CN101590041B - Pharmaceutical composition for relieving cough - Google Patents
Pharmaceutical composition for relieving cough Download PDFInfo
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- CN101590041B CN101590041B CN2008100507487A CN200810050748A CN101590041B CN 101590041 B CN101590041 B CN 101590041B CN 2008100507487 A CN2008100507487 A CN 2008100507487A CN 200810050748 A CN200810050748 A CN 200810050748A CN 101590041 B CN101590041 B CN 101590041B
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Abstract
The invention relates to a pharmaceutical composition for relieving cough, which belongs to the field of medicine. The pharmaceutical composition is prepared from the following compounds according to the parts by weight: 1 part of hydantoin and 0.5-2 part of 5,5-dimethyl hydantoin. A medicament prepared from the pharmaceutical composition has obvious cough relieving effect, and the cough relieving effect achieved after matching the hydantoin and the 5,5-dimethyl hydantoin is obviously better than the cough relieving effect achieved by singly using the hydantoin, the 5,5-dimethyl hydantoin or 1-methyl hydantoin and the cough relieving effect achieved by codeine phosphate which is a positive medicament.
Description
Technical field
The invention belongs to field of medicaments.
Background technology
Hydantoin-based compound is meant and contains various substituent five member ring heterocyclic compounds that general formula is:
R
1, R
2Can be multiple alkyl, thiazolinyl, aryl; R
3, R
4Be hydroxyalkyl, glycidyl, cyanoalkyl, amine alkyl etc.They are to be made in 1875 by Urech the earliest, though the preparation method of glycolylurea is come out already, but fail to cause people's interest always, up to the sixties, along with going deep into gradually of research work, it is found that the premium properties of many hydantoin-based compounds, the extensive use of glycolylurea and derivant thereof just is familiar with by people.Owing to have polyfunctional group and bigger reactivity is arranged in its structure, various different glycolylurea and the derivants thereof that replace have a wide range of applications, as fields such as medicine, pesticide, chemical industry and weavings.
1, pharmacological action
That the pharmacological action of hydantoin-based compound mainly shows is antibiotic, the generation of antiinflammatory, blood sugar lowering, sodium ion channel blocker, inhibition uremic toxins etc.
1.1, the killing microorganisms effect
Halo dimethyl hydantion compounds is the novel halogen amine of a class type broad-spectrum bactericide disinfectant.Bacterial propagule, virus, fungus and bacterial spore all there is killing action.Its bactericidal action mainly is to discharge hypochlorous acid and Hydrogen oxybromide (HOBr), the Oxidation that is decomposed to form in water; The react metabolic effect of interference bacterial cell of formation ammonia chloride and amine bromide of chlorine and activation bromine and nitrogenous material that activates freely that has hypochlorous acid and Hydrogen oxybromide (HOBr) to be decomposed to form the newborn oxygen effect of nascent oxygen and to discharge.
1.1.1, kill vegetative forms of bacteria
It is reported that the halo dimethyl hydantion all has in various degree inhibition or killing action to staphylococcus aureus, escherichia coli, Hemolytic streptococcus, bacillus pyocyaneus, Bacillus typhi etc.Reported respectively that as Liu Jimin etc. and Chen Qiang etc. compound of bromo-chloro-dimethyl hydantoin disinfectant, main component are BCDMH, at room temperature to staphylococcus aureus, colibacillary killing action.Chen Rongfeng etc. have reported dibromo dimethyl hydantoin, and main component is DBDMH, and to staphylococcus aureus, escherichia coli have good killing action.Zhang Tianbao etc. and Li Qinglu etc. have reported that respectively compound recipe two chlordantoin disinfectant are to staphylococcus aureus, colibacillary killing action.Zhang Shengli etc. have reported that DBDMH and DCDMH kill the research of staphylococcus aureus, bacillus pyocyaneus, Bacillus typhi.According to WaLker etc., in cooling tower, when the concentration of bromine chlorine hydantoin is 4～6mg/L, can make legion in the water have a liking for lung bacillus content 3 orders of magnitude that descend.Bromine chlorine hydantoin and DBDMH are also more obvious to the inhibitory action of Aeromonas hydrophila and the bent oar bacillus of column, as the relevant report of punishment China.
