KR101243977B1 - Pharmaceutical composition containing a herbal mixture extract - Google Patents

Abstract

The present invention relates to an agent for the prevention and treatment of respiratory diseases such as antitussive expectoration and asthma, which contains a mixed extract of ivy leaf and coarse leaf ( Coptidis rhizoma ) as an active ingredient, and a mixture of ivy leaf and sulfur leaf according to the present invention, respectively. It is characterized in that the extract exhibits significantly superior antitussive action, expectorant action, antihistamine action, bronchial contraction action, airway hypersensitivity action, lung tissue blockage inhibition and inflammatory cell infiltration inhibition effect.

Description

Pharmaceutical composition containing a herbal mixture extract

The present invention relates to a method for preventing and treating respiratory diseases such as Jinhae Geodam, asthma, and a method for preparing the same, containing a mixed extract of ivy leaves and Coptidis rhizoma as an active ingredient. Each extract is characterized by showing remarkably superior antitussive action, expectorant action, antihistamine action, bronchoconstriction inhibitory action, airway hypersensitivity inhibitory action, bronchial obstruction of lung tissue, and inhibition of inflammatory cell infiltration than when each extract is present alone. .

The respiratory system of our body is one of the organs that constantly defends against physicochemical stimulation. When an irritant enters the respiratory tract, most of the irritants get caught in the nose hairs and cannot enter the respiratory tract, but the fine irritants that pass through it are surrounded by mucus and the airways. It is pushed up or out by the movement of the fine cilia located on the wall, which is the basic working principle of coughing.

As described above, cough is a defense mechanism that occurs reflexively by irritation of the airway mucosa, and when persistent cough is induced by excessive irritation, the quality of life of the patient is reduced and worsened. In addition, when dust or irritants are introduced from the outside on the same principle as coughing, the bronchi of our body performs muscle movements with saliva and pushes them out. This is the cause of the formation of sputum (sputum) and inflammation of the bronchi such as lungs. By this, thick purulent sputum is produced.

As a result, cough and sputum are caused by physical and chemical factors such as cold air, foreign substances including pathogenic microorganisms, air pollutants, and allergens, which can be largely divided into three categories.

First, when stimulating cough receptors such as the larynx, trachea, bronchi, pharynx, sinuses, and diaphragm due to physicochemical factors, the stimulation is transmitted to the cough center of the brain and the cough reflex occurs. The mechanisms of antitussive drugs, which are closely related to the irritating cough reflex, are broadly classified into centrality and peripherality, and the mechanisms of central antitussive drugs are drugs that control cough by suppressing the remission center of soft water, codeine and dextromethorphan ( dextromethorphan), noscapine, ephedrine, and zipeprol.These ingredients often cause side effects such as cardiovascular thrombosis, myocardial infarction, respiratory depression, sedation, and gastrointestinal disorders. There is. Peripheral antitussive drugs act on the stretch receptor in the peripheral to control cough. They are relatively safe by compensating for the shortcomings of central antitussive drugs. Recently, many attempts have been made to develop such antitussive drugs. Pidgin (levopropizine), benzonatate (benzonatate), benzozaine (benzozaine), benzyl alcohol (benzyl alcohol) and the like are used.

Second, when the parasympathetic nervous system is activated due to physicochemical factors, bronchial smooth muscle contracts and thus symptoms such as bronchospasm or bronchial contraction may appear. At this time, the beta 2 agonist (β2-adrenergic receptor agonist) stimulates the beta 2 receptor to relax smooth muscle, and the xanthine derivative increases cAMP by inhibition of phosphodiesterase or It plays a role of directly relaxing smooth muscles, increasing mucus secretion, dissolving mucus, promoting ciliary movement, and exhibiting antitussive and expectorant activity. Drugs exhibiting such an action include clenbuterol, bambuterol, formoterol, and the like as beta 2 agonists, and as xanthine derivatives, theophylline, aminophylline ( aminophylline), acepipylline, and bamifylline.

In addition, there are mucolytic agents or expectorant agents that reduce the viscosity by dissolving the generated mucus and promote ciliary movement of the bronchi, thereby promoting sputum discharge. Airway mucus has several important functions in the airways. In other words, it protects the airways from particles entering the airways from the outside, maintains the humidity of the inhaled air, and removes the inhaled chemical substances or gases through the binding of mucus proteins and cilia. In addition, mucus contains substances that play an important role in immune function, such as immunoglobulin A (IgA), lysozyme, and lactoferrin. Most expectorant agents have been used as folk medicines or empirical prescriptions for thousands of years using plants, etc., and as compounds, cysteine derivatives such as carbocysteine, N-acetylcysteine, and cysteine ethyl ester hydrochloride are used as expectorant agents. It is being used as. When the above-described cysteine derivatives are used as expectorants, they are not completely satisfactory, and in particular, N-acetyl cysteine and cysteine ethyl ester hydrochloride are both highly toxic and chemically unstable. Therefore, development of an expectorant agent having good physical and chemical stability, less side effects, toxicity, and excellent expectorant effect has been required.

Third, inflammatory mediators are released from mast cells due to physicochemical factors. Mast cells contain small cytoplasmic granules containing inflammatory mediators such as histamine and cytokines. When exposed to an allergen, an antibody called IgE is produced in B cells in the body, which attaches to the surface of mast cells. Afterwards, when exposed to allergens again, chemical substances including histamine, a strong inflammatory mediator, are released from mast cells with IgE attached, thereby increasing secretions in the airways, effusion due to inflammation, inhalation foreign matter, bacteria, etc., which results in the formation of sputum. Leads to Existing drugs such as codeine, which are widely used as antitussives, are excellent in sedative action against breathing and cough, but have side effects of releasing histamine by inducing degranulation of mast cells.

As described above, existing antitussive expectorants have problems due to side effects, toxicity, and chemical instability of the drug itself. In order to solve this problem, researches on antitussive expectorant drugs derived from natural substances have been actively conducted in recent years, and a representative study related to this is to stimulate the vagus nerve of the airways to promote the secretion of the mucous membrane, thereby expressing the expectorant function and at the same time Plants containing saponin, alkaloid, etc., which play an auxiliary role (Sook-young Kim et al ., Kor . J. Pharmacogn . 19(2):133-140, 1998) have been reported, but the results have not yet been achieved. This is insignificant.

Asthma, a typical respiratory disease, is a recurring seizure of symptoms such as shortness of breath, coughing, and flickering, rough breathing (wheezing).In about 30% of asthmatic patients, in about 80% within 1 year of life. The first symptoms of asthma appear at the age of 4-5, and the incidence rate is around 10% in Korea, and there are cardiac asthma and bronchial asthma. The former is a paroxysmal respiratory distress that can be seen in heart disease or high blood pressure, and occurs due to irritability in the respiratory center due to pulmonary congestion or tissue congestion, and the prognosis is poor. The latter is a paroxysmal dyspnea caused by narrowing of breathing due to bronchospasm, narrowing, and mucosal swelling. In addition, there are cerebral asthma caused by disorders in the respiratory center or uremic asthma in kidney disease patients.

The incidence rate of asthma varies according to country, race, and age, but according to the British report in 2007, it was reported as about 7.9% of adults, 13.7% of children, and 9.4% of the elderly. It is gradually increasing as stress increases. Such asthma varies depending on its cause, but in modern times when environmental pollution such as pollution is severe, the age of onset is lowered and the symptoms are prolonged, and the severity of asthma is maximized.

The characteristic airway obstruction in asthma occurs in a three-step process. In other words, the contraction of the bronchial smooth muscle, thickening of the lung mucosa, and sticky mucus in the bronchi and bronchioles accumulates and the airway is blocked. Of these, only the contraction of the bronchial smooth muscle is easily recovered.

The mechanism of exogenous (allergic) asthma attacks is of particular importance to the antibody IgE, some of which are associated with IgG. IgE activates mast cells and releases mediators (histamine, SRS-A, ECF-A, NCF, PAF, Kinin, PGs) that cause hypersensitivity reactions. The mechanism of non-allergy asthma attacks is unknown, but seems to be mediated by the autonomic nervous system. Cholinergic stimulation to endogenous patients is not only beneficial from mast cells to mediators such as histamine through terminal organs, but also secretion of goblet cells is increased, blood vessels in the lungs are expanded, and trachea, bronchi, and giant bronchioles are constricted. Bronchospasm and mucus secretion increase.

Currently, there is no fundamental cure for asthma, and various methods and drugs are used to prevent seizures and prevent complications, but they are not satisfactory. The treatment of asthma is mainly inhaled bronchodilators, oral or injectable bronchodilators (sympathetic stimulants and theophylline drugs), stereo drugs (inhaled, oral, injectable, etc.), leukotriene antagonists (monterukast, tranlucast, etc.). , Zyluton, etc.), and anti-allergic drugs (disodium chloroclicate, chromoline sodium, ketotifen), etc. are being used. Airway dilators such as anticholinergic drugs and beta 2 receptor agonists do not have an effect on inflammation that aggravates the disease, but simply alleviate symptoms, so long-term use may cause drug resistance and worsen disease. Steroids, which are known to be effective against inflammation, have become a problem when used for a long time due to severe side effects. Therefore, there are many cases of co-prescribing both, but due to the side effects of steroids, it is developed in the form of an inhalant rather than an oral drug, so that it is difficult to take, there is a problem in that the dosage compliance is poor.

