CN101222930B - A composition comprising an extract of tiarell polyphylla and tiarellic acid isolated therefrom having antiinflammatory, antiallergic and antiasthmatic activity - Google Patents

A composition comprising an extract of tiarell polyphylla and tiarellic acid isolated therefrom having antiinflammatory, antiallergic and antiasthmatic activity Download PDF

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CN101222930B
CN101222930B CN2006800263180A CN200680026318A CN101222930B CN 101222930 B CN101222930 B CN 101222930B CN 2006800263180 A CN2006800263180 A CN 2006800263180A CN 200680026318 A CN200680026318 A CN 200680026318A CN 101222930 B CN101222930 B CN 101222930B
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acid
extract
herba tiarellae
tiarellae polyphyllae
herba
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CN101222930A (en
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李烔圭
吴世湸
安璄燮
李重求
李相龟
金正姬
金斗英
全桂花
权玉京
金银娥
崔顺子
沈光海
金美真
朴普映
闵炳善
韩均熙
朴惠英
金健哲
金柱宪
金素英
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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Priority claimed from PCT/KR2006/002807 external-priority patent/WO2007011148A1/en
Priority claimed from KR1020060066866A external-priority patent/KR100822760B1/en
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03—Organic compounds
    • A23L29/035—Organic compounds containing oxygen as heteroatom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/304—Foods, ingredients or supplements having a functional effect on health having a modulation effect on allergy and risk of allergy
    • 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
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/314—Foods, ingredients or supplements having a functional effect on health having an effect on lung or respiratory system
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    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00—Drug, bio-affecting and body treating compositions
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Abstract

The present invention relates to a composition comprising an extract of Tiarella polyphylla, and tiarellic acid isolated therefrom having anti-inflammatory, anti-allergic and anti-asthmatic activity. The extract of Tiarella polyphylla and the tiarellic acid isolated therefrom shows the inhibitory effect on the LTC4 release in vitro test and the suppressive effect on the IgE level and the cytokine(IL-4, IL-5 and IL- 13) production, airway hyperresponsiveness, and leukocyte infiltration in OVA-induced asthmatic mice. Therefore, it can be used as the therapeutics or functional health food for treating and preventing inflammatory, allergic and asthmatic disease.

Description

Have anti-inflammatory, antiallergic and asthma effect comprise the Herba tiarellae polyphyllae extract and from the compositions of its isolating Herba tiarellae polyphyllae acid
Technical field
The present invention relates to a kind of have anti-inflammatory, antiallergic and asthma effect comprise Herba tiarellae polyphyllae (Tiarella polyphylla) extract and from the compositions of its isolating Herba tiarellae polyphyllae acid (tiarellic acid).
Background technology
It is a kind of complicated syndrome that occurs in air flue that asthma has been construed to, it is shown out to such as airflow obstruction, acute or various disorders (Kumar R.K.Pharmacol.Ther. such as chronic inflammatory disease, airway hyperreactivity (AHR) and structural remodeling, 91, pp 93-104,2001).
According to reports, the allergic inflammation that occurs in the air flue plays a crucial role in asthma development, and allergic asthma patient number has increased in the recent period and accounts for 10% of world population.According to reports, reached 1,700 ten thousand people, and the allergic asthma medicine 6,400 hundred million dollars have been extended to so far in the market scale of the U.S. in U.S. patient number.
Asthma can be divided into two types, i.e. extrinsic asthma and intrinsic asthma.Because of contact shows positive reaction to antigen such as the extrinsic asthma that causes as antigens such as the indoor micronic dust demodicid mite of major antigen, pollen, animal epithelium, funguses in tuerculoderma or bronchus irritant test, and usually occur in the youngster.Upper respiratory infection, exercise, emotional instability, cold snap, humidity change the intrinsic asthma that causes and occur among the adult patient.
According to the pathophysiology viewpoint, it is the chronic inflammatory disease that takes place according to the following procedure that asthma has been construed to: the inflammatory cell hypertrophy spreads, breaks up and activated by regenerated cytokine in the complementary T2 immunocyte, moves to air flue or its adjacent tissue then.Discharge various inflammatory mediators such as activatory inflammatory cells such as neutrophil cell, mastocytes, as cytokine, chemotactic factor, signaling molecule, adhesion molecule and somatomedin, and the structure cell in the air flue participates in each stage (Elias JA etc. of asthma, J Clin Invest., 111, pp 291-7,2003).In the various researchs and clinical research of using knock-out mice model, the critical observation of asthma may be divided into the several characteristic parameter, as immunne response, eosinophilia, AHR and structural remodeling (Moffatt JD.Pharmacol Ther, 107, pp343-57,2005; Spina D etc., Trends Pharmacol Sci, 23, pp 311-5,2002).As if each parameter does not have directly related property each other, and still, the immunne response of IgE mediation and eosinophilia are outstanding symptom (Bochner B.S. etc., Annu.Rev.Immunol., 12, pp 295-335,1994 in the allergic asthma air flue; Bousquet J etc., N.Engl.J.Med., 323, pp1033-9,1990), and in irritated process, produce such as cytokines such as IL-4, IL-5 and IL-13 (the Riffo-Vasquez Y etc. that in AHR development and airway remodeling, also play an important role, Pharmacol.Ther., 94, pp 185-211,2002).In fact, asthma is the result of the inflammatory episode allocated, wherein many incidents relate to the special inhibitor that acts on the asthma approach, for example histamine H 1 antagonist, blood plasma thromboxane antagonist, platelet activating factor antagonist, cox-2 inhibitors, nitrogen monooxygenase inhibitor and prostaglandin inhibitor, and carried out overtesting, but in clinical experiment failure (Moffatt J.D., Pharmacol.Ther., 107, pp 343-57,2005).Comparatively speaking, the origin level of inflammatory cell is suppressed to the glucocorticoid of baseline by the synthetic and cytokine mediated immunocyte survival of extensive inhibition cytokine, so far be used to control symptom (the Baatjes A.J. etc. of asthmatic patient over more than 30 year, Pharmacol, Ther., 95, pp 63-72,2002).These reports show that control treatment of asthma method should concentrate on the balance of recovering the asthma parameter, rather than seeks effective inhibitor of specific asthma process approach.
