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WO2012091492A2 - Extrait de plantes, composition pharmaceutique comprenant celui-ci et aliment fonctionnel diététique comprenant celle-ci - Google Patents

Extrait de plantes, composition pharmaceutique comprenant celui-ci et aliment fonctionnel diététique comprenant celle-ci Download PDF

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Publication number
WO2012091492A2
WO2012091492A2 PCT/KR2011/010314 KR2011010314W WO2012091492A2 WO 2012091492 A2 WO2012091492 A2 WO 2012091492A2 KR 2011010314 W KR2011010314 W KR 2011010314W WO 2012091492 A2 WO2012091492 A2 WO 2012091492A2
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Prior art keywords
extract
corydalis tuber
pharbitidis semen
weight ratio
gastrointestinal motility
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WO2012091492A3 (fr
Inventor
Soon Hoe Kim
Miwon Son
Hyun Joo Shim
Tae Ho Lee
Junghoon Kim
Yong Sam Kwon
Hye Ju Kim
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Dong A Pharmaceutical Co Ltd
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Dong A Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/50—Fumariaceae (Fumitory family), e.g. bleeding heart
    • A61K36/505—Corydalis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/39—Convolvulaceae (Morning-glory family), e.g. bindweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a herbal extract containing a Pharbitidis semen extract and a Corydalis tuber extract, a pharmaceutical composition including the same and a health functional food including the same.
  • gastrointestinal motility disorders act together manifesting one or usually multiple symptoms.
  • functional gastrointestinal diseases are classified into ulcer-like dyspepsia, dysmotility-like dyspepsia, reflux-like dyspepsia, nonspecific or unspecified functional dyspepsia, and the like.
  • Symptomatic causes of these functional gastrointestinal diseases usually remain unclear although some of them have been identified.
  • Functional gastrointestinal diseases with unknown symptomatic causes are defined in terms of functional symptoms, not histopathological and biochemical organic lesions and therefore have been treated aimed at reducing symptoms.
  • Various symptoms manifested in functional gastrointestinal disorders may be treated mainly by promoting gastrointestinal motility.
  • Functional dyspepsia which is a representative gastrointestinal motility disorder, is also diagnosed based on various dyspepsia symptoms without apparent organic lesions, and therefore therapeutic treatment thereof is not simple and most symptoms alternate between amelioration and worsening being affected severely by diet and stress. These pathological mechanisms act together manifesting one or usually multiple symptoms.
  • a therapeutic agent for the treatment of functional dyspepsia include gastrointestinal prokinetic agents such as domperidone, metoclopramide, levosulpiride, mosapride, itopride, and erythromycin.
  • gastrointestinal prokinetic agents such as domperidone, metoclopramide, levosulpiride, mosapride, itopride, and erythromycin.
  • gastric acid suppressants and antacid agents are used for the treatment of functional dyspepsia but these drugs including H2 antagonists usually have transient effects (Vincenzo Stanghellini et al., Delayed Gastric Emptying in Functional Dyspepsia, Current Treatment Options in Gastroenterology, 7, 259-264, 2004).
  • a 5-HT 4 receptor agonist whish is one of gastrointestinal prokinetic drugs recently and newly used for the treatment of functional dyspepsia, improves the symptoms without increasing the tension at the gastric fundus.
  • Cisapride which is one of 5-HT 4 receptor agonists, has an effect of accelerating gastric emptying and is recognized as having a statistically significant effect when compared to other drugs, but as to the duodenum or intragastric pressure wavelength (>6 cm), cisapride increases the threshold value of recognizing gastric distension in healthy individuals as well as in patients and may also exhibit adverse side effects fatal to the heart.
  • Korean Patent Application No. 10-2007-0019560 discloses that at least one herbal extract selected from the group consisting of Sinapis semen, Corydalis tuber, Pharbitidis semen and Strychnos ignatii semen extracts is effective for the prevention or treatment of gastrointestinal motility disorders.
  • a herbal extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a specific ratio has excellent effects particularly on gastrointestinal motility disorders.
  • the present invention provides a mixed extract containing a Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:5.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of a gastrointestinal motility disorder, including a mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:5.
  • the present invention provides a health functional food including a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the present invention provides use of a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5, for the prevention or treatment of a gastrointestinal motility disorder.
  • the present invention provides a method for the prevention or treatment of a gastrointestinal motility disorder, including administering a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 to a subject.
  • the present invention provides a mixed extract containing a Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:5.
  • Pharbitidis semen refers to a seed of Pharbitis nil Choisy belonging to the family Convolvulaceae , contains roughly 11% of fatty oil and 2% of pharbitin which is a resinous glucoside, and is known to have cathartic, diuretic and insecticidal effects. (The Korean Pharmacopeia V, Part 2, pp 651).
  • Corydalis tuber refers to Corydalis ternata Nakai and other tuberous plants belonging to the family Papaveraceae , contains Berberine, 1-Canadine, Protopine and 1-tetrahydrocoptisine, and has analgesic, sedative, antispasmodic, antiemetic and ACTH hypersecretion actions. (The Korean Pharmacopeia V, Part 2, pp 664).