It is necessary to develop a new therapeutic agent that can fundamentally treat the cause and effectively improve symptoms by overcoming the limitations of these current drug treatments. However, since respiratory diseases involve various white blood cells, various cytokines and inflammatory mediators released therefrom, as described above, effective treatment with a single component chemical is difficult, so natural extracts having various components and mechanisms are effective therapeutic agents. Can be.

Accordingly, the present inventors studied to develop a therapeutic agent for respiratory diseases such as Jinhae Geodam, asthma, etc., as a result, ivy leaf extract and Coptidis rhizoma ) extracts were found to have excellent expectorant activity, antitussive activity, antihistamine activity, bronchoconstriction inhibitory activity, airway hypersensitivity inhibitory activity, bronchial obstruction of lung tissue, and inflammatory cell invasion inhibitory activity. The present invention was completed by confirming that the effect was increased by mixing the ivy leaf extract and the Coptis Coptis extract rather than the extract itself or the Coptis Coptis extract itself.

Accordingly, an object of the present invention is to provide a mixture having an optimal combination ratio having the most excellent pharmacological activity synergistic effect by mixing an ivy leaf extract and a Coptis chinensis extract.

The present invention is ivy leaf extract and Coptidis rhizoma ) containing a mixture of extracts as an active ingredient, and to a method for preventing and treating respiratory diseases such as Jinhae Geodam, asthma, etc., and a manufacturing method thereof. It is characterized by showing remarkably superior antitussive action, expectorant action, antihistamine action, bronchoconstriction inhibitory action, airway hypersensitivity inhibitory action, bronchial obstruction of lung tissue and inhibition of inflammatory cell infiltration.

In other words, the inventors of the present invention in the case of a mixture of ivy leaf extract and Coptis chinensis extract in a specific ratio, significantly increased antitussive effect, expectorant effect, antihistamine effect, bronchi The present invention was completed by confirming that it has the effect of inhibiting contraction, inhibiting airway hypersensitivity, inhibiting bronchial obstruction of lung tissue, and inhibiting inflammatory cell invasion, and finding the optimal mixing ratio between the ivy leaf extract and the Coptis Coptis extract to obtain the best synergistic effect. will be.

Ivy belongs to the Araliaceae family, and plants of the genus Heedera ( Hedera spp.), for example, Hedera algeriensis , Hedera azorica, Hedera canariensis , Hedera colchica , Hedera helix , Hedera hibernica, Hedera maderensis, Hedera nepalensis , Hedera pastuchowii , Hedera It may be rhombea, etc., but is not limited thereto. In respiratory diseases, the therapeutic effect of the dried ivy leaf extract is due to the mucolytic, antispasmodic, and antitussive effects of glycoside saponins contained in the formulation. While it is clear that the mucolytic activity of the extract is due to the saponin properties of hederaglycoside, the antispasmodic effect, which has an effect on inflammatory bronchi, is partially parasympathetic inhibition of glycosides. It is judged to be due to the effect. The antitussive effect of the extract is based on a weak soothing effect as a central inhibitory mechanism by having a special effect on the cough center. While having these effects, the extract has the advantage of not causing damage to the respiratory control center. In addition, there are no reports of any side effects that occur when the ivy leaf extract is administered in combination with other agents.

On the other hand, Coptidis rhizoma is a perennial herb belonging to the Ranunculaceae family and is known to have pharmacological effects such as antimicrobial action, blood pressure lowering action, and anti-inflammatory action. It is used as a bladder, bronchial and nervous system agent. It is believed that it mainly contains alkaloids such as berberine and magnoflorine as a pharmacological ingredient (Boo Seop Bo, Shin Min-gyo, Dohae Herbal Medicine Daejeon, 490-493, 1990).

As described above, the present invention has antitussive action, expectorant action, antihistamine action, bronchoconstriction inhibitory action, airway hypersensitivity inhibitory action, bronchial obstruction of lung tissue, and inflammatory cell infiltration inhibitory action in a mixture of ivy leaf extract and Coptis chinensis extract. It is an object of the present invention to provide a mixture and a preparation method having an optimal combination ratio in which the pharmacologically active synergistic effect is the greatest by confirming that the increase was increased from the ivy leaf extract alone or the Coptis chinensis extract alone.

First of all, the present invention relates to a mixed extract having antitussive expectorant action, airway hypersensitivity inhibitory action, bronchoconstriction inhibitory action, bronchial obstruction of lung tissue, and inflammatory cell infiltration inhibitory action, containing a mixed extract of ivy leaf and Coptis chinensis.

In the present invention, the term'mixed extract of ivy leaf and Coptis Crusade' refers to both extracts obtained by extracting ivy leaf and Coptis Coptis leaf extract and a mixture of Coptis Coptis leaf extract and Coptis Coptis extract, respectively. It is used to mean. In addition, the'extract' refers to a crude extract or a specific solvent-soluble extract (fraction), and may be in the form of a solution, a concentrate, or a powder.

The present invention uses a mixed extract of ivy leaf and Coptis chinensis, compared to the case of using ivy leaf extract and Coptis chinensis extract alone, with antitussive action, expectorant action, antihistamine action, airway hypersensitivity inhibitory action, bronchoconstriction inhibitory action, and bronchobronchial obstruction suppression of lung tissue. And it is technically characterized in that synergistic effect can be obtained in the inhibitory effect of inflammatory cell infiltration, and the antitussive expectorant, antihistamine, inhibition of bronchial contraction, inhibition of airway hypersensitivity, inhibition of bronchial obstruction of the lung tissue by mixing ivy leaf extract and Coptis chinensis extract. And in order to maximize the synergistic effect of the inhibitory effect on inflammatory cell invasion, the content ratio of the ivy leaf extract and the Coptis Rhizoma extract in the mixed extract is 0.1:1 to 10:1 based on the weight of the solid content. The same), preferably 0.2:1 to 5:1, more preferably 1:1 to 4:1, more preferably 1.5:1 to 3.5:1, most preferably 2.5:1 to 3.5:1 It is good. The'solid content' refers to a state in which the solvent used to prepare the extract is removed, and the same is hereinafter.

In one embodiment, the mixed extract according to the present invention may be a mixture of an ivy leaf extract and a yellow lotus extract. The ivy leaf extract is a crude extract obtained by extracting dried ivy leaves with water and at least one selected from the group consisting of straight chain or branched alcohols having 1 to 4 carbon atoms, or a lower alcohol aqueous solution having 1 to 6 carbon atoms in the crude extract, Preferably, it may be a solvent-soluble extract obtained by adding at least one selected from the group consisting of an aqueous propyl alcohol solution, an aqueous isopropyl alcohol solution, and water saturated butyl alcohol. The ivy used in the manufacture of ivy leaf extract is Hedera spp. For example, Hedera algeriensis , Hedera azorica , Hedera canariensis , Hedera colchica , Hedera helix , Hedera hibernica , Hedera maderensis , Hedera nepalensis , Hedera pastuchowii, Hedera It may be one or more selected from the group consisting of rhombea, etc., but is not limited thereto.

In addition, the Coptis Coptis extract is Coptidis rhizoma ), preferably a crude extract obtained by extracting the rhizome region of Coptis chinensis with water and at least one selected from the group consisting of straight chain or branched alcohols having 1 to 4 carbon atoms, or a lower alcohol aqueous solution having 1 to 6 carbon atoms in the crude extract , Preferably, it may be a solvent-soluble extract obtained by adding at least one selected from the group consisting of an aqueous propyl alcohol solution, an aqueous isopropyl alcohol solution, and water saturated butyl alcohol.

In a preferred embodiment, the solvent used to prepare the crude extract of ivy leaves or Coptis chinensis is water, or 10 to 70% (v/v), preferably 20 to 60% (v/v), more preferably about It may be one or more selected from the group consisting of 25 to 55% (v/v) straight chain or branched alcohol aqueous solution having 1 to 4 carbon atoms, preferably methanol aqueous solution, ethanol aqueous solution, and water saturated butyl alcohol.

In addition, the solvent used in the preparation of the solvent-soluble extract of the ivy leaf or Coptis chinensis is 10 to 70% (v/v), preferably 20 to 60% (v/v), more preferably about 25 to 55% It may be at least one selected from the group consisting of (v/v) an aqueous solution of a lower alcohol having 1 to 6 carbon atoms, preferably an aqueous propyl alcohol solution, an aqueous isopropyl alcohol solution, and saturated butyl alcohol.

