WO2010025621A1 - 含黄酮中药的提取物及其提取方法、药物组合物和应用 - Google Patents
含黄酮中药的提取物及其提取方法、药物组合物和应用 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Extract containing flavonoids and its extraction method, pharmaceutical composition and application Extract containing flavonoids and its extraction method, pharmaceutical composition and application
- the invention belongs to the technical field of medicine, in particular to an extract of a traditional Chinese medicine plant containing flavonoids, wherein the content of the index component is stable, and the antibacterial, anti-inflammatory, anti-cancer, hypolipidemic is improved relative to the existing extract. , or lowering blood sugar and other effects. Further, the present invention relates to a method for extracting the extract, a pharmaceutical composition containing the extract (especially a composition formulated with hydrazine or a zinc salt), and a therapeutic or pharmaceutical application. Background technique
- the extracts of traditional Chinese medicine plants are still indispensable in the medical products of China, India, Japan and other countries, and in recent years Natural concepts are also commonly accepted by patients in Europe and the United States for treatment or health care. Due to the large number of components in the extracts of traditional Chinese medicine plants, it is difficult to fully reveal the mechanism. Therefore, some index components are usually used to control the quality of the extracted and formulated drugs.
- the extracts of traditional Chinese medicine plants containing flavonoids usually use the total flavonoids. Or certain specific flavonoids and/or their amounts are used as quality control indicators and are used to characterize traditional Chinese medicine plant extracts and pharmaceutical compositions formulated therewith.
- Extracts of flavonoid-containing traditional Chinese medicine plants such as licorice are usually extracted directly from the corresponding plants with organic solvents such as ethanol, methanol and petroleum ether.
- organic solvents such as ethanol, methanol and petroleum ether.
- the inventors have surprisingly found that when the amount of flavonoids and the ratio of plant acid in the extract are in an appropriate range, they are antibacterial, anti-inflammatory, anti-cancer, and blood-lowering. , or lowering blood sugar, etc. can achieve excellent results, even lower extracts of plant acid content due to higher flavonoid content; more surprisingly, the inventors found that before extracting the corresponding plants directly with an organic solvent The content of the above-mentioned flavonoids and vegetable acids can be achieved by immersing in an appropriate proportion of water, and such extracts have not been completely revealed despite the specific composition and content ratio. However, the effect is excellent, and the steps are still simple, and the cost of production equipment is not significantly improved. Therefore, the present inventors have provided an extract of such a flavonoid-containing traditional Chinese medicine plant, a preparation method thereof, a pharmaceutical application, and the like.
- Helicobacter pylori is a spiral, micro-anaerobic, very demanding bacteria.
- Helicobacter pylori diseases include gastritis caused by Helicobacter pylori infection, peptic ulcer, lymphoproliferative gastric lymphoma, and the like.
- a poor prognosis for Helicobacter pylori-associated stomach disease is gastric cancer.
- Epidemiological studies have shown that Helicobacter pylori infects more than half of the world's population, and its incidence varies from country to country and even from region to region. It is currently known that the incidence rate is closely related to socio-economic level, population intensity, public health conditions, and water supply.
- HP Helicobacter spp. infection has a distinct seasonal distribution, with peaks from July to August. In Asia, the infection rates of Helicobacter pylori in China, Hong Kong, Vietnam, India, etc. are 60%, 50%, 40%, and 70%, respectively.
- the detection rate of HP in gastric mucosal biopsy specimens of patients with chronic gastritis can reach 80% ⁇ 90%, while those with peptic ulcers are higher, more than 95%, or even close to 100%.
- the general principles of Western medicine treatment are antibiotics, supplemented with acid inhibitors (such as expectorants), commonly used antibiotics such as amoxicillin, gentamicin, clarithromycin and amoxicillin.
- Antibiotic therapy has a history of more than 50 years. Long-term use of antibiotics can lead to drug resistance, because pathogenic microorganisms produce genetic factor variations that form resistant strains.
- Traditional Chinese medicine treatment with single-flavored traditional Chinese medicine and Chinese patent medicine. Many traditional Chinese medicines have the effect of inhibiting HP and resisting HP infection, but they are not effective and have poor stability.
- Chen Xianglu Bailu Tablets is included in the eighth volume of Chinese medicine preparations for the Chinese medicine and medicine. It has one of the typical representatives of Chinese and Western combined treatment. It has good stomach and qi and qi and analgesic effects. It is clinically used for gastric ulcer and erosive. Gastritis, hyperacidity, acute, chronic gastritis, gastrointestinal neurosis and duodenitis.
- the drug has been clinically applied for many years and has curative effect. It is one of the commonly used drugs for gastric ulcer, acute and chronic gastritis, and it has been designated as a national Class A over-the-counter drug.
- the prescription contains four kinds of chemical substances (Western medicine) of licorice, dried tangerine peel, Chuanmuxiang, rhubarb and scutellaria, and bismuth subnitrate, magnesium carbonate, magnesium oxide and sodium hydrogencarbonate.
- a major pharmaceutical ingredient is bismuth subnitrate, which protects the gastric mucosa and astringent, and has anti-Helicobacter pylori function, but the antibacterial effect is not obvious, especially it is not easily absorbed by the human body, and is not easily dispersed in the stomach and intestine. Hard to last.
- Another herb is licorice.
- the licorice is sweet and flat, has obvious inhibitory effects on peptic ulcer, and also inhibits gastric acid, antispasmodic, detoxification, lipid-lowering, hypoglycemic, and anti-tumor effects; but licorice is prescribed in the form of crude drug powder in the prescription, effective Low in quality, quality is difficult to guarantee, and the human body is not easy to absorb. Moreover, if long-term use of glycyrrhizic acid in licorice causes imbalance of sodium and potassium ions on the cell membrane, it causes hypertension.
- an object of the present invention is to provide an extract of a traditional Chinese medicine plant containing flavonoids and vegetable acids, wherein the index component is stable in content, controllable in quality, and antibacterial, anti-inflammatory, anti-cancer, hypolipidemic, or It has excellent effects in many aspects such as blood sugar lowering. Further, it is an object of the present invention to provide a method for extracting the extract, a pharmaceutical composition containing the extract (especially a composition formulated with strontium or zinc salt), and a therapeutic or pharmaceutical application.
- the present invention provides an extract of a flavonoid-containing traditional Chinese medicine plant, wherein the total flavonoid of the plant accounts for ⁇ 10% (wt/wt) of the extract, preferably 12-35 More preferably, it is 16-32%, and most preferably 20-26%, and the plant acid of the plant accounts for ⁇ 0.3% (wt/wt) of the extract, preferably 0.4-1%, more preferably It is 0.5-0.9%, and most preferably 0.6-0.8%.
- the flavonoid-containing traditional Chinese medicine plant is licorice, preferably selected from the group consisting of Ural and Glycyrrhiza glabra.
- the vegetable acid is glycyrrhizic acid.
- the four specificities of glycyrrhizin, glycyrrhizin, isoglycyrrhizin and isoliquiritin comprise from ⁇ 4%, preferably from 6 to 16%, more preferably from 8 to 15%, most preferably from 11 to 13%, of the extract.
- the extract is prepared by an extraction method comprising, in order, immersing in water and extracting with alcohol.
- the step of soaking with water enables the ratio of the amount of flavonoids and the content of vegetable acid to be relatively high, so that the step of soaking with water is added before the step of extracting with alcohol.
- the ratio of the weight of the flavonoid-containing traditional Chinese medicine plant to the water used for soaking with water is less than 1:5, more preferably less than 1:6, more preferably the weight ratio is 1:7-12, the most Preferably, the weight ratio is 1: 8-10.
- the inventors have found that the use of a suitable ratio of Chinese herbal plant to water can significantly improve the amount of flavonoids and the amount of vegetable acid.
- the water temperature for soaking in water is preferably 75-90'C, more preferably 80-88'C, and most preferably 85 °C. Also preferred is that it is soaked in water for 5-10 hours, more preferably 6-8 hours, and most preferably 7 hours. Further, it is also preferred to wash with water once or several times with water, more preferably 2 to 5 times, and most preferably 3 times.
- the water temperature for each water washing is preferably 50-70 ° C, more preferably 55-65 ° C, and most preferably 60 ° C. Also preferably, it is washed with water for 3 to 10 minutes, more preferably 4 to 6 minutes, and most preferably 5 minutes.
- the alcohol extraction is soaked with an alcohol, preferably the temperature of the alcohol used for soaking is 75-90 ° C, more preferably 80-88 ° C, most preferably 85 ° C; it is also preferred to soak for 1-5 hours with alcohol. More preferably, it is 2-3 hours, and most preferably 2.5 hours.
- the ratio of the amount of the alcohol to the volume of water used for soaking in water in the previous step is 1: 0.5-3, more preferably 1: 1-2.5, and most preferably the weight ratio is 1: 1.8-2.2.
- the above alcohol soaking is carried out in a closed vessel, such as by avoiding the loss of alcohol by refluxing in a water bath, preferably by refluxing in a water bath at 85 °C.
- the alcohol is selected from the group consisting of ethanol, methanol, and propanol, more preferably 95% ethanol or methanol, such as 95% ethanol.
- the extract of the first aspect of the invention is prepared by an extraction method comprising the steps of:
- the solid obtained in the step (1) is extracted with an alcohol, and the extract is retained, followed by drying.
- immersing in water is preferably completely immersing the flavonoid-containing Chinese medicinal plant with water and allowing to stand; wherein, retaining the solid matter, the liquid portion can be removed in a dry manner, and in one embodiment of the invention, the drying can be carried out in an oven at 55. Dry at -65 ° C, preferably at 60 ° C; wherein the retained extract can be filtered to remove the solid portion.
