CN1546019A - Compound abiduoer preparation with wide spectrum in resisting influenza viral - Google Patents
Compound abiduoer preparation with wide spectrum in resisting influenza viral Download PDFInfo
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Abstract
The invention provides a compound Arbidol hydrochloride wide spectrum antiviral influenza medicament, which is prepared from Arbidol hydrochloride, acetaminopher and chlorpheniramine or Loratadine. The compound can be prepared into oral medication through the conventional preparation process.
Description
Technical field:
The present invention relates to a kind of novel broad-spectrum antiviral medicament, say it is to disclose a kind of compound recipe Abiduoer broad-spectrum antiviral cold medicine clearly, belong to the antiviral drugs production technical field.
Background technology:
Former medicine arbidol HCl (6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxylic acid carbethoxy hydrochloride monohydrate, Arbidol hydrochloride) be to draw from Muscovite a kind of novel antiviral medicine, it has certain inhibitory action to Respirovirus, but for not reaction of analgesic, analgesia, antiinflammatory and antiallergic clinical trial.
Summary of the invention:
The invention provides a kind of compound recipe Abiduoer broad-spectrum antiviral medicament, influenza A virus H1N1 hypotype, respiratory syncytial virus all there is stronger inhibitory action, adenovirus type III is also had certain inhibitory action, and have analgesic, analgesia, antiinflammatory and anti-allergic effects.
The present invention is made by following parts by weight crude drug:
50～500 parts of Abiduoers, 150～400 parts of acetaminophen.
Optimum ratio of the present invention is:
100 parts of Abiduoers, 250～350 parts of acetaminophen.
Also have following raw material in the medicine of the present invention:
1～2 part of chlorphenamine.
Also can add following raw material in the medicine of the present invention:
1～5 part of loratadine.
Crude drug of the present invention can with the medicinal adjuvant of routine as: excipient, disintegrating agent, binding agent, lubricant, antioxidant, coating materials, coloring agent, aromatic, surfactant etc. mix, and make oral medicine regular dosage forms such as granule, capsule, tablet.Other project should meet 2000 editions relevant dosage form project relevant requirements of Pharmacopoeia of People's Republic of China.
Production technology of the present invention is as follows:
Take by weighing Abiduoer, acetaminophen raw material and pharmaceutic adjuvant Icing Sugar, starch, paste producing starch, magnesium stearate etc. according to the above ratio, former, adjuvant are pulverized in pulverizer respectively, sieved, made corresponding oral medicine dosage form according to the conventional production process on the pharmaceutics.
The present invention is an oral administration, dosage (adult) 500～1720mg every day, and the child reduces by half.
The specific embodiment:
But following experimental example, the present invention of embodiment more detailed description, but do not limit the present invention in any form.
Embodiment 1
Take by weighing Abiduoer 10kg, acetaminophen 25kg, loratadine 0.2kg raw material and adjuvant Icing Sugar 1.9kg, starch 3.6kg, paste producing starch 1.4kg, magnesium stearate 0.5kg for preparing 100,000 tablets of medicines.
Former, adjuvant are pulverized 30min respectively in pulverizer, after sieve through 100 mesh sieves respectively, standby.Take by weighing supplementary material respectively, mix homogeneously by 80 mesh sieves, makes it abundant mixing again.
Operating procedure:
With Abiduoer, acetaminophen, loratadine, Icing Sugar, dried starch drop in the pot material of wet mixing pelletizer, and the dried even back that is mixed adds starch slurry and makes wet grain.
The starch slurry collocation method: place soybean milk boiling tank to add pure water the mashing off starch in the batch of material and be made into 15% concentration, stir and make it become to be heated to behind the uniform suspension 75 ℃ of left and right sides gelatinizings for well, exit to 30 ℃～60 ℃ stand-by.
Do and mix: 800 rev/mins of mixing speeds, chopping speed are low-grade, dried doing time 5 minutes.
Granulate: 800 rev/mins of mixing speeds, chopping speed are high-grade, stir, shred and be advisable in 1 minute.
Dry: the baking temperature of wet granular should be at 55 ℃, are dried to water content and are 2～5% and be advisable.
Granulate: dry back granulate in waving granulation machine, granulate order number is 14 orders.