In another embodiment, the mixed extract according to the present invention may be an extract of a mixture of ivy leaves and Coptis chinensis. For example, the mixed extract is a crude extract obtained by mixing the ivy leaves and Coptis chinensis, and then extracting the mixture with water and at least one selected from the group consisting of straight chain or branched alcohols having 1 to 4 carbon atoms. It may be a solvent-soluble extract obtained by adding at least one selected from the group consisting of an aqueous solution of a lower alcohol having 1 to 6 carbon atoms, preferably an aqueous propyl alcohol solution and an aqueous isopropyl alcohol solution, and water saturated butyl alcohol.

In a preferred embodiment, the solvent used for preparing the crude extract of the mixture of ivy leaves and Coptis chinensis is water, or 10 to 70% (v/v), preferably 20 to 60% (v/v), more preferably It may be about 25 to 55% (v/v) of an aqueous methanol solution, an aqueous ethanol solution, or water saturated butyl alcohol. In addition, the solvent used in the preparation of the solvent-soluble extract is 10 to 70% (v/v), preferably 20 to 60% (v/v), more preferably about 25 to 55% (v/v) It may be at least one selected from the group consisting of an aqueous solution of lower alcohol having 1 to 6 carbon atoms, preferably an aqueous propyl alcohol solution, an aqueous isopropyl alcohol solution, and saturated butyl alcohol.

In another aspect, it relates to a method for preparing a mixed extract of ivy leaf and Coptis chinensis having inhibitory activity against antitussive expectorant, antihistamine, bronchoconstriction suppression, airway hypersensitivity suppression, bronchial obstruction of lung tissue and inflammatory cell infiltration.

In one embodiment, the manufacturing method comprises at least one selected from the group consisting of water and a straight chain or branched alcohol having 1 to 4 carbon atoms, such as water, or 10 to 70% (v/v), Preferably 20 to 60% (v/v), more preferably about 25 to 55% (v/v) of methanol, ethanol, or water-saturated butyl alcohol to obtain an ivy leaf extract;

Coptis Rhizoma, preferably Coptis Rhizoma, is at least one selected from the group consisting of water, and a straight chain or branched alcohol having 1 to 4 carbon atoms, such as water, or 10 to 70% (v/v), preferably 20 To 60% (v/v), more preferably about 25 to 55% (v/v) of methanol aqueous solution, ethanol aqueous solution, or water-saturated butyl alcohol extraction to obtain a Coptis chinensis extract; And 0.1:1 to 10:1 based on the weight of the solid content of the obtained ivy leaf extract and Coptis Rhizoma extract (Ivy leaf extract weight: Coptis Coptis extract weight), preferably 0.2:1 to 5:1, more preferably 1:1 To 4:1, more preferably 1.5:1 to 3.5:1, and most preferably 2.5:1 to 3.5:1.

At this time, each of the ivy leaf extract preparation step and the Coptis chinensis extract preparation step is 1 selected from the group consisting of a lower alcohol aqueous solution having 1 to 6 carbon atoms in each extract, preferably water saturated butyl alcohol, propyl alcohol, and isopropyl alcohol. It may further include the step of purifying the extract by taking the solvent-soluble extract obtained by adding more than one species.

In the above embodiment, the manufacturing process of the ivy leaf extract according to the present invention will be described in more detail as follows: After cutting the ivy leaf and washing with water to remove the constriction and drying, the weight of the dried ivy leaf About 5 to 20 times by volume, preferably 7 to 15 times by volume of water, and at least one selected from the group consisting of straight chain or branched alcohols having 1 to 4 carbon atoms, such as water, or 10 to 70% (v /v), preferably 20 to 60% (v/v), more preferably about 25 to 55% of aqueous methanol, aqueous ethanol solution, or water-saturated butyl alcohol under reflux extraction. The extraction temperature is preferably 40 to 110°C, preferably 55 to 90°C.

After extraction, the filtrate is collected by filtration, and the residue is again at least one selected from the group consisting of about 5 to 15 times by volume, preferably 8 to 12 times by volume of water, and a straight chain or branched alcohol having 1 to 4 carbon atoms, For example, water, or 10 to 70% (v/v), preferably 20 to 60% (v/v), more preferably about 25 to 55% (v/v) of aqueous methanol, aqueous ethanol or water Extracted under reflux with saturated butyl alcohol. The extraction temperature is not particularly limited, but is preferably 40 to 110°C, preferably 55 to 90°C. After extraction, it is filtered, combined with the filtrate obtained previously, and concentrated under reduced pressure to prepare an ivy leaf extract. As described above, extraction efficiency may be increased by mixing the second extraction and the filtrate obtained after each extraction, but the extract of the present invention is not limited to the number of extractions.

If the amount of solvent used in the preparation of the ivy leaf extract is too small, stirring becomes difficult and the solubility of the extract decreases, resulting in lower extraction efficiency, and if too large, the amount of lower alcohol used in the next purification step increases, making it economical. This is not possible to cause problems in handling, so the amount of the solvent is preferably within the above range.

In a preferred example of the present invention, a method of re-extraction after the first extraction can be adopted. This is because even if the herbal medicine extract is effectively filtered, loss occurs because the water content of the herbal medicine itself is high. Extraction alone is to prevent this because the extraction efficiency is lowered. In addition, as a result of verifying the extraction efficiency of each step, it was found that about 80 to 90% of the total amount of extraction was extracted by the second extraction, and it is judged that multi-step extraction of the third or higher is not economical.

The concentrate obtained as described above is used 2 to 3 times with water of about 10 to 30 times by weight, preferably about 15 to 25 times by weight of the total amount of the concentrate in order to control the content of the remaining lower alcohol so as to be suitable for use as a pharmaceutical ingredient. It can be prepared as a powdery ivy leaf extract by azeotropic concentration and homogeneous suspension by adding an equal amount of water again and lyophilization.

The manufacturing process of the Coptis Rhizoma extract according to the present invention will be described as follows: After slicing the rhizome of Coptidis rhizoma, 3 to 20 times the weight of the raw material, preferably 5 to 15 times the volume of water , And one or more selected from the group consisting of a linear or branched alcohol having 1 to 4 carbon atoms, such as water, or 10 to 70% (v/v), preferably 20 to 60% (v/v), more Preferably, about 25 to 55% (v/v) of an aqueous methanol solution, an aqueous ethanol solution or saturated butyl alcohol is added, followed by reflux extraction for 1 to 10 hours, preferably 2 to 5 hours. The extraction temperature is not particularly limited, but is preferably 40 to 110°C, preferably 55 to 90°C. After extraction, the filtrate is collected by filtration, and at least one selected from the group consisting of 1 to 10 times the weight of the raw material, preferably 4 to 7 times the weight of water, and a straight chain or branched alcohol having 1 to 4 carbon atoms in the residue , For example, water, or 10 to 70% (v/v), preferably 20 to 60% (v/v), more preferably about 25 to 55% (v/v) of an aqueous methanol solution, an aqueous ethanol solution, or Water-saturated butyl alcohol is added, heated, re-extracted for 1 to 10 hours, preferably 2 to 5 hours, filtered, mixed with the previous filtrate, and concentrated under reduced pressure to obtain a Coptis Coptis extract.

As described above, extraction efficiency may be increased by mixing the second extraction and the filtrate obtained after each extraction, but the extract of the present invention is not limited to the number of extractions.

If the amount of the solvent used in the manufacture of the Coptis chinensis extract is too small, stirring becomes difficult and the solubility of the extract decreases, resulting in lower extraction efficiency, and if too large, the amount of lower alcohol used in the next purification step increases, making it economical. This may cause problems in handling, so the amount of the solvent is preferably within the above range.

In a preferred example of the present invention, a method of re-extraction after the first extraction may be adopted. This is because even if the herbal medicine extract is effectively filtered, loss occurs because the extract content of the herbal medicine itself is high. Extraction alone is to prevent this because the extraction efficiency is lowered. In addition, as a result of verifying the extraction efficiency of each step, it was found that about 80 to 90% of the total amount of extraction was extracted by the second extraction, and it is judged that multi-step extraction of the third or higher is not economical.

In order to purify impurities such as unnecessary proteins, polysaccharides, and fatty acids contained in the filtrate, after filtering and concentrating the Coptis Coptisium extract obtained by extraction with aqueous methanol or aqueous ethanol or water saturated butyl alcohol in the first and second steps as described above, Purifying impurities may be further performed by performing layer separation once to 10 times, preferably 2 to 4 times, with the same amount of lower alcohol as the filtrate to obtain a solvent fraction. In this case, a straight chain or branched alcohol having 1 to 6 carbon atoms may be used as the lower alcohol, and at least one selected from the group consisting of butyl alcohol, propyl alcohol and isopropyl alcohol may be used. If the amount of the lower alcohol used is less than that of the filtrate, fine particles are formed by unnecessary components such as fatty acids, which makes it difficult to separate the layers, as well as lower the extraction content of the active ingredient, which is not efficient.

The lower alcohol fraction obtained after layer separation was concentrated under reduced pressure at 50 to 60° C. to remove the solvent remaining in the sample.

