KR20200052221A - Composition for treating, alleviating or preventing pain comprising bupleuri radix extract or its ingredient - Google Patents
Composition for treating, alleviating or preventing pain comprising bupleuri radix extract or its ingredient Download PDFInfo
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- KR20200052221A KR20200052221A KR1020190134282A KR20190134282A KR20200052221A KR 20200052221 A KR20200052221 A KR 20200052221A KR 1020190134282 A KR1020190134282 A KR 1020190134282A KR 20190134282 A KR20190134282 A KR 20190134282A KR 20200052221 A KR20200052221 A KR 20200052221A
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- South Korea
- Prior art keywords
- neuropathic pain
- extract
- pain
- trpa1
- psychosaponin
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Abstract
Description
본 발명은 시호 추출물 또는 이의 성분, 특히 사이코사포닌 또는 이의 약학적으로 허용가능한 염 중 하나 이상을 유효성분으로 함유하는, 신경병증 통증 치료, 완화 또는 예방용 조성물에 관한 것이다.The present invention relates to a composition for treating, alleviating or preventing neuropathic pain, which contains at least one of shiho extract or a component thereof, particularly psychosaponin or a pharmaceutically acceptable salt thereof, as an active ingredient.
통증은 신체가 침해성 요인에 반응하여 나타나는 생리기전이며, 이는 크게 통각수용성 통증과 신경병증 통증으로 구분할 수 있다. 상기 신경병증 통증은 체성감각신경계(somatosensory system)의 손상 또는 병적 요인 등에 의해 발생하는데, 해부학적으로 말초성 통증과 중추성 통증으로 구분할 수 있으며, 그 원인에 근거하여 유전성, 대사성, 외상성, 혈관성, 면역학적, 감염성, 독성에 의한 통증으로 분류할 수 있다. 이처럼 다양한 원인이 있기 때문에 신경병증 통증을 하나의 병변이나 특정 부위의 손상만으로 설명하기 어려우며, 증상을 초래하는 기전을 고려하여 치료제를 선택해야 한다.Pain is a physiological mechanism in which the body responds to an invasive factor, which can be largely divided into nociceptive pain and neuropathic pain. The neuropathic pain occurs due to damage or pathological factors of the somatosensory system, and can be anatomically divided into peripheral pain and central pain, and based on the cause, hereditary, metabolic, traumatic, vascular, and immune It can be classified as a pain caused by medical, infectious or toxic. Because of these various causes, it is difficult to describe neuropathic pain with only one lesion or damage to a specific area, and a therapeutic agent should be selected in consideration of the mechanism causing symptoms.
상기 말초성 신경병증 통증(말초신경병증 통증이라고도 지칭됨)은 말초신경의 손상 또는 질병에 의해 나타나는 증상으로, 감각 소실과 같은 음성적 증상과 실제 통증(이질통, 통각과민)을 느끼는 양성적 증상이 나타난다. 상기 이질통(allodynia)이란 정상적인 상황에서는 통증을 유발하지 않는 미세한 자극(예: 옷깃 스침)에 의해 심한 통증을 느끼는 상태이며, 여기에는 냉이질통과 기계적 이질통 등이 포함된다. 상기 통각과민(hyperalgesia)이란 정상상태에서 통증을 유발하는 자극에 대하여 훨씬 더 민감하게 통증반응을 일으키는 상태이다. 따라서, 말초신경병증 통증의 치료는 신경의 과흥분을 억제하는 기전이 이용되어야 한다.The peripheral neuropathic pain (also referred to as peripheral neuropathic pain) is a symptom caused by damage or disease of the peripheral nerve, and a negative symptom such as loss of sensation and a positive symptom feeling real pain (dyssia, hyperalgesia). The allodynia is a state in which severe pain is caused by a microscopic stimulus (eg, lapping) that does not cause pain in a normal situation, and includes cold and mechanical allodynia. The hyperalgesia is a state in which the pain response is more sensitive to a stimulus causing pain in a normal state. Therefore, in the treatment of peripheral neuropathic pain, a mechanism for suppressing hyperexcitation of nerves should be used.
현재 말초신경병증 통증의 치료제로서 사용되는 약물은 항우울제, 항경련제, 국소진통제, NMDA 수용체 길항제, 마약성 진통제 등이 있으며, 일차적으로 아미트리프틸린(삼환계 항우울제), 가바펜틴, 프레가발린(항경련제), 세로토닌-노르에피네프린 재흡수억제제(항우울제) 등이 많이 처방된다. 그러나, 마약성 진통제는 약물 오남용의 우려와 다양한 부작용을 유발할 수 있는 단점이 있다. 또한, 항경련제와 항우울제는 모든 환자에게 효과적인 것은 아니며, 단지 30% 이하의 환자만이 평균 50% 정도의 진통 효과를 경험하는 것으로 보고되고 있다. 따라서, 마약성 진통제의 부작용을 회피하고 진통 효능이 미흡한 항우울제 및 항경련제를 대체할 수 있는 새로운 통증 치료제 개발이 절실히 요구된다.Drugs currently used for the treatment of peripheral neuropathy pain include antidepressants, anticonvulsants, topical analgesics, NMDA receptor antagonists, and narcotic analgesics, primarily amitriptyline (tricyclic antidepressants), gabapentin, and pregabalin (anticonvulsants) ), Serotonin-norepinephrine reuptake inhibitors (antidepressants) and many are prescribed. However, narcotic analgesics have the disadvantage of causing abuse and various side effects of drug abuse. In addition, anticonvulsants and antidepressants are not effective for all patients, and only 30% of patients have been reported to experience an analgesic effect of about 50% on average. Therefore, there is an urgent need to develop new pain treatments that can avoid the side effects of narcotic analgesics and replace antidepressants and anticonvulsants that lack analgesic efficacy.
현재 임상 진행 중인 약물의 작용기전 현황을 보면 오피오이드 수용체를 표적으로 하는 약물이 46%로 가장 많고, 다음으로 프로스타글란딘-엔도퍼옥사이드 신타제(prostaglandin-endoperoxide synthase) (21%), 전압 작동 이온 채널(voltage-gated ion channel) (17%) 순으로 나타난다. 이 외에도 solute carrier family 6, Transient Receptor Potential (TRP) 양이온 채널, 칸나비노이드 수용체 등이 통증 치료약물의 표적으로 이용되고 있다.According to the current mechanism of action of drugs currently in clinical trial, 46% of drugs targeting opioid receptors are the most, followed by prostaglandin-endoperoxide synthase (21%), voltage-operated ion channels ( voltage-gated ion channel) (17%). In addition, and the like
상기 TRP 양이온 채널은 다양한 조직(신경, 피부, 심장, 호흡기관, 신장 등)에 발현되는 막 단백질이며, 활성화되었을 때 양이온의 세포 내 유입을 일으킴으로써 세포를 자극한다. 현재까지 여러 가지 자극원에 반응하는 다양한 형태의 TRP 막 단백질이 존재하며 대표적으로 TRPA, TRPC, TRPV, TRPM 등이 알려졌다. 이 중에서 통증과 관련된 것은 TRPA1으로, 조직 손상과 염증 반응시 생성되는 케토알데하이드, 사이클로펜탄 프로스타글란딘, 활성산소 등에 의해 활성화되어 통증을 유발시킨다고 보고되고 있다. 유전적 요인에 의한 TRPA1 기능항진으로 초래되는 유전병(Familial episodic pain syndrome)은 TRPA1이 통증과 밀접한 연관이 있음을 알려주는 좋은 예이다. The TRP cation channel is a membrane protein expressed in various tissues (nerves, skin, heart, respiratory organs, kidneys, etc.), and when activated, stimulates cells by causing influx of cations into cells. To date, various types of TRP membrane proteins that respond to various stimuli exist, and TRPA, TRPC, TRPV, and TRPM are known. Among them, pain is related to TRPA1, which has been reported to cause pain by being activated by ketoaldehyde, cyclopentane prostaglandin, and free radicals generated during tissue damage and inflammatory reaction. Familial episodic pain syndrome, which is caused by hypertension of TRPA1 by genetic factors, is a good example of the fact that TRPA1 is closely related to pain.