(Herba Saxifragae is to belong to the kind that Korea S should belong to Saxifragaceae) to Herba tiarellae polyphyllae.It grows in southwest China, but only is grown in the highest point of Korea S Yu Ling island (Ullung Island).Before this, use Corosolic acid (corosolic acid), termentic acid (tormentic acid) etc. to isolate Herba tiarellae polyphyllae acid (Park etc., Arch Pharm Res., 25, pp 57-60,2002), and other people have reported its inhibitory action (Moon etc., J Ethnopharmacol., 98 to MMP-1 in the skin fiber archeocyte of ultraviolet radiation and the expression of type 1 procollagen, pp 185-189,2005).
Yet, in office how going up in the document of being quoted all less than report or open Herba tiarellae polyphyllae extract with from the inhibitory action of its isolating Herba tiarellae polyphyllae acid to inflammatory, anaphylaxis and asthma, the disclosure that this paper introduces these documents is as a reference.
Therefore, the present inventor has found the Herba tiarellae polyphyllae extract and has demonstrated Herba tiarellae polyphyllae acid to external LTC from its isolating Herba tiarellae polyphyllae acid 4The inhibitory action that discharges, and in the asthma mice that OVA brings out to the inhibitory action of generation, airway hyperreactivity and the leukocyte infiltration of IgE level and cytokine (IL-4, IL-5 and IL-13), expect that they can be used for controlling asthma.
Summary of the invention
Technical problem
Therefore, up to now, still need to find to treatment and prevention inflammatory, anaphylaxis and the more effective avirulence medicine of asthma.
Technical scheme
Therefore, the purpose of this invention is to provide a kind of compositions that is used for the treatment of and prevents inflammatory, anaphylaxis and asthma, it comprises that Herba tiarellae polyphyllae crude extract or its organic solvent soluble extract are as active component.
Term disclosed herein " crude extract " comprises by making water, C 1-C 4Lower alcohol such as methanol, ethanol, particular methanol etc. or its mixture extract vegetable material and the extract for preparing.
Term disclosed herein " organic solvent soluble extract " can (as butanols, acetone, ethyl acetate, chloroform, dichloromethane or normal hexane, preferred butanols) extract above-mentioned crude extract and prepare by with an organic solvent.
The invention provides a kind of pharmaceutical composition, it comprise from Herba tiarellae polyphyllae crude extract or its organic solvent soluble extract separate obtain by the Herba tiarellae polyphyllae acid of following chemical formula (I) representative or the acceptable salt of its medicine as active component, inflammatory, anaphylaxis and asthma can be treated and prevent to the amount of described active component effectively.
Figure S2006800263180D00031
According to another aspect of the present invention, Herba tiarellae polyphyllae crude extract or its organic solvent soluble extract also are provided or have been used to prepare the purposes of the medicine that is used for treating or prevent inflammatory, anaphylaxis and asthma from its isolating Herba tiarellae polyphyllae acid.
According to another aspect of the present invention, a kind of method for the treatment of or preventing mammiferous inflammatory, anaphylaxis and asthma also is provided, and wherein said method comprises with the treatment Herba tiarellae polyphyllae crude extract of effective dose or its organic solvent soluble extract or from its isolating Herba tiarellae polyphyllae acid and giving to the mammal that suffers from inflammatory, anaphylaxis and asthma.
Can prepare from Herba tiarellae polyphyllae according to following embodiment preferred and to separate the extract of the present invention obtain and from its isolating Herba tiarellae polyphyllae acid.
The present invention will be described in detail belows.
For the present invention, for example, yellow fluid reducing branch whole plant is cut into pieces, and with the polar solvent of small pieces and 2～20 times of volumes, preferred 5～10 times of volumes such as water, C 1-C 4Lower alcohol (as methanol, ethanol, butanols or its mixture, particular methanol) mixes; And under 20～100 ℃, preferred 20～50 ℃ temperature, heated 10～48 hours, preferred 20～30 hours, use hot water reflux, extract,, cold water extraction, ultrasound wave or conventional the extraction, preferably use cold water extraction; Residue is filtered, and dried filtrate obtains its polar solvent soluble extract then.
To use the above-mentioned crude extract of above-mentioned steps preparation to suspend in water, mix with the organic solvent of 1～100 times of volume, preferred 1～5 times of volume such as butanols, acetone, ethyl acetate, chloroform, dichloromethane or hexane, preferred butanols then, obtain organic solvent soluble extract of the present invention.
Silicagel column (the 70-230 order that above-mentioned organic solvent soluble extract is further filled with silica gel, 8.5 * 65cm) carry out chromatography, use normal hexane: ethyl acetate (10-20% ethyl acetate, the substep gradient) and chloroform: methanol (0-100% methanol, the substep gradient) mixed solvent eluting obtains 9 components.In these components, use normal phase silicagel column that component 6 is repeated silica gel column chromatography (silica gel, 230-400 order, 6.0 * 60cm, chloroform-methanol mixture, 5-50% methanol, substep gradient), obtain Herba tiarellae polyphyllae acid of the present invention.Those methods (Park etc., ArchPharm Res., 25, pp 57-60,2002) of report before using, by NMR ( 1H, 13C, DEPT, HMQC HMBC), EI-MS and its structure of angle-of-rotation measuring, uses HPLC (the Shimadzu SCL-10A that has SPD-M 10Avp PDA detector of system, post: Phenomenex Synergi 4 μ mFusion RP-80,4.6 * 150nm, eluting: the ACN/0.1%TFA in the distilled water (DW), 4/1, v/v) analyze its purity, purity is higher than 99.5%.
