CN1245972C - Naringin and its salt used for preparing cough suppressing phlegm tramsforming medicine - Google Patents
Naringin and its salt used for preparing cough suppressing phlegm tramsforming medicine Download PDFInfo
- Publication number
- CN1245972C CN1245972C CN 200410015024 CN200410015024A CN1245972C CN 1245972 C CN1245972 C CN 1245972C CN 200410015024 CN200410015024 CN 200410015024 CN 200410015024 A CN200410015024 A CN 200410015024A CN 1245972 C CN1245972 C CN 1245972C
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- China
- Prior art keywords
- naringenin
- salt
- hydrolysis
- acid
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Abstract
The present invention relates to an application of naringenin and naringenin salts to the preparation of medicine for relieving cough and reducing sputum. Used naringenin can be obtained by hydrolyzing crude products of naringin or naringin monomers or obtained by the extraction from various kinds of medicinal material containing naringenin or obtained by the synthesization of other chemical modes; the naringenin salts can be obtained by the reaction of naringenin with corresponding alkali. The medicine using naringenin or/and naringenin salts as effective components has the good functions of relieving cough and reducing sputum and has remarable curative effects on various cough and dyspnea caused by acute and chronic bronchitis, common cold, etc. without toxic or side effects.
Description
Technical field
The present invention relates to the purposes that naringenin (Naringenin) and salt thereof are used to prepare the relieving cough and resolving phlegm medicine.
Background technology
Cough, expectorant, to breathe heavily be the common sympton of respiratory system disease, especially being common in institutes such as acute and chronic bronchitis, flu in the daily life causes, being feature to cough, to cough up phlegm with panting and showing effect repeatedly clinically, is because the acute and chronic nonspecific inflammation of trachea, bronchial mucosa and surrounding tissue that infection or non-infective agent cause.Belonging to cough, phlegm retention, the asthma category of Chinese medicine, is a kind of commonly encountered diseases, frequently-occurring disease.Particularly middle-aged and elderly people is because the influence of environmental factors and living habit, bronchitis symptom such as be easy to generate cough, cough up phlegm, and their early stage is not well treated control, and develops into disease gradually.
For coming relieving cough and resolving phlegm with Chinese medicine, people have carried out a lot of effort, as Juhong Wan, cough-relieving tablets etc., come into the market.But from its characteristics, such medicine that has gone on the market at present also has the many and inconvenient shortcoming of dosage.Therefore be necessary to continue to develop and take safety, the reliable relieving cough and resolving phlegm novel drugs of curative effect.Naringenin (Naringenin), chemical name are 5,7; 4 '-the trihydroxy flavanone, be the aglycon of flavone compound naringin (naringin), extensively be present in the alabastrum of oriental cherry; alabastrum of prunus mume (sieb.) sieb.et zucc. and Fructus Aurantii Immaturus in the plant tissues such as mandarin orange, are a kind of Flavonoid substances; have antibiotic; antiinflammatory, anticancer, spasmolytic and function of gallbladder promoting; the treatment cardiovascular disease, the effect of aspects such as cholesterol reducing.But, still do not report the application of naringenin aspect relieving cough and resolving phlegm.
The molecular formula of naringenin is: C
15H
12O
5
The structural formula of naringenin:
Naringenin
Summary of the invention
The purpose of this invention is to provide naringenin (naringenin) and salt thereof are used for the relieving cough and resolving phlegm medicine in preparation application.
Naringenin salt of the present invention is meant that naringenin and the slaine that corresponding alkali (normally sodium hydroxide or potassium hydroxide) reaction is generated (are naringenin molecule 5,7 or/and on 4 ' position the H of hydroxyl replaced normally naringenin sodium salt or potassium salt by alkali metal ion).The molecular formula of naringenin salt is: C
15H
nO
5Y
m, n=9-11, m=1-3, Y are metal ion (normally sodium or potassium ion).
The present invention is by the pharmacological effect experiment confirm, and naringenin is or/and naringenin salt has good relieving cough and resolving phlegm effect, and the diseases such as cough with copious phlegm that acute and chronic bronchitis and flu etc. are caused have tangible curative effect.
We are to the experimentize cough-relieving experiment of animal white mice of naringenin and naringenin salt.The result shows: naringenin and naringenin salt pair stimulate mice to cause the tolerance time of cough, compare with the blank group, and significant prolongation is all arranged, and there were significant differences statistically; Compare with positive control medicine dextromethorphan hydrobromide tablets, tolerance time prolongs, and curative effect is remarkable than positive control medicine dextromethorphan hydrobromide tablets.
We are to the experimentize experiment of reducing phlegm of animal white mice of naringenin and naringenin salt.The result shows: naringenin and naringenin salt pair mouse bronchial juice increase, and compare with the blank group, and significant increase is arranged, and there were significant differences statistically.Compare with positive control medicine TANKEJING, the mouse bronchial juice is had remarkable increase, there were significant differences statistically, and curative effect is remarkable than the positive drug TANKEJING.Illustrate that naringenin and naringenin salt have the expectorant effect.
Of the present inventionly experiment showed, naringenin, and in mouse animal experiment, almost do not show toxicity or/and naringenin salt not only has fine relieving cough and resolving phlegm effect.Zoopery shows, when the naringenin of 300mg/kg dosage or naringenin salt oral administration animal, animal does not see toxic reaction, and it is 4-6g naringenin or naringenin salt/kg body weight that this dosage is equivalent to people's taking dose.
