WO2016068607A1 - Antitussive and expectorant composition containing, as active ingredient, mixture extract of coptidis rhizome and pelargonium sidoides - Google Patents

Abstract

The present invention relates to a use of a mixture extract of Coptidis rhizome and Pelargonium Sidoides as an antitussive or expectorant agent, and a use of the same for preventing or treating respiratory diseases or respiratory infection.

Description

A composition for antitussive expectoration, comprising a mixture of hulls and pelargonium sidoides as an active ingredient

The present invention relates to the use of Coptidis rhizome and Pelargonium Sidoides mixed extracts as antitussive or expectorant and for the prevention or treatment of respiratory diseases or airway infections.

Coughing is one of our body's most important defensive actions, preventing harmful substances such as bacteria and other substances from entering our airways. In addition, the inhaled foreign matter or secretions of the airways to be discharged out of the airways to act to keep the airways clean at all times. Cough is the most common symptom of respiratory illness, and if excessive, reduces and worsens the patient's quality of life. Therefore, cough suppression treatment is needed to reduce cough. Sputum, on the other hand, is a mucous substance secreted from the respiratory tract and is an element of the defense mechanism that protects the airway epithelium and removes external aspirants. Normally, sputum is not conscious, but it is continuously produced and processed through the larynx and swallowed by the gastrointestinal tract.However, if secretion and discharge increase due to lung disease, sputum is retained in the airways, which can cause symptoms such as coughing and shortness of breath. . Therefore, there has been a need for the development of therapeutic agents that can effectively ameliorate such cough or sputum.

Coptidis rhizome , on the other hand, is an evergreen perennial plant of the dicotyledonous plant, the herbaceous perennial herbaceous plant, also known as the honeysuckle . It is known to be distributed in Korea, Japan, and China, and its name comes from the yellow color of the stem and the stem of the ground. These yellow lotuses have long been known to have efficacy in tonic, arteriosclerosis, disease weakness or stroke. Also, Pelargonium Sidoides is a plant native to the highlands of the inland and coastal areas of South Africa, and is known to be effective for acute bronchitis, sore throat and colds (Planta Medica 2008 74: 6 (661-666). )), Currently sold as umkaron syrup. However, there is no known example of using the Pelargonium sidoides and the yellow lotus together for Jinhae expectorant.

Under these circumstances, the present inventors have made intensive efforts to develop a drug having an antitussive expectorant effect, and therefore, when using a mixed extract of rhubarb and pelargonium sidoides, the present inventors compared to the antitussive expectorant as compared to the rhubarb extract and the pelargonium sidoides extract alone. It was confirmed that it shows a synergistic effect, and through this it was confirmed that the mixed herbal extracts of the barberry and pelargonium sidoides can be usefully used as a prophylactic or therapeutic agent for antitussives or respiratory diseases, and completed the present invention.

One object of the present invention is to provide a pharmaceutical composition for antitussive or expectorant, comprising a Coptidis rhizome and Pelargonium Sidoides mixed extract as an active ingredient.

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of respiratory diseases, comprising a mixture of rhubarb and pelargonium sidoides as an active ingredient.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating respiratory tract infections, which comprises a mixture of rhubarb and pelargonium sidoides as an active ingredient.

Still another object of the present invention is to provide a tablet for oral administration comprising the composition.

Another object of the present invention to provide a liquid formulation for oral administration comprising the composition.

Still another object of the present invention comprises a mixture of rhubarb and pelargonium sidoides as an active ingredient, for Jinhae or expectorant; Or to provide a health functional food for preventing or improving respiratory diseases or airway infections.

Still another object of the present invention is to provide a method for treating a respiratory disease or airway infection, comprising administering a mixture of barberry and pelargonium sidoides to an individual suspected of respiratory disease or airway infection.

It is yet another object of the present invention to provide a method for relieving coughing or sputum, comprising administering a mixture of barberry and pelargonium sidoides to a subject.

As one aspect for achieving the above object, Coptidis rhizome and Pelargonium sidoides Sidoides ) Provides a pharmaceutical composition for antitussive or expectorant, comprising a mixed extract as an active ingredient.

As another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of respiratory diseases, comprising as an active ingredient extracts of sulfur and pelargonium sidoides.

As another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of respiratory tract infection, comprising a mixture of sulfur and pelargonium sidoides as an active ingredient.

As another aspect, the present invention provides a tablet for oral administration comprising the composition.

As another aspect, the present invention provides a liquid formulation for oral administration comprising the composition.

As another aspect, the present invention comprises a rye and pelargonium sidoides mixed extract as an active ingredient, for Jinhae or expectorant; Or it provides a health functional food for preventing or improving respiratory diseases or airway infections.

As another aspect, the present invention provides a method of treating a respiratory disease or airway infection, comprising administering a mixture of the barberry and pelargonium sidoides to a suspected respiratory disease or airway infection.

In another aspect, the present invention provides a method for alleviating cough or sputum, comprising administering a mixture of sulfur and pelargonium sidoides to a subject.

The composition comprising the mixed herbal extract of the barberry and pelargonium sidoides of the present invention in a predetermined ratio is superior to the antitussive expectorant in comparison with the same dose of the barberry and pelargonium sidoides extract, which have fewer side effects as a natural product. Since it shows a synergistic effect, it can be usefully used as an antitussive expectorant or a therapeutic agent for respiratory diseases.