- the present invention provides a method of extracting a flavonoid-containing traditional Chinese medicine plant to prepare an extract, which in turn comprises the steps of soaking with water and extracting with alcohol.
- the extract is an extract of a flavonoid-containing traditional Chinese medicine plant of the first aspect of the invention.
- the total flavonoids of the plant account for ⁇ 10% (wt/wt) of the extract, preferably 12-35%, more preferably 16-32%, and most preferably 20-26%
- the plant acid of the plant accounts for ⁇ 0.3% (wt/wt) of the extract, preferably from 0.4 to 1%, more preferably from 0.5 to 0.9%, most preferably from 0.6 to 0.8%.
- the flavonoid-containing traditional Chinese medicine plant is licorice, preferably selected from the group consisting of Ural and Glycyrrhiza glabra.
- the ratio of the weight of the flavonoid-containing traditional Chinese medicine plant to water used for soaking with water is less than 1:5, more preferably less than 1:6, more preferably the weight ratio is 1:7-12, most preferably The weight ratio is 1: 8-10.
- the water temperature for each water washing is preferably 50 to 70 ° C, more preferably 55 to 65 ° C, and most preferably 60 ° C. Also preferably, it is washed with water for 3 to 10 minutes, more preferably 4 to 6 minutes, and most preferably 5 minutes.
- the extraction with alcohol is preferably soaked with an alcohol, preferably the temperature of the alcohol used for soaking is 75-90 ° C, more preferably 80-88 ° C, most preferably 85 ° C; 1-5 hours, more preferably 2-3 hours, most preferably 2.5 hours.
- the ratio of the amount of the alcohol to the volume of water used for soaking in water in the previous step is 1: 0.5-3, more preferably 1: 1-2.5, and most preferably the weight ratio is 1: 1.8-2.2.
- the above alcohol soaking is carried out in a closed vessel, such as by refluxing in a water bath to avoid loss of alcohol volatilization.
- the alcohol is selected from the group consisting of ethanol, methanol, and propanol, more preferably 95% ethanol or methanol, such as 95% ethanol.
- the method of the second aspect of the invention comprises the extraction method of the following steps:
- the solid obtained in the step (1) is extracted with an alcohol, and the extract is retained, followed by drying.
- immersing in water is preferably completely immersing the flavonoid-containing Chinese medicinal plant with water and allowing to stand; wherein, retaining the solid matter, the liquid portion can be removed in a dry manner, and in one embodiment of the present invention, the drying may be at 55- Drying at 65 ° C, preferably at 60 ° C, for example, drying in an oven at 60 ° C for more than 10 hours, preferably 12-25 hours, more preferably 15-22 hours, such as 17 hours or 20 hours; wherein, the extract is retained The solid portion can be removed by filtration.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the extract of the first aspect of the invention and a pharmaceutically acceptable adjuvant.
- the carrier can be formulated into various dosage forms such as tablets, liquids, capsules, granules, powders, or injections, and the like.
- the extract of the first aspect of the present invention generally has poor water solubility and is not easily dispersed after drying, and therefore preferably may include a dispersing agent added during formulation preparation, such as a nanosized dispersing agent such as nano starch, nanodextrin, nano Si0 2 , nano CaC0 3 , nano ⁇ 0 2 , nano zinc oxide, nano indium, nano silver, nano aluminum hydroxide, nano iron oxide, nano iron chloride, nano carbon, nano selenium, nano aluminum oxide, nano magnesium oxide. It may also be preferred to disperse into the formulation granules by other physical means (e.g., mechanical disruption) during formulation of the formulation.
- a dispersing agent added during formulation preparation such as a nanosized dispersing agent such as nano starch, nanodextrin, nano Si0 2 , nano CaC0 3 , nano ⁇ 0 2 , nano zinc oxide, nano indium, nano silver, nano aluminum hydroxide, nano iron oxide, nano iron chloride, nano carbon, nano selenium,
- an extract of a traditional Chinese medicine plant of flavonoids may be combined with one or more of the following materials: dried tangerine peel, magnesium carbonate, Chuanmuxiang, magnesia, rhubarb, sodium hydrogencarbonate, aluminum hydroxide, sarcophagus, Licorice extract, Frangipani, celandine, South American milk dish, calcium carbonate, and/or sorghum root.
- the licorice extract of the present invention replaces the licorice component of Chen Xianglu Bailu Tablets.
- the pharmaceutical composition of the present invention further comprises a phosphonium salt and/or a zinc salt, preferably including a barium inorganic salt and/or a zinc inorganic salt such as barium aluminate, barium oxide, barium gallate, barium.
- barium strontium, barium chloride, barium carbonate, barium nitrate, barium hyponitrate, barium ingot, etc. such as zinc oxide, zinc sulfate, zinc carbonate, zinc chloride, zinc gluconate, zinc taurate, zinc citrate , zinc hydroxide, etc.
- the weight ratio of the extract of the first aspect of the invention to the onium salt is from 1:1 to 100, more preferably from 1:10 to 50; also preferred are the extracts and zinc salts of the first aspect of the invention.
- the weight ratio is 1: 1-100, more preferably 1: 10-50.
- the present invention provides a method of preparing the above pharmaceutical composition, which comprises the extract, the onium salt and/or the zinc salt of the first aspect of the invention, and a pharmaceutically acceptable adjuvant Therein, the step of mixing the extract of the first aspect of the invention with a phosphonium salt and/or a zinc salt is included.
- the extract of the first aspect of the invention may be uniformly dispersed in a solvent and then dried and pulverized into a dispersion.
- the solvent includes, but is not limited to, an acid or a derivative thereof, including but not limited to hydrochloric acid, sulfuric acid, glacial acetic acid, potassium acetate, sodium acetate, ethyl acetate, butyl acetate, and most preferably acetic acid.
- the concentration of the onium salt and/or the zinc salt in the solvent does not exceed 5% (g/mL), preferably from 1 to 1.5%.
- a dispersant may be added to the solvent, including but not limited to one or more of the following: nanostarch, nanodextrin, Nano Si0 2 , nano CaC0 3 , nano ⁇ 0 2 , nano sodium oxide, nano indium, nano silver, nano aluminum hydroxide, nano iron oxide, nano iron chloride, nano carbon, nano selenium, nano aluminum oxide, nano magnesium oxide, The most preferred of these is nano Si0 2 .
- the present invention provides the use of the extract of the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention as a medicament, that is, a method of treatment, preferably antibacterial, anti-inflammatory, anti-cancer, A method of lowering blood fat, lowering blood sugar and/or antiviral, which comprises administering to a patient an effective amount of the extract of the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention.
- the antibacterial is anti-Helicobacter pylori; in another embodiment of the invention, the anti-cancer is anti-colon cancer.
- the present invention provides the use of the extract of the first aspect of the invention for the preparation of a medicament, preferably the medicament for use in antibacterial, anti-inflammatory, anti-cancer, hypolipidemic, hypoglycemic and/or antiviral drugs .
- Particularly preferred Applications include the preparation of a drug containing a bismuth salt and/or a zinc salt.
- the antibacterial is anti-Helicobacter pylori; in another embodiment of the invention, the anti-cancer is anti-colon cancer.
- the object of the present invention is to provide an extract of a traditional Chinese medicine plant containing flavonoids and vegetable acids, especially a licorice extract, wherein the index component is stable in content, controllable in quality, and antibacterial, anti-inflammatory, anti-cancer, hypolipidemic, or It has excellent effects in many aspects such as blood sugar lowering. Further, it is an object of the present invention to provide a method for extracting the extract, a pharmaceutical composition containing the extract (especially a composition formulated with strontium or zinc salt), and the like, which can treat human diseases and have a wide range of human bodies.
- the health care function has a good preventive effect on gastrointestinal diseases, especially gastrointestinal diseases and cancers related to Helicobacter pylori.
- the present invention provides an extract of a flavonoid-containing traditional Chinese medicine plant, wherein the total flavonoids of the plant account for ⁇ 10% (wt/wt) of the extract, preferably 12-35%, more preferably It is 16-32%, most preferably 20-26%, and the plant acid of the plant accounts for ⁇ 0.3% (wt/wt) of the extract, preferably 0.4-1%, more preferably 0.5-0.9 %, the best is 0.6-0.8%. Also preferably, wherein the flavonoid-containing traditional Chinese medicine plant is licorice, preferably selected from the group consisting of Ural and Glycyrrhiza glabra.
- the total flavonoids of licorice include glycyrrhizin, glycyrrhizin, isoglycyrrhizin and isoliquiritin, wherein four specific flavonoids such as glycyrrhizin, glycyrrhizin, isoglycyrrhizin and isoliquiritin account for the content of the extract. >4%, preferably 6-16%, more preferably 8-15%, most preferably 11-13%. It is also preferred that the extract is prepared by an extraction method which in turn comprises soaking with water and extracting with alcohol, for example, which is prepared by an extraction method comprising the following steps:
- the ratio of the weight of the flavonoid-containing Chinese herbal plant to water used for soaking with water is less than 1:5, more preferably less than 1:6, more preferably the weight ratio is 1:7-12, and most preferably the weight ratio is 1. : 8-10.
- flavonoids refers to a mixture or isolated product of a flavonoid structural analog that can be extracted from natural plants, wherein the mixture is also referred to herein as “total flavonoids.”
