KR101066371B1 - Health food and therapeutic agent containing flavonoid compounds extracted from silk of Zea mays linne for improving urinary system disorder - Google Patents
Health food and therapeutic agent containing flavonoid compounds extracted from silk of Zea mays linne for improving urinary system disorder Download PDFInfo
- Publication number
- KR101066371B1 KR101066371B1 KR1020110062250A KR20110062250A KR101066371B1 KR 101066371 B1 KR101066371 B1 KR 101066371B1 KR 1020110062250 A KR1020110062250 A KR 1020110062250A KR 20110062250 A KR20110062250 A KR 20110062250A KR 101066371 B1 KR101066371 B1 KR 101066371B1
- Authority
- KR
- South Korea
- Prior art keywords
- bladder
- glucopyranoside
- chryseriol
- urinary system
- compounds
- Prior art date
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Abstract
본 발명은 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드, 크리세리올 또는 루테올린 화합물을 포함하는 플라보노이드계 화합물을 함유하는 비뇨기계 질환 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제에 관한 것이다.
본 발명에 따른 플라보노이드계 화합물인 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드, 크리세리올 및 루테올린 화합물은 옥미수(玉米鬚)로부터 분리될 수 있으며, 페닐에프린 및 아세틸콜린에 의한 방광 평활근 및 전립선 평활근의 수축을 현저히 억제하여 비뇨기계 질환 즉, 전립선비대증 및 과민성방광에 효과를 나타냄으로써 비뇨기계 질환 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제로 사용할 수 있다.The present invention improves the symptoms of urinary system diseases containing flavonoid-based compounds including chrysriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside, chryseriol or luteolin compounds Health functional foods and urinary system diseases treatment agent.
The flavonoid compound according to the present invention, chryseriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside, chryseriol and luteolin compounds are isolated from jade water (玉米 鬚) Health functional food and urinary system for improving symptom of urinary tract disease by suppressing urinary bladder smooth muscle and prostate smooth muscle contraction by phenylephrine and acetylcholine remarkably. It can be used to treat diseases.
Description
본 발명은 하기 화학식 1로 표시되는 플라보노이드계 화합물을 함유하는 비뇨기계 질환 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제에 관한 것이다.The present invention relates to a dietary supplement for treating urinary tract disease symptoms and a therapeutic agent for urinary tract diseases containing the flavonoid compound represented by the following formula (1).
<화학식 1><
배뇨장애 관련 질환 중 대표적인 질환이 전립선비대증이다. 전립선비대증은 60대 노인의 50%에서 확인되고 주된 병태는 전립선 상피조직과 간질조직의 과증식과 비대이다. 전립선 세포의 증식과 사망을 조절하는 요인으로는 내분비 인자(endocrine factors), 각종 성장인자들, 간질세포와 상피세포의 상호작용, 신경내분비세포 및 신경전달물질, 세포주기와 사망을 조절하는 물질, 염증 등이 거론되고 있다.
Representative disease of urination disorder is prostate hyperplasia. Prostatic hyperplasia is found in 50% of elderly people in their 60s, and the main condition is hyperproliferation and hyperplasia of prostate epithelial and interstitial tissue. Factors that control prostate cell proliferation and death include endocrine factors, growth factors, interstitial and epithelial cell interactions, neuroendocrine and neurotransmitters, cell cycle and death control agents, Inflammation is mentioned.
전립선비대증의 병태를 결정하는 또 하나의 주요한 부분은 소변 배출의 장애로 인한 방광의 이차적인 변화이다. 방광 출구의 폐색에 의하여 방광근의 비대가 발생하고 이는 배뇨근 과활동으로 인한 과민성방광을 유발시키며, 또한 폐색이 오래 지속되면 배뇨근의 수축력이 부적절해져 잔뇨량 증가, 요폐 등이 발생하고 이의 결과로 요로감염, 방광결석, 신부전 등의 합병증이 발생된다.
Another major part of determining the condition of prostatic hyperplasia is secondary changes in the bladder due to impaired urine output. The obstruction of the bladder outlet causes hypertrophy of the bladder muscle, which causes irritable bladder due to excessive activity of the detrusor muscle, and if the obstruction persists for a long time, the contractile force of the detrusor muscle becomes inadequate, resulting in an increase in residual urine volume and urinary tract, resulting in urinary tract infections, Complications such as bladder stones and kidney failure occur.
또한, 방광 자극증상을 일으키는 상태를 과민성방광, 하부요로증상 등으로 통합하여 부르고 있으며, 하부요로증상에 전립선비대증도 포함된다.
In addition, the state causing bladder irritation symptoms are referred to as an overactive bladder, lower urinary tract symptoms, etc., including prostate hyperplasia in the lower urinary tract symptoms.
과민성방광(overactive bladder, OAB)은 의지와 상관없이 갑작스러운 요의를 느끼는 급박뇨를 주 증상으로 하는 질환으로 요실금을 동반하거나 하지 않을 수 있다. 과민성방광은 전립선비대증 환자에서 동반이 될 수도 있으며, 질환의 발생빈도가 평균적으로 15-20%로 매우 높고, 더구나 60세 이상이 되면 남녀를 불문하고 노령인구의 1/3 이상이 과민성방광이 있다고 알려져 있다. 이런 환자들의 대부분은 수분섭취를 줄임으로써 소변보는 횟수를 조절하기도 하나 이로 인해 외부 활동이 저하되기도 한다. 이러한 상황은 노인에서 변비 등의 문제를 야기하고 변비가 생기면 다시 배뇨증상이 악화되는 악순환이 반복될 수 있다.