In sum, naringenin is described, does not see toxic and side effects or/and naringenin salt has good relieving cough and resolving phlegm effect, can well treat clinical in because the cough with copious phlegm that acute and chronic bronchitis and flu etc. cause.Therefore, can be used for preparing the relieving cough and resolving phlegm medicine.
The above-mentioned said usefulness naringenin of the present invention is or/and the medicine (hereinafter referred to as the naringenin medicine) of the relieving cough and resolving phlegm of naringenin salt preparation can contain the 0.1-100%wt. naringenin in its composition or/and naringenin salt.Said naringenin medicine can be merely by naringenin or/and the naringenin salt monomer form, perhaps by as the naringenin of effective ingredient or/and naringenin salt and other effective ingredient or/and conventional pharmaceutical aids form.When naringenin and naringenin salt use together, can be arbitrary proportion between the two.
Above-mentioned said naringenin medicine can be fit to the conventional adjuvant of corresponding dosage form or not add adjuvant by selecting, and is prepared into the pharmaceutical preparation of required different dosage form with conventional method.The adjuvant that adds can be solid, semisolid or liquid substance, as naringenin or/and the carrier of naringenin salt, excipient or medium.Therefore, said naringenin and salt pharmaceutical preparation thereof can be tablet, powder, sachets, elixir, suspensoid, Emulsion, solution, syrup, aerosol, inhalant, soft or various dosage forms such as hard capsule, aseptic parenteral solution.
The capsule of above-mentioned said naringenin medicine, its inclusions contain the naringenin of 0.5-100%wt. or/and naringenin salt; Usually can be by the naringenin that is no less than 0.5%wt. or/and naringenin salt and other effective ingredient or/and various conventional adjuvant form.The tablet of said naringenin medicine, contain in its composition be no less than 0.1%wt. naringenin or/and naringenin salt; Can be by the naringenin that is no less than 0.1%wt. or/and naringenin salt and other effective ingredient or/and various conventional adjuvant form.The inhalant of said naringenin medicine, its inclusions contain the naringenin of 0.1-100%wt. or/and naringenin salt; Usually can be by the naringenin that is no less than 0.1%wt. or/and naringenin salt and other effective ingredient or/and various conventional adjuvant form.
Or/and naringenin salt/kg body weight/day has good relieving cough and resolving phlegm effect, preferred daily dose is about the 1-100mg naringenin or/and naringenin salt/kg body weight/day to naringenin medicine of the present invention at the 0.1-700mg naringenin.
Naringenin medicine of the present invention has good relieving cough and resolving phlegm effect.Can effectively treat the cough with copious phlegm disease that acute and chronic bronchitis and flu etc. cause.And have steady quality, dose is little, curative effect is rapid, characteristics such as safe.
The said naringenin of the present invention can be naringenin crude product or the naringenin monomer (pure product) for preparing one of by the following method:
Method one: obtain by naringin (naringin) crude product or monomer method by hydrolysis.The method of hydrolysis can be acid hydrolysis, basic hydrolysis or enzyme hydrolysis.Concrete grammar can carry out according to following steps; Naringin crude product or monomer are dissolved in water, and stir, and add acid, alkali or enzyme, mix homogeneously; Mixed solution room temperature/heating hydrolysis; Hydrolysis finishes, and precipitation filters, and gets the naringenin crude product; Again through organic solvent or water recrystallization repeatedly, the naringenin monomer.
In the said method one, the water yield (volume) that hydrolysis adds can be naringin crude product or monomer (weight) 1～1000 times, and amount of water is not too much limit; Acid in the acid hydrolysis can be various acid such as hydrochloric acid, sulphuric acid, phosphoric acid or nitric acid, and the consumption of acid can be to add the consumption that makes solution PH≤7 after the acid, and acid-hydrolyzed temperature can be room temperature～100 ℃, and the time of hydrolysis can be 0.1～170 hour; Alkali in the basic hydrolysis can be various inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and the consumption of alkali can be to add the consumption that makes solution PH 〉=7 behind the alkali, and the temperature of basic hydrolysis can be room temperature～100 ℃, and the time of hydrolysis can be 0.1～170 hour; Enzyme in the enzyme hydrolysis can be the enzyme of various fracture hexoses such as glycuronidase, the consumption of enzyme can be that to add the concentration that makes enzyme in the solution behind the enzyme be 0.1 micromoles per liter～0.1 mole/milliliter, the temperature of enzyme hydrolysis can be room temperature～70 ℃, and the time of hydrolysis can be 0.1-120 hour.The time lengthening of acid, alkali or enzyme hydrolysis is not limit.
In the said method one, used naringin crude product or monomer can be according to existing method (for example Chinese patent application CN1431216A disclosed method) from the various medical materials that contain naringin (for example: Fructus Aurantii, Fructus Aurantii Immaturus, Citrus, Fructus Citri Limoniae, grapefruit, dried tangerine peel, orange, Fructus Citri grandis etc.) in extract and obtain; Also can synthesize and obtain by chemical method.
Method two: from the various medical materials (for example: the alabastrum of oriental cherry, the alabastrum of prunus mume (sieb.) sieb.et zucc., Fructus Aurantii Immaturus, Citrus, grapefruit, orange etc.) that contain naringenin, extract and obtain naringenin crude product or naringenin monomer (pure product).The method of extracting can be carried out according to following steps: pulverizing medicinal materials, and one to multiple inferior through organic solvent extraction, filter merging filtrate; Filtrate is condensed into extractum, and extractum is placed precipitation, gets the naringenin crude product; Again through organic solvent or water recrystallization repeatedly, the naringenin monomer.