- Flavonoids include, but are not limited to, phenols, polyphenols, ketones, steroids, flavonoids, isoflavones, glycosides, chalcones, and suitable examples include, five-eye flavonoids (see CN1139673A:), hawthorn Flavonoids (see CN 1232031A:), chestnut flavonoids (see CN 1323797A, CN 1569869A:), isoquercetin (see CN 1355797A), safflower flavonoids See CN 1363684A) Soy Isoflavones (see CN 1375492), Puhuang Flavonoids (see CN 1468859), Puerarin (see CN 15118, US4985
- flavonoids-containing traditional Chinese medicine plant refers to a plant or a part thereof which has been found to contain flavonoids and is used as a Chinese medicinal material, such as five-eyed fruit, hawthorn, chestnut flower, safflower, soybean, puhuang, corresponding to the aforementioned examples. Pueraria, yellow fine heart, water flower, Nepal iris, vinegar and licorice.
- plant part refers to an organ of a plant, such as roots, stems, leaves, skin, and the like.
- plant acid refers to a carboxyl-containing and acidic molecule that can be extracted from natural plants.
- the vegetable acid refers to glycyrrhizic acid.
- the present invention provides a method of extracting a flavonoid-containing traditional Chinese medicine plant to prepare an extract, which in turn comprises the steps of soaking with water and extracting with alcohol.
- the extract is an extract of a flavonoid-containing traditional Chinese medicine plant of the first aspect of the invention.
- the total flavonoids of the plant account for ⁇ 10% (wt/wt) of the extract, preferably 12-35%, more preferably 16-32%, and most preferably 20-26%
- the plant acid of the plant accounts for ⁇ 0.3% (wt/wt) of the extract, preferably from 0.4 to 1%, more preferably from 0.5 to 0.9%, most preferably from 0.6 to 0.8%.
- the flavonoid-containing traditional Chinese medicine plant is licorice, preferably selected from the group consisting of Ural and Glycyrrhiza glabra.
- the ratio of the weight of the flavonoid-containing traditional Chinese medicine plant to water used for soaking with water is less than 1:5, more preferably less than 1:6, more preferably the weight ratio is 1:7-12, most preferably The weight ratio is 1: 8-10. Also preferred is that it is soaked in water for 5-10 hours, more preferably 6-8 hours, and most preferably 7 hours. Further, it is also preferred to wash with water once or several times with water, more preferably 2 to 5 times, and most preferably 3 times. Among them, the water temperature for each water washing is preferably 50 to 70 ° C, more preferably 55 to 65 ° C, and most preferably 60 ° C.
- the extraction with an alcohol is preferably soaked with an alcohol, preferably at a temperature of 75-90 ° C, more preferably 80-88 ° C, most preferably 85 ° C ; preferably also soaked with alcohol 1-5 hours, more preferably 2-3 hours, most preferably 2.5 hours.
- the ratio of the amount of alcohol used to the volume of water used for soaking in water in the previous step is 1: 0.5-3, more preferably 1: 1-2.5, and most preferably the weight ratio is 1: 1.8-2.2.
- the above alcohol soaking is in the closed state.
- the volatilization loss of the alcohol can be avoided by refluxing in a water bath.
- the alcohol is selected from the group consisting of ethanol, methanol, and propanol, more preferably 95% ethanol or methanol, such as 95% ethanol.
- the method of the second aspect of the invention comprises the extraction method of the following steps:
- immersing in water is preferably completely immersing the flavonoid-containing Chinese medicinal plant with water and allowing to stand; wherein, retaining the solid matter, the liquid portion can be removed in a dry manner, and in one embodiment of the invention, the drying can be carried out in an oven at 55. Drying at -65 ° C, preferably at 60 ° C; wherein the retained extract can be filtered to remove the solid portion.
- the term "pharmaceutically acceptable adjuvant” includes pharmaceutically acceptable carriers, excipients, diluents and the like which are compatible with the active ingredient.
- the preparation of pharmaceutical preparations using pharmaceutically acceptable adjuvants is well known to those of ordinary skill in the art.
- the pharmaceutical preparation of the present invention comprises, as an active ingredient, one or more of the pharmaceutical compositions of the first aspect of the invention, the pharmaceutical composition and a pharmaceutically acceptable adjuvant (as is well known to those skilled in the art)
- the carrier, excipient, diluent, and the like are combined and formulated into various preparations, preferably solid preparations and liquid preparations.
- the preparation of the present invention may be in unit dosage form, such as tablets, pills, capsules (including sustained release or delayed release forms), powders, suspensions, granules, elixirs, syrups, emulsions, suspensions, injections, etc.
- the dosage form and various sustained release dosage forms are suitable for various administration forms, such as oral, parenteral injection, mucosal, intramuscular, intravenous, subcutaneous, intraocular, intradermal or transdermal administration.
- the carrier, excipient, diluent are pharmaceutically acceptable and compatible with the active ingredient.
- the preferred dosage form is an oral dosage form.
- the adjuvant in the pharmaceutical composition of the present invention preferably comprises an adjuvant which is capable of having a surfactant action, is pharmaceutically acceptable, and is compatible with the active ingredient.
- adjuvants can form void solid solutions with the active ingredients in the pharmaceutical compositions of the present invention to further increase drug dissolution rates and bioavailability.
- Suitable adjuvant There are polyethylene glycol and povidone water-soluble carriers, including PEG2000-20000 or PVP K15-K90 or PVA or PVP-PVA or CPD.
- the pharmaceutical composition of the present invention further comprises a phosphonium salt and/or a zinc salt, preferably comprising a barium inorganic salt and/or a zinc inorganic salt such as barium aluminate, barium oxide, barium gallate, barium Barium citrate, barium chloride, barium carbonate, barium nitrate, barium hyponitrate, barium ingot, etc., such as zinc oxide, zinc sulfate, zinc carbonate, zinc chloride, zinc gluconate, zinc taurate, citric acid Zinc, zinc hydroxide, etc.
- a barium inorganic salt and/or a zinc inorganic salt such as barium aluminate, barium oxide, barium gallate, barium Barium citrate, barium chloride, barium carbonate, barium nitrate, barium hyponitrate, barium ingot, etc., such as zinc oxide, zinc sulfate, zinc carbonate, zinc chloride, zinc gluconate, zinc taurate
- the weight ratio of the extract of the first aspect of the invention to the onium salt is from 1:1 to 100, more preferably from 1:10 to 50; also preferred are the extracts and zinc salts of the first aspect of the invention.
- the weight ratio is 1: 1-100, more preferably 1: 10-50.
- the present invention provides the use of the extract of the first aspect of the present invention or the pharmaceutical composition of the third aspect of the present invention as a medicament, that is, a therapeutic method, preferably antibacterial, anti-inflammatory, anti-cancer, A method of lowering blood fat, lowering blood sugar and/or antiviral, which comprises administering to a patient an effective amount of the extract of the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention.
- a patient refers to a mammal, preferably a human, in need of treatment.
- the antibacterial is anti-Helicobacter pylori; in another embodiment of the invention, the anti-cancer is anti-colon cancer.
- the dosage and form of administration will generally be determined by the physician based on the particular circumstances of the patient (e.g., age, weight, sex, time of illness, physical condition, etc.).
- the dose of the extract of the first aspect of the invention in the pharmaceutical composition is from 1 to 1000 mg/kg of the patient's body weight, preferably from 10 to 100 mg/kg. It is to be noted that although a certain dose is administered in the specific embodiment of the present invention, the doses covered by the present invention are not limited thereto, and the dose to be administered may vary depending on the specific circumstances of the patient. Changes will also occur, and choosing the right amount is within the capabilities of the clinician.
- the form of administration is determined according to the dosage form of the pharmaceutical composition, and the suitable administration forms are oral, parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular, intradermal or transdermal, preferably oral.
- the form of administration is determined according to the dosage form of the pharmaceutical composition, and the suitable administration forms are oral, parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular, intradermal or transdermal, preferably oral.
- the present invention provides the use of the extract of the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention for the preparation of a medicament, preferably the medicament is for antibacterial, anti-inflammatory, anti-cancer, hypolipidemic , blood sugar lowering and / or antiviral drugs.
- the application comprises the preparation of a medicament comprising a phosphonium salt and/or a zinc salt.
- the antibacterial is anti-Helicobacter pylori; in another embodiment of the invention, the anti-cancer is anti-colon cancer.
- a dosage form having a determined active ingredient content can be prepared.
- each tablet containing the first aspect of the present invention can be prepared.
- a 360mg tablet is convenient to take.
- the present invention is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in the the the the the the the the the the the the the
- Ural licorice purchased from Beijing Tongrentang, Beijing, China
- 800ml of water to it, immerse, and bath at 85 °C for 7 hours.
- the licorice residue solid was filtered and washed three times with warm water of 60 ° C, wherein the licorice residue was soaked in 800 ml of water for each wash for 5 minutes, and then filtered to remove water.
- the washed licorice residue was dried in an oven at 60 ° C for 17 hours.
- the preparation of CK1 and the preparation of G007 differ only in the amount of water used in water treatment.
- Ural licorice purchased from Beijing Tongrentang, Beijing, China
- water 500ml to it, immerse in water bath at 85 °C for 7 hours.
- the licorice residue solid was filtered and washed three times with warm water of 60 ° C, wherein the licorice residue was soaked in 500 ml of each wash water for 5 minutes, and then filtered to remove water.
- the washed licorice residue was dried in an oven at 60 ° C for 17 hours.
- the dried licorice residue was added to 500 ml of 95% ethanol, refluxed in a water bath at 85 ° C for 2.5 hours, then the liquid was filtered off, rotary evaporated, concentrated, and dried in an oven at 60 ° C for 20 hours to obtain licorice extract 4.6 g. , was named CK1.
- the preparation of CK2 is a commonly used preparation method, and the preparation thereof with G007 mainly lies in the step without water treatment.