Overactive bladder (OAB) is a condition that is mainly caused by urinary urges that cause sudden urinary irrespective of the will, with or without urinary incontinence. Overactive bladder may be accompanied by an enlarged prostate, and the incidence of the disease is very high (15-20%) on average, and more than one-third of the elderly population, regardless of gender, are over 60 years old. Known. Most of these patients control urination by reducing fluid intake, but this also reduces external activity. This situation causes problems such as constipation in the elderly, and when a constipation can be repeated a vicious cycle that worsens the symptoms of urination again.
하부요로증상(lower urinary tract symptoms, LUTs)은 요저장 및 배출 증상을 말하는 것으로, 전립선비대증, 방광경부장애, 신경인성장애 등이 포함된다. 전립선비대증은 방광 출구가 막혀서 소변배출이 어려우므로 병의 경과에 따라 3가지 유형의 문제가 생긴다. 첫째는 방광 근육에 정상보다 많은 부하가 걸리므로 방광 벽이 두꺼워지면서 예민해져 빈뇨, 야간뇨, 잔뇨감이 발생하는 것이다. 둘째는 방광근육이 방광에 있는 소변을 완전히 배출하지 못하면서 예민해지는 경우 잔뇨가 남는 증상이다. 셋째는 방광이 약해져서 정상적인 배출을 거의 못하는 경우 요폐가 올 수 있는 유형이다.
Lower urinary tract symptoms (LUTs) refer to symptoms of urinary storage and discharge, including prostate hyperplasia, bladder neck disorders, and neurogenic disorders. Since prostatic hyperplasia is blocked by the bladder outlet, it is difficult to discharge urine, so there are three types of problems according to the course of the disease. The first is that the bladder muscle takes more load than normal, so the bladder walls become thicker and more sensitive, causing frequent urination, nocturia, and residual urination. Second, if the bladder muscle becomes sensitive without fully draining the urine in the bladder, residual urine remains. Third is the type of urinary tract can come when the bladder is weakened and can not be normally discharged.
방광은 주로 교감신경의 자극으로 방광체부의 muscarinic 수용체를 활성화시켜 수축하게 되며, 교감신경은 방광 체부에서 β 수용체를 통해 방광을 이완시키기도 하고 purine 수용체를 통해 수축시키기도 한다. 또한 방광 경부 및 전립선 요도에는 교감신경이 a1 수용체를 통해 수축을 유발하며, 막양부 요도에 위치한 외요도 괄약근은 체신경에 의해 수축이완을 수의적으로 조절하게 된다. 요로상피 및 신경말단에는 vanilloid 수용체 등에 의해 해로운 자극을 인지하는 기능이 있다.
The bladder is primarily a sympathetic nerve stimulator that activates and contracts the muscarinic receptors in the bladder. In addition, the sympathetic nerve causes contraction through the a1 receptor in the bladder neck and prostate urethra, and the external urethral sphincter located in the mesothelial urethra may control the contraction relaxation by the body nerve. Urinary epithelium and nerve endings have the function of recognizing harmful stimuli by vanilloid receptors.
현재 전립선비대증의 약물 치료에 가장 많이 쓰이는 약제로는 알파차단제가 있다. 알파 차단제(tamsulosin, doxazosin, alfuzosin 등)는 전립선요도가 잘 벌어지게 하여 방광 출구를 이완시킨다. 그러나 전립선 비대증 환자의 약 1/5은 알파차단제 단독으로 부족하여 방광의 과민성을 억제하는 약제 즉 항무스카린성 약제(antimuscarinic agents; 예를 들면, 디트로판(ditropan), 톨테로딘(tolterodine), 솔리페나신(solifenacin) 등) 및 antipurinergic agent(propiverine HCl) 등의 약제를 병합 투여하게 되며, 이 때 치료효과를 보인다.
Currently, the most commonly used drug for the treatment of prostatic hyperplasia is alpha blocker. Alpha blockers (tamsulosin, doxazosin, alfuzosin, etc.) relax the bladder outlet by causing the prostate to develop well. However, about one-fifth of patients with prostatic hyperplasia lack an alpha-blocking agent alone, which prevents bladder hypersensitivity, that is, antimuscarinic agents (e.g., ditropan, tolterodine, Solifenacin (solifenacin, etc.) and antipurinergic agents (propiverine HCl), such as a combination administration, and will show a therapeutic effect.
한편, 옥미수(玉米鬚)는 벼과(Graminese) 식물로 옥촉서(玉蜀黍)의 수염을 일컬으며, 옥맥수(玉麥鬚), 봉자모(棒子毛), 옥촉서예(玉蜀黍蘂)라고도 불리운다. 옥미수(玉米鬚)는 지방 2%, 휘발성 정유 성분 0.12%, gum 3.8%, resin 1.15%, saponin 3.2%, alkaloid 0.05% 등의 조성을 갖는 것으로 보고된 바 있다.
On the other hand, Okmi-su is a graminse plant and is called Okmokseo's beard. It is also called Okmaeksu, Bonjamo, and Okmok calligraphy. Okmi water has been reported to have 2% fat, 0.12% volatile essential oil, 3.8% gum, 1.15% resin, 3.2% saponin, and 0.05% alkaloid.