According to another aspect of the present invention, a kind of pharmaceutical composition that is used for the treatment of and prevents inflammatory, anaphylaxis and asthma is provided, it comprise the Herba tiarellae polyphyllae crude extract that uses above-mentioned preparation method preparation and its organic solvent soluble extract or from its isolating Herba tiarellae polyphyllae acid as active component.
According to another aspect of the present invention, the Herba tiarellae polyphyllae crude extract that uses the preparation of above-mentioned preparation method and its organic solvent soluble extract also are provided or have been used to prepare the purposes of the medicine that is used for treating and prevent inflammatory, anaphylaxis and asthma from its isolating Herba tiarellae polyphyllae acid.
According to another aspect of the present invention, the method of a kind of treatment or prevention inflammatory, anaphylaxis and asthma also is provided, and wherein said method comprises that the Herba tiarellae polyphyllae crude extract of the above-mentioned preparation method preparation of the use for the treatment of effective dose is with its organic solvent soluble extract or from its isolating Herba tiarellae polyphyllae acid.
The The compounds of this invention of chemical formula (I) representative can be converted into acceptable salt of its medicine and solvate by conventional method well known in the art.For described salt, its acid-addition salts that is formed by the acceptable free acid of its medicine is useful, and the preparation of available conventional method.For example, after with excess acid solution dissolved compound, as described in making as methanol, ethanol, acetone or acetonitrile, salt out with the miscible organic solvent of water, to prepare its acid-addition salts, further can add heat equivalent chemical compound and dilute acid and water or alcohol mixture then as glycol monoethyl ether, evaporation drying or filtration under diminished pressure obtain its dry salt form subsequently.
As the free acid of said method, can use organic acid or mineral acid.For example; spendable organic acid for example is methanesulfonic acid, p-methyl benzenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, lactic acid, glycolic, gluconic acid, galacturonic acid, glutamic acid, 1,3-propanedicarboxylic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acyl radical acid (carbonylic acid), vanillic acid, hydroiodic acid etc. among the present invention, and spendable mineral acid for example is hydrochloric acid, phosphoric acid, sulphuric acid, nitric acid, tartaric acid etc.
In addition, use alkali can prepare the acceptable metallic salt form of medicine of The compounds of this invention.Can prepare its alkali metal or alkali salt by conventional method, for example, dissolve described chemical compound with excessive alkali metal hydroxide or alkaline earth metal hydroxide solution after, filter not dissolved salt and residual filtrate evaporated and dry, obtain its slaine.As slaine of the present invention, sodium, potassium or calcium salt are that medicine is available, and can prepare corresponding silver salt by alkali metal salt or alkali salt and the silver salt that is fit to such as silver nitrate reaction.
If this paper does not spell out, the acceptable salt of the medicine of The compounds of this invention comprises all acids or the basic salt that can compound form exists.For example, the acceptable salt of medicine of the present invention comprises hydroxy salt, as its sodium, calcium and potassium salt; Amide, as hydrogen bromide salt, sulfate, disulfate, phosphate, hydrophosphate, dihydric phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, metilsulfate (mesylate) and tosilate etc., these can use conventional method preparation well known in the art.
Be used for the treatment of and prevent the present composition of inflammatory, anaphylaxis and asthma can comprise said extracted thing or the chemical compound that accounts for described compositions gross weight 0.1～50 weight %.
Compositions of the present invention can be the pharmaceutical composition that contains medicine acceptable carrier, adjuvant or diluent, as lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltose alcohol, starch, Radix Acaciae senegalis, alginate, gel, calcium phosphate, calcium silicates, cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl-hydroxy benzoate, propyl group-hydroxy benzoate, Pulvis Talci, magnesium stearate and mineral oil.These preparations can also comprise filler, anti-agglutinant, lubricant, humidizer, flavoring agent, emulsifying agent, antiseptic etc.Use any process well known in the art, compositions of the present invention can be mixed with make after patient's administration can be fast, continue or release of active ingredients lingeringly.
For example, compositions oil-soluble of the present invention, propylene glycol or be usually used in producing other solvents of injection.The suitable example of described carrier comprises normal saline, Polyethylene Glycol, ethanol, vegetable oil, isopropyl myristate etc., but is not limited thereto.For topical, extract of the present invention can be mixed with ointment and cream forms.
The pharmaceutical preparation that contains the present composition can be prepared into any form, as peroral dosage form (powder, tablet, capsule, soft capsule, watery medicine, syrup, elixir, pill, XIANGFEN, granule), perhaps topical formulations (emulsifiable paste, ointment, washing liquid, gel, balsam, patch, pasty state agent, spray solution, aerosol etc.), perhaps ejection preparation (solution, suspension, emulsion).
The medicine type of the present composition can the acceptable salt of its medicine form use, also can be separately or with suitable cooperative programs use, also can be used in combination with the other drug reactive compound.
The required dosage of extract of the present invention or chemical compound is with experimenter's disease and body weight, the order of severity, dosage form, route of administration and time and different, and can be selected by those skilled in the art.Yet in order to obtain required effect, the administered dose of recommendering folder invention extract is 0.0001～100mg/kg body weight/day usually, preferred 0.001～10mg/kg body weight/day.This dosage can be individually dosed or be divided administration several times every day.
Pharmaceutical composition of the present invention can be by all means to animal subject such as mammal (rat, mice, domestic animal or the mankind) administration.Can anticipate all administering modes, for example, can be taken orally, rectally or by in vein, muscle, subcutaneous, Intradermal, the film, cerebral dura mater or intracerebral ventricle injection administration.
