CN1589845A - Preparation technology of crataegus total phenolic acid portion and application - Google Patents
Preparation technology of crataegus total phenolic acid portion and application Download PDFInfo
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Abstract
A crab phenolic acid extracted from the leaf and fruit of crab can be used to prepare the medicine in the form of injection, or the orally taken forms for preventing and treating ischemic cardiovascular and cerebrovascular diseases, senile dementia and hyperlipemia. Its preparing process is also disclosed.
Description
Technical field:
The invention belongs to field of medicaments, is to separate preparation technology, preparation and the potential application on medicine and health food that obtains total phenolic acid part from Folium Crataegi or fruit specifically.
Background technology:
Cardiovascular and cerebrovascular disease is one of present countries in the world sickness rate disease with high.Along with The development in society and economy, the raising of living standards of the people, the prevalence of cardiovascular and cerebrovascular disease is also increasing year by year.According to interrelated data, calendar year 2001 the whole world 5,600 ten thousand people's death are arranged.Two kinds of main diseases of coronary heart disease and apoplexy are because of relevant with 7,000,000 and 5,500,000 people's death respectively.Just because of this, the research and the control of cardiovascular and cerebrovascular disease all paid much attention in countries in the world.But up to the present, although many cardiovascular and cerebrovascular vessel medicines are arranged in clinical practice, the treatment cardiovascular and cerebrovascular disease has been brought into play good effect, but and fail to control the impetus that the cardiovascular and cerebrovascular disease prevalence increases, this reflects from a side also needs to carry out continuous effort, develop more effective new drug, put into clinical practice.Owing to the economic development imbalance, the medical expense of cardiovascular and cerebrovascular vessel can not well be treated many patients at present simultaneously, also needs to develop and can satisfy the new drug extensive patients needs, that price is lower, for the control cardiovascular and cerebrovascular disease is contributed.
Fructus Crataegi is the Rosaceae Crataegus plant, and there is kind surplus this platymiscium 280 in the whole world, in state-owned 19 kinds.Its fruit is a conventional Chinese medicine, also is China's pharmacopeia kind.Put down in writing according to Compendium of Material Medica: these product " sour sugariness temperature, it is long-pending to help digestion, spleen reinforcing ".Containing multiple physiologically active ingredient in its fruit, as flavones ingredient, ursolic acid, oleanolic acid, chlorogenic acid, organic acid, mineral and trace element etc., have multiple pharmacological effect, is the important living resources of China, is classified as the dietotherapeutic kind by country.After the fifties, research worker finds that Folium Crataegi also has multiple physiologically active.Studying more is the Folium Crataegi total flavones constituents, the extract and the Folium Crataegi total flavones preparation (as Yixintong sheet and capsule) of existing several Folium Crataegi total flavoness at present, the treatment that is mainly used in diseases such as coronary heart disease, hyperlipidemia.
What think performance pharmacological action in the Fructus Crataegi at present is wherein total flavonoid composition, also have some separation and Extraction patents about Fructus Crataegi total flavones (as application number be: 01103986.8 and application number be: 01118628.3), but we are through discovering, after the flavones content in the Fructus Crataegi total flavones extract was further improved, activity descended on the contrary.What this pointed out in our Fructus Crataegi performance pharmacological action may be the non-flavones ingredient in the Fructus Crataegi.
Summary of the invention:
The invention provides a kind of preparation method that obtains haw total phenolic acid part of from crataegus pin natifida var. Major leaf or fruit, separating, reach the potential using value of this position in medicine and health food.
In accordance with the following methods, we have obtained haw total phenolic acid part.That is: with Folium Crataegi or fruit through hydrous alcohol extraction, the extracting solution concentrating under reduced pressure is placed precipitation, supernatant is through macroporous adsorption resin chromatography, and water elution is used ethyl acetate extraction after partly regulating pH value to 1～2, behind the extract concentrating under reduced pressure with water dissolution, through macroporous adsorption resin chromatography, behind the water elution, continuous again with aqueous alcohol or aqueous acetone eluting, the eluent concentrating under reduced pressure, spray drying obtains yellow powder, is haw total phenolic acid part.