In the said method two, the used organic solvent of organic solvent extraction can be various organic solvents commonly used such as ethanol, methanol, chloroform, ethyl acetate, acetone or petroleum ether, can adopt the various concentration organic solvent of (comprising that concentration is 100%); Organic solvent extraction can adopt under ℃ condition of room temperature～100 or/and carry out under the ultrasound wave condition, and extraction time is generally one to three time, and the number of times increase is not limit; The consumption of organic solvent is not for having medical material at least, and consumption is not too much limit; Each extraction time was generally 0.1-144 hour, and time lengthening is not limit: heat or/and extract under the ultrasound wave condition and can shorten extraction time.
In said method one and the method two, the used organic solvent of recrystallization can adopt various organic solvents commonly used such as ethanol, methanol, chloroform, ethyl acetate, acetone or petroleum ether, and the number of times of recrystallization can be for once to ten times, and the number of times increase is not limit.
Adopt said method one of the present invention and method two, obtain naringenin (pure product) from the naringin hydrolysis and obtain naringenin (pure product), extract yield, extract the yield height all more than 85% with extracting naringenin/naringin medical material from different containing.Resulting naringenin monomer (pure product), through " Chinese people republic pharmacopeia " 2000 editions one high effective liquid chromatography for measuring all, it is quantitative that the naringenin reference substance that provides with Nat'l Pharmaceutical ﹠ Biological Products Control Institute carries out external standard method, must extract the monomeric content of naringenin in the gained naringenin sample.The result shows that the monomeric content of naringenin is higher than 95% in the sample.Show technology simple possible of the present invention.
Above-mentioned naringenin preparation method of the present invention, it is simple to have extraction process, and the extraction ratio height extracts the characteristics such as naringenin monomer purity height that obtain.
Method three: obtain by other chemical methodes are synthetic.
The specific embodiment
The present invention is described further below in conjunction with embodiment.
Material usage proportioning and the solid in the component content related among each embodiment calculate with wt/wt (weight ratio), v/v (volume ratio), wt/v (by weight/volume) respectively with solid ratio with liquid and liquid with solid, liquid, except as otherwise noted.Embodiment 1～4 used naringin monomer and naringin crude product prepares according to Chinese patent application CN1431216A disclosed method.Embodiment 15～20 used naringenins are respectively the naringenin monomer that obtains according to embodiment 1～6 described method, and purity is more than 95%.
Embodiment 1:
Naringin monomer (purity 97.3%) adds 10 times of water, and mix homogeneously adds concentrated hydrochloric acid and makes solution PH=1, mix homogeneously; 100 ℃ of heating hydrolysis 2 hours; After hydrolysis finishes, filter, get the naringenin crude product; Behind dehydrated alcohol recrystallization five times, get the naringenin monomer.Yield is 91.4%.
Embodiment 2:
Naringin crude product (purity 98.2%) adds 20 times of water, and mix homogeneously adds concentrated sulphuric acid and makes solution PH=0, mix homogeneously; 80 ℃ of heating hydrolysis 3 hours; After hydrolysis finishes, filter, get the naringenin crude product; After re-crystallizing in ethyl acetate six times, get the naringenin monomer.Yield is 89.3%.
Embodiment 3:
Naringin crude product (purity 98.5%) adds 50 times of water, and mix homogeneously adds sodium hydroxide solution and makes solution PH=13, mix homogeneously; 80 ℃ of heating hydrolysis 1.5 hours; After hydrolysis finishes, filter, get the naringenin crude product; Behind acetone recrystallization three times, get the naringenin monomer.Yield is 86.9%.
Embodiment 4:
Naringin monomer (purity 96.7%) adds 35 times of water, mix homogeneously, add the glucuronic acid enzyme make the concentration of enzyme in the sample be 0.1 mM/liter, mix homogeneously; 37 ℃ of heating in water bath hydrolysis 8 hours; After hydrolysis finishes, filter, get the naringenin crude product; Behind dehydrated alcohol recrystallization four times, get the naringenin monomer.Yield is 94.8%.
Embodiment 5:
The oriental cherry alabastrum adds dehydrated alcohol and did not have medical material, extracts three times, and extracting temperature is 50 ℃, each one hour, filters; Filtrate is condensed into extractum, produces precipitation, filters, and gets the naringenin crude product; Precipitation gets the naringenin monomer with ethyl acetate crystallization three times.Yield is 90.7%.
Embodiment 6:
The alabastrum of prunus mume (sieb.) sieb.et zucc. adds acetone and did not have medical material, and soaking at room temperature is extracted three times, each 48 hours, filters merging filtrate; Filtrate is condensed into extractum, and placement is spent the night, and must precipitate, and precipitation is dry, gets the naringenin crude product; Behind chloroform recrystallization five times, get the naringenin monomer.Yield is 87.4%.
Embodiment 7:
The Fructus Aurantii Immaturus medical material is cut into decoction pieces, through 100 ℃ of water extraction twice, each 3 hours, filters merging filtrate; Filtrate is condensed into extractum, produces precipitation, filters, and gets the naringenin crude product; Precipitation re-crystallizing in ethyl acetate six times get the naringenin monomer.Yield is 85.3%.
Embodiment 8:
The grapefruit medical material is not pulverized, and through ultrasound wave ethyl acetate extraction 4 times, each 1 hour, filters merging filtrate; Concentrated, get extractum, extractum is placed and is spent the night, and produces precipitation, and precipitation separation is drying precipitated, gets the naringenin crude product; Precipitation acetone recrystallization secondary gets the naringenin monomer.Yield is 86.1%.