Another object of the present invention provides a kind of functional health food that is used to prevent and alleviate inflammatory, anaphylaxis and asthma, and it comprises the Herba tiarellae polyphyllae extract or from its isolated compound and diet acceptable additive.
Be development functional health food, the example that comprises the addible food of said extracted thing of the present invention or chemical compound is various food, beverage, chewing gum, vitamin complex, improves healthy food or the like, and they can be used as powder, granule, tablet, chewable tablet, capsule or beverage etc.
Above-mentioned composition of the present invention can join in food, additive or the beverage, wherein, the amount of said extracted thing or chemical compound accounts for about 0.01～80w/w% of the food gross weight of health food composition usually in the Foods or drinks, preferred 0.01～15w/w%, and by 100ml healthy beverage compositions, be 0.02～5g, preferred 0.3～1g.
As long as the said extracted thing of ratio or chemical compound shown in healthy beverage compositions of the present invention contains do not have particular restriction to other liquid components so as essential composition, wherein other compositions can be deodorizer or natural carbohydrate etc., as conventional beverage.The example of above-mentioned natural carbohydrate is a monosaccharide, as glucose, fructose etc.; Disaccharide is as maltose, sucrose etc.; Conventional table sugar is as dextrin, cyclodextrin; And sugar alcohol, as xylitol, erythritol etc.As other deodorizer except that above-mentioned, can use natural deodorant well, as sweet protein, stevioside extract such as levaudioside A, glycyrrhizin etc., and synthetic deodorizer, as glucide, aspartame (aspartame) etc.The consumption of above-mentioned natural carbohydrate is generally about 1～20g by 100ml beverage composition for treating dental erosion of the present invention, preferred 5～12g.
Other compositions except that foregoing be in various nutrient substance, vitamin, mineral or electrolyte, synthetic flavoring agent, the cheese chocolate etc. coloring agent and improving agent, pectic acid and salt thereof, alginic acid and salt thereof, organic acid, protectiveness rubstick, pH controlling agent, stabilizing agent, antiseptic, glycerol, alcohol, be used for the carbonating agent of soda pop etc.Other compositions in addition to the foregoing can be fruit juice, fruit drink or the vegetable beverages that is used to prepare natural fruit juice, and wherein said composition can be used alone or in combination.Each components in proportions is not really important, but is about 0～20w/w% in every 100w/w% present composition usually.The example that comprises the addible food of the aforementioned extract of the present invention is various food, beverage, chewing gum, vitamin complex, improves healthy food or the like.
Extract of the present invention does not have toxicity and negative effect, therefore can use safely.
Following examples have more specifically been explained the present invention.It should be understood, however, that the present invention is subject to these embodiment never in any form.
Beneficial effect
The invention provides and a kind ofly comprise the Herba tiarellae polyphyllae extract or from pharmaceutical composition and the health food of its isolating Herba tiarellae polyphyllae acid as active component, inflammatory, anaphylaxis and asthma can be treated and prevent to the amount of described active component effectively.
Description of drawings
In conjunction with the accompanying drawings, from following detailed description, can more be expressly understood above-mentioned and other purposes, feature and other advantages of the present invention, in the accompanying drawings:
Fig. 1 shows by using the tissue examination of bronchoalveolar lavage, Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid are to the effect (A: normal control group mice, the mice that B:PBS handles, C: the mice of Herba tiarellae polyphyllae extract-treated of lung tissue cell, D: the acid-treated mice of Herba tiarellae polyphyllae)
Fig. 2 shows the inhibitory action of the inflammation that Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid are brought out OVA in the lung tissue.
The specific embodiment
Those skilled in the art obviously can carry out various modifications and change to compositions of the present invention, purposes and preparation in the spirit or scope of the present invention.
Following examples have more specifically been explained the present invention.It should be understood, however, that the present invention is subject to these embodiment never in any form.
Embodiment
Following reference example, embodiment and experimental example be in order to further illustrating the present invention, but do not limit the scope of the invention.
The preparation of embodiment 1 Herba tiarellae polyphyllae crude extract
Gather Herba tiarellae polyphyllae in August, 2003 on Korea S Yu Ling island, its voucher specimen (PEB 3068) is by being positioned at Taejon city, Korea (Daejeon, Korea) Korea S's bioscience and Bioteknologisk Institut (Korea Research Institute of Bioscience and Biotechnology, plant extract storehouse preservation KRIBB).
1.1kg yellow fluid reducing branch is cut into pieces,, at room temperature stirred the mixture 24 hours, use cold water extraction three times with the 5L methanol mixed.With the filter paper filtering extract to remove residue.Collect filtrate, use Rotary Evaporators at 55～65 ℃ of following concentrating under reduced pressure, and use the freezer dryer drying, obtain the exsiccant Herba tiarellae polyphyllae crude extract of 100.5g.
The preparation of embodiment 2 butanols soluble components
In the 100.5g crude extract that embodiment 1 obtains, add the 1L distilled water, place separatory funnel, add the 1L butanols, and concuss, make it be divided into butanols dissolvable layer and water miscible coating.
Use Rotary Evaporators to concentrate above-mentioned butanols dissolvable layer, and use the freezer dryer drying, obtain the butanols soluble extract, finally obtain 80.0g butanols soluble extract and water solubility extract, in following experiment, be used as sample.