1 is a diagram showing the sputum excretion of the dosage of the extract of the barberry or Pelargonium sidoides alone and 1: 1 mixture thereof. A represents the rhubarb extract, B represents the Pelargonium sidoides extract, and A + B represents the 1: 1 mixture thereof. Staging numbers are the total dose (mg / kg) calculated based on the dry matter of the 1: 1 mixed extract.

Figure 2 is a diagram showing the sputum discharge capacity according to the mixing ratio of the rhubarb and pelargonium sidoides extract when the total dose is fixed to 200 mg / kg. A represents the rhubarb extract, B represents the Pelargonium sidoides extract, and the number is the dosage of each extract calculated based on the dry matter.

As one embodiment for achieving the above object, the present invention is Coptidis rhizome and Pelargonium sidoides Sidoides ) Provides a pharmaceutical composition for antitussive or expectorant, comprising a mixed extract as an active ingredient.

As used herein, the term " Coptidis rhizome " refers to Ranuculaceae. A plant belonging to a family). The nasturtium is specifically known as Coffis chinensis Franch, Coptis del Toides ( Coptis). dltoides ), Coptis japonica or dried rhizome of other species of the same species, including berberine. In addition, the yellow lotus used in the composition of the present invention may be purchased commercially, or may be used collected or cultivated in nature.

In the present invention, the term "Pelagonium sidoides ( Pelargonium) sidoides ) "is known as a plant native to highlands inland and coastal of South Africa, and is also named kaloba, umcka or zucol. For the purposes of the present invention, the pelargonium sidoides Is a plant having an antitussive or expectorant effect, and its extract may be used in a composition for antitussive or expectorant The pelargonium sidoides may be purchased commercially, collected from nature, or may be used. There is no limitation to this, and flowers, seeds, stems, roots or outposts may be used as raw materials.

In one aspect of the present invention, when the mixture of the rhubarb extract and pelargonium sidoides extract in a specific ratio, it was confirmed that each of the extracts have a synergistic effect in Jinhae expectoration compared to the case of using the same amount alone as the mixture Thus, it was confirmed that the combination of the barberry and pelargonium sidoides is an herbal combination with an excellent antitussive expectorant effect. Therefore, the composition of the present invention comprising a mixed herbal extract of rhubarb and pelargonium sidoides can be usefully used as an antitussive or expectorant.

As used herein, the term "mixed extract" refers to a form of an extract obtained by mixing natural products and then extracting with one or more solvents, or a mixture of extracts obtained by extracting each natural product with a solvent. For example, in the present invention, the mixed extract may be a mixture including rhubarb and pelargonium sidoides as an extraction solvent, or a mixture of the rhubarb extract and pelargonium sidoides extract may be mixed with each other. In addition, the mixed extract includes all of the crude extract or a specific solvent soluble extract (fraction) form, may be an extract extracted using an extraction method such as hot water extraction, cold needle extraction, reflux cooling extraction or ultrasonic extraction, and further The resultant was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain an extract available in water, alcohol or a mixed solvent thereof, but the present invention is not limited thereto, and the extract, the dilution or concentrate of the extract, and the extract are dried. It includes all the dried products obtained, or these modifiers or purified products.

The solvent used in the preparation of the mixed extract may be water, various alcohols, or a mixture thereof. The alcohol may be a linear or branched alcohol having 1 (C ₁ ) to 4 (C ₄ ) carbon atoms, preferably methanol, ethanol or butanol, or a mixed solvent thereof, but is not limited thereto. The extraction method may be a solvent extraction, hot water extraction, cold needle extraction, reflux cooling extraction, ultrasonic extraction, or steam extraction, but is not limited thereto. In addition, the extracts include, without limitation, extracts, fractions of the extracts, all of the crude or purified thereof.

On the other hand, the extract, fractions of the extract, the crude or purified product thereof may be used as it is in the form of a liquid, or concentrated and / or dried it. The concentration and / or drying methods include, but are not limited to, methods such as freeze drying, vacuum drying, hot air drying, spray drying, reduced pressure drying, foam drying, high frequency drying, infrared drying, and the like.

As used herein, the term "naphtha extract" refers to an extract obtained by extracting the yellow lotus. The yellow lotus may specifically be a root portion of the yellow lotus. The sulfur extract is obtained by extracting pulverulent pulverized with water, alcohols of various carbon atoms, such as linear or branched alcohols having 1 (C ₁ ) to 4 (C ₄ ) carbon atoms, or a mixed solvent thereof as an extraction solvent. It may be, but is not limited thereto. The alcohol is preferably ethanol, methanol or butanol, but is not limited thereto. For example, the yellow lotus extract may be a water extract, specifically, a hydrothermal extract, which may be used in the form of a dried product, but is not limited thereto.

In the present invention, the term "pelargonium sidoides extract" means an extract obtained by extracting the pelargonium sidoides. The pelargonium sidoides extract extracts pelargonium sidoides pulverized water, alcohols having various carbon atoms, such as linear or branched alcohols having 1 (C ₁ ) to 4 (C ₄ ) carbon atoms, or a mixed solvent thereof. It may be obtained by extraction using a solvent. It may be in the form of a mixture of other solvents such as glycerol, such as pelargonium sidoides 11% ethanol extract (1 → 8 ~ 10) and glycerol (8: 2) mixture (w: w). For example, the Pelargonium sidoides extract may be a Pelargonium sidoides 11% ethanol extract (1 → 8 ~ 10) glycerol (8: 2) mixture (w: w) or the ethanol extract of Pelargonium sidoides have. In addition, the extract may be dried to be used in the form of a dried product, but is not limited thereto.