Embodiment 9:
The Fructus Aurantii Immaturus pulverizing medicinal materials is crossed 20 mesh sieves, and water extraction is three times under the room temperature, each two days, filters merging filtrate; Filtrate concentrates, and adds the PH=3 that concentrated hydrochloric acid makes liquid, 90 ℃ of heating hydrolysis, and hydrolysis finishes, and filters, and must precipitate, and is drying precipitated, gets the naringenin crude product; Precipitation re-crystallizing in ethyl acetate four times get the naringenin monomer.Yield is 90.7%.
Embodiment 10:
The grapefruit medical material is cut into decoction pieces, adds 100 ℃ of water and does not have medical material, extracts secondary, each 2 hours, filters merging filtrate; Filtrate concentrates, and the adding sodium hydroxide is to solution PH=11,70 ℃ heating hydrolysis, and hydrolysis finishes, and filters, and must precipitate, and precipitation is dry, gets the naringenin crude product; Precipitation acetone recrystallization three times get the naringenin monomer.Yield is 89.2%.
Embodiment 11:
Tangerine medical material is not pulverized, and through acetone extraction 4 times, each 24 hours, filters merging filtrate; Concentrate, get extractum, extractum adds 30% dissolve with ethanol, and the adding strong phosphoric acid makes the PH=2 of liquid, 95 ℃ of heating hydrolysis, and hydrolysis finishes, and filters, and must precipitate, and the precipitation drying gets the naringenin crude product; Precipitation chloroform recrystallization five times get the naringenin monomer.Yield is 87.7%.
Embodiment 12:
The Fructus Aurantii medical material is cut into decoction pieces, adds 100 ℃ of water and does not have medical material, adds concentrated hydrochloric acid and makes solution PH=2.5, extracts three times, each 1.5 hours, filters merging filtrate; Filtrate concentrates, and gets extractum, and extractum is placed and spent the night, and must precipitate; Precipitation separation is used acetone solution, filters, and abandons precipitation, and filtrate is reclaimed acetone, must precipitate, and is drying precipitated, gets the naringenin crude product; Precipitation chloroform recrystallization three times get the naringenin monomer.Yield is 90.4%.
Embodiment 13:
The shatian pomelo pulverizing medicinal materials adds 12 times of 100 ℃ of water and there was not medical material, adds potassium hydroxide and makes solution PH=14, extracts secondary, each 45 hours, filters merging filtrate; Filtrate concentrates, and gets extractum, and extractum is placed and spent the night, and must precipitate; Precipitation separation is used anhydrous alcohol solution, filters, and abandons precipitation, and filtrate recycling ethanol must precipitate, and is drying precipitated, gets the naringenin crude product; Precipitation acetone recrystallization four times get the naringenin monomer.Yield is 88.3%.
Embodiment 14: naringenin monomer purity determination experiment
It is an amount of to get the naringenin monomer that the said extracted method prepares, the dissolve with methanol standardize solution is in volumetric flask, after reuse microporous filter membrane (0.45um) filters, inject high performance liquid chromatograph, it is quantitative that the naringenin reference substance that provides with Nat'l Pharmaceutical ﹠ Biological Products Control Institute carries out external standard method, must extract the monomeric content of naringenin in the gained naringenin sample.The results are shown in Table 1.Sample 1～11 is respectively the naringenin monomer of embodiment 1～11 preparation in the table 1.
Chromatographic condition: Agilent1100 high performance liquid chromatograph (automatic sampler, vacuum degassing machine, quaternary pump, column oven, diode array detector); Chromatographic column: MARKERODS post (5um, 4.0 * 250mm); Mobile phase: methanol-water (50: 50); Detect wavelength: 288nm; 30 ℃ of column temperatures; Flow velocity: 1ml/min; Sample size: 5 μ l.
Table 1: sample size determination test result
| Sample number | Sample concentration (mg/ml) | Sample size (μ l) | Peak area | Record naringenin concentration (mg/ml) | Naringenin content (%) |
| Naringenin reference substance sample 1 sample 2 samples 3 samples 4 samples 5 samples 6 samples 7 samples 8 samples 9 samples 10 samples 11 | 0.500 0.462 0.472 0.521 0.483 0.512 0.502 0.439 0.494 0.508 0.517 0.486 | 5 5 5 5 5 5 5 5 5 5 5 5 | 3145.74885 2850.04845 2925.54643 3189.78933 2925.54649 3189.78934 3019.91890 2661.30353 3032.50189 3095.41687 3196.08083 2988.46141 | 0.500 0.453 0.465 0.507 0.465 0.507 0.480 0.423 0.482 0.492 0.508 0.475 | 100 98.1 98.5 97.4 96.3 99.0 95.6 96.3 97.5 96.9 98.3 97.7 |
The result finds out from table 1, and the monomeric content of naringenin all is higher than 95% in the extraction gained sample, and the resulting naringenin sample purity of extracting method of the present invention height is described.
From the foregoing description 1～14 as can be known, naringenin preparation method of the present invention, can effectively, naringin crude product/monomer obtain the naringenin monomer by being hydrolyzed into naringenin, can from contain naringenin/naringin medical material, extract effectively and obtain the naringenin monomer, gained naringenin sample purity height, content all is higher than more than 95%.The technology simple possible.