옥미수(玉米鬚)로부터 플라보노이드 계열의 화합물들인 크리세리올(Chrysoeriol), 크리세리올-6-C-β보이비노피라노실-7-O-β-글루코피라노사이드(Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside) 및 루테올린(Luteolin)이 추출 분리되었으며, 상기 화합물들은 당뇨치료를 위한 활성이 있는 것으로 보고되었다(Chem. Pharm. Bull., 2007, 55(1), 153 ~ 155 및 J. Nat. Prod., 2003, 66(4), 564 ~ 565).
Chrysoeriol and chryseriol-6-C-βvobinopyranosyl-7-O-β-glucopyranoside (Chrysoeriol-6-C-), which are flavonoid compounds from jade water β-boivinopyranosyl-7-O-β-glucopyranoside) and luteolin were extracted and isolated, and the compounds were reported to be active for the treatment of diabetes (Chem. Pharm. Bull., 2007, 55 (1)). , 153-155 and J. Nat. Prod., 2003, 66 (4), 564-565).
또한, 쑥(Artemisia vulgaris)의 전초의 수용성 에탄올추출물로 부터 크리세리올, 루테올린 등의 플라보노이드 화합물이 분리되었으며, 이들 분리된 각 플라보노이드 화합물들의 항산화효과는 비타민 E와 비교하였을 때 높은 활성을 나타내는 것으로 보고된 바 있다(한국식품과학회지, 1999, 31권, 3호, 815~822).
In addition, flavonoid compounds such as chryseriol and luteolin were isolated from the water-soluble ethanol extract of Artemisia vulgaris outpost, and the antioxidant effect of each of these isolated flavonoid compounds showed high activity compared to vitamin E. It has been reported (Korean Journal of Food Science and Technology, 1999, Vol. 31, No. 3, 815 ~ 822).
본 발명자들은 플라보노이드 계열의 화합물들인 크리세리올(Chrysoeriol), 크리세리올-6-C-β보이비노피라노실-7-O-β-글루코피라노사이드(Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside), 및 루테올린(Luteolin)을 옥미수(玉米鬚)로부터 추출 분리하여 상기 플라보노이드계의 화합물에 관한 용도를 연구하던 중에 상기 플라보노이드계 화합물들에 관하여 전립선비대증 발생에 대한 억제 효과와 방광의 이차적인 변화과정에 대한 병태생리를 규명함으로써 비뇨기계 질환 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제로 유용하게 활용할 수 있는 본 발명을 완성하였다.
The inventors of the present invention are flavonoid-based compounds Chrysoeriol, Chryseriol-6-C-β boinopyranosyl-7-O-β-glucopyranoside (Chrysoeriol-6-C-β-boivinopyranosyl- 7-O-β-glucopyranoside) and Luteolin were extracted and separated from jade water to investigate the use of the flavonoid compound, and the flavonoid compound was investigated for the development of prostatic hyperplasia. By identifying the pathophysiology of the inhibitory effect and secondary changes of the bladder, the present invention can be usefully utilized as a dietary supplement for improving the symptoms of urinary tract diseases and the treatment of urinary tract diseases.
본 발명은 옥미수(玉米鬚)로부터 추출 분리된 플라보노이드 계열의 화합물들인 크리세리올(Chrysoeriol), 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드(Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside), 및 루테올린(Luteolin)에 관한 새로운 용도를 갖는 건강기능식품 및 치료제를 제공하는 것을 목적으로 한다.
In the present invention, chrysoeriol and chryseriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside, which are flavonoid-based compounds extracted and separated from jade water (玉米 鬚) (Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside), and nutraceuticals and therapeutic agents having new uses for Luteolin.
상기와 같은 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 플라보노이드계 화합물을 함유하는 비뇨기계 질환 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제를 제공한다.In order to achieve the above object, the present invention provides a dietary supplement for treating the symptoms of urinary tract diseases and the treatment of urinary tract diseases containing a flavonoid compound represented by the following formula (1).
<화학식 1><
상기 식에서, R1은 수소 또는 C1~C5 알킬, R2는 수소 또는 β-보이비노피라노실(β-boivinopyranosyl), R3는 수소 또는 β-글루코피라노사이드(β-glucopyranoside)이다.
Wherein R 1 is hydrogen or C 1 -C 5 alkyl, R 2 is hydrogen or β-boivinopyranosyl, R 3 is hydrogen or β-glucopyranoside.
본 발명에 따른 화학식 1로 표시되는 플라보노이드계 화합물은 옥미수(Zea mays linne , 玉米鬚, 옥수수수염)로부터 추출 분리될 수 있다(Chem. Pharm. Bull., 2007, 55(1), 153 ~ 155 및 J. Nat. Prod., 2003, 66(4), 564 ~ 565).
Flavonoid compounds represented by Formula 1 according to the present invention can be extracted and separated from jade water ( Zea mays linne ,玉米 鬚, corn beard) (Chem. Pharm. Bull., 2007, 55 (1), 153 ~ 155 And J. Nat. Prod., 2003, 66 (4), 564-565).
본 발명에서는 옥미수 에틸아세테이트(EtOAc) 분획으로부터 플라보노이드 계열의 화합물들인 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드(Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside), 크리세리올(Chrysoeriol) 및 루테올린(Luteolin) 화합물을 단리시켰다.