Batch mixing: will add magnesium stearate batch mixing in the batch mixing machine of lot number amount in the dried granule behind the granulate, the batch mixing time is 0.5 hour, and rotating speed is 70 rev/mins.
Tabletting: the granule that is up to the standards is according to the content detection result, and it is heavy to calculate sheet, last machine tabletting, 100,000.
Experimental example 1
Acetaminophen 250mg/kg and embodiment 2355mg/kg, 118mg/kg, 71mg/kg has certain analgesic activity to 60 minutes heavy doses of mice hot plate method test administration; Writhing response test mice acetaminophen 250mg/kg and embodiment 2355mg/kg there is analgesic activity.To 10
7Rat fever due to/0.5ml escherichia coli, acetaminophen 160mg/kg and embodiment 2 heavy dose of 227mg/kg have certain refrigeration function, and 114mg/kg, 57mg/kg refrigeration function are not obvious.
Purpose
Set up sensitive animal model according to the indication of embodiment 2, observe its main pharmacodynamics effect, for clinical practice provides the laboratory theoretical foundation.
Test material
The medicine acetaminophen, embodiment 2, provide by the too medical group of Wu.
The clean level of animal ICR white mice, body weight 18～20g, quality certification numbering: scxk (Ji) 2003-0001; Wistar rat, body weight are 190～200g, quality certification numbering: scxk (Ji) 2003-0001; Provide by animal portion of preclinical medicine institute of Jilin University.
Instrument YLS-6A intelligence hot-plate instrument is produced factory number: 6007274 by equipment station, the Academy of Medical Sciences, Shandong.
Result and method.
One, the influence of 2 pairs of mice hot plates of embodiment analgesic activity
With YLS-6A intelligence hot-plate instrument temperature is set in 55 ℃, as thermostimulation, the record mice causes and the incubation period of metapedes occurs licking as this Mus pain threshold from dropping into hot-plate instrument, before administration, measure the pain threshold of every mice earlier as basic pain threshold, reject the happiness leaper, with 5～30s person is qualified, 50 qualified of female mices of screening is divided into 5 groups, both positive controls acetaminophen (250mg/kg); Embodiment 2 high, medium and low three dosage groups (355mg/kg, 118mg/kg, 71mg/kg); Blank gives with the volume normal saline, behind the gastric infusion 30,, measured the pain threshold of respectively organizing mice respectively in 60,90 minutes, the results are shown in Table 1.
The influence of 2 pairs of mice hot plate methods of table 1 embodiment analgesic activity (X ± S n=10)
Group dosage
(mg/kg) behind the medicine prodrug 30 minutes
Blank 16.56 ± 5.63 13.69 ± 4.34
To acetyl
Amino phenols 250 13.16 ± 5.48 17.31 ± 7.64
Prescription is big by 355 14.59 ± and 6.29 16.64 ± 9.51
In the prescription 118 15.36 ± 5.16 15.36 ± 9.43
Prescription is little by 71 12.93 ± and 5.12 15.35 ± 6.01
Compare P＞0.05 with the blank group
Group dosage
(mg/kg) behind the medicine behind 60 fens medicines 90 minutes
Blank 13.54 ± 4.79 15.85 ± 5.06
To acetyl
Amino phenols 250 13.08 ± 5.36 17.26 ± 7.81
Prescription is big by 355 15.36 ± 7.61
*13.49 ± 4.64
In the prescription 118 16.33 ± 4.77 15.36 ± 8.16
Prescription is little by 71 15.82 ± and 8.67 19.60 ± 4.64
Compare with the blank group:
*P＜0.05;
By table 1 as seen, administration after 60 minutes embodiment 2 high dose group inhibited to mice by the pain that hot plate causes, with the blank group statistical significance (P＜0.05) is arranged relatively, but in, low dose group and blank group not statistically significant (P＞0.05) relatively; Positive controls does not also show obvious analgesic activity simultaneously.
Two, the analgesic activity of 2 pairs of mouse writhing tests of embodiment
Get 50 of mices, male and female half and half, grouping and administration are the same, behind the gastric infusion 30 minutes, respectively each group mouse peritoneal is injected 0.6% glacial acetic acid, every 0.2ml observes that the injection glacial acetic acid occurs in 15 minutes turns round body number of times and medicine to the suppression ratio of writhing response, implements to judge
The analgesic effect of example 2 the results are shown in Table 2.