- Ural licorice purchased from Beijing Tongrentang, Beijing, China
- whole grass 100g crushed
- 500 ml of 100% ethanol was added thereto, and immersed at room temperature for 5 hours, and then the liquid was filtered off, rotary evaporated, concentrated, and dried in an oven at 60 ° C for 20 hours to obtain 5 g of licorice extract, which was designated as CK2.
- CK2 prepared by the method of Example 1 (3) was immersed in 5 times (wt/wt) petroleum ether at room temperature for 5 hours, then the liquid was filtered off, rotary evaporated, concentrated, and placed in an oven at 60°. C was dried for 20 hours to obtain a licorice extract, which was named CK3.
- the weight percentage of the components contained in each licorice extract was calculated by HPLC as shown in Table I. Among them, the total flavonoid content as an indicator component in G007-1 and G007-2 was stabilized at 20% or more, the total content of the four flavonoids was stabilized at 10% or more, and the content of glycyrrhizic acid was stabilized at 0.5% or more.
- # ⁇ flavones refer to glycyrrhizin, glycyrrhizin, isoglycyrrhizin and isoliquiritin.
- the licorice extract prepared in Example 1 was tested to gradually reduce the concentration of the solution to the concentration necessary to inhibit bacterial growth in an environment in which the bacteria can grow, using the minimum inhibitory concentration (MIC) measurement method described in the conventional microbial technique.
- MIC minimum inhibitory concentration
- Example 1 The anti-tumor effect of the licorice extract prepared in Example 1 on an animal model of human cancer xenograft tumor was examined by the method described in "Chinese Pharmacological Research Methodology". Briefly, human colon cancer cell line HT-29 was inoculated subcutaneously in BAL/C nude mice weighing 18-23 g, and licorice extract prepared in Example 1 was administered intragastrically 24 hours after inoculation. The results after week are shown in Table III below. The results showed that G007-1 and G007-2 were superior to other licorice extracts, and their anti-tumor effects were very similar.
- Tumor inhibition rate (%) (control CK average tumor weight - experimental group average tumor weight) / control CK average tumor weight X 100%
- cerium nitrates 15, 30, 45, and 75 g were sequentially dissolved in 99.5% (g/mL) glacial acetic acid solution to prepare a cerium salt solution having a concentration of 1-1.5% (g mL); 1 g of the prepared G007-2 powder is dissolved in 99.5% of glacial acetic acid solution at a concentration of 1-1.5% (g/mL), and mixed with the above-mentioned cerium salt solution, and dried to obtain G007-2 and strontium salt.
- the composition named G007 ⁇ -1 (G007 and ⁇ weight ratio 1:15), G007 ⁇ -2 (G007 and ⁇ weight ratio 1:30), G007 ⁇ -3 (G007 and The weight ratio of ⁇ is 1:45) and G007 ⁇ -4 (the weight ratio of G007 to ⁇ is 1:75).
- mice Male and female were administered with Helicobacter pylori and Helicobacter Pylori (Hp; Helicobacter felis, Hf) by using the method described in the Chinese Pharmacological Research Methodology.
- Hp Helicobacter pylori and Helicobacter Pylori
- Saline administered once a day for four weeks.
- Example 7 Modification of the existing pharmaceutical preparation (Chenxianglu Bailu Tablet) by the composition of the licorice extract and the onium salt of the present invention
- Chen Xianglu Bailu Tablet is an existing pharmaceutical preparation, which can be found in the “Pharmaceutical Standard Chinese Medicine Formula of the Ministry of Health of the People's Republic of China” (Volume 8). Since the licorice extract of the present invention is far superior to the licorice component in the Chen Xianglu Bailu tablet, it can be used instead.
- the process of the modified preparation is as follows: According to Example 3, 250 g of licorice extract G007-2 and 1800 g of bismuth subnitrate are used to prepare a composition of G007-2 and a cerium salt; and then the composition is combined with 2500g Chinese medicine filling agent [The traditional Chinese medicine filling agent is prepared by taking dried pork peel 500-3000g, Chuanmuxiang 100-1000g, rhubarb 100-500g, Shichangpu 100-300g, mixing and pulverizing into fine powder, and magnesium carbonate 100 -1000g, magnesium oxide 100-1000g, sodium bicarbonate 500-2000g powder mixed and mixed] mixed, then add tablet molding agent to 10kg, fully mixed and hooked, granulation to obtain 30,000.
