WO1999047148A1 - Compositions a base de feuilles de ginkgo biloba, leurs procedes de preparation et leurs applications - Google Patents
Compositions a base de feuilles de ginkgo biloba, leurs procedes de preparation et leurs applications Download PDFInfo
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- WO1999047148A1 WO1999047148A1 PCT/CN1999/000038 CN9900038W WO9947148A1 WO 1999047148 A1 WO1999047148 A1 WO 1999047148A1 CN 9900038 W CN9900038 W CN 9900038W WO 9947148 A1 WO9947148 A1 WO 9947148A1
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- ginkgolide
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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
- A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
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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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/967—Standards, controls, materials, e.g. validation studies, buffer systems
Definitions
- the invention relates to a botanical medicine preparation, in particular to a ginkgo biloba composition and a preparation method and application thereof.
- Ginkgo Biloba is the oldest of the existing seed plants and the sole survivor of the Ginkgo family dating back more than 200 million years to the Permian. In China, ginkgo biloba preparations have been used for treatment for more than 5,000 years, that is, they have been used for treatment since the earliest origin of Chinese herbal medicine. Since the 1960s, botanical extracts of Ginkgo biloba have been used in many countries to treat cerebrovascular and peripheral vascular diseases, such as Germany, France, Japan and South Korea.
- flavonoids The main active ingredient in Ginkgo biloba is flavonoids, which includes at least 14 different compounds, such as flavonols, flavones, flavanones, and diflavones.
- flavonol glycosides and flavonol glycosides include kaempferin , Quercetin and isorhamnetin in combination with glucose or rhamnose are the most significant components of Ginkgo biloba extract (Tebonin®, Tanakan®, Roekan® or "EGb761") for therapeutic purposes on the market
- flavonoid glycosides and flavonol glycosides are powerful antioxidants that scavenge oxygen free radicals to avoid cell and tissue damage caused by aging.
- Ginkgo biloba the other main active ingredient in Ginkgo biloba is terpene lactones, including ginkgolides A, B,:, J, M, and ginkgolides.
- Ginkgolides are terpenes that contain a lactone structure. See K. Nakanishi, Pure and Applied Chemistry, Vol. 14 (1967) 89-113; M. Maruyama et al., Tetrahedron Letters (1967), 299-302 and 303-319 and K. Okabe et al., GinkgoUdes, J chem. Soc.
- the five-membered ring includes a spiro [4.4 ⁇ nonane, a tetrahydrofuran ring, and three lactone rings.
- the different ginkgolide structures are only the number and position of the hydroxyl groups on the spirononane skeleton, Cl, C3 or C7.
- ginkgolides A, B, C and M can effectively treat platelet activating factor-induced diseases such as asthma, bronchitis, senile dementia, Allergies, cardiac dysfunction, rheumatism, etc. and other circulatory diseases, see US Patent No. 4,734,280; P. Braquet, Drug of the Future, 12, 64, 1987; V Lamant et al., Biochem Pharmacol Vol. 36 (1987) 2749-52; K. Becker et al., Biomed Biochim Acta Vol 47 (1988) 10-11; P. Braquet et al., J Ethnopharmacol Vol.
- PAF platelet activating factor
- the antibacterial activity of ginkgolides against Pneumocystis carinii is mainly used to treat AIDS-associated infections.
- Ginkgo biloba contains at least 12 alkyl phenolic compounds, including Ginkgo Acid (lacuronic acid), which is 6-alkylsalicylic acid, and the alkyl group is an alkyl group having 0 to 3 double bonds from n 13 to n 19 carbons, see JL Gellermann et al., Phyto chemistry, Vol. l5 (1976), 1959-1961 and AnaIytic. Chem "VoI. 40 (1968), 739- 743. Similar to the structure of the stimulant in the poison ivy, ginkgoic acid is a factor in the toxic effects of ginkgo leaf extracts.
- Ginkgo Acid lacuronic acid
- the alkyl group is an alkyl group having 0 to 3 double bonds from n 13 to n 19 carbons
- DE-B 21 17 429 developed a technology to remove polyphenolic compounds (proanthocyanidins) with tannin properties and used in the process
- polyphenolic compounds proanthocyanidins
- the problems with these processes are that they can endanger the health of the operator, potential threats to the environment, and harmful residues in medicines.
- ginkgo biloba extract (Tebonm®, Tanakan®, Roekan® or "EGb 761") currently used for therapeutic purposes contains 24% flavonoid glycosides and 6% terpene lactones; see K. Driau La Presse Medicale Vol. 15 (1986), 1455-1457, Ginkgolide
- ginkgo biloba extract usually contains less than 10 ppm alkylphenol compounds, with a daily therapeutic dose of 120 mg.
- U.S. Patent No. 5,399,348 refers to a method for preparing ginkgo biloba extract, which does not use chloro aliphatic hydrocarbons to separate alkylphenol compounds, but first passes through a precipitation filtration process, and then performs multi-step liquid-liquid extraction from the aliphatic hydrocarbons.
- the diluted aqueous solution is cooled to precipitate to remove lipophilic components, and then treated with ammonium sulfate and extracted with methyl ethyl ketone, acetone or methyl ethyl ketone, and acetone mixture.
- the extract is diluted with water and alcohol to obtain a monohydrate alcohol solution, and then the lead compound or insoluble polymer is used. Amide treatment.
- the treated hydroalcoholic solution is finally extracted with an aliphatic hydrocarbon or alicyclic hydrocarbon solvent to further remove the alkylphenol compound, and finally a dry extract is obtained.