이에 따라, TRPA1 길항제를 신경병증 통증 치료제로서 개발하려는 연구가 이루어지고 있다. 다만, TRPA1 길항제라고 하더라도 신경병증 통증의 구체적인 종류가 무엇인지에 따라 치료 또는 예방 효과를 나타내거나 나타내지 못한다. 이는 전술한 바와 같이 신경병증 통증이 나타나는 원인이 다양하기 때문이며, 이에 따라 신경병증 통증의 치료제는 그 증상의 원인 및 기전에 따라 특이적으로 선별되어야 할 필요가 있다.Accordingly, research has been conducted to develop a TRPA1 antagonist as a therapeutic agent for neuropathic pain. However, even if it is a TRPA1 antagonist, it does not or does not show a therapeutic or preventive effect depending on what specific type of neuropathic pain is. This is because there are various causes of neuropathic pain as described above, and accordingly, a therapeutic agent for neuropathic pain needs to be specifically screened according to the cause and mechanism of the symptom.
이에 본 발명자들은 신경병증 통증에 유용한 후보 물질을 발굴하기 위하여 예의 노력한 결과, 사이코사포닌 및 이의 염과 시호 추출물이 TRPA1 활성을 억제하고 신경병증 통증 치료 효과가 있음을 확인하였으며, 이에 기초하여 본 발명을 완성하기에 이르렀다.Accordingly, the present inventors confirmed that as a result of diligent efforts to discover candidate substances useful for neuropathic pain, psychosaponin and its salt and shiho extract inhibit TRPA1 activity and have a neuropathic pain treatment effect, based on this. Came to completion.
본 발명의 일 목적은 신경병증 통증 치료 또는 예방용 약학 조성물을 제공하는 것이다. One object of the present invention is to provide a pharmaceutical composition for the treatment or prevention of neuropathic pain.
본 발명의 다른 목적은 신경병증 통증 완화 또는 예방용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for alleviating or preventing neuropathic pain.
본 발명의 일 양태는 사이코사포닌 또는 이의 약학적으로 허용가능한 염 및 시호 추출물 중 하나 이상을 유효성분으로 함유하는, 신경병증 통증 치료 또는 예방용 약학 조성물을 제공한다.One aspect of the present invention provides a pharmaceutical composition for the treatment or prevention of neuropathic pain, which contains at least one of psychosaponin or a pharmaceutically acceptable salt and extract thereof.
본 명세서에서, 용어 "사이코사포닌(saikosaponin)"은 트리테르페노이드계의 사포닌 배당체를 의미한다. 상기 사이코사포닌에는 예를 들어 사이코사포닌 A, 사이코사포닌 B1, 사이코사포닌 B2, 사이코사포닌 B3, 사이코사포닌 B4, 사이코사포닌 C, 사이코사포닌 D, 사이코사포닌 E, 사이코사포닌 F, 사이코사포닌 G, 사이코사포닌 H, 사이코사포닌 I 등이 포함된다. 각각의 사이코사포닌 화합물들의 구조는 당업계에 이미 잘 알려져 있다.In the present specification, the term "saikosaponin" means a triterpenoid-based saponin glycoside. The psycho saponins include, for example, psycho saponin A, psycho saponin B1, psycho saponin B2, psycho saponin B3, psycho saponin B4, psycho saponin C, psycho saponin D, psycho saponin E, psycho saponin F, psycho saponin G, psycho saponin H , Psychosaponin I, and the like. The structure of each psychosaponin compound is well known in the art.
본 발명에서 사용되는 사이코사포닌은 바람직하게는 사이코사포닌 A, B1, B2, C, D, E 또는 F이며, 더 바람직하게는 사이코사포닌 D이다. 예를 들어, 상기 사이코사포닌 D는 하기 화학식 1의 구조식을 가지며, (3β,4α,16α)-13,28-에폭시-16,23-디하이드록시올리언-11-엔-3-일-6-디옥시-3-O-β-D-글루코피라노실-β-D-갈락토피라노시드라고도 명명된다.The psychosaponin used in the present invention is preferably psychosaponin A, B1, B2, C, D, E or F, more preferably psychosaponin D. For example, the psycho-saponin D has the structural formula of
[화학식 1][Formula 1]
또한, 본 발명의 약학 조성물은 사이코사포닌 화합물 뿐만 아니라 사이코사포닌의 약학적으로 허용가능한 염을 포함할 수 있다. 상기 사이코사포닌 화합물의 약학적으로 허용가능한 염은 사이코사포닌 또는 이의 이성질체가 가질 수 있는 임의의 모든 유기 또는 무기 부가염을 나타내며, 사이코사포닌과 동등하거나 유사한 수준의 신경병증 통증 치료 효과를 나타내는 한 제한되지 않는다.In addition, the pharmaceutical composition of the present invention may include a psychosaponin compound as well as a pharmaceutically acceptable salt of psychosaponin. The pharmaceutically acceptable salt of the psychosaponin compound represents any and all organic or inorganic addition salts that the psychosaponin or its isomers may have, and is not limited as long as it has an equivalent or similar level of neuropathic pain treatment effect to the psychosaponin. Does not.
용어 "시호(柴胡, Bupleuri Radix)"는 학명이 Bupleurum falcatum L.이며, 쌍떡잎 식물 산형화목 미나리과의 여러해살이 풀이다. 본 발명에 따른 조성물에 있어서, 시호는 재배한 것, 채취한 것 또는 시판되는 것 등이 제한 없이 사용될 수 있다.The term "Shiho (柴胡, Bupleuri Radix)" is the scientific name Bupleurum falcatum L., and is a perennial plant of the dicotyledonous family, Asteraceae. In the composition according to the present invention, cultivation, harvested or commercially available can be used without limitation.