Embodiment 3 prepares Herba tiarellae polyphyllae acid by the Herba tiarellae polyphyllae extract
At room temperature use methanol (10L) to extract the exsiccant Herba tiarellae polyphyllae whole plant twice of 3.29kg, obtain the 352g extract.This extract is suspended in the 1L water, and is separated with isopyknic normal hexane.Then 65.1g normal hexane soluble component is carried out silica gel column chromatography (70-230 order, 8.5 * 65cm), and use normal hexane-ethyl acetate mixture (10-20% ethyl acetate in succession, the substep gradient) and chloroform-methanol mixture (0-100% methanol, the substep gradient) eluting obtains 9 components (Fr.1-Fr.9).Use normal phase silicagel column that 7.4g component 6 (chloroform-methanol 9/1-7/3 is between the v/v) is carried out column chromatography (silica gel, 230-400 order, 6.0 * 60cm, chloroform-methanol mixture, 5-50% methanol, substep gradient), obtain the acid of 400mg Herba tiarellae polyphyllae.Those methods (Park etc., ArchPharm Res., 25, pp 57-60,2002) of report before using, by NMR ( 1H, 13C, DEPT, HMQC HMBC), EI-MS and its structure of angle-of-rotation measuring, uses HPLC (the Shimadzu SCL-10A that has SPD-M 10Avp PDA detector of system, post: Phenomenex Synergi 4 μ mFusion RP-80,4.6 * 50mm, eluting: the ACN/0.1%TFA in the distilled water (DW), 4/1, v/v) analyze its purity, purity is higher than 99.5%.
Herba tiarellae polyphyllae acid
Needle-like (MeOH);
mp?254-256℃；
[α] D 23+ 94 (pyrimidines, c 0.14);
IR (KBr, cm -1): 3491 (OH), 1689 (CO), 1645 (C=C), 1450,1388,1262,1222,1044; HRMS m/z 472.3552 (M +, for C 30H 48O 4Value of calculation: 472.3553);
EIMS(rel.int.)m/z：472[M] +(61)，454[M-H 2O] +(34)，436[M-2H 2O] +(62)，424(42)，396(26)，205(75)，187(71)，175(87)，173(100)；
13C-NMR (150MHz, pyrimidine-d 5): 13.0 (C-24), 17.4 (C-25), 17.5 (C-26), 18.7 (C-6), 18.8 (C-28), 19.4 (C-30), 21.3 (C-11), 25.8 (C-15), 26.7 (C-12), 27.9 (C-2), 30.1 (C-21), 37.7 (C-10), 38.2 (C-7), 38.3 (C-16), 39.2 (C-1), 39.6 (C-13), 40.4 (C-22), 40.8 (C-8), 42.9 (C-4), 43.0 (C-17), 48.1 (C-19), 49.2 (C-5), 51.4 (C-18), 51.6 (C-9), 60.4 (C-14), 68.2 (C-23), 73.6 (C-3), 110.2 (C-29), 150.9 (C-20), 178.3 (C-27);
1H-NMR (600MHz, pyrimidine-d 5): 1.05,1.71 (2H, m, each hydrogen, H-1), 1.82,1.91 (2H, m, each hydrogen, H-2), 4.02 (1H, dd, J=4.7,11.6Hz, H-3), 1.51 (1H, dd, J=1.5,12.0Hz, H-5), 1.48,1.65 (2H, m, each hydrogen, H-6), 1.87,2.06 (2H, m, each hydrogen, H-7), 2.02 (1H, dd, J=1.7,12.7Hz, H-9), 1.32,1.64 (2H, m, each hydrogen, H-11), 1.87,2.60 (2H, m, each hydrogen, H-12), 1.88 (1H, m, H-13), 1.67,2.28 (2H, m, each hydrogen, H-15), 1.70,1.78 (2H, m, each hydrogen, H-16), 1.81 (1H, m, H-18), 2.60 (1H, m, H-19), 1.36,1.97 (2H, m, each hydrogen, H-21), 1.16,1.40 (2H, m, each hydrogen, H-22), 3.57,4.07 (2H, d, J=10.4, each hydrogen, H-23), 1.04 (3H, s, H-24), 1.01 (3H, s, H-25), 1.21 (3H, s, H-26), 0.90 (1H, s, H-28) .4.76,4.96 (2H, s, each hydrogen, H-29), 1.86 (3H, d, J=6.4Hz, H-30).
Experimental example 1 animal sensitization and air flue excite
(n=5-6) studies to several groups of mices; They have been subjected to following processing: (1) uses phosphate buffered saline (PBS) (PBS; IpNeb) false responsive and exciting; (2) use OVA (ovalbumin: SigmaA5503; Sigma, St.Louis, MO) sensitivity of (ipNeb) and exciting; (3) use the sensitization of OVA (ip) and use OVA (Neb) and sample (Herba tiarellae polyphyllae acid or zileuton, exciting po).In brief, the 0th and 11 day by peritoneal injection 20 μ g OVA sensitized mices, wherein OVA is with the 2mg aluminium hydroxide emulsifying in the 100 μ lPBS buffer solution (pH 7.4).Used ultrasonic sprayer mice to be excited 20min by air flue in the 19th, 20,21 and 25 day after initial sensitization with OVA (1%, among the PBS).In the end excited 48 hours of back (the 27th day) to put to death mice, and measured Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid inhibitory action the allergic asthma air flue.
Experimental example 2 MTT analyze
For studying Herba tiarellae polyphyllae extract of the present invention and from the cytotoxic effect of its isolating Herba tiarellae polyphyllae acid, carry out bromination (3-[4 according to the following procedure, 5-dimethylthiazole-2-yl]-2,5-diphenyl tetrazolium salts (MTT) is analyzed (Wang Z etc., Biol., Pharm.Bull., 24, pp 159-162,2001).
Under the condition of no NGF with promyelocyte HL-60 cell (HL-18103,5 * 10 5Individual cell/ml) be inoculated on 96 orifice plates.Cultivate after 24 hours, handle cell, under condition of similarity, cultivated 4 hours with the sample mixture that is dissolved in 10 μ l DMSO and 10 μ l MTT solution (5mg/ml).After 4 hours, remove MTT and 100 μ l DMSO are splashed in each hole with the dissolving crystal.(BIO-RAD U.S.A.) measures ultraviolet absorbance and calculates cell survival rate with the micropore reader under 570nm.