The concentrate thus obtained is about 10 to 30 times, preferably 15 to 25 times, more preferably about 20 weight times of the total amount of the concentrate in order to control the content of the remaining lower alcohol so as to be suitable for use as a pharmaceutical raw material. 1 to 5 times, preferably 2 to 3 times, azeotropically concentrated with water of 1 to 5 times, and homogeneously suspended by adding the same amount of water again, and then freeze-dried to prepare a powdery Coptis Coptis extract.

The first step of dividing the obtained Coptis Rhizoma extract into five small fractions by performing silica gel column chromatography with a mixed solvent of methylene chloride and methanol (30: 1 to 7: 1 (v/v)), the first Components contained in the extract of the present invention were identified through a second step of performing high-speed liquid chromatography (HPLC) on the fractions of the step. In other words, as a result of analyzing the components of the Coptis chinensis extracts of the present invention, it was confirmed that berberine, palmatin, coptisine, columbamine, and jatrorizine were included.

Coptis Coptis extract of the present invention comprises berberine, palmatin, coptisine, columbamine, and jatrorizine, and preferably the composition is berberine 15 to 30 parts by weight, palmatin 4 to 10 parts by weight, copticine 4 to It may include 10 parts by weight, 0.3 to 5 parts by weight of columbamine, and 0.3 to 5 parts by weight of jatrorizine.

The process of analyzing the components contained in the Coptis chinensis extract will be described below.

High-speed liquid chromatography was measured using a Waters Alliance 2695 model and a Waters PDA (PDA) 2996. The column was a YMC Hydrosphere C18 (YMC Hydrosphere C18, S-5㎛, 120nm, 4.6×250mm I.D), and the sample temperature was 25°C±1, and the column temperature was maintained at 30°C±1. Sample concentration was prepared at 1mg/ml, 10µl was injected, and flow rate was analyzed at 1.0ml/min. In addition, standard materials such as berberine, palmatin, and coptisine were commercially available from Sigma and used, and columbamine and jatrorizine were separated and purified from Coptis Coptis. The mobile phase is a gradient of 0.2% phosphoric acid solution (solvent A) and methanol (solvent B) for 0 to 60 minutes (A:B=9:1 to 6:4), 60 to 70 minutes (A:B=6). :4~5:5), 70~90 minutes (A:B=5:5~0:10). The calculation of the content of the active ingredient in the extract was performed by indicating the area ratio for each standard substance as a weight percentage.

The manufacturing process of the mixed composition for the two extracts prepared as described above will be described as follows.

The ivy leaf extract and Coptis chinensis extract obtained above are 0.1:1 to 10:1 (Ivy leaf extract weight: Coptis chinensis extract weight), preferably 0.2:1 to 5:1, more preferably 1:1 To 4:1, more preferably 1.5:1 to 3.5:1, and most preferably 2.5:1 to 3.5:1.

In order to homogeneously mix each of the extracts in the mixed extract, about 2 to 3 times by weight of water was added to the mixed extract, and then concentrated under reduced pressure at a temperature of 50 to 60°C, and the same amount of water was added to the concentrate. It is added again, homogeneously suspended, and then freeze-dried to prepare a powdery composition.

In another embodiment, the manufacturing method is a dry ivy leaf and Coptis Rhizoma, preferably 1:4 to 7:1 (Ivy leaf weight: Coptis Coptis weight), preferably 1:1 to 6 :1, more preferably 2:1 to 5:1 by mixing to prepare a mixture of ivy leaves and Coptisaceae; And in the mixture, water, and at least one selected from the group consisting of a straight chain or branched alcohol having 1 to 4 carbon atoms, such as water, or 10 to 70% (v/v), preferably 20 to 60% (v /v), more preferably about 25 to 55% (v/v) of an aqueous methanol solution, an aqueous ethanol solution, or a water-saturated butyl alcohol extract to obtain an extract of a mixture of ivy leaves and Coptis chinensis.

The method comprises, after the step of obtaining an extract of a mixture of ivy leaves and Coptis chinensis, 1 selected from the group consisting of a straight-chain or branched lower alcohol aqueous solution having 1 to 6 carbon atoms, preferably propyl alcohol, isopropyl alcohol, and saturated butyl alcohol. It may further include the step of purifying the extract by taking the solvent-soluble extract obtained by adding more than one species.

The details of the preparation step of the crude extract and the solvent-soluble extract are the same as the preparation of each of the herbal extracts described above.

The extraction method used in the present invention may be any method commonly used, for example, cold sedimentation, hot water extraction, ultrasonic extraction, or reflux cooling extraction method, but is not limited thereto.

In yet another aspect, the present invention provides an antitussive composition containing the mixed extract of the ivy leaf extract and the Coptis chinensis extract as an active ingredient as described above. In addition, the present invention provides an expectorant composition containing as an active ingredient a mixed extract of the ivy leaf extract and Coptis chinensis extract as described above.

In addition, the mixed extract of the ivy leaf extract and Coptis chinensis extract according to the present invention has an increased antitussive action, expectorant action, antihistamine action, bronchoconstriction inhibitory action, airway hypersensitivity inhibitory action, bronchial obstruction inhibition and inflammation of lung tissue. Since it exhibits a cell invasion inhibitory effect, it can be usefully used in the prevention, treatment, or symptom relief of respiratory diseases related thereto. Accordingly, the present invention provides a composition for preventing or treating respiratory diseases, containing a mixed extract of an ivy leaf extract and a Coptis chinensis extract as an active ingredient.

The respiratory disease may be any disease accompanied by cough and phlegm, for example, general cough or phlegm; Emphysema with cough or phlegm; Bronchitis such as chronic bronchitis, acute bronchitis, catarrhal bronchitis, obstructive or inflammatory bronchitis; Asthma such as bronchial asthma, atopic asthma, atopic bronchial IgE mediated asthma, non-topic asthma, allergic asthma, nonallergic asthma, etc.; Chronic or acute bronchoconstriction; Wheezing infant syndrome; Chronic obstructive pulmonary disease; Bronchial adenoma; Isolated pulmonary nodule; tuberculosis; Empyema; Lung abscess; cold; flu; And it may be one or more diseases selected from the group consisting of pulmonary histocytosis, etc.

The content of the mixed extract as an active ingredient in the composition according to the present invention can be appropriately adjusted according to the form and purpose of use, the condition of the patient, the type and severity of symptoms, etc., based on the weight of the solid content 0.001 to 99.9% by weight, preferably 0.1 to It may be 50% by weight, but is not limited thereto.

The composition according to the present invention can be administered to mammals, including humans, by various routes. The mode of administration may be any mode commonly used, and may be administered by, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerebroventricular injection. The compositions of the present invention are formulated in parenteral formulations in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and other oral formulations, transdermal formulations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. It can be used in harmony.

The composition of the present invention may further contain adjuvants such as a pharmaceutically suitable and physiologically acceptable carrier, excipient, and diluent in addition to the mixed extract. Carriers, excipients and diluents that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils. In the case of formulation, diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants can be used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the extract, such as starch, calcium carbonate, and sucrose. ) Or lactose (lactose), gelatin, etc. can be prepared by mixing. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. . Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories, transdermal preparations, and the like. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

In a specific embodiment of applying the composition of the present invention to humans, the herbal extract composition of the present invention may be administered alone, but generally, a pharmaceutical carrier selected in consideration of the mode of administration and standard phamaceutical practice, and It can be administered in combination. For example, the composition containing the mixed extract of the present invention is in the form of a tablet containing starch or lactose, alone or in the form of a capsule containing an excipient, or an elixir or suspension containing a chemical agent to give taste or color. It can be administered orally, intraorally or sublingually in its form. Such liquid formulations can be used as suspending agents (e.g., semisynthetic glycerides such as methylcellulose, witepsol, or a mixture of apricot kernel oil and PEG-6 esters, or PEG-8 and caprylic/capric. Glyceride mixtures such as mixtures of glycerides).

The dosage of the composition containing the mixed extract of the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease degree, and may vary from once a day to several times a day at regular intervals according to the judgment of a doctor or pharmacist. It can also be administered in divided cycles. For example, the daily dosage may be 0.5 to 500 mg/kg, preferably 1 to 300 mg/kg based on the content of the active ingredient. The above dosage is an example of an average case, and the dosage may be high or low depending on individual differences. If the daily dosage of the composition containing the mixed extract of the present invention is less than the above dosage, a significant effect cannot be obtained, and if it exceeds that, it is not only uneconomical, but also outside the range of the normal dosage, there is a concern that undesirable side effects may occur. Since it may occur, it is better to set it within the above range.

In another aspect, the present invention provides a health functional food for preventing or improving respiratory diseases such as Jinhae, Geodam, asthma, etc. containing a mixed extract of ivy leaf and Coptis chinensis. The health functional food may be various foods, beverages, food additives, and the like.

The content of the mixed extract as an active ingredient contained in the health functional food is not particularly limited appropriately depending on the form of the food, the desired use, etc., and may be added in an amount of 0.01 to 15% by weight of the total food weight, and a health beverage composition Silver may be added in an amount of 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 ml.