용어 "시호 추출물"은 시호로부터 수득한 추출물을 의미한다. 본 발명의 약학 조성물에 포함되는 시호 추출물은 시호의 뿌리, 줄기, 가지, 꽃, 잎 및 열매로 이루어진 군에서 선택되는 하나 이상을 추출한 것일 수 있으며, 바람직하게는 시호의 뿌리를 추출한 것일 수 있다. 상기 시호 추출물은 바람직하게는 사이코사포닌 A, B1, B2, C, D, E 및 F 중 하나 이상을 포함하는 것이며, 특히 바람직하게는 사이코사포닌 D를 포함하는 것이다.The term "shoe extract" means an extract obtained from shou. The Siho extract contained in the pharmaceutical composition of the present invention may be one or more selected from the group consisting of Siho's roots, stems, branches, flowers, leaves, and fruits, and preferably, the Siho's roots may be extracted. The Siho extract preferably comprises one or more of Psychosaponins A, B1, B2, C, D, E and F, particularly preferably Psychosaponin D.
용어 "추출물"은 생약을 적절한 추출용매로 추출하고 추출용매를 증발시켜 농축한 제제를 의미하는 것으로, 추출처리에 의해 얻어지는 추출액, 추출액의 희석액 또는 농축액, 추출액을 건조하여 얻어지는 건조물, 이들의 조정제물 또는 정제물일 수 있다. 본 발명에 따른 시호 추출물은 당업계에 공지된 일반적인 추출방법을 이용하여 제조할 수 있으며, 예를 들어 열탕 추출, 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 방법을 사용할 수 있다.The term "extract" refers to a formulation obtained by extracting a crude drug with an appropriate extraction solvent and evaporating the extraction solvent, and extracts obtained by an extraction process, diluents or concentrates of extracts, dried products obtained by drying extracts, and their control agents Or it may be a purified product. Siho extract according to the present invention can be prepared using a general extraction method known in the art, for example, hot water extraction, hot water extraction, cold extraction, reflux cooling extraction or ultrasonic extraction may be used.
본 발명의 약학 조성물에 유효성분으로서 포함되는 사이코사포닌 또는 이의 약학적으로 허용가능한 염 또는 시호 추출물은 TRPA1(Transient receptor potential cation channel, subfamily A, member 1) 길항제 활성을 나타낸다. Psychosaponins or pharmaceutically acceptable salts or extracts thereof, which are included as an active ingredient in the pharmaceutical composition of the present invention, exhibit antagonist activity of TRPA1 (Transient receptor potential cation channel, subfamily A, member 1).
용어 "신경병증 통증"은 신경계의 일차적 병변이나 기능장애로 오는 통증을 의미한다. 상기 신경병증 통증에는 통각과민, 감각과민, 신경병증, 당뇨성 신경병증 통증, 대상포진 유래 신경병성 통증, 신경염, 신경통, 작열통, 이질통, 말초신경병증 통증 등이 포함될 수 있다. 상기 신경병증 통증은 바람직하게는 말초신경병증 통증일 수 있다. The term "neuropathic pain" refers to pain resulting from a primary lesion or dysfunction of the nervous system. The neuropathic pain may include hyperalgesia, sensitization, neuropathy, diabetic neuropathic pain, shingles-derived neuropathic pain, neuritis, neuralgia, burning pain, allodynia, peripheral neuropathic pain, and the like. The neuropathic pain may preferably be peripheral neuropathic pain.
본 발명의 일 구현예에서, 상기 신경병증 통증은 당뇨성 신경병증 통증일 수 있다.In one embodiment of the invention, the neuropathic pain may be diabetic neuropathic pain.
당뇨성 신경병증 통증은 만성 고혈당으로 인한 신경 손상 또는 신경의 비정상적인 기능 때문에 발생하는 통증으로서, 당뇨병 환자의 30% 이상에서 확인될 정도로 흔하며 신체의 여러 부위에서 증상이 나타나며 특히 발 부위에서 많이 나타난다. 당뇨성 신경병증 통증에는 symmetric distal polyneuropathy, acute diabetic mononeuropathy, diabetic amyotrophy, diabetic radiculopathy, diabetic autonomic neuropathy 등 여러 아형들이 있다. 고혈당에 의해 말초혈관과 신경이 손상되지 않도록 혈당 조절을 하면 신경병증 통증을 완화시킬 수 있으나, 이와 같이 혈당을 조절해도 신경병증 통증이 계속되는 경우가 많으며, 현재 시판되는 당뇨병 약물에 의해서는 당뇨성 신경병증 통증에 대해 특이적으로 치료 효과를 나타내지 못하는 경우가 많다.Diabetic neuropathic pain is a pain caused by nerve damage caused by chronic hyperglycemia or abnormal function of the nerve. It is common enough to be found in more than 30% of diabetic patients. Symptoms appear in various parts of the body, especially in the foot area. Diabetic neuropathic pain includes several subtypes, including symmetric distal polyneuropathy, acute diabetic mononeuropathy, diabetic amyotrophy, diabetic radiculopathy, and diabetic autonomic neuropathy. By adjusting blood sugar so that peripheral blood vessels and nerves are not damaged by high blood sugar, neuropathic pain can be alleviated, but neuropathic pain often persists even if blood sugar is regulated as described above. In many cases, it does not have a specific therapeutic effect on symptomatic pain.
본 발명의 일 구현예에서, 상기 신경병증 통증은 대상포진 유래 신경병성 통증(또는 '대상포진 후 신경통'이라고 지칭됨)일 수 있다. In one embodiment of the present invention, the neuropathic pain may be neuropathic pain derived from shingles (or referred to as 'neural pain after shingles').
대상포진은 수두 대상포진 바이러스에 의해 유발되는 질환으로서, 면역체계가 약화된 개체에게서 자주 발생한다. 대상포진에 걸리게 되면 피부 발진과 함께 또는 피부 발진 이후에 수포가 발생하며, 또한 신경병성 통증을 일으킨다. 대상포진으로부터 유래되는 신경병성 통증은 바늘로 찌르거나 전기에 감전한 듯한 통증을 나타내며, 대상포진에 의해 나타나는 피부 발진 또는 수포는 2~4주 내에 치료되더라도 대상포진 후 발생하는 신경병성 통증은 4개월이 경과하여도 치료되지 않고 지속되는 경우가 있다. 이러한 경우 환자는 피부 발진 또는 수포가 치유되었다고 하더라도 대상포진 후 신경병성 통증으로 인해 정상적인 일상생활이나 사회생활을 유지하기 어렵다. 대상포진의 원인이 되는 수두 대상포진 바이러스를 증식 억제 또는 사멸시키기 위하여 항바이러스제가 주로 사용되며, 신경병성 통증이 심한 경우에는 진통제가 함께 투여된다. 그러나, 항바이러스제는 대상포진에서 유래된 신경병성 통증을 완화 또는 치료해주지 못하며, 항바이러스제와 함께 투여될 수 있는 진통제는 신경병성 통증을 일시적으로 완화시킬 수 있는 효과는 있어도 근본적으로 신경병성 통증을 치료해주지는 못 한다.Shingles is a disease caused by the varicella zoster virus, which often occurs in individuals with weakened immune systems. When shingles develop, blisters develop with or after skin rashes and also cause neuropathic pain. Neuropathic pain resulting from shingles indicates pain as if piercing with a needle or electric shock, and even if the skin rash or blisters caused by shingles are treated within 2 to 4 weeks, the neuropathic pain that occurs after shingles is 4 months Even after this, there are cases where the treatment continues without treatment. In this case, even if the skin rash or blister is cured, it is difficult to maintain a normal daily or social life due to neuropathic pain after shingles. Antiviral drugs are mainly used to suppress or kill the varicella zoster virus, which is the cause of herpes zoster, and in the case of severe neuropathic pain, analgesics are also administered. However, antiviral agents do not alleviate or treat neuropathic pain derived from shingles, and analgesics that can be administered with antiviral agents fundamentally treat neuropathic pain, although they have the effect of temporarily alleviating neuropathic pain. I can't do it.