- the extract can be concentrated to a solid content of 50 to 70%, and then diluted with water and alcohol to obtain a solid content of 10% by weight and 50% by weight of alcohol and 50% by weight of alcohol.
- U.S. Patent No. 5,399,348 found that by using the above method, the obtained ginkgo biloba preparation contains flavonoid glycosides of 20 to 30%, ginkgolides A, B, C, J 2.5-4.5%, ginkgolides 2.0-4.0%, alkylphenol compounds Less than 10 ppm and less than 10% proanthocyanidins.
- U.S. Patent No. 5,322,688 developed a process similar to that described above for removing alkylphenol compounds, but unlike lead removal of proanthocyanidins, U.S. Patent No. 5,322,688 employs an extraction process that is immiscible with water 4 or 5 carbon alcohols such as n-butanol.
- the method is characterized in that ginkgo biloba leaves are extracted with an acetone aqueous solution, an alcohol aqueous solution of one to three carbons or anhydrous methanol, and most of the organic solvents in the extract are evaporated or distilled off.
- the obtained aqueous solution is diluted with water to a solid content of 5- 25%.
- the diluted aqueous solution is cooled and precipitated to remove water-insoluble lipophilic components.
- the aqueous solution is then treated with 10-30% ammonium sulfate and extracted with methyl ethyl ketone or methyl ethyl ketone acetone mixture.
- the extract is extracted with butanol or pentanol, and the butanol or pentanol extract It is diluted with water and alcohol, and the obtained hydroalcoholic solution is extracted with an aliphatic hydrocarbon or alicyclic hydrocarbon solvent to further remove the alkylphenol compound.
- the aqueous phase solution is concentrated, and the obtained concentrate is dried to obtain an extract.
- the extract can also be concentrated to a solid content of 50 to 70%, and then diluted with water to a solid content of 10% by weight.
- the water concentrated solution is not miscible with water.
- C 4 or C 5 alcohol extraction the alcohol layer was concentrated to a solid content of 50 to 70%, and the concentrated solution was diluted with water and alcohol to obtain an alcohol containing 20 to 60% by weight of a dry extract containing 5 to 20% alcohol.
- the aqueous solution is extracted with an aliphatic hydrocarbon or an alicyclic solvent to further remove the alkylphenol compound. Finally, the aqueous phase concentrate is concentrated and dried to obtain a dry extract.
- U.S. Patent No. 5,322,688 proposes that the apricot leaf preparation obtained by the above method contains 20 to 30% of flavonoid glycosides, ginkgolides A, B, C, and J 2.5 to 4.5%, ginkgolides 2.0 to 4.0%, and alkylphenol compounds Less than 10 ppm and less than 10% proanthocyanidins.
- U.S. Patent No. 5,389,370 also employs the method described in U.S. Patent No. 5,322,688 for removing alkylphenol compounds and proanthocyanidins, but provides the preparation of ginkgo biloba extracts containing high concentrations of active ingredients and their compositions method.
- the process of U.S. Patent No. 5,389,370 is characterized in that: Ginkgo biloba leaves containing at least 1.4% of flavonoid glycosides are extracted with an acetone aqueous solution, an alcoholic aqueous solution of up to three carbons or anhydrous methanol, and most of the organic solvents are separated and removed until the concentration is not greater than 10%.
- the concentrated aqueous solution was diluted with water to a solid content of 15 to 20% by weight, and then left to cool until precipitates formed. These precipitates consisted of lipophilic components that were not easily soluble in water and were removed by filtration.
- the remaining aqueous solution was formic acid Ester or acetate such as ethyl acetate or a mixture of ethyl acetate and an aliphatic or alicyclic hydrocarbon is subjected to multi-step extraction.
- the esters dissolved in the aqueous phase can be completely removed by distillation, and the remaining solution is insoluble in water. -4 or C-5 alcohol extraction, the alcohol phase was washed with water, and then concentrated.
- the residual solvent was completely removed by azeotropic distillation.
- the residue was diluted with a 40% (by weight) alcohol aqueous solution to form a diluted residue.
- the extract in order to remove the extraction concomitant from ethyl acetate or ethyl acetate / hydrocarbon extract, the extract may be treated with activated carbon or silica gel column chromatography.
- the ethyl acetate or ethyl acetate / hydrocarbon mixed extract in the above process can be first treated with activated carbon to remove the accompanying The impurities are then crystallized out, and the pure ginkgolide and the remaining ginkgolide are separated from the mother liquor by column chromatography.
- the diluted residue obtained in the last step of the above process can be further extracted with an aliphatic hydrocarbon or alicyclic hydrocarbon solvent to reduce the content of the alkylphenol compound, and the aqueous phase is concentrated and evaporated to obtain a dry extract.
- U.S. Patent No. 5,389,370 reports using the above method to obtain a ginkgo biloba preparation containing 40-60% of flavonoids; ginkgolides A, B, C, and J 5.5-8% and ginkgolide 5-7%, or ginkgolide 5.5 ⁇ 8% and ginkgolides less than 0.1%, or ginkgolides 5-7% and ginkgolides not more than 0.1%; proanthocyanidins 0-10% and alkylphenol compounds with a maximum concentration of 10 ppm, preferably low in content At lppm.
- U.S. Patent No. 5,637,302 relates to a method for preparing a ginkgo biloba extract, where the crude ginkgo biloba extract is extracted with a solvent composed of n-butanol and toluene to avoid the use of chlorinated aliphatic hydrocarbons and lead compounds In addition, using this process can also solve the problem of using a large number of different solvents that are miscible with each other in other inventions.
