RU2540511C2 - Pharmaceutical composition and food functional therapeutic composition for preventing, treating or relieving gastrointestinal dysmotilities - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a composition for preventing or treating gastrointestinal dysmotilities and to a food functional therapeutic composition for preventing or treating gastrointestinal dysmotilities; the above compositions contain mixture of two or more herbs specified in a group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma.

EFFECT: compositions provide the synergetic effect on preventing or treating gastrointestinal disorders, particularly functional dyspepsia associated with a rate of gastric emptying or a gastrointestinal transit.

6 cl, 5 tbl, 13 ex

Description

Technical field

The invention relates to a pharmaceutical composition and a functional food health composition for preventing, treating or alleviating gastrointestinal dyskinetic diseases, and in particular, a pharmaceutical composition for preventing and treating gastrointestinal dyskinetic diseases and a functional food health composition for preventing or alleviating gastrointestinal dyskinetic diseases which include a plant complex.

State of the art

Functional dyspepsia (PD) is a multifactorial disease caused by many pathogenic factors, including excessive secretion of gastric juice, abnormal motility of the gastrointestinal tract, visceral hypersensitivity, Helicobacter pylori infection, increased local irritating factors, stress and genetic factors. This is a syndrome characterized by pain or discomfort in the upper abdomen, diagnosed as sporadically occurring in the upper parts of the gastrointestinal tract without manifesting organic abnormalities during endoscopic, histological and biochemical examinations, and its pathophysiology remains unclear. Clinical symptoms of discomfort in the upper abdomen may include a feeling of fullness of the stomach, early satiety, bloating, nausea, belching, vomiting, vomiting, and these symptoms can be present in any combination.

Although functional dyspepsia is not fatal, its prevalence is considered high, and a growing interest in this disease has arisen with increased attention to quality of life. However, as mentioned above, its detection and pathophysiology are not clearly clarified, unlike other diseases of the digestive tract, and thus there were practically no therapeutic suggestions, and none of the drugs used in clinical practice proved to be effective for their treatment . In addition, 20-60% of patients with functional dyspepsia show an improvement in symptomatology in placebo treatment, which makes it difficult to evaluate drug therapy trials.

The motility of the gastrointestinal tract is usually modulated by the antagonistic double innervation of the autonomic nervous system and is regulated by a complex balance of excitation and inhibition of nerve factors. Acetylcholine (AH), released from cholinergic nerve endings, activates gastrointestinal motility, and its action is terminated by acetylcholinesterase (AChE), while dopamine interacts with dopamine receptors (D2) present on the preganglionic fibers of the cholinergic nerve to suppress leads to a decrease in motility of the gastrointestinal tract. The main therapeutic agents for dyskinetic diseases of the gastrointestinal tract include prokinetic agents, H2 receptor antagonists, PPI (proton pump inhibitors).

In particular, H. pylori infection was detected in ulcer-like illness or dyspepsia with impaired motor function, and it was indicated that 68% of patients with functional dyspepsia are actually infected with H. pylori . Practically ulcerative-like dyspepsia is treated with H2 receptor antagonists and PPIs, and dyspepsia with abnormal motility is treated with prokinetic drugs (metoclopramide, domperidone, mosapride, etc.), or antidepressants, or sedatives.

Prokinetic agents act as antidopaminergic agents, serotonergic agents and / or motilin receptor agonists to stimulate smooth muscle of the gastrointestinal tract, which increases the pressure of the lower esophageal sphincter and improves esophageal clearance and gastric emptying, which reduces the transit time of food through the gastrointestinal tract . Medications currently used as gastroprokinetic or antiemetic agents include metoclopramide, domperidone, cisapride, itopride, levosulpiride, mosaicride and the like. These drugs increase gastrointestinal motility, thereby improving the digestive symptoms accompanying chronic gastritis or dropping syndrome, but possible side effects have become a problem when prescribing these drugs.

Metoclopramide and domperidone are antagonists of dopamine D2 receptors and stimulate the motor function of the stomach. Metoclopramide enhances the release of AH in the myenteric plexus, but domperidone does not have such functions. Thus, the first of these agents is inhibited by cholinergic antagonists, while the other of these agents is not. In addition, these drugs may have side effects, including side effects on the central nervous system, discharge from the nipple, and gynecomastia.

Cisapride, often prescribed for functional dyspepsia, activates the 5-HT4 receptors on the myenteric plexus of the gastrointestinal tract to facilitate the release of AH and accelerates the physiological movements of the gastrointestinal tract. Cisapride is not an antagonist of dopamine D2 receptors, and therefore it does not have an antiemetic effect. However, it is contraindicated because of the risk of potentially fatal cardiac arrhythmias.

Itopride is an antagonist of dopamine D2 receptors, and also inhibits AChE and, therefore, activates the motility of the gastrointestinal tract through synergism.

Mozapride, like cisapride, activates 5-HT2 receptors to improve gastrointestinal motility. It lacks the antagonistic effect on dopamine D2 receptors, and, therefore, it does not cause adverse reactions of the central nervous system.