용어 "치료"는 본 발명에 따른 조성물의 투여로 신경병증 통증의 증상이 호전되거나 완치되는 모든 행위를 의미한다. 또한, 용어 "예방"은 본 발명에 따른 조성물의 투여로 신경병증 통증의 증상을 억제 또는 지연시키는 모든 행위를 의미한다.The term "treatment" refers to any action in which symptoms of neuropathic pain are improved or cured by administration of a composition according to the invention. In addition, the term "prevention" means any action that suppresses or delays the symptoms of neuropathic pain by administration of a composition according to the invention.
본 발명에 따른 약학 조성물 내의 사이코사포닌 또는 이의 염 또는 시호 추출물의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라 적절히 조절 가능하다. 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9 중량%, 0.1 내지 90 중량%, 1 내지 80 중량%, 1 내지 70 중량%, 1 내지 60 중량%, 또는 1 내지 50 중량%로 함유할 수 있다.The content of psychosaponin or its salt or shiho extract in the pharmaceutical composition according to the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, and the condition of the patient. For example, it may contain 0.0001 to 99.9% by weight, 0.1 to 90% by weight, 1 to 80% by weight, 1 to 70% by weight, 1 to 60% by weight, or 1 to 50% by weight based on the total composition weight.
본 발명의 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다. 조성물에 함유될 수 있는 담체, 부형제 및 희석제는 예를 들어 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유일 수 있으나, 이에 제한되지 않는다. The pharmaceutical composition of the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. Carriers, excipients and diluents that may be included in the composition include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil, but is not limited thereto.
본 발명의 약학 조성물은 경구 투여 제형일 수 있다. 또다르게는, 본 발명에 따른 약학 조성물은 당업자에게 잘 알려진 기술을 이용하여 국소 투여를 위한 적합한 투여 제형으로 제형화될 수 있고, 국소 투여 제형은 외용제, 발포정, 좌제 등을 포함할 수 있다. 일 구체예에서, 본 발명의 약학 조성물은 상기 추출물을 당해 기술분야에서 잘 알려지고 일반적으로 사용되는 기제(base)와 혼합하여 외용제로 제형화될 수 있다. 상기 외용제는 에멀젼, 겔, 연고, 크림, 패치, 리니먼트, 파우더, 에어로졸, 스프레이, 로숀, 세럼, 페이스트, 폼, 점적제, 현탁액, 및/또는 팅크를 포함할 수 있다.The pharmaceutical composition of the present invention may be an oral dosage form. Alternatively, the pharmaceutical composition according to the present invention may be formulated into a suitable dosage form for topical administration using techniques well known to those skilled in the art, and the topical dosage form may include external preparations, buccal tablets, suppositories, and the like. In one embodiment, the pharmaceutical composition of the present invention may be formulated as an external preparation by mixing the extract with a base well known and commonly used in the art. The external preparation may include emulsions, gels, ointments, creams, patches, linens, powders, aerosols, sprays, lotions, serums, pastes, foams, drops, suspensions, and / or tinctures.
본 발명의 약학 조성물은 통상의 방법에 따라 환제, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 추출물에 적어도 하나 이상의 부형제, 예를 들어 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들어 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함될 수 있다.The pharmaceutical composition of the present invention can be used in the form of pills, powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and the like, in the form of oral formulations, external preparations, suppositories, and sterile injectable solutions, according to a conventional method. have. In the case of formulation, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in the extract, for example starch, calcium carbonate, sucrose or lactose, gelatin, etc. It can be prepared by mixing. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. . Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
본 발명의 약학 조성물은 약학적으로 유효한 양으로 개체에 투여된다. 본 발명에서 사용된 용어 "약학적으로 유효한 양"은 의학적 치료에 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여되거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. The pharmaceutical composition of the present invention is administered to a subject in a pharmaceutically effective amount. The term "pharmaceutically effective amount" as used herein refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment for medical treatment, and the effective dose level is the individual type and severity, age, It can be determined by gender, drug activity, sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And it can be administered single or multiple. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, and can be easily determined by those skilled in the art.
본 발명의 약학 조성물은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 구체적으로 신경병증 통증으로 고통받는 환자가 갖는 통증의 정도에 따라 본 발명의 조성물을 0.1 내지 100 mg/kg을 일일 1회 내지 수회 투여할 수 있다. 또한, 그 투여량은 투여 경로, 통증의 정도, 성별, 체중, 나이, 특히 환자의 통증 정도 등에 따라 증감될 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The pharmaceutical composition of the present invention may vary depending on the patient's age, gender, weight, and specifically, the composition of the present invention 0.1 to 100 mg / kg once a day depending on the degree of pain a patient suffers from neuropathic pain To several times. In addition, the dosage may be increased or decreased depending on the route of administration, the degree of pain, sex, weight, age, and especially the pain level of the patient. Therefore, the above dosage does not limit the scope of the present invention in any way.
본 발명의 또다른 양태는 사이코사포닌 또는 이의 식품학적으로 허용가능한 염 및 시호 추출물 중 하나 이상을 유효성분으로 함유하는, 신경병증 통증 완화 또는 예방용 식품 조성물을 제공한다.Another aspect of the present invention provides a food composition for alleviating or preventing neuropathic pain, containing as an active ingredient at least one of psychosaponin or a food-acceptable salt thereof and extract of seaweed.
본 발명에 따른 식품 조성물에 있어서 상기 사이코사포닌 및 이의 염, 시호 추출물 및 신경병증 통증은 특별한 언급이 없는 한, 각각 상기 약학 조성물에서 언급한 바와 같다.In the food composition according to the present invention, the psychosaponin and its salt, shiho extract and neuropathic pain are as mentioned in the pharmaceutical composition, unless otherwise specified.
용어 "개선"은 본 발명에 따른 조성물의 투여로 신경병증 통증의 정도가 적어도 감소 또는 호전되거나 이롭게 되는 모든 행위를 의미한다.The term "improvement" refers to any action in which the degree of neuropathic pain is at least reduced, improved or ameliorated by administration of the composition according to the invention.
