WO2011139118A2

WO2011139118A2 - A pharmaceutical composition and a health functional food composition for preventing, treating or improving a gastrointestinal dyskinetic disease

Info

Publication number: WO2011139118A2
Application number: PCT/KR2011/003397
Authority: WO
Inventors: Young Ryool Kim; Il Hwan Cho; Geun Seog Song; Byoung Seok Moon; Chi Hye Park; Young Mee Chung; Oh Eok Kwon; Ye Kyung Cho
Original assignee: Cj Cheiljedang Corporation; Scigreen
Priority date: 2010-05-06
Filing date: 2011-05-06
Publication date: 2011-11-10
Also published as: CN104800309A; RU2540511C2; UA105685C2; RU2012134195A; CN102858357A; BR112012020342A2; MY162542A; WO2011139118A3; KR101263191B1; KR20110123114A

Abstract

The present invention provides a pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic diseases and a health functional food composition for the prevention or improvement of gastrointestinal dyskinetic diseases, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. The composition according to the present invention comprises a combination of two or more of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, and significantly facilitates gastrointestinal motility, in particular, gastric emptying rate and gastrointestinal transit, thereby being used for the prevention, improvement, or treatment of gastrointestinal dyskinetic diseases, in particular, functional dyspepsia associated with gastric emptying rate or gastrointestinal transit. In addition, the composition according to the present invention consists of natural substances, and thus there is little concern regarding undesirable toxicity.

Description

A PHARMACEUTICAL COMPOSITION AND A HEALTH FUNCTIONAL FOOD COMPOSITION FOR PREVENTING, TREATING OR IMPROVING A GASTROINTESTINAL DYSKINETIC DISEASE

The present invention relates to a pharmaceutical composition and a health functional food composition for preventing, treating, or improving gastrointestinal dyskinetic diseases, and more particularly, to a pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic diseases and a health functional food composition for the prevention or improvement of gastrointestinal dyskinetic diseases, comprising a herb complex.

Functional dyspepsia (FD) is a multifactorial disease, caused by many pathogenic factors including excessive gastric acid secretion, abnormal gastrointestinal motility, visceral hypersensitivity, Helicobacter pylori infection, an increase in local irritation factors, stress, and genetic factors. It is a syndrome characterized by upper abdominal pain or discomfort, diagnosed as sporadically occurring in the upper gastrointestinal tract without manifestation of organic abnormality under endoscopic, histological, and biochemical examination, and its pathophysiology remains unclear. The clinical symptoms of discomfort are upper abdominal fullness, early satiety, bloating, nausea, belching, vomiting, and retching, and these symptoms may be present in any combination.

Although functional dyspepsia is not fatal, its prevalence is considered to be high, and growing interest in this disorder has arisen with an increased focus on quality of life. As mentioned above, however, its definition and pathophysiology have not been clearly elucidated unlike other digestive diseases, and thus there have been virtually no therapeutic suggestions, and none of the drugs used in clinical practice have been proven effective for the treatment thereof. Further, between 20 and 60% of patients with functional dyspepsia have shown symptom improvement on placebo treatment, which hampers the evaluation of drug treatment trials.

Gastrointestinal motility is generally modulated by antagonistic double innervation of the autonomic nervous system, and regulated by a complex balance of excitatory and inhibitory neural factors. Acetylcholine (ACh) released from cholinergic nerve terminals promotes gastrointestinal motility, and its action is terminated by acetylcholinesterase (AChE), whereas dopamine interacts with dopamine receptors (D2) present on preganglionic fibers of the cholinergic nerve to inhibit the action of ACh, leading to a reduction of gastrointestinal motility. Major therapeutic agents for gastrointestinal dyskinetic diseases include prokinetic agents, H2 receptor antagonists, PPIs (Proton pump inhibitors).

In particular, H.pylori infection is found in ulcer- or dysmotility-like dyspepsia at a high rate, and it has been reported that 68% of patients with functional dyspepsia are actually infected with H.pylori. Practically, ulcer-like dyspepsia is treated with H2 receptor antagonists and PPIs, and dysmotility-like dyspepsia is treated with prokinetic agents (metoclopramide, domperidone, mosapride, etc.), or antidepressants or antianxiety agents.

Prokinetic agents act as antidopaminergic agents, serotonergic agents, and/or motilin receptor agonists to stimulate smooth gastrointestinal tract muscle contractions, which enhances the lower esophageal sphincter pressure and improves esophageal clearance and gastric emptying, leading to shortening of gastrointestinal transit time. Drugs currently used as a gastroprokinetic or antiemetic drug include metoclopramide, domperidone, cisapride, itopride, levosulpiride, mosapride or the like. These drugs enhance gastrointestinal motility, thereby improving digestive symptoms accompanying chronic gastritis or postgastrectomy syndrome, but possible side effects become problems in the prescription of these drugs.

Metoclopramide or domperidone antagonizes dopamine D2 receptors to stimulate gastric motility. Metoclopramide enhances the release of ACh at the myenteric plexus, but domperidone does not have the function. Thus, the former is inhibited by cholinergic antagonists, but the latter is not. Further, these drugs may create side effects, including central nerve system side effects, nipple discharge and gynecomastia.

Cisapride, commonly prescribed for functional dyspepsia, activates 5-HT4 receptors at the myenteric plexus of the gastrointestinal tract to facilitate ACh release and promote physiological movement of the gastrointestinal tract. Cisapride does not antagonize dopamine D2 receptors, and therefore it does not possess antiemetic actions. However, it is contraindicated due to risk of potentially fatal cardiac arrhythmias.

Itopride antagonizes dopamine D2 receptors and also inhibits AChE, and therefore activates gastrointestinal motility through synergism.

Mosapride, like cisapride, activates 5-HT2 receptors to promote the gastrointestinal motility. It lacks antagonist action over dopamine D2 receptors, and therefore does not cause adverse central nervous system reactions.