Functional dyspepsia is a common functional disorder of the gastrointestinal tract associated with mental stress, and therefore is accompanied by neuropathy, anxiety and depression. Thus, psychosocial interventions can play a role in treatment, and the combination of Western and Eastern medicine has been shown to be more effective in improving the symptoms of multifactorial disease. Thus, functional dyspepsia with multifactorial pathogenesis cannot be successfully treated with one type of drug, and there is a need to develop prokinetic agents with several mechanisms.

The above medicines demonstrate their effectiveness in disorders of the motility of the gastrointestinal tract, but also cause toxic side effects. Thus, there is a need for the development of safe drugs, as well as compositions that will be used to treat, prevent, or alleviate functional dyspepsia without causing side effects.

Bupleuri Radix is the root of Bupleurum falcatum L. or a variety thereof, which is a perennial herb from the family of umbellates. The dried sample should include 0.3% or more of Saicosaponin a (C ₄₂ H ₆₈ O ₁₃ : 780.99), not more than 10% of the stems and leaves, not more than 6.5% of the ashes and not more than 2.0% of the acid-insoluble ash (The Korean Pharmacopoeia 9 ^th Edition, 2007). Bupleuri Radix is harvested in spring and autumn, extracted from the aerial parts and soil, and dried in the sun. It contains ingredients such as oil, buplerumol, fatty acids, sugars and saponins, and its pharmacological activity includes anti-inflammatory, antipyretic, diuretic, antiulcer, sedative and antispasmodic and anti-pathogenic effects (Bo-sup Jung, Min-Kyo Shin Dohae native Korean medicine (herbal medicine) dictionary, Yeongnimsa, 2003: 412-414).

Coptis Rhizoma is a rhizome that is almost completely isolated from the roots of Coptis japonica Makino, Coptis chinensis Franchet or Coptis teeta Wallich , which is a perennial herbaceous plant from the ranunculus family. It should include 4.2% or more of berberine (like berberine chloride (C ₂₀ H ₁₈ ClNO ₄ : 371.81)) based on a dried plant, and drying loss should be no more than 9.0%, ash should be no more 4.0%, and the acid-insoluble ash shall not exceed 1,05% (The Korean Pharmacopoeia 9 ^th Edition, 2007). Coptis Rhizoma is harvested in autumn and isolated from leaves, roots and soil. After drying in the sun, the cork layer is removed. It contains alkaloids such as berberine, koptizin, vorenin, palmatin and zhateoresin, obakunon and obakulakton as the main ingredients, and its pharmacological activity includes anti-inflammatory, antiulcer, anti-cancer, anti-radiation, anti-microbial and anti-pathogenic effects (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 Glycyrrhizae uralensis Fischer, Glycyrrhiza glabra Linn, or Glycyrrhiza inflata Bat. , which is a perennial herb of the family of siliculose. It should include 2.5% or more of glycyrrhizic acid (C ₄₂ H ₆₂ O ₁₆ : 822.93) and 0.7% or more of liquiquitigenin (C ₁₅ H ₁₂ O ₄ : 256.27) based on the dried plant, and loss on drying should be no more than 12.0%, ash should be no more than 7.0%, and acid-insoluble ash should be no more than 2.0% (The Korean Pharmacopoeia 9 ^th Edition, 2007). The root is harvested in the fall. After removal of the processes of the rhizome and roots, the root is cut and dried under the sun. It contains triterpene-based saponins, glycyrrhizin, uralenic acid and flavonoids as the main components, and its pharmacological activity includes detoxification, anti-diuretic, antitussive, anti-inflammatory, anti-allergic, anti-ulcer and hepatoprotective effects (Bo-sup Jin Min. 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 an antiulcer effect, but there was no evidence of their therapeutic efficacy in functional dyspepsia. Traditionally, oriental medicines (such as cold powder at the extreme ends of plants and Pinellia Decoction Drain the Epigastrium) have been used only to improve symptoms along with other treatments that affect gastrointestinal motility and stress-related digestive upsets. It was found that isoliquiritigenin, a flavonoid isolated from Glycyrrhizae Radix et Rhizoma, plays a role in regulating the transit of food through the gastrointestinal tract due to the spasmogenic and antispasmodic effects on spasm during transit of food through the gastrointestinal tract. An antispasmodic effect can lead to activation of muscarinic receptors, while an antispasmodic effect is mainly due to the blockade of calcium channels (Chen G. et al. Phytother. Res. 2009, 23: 498-506).

Disclosure of invention

Technical problems

The inventors came to the conclusion that a composition should be developed for the prevention, relief or treatment of gastrointestinal dyskinetic diseases, and they put a lot of effort into developing a pharmaceutical composition having excellent efficacy and fewer side effects. They developed a combination of medicinal plants similar to a mosaicpride, which is commonly used as a prokinetic agent, thereby practicing the invention.

Solution

In view of the foregoing, an object of the present invention is to provide an effective pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic diseases, comprising a mixture of medicinal plants as an active ingredient.