상기 식품은 건강기능성 식품일 수 있다. 용어 "건강기능성 식품"이란, 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 의미한다. 여기서 "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다.The food may be a health functional food. The term "health functional food" means a food product manufactured and processed in the form of tablets, capsules, powders, granules, liquids and pills using ingredients or ingredients having useful functionality for the human body. Here, the term "functionality" means to obtain a useful effect for health purposes such as adjusting nutrients or physiological effects on the structure and function of the human body.
본 발명에 따른 식품 조성물은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조 시에는 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나므로, 본 발명의 식품 조성물은 신경병증 통증 치료 효과를 증진 또는 개선시키기 위한 보조제로 섭취가 가능하다.The food composition according to the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it may be prepared by adding raw materials and ingredients that are conventionally added in the art. In addition, unlike general medicines, the food composition of the present invention has the advantage of not having side effects and the like that may occur during long-term use of the medicine by using food as a raw material, and since it is excellent in portability, the food composition of the present invention enhances or improves the neuropathic pain treatment effect It can be consumed as an adjuvant.
본 발명에 따른 식품 조성물의 유효 성분인 사이코사포닌 또는 시호 추출물의 양은 사용 목적(예방, 개선 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품의 제조 시에 사이코사포닌 또는 시호 추출물은 원료 조성물 중 0.001 내지 20 중량%, 0.001 내지 15 중량% 또는 0.001 내지 10 중량%의 양으로 포함될 수 있다. 건강음료의 경우 100 mL를 기준으로 0.01 내지 2 g, 구체적으로 0.02 내지 2 g, 보다 구체적으로 0.3 내지 1 g을 가할 수 있다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하로도 사용될 수 있다.The amount of the active ingredient of the food composition according to the present invention, psychosaponin or shiho extract, can be appropriately determined according to the purpose of use (prevention, improvement or therapeutic treatment). In general, when preparing food, psychosaponin or shiho extract may be included in an amount of 0.001 to 20% by weight, 0.001 to 15% by weight, or 0.001 to 10% by weight in the raw material composition. In the case of healthy beverages, 0.01 to 2 g, specifically 0.02 to 2 g, and more specifically 0.3 to 1 g may be added based on 100 mL. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, the amount may be used below the above range.
본 발명의 식품 조성물을 제조하는 과정에서 식품 조성물에 첨가되는 사이코사포닌 또는 시호 추출물은 필요에 따라 그 함량을 적절히 가감할 수 있다.Psychosaponin or Siho extract added to the food composition in the process of preparing the food composition of the present invention can appropriately adjust the content as necessary.
상기 식품 조성물은 환제, 정제, 과립, 분말, 캡슐, 액상의 용액으로 이루어진 군으로부터 선택된 어느 하나의 제형일 수 있다.The food composition may be any one formulation selected from the group consisting of pills, tablets, granules, powders, capsules, and liquid solutions.
또한, 상기 식품의 종류는 특별한 제한되지 않는다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.In addition, the type of food is not particularly limited. Examples of foods to which the above substances can be added are meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other dairy products including noodles, gums, ice cream, various soups, beverages, teas, drinks, Alcoholic beverages, vitamin complexes, and the like, and include all foods in the ordinary sense.
본 발명의 식품 조성물은 통상의 식품과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토스, 수크로스와 같은 디사카라이드, 및 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물 등과 같은 천연 감미제, 또는 사카린, 아스파르탐 등과 같은 합성 감미제 등을 사용할 수 있다. The food composition of the present invention may contain various flavoring agents, natural carbohydrates, and the like as additional ingredients, like a conventional food. The aforementioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol, and erythritol. As the sweetener, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used.
본 발명의 식품 조성물이 음료 조성물일 경우 필수 성분으로서 상기 추출물을 지시된 비율로 함유하는 외에는 액체 성분에 특별한 제한은 없으며, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다.When the food composition of the present invention is a beverage composition, there is no particular limitation on the liquid component except that the extract is contained in the indicated ratio as an essential component, and as a normal beverage, various flavors or natural carbohydrates, etc. may be contained as additional components. Can be.
본 발명에 따른 조성물은 TRPA1 활성을 유의적으로 억제하며, 신경병증 통증에 대해 치료, 예방 및 완화 효과를 제공한다.The composition according to the present invention significantly inhibits TRPA1 activity and provides treatment, prevention and alleviation effects against neuropathic pain.
도 1은 TRPA1 발현 세포주가 TRPA1 항진제(agonist) 폴리고디알(polygodial)에 반응하는 것을 보여주는 그래프이다.
도 2는 TRPA1 발현 세포주에서 TRPA1 길항제(antagonist)로 알려진 A967970 화합물의 폴리고디알에 의한 Ca2+ 이동 억제 효과를 보여주는 그래프이다.
도 3은 TRPA1 발현 세포주에서 사이코사포닌 D 화합물의 폴리고디알에 의한 Ca2+ 이동 억제 효과를 보여주는 그래프이다.
도 4는 TRPA1 발현 세포주에서 사이코사포닌 화합물들의 폴리고디알에 의한 Ca2+ 이동 억제 효과를 보여주는 그래프이다.
도 5는 TRPA1 발현 세포주에서 시호 추출물의 폴리고디알에 의한 Ca2+ 이동 억제 효과를 보여주는 그래프이다.
도 6은 streptozotocin 유도 당뇨병 동물 모델을 구축하는 실험일정과 사이코사포닌 D(SSD)의 진통 효능 검증을 위한 실험 설계도를 나타낸다. STZ: streptozotocin.
도 7은 streptozotocin 유도 당뇨병 동물 모델에서 사이코사포닌 D(SSD) 화합물의 생체 내 진통 효능 결과를 보여주는 그래프이다.1 is a graph showing that a TRPA1 expressing cell line responds to a TRPA1 agonist polygodial.
Figure 2 is a graph showing the inhibitory effect of Ca 2+ migration by a polygodial of the A967970 compound known as a TRPA1 antagonist in the TRPA1 expressing cell line.
3 is a graph showing the effect of inhibiting Ca 2+ migration by a polygodial of a psychosaponin D compound in a TRPA1 expressing cell line.
4 is a graph showing the effect of inhibiting Ca 2+ migration by polygodials of psychosapolin compounds in the TRPA1 expressing cell line.
FIG. 5 is a graph showing the effect of inhibiting Ca 2+ migration by polygodial of Shiho extract in a TRPA1 expressing cell line.
6 shows an experimental schedule for constructing a streptozotocin-induced diabetic animal model and an experimental design for verifying analgesic efficacy of psychosaponin D (SSD). STZ: streptozotocin.
7 is a graph showing in vivo analgesic efficacy results of a psychosaponin D (SSD) compound in a streptozotocin-induced diabetic animal model.
이하 본 발명을 실시예에 의해 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail by examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.