Medical material used in the present invention can be Folium Crataegi or Fructus Crataegi, but the total phenolic content in the Folium Crataegi will be higher than Fructus Crataegi, and because of sugar and content of starch height in the Fructus Crataegi, therefore, the actual Folium Crataegi that uses is better than Fructus Crataegi.
The employed aqueous alcohol of this technology can be methanol, the lower aliphatic alcohols of ethanol and other C1～C5.The concentration of extracting used aqueous alcohol is 50%～90%, and the eluting macroporous adsorbent resin adopts 20%～60% aqueous alcohol or aqueous acetone.
The macroporous adsorbent resin that this technology adopted comprises various nonpolar, low poles, Semi-polarity, polar homemade or import macroporous adsorbent resin.
Above-mentioned effective site contains phenolic acid compositions such as caffeic acid, coffee mesitoyl quinine acid compounds, caffeoyl threose acid compounds.The content of using the chemical constituent that HPLC was familiar with occupies imitates more than 50% of position.
Utilize this effective site to can be made into various clinically preparations: injection, powder ampoule agent for injection, oral tablet, electuary, capsule, drop pill, oral liquid etc.
Above-mentioned preparation can be used for preventing and treating the application of various ischemic cardio cerebrovascular diseases, senile dementia, hyperlipidemia aspect.
Following animal experiment study further illustrates haw total phenolic acid part useful effect of the present invention:
1. acute toxicity test
40 of healthy Kunming mouses, male and female half and half, body weight 18～22g; 40 of healthy SD rats, male and female half and half are about body weight 150g.
The orally give haw total phenolic acid part can not surveyed the LD50 value, so its maximum tolerated dose to mice and rat (MTD) is measured in this experiment respectively.Big mice all gavages administration by maximum administration volume, and morning and afternoon respectively once.The mice fasting be can't help water 5 hours before the administration, and the rat fasting be can't help water 12 hours.
Experimental result shows: mice oral haw total phenolic acid part 2.2g/ kilogram (gavaging at twice) on the one, and can cause independent activity of animals to reduce, appetite descends, and body weight gain slowly waits reaction, and above-mentioned being reflected in two weeks recovered, and do not cause animal dead.The maximum tolerated dose that the oral haw total phenolic acid part of mice is described is greater than 2.2g/ kilogram (be equivalent to clinical dosage 550 times).
Rat oral haw total phenolic acid part 2.8g/ kilogram (gavaging at twice) on the one can cause independent activity of animals to reduce, degradation reaction under the appetite, and above-mentioned being reflected in two weeks recovered, and do not cause animal dead.The maximum tolerated dose that the oral haw total phenolic acid part of mice is described is greater than 2.8g/ kilogram (be equivalent to clinical dosage 700 times).Show that haw total phenolic acid part has higher safety.
2. to the influence of focal cerebral ischemia in rats
Get 70 of male SD rats, body weight 300～400g, be divided into 6 groups at random by body weight, be respectively Fructus Crataegi total phenolic acids high dose group (8mg/ kilogram), middle dosage group (4mg/ kilogram), low dose group (2mg/ kilogram), positive control nimotop group (1.2mg/ kilogram), sham operated rats and ischemia model matched group (all giving equivalent 0.5%CMC-Na).
7d before experiment, every day, ig was 1 time, 60min administration before ischemia for the last time in the 7th day.Adopt internal carotid artery line bolt legal system to be equipped with intraluminal middle cerebral artery occlusion in rats obturation (MCAO) model.Rat is anaesthetized with 10% chloral hydrate (300mg/ kilogram) ip, the cervical region median incision on the constant temperature operating-table of lying on the back, expose right carotid, outwards draw digastric and sternocleidomastoid, free successively by common carotid artery crotch head-end, ligation and the branch of cutting off external carotid artery: tremulous pulse and superior thyroid artery under the occipital bone, in the ligation of external carotid artery far-end, cutting off external carotid artery makes its trunk free standby, separate internal carotid artery then, make a call to one with silk thread at the external carotid artery root and release, folder closes common carotid artery and internal carotid artery.Nylon wire through external carotid artery trunk otch, is slowly gone into the cranium direction to internal carotid artery and advanced, and is labelling with the common carotid artery crotch, feel resistance when advancing the 20mm left and right sides, promptly reached in the thinner anterior cerebral artery, all blood of having blocked MCA are tightened the external carotid artery root and are released for the source.Behind the 1h, extract nylon wire, tighten the tremulous pulse stump.Skin suture is finished MCAO and is caused focal cerebral ischemia-irritate again model.Behind the sham operated rats rat anesthesia, only expose the inside and outside aortic bifurcation of neck, not inaccessible middle cerebral artery.Postoperative 24h carries out rank scores by the method for Bederson to the behavioral deficiency of animal.Behind the MCAO 24h, the sacrificed by decapitation rat is taken out full brain, and left and right sides brain cuts respectively, weighs.At right brain optic chiasma and each 2mm place, front and back thereof, do crown section, brain section in 1%TTC solution lucifuge 37 (C is hatched 25min, separates pale district (infarct) and non-pale district (normal district), calculates infraction percentage ratio.With the oven dry of the cerebral tissue after the dyeing, contrast brain weight in wet base is obtained brain water content.