Functional dyspepsia is a common functional gastrointestinal disorder associated with mental stress, and is thus accompanied with neuropathy, anxiety, and depression. Accordingly, psychosocial interventions may have a role in treatment, and a mix of Western and oriental medicine was shown to be more efficacious for the improvement of the symptoms of multifactorial disease. Therefore, functional dyspepsia with multifactorial pathogenesis cannot be sufficiently treated with one type of drug, and requires development of prokinetic agents with multi-mechanisms.

The above drugs have exhibited efficacy on gastrointestinal motility disorders, but problematically cause toxic side effects. Thus, there is a need to develop safe drugs, and also, a composition to be used for the treatment, improvement or prevention of functional dyspepsia without causing side effects.

Meanwhile, Bupleuri Radix is the root of Bupleurum falcatum L. or its varieties, which is a perennial herb of the umbelliferae family. A dried sample should include 0.3% or more of Saikosaponin a (C₄₂H₆₈O₁₃: 780.99), and stems or leaves should include not more than 10%, ash is not more than 6.5%, and acid-insoluble ash is not more than 2.0% [The Korean Pharmacopoeia 9^th Edition, 2007]. Bupleuri Radix is collected in Spring and Autumn, removed from the aerial part and soil, and dried under the sun. It contains ingredients of oil, bupleurumol, fatty acids, sugars and saponins, and its pharmacological actions include anti-inflammatory, antipyretic, diuretic, anti-ulcer, sedative and antispasmodic, and anti-pathogenic actions [Bo-sup Jung, Min-Kyo Shin. Dohae native Korean medicine (herbal medicine) dictionary, Yeongnimsa, 2003: 412-414].

Coptis Rhizoma is the rhizome which is almost removed from roots of Coptis japonica Makino, Coptis chinensis Franchet, or Coptis teeta Wallich, which is a perennial herb of the Ranunculaceae family. It should include 4.2% or more of berberine [as berberine chloride (C₂₀H₁₈ClNO₄: 371.81)], based on dried herb, and a loss on drying should not be more than 9.0%, ash should not be more than 4.0%, and acid-insoluble ash should not be more than 1.05% [The Korean Pharmacopoeia 9^th Edition, 2007]. Coptis Rhizoma is collected in autumn, and removed from leaves, roots and soil. After drying under the sun, the cork layer is removed. It contains alkaloids such as berberine, coptisine, worenine, palmatine, and jateorrhizine, obacunone, and obaculactone as main ingredients, and its pharmacological actions include anti-inflammatory, anti-ulcer, anti-cancer, anti-radiation, anti-microbial and anti-pathogenic actions [Bo-sup Jung, Min-Kyo Shin. Dohae native Korean medicine (herbal medicine) dictionary, Yeongnimsa, 2003: 490-493].

Glycyrrhizae Radix et Rhizoma is the root and rhizome of Glycyrrhiza uralensis Fischer, Glycyrrhiza glabra Linn, or Glycyrrhiza inflata Bat., which is a perennial herb of the Leguminosae family. It should include 2.5% or more of glycyrrhizic acid (C₄₂H₆₂O₁₆: 822.93) and 0.7% or more of liquiritigenin (C₁₅H₁₂O₄: 256.27), based on the dried herb, and a loss on drying should not be more than 12.0%, ash should not be more than 7.0%, and acid-insoluble ash should not be more than 2.0% [The Korean Pharmacopoeia 9^th Edition, 2007]. The root is collected in autumn. After removal of the branches of the rhizome and rootlets, the root is cut and dried under the sun. It contains triterpene-based saponins, glycyrrhizin, uralenic acid, and flavonoids as main ingredients, and its pharmacological actions include deintoxication, anti-diuretic, antitussive, anti-inflammatory, anti-allergic, anti-ulcer, and hepatoprotective actions [Bo-sup Jung, Min-Kyo Shin. Dohae native Korean medicine (herbal medicine) dictionary, Yeongnimsa, 2003: 684-687].

Each of Bupleuri Radix, Coptis Rhizoma, and Glycyrrhizae Radix et Rhizoma is known to have anti-ulcer action, but there have been no reports of their therapeutic effects on functional dyspepsia. Traditionally, oriental medicines (such as frigid extremities powder and Pinellia Decoction to Drain the Epigastrium) have been used only to improve symptoms along with other therapies having an effect on gastrointestinal motility and stress-induced digestive disorders. It was revealed that isoliquiritigenin, a flavonoid isolated from Glycyrrhizae Radix et Rhizoma, plays a role in regulating gastrointestinal transit by both spasmogenic and spasmolytic effect on the convulsion of gastrointestinal transit. The spasmogenic effect may involve the activating of muscarinic receptors, while the spasmolytic effect is predominantly due to a blockade of the calcium channels [Chen G. et al. Phytother. Res. 2009, 23: 498-506].

Accordingly, the present inventors have realized that a composition for the prevention, improvement, or treatment of gastrointestinal dyskinetic diseases should be developed, and they have made many efforts to develop a pharmaceutical composition having excellent efficacy and fewer side effects. They have developed a combination of herbal medicines similar to mosapride that is a commonly used prokinetic agent, thereby completing the present invention.

Therefore, it is an object of the present invention to provide an effective pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic disease, comprising a mixture of herbal medicines as an active ingredient.

It is another object of the present invention to provide an effective health functional food composition for the prevention or improvement of gastrointestinal dyskinetic diseases, comprising the mixture of herbal medicines as an active ingredient.

As described above, the composition according to the present invention comprises a combination of two or more of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, thereby significantly improving gastrointestinal dyskinetic disease, in particular, gastric emptying rate and gastrointestinal transit. Therefore, the composition exhibits surprising effects in the prevention, improvement or treatment of gastrointestinal disorders due to functional dyspepsia. In addition, it consists of herbal medicines which have been traditionally used for a long period of time, and thus there is little concern of undesirable side-effects or toxicity.