In addition to containing the extract as an essential component in the indicated ratio, the health beverage composition of the present invention has no particular limitation on the liquid component, and may contain various flavoring agents or natural carbohydrates as an additional component, such as in a conventional beverage. Examples of the above-described natural carbohydrates are monosaccharides, such as disaccharides such as glucose and fructose, such as maltose, sucrose, and the like, and polysaccharides, such as dextrin, cyclodextrin, and the like. These are sugars and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.

In addition to the above, the composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may be contained. In addition, the compositions of the present invention may contain natural fruit juice and flesh for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination. The proportion of these additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

In particular, when the herbal composition of the present invention is administered to the human body, it is considered that there is no fear of side effects compared to other synthetic drugs in view of the general characteristics of natural extracts. It turned out to be missing.

The mixture of the ivy leaf extract and the Coptis chinensis extract according to the present invention is an ivy leaf extract and a Coptis chinensis in expectorant activity, antitussive activity, antihistamine activity, bronchoconstriction inhibitory activity, airway hypersensitivity inhibitory activity, bronchial obstruction inhibition of lung tissue and inflammatory cell infiltration inhibitory activity, etc. It shows an effect superior to that of the extract alone. That is, not only the antihistamine activity, bronchoconstriction inhibitory activity, airway hypersensitivity inhibitory activity, lung tissue, as well as the antihistamine activity, which is far superior to the existing Jinhae expectorant activity by mixing it with the Coptis chinensis extract in the optimal ratio to the ivy leaf extract, which is currently widely used as an antitussive agent. It is believed that it will be able to broaden the indications for a wide range of respiratory diseases such as asthma and bronchitis, as well as antitussive expectorants, due to its activities such as suppressing bronchial obstruction and inhibiting inflammatory cell infiltration.

1 shows the expectorant activity of Preparation Examples 1 to 11 and Reference Examples 1 and 2, and shows the results measured by the phenol red method using a mouse.
2 shows the antitussive activity of Preparation Examples 1 to 11 and Reference Examples 1 and 2, and shows the results of a cough suppression test using guinea pigs.
Figure 3 shows the bronchoconstriction inhibitory activity of Preparation Examples 1 to 11 and Reference Examples 1 and 2, and shows the relaxation rate (%) for the contraction inducing agent using guinea pig-extracted bronchi.
Figure 4 shows the effect of Preparation Example 7 on the inhibitory activity of bronchoseal occlusion and bronchial inflammatory cell infiltration in lung tissues of mice sensitized with OVA and tested.

Hereinafter, the present invention will be described in more detail by the following examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

[ Example 1: Preparation of raw material extract]

Reference example One: Ivy leaves Preparation of extract

The leaves of ivy ( Hedera helix ) were washed with water to remove impurities and dried completely. To 250 g of ivy leaves prepared in this way, 3 ℓ of 30% (v/v) ethanol aqueous solution was added, extracted under reflux cooling for 6 hours, filtered to collect the filtrate, and 2.5 ℓ of 30% (v/v) ethanol aqueous solution was added to the residue. The filtrate obtained by reheating extraction at 80° C. for 3 hours was mixed with the previously collected filtrate and concentrated under reduced pressure. In a state in which most of the solvents were evaporated, 0.2 ℓ of water was added to azeotropic concentration, repeated twice, and homogeneously suspended by adding the same amount of water again, and then freeze-dried to obtain 42.4 g of a powdery ivy leaf extract. .

Reference example 2: goldthread Preparation of extract

Coptidis rhizoma was washed with water to remove impurities and dried completely. 250 g of Coptisium Rhizoma, prepared as described above, was refluxed twice with 2.0 L of 50% (v/v) ethanol aqueous solution at 80° C. for 3 hours each, and then the extract was filtered and concentrated under reduced pressure to obtain 57.5 g of crude extract. 0.3 L Was suspended by adding water, and 0.6 L of water-saturated butyl alcohol was added thereto, the layers were separated twice, and then only the butyl alcohol fraction was collected and concentrated under reduced pressure until dryness. While most of the butyl alcohol and water were evaporated, 0.2 ℓ of water was added to azeotropically concentrated, and then repeated twice. Finally, the same amount of distilled water was added and suspended, and then freeze-dried to obtain 31.8 g of a powdery Coptis Coptis extract.

[ Example 2: Ivy leaves Extract and goldthread Preparation of mixed extract of extract]

Manufacturing example 1: mixed extract (0.2:1)

The ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 were mixed at a weight of 0.2: 1 (weight of ivy leaf extract: weight of yellow lotus extract). In order to achieve homogeneous mixing, 2 to 3 times by weight of water was added to the mixed extract, then concentrated under reduced pressure at a temperature of 50 to 60°C, and the same amount of water was added again to the obtained concentrate to homogeneously suspend. A powdery mixed extract was prepared by lyophilizing.

Manufacturing example 2: mixed extract (0.4:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 is 0.4:1 (Ivy leaf extract weight: Hwangryeon extract weight) based on weight. The extract was prepared.

Manufacturing example 3: mixed extract (1:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 is 1:1 (weight of ivy leaf extract: weight of yellow lotus extract) based on weight. The extract was prepared.

Manufacturing example 4: mixed extract (1.5:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 is 1.5:1 (Ivy leaf extract weight: Hwangryeon extract weight) based on weight. The extract was prepared.

Manufacturing example 5: mixed extract (2:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 was 2:1 (weight of ivy leaf extract: weight of yellow lotus extract) based on weight. The extract was prepared.

Manufacturing example 6: mixed extract (2.5:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 was 2.5:1 (weight of ivy leaf extract: weight of yellow lotus extract) based on weight. The extract was prepared.

Manufacturing example 7: mixed extract (3:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 was 3:1 (Ivy leaf extract weight: Hwangryeon extract weight) based on weight. The extract was prepared.

Manufacturing example 8: mixed extract (3.5:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 was set to 3.5:1 by weight (Ivy leaf extract weight: Hwangryeon extract weight). The extract was prepared.

Manufacturing example 9: mixed extract (4:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 was 4:1 (Ivy leaf extract weight: Hwangryeon extract weight) based on weight. The extract was prepared.

Manufacturing example 10: mixed extract (4.5:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 is 4.5:1 (Ivy leaf extract weight: Hwangryeon extract weight) based on weight. The extract was prepared.

Manufacturing example 11: mixed extract (5:1)

Mixing in the same manner as in Preparation Example 1, except that the mixing ratio of the ivy leaf extract of Reference Example 1 and the Coptis chinensis extract of Reference Example 2 was set to 5:1 by weight (weight of ivy leaf extract: weight of yellow lotus extract). The extract was prepared.

[ Example 3: pharmacological activity test]

Experimental example 1: Expectant activity evaluation test

In order to evaluate the expectorant activity of the mixed extracts prepared according to Preparation Examples 1 to 11, and Reference Example 1 and Reference Example 2, each of which is a single extract, using the method of Engler et al. (Engler H, Szelenyi I, J. Pharmacol. Moth. 11,151-157, 1984., Bao-quin Lin et., Pulmonary Pharmacology & Therapeutics 21, 259-263, 2008.) Evaluation experiments were performed, and the results are shown in FIG. In FIG. 1, the positive control group (Ambroxol) was administered orally at 250 mg/kg and the remaining test drugs at 500 mg/kg. In addition, expectorant activity was evaluated for each dose of Preparation Example 7 having the most excellent activity, and the results are shown in Table 1 below.

[Experiment method]

The positive control drug (ambroxol, ambroxol, Sigma) and the test drug were administered orally to male mice (8 weeks old, Samtaco Bio Korea), and 30 minutes later, phenol red was injected intraperitoneally (administered at a dose of 500 mg/kg). , Phenol red was dissolved in physiological saline and used). After 30 minutes, anesthesia was performed with diethyl ether, the abdominal aorta was cut to bleed, and the entire trachea was excised. The separated organ was washed for 30 minutes by putting it in 1 ml of physiological saline, and 1 N caustic soda (NaOH) was added to the supernatant obtained by centrifugation at 10,000 rpm for 5 minutes at room temperature (0.1 ml of 1N NaOH per 1 ml of the supernatant). I did. The absorbance at 546 nm was measured for these, and the expectorant activity was evaluated as the concentration of the discharged phenol red.

[Experiment result]

Table 1 below shows the sputum excretion capacity according to the doses of the ambroxol used as a positive control drug and the substance obtained in Preparation Example 7.

division Dosage (mg/kg) Sputum discharge capacity (%) Manufacturing Example 7 50 17 100 30 150 38 200 44 500 56 Positive control Ambroxol 250 34

As can be seen in Table 1, the material of Preparation Example 7 according to the present invention was found to have superior sputum discharge capacity than the positive control drug.