  • the Pharbitidis semen extract or the Corydalis tuber extract individually exhibits preventive or therapeutic effects on gastrointestinal motility disorders.
  • a mixed extract of the Pharbitidis semen extract and the Corydalis tuber extract exhibits superior effects on gastrointestinal motility disorders, as compared with effects of either extract alone.
  • a mixed extract containing the Pharbitidis semen extract and the Corydalis tuber extract in a weight ratio of 1:5 exhibits remarkably excellent effects on gastrointestinal motility disorders, as compared to compositions containing the Pharbitidis semen extract and the Corydalis tuber extract in a weight ratio other than the above specified ratio of 1:5.
  • the mixed extract containing the Pharbitidis semen extract and the Corydalis tuber extract in a weight ratio of 1:5 exhibits excellent effects particularly on gastrointestinal motility disorders resulting from 5-HT 3 receptor overactivity and/or 5-HT 4 receptor antagonistic activity.
  • Gastrointestinal motility disorders of unidentified causes are defined in terms of functional symptoms, not histopathological and biochemical organic lesions and therefore have been treated from the viewpoint of reducing symptoms.
  • Various symptoms manifested in functional gastrointestinal disorders may be treated mainly by promoting gastrointestinal motility.
  • gastrointestinal motility disorder examples include functional dyspepsia such as early satiety, pain, epigastric distress, a false sense of satiety, heartburn, nausea and vomiting; ulcerative dyspepsia, non-ulcerative dyspepsia; a gastroesophageal reflux disease, reflux esophagitis, gastric atony, intestinal pseudo-obstruction, gastroparesis; constipation; irritable bowel syndrome such as general hypersensitive colitis, hypersensitive colitis accompanied by constipation or hypersensitive colitis accompanied by diarrhea; a diabetic gastrointestinal motility disorder; chemotherapy-induced gastrointestinal motility disorder, visceral obstruction due to gastrointestinal dysmotility and a gastrointestinal motility disorder due to myotonic dystrophy, and noncardiac chest pain.
  • functional dyspepsia such as early satiety, pain, epigastric distress, a false sense of satiety, heartburn, nausea and vomiting
  • ulcerative dyspepsia non-ulcer
  • functional dyspepsia is not a pathological or biochemical organic lesion but a functional symptom with manifestation of continuous epigastric distress or pain. Medically it means various symptoms associated with continuous and repetitive discomfort or pain confined to the epigastric part. Specifically, functional dyspepsia includes all the symptoms relating to the digestive system including postprandial fullness, anorexia, abdominal distention, early satiety, belching, epigastric distress or pain, heartburn, nausea, vomiting, gastric reflux, and heartburn.
  • Irritable bowel syndrome is a disease with manifestation of abdominal pain and altered bowel habits, that is, diarrhea, constipation, or repetition of diarrhea and constipation. Symptoms of irritable bowel syndrome are intermittent but may be continuous. Irritable bowel syndrome is a chronic disease with the manifestation of symptoms for a minimum of more than three months. Irritable bowel syndrome may be generally classified into three types in terms of clinical aspect: one type mainly accompanying constipation, one type mainly accompanying diarrhea, and one type with alternating symptoms of constipation and diarrhea.
  • Irritable bowel syndrome patients may exhibit symptoms such as epigastric discomfort, dyspepsia, nausea, vomiting, headache, irregular menstruation, and frequent urination, in addition to altered bowel habits and abdominal pain.
  • Irritable bowel syndrome may include general colitis diseases including hypersensitive colitis. Since there is no finding of constitutional, biochemical or infectious causes for the disease, irritable bowel syndrome is considered to be a disease due to functional disorders. Functional abnormalities are associated with disorders of sensory and motility functions of the intestinal tract. In therapy of irritable bowel syndrome, an anticholinergic agent or an anticonvulsant is used for a disease with a main symptom of diarrhea, whereas a gastrointestinal prokinetic agent is used for a disease with a symptom of constipation.
  • Gastroesophageal reflux disease is a disease in which reflux of gastric or duodenal contents into the esophagus results in symptoms or tissue damage.
  • Symptoms of gastroesophageal reflux disease include chest burning at the back side of the sternum and reflux symptoms, i.e., reflux of gastric juice or gastric contents into the pharynx, chest pain, swallowing difficulty, painful swallowing, chronic laryngeal symptoms, foreign body sensation in the throat, coughing, and hoarseness.
  • esophageal reflux of gastric acid or gastric contents occurs to irritate the lower esophagus, thus causing various related symptoms.
  • Medication of gastroesophageal reflux diseases is carried out using an antacid agent, an H2 receptor blocker, a gastrointestinal prokinetic agent, or a gastric acid suppressant.
  • An antacid agent is beneficial for the treatment of mild reflux symptoms which take place occasionally.
  • An H2 receptor blocker is not effective in more than about 1/3 of disease cases in terms of symptomatic alleviation effect, particularly fails to provide complete mucosal healing in more than a half of disease cases with attendant esophagitis.
  • a gastrointestinal prokinetic agent increases the pressure of the lower esophageal sphincter, enhances esophageal peristalsis, and accelerates gastrointestinal evacuation, thus being beneficial for the treatment of gastroesophageal reflux diseases.