This compounds kill vegetative forms of bacteria effect is fine as can be seen from above report.
1.1.2 kill bacteria spore
The halo dimethyl hydantion is a lot of to the report of bacillus subtilis black variety gemma killing action, and the report of the killing effect of DBDMH significantly better than two chlordantoins arranged.As: Chen Qiang etc. have reported the effective bromine chlorine hydantoin effect of 200mg/L 60min, and killing rate reaches 99.9%; Li Qinglu etc. have reported 400mg/L effective chlorine effect 60min, killing rate 99.9%; Chen Rongfeng etc. have reported that DBDMH may increase its permeability for effective bromine acts on the cells of microorganisms wall to the sterilization mechanism of bacillus subtilis black variety gemma, and protein and core substance in the cell spill, and the dna double chain takes place to rupture and makes antibacterial death.
1.1.3 kill fungus
According to reports such as Zhou Shiliang two chlordantoins industry is mixed mycete, comprise that aspergillus niger, variable color aspergillosis, Aspergillus citrimum, Trichoderma viride, Aspergillus flavus, paecilomyces varioti, cladosporium herbarum, Chaetomium globosum are invalid, and Li Mingwei etc.
[13]Reported 50～100ppm effective chlorine density effect, 2～5min, the killing rate that can make Candida albicans is up to 99.9%.Liu Jimin etc. have reported that containing effective chlorine 400mg/L person acts on 5min, and the killing rate of Candida albicans on the cloth sheet is reached 100%.Action site and model of action about free chlorine in two chlordantoins have multiple hypothesis, think that mostly its mechanism is that chlorine has Oxidation to important enzyme or responsive enzyme.
1.1.4 kill virus
The halo dimethyl hydantion has stronger deactivation to virus, has reported that as Chen Qiang etc. bromine chlorine hydantoin reaches 100% to the strong poison of swine pox, swine fever virus and pig parvoviral inactivation ratio.Fine to the destructive effect of HBsAg antigenicity, contain the antigenicity that effective chlorine 500mg/L effect 20min or 400mg/L effective chlorine effect 30min can destroy HBsAg as reports such as Li Qinglu; Reports such as Liu Jimin contain effective chlorine 1000mg/L person and act on 45min, stainless steel surfaces HBsAg antigenicity can be destroyed fully; The solution effects 20min that reports such as Zhao Chunlan contain effective chlorine 1000mg/L can destroy HBsAg antigenicity in the suspension etc. fully.
In addition, temperature, acid-base value, Organic substance etc. have certain influence to the performance of halo dimethyl hydantion compounds bactericidal action.Temperature raises and makes the required time shortening of killing, this compounds bactericidal effect in the environment of slant acidity is better, particularly chloride methyl hydantoin is the easier hypochlorous acid that discharges in the environment of slant acidity (PH scope the best is 5.8～7.0), if PH can decompose rapidly greater than 9 o'clock two chlordantoins.And DBDMH can be applicable to that pH value changes bigger environment, even containing NH
3And H
2In the environment of S, also can bring into play the good sterilization effect.Organic substance has bigger influence to the bactericidal effect of this compounds.Zhang Tianbao etc. and Liu Jimin etc. have reported that respectively the influence of calf serum to its bactericidal effect, result all are that its bactericidal effect weakens with the increase of the medium and small bovine serum concentration of solution.
1.2, effectively elimination activity oxygen and free radical
According to the literature, 1-methyl hydantoin compounds can be eliminated the active and inhibition activated lymphocytes destruction endotheliocyte of hydroxyl radical free radical.By free seizure ESR technology (if measured matter the hydroxyl radical free radical elimination activity is arranged, then signal is suppressed), find that signal intensity has reduced 50% with comparing originally.
1.3, antiinflammatory
Reports such as Iwanowicz Edwin, 1-methyl hydantoin compounds can be used as anti-inflammatory preparation, is the effective ingredient of treatment inflammation or immune disease, for leukocyte polymerization element and ICAM antagonism is arranged all.
1.4, blood sugar lowering
Lenaga, Kazuharu etc.
[17]Report, in the normal experiment of rat, the dosage of 1-methyl-5-hydroxyl glycolylurea 25mg/kg can blood sugar lowering 33.9%.