Another objective of the present invention is the creation of an effective nutritional functional wellness composition for the prevention or alleviation of gastrointestinal dyskinetic diseases, including a mixture of medicinal plants as an active ingredient.

Preferred Embodiments

As described above, the composition according to the present invention includes a combination of two or more components selected from Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, thereby greatly alleviating dyskinetic diseases of the gastrointestinal tract, in particular, gastric emptying rate and gastrointestinal transit intestinal tract. Thus, the composition exhibits amazing effects in preventing, alleviating or treating gastrointestinal disorders caused by functional dyspepsia. In addition, it consists of medicinal plants, which are traditionally used for a long period of time, and therefore little attention is paid to undesirable side effects or toxicity.

To achieve the above objectives, the present invention relates to a pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic disease, comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. The present invention also relates to a method for the prevention or treatment of gastrointestinal dyskinetic disease, which comprises administering to a subject in need of this pharmaceutical composition comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. The present invention further relates to a pharmaceutical composition for the prevention or treatment of a dyskinetic disease comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. The present invention further relates to the use of a pharmaceutical composition comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, for the manufacture of a medicament for the prevention or treatment of dyskinetic disease.

In addition, the present invention relates to a functional food health composition for the prevention or alleviation of gastrointestinal dyskinetic diseases, comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. The present invention further relates to a method for preventing or alleviating a gastrointestinal dyskinetic disease, comprising administering to a subject in need of this nutritional functional wellness composition comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. Further, the present invention relates to a functional food health composition used to prevent or alleviate a dyskinetic disease comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. Further, the present invention relates to the use of a functional food health composition comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, for the manufacture of a medicament for the prevention or alleviation of dyskinetic disease.

The present invention will now be described in more detail.

The inventors made efforts to develop a herbal composition that has an effective effect on gastrointestinal motility without causing side effects, and they have found that gastrointestinal motility can be alleviated by using a combination of two or more Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, which are widely known medicinal plants and cause minor side effects. Thus, a combination of two or more Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma can be used as an active ingredient in a pharmaceutical composition for preventing or treating a gastrointestinal disease, as well as in a functional food health composition for preventing or alleviating gastrointestinal diseases .

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

In another aspect, the present invention relates to a nutritional functional wellness composition for preventing or alleviating a dyskinetic disease of the gastrointestinal tract, comprising a combination of two or more components selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma.

Further, the herbal composition will be used as a term encompassing the pharmaceutical composition and the nutritional functional health composition.

In the plant composition, the 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 with respect to 100 parts by weight of Bupleuri Radix.

Medicinal plants constituting the herbal composition of the present invention belong to the same category as is generally understood by those skilled in the art, and any medicinal plant having an effective effect on gastrointestinal motility can also be included.

Each of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma may be included in the composition as a liquid extract of a medicinal plant or as a powdered plant or dried plant powder. Thus, the type or method is not particularly limited. Liquid extracts of medicinal plants can be prepared separately or together with each other, extracting them with water, an organic solvent, or a combination thereof, in which the organic solvent may be C ₁ -C ₄ alcohols, acetone, chloroform, methylene chloride, ether, ethyl acetate, hexane or combinations thereof, but not limited to. As the C ₁ -C ₄ alcohols, there may be methanol, ethanol, propanol and butanol, and most preferably ethanol.

Liquid extracts of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma can be obtained by any extraction method known in the art and at a temperature of from 10 ° C to 80 ° C, preferably at room temperature (about 25 ° C), from 10 to 80 hours, preferably from 2 to 3 days, by extraction methods such as hot water extraction, cold immersion extraction, cold extraction with reflux condenser or ultrasound, and preferably cold immersion extraction from one to 5 times. The resulting liquid extract was filtered under reduced pressure and the filtrate was concentrated at a temperature of from 20 to 100 ° C, preferably at room temperature (about 25 ° C), under reduced pressure using a rotary evaporator to obtain the final extract.

A herbal composition comprising a combination of two or more Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma in accordance with the present invention, is effective for the prevention, relief or treatment of gastrointestinal dyskinetic diseases and, in particular, for the prevention, relief or treatment of functional dyspepsia associated with the rate of gastric emptying and the transit of food through the gastrointestinal tract. Such effects have been demonstrated in the following experimental examples.

In detail, to evaluate its inhibitory effect on the delayed gastric emptying rate, rats that were not fed for 24 hours were orally administered the herbal composition of the present invention once and then orally fed a semi-solid test meal and the weight of the stomach was measured to calculate the gastric emptying rate (GER). The results showed a significantly superior inhibitory effect on the delay in the rate of gastric emptying compared with the untreated group (control group), and the effect was similar to the group that was injected with mosapride as a positive control group.

Compared to each individual delivery of the extracts of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma as the main ingredients, the delivery of a herbal composition comprising a combination of two or more of the extracts showed an exceptionally excellent inhibitory effect on the delay in the rate of gastric emptying when each was introduced into equal doses. The results show that the combination exhibits a synergistic effect on the prevention or treatment of dyskinetic gastrointestinal diseases.