In order to achieve the above objects, the present invention provides a pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic disease, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma. Futher, the present invention provides a method of preventing or treating gastrointestinal dyskinetic disease, which comprises administering to a subject in need thereof a pharmaceutical composition comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma. Futher, the present invention provides a pharmaceutical composition for use in the prevention or treatment of dyskinetic disease, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma. Futher, the present invention provides use of a pharmaceutical composition comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma, for the manufacture of a medicament for preventing or treating dyskinetic disease.

Further, the present invention provides a health functional food composition for the prevention or improvement of gastrointestinal dyskinetic diseases, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma. Futher, the present invention provides a method of preventing or improving gastrointestinal dyskinetic disease, which comprises administering to a subject in need thereof a health functional food composition comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma. Futher, the present invention provides a health functional food composition for use in the prevention or improvement of dyskinetic disease, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma. Futher, the present invention provides use of a health functional food composition comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma, for the manufacture of a medicament for preventing or improving dyskinetic disease.

Hereinafter, the present invention will be described in more detail.

The present inventors have endeavored to develop an herbal composition which effectively facilitates gastrointestinal motility without causing side effects, and they found that gastrointestinal motility can be facilitated by the use of a combination of two or more of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma, which are the widely known herbal medicines and cause little side effects. Thus, a combination of two or more of the Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma can be used as an active ingredient of a pharmaceutical composition for the prevention or treatment of gastrointestinal disease, and also of a health functional food composition for the prevention or improvement of gastrointestinal diseases.

In one aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic disease, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma.

In another aspect, the present invention provides a health functional food composition for the prevention or improvement of gastrointestinal dyskinetic diseases, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma.

Hereinbelow, an herbal composition will be used as a term embracing the pharmaceutical composition and the health functional food composition.

In the herbal composition, the composition ratio of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma is not particularly limited. Preferably, the herbal composition may include 10-30 parts by weight of Coptidis Rhizoma and 10-30 parts by weight of Glycyrrhizae Radix et Rhizoma, based on 100 parts by weight of Bupleuri Radix.

The herbal medicines constituting the herbal composition of the present invention are classified into the same category, as commonly understood by those skilled in the art, and any herbal medicine having the effect of facilitating gastrointestinal motility may be included.

Each of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma may be included in the composition as a solvent extract of the herbal medicine, or in the form of the pulverized herb itself or dried herb powder. Thus, the type or method is not particularly limited. The solvent extracts of the herbal medicines may be prepared separately or together with each other by extracting them with water, an organic solvent or a combination thereof, in which the organic solvent may be C₁-C₄ alcohols, acetone, chloroform, methylene chloride, ether, ethyl acetate, hexane, or combinations thereof, but is not limited thereto. C₁-C₄alcohols may be exemplified by methanol, ethanol, propanol and butanol, and is most preferably ethanol.

The solvent extracts of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma may be prepared by any extraction method known in the art, and at 10°C to 80°C, preferably at room temperature (approximately 25°C), for 10 to 80 hrs, preferably 2 to 3 days, by an extraction method such as hot water extraction, cold-immersion extraction, reflux cold extraction or sonication, and preferably cold-immersion extraction once to 5 times. The obtained solvent extract is filtered under reduced pressure, and the filtrate is concentrated at 20 to 100°C, preferably room temperature (approximately 25°C), under reduced pressure using a rotary evaporator to obtain a final extract.

The herbal composition comprising a combination of two or more of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma according to the present invention is effective for the prevention, improvement or treatment of gastrointestinal dyskinetic diseases, and in particular, for the prevention, improvement or treatment of functional dyspepsia associated with gastric emptying rate and gastrointestinal transit. Such effects were demonstrated in the following Experimental Examples.

In detail, to evaluate its inhibitory effect on delayed gastric emptying rate, rats fasted for 24 hrs were orally administered once with the herbal composition of the present invention, and then orally fed with a semisolid test meal, and the stomach weight was measured to calculate gastric emptying rate (GER). The results showed a significantly excellent inhibitory effect on delayed gastric emptying rate, compared to the non-treated group (control group), and the effect was found to be similar to that of the mosapride-treated group as a positive control group.

Compared to each single administration of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma extracts as main ingredients, the administration of the herbal composition comprising a combination of two or more thereof showed a remarkably excellent inhibitory effect on delayed gastric emptying rate, when each of them was administered at an equal dose. The results indicate that the combination thereof exhibits a synergistic effect on the prevention and treatment of gastrointestinal dyskinetic disease.

A rat model was used to examine the therapeutic effect of the herbal composition of the present invention on stress-induced anorexia and delayed gastric emptying rate, and an atropine and dopamine-treated rat model was used to examine therapeutic effect of the herbal composition on drug-induced inhibition of gastrointestinal transit. The results showed that the herbal composition of the present invention exhibited a significant improving therapeutic effect on gastrointestinal transit.

Moreover, the herbal composition of the present invention comprises safety-approved herbal medicines which have been traditionally used for a long period of time, and thus there is little concern of undesirable side-effects and toxicity, which allows long-term use of the composition for the purpose of prevention or treatment of gastrointestinal diseases.

Therefore, the pharmaceutical composition according to one aspect of the present invention may include a pharmaceutically acceptable carrier or additive.