Suppression ratio (%)=(blank group is turned round body mean-reagent group and turned round the body mean)/blank group is turned round body
Mean * 100%
The analgesic activity of 2 pairs of mouse writhing tests of table 2 embodiment.(X±S?n＝10)
Group dosage is turned round body number of times suppression ratio
(mg/kg) (behind the medicine 45 minutes) (%)
Blank 42.1 ± 13.54
To acetyl
Amino phenols 250 27.1 ± 16.60
*35.6
Prescription is big by 355 25.3 ± 18.32
*39.9
In the prescription 118 34.6 ± 13.08 17.8
Prescription is little by 71 37 ± and 18.96 12.0
Compare with the blank group
*P＜0.05
By table 2 as seen, positive drug acetaminophen and embodiment 2 high doses can reduce mice and turn round the body number of times by what glacial acetic acid caused, but suppression ratio is all less than 50%, and acetyl aminophenol and embodiment 2 high dose group and blank group relatively have statistical significance (P＜0.05).
Three, the influence of 2 pairs of rat fever reactions of embodiment
Getting body weight is 50 of 190～200g rats, is divided into 5 groups, 10 every group, male and female half and half, be positive control acetaminophen group (160mg/kg), 2 three dosage groups of embodiment (227mg/kg, 114mg/kg, 57mg/kg), blank group, before the administration rat anus thermometre is coated vaseline, after making it lubricated anus temperature meter is inserted rat anus 2cm, place after 3 minutes, take out reading, write down the normal body temperature (Celsius temperature) of every rat, each organizes rat by tail vein injection 10
7Gastric infusion behind the Escherichia coli bacteria liquid 150min of/0.5ml bacterial concentration, the blank group gives with the volume normal saline, with the rat temperature with 1h, 2h, 3h, 4h, 5h after the quadrat method measurement administration, relatively the difference condition of administration group and control rats body temperature the results are shown in Table 3.
The influence (X ± S n=10) of 2 pairs of rat fever reactions of table 3 embodiment
1h 2h 3h before group dosage (mg/kg) medicine
Blank 38.3 ± 0.39 39.09 ± 0.44 39.56 ± 0.41 39.61 ± 0.31
To acetyl
Amino phenols 160 38.35 ± 0.39 38.93 ± 0.18 39.46 ± 0.28 38.89 ± 0.26
*
Prescription is big by 227 38.43 ± and 0.38 38.89 ± 0.57 39.1 ± 0.54 38.89 ± 0.46
*
In the prescription 114 38.4 ± 0.41 38.93 ± 0.44 39.41 ± 0.37 39.25 ± 0.42
Prescription is little by 57 38.38 ± and 0.23 38.95 ± 0.21 39.54 ± 0.28 39.35 ± 0.59
Compare with the blank group:
*P＜0.01
Group dosage (mg/kg) 4h 5h
Blank 39.69 ± 0.14 39.88 ± 0.33
To acetyl
Amino phenols 160 38.9 ± 0.36
* *39.71 ± 0.47
Prescription is big by 227 39.13 ± 0.34
* *39.24 ± 0.79
In the prescription 114 39.4 ± 0.57 39.55 ± 0.57
Prescription is little by 57 39.49 ± and 0.74 39.74 ± 0.42
Compare with the blank group:
* *P＜0.01
The result shows that acetaminophen and embodiment 2 administration groups all have refrigeration function in administration after 30 minutes.Embodiment 2 is identical with the effect of acetaminophen, among the embodiment 2, the low dose group effect is not obvious, with blank group not statistically significant relatively.
Discuss
Pharmacodynamic study result to embodiment 2 shows, these embodiment 2 Western medicine preparations high dose have certain analgesic, analgesic activity is similar to the effect of embodiment 1, but the analgesia intensity of writhing method analgesic test is weaker than embodiment 1.May lack relevant with the central inhibitory action of chlorphenamine maleate.Certain analgesic effect still can be seen in the administration high dose group in the hot plate method analgesic model, and writhing method acetyl aminophenol and embodiment 2 high doses also can be seen certain analgesic effect, can prove that thus this medical instrument has certain analgesic activity.In refrigeration function, as seen this test obvious body temperature occurred and descends (P＜0.01) during high dose group 3-4 hour, can illustrate that embodiment 2 has refrigeration function.But how to determine the best compatibility of embodiment 2, still needing further, the side's of tearing open test proves.