Experimental result shows: the result shows, behind rat ig Fructus Crataegi total phenolic acids 2,4, the 8mg/kg, animal behavior variation and infarction size and normal saline matched group relatively have clear improvement, and behavior scoring has reduced by 43.25% (p＜0.01), 60.70 (p＜0.001), 63.88 (p＜0.001) respectively behind the 24h; Cerebral infarct size has on average dwindled 30.2% (p＜0.01), 47.3 (p＜0.01), 50.9 (p＜0.001).High dose group is suitable with nimotop group action intensity.2) to the influence of focal rats with cerebral ischemia biochemical indicator get 70 of male rats (300～400g), the grouping administration, operation method such as preceding.Behind the MCAO 24h, the rat sacrificed by decapitation is got brain, removes cerebellum.Brain is made 10% homogenate with normal saline, measure the superoxide dismutase (SOD) in the cerebral tissue, glutathion (GSH), the content of malonaldehyde (MDA) and lactic acid (LA) etc.Experimental result shows: Fructus Crataegi total phenolic acids can make the interior MDA of cerebral tissue of rat reperfusion injury, and the LA equal size reduces, and shows that tissue ischemia anoxia and peroxidating degree are subjected to obvious inhibition; SOD and GSH content increase simultaneously, have reflected that medicine has raising to antioxidant ability of organism and the ability of removing free radical.
3. to the therapeutical effect and the hemodynamic effects of dog myocardial ischemia
30 of dogs are divided into 6 groups.Left anterior descending coronary artery (LAD) sham-operation normal saline group, LAD blocking-up normal saline group, LAD blocking-up Propranolol group, 3 dosage groups of LAD blocking-up Fructus Crataegi total phenolic acids (2,4,8mg/kg).Iv pentobarbital sodium 30mg/kg anesthesia, tracheal intubation pedestrian worker breathes, and the 4th intercostal is opened breast in a left side, separates the LCA root, places the electromagnetic flowmeter probe, the record blood flow.Common carotid artery intubate record common carotid artery blood pressure.Measure left constant pressure from apex of the heart intubate to left chamber, and measure left chamber diastasis and left ventricular pressure rate of change maximum.With heart rate instrumentation centering rate, observe the II lead electrocardiogram simultaneously.After postoperative is stablized 10min,, be data before the administration in the above-mentioned all indexs of RM-6000 type physiograph.The vena femoralis injection administration, ligation LAD behind the 5min, record LAD blocking-up back 1,2,5,10,20,30,60,90,120,240, the above-mentioned all indexs during 360min (data behind the medicine).Before administration and after the administration 20,40,60,90,120min gets blood simultaneously from coronary sinus vein and common carotid artery, measures oxygen content with CORNING178 type blood gas analyzer.Calculating myocardium blood flow, coronary resistance, myocardial oxygen consumption, myocardial oxygen consumption index, myocardium coefficient of oxygen utilization.
Result of the test shows that infusion haw total phenolic acid part 2mg/kg does not have obvious influence to the every index of hemodynamics; 4,8mg/kg can obviously increase myocardial flow, reduces coronary resistance, significantly reduces myocardial oxygen consumption and myocardial oxygen consumption index, reduces myocardium coefficient of oxygen utilization.