- Chinese medicine filling agent is prepared by taking dried pork peel 500-3000g, Chuanmuxiang 100-1000g, rhubarb 100-500g, Shichangpu 100-300g, mixing and pulverizing into fine powder, and magnesium carbonate 100 -1000
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Description
含黄酮中药的提取物及其提取方法、 药物组合物和应用
技术领域
本发明属于医药技术领域,具体而言,本发明涉及一种含黄酮的中药植物的提取物, 其中指标成分含量稳定, 而且相对于现有提取物提高了在抗菌、 消炎、 抗癌、 降血脂、 或降血糖等多方面的效果。另外, 本发明还涉及该提取物的提取方法、含有该提取物的 药物组合物(尤其是和铋或锌盐配制成的组合物) 以及治疗或制药应用等。 背景技术
在中国, 中药植物的药物利用历史悠久, 通过用水、酒等来煎煮中药植物以提取出 中药, 在历史上得到了广泛的使用并挽救了大量人的生命。现代研究发现, 有许多中药 植物通过其中的黄酮类化合物来起作用, 并分离出单一组分制备成现代药物。但是, 无 论是中医药理论还是临床实践, 都发现中药(或中药植物的提取物)中多种成分除了各 自单一起作用外, 还互相之间协同作用, 用以增加疗效或降低毒副作用。 由于其中成分 众多,这种协同作用的机制十分复杂, 没有为现代医学所一一揭示, 因此中药植物的提 取物仍旧是中国、 印度、 日本等国家医药产品中必不可少的, 而且近年来其天然的概念 也普遍为欧美等患者所接受, 用于治疗或保健。 由于中药植物的提取物中成分众多, 要 用机理难以完全揭示, 因此通常采用某些指标成分来控制提取、配制药物中的质量, 例 如, 含黄酮的中药植物的提取物通常采用其中的总黄酮或某些特定黄酮类化合物和 /或 它们的量作为质量控制指标, 并用于表征中药植物提取物及其配制的药物组合物。
甘草等含黄酮的中药植物的提取物通常是用乙醇、 甲醇、石油醚等有机溶剂直接对 相应植物提取的,如可参见 "刘晓风等.甘草黄酮的提取工艺研究.安徽农业科学, 37 (6): 2542 一 2543 "、 "石忠峰等.甘草总黄酮提取纯化工艺研究. 中药新药与临床药 理, 19(1):67-69"等, 经过一定的步骤可以得到高黄酮含量的提取物。然而, 本发明人经 过艰苦的试验和长期的研究,令人意外地发现了当提取物中黄酮的量和植物酸的含量比 例在适当的范围时, 其在抗菌、 消炎、抗癌、 降血脂、 或降血糖等多方面能取得优异的 效果, 甚至由于更高黄酮含量而较低植物酸含量的提取物; 更令人意外的是, 本发明人 发现在用有机溶剂直接对相应植物提取前,采用适当比例的水浸泡就能够达到上述黄酮 和植物酸的指标含量,而且这样的提取物尽管具体成分组成及含量配比还没有被完全揭
示, 但是其效果优异, 而且步骤仍旧简单, 生产设备成本没有显著提高。 因此, 本发明 人提供了这种含黄酮的中药植物的提取物以及其制备方法和药物应用等。
另外, 幽门螺旋杆菌 (HP) 是一种螺旋形、 微厌氧、 对生长条件要求十分苛刻的 细菌。幽门螺旋杆菌病包括由幽门螺旋杆菌感染引起的胃炎、消化道溃疡、淋巴增生性 胃淋巴瘤等。幽门螺旋杆菌相关胃病的不良预后是胃癌。流行病学研究表明幽门螺杆菌 感染了世界范围内一半以上的人口,其发病率各个国家不同,甚至同一国家的各个地区 也不相同。 目前已知发病率的高低与社会经济水平、人口密集程度、公共卫生条件以及 水源供应有较密切的关系。 也有报道指出, HP (螺旋杆菌) 的感染有明显的季节分布 特征, 以 7〜8月份为高峰。 在亚洲地区, 中国内地、 中国香港、 越南、 印度等少年幽 门螺杆菌的感染率分别 60%、 50%、 40%、 70%。慢性胃炎患者的胃粘膜活检标本中 HP 检出率可达 80%〜90%, 而消化性溃疡患者更高, 可达 95%以上, 甚至接近 100%。
一般西医的治疗原则是以抗生素为主, 辅加抑酸剂 (如铋剂), 常用抗生素羟氨苄 青霉素、 庆大霉素、 克拉霉素和阿莫西林等。 抗生素疗法己有 50年以上的历史。 长期 使用抗生素会导致抗药性, 因为致病微生物会产生遗传因子变异而形成抗药病株。中药 治疗用单味中药及中成药治疗。 许多中药具有抑杀 HP、 抗 HP感染的功效, 但药效不 佳, 且稳定性不好。
中医常用一些中药配方或中药制剂治疗,但疗效均不稳定。原因在于难以了解中药 配方及药剂的中药成份与适应症的相关性。因而难以保证药物成份的一致性从而达到稳 定的疗效。陈香露白露片收载于***药品标准中药成方制剂第八册,是中西合并治疗 的典型代表之一, 具有良好的健胃和中、理气止痛的功效, 临床上用于胃溃疡, 糜烂性 胃炎, 胃酸过多, 急性、 慢性胃炎, 肠胃神经官能症和十二指肠炎等。 该药临床应用多 年, 疗效确切, 是胃溃疡、 急性、慢性胃炎的常用药品之一, 被指定为国家甲类非处方 药品。其处方中含有甘草、陈皮、川木香、大黄和石菖蒲五味中药及次硝酸铋、碳酸镁、 氧化镁和碳酸氢钠四种化学药(西药)成份。其中, 一主效药物成分是次硝酸铋, 有保 护胃黏膜及收敛作用, 还有抗幽门螺杆菌的作用, 但抗菌作用不明显, 尤其是不易被人 体吸收, 且在肠胃中不易分散, 效果难以持久。 另一味药是甘草。 甘草性味甘、平, 有 明显抑制消化性溃疡的作用, 还有抑制胃酸、解痉、解毒、 降脂, 降糖, 及抗肿瘤作用; 但甘草在处方中以生药粉末的形态入药, 有效性低, 质量难以保证, 人体也不易吸收。 况且甘草中的甘草酸如果长期使用会导致细胞膜上的钠钾离子失调而引发高血压。近年 来,多项研究表明甘草以多酚类包括黄酮类为主的非水溶性部位亦有多种药物成份,但
因该类物质属植物对环境逆境刺激所产生的次生代谢产物,甘草药材中该类产物的种类 繁多,其含量以及各种类间的比例差异极大,导致已报道过的提取制备方法难以确定所 提取部位的药物组成及生物活性。换言之, 用同一制备方法, 但药材来源或质量不同则 得不到相同的药物组合物, 从而也达不到相同的药物效果。 发明内容
一, 涉及的技术方案 本发明的目的在于提供了一种含黄酮和植物酸的中药植物的提取物, 其中指标成分 含量稳定, 质量可控, 而且在抗菌、 消炎、抗癌、 降血脂、或降血糖等多方面的效果优 异。另外, 本发明的目的还在于提供了该提取物的提取方法、含有该提取物的药物组合 物(尤其是和铋或锌盐配制成的组合物) 以及治疗或制药应用等。 具体而言, 在第一方面, 本发明提供了含黄酮的中药植物的提取物, 其中所述植物 的总黄酮占所述提取物的含量≥10% (wt/wt), 优选为 12-35%, 更优选为 16-32%, 最优 选为 20-26%, 而且所述植物的植物酸占所述提取物的含量≥0.3% ( wt/wt ) , 优选为 0.4-1%, 更优选为 0.5-0.9%, 最佳为 0.6-0.8%。 优选在第一方面中, 所述含黄酮的中药植物是甘草, 优选选自乌拉尔和光果甘草。 更优选在第一方面中, 所述植物酸是甘草酸。另外, 除了甘草的总黄酮占所述提取物的 含量≥10% (wt/wt)之外, 也优选在第一方面中, 甘草素、 甘草苷、 异甘草素和异甘草 苷这四种特定黄酮类物质占所述提取物的含量≥4%, 优选为 6-16%, 更优选为 8-15%, 最优选为 11-13%。 优选在第一方面中, 所述提取物由依次包括用水浸泡和用醇提取的提取方法制备而 得。本发明人发现,采用用水浸泡的步骤能够使黄酮的量和植物酸的含量比例都在相对 比较高的水平,因此在用醇提取得步骤前加入了用水浸泡的步骤。更优选在第一方面中, 所述含黄酮的中药植物与用水浸泡所用的水的重量之比小于 1 : 5, 更优选小于 1 : 6, 更优选重量之比为 1 : 7-12, 最优选重量之比为 1 : 8-10。 本发明人发现, 采用合适的 中药植物与水的比例能够显著改善黄酮的量和植物酸的含量。其中,用水浸泡所用的水 温优选是 75-90'C, 更优选是 80-88'C, 最优选是 85°C。 也优选, 其中用水浸泡 5-10小 时, 更优选 6-8小时, 最优选 7小时。
另外, 也优选用水浸泡后用水洗涤一次或几次, 更优选洗涤 2-5次, 最优选洗涤 3 次。 其中, 每次用水洗涤用的水温优选是 50-70'C, 更优选是 55-65°C, 最优选是 60°C。 其中也优选, 每次用水洗涤 3至 10分钟, 更优选 4-6分钟, 最优选 5分钟。 另外, 也优选用醇提取是用醇浸泡, 优选浸泡所用醇的温度是 75-90°C, 更优选是 80-88 °C ,最优选是 85 °C ;也优选用醇浸泡 1-5小时,更优选 2-3小时,最优选 2.5小时。 醇的用量与前一步骤用水浸泡所用的水的体积之比为 1 : 0.5-3, 更优选为 1 : 1-2.5, 最 优选重量之比为 1 : 1.8-2.2。 为了防止醇挥发掉而影响提取效率, 上述醇浸泡是在封闭 的容器内进行的, 如可以通过水浴回流的方式避免醇的损失, 优选通过 85°C水浴回流。 另外, 也优选醇选自乙醇、 甲醇、 丙醇, 更优选是 95%的乙醇或甲醇, 如 95%乙 醇。 在一个具体实施方式中, 本发明第一方面的提取物, 其由包括以下步骤的提取方法 制备:
( 1 )将待提取的所述含黄酮的中药植物粉碎后, 用水浸泡并任选用水洗涤, 然后保留 固体物;