Rat models were used to study the therapeutic effect of the plant composition of the present invention on stress-induced anorexia and a slower rate of gastric emptying, and rat models treated with atropine and dopamine were used to study the therapeutic effect of the plant composition on drug-induced inhibition of gastrointestinal transit of food intestinal tract. The results showed that the herbal composition of the present invention shows a significant improvement in the therapeutic effect on food transit through the gastrointestinal tract.

In addition, the herbal composition of the present invention includes approved safe medicinal plants that are traditionally used for a long period of time, and therefore little attention is paid to undesirable side effects and toxicity, which allows long-term use of the composition in order to prevent or treat gastrointestinal diseases.

Thus, a pharmaceutical composition in accordance with one aspect of the present invention may include a pharmaceutically acceptable carrier or additive.

The pharmaceutical composition can be administered to mammals, including rats, mice, livestock and humans, in various ways, for example, orally, rectally, intravenously, intramuscularly, subcutaneously, by intrauterine administration under the membranes of the brain or intracerebroventricularly. Thus, the pharmaceutical composition may be included in typical pharmaceutical preparations known in the art. The pharmaceutical composition may be included in, but not limited to, oral preparations, injectable preparations, suppositories, transdermal preparations, and nasal preparations. It can be made in the form of any preparation, and preferably in the form of a liquid, suspension, powder, granules, tablets, capsules, pills, emulsions, syrup, aerosol, or oral preparations such as extracts.

When creating such preparations, a pharmaceutically acceptable carrier or an additive necessary for each preparation can be added. When creating oral preparations, one or more selected from diluents, lubricants, binders, disintegrants, sweeteners, stabilizers and preservatives can be used as a carrier, and one or more selected from flavorings, vitamins and antioxidants can be used as additives.

Carriers and additives may be selected from any pharmaceutically acceptable. In particular, preferred examples of the diluent may include lactose, dextrose, sucrose, corn starch, soybean oil, microcrystalline cellulose, sorbitol, xylitol and mannitol, preferred examples of lubricants may include magnesium stearate and talc, and preferred examples of a binder may include polyvinylpyrrolidone or hydroxypropyl. In addition, preferred examples of the disintegrant may include calcium carboxymethyl cellulose, sodium carboxymethyl starch, potassium polyacrylate or crospovidone, preferred examples of the sweetener may include white sugar, fructose, sorbitol or aspartame, preferred examples of the stabilizer may include sodium carboxymethyl cellulose b, , white beeswax and xanthan gum, and preferred examples of a preservative may include methyl parahydroxybenzoate, propyl parahydroxy enzoat and potassium sorbate.

In addition to these ingredients, well-known flavoring additives, for example, a natural flavor, such as plum, lemon, pineapple or a vegetable flavor, natural fruit juice, a natural color, such as chlorophyllin or flavonoid, a sweetener, such as fructose, honey, sugar alcohol or sugar, or an acidifier, such as citric acid or sodium citrate, may also be included.

Examples of preparations for parenteral administration include aseptic aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized agent and suppositories. Propylene glycol, polyethylene glycol, vegetable oil, such as olive oil, or injectable ether, such as ethyl oleate, can be used to prepare a non-aqueous solvent and suspension. As a suppository base, vitepsol, macrogol, tween 61, cocoa butter, lauric oil or glycerogelatin can be used.

The pharmaceutical composition can be made by varying the proportions in the composition of plant components within the range of maintaining therapeutic or prophylactic effects on dyskinetic gastrointestinal disease, and the composition may comprise 0.01-80% by weight and preferably 1-50% by weight of plant components in accordance with the present invention.

To achieve a therapeutic or prophylactic effect on dyskinetic gastrointestinal disease, the active ingredient of the composition may be administered once or more at a daily dose of 0.01-10 g / kg / day, preferably 1-5 g / kg / day, based on dry powder liquid extract, and this can be correctly determined depending on the patient’s age, gender, body weight, nutrition, level of secretion or other drugs that the patient is taking. Thus, the pharmaceutical composition must be made taking into account the effective range of doses, and if necessary, specific dosage regimens can be adjusted over time depending on individual needs and at the discretion of the specialist or those who oversee the administration of the compositions, or each dosage unit of the prepared composition can be entered several times at a specified time interval.

A nutritional functional health composition in accordance with another aspect of the present invention may include a sitologically acceptable carrier or additive.

The term “functional health food” as used herein means a functional health food product including ingredients that are on the permitted list of ingredients in accordance with communication of the Korean Food and Drug Administration (KFDA) No. 2008-72, and their functionality and safety established by the act of functional wellness products specified in 2008.

A functional food health composition in accordance with the present invention can be made in the form of a typical food health composition known in the art. A functional functional food composition may be in the form of a powder, granules, tablets, pills, capsules, suspension, emulsion, syrup, tincture, liquid, extract, chewing gum, tea, jelly or drink. As a sitologically acceptable carrier or additive, there may be any carrier or additive known in the art.