- the characteristics of the process of U.S. Patent No. 5,737,302 are as follows. Ginkgo biloba leaves are extracted with an aqueous solvent of acetone or methanol and / or ethanol and water.
- aqueous extracts are directly extracted with n-hexane or n-heptane or toluene / butanol mixture to Remove inactive lipophilic substances such as alkylphenols and polyfluorene.
- the degreased solution is concentrated to a certain volume, which is equivalent to the weight of the crude drug, and then placed in the refrigerator for 24 hours, and then centrifuged to obtain a semi-crystalline substance composed of diclustered flavones.
- the aqueous phase was extracted countercurrently with toluene / butanol in a volume ratio of 1: 2 to 1: 4.
- the toluene-butanol phase was washed with water countercurrently, concentrated into an extract, and washed with water or a water-alcohol mixture to further remove the residual traces of methylbenzyl and butanol, and finally dried.
- the degreased aqueous solution still contains a certain proportion of dimer flavonoids, which can be passed through an adsorption resin such as an aromatic polymer resin, which has a significant activity on phenol, and can easily adsorb many active ingredients.
- organic solvent such as a lower alcohol - one (d C 4), or a water-miscible and then eluted from the resin.
- U.S. Patent No. 5,637,302 found that by using the above method, a ginkgo biloba extract preparation containing 22 to 26% flavonoid glycosides, 2.5 to 4.5% ginkgolides, 2.5 to 4.5% ginkgolides, and almost no alkylphenol compounds and Proanthocyanidins are less than 10%.
- the purpose of the present invention is to further determine each flavonoid component and provide a more refined ginkgo biloba extract.
- the content can be measured and the ratio between them can be adjusted.
- These single components include flavonols, flavones, flavanols, and flavonol glycosides.
- the content of the product meets the drug testing requirements and component reproducibility formulated by the country, regardless of the differences in the various components in the raw materials of Ginkgo biloba.
- This more defined Ginkgo biloba extract aggregates effective active ingredients and reduces unknowns. Has more standardized production processes and quality control standards.
- the invention improves the safety of the prepared medicine, and enhances the confidence of doctors and patients in medication and the reproducibility of drug screening.
- Another object of the present invention is to provide a high-content ginkgo biloba extract, the content indicators of which are 44-78% of flavonoids; 2.5-10% of ginkgolides; 2.5-10% of ginkgolides.
- High-level ginkgo extracts are required by many national pharmaceutical standards, but since these clauses apply only to purified compounds, ordinary extracts are difficult to meet. It has not been possible to prepare such a high-level ginkgo extract.
- Another advantage is that the high content of the extract greatly removes the inactive ingredients.
- the large amount of inactive ingredients increases the safety of the drug.
- the more active ingredients make the testing of the main ingredients and the determination of impurities more convenient.
- the purified Ginkgo biloba extract can be used to suppress allogeneic rejection during organ transplantation.
- Another purpose of this invention is to remove ginkgoic acid and eliminate the occurrence of allergic reactions.
- Another object of the present invention is to provide a method for treating angina pectoris caused by coronary heart disease.
- the ginkgo extract provided by the present invention contains 44 ⁇ 78% of flavonoids, 2.5 ⁇ 10% of ginkgolide, 2.5 ⁇ 10% of ginkgolide, and 0.1 ⁇ 5ppm of ginkgo acid.
- the present invention relates to components extracted from ginkgo biloba leaves, and in particular includes different components containing new active ingredients and mixtures thereof. Provided are methods for preparing these same extracts, methods for identifying and determining their contents, and medicines containing these active ingredients and mixtures, and methods for treating angina pectoris caused by coronary heart disease.
- the present invention provides a composition comprising about 44% to 78% of flavonoids. Ester 2.5% ⁇ 10% (including ginkgolides A, B, C and J or their mixtures), ginkgolide 2.5-10% and ginkgo acid 0.1 ⁇ 5ppm.
- the invention provides a composition containing about 44% to 78% of flavonoids (including flavonols, flavanols and flavonoid glycosides), and 2.5% to 10% of gingkolides (including ginkgolides, B, C And J or its mixture), ginkgolide 2.5 ⁇ 10% and ginkgo acid 0.1 ⁇ 5ppm.
- the present invention provides a composition containing about 44% to 78% of flavonoids (of which 20 to 75% of flavonoids) and 2.5% to 10% of gingkolides (including gingkolides A, B, C, and J or Its mixture), ginkgolide 2.5 ⁇ 10% and ginkgo acid 0.1 ⁇ 5ppm.
- the invention provides a composition containing about 44% to 78% of flavonoids (wherein the ratio of flavonoid glycoside to flavonol is 1 to 30: 1), and 2.5% to 10% of ginkgolides (including ginkgolide A , B, C and J or a mixture thereof), ginkgolides 2.5 to 10% and ginkgoic acid 0.1 to 5 ppm.
- the invention provides a composition, which contains about 44% to 78% of flavonoids (which contains flavonoid glycosides), 5 to 20% of lactones (which consists of 2.5% to 10% of ginkgolides A, B (C, J, and a single component or a mixture thereof, and 2.5-10% ginkgolide), wherein the ratio of flavonoid glycoside and lactone is about 3.5 ⁇ 4.5: 1, and also contains ginkgoic acid 0.1 ⁇ 5ppm.