(2)用醇提取步骤 (1 )得到的固体物, 并保留提取液, 然后干燥。 其中, 用水浸泡优选是用水完全浸没所述含黄酮的中药植物并静置; 其中, 保留固 体物可以采用干燥的方式去除液体部分,在本发明的一个具体实施方式中,干燥可以用 烘箱在 55-65'C干燥, 优选在 60°C干燥; 其中, 保留提取液可以用过滤的方式去除固体 部分。 这些单一步骤本身对于本领域技术人员来说是很常规的。 在第二方面, 本发明提供了提取含黄酮的中药植物以制备提取物的方法, 其依次包 括用水浸泡和用醇提取的步骤。优选其中所述提取物是本发明第一方面的含黄酮的中药 植物的提取物。 例如, 其中所述植物的总黄酮占所述提取物的含量≥10% (wt/wt), 优 选为 12-35%, 更优选为 16-32%, 最优选为 20-26%, 而且所述植物的植物酸占所述提 取物的含量≥0.3% (wt/wt), 优选为 0.4-1%, 更优选为 0.5-0.9%, 最佳为 0.6-0.8%。 优选在第二方面中, 所述含黄酮的中药植物是甘草, 优选选自乌拉尔和光果甘草。 优选在第二方面中,所述含黄酮的中药植物与用水浸泡所用的水的重量之比小于 1 : 5, 更优选小于 1 : 6, 更优选重量之比为 1 : 7-12, 最优选重量之比为 1 : 8-10。也优选,
其中用水浸泡 5-10小时, 更优选 6-8小时, 最优选 7小时。 另外, 也优选用水浸泡后 用水洗涤一次或几次, 更优选洗涤 2-5次, 最优选洗涤 3次。 其中, 每次用水洗涤用的 水温优选是 50-70°C, 更优选是 55-65°C, 最优选是 60°C。 其中也优选, 每次用水洗涤 3至 10分钟, 更优选 4-6分钟, 最优选 5分钟。 优选在第二方面中, 用醇提取优选是用醇浸泡, 优选浸泡所用醇的温度是 75-90 °C, 更优选是 80-88°C, 最优选是 85°C ; 也优选用醇浸泡 1-5小时, 更优选 2-3小时, 最优 选 2.5小时。 醇的用量与前一步骤用水浸泡所用的水的体积之比为 1 : 0.5-3 , 更优选为 1: 1-2.5, 最优选重量之比为 1 : 1.8-2.2。 通常上述醇浸泡是在封闭的容器内进行的, 如可以通过水浴回流的方式避免醇的挥发损失。另外,也优选醇选自乙醇、甲醇、丙醇, 更优选是 95%的乙醇或甲醇, 如 95%乙醇。 在一个具体实施方式中, 本发明第二方面的方法包括以下步骤的提取方法:
( 1 )将待提取的所述含黄酮的中药植物粉碎后, 用水浸泡并任选用水洗涤, 然后保留 固体物;
(2 )用醇提取步骤 (1 )得到的固体物, 并保留提取液, 然后干燥。 其中, 用水浸泡优选是用水完全浸没所述含黄酮的中药植物并静置; 其中, 保留固 体物可以采用干燥的方式去除液体部分,在本发明的一个具体实施方式中,干燥可以是 在 55-65°C干燥,优选在 60°C干燥,例如,可用烘箱在 60'C干燥 10小时以上,优选 12-25 小时, 更优选 15-22小时, 如 17小时或 20小时; 其中, 保留提取液可以用过滤的方式 去除固体部分。 在第三方面, 本发明提供了一种药物组合物, 其包括本发明第一方面的提取物和药 学上可接受的辅剂。 所述载体可以使本发明的药物组合物配制成各种剂型, 例如片剂、 液体剂、胶囊、 颗粒、 粉剂、 或针剂等。本发明第一方面的提取物通常水溶性不佳, 干 燥后不易分散, 因此优选可以包括在制剂配制过程中加入的分散剂, 如纳米化分散剂, 如纳米淀粉、 纳米糊精、 纳米 Si02、 纳米 CaC03、 纳米 Ή02、 纳米氧化锌、 纳米铟、 纳米银、 纳米氢氧化铝、 纳米氧化铁、 纳米氯化铁、 纳米碳、 纳米硒、 纳米氧化铝、 纳 米氧化镁。也可优选制剂配制过程中通过其它物理法(如,机械破碎)分散成制剂颗粒。 由于本发明的第一方面的提取物效果优异, 因此它可以替代现有中药配方中相应含
黄酮的中药植物的提取物, 优选替代后它可以与下列物质中的一种或多种组合: 陈皮、 碳酸镁、 川木香、 氧化镁、 大黄、 碳酸氢钠、 氢氧化铝、 石菖蒲、 甘草浸膏、 弗朗鼠李 皮、 白屈菜、 南美牛奶菜、 碳酸钙、 和 /或东莨菪根。 在本发明的一个具体实施方式中, 本发明的甘草提取物替代了陈香露白露片中的甘草成分。 优选在第三方面中,本发明的药物组合物还包括铋盐和 /或锌盐,优选包括铋无机盐 和 /或锌无机盐, 如铝酸铋、 氧化铋、 次没食子酸铋、 枸橼酸铋、 氯化铋、 硫酸次碳酸 铋、硝酸铋、 次硝酸铋、铋锭等, 又如氧化锌、硫酸锌、碳酸锌、氯化锌、葡萄糖酸锌、 牛磺酸锌、柠檬酸锌、氢氧化锌等。优选其中的本发明第一方面的提取物和铋盐的重量 之比为 1 : 1-100, 更优选为 1 : 10-50; 也优选其中的本发明第一方面的提取物和锌盐 的重量之比为 1: 1-100, 更优选为 1: 10-50。 在另一个独立的方面, 本发明提供了制备上述药物组合物的方法, 所述药物组合物 包括本发明第一方面的提取物、 铋盐和 /或锌盐、 和药学上可接受的辅剂, 其中包括本 发明第一方面的提取物同铋盐和 /或锌盐混合的步骤。 为了使得本发明第一方面的提取 物同铋盐和 /或锌盐混合分散得均匀, 可以将它们于溶剂中分散均匀, 然后干燥粉碎成 分散体。所述溶剂包括但不限于酸或其衍生物, 包括但不限于盐酸、硫酸、冰醋酸、醋 酸钾、 醋酸钠、 醋酸乙酯、 醋酸丁酯, 最优选为醋酸。 优选铋盐和 /或锌盐在溶剂中的 浓度不超过 5% (g/mL), 优选为 1-1.5%。 尽管不优选, 但是当铋盐和 /或锌盐在溶剂中 的浓度超过 5%时, 可向溶剂中加入分散剂, 包括但不限于下述一种或多种:纳米淀粉、 纳米糊精、 纳米 Si02、 纳米 CaC03、 纳米 Ή02、 纳米氧化钠、 纳米铟、 纳米银、 纳米 氢氧化铝、 纳米氧化铁、 纳米氯化铁、 纳米碳、 纳米硒、 纳米氧化铝、 纳米氧化镁, 其 中最优选是纳米 Si02。 在第四方面, 本发明提供了本发明第一方面的提取物或本发明第三方面的药物组合 物作为药物中的应用, 即提供了一种治疗方法, 优选是抗菌、 消炎、 抗癌、 降血脂、 降 血糖和 /或抗病毒的方法, 其包括向患者给药有效量的本发明第一方面的提取物或本发 明第三方面的药物组合物。 在本发明的一个具体实施方式中, 抗菌是抗幽门螺旋杆菌; 在本发明的另一个具体实施方式中, 抗癌是抗结肠癌。 在第五方面, 本发明提供了本发明第一方面的提取物在制备药物中的应用, 优选所 述药物是用于抗菌、 消炎、 抗癌、 降血脂、 降血糖和 /或抗病毒的药物。 特别优选所述
应用包括制备含铋盐和 /或锌盐的药物。 在本发明的一个具体实施方式中, 抗菌是抗幽 门螺旋杆菌; 在本发明的另一个具体实施方式中, 抗癌是抗结肠癌。
二, 发明详述及术语解释
本发明的目的在于提供了一种含黄酮和植物酸的中药植物的提取物,尤其是甘草提 取物, 其中指标成分含量稳定, 质量可控, 而且在抗菌、 消炎、 抗癌、 降血脂、 或降血 糖等多方面的效果优异。另外, 本发明的目的还在于提供了该提取物的提取方法、含有 该提取物的药物组合物(尤其是和铋或锌盐配制成的组合物)等, 能治疗人体疾病并对 人体有广泛的保健作用,对胃肠疾病有很好的防治作用,尤其是对与幽门螺杆菌有关的 肠胃病及癌症等。 在第一方面, 本发明提供了含黄酮的中药植物的提取物, 其中所述植物的总黄酮占 所述提取物的含量≥10% (wt/wt),优选为 12-35%,更优选为 16-32%,最优选为 20-26%, 而且所述植物的植物酸占所述提取物的含量≥0.3% (wt/wt), 优选为 0.4-1%, 更优选为 0.5-0.9%, 最佳为 0.6-0.8%。 也优选, 其中所述含黄酮的中药植物是甘草, 优选选自乌 拉尔和光果甘草。 更优选, 甘草的总黄酮包含甘草素、 甘草苷、 异甘草素和异甘草苷, 其中甘草素、甘草苷、异甘草素和异甘草苷这四种特定黄酮类物质占所述提取物的含量 >4%, 优选为 6-16%, 更优选为 8-15%, 最优选为 11-13%。还优选所述提取物由依次包 括用水浸泡和用醇提取的提取方法制备而得,例如,其由包括以下步骤的提取方法制备:
( 1 )将待提取的所述含黄酮的中药植物粉碎后, 用水浸泡并任选用水洗涤, 然后保留 固体物;
(2)用醇提取步骤 (1 ) 得到的固体物, 并保留提取液, 然后干燥。
优选其中所述含黄酮的中药植物与用水浸泡所用的水的重量之比小于 1 : 5,更优选 小于 1 : 6, 更优选重量之比为 1 : 7-12, 最优选重量之比为 1 : 8-10。
在本文中, 术语 "黄酮"或 "黄酮类化合物"指的是能从天然植物中提取的黄酮结 构类似物的混合物或分离产物, 其中所述混合物在本文中也被称为 "总黄酮"。 黄酮包 括但不限于酚类、 多酚类、 酮类、 素类、 黄酮类、 异黄酮类、 苷类、 査尔酮类, 合适的 例子还包括, 五眼果黄酮 (参见 CN1139673A:)、 山楂黄酮(参见 CN 1232031A:)、 板栗花 黄酮 (参见 CN 1323797A、 CN 1569869A:)、异槲皮素 (参见 CN 1355797A)、红花黄酮(参
见 CN 1363684A) 大豆异黄酮(参见 CN 1375492)、 蒲黄黄酮 (参见 CN 1468859)、 葛 根素 (参见 CN 15118碰, US4985408A), 竹叶黄酮 (参见 CN 1513447A), 黄细心黄酮 糖苷(参见 CN 1515583)、 水翁花类黄酮 (参见 CN 1544428)、 尼泊尔鸢尾异黄酮 (参 见 CN 1594307A)、 醋柳黄酮 (参见 CN 1686107) 以及甘草总黄酮等等, 这些文献中的 内容都纳入本文参考。相应地, 术语"含黄酮的中药植物"指的是已经发现含有黄酮并 用作为中药材的植物或其部分,如对应前述例子的五眼果、 山楂、板栗花、红花、大豆、 蒲黄、葛根、黄细心、水翁花、尼泊尔鸢尾、醋柳以及甘草等。其中, 术语"植物部分" 指的是植物的器官, 如根、 茎、 叶、 皮等。
在本文中, 术语 "植物酸"指的是能从天然植物中提取的含羧基并呈酸性的分子。 在本发明针对甘草的具体实施方式中, 植物酸指的是甘草酸。