Embodiment 15: the cough-relieving pharmacological experiment of naringenin medicine
1, laboratory animal: the NIH mice, male, body weight 18.2-21.7g, regular grade standard, totally 130.Earlier animal is weighed, numbering is selected healthyly, and body weight is totally 120 of the mices of 18.5-21.0g gram.By the ordering of body weight size, be divided into eight groups with randomized blocks, 15 every group.If negative control group, dosage group, naringenin sodium salt drug sample high dose group in dosage group, naringenin drug sample high dose group, naringenin sodium salt drug sample low dose group, the naringenin sodium salt drug sample in positive controls and naringenin drug sample low dose group, the naringenin drug sample.
2, sample source and processing:
1) blank group: normal saline, NaCl content 0.9%.
2) positive controls: get two of dromethans and be dissolved in 20 ml physiological salines, promptly get positive control dromethan solution, dromethan concentration is 1.5mg/ml.
3) naringenin sample low dose group: it is an amount of to get naringenin, and in volumetric flask, naringenin concentration is 0.5mg/ml with the normal saline standardize solution.
4) dosage group in the naringenin sample: it is an amount of to get naringenin, and in volumetric flask, naringenin concentration is 1.5mg/ml with the normal saline standardize solution.
5) naringenin sample high dose group: it is an amount of to get naringenin, and in volumetric flask, naringenin concentration is 4.5mg/ml with the normal saline standardize solution.
6) naringenin sodium salt sample low dose group: it is an amount of to get the naringenin sodium salt, and in volumetric flask, naringenin sodium salt concentration is 0.5mg/ml with the normal saline standardize solution.
7) dosage group in the naringenin sodium salt sample: it is an amount of to get the naringenin sodium salt, and in volumetric flask, naringenin sodium salt concentration is 1.5mg/ml with the normal saline standardize solution.
8) naringenin sodium salt sample high dose group: it is an amount of to get the naringenin sodium salt, and in volumetric flask, naringenin sodium salt concentration is 4.5mg/ml with the normal saline standardize solution.
3, experimental technique: (strong aqua ammonia nebulization)
Behind the mouse stomach 1 hour, begin to accept spraying.Spray into the strong aqua ammonia aerosol by certain hour, spraying finishes, and takes out mice immediately, observes to have or not the cough reaction.Observe the number of times of coughing in a minute,, can be regarded as " cough is arranged " if occur typical case's cough action (abdominal muscle shrinks or the breast that contracts, and magnifies mouth simultaneously, can cough sound sometimes) person more than 3 times in 1 minute.Otherwise can be regarded as " not having cough ".
4, experimentation:
Obtain the spray time (EDT that causes the half mouse cough with sequential method (going up purgation)
50).Calculate the R value, if the R value greater than 130%, illustrates that medicine has antitussive action.If the R value is greater than 150%, then showing has significant antitussive action.Computing formula is as follows:
EDT
50=log
-1(n is a number of animals to c/n in the formula, and c is the summation of rx value, and r is the number of animals of every dosage group, and x is the logarithm of dosage (being spray time).)
5 experimental results:
By statistics, each sample sets half cough time and cough suppressing effect see Table 1.
The cough suppressing effect of each sample of table 1.
| Group | Dosage (ml/20g) | Sample concentration (mg/ml) | EDT 50(second) | R value (%) | Cough suppressing effect | |
| Code name | The sample name | |||||
| 1 2 3 4 5 6 7 8 | Dosage group naringenin sodium salt sample high dose group in the dosage group naringenin sample high dose group naringenin sodium salt sample low dose group naringenin sodium salt sample in the physiological saline group dextromethorphan group naringenin sample low dose group naringenin sample | 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 | 0 1.5 0.5 1.5 4.5 0.5 1.5 4.5 | 38.9 53.70 51.29 66.07 66.61 55.35 69.48 73.56 | - 138.05 131.85 169.85 171.23 142.3 178.6 189.1 | -effective effective produce effects produce effects of produce effects produce effects |
From naringenin sample and positive control medicine dromethan, oral administration causes that to stimulating mice the tolerance time of cough compares, naringenin has significant prolongation to the mice tolerance time, and longer than the tolerance time of positive control medicine dromethan, there were significant differences statistically.From naringenin sodium salt sample and positive control medicine dromethan, oral administration causes that to stimulating mice the tolerance time of cough compares, to significant prolongation being arranged, longer than the tolerance time of positive control medicine dromethan, there were significant differences statistically to mice tolerance for the naringenin sodium salt.Illustrate that naringenin and/or naringenin salt pair stimulate mice to cause that the tolerance time of cough and dromethan compare, tolerance time prolongs, and is evident in efficacy.Have good relieving cough and resolving phlegm effect, the diseases such as cough with copious phlegm that acute and chronic bronchitis and flu etc. are caused have tangible curative effect.
Embodiment 16: the pharmacological experiment that reduces phlegm of naringenin medicine
1, laboratory animal: the NIH mice, female, body weight 18.0-22.1g, the cleaning grade standard, the quality certification number: Guangdong probatio inspectionem pecuoarem word 2002A022 number, on October 12nd, 2003 was provided by No.1 Military Medical Univ.'s Experimental Animal Center.Totally 90.Earlier animal is weighed, numbering is selected healthyly, and body weight is totally 80 of the mices of 18.5-22.0 gram.By body weight size ordering, be divided into eight groups, 10 every group with district's group method of dividision into groups at random.If negative control, positive control and naringenin are high, medium and low, high, medium and low eight the dosage groups of naringenin sodium salt.All by oral administration of filling stomach amount of 10ml/kg body weight.