In one example, the extract may be included in 0.001 to 50% by weight, more preferably 0.01 to 10% by weight relative to the total weight of the pharmaceutical composition.

As used herein, "Jinhae" means to stop coughing. In addition, the term "sputum" in the present invention refers to the release of sputum, which includes alleviating, ameliorating or treating the retention of mucus in the airways. Specifically, the expectorant acts to remove the sputum in the airway, such as the peripheral airway, into the central airway to remove it by coughing, and / or to increase mucus secretion to induce coughing, and / or to dissolve mucus. The concept includes both reducing the viscosity to facilitate sputum discharge. For example, the expectorant activity was confirmed by administering the composition according to the present invention to mice and measuring sputum excretion using a phenol red solution, and according to the specific dosage and / or the mixing ratio of the total extract dose and / or dosage of the mixed extract, It was confirmed that the synergistic expectorant activity was significantly increased compared to using the same extract alone in the same ratio (Fig. 1 and 2).

As another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of respiratory diseases, comprising as an active ingredient extracts of sulfur and pelargonium sidoides.

As another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of respiratory tract infection, comprising a mixture of sulfur and pelargonium sidoides as an active ingredient.

The sulfur, pelargonium sidoides, mixed extract and the pharmaceutical composition are as described above.

As used herein, the term "respiratory disease" refers to a disease accompanied by symptoms such as coughing, bronchial spasms, dyspnea, or sputum, for example, emphysema accompanied by bronchitis, asthma, whooping cough, pneumonia, cough, or sputum. Colds, flu, and the like, but are not limited thereto. In particular, berberine, the main component of the sulfur extract, has an effect such as bronchial dilation, which can prevent or treat respiratory diseases. In addition, since the composition of the present invention has an antitussive or expectorant effect, it can alleviate symptoms such as cough and sputum, and thus can be usefully used for the prevention or treatment of respiratory diseases involving these symptoms.

In the present invention, the term "airway infection" refers to a phenomenon in which a mucosa of the nose or pharynx of an individual who inhales pathogens scattered in the air mixed with saliva or sputum when another person coughs, sneezes, or talks is infected. Non-limiting examples can include upper or lower respiratory tract infections such as acute or chronic rhinitis, sinusitis, sore throat, otitis media and bronchitis. Since the pharmaceutical composition of the present invention includes the Pelargonium sidoides extract, the composition of the present invention containing it as an active ingredient can be used for the prevention or treatment of airway infection.

As used herein, the term "prevention" refers to any action that inhibits or delays the development of a respiratory disease or airway infection by administration of the pharmaceutical composition, and "treatment" refers to a respiratory disease or airway infection by administration of the composition. This means any action that improves or beneficially alters the symptoms of a suspicious or diseased individual. For example, prevention may be any action that inhibits or delays the storage of sputum in the airways by inhibiting cough, which is a representative symptom of respiratory disease, or by increasing sputum discharge, by administering the pharmaceutical composition, and the treatment may be Administration of an antimicrobial composition may mean any action that improves or benefits from cough or sputum retention.

According to an embodiment of the present invention, the mixture of the rhubarb extract and the Pelargonium sidoides extract, showed a synergistic effect on the sputum discharge capacity than when using each of the rhubarb extract or Pelargonium sidoides extract alone. For example, compared to the case of using the Lactobacillus extract or Pelargonium sidoides extract alone, the amount of the total mixture is determined by the weight ratio of the extracts administered alone and in the 1: 1 weight ratio of the Lactobacillus extract and Pelargonium sidoides extract. When administered in the same way, it showed a significantly increased sputum discharge capacity, it was confirmed that the combination of the extract showed a synergistic synergistic effect on expectorant activity. For example, the content ratio of the rhubarb extract and pelargonium sidoides in the mixed extract is not particularly limited thereto, but is not particularly limited to 1: 0.3 to 5 (based on the dry weight, the rhubarb extract weight: the pelargonium sidoides extract weight), or 1 : 0.5 to 3 may be. Preferably 1: 1, but is not limited thereto.

For example, according to a specific embodiment of the present invention, when the mixture of nasturtium extract and pelargonium sidoides extract was administered in a weight ratio of 1: 2, it showed the best expectorant activity, while keeping the total dose constant pelagoni When the content of the extract of Siumides extract was reduced gradually, the sputum discharge capacity gradually decreased, showing little synergistic effect when reduced to the level of 1: 0.25 (FIG. 2).

Preferably, in the pharmaceutical composition of the present invention, the sulfur extract may include berberine or a pharmaceutically acceptable salt thereof. For example, the pharmaceutically acceptable salt of berberine may be berberine chloride, but is not limited thereto. For example, the sulfur extract may contain 1 to 30% by weight of berberine or a pharmaceutically acceptable salt thereof based on the dry matter. Preferably it may include 1.26 to 30% by weight, or 2 to 25% by weight, but is not limited thereto.

Meanwhile, in the pharmaceutical composition of the present invention, the pelargonium sidoides extract may include a phenolic compound including catechin or a pharmaceutically acceptable salt thereof. For example, the phenolic compound or a pharmaceutically acceptable salt thereof may include 25 to 45% by weight based on the dry matter of the Pelargonium sidoides extract. Preferably, the phenolic compound including catechin or a pharmaceutically acceptable salt thereof may include 30 to 40% by weight, but is not limited thereto.