在本文中, 百分含量如未加特别指明, 如果所含的物质是固体, 则指重量百分比含 量; 如果所含的物质是液体, 并包含在液体溶剂中, 则指体积百分比含量。 在第二方面, 本发明提供了提取含黄酮的中药植物以制备提取物的方法, 其依次包 括用水浸泡和用醇提取的步骤。优选其中所述提取物是本发明第一方面的含黄酮的中药 植物的提取物。 例如, 其中所述植物的总黄酮占所述提取物的含量≥10% (wt/wt) , 优 选为 12-35%, 更优选为 16-32%, 最优选为 20-26%, 而且所述植物的植物酸占所述提 取物的含量≥0.3% (wt/wt), 优选为 0.4-1%, 更优选为 0.5-0.9%, 最佳为 0.6-0.8%。 优选在第二方面中, 所述含黄酮的中药植物是甘草, 优选选自乌拉尔和光果甘草。 优选在第二方面中,所述含黄酮的中药植物与用水浸泡所用的水的重量之比小于 1 : 5, 更优选小于 1 : 6, 更优选重量之比为 1 : 7-12, 最优选重量之比为 1 : 8-10。也优选, 其中用水浸泡 5-10小时, 更优选 6-8小时, 最优选 7小时。 另外, 也优选用水浸泡后 用水洗涤一次或几次, 更优选洗涤 2-5次, 最优选洗涤 3次。 其中, 每次用水洗涤用的 水温优选是 50-70°C, 更优选是 55-65'C, 最优选是 60°C。 其中也优选, 每次用水洗涤 3至 10分钟, 更优选 4-6分钟, 最优选 5分钟。 优选在第二方面中, 用醇提取优选是用醇浸泡, 优选浸泡所用醇的温度是 75-90'C, 更优选是 80-88°C, 最优选是 85°C ; 也优选用醇浸泡 1-5小时, 更优选 2-3小时, 最优 选 2.5小时。 醇的用量与前一步骤用水浸泡所用的水的体积之比为 1 : 0.5-3 , 更优选为 1: 1-2.5, 最优选重量之比为 1 : 1.8-2.2 通常上述醇浸泡是在封闭的容器内进行的,
如可以通过水浴回流的方式避免醇的挥发损失。另外,也优选醇选自乙醇、甲醇、丙醇, 更优选是 95%的乙醇或甲醇, 如 95%乙醇。 在一个具体实施方式中, 本发明第二方面的方法包括以下步骤的提取方法:
( 1 )将待提取的所述含黄酮的中药植物粉碎后, 用水浸泡并任选用水洗涤, 然后保留 固体物;
(2)用醇提取步骤 (1 )得到的固体物, 并保留提取液, 然后干燥。
其中, 用水浸泡优选是用水完全浸没所述含黄酮的中药植物并静置; 其中, 保留固 体物可以采用干燥的方式去除液体部分,在本发明的一个具体实施方式中,干燥可以用 烘箱在 55-65°C干燥, 优选在 60°C干燥; 其中, 保留提取液可以用过滤的方式去除固体 部分。
本发明第二方面的方法取同地域同年甘草重复(n=10)进行提取, 其作为质量控制 指标的成分稳定: 总黄酮含量处于 20-26% (wt/wt),其中四种黄酮(甘草素、 甘草苷、 异甘草素和异甘草苷)含量处于 8-12% (wt/wt), 甘草酸含量处于 0.5-1% (wt/wt)0 在第三方面, 本发明提供了一种药物组合物, 其包括本发明第一方面的提取物和药 学上可接受的辅剂。在本文中,术语"药学上可接受的辅剂"包括药学上可接受的载体、 赋形剂、稀释剂等, 它们与活性成分相容。运用药学上可接受的辅剂制备药物制剂对本 领域普通技术人员来说是公知的。本发明的药物制剂包含一种或多种本发明第一个方面 所述的药物组合物作为活性成分,将该药物组合物和药学上可接受的辅剂(如本领域普 通技术人员所熟知的载体、赋形剂、稀释剂等)组合在一起, 配制成各种制剂, 优选为 固体制剂和液体制剂。 本发明的制剂可以为单位剂量形式, 如片剂、 丸剂、 胶囊 (包括 持续释放或延迟释释放形式)、 粉剂、 混悬剂、 颗粒剂、 酊剂、 糖浆剂、 乳液剂、 悬浮 液、 针剂等剂型以及各种缓释剂型, 从而适合各种给药形式, 例如口服、 非肠道注射、 粘膜、肌肉、静脉内、皮下、眼内、皮内或经过皮肤等的给药形式。其中载体、赋形剂、 稀释剂是药学上可接受的并与活性成分相容。在本发明的具体实施方式中,优选的剂型 是口服剂型。 优选在第三方面中, 本发明的药物组合物中的辅剂优选包括能够具有表面活性剂作 用的、药学上可接受的并与活性成分相容的辅剂。这样的辅剂能与本发明药物组合物中 的活性成分形成空隙固溶体,用以进一步提高药物溶出速率和生物利用度。合适的辅剂
有聚乙二醇类、 聚维酮类水溶性载体, 包括 PEG2000-20000或 PVP K15-K90或 PVA 或 PVP-PVA或 CPD等。 特别优选在第三方面中,本发明的药物组合物还包括铋盐和 /或锌盐,优选包括铋无 机盐和 /或锌无机盐, 如铝酸铋、 氧化铋、 次没食子酸铋、 枸橼酸铋、 氯化铋、 硫酸次 碳酸铋、 硝酸铋、 次硝酸铋、 铋锭等, 又如氧化锌、硫酸锌、 碳酸锌、 氯化锌、 葡萄糖 酸锌、 牛磺酸锌、柠檬酸锌、氢氧化锌等。优选其中的本发明第一方面的提取物和铋盐 的重量之比为 1 : 1-100, 更优选为 1 : 10-50; 也优选其中的本发明第一方面的提取物 和锌盐的重量之比为 1 : 1-100, 更优选为 1 : 10-50。 组合使用铋盐和 /或锌盐以及本发 明第一方面的提取物, 能够产生协同效应, 提高疗效。 在第四方面, 本发明提供了本发明第一方面的提取物或本发明第三方面的药物组合 物作为药物中的应用, 即提供了一种治疗方法, 优选是抗菌、 消炎、抗癌、 降血脂、 降 血糖和 /或抗病毒的方法, 其包括向患者给药有效量的本发明第一方面的提取物或本发 明第三方面的药物组合物。在本文中,患者指的是需要接受治疗的哺乳动物,优选是人。 在本发明的一个具体实施方式中,抗菌是抗幽门螺旋杆菌;在本发明的另一个具体实施 方式中,抗癌是抗结肠癌。给药的剂量和形式一般由医师根据患者的具体情况(如年龄、 体重、 性别、 患病时间、 身体状况等)确定。 一般而言, 以药物组合物中的本发明第一 方面的提取物计, 给药的剂量为 l~1000mg/kg患者体重, 优选为 10~100mg/kg。需要特 别指出的是,尽管在本发明的具体实施方式中给出了一定的给药剂量,但是本发明所涵 盖的剂量并不受此限制,由于患者具体情况会发生变化,因此给药的剂量也会发生变化, 选取合适的量是在临床医师的能力范围内的。 给药形式根据药物组合物的剂型来确定, 适合的给药形式有口服、 非肠道注射、 粘膜、肌肉、 静脉内、 皮下、 眼内、 皮内或经过 皮肤等给药形式, 优选口服的给药形式。 在第五方面, 本发明提供了本发明第一方面的提取物或本发明第三方面的药物组合 物在制备药物中的应用, 优选所述药物是用于抗菌、 消炎、 抗癌、 降血脂、 降血糖和 / 或抗病毒的药物。 特别优选所述应用包括制备含铋盐和 /或锌盐的药物。 在本发明的一 个具体实施方式中, 抗菌是抗幽门螺旋杆菌; 在本发明的另一个具体实施方式中,抗癌 是抗结肠癌。其中针对同一大类患者, 可以制备出有效成分含量确定的剂型, 例如在本 发明的一个具体实施方式中,对于中老年高血糖高血脂病人,可以制成每片含本发明第 一方面的提取物 360mg的片剂, 以方便服用。
本发明引用了现有公开文献, 这些文献是为了更清楚地描述本发明, 它们的全文内 容均纳入本文之中, 就好像它们的全文已经在本文中重复叙述过一样。
为了便于理解, 以下将通过具体的实施例对本发明进行描述。 需要特别指出的是, 这些描述仅仅是示例性的描述,并不构成对本发明范围的限制。利用本发明实施例所述 的方法,也可以获得本发明其他的技术方案。依据本说明书的论述,本发明的许多变化、 改变对所属领域技术人员来说都是显而易见了。 具体实施方式
实施例 1甘草提取物的制备和比较
( 1 )甘草提取物 G007-1和 G007-2的制备
取乌拉尔甘草(购自北京同仁堂,北京,中国)全草 100g,粉碎,向其加入水 800ml 浸没,于 85°C水浴 7小时。然后,过滤保留甘草渣(固体),对其用 60°C温水洗涤 3次, 其中每次洗涤用水 800ml浸泡甘草渣 5分钟后过滤去除水。将洗涤过的甘草渣置于烘箱 中以 60°C干燥 17小时。 取干燥后的甘草渣加入 95% (V/V) 乙醇 500ml, 于 85°C水浴 回流 2.5小时, 然后滤出液体, 旋转蒸发, 浓缩, 并置于烘箱中以 60°C干燥 20小时, 得甘草提取物 4.5克, 被命名为 G007-l。
重复以上过程, 其中唯一的不同是用于浸泡和洗涤的水量为 1000ml, 得甘草提取 物 4.9克, 被命名为 G007-2。
(2)甘草提取物 CK1的制备
作为比较的实例, CK1的制备与 G007的制备仅在水处理时用水量有区别。取乌拉 尔甘草(购自北京同仁堂, 北京, 中国)全草 100g全草 100g,粉碎, 向其加入水 500ml 浸没,于 85°C水浴 7小时。然后,过滤保留甘草渣(固体),对其用 60°C温水洗涤 3次, 其中每次洗涤用水 500ml浸泡甘草渣 5分钟后过滤去除水。将洗涤过的甘草渣置于烘箱 中以 60°C干燥 17小时。 取干燥后的甘草渣加入 95%乙醇 500ml, 于 85°C水浴回流 2.5 小时, 然后滤出液体, 旋转蒸发, 浓缩, 并置于烘箱中以 60'C干燥 20小时, 得甘草提 取物 4.6克, 被命名为 CK1。
(3 )甘草提取物 CK2的制备
作为比较的实例, CK2的制备是现有常用的制备方法, 其与 G007的制备主要在于 没有水处理的步骤。 取乌拉尔甘草(购自北京同仁堂, 北京, 中国)全草 100g, 粉碎,
向其加入 500ml的 100%乙醇, 于室温浸泡 5h, 然后滤出液体, 旋转蒸发, 浓缩, 并置 于烘箱中以 60°C干燥 20小时, 得甘草提取物 5克, 被命名为 CK2。
(4)甘草提取物 CK3的制备
对用实施例 1 (3 )的方法制备的 10克 CK2, 用 5倍(wt/wt)石油醚于室温浸泡 5 小时, 然后滤出液体, 旋转蒸发, 浓缩, 并置于烘箱中以 60°C干燥 20小时, 得甘草提 取物, 被命名为 CK3。