A functional food health composition may include the herbal components that make up the composition of the present invention in an amount of from 0.01 to 15% by weight, preferably from 0.2 to 10% by weight of the total weight of the product and from 0.1 to 30 g , preferably from 0.2 to 5 g per 100 ml of the drink.

The beverage may further include other components, in addition to the herbal ingredients described above, in which the other components may be various flavors or natural carbohydrates used in conventional drinks. As examples of the aforementioned natural carbohydrates, there may be conventional sugars such as a monosaccharide (e.g. glucose, fructose, etc.), a disaccharide (e.g. maltose, sucrose, etc.) and a polysaccharide (e.g. dextrin, cyclodextrin, etc. .) and sugar alcohol, such as xylitol, sorbitol and erythritol. As another flavoring agent, a natural flavoring agent (e.g., thaumatin, stevia extract, etc.) and a synthetic flavoring agent (e.g., saccharin, aspartame, etc.) may be included. Preferably, the natural carbohydrates described are contained in an amount of from 1 to 20 g, preferably from 5 to 12 g, based on 100 ml of the beverage.

The active ingredients Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma included in the pharmaceutical composition and the functional food health composition in accordance with the present invention can be administered simultaneously or sequentially for a predetermined period of time within the framework of achieving preventive, reclamation or therapeutic effects on dyskinetic gastrointestinal diseases. If the combination of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma is intended to be administered at a specific time interval, each active ingredient is prepared separately. If a combination of two or more Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma is delivered at the same time, their homogeneous mixture can be prepared as a single formulation, or they can be prepared separately, and then separate formulations can be entered into same time.

The implementation of the invention

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

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

Dried Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma were purchased from eastern medicine suppliers, washed with water to remove impurities, and dried herbal medicines were used to make extracts. Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were pulverized using a grinder, and 400 ml of an 80% aqueous ethanol solution was added to 200 g of each. The cold immersion process was carried out 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 a temperature of 50 ° C, and the solvent was completely removed and dried in a vacuum oven to give dried ethanol extracts. 31 g of Radix Bupleuri 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 powder form.

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

Dried Bupleuri Radix, Coptidis Rhizoma, and Glycyrrhizae Radix et Rhizoma were purchased from eastern medicine suppliers, washed with water to remove impurities, and dried herbal medicines were used to make 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 Rhoma , and 500 g of each of Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma (Example 3) were added to the extractor, respectively. 2 L of an 80% aqueous ethanol solution was added to each combination, and the extraction, filtration, concentration and drying processes were carried out in the same order as in comparative example 1-3 to obtain a dry ethanol extract. 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 extract (Example 3) were obtained.

Example 4: Preparation of the 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 eastern medicine suppliers, washed with water to remove impurities, and dried herbal medicines were used to make extracts.

Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma were pulverized using a grinder, then 6.5 kg of Bupleuri Radix, 1.5 kg of Coptidis Rhizoma and 1.5 kg of Glycyrrhizae Radix et Rhizoma were placed in an extractor. To them was added 20 l of an 80% aqueous ethanol solution, and the extraction, filtration, concentration and drying process was carried out in the same order as in Example 1-3 to obtain a dry ethanol extract. 1.6 kg of Bupleuri Radix-Coptidis Rhizoma - Glycyrrhizae Radix et Rhizoma was obtained.

Experimental example 1: Test for the inhibitory effect of a plant composition on the delay in the rate of gastric emptying

In order to measure the inhibitory effect of herbal compositions on delaying the rate of gastric emptying, rat models were used to perform the following experiment.

Firstly, each extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma of Comparative Example 1-3 and two combined extracts of Example 1-3 and the complex extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma of Example 4 were used in experimental groups, and their effectiveness on the rate of gastric emptying was compared with each other. The water treated group was used as a control group, and the mosprid group was used as a positive control group.

7 week old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After 1 week of acclimatization, healthy rats weighing 270-280 g were used for research. The prepared herbal composition (20, 60, 200 mg / kg) and 10 mg / kg of mosapride as a positive control were once administered orally to rats that did not receive food for 24 hours and did not have access to drinking water for 3 hours. After 60 minutes, 2 ml of a semi-solid test meal (30 g of feed in 90 ml of 0.5% methylcellulose) was forcibly administered orally using a single-use probe. 30 minutes after feeding the semi-solid test food, the animals were anesthetized with CO ₂ and then a laparotomy was performed to excise the stomach. The cardiac or pyloric ends of the stomach were clamped and weighed. After weighing, the stomach was opened along the greater curvature, the contents of the stomach were washed with distilled water, and then a dry empty stomach was weighed.

The experiment was repeated three times, and then the results were analyzed to calculate the average gastric emptying rate (GER), for which the measured weight of the semi-solid test meal remaining in the stomach was used using the following mathematical formula 1. The results are shown in Table 1.