4. to Carnis Coturnicis japonicae hyperlipemia and atherosclerotic effect
Get 60 of healthy male Carnis Coturnicis japonicaes, be divided into 6 groups at random, 10 every group.Normal feedstuff group; Hyperlipidemia model group: feed high lipid food (including 79% normal feedstuff, 1% cholesterol, 20% Adeps Sus domestica); Haw total phenolic acid part is little, in, heavy dose of group 40,80 and 160mg/kg.d; Lovastatin positive controls 4mg/kg.d.Give normal feedstuff and hyperlipidemia model group except that the normal control group and give the high lipid food, each group is given different medicines respectively when giving high lipid food.Each treated animal sub-cage rearing, quantitative feeding, administration every day 1 time, jugular vein is got blood behind the successive administration 60d, measure serum TC, TG and HDL-C respectively, LDLC-C by formula LDL-C=TC-(1/2.2TG+HDLC-C) calculates, and puts to death animal then, take out aorta and liver, observe sick damage situation of arterial wall and liver fat denaturation degrees.
Experimental result shows: 1) to after the influencing Carnis Coturnicis japonicae and gavage haw total phenolic acid part 60d of blood fat, middle dosage group (80mg/kg.d) can obviously reduce the content (p＜0.05) of serum TC, TG and LDL-C, reduces percentage rate and is respectively 36.21%, 29.18% and 35.27%.Heavy dose of group (160mg/kg.d) can significantly reduce the content (p＜0.01) of serum TC, TG and LDL-C, reduce percentage rate and be respectively 47.29%, 43.38% and 45.87%, simultaneously can make TC/HDL-C ratio obviously reduce (p＜0.05), reducing percentage rate is 36.92%.2) to atherosclerotic plaque form influence Carnis Coturnicis japonicae and gavage haw total phenolic acid part after, plaque area percentage rate and average gray can descend 7.3%～29.8% and 8.4%～21.9% respectively 3 kinds of various dose groups, and heavy dose of group reduces the effect highly significant (p＜0.01) of plaque area percentage rate and average gray.The microscopically observation also higher fat model group of aortic tunica intima thickness of visible haw total phenolic acid part group is thin, and the foam cell number of appearance is also less.3) to after the influencing Carnis Coturnicis japonicae and gavage haw total phenolic acid part 80mg/kg and 160mg/kg 60d of liver, the liver weight coefficient has obvious reduction (p＜0.01).The hepatic tissue section microscopy also higher fat model group of fatty degeneration of liver degree of visible medication group obviously alleviates.Above-mentioned experimental result shows that haw total phenolic acid part has tangible blood fat reducing and the atherosis effect of prevention of arterial.
The present invention has the following advantages or good effect compared with the prior art:
1. with respect to other some cardiovascular medicaments, Folium Crataegi or fruit have sufficient raw, low price, and cost is low.
2. prior art it is generally acknowledged that the active site of Fructus Crataegi is a total flavonoid composition wherein.Our result of study shows that the activity of haw total phenolic acid part is better than the Fructus Crataegi total flavones position.
3. existing all is Fructus Crataegi total flavones constituents at wherein about Fructus Crataegi extract and preparation.The invention provides the preparation technology, quality standard of haw total phenolic acid part and in pharmaceutically application.
4. the quality standard of extract of existing Fructus Crataegi and preparation is to measure content of total flavone to formulate, and assay method is also many to be measured with ultraviolet method, and because of ultraviolet method disturbs greatly, assay method is inaccurate.And the present invention uses HPLC method mensuration, and wherein recognizable content of effective reaches more than 50%.
5. because the difference of composition is existing about the hawthorn preparation poorly water-soluble, generally can only make oral formulations, as tablet, capsule, drop pill.And the haw total phenolic acid part that the present invention obtains can be made the several formulations that comprises injection type.
Description of drawings:
Fig. 1 is the extraction process flow chart of haw total phenolic acid part of the present invention.
