었다. The bulk density, the tapped density, the Hausner ratio, and the compressibility index of the tablet 755 mg (including 300 mg of the active ingredient) prepared in Preparation Example 5 were measured to determine the fluidity. ), And the angle of repose (Angle of repose). The results are shown in Table 14 below.
Claims (20)
[화학식 1]
[화학식 2]
The extracts of Zanthoxylum piperitum leaves with at least one solvent selected from the group consisting of C 1 -4 alcohols and aqueous C 1 -4 alcohols, comprising quercetin-3-O-alpha-L- Laminoside or camphorol-3-O-alpha-L-lambsoside represented by the following formula (2) or a mixture thereof is contained as an active ingredient.
[Chemical Formula 1]
(2)
상기 추출에 사용된 용매는 90 ~ 95% 에탄올 수용액인 것을 특징으로 하는 염증 또는 통증 치료 및 예방용 약제 조성물.
The method according to claim 1,
Wherein the solvent used for the extraction is an aqueous 90 to 95% ethanol solution.
A pharmaceutical composition for treating or preventing inflammation or pain, comprising the ethyl acetate fraction obtained by extracting the Zanthoxylum piperitum extract of claim 1 with ethyl acetate.
상기 초피 (Zanthoxylum piperitum)의 추출물 또는 에틸아세테이트 분획물은 활성성분으로서 4'-히드록시-아세토페논, 2,4-디-tert-부틸페놀 및 1,2-벤젠디카르복시산으로 이루어진 군으로부터 선택된 1종 이상의 화합물이 포함되어 있는 것을 특징으로 하는 염증 또는 통증 치료 및 예방용 약제 조성물.
4. The method according to any one of claims 1 to 3,
The Zanthoxylum piperitum or ethyl acetate fraction contains at least one compound selected from the group consisting of 4'-hydroxy-acetophenone, 2,4-di- tert -butylphenol and 1,2-benzenedicarboxylic acid as active ingredients Or a pharmaceutically acceptable salt thereof.
[화학식 1]
[화학식 2]
3-O-alpha-L-rhamnoside represented by the following formula (1), camphorol-3-O-alpha-L-lamboside represented by the following formula (2) A pharmaceutical composition for the treatment and prevention of inflammation or pain.
[Chemical Formula 1]
(2)
4'-히드록시-아세토페논, 2,4-디-tert-부틸페놀, 및 1,2-벤젠디카르복시산으로 이루어진 군으로부터 선택된 1종 이상의 화합물이 더 포함되어 있는 것을 특징으로 하는 염증 또는 통증 치료 및 예방용 약제 조성물.
6. The method of claim 5,
4-hydroxy-acetophenone, 2,4-di- tert -butylphenol, and 1,2-benzenedicarboxylic acid. ≪ / RTI >
상기 염증은 관절염인 것을 특징으로 하는 염증 또는 통증 치료 및 예방용 약제 조성물.
6. The method according to any one of claims 1 to 3, 5 and 6,
Wherein said inflammation is arthritis.
상기 관절염은 류마티스 관절염 또는 퇴행성 관절염인 것을 특징으로 하는 염증 또는 통증 치료 및 예방용 약제 조성물.
8. The method of claim 7,
Wherein said arthritis is rheumatoid arthritis or degenerative arthritis.
정제 형태로 제형화된 것을 특징으로 하는 염증 또는 통증 치료 및 예방용 약제 조성물.
6. The method according to any one of claims 1 to 3, 5 and 6,
A pharmaceutical composition for treating or preventing inflammation or pain, characterized by being formulated in tablet form.
[화학식 1]
[화학식 2]
A herbal extract obtained by extracting Zanthoxylum piperitum leaves with at least one solvent selected from the group consisting of C 1 -4 alcohols and C 1 -4 alcohols, quercetin-3-O-alpha-L- Side or camphorol-3-O-alpha-L-lambsoside represented by the following formula (2) or a mixture thereof is contained as an active ingredient.
[Chemical Formula 1]
(2)
상기 추출에 사용된 용매는 90 ~ 95% 에탄올 수용액인 것을 특징으로 하는 염증 또는 통증 개선용 건강식품 조성물.
11. The method of claim 10,
Wherein the solvent used for the extraction is a 90 to 95% aqueous solution of ethanol.
A health food composition for improving inflammation or pain comprising an ethyl acetate fraction obtained by extracting Zanthoxylum piperitum extract of claim 10 with ethyl acetate.
상기 초피 (Zanthoxylum piperitum)의 추출물 또는 에틸아세테이트 분획물은 활성성분으로서 4'-히드록시-아세토페논, 2,4-디-tert-부틸페놀 및 1,2-벤젠디카르복시산으로 이루어진 군으로부터 선택된 1종 이상의 화합물이 포함되어 있는 것을 특징으로 하는 염증 또는 통증 개선용 건강식품 조성물.
13. The method according to any one of claims 10 to 12,
The extract or ethyl acetate fraction of Zanthoxylum piperitum may contain, as active ingredient, one kind selected from the group consisting of 4'-hydroxy-acetophenone, 2,4-di- tert -butylphenol and 1,2-benzenedicarboxylic acid Or a pharmaceutically acceptable salt or solvate thereof.