In addition, the expectorant effect of the ivy leaf extract of Reference Example 1, the Coptis chinensis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 were measured and shown in FIG. 1. As shown in FIG. 1, it was confirmed that the ivy leaf extract of Reference Example 1, the Coptis Coptis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 all had an expectorant effect. Moreover, in all of the preparation examples, the extracts of Reference Example 1 and Reference Example 2 exhibited an improved expectorant effect than when used alone, and the synergistic effect of the pharmacological activity of the mixed composition according to the present invention can be confirmed from the above results. In particular, in the case of Preparation Examples 3 to 9, it exhibits a superior expectorant effect than the existing expectorant ambroxol used as a positive control, and when the ivy leaf extract and the Coptis Coptis extract are mixed at a mixing ratio of 1:1 to 4:1 by weight. , It can be seen that it shows an improved expectorant effect that is better than that. In addition, Table 1 above is an evaluation of Preparation Example 7 with the highest activity by dose, showing an effect comparable to that of the positive control group at a dose of 100 mg/kg or more, and particularly superior effect to the positive control group at 150 mg/kg or more. Can be seen.

Experimental example 2: antitussive activity evaluation test

In order to measure the antitussive activity for the mixed extracts prepared according to Preparation Examples 1 to 11, and Reference Examples 1 and 2, which are individual extracts, respectively, using a method such as Tanaka (Motomu Tanaka and Kei Maruyama., J. Pharmacol. Sci. 93, 465-470, 2003., Daoui, Cognon, Naline et., Am. J. Respir. Crit. Care. Med. 158, 42-48, 1998.) It is shown in Figure 2. In FIG. 2, 50 mg/kg of positive controls (Theobromine, Sigma) and 200 mg/kg of the remaining test drugs were administered orally. Among them, the antitussive activity was evaluated for each dose for Preparation Example 7 having the most excellent activity, and the results are shown in Table 2 below.

[Experiment method]

The drug was orally administered to male guinea pigs (6 weeks old, Samtaco Bio Korea), and 1 hour later, the guinea pig was placed in a plethysmograph chamber (Buxco, U.S.A.), and a cough inducing agent (citric acid) was sprayed to induce a cough. Theobromine (50 mg/kg), which is used as an antitussive, was used as a positive control, and guinea pigs were exposed to 2 M citric acid for 10 minutes, and the number of coughs generated at this time was measured for 15 minutes.

[Experiment result]

Table 1 below shows the antitussive activity according to the dosage of theobromine used as a positive control drug and the substance obtained in Preparation Example 7.

division Dosage (mg/kg) Antitussive activity (%) Manufacturing Example 7 50 29 100 51 150 69 200 83 Positive control Theobromine 50 56

In addition, the antitussive effect of the ivy leaf extract of Reference Example 1, the Coptis chinensis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 are shown in FIG. 2. As shown in FIG. 2, it was confirmed that the ivy leaf extract of Reference Example 1, the Coptis Coptis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 all had antitussive effects. Moreover, in all of the preparation examples, the extracts of Reference Example 1 and Reference Example 2 exhibited an improved antitussive effect than when used alone, and the synergistic effect of the pharmacological activity of the mixed composition according to the present invention can be confirmed from the above results. In particular, in the case of Preparation Examples 3 to 9, the antitussive effect is better than that of the conventional antitussive agent theobromine used as a positive control, and when the ivy leaf extract and the Coptis Coptis extract are mixed at a mixing ratio of 1:1 to 4:1 by weight, more It can be seen that it shows an excellent enhanced antitussive effect. In addition, Table 2 above is an evaluation of Preparation Example 7, which is the most active, by dose, showing an effect comparable to that of the positive control group at a dose of 100 mg/kg or more, and exhibiting an effect superior to that of the positive control group, especially at 150 mg/kg or more. Can be seen.

Experimental example 3: Antihistamine effect test

In order to measure the antihistamine efficacy in mast cells with respect to the mixed extracts prepared in Preparation Examples 1 to 11, and each single extract, using the method of Honuchi et al. (Masako Honuchi and Yoshiyuki Seyama, J. Health Sci., 52(6), 711~717, 2006., Naoki Inagaki et. Biol. Pharm. Bull. 24(7), 829~834, 2001.) were evaluated, and the results are shown in Table 3 below. In addition, the antihistamine efficacy was evaluated for each dose of Preparation Example 7 having excellent activity, and the results are shown in Table 4 below.

[Experiment method]

The antihistamine effect was measured using peritoneal cells of male rats (7 weeks old, Samtaco Bio Korea) sensitized with egg white albumin (Sigma). As a positive control, ketotifen (Sigma) was used. To rats sensitized with egg white albumin, ketotifen was administered orally at a concentration of 5 mg/kg and each test drug at a concentration of 200 mg/kg for 3 days, and then peritoneal mast cells were isolated. In the isolated peritoneal mast cells (2 x 10 ⁵ cells/ml), ketotifen at concentrations of 0.01 mg/ml, 0.1 mg/ml, 1.0 mg/ml, test drug 0.1 mg/ml, 1.0 mg/ml, It was treated at a concentration of 10 mg/ml. Finally, compound 48/80 (Sigma), a substance that secretes histamine by inducing degranulation of mast cells by a non-immunological method, was treated equally at a concentration of 10 μg/ml. The amount of free histamine was quantified to determine whether the test substances inhibited histamine release from mast cells. Relative to the amount of histamine released from mast cells of rats to which no drug was administered was measured.

[Experiment result]

division Oral dose (mg/kg) Mast cell treatment
(mg/ml) Histamine release (%) Manufacturing Example 1 200 0 48 0.1 42 1.0 39 10.0 32 Manufacturing Example 2 200 0 47 0.1 41 1.0 38 10.0 31 Manufacturing Example 3 200 0 41 0.1 37 1.0 34 10.0 28 Manufacturing Example 4 200 0 39 0.1 37 1.0 33 10.0 26 Manufacturing Example 5 200 0 37 0.1 34 1.0 31 10.0 25 Manufacturing Example 6 200 0 36 0.1 34 1.0 31 10.0 24 Manufacturing Example 7 200 0 34 0.1 32 1.0 29 10.0 20 Manufacturing Example 8 200 0 35 0.1 33 1.0 30 10.0 22 Manufacturing Example 9 200 0 38 0.1 35 1.0 31 10.0 27 Manufacturing Example 10 200 0 42 0.1 39 1.0 36 10.0 31 Manufacturing Example 11 200 0 49 0.1 44 1.0 39 10.0 30 Reference Example 1 200 0 45 0.1 40 1.0 35 10.0 34 Reference Example 2 200 0 39 0.1 33 1.0 32 10.0 25 division Oral dose (mg/kg) Mast cell treatment
(mg/ml) Histamine release (%) positivity
Control Ketotifen
(Ketotifen) 5 0 44 0.01 41 0.1 32 1.0 19

division Oral dose (mg/kg) Mast cell treatment concentration
(mg/ml) Histamine release (%) Manufacturing Example 7 100 0 49 0.1 39 1.0 35 10.0 34 200 0 34 0.1 32 1.0 29 10.0 20 400 0 21 0.1 18 1.0 17 10.0 17 Reference Example 1 200 0 45 0.1 40 1.0 35 10.0 34 Reference Example 2 200 0 39 0.1 33 1.0 32 10.0 25 positivity
Control Ketotifen
(Ketotifen) 5 0 44 0.01 41 0.1 32 1.0 19

As shown in Table 3, it can be seen that the ivy leaf extract of Reference Example 1, the Coptis chinensis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 according to the present invention have an antihistamine effect, and in more detail It can be seen that when the extracts of Reference Example 1 and Reference Example 2, which individually exhibit antihistamine activity, are mixed, there is a synergistic effect of further enhancing the activity. In addition, Table 4 shows the excellent antihistamine activity by evaluating Preparation Example 7 having the best activity by dose.

Experimental example 4: Bronchial contraction inhibition test ( in vitro )

In order to measure the effect of inhibiting airway contraction for the mixed extracts prepared in Preparation Examples 1 to 11, and each single extract, using a method such as Casoni GL ( Clin Exp Allergy ., 33, 999-1004, 2003, Anesth Analg., 89, 191-196, 1999 ,. Br J Pharmacol, 128, 577-584, 1999) was evaluated, the results are shown in Fig. In FIG. 3, the positive control (sodium nitroprusside dihydrate) was 2.6 x 10 ^-5 mg/ml, and the rest of the test drug was 0.50 mg/ml, and the bronchoconstriction inhibitory ability by dose was evaluated for Preparation Example 7 having the most activity. Is shown in Table 5 below.

[Experiment method]

The bronchi were anesthetized by intraperitoneal administration of pentobarbital sodium (75 mg/kg) to Hartely male guinea pigs (350 ~ 400 g, Daehan Biolink). In the Krebs-Henseleit liquid, the extracted bronchus are cut into about 3~5 mm, divided into segments, fixed in an organ bath ^{, perfused with 10 -4} M histamine, contracted the extracted bronchi, and then a test substance was added to change the tension of the extracted bronchi. Was measured. 10 ^-4 M The relaxation rate of the test substance-administered group (%) by subtracting the excipient control relaxation rate (%) calculated under the same conditions from the test substance-administered relaxation rate (%) calculated by assuming 100% of the contractile force induced by histamine ) Was calculated.