2, sample source and processing:
1) blank group: normal saline, NaCl content 0.9%.
2) positive controls: get 0.2 gram TANKEJING powder and be dissolved in 10 ml physiological salines, promptly get positive control TANKEJING solution, concentration is 20mg/ml.
3) naringenin sample low dose group: precision weighing naringenin sample 5mg, in the 10ml volumetric flask, ultrasound wave dissolving 5min shakes up, promptly with the distilled water standardize solution.Concentration is 0.5mg/ml.
4) dosage group in the naringenin sample: precision weighing naringenin sample 15mg, in the 10ml volumetric flask, ultrasound wave dissolving 5min shakes up, promptly with the distilled water standardize solution.Concentration is 1.5mg/ml.
5) naringenin sample high dose group: precision weighing naringenin sample 45mg, in the 10ml volumetric flask, ultrasound wave dissolving 5min shakes up, promptly with the distilled water standardize solution.Concentration is 4.5mg/ml.
6) naringenin sodium salt sample low dose group: precision weighing naringenin sodium salt sample 5mg, in the 10ml volumetric flask, ultrasound wave dissolving 5min shakes up, promptly with the distilled water standardize solution.Concentration is 0.5mg/ml.
7) dosage group in the naringenin sodium salt sample: precision weighing naringenin sodium salt sample 15mg, in the 10ml volumetric flask, ultrasound wave dissolving 5min shakes up, promptly with the distilled water standardize solution.Concentration is 1.5mg/ml.
8) naringenin sodium salt sample high dose group: precision weighing naringenin sodium salt sample 45mg, in the 10ml volumetric flask, ultrasound wave dissolving 5min shakes up, promptly with the distilled water standardize solution.Concentration is 4.5mg/ml.
3, experimental technique:
1) drafting of standard phenol Monas cuspurpureus Went line: accurately take by weighing a certain amount of phenol red with analytical balance, with the dissolving of 5% sodium bicarbonate, be made into every 1ml and contain 12.5ng, carry out doubling dilution then in turn and become every milliliter to contain phenol red 6.25ng, 3.125ng, 1.5625ng, 0.7813ng, 0.3906ng, 0.1953ng, 0.0977ng 0.0488ng is with spectrophotometric instrumentation OD value.With the phenol red concentration is vertical coordinate, and the OD value is an abscissa, calculates regression equation according to phenol red concentration and OD value.Go out the phenol red excretion of each Mus according to regression equation calculation.
2) water 12h is can't help in the mice fasting.
3) gastric infusion.By the animal order, stopped behind every mouse stomach 3 minutes, irritate other one again, interval is 3 minutes, 10 every group are irritated the stomach time altogether is 30 minutes.
4) half an hour behind each Mus filling stomach is through lumbar injection 5% phenol red normal saline solution 0.2ml.In order, promptly each mouse peritoneal was injected phenol red back 3 minutes, injected other one again, 10 mices totally 30 minutes.
5) half an hour behind each Mus lumbar injection, take off cervical vertebra in order and put to death mice, put to death interval 3 minutes.Behind the sacrifice of animal, face upward the position and be fixed on the operation plate, cut off neck center skin, separate trachea, prop trachea with pincet.
6) draw normal saline flushing trachea outer wall with big syringe, phenol red in flush away blood and the trachea outer wall, filter paper blots washing liquid.
7) cut trachea prior to the trachea bifurcation, cut trachea (the ring-type thyroid cartilage is included) in other end thyroid cartilage upper end again.
8) each trachea section is put into the 5%NaHCO that fills 1.5ml in advance
3In the solution test tube.
9) in 3 minutes, finish above-mentioned tracheorrhaphy from shearing work.Reuse is handled second mice with quadrat method.Method as above.
10) each test tube is put on the ultrasonic cleaner ultrasonic 5 minutes, made phenol red the discharging in the trachea section.
11) solution in each test tube is surveyed the OD value in 721 type spectrophotometer 546nm places.
12) the OD value of resurveying behind the 24h is spent the night in each test tube gassiness pipeline section placement.
13) go out phenol red content according to regression equation calculation.Computing formula: Y=7.6266X-0.0554.X is the OD value, and Y is phenol red content.
14) calculate the phenol red content of correction according to phenol red content and the weight of animals, carry out variance analysis with the SPSS8.0 statistical software.Proofread and correct phenol red content=phenol red content (ng)/mice body weight (kg)
4. experimental result:
By statistics, each dosage group phenol red output, see the following form.