  • a gastric acid suppressant is used for the treatment of severe esophagitis patients with serious esophagitis and complications.
  • Gastric atony is a disease referring to diminished muscle tone of stomach walls and is generally accompanied by decline of peristalsis as well. Gastric atony may take place when there is independent neurosis such as nervous breakdown, one symptom of systemic neurosis or a genital disease as reflex neurosis. Gastric atony may also occur as sequela of various diseases such as gastroptosis, chronic gastritis, dyspepsia, and chronic appendicitis. Subjective symptoms thereof include gastric fullness. Although there is no abnormality of appetite, fasting of food due to being afraid of postprandial gastric fullness results in great loss of body weight. An individual with gastric atony usually experiences belching, a feeling of nauseation and also intestinal atony. This condition results in constipation, and a serious illness leads to headaches and vertigo. Gastric atony is generally treated using a gastrointestinal prokinetic agent.
  • Constipation may be divided into atonic constipation in which intestinal motility is generally decreased, spastic constipation in which intestinal motility is accelerated but is incapable of pushing the feces out, and rectal constipation in which intestinal motility is normal but an evacuation fails due to anorectal hanging of feces.
  • a gastrointestinal prokinetic agent is used in the treatment of constipation.
  • gastrointestinal motility disorders may appear individually or simultaneously.
  • functional dyspepsia patients also experience irritable bowel syndrome.
  • functional dyspepsia is commonly accompanied by gastroesophageal reflux disease, aerophagia, cholelithiasis or the like.
  • about 90% of patients with irritable bowel syndrome also experience functional dyspepsia.
  • the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of improving gastric emptying of food, gastric accommodation and gastrointestinal transit, is also capable of activating gastrointestinal motility, and is capable of inhibiting gastrointestinal hypersensitivity.
  • the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of much more smoothly promoting gastric emptying of food, as compared to compositions containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than the above specified ratio of 1:5, is capable of preventing or treating delayed gastrointestinal transit, is capable of accelerating gastric distention upon intake of food, and is capable of effectively inhibiting visceral hypersensitivity.
  • the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 exhibits excellent effects particularly on gastrointestinal motility disorders such as gastroesophageal reflux disease, noncardiac chest pain, functional dyspepsia, gastric atony, intestinal pseudo-obstruction, constipation, and irritable bowel syndrome.
  • the mixed extract of the present invention is also capable of exhibiting excellent effects on multiple gastrointestinal motility disorders.
  • the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of improving gastric emptying capacity, gastric accommodation and gastrointestinal transit without adverse side effects such as by having adverse effects on the heart and is also capable of improving gastrointestinal motility.
  • the present invention includes congeneric herbs of Pharbitidis semen and Corydalis tuber that are known in the art and may be used for the same or similar use as in the prevention or treatment applications of the present invention.
  • the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 may be prepared by obtaining the Pharbitidis semen extract and the Corydalis tuber extract and mixing the extracts in a weight ratio of 1:5. Alternatively, after mixing Pharbitidis semen and Corydalis tuber in a weight ratio of 1:5, the mixed extract may be obtained from the resulting mixture.
  • the mixed extract may be obtained as follows. Pharbitidis semen and Corydalis tuber are respectively ground by a mill, and then the ground Pharbitidis semen and the ground Corydalis tuber are mixed in a weight ratio of 1:5. The ground mixture of Pharbitidis semen and Corydalis tuber is extracted using about 1 to 25-fold, preferably 5 to 15-fold volume of a suitable solvent, thereby obtaining a mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the solvent may be water, lower alcohol (such as ethanol or methanol) or a mixture thereof, preferably a mixture of water and ethanol.
  • the extraction may be carried out at a temperature of about 20 to 100°C, preferably 45 to 75°C for about 1 hour to 100 hours, preferably 65 hours 80 hours.
  • the extraction may be carried out by a conventional extraction process such as hot water extraction, cold precipitation extraction, reflux cooling extraction, or ultrasonic extraction. Preferred is hot water extraction.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of a gastrointestinal motility disorder, including the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of preventing or treating various symptoms of gastrointestinal motility disorders
  • a composition including such a mixed extract is capable of effectively preventing or treating gastrointestinal motility disorders.
  • the pharmaceutical composition of the present invention includes about 0.01 to about 80% by weight, preferably about 1 to about 50% by weight of the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the pharmaceutical composition of the present invention may further include an active ingredient having a therapeutic effect on gastrointestinal motility disorders including functional dyspepsia, in addition to the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the pharmaceutical composition may further include domperidone, metoclopramide, levosulpiride, mosapride, itopride, erythromycin, cisapride, or the like.
  • the pharmaceutical composition of the present invention may further include other pharmaceutical active ingredients having a therapeutic effect on diseases other than the foregoing gastrointestinal motility disorders.
  • the pharmaceutical composition of the present invention may be used alone or in combination with methods employing surgical operation, hormone therapy, medication therapy or biological response modifiers.
  • the pharmaceutical composition of the present invention may further include an appropriate carrier, excipient or diluent commonly used in the art, in addition to the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • Examples of the carrier, excipient and diluent that may be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), depending on desired applications. Preferred is oral administration.