Conclusion: embodiment 2 has certain analgesic, analgesic activity
Experimental example 2
The main pharmacodynamics research (external) of arbidol HCl treatment influenza effect
Summary: by studies show that to the Respirovirus cytopathogenic effect is inhibiting, arbidol HCl and compound preparation thereof all have stronger inhibitory action to influenza A virus H1N1 hypotype and respiratory syncytial virus (RSV), and (Ad3) also has certain inhibitory action to adenovirus type III.Prompting: arbidol HCl and arbidol HCl compound preparation are to having certain prevention and therapeutical effect by the caused influenza of Respirovirus.
Test objective: former medicine arbidol HCl is to draw from Muscovite a kind of novel antiviral medicine.Bibliographical information is arranged, it has certain inhibitory action to Respirovirus, in order further to determine the effect of its preventing respiratory viruses, we have carried out the experimentation of preliminary preventing respiratory viruses to the arbidol HCl folk prescription, be equipped with acetaminophen and loratadine simultaneously and formed the compound hydrochloric acid Abiduoer, and carried out relevant pharmacodynamics and clinical practice medicine contrast test, be used for the treatment of grippal pharmacy effect to determine it.
Be subjected to the reagent thing: title, arbidol HCl (6-bromo-5-hydroxyl-4-dimethyl aminomethyl-2-benzene sulfidomethyl indole-3-carboxylic acid carbethoxy hydrochloride monohydrate, Arbidol hydrochloride).Experiment is made up of arbidol HCl, acetaminophen, three kinds of Western medicine of loratadine with the arbidol HCl compound preparation, is provided by preclinical medicine institute of Jilin University Pharmacology Lab.
Compound method: arbidol HCl, acetaminophen and loratadine are used the oxirane degerming respectively, the configuration proportion of arbidol HCl compound preparation is an arbidol HCl: acetaminophen: loratadine=1: 1.17: 0.02, it is stand-by to be mixed with desired concn with the IMDM cell culture fluid during experiment.
Dosage is selected: according to each medicine the toxicity test result of cultured cell is determined respectively to organize test dose (seeing Table 1).
Instrument: use the gas incubator, NCPC03100-1, the U.S. more; The profound hypothermia refrigerator, SANYO, Japan; Double superclean bench, SW-CT-ZF type, Suzhou; Centrifugal precipitation mechanism, LXT-II type, Shanghai; Microplate reader, G3022 type, Nanjing; Vacuum freeze drier, MRK, Japan.
Reagent: IMDM cell culture fluid, HyClone company, the U.S.; Newborn calf serum, Dalian biochemical reagents factory; Trypsin, Difco import packing, Shanghai; Tetrazolium bromide (MTT, [3-4,5-dimethylthiazo (2-yl)-2,5-diphenylte-trazoliumdromide], Sigma) product.
The positive control medicine: guanidine hydrochloride (Guanidine HCL), SIGMA, the U.S. faces the time spent with IMDM cell culture fluid preparation desired concn (only in vitro tests is used).
Clinical practice medicine matched group: virazole (ribavirin injection), Suzhou No.6 Pharmaceutical Factory, lot number: 021027, application dose is mixed with experiment required each concentration with the IMDM cell culture fluid with reference to cytotoxicity experiment result (seeing Table 1) during application.
Cell: Testis et Pentis Canis passage cell (MDCK), the U.S. introduces, and is provided by Chinese Academy of Sciences's cell bank, and human cervical carcinoma cell (Hela) and human amniotic cell (FL) are by this chamber preservation.
Strain: influenza A virus H1N1 hypotype, by Changchun Biological Products Institute provide, respiratory syncytial virus (RSV) standard Long strain and adenovirus type III (Ad3) standard strain preserve by this chamber.