실시예 1: TRPA1 억제제 스크리닝Example 1: TRPA1 inhibitor screening
TRPA1 길항제(antagonist)를 발굴하기 위하여, TRPA1 항진제(agonist) 폴리고디알에 의한 Ca2+ 이동을 억제하는 화합물을 다음과 같이 스크리닝하였다.In order to discover a TRPA1 antagonist, compounds that inhibit Ca 2+ migration by the TRPA1 agonist polygodial were screened as follows.
1-1. TRPA1 억제제 스크리닝 시스템 구축1-1. Established TRPA1 inhibitor screening system
(1) TRPA1 발현 안정 세포주의 제작(1) Production of TRPA1 expressing stable cell line
HEK293 세포를 60 ㎜ 배양용기에 5x105 cells/㎖가 되도록 분주하고, 37℃, 5% CO2 인큐베이터에서 하루 동안 배양하였다(배지 조성: DMEM + 10% FBS + 1% 페니실린-스트렙토마이신). TRPA1(Human) DNA 5 ㎍ 및 FuGENE HD 7.5 ㎕를 2개의 Opti-MEM 배지에 각각 넣고 상온에서 5분간 반응시킨 후, 혼합하여 15분간 더 반응시켰다. 이에 따라 수득한 반응액을 상기 세포 배양액에 첨가하고 48시간 동안 배양하였다. 이어서, 세포를 트립신 처리하여 6-웰 플레이트로 이동시킨 후, G418을 800, 500, 250, 125, 62.5, 0 ㎍/㎖ 농도로 처리하고 2주간 세포를 배양하였다. 그 결과, G418의 농도가 500㎍/㎖일 때, HEK293 세포는 사멸하고 TRPA1 세포주만 살아있었다. HEK293 cells were dispensed to a size of 5x10 5 cells / ml in a 60 mm culture vessel, and cultured for one day in a 37 ° C, 5% CO 2 incubator (medium composition: DMEM + 10% FBS + 1% penicillin-streptomycin). 5 [mu] g of TRPA1 (Human) DNA and 7.5 [mu] l of FuGENE HD were placed in two Opti-MEM media, respectively, and reacted at room temperature for 5 minutes, followed by mixing for further 15 minutes. The reaction solution thus obtained was added to the cell culture solution and cultured for 48 hours. Subsequently, the cells were trypsinized and transferred to a 6-well plate, and then G418 was treated at a concentration of 800, 500, 250, 125, 62.5, 0 μg / ml, and the cells were cultured for 2 weeks. As a result, when the concentration of G418 was 500 µg / ml, HEK293 cells were killed and only the TRPA1 cell line was alive.
TRPA1 세포주가 성장 및 증식하면 384-웰 플레이트에 0.5~2 cells/well이 되도록 분주한 후, 단클론 선별을 수행하였다. 단클론으로 선별된 TRPA1 세포에 대해 myc 항체로 면역형광 염색을 실시하여, 발현 여부를 확인하였다.When the TRPA1 cell line grows and proliferates, it is divided into 0.5 ~ 2 cells / well in a 384-well plate, and then monoclonal screening is performed. Immunofluorescence staining was performed on the TRPA1 cells selected by monoclonal with myc antibody to confirm expression.
(2) TRPA1 발현 안정 세포주의 TRPA1 항진제 반응 여부 테스트 (2) TRPA1 expression stable cell line TRPA1 anti-inflammatory test
TRPA1 발현 안정 세포주가 TRPA1 항진제에 반응하는지 여부를 테스트하기 위하여, Fluo-4 DirectTM Calcium assay를 이용하였다. TRPA1은 양이온 채널이므로 자극원에 반응하여 Ca2+와 같은 양이온을 세포 내로 유입시킴으로써 세포를 자극한다. 이와 같이 세포 내로 유입된 Ca2+ 양이온과 Fluo-4 DirectTM이 결합하여 형광을 나타내는 성질을 이용하는 기법이 Fluo-4 DirectTM Calcium assay이다.To test whether the TRPA1 expressing stable cell line responds to the TRPA1 anti-inflammatory agent, a Fluo-4 Direct ™ Calcium assay was used. Since TRPA1 is a cation channel, it stimulates cells by introducing cations such as Ca 2+ into cells in response to a stimulus source. Fluo-4 Direct TM Calcium assay is a technique that uses fluorescence by combining Ca 2+ cations and Fluo-4 Direct TM introduced into cells.
실험 방법은 구체적으로 다음과 같다. The experimental method is specifically as follows.
96-웰 블랙 클리어 플레이트에 HEK293 세포 또는 TRPA1 발현 세포주를 4x104 cells/well, 100 ㎕를 분주하고 상온에서 1,000 rpm으로 1분 동안 원심분리한 후, 37℃, 5% CO2 인큐베이터에서 48시간 동안 배양하였다. Fluo-4 DirectTM Calcium assay 키트에 포함되어 있는 프로베네시드 77mg 1 바이알에 Fluo-4 DirectTM Calcium assay 버퍼 1 ㎖를 넣고, 교반하였다(최종 농도 250 mM 프로베네시드). Fluo-4 DirectTM Calcium assay 시약에 10 ㎖의 Fluo-4 DirectTM Calcium assay 버퍼와 200 ㎕의 250 mM 프로베네시드를 넣은 후, 잘 혼합하였다 (2 X Fluo-4 DirectTM calcium 시약). 세포에 2 X Fluo-4 DirectTM calcium 시약을 100 ㎕씩 넣고, 37℃ 인큐베이터에서 1시간 동안 반응시킨다. 그 후, Flexstation의 Calcium assay 프로토콜에 따라 측정한 결과, TRPA1 발현 세포주가 TRPA1 항진제(agonist) 폴리고디알 화합물에 반응하여 Ca2+ 이온이 이동한다는 것이 확인되었다 (도 1).HEK293 cells or TRPA1 expressing cell lines were dispensed into 4x10 4 cells / well, 100 µl in 96-well black clear plates, centrifuged at 1,000 rpm for 1 minute at room temperature, and then for 48 hours in a 37 ° C, 5% CO 2 incubator. Cultured. 1 ml of Fluo-4 Direct TM Calcium assay buffer was added to a vial of 77 mg probeneside included in the Fluo-4 Direct TM Calcium assay kit and stirred (final concentration of 250 mM probenecid). After adding 10 ml of Fluo-4 Direct TM Calcium assay buffer and 200 μl of 250 mM probenecid to Fluo-4 Direct TM Calcium assay reagent, it was mixed well (2 X Fluo-4 Direct TM calcium reagent). Add 100 μl of 2 X Fluo-4 Direct ™ calcium reagent to the cells, and react for 1 hour in an incubator at 37 ° C. Then, as a result of measurement according to the Calcium assay protocol of Flexstation, it was confirmed that the Ca 2+ ions migrate in response to the TRPA1 expressing cell line in response to the TRPA1 agonist polygodial compound (FIG. 1).