- flavonoids which contains flavonoid glycosides
- lactones which consists of 2.5% to 10% of ginkgolides A, B (C, J, and a single component or a mixture thereof, and 2.5-10% ginkgolide
- the present invention provides a composition in which the flavonoid compound containing flavonoid glycosides is not less than 44%, and which contains the single component of ginkgolide A, B, C and J or a mixture thereof with not less than 6 % And contains 0.1 ⁇ 5ppm of ginkgoic acid.
- the ginkgo acid content in the above composition provided by the present invention is about 0.1 to 0.5 ppm.
- composition provided by the present invention has its constituents extracted from Ginkgo biloba leaves.
- composition of the above-mentioned composition provided by the present invention is extracted from ginkgo biloba leaves obtained from artificially cultivated plants.
- the present invention provides a method for obtaining a ginkgo composition, the steps are as follows:
- step (f) The concentrated solution in step (e) should be treated with at least two kinds of resins under the condition that the flavonoids and lactones can be combined.
- the invention provides a chromatography method, that is, a column chromatography method for performing column chromatography.
- the resins used in the chromatography method provided by the present invention include, but are not limited to, porous polymers, silica gel, alumina, polyamide, activated carbon, cellulose, and glucose gel.
- the chromatography method provided by the present invention wherein the column is eluted with water, a fatty alcohol of 1 to 3 carbons, acetone and a mixture or an ester thereof (methyl ester or ethyl ester).
- the invention provides a method for identifying and analyzing flavonoids in a ginkgo composition, the steps are as follows:
- the invention provides a method for identifying and analyzing terpene lactones in a ginkgo composition. The steps are as follows:
- test solution reflux the ginkgo composition with ethyl acetate, then filter, and concentrate the filtrate to dryness, and dissolve in methanol.
- the present invention provides a method for determining total flavonoids in a ginkgo composition, the steps are as follows:
- the present invention provides a method for determining flavonoid glycosides in a ginkgo composition, the steps are as follows:
- test solution Dissolve the sample composition with methanol and 25% hydrochloric acid sugar, reflux, remove salts and insolubles, place to cool and transfer the volumetric flask, wash the flask with methanol, pour the washing solution into the volumetric flask, and then Dilute to the mark with methanol.
- the present invention provides a method for determining the content of terpene lactone in ginkgo extract, the steps are as follows: (a) Preparation of sample solution: The composition was refluxed with acetone, filtered, and the filtrate was concentrated. The residue was dissolved in methyl acetate, extracted with water, and the aqueous layer was extracted once more with methyl acetate. The two methyl acetate layers were combined and evaporated to dryness and then dissolved in methanol.
- the present invention provides a method for testing the content of lactone in a ginkgo composition using ginkgolide A, B, J and ginkgolide monomers as standards.
- the present invention provides a method for measuring the content of ginkgoic acid in a ginkgo composition using a ginkgoic acid monomer as a standard.
- the invention provides a method for determining flavonoids by using rutin monomer as a standard.
- the invention provides a method for determining flavonols and glycosides thereof using quercetin, kaempferin and isorhamnetin monomers as standards.
- composition provided by the present invention can be used in food additives or added to beverages.
- composition provided by the present invention can be used in creams, ointments or raw materials appearing in the preparation.
- the present invention provides an oral preparation containing the above-mentioned ingredients.
- the above oral dosage forms include: pills, capsules, granules, tablets or suspensions.
- the present invention provides an injectable preparation, which can be used in different ways, such as intravenous, intramuscular, subcutaneous, or intraperitoneal injection.
- the present invention provides cosmetics using the above ingredients.
- the present invention provides a pharmaceutical composition prepared by the above method, which contains the above-mentioned effective amount of the above-mentioned composition and a pharmaceutically acceptable carrier.
- the invention also provides a method for preparing the pharmaceutical composition.
- the pharmaceutically acceptable carrier of the invention refers to any standard pharmaceutically acceptable carrier.
- these carriers are well known and include, but are not limited to, standard pharmaceutical carriers, such as buffered saline solution of osmate, oil / water suspensions containing polysorbate 80, water, and various types of wetting agents Phosphate-buffered saline, other carriers include sterilized solutions, tablets, coated tablets, and capsules.
- Typical carriers include excipients, such as: starch, milk, sugar, specialty clays, gelatin, Stearic acid or salt (including rhenium stearate, calcium), talc, vegetable fat or vegetable oil, gum, glycol or other known excipients. Carriers also include flavorings and colors or other additives.
- the carrier-containing composition is formulated in a conventional manner.
- the present invention provides a method for treating various types and degrees of angina pectoris caused by coronary heart disease.
- the method is to administer an effective dose of the above pharmaceutical composition to a patient.
- the present invention provides a method for improving tachycardia caused by ischemia by administering an effective dose of the above pharmaceutical composition to a patient.
- the present invention provides a method for alleviating angina pectoris by administering to a patient an effective dose of the above pharmaceutical components.
- the present invention provides a method for reducing the amount of glyceryl trinitrate by administering to a patient an effective dose of the above pharmaceutical component.
- the present invention provides a method for alleviating palpitations by administering to a patient an effective dose of an addictive drug component.
- the present invention provides a method for reducing cholesterol and triglyceride in the blood of a patient with abnormal blood lipids by administering to the patient an effective dose of the above pharmaceutical component.
- the present invention provides a method for reducing platelet aggregation in blood by administering to a patient an effective dose of the above-mentioned pharmaceutical component.