Extracorporeal antivirus effect experiment key step and result
1. arbidol HCl, acetaminophen, loratadine, ribavirin injection and guanidine hydrochloride are to the toxic mensuration of cultured cell in vitro: medicine to be measured is mixed with 2000 μ g/ml, 1500 μ g/ml, 1000 μ g/ml, 800 μ g/ml, 600 μ g/ml, 400 μ g/ml, 200 μ g/ml, 100 μ g/ml, 50 μ g/ml respectively measures maximal non-toxic concentration (TD0) and median toxic concentration (TD50) respectively on human cervical carcinoma cell (Hela).The results are shown in Table 1, the non-toxic concn of arbidol HCl pair cell (TD0) is 1500 μ g/ml, and median toxic concentration (TD50) is not measured in this experiment; The non-toxic concn of acetaminophen (TD0) is 200 μ g/ml, and median toxic concentration (TD50) is 1500 μ g/ml; The non-toxic concn of loratadine (TD0) is 200 μ g/ml, and median toxic concentration (TD50) is 600 μ g/ml; The non-toxic concn of ribavirin injection (TD0) is 800 μ g/ml, and median toxic concentration (TD50) is 1500 μ g/ml; The non-toxic concn of guanidine hydrochloride (TD0) is 250 μ g/ml, and median toxic concentration (TD50) is 500 μ g/ml.
2. experiment grouping: normal cell matched group, complete virus infected group, positive drug guanidine hydrochloride matched group, clinical practice medicine ribavirin injection matched group and experimental group are established in experiment.Arbidol HCl folk prescription experimental group begins to establish 1000 μ g/ml from TD0,500 μ g/ml, and 250 μ g/ml are totally 3 concentration experimental grouies.Compound hydrochloric acid Abiduoer experimental group begins to establish 250 μ g/ml from TD0,125 μ g/ml, and 62.5 μ g/ml are totally 3 concentration experimental grouies.According to positive drug toxicity test result, positive drug guanidine hydrochloride experimental concentration is 250 μ g/ml.Clinical practice medicine ribavirin injection experimental concentration is 800 μ g/ml.
3. the respiratory virus infection cytopathy is suppressed experiment: each concentration group is further divided into viral adsorption group after the first dosing; Viral adsorption dosing simultaneously group; Dosing group behind elder generation's viral adsorption.With 200,000/ml cell, 0.1ml/ inoculates in the hole 96 orifice plates, is used for experiment after 2 days, all establishes 8 parallel holes for every group, and the virulence of infective virus is 100TCID50/0.1ml.Begin to examine under a microscope cell CPE after 72 hours, treat that virus control group CPE is ++ ++ time record result, and measure the OD570 value in each hole with mtt assay, to determine the pathological changes inhibition degree of each experimental group medicine to virus infected cell.The results are shown in Table 2,3,4,5,6,7.Suppressing experimental result by the cytopathy of 100TCID50 viral infection shows: the cytopathogenic effect to influenza A virus H1N1 hypotype and respiratory syncytial virus (RSV) standard Long strain has stronger inhibitory action, and the cytopathogenic effect of adenovirus type III (Ad3) is also had certain inhibitory action.
Discuss: experimental result shows that arbidol HCl and compound preparation all have stronger inhibitory action to influenza A virus H1N1 hypotype, respiratory syncytial virus, and adenovirus type III is also had certain inhibitory action.Obviously; arbidol HCl and compound hydrochloric acid Abiduoer have stronger inhibitory action to the main infective virus that causes influenza and respiratory system disease, again the In vitro culture host cell by respiratory virus infection are had the certain protection effect simultaneously.Because arbidol HCl has been proved to be a kind of novel broad-spectrum antiviral medicament, our experiment has proved further that again this medicine and compound preparation thereof all have stronger inhibition breeding effect to causing respiratory tract infection and grippal main Causative virus, its effect is apparently higher than clinical practice drugs compared ribavirin injection, so it can be used as and a kind ofly is used for the treatment of grippal new drug and develops.
Conclusion: in sum, arbidol HCl and compound preparation can reach treatment flu, grippal main pharmacodynamics effect.The arbidol HCl compound preparation is compared with clinical practice medicine ribavirin injection with positive control medicine guanidine hydrochloride, has tangible raising on antivirus action.
Embodiment 2
Take by weighing raw material Abiduoer 10kg, acetaminophen 25kg, chlorphenamine 0.2kg and adjuvant Icing Sugar 1.9kg, starch 3.6kg, paste producing starch 1.4kg, magnesium stearate 0.5kg for making 100,000 medication amount.