In the present invention, chryseryol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside (Chrysoeriol-6-C-β), which is a flavonoid-based compound from oxime water ethyl acetate (EtOAc) fraction -boivinopyranosyl-7-O-β-glucopyranoside), chrysoeriol and luteolin compounds were isolated.
본 발명에 따른 옥미수로부터 플라보노이드 계열의 화합물을 단리시킨 모식도를 하기와 같이 간단하게 나타내었다.Schematic diagram of isolating the flavonoid family of compounds from jade water according to the present invention is shown briefly as follows.
본 발명에서 크리세리올(Chrysoeriol) 및 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드(Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside) 화합물은 칼슘 통로 활성화 조건인 고농도의 K 용액으로 수축을 유발한 상태에서 방광 수축 억제 효과를 나타내었으며, 각종 K 통로 차단제(1 mM 및/또는 10 mM TEA, 10μM 4-AP)를 투여한 경우에도 방광 수축 억제 효과를 나타내었고, 루테올린(Luteolin) 화합물은 고농도에서는 칼슘 통로 차단을 통해 방광의 수축을 억제하나, 저농도에서는 Rho kinase 경로를 활성화시켜 방광의 비정상적인 수축을 유발할 가능성이 있어 이중 효과(dual effect)를 가지며, 고농도를 투여하면 과민성 방광에 적용될 수 있다.
In the present invention, chrysoeriol and chrysoriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside (Chrysoeriol-6-C-β-boivinopyranosyl-7-O- β-glucopyranoside) showed inhibition of bladder contraction in the condition of contraction with a high concentration of K solution, which is a condition of calcium channel activation, and various K channel blockers (1 mM and / or 10 mM TEA, 10 μM 4-AP). Even when administered, it showed an effect of inhibiting bladder contraction, and the Luteolin compound inhibits the bladder contraction by blocking calcium channel at high concentrations, but at low concentrations, it may activate the Rho kinase pathway to cause abnormal contraction of the bladder. It has a dual effect and can be applied to an overactive bladder when administered at high concentrations.
또한, 본 발명에 따른 플라보노이드 계열의 화합물은 페닐에프린에 의한 수축을 현저히 억제시켜 전립선 비대증이 있는 환자에서 흔히 쓰이는 알파 차단제와 같이 요도를 이완시키는 효과를 나타내었다.
In addition, the flavonoid-based compound according to the present invention significantly inhibits contraction caused by phenylephrine, and has an effect of relaxing the urethra like an alpha blocker commonly used in patients with prostatic hyperplasia.
본 발명에 따른 플라보노이드계 화합물은 약학적으로 허용가능한 통상의 부형제, 결합제, 붕해제, 활택제, 감미제 등을 혼합하여 경구투여용 제제를 제조할 수 있다. 이때, 부형제로는 미결정셀룰로오스, 유당, 옥수수전분, 만니톨, 저치환도히드록시프로필셀룰로오스, 메타규산알루민산마그네슘, 콜로이드성 이산화규소 등이 바람직하고, 결합제로는 히드록시프로필메칠셀룰로오스, 포비돈, 히드록시프로필셀룰로오스 등이 바람직하고, 붕해제는 크로스카르멜로오스나트륨, 전분글리콘산나트륨, 카르복시메칠셀룰로오스칼슘, 크로스포비돈 등이 바람직하며, 활택제는 스테아린산 마그네슘, 탈크, 스테아릴푸마르산나트륨 등이 바람직하다. 본 발명은 경구투여용 제제로 환제, 산제, 과립제, 정제, 캡슐제, 액제 제형 등의 제조가 가능하며, 음료 또는 다류로 제조될 수 있으며, 또한 본 발명은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용가능한 담체를 1종 이상 포함하여 제조되며, 약제학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형으로 제조될 수 있다.
Flavonoid compounds according to the present invention can be prepared by oral administration by mixing pharmaceutically acceptable conventional excipients, binders, disintegrants, lubricants, sweeteners and the like. At this time, as an excipient, microcrystalline cellulose, lactose, corn starch, mannitol, low-substituted hydroxypropyl cellulose, magnesium metasilicate aluminate, colloidal silicon dioxide, etc. are preferable, and as a binder, hydroxypropyl methyl cellulose, povidone, hydride, etc. Roxypropyl cellulose is preferred, and disintegrant is preferably croscarmellose sodium, sodium starch glycolate, calcium carboxymethyl cellulose, crospovidone and the like, and the lubricant is preferably magnesium stearate, talc, sodium stearyl fumarate, or the like. Do. The present invention is a preparation for oral administration, it is possible to manufacture pills, powders, granules, tablets, capsules, liquid formulations, and the like, can be prepared as a beverage or a tea, and the present invention is in addition to the active ingredient described above for administration In addition, it is prepared containing one or more pharmaceutically acceptable carriers, pharmaceutically acceptable carriers are saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol and these components One or more components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to prepare injectable formulations such as aqueous solutions, suspensions, emulsions and the like.
더불어, 본 발명에 따른 플라보노이드계 화합물의 투여량 또는 복용량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하며, 성인 기준으로 투여량 0.01 mg/kg 내지 1000 mg/kg을 1일 1회 내지 수회에 나누어 복용하는 것이 바람직하다.