- the present invention provides to improve exercise tolerance by administering an effective dose of a drug addictive component to a patient, extending the duration of exercise, extending the onset of exercise to the occurrence of angina pectoris, and the beginning of exercise to
- the present invention provides a method for treating impotence by administering the above effective dose of a pharmaceutical composition to a patient.
- the present invention provides a method for treating psoriasis by administering the above effective dose of a pharmaceutical composition to a patient.
- the present invention provides a method for treating pigmentation by administering the above effective dose of a pharmaceutical composition to a patient.
- the present invention provides the treatment of amnesia, AIDS, Alzheimer's disease (Alzheimer's disease), angina pectoris, arteriosclerosis, arthritis, asthma, atherosclerosis, Autism, enuresis, brain trauma, arrhythmia, frostbite, T 99/00038 Cold, coronary heart disease, deafness, dementia, depression, diabetic vasoconstriction with bad acne and colic, dizziness, blurred vision, memory loss, fatigue, filariasis, headache, hyperlipidemia, hypertension, intermittent Methods of sexual claudication, renal dysfunction, leg cramps, myocardial infarction, Parkinson's disease, blood circulation disorders, embolism syndrome, Raynaud's disease, rheumatism, aging, chest tightness, tinnitus, tuberculosis, varicose veins, vertigo.
- compositions are used to treat diseases because they have the following effects: analgesia, analgesic, relieve asthma, anti-inflammatory, prevent atherosclerosis, antibacterial, anticancer, anticoagulant, antidiabetic, hypolipidemic, Antihypertensive, anti-nuclear radiation, anti-platelet aggregation, anti-oxidation, anti-thrombosis, anti-tuberculosis, anti-cough, bronchiectasis, capillary dilation, capillary protection, cerebral circulation stimulants, cerebral vasodilators, focus attention, improve memory , Improve hearing, improve peripheral circulation, increase dopamine, epinephrine, norepinephrine, nerve conduction, regulators, prevent carotid atherosclerosis and vasodilators, etc.
- the present invention provides a method for preparing a ginkgo composition, the steps are as follows:
- step (c) Precipitation: Dissolve the viscous extract of step (b) with twice the amount of hot water. After cooling, a precipitate is formed, and the precipitate is removed by filtration.
- step (d) Column chromatography: Place the filtrate from step (c) on a macroporous resin column (XAD-4) to make resin and leaves The ratio of 1: 1 was eluted with twice the amount of pure water, 6%, 18%, and 30% water-containing ethanol, and finally with 65% ethanol, until the color of the fraction became light. The 18% and 30% fractions were combined and concentrated in vacuo to a small volume containing no alcohol. The concentrated solution was then placed on a polyamide column. The ratio of polyamide to crude leaves was 1: 3, and eluted with pure water and 95% ethanol. Combine the 95% fraction with the 65% fraction of the macroporous resin column and concentrate in vacuo to contain no alcohol.
- XAD-4 macroporous resin column
- step (e) Removal of ginkgoic acid: The concentrated solution of step (d) was extracted three times with two-thirds of the volume of cyclohexane, and the water-containing portion was concentrated under reduced pressure.
- the finished product is a brown-yellow powder with a special fragrance and slightly bitter taste.
- column chromatography is characterized by secondary treatment, that is, the extract is first loaded on a macroporous resin column (XAD-4), and the ratio of the column to the leaf is 1: 1, and then the polyamide column, the column and the leaf The ratio is 1: 3.
- XAD-4 macroporous resin column
- the feature of removing ginkgoic acid is through secondary treatment, that is, the extract is passed through a macroporous resin column (XAD-4) chromatography, and then treated with cyclohexane three times.
- XAD-4 macroporous resin column
- the present invention provides a method for preparing a ginkgo composition, the steps are as follows:
- step (c) Precipitation: The extract obtained in step (b) is dissolved in 2 times the amount of boiling water, cooled to about 12 ° C, a precipitate is formed, and separated by filtration.
- step (d) Column chromatography: The extract obtained in step (c) is applied to a resin column and eluted with water or a mixed solvent of water and an organic solvent.
- the mixed solvent can be an alcohol of 1 to 3 carbons and acetone.
- the eluted fraction is concentrated and loaded on another resin column, and eluted with one or two solvent systems.
- the solvent system can be selected from water, alcohols of 1 to 3 carbons, ketones and esters, and then a high content of lactone can be obtained. And flavonoids, This fraction was concentrated under reduced pressure to remove aqueous alcohol.
- step (e) Removal of ginkgoic acid: The concentrate obtained in step (d) is extracted three times with two-thirds of a volume of saturated or unsaturated alkane, and the water portion is concentrated in vacuo.
- the filtrate was mixed with a macroporous resin and polyamide mixed column, and eluted with 100k of water, 100kg of 30% ethanol solution, 100kg of 60% ethanol solution, and 100kg of 90% ethanol solution, and combined the 30%, 60%, and 90% ethanol solutions.
- the eluent of the aqueous solution was concentrated in vacuo to a extract of about 70k, the extract was extracted three times with n-hexane, and the aqueous phase was concentrated and dried in vacuo.
- the final product of 1.5kg contains less than 5% water, contains 47.2% flavonoids, of which about 24.8% are flavonoid glycosides, 6.3% are lactones, and less than 5 ppm ginkgoic acid.