The pharmaceutical composition can be administered to mammals, including rats, mouse, livestock, and human beings, through various routes, e.g., orally, rectally, intravenously, intramuscularly, subcutaneously, through intrauterine dura mater injection, or through intracerebroventricular injection. Accordingly, the pharmaceutical composition may be formulated into typical pharmaceutical preparations known in the art. The pharmaceutical composition may be formulated into oral preparations, injectable preparations, suppositories, percutaneous preparations, and pernasal preparations, but is not limited thereto. It may be formulated into any preparation, and preferably, into liquid, suspension, powder, granule, tablet, capsule, pill, emulsion, syrup, aerosol, or oral preparations such as extracts.

Upon formulation of such preparations, a pharmaceutically acceptable carrier or additive required for each preparation may be added. Upon formulation into oral preparations, one or more selected from diluents, lubricants, binders, disintegrating agents, sweetening agents, stabilizing agents, and preservatives may be used as the carrier, and one or more selected from flavoring agents, vitamins and antioxidants may be used as the additive.

The carriers and additives may be any pharmaceutically acceptable example. Specifically, preferred examples of the diluent may include lactose, dextrose, sucrose, corn starch, soybean oil, microcrystalline cellulose, sorbitol, xylitol, and mannitol, preferred examples of the lubricant may include magnesium stearate and talc, and preferred examples of the binder may include polyvinylpyrrolidone or hydroxypropyl cellulose. In addition, preferred examples of the disintegrating agent may include calcium carboxymethyl cellulose, sodium starch glycolate, potassium polyacrylate, or crospovidone, preferred examples of the sweetening agent may include white sugar, fructose, sorbitol or aspartame, preferred examples of the stabilizing agent may include sodium carboxymethylcellulose, beta-cyclodextrin, white bee's wax, and Xhantan gum, and preferred examples of the preservative may include methyl parahydroxybenzoate, propyl parahydroxybenzoate and potassium sorbate.

In addition to these ingredients, known additives for improving flavor, for example, a natural flavoring agent such as plum, lemon, pineapple or herb flavor, a natural fruit juice, a natural dye such as chlorophyllin or flavonoid, a sweetening component such as fructose, honey, sugar alcohol, or sugar, or an acidulant such as citric acid or sodium citrate may also be included.

Examples of the preparation for parenteral administration include an aseptic aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized agent, and a suppository. For the preparation of the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, plant oil such as olive oil, or an injectable ester such as ethyloleate may be used. As a suppository base, witepsol, macrogol, tween 61, cacao butter, lauric butter, or glycerogelatin may be used.

The pharmaceutical composition may be prepared by varying the composition ratio of the herbal components within the range of maintaining the therapeutic or prophylactic effects on gastrointestinal dyskinetic disease, and the composition may include 0.01-80% by weight, and preferably 1-50% by weight of the herbal components according to the present invention.

To obtain the therapeutic or prophylactic effects on gastrointestinal dyskinetic disease, the active ingredient of the composition may be administered once or several times at a daily dose of 0.01-10 g/kg/day, preferably 1-5 g/kg/day, based on the dry powder of the solvent extract, and it may be properly determined depending on a patient's age, gender, body weight, diet, secretion rate, or other drugs taken by the patient. Therefore, the pharmaceutical composition should be prepared considering the effective dosage range, and if necessary, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, or each dosage unit of the formulated preparation may be administered several times at a predetermined time interval.

The health functional food composition according to another aspect of the present invention may include a sitologically acceptable carrier or additive.

As used herein, the term "health functional food" means a health functional food containing ingredients that are on the authorized list of ingredients according to the Korean Food and Drug Administration (KFDA) Announcement # 2008-72, and their functionality and safety are established by the Health Functional Food Act amended in 2008.

The health functional food composition according to the present invention may be formulated into a typical health functional food preparation known in the art. The health functional food may be prepared in the form of powder, granule, tablet, pill, capsule, suspension, emulsion, syrup, infusion, liquid, extract, gum, tea, jelly, or beverage. The sitologically acceptable carrier or additive may be any carrier or additive known in the art.

The health functional food composition may include the herbal components constituting the composition of the present invention in an amount of 0.01 to 15% by weight, preferably 0.2 to 10% by weight, based on the total weight of the food, and 0.1 to 30 g, preferably 0.2 to 5 g, based on 100 ml of a beverage.

The beverage may further include other components in addition to the above described herbal components, in which the other component may be various flavoring agents or natural carbohydrates used in conventional beverages. Examples of the aforementioned natural carbohydrates are conventional sugars such as monosaccharide (e.g., glucose, fructose, etc.), disaccharide (e.g., maltose, sucrose, etc.), and polysaccharide (e.g., dextrin, cyclodextrin, etc.), and sugar alcohol such as xylitol, sorbitoal and erythritol. As the other flavoring agent, a natural flavoring agent (e.g., taumatin, stevia extract, etc.) and a synthetic flavoring agent (e.g., saccharin, aspartame, etc.) may be included. Preferably, the described natural carbohydrate is included in an amount of about 1 to 20 g, preferably 5 to 12 g, based on 100 ml of the beverage.

The active ingredients, Bupleuri Radix, Coptidis Rhizoma and/or Glycyrrhizae Radix et Rhizoma included in the pharmaceutical composition and health functional food composition according to the present invention may be administered at the same time or sequentially at a predetermined time interval within the range of showing the prophylactic, ameliorative or therapeutic effects on gastrointestinal dyskinetic disease. When the combination of Bupleuri Radix, Coptidis Rhizoma and/or Glycyrrhizae Radix et Rhizoma is intended to be administered at a predetermined time interval, each active ingredient is separately formulated. When the combination of two or more of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma is administered at the same time, a uniform mixture thereof may be formulated into a single preparation, or they may be separately formulated, and then the separate formulations may be administered at the same time.

Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are for illustrative purposed only, and the invention is not intended to be limited by these Examples.