In addition, the dosage or dosage of the flavonoid compound according to the present invention varies depending on the weight, age, sex, health condition, diet, time of administration, administration method, excretion rate and severity of the disease of the patient, the adult standard It is preferable to take a dose of 0.01 mg / kg to 1000 mg / kg divided once to several times a day.
본 발명에 따른 플라보노이드계 화합물인 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드(Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-glucopyranoside), 크리세리올(Chrysoeriol) 및 루테올린(Luteolin) 화합물은 페닐에프린 및 아세틸콜린에 의한 방광 평활근 및 전립선 평활근의 수축을 현저히 억제하여 비뇨기계 질환 즉, 전립선비대증 및 과민성방광에 효과를 나타냄으로써 비뇨기계 질환 환자의 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제로 유용하게 이용될 수 있다.
Chryseriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside (Chrysoeriol-6-C-β-boivinopyranosyl-7-O-β-, which is a flavonoid compound according to the present invention) Glucopyranoside, Chrysoeriol and Luteolin compounds significantly inhibit the contraction of bladder smooth muscle and prostate smooth muscle by phenylephrine and acetylcholine, which have effects on urinary system diseases such as prostatic hypertrophy and overactive bladder As a health functional food for improving the symptoms of patients with urinary system diseases and can be used as a therapeutic agent for urinary system diseases.
도 1은 옥미수 에틸아세테이트(EtOAc) 분획층의 TLC 패턴을 나타낸 것으로서,
도 1a는 UV로 발색정도를 나타낸 것이며,
도 1b는 10%황산 용액으로 발색정도를 나타낸 것이고,
도 1c는 FeCl3 용액으로 발색정도를 나타낸 것이다.
도 2는 옥미수 에틸아세테이트(EtOAc) 분획층으로부터 분리된 본 발명에 따른 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물에 관한 것으로서,
도 2a는 TLC 패턴을 나타낸 것이며,
도 2b는 1H-NMR spectroscopy를 나타낸 것이고,
도 2c는 13C-NMR spectroscopy를 나타낸 것이고,
도 2d는 Mass spectroscopy를 나타낸 것이다.
도 3은 옥미수 에틸아세테이트(EtOAc) 분획층으로부터 분리된 본 발명에 따른 크리세리올 화합물에 관한 것으로서,
도 3a는 TLC 패턴을 나타낸 것이며,
도 3b는 1H-NMR spectroscopy를 나타낸 것이고,
도 3c는 13C-NMR spectroscopy를 나타낸 것이고,
도 3d는 Mass spectroscopy를 나타낸 것이다.
도 4는 옥미수 에틸아세테이트(EtOAc) 분획층으로부터 분리된 본 발명에 따른 루테올린 화합물에 관한 것으로서,
도 4a는 TLC 패턴을 나타낸 것이며,
도 4b는 1H-NMR spectroscopy를 나타낸 것이고,
도 4c는 13C-NMR spectroscopy를 나타낸 것이고,
도 4d는 Mass spectroscopy를 나타낸 것이다.
도 5a는 정상 SD rat 방광에 대한 PE에서의 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물의 효과를 나타낸 그래프이며,
도 5b는 정상 SD rat 방광에 대한 ACh에서의 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물의 효과를 나타낸 그래프이다.
도 6a는 정상 SD rat 방광에 대한 PE에서의 크리세리올 화합물의 효과를 나타낸 그래프이며,
도 6b는 정상 SD rat 방광에 대한 ACh에서의 크리세리올 화합물의 효과를 나타낸 그래프이다.
도 7a는 정상 SD rat 방광에 대한 PE에서의 루테올린 화합물의 효과를 나타낸 그래프이며,
도 7b는 정상 SD rat 방광에 대한 ACh에서의 루테올린 화합물의 효과를 나타낸 그래프이다.
도 8은 정상 가토 전립선 및 전립선 요도 조직에 대한 PE에서의 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물의 효과를 나타낸 그래프이다.
도 9는 정상 가토 전립선 및 전립선 요도 조직에 대한 PE에서의 크리세리올 화합물의 효과를 나타낸 그래프이다.
도 10은 정상 가토 전립선 및 전립선 요도 조직에 대한 PE에서의 루테올린 화합물의 효과를 나타낸 그래프이다.Figure 1 shows the TLC pattern of the jade water ethyl acetate (EtOAc) fractionation layer,
Figure 1a shows the degree of color development in UV,
Figure 1b shows the degree of color development with 10% sulfuric acid solution,
Figure 1c shows the degree of color development with FeCl 3 solution.
Figure 2 relates to a chryseryol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound according to the present invention isolated from the octaethylethyl acetate (EtOAc) fractionation layer,
2a shows a TLC pattern,
2b shows 1 H-NMR spectroscopy,
2C shows 13C-NMR spectroscopy,
2D shows Mass spectroscopy.
Figure 3 relates to a chryseriol compound according to the present invention isolated from the jade water ethyl acetate (EtOAc) fractionation layer,
3A shows a TLC pattern,
3b shows 1 H-NMR spectroscopy,
3C shows 13C-NMR spectroscopy,
3D shows Mass spectroscopy.
Figure 4 relates to a luteolin compound according to the present invention isolated from the jade water ethyl acetate (EtOAc) fractionation layer,
4A shows a TLC pattern,
4B shows 1 H-NMR spectroscopy,
4C shows 13C-NMR spectroscopy,
4D shows Mass spectroscopy.