Operating procedure:
1 pulverizes 30min respectively with the supplementary material that is up to the standards in pulverizer, after sieve through 100 mesh sieves respectively, standby.
2 take by weighing supplementary material respectively according to recipe quantity, and mix homogeneously by 80 mesh sieves, makes it abundant mixing again.
3 wet granulations
3.1 with Abiduoer, acetaminophen, chlorphenamine, Icing Sugar, dried starch drop in the pot material of wet mixing pelletizer, the dried even back that is mixed adds starch slurry and makes wet grain.
3.2 technological parameter
The starch slurry collocation method: place soybean milk boiling tank to add pure water the mashing off starch in the batch of material and be made into 15% concentration, stir and make it become to be heated to behind the uniform suspension 75 ℃ of left and right sides gelatinizings for well, exit to 30 ℃～60 ℃ stand-by.
Do and mix: 800 rev/mins of mixing speeds, chopping speed are low-grade, dried doing time 5 minutes.
Granulate: 800 rev/mins of mixing speeds, chopping speed are high-grade, stir, shred and be advisable in 1 minute.
4 dryings: the baking temperature of wet granular should be at 55 ℃, are dried to water content and are 2～5% and be advisable
5 granulate: dry back granulate in waving granulation machine, granulate order number is 14 orders.
6 batch mixings: will add magnesium stearate batch mixing in the batch mixing machine of lot number amount in the dried granule behind the granulate, the batch mixing time is 0.5 hour, and rotating speed is 70 rev/mins.
7 tablettings:
The granule that is up to the standards is according to the content detection result, and it is heavy to calculate sheet, last machine tabletting.
Experimental example 2
Acetaminophen 250mg/kg and embodiment 1352mg/kg, 117.2mg/kg, 70.4mg/kg has obvious analgesic activity to the writhing response test mice; 60 minutes heavy doses of mice hot plate method test administration had certain analgesic activity.To 10
7Rat fever due to/0.5ml escherichia coli, acetaminophen 160mg/kg and embodiment 1 heavy dose of 225mg/kg have certain refrigeration function, and 112.5mg/kg, 56.2mg/kg refrigeration function are not obvious.
Purpose: set up sensitive animal model according to the indication of embodiment 1, observe its main pharmacodynamics effect, for clinical practice provides the laboratory theoretical foundation.
Test material:
The medicine acetaminophen, embodiment 1, provides by the too medical group of Wu.
The clean level of animal ICR white mice, body weight 18～20g, quality certification numbering: scxk (Ji) 2003-0001; Wistar rat, body weight are 190～200g, quality certification numbering: scxk (Ji) 2003-0001; Provide by animal portion of preclinical medicine institute of Jilin University.
Instrument YLS-6A intelligence hot-plate instrument is produced factory number: 6007274 by equipment station, the Academy of Medical Sciences, Shandong.
Result and method.
One, the influence of 1 pair of mice hot plate of embodiment analgesic activity
With YLS-6A intelligence hot-plate instrument temperature is set in 55 ℃, as thermostimulation, the record mice causes and the incubation period of metapedes occurs licking as this Mus pain threshold from dropping into hot-plate instrument, before administration, measure the pain threshold of every mice earlier as basic pain threshold, reject the happiness leaper, with 5～30s person is qualified, 50 qualified of female mices of screening is divided into 5 groups, both positive controls acetaminophen (250mg/kg); Embodiment 1 high, medium and low three dosage groups (352mg/kg, 117.2mg/kg, 70.4mg/kg); Blank gives with the volume normal saline, measures the pain threshold of respectively organizing mice respectively in 30,60,90 minutes behind the gastric infusion, the results are shown in Table 1.