Phenolic compounds including berberine and pelargonium sidoides extract contained in the sulfur extract may be present in the form of pharmaceutically acceptable salts. As salts are acid salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention is a concentration that has a relatively nontoxic and harmless effective action in a patient, and the side effects caused by this salt do not reduce the beneficial efficacy of phenolic compounds including berberine and / or catechin. Any organic or inorganic addition salt of any of the above compounds is meant.

Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid may be used as the organic acid. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. It is not limited to these.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium, or calcium salt, but is not limited thereto. Corresponding silver salts can also be obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).

Pharmaceutically acceptable salts of the compounds of this invention include salts of acidic or basic groups which may be present in the phenolic compounds including berberine and / or catechin, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate , Dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like. It can be prepared through the method.

Preferably, the pharmaceutical composition of the present invention may comprise 100 to 380 mg / kg, more preferably 150 to 300 mg / kg, based on the daily dose of the mixture of sulfur and pelargonium sidoides This is not restrictive. For example, in the case of Pelargonium sidoides extract, the expectorant activity also increased up to a certain level as the dosage was increased, but when the dose was increased above a certain level, the expectorant activity was significantly decreased. Specifically, as shown in Table 4, when the pelargonium sidoides extract alone administration of 100 mpk and 200 mpk sputum discharge capacity is improved according to the dose, but when administered at 400 mpk it can be seen that significantly reduced there was.

For example, the composition may be administered once a day or may be dividedly administered several times. For example, the composition may be administered three times a day, but is not limited thereto. On the other hand, the dose per dose (dose) in the case of a liquid formulation is preferably 4 to 20 ml for convenience, but is not limited thereto.

In addition, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable diluent, excipient or carrier.

The composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may comprise at least one excipient such as starch, calcium carbonate, sucrose or lactose (at least one compound). lactose) and gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used. In addition, the carrier may include a non-naturally occuring carrier.

The pharmaceutical composition may be administered in a pharmaceutically effective amount.

As used herein, the term "administration" refers to introducing the pharmaceutical composition of the present invention to an individual in any suitable manner, and the route of administration of the composition may be various oral or nasal oral routes as long as the target tissue can be reached. And may be administered in a conventional manner, specifically via the oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, nasal, inhaled or intradermal routes.

As used herein, the term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is defined as the type and severity, age, sex, Activity, sensitivity to drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrently used drugs, and other factors well known in the medical arts. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art. In addition, the composition may be administered to a variety of mammals, such as rats, livestock, humans, etc. by various routes.

In one embodiment of the present invention, a hot water extract and a dried product thereof were prepared as a representative yellow lotus extract (Example 1), and an ethanol extract of pelargonium sidoides as a representative pelargonium sidoides extract was obtained to obtain a glycerin mixed solution ( 8: 2) and in the form of dry matter (Example 2). Then, a mixture of the above-prepared rhubarb extract and pelargonium sidoides extract was prepared at various doses and / or mixing ratios to confirm the effect. It showed an excellent sputum discharge effect compared to the alone, it was shown that the rye extract and pelargonium sidoides extract is a herbal combination that can exhibit a synergistic effect in Jinhae expectoration (Example 3 (5) and (6)).

The pharmaceutical composition of the present invention exhibits an antihistamine effect. In this way, not only acts as an antagonist to histamine, it can exhibit an anti-inflammatory effect by inhibiting the secretion of chemical mediators in apoptotic cells and basophils. Specifically, H1 receptor blockade prevents endogenous histamine-mediated inflammatory reactions and bronchial smooth muscle contraction, thereby reducing capillary permeability, reducing edema, redness, pruritus, and suppressing bronchial spasms, resulting in mumps, rhinitis, conjunctivitis, pruritus. It can also be effective in the treatment of diseases such as asthma.

As another aspect, the present invention provides a tablet for oral administration comprising the pharmaceutical composition.

As another aspect, the present invention provides a liquid formulation for oral administration comprising the pharmaceutical composition.

In the present invention, the term "tablet" refers to a form of a medicine prepared by compressing a medicine into a certain shape as a kind of solid preparation, which is a dosage form having a certain shape. For this purpose, the tablet may further include an excipient, a binder, a disintegrant, a lubricant, etc. in addition to the active ingredient.

The excipient serves to increase the volume to make a tablet of the desired size is not limited if the pharmaceutically acceptable type, and examples thereof include lactose, starch, white sugar, mannitol, sorbitol, microcrystalline cellulose and the like. . It may preferably be a lactose monohydrate, microcrystalline cellulose or a mixture thereof.

The binder serves to increase the adhesion between the particles to facilitate granulation and to maintain the physical form of the final molding, and the binder is not limited if it is pharmaceutically acceptable, and includes white sugar, glucose, starch, gelatin, and Libyan rubber, povidone, etc. are mentioned. Preferably povidone.

The disintegrant absorbs moisture when the solid preparation is taken and promotes disintegration of the solid preparation into small particles, and the disintegrant is not limited if the pharmaceutically acceptable, crystal cellulose, starch, croscarmellose Sodium ossium and the like. Preferably may be croscarmellose sodium.

The lubricant is to facilitate the compression and release of the solid preparation prepared by improving the fluidity of the tablets to reduce the friction between the tablets and the tableting period, if the pharmaceutically acceptable is not limited, stearic acid, stearates And talc, carnauba wax, sodium stearyl fumarate, colloidal silicon oxide, magnesium silicate and the like. Preferably sodium stearyl fumarate, colloidal silicon oxide, or mixtures thereof.