FIG. 5A is a graph showing the effect of chrysriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound in PE on normal SD rat bladder,
FIG. 5B is a graph showing the effect of chrysriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound on ACh on normal SD rat bladder.
6a is a graph showing the effect of chryseriol compounds in PE on normal SD rat bladder,
6B is a graph showing the effect of chryseriol compounds on ACh on normal SD rat bladder.
7A is a graph showing the effect of luteolin compounds in PE on normal SD rat bladder,
7B is a graph showing the effect of luteolin compounds on ACh on normal SD rat bladder.
FIG. 8 is a graph showing the effect of chrysriol-6-C-β-boibinopyranosyl-7-O-β-glucopyranoside compound in PE on normal rabbit prostate and prostate urethral tissue.
9 is a graph showing the effect of chryseriol compounds in PE on normal rabbit prostate and prostate urethral tissue.
10 is a graph showing the effect of luteolin compounds in PE on normal rabbit prostate and prostate urethral tissue.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.
However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.
<< 실시예Example 1> 1> 옥수수수염 추출액으로부터 본 발명에 의한 화합물의 분리 동정Isolation and Identification of the Compounds According to the Invention from Corn Beard Extract
1) sub-fraction 추출1) sub-fraction extraction
옥미수를 열수 추출한 옥미수 추출물(658.82g)을 감압 여과하여 수용성 부분을 627.54g을 얻었으며, 그 수용성 부분을 에틸아세테이트(EA)와 용매 분획을 실시하여 에틸아세테이트 분획물 62.83g을 얻었다. 에틸아세테이트 분획물을 30% 메탄올부터 10%씩 gradient를 가하여 100% 메탄올 농도까지 높여가며 Low pressure liquid column chromatography를 실시하여 7개의 sub-fraction을 분리 하였으며, TLC를 이용하여(전개용매는 클로로포름:메탄올:물=80:20:2) 3, 4번 sub-fraction에서 다양한 성분들이 분포되어 있음을 UV, 10%황산 및 FeCl3으로 각각 발색하여 확인하였다(도 1a 내지 도 1c).
Filtration of hot water extracted from hot water (658.82 g) was filtered under reduced pressure to obtain 627.54 g of an aqueous part. The aqueous part was subjected to solvent fractionation with ethyl acetate (EA) to obtain 62.83 g of an ethyl acetate fraction. Ethyl acetate fractions were added from 30% methanol to 10% gradient to raise the concentration to 100% methanol , and then separated into 7 sub-fractions by low pressure liquid column chromatography, and TLC (developing solvent was chloroform: methanol: Water = 80: 20: 2) Various components were distributed in 3 and 4 sub-fractions by UV, 10% sulfuric acid, and FeCl 3 , respectively, to confirm color development (FIGS. 1A to 1C).
2) 본 발명에 의한 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물의 분리정제2) Separation and purification of chrysriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound according to the present invention
상기 3번 sub-fraction(3.07g)을 60% 메탄올부터 10%씩 gradient를 가하여 100% 메탄올 농도까지 높여가며 Sephadex LH-20 column chromatography를 수행하고 얻어진 용액을 농축하고, 이 농축액을 50% 메탄올부터 10%씩 gradient를 가하여 100% 메탄올 농도까지 높여가며 MCI gel CHP 20P를 수행하여 얻은 메이져 스팟을 prep-TLC(클로로포름:메탄올:물=75:25:3)를 실시하여 하기 화학식 2 화합물인 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물 24mg을 분리 정제하였다.The third sub-fraction (3.07g) was added from 60% methanol to 10% gradient to increase the concentration to 100% methanol, Sephadex LH-20 column chromatography was performed, and the resulting solution was concentrated. A major spot obtained by performing MCI gel CHP 20P while increasing the concentration to 100% methanol by 10% gradient was prep-TLC (chloroform: methanol: water = 75: 25: 3) to carry out a crystal of the following
<화학식 2><
TLC patterns을 통해 단일 화합물로 분리되었음을 확인하고 도 2a에 나타내었으며, 1H, 13C-NMR spectroscopy 및 Mass spectroscopy를 각각 실시하여 분석하여 도 2b 내지 도 2d에 나타내었다.
It was confirmed that it was separated into a single compound through TLC patterns and is shown in Figure 2a, 1H, 13C-NMR spectroscopy and mass spectroscopy were carried out and analyzed as shown in Figures 2b to 2d.