(5) 各甘草提取物中成分的比较
通过 HPLC对各成分峰的计算,各甘草提取物中所含成分占提取物的重量百分比如 表 I所示。 其中, G007-1和 G007-2中作为指标成分的总黄酮含量稳定在 20%以上, 四 种黄酮总和的含量稳定在 10%以上, 而且甘草酸的含量稳定在 0.5%以上。
表 I各甘草提取物的指标成份含量
#四种黄酮指的是甘草素、 甘草苷、 异甘草素和异甘草苷。 实施例 2甘草提取物的抗菌试验
利用常用微生物技术所述的最低抑菌浓度(MIC)测定方法, 检测实施例 1所制备 的甘草提取物以逐渐稀释溶液浓度在细菌能够生长的环境中抑制细菌繁殖的必要浓度。 结果表明, G007-1和 G007-2明显优于其他甘草提取物, 而且两者抗菌非常相近。
表 II各甘草提取物对 HP的 MIC
CK3 3.06 mg/ml
阳性对照:洗必泰
0.013mg/ml
(chlorhexidine)
* MIC值为 5个独立重复实验的平均值。 实施例 3甘草提取物的抗肿瘤效果
利用《中药药理研究方法学》所述的方法, 检测实施例 1所制备的甘草提取物对人 癌异种移植瘤动物模型的抗肿瘤效果。简而言之,用人结肠癌细胞株 HT-29接种在体重 18-23克重的 BAL/C裸小鼠皮下, 接种 24小时后开始灌胃给药实施例 1所制备的甘草 提取物, 六周后结果如下表 III所示。 结果表明, G007-1和 G007-2明显优于其他甘草 提取物, 而且两者抗肿瘤效果非常相近。
表 ΠΙ肿瘤生长抑制效果
*抑瘤率(%) = (对照 CK平均瘤重一实验组平均瘤重) /对照 CK平均瘤重 X 100% 实施例 4甘草提取物对高血糖高血脂("双髙")病人的药效临床观察。
根据国家食品药品管理局的临床实验标准执行,对不同组的病人(年龄在 45-55岁, 十人一组, 男女各半, 其空腹血糖 7.5mM/L以上, 血清胆固醇 300mg/100ml以上)分 别口服给药 G007-1和 CK2, 每次给药 G007-1和 CK2 360mg, 每日三次, 进行三周。 三周后抽血化验血糖、血脂, 结果如下表 IV-A和 IV-B所示。结果表明, G007-1对"双 高"病人的血糖平均降低约 22%,血清胆固醇平均降低约 38%, 远远优于 CK2降血糖、 血脂不到 10%的效果。
表 IV-A G007-1用药前后的血糖、 血脂比较
病人编号 性别 年龄 治疗前 治疗后
血糖 胆固醇 血糖 胆固醇 (mM/L) (mg 100ml) (mM/L) (mg/100ml)
05-11 M 51 9.0 330 8.7 311
05-12 M 51 7.9 309 7.6 301
05-13 M 53 8.6 364 8.3 303
06-14 F 47 8.3 345 7.9 316
07-15 F 50 9.5 401 9.0 398
07-16 F 48 10.6 506 9.8 489
07-17 M 61 8.4 308 8.0 303
07-18 M 65 8.1 310 8.1 296
07-19 F 56 7.8 335 7.8 308
07-20 F 58 9.6 360 9.0 351 平均 54 8.7 356.8 8.42 337.6
实施例 5 甘草提取物和铋或锌盐的组合物配制
依次取次硝酸铋 15、 30、 45、 和 75g, 分别溶于 99.5% (g/mL)冰醋酸溶液中, 配 制成浓度为 1-1.5% (g mL) 的铋盐溶液; 各取实施例 1所制备的 G007-2粉末 1克, 溶 于 99.5%的冰醋酸溶液中, 浓度为 1-1.5% (g/mL), 分别与上述铋盐溶液混合, 干燥可 制得 G007-2和铋盐的组合物, 依次分别被命名为 G007铋 -1 (G007与铋的重量比为 1 : 15)、 G007铋 -2 (G007与铋的重量比为 1 : 30)、 G007铋 -3 (G007与铋的重量比为 1 : 45)和 G007铋 -4 (G007与铋的重量比为 1 : 75)。
重复以上步骤, 其中次硝酸铋被替换成葡萄糖酸锌 45g, 可制得 G007-2和锌盐的 组合物, 依次分别被命名为 G007锌 -3。 实施例 6甘草提取物对小鼠实验性胃螺旋杆菌感染性胃炎的作用
利用《中药药理研究方法学》所述的方法, 对 Balb/C小鼠(雌雄各半)灌服幽门螺 旋杆菌和猫胃螺旋杆菌(Helicobacter Pylori, Hp; Helicobacter felis, Hf)菌液, 形成 的幽门螺旋杆菌感染性胃炎动物模型, 然后分别灌胃给药 G007-2、 CK1、 CK2、 CK3、 G007铋 -3、 G007锌 -3、 次硝酸铋及葡萄糖酸锌, 空白对照组灌胃给药生理盐水, 每天 给药 1次, 持续四周。然后根据《中药药理研究方法学》所述的细菌学检査及炎症程度 检查方法来评价疗效, 其中细菌培养转阴者为根治; 炎症程度分级标准: 炎细胞浸润累 及黏膜浅层 1/3以内为轻度, 1/3-2/3为中度, 超过 2/3者为重度, 结果如表 V-A和表 V-B所示。 结果表明, G007铋 -3控制炎症、 根除感染的效果最佳, 其次是 G007-2, 都 高于其他对照组。
表 V-A 对 HP感染的根除作用
生理盐水对照组 25 ml 0/12 表 V-B 对 HP感染造成的炎症药效学试验
实施例 7本发明的甘草提取物和铋盐的组合物对现有药物制剂 (陈香露白露片) 的改 造
陈香露白露片是现有药物制剂, 可参见《中华人民共和国***药品标准中药成方 制剂》(第八册)。
由于本发明的甘草提取物远优于陈香露白露片中的甘草成分, 因此可以替代使用。 具体而言, 改造的制剂的工艺流程为: 按实施例 3, 取 250克甘草提取物 G007-2、 1800 克次硝酸铋制成 G007-2和铋盐的组合物;然后将该组合物与 2500克中药填充剂【该中 药填充剂的制法为:取陈皮 500- 3000g、 川木香 100- 1000g、 大黄 100- 500g、 石菖蒲 100-300g, 混合并粉碎成细粉, 与碳酸镁 100-1000g、 氧化镁 100- 1000g、 碳酸氢钠 500- 2000g粉末混合混匀】混合, 再加入片剂成型剂至 10kg, 充分混合均勾, 制粒得 3 万。
Claims
1. 含黄酮的中药植物的提取物, 其特征在于, 所述提取物中, 所述植物的总黄酮占所 述提取物的含 ¾≥10%(wt/wt),优选为 12-35%,更优选为 16-30%,最优选为 20-26%, 而且所述植物的植物酸占所述提取物的含量≥0.3% (wt/wt),优选为 0.4-1%, 更优选 为 0.5-0.9%, 最佳为 0.6-0.8%。
2. 权利要求 1所述的提取物, 其中所述含黄酮的中药植物是甘草, 优选选自乌拉尔和 光果甘草。
3.权利要求 1所述的提取物,其由依次包括用水浸泡和用醇提取的提取方法制备而得。
4. 权利要求 3所述的提取物, 其由包括以下步骤的提取方法制备:
( 1 )将待提取的所述含黄酮的中药植物粉碎后, 用水浸泡并任选用水洗涤, 然后保留 固体物;
(2)用醇提取步骤 (1 )得到的固体物, 并保留提取液, 然后干燥。
5. 权利要求 3或 4所述的提取物, 其中所述含黄酮的中药植物与用水浸泡所用的水的 重量之比小于 1 : 5, 更优选小于 1 : 6, 更优选重量之比为 1 : 7-12, 最优选重量之 比为 1 : 8-10。
6. 提取含黄酮的中药植物以制备提取物的方法, 其依次包括用水浸泡和用醇提取的步 骤。
7. 权利要求 6所述的方法, 其中所述提取物是权利要求 1-5之任一所述的提取物。
8. —种药物组合物, 其包括权利要求 1-5之任一所述的提取物和药学上可接受的辅剂。
9.权利要求 8所述的方法,其还包括铋盐和 /或锌盐,优选包括铋无机盐和 /或锌无机盐。
10. 权利要求 1-5之任一所述的提取物在制备药物或用作为药物中的应用, 优选所述药 物是用于抗菌、 消炎、 抗癌、 降血脂、 降血糖和 /或抗病毒的药物, 更优选所述抗菌 是抗幽门螺旋杆菌, 也优选抗癌是抗结肠癌。
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Cited By (2)
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WO2012130122A1 (zh) * | 2011-04-01 | 2012-10-04 | 桂林商源植物制品有限公司 | 控制血糖、血脂及体重的药物组合物 |
CN112034053A (zh) * | 2019-06-03 | 2020-12-04 | 中国农业科学院农产品加工研究所 | 一种检测中药材中农药残留的方法 |
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WO2012130122A1 (zh) * | 2011-04-01 | 2012-10-04 | 桂林商源植物制品有限公司 | 控制血糖、血脂及体重的药物组合物 |
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CN103608024A (zh) * | 2011-04-01 | 2014-02-26 | 桂林商源植物制品有限公司 | 控制血糖、血脂及体重的药物组合物 |
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CN112034053A (zh) * | 2019-06-03 | 2020-12-04 | 中国农业科学院农产品加工研究所 | 一种检测中药材中农药残留的方法 |
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CN102076346B (zh) | 2012-05-30 |
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