As used herein, the term "liquid formulation" refers to a form of medicine that is to be taken in the form of a potion dissolved in water or an organic solvent. The liquid preparation is more effective in absorbing the drug into the systemic circulation in the intestinal tract than the suspension or solid preparation, and the liquid preparation may include additional solutes in addition to the medicine, and may include additives that impart color, odor, sammi, or stability. can do. Non-limiting examples of the liquid formulation may include a syrup.

The syrup means a concentrated homemade sugar or sugar substitute. In the present invention, the syrup is an unpleasant taste, such as a bitter taste of the medicine is easy to take as a liquid formulation, and is particularly suitable for children to take. In the present invention, the syrup is 1) a surrogate of sucrose or sugar used for imparting sweetness and viscosity, 2) an antimicrobial preservative, 3) a flavor flavor, or 4, in addition to rhubarb and pelargonium sidoides extract and purified water. ) May include a colorant, but is not limited thereto. Examples of sweeteners that may be included in such syrups include, but are not limited to, sucrose, mannitol, sorbitol, xylitol, aspartame, stevioside, fructose, lactose, sucralose, saccharin or menthol.

As another aspect, the present invention comprises a rye and pelargonium sidoides mixed extract as an active ingredient, for Jinhae or expectorant; Or it provides a health functional food for preventing or improving respiratory diseases or airway infections.

The barberry, Pelargonium sidoides, mixed extract, Jinhae, expectorant, respiratory disease and airway infection are as described above.

When the mixed extract is used as a health functional food, the mixed extract may be added as it is or used in combination with other foods or ingredients, and may be appropriately used according to a conventional method. When the health care food is prepared by adding the mixed extract to a food or beverage, the amount thereof is not particularly limited, but is, for example, 1 to 5% by weight, or 1 to 3% by weight based on the weight of the final food. Can be added. However, in the case of prolonged ingestion, the added amount may be below the above range, and since the mixed extract is a herbal ingredient, there is no problem in terms of safety, and thus the active ingredient may be used in an amount above the above range.

In addition, the type of health functional food of the present invention is not particularly limited. Examples of foods that include all foods or beverages in a conventional sense and to which the extracts can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums and ice cream. Dairy products, including various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes, etc., and also includes food used as feed for animals.

In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Alcohol, a carbonation agent used for carbonated drinks, and the like. Others may contain pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. In addition, the food may also be prepared in the form of tablets, granules, powders, capsules, liquid solutions and pills according to known production methods. There is no particular limitation on other components except for including the mixed herbal extract according to the present invention as an active ingredient, and various conventional flavoring agents or natural carbohydrates may be included as additional ingredients.

As another aspect, the present invention provides a method of treating a respiratory disease or airway infection, comprising administering a mixture of the barberry and pelargonium sidoides to a suspected respiratory disease or airway infection.

The nasturtium, pelargonium sidoides, mixed herbal extract and respiratory disease are the same as described above.

Specifically, the method of treatment of the present invention comprises administering the mixed extract of the barberry and pelargonium sidoides in the form of a pharmaceutical composition to a subject suspected of respiratory disease in a pharmaceutically effective amount. The subject means an entire mammal including a dog, cow, horse, rabbit, mouse, rat, chicken or human, but the mammal of the present invention is not limited to the above examples. The pharmaceutical composition may be administered orally, orally, subcutaneously, intraperitoneally, pulmonary, and intranasally, and may be administered by a suitable method including topical administration if necessary for local treatment. Non-oral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Preferably oral administration, but is not limited thereto.

The preferred dosage of the pharmaceutical composition of the present invention may vary depending on the condition and weight of the individual, the extent of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by those skilled in the art.

In another aspect, the present invention provides a method for alleviating cough or sputum, comprising administering to a subject a mixed herbal extract of rhubarb and pelargonium sidoides.

The nasturtium, pelargonium sidoides, mixed herbal extract and respiratory disease are the same as described above.

The mixed extracts of the rhubarb and pelargonium sidoides of the present invention show excellent antitussive expectorant efficacy which is synergistically markedly increased compared to the same amount alone when mixed in a predetermined ratio, so that the mixed herbal extract coughs // And by administering to a subject in need of relief of sputum, the effect of relieving cough or sputum can be obtained.

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

Example 1: Preparation of Rhubarb Extract

Coptidis rhizome , especially 1 kg of root diameter of hull , was selected and adjusted according to Pharmacopoeia's theft and powderiness. 10 times of water was added and extracted at 100 ° C for 3 hours, and the filtrate was concentrated under reduced pressure at 60 ° C. About 112 g of dry matter were obtained.

As a result of quantifying the dried product of the sulfur extract prepared as described above, it was confirmed that the content of berberine chloride was contained in 180.6 mg / g content.

In addition, the dried product of the sulfur extract was tested for the concentration of heavy metals, microorganisms and residual pesticides contained in it to confirm that it is suitable for use as a pharmaceutical composition in all items.

Example 2: Preparation of Pelargonium sidoides Extract

Pelargonium Sipeides sidoides , Geraniaceae) , cut the dried root to the appropriate size (> 10 mm or more, 95% or more), wet it with 35% ethanol (2 parts), add 5.3% ethanol (8 parts), and filter the extracted solution. 11 g of extract was obtained from about 1 g of dry roots as what was heated for a second. This solution was mixed with 85% glycerol in an 8: 2 (w / w) ratio (Example 2-1).