3) 본 발명에 의한 크리세리올 및 루테올린 화합물의 분리정제3) Separation and purification of chryseriol and luteolin compounds according to the present invention
상기 4번 sub-fraction(3.08g)을 물부터 10%씩 gradient를 가하여 100% 메탄올 농도까지 높여가며 YMC-gel ODS-A를 수행한후 얻어진 용액을 농축하고, 농축액을 100% 에탄올부터 10%씩 gradient를 가하여 물까지 낮추어가며 Sephadex LH-20 column chromatography를 진행하고 얻어진 스팟중 두 번째 스팟을 prep-TLC(클로로포름:메탄올=10:1)를 실시하여 하기 화학식 3인 크리세리올 32mg를 분리정제하고, 나머지 메이저 스팟을 다시한번 100% 에탄올부터 10%씩 gradient를 가하여 물까지 낮추어가며 Sephadex LH-20 column chromatography를 수행하여 하기 화학식 4의 화합물인 루테올린 73mg을 분리정제하였다.The fourth sub-fraction (3.08g) was added to 10% gradient from water to increase the concentration to 100% methanol, and the solution obtained after YMC-gel ODS-A was concentrated, and the concentrate was concentrated from 100% ethanol to 10%. Sephadex LH-20 column chromatography was performed by adding a gradient to the water, and the second spot was obtained by prep-TLC (chloroform: methanol = 10: 1) to separate and purify 32 mg of chryseriol of
<화학식 3><
<화학식 4><
TLC patterns을 통해 크리세리올 및 루테올린이 단일 화합물로 분리되었음을 확인하고 도 3a 및 도 4a로 나타내었으며, 1H, 13C-NMR spectroscopy 및 Mass spectroscopy를 각각 실시하여 분석한 결과를 각각 도 3b 내지 도 3d 및 도 4b 내지 도 4d에 나타내었다.
It was confirmed that chryseriol and luteolin were separated into a single compound through TLC patterns, and are shown in FIGS. 3A and 4A. 4b to 4d.
<< 실험예Experimental Example 1> 1> 본 발명에 따른 화합물들의 과민성 방광 질환에 미치는 영향Effect of the compounds according to the invention on irritable bladder disease
1) 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물1) chrysriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound
정상 SD rat의 방광을 적출하여 2x5 mm 평활근 절편을 만들어 organ bath (Organ bath model : 조직을 적출하여 처리 물질에 대한 평활근의 수축/이완 정도를 정량한다)에 위치시킨 후 약물에 대한 반응을 isometric tension으로 기록하였다.
Bladder was extracted from normal SD rats to create 2x5 mm smooth muscle slices, which were placed in an organ bath (Organ bath model) to determine the degree of contraction / relaxation of smooth muscle to the treated material. Recorded as.
크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물을 각각 0.005, 0.05, 0.5 mg/ml로 처리하고, 처리를 하지 않은 Control과 함께 페닐에프린(alpha-1 adrenergic agonist, PE)과 아세틸콜린(muscarinic, nicotinic receptor agonist, ACh)의 농도 변화에 대해 상기 화합물을 처리하기 전 샘플과 농도별로 처리한 샘플에 대한 방광평활근의 수축 및 이완 반응의 변화를 측정하여 그 값을 도 5a 및 도 5b에 나타내었다.
Phenylephrine with Criesriol-6-C-β-boibinopyranosyl-7-O-β-glucopyranoside compound at 0.005, 0.05 and 0.5 mg / ml, respectively, and without treatment Changes in bladder smooth muscle contraction and relaxation in samples treated with different concentrations (alpha-1 adrenergic agonist (PE)) and acetylcholine (muscarinic, nicotinic receptor agonist, ACh) before treatment with the compound Was measured and the values are shown in FIGS. 5A and 5B.
도 5a 및 도 5b에서 알 수 있는 바와 같이, 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물은 PE 및 ACh에 의한 방광의 수축을 농도 의존적으로 현저히 억제하며, 특히 PE에 대한 반응이 더 강력하였다.
As can be seen in FIGS. 5A and 5B, the chryseriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound is concentration dependent on the contraction of the bladder by PE and ACh. Markedly inhibited, especially in response to PE.
2) 크리세리올 화합물2) chryseryol compounds
상기 1)과 동일한 방법으로 크리세리올 화합물을 각각 0.005, 0.05, 0.5 mg/ml로 처리하면서 처리 전후를 페닐에프린(alpha-1 adrenergic agonist, PE)과 아세틸콜린(muscarinic, nicotinic receptor agonist, ACh)의 농도변화에 대한 방광평활근의 수축 및 이완 반응의 변화를 측정하여 그 값을 도 6a 및 도 6b에 나타내었다.
In the same manner as in 1), the glycerol compound was treated with 0.005, 0.05 and 0.5 mg / ml, respectively, before and after treatment with phenylephrine (alpha-1 adrenergic agonist, PE) and acetylcholine (muscarinic, nicotinic receptor agonist, ACh). The change in the contraction and relaxation response of the bladder smooth muscle with respect to the concentration change of) is measured and the values are shown in FIGS. 6A and 6B.
도 6a 및 도 6b에서 알 수 있는 바와 같이, 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 화합물은 PE 및 ACh에 의한 방광의 수축을 농도 의존적으로 현저히 억제하며, 특히 PE에 대한 반응이 더 강력하였다.
As can be seen in FIGS. 6A and 6B, the chryseryol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside compound is concentration dependent on the contraction of the bladder by PE and ACh. Markedly inhibited, especially in response to PE.
3) 루테올린 화합물3) Luteolin Compound
상기 1)과 동일한 방법으로 루테올린 화합물을 각각 10-6~10-4M로 처리하면서 처리 전후를 페닐에프린(alpha-1 adrenergic agonist, PE)과 아세틸콜린(muscarinic, nicotinic receptor agonist, ACh)의 농도변화에 대한 방광평활근의 수축 및 이완 반응의 변화를 측정하여 그 값을 도 7a 및 도 7b에 나타내었다.
The luteolin compound was treated with 10 -6 to 10 -4 M in the same manner as in 1), before and after treatment with phenylephrine (alpha-1 adrenergic agonist, PE) and acetylcholine (muscarinic, nicotinic receptor agonist, ACh). The change in the contraction and relaxation response of the bladder smooth muscle with respect to the concentration change of was measured and shown in Figures 7a and 7b.