Comparative Example 1-3: Preparation of single extracts of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma

Dried Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were purchased from an oriental medicine trader, washed with water to remove impurities, and the dried herbal medicines were used to prepare extracts. Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were pulverized using a grinder, and 400 ml of 80% ethanol aqueous solution was added to each 200 g thereof. A cold-immersion process was performed twice at room temperature for 3 days to obtain each liquid extract. Each liquid extract was filtered, and concentrated under reduced pressure using a rotary evaporator at 50°C, and the solvent was completely removed and dried in a vacuum oven so as to obtain dried ethanol extracts. 31 g of Bupleuri Radix extract (Comparative Example 1), 36 g of Coptidis Rhizoma extract (Comparative Example 2), and 48 g of Glycyrrhizae Radix et Rhizoma extract (Comparative Example 3) were obtained in a powder form.

Example 1-3: Preparation of two combination extracts of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma

Dried Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were purchased from an oriental medicine trader, washed with water to remove impurities, and the dried herbal medicines were used to prepare extracts. Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were pulverized using a grinder, and 780 g of Bupleuri Radix and 180 g of Coptidis Rhizoma (Example 1), 780 g of Bupleuri Radix and 180 g of Glycyrrhizae Radix et Rhizoma (Example 2), and each 500 g of Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma (Example 3) were added to an extractor, respectively. 2 L of 80% ethanol aqueous solution was added to each combination, and the processes of extraction, filtration, concentration and drying were conducted in the same manner as in Comparative Example 1-3 so as to obtain dried ethanol extracts. 165 g of Bupleuri Radix-Coptidis Rhizoma extract (Example 1), 192 g of Bupleuri Radix-Glycyrrhizae Radix et Rhizoma extract (Example 2) and 210 g of Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (Example 3) were obtained.

Example 4: Preparation of complex extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma

Dried Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were purchased from an oriental medicine trader, washed with water to remove impurities, and the dried herbal medicines were used to prepare extracts.

Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were pulverized using a grinder, and 6.5 kg of Bupleuri Radix, 1.5 kg of Coptidis Rhizoma and 1.5 kg of Glycyrrhizae Radix et Rhizoma were put in an extractor. 20 L of 80% ethanol aqueous solution was added thereto, and the processes of extraction, filtration, concentration and drying were conducted in the same manner as in Example 1-3 so as to obtain a dried ethanol extract. 1.6 kg of Bupleuri Radix-Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract was obtained.

Experimental Example 1: Test on inhibitory effect of herbal composition on delayed gastric emptying

In order to measure the inhibitory effect of the above herbal compositions on delayed gastric emptying, a rat model was used to perform the following experiment.

First, each extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma of Comparative Example 1-3 and two combination extracts of Example 1-3, and the complex extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma of Example 4 were used as experimental groups, and their efficacy on gastric emptying rate was compared to each other. A water-treated group was used as a control group, and a mosapride-treated group was used as a positive control group.

7 week-old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After a 1-week acclimation, healthy rats weighing 270 - 280 g were used for the experiments. The prepared herbal composition (20, 60, 200 mg/kg) and 10 mg/kg of mosapride as a positive control were orally administered once to rats that were fasted for 24 hrs and not allowed access to drinking water for 3 hrs. After 60 min, 2 mL of semisolid test meal (30 g of feed in 90 mL of 0.5 % methylcellulose) was orally administered by force using a disposable sonde. 30 min after feeding of semisolid test meal, the animals were anesthetized with CO₂, and then a laparotomy is performed to excise the stomach. The cardiac and pyloric ends of the stomach were clamped, and weighed. After weighing, the stomach was opened along the greater curvature, and the gastric contents were washed out with distilled water, and then the dry empty stomach was weighed.

The experiment was repeated three times, and the results were analyzed to calculate an average gastric emptying rate (GER) using the measured weight of semisolid test meal remaining in the stomach by the following mathematical formula 1. The results are shown in the following Table 1.

[Mathematical Formula 1]

Gastric emptying (%) = [1 - (Weight of semisolid test meal remaining in stomach after drug treatment / Weight of semisolid test meal remaining in 0 hour's stomach)] x 100

Table 1

Effect of herbal composition on gastric emptying rate
Section		Gastric emptying rate (%, mean ± standard error)
Control group	Water	16.31 ± 2.40
Positive control group	Mosapride (10 mg/kg)	51.16 ± 4.97*
Comparative Example 1	Bupleuri Radix extract (20 mg/kg)	12.34 ± 7.56
	Bupleuri Radix extract (60 mg/kg)	15.16 ± 4.58
	Bupleuri Radix extract (200 mg/kg)	10.25 ± 6.35
Comparative Example 2	Coptidis Rhizoma extract (20 mg/kg)	17.35 ± 5.89
	Coptidis Rhizoma extract (60 mg/kg)	20.54 ± 4.86
	Coptidis Rhizoma extract (200 mg/kg)	15.33 ± 5.65
Comparative Example 3	Glycyrrhizae Radix et Rhizoma extract (20 mg/kg)	18.75 ± 6.64
	Glycyrrhizae Radix et Rhizoma extract (60 mg/kg)	22.84 ± 5.84*
	Glycyrrhizae Radix et Rhizoma extract (200 mg/kg)	25.68 ± 7.61
Example 1	Bupleuri Radix-Coptidis Rhizoma extract (20 mg/kg)	18.44 ± 5.21
	Bupleuri Radix-Coptidis Rhizoma extract (60 mg/kg)	23.51 ± 4.24
	Bupleuri Radix-Coptidis Rhizoma extract (200 mg/kg)	17.54 ± 3.59
Example 2	Bupleuri Radix-Glycyrrhizae Radix et Rhizoma extract (20 mg/kg)	20.35 ± 7.72
	Bupleuri Radix-Glycyrrhizae Radix et Rhizoma extract (60 mg/kg)	25.68 ± 4.89
	Bupleuri Radix-Glycyrrhizae Radix et Rhizoma extract (200 mg/kg)	23.95 ± 5.28
Example 3	Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (20 mg/kg)	25.68 ± 5.44*
	Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (60 mg/kg)	29.57 ± 4.86
	Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (200 mg/kg)	20.30 ± 5.33
Example 4	Bupleuri Radix-Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (20 mg/kg)	28.57 ± 6.25
	Bupleuri Radix-Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (60 mg/kg)	34.89 ± 3.56*
	Bupleuri Radix-Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extract (200 mg/kg)	13.28 ± 4.07