On the other hand, 1 kg of pelargonium sidoides was extracted with 11% ethanol (8-10 parts) and lyophilized to obtain 36 g of dried product (Example 2-2).

As a result of quantifying the dried Pelargonium sidoides of Example 2-2 prepared as above, it was confirmed that 1 g of the dried Pelargonium sidoides contained 389 mg of epicatechin (38.9%). At this time, as confirmed by the Karl Fischer method, the dried material contained 8.86% moisture.

Further, the dried product of the Pelargonium sidoides extract was tested for the concentration of heavy metals, microorganisms and residual pesticides contained in it to confirm that it is suitable for use as a pharmaceutical composition in all items.

Example 3: Pharmacological Activity Test- in vivo  Expected expectation activity test method

In vivo expectorant activity evaluation was performed by measuring the sputum excretion capacity according to the dose and / or composition ratio of the mixture of the rye extract and pelargonium sidoides extract.

(1) Establishment of Dose of Test Substance

The test substance was prepared by weighing the dried product obtained in Examples 1 and 2-2 as it was, adding some excipient to dissolve, and then adding the excipient to a prescribed concentration. The test substance dissolved in the excipient was filtered and sterilized and then treated in the experimental animal. Preparation was carried out on the day of administration.

First, in order to confirm the synergistic improvement in the expectorant activity by the combination of the rhubarb extract and the Pelargonium sidoides extract, each experimental group was administered with 100, 200 or 400 mg / kg (G1 to G3, respectively). And G4 to G6) and the experimental groups (G7 to G10) administered so that the total amount of the mixture of these extracts mixed 1: 1 was 50, 100, 200 or 400 mg / kg, respectively (Table 1). Ambroxol was used as a control.

sample	group	Dose (mg / kg)	Dosage amount (ml)
G1	Huangshan administration group 1	100	10
G2	Huangshan administration group 2	200	10
G3	Huangshan administered group 3	400	10
G4	Pelargonium sidoides group 1	100	10
G5	Pelargonium sidoides group 2	200	10
G6	Pelargonium sidoides group 3	400	10
G7	Mixture administration group 1	50 (25 + 25)	10
G8	Mix dose group 2	100 (50 + 50)	10
G9	Mix dose group 3	200 (100 + 100)	10
G10	Mix dose group 4	400 (200 + 200)	10
G11	Positive control group (ambroxol)	250	10

(2) test animals

This experiment was approved by the Animal Experimentation Ethics Committee in accordance with the Animal Protection Act (Law No. 12051 of August 13, 2013) (Approval No. 15M023). ICR mice used in the test were obtained 7-week-old males and the general symptoms were observed every day, while acclimating more than a week. The test animals were compared with the body weight measured on the day of acquisition and the weight of the test day, and the animals without weight loss and no abnormal symptoms were selected and grouped based on the weight, and the test substance was administered to the 8-week-old mice. Radiation-sterilized rat animal feed (TEKLAD CERTIFIED IRRADIATED GLOBAL 18% PROTEIN RODENT DIET, 2918C, Harlan Laboratories Inc., USA) was supplied from Coatech and freely ingested and watered with UV sterilizers and microfiltration equipment. Free bottle ingestion. Immediately after administration of the test substance and the control substance, the test animals were observed prior to administration of the phenol red solution and before organ extraction to confirm death. When the animals died during the observation period, the autopsy examined the symptoms.

(3) sputum Discharge capacity  Measure

60 minutes after oral administration of the test substance, phenol red solution (w / v) prepared at 10% concentration in physiological saline was intraperitoneally administered to ICR mice at a dose of 0.2 mg / morning, and after 30 minutes, euthanized with carbon dioxide gas to trachea (trachea) was extracted. The extracted organ was placed in a microcentrifuge tube and subjected to sonication for 15 minutes by adding 1 ml of physiological saline and centrifuged (10,000 rpm, 5 minutes). 0.5 ml of supernatant was taken and placed in a new centrifuge tube and 0.5 ml of 1N sodium hydroxide was added. The supernatant of the solution to which sodium hydroxide was added was stirred with a vortex mixer, and then 0.2 ml of the solution was dispensed into a 96-well plate. Measure absorbance at 546 nm with a microplate reader and substitute the measured absorbance into the formula obtained from the phenol red standard curves (100.0, 50.0, 20.0, 10.0, 5.0, 2.0 and 1.0 ng / ml) to calculate the amount of phenol red emitted Subsequently, the sputum discharge capacity of the test substance was calculated by substituting the following formula.

Sputum excretion (%) = [(A / B) -1] * 100 (%)

A: Test substance administration group

B: negative control group

(4) goldthread  Extract and Pelargonium Shidoidesu  Determination of expectorant activity of extract

On the other hand, in order to confirm the expectorant activity according to the dosage by each of the extract alone, as shown in Table 1, the administration of sputum extract or Pelargonium sidoides extract while varying the dosage to the mouse to measure the sputum discharge capacity And the results are shown in Figure 1, Table 2 and Table 3.

sample	group	Dose (mg / kg)	Sputum discharge capacity (%)	± SD
G1	Huangshan administration group 1	100	63.9	9.6
G2	Huangshan administration group 2	200	93.7	11.7
G3	Huangshan administered group 3	400	110.0	6.4
G11	Positive control group (ambroxol)	250	68.4	6.4

sample	group	Dose (mg / kg)	Sputum discharge capacity (%)	± SD
G4	Pelargonium sidoides group 1	100	66.9	5.8
G5	Pelargonium sidoides group 2	200	98.1	17.8
G6	Pelargonium sidoides group 3	400	3.0	6.9
G11	Positive control group (ambroxol)	250	68.4	6.4

As shown in Table 2, the rhubarb extract showed an expectorant effect, and the effect was increased in proportion to the dose, but the increase rate was decreased as the dose was increased. On the other hand, as shown in Table 3, in the case of Pelargonium sidoides up to 200 mg, the expectorant effect increased as the dose was increased, but when the dose was increased to 400 mg, the effect was significantly reduced.