1.5, as sodium ion channel blocker
According to the literature, the hydantoin-based compound that alkyl replaces can utilize the forebrain meninges of mice to participate in the adjustment of neural sodium-ion channel current potential, sodium-ion channel is big transmembrane transporter, expression is all arranged in different tissues, they have sensitivity to voltage, along with the increase of sodium ion permeability, thereby produce depolarization, this effect is present in a lot of excitable cells, for example: in muscle, nerve and the heart cell.
2, use
Up to the present, domestic less as medicinal application in clinical report to glycolylurea and derivant thereof, mainly be some external reports.
2.1, disinfection sanitizer
5,5-dimethyl hydantion (5,5-dimethylhydantoin) and derivant be a kind of effectively disinfection sanitizer, advantages such as two chlordantoins (DCDMH), DBDMH (DBDMH) and bromine chlorine hydantoin (BCDMH) is the disinfectant of novel halogenated amine type, and effectively little, the good stability of content of halogen height, abnormal smells from the patient, effect relax, chafe and mucosa, shelf storage life be not long, cheap doubly are popular.Now be widely used in daily-use chemical industry (as 1,3-dihydroxymethyl-5,5-methyl hydantoin are a kind of high-efficiency broad spectrum cosmetics preservatives), many-sides such as agricultural (aquaculture, insect pest preventing and controlling, foot and mouth disease control, the control of crops mildew, fruit antistaling agent etc.), medical and health sterilization, diet, drinking water, public place of entertainment, swimming sterilizing, recirculating cooling water system (killing algae).
2.2, the control medicine of premature labor
Hydantoin-based compound can be applicable to the obstetrics aspect, and for example butanimide replaces the control that hydantoin-based compound is usually used in premature labor, is used for caesarean operation and treatment dysmenorrhea etc.
2.3, the treatment diabetes
Hydantoin-based compound is more at the report of treatment diabetes and diabetic complication and blood circulation diseases fermentation.This analog derivative or its esters are a kind ofly can take the active substance for the treatment of diabetes with oral way.This compounds can be used as the activator of glucokinase, thereby insulin is increased, the treatment type ii diabetes.
2.4, treatment nephropathy aspect
Hydantoin-based compound is the active substance of effectively treatment or prevention renal failure, and is inhibited for uremic toxins, thereby can improve renal function, toxicity is extremely low, take safety, can be used as the oral formulations that continues medication for a long time, be used for treatment of chronic diseases.For example: Okamoto, Kaoru etc. have reported that the R type of 5-hydroxyl-1-methyl hydantoin and S type can be used for treating renal failure as diuretic, and the S type is difficult for metabolism, and R type drug effect is better than the S type and is better than practolol.
2.5, the treatment hypoalbuminemia
5-hydroxyl-1-methyl hydantoin is given six the oral 200g/ of patient days of suffering from hypoalbuminemia according to the literature, the concentration of monitoring serum albumin before treatment, administration 24 Zhou Houzai measure, find by oral this medicine, the concentration of serum albumin is obviously increased, thereby determines the effect of its treatment hypoalbuminemia.With the serum albumin concentration of same test determination healthy human body, find that administration front and back serum protein does not change.Therefore, proved that this compounds is the medicine of well treating hypoalbuminemia,, illustrated that it only works for the patient because its serum albumin to the normal human does not have influence.
In addition, 1-methyl hydantoin compounds can be used for the treatment of a series of because the disease that active oxygen and free radical cause as the active substance of elimination activity oxygen and free radical, as: myocardial infarction, again pour into obstacle, Active immunity disease, lung fibrosis disease, dermatosis, arthrosis, cancer therapy drug side effect, radiation disease, septic shock, cataract etc.Hydantoin-based compound also has the antagonism to pyrophosphotransferase, and the report as cancer therapy drug is also arranged.The DMDM glycolylurea can be used for the treatment of mammal and human skin mucosal disease, as: skin class diseases such as acne, herpes, ichthyosis, dermatitis.Dilantin (DPH) is used as convulsion, antiarrhythmic medicine as far back as nineteen eighty-three, find again that in the recent period DPH can combine with T-lymphocyte film, and to special shielding action of HTLV-III/LAV type virus receptor generation, therefore the treatment to AIDS should be effectively.Alkyl replaces that hydantoin-based compound can be used for the treatment of and prevent part or whole body ischemia as sodium channel inhibitor and the function of nervous system that causes loses, and degenerative neurological disorders, comprise motor neuron disease, anxiety, epilepsy etc., and nervous system disease, the surgical operation disease, chronic pain and tinnitus etc. also can be used as anti-arrhythmic, anesthetics and antimanic drugs.