Experimental animal: SD rat, Route: oral administration

*p-value evaluated by comparison with control group (p<0.05, Student's t-test)

As shown in Table 1, administration of two or more combinations of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma of Example 1-3 showed a significantly higher inhibitory effect on delayed gastric emptying rate than administration of each extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. Furthermore, administration of the complex extract of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma of Example 4 showed a significantly higher inhibitory effect on delayed gastric emptying rate than administration of each extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma as well as administration of two or more combinations thereof.

Accordingly, the results indicate that the complex extract of two or more of Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma according to the present invention exhibits a synergistic effect on the prevention and treatment of gastrointestinal diseases associated with functional dyspepsia, compared to single administration thereof. In addition, it can be seen that the herbal complex extract of Example 4 shows a significant inhibitory effect on delayed gastric emptying rate, similar to mosapride currently used for the treatment of functional dyspepsia.

Experimental Example 2: Effect of herbal composition on restraint stress-induced anorexia

On the basis of the results of Experimental Example 1, a rat model was used to perform the following experiment in order to measure the effect of the herbal composition prepared in Example 4 on gastrointestinal transit.

7 week-old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After a 1-week acclimation, healthy rats weighing 270 - 280 g were used for the experiment. In order to evaluate its salutary effect on anorexia, rats were fasted for 20 hrs and not allowed access to drinking water for 3 hrs, and then restrained in a restrainer for 6 hrs to induce stress. Thereafter, the rats were orally administered once with 3, 10, and 30 mg/kg of the herbal composition prepared in Example 4 and 3 mg/kg of the control mosapride, and then restrained for another 60 min. Normal rats were orally administered with a vehicle, and no stress was induced. After drug treatment, the rats were fed with pre-weighed meal, and the feed consumption for 30 min was measured. The results are shown in the following Table 2. As the vehicle, a 0.5% methylcellulose aqueous solution was used.

Table 2

Effect of herbal composition on restraint stress-induced anorexia
Section		Feed consumption (g) (mean ± standard	Improvement (%)
Normal group	Vehicle	4.23 ± 1.13
Control group	Vehicle (stress-induced)	1.84 ± 1.01*(p=0.0001)
Positive control group	Mosapride (3 mg/kg)	1.91 ± 0.49	2.9
Experimental group(Example 4)	Herbal composition (3 mg/kg)	1.87 ± 0.60	1.3
	Herbal composition (10 mg/kg)	1.55 ± 1.01	-
	Herbal composition (30 mg/kg)	2.38 ± 1.54	22.6

Experimental animal: SD rat (N=8), Route: oral administration

*p-value evaluated by comparison with normal group (p<0.01, Student's t-test)

As a result, no significant improvement in stress-induced anorexia was observed in all groups treated with the herbal composition of Example 4 and the mosapride-treated group. However, 22.6% improvement in stress-induced anorexia was observed in the group treated with 30 mg/kg of the herbal composition, indicating a more excellent result than the positive control, mosapride.

Experimental Example 3: Effect of herbal composition on restraint stress-induced delay of gastric emptying

In order to measure the effect of the herbal composition prepared in Example 4 on gastrointestinal transit, a rat model was used to perform the following experiment.

7 week-old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After a 1-week acclimation, healthy rats weighing 270 - 280 g were used for the experiment. In order to evaluate its effect on gastric emptying rate, rats were fasted for 24 hrs and not allowed access to drinking water for 3 hrs before drug treatment, and then administered with 1, 3, 10, 30, and 100 mg/kg of the herbal complex extract prepared in Example 4 and 30 mg/kg of the positive control itopride. 60 min after drug treatment, the rats were allowed access to 1.5 g of pre-weighed feed for 10 min, and their feed consumption was measured. Thereafter, the rats were restrained in a restrainer for 90 min to induce stress. The stress-induced rats were killed with CO₂ gas, and the stomach was excised. The gastric contents were removed, and the stomach was dried to calculate the gastric emptying rate. The results are shown in the following Table 3.

Table 3

Experimental animal: SD rat, Route: oral administration

*p-value evaluated by comparison with normal group (p<0.01, Student's t-test)

#p-value evaluated by comparison with stress-induced group (p<0.05, Student's t-test)

As a result, a significant improvement in restraint stress-induced delay of gastric emptying was observed in the group treated with 3 mg/kg of the herbal composition of Example 4, compared to the stress-induced group (π<0.05). Also, 100 mg/kg of herbal composition showed a higher inhibitory effect on stress-induced delay of gastric emptying.

Experimental Example 4: Effect of herbal composition on atropine-induced delay of gastrointestinal transit

7 week-old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After a 1-week acclimation, healthy rats weighing 270 - 280 g were used for the experiment. Rats were fasted for 24 hrs, and intraperitoneally administered with 1.5 mg/kg of atropine. Immediately, the rats were orally administered with 10, 30, and 100 mg/kg of the herbal composition prepared in Example 4, 30 mg/kg of itopride and 3 mg/kg of mosapride as the positive control, respectively. After 1 hr, 2 ml of semisolid test meal containing 0.05% Phenol red as a marker was orally administered to each rat. After 30 min, the rats were euthanized, and the small intestine was excised. The total length of the small intestine and the distance travelled by the marker along the small intestine from the pyloric portion were measured to calculate gastrointestinal transit. The experiment was repeated twice, and the results were compiled and analyzed. On the basis of the calculated values, the statistical significance in the gastrointestinal transit rate between the experimental and control groups was analyzed by Student's t-test, and thus the gastrointestinal transit between the normal group, positive control groups, and test material-treated groups was compared with each other, and the results are shown in the following Table 4.