(5) goldthread  Extract and Pelargonium Shidoidesu  Determination of expectorant activity according to the total dose of the mixture of extracts

In order to confirm synergistic improvement of expectorant activity by the mixture of the Rhododendron extract and the Pelargonium sidoides extract, the two extracts were mixed in the same weight (1: 1 weight ratio, on a dry basis), but the total extract amount was from 50 mg to 400 Mice were dosed with increasing up to mg. The sputum ejection capacity thus measured was evaluated in comparison with the values measured for the same amount of the single extract administration group (Tables 2 and 3), and more when the mixed extract was used compared to the same amount of the single extract. Dosages showing high activity were identified. The measured results are shown in FIG. 1 and Table 4 below. As a positive control, 250 mg of ambroxol was used.

sample	Dose extract dose (mg / kg)	Pelargonium sidoides extract dosage (mg / kg)	Total dose (mg / kg)	Sputum discharge capacity (%)	SD
G7	25	25	50	1.5	4.9
G8	50	50	100	52.0	10.2
G9	100	100	200	150.2	10.9
G10	200	200	400	22.3	6.6
G11	Positive control group (ambroxol)		250	68.4	6.4

As a result, the total dose was 200 mg / kg showed an increased sputum discharge capacity of about 60% and 53%, respectively, compared with the 200 mg of each alone extract. Furthermore, the sputum excretion capacity measured by the administration of 100 mg of each showed more than 15% higher activity than the simply summed value. In addition, it was confirmed that the activity was more than two times higher than the positive control group administered with Ambroxol 250 mg / kg. This is because the combination of the rhubarb extract and the pelargonium sidoides extract according to the present invention showed a markedly increased activity compared to the case where each of them was used alone or the value of each activity simply added. Induce synergistic increase.

Thus, 200 mg / kg showing the best activity in the 1: 1 mixed extract as a total dose was carried out after the experiment.

(6) goldthread  And Pelargonium Shidoidesu  Expectation of expectorant activity according to the mixing ratio of the mixed extract

In order to confirm the other expectorant activity in the mixing ratio of the extracts of the rhubarb and pelargonium sidoides mixed extracts according to the present invention, the total 200 mg confirmed to have the best sputum discharge ability through Example 3 (5) The dose was set and a sample was prepared while adjusting the ratio (dry basis weight ratio) of the extract of Pelargonium sidoides (dry weight basis) from 1: 2 to 1: 0.2, and the sputum discharge capacity was measured. The composition and measured sputum discharge capacity of the mixed extract are shown in Table 5 and FIG. 2.

In addition, based on the dose (200 mg / kg) determined to exhibit a synergistic effect in a 1: 1 mixture compared to the extract alone, as shown in Table 5 below, the total dose is kept constant at 200 mg / kg A series of test groups were prepared with varying mixing ratio of Peonynium extract: Pelargonium sidoides extract from 1: 2 to 1: 0.2, and the expectorant activity against them was confirmed. The total dose was adjusted to 10 ml.

sample	Dose extract dose (mg / kg)	Pelargonium sidoides extract dosage (mg / kg)	Total dose (mg / kg)	Lactobacillus extract: Pelargonium sidoides extract mixture ratio (based on dry weight)	Sputum discharge capacity (%)	SD
G12	67	133	200	1: 2	194.2	12.3
G13	100	100	200	1: 1	163.6	6.6
G14	133	67	200	1: 0.5	145.9	22.3
G15	150	50	200	1: 0.3	121.8	18.2
G16	160	40	200	1: 0.25	73.5	9.2
G17	167	33	200	1: 0.2	52.6	10.3
G11	Positive control group (ambroxol)		250	Exclusive	68.4	6.4

As a result, the ratio of pelargonium sidoides extract to rhubarb extract was the highest when the ratio of sputum was 2, and even if the ratio was reduced to 0.3, the sputum was still higher than when the same amount of the single extract was administered. Emission capacity is shown (see results for Table 2 G2 and Table 3 G5).