In sum, hydantoin-based compound and derivant thereof are a kind of excellent prevention and treatment chronic disease and the suitable medicine of taking for a long time, aspect treatment diabetes, nephropathy and even immune disease and the hematopathy good application prospects is being arranged all, and as a kind of broad-spectrum disinfection sanitizer, the market prospect of hydantoin-based compound is also with boundless.
Summary of the invention
The invention provides a kind of pharmaceutical composition of antitussive, purpose is to utilize the compositions of hydantoin-based compound to carry out antitussive.The technical scheme that the present invention takes is: be to be made by ratio of weight and the number of copies by following compounds: glycolylurea: 5, and 5-dimethyl hydantion=1: (0.5～2).
Be preferably:
Make by ratio of weight and the number of copies by following compounds: glycolylurea: 5,5-dimethyl hydantion=1: 1.
The invention provides glycolylurea and 5, combination back, 5-dimethyl sea is at the medicine that is used to prepare antitussive.The medicine antitussive effect of making is remarkable.
When the present invention was used to prepare the medicine of antitussive, its oral or non-oral administration all was safe.Under oral situation, it can be any conventionally form administration, as slow releasing agent, powder, granule, tablet, capsule, pill, drop pill, soft capsule, leafing agent, oral liquid, suspension, syrup, buccal tablets, spray or aerosol etc.
When the non-oral administration of this medicine, can adopt any conventionally form, as injection (intravenous injection, intramuscular injection), ointment, inhalant etc.
The medicine that the present invention prepares antitussive is that its excipient with solid or liquid constitutes, solid used herein or liquid excipient are well known in the art, lift several object lessons below, the excipient of solid preparation has lactose, starch, paste essence, calcium carbonate, synthetic or puritan filler aluminum, magnesium chloride, magnesium stearate, sodium bicarbonate, dry yeast etc.; The excipient of liquid preparation has water, glycerol, propylene glycol, simple syrup, ethanol, ethylene glycol, Polyethylene Glycol, Sorbitol etc.; The excipient of ointment can use fatty oil, agnolin, vaseline, glycerol, Cera Flava, wood are cured, liquid paraffin, resin, advanced wax etc. are combined into water-repelling agent or hydrophilizing agent.
Dosage of the present invention can be according to the mode of taking, and patient's age and body weight and the degree that is in a bad way change with other similar factor, and oral dose is: 50～500mg/ day people, divide and take for one～three time every day; The injection consumption is 10～100mg/ people, once a day.
The medicine antitussive effect that the present invention makes is remarkable, and effect of drugs is by following experiment the pharmacological action of pharmaceutical composition of the present invention to be studied.Glycolylurea, 1-methyl hydantoin, 5, the 5-dimethyl hydantion all has obvious antitussive effect, no significant difference between each trial drug to Cavia porcellus citric acid spraying cough model, mice ammonia cough model and mice sulfur dioxide cough model.Glycolylurea and 5, the 5-dimethyl hydantion obviously strengthens by antitussive effect behind 1: 1,1: 2 and 2: 1 compatibilities.Total dose is single with glycolylurea, 5 behind the two medicine compatibilities, 5-dimethyl hydantion and 1-methyl hydantoin 2/4 o'clock, with single suitable with the antitussive effect of 3 medicines, total dose is single with glycolylurea, 5 behind the two medicine compatibilities, 5-dimethyl hydantion and 1-methyl hydantoin 3/4 o'clock, be better than single antitussive effect with 3 medicines, total dose is single with glycolylurea, 5 behind the two medicine compatibilities, 5-dimethyl hydantion and 1-methyl hydantoin 4/4 o'clock, obviously be better than single antitussive effect, and obviously be better than the positive drug codeine phosphate with 3 medicines.Result of study prompting, glycolylurea and 5, the 5-dimethyl hydantion by a certain percentage behind the compatibility shown antitussive effect effect obvious.