  • the pharmaceutical composition of the present invention may be formulated into a variety of dosage forms.
  • the pharmaceutical composition of the present invention may be formulated into tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions, emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.
  • the pharmaceutical composition may be formulated into a solid preparation for oral administration, such as a tablet, a pill, a powder, a granule or a capsule, or a liquid preparation for oral administration, such as a suspension, a liquid for internal use, an emulsion or a syrup.
  • a preparation for parenteral administration such as a sterile aqueous solution, a non-aqueous solution, a suspension, an emulsion, a freeze-dried preparation and a suppository.
  • the solid preparation may be formulated with the addition of (a) a filler or an extender, for example starch, lactose, sucrose, glucose, mannitol or silicic acid, (b) a binder, for example carboxymethylcellulose, alginate, polyethylene glycol, microcrystalline cellulose, highly dispersive silica, natural gum, synthetic gum, povidone, copovidone, polyvinylpyrrolidone or gelatin, (c) a humectant, for example glycerol, (d) a disintegrant, for example agar, calcium carbonate or sodium carbonate, (e) a solution retarder, for example paraffin, and (f) an absorption enhancer, for example quaternary ammonium compound, (g) a wetting agent, for example cetyl alcohol or glycerol mono
  • the liquid preparation When the pharmaceutical composition is formulated into a liquid preparation such as a suspension, a liquid for internal use, an emulsion or a syrup, the liquid preparation may be formulated with the addition of a simple diluent such as water or liquid paraffin, and a variety of additives such as a wetting agent, a sweetening agent, a fragrance, a preservative, an antiseptic and a colorant to the pharmaceutical composition.
  • the liquid preparation may be formulated with further addition of peppermint oil, eucalyptus oil, or a sweetener such as saccharin to the pharmaceutical composition.
  • the suppository may be formulated with the use of water-soluble or water-insoluble excipients, for example polyethylene glycol, fat (such as cacao fat), higher ester (for example, C14-alcohol with C16-fatty acid), witepsol, macrogol, tween 61, laurin fat and glycerol gelatin or a mixture thereof.
  • water-soluble or water-insoluble excipients for example polyethylene glycol, fat (such as cacao fat), higher ester (for example, C14-alcohol with C16-fatty acid), witepsol, macrogol, tween 61, laurin fat and glycerol gelatin or a mixture thereof.
  • the suspension may be formulated with the use of liquid diluents, for example water, ethyl alcohol, propylene glycol and polyethylene glycol, and suspending agents, for example ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, injectable ester (such as ethyl oleate), oil (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil or sesame oil), or a mixture thereof.
  • liquid diluents for example water, ethyl alcohol, propylene glycol and polyethylene glycol
  • suspending agents for example ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, injectable ester (such as e
  • such a formulation may contain animal or vegetable fat, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide, or a mixture thereof.
  • such a formulation may contain a conventional excipient, for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof.
  • the spray may further contain a conventional propellant, such as chlorofluorohydrocarbon.
  • a nasal spray may also be formulated using PEG-4000 and glycerin.
  • the pharmaceutical composition of the present invention may be provided in the form of a sustained- or immediate-release formulation, using a carrier, a diluent, a dispersant, a surfactant, a binder, a lubricant and an additive.
  • the pharmaceutical composition of the present invention may be formulated into a sustained- or immediate-release formulation such that it is capable of releasing an active ingredient of the pharmaceutical composition only in a certain part of the intestinal tract.
  • the sustained-release dosage form may be formulated using a polymeric material such as an enteric polymer, a water-insoluble polymer, a hydrophobic polymer or a hydrophilic polymer, or using an embedding composition such as wax.
  • a polymeric material such as an enteric polymer, a water-insoluble polymer, a hydrophobic polymer or a hydrophilic polymer, or using an embedding composition such as wax.
  • a polymeric material such as an enteric polymer, a water-insoluble polymer, a hydrophobic polymer or a hydrophilic polymer
  • an embedding composition such as wax
  • the content of an excipient or additive to be added is not particularly limited and may be appropriately adjusted within the content range used in common formulation.
  • the dose of the pharmaceutical composition of the present invention may vary depending on weight, age, gender, health status and dietary habits of the patient, administration timing and routes, administration duration or interval, excretion rates, particularity of physical constitution, the nature of the formulation, and severity of the disease.
  • the pharmaceutical composition of the present invention may be administered in an amount of about 0.01 to about 10g/kg, preferably about 1 to 5g/kg once or several times a day, in terms of a ground mixture prior to extraction of the foregoing mixed extract.
  • the pharmaceutical composition of the present invention may be administered to a mammal, such as rat, mouse, livestock or human, via various administration routes.
  • a mammal such as rat, mouse, livestock or human
  • Any administration route may be adopted without particular limitation and therefore the administration may be carried out by, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intrathecal or intracerebroventricular injection.
  • the herbal extracts of the present invention have little toxicity or adverse side effects and therefore can be safely used even upon long-term administration thereof for the purpose of disease prevention.