[Experiment result]

SNP (sodium nitroprusside dihydrate, Sigma) used as a positive control drug and the bronchoconstriction inhibitory activity according to the concentration of the test substance obtained in Preparation Example 7 are shown in Table 5 below.

division Concentration (mg/ml) Bronchial relaxation rate (%) Manufacturing Example 7 0.25 20 0.50 48 1.00 83 Positive control SNP 2.6 x 10 ^-5 30

In addition, the effect of the ivy leaf extract of Reference Example 1, the Coptis Coptis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 are shown in FIG. 3. As shown in FIG. 3, it was confirmed that the ivy leaf extract of Reference Example 1, the Coptis chinensis extract of Reference Example 2, and the mixed extract of Preparation Examples 1 to 11 all had bronchoconstriction inhibitory effects. Moreover, in all of the preparation examples, the extracts of Reference Example 1 and Reference Example 2 exhibited an enhanced bronchoconstriction inhibitory effect compared to the case where the extracts of Reference Example 1 and Reference Example 2 were used alone. It can be seen that it exhibits a contraction inhibitory activity.

Experimental example 5: Using the mouse asthma model Anti-asthma in vivo Effect test

In order to confirm the anti-asthma effect using the mouse asthma model of Preparation Example 7 according to the results of Experimental Examples 1 to 4, Tang M.L.K. (Pulmonary Pharmacology & Therapeutics, 14, 203-210, 2001, Immunology and Cell Biology 79, 141-144, 2001, Journal of Experimental Medicine 189(10), 1621-1629, 1999) was tested using the method such as, The evaluation items were airway hyper-responsiveness (AHR) investigation, plasma IgE level investigation, bronchoalveolar lavage fluid (BALF) cell count and immune cell distribution investigation, lung Tissue observation and RT-PCR (IL-1β, IL-4, IL-13r2a) were confirmed.

[Experiment method]

To Balb/c mice (18 ~ 21 g, Orient Bio Co., Ltd.), ovalbumin (OVA, Sigma) intraperitoneally administered 500 ul per animal (20 ug as OVA) intraperitoneally on Day 0 and Day 7 The solution prepared for OVA inhalation was sensitized using a nubulizer (NE-U17, OMRON Co. Ltd, Japan), and then a 5% OVA solution prepared every 30 minutes from Day 14 to Day 20 was inhaled and administered. As the positive control drug, montelukast sodium was 30 mg/kg and all test substances were 200 mg/kg.The positive control drug and test substance were OVA inhalation for 7 days from Day 14 to Day 20 after sensitization. After oral administration 1 hour before the following, tests were performed according to the following evaluation items.

1) Investigation of Airway hyper-responsiveness (AHR) to Methacholine

24 hours after the last inhalation of OVA (Day 21), the mouse was placed in a whole body plethysmograph (BUXCO, USA), and 0.4 ml of methacholine 0, 10, and 20 mg/ml solution were added to an aerosol and inhaled for 3 minutes each. Penh was measured for 4 minutes from the time of administration, and the average value was taken as the Penh (enhanced pause) value at the methacholine dose.

2) Investigation of IgE levels in plasma (Day 21)

After the measurement of 1) is completed, about 0.05 ml of blood is obtained by orbital blood collection, centrifuged, and the obtained plasma is subdivided into two, diluted 1:10, and the IgE enzyme linked immunosorbent assay (ELISA; IgE ELISA kit for mouse, ME- 151, SHIBAYAGI Co., Ltd., JAPAN) to investigate the level of immunoglobulin E (IgE) in plasma.

3) Investigation of cell number and immune cell distribution in bronchoalveolar lavage fluid (BALF) (Day 22)

After blood collection in 2) is completed, pentotal sodium (50mg/kg) is injected intraperitoneally to anesthetize the left lung and then inject it into the bronchi and lungs using 0.4 ml of PBS solution with forceps, and take out the washing solution. This was repeated three times and centrifuged at 1,500 g to discard the supernatant, and 0.2 ml of PBS was added to the precipitate and suspended again. The total number of leukocytes, neutrophils, eosinophils, neutrophils and lymphocytes were measured using an automatic hematology analyzer (Advia 120 coulter counter, BAYER, Germany).

4) Observation of lung tissue

The left lung fixed with forceps was removed and fixed in 10% formalin solution for one day, and then the tissue infiltrated with paraffin using a tissue processor was cut to a thickness of 3-4 um using a microtome to make a tissue section. The prepared slide was stained with Eosin, covered with a cover slide with balsam, and observed under a microscope to observe the degree of occlusion of bronchioles and infiltration of inflammatory cells.

5) RT-PCR

The right lung tissue was quickly removed and stored at -80°C until the test was conducted. RNA was isolated from tissues using RNA-Bee (Tel-Test Inc.USA), and the separated RNA was quantified at 260nm using a spectrophotometer, and then 4ug of RNA, Oligo dT 2 ul (Promega), and DEPC water were added. Add 10 ul and react at 65°C for 5 minutes, add 5x reaction buffer 5 ul + RTase 2 ul + dNTP 5 ul + RNase inhibitor 1 ul + DEPC water 2 ul, and add a total of 25 ul at 42 ℃ for 1 hour. And reacted at 100° C. for 5 minutes to produce cDNA. All of the reagents used were purchased from Promega and used. This was PCR with the prepared primers (IL-1β, IL-4, IL-13r2a). The primers used were as follows:

IL-1β forward: 5'-TCATGGGATGATGATGATAACCTGCT-3' (SEQ ID NO: 1),

IL-1β reverse: 5'-CCCATACTTTAGGAAGACACGGATT-3' (SEQ ID NO: 2);

IL-4 forward: 5'-TCATCGGCATTTTGAACGAG-3' (SEQ ID NO: 3),

IL-4 reverse: 5'-GAATCCAGGCATCGAAAAGC-3' (SEQ ID NO: 4);

IL-13r2a forward: 5'-GGTTATGCCAAATGCACTTGAG-3' (SEQ ID NO: 5),

IL-13r2a reverse: 5'-ATGGCTTTTTGTGCATATCAGAT-3' (SEQ ID NO: 6).

The PCR conditions are 94℃ for 30 seconds, 56℃ for 30 seconds, and 72℃ for 1 minute for 32 cycles, and the PCR reaction product is electrophoresed on a 2% agarose gel, stained with EtBr, and then irradiated with UV to compare the density of actin. The value was analyzed by dividing it by the density value.

[Experiment result]

1) Investigation of airway hyper-responsiveness (AHR) to methacholine

The hypersensitivity reaction to methacholine according to the concentration of montelukast (DR. REDDY'S) used as a positive control drug and the test substances obtained in Reference Examples 1, 2, and 7 are shown in Table 6 below.

division Penh value according to methacholine dosage 0 mg/ml 10 mg/ml 20 mg/ml Normal 1.2 ± 0.1 1.7 ± 0.2 6.0 ± 2.4 Yodo-gun 1.5 ± 0.2 14.3 ± 3.0 29.7 ± 12.2 Preparation Example 7 (200mg/kg) 1.5 ± 0.2 7.5 ± 2.1 15 ± 4.9 Reference Example 1 (200mg/kg) 1.4 ± 0.2 8.2 ± 2.5 18.1 ± 5.9 Reference Example 2 (200mg/kg) 1.5 ± 0.2 11.1 ± 3.8 25.1 ± 4.7 Positive control Montelukast (30mg/kg) 1.5 ± 0.2 8.4 ± 2.4 19.8 ± 5.4

As shown in Table 6, the material of Preparation Example 7 according to the present invention was found to have superior airway hypersensitivity inhibitory activity than the positive control drug. In addition, enhanced airway hypersensitivity inhibitory activity can be confirmed than when the extracts of Reference Example 1 and Reference Example 2 were used alone.

2) Investigation of IgE levels in plasma

Plasma IgE values according to the concentrations of montelukast used as a positive control drug and the test substances obtained in Reference Examples 1, 2, and 7 are shown in Table 7 below.

division IgE level (ng/ml) Normal 0.6 ± 0.2 Yodo-gun 19.7 ± 6.1 Preparation Example 7 (200mg/kg) 9.6 ± 3.2 Reference Example 1 (200mg/kg) 11.0 ± 4.8 Reference Example 2 (200mg/kg) 14.4 ± 4.6 Positive control Montelukast (30mg/kg) 13.7 ± 5.7

As shown in Table 7, it can be seen that the group to which the substance of Preparation Example 7 according to the present invention was administered has a lower level of IgE, an inflammatory mediator, than the group to which the positive control drug was administered. In addition, lower IgE levels can be confirmed than when the extracts of Reference Example 1 and Reference Example 2 were used alone.