Further verify the present invention below by concrete pharmacodynamic experiment.Select different animal cough models for use, to glycolylurea and 5, the antitussive effect behind the 5-dimethyl hydantion different proportion compatibility is studied, and proves the potentiation behind its compatibility.
Test drug: glycolylurea, 1-methyl hydantoin and 5, the 5-dimethyl hydantion is white powder, is not soluted in water, and is made into desired concn with 0.5% sodium carboxymethyl cellulose before the test; Codeine phosphate, the 30mg/ sheet is made into desired concn with 0.5% sodium carboxymethyl cellulose before the test; Citric acid, being made into concentration with distilled water during test is 17.5% solution; Ammonia is Gongzhuling City chemical reagent factory product; Anhydrous sodium sulfite and sulphuric acid are Beijing Chemical Plant's product.
Experimental animal: Cavia porcellus, body weight 200～250g, male and female half and half, Kunming mouse, body weight 18～22g, male and female half and half provide by preclinical medicine institute of Jilin University Experimental Animal Center, the quality certification number: SCXK-(Ji) 2003-0001.
1. to the influence of Cavia porcellus citric acid spraying cough model
Test method
Get 60 of Cavia porcelluss, body weight 200～250g, male and female half and half are divided into 10 groups at random according to body weight, 6 every group.1. matched group is irritated stomach and is given 0.5% sodium carboxymethyl cellulose, 2. the glycolylurea group is irritated stomach and is given glycolylurea 80mg/kg, 3. 5,5-dimethyl hydantion group is irritated stomach and is given 5,5-dimethyl hydantion 80mg/kg, 4. 1-methyl hydantoin group is irritated stomach and is given 1-methyl hydantoin 80mg/kg, 5. positive drug is irritated stomach and is given codeine phosphate 10mg/kg, 6. glycolylurea+5, and 1: 1 compatibility low dose group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 20mg/kg+5,5-dimethyl hydantion 20mg/kg, 7. glycolylurea+5, the dosage group is irritated stomach and is given glycolylurea 30mg/kg+5,5-dimethyl hydantion 30mg/kg in 1: 1 compatibility of 5-dimethyl hydantion, 8. glycolylurea+5,1: 1 compatibility high dose group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 40mg/kg+5,5-dimethyl hydantion 40mg/kg, 9. glycolylurea+5,1: 2 compatibility group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 20mg/kg+5,5-dimethyl hydantion 40mg/kg, 10. glycolylurea+5,2: 1 compatibility groups of 5-dimethyl hydantion are irritated stomach and are given glycolylurea 40mg/kg+5,5-dimethyl hydantion 20mg/kg irritates the long-pending 10ml/kg that is of body of stomach.Each organized successive administration 7 days, and behind the 7th day medicine 1 hour, each group Cavia porcellus is put into spray tank, spray into the aerosol 1 minute of 17.5% citric acid soln in the spray tank with 0.2MPa pressure, write down the cough number of times in each Mus 10 minutes.Experimental data with
Expression adopts the multifactor analysis of variance to carry out statistical analysis.
Result of the test
Compare with matched group, glycolylurea and 5,1: 1 compatibility low dosage (20mg/kg+20mg/kg) of 5-dimethyl hydantion group, glycolylurea (80mg/kg) group, 5,5-dimethyl hydantion (80mg/kg) group, 1-methyl hydantoin (80mg/kg) group and positive drug codeine phosphate (10mg/kg) group all can obviously reduce the cough number of times (p＜0.05) in the Cavia porcellus due to the 17.5% citric acid aerosol 10 minutes, no significant difference between each medicine (p＞0.05); Glycolylurea and 5, dosage (30mg/kg+30mg/kg) group and 1: 1 compatibility high dose (40mg/kg+40mg/kg) group all can obviously reduce the cough number of times (p＜0.001) of Cavia porcellus in 1: 1 compatibility of 5-dimethyl hydantion, its action intensity obviously is better than single with glycolylurea, 5,5-dimethyl hydantion and 1-methyl hydantoin (p＜0.05 or p＜0.01) also obviously are better than positive drug codeine phosphate (p＜0.05 or p＜0.01); Glycolylurea and 5,1: 2 compatibility (20mg/kg+40mg/kg) group of 5-dimethyl hydantion and glycolylurea and 5,2: 1 compatibilities (40mg/kg+20mg/kg) of 5-dimethyl hydantion group all can obviously reduce the cough number of times (p＜0.001) of Cavia porcellus, its action intensity and isodose glycolylurea and 5,1: 1 compatibility (30mg/kg+30mg/kg) of 5-dimethyl hydantion group no significant difference (p＞0.05) sees Table 1.