  • the present invention provides a health functional food including a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the health functional food as defined in the present invention has the characteristics of health functional food ingredients listed in the Korean FDA notification No. 2004-12 based on the functions and safety on humans, newly defined in Health Functional Food Act of 2002.
  • the health functional food of the present invention contains only herbal ingredients such as the foregoing Pharbitidis semen extract and Corydalis tuber extract and is therefore safe and enables long-term application thereof in the form of a food. Further, since the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 exhibits remarkably excellent effects on gastrointestinal motility disorders, long-term application of the mixed extract in the form of a food is capable of effectively preventing or ameliorating symptoms of gastrointestinal motility disorders in which symptoms frequently and unexpectedly appear in daily life.
  • the mixed extract of a Pharbitidis semen extract and a Corydalis tuber extract may be provided in the form of a health functional food including various foods like drinks, gum, tea, vitamin complex, and health supplementary food.
  • a health functional food containing the mixed extract of a Pharbitidis semen extract and a Corydalis tuber extract may be in the form of a pill, powder, granule, infusion, tablet, capsule or drink.
  • the health functional food containing the mixed extract of a Pharbitidis semen extract and a Corydalis tuber extract may contain about 0.01 to about 15% by weight, preferably about 0.2 to 10% by weight of the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5, based on the total weight of the food.
  • the health functional food is a drink
  • the drink may contain about 0.1 to 30g/100mL, preferably about 0.2 to 5g/100mL of the mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • the health functional food may further contain a sitologically acceptable food additive, in addition to the mixed extract of a Pharbitidis semen extract and a Corydalis tuber extract.
  • the drink may contain various liquid components, in addition to the mixed extract of a Pharbitidis semen extract and a Corydalis tuber extract.
  • the drink may further contain a sweetening agent or a natural carbohydrate.
  • the content of natural carbohydrate in the drink may be in the range of about 1 to 20 g/100mL, preferably about 5 to 12 g/100mL.
  • the natural carbohydrate that can be added to the drink is not particularly limited and examples thereof include monosaccharide, disaccharide such as glucose or fructose, polysaccharide such as maltose or sucrose, general sugar such as dextrin or cyclodextrin, and sugar alcohol such as xylitol, sorbitol or erythritol.
  • the sweetening agent that can be added to the drink may be a natural or synthetic sweetening agent.
  • the sweetening agent include a natural sweetening agent such as thaumatin, a stevia extract (for example, Rebaudioside A or glycyrrhizin) and a synthetic sweetening agent such as saccharine or aspartame.
  • the drink may further contain additives, in addition to the natural carbohydrate and sweetening agent.
  • the drink may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents (such as synthetic and natural flavoring agents), colorants, extenders (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used for carbonated drinks, etc.
  • the health functional food of the present invention may contain fruit flesh used for preparing natural fruit juices, fruit juice drinks or vegetable drinks. These ingredients may be used alone or in any combination thereof.
  • additives are not particularly limited and may be appropriately adjusted if necessary.
  • the additives may be incorporated in an amount of less than 20 parts by weight based on 100 parts by weight of the drink.
  • the present invention provides use of a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5, for the prevention or treatment of a gastrointestinal motility disorder.
  • the present invention provides a method for the prevention or treatment of a gastrointestinal motility disorder, including administering a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 to a subject.
  • the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 has remarkably excellent effects on gastrointestinal motility disorders. Therefore, a pharmaceutical composition containing the same mixed extract is capable of effectively preventing or treating gastrointestinal motility disorders, and a food containing the same mixed extract is capable of effectively preventing or ameliorating gastrointestinal motility disorders.
  • Fig. 1 shows therapeutic effects of the mixed extract of the present invention containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 on impaired gastric accommodation.
  • reagents and solvents referred to hereinafter were purchased from Sigma.
  • a statistical analysis of the experimental results of Experimental Examples were carried out by ANOVA (one way analysis of variance), and when recognized as being statistically significant, a test of significance at a level of p ⁇ 0.05 or p ⁇ 0.01 was carried out by a Student-Newman-Keuls Test.
  • Example 1 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:5
  • Dried Corydalis tuber and Pharbitidis semen were purchased from a herbal medicine shop (located in the Gyeongdong Market area, Jaegi-dong, Seoul, South Korea), followed by removal of impurities and experimental use.
  • the dried Corydalis tuber and Pharbitidis semen were ground. 20g of the ground Pharbitidis semen and 100g of the ground Corydalis tuber were mixed, and 960mL of a 50% ethanol aqueous solution was added thereto. The mixture was thoroughly stirred at room temperature for 72 hours, extracted with hot water and filtered.
  • the filtrate was concentrated under reduced pressure at a temperature of 55 to 65°C and then freeze-dried to obtain a mixed extract as a soft extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5.
  • Comparative Example 1 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:1
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:1 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 20g of the ground Corydalis tuber were used.
  • Comparative Example 2 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:2
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:2 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 40g of the ground Corydalis tuber were used.
  • Comparative Example 3 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:3
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:3 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 60g of the ground Corydalis tuber were used.
  • Comparative Example 4 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:4
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:4 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 80g of the ground Corydalis tuber were used.