3) Cell count in bronchoalveolar lavage fluid (BALF)

The number of neutrophils and eosinophils in the bronchial and lung lavage fluid according to the concentration of montelukast used as a positive control and the test substances obtained in Reference Examples 1, 2, and 7 are shown in Table 8 below.

division WBC (x10 ³ cells) NEU EOS Normal 16.3 ± 3.4 4.7 ± 2.7 Yodo-gun 24.0 ± 6.1 414.7 ± 168.2 Preparation Example 7 (200mg/kg) 16.3 ± 11.3 296.7 ± 300.1 Reference Example 1 (200mg/kg) 18.7 ± 7.1 369.3 ± 232.2 Reference Example 2 (200mg/kg) 17.3 ± 6.4 302.3 ± 267.9 Positive control Montelukast (30mg/kg) 22.3 ± 7.2 466.0 ± 207.0

NEU; neutrophil (neutrophil), EOS; eosinophil (eosinophil)

As shown in Table 8, it can be seen that the group administered with the substance of Preparation Example 7 according to the present invention has a lower level of white blood cells (neutrophils, eosinophils) related to inflammation than the group administered with the positive control drug. In addition, it shows a lower number of neutrophils and eosinophils than when the extracts of Reference Example 1 and Reference Example 2 were used alone.

4) Observation of lung tissue

Table 9 shows the degree of occlusion of bronchioles and infiltration of inflammatory cells according to the concentration of montelukast used as a positive control and the test substances obtained in Reference Examples 1, 2, and 7 And, a picture of the lung tissue stained using the H & E staining method is shown in FIG. 4. The values shown in Table 9 below are expressed as 1=No, 2=slight, 3=thin, 4=moderate, 5=thick depending on the degree of occlusion and inflammatory cell infiltration.

division Microscopic observation Degree of bronchial obstruction Degree of inflammatory cell infiltration Normal 0 ± 0 0 ± 0 Yodo-gun 3.3 ± 0.5 3.8 ± 0.4 Preparation Example 7 (200mg/kg) 1.8 ± 0.4 1.9 ± 0.4 Reference Example 1 (200mg/kg) 2.0 ± 0.0 2.3 ± 0.5 Reference Example 2 (200mg/kg) 2.0 ± 0.0 2.8 ± 0.4 Positive control Montelukast (30mg/kg) 3.5 ± 0.5 3.7 ± 0.5

As shown in Table 9, the material of Preparation Example 7 according to the present invention was found to have superior bronchoblockade inhibition and inflammatory cell invasion inhibitory activity than the positive control drug. In addition, it can be confirmed that the extracts of Reference Example 1 and Reference Example 2 are superior to the case where they are used alone, inhibiting bronchial obstruction and inhibiting inflammatory cell infiltration.

5) RT-PCR

The expression rates of the inflammation-mediated cytokines (IL-1β, IL-4, IL-13r2a) according to the concentration of montelukast used as a positive control drug and the test substance obtained in Preparation Example 7 are shown in Table 10 below. The values in Table 10 below are values obtained by dividing the density of each cytokine according to UV irradiation by the density of actin.

division Level of cytokine expression IL-1β IL-4 IL-13r2a Normal 0.58 ± 0.27 0.58 ± 0.21 0.56 ± 0.49 Yodo-gun 0.94 ± 0.39 1.96 ± 0.98 1.20 ± 0.67 Preparation Example 7 (200mg/kg) 0.16 ± 0.74 0.83 ± 0.67 0.29 ± 0.96 Reference Example 1 (200mg/kg) 1.21 ± 0.62 0.14 ± 0.70 0.60 ± 0.70 Reference Example 2 (200mg/kg) 0.52 ± 0.38 0.59 ± 0.52 0.57 ± 0.39 Positive control Montelukast (30mg/kg) 0.51 ± 0.26 1.47 ± 0.48 0.37 ± 0.31

As shown in Table 10, the group administered with the substance of Preparation Example 7 according to the present invention had the expression of inflammation-mediated cytokines (IL-1β, IL-4, IL-13r2a) compared to the group administered with the positive control drug. It has been shown to be suppressed. In addition, it can be seen that the expression of inflammation-mediated cytokines (IL-1β, IL-4, IL-13r2a) is suppressed than when the extracts of Reference Example 1 and Reference Example 2 were used alone.

[ Example 4: Preparation of tablets]

200 mg of the mixed extract of Preparation Example 7, 10 mg of light anhydrous silicic acid, 2 mg of magnesium stearate, 50 mg of microcrystalline cellulose, 25 mg of sodium starch glycolate, 113 mg of corn starch, and an appropriate amount of ethanol anhydrous were mixed by a conventional method. It was compressed into tablets.

[ Example 5: Preparation of healthy food]

Mixed extract (Preparation Example 7) 1000mg

Vitamin A acetate　　　　　　　　　　　　　　　　 70 ㎍

Vitamin E　　　　　　　　　　　　　　　　　　　　　 1.0 mg

Vitamin B1 　　　　　　　　　　　　　　　　　　　 0.13 mg

Vitamin B2　　　　　　　　　　　　　　　　　　　　 0.15 mg

Vitamin B6　　 　　　　　　　　　　　　　　　　　　 0.5 mg

Vitamin B12　 　　　　　　　　　　　　　　　　　 0.2 ㎍

Vitamin C　　 　　　　　　　　　　　　　　　　　　　 10 mg

Biotin　　 　　　　　　　　　　　　　　　　　　　　 10 ㎍

Nicotinamide　　　 　　　　　　　　　　　 1.7 mg

Folic acid　　 　　 50 ㎍

Calcium pantothenate　 　　　　　　　　　　　　 0.5 mg

Mineral mixture　　 　　　　　　　　　　　　　　 Proper amount

Ferrous sulfate　 　　　　　　　　　　　　　　　　 1.75 mg

Zinc oxide　　　　　　　　　　　　　　　　　 0.82 mg

Magnesium carbonate　 　　　　　　　　　　 25.3 mg

Potassium Phosphate 　　 　　　　　　　　　　　　　　　　 15 mg

Dicalcium Phosphate　 　　　　　　　　　　　　　　　　 55 mg

Potassium citrate　　 　　　　　　　　　　　　　　　　　 90 mg

Calcium carbonate　　　　　　　　　　　　　　　　　　　　　 100 mg

Magnesium chloride　　 　　　　　　　　　　　　　　 24.8 mg

The composition ratio of the vitamin and mineral mixture is relatively suitable for health food, but it may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. , Granules can be prepared, and used for preparing a health food composition according to a conventional method.

[ Example 6: Preparation of healthy beverages]

Mixed extract (Preparation Example 7) 1000 mg

Citric acid　　　　　　　　　　　　　　　　　　　　　 1000 mg

Oligosaccharide　　　　　　　　　　　　　　　　　　　　　 100 g

Plum concentrate 　　　 2 g

Taurine　　　　 　　　　　　　　　　　　　　　　　　 1 g

Purified water 　 total 900 ㎖

After mixing the above ingredients according to a normal health drink manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 liter container, sealed and sterilized, and then stored in a refrigerator It is used in the manufacture of health drink composition.

The composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.

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Claims (6)

It contains a mixed extract of ivy leaf and yellow lotus as an active ingredient,
The mixed extract of the ivy leaf and the yellow lotus is a mixture of the ivy leaf and the sulfur extract, or an extract of the mixture of the ivy leaf and the yellow lotus,
The extract of the ivy leaf, the extract of the yellow lotus or the mixture of the ivy leaf and the yellow lotus is added to at least one solvent selected from the group consisting of a linear or branched alcohol solution of 1 to 4 carbon atoms to the mixture of ivy leaf, yellow lotus or ivy leaf The crude extract obtained, or a solvent-soluble extract obtained by adding a linear or branched alcohol aqueous solution of 1 to 6 carbon atoms to the crude extract,
A pharmaceutical composition for the prevention, treatment or alleviation of symptoms of at least one respiratory disease selected from the group consisting of wheezing infant syndrome, cold, and flu.  The pharmaceutical composition according to claim 1, wherein the content ratio of the ivy leaf extract and the rhubarb extract in the mixed extract is 0.1: 1 to 10: 1 (the ivy leaf weight: strawberry extract weight) based on the solids weight. The pharmaceutical composition according to claim 1, wherein the content ratio of the ivy leaf extract and the rhubarb extract in the mixed extract is 0.2: 1 to 5: 1 (weight of the ivy leaf extract: strawberry extract weight) based on the weight of solids. The pharmaceutical composition of claim 1, wherein the composition is formulated as a powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, transdermal, suppository, or sterile injectable solution. The pharmaceutical composition of claim 1, wherein the daily dosage of the composition is 0.7 to 500 mg / kg based on the active ingredient content. Contains a mixed extract of ivy leaf and rhubarb,
The mixed extract of the ivy leaf and the yellow lotus is a mixture of the ivy leaf and the sulfur extract, or an extract of the mixture of the ivy leaf and the yellow lotus,
The extract of the ivy leaf, the extract of the yellow lotus or the mixture of the ivy leaf and the yellow lotus is added to at least one solvent selected from the group consisting of a linear or branched alcohol solution of 1 to 4 carbon atoms to the mixture of ivy leaf, yellow lotus or ivy leaf The crude extract obtained, or a solvent-soluble extract obtained by adding a linear or branched alcohol aqueous solution of 1 to 6 carbon atoms to the crude extract,
A dietary supplement for the prevention or amelioration of one or more respiratory diseases selected from the group consisting of wheezing infant syndrome, cold, and flu.

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