Table 1 glycolylurea and 5,5-dimethyl hydantion compatibility is to the influence of guinea pig cough due to the citric acid
Compare with matched group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
With glycolylurea+5,5-dimethyl hydantion (30mg/kg+30mg/kg) group compares #P＜0.05, ##P＜0.01
With glycolylurea+5,5-dimethyl hydantion (40mg/kg+40mg/kg) group compares △ P＜0.05, △ △ P＜0.01
2. to the influence of ammonia induced mice cough latent period and number of times
Test method
Get 100 of male mouse of kunming, body weight 18～22g is divided into 10 groups at random according to body weight, 10 every group.1. matched group is irritated stomach and is given 0.5% sodium carboxymethyl cellulose, 2. the glycolylurea group is irritated stomach and is given glycolylurea 120mg/kg, 3. 5,5-dimethyl hydantion group is irritated stomach and is given 5,5-dimethyl hydantion 120mg/kg, 4. 1-methyl hydantoin group is irritated stomach and is given 1-methyl hydantoin 120mg/kg, 5. positive drug is irritated stomach and is given codeine phosphate 20mg/kg, 6. glycolylurea+5, and 1: 1 compatibility low dose group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 30mg/kg+5,5-dimethyl hydantion 30mg/kg, 7. glycolylurea+5, the dosage group is irritated stomach and is given glycolylurea 45mg/kg+5,5-dimethyl hydantion 45mg/kg in 1: 1 compatibility of 5-dimethyl hydantion, 8. glycolylurea+5,1: 1 compatibility high dose group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 60mg/kg+5,5-dimethyl hydantion 60mg/kg, 9. glycolylurea+5,1: 2 compatibility group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 30mg/kg+5,5-dimethyl hydantion 60mg/kg, 10. glycolylurea+5,2: 1 compatibility groups of 5-dimethyl hydantion are irritated stomach and are given glycolylurea 60mg/kg+5,5-dimethyl hydantion 30mg/kg irritates the long-pending 10ml/kg that is of body of stomach.Each organized successive administration 7 days, behind the 7th day medicine 1 hour, mice is placed the 500ml port grinding bottle, with 402AI type ultrasound atomizer (Yuyue Medical Apparatus Co., Ltd., Jiangsu's manufacturing) constant-pressure atomization strong aqua ammonia in 8 second, observe mouse cough incubation period (beginning to cough the time for the first time) and the number of times of coughing in 2 minutes to mice from ammonia spraying.Shrinking and magnify mouth with the mice abdominal muscle is cough action indication.Experimental data with
Expression adopts the multifactor analysis of variance to carry out statistical analysis.