도 7a 및 도 7b에서 알 수 있는 바와 같이, PE 및 Ach에 대한 수축반응이 낮은 농도 (10-6M~10-5M)에서는 증가되나 고농도(10-4M)에는 억제되었다.
As can be seen in Figures 7a and 7b, the contraction response to PE and Ach was increased at low concentrations (10 -6 M ~ 10 -5 M) but inhibited at high concentrations (10 -4 M).
따라서, 본 발명에 따른 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드, 크리세리올 및 루테올린 화합물은 페닐에프린 및 아세틸콜린에 의한 방광의 수축을 억제하여 과민성방광 경향이 있는 환자의 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제로 유용하게 이용될 수 있다.
Thus, the chryseriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside, chryseriol and luteolin compounds according to the present invention are used for the bladder with phenylephrine and acetylcholine. It can be usefully used as a dietary supplement for improving the symptoms of patients with a tendency to overactive bladder and to treat urinary system diseases by inhibiting contraction.
<< 실험예Experimental Example 2> 2> 본 발명에 따른 화합물들의 전립선에 미치는 영향Effect on the Prostate of the Compounds According to the Invention
정상 수컷 가토(NewZealand white rabbit)의 전립선 조직 및 전립선 요도를 적출하여 2x5 mm 평활근 절편을 만들어 organ bath(Organ bath model : 조직을 적출하여 처리 물질에 대한 평활근의 수축/이완 정도를 정량 한다)에 위치시킨 후 각 농도의 페닐에프린(alpha-1 adrenergic agonist, PE)에 대한 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드, 크리세리올 및 루테올린 화합물을 각각 10-6, 10-5 및 10-4M로 처리하여 처리 전후의 반응을 비교분석하고 값을 각각 도 8 내지 도 10에 나타내었다.
Prostate tissue and prostate urethra from NewZealand white rabbits were extracted to make a 2x5 mm smooth muscle section, which is located in an organ bath (Organ bath model: quantifying the degree of contraction / relaxation of smooth muscle to the treated material). Chryseriol-6-C-β-boibinopyranosyl-7-O-β-glucopyranoside, chryserinol and lutein for each concentration of phenylephrine (alpha-1 adrenergic agonist, PE) The raised compounds were treated with 10 −6 , 10 −5, and 10 −4 M, respectively, to compare the reactions before and after the treatment and the values are shown in FIGS. 8 to 10, respectively.
도 8 내지 도 10에서 알 수 있는 바와 같이, 본 발명에 따른 크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드, 크리세리올 및 루테올린 화합물은 PE에 의한 수축을 현저히 억제시켜 전립선 비대증이 있는 환자에서 흔히 쓰이는 알파 차단제와 같이 요도를 이완시키는 효과가 있어 향후 전립선 비대증 환자의 증상 개선용 건강기능식품 및 비뇨기계 질환 치료제로 유용하게 이용될 수 있다.
As can be seen in Figures 8 to 10, the chryseriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside, chryserinol and luteolin compounds according to the present invention are Significantly suppresses the contraction caused by PE, so it has the effect of relaxing the urethra like alpha blocker commonly used in patients with enlarged prostate. .
<< 제제예Formulation example 1> 정제의 제조 1> Preparation of Tablet
크리세리올-6-C-β-보이비노피라노실-7-O-β-글루코피라노사이드 60 mgChrysriol-6-C-β-vobinopyranosyl-7-O-β-glucopyranoside 60 mg
규산칼슘 20 mg
유당 130 mg
미결정셀룰로오스 100 mg100 mg of microcrystalline cellulose
스테아린산마그네슘 적량Magnesium stearate appropriate amount
탈크 적량Talc proper amount
코팅제 적량Coating amount
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
<< 제제예Formulation example 2> 캅셀제의 제조 2> Preparation of capsule
크리세리올 60 mgChryseriol 60 mg
유당 160 mg
전분 적량Starch
통상의 캅셀제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캅셀제를 제조한다.
According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
<< 제제예Formulation example 3> 음료의 제조 3> Manufacturing of beverage
꿀 0.26 중량%, 치옥토산아미드 0.0002 중량%, 니코틴산아미드 0.0004 중량%, 염산리보플라빈나트륨 0.0001 중량%, 염산피리독신 0.0001 중량%, 이노시톨 0.001 중량%, 오르트산 0.002 중량% 및 물 89.7362 중량%와 루테올린 10 중량%을 배합하여 통상의 방법으로 음료를 제조하였다.0.26% by weight of honey, 0.0002% by weight of thioctoamide, 0.0004% by weight of nicotinic acid, 0.0001% by weight of sodium riboflavinate, 0.0001% by weight of pyridoxine hydrochloride, 0.001% by weight of inositol, 0.002% by weight of orthoic acid and 89.7362% by weight of water and luteolin A beverage was prepared by the conventional method by combining 10% by weight.
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New flavone c-flycosides from corn(Zea mays L.) for the control of the corn earworm, ISBN13: 9780841229181 eISBN: 9780841214552(1994.05.27.) |
식품의약품안전청, 최종연구보고서 ‘건강기능식품의 원료 및 성분의 DB 구축’(2003.11.07.) |
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