[화학식 1]
[화학식 2]
3-O-alpha-L-rhamnoside represented by the following formula (1), camphorol-3-O-alpha-L-lamboside represented by the following formula (2) A health food composition for improving inflammation or pain.
[Chemical Formula 1]
(2)
4'-히드록시-아세토페논, 2,4-디-tert-부틸페놀, 및 1,2-벤젠디카르복시산으로 이루어진 군으로부터 선택된 1종 이상의 화합물이 더 포함되어 있는 것을 특징으로 하는 염증 또는 통증 개선용 건강식품 조성물.
15. The method of claim 14,
Wherein at least one compound selected from the group consisting of 4'-hydroxy-acetophenone, 2,4-di- tert -butylphenol, and 1,2-benzenedicarboxylic acid is further contained. ≪ / RTI >
상기 염증은 관절염인 것을 특징으로 하는 염증 또는 통증 개선용 건강식품 조성물.
15. A method according to any one of claims 10 to 12, 14 or 15,
Wherein the inflammation is arthritis.
ⅱ) 상기 알콜 추출물을 물로 현탁한 후, 노르말 헥산, 디클로로메탄, 에틸아세테이트로 및 노르말 부탄올로 차례로 분획하여, 에틸아세테이트 분획물을 얻는 단계; 및
ⅲ) 상기 에틸아세테이트 분획물을 실리카겔 컬럼 크로마토그래피와 중압 크로마토그래피 (MPLC)를 수행하여 하기 화학식 1로 표시되는 쿼세틴-3-O-알파-L-람노사이드 또는 하기 화학식 2로 표시되는 캠퍼롤-3-O-알파-L-람노사이드를 각각 수득하는 단계;
를 포함하는 활성화합물의 분리방법.
[화학식 1]
[화학식 2]
I) extracting a leaf of Zanthoxylum piperitum with at least one extraction solvent selected from the group consisting of C 1-4 alcohol and C 1-4 alcohol aqueous solution to obtain an alcoholic extract;
Ii) suspending the alcohol extract in water, and subsequently fractionating the mixture with normal hexane, dichloromethane, ethyl acetate and normal butanol to obtain an ethyl acetate fraction; And
Iii) The ethyl acetate fraction was subjected to silica gel column chromatography and medium pressure chromatography (MPLC) to obtain quercetin-3-O-alpha-L-rhamnoside represented by the following formula 1 or camphor- -O-alpha-L-rhamnoside, respectively;
≪ / RTI >
[Chemical Formula 1]
(2)
상기 ⅰ)과정에서의 추출에 사용된 용매는 90 ~ 95% 에탄올 수용액인 것을 특징으로 하는 활성화합물의 분리방법.
18. The method of claim 17,
Wherein the solvent used for the extraction in step i) is a 90 to 95% aqueous solution of ethanol.
상기 ⅰ)과정에서의 추출은 20 ~ 80℃ 온도에서 수행하는 것을 특징으로 하는 활성화합물의 분리방법.
18. The method of claim 17,
Wherein the extraction in step i) is carried out at a temperature of 20 to 80 ° C.
상기 ⅰ)과정에서의 얻은 알콜 추출물을 원심분리하여 에멀젼을 제거하는 단계를 더 포함하는 것을 특징으로 하는 활성화합물의 분리방법.
18. The method of claim 17,
Further comprising the step of removing the emulsion by centrifuging the alcohol extract obtained in the step i).
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WO2019078386A1 (en) * | 2017-10-20 | 2019-04-25 | 메콕스큐어메드 주식회사 | Fraction of zanthoxylum piperitum leaf extract, effective for pain relief |
KR20200039377A (en) * | 2018-10-05 | 2020-04-16 | 대한민국(산림청 국립산림과학원장) | Composition comprising essential oil extract derived anthoxylum coreanum Nakaiis for prevention or treatment of allergic diseases |
WO2020171682A1 (en) * | 2019-02-22 | 2020-08-27 | 주식회사 엘지생활건강 | Composition for inhibiting release of neurotransmitters |
KR20200102920A (en) * | 2019-02-22 | 2020-09-01 | 주식회사 엘지생활건강 | Composition for inhibiting neurotransmitter secretion |
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2016
- 2016-04-20 KR KR1020160048071A patent/KR101841092B1/en active IP Right Grant
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2019078386A1 (en) * | 2017-10-20 | 2019-04-25 | 메콕스큐어메드 주식회사 | Fraction of zanthoxylum piperitum leaf extract, effective for pain relief |
KR20200039377A (en) * | 2018-10-05 | 2020-04-16 | 대한민국(산림청 국립산림과학원장) | Composition comprising essential oil extract derived anthoxylum coreanum Nakaiis for prevention or treatment of allergic diseases |
WO2020171682A1 (en) * | 2019-02-22 | 2020-08-27 | 주식회사 엘지생활건강 | Composition for inhibiting release of neurotransmitters |
KR20200102920A (en) * | 2019-02-22 | 2020-09-01 | 주식회사 엘지생활건강 | Composition for inhibiting neurotransmitter secretion |
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