Mathematical formula 1

Gastric emptying (%) = (1- (weight of a semi-solid test food remaining in the stomach after drug treatment / weight of a semi-solid test food remaining in the stomach after 0 hours)) × 100

Table 1

Table 1
The effect of plant composition on the rate of gastric emptying Section Gastric emptying rate (%, mean ± standard error) Control group Water 16.31 ± 2.40 Positive control group Mozapride (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 Reference 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 Reference 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 animals: SD rats, route of administration: oral delivery
* P-value calculated in comparison with the control group (p <0.05, Student t-test)

As shown in Table 1, the delivery 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 gastric emptying delay than the delivery of each extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma. In addition, the delivery of the complex extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma of Example 4 showed a significantly higher inhibitory effect on the gastric emptying delay rate than the delivery of each extract of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhhae Radix et Rhizoma, as well or more combinations thereof.

Thus, the results show that the complex extract of two or more Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma in accordance with the present invention has a synergistic effect on the prevention or treatment of gastrointestinal diseases associated with functional dyspepsia compared with their separate delivery . In addition, it can be noted that the plant complex extract of Example 4 shows a significant inhibitory effect on the delay rate of gastric emptying, which is identical to the effect exerted by mosapride, which is currently used to treat functional dyspepsia.

Experimental Example 2: Effect of Herbal Composition on Limited Stress Induced Anorexia

Based on the results of Experimental Example 1, rat models were used to perform the following experiment in order to determine the effect of the plant composition on food transit through the gastrointestinal tract obtained in Example 4.

7 week old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After 1 week of acclimatization, healthy rats weighing 270-280 g were used for research. In order to evaluate its beneficial effect on anorexia, the rats were not fed for 20 hours and were not given access to drinking water for 3 hours, and then they were kept in a fixation device for 6 hours to cause stress. Then, 3, 10 and 30 mg / kg of the herbal composition obtained in Example 4 and 3 mg / kg of the control mosapride were orally administered to rats one-time, and then fixed for another 60 min. For normal rats, only the vehicle was orally administered and did not cause stress. After drug treatment, rats were fed pre-weighed food and food intake was measured for 30 minutes. The results are shown in Table 2. An aqueous solution — a 0.5% methylcellulose solution — was used as a carrier.

table 2

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

Experimental Example 3: Effect of a Herbal Composition on Limited Stress-Induced Delayed Gastric Emptying

In order to measure the effect of the plant composition obtained in Example 4 on the transit of food through the gastrointestinal tract, rat models were used to perform the following experiment.

7 week old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After 1 week of acclimatization, healthy rats weighing 270-280 g were used for research. In order to assess the effect on the rate of gastric emptying, the rats were not fed for 24 hours and were not given access to drinking water for 3 hours before drug treatment, and then they were administered with 1, 3, 10, 30, and 100 mg / kg of herbal complex extract obtained in Example 4, and 30 mg / kg of itopride as a positive control. 60 minutes after drug administration, rats were allowed access to 1.5 g of pre-weighed feed for 10 minutes and the amount of feed consumed was measured. The rats were then enclosed in a fixture for fixation for 90 minutes to cause stress. Stress-induced rats were sacrificed with CO ₂ gas and the stomach was excised. The contents of the stomach were removed and the stomach was dried to calculate the rate of gastric emptying. The results are shown in the following table 3.

Table 3

As a result, a significant improvement in limiting the stress-induced delay in gastric emptying was observed in the group receiving 3 mg / kg of the herbal composition of Example 4, compared with the stress-induced group (p <0.05). In addition, 100 mg / kg of the plant composition showed a higher inhibitory effect on the stress-induced delay in the rate of gastric emptying.

Experimental Example 4: Effect of plant composition on atropine-induced gastrointestinal transit of food

In order to measure the effect of the plant composition obtained in Example 4 on the transit of food through the gastrointestinal tract, rat models were used to perform the following experiment.

7 week old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After 1 week of acclimatization, healthy rats weighing 270-280 g were used for research. Rats were not fed for 24 hours and 1.5 mg / kg of atropine was intraperitoneally administered. Immediately after this, the rats were orally administered with 10, 30 and 100 mg / kg of the plant composition obtained in Example 4 and 30 mg / kg of itopride and 3 mg / kg of mosaicride as a positive control, respectively. After 1 hour, 2 ml of a semi-solid test meal containing 0.05% red phenol as a marker was orally administered to each rat. After 30 minutes, the rats were euthanized and the small intestine was excised. The total length of the small intestine and the distance traveled by the marker along the small intestine from the pylorus was measured to calculate the transit of food along the gastrointestinal tract. The experiment was repeated twice, and the results were summarized and analyzed. Based on the calculated values, the statistical significance of food transit through the gastrointestinal tract between the experimental and control groups was analyzed by Student's t-test, and therefore, food transit through the gastrointestinal tract between the normal group, the positive control group and the test groups was compared with each other , and the results were presented in Table 4.

Table 4

The introduction of from 30 to 100 mg / kg of the herbal composition of Example 4 significantly improved the delayed transit of food through the gastrointestinal tract caused by atropine compared with the control group. On the other hand, the positive control of the groups receiving itopride (30 mg / kg) and mosapride (3 mg / kg) did not show a significant effect on improving food transit through the gastrointestinal tract.