Result of the test
Compare with matched group, glycolylurea and 5, dosage (45mg/kg+45mg/kg) group, 5 in 1: 1 compatibility of 5-dimethyl hydantion, 5-dimethyl hydantion (120mg/kg) group, 1-methyl hydantoin (120mg/kg) group and positive drug codeine phosphate (20mg/kg) group all can obviously prolong the incubation period (p＜0.05 or p＜0.01) of ammonia induced mice cough, glycolylurea and 5 has prolongation trend (p＞0.05) incubation period that 5-dimethyl hydantion 1: 1 compatibility low dosage (30mg/kg+30mg/kg) group and glycolylurea (120mg/kg) group are coughed to the ammonia induced mice; Glycolylurea and 5, dosage (45mg/kg+45mg/kg) group, glycolylurea (120mg/kg) group, 5 in 5-dimethyl hydantion 1: 1 compatibility low dosage (30mg/kg+30mg/kg) group, 1: 1 compatibility, 5-dimethyl hydantion (120mg/kg) group, 1-methyl hydantoin (120mg/kg) group and positive drug codeine phosphate (20mg/kg) group all can obviously all reduce the cough number of times (p＜0.05 or p＜0.01) of mice, no significant difference between each medicine (p＞0.05); Glycolylurea and 5,1: 1 compatibility high dose (60mg/kg+60mg/kg) of 5-dimethyl hydantion group can obviously prolong the incubation period of ammonia induced mice cough, and obviously reduce the cough number of times (p＜0.001) of mice, its action intensity obviously is better than single with glycolylurea, 5,5-dimethyl hydantion and 1-methyl hydantoin (p＜0.05) also obviously are better than positive drug codeine phosphate (p＜0.05); Glycolylurea and 5,1: 2 compatibility (30mg/kg+60mg/kg) group of 5-dimethyl hydantion and glycolylurea and 5,2: 1 compatibilities (60mg/kg+30mg/kg) of 5-dimethyl hydantion group all can obviously prolong the incubation period of ammonia induced mice cough, and obviously reduce the cough number of times (p＜0.001) of mice, its action intensity and isodose glycolylurea and 5,1: 1 compatibility (45mg/kg+45mg/kg) of 5-dimethyl hydantion group no significant difference (p＞0.05) sees Table 2.
Table 2 glycolylurea and 5,5-dimethyl hydantion compatibility is to the influence of ammonia induced mice cough latent period and cough number of times
Compare with matched group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
With glycolylurea+5,5-dimethyl hydantion (60mg/kg+60mg/kg) group compares △ P＜0.05, △ △ P＜0.01
3. to the influence of sulfur dioxide induced mice cough latent period and number of times
Test method
Get 100 of female kunming mices, body weight 18～22g is divided into 10 groups at random according to body weight, 10 every group.1. matched group is irritated stomach and is given 0.5% sodium carboxymethyl cellulose, 2. the glycolylurea group is irritated stomach and is given glycolylurea 120mg/kg, 3. 5,5-dimethyl hydantion group is irritated stomach and is given 5,5-dimethyl hydantion 120mg/kg, 4. 1-methyl hydantoin group is irritated stomach and is given 1-methyl hydantoin 120mg/kg, 5. positive drug is irritated stomach and is given codeine phosphate 20mg/kg, 6. glycolylurea+5, and 1: 1 compatibility low dose group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 30mg/kg+5,5-dimethyl hydantion 30mg/kg, 7. glycolylurea+5, the dosage group is irritated stomach and is given glycolylurea 45mg/kg+5,5-dimethyl hydantion 45mg/kg in 1: 1 compatibility of 5-dimethyl hydantion, 8. glycolylurea+5,1: 1 compatibility high dose group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 60mg/kg+5,5-dimethyl hydantion 60mg/kg, 9. glycolylurea+5,1: 2 compatibility group of 5-dimethyl hydantion is irritated stomach and is given glycolylurea 30mg/kg+5,5-dimethyl hydantion 60mg/kg, 10. glycolylurea+5,2: 1 compatibility groups of 5-dimethyl hydantion are irritated stomach and are given glycolylurea 60mg/kg+5,5-dimethyl hydantion 30mg/kg irritates the long-pending 10ml/kg that is of body of stomach.Each organized successive administration 7 days, behind the 7th day medicine 1 hour, the 4g anhydrous sodium sulfite places the continuous sample injector of 10ml, splash into the 8ml50% concentrated sulphuric acid, the gas 30ml that produces is added in the 500ml port grinding bottle of placing mice, observes mouse cough incubation period (beginning to cough the time for the first time) immediately and the number of times of coughing in 2 minutes to mice from adding gas.Shrinking and magnify mouth with the mice abdominal muscle is cough action indication.Experimental data with
Expression adopts the multifactor analysis of variance to carry out statistical analysis.