- Example 3 Starting from the column chromatography of Example 3: The fraction eluted with a 30% ethanol solution from the column was concentrated under reduced pressure, the ethanol was removed, and the concentrated solution was extracted three times, each time using two-thirds of ethyl acetate. extraction. The ethyl acetate phase was evaporated under reduced pressure at 45 ° C, and the residue was dissolved by heating with a 50% ethanol aqueous solution and left for 24 hours to form ginkgolides. After separation and crystallization, the mother liquor was evaporated under reduced pressure, and layered column separation was performed with 1.5 times the weight of activated carbon and silica gel, respectively. All the ginkgolides and ginkgolides were collected separately; concentrated to dryness, and combined with 10g of ginkgolide (A) The total terpene lactone content is not less than 80%.
- the 60% ethanol aqueous portion and 70% ethanol aqueous portion eluted from the column in the combined Example 3 were collected. It was concentrated under reduced pressure to be completely alcohol-free. This concentrate was applied to a polyamide column, eluting with 10%, 20%, 75%, and 90% ethanol in water, respectively. The 75% fraction was concentrated to dryness, the powder was dissolved in anhydrous ethanol, and the mixture was loaded on a polyamide column and eluted with 100% ethanol, 70% ethanol aqueous solution, and 20% ethanol aqueous solution. The 70% ethanol aqueous solution was collected, and 2 kg of silica gel was collected. To mix It was concentrated to dryness and eluted with ethyl acetate and ethanol, respectively. The ethanol portion was concentrated to dryness to give (B) 90 g. The total flavonoid content is not less than 80%.
- lactone (A) and flavonoid (B) extracts are mixed in different proportions to obtain different final products, such as 10 g (A) and 90 g (B). 100 g (A + B) is obtained. This mixture contains 77% flavonoids and 8% lactone, 10g (A) and 70g (B) are mixed to obtain 80g (A + B), then this product contains 70% flavonoid and 10% lactone.
- the invention provides a method for identifying and quantitatively analyzing flavonoids in a ginkgo biloba composition, the steps are as follows:
- test solution The O.lg composition was dissolved in 1 ml of methanol.
- the invention provides a method for identifying and quantifying lactones in a ginkgo composition, the steps are as follows:
- test solution reflux 0.5 g of the composition with 20 ml of ethyl acetate for 30 min, filter, and concentrate the filtrate to dryness: dissolve in 2 ml of methanol.
- Test solution 10 ⁇ l of each of the above solutions was drawn, spotted on the same silica gel GF254 plate, and developed with a mixed solvent of ethyl acetate: methylbenzyl: acetone: cyclohexane (4: 3: 2: 1) After that, the solvent was blown dry in air, heated at 150 ° C for 1 hour, and observed under 254nm wavelength light. The test sample and the standard sample could see colored spots of the same color at the specified position.
- the invention provides a method for identifying and quantitatively analyzing ginkgo acid in a ginkgo mixture, the steps are as follows:
- test solution 4 g of the composition was added with 100 ml of n-hexane under reflux for 2 hours, filtered, and the filtrate was concentrated to dryness, and dissolved in 1 ml of ethyl acetate.
- Test solution 10 ⁇ l of each of the above solutions was spotted on the same silica gel GF254 thin plate, and the mixture was developed with a mixed solvent of n-hexane: ethyl acetate: acetic acid (80: 15: 5), and then blown in air.
- the dry solvent when observed under an ultraviolet lamp at a wavelength of 315nm and a wavelength of 368nm, the absorption of the test solution should be lower than that of the standard solution (0.0005%).
- the invention provides a method for quantitatively analyzing the total content of flavonoids in a ginkgo biloba composition, the steps are as follows:
- the invention provides a method for determining the flavonoid glycoside content. The steps are as follows:
- test solution Dissolve 75 mg of ginkgo biloba composition with 20 ml of methanol and 5 ml of 25% hydrochloric acid and reflux for 60 min. After separation, leave to cool and immediately transfer to a 50 ml volumetric flask. Wash the flask 3 times with 5 ml of methanol Wash the washing solution into a volumetric flask and dilute to the mark with methanol.
- Test solution Calculate relative peak area of HPLC to determine kaempferin, quercetin and isorat The content of Lisu.
- Total flavone glycoside content quercetin content x 2.50 + amount of kaempferol X 2.63 + amount of isorhamnetin X 2.36.
- the invention provides a method for determining the content of terpene lactones. The steps are as follows:
- the above method specifically uses a highly purified rutin monomer having a chemical structure of C 27 H 3 Q0 16 as a standard to determine the total flavonoid content of ginkgo biloba.
- the above method uses the highly purified monomers of quercetin, kaempferin and isorhamnetin as standards to determine the flavonol glycosides and flavonoid glycosides in the ginkgo leaf composition.
- the above method specifically uses GA, GB, GC, GJ, and BB with highly purified and well-defined chemical structures as standards to identify lactones and determine lactone content.
- the above method specifically uses ginkgoic acid with a highly purified and well-defined chemical structure as a standard to identify ginkgoic acid in a ginkgo leaf composition.
- each tablet contains
- 500ml drinks include: Ginkgo Extract 2.0g
- the ginkgo extract described in the present invention can be formulated in a conventional manner, for example, it can be made into an oral solution, a coated tablet, a tablet or an injection.
- the preparation of the present invention can be used to treat cerebrovascular and peripheral vascular circulation disorders, especially angina pectoris caused by coronary artery disease.
- Clinical trials conducted in China have shown that a total of 243 cases have confirmed that Ginkgo biloba extract is used to treat coronary heart disease. Angina pectoris caused by the disease is safe and effective. The clinical trial details are summarized as follows:
- the patient selection criteria are as follows:
- Inclusion criteria The patient was clearly diagnosed with angina pectoris, and chest pain occurred more than twice a week. An ischemic change or exercise test result on the ECG is positive.