1-2. TRPA1 억제제 스크리닝 시스템 검증1-2. TRPA1 inhibitor screening system validation
앞서 구축된 TRPA1 억제제 스크리닝 시스템을 검증하기 위하여, 폴리고디알 화합물에 의한 Ca2+ 이동이 대조약물(길항제 A967970, 10 μM)에 의해 억제되는지 여부를 시험하였다. 그 결과, A967970 화합물이 농도 의존적으로 폴리고디알 화합물의 활성을 억제하는 것이 관찰되었으며, 이에 따라 TRPA1 억제제 스크리닝 시스템이 유효하다는 것이 검증되었다 (도 2). To verify the previously established TRPA1 inhibitor screening system, it was tested whether Ca 2+ migration by the polygodial compound was inhibited by the control drug (antagonist A967970, 10 μM). As a result, it was observed that the A967970 compound inhibits the activity of the polygodial compound in a concentration-dependent manner, thus verifying that the TRPA1 inhibitor screening system is effective (FIG. 2).
또한, 96-웰 플레이트에서 A967970 화합물의 효과가 일정하게 나타나는지 여부를 확인하기 위하여 플레이트의 모든 웰에 100 μM의 A967970 화합물을 각각 처리하였다. 그 결과, 웰마다 값이 균질하게 도출되었으며, Z' factor가 0.830으로 HTS에 적합한다는 점이 확인되었다.In addition, in order to confirm whether the effect of the A967970 compound was constant in the 96-well plate, each well of the plate was treated with 100 μM of the A967970 compound, respectively. As a result, it was confirmed that the value was well derived for each well, and the Z 'factor was 0.830, which was suitable for HTS.
1-3. TRPA1 억제제 스크리닝 수행1-3. Perform TRPA1 inhibitor screening
상기에서 구축된 TRPA1 억제제 스크리닝 시스템 및 Fluo-4 DirectTM Calcium assay 실험법을 사용하여 천연물 유래 표준품 2,880개 화합물을 테스트하였다. 구체적인 방법은 다음과 같다.Using the TRPA1 inhibitor screening system and Fluo-4 Direct TM Calcium assay test method constructed above, 2,880 compounds derived from natural products were tested. The specific method is as follows.
96-웰 블랙 클리어 플레이트에 TRPA1 발현 세포주를 4x104 cells/well, 100 ㎕를 분주하고 상온에서 1,000 rpm으로 1분 동안 원심분리한 후, 37℃, 5% CO2 인큐베이터에서 48시간 동안 배양하였다. 스크리닝에 사용하는 화합물을 최종농도 10 μM으로 첨가하였으며, 3분간 반응시킨 후 2 X Fluo-4 DirectTM calcium 시약을 100 ㎕씩 첨가하고 37℃ 인큐베이터에서 1시간 동안 반응시켰다. Flexstation의 Calcium assay 프로토콜 [Fluorescence at EX. 495 nm /Em. 516, 140s read, 67번 read, 25s 항진제 [폴리고디알, 250 nM], 25 ㎕ injection(Flexstation)]을 이용하여 형광세기를 측정하였다. TRPA1 expressing cell lines were dispensed at 4 × 10 4 cells / well, 100 μl in a 96-well black clear plate, centrifuged at 1,000 rpm for 1 minute at room temperature, and cultured for 48 hours in a 37 ° C., 5% CO 2 incubator. The compound used for screening was added at a final concentration of 10 μM, and after reacting for 3 minutes, 100 μl of 2 X Fluo-4 Direct ™ calcium reagent was added and reacted for 1 hour in an incubator at 37 ° C. Flexstation's Calcium assay protocol [Fluorescence at EX. 495 nm / Em. Fluorescence intensity was measured using 516, 140s read, 67 reads, and 25s anti-inflammatory drug [Polygodial, 250 nM], 25 μl injection (Flexstation).
250 nM의 폴리고디알을 처리한 값을 0% 억제율로 설정하고, 10 μM의 A967970을 처리한 값을 100% 억제율로 설정하여, 각 화합물들의 결과 값을 비교하였다. HTS 결과 Z' factor는 평균 0.7이 산출되었다. 2,880종의 표준품 중에서 사이코사포닌 D의 억제 활성이 가장 우수하였으며, 농도별 활성을 측정한 결과 IC50 값은 1.74±0.13 μM로 나타났다 (도 3).The value treated with 250 nM polygodial was set to 0% inhibition, and the value treated with 10 μM A967970 was set to 100% inhibition, and the results of each compound were compared. As a result of HTS, the average of Z 'factor was 0.7. Among 2,880 kinds of standard products, the inhibitory activity of Psychosaponin D was the best, and as a result of measuring the activity by concentration, the IC 50 value was 1.74 ± 0.13 μM (FIG. 3).
실시예 2: 사이코사포닌의 활성 분석Example 2: Analysis of the activity of psychosaponin
실시예 1에서 활성이 확인된 사이코사포닌 D에서 출발하여, 사이코사포닌 A, B1, B2, C, E, F에 대해 실시예 1의 방법에 따라 TRPA1 억제 여부를 시험하였다. 그 결과, 사이코사포닌 A, B1, B2, C, E, F도 TRPA1 억제 활성을 유의적인 수준으로 나타낸다는 점이 확인되었다 (도 4).Starting from Psychosaponin D whose activity was confirmed in Example 1, it was tested for inhibition of TRPA1 according to the method of Example 1 for Psychosaponin A, B1, B2, C, E, F. As a result, it was confirmed that psychosaponins A, B1, B2, C, E, and F also show TRPA1 inhibitory activity at a significant level (FIG. 4).
실시예 3: 시호 추출물의 활성 측정Example 3: Measurement of activity of Shiho extract
사이코사포닌 계열 화합물은 시호에 존재한다고 보고되고 있으므로, 본 발명자들은 시호 추출물의 TRPA1 억제 여부를 테스트하였다. Psychosaponin-based compounds are reported to be present in Shiho, so the present inventors tested whether the Shiho extract inhibits TRPA1.
3-1. 시호 추출물의 제조3-1. Preparation of shiho extract
시호의 뿌리를 세척한 후 50℃의 열풍건조기에서 1일간 건조하였다. 건조된 시료는 분쇄기를 통해 분쇄한 후, 열수추출을 통해 시호 추출물을 수득하였다.After washing the roots of Shiho, it was dried in a hot air dryer at 50 ℃ for 1 day. The dried sample was pulverized through a grinder, and then Siho extract was obtained through hot water extraction.
3-2. 시호 추출물의 TRPA1 억제 테스트3-2. TRHO1 inhibition test of Siho extract
상기에서 수득한 시호 추출물의 TRPA1 억제 활성을 확인하기 위하여, 실시예 1의 방법에 따라 시호 추출물이 폴리고디알 화합물에 의한 Ca2+ 이동을 억제하는지 여부를 테스트하였다. In order to confirm the TRPA1 inhibitory activity of the obtained Siho extract, it was tested whether the Siho extract inhibits Ca 2+ migration by the polygodial compound according to the method of Example 1.