  • Comparative Example 5 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:6
  • a mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:6 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 120g of the ground Corydalis tuber were used.
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:7 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 140g of the ground Corydalis tuber were used.
  • Comparative Example 7 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:8
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:8 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 160g of the ground Corydalis tuber were used.
  • Comparative Example 8 Preparation of mixed extract containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:9
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:9 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 180g of the ground Corydalis tuber were used.
  • a mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:10 was prepared in substantially the same manner as in Example 1, except that 20g of the ground Pharbitidis semen and 200g of the ground Corydalis tuber were used.
  • mice Male Sprague-Dawley (SD) rats, weighing approximately 250g, were grouped on the basis of body weight. Animals were given a one-week acclimation period with a supply of standard diet and water at a temperature of 22 to 24°C and humidity of 60 to 80%, and were fasted for 24 hours prior to the experiment. The animals were allowed to freely access water during fasting and a supply of water was also stopped from 3 hours before start of the experiment. Mixed extracts of Example 1 or Comparative Examples 1 to 9 were each suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose, followed by oral administration of 1mL/animal.
  • a semisolid test meal which was prepared by adding and grinding animal feed in water, was orally administered at a dose of 2mL/animal. After 35 minutes, the animals were sacrificed and the stomach was excised and weight of the stomach having residual semisolid test meal was measured. Thereafter, the stomach was washed with distilled water to remove gastric contents and then weighed again. The gastric emptying rate was calculated according to the following equation. The results are given in Table 1 below.
  • a control group 1 in Table 1 was orally given only physiological saline at a dose of 1mL/animal.
  • Control groups 2 to 5 in Table 1 were orally given cisapride, mosapride, itopride, and dompeiridone, respectively. Each of cisapride, mosapride, itopride, and dompeiridone was suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose, followed by oral administration of 1mL/animal.
  • Gastric emptying (%) [1-(weight of semisolid test meal remaining in stomach/weight of semisolid test meal at a time of 0)] x100
  • Weight of semisolid test meal at a time of 0 is a measured weight of semisolid test meal remaining in the stomach of animals sacrificed immediately after administration of semisolid test meal
  • Example 1 As can be seen from Table 1, the use of the mixed extract of Example 1 containing Pharbitidis semen extract and Corydalis tuber extract in a weight ratio of 1:5 exhibited the highest value of gastric emptying of 73.8%. In addition, the extract of Example 1 exhibited about 50% to 100% higher gastric emptying, as compared to the mixed extracts of Comparative Examples 1 to 9 containing the Pharbitidis semen extract and the Corydalis tuber extract in a weight ratio other than the above specified ratio of 1:5.
  • the mixed extract of Example 1 exhibited about 40% to 120% higher gastric emptying, as compared to the conventional drug used for treating gastrointestinal motility disorders. Particularly, the mixed extract of Example 1 exhibited a superior effect to cisapride.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 has effectively prevented and ameliorated the symptoms of the gastrointestinal motility disorder.
  • the delayed gastrointestinal transit model employed a model in which migrative motor complex (MMC) has effects mainly on gastric emptying and intestinal motility and which is used in the evaluation of medicinal efficacy of prokinetics focusing on gastrointestinal motility function of functional dyspepsia patients (De Winter, B.Y., et al., Effects of mu- and kappa-opioid receptors on postoperative ileus in rats. Eur J Pharmacol, 1997. 339(1): p. 63-7.)
  • MMC migrative motor complex
  • SD rats weighing approximately 250g were grouped on the basis of body weight. Animals were given a one-week acclimation period with a supply of standard diet and water at a temperature of 22 to 24°C and humidity of 60 to 80%, and were fasted for 24 hours prior to the experiment. The animals were allowed to freely access water during fasting and a supply of water was also stopped from 3 hours before start of the experiment. The SD rats treated as thus were anesthetized with ether, and the region for surgical operation was shaved with a clipper and disinfected with povidone iodine.
  • Example 1 After performing a 5cm incision of the skin, a 3cm abdominal incision of the abdominal wall and the peritoneum was made along the midline and mild inflammation was induced by manual massage. Thereafter, skins of the abdominal wall and peritoneum were sutured using an auto clip, followed by sterilization with povidone iodine. After a recovery period of 4 hours, the mixture of Example 1 or the mixtures of Comparative Examples 1 to 9 were each suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose and were orally administered at a dose of 1mL/animal.
  • fluorescein isocyanate-labeled dextran (FITC, a 10-fold dilution of 5mM solution in physiological saline was used) was administered to animals which were then dissected after 15 minutes.
  • the small intestine from the duodenal to the appendix was incised and divided equally to 10 pieces.
  • the equally divided tissues were placed on a 12-well plate and 1mL of physiological saline was added thereto, followed by storage at a temperature of 0 to 4°C for 24 hours. Thereafter, the supernatant of the well plate was subjected to a fluorescence assay.
  • control groups 2 to 5 in Table 2 were orally given cisapride, mosapride, itopride, and dompeiridone, respectively.
  • Each of cisapride, mosapride, itopride, and dompeiridone was suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose, followed by oral administration of 1mL/animal.