- Exclusion criteria (1) Patients with active myocardial defect or other cardiopulmonary diseases, and chest pain caused by severe neurosis, menopause syndrome, and neck syndrome. (2) Patients with angina pectoris and hypertension (BP> 24 / 14.87 Kpa). (3) Patients with severe cardiopulmonary failure, severe arrhythmia, liver and kidney dysfunction, and hematopoietic dysfunction. (4) Lactating women and patients with allergies. (5) Those who are younger than 18 years old or older than 70 years old.
- Data deletion criteria Patients who did not take medications as prescribed and patients who lacked data and whose clinical trial results could not be determined.
- the diagnostic criteria for the severity of angina in the clinical trial center are based on the following: 1979 Symposium on Angina Pectoris and ECG Efficacy Evaluation of Coronary Heart Disease in the Treatment of Coronary Heart Disease Angina Pectoris and Arrhythmia with Chinese and Western Medicines.
- Mild A typical angina pectoris usually lasts for a few minutes. It occurs 1-3 times a day or 2-3 times a week. The attack is not serious, but patients sometimes need to take nitroglycerin.
- Moderate More than three episodes of angina pectoris per day, each lasting several minutes to 10 minutes. The pain is more severe than mild attacks, and patients usually need to take nitroglycerin.
- the diagnostic criteria for the type of colic in the clinical trial center is the "Clinical Diagnostic Criteria for Ischemic Heart Disease” developed by the International Cardiology Association and the World Health Organization Joint Committee. The diagnostic criteria are detailed below:
- Overworked angina pectoris A transient episode of chest pain due to excessive fatigue or other increased myocardial oxygen demand. Pain can be quickly relieved by rest or by taking nitroglycerin.
- the clinical trial was conducted as follows: 243 patients with angina due to coronary artery disease participated in the trial.
- the researchers used 153 patients as the ginkgo test group and 90 patients as the control group.
- the gingko test group randomly divided 123 patients into the test group and 30 patients into the open group. These 213 cases were compared with the control group. Double-blind, scale-up parallel controls and open treatment were used.
- the medicine used in the ginkgo group is a preparation of the ginkgo extract according to the present invention.
- the lg preparation contains 40 mg of ginkgo extract, 480 mg of dextrin, 420 mg of sucrose, 20 mg of starch, 20 mg of low-substituted hydroxypropyl cellulose, and 20 mg of stevioside.
- the ginkgo preparation is first made into granules and then filled into small bags. In a clinical trial, a patient takes 1 bag of ginkgo preparations 3 times a day. The treatment cycle is 6 weeks
- the drug used in the control group was Brainway®, produced by Shanghai Xinyi Pharmaceutical Factory, located at 70 North Sichuan Road, Shanghai, China. In clinical trials, patients took 1 capsule of Beloda 3 times a day. As a positive control, the treatment cycle was also 6 weeks.
- each group is given a blank placebo in a different dosage form, that is, the treatment group is given a blank capsule (placebo) in addition to the ginkgo granules, and the control group is given Bailu To reach out, add blank granules (placebo).
- the packaging and appearance of each placebo are exactly the same as the corresponding drug.
- Chest pain symptoms are the same as before treatment (4) Aggravation: Severe chest pain symptoms (or meet the "critical criteria").
- ginkgo biloba extract preparation in this invention is safe and effective in treating coronary heart disease and angina pectoris.
- Ginkgo preparations show strong biological activity. Compared with the existing Chinese medicine preparations for treating angina pectoris, in terms of safety and effectiveness, the ginkgo preparations have surpassed the existing preparations in one or more aspects, and can reduce the nitroglycerin. use.
- Ginkgo biloba preparations are effective in the treatment of coronary heart disease and angina pectoris, and the efficacy exceeds the control drugs.
- Table 6 Effect of Ginkgo biloba extract on angina pectoris patients
- the medicinal ingredients of Ginkgo biloba preparation are effective in improving ischemic electrocardiogram, and the effective rate exceeds that of the control group.
- the medicinal ingredients of Ginkgo biloba preparation are effective in reducing angina pectoris, and have a stronger effect on reducing the use of nitroglycerin than the control group.
- the effective ingredients of Ginkgo biloba preparation can effectively reduce the cholesterol and triglyceride levels in patients with dyslipidemia.
- the medicinal ingredients of Ginkgo biloba can reduce the proportion of medium and low density whole blood, inhibit platelet aggregation, and there is a significant difference before and after administration. Effect of ginkgo biloba extract on the hemogram changes in patients
- the medicinal ingredients of Ginkgo biloba preparation have the ability to improve exercise tolerance and prolong the duration of exercise, extend the interval between the beginning of exercise and angina pectoris, and reduce the interval between the beginning of exercise and the ST segment by 1mm. And this effect is stronger than the control drug.
- Exercise amount (mets) Exercise starts to ST 5.88 ⁇ 1.40 7.09 ⁇ 1.75 ** 6.30 ⁇ 2 6.31 ⁇ 2.15,
- Ginkgo biloba preparation can be used for various types and different levels of angina pectoris (Tables 13 and 14), and it does not affect blood pressure and heart rate (Table 15), and it does not affect liver and kidney function.