Table 4

Effect of herbal composition on atropine-induced delay of gastrointestinal transit
Section		Number (N)	Transit rate (%) (mean ± standard deviation)
Normal group	Vehicle (saline solution, i.p)	12	64.6 ± 7.07
Control group	Vehicle (atropine, i.p)	12	50.3 ± 7.88^#
Positive control group	Itopride (30 mg/kg)	12	49.7 ± 9.03
Positive control group	Mosapride (3 mg/kg)	12	51.9 ± 6.78
Experimental group(Example 4)	Herbal composition (10 mg/kg)	11	56.6 ± 7.80
	Herbal composition (30 mg/kg)	11	60.6 ± 16.1*
	Herbal composition (100 mg/kg)	12	64.5 ± 16.0*

*p-value evaluated by comparison with control group (p<0.05, Student's t-test)

#p-value evaluated by comparison with normal group (p<0.001)

Administration of 30 and 100 mg/kg of the herbal composition of Example 4 significantly improved the atropine-induced delay of gastrointestinal transit, compared to the control group. In contrast, the positive control, itopride (30 mg/kg) and mosapride (3 mg/kg)-treated groups did not show a significant effect of improving gastrointestinal transit.

These results suggest that the herbal composition of Example 4 antagonizes the delayed gastrointestinal transit that is caused by blockade of muscarinic receptors by atropine, and facilitates gastrointestinal motility in a dose-dependent manner, and thus it can be developed as a therapeutic agent for functional dyspepsia (FD).

Experimental Example 5: Effect of herbal composition on dopamine-induced delay of gastrointestinal transit

7 week-old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After a 1-week acclimation, healthy rats weighing 270 - 280 g were used for the experiment. Rats were fasted for 24 hrs, and orally administered with the herbal composition (10, 30, 100 mg/kg) and itopride (30 mg/kg) and mosapride (3 mg/kg) as positive controls. After 1 hr, the rats were intraperitoneally administered with 1.5 mg/kg of dopamine. Immediately, 2 ml of semisolid test meal containing 0.05% Phenol red as a marker was orally administered to each rat. After 30 min, the rats were euthanized, and the small intestine was excised. The total length of the small intestine and the distance travelled by the marker along the small intestine from the pyloric portion were measured to calculate gastrointestinal transit. On the basis of the calculated values, a statistical significance in the gastrointestinal transit rate between the experimental and control groups was analyzed by Student's t-test, and thus the gastrointestinal transit between the positive control- and test material-treated groups was compared with each other, and the results are shown in the following Table 5.

Table 5

Effect of herbal composition on dopamine-induced delay of gastrointestinal transit
Section		Gastrointestinal transit rate (%) (mean ± standard deviation)
Normal group	Vehicle (saline solution, i.p)	72.2 ± 2.31
Control group	Vehicle (dopamine, i.p)	51.8 ± 7.23^#
Positive control group	Itopride (30 mg/kg)	71.9 ± 4.13*
Positive control group	Mosapride (3 mg/kg)	70.3 ± 13.8
Experimental group(Example 4)	Herbal composition (10 mg/kg)	62.6 ± 13.2
	Herbal composition (30 mg/kg)	75.3 ± 9.57*
	Herbal composition (100 mg/kg)	76.6 ± 7.01*

Experimental animal: SD rat (N=6), Route: oral administration

*p-value evaluated by comparison with control group (p<0.05, Student's t-test)

#p-value evaluated by comparison with normal group (p<0.001)

The results of calculating gastrointestinal transit (%) by measuring the total length of the small intestine and the distance travelled by the marker showed that the normal group (no dopamine) showed higher gastrointestinal transit than the control group (treated with dopamine only), indicating that the dopamine treatment significantly delays gastrointestinal transit.

Administration of 30 and 100 mg/kg of the herbal composition of Example 4 significantly improved gastrointestinal transit (p<0.05), which was in a dose-dependent manner. Among the control substances, the dopamine receptor antagonist, itopride (30 mg/kg) had a significant effect of improving gastrointestinal transit (p=0.002), but mosapride (3 mg/kg) did not, compared to the control group.

Preparation Example 1: Preparation of tablet

According to the following composition, the herbal composition prepared in Example 4 was used to prepare granules by wet and dry granulation methods, and was then tabletted to prepare a tablet for oral administration.

Herbal composition..............................200 mg

Light anhydrous silicic acid.....................10 mg

Magnesium stearate................................2 mg

Microcrystalline cellulose.......................50 mg

Sodium starch glycolate..........................25 mg

Corn starch.....................................113 mg

Ethanol absolute and purified water.........proper amount

Preparation Example 2: Preparation of capsule

According to the following composition, the herbal composition prepared in Example 4 was packed into a gelatin capsule to prepare a capsule.

Herbal composition.............................300 mg

Lactose.........................................50 mg

Starch..........................................50 mg

Talc.............................................2 mg

Magnesium stearate..........................proper amount

Preparation Example 3: Preparation of ointment

According to the following composition, the herbal composition prepared in Example 4 was used to prepare an ointment.

Herbal composition..............................5 g

Cetyl palmitate................................20 g

Cetyl alcohol..................................40 g

Stearyl alcohol................................40 g

Isopropyl myristate............................80 g

Sorbitan monostearate..........................20 g

Polysorbate....................................60 g

Propyl paraoxybenzoate..........................1 g

Methyl paraoxybenzoate..........................1 g

Phosphoric acid and purified water..........proper amount

Preparation Example 4: Preparation of injectable formulation

According to the following composition, the herbal composition prepared in Example 4 was used to prepare an injectable formulation.