As shown in table 1, verified, extract of the present invention or chemical compound do not demonstrate cytotoxicity.
[table 1] Herba tiarellae polyphyllae extract and by of the effect of its isolated compound to the HL-60 cell
Sample Cell survival rate (%)
50μM ?100μM
The Herba tiarellae polyphyllae extract 100 ?102
Herba tiarellae polyphyllae acid 100 ?102
The preparation and the activation of the mastocyte (BMMC) of experimental example 3 bone marrow derived
Obtain BMMC by male Balb/c mice, and with containing IL-3 (Sigma I4144,2ng/ml) (Murakami M etc., J.Bio.Chem., 39, pp 22653-22656,1995) be cultured to for 4 weeks in 50% enrichment medium (RPMI contains 2mM L-glutamic acid, 25mMHEPES buffer, 2mg/ml sodium bicarbonate, 100 units/ml benzylpenicillin, 100 μ g/ml streptomycin sulfates, 0.25 μ g/ml amphotericin B) that 10% hyclone replenishes.After cultivating for 3 weeks, assess, find in cell, to have to be higher than 98% BMMC by the Toluidine blue staining method.
With BMMC with 1 * 10 6The cell density of individual cell/ml is suspended in the enrichment medium, then under 37 ℃ in DMSO (the DMSO final concentration is less than 0.5%), to be with or without under the situation of sample in humidity be 5% CO 2Cultivate 30min in the incubator.(SCF, Sigma S9915 100ng/ml) behind the stimulation 20min, use enzyme immunoassay (EIA) test kit (Cayman Chemical, Ann Arbor, MI, U.S.A.) LTC in the mensuration supernatant by manufacturer's explanation using stem cell factor 4Release.All experiments are carried out three times, and by calculating with respect to matched group LTC 4The minimizing percentage rate that discharges is measured LTC 4The inhibition (Lee SH etc., Biol.Pharm.Bull., 27, pp 786-788,2004) that discharges.
Experimental example 4 Herba tiarellae polyphyllae extracts and Herba tiarellae polyphyllae acid are to LTC 4The effect that discharges
As described in experimental example 3, use LTC 4The inhibitory action that monoclonal antibody ELISA method mensuration Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid discharge cysteinyl leukotriene among the BMMB.
The result proves the IC of Herba tiarellae polyphyllae acid 50Significantly, but be lower than the zileuton (zileuton) (referring to table 2) that is known as 5-fat oxidation enzyme inhibitor.
[table 2]
Sample LTC 4Discharge and suppress (IC 50)
The Herba tiarellae polyphyllae extract 19.5μg/ml
Herba tiarellae polyphyllae acid 2.49μM
Zileuton 0.11μM
Experimental example 5 Herba tiarellae polyphyllae extracts and Herba tiarellae polyphyllae acid are to the effect of airway hyperreactivity (AHR)
Use whole body volume recorder (OCP3000; Allmedicus, Korea) (Hamelmann E etc., Am J Respir Crit Care Med., 156, pp 766-775,1997) are measured last aerosol and are excited back 24 hours AHR.Every mice is placed the bio-measurement plethysmography box, and excite, increase the concentration (12.5,25 and 50mg/ml) 3 minutes of mist methacholine subsequently with mist PBS.Under each concentration, bronchoconstriction is write down 5min again.In each methacholine excites, obtain the highest Penh value of each sample, and excite, be expressed as the percent of basic Penh value in response to contrast (PBS).
As shown in table 3, under any concentration of the 5-20mg/ml of methacholine, the Penh value of OVA-processed group is significantly higher than the value (p＜0.05) of PBS matched group.Excite in the group at Herba tiarellae polyphyllae acid+OVA, compare with the OVA-processed group, its Penh value significantly reduces (p＜0.05).The zileuton positive controls that is developed as anti-asthmatic medicament demonstrates the AHR reduction, but is lower than Herba tiarellae polyphyllae acid (referring to as Fig. 2).
[table 3] Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid are to the effect of airway hyperreactivity (AHR)
Sample The Penh value
Methacholine (mg/ml)
0 ?5 ?10 ?20
The OVA-contrast 0.73±0.20 ?1.23±0.48 ?2.19±0.58 ?2.89±0.73
The Herba tiarellae polyphyllae extract 0.60±0.06 ?1.79±0.47 ?3.25±0.75 ?2.54±0.57 *
Herba tiarellae polyphyllae acid (30mg/ml) 0.46±0.08 ?0.96±0.45 * ?1.54±0.74 * ?2.15±0.52 *
Zileuton (30mg/ml) 0.55±0.14 ?1.17±0.59 ?1.97±0.83 ?2.49±0.90
*With the significant difference of OVA processed group, p＜0.05
Experimental example 6 Herba tiarellae polyphyllae acid are to the effect of OVA-specific IgE
Excite back 48 hours at last, put to death mice, carry out tracheotomy with excessive pentobarbital (Sigma P3761).Ice-cold PBS (0.5ml) is injected lung, obtain bronchoalveolar lavage fluid (BALF) (total amount 1.5ml) air-breathing three times by tracheal intubation.Centrifugal BALF also collects supernatant, stores down at-70 ℃ before using.Use specific mice ELISA test kit (R﹠amp according to manufacturer's explanation; D Systems; Minneapolis, MN) IL-4, IL-5 among the mensuration BALF and the amount of IL-13.The detectability of test is 250pg/ml.