The influence of 1 pair of mice hot plate method of table 1 embodiment analgesic activity (X ± S n=10)
Behind group dosage (mg/kg) the medicine prodrug 30 minutes
Blank 16.16 ± 5.71 18.23 ± 8.55
To acetyl
Amino phenols 250 17.03 ± 7.10 18.07 ± 9.66
Prescription is big by 352 17.08 ± and 6.77 16.61 ± 8.16
In the prescription 117.2 16.21 ± 7.54 20.11 ± 10.70
Prescription is little by 70.4 16.67 ± 4.25 18.49 ± 6.98
Compare P＞0.05 with the blank group
Behind group dosage (mg/kg) medicine behind 60 fens medicines 90 minutes
Blank 25.93 ± 13.78 19.43 ± 5.73
To acetyl
Amino phenols 250 21.47 ± 13.17 21.40 ± 12.76
Prescription is big by 352 15.86 ± 5.34
*16.05 ± 6.74
In the prescription 117.2 18.34 ± 7.79 24.36 ± 15.95
Prescription is little by 70.4 27.95 ± 4.85 20.52 ± 7.70
Compare P＞0.05 with the blank group,
*P＜0.05;
By table 1 as seen, administration after 60 minutes embodiment 1 high dose group inhibited to mice by the pain that hot plate causes, with the blank group statistical significance (P＜0.05) is arranged relatively, but in, low dose group and blank group not statistically significant (P＞0.05) relatively; Positive controls does not also show obvious analgesic activity simultaneously.
Two, the analgesic activity of 1 pair of mouse writhing test of embodiment
Get 50 of mices, male and female half and half, grouping and administration are the same, behind the gastric infusion 30 minutes, respectively each group mouse peritoneal is injected 0.6% glacial acetic acid, every 0.2ml observes that the injection glacial acetic acid occurs in 15 minutes turns round body number of times and medicine to the suppression ratio of writhing response, to judge the analgesic effect of embodiment 1, the results are shown in Table 2.
Suppression ratio (%)=(blank group is turned round body mean-reagent group and turned round the body mean)/blank group is turned round body mean * 100%
The analgesic activity of 1 pair of mouse writhing test of table 2 embodiment.(X±S?n＝10)
Group dosage (mg/kg) is turned round body number of times (behind the medicine 45 minutes) suppression ratio (%)
Blank 30.9 ± 9.81
To acetyl
Amino phenols 250 10.7 ± 11.22
* *65.37
Prescription is big by 352 4 ± 8.75
* *87.06
In the prescription 117.2 4.2 ± 7.81
* *86.41
Prescription is little by 70.4 8.9 ± 10
* *71.20
Compare with the blank group
* *P＜0.001
By table 2 as seen, positive drug acetaminophen and embodiment 1 high, medium and low dosage can reduce mice and turn round the body number of times by what glacial acetic acid caused, suppression ratio is all greater than 50%, with the blank group significant statistical significance (P＜0.001) is arranged relatively, dose-effect relationship is obvious, but the standard too high difference is respectively organized in administration, even surpasses average.According to test data sheet, each group has the null value of different routine numbers in acetaminophen and the administration group, causes the standard too high difference thus.
Three, the influence of 1 pair of rat fever reaction of embodiment:
Getting body weight is 50 of 190～200g rats, is divided into 5 groups, 10 every group, male and female half and half, be positive control acetaminophen group (160mg/kg), 1 three dosage groups of embodiment (225mg/kg, 112.5mg/kg, 56.2mg/kg), blank group, before the administration rat anus thermometre is coated vaseline, after making it lubricated anus temperature meter is inserted rat anus 2cm, place after 3 minutes, take out reading, write down the normal body temperature (Celsius temperature) of every rat, each organizes rat by tail vein injection 10
7Gastric infusion behind the Escherichia coli bacteria liquid 150min of/0.5ml bacterial concentration, the blank group gives with the volume normal saline, with the rat temperature with 1h, 2h, 3h, 4h, 5h after the quadrat method measurement administration, relatively the difference condition of administration group and control rats body temperature the results are shown in Table 3.