These results show that the herbal composition of Example 4 counteracts a delay in the transit of food through the gastrointestinal tract, which is caused by blockade of muscarinic receptors by atropine, and also facilitates gastrointestinal motility depending on the dose, and thus it can be developed as a therapeutic agent for the treatment of functional dyspepsia (PD).

Experimental Example 5: Effect of Plant Composition on Dopamine-Caused Gastrointestinal Transit

In order to measure the effect of the plant composition obtained in Example 4 on the transit of food through the gastrointestinal tract, rat models were used to perform the following experiment.

7 week old male Sprague-Dawley rats were purchased from Jung-Ang Lab. Animal, Inc. After 1 week of acclimatization, healthy rats weighing 270-280 g were used for research. The rats were not fed for 24 hours and then the herbal composition (10, 30, 100 mg / kg) and itopride (30 mg / kg) and mosapride (3 mg / kg) were orally administered as a positive control. After 1 hour, 1.5 mg / kg of dopamine was intraperitoneally administered to rats. Immediately afterwards, 2 ml of a semi-solid test food containing 0.05% red phenol as a marker was orally administered to each rat. After 30 minutes, the rats were euthanized and the small intestine was excised. The total length of the small intestine and the distance traveled by the marker along the small intestine from the pylorus was measured to calculate the transit of food along the gastrointestinal tract. Based on the calculated values, the statistical significance of food transit through the gastrointestinal tract between the experimental and control groups was analyzed using the Student t-test, and thus, the transit of food along the gastrointestinal tract between the positive control group and the test groups was compared with each other , and the results were presented in the following table 5.

Table 5

Table 5
The effect of plant composition on dopamine-induced gastrointestinal transit of food Section Gastrointestinal transit (%) (mean standard deviation) Normal group Carrier (physical solution, etc.) 72.2 ± 2.31 Control group Carrier (dopamine, etc.) 51.8 ± 7.23 ^# Positive control group Itopride (30 mg / kg) 71.9 ± 4.13 * Mozapride (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 animals: SD rats (N = 6), route of administration: oral delivery
* P - value calculated in comparison with the control group (p <0.05, Student t-test)
# P - value calculated in comparison with the normal group (p <0.001)

The results of calculating the transit of food along the gastrointestinal tract (%) by measuring the total length of the small intestine and the distance traveled by the marker showed that the normal group (not dopamine) showed a higher transit of food along the gastrointestinal tract than in the control group (receiving dopamine only), indicating that dopamine treatment significantly slows down the transit of food through the gastrointestinal tract.

The introduction of from 30 to 100 mg / kg of the herbal composition of Example 4 significantly improved the transit of food along the gastrointestinal tract (p <0.05), which was dose dependent. Between the control substances, the dopamine receptor antagonist, itopride (30 mg / kg), a significant effect was shown to improve the transit of food through the gastrointestinal tract (p = 0.002), and the mosapride (3 mg / kg) did not show such an effect compared to control group.

Preparation Example 1: Preparation of a Tablet

According to the following composition, the herbal composition obtained in Example 4 was used for the manufacture of granules using wet and dry granulation methods, and then tabletted for the manufacture of tablets for oral use.

Herbal composition 200 mg

Clarified Anhydrous Silicic Acid 10 mg

Magnesium Stearate 2 mg

Microcrystalline Cellulose 50 mg

Sodium Carboxymethyl Starch 25 mg

Corn Starch 113 mg

Absolute ethanol and purified water - the required amount

Preparation Example 2: Production of Capsules

According to the following composition, the herbal composition obtained in Example 4 was packaged in gelatin capsules to make the capsule.

Herbal composition 300 mg

Lactose 50 mg

Starch 50 mg

Talcum 2 mg

Magnesium Stearate - Amount Required

Preparation Example 3: Preparation of Ointment

According to the following composition, the herbal composition obtained in Example 4 was used to make 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 - the required amount

Preparation of Example 4: Preparation of an Injectable Composition

According to the following composition, the herbal composition obtained in Example 4 was used to make an injection composition.

Herbal composition 100 mg

Mannitol 180 mg

Dibasic Sodium Phosphate 25 mg

Methylparaben 0.8 mg

Propylparaben 0.1 mg

Sterile water for injection - the required amount

Preparation Example 5: Preparation of a Liquid Composition

According to the following composition, the herbal composition obtained in Example 4 was used to make a liquid composition.

Herbal composition 300 mg

Sugar 20 g

High fructose corn syrup 20 g

Lemon Flavor - Amount Required

Purified water - add up to 100 ml

Preparation Example 6: Preparation of a Powdered Composition

According to the following composition, the ingredients and the herbal composition obtained in Example 4 were mixed and placed in an airtight bag for the manufacture of powder products

Herbal composition 0.2 g

Lactose 1.5 g

Talc 0.5 g

Preparations of Example 7: Preparation of a Pill

100 ml of honey was heated and filtered, and this procedure was repeated three or four times until it became viscous and began to form yellow trickles, but did not stick to fingers after cooling. Water, chestnut oil and vinegar can be used instead of honey. 5 g of the herbal composition obtained in Example 4 was added to heated honey and kneaded. The mixture was formed into balls of the same size using the pill manufacturer in such a way as to make pills. The prepared pills were dried in a cool and dry place, and then tightly closed and stored in a cool and dark place.