The tracheotomy postoperative obtains blood plasma by cardiac puncture.Antibody is caught and detected to the complementation that is used for mice IgE antibody to (San Diego CA), and carries out enzyme linked immunological absorption according to manufacturer's explanation and detects (ELISA) available from BD OptEIA.By dilution in 1: 100, the mensuration optical density readings obtained the IgE level in each sample under 450nm with two plasma samples, calculated OVA specific IgE concentration from standard curve, and wherein (5-2 000ng/ml) generates standard curve with reorganization IgE.
As shown in table 4, the IgE level of Herba tiarellae polyphyllae acid treatment mice significantly reduces, and zileuton demonstrates and the similar inhibitory action of Herba tiarellae polyphyllae acid.
[table 4]
Sample The OVA-specific IgE
The OVA-contrast 26.0±10.9
OVA+ Herba tiarellae polyphyllae acid (30mg/ml) (suppressing %) 13.3±5.27 *(48.8±20.3％)
OVA+ zileuton (30mg/ml) (suppressing %) 14.1±1.0 *(45.8±15.3％)
*With the significant difference of OVA processed group, p＜0.05
The effect of experimental example 7 Herba tiarellae polyphyllae extracts and Herba tiarellae polyphyllae acid pair cell factor level
For measuring Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid OVA is brought out the influence of release of cytokines in the asthma mice, excite back 48 hours at last, use the ELISA method to measure the level of cytokine (IL-4, IL-5 and IL-13) among the BALF.
As shown in table 5, the cytokine in the Herba tiarellae polyphyllae acid treatment group is subjected to remarkable inhibition; In IL-4, IL-5 and IL-13 than at OVA, excite and reduce (p＜0.05) more than 90.5 ± 4.0%, 54.6 ± 23.0% and 43.7 ± 28.2% in the group respectively.Zileuton also demonstrates the reduction effect bigger than matched group, but still far below Herba tiarellae polyphyllae acid.These results prove that Herba tiarellae polyphyllae acid has significantly reduced IL-4, IL-5 among the BALF of asthmatic model and the concentration of IL-13.
[table 5]
Sample IL-4(pg/ml) IL-5(pg/ml) IL-13(pg/ml)
The OVA-contrast 356.1±14.7 180.4±17.3 145.0±10.9
OVA+ Herba tiarellae polyphyllae extract (30mg/ml) (suppressing %) 294.7±38.2 *(18.9％) 379.5±94.9 *(26.8％) 32.3±9.7 **(62.4％)
OVA+ Herba tiarellae polyphyllae acid (30mg/ml) (suppressing %) 33.8±14.3 *(90.5％) 81.9±41.4 *(54.6％) 81.7±40.9 *(43.7％)
OVA+ zileuton (30mg/ml) (suppressing %) 289.5±59.0(18.7％) 157.8±41.3(12.5％) 130.1±16.8(10.3％)
*With the significant difference of OVA processed group, p＜0.01 **With the significant difference of OVA processed group, p＜0.05
The effect of inflammation is brought out in experimental example 8 Herba tiarellae polyphyllae extracts and Herba tiarellae polyphyllae acid to OVA in the lung tissue
Lung tissue is fixed 24 hours with 10% neutral buffered formalin, after paraffin embedding, tissue is cut into the thick fragment of 4-μ m, use H﹠amp then; E solution (haematoxylin, Sigma MHS-16 and eosin, Sigma HT110-1-32) dyeing.Subsequently, with Dako-mounting medium (Dakocytomation; Denmark Carpinteria CA) fixing painted tissue and covered.By two independently research worker carry out double blind experiment, to the cellular infiltration degree in air flue scoring (Myou S etc., J.Exp.Med., 198, pp 1573-1582,2003).Use specific criteria to estimate peribronchiolitis and perivasculitis, promptly score value is 0-3, wherein 0, and acellular; 1, a few cell; 2, the degree of depth is the cell ring of 1～5 cellular layer; 3, the degree of depth is greater than the thick cell ring of 5 cellular layers.For estimating Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid inhibitory action,, in lung tissue, carry out quantitative analysis to inflammation degree scoring (referring to Fig. 2) by in the end exciting back 48 hours to leukocyte infiltration.
As shown in Figure 1, the inflammation that Herba tiarellae polyphyllae acid is brought out OVA in the lung tissue of mice has the most effective inhibitory action, is Herba tiarellae polyphyllae extract and zileuton then.H﹠amp in lung tissue; In the E dyeing, the leukocyte that OVA handles mice soaks in the bronchioles week and Perivascular conjunctive tissue of normal mouse in large quantities.In Herba tiarellae polyphyllae extract or the acid-treated mice of Herba tiarellae polyphyllae, rich eosinophilic leukocytic infiltration is compared remarkable weakening with the mice that OVA handles.
The effect of the Mus pawl edema that experimental example 9 Herba tiarellae polyphyllae extracts and Herba tiarellae polyphyllae acid on Carrageenan are brought out
The Herba tiarellae polyphyllae extract and the Herba tiarellae polyphyllae acid of pressing the foregoing description preparation are as follows to the inhibiting mensuration that edema in the ICR mice forms.
Mice is divided into three groups, and every group is made of 6 mices, that is, be respectively only with the T1 of solvent processing, the T3 that handles with the T2 of the Herba tiarellae polyphyllae extract-treated of 50mg/kg, with the aspirin of 50mg/kg as negative control group.Handle after 1 hour, 1% carrageenin solution is injected in the Mus ankle bringing out edema, and it is thick to use the Vernier caliper to measure ankle, thereby measures the edema degree.Calculate the thickness of measuring by following mathematical expression 1.
[mathematical expression 1]
Ankle thickness ratio (%)=[(maximum ga(u)ge of Mus pawl edema)-(thickness of Mus pawl edema before handling)/(thickness of Mus pawl edema before handling)] * 100
As shown in table 6, handle that edema reaches maximum after 4 hours.Therefore, verified, Herba tiarellae polyphyllae extract and Herba tiarellae polyphyllae acid demonstrate effective inhibitory action to Mus pawl edema.