Herbal composition..............................100 mg

Mannitol........................................180 mg

Dibasic sodium phosphate.........................25 mg

Methylparaben...................................0.8 mg

Propylparaben...................................0.1 mg

Sterile water for injection................proper amount

Preparation Example 5: Preparation of liquid formulation

According to the following composition, the herbal composition prepared in Example 4 was used to prepare a liquid formulation.

Herbal composition..............................300 mg

Sugar............................................20 g

High fructose corn syrup.........................20 g

Lemon flavor................................proper amount

Purified water.............................added to 100 mL

Preparation Example 6: Preparation of powder formulation

According to the following composition, the ingredients and the herbal composition prepared in Example 4 were mixed and filled in an airtight sac to prepare a powder agent

Herbal composition..............................0.2 g

Lactose.........................................1.5 g

Talc............................................0.5 g

Preparation Example 7: Preparation of pill

100 mL of honey was heated and filtered, and this procedure was repeated three or four times, until it became viscous and formed yellow threads, but did not stick to fingers after cooling. Water, chestnut oil and vinegar may be used instead of honey. 5 g of the herbal composition prepared in Example 4 was added to the heated honey and kneaded. The mixture was made into balls with a uniform size using a pill maker so as to prepare pills. The prepared pills were dried in a cool and dry place, and then sealed and stored in a cool and dark place.

Preparation Example 8: Preparation of suspension

0.1 g of the herbal composition prepared in Example 4 was added to 100 mL of water together with polyethylene glycol, polyvinyl pyrrolidone, carboxymethyl cellulose, bentonite or polysorbate 80 as a suspending agent, and mixed by stirring. As a sweetening agent, sodium saccharin, syrup, white sugar, honey or D-maltitol was mixed therewith to prepare a suspension according to a typical preparation method.

Preparation Example 9: Preparation of transdermal formulation

According to the following composition, the herbal composition prepared in Example 4 was used to prepare a transdermal formulation by a typical method.

Herbal composition...........................0.4 mg

Sodium polyacrylate...........................1.3 g

Glycerin......................................3.6 g

Aluminum hydroxide...........................0.04 g

Methylparaben.................................0.2 g

Purified water proper amount

Preparation Example 10: Preparation of chewing gum

According to the following composition and content, the herbal composition prepared in Example 4 was used to prepare a chewing gum by a typical method.

Herbal composition......................0.24 ~ 0.61%

Gum base....................................20%

Sugar..................................76.36 ~ 76.76%

Fruit flavor.................................1%

Purified water...............................2%

Preparation Example 11: Preparation of beverage

According to the following composition and content, the herbal composition prepared in Example 4 was used to prepare a beverage by a typical method.

Herbal composition.........................0.5 g ~ 1.3 g

Honey .......................................522 mg

Thioctic acid amide............................5 mg

Nicotinic acid amide..........................10 mg

Riboflavin sodium hydrochloride................3 mg

Pyridoxine hydrochloride.......................2 mg

Inositol......................................30 mg

Orotic acid ..................................50 mg

Purified water...............................300 mL

Preparation Example 12: Preparation of candy

According to the following composition and content, the herbal composition prepared in Example 4 was used to prepare a candy by a typical method.

Herbal composition ...........................20%

Crystalline lactitol..........................80%

Purified water...........................proper amount

Acesulfame...............................proper amount

Blueberry flavor.........................proper amount

Citric acid..............................proper amount

A mixture of 20% herbal composition and 80% crystalline lactitol was diluted with purified water, and put in a saucepan. The batch was first heated on a high-temperature plate until all substances became soluble. Subsequently, the batch was transferred to a vacuum cooker, and additionally heated. The resulting blend formed a viscous mass at a relatively low temperature. The syrup was transferred from the cooker to the rear plate, and hardened suitable for drop rolling. The hard mass was supplied through the drop roller. The candies were molded to have an acceptable quality.

Preparation Example 13: Preparation of liquor

650 g of Bupleuri Radix, 150 g of Coptidis Rhizoma and 150 g of Glycyrrhizae Radix et Rhizoma were washed and put in an extractor. 10,000 mL of water was added thereto, and concentrated at 100°C for about 3 hrs to obtain a liquid extract. Separately, steamed rice made of 4 kg of rice, 1 kg of traditional nuruk, and 5 kg of mother liquor were homogeneously mixed, and the liquid extract was added thereto, followed by fermentation at 10 - 25°C for about 3 days. The fermented liquor was filtered to separate liquid from solid, and heated at 55 - 60°C. Purified water was added to the filtrate up to 10,000 mL to prepare a liquor.

Claims

A pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic disease, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma.
A health functional food composition for the prevention or improvement of gastrointestinal dyskinetic diseases, comprising a combination of two or more selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma.
The composition according to claim 1 or 2, wherein the composition includes 10-30 parts by weight of Coptidis Rhizoma and 10-30 parts by weight of Glycyrrhizae Radix et Rhizoma, based on 100 parts by weight of Bupleuri Radix.
The composition according to claim 1 or 2, wherein each of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma is a pulverized herb itself, a dried herb powder or a crude extract of a solvent selected from the group consisting of water, C₁-C₄ alcohols and combinations thereof.
The composition according to claim 1 or 2, wherein the gastrointestinal dyskinetic disease is functional dyspepsia associated with delayed gastric emptying rate or gastrointestinal transit.
The composition according to claim 1, wherein the composition is in a form of powder, granule, tablet, capsule, suspension, emulsion, syrup, liquid, aerosol, extract, injectable preparation, percutaneous preparation, or suppository.
The composition according to claim 2, wherein the composition is in a form of liquid, suspension, powder, granule, tablet, capsule, pill, extract, tea, jelly or beverage.