Result of the test
Compare with matched group, glycolylurea and 5, dosage (45mg/kg+45mg/kg), glycolylurea (120mg/kg) group, 5 in 5-dimethyl hydantion 1: 1 compatibility low dosage (30mg/kg+30mg/kg) group, 1: 1 compatibility, 5-dimethyl hydantion (120mg/kg) group, 1-methyl hydantoin (120mg/kg) group and positive drug codeine phosphate (20mg/kg) group all can obviously prolong the incubation period (p＜0.05～p＜0.001) of sulfur dioxide induced mice cough; Glycolylurea and 5, dosage (45mg/kg+45mg/kg), glycolylurea (120mg/kg) group, 1-methyl hydantoin (120mg/kg) group and positive drug codeine phosphate (20mg/kg) group all can obviously all reduce the cough number of times (p＜0.05 or p＜0.01) of mice, no significant difference between each medicine (p＞0.05) in 1: 1 compatibility of 5-dimethyl hydantion; Glycolylurea and 5,1: 1 compatibility high dose (60mg/kg+60mg/kg) of 5-dimethyl hydantion group can obviously prolong the incubation period of sulfur dioxide induced mice cough, and obviously reduce the cough number of times (p＜0.001) of mice, its action intensity obviously is better than single glycolylurea of using, 5,5-dimethyl hydantion and 1-methyl hydantoin (p＜0.05), but the not obvious positive drug codeine phosphate (p＞0.05) that is better than, glycolylurea and 5,1: 2 compatibility (30mg/kg+60mg/kg) group of 5-dimethyl hydantion and glycolylurea and 5,2: 1 compatibilities (60mg/kg+30mg/kg) of 5-dimethyl hydantion group all can obviously prolong the incubation period of sulfur dioxide induced mice cough, and obviously reduce the cough number of times (p＜0.001) of mice, its action intensity and isodose glycolylurea and 5,1: 1 compatibility (45mg/kg+45mg/kg) of 5-dimethyl hydantion group no significant difference (p＞0.05) sees Table 3.
Table 3 glycolylurea and 5,5-dimethyl hydantion compatibility is to the influence of sulfur dioxide induced mice cough latent period and cough number of times
Compare with matched group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
With glycolylurea+5,5-dimethyl hydantion (60mg/kg+60mg/kg) group compares △ P＜0.05, △ △ P＜0.01
The specific embodiment
Embodiment 1
Recipe quantity: glycolylurea 30g, 5,5-dimethyl hydantion 30g, HPMCE4CR84g, anhydrous citric acid 60g, lactose 145.3g, magnesium stearate 0.7g make 1000 altogether.
Preparation method: get glycolylurea, 5,5-dimethyl hydantion, HPMCE4CR, anhydrous citric acid, lactose and lubricant are crossed 100 mesh sieves, and mix homogeneously is put in the tablet machine loading hopper, regulates pressure and loading, and compacting is in blocks, promptly.
Embodiment 2
Recipe quantity: 1000 glycolylureas, 5,5-dimethyl hydantion composition sustained-release sheet label-glycolylurea 30g, 5,5-dimethyl hydantion 60g, methylcellulose 40g, carboxymethyl cellulose rope sodium 50g, ethyl cellulose 10g, hydrogenated vegetable oil 50g, Pulvis Talci 3 magnesium stearate 2g; The 3g hydroxypropyl emthylcellulose adds 85% ethanol and makes thin film coating material to 100ml.
Preparation method: measure glycolylurea, 5 by prescription, 5-dimethyl hydantion, methylcellulose, sodium carboxymethyl cellulose, hydrogenated vegetable oil mix homogeneously, the alcoholic solution that adds ethyl cellulose is made soft material, 20 mesh sieves are granulated, 65 ℃ of dryings, granulate, add Pulvis Talci, magnesium stearate mixing, tabletting.With the Gonak coating for preparing promptly.
Embodiment 3
Get glycolylurea 60g, 5,5-dimethyl hydantion 30g, porphyrize adds starch 100g, and mixing is granulated, and incapsulates, and gets final product.
Claims (2)
1. the pharmaceutical composition of an antitussive is characterized in that being made by ratio of weight and the number of copies by following compounds: glycolylurea: 5, and 5-dimethyl hydantion=1: (0.5～2).
2. the pharmaceutical composition of antitussive as claimed in claim 1 is characterized in that being made by ratio of weight and the number of copies by following compounds: glycolylurea: 5, and 5-dimethyl hydantion=1: 1.
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