[table 6]
Hour T1 ?T2 ?T3
Ankle thickness ratio (%) Ankle thickness ratio (%) Suppress (%) Ankle thickness ratio (%) Suppress (%)
?0 ?100 ?- ?- ?- ?-
?1 ?119.2±15.6 ?125.1±1.5 ?-5.0±1.3 ?139.3±40.6 ?-16.8±34.0
?2 ?158.0±9.0 ?146.4±19.4 ?7.3±12.3 ?170.4±34.5 ?-7.8±21.8
?3 ?194.9±12.4 ?166.8±18.8 ?14.4±9.7 ?180.6±28.6 ?7.3±14.7
?4 ?205.9±19.0 ?180.6±26.9 ?12.3±13.1 ?196.9±15.4 ?4.3±7.5
?5 ?201.6±5.1 ?193.4±22.4 ?4.1±11.1 ?198.5±12.6 ?1.5±6.3
T1: contrast T2:50mg/kg Herba tiarellae polyphyllae extract T3:50mg/kg aspirin
To describe compound method and various excipient hereinafter, but the invention is not restricted to this.Representative preparation example is as follows.
The preparation of injection
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 100mg
Inclined to one side sulfurous acid cyanogen sodium 3.0mg
Methyl parahydroxybenzoate 0.8mg
Propyl p-hydroxybenzoate 0.1mg
Distilled water for injection is an amount of
By lytic activity composition, control pH to about 7.5, all components is filled in the 2ml ampoule then and sterilizes and prepare injection type with conventional injection preparation method.
The preparation of powder
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 500mg
Corn starch 100mg
Lactose 100mg
Pulvis Talci 10mg
By mixing said ingredients and be packed into to pack and prepare powder.
The preparation of tablet
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 200mg
Corn starch 100mg
Lactose 100mg
Magnesium stearate is an amount of
Prepare tablet by mixing said ingredients and tabletting.
The preparation of capsule
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 100mg
Lactose 50mg
Corn starch 50mg
Pulvis Talci 2mg
Magnesium stearate is an amount of
Also prepare capsule by mixing said ingredients with the gel filled capsule of conventional preparing gel method.
The preparation of liquid agent
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 1000mg
Sugar 20g
Polysaccharide 20g
Lemon flavouring 20g
By the lytic activity composition, all components is filled in the 1000ml ampoule then and prepares liquid dosage form with the sterilization of conventional liq agent preparation method.
The preparation of health food
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 1000mg
Vitamin mixtures is an amount of
Vitamin A acetate 70 μ g
Vitamin E 1.0mg
Vitamin B 10.13mg
Vitamin B 20.15mg
Vitamin B 60.5mg
Vitamin B 120.2 μ g
Vitamin C 10mg
Biotin 10 μ g
Nicotinamide 1.7mg
Folic acid 50 μ g
Calcium pantothenate 0.5mg
The mixture of mineral is an amount of
Ferrous sulfate 1.75mg
Zinc oxide 0.82mg
Magnesium carbonate 25.3mg
Potassium dihydrogen phosphate 15mg
Calcium hydrogen phosphate 55mg
Potassium citrate 90mg
Calcium carbonate 100mg
Magnesium chloride 24.8mg
The mixture of said vitamin and mineral can change in many ways.These variations are not considered to break away from the spirit and scope of the present invention.
The preparation of healthy beverage
The dry powder of embodiment 1 or Herba tiarellae polyphyllae acid 1000mg
Citric acid 1000mg
Oligosaccharide 100g
Fructus Pruni concentrate 2g
Taurine 1g
Distilled water 900ml
By lytic activity composition, mixing, 85 ℃ stir down 1 hour, filter, then all components be filled to sterilize in the 1000ml ampoule and with conventional healthy beverage preparation method and prepare healthy beverage.
However describe the present invention, but clearly can change the present invention in many ways.These change and not to be considered to break away from the spirit and scope of the present invention, and change in the tangible institute of those skilled in the art and all to be intended to comprise within the scope of the appended claims.
Industrial applicibility
As described herein, the himalayan foamflower herb extract demonstrates external LTC with the tiarellic acid that separates from it4The inhibitory action that discharges, and in the asthma mouse that OVA brings out to the inhibitory action of generation, airway hyperreactivity and the leukocyte infiltration of IgE level and cell factor (IL-4, IL-5 and IL-13). Therefore, they can be used as therapeutic agent or the functional health food that is used for the treatment of and prevents inflammatory, anaphylaxis and asthma.

Claims (3)

1. the butanols soluble extract of the thick methanolic extract of Herba tiarellae polyphyllae or Herba tiarellae polyphyllae is used to prepare and is used for treating or the purposes of the medicine of prevention of asthma disease.
2. the butanols soluble extract of the thick methanolic extract of Herba tiarellae polyphyllae or Herba tiarellae polyphyllae is used to prepare the purposes that is used for preventing and improving the functional health food of asthma disease, and described functional health food contains the butanols soluble extract and the diet acceptable additive of the thick methanolic extract or the Herba tiarellae polyphyllae of described Herba tiarellae polyphyllae.
3. the purposes of the butanols soluble extract of the thick methanolic extract of Herba tiarellae polyphyllae as claimed in claim 2 or Herba tiarellae polyphyllae, wherein said health food can be the form of pill, powder, granule, tablet, capsule or beverage.
CN2006800263180A 2005-07-18 2006-07-18 A composition comprising an extract of tiarell polyphylla and tiarellic acid isolated therefrom having antiinflammatory, antiallergic and antiasthmatic activity Expired - Fee Related CN101222930B (en)

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