Fluo-4 DirectTM Calcium assay를 이용하여 측정한 결과, 시호의 뿌리 추출물이 농도 의존적으로 TRPA1 항진제(agonist) 폴리고디알 화합물의 활성을 억제하는 것이 관찰되었다. 이때, IC50 값은 35.87±3.31 μg/mL로 확인되었다 (도 5).As a result of measurement using the Fluo-4 Direct TM Calcium assay, it was observed that the root extract of Shiho inhibits the activity of the TRPA1 anti-agonist polygodial compound in a concentration-dependent manner. At this time, the IC 50 value was confirmed to be 35.87 ± 3.31 μg / mL (FIG. 5).
실시예 4: 당뇨성 신경병증 통증 모델을 이용한 생체 내 테스트Example 4: In vivo testing using a diabetic neuropathic pain model
4-1. STZ 유도 신경병증성 통증 모델4-1. STZ-induced neuropathic pain model
STZ(Streptozotocin)에 의해 유도되는 당뇨병성 신경병증성 통증 모델을 구축하기 위하여, 8주령의 수컷 ICR 생쥐에게 STZ 100 mg/kg를 1주 간격으로 2회 복강 내 주사 후 당뇨를 유도하였다 (도 6). STZ 투여 후 매주 체중과 공복 혈당을 체크하고, 평균 400 mg/dL 고혈당이 유도되는 생쥐를 선별하였다. To build a diabetic neuropathic pain model induced by streptozotocin (STZ), diabetes was induced after intraperitoneal injection of 100 mg / kg of STZ to the 8 week old male ICR mice at 1 week intervals (Fig. 6). ). After STZ administration, body weight and fasting blood glucose were checked weekly, and mice with an average of 400 mg / dL hyperglycemia were selected.
STZ 투여 4주 후에 von Frey test에 의해 통증 반응을 평가하였다. 구체적으로, 기계적 통증을 특정하는 대표적인 도구인 von Frey 필라멘트를 이용하여 통증 반응은 측정하였다. 신경병증이 유도된 생쥐를 알루미늄 망 위에 올려 놓고 유리용기로 가두고 안정화시킨 후, von Frey 필라멘트를 사용하여 생쥐의 뒷발바닥을 찔러서 회피하는 통증반응 강도(g)를 측정하였다. Pain response was evaluated by
4-2. 사이코사포닌 D 화합물의 진통 효능 검증4-2. Verification of analgesic efficacy of psychosaponin D compounds
STZ 투여 4주 후 신경병증성 통증이 유발된 것으로 앞서 실험에서 확인된 생쥐에게 사이코사포닌 D 화합물(도 7에서 SSD라고 약칭함)을 경구 투여하였다. Psychosaponin D compound (abbreviated as SSD in FIG. 7) was orally administered to the mice identified in the previous experiment as neuropathic pain was induced 4 weeks after STZ administration.
1시간 후 von Frey test를 통해 생쥐가 뒷발바닥을 회피하는 반응 강도(paw withdrawal threshold)를 측정하였다. 사이코사포닌 D 화합물 투여군에서 농도는 10 mg/kg 및 20 mg/kg을 사용하였다. 대조약물로서 프레가발린(pregabalin)을 30 mg/kg의 농도로 사용하였으며, 전술한 바와 같이 프레가발린은 말초신경병증 통증의 치료제로서 사용되어 오고 있는 항경련제 중 하나이다.After 1 hour, the von Frey test was used to measure the response intensity (paw withdrawal threshold) of the mouse avoiding the hind paw. In the group administered with the psychosaponin D compound, concentrations of 10 mg / kg and 20 mg / kg were used. As a control drug, pregabalin was used at a concentration of 30 mg / kg, and as described above, pregabalin is one of anticonvulsants that have been used as a treatment for peripheral neuropathic pain.
실험 결과, 사이코사포닌 D 화합물 투여 군에서 통증 반응이 유의적으로 억제되는 것이 확인되었으며, 특히 농도의존적으로 나타났다(도 7).As a result of the experiment, it was confirmed that the pain response was significantly suppressed in the group administered with the psychosaponin D compound, and it was found to be particularly concentration-dependent (FIG. 7).
Claims (10)
상기 조성물은 TRPA1(Transient receptor potential cation channel, subfamily A, member 1) 길항제 활성을 가지며 신경병증 통증을 치료 또는 예방하기 위한 것을 특징으로 하는 약학 조성물.As a pharmaceutical composition containing at least one selected from the group consisting of psycho saponin, a pharmaceutically acceptable salt of psycho saponin, and shiho extract,
The composition is a pharmaceutical composition characterized in that it has a TRPA1 (Transient receptor potential cation channel, subfamily A, member 1) antagonist activity and for treating or preventing neuropathic pain.
상기 사이코사포닌은 사이코사포닌 A, B1, B2, C, D, E 또는 F인 것을 특징으로 하는 약학 조성물.According to claim 1,
The psycho-saponin is a pharmaceutical composition characterized in that the psycho-saponin A, B1, B2, C, D, E or F.
상기 시호 추출물은 시호 추출물인 것을 특징으로 하는 약학 조성물.According to claim 1,
The Siho extract is a pharmaceutical composition characterized in that the Siho extract.
상기 신경병증 통증은 말초신경병증 통증인 것을 특징으로 하는 약학 조성물.According to claim 1,
The neuropathic pain is a pharmaceutical composition characterized in that the peripheral neuropathic pain.
상기 신경병증 통증은 당뇨성 신경병증 통증, 또는 대상포진 유래 신경병성 통증인 것을 특징으로 하는 약학 조성물.According to claim 1,
The neuropathic pain is diabetic neuropathic pain, or a pharmaceutical composition characterized by neuropathic pain derived from shingles.
상기 조성물은 TRPA1(Transient receptor potential cation channel, subfamily A, member 1) 길항제 활성을 가지며 신경병증 통증을 완화 또는 예방하기 위한 것을 특징으로 하는 식품 조성물.As a food composition containing as an active ingredient at least one selected from the group consisting of psycho saponin, a food acceptable salt of psycho saponin, and shiho extract,
The composition is a food composition characterized in that it has a TRPA1 (Transient receptor potential cation channel, subfamily A, member 1) antagonist activity to alleviate or prevent neuropathic pain.
상기 사이코사포닌은 사이코사포닌 A, B1, B2, C, D, E 또는 F인 것을 특징으로 하는 식품 조성물.The method of claim 6,
The psychosaponin is a psychosaponin A, B1, B2, C, D, E or F, characterized in that the food composition.
상기 시호 추출물은 시호 추출물인 것을 특징으로 하는 식품 조성물.The method of claim 6,
The Siho extract is a food composition characterized in that the Siho extract.
상기 신경병증 통증은 말초신경병증 통증인 것을 특징으로 하는 식품 조성물.The method of claim 6,
The neuropathic pain is a peripheral neuropathic pain food composition.
상기 신경병증 통증은 당뇨성 신경병증 통증, 또는 대상포진 유래 신경병성 통증인 것을 특징으로 하는 식품 조성물.The method of claim 6,
The neuropathic pain is diabetic neuropathic pain, or a food composition characterized by neuropathic pain derived from shingles.
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