Preparation Example 8: Preparation of the suspension

0.1 g of the herbal composition obtained in Example 4 was added to 100 ml of water together with polyethylene glycol, polyvinylpyrrolidone, carboxymethyl cellulose, bentonite or polysorbate 80 as a suspending agent, and stirred by shaking. As a sweetener, sodium saccharin, syrup, white sugar, honey or D-maltitol were mixed with them to make a suspension in accordance with the usual manufacturing method.

Preparation Example 9: Preparation of Transdermal Composition

According to the following composition, the herbal composition obtained in Example 4 was used to prepare the transdermal composition in a conventional manner.

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 - Amount Required

Preparation Example 10: Making Chewing Gum

According to the following composition and its composition, the herbal composition obtained in Example 4 was used to make chewing gum in the usual way.

Herbal composition 0.24 ~ 0.61%

Chewing base 20%

Sugar 76.36 ~ 76.76%

Fruit Flavor 1%

Purified Water 2%

Preparation Example 11: Preparation of a Beverage

According to the following composition and its composition, the herbal composition obtained in Example 4 was used to make a drink in the usual way.

Herbal composition 0.5 g ~ 1.3 g

Honey 522 mg

Lipoic 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: Making Candy

According to the following composition and its composition, the plant composition obtained in Example 4 was used to make candy in the usual way.

Herbal composition 20%

Crystalline Lactitol 80%

Purified Water - Amount Required

Acesulfame - the required amount

Blueberry Flavor - Amount Required

Citric Acid - Amount Required

A mixture of 20% plant composition and 80% crystalline lactitol was diluted with distilled water and placed in a pan. The mixture was first heated on a high temperature stove until all substances dissolved. The mixture was then transferred to a vacuum cooker and further heated. As a result, a viscous mass formed at a relatively low temperature. The syrup was moved from the plate to the back panel and imparted the hardness necessary for rolling the sweets. The solid mass was fed through a candy roller. Thus, sweets with acceptable quality were obtained.

Preparation Example 13: Making Liquor

650 g of Bupleuri Radix, 150 g of Coptidis Rhizoma and 150 g of Glycyrrhizae Radix et Rhizoma were washed and placed in an extractor. 10000 ml of water was added and concentrated at 100 ° C for about 3 hours to obtain a liquid extract. Separately, steamed rice obtained from 4 kg of rice, 1 kg of traditional nuruk and 5 kg of mother liquor was mixed to a homogeneous mass, and liquid extract was added to this mass, and then left to ferment at 10-25 ° C for 3 days. The fermented beverage was filtered to separate the liquid from the solids and heated at 55-60 ° C. Purified water was added to the filtrate to 10,000 ml for the preparation of drinks.

Claims (6)

1. A pharmaceutical composition for the prevention or treatment of gastrointestinal dyskinetic diseases, comprising a mixture of extracts of two or more herbaceous plants selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, where a mixture of extracts of herbaceous plants obtained by solvent extraction of herbaceous plants selected from the group consisting of water, C1-C4 alcohols and combinations thereof, and where herbaceous plants include 10-30 parts by weight of Coptidis Rhizoma and 10-30 parts by weight of Glycyrrhizae Radix et Rhizoma with respect to 100 parts to the parts of Bupleuri Radix. 2. A functional food health composition for the prevention or treatment of dyskinetic gastrointestinal diseases, comprising a mixture of extracts of two or more herbaceous plants selected from the group consisting of Bupleuri Radix, Coptidis Rhizoma and Glycyrrhizae Radix et Rhizoma, where a mixture of extracts of herbaceous plants obtained by extraction of herbaceous plants with a solvent selected from the group consisting of water, C1-C4 alcohols and combinations thereof, and where herbaceous plants include 10-30 parts by weight of Coptidis Rhizoma and 10-30 parts by weight of Glycyrrhizae Radix et Rhizoma of respect to 100 parts by mass of Bupleuri Radix. 3. The composition according to claim 1, in which the gastrointestinal dyskinetic disease is functional dyspepsia associated with a delay in the rate of emptying of the stomach or transit of food through the gastrointestinal tract. 4. The composition according to claim 2, in which the gastrointestinal dyskinetic disease is functional dyspepsia associated with a delay in the rate of gastric emptying or food transit through the gastrointestinal tract. 5. The composition according to claim 1, where the composition is in the form of a powder, granules, tablets, capsules, suspensions, emulsions, syrups, liquids, aerosols, extracts, injectables, transdermal preparations or suppositories. 6. The composition according to claim 2, where the composition is in the form of a liquid, suspension, powder, granules, tablets, capsules, pills, extracts, tea, jellies or drinks.