The specific embodiment:
Embodiment one: the preparation of effective site
Get exsiccant Folium Crataegi 100kg, be ground into coarse powder, divide reflux, extract, three times with 10 times of amount 60% ethanol, merge extractive liquid, is evaporated to 50L, places precipitation, centrifugal, supernatant is through the AB-8 macroporous adsorption resin chromatography, and water elution is used ethyl acetate extraction after partly regulating pH value to 1, behind the extract concentrating under reduced pressure with water dissolution, through the AB-8 macroporous adsorption resin chromatography, be 3～5 again, continue rare acetone eluting with 60% with water elution to pH value, the eluent concentrating under reduced pressure, spray drying obtains buff powder 0.52kg, is haw total phenolic acid part (is 0.52% by crude drug amount yield).Through assay, purity is 84.79%.
Embodiment two: the preparation of effective site
Get exsiccant Fructus Crataegi 100kg, pulverize, divide percolation to extract with 20 times of amount 80% methanol, merge percolate, be evaporated to 50L, place precipitation, centrifugal, supernatant is through D
101Macroporous adsorption resin chromatography, after water elution is partly regulated pH value to 2, use ethyl acetate extraction, behind the extract concentrating under reduced pressure with water dissolution, again through the AB-8 macroporous adsorption resin chromatography, with water elution to pH value is 3～5, continuation is with 20% Diluted Alcohol eluting, eluent concentrating under reduced pressure, spray drying, obtain buff powder 0.42kg, be haw total phenolic acid part (is 0.42% by crude drug amount yield).Through assay, purity is 67.25%.
Embodiment three: the preparation of tablet
Get position 100g of the present invention, starch 80g, dextrin 5g mix homogeneously, add 10% starch slurry system soft material, granulate with 14 order nylon screens, 60～70 ℃ of aeration-dryings, 16 mesh sieve granulate add magnesium stearate 1.5g, carboxymethyl starch and receive the 5g mixing, be pressed into 1000, coating promptly.Every contains position 100mg of the present invention.Adult every day 2～5 times, each 1～10.
Embodiment four: the preparation of oral liquid
Get position 20g of the present invention, mix with Mel 30g, sucrose 50g, sodium benzoate 2g and distilled water 300ml, be heated to 85～90 ℃, stir and make dissolving, insulation 30min filters, and the filtrate thin up stirs evenly to 1000ml, embedding (every 10ml), and sterilization is promptly.Adult every day 2～5 times, each 1～5.
Embodiment five: the preparation of injection
Get position 50g of the present invention, add the injection water and make dissolving in right amount, 0.02% active carbon that adds amount of preparation stirs 5～10min, filter, filtrate is diluted to about 10L, adds sodium chloride adjusting osmotic pressure and oozes to waiting, regulate pH5.5～7.5, ultrafiltration, embedding become 1000 (10ml/ props up), and 100 ℃ of 30min sterilizations promptly.Adult's vein or administered intramuscular, every day 1～2 time, each 1～5.
Embodiment six: the preparation of injectable powder
Get position 50g of the present invention, add the injection water and make dissolving in right amount, 0.02% active carbon that adds amount of preparation stirs 5～10min, filters, and filtrate is diluted to 1L, regulates pH5.5～7.5, ultrafiltration, and spray drying, dry powder is promptly aseptic subpackaged.Every 50mg faces with before adding the injection water and makes dissolving in right amount, with the slowly intravenous drip of sodium chloride transfusion 100～500ml dilution back.Adult every day 1～2 time, each 1～5.
Claims (9)
1, extracts the preparation technology of effective site in a kind of Folium Crataegi or the fruit, it is characterized in that Folium Crataegi or fruit obtain wherein total phenolic acid part through extraction.
2. total phenolic acid part according to claim 1, it is characterized in that its extraction process can be obtained by following extracting method: Folium Crataegi or fruit are after crushed, with hydrous alcohol extraction, the extracting solution concentrating under reduced pressure, place precipitation, supernatant is through macroporous adsorption resin chromatography, water elution is partly regulated pH value to 1-2, uses ethyl acetate extraction, behind the extract concentrating under reduced pressure with water dissolution, again through macroporous adsorption resin chromatography, aqueous alcohol or aqueous acetone eluting, eluent concentrating under reduced pressure, spray drying, obtain buff powder, be haw total phenolic acid part.