The effect of reducing phlegm of table 2. naringenin and salt thereof (X ± S)
| Group | Dosage (mg/kg) | The phenol red content of animal trachea (ng) | Proofread and correct phenol red content a (ng/kg) | The P value | The rate of reducing phlegm b (％) | |
| Code name | The sample name | |||||
| 1 2 3 4 5 6 7 8 | Dosage group naringenin sodium salt high dose group in the dosage group naringenin high dose group naringenin sodium salt low dose group naringenin sodium salt in the physiological saline TANKEJING naringenin low dose group naringenin | 0 200 5 15 45 5 15 45 | 0.9385±0.4148 1.3343±0.7932 1.2757±0.4020 1.3523±0.9303 1.9257±0.6713 1.3029±0.3069 1.4225±0.7361 1.9705±0.6898 | 46.7282±22.6106 70.3811±43.6970 68.2832±23.6102 74.7504±57.2020 102.7325±41.0313 69.4942±16.3724 75.8773±39.2651 105.1057±36.7945 | - P＜0.05 P＜0.05 P＜0.05 P＜0.01 P＜0.05 P＜0.05 P＜0.01 | - 150.62 146.13 159.97 219.85 148.72 162.38 224.93 |
A: proofread and correct phenol red content=phenol red content/the weight of animals
B: the rate of reducing phlegm=administration group/blank group * 100%
Phenol red cubage method (ng): OD value * 7.6266-0.0554
From naringenin sample and positive drug TANKEJING, oral administration increases experiment to the mouse bronchial juice and sees that naringenin is low, in, each dosage group of high dose group compares with the blank group the secretion of mouse bronchial juice, significant increase is all arranged, and there were significant differences statistically.High dose group and positive control medicine TANKEJING relatively have remarkable increase to the mouse bronchial juice, and there were significant differences statistically, and curative effect is remarkable than the positive drug TANKEJING.Naringenin sodium salt sample and positive drug TANKEJING, oral administration increase experiment to the mouse bronchial juice and see that the naringenin sodium salt is low, in, each dosage group of high dose group compares with the blank group the secretion of mouse bronchial juice, significant increase is all arranged, and there were significant differences statistically.High dose group and positive control medicine TANKEJING relatively have remarkable increase to the mouse bronchial juice, and there were significant differences statistically, and curative effect is remarkable than the positive drug TANKEJING.Illustrate that naringenin and/or naringenin salt have good relieving cough and resolving phlegm effect, the diseases such as cough with copious phlegm that acute and chronic bronchitis and flu etc. are caused have tangible curative effect.
Embodiment 17: the toxicological experiment of naringenin medicine
28 ± 1 ℃ temperature, under 70 ± 5% the damp condition, choose 7-8 age in week, 20 of healthy cleaning level NIH mices, male and female half and half, body weight is at 20-22g.With feedstuff and water sterilization, before the test and in the observation period of test, all raise by normal feedstuff condition.
Naringenin is dissolved among the 0.5%Tween80, and concentration is 300mg/ml, and with this liquid oral administration mice, dosage is a 0.4ml/20g mice body weight.Observed after the administration 1,4,8,12 hours, observed once in later per 12 hours.Observe death condition, write down mice body weight change and other symptom every day.The 10th day, disconnected neck was put to death mice, gets each organ and carries out pathologic finding.
At the 10th day, all mice survivals, the naringenin of 6.0g/kg dosage is not seen toxic reaction.Each organ pathologic finding of mice is normal, does not find pathological changes, and the mice body weight is not seen and alleviated in 10 days.Therefore, illustrate that naringenin medicine of the present invention do not see toxicity when the oral administration animal.
Embodiment 18: the naringenin capsule preparations
Be prepared into gelatine capsule by following composition proportion:
Naringenin 60
Dry starch 35
Micropowder silica gel 5
With adjuvant and naringenin mix homogeneously, in the gelatine capsule of packing into, promptly.Loading amount: 100mg/ capsule.
Embodiment 19: the naringenin tablet
Be prepared into tablet by following composition proportion:
Naringenin 500g
Starch 472.5g
Starch slurry (14%) 25.0g
Magnesium stearate 2.5g
Amount to 1000g
With naringenin and starch uniform mixing, add starch slurry continuation stirring and make into soft material, granulate with 10 order nylon mesh, 80-90 ℃ of aeration-drying, dry granular adds magnesium stearate, and through 12 mesh sieve granulate, mixing is pressed into tablet.Altogether 10000, every sheet heavily is about 0.1g.
Embodiment 20: the naringenin inhalant
Be prepared into inhalant by following composition proportion:
Naringenin 100g
Lactose 500g
Poloxamer 1g
Micropowder silica gel 10g
L-leucine 0.5g
PEG400 (50%) aqueous solution 300g
Amount to 911.5g
Naringenin, lactose, poloxamer and L-leucine with the dissolving of PEG400 aqueous solution, are carried out spray drying again, and the gained spray-dried powders adds micropowder silica gel, and mix homogeneously is sub-packed in the capsule type dry powder suction apparatus.
Claims (12)
1. naringenin and salt thereof are used for the application of the medicine of relieving cough and resolving phlegm in preparation.
2. according to the described application of claim 1, it is characterized in that said medicine contains the naringenin of 0.1-100%wt. or/and naringenin salt.
3. according to the described application of claim 1, it is characterized in that said medicine by simple naringenin or/and naringenin salt form, perhaps by as the naringenin of effective ingredient or/and naringenin salt and other effective ingredient or/and conventional pharmaceutical aids form.
4. according to the described application of claim 3, it is characterized in that said medicine is a capsule, its inclusions contains the naringenin of 0.5-100%wt. or/and naringenin salt.
5. according to the described application of claim 3, it is characterized in that said medicine is tablet or inhalant, its contain be no less than 0.1%wt. naringenin or/and naringenin salt.
6. according to the described application of one of claim 1～5, it is characterized in that said naringenin and naringenin salt obtain by chemical method is synthetic.
7. according to the described application of one of claim 1～5, it is characterized in that said naringenin is obtained through acid, alkali or enzyme hydrolysis by naringin crude product or monomer.