- Table 13 Effects of Ginkgo biloba extract on 3 levels of angina Pectoris Severity Severity Cases with significant effect Effective but ineffective Mild 55 23 33 1 Moderate 80 33 46 1 Severe 18 3 7 8
- Table 14 Effects of Angina Pectoris Types The number of cases of angina pectoris is markedly effective and ineffective tired type 119 48 65 6 white hair type 25 6 16 3 mixed type 9 5 3 1
- the present invention provides a new ginkgo biloba extract composition, a method for preparing the composition, and a method for detecting various components in the composition.
- the composition can be used as a food additive or added to beverages, and can also be added to creams, ointments, or raw materials for making them.
- the composition can also be formulated as an oral preparation, injection or cosmetic.
- Combining the composition of the present invention with a pharmaceutically acceptable carrier can be used to make a pharmaceutical composition to treat different types of angina pectoris, ischemic heart disease, palpitations, reduce platelet aggregation, improve exercise tolerance and prolongation Exercise endurance, treatment of impotence, psoriasis, pigmentation and other diseases.
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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AU28247/99A AU741628B2 (en) | 1998-03-19 | 1999-03-19 | Composition from ginkgo biloba leaves, preparation and uses |
GB0024213A GB2352177B (en) | 1998-03-19 | 1999-03-19 | Composition from ginkgo biloba leaves preparation and uses |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US09/044,551 | 1998-03-19 | ||
US09/044,551 US6030621A (en) | 1998-03-19 | 1998-03-19 | Ginkgo biloba composition, method to prepare the same and uses thereof |
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WO1999047148A1 true WO1999047148A1 (fr) | 1999-09-23 |
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PCT/CN1999/000038 WO1999047148A1 (fr) | 1998-03-19 | 1999-03-19 | Compositions a base de feuilles de ginkgo biloba, leurs procedes de preparation et leurs applications |
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US (4) | US6030621A (zh) |
CN (4) | CN100371707C (zh) |
AU (1) | AU741628B2 (zh) |
GB (1) | GB2352177B (zh) |
HK (3) | HK1065596A1 (zh) |
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Cited By (12)
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US20120269909A1 (en) * | 2009-10-28 | 2012-10-25 | Hangzhou Adamerck Pharmlabs Inc. | Preparation comprising amino acids and plants and its activity in the alcohol detoxification |
US20140220162A1 (en) * | 2009-10-28 | 2014-08-07 | Hangzhou Adamerck Pharmlabs Inc. | Preparation comprising amino acids and plants and its activity in the alcohol detoxification |
US9192638B2 (en) | 2009-10-28 | 2015-11-24 | Modutech S.A. | Preparation comprising amino acids and plants and its activity in the alcohol detoxification |
US9526753B2 (en) * | 2009-10-28 | 2016-12-27 | Modutech S.A. | Preparation comprising amino acids and plants and its activity in the alcohol detoxification |
CN104688784A (zh) * | 2013-12-10 | 2015-06-10 | 成都百裕科技制药有限公司 | 银杏内酯在制备降血压的药物中的用途 |
CN104535527A (zh) * | 2014-12-26 | 2015-04-22 | 宁波立华植物提取技术有限公司 | 一种应用近红外实时监测银杏叶提取过程中槲皮素的方法 |
CN104535527B (zh) * | 2014-12-26 | 2017-02-01 | 宁波立华植物提取技术有限公司 | 一种应用近红外实时监测银杏叶提取过程中槲皮素的方法 |
WO2020037737A1 (zh) * | 2018-08-20 | 2020-02-27 | 上海上药杏灵科技药业股份有限公司 | 一种银杏酮酯及其制备方法 |
RU2772016C1 (ru) * | 2018-08-20 | 2022-05-16 | Спх Син Лин Сай. & Тек. Фармасьютикал Ко., Лтд. | Экстракт листьев гинкго билоба и способ его получения |
CN110231296A (zh) * | 2019-07-16 | 2019-09-13 | 郑州轻工业学院 | 一种快速绿色高效提取蚕沙黄酮的方法及其检测方法 |
CN110231296B (zh) * | 2019-07-16 | 2021-09-17 | 郑州轻工业学院 | 一种快速绿色高效提取蚕沙黄酮的方法及其检测方法 |
EP4299059A1 (en) | 2022-07-01 | 2024-01-03 | Labelic Analysis, S.L. | Composition for the treatment of tinnitus |
Also Published As
Publication number | Publication date |
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US6475534B2 (en) | 2002-11-05 |
AU2824799A (en) | 1999-10-11 |
CN1292704A (zh) | 2001-04-25 |
GB0024213D0 (en) | 2000-11-15 |
CN1740786A (zh) | 2006-03-01 |
CN1508542A (zh) | 2004-06-30 |
HK1087176A1 (en) | 2006-10-06 |
CN100344957C (zh) | 2007-10-24 |
GB2352177A (en) | 2001-01-24 |
US6187314B1 (en) | 2001-02-13 |
US20010055629A1 (en) | 2001-12-27 |
CN1740787A (zh) | 2006-03-01 |
HK1065596A1 (en) | 2005-02-25 |
GB2352177B (en) | 2003-08-06 |
HK1087178A1 (en) | 2006-10-06 |
CN100371707C (zh) | 2008-02-27 |
CN1267727C (zh) | 2006-08-02 |
US6030621A (en) | 2000-02-29 |
CN1159022C (zh) | 2004-07-28 |
AU741628B2 (en) | 2001-12-06 |
US6632460B2 (en) | 2003-10-14 |
US20030152654A1 (en) | 2003-08-14 |
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