3. according to claim 1,2 described haw total phenolic acid parts, it is characterized in that this effective site contains caffeic acid, coffee mesitoyl quinine acid compounds, caffeoyl threose acid compounds.
4. the extracting method of haw total phenolic acid part according to claim 2 is characterized in that said alcohol is the lower aliphatic alcohols of methanol, ethanol and other C1～C5.
5. the extracting method of haw total phenolic acid part according to claim 2 is characterized in that the concentration of aqueous alcohol used when medical material extracted is 50%～90%.
6. the extracting method of haw total phenolic acid part according to claim 2, the used aqueous alcohol or the concentration of aqueous acetone are 20%～60% when it is characterized in that the eluting macroporous adsorbent resin.
7,, it is characterized in that total phenolic content is more than 50% according to claim 1,2 described haw total phenolic acid parts.
8. by claim 1,2 described haw total phenolic acid parts, it is characterized in that and to cooperate the back to make various oral and injection types such as tablet, capsule, drop pill, granule, oral liquid, injection separately or with the adjuvant of other medicinal permission at this position by existing method.
By the described Fructus Crataegi total phenolic acids preparation of claim 8 in prevention with treat application aspect various ischemic cardio cerebrovascular diseases, senile dementia, the hyperlipidemia.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB031505449A CN100421689C (en) | 2003-08-26 | 2003-08-26 | Preparation technology of crataegus total phenolic acid portion and application |
| CNA2006101490499A CN101143168A (en) | 2003-08-26 | 2003-08-26 | Technology for preparing haw total phenolic acid part |
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| CNB031505449A CN100421689C (en) | 2003-08-26 | 2003-08-26 | Preparation technology of crataegus total phenolic acid portion and application |
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| CNA2006101490499A Division CN101143168A (en) | 2003-08-26 | 2003-08-26 | Technology for preparing haw total phenolic acid part |
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| CN1589845A true CN1589845A (en) | 2005-03-09 |
| CN100421689C CN100421689C (en) | 2008-10-01 |
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| CNA2006101490499A Pending CN101143168A (en) | 2003-08-26 | 2003-08-26 | Technology for preparing haw total phenolic acid part |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104717892A (en) * | 2012-10-16 | 2015-06-17 | 因德纳有限公司 | Process for obtaining caffeoylquinic acids-rich extracts from helianthus annuus |
| CN106389568A (en) * | 2016-11-07 | 2017-02-15 | 中国农业科学院郑州果树研究所 | Pear mature fruit total phenol extraction method |
| CN112675228A (en) * | 2021-01-18 | 2021-04-20 | 南京邮电大学 | Ointment for promoting wound healing and preparation method thereof |
| CN114031588A (en) * | 2021-11-02 | 2022-02-11 | 东营市人民医院 | Phenol derivative, preparation method thereof and application thereof in preparation of medicaments with anti-inflammatory and/or antioxidant effects |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1027574C (en) * | 1991-05-08 | 1995-02-08 | 安阿玥 | Preparation method of injection for treating hemorrhoids |
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2003
- 2003-08-26 CN CNB031505449A patent/CN100421689C/en not_active Expired - Fee Related
- 2003-08-26 CN CNA2006101490499A patent/CN101143168A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104717892A (en) * | 2012-10-16 | 2015-06-17 | 因德纳有限公司 | Process for obtaining caffeoylquinic acids-rich extracts from helianthus annuus |
| CN106389568A (en) * | 2016-11-07 | 2017-02-15 | 中国农业科学院郑州果树研究所 | Pear mature fruit total phenol extraction method |
| CN106389568B (en) * | 2016-11-07 | 2019-06-11 | 中国农业科学院郑州果树研究所 | A kind of pears mellow fruit total phenol extracting method |
| CN112675228A (en) * | 2021-01-18 | 2021-04-20 | 南京邮电大学 | Ointment for promoting wound healing and preparation method thereof |
| CN114031588A (en) * | 2021-11-02 | 2022-02-11 | 东营市人民医院 | Phenol derivative, preparation method thereof and application thereof in preparation of medicaments with anti-inflammatory and/or antioxidant effects |
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| Publication number | Publication date |
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| CN101143168A (en) | 2008-03-19 |
| CN100421689C (en) | 2008-10-01 |
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