8. according to the described application of claim 7, it is characterized in that the concrete grammar of said naringin crude product or monomeric acid hydrolysis, basic hydrolysis or enzyme hydrolysis is: naringin crude product or monomer are dissolved in water, and stir, and add acid, alkali or enzyme, mix homogeneously; Mixed solution room temperature/heating hydrolysis; Hydrolysis finishes, and precipitation filters, and gets the naringenin crude product; Repeatedly heavily tie product through organic solvent or water again, get the naringenin monomer; Described be dissolved in water the water yield that adds by volume/weight ratio is naringin crude product or monomeric 1～1000 times; Acid in the acid hydrolysis is hydrochloric acid, sulphuric acid, phosphoric acid or nitric acid, and the consumption of acid is to add the consumption that makes solution PH≤7 after the acid, and acid-hydrolyzed temperature is room temperature～100 ℃, and the time of hydrolysis is 0.1～170 hour; Alkali in the basic hydrolysis is sodium hydroxide, potassium hydroxide, calcium hydroxide, and perhaps organic base, the consumption of alkali are to add the consumption that makes solution PH 〉=7 behind the alkali, and the temperature of basic hydrolysis is room temperature～100 ℃, and the time of hydrolysis is 0.1～170 hour; Enzyme in the enzyme hydrolysis is the enzyme of various fracture hexoses, and the consumption of enzyme is that to add the concentration that makes enzyme in the solution behind the enzyme be 0.1 micromoles per liter～0.1 mole/milliliter, and the temperature of enzyme hydrolysis is room temperature～70 ℃, and the time of hydrolysis is 0.1-120 hour; The used organic solvent of recrystallization is ethanol, methanol, chloroform, ethyl acetate, acetone or petroleum ether, and the number of times of recrystallization is for once to ten times.
9. according to the described application of one of claim 1～5, it is characterized in that said naringenin is to extract naringenin crude product or the naringenin monomer that obtains from the medical material that contains naringenin.
10. according to the described application of claim 9, it is characterized in that the said concrete grammar that extracts naringenin from the medical material that contains naringenin is: pulverizing medicinal materials, one to multiple inferior through water/organic solvent extraction, filter merging filtrate; Filtrate is condensed into extractum, and extractum is placed precipitation, gets the naringenin crude product; Again through organic solvent or water recrystallization repeatedly, the naringenin monomer; The used organic solvent of described organic solvent extraction is ethanol, methanol, chloroform, ethyl acetate, acetone or petroleum ether, water or organic solvent extraction adopt under ℃ condition of room temperature～100 or/and carry out under the ultrasound wave condition, extraction time is one to three time, the consumption of water or organic solvent is not for having medical material at least, and each extraction time is 0.1-144 hour; The used organic solvent of recrystallization adopts ethanol, methanol, chloroform, ethyl acetate, acetone or petroleum ether, and the number of times of recrystallization is for once to ten times.
11., it is characterized in that said naringenin salt is meant the slaine that naringenin and corresponding alkali are generated according to the described application of one of claim 1～5; The molecular formula of this naringenin salt is: C
15H
nO
5Y
m, n=9-11, m=1-3, Y are metal ion.
12. according to the described application of claim 11, it is characterized in that said naringenin salt is meant naringenin and sodium hydroxide or potassium hydroxide reaction and the naringenin sodium salt or the potassium salt that obtain, its molecular formula is: C
15H
nO
5Y
m, n=9-11, m=1-3, Y are K or Na ion.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410015024 CN1245972C (en) | 2004-01-08 | 2004-01-08 | Naringin and its salt used for preparing cough suppressing phlegm tramsforming medicine |
| AT04701576T ATE439848T1 (en) | 2003-01-21 | 2004-01-13 | USE OF NARINGENIN, NARINGIN AND SALTS THEREOF AS MUSCULATORS IN THE TREATMENT OF COUGH AND COMPOSITIONS THEREOF |
| EP04701576A EP1591123B1 (en) | 2003-01-21 | 2004-01-13 | Uses of naringenin, naringin and salts thereof as expectorants in the treatment of cough, and compositions thereof |
| DE602004022635T DE602004022635D1 (en) | 2003-01-21 | 2004-01-13 | USE OF NARINGENINE, NARINGIN AND SALTS, AS A SLICE SOLVENT IN THE TREATMENT OF HUSTS AND COMPOSITIONS THEREOF |
| JP2006500456A JP4651611B2 (en) | 2003-01-21 | 2004-01-13 | Therapeutic use of naringenin, naringin and their salts in antitussive expectorant and their pharmaceutical compositions |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410015024 CN1245972C (en) | 2004-01-08 | 2004-01-08 | Naringin and its salt used for preparing cough suppressing phlegm tramsforming medicine |
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| CN1555793A CN1555793A (en) | 2004-12-22 |
| CN1245972C true CN1245972C (en) | 2006-03-22 |
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| US8901556B2 (en) | 2012-04-06 | 2014-12-02 | Semiconductor Energy Laboratory Co., Ltd. | Insulating film, method for manufacturing semiconductor device, and semiconductor device |
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| CN110205351A (en) * | 2019-05-23 | 2019-09-06 | 广东金骏康生物技术有限公司 | A kind of preparation method and applications glycosylating naringenin |
| CN110327313A (en) * | 2019-06-21 | 2019-10-15 | 中山大学 | A kind of naringenin aerosol inhalation solution preparation and preparation method thereof |
| CN113041220B (en) * | 2021-04-15 | 2022-09-30 | 中国医学科学院药用植物研究所 | Naringin nano suspension taking TPGS as carrier, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8901556B2 (en) | 2012-04-06 | 2014-12-02 | Semiconductor Energy Laboratory Co., Ltd. | Insulating film, method for manufacturing semiconductor device, and semiconductor device |
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