Production Example  1 to 7: Preparation of tablets

According to the component contents shown in Table 6, as an active ingredient, it comprises a rhubarb extract and a pelargonium sidoides extract, further mixed with microcrystalline cellulose, lactose monohydrate, povidone, calcium silicate, and then fed and granulated by adding purified water And dried at a temperature of 50-60 ° C. in a cabinet drier (LOD 2% or less). After sizing, the remaining disintegrant and glidants were mixed.

division	Classification	ingredient	Preparation Example 1	Preparation Example 2	Preparation Example 3	Preparation Example 4	Preparation Example 5	Preparation Example 6	Preparation Example 7
Pelargonium layer	chief ingredient	Pelargonium sidoides extract dried	1235.5	1235.5	1235.5	1235.5	1235.5	1235.5	1235.5
	Excipient	Microcrystalline cellulose	234.0	224.0	204.0	184.0	184.0	184.0	154.0
	Excipient	Lactose Carb	100.0	100.0	100.0	100.0	100.0	100.0	100.0
	Binder	Povidone	10.0	10.0	10.0	10.0	10.0	10.0	10.0
	Excipient	Calcium silicate	0.0	0.0	20.0	40.0	40.0	40.0	60.0
	Disintegrant	Croscarmellose sodium	10.0	10.0	10.0	10.0	10.0	10.0	10.0
	Lubricant	Colloidal silicon dioxide	0.0	10.0	10.0	10.0	10.0	10.0	10.0
	Lubricant	Sodium stearyl fumarate	15.0	15.0	15.0	15.0	15.0	15.0	15.0
Yellow lotus layer	chief ingredient	Rhubarb Extract	8.0	8.0	8.0	8.0	8.0	8.0	8.0
	Excipient	Microcrystalline cellulose	100.0	100.0	100.0	90.0	75.0	70.0	60.0
	Excipient	Lactose Carb	50.0	50.0	50.0	50.0	50.0	50.0	50.0
	Binder	Povidone	5.0	5.0	5.0	5.0	5.0	5.0	5.0
	Excipient	Calcium silicate	0.0	0.0	0.0	10.0	20.0	20.0	30.0
	Disintegrant	Croscarmellose sodium	5.0	5.0	5.0	5.0	5.0	5.0	5.0
	Lubricant	Colloidal silicon dioxide	0.0	0.0	0.0	0.0	5.0	10.0	10.0
	Lubricant	Sodium stearyl fumarate	8.0	8.0	8.0	8.0	8.0	8.0	8.0
	Coating	Opadry OY-C-7000A	25.0	25.0	25.0	25.0	25.0	25.0	25.0
Total (mg / tablet)			1805.5	1805.5	1805.5	1805.5	1805.5	1805.5	1805.5

By preparing a bilayer tablet including two active ingredients in separate layers as described above, it is possible to prevent undesirable phenomena that may occur due to the mixing of the respective active ingredients during manufacture, storage and / or distribution.

Preparation Example 8 Preparation of Syrup

Add 110.8 mg of rhubarb extract and 17160.0 mg of Pelargonium sidoides extract, add 30 g of fructose and 40 g of sorbitol, and adjust the total volume to 100 ml by adding 0.4 g of ion exchange resin to mask the bitter taste of the rhubarb extract. To prepare a syrup. Each component was prepared by dissolving in purified water and mixing so that the amount of the active ingredient was the said amount, respectively. Lemon flavor or cherry flavor can be added to the appropriate amount. The final mixture prepared was filled into brown bottles and sterilized to prepare a liquid.

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (16)

1. Coptidis rhizome and Pelargonium Sidoides ) pharmaceutical composition for antitussive or expectorant comprising a mixed extract as an active ingredient.
2. A pharmaceutical composition for preventing or treating respiratory diseases, comprising a mixture of sulfur and pelargonium sidoides as an active ingredient.
3. The method of claim 2,

   The respiratory disease is a disease, asthma, or cold, accompanied by coughing, bronchial spasms, dyspnea, or sputum symptoms.
4. A pharmaceutical composition for preventing or treating respiratory tract infection, which comprises a mixture of sulfur and pelargonium sidoides as an active ingredient.
5. The method of claim 4, wherein

   The airway infection is one or more upper respiratory tract infection or lower respiratory tract infection selected from the group consisting of acute or chronic rhinitis, sinusitis, sore throat, otitis media and bronchitis.
6. The method according to any one of claims 1 to 5,

   The weight ratio of the sulfur extract: pelargonium sidoides extract is 1: 0.3 to 5 on a dry basis, the pharmaceutical composition.
7. The method according to any one of claims 1 to 5,

   The weight ratio of the sulfur extract: pelargonium sidoides extract is 1: 0.5 to 3 on a dry basis, the pharmaceutical composition.
8. The method according to any one of claims 1 to 5,

   The sulfur extract is berberine or a pharmaceutically acceptable salt thereof, the pharmaceutical composition.
9. The method of claim 8,

   The sulfur extract is a pharmaceutical composition that comprises 1 to 30% by weight of berberine or a pharmaceutically acceptable salt thereof on a dry basis.
10. The method according to any one of claims 1 to 5,

    Wherein the pelargonium sidoides extract is a phenolic compound comprising a catechin or a pharmaceutically acceptable salt thereof, pharmaceutical composition.
11. The method of claim 10,

    The pelargonium sidoides extract is a pharmaceutical composition comprising 25 to 45% by weight of the phenolic compound or pharmaceutically acceptable salt thereof, including the catechin on a dry basis.
12. The method according to any one of claims 1 to 5,

    The composition is a pharmaceutical composition, comprising a mixture of sulfur and pelargonium sidoides at 150 to 300 mg / kg on a daily dosage basis.
13. The method according to any one of claims 1 to 5,

    The composition is administered three times a day, the dose per dose (dose) is 4 to 20 ml, pharmaceutical composition.
14. Tablet for oral administration comprising a composition according to any one of claims 1 to 5.
15. A liquid formulation for oral administration comprising the composition according to any one of claims 1 to 5.
16. Huanghae or expectorant for containing, as an active ingredient, extracts of rhubarb and pelargonium sidoides; Or dietary supplement for the prevention or improvement of respiratory diseases or airway infections.

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