  • Geometric center [ ⁇ (fluorescence fraction (%) per segment x segment number)]/100
  • Example 2 when the mixed extract of Example 1 containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 was administered, the value of geometric center was about 2-fold higher than the mixed extracts of Comparative Examples 1 to 9 containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than a weight ratio of 1:5.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of more effectively treating delayed gastrointestinal motility, as compared to compositions containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than a ratio of 1:5.
  • the mixed extract of Example 1 exhibited about 40% to 80% higher value of geometric center, as compared to the conventional drug used for treating gastrointestinal motility disorders. Particularly, the mixed extract of Example 1 exhibited a superior effect to cisapride.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 has effectively prevented and ameliorated the symptoms of the gastrointestinal motility disorder.
  • Gastric accommodation is a response which normally occurs upon intake of food. About 40% of functional dyspepsia patients have impairments in gastric accommodation response which correlates with early satiety and weight loss exhibited by functional dyspepsia patients.
  • Beagle dogs were housed in single cages and were given a one-week acclimation period with a supply of standard diet and water at a temperature of 22 to 24°C and humidity of 60 to 80%.
  • a gastric mucosa was continuously sutured with an absorbable suture. After confirming the fixation of fistula, the muscular layer of curvatura ventriculi major of the stomach was subjected to Lambert suture, a fixing ring was inserted, and then the stomach was returned to the original position. After confirming the position of fistula, the peritoneum and the muscular layer were sutured with an absorbable suture to provide solid fixation thereof, and a fistula cap was installed to prevent release of gastric contents.
  • An antibiotic cephalexin 30mg/kg, b.i.d.
  • an anti-inflammatory agent serratiopeptidase 0.2mg/kg, b.i.d.
  • a 24-hour fasted beagle dog was placed in a sling, followed by fixation. Thereafter, a gastric fistula cap was opened, the inside of the stomach was washed with water of the same temperature as body temperature, a balloon connected to a barostat (G&J Electronics) was inserted through a distal portion, and the position of the balloon was confirmed by X-ray photography.
  • G&J Electronics barostat
  • Example 1 By inflating the balloon in 1-mmHg increments of intra-balloon pressure beginning at 0mmHg pressure such that evident respiratory excursions were observed and by taking a pressure at which a balloon volume was >30 cc as a minimal distending pressure (MDP), the experiment was carried out at a pressure of MDP+2mmHg. After the state where air of the balloon was completely removed was taken to be 0 mL, a folded balloon was inflated to 200 mL to be unfolded, thus confirming normal operation thereof. After allowing the animals to become stable for 5 minutes, any extract of Example 1 or Comparative Examples 1 to 9 was suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose and orally administered at a dose of 1mL/kg.
  • MDP minimal distending pressure
  • a basal accommodation volume was measured for 10 minutes.
  • An ensure powder 250kcal/200cc was dissolved in 200 cc of water and was supplied by a 50 mL syringe such that the animals voluntarily take as much as they can.
  • a gastric accommodation volume was measured at a pressure of MDP+2mmHg. Gastric accommodation volume values over time when administering the mixed extract of Example 1 are shown in Fig. 1.
  • Control group 1 is a group to which 1mL/kg of physiological saline alone was orally administered in place of mixed extracts of Example 1 or Comparative Examples 1 to 9
  • Control group 2 is a group to which sumatriptan was orally administered at a dose of 1 mL/kg of body weight of experimental animals, in place of mixed extracts of Example 1 or Comparative Examples 1 to 9.
  • Example 1 when the mixed extract of Example 1 containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 was administered, the area value was about 20% to 60% higher than the mixed extracts of Comparative Examples 1 to 9 which were soft extracts containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than a weight ratio of 1:5. Further, Example 1 exhibited about a 90% higher area value than Control group 1 to which physiological saline alone was administered and exhibited about a 40% higher area value than Control group 2 to which sumatriptan was orally administered.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of much more effectively treating impaired gastric accommodation, as compared to mixed extracts containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than a ratio of 1:5 and a conventionally used drug, sumatriptan.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 has effectively prevented and ameliorated the symptoms of the gastrointestinal motility disorder.
  • Pain occurring due to visceral hypersensitivity is one of symptoms common throughout functional gastrointestinal disorders (FGIDs) including functional dyspepsia.
  • FGIDs functional gastrointestinal disorders
  • the experiment was carried out according to the method disclosed in Lin, C. and E.D. Al-Chaer, Long-term sensitization of primary afferents in adult rats exposed to neonatal colon pain. Brain Research, 2003. 971(1): p. 73-82.
  • the hypersensitive rectum was induced by colorectal distension, according to the following procedure.
  • An angioplasty balloon (Advanced Polymers Inc., length: 20.0mm; diameter: 3mm) was inserted 3cm into a descending rectum via the anus.
  • a pressure of 60mmHg (as measured by a blood-pressure gauge) was applied through the angioplasty balloon to rats when being 8, 10 and 12-days old, once a day for 1 minute, thereby resulting in colorectal distension to induce hypersensitive rectum.
  • Hypersensitive rectum-induced rats and normal rats with body weight of about 250g were given orally 1mL/animal of any one of mixed extracts of Example 1 or Comparative Examples 1 to 9 suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose.
  • the rats were anesthetized by intraperitoneal administration of pentobarbital sodium at a dose of 50mg/kg.
  • the carotid artery was exposed by skin incision under the anesthetic state, followed by insertion and fixation of a PE-50 tube connected to a blood pressure sensor, and the skin was restored and temporally sutured.
  • CCD colorectal distension
  • Changes in blood pressure were recorded throughout a period of colorectal distension (CRD) with a pressure of 20 to 90mmHg.
  • CRD colorectal distension
  • a mean of blood pressure values of more than at least 5 cycles at a time point exhibiting a stable blood pressure of a basal blood pressure level before application of CRD and a mean of blood pressure values of more than at least 5 cycles at a time point exhibiting the lowest blood pressure after application of CRD were analyzed, and a difference between two mean blood pressure values was taken as a changed blood pressure value.
  • a changed value of more than 15mmHg in blood pressure was defined as a changed amount of blood pressure when feeling pain.
  • Control group 1 is a group to which 1mL/animal of physiological saline alone was administered to rats with induced hypersensitive rectum, in place of the mixed extract of a Pharbitidis semen extract and a Corydalis tuber extract, and Control group 2 is a normal group with no induction of hypersensitive rectum.
  • the control group 3 in Table 4 was orally given amitriptyline. Amitriptyline was suspended to a concentration of 4 mg/mL in 3% hydroxypropyl methylcellulose, followed by oral administration of 1mL/animal.
  • Example 1 As can be seen from Table 4, when the mixed extract of Example 1 containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 was administered, the colorectal distension pressure leading to a blood pressure change of 15mmHg, that is, pain threshold, was about 30% to 68% higher than the mixed extracts of Comparative Examples 1 to 9 containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than a weight ratio of 1:5. Further, Example 1 exhibited an increase of more than about 100% in pain threshold, as compared to the control group.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 is capable of effectively treating visceral hypersensitivity, as compared to mixed extracts containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio other than a ratio of 1:5.
  • Example 1 exhibited about 70% higher pain threshold, as compared to amitriptyline used for treating gastrointestinal motility disorders.
  • the inventive mixed extract containing a Pharbitidis semen extract and a Corydalis tuber extract in a weight ratio of 1:5 has effectively prevented and ameliorated the gastrointestinal motility disorder.

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Abstract

La présente invention concerne un mélange d'extraits contenant un extrait de Pharbitidis semen et un extrait de Corydalis tuber en un rapport en poids de 1/5, une composition pharmaceutique destinée à la prévention ou au traitement de troubles de la motilité gastro-intestinale comprenant celui-ci et un aliment fonctionnel diététique comprenant celle-ci. Le mélange d'extraits améliore la vidange gastrique, l'accommodation gastrique et le transit gastro-intestinal, accélère la motilité gastro-intestinale, et inhibe l'hypersensibilité viscérale afin de prévenir ou de traiter efficacement les troubles de la motilité gastro-intestinale.
PCT/KR2011/010314 2010-12-29 2011-12-29 Extrait de plantes, composition pharmaceutique comprenant celui-ci et aliment fonctionnel diététique comprenant celle-ci Ceased WO2012091492A2 (fr)

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CN104162032A (zh) * 2014-08-05 2014-11-26 施怀杰 治疗肠梗的中药
CN113009003A (zh) * 2019-12-22 2021-06-22 珠海润都制药股份有限公司 一种盐酸伊托必利制剂中有关物质的检测方法

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KR101199946B1 (ko) * 2012-07-12 2012-11-12 김현민 현호색 및 흑축 추출물의 독성 저감화 방법, 이로부터 제조된 독성이 저감화된 생약추출물, 및 그 생약추출물을 함유하는 위장관 운동장애질환 치료용 조성물
KR101579688B1 (ko) * 2014-07-08 2015-12-24 재단법인 전남생물산업진흥원 좁쌀풀 추출물을 유효성분으로 함유하는 과민성 대장증후군에 의한 내장 통증 억제예방 또는 치료용 약학 조성물

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JP4493125B2 (ja) * 1999-05-07 2010-06-30 独立行政法人理化学研究所 相互作用するタンパク質の検出方法
BRPI0708339A2 (pt) * 2006-02-28 2011-05-24 Dong A Pharm Co Ltd extrato herbário e a composição contendo o mesmo
KR101483440B1 (ko) * 2008-05-02 2015-01-19 (주)아모레퍼시픽 포제를 활용한 약용식물 추출물 및 이를 함유하는 피부외용제 조성물
KR100972116B1 (ko) * 2009-10-29 2010-07-23 (주)한국파비스 알엔디 생약 발효물의 제조 방법, 이에 의해 제조된 생약 발효물 및 이를 포함하는 식품

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* Cited by examiner, † Cited by third party
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CN104162032A (zh) * 2014-08-05 2014-11-26 施怀杰 治疗肠梗的中药
CN113009003A (zh) * 2019-12-22 2021-06-22 珠海润都制药股份有限公司 一种盐酸伊托必利制剂中有关物质的检测方法

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