The influence (X ± S n=10) of 1 pair of rat fever reaction of table 3 embodiment
1h 2h 3h before group (mg/kg) the dosage medicine
Blank 38.49 ± 0.53 39.08 ± 0.39 39.52 ± 0.39 39.53 ± 0.34
To acetyl
Amino phenols 160 38.53 ± 0.52 39.01 ± 0.25 39.44 ± 0.28 38.98 ± 0.30
*
Prescription is big by 225 38.6 ± and 0.50 38.95 ± 0.53 39.13 ± 0.48 38.98 ± 0.46
*
In the prescription 112.5 38.56 ± 0.50 39.01 ± 0.44 39.43 ± 0.43 39.29 ± 0.39
Prescription is little by 56.2 38.54 ± 0.41 38.98 ± 0.20 39.51 ± 0.32 39.43 ± 0.56
Compare P＞0.05 with the blank group;
*P＜0.01
Group (mg/kg) dosage 4h 5h
Blank 39.6 ± 0.22 39.82 ± 0.32
To acetyl
Amino phenols 160 38.92 ± 0.35
* *39.78 ± 0.44
Prescription is big by 225 39.15 ± 0.31
*39.33 ± 0.73
In the prescription 112.5 39.44 ± 0.53 39.57 ± 0.54
Prescription is little by 56.2 39.6 ± 0.69 39.8 ± 0.39
Compare P＞0.05 with the blank group;
* *P＜0.01
The result shows that acetaminophen and embodiment 1 administration group all have refrigeration function in administration after 30 minutes.Embodiment 1 is identical with the effect of acetaminophen, among the embodiment 1, the low dose group effect is not obvious, with blank group not statistically significant relatively.
Discuss
Pharmacodynamic study result to embodiment 1 shows that this embodiment 1 Western medicine preparation has certain analgesic, analgesic activity at high dose.The hot plate method analgesic model is the acute sharp pain that a kind of physical method causes, under acetaminophen conventional animal consumption, do not see analgesic activity, and the administration high dose group still can be seen certain analgesic effect, can prove that thus this medical instrument has certain analgesic activity. the writhing method experimental result is supported the conclusion of front.In refrigeration function, utilize the high concentration escherichia coli of survival condition to cause exothermic reaction, it is a reliable animal model, its characteristics are that exothermic reaction occurs slowly, reached the peak at 3.5 hours, but because the continuous release of pyrogeies such as endotoxin, heating continuing time is longer, and general medicine still is difficult to control.As seen this test obvious body temperature occurred and descends (P＜0.01) during 3-4 hour, can illustrate that embodiment 1 has refrigeration function.But how to determine the best compatibility of embodiment 1, still needing further, the side's of tearing open test proves.
Conclusion: embodiment 1 has certain analgesic, analgesic activity
Experimental example 2
Arbidol HCl is treated grippal main pharmacodynamics research (in the body)
Summary: by studies show that infection model antivirus action in the influenza virus body: arbidol HCl and arbidol HCl compound preparation have stronger inhibitory action to the propagation of influenza A1 type virion in the mouse lung.Prompting: the arbidol HCl compound recipe has certain prevention and therapeutical effect to the influenza that is caused by virus.
Test objective: grippal morbidity is relevant with the inflammation in respiratory system that is caused by influenza virus coup injury histiocyte.The purpose of this experiment is by the animal body inner model, observes the arbidol HCl compound recipe is organized influenza infection to mouse lung inhibitory action.
Be subjected to the reagent thing: be the white powder that Western medicine arbidol HCl, acetaminophen and loratadine are formed.The configuration proportion of arbidol HCl compound recipe is an arbidol HCl: acetaminophen: loratadine=100g: 250g: this compound recipe of 2g configuration proportion is provided by pharmacology teaching and research room of preclinical medicine institute of Jilin University.
Compound method and dosage are selected: with mixings of filling a prescription according to the above ratio of arbidol HCl, acetaminophen and loratadine, be ground into fine powder, drying.In vivo test reconciles into suspension with arbidol HCl compound preparation water, arbidol HCl compound recipe high dose group: 49.28mg/ml, and wherein the arbidol HCl net content is 14mg/ml; Dosage group: 16.408mg/ml in the arbidol HCl compound recipe, wherein the arbidol HCl net content is 4.6614mg/ml; Arbidol HCl compound recipe low dose group: 9.856mg/ml, wherein the arbidol HCl net content is: 2.8mg/ml; Arbidol HCl matched group: 49.28mg/ml, each dosage group content Pass Test requirement.
The positive control medicine: the moroxydine hydrochloride sheet, Toshiba's hall Pharmaceutical (Anhui) company limited is produced, lot number: 030318, specification: 0.1g.Be mixed with the solution for standby of 1.9mg/ml.
Instrument: use the gas incubator, NCPC03100-1, the U.S. more; The profound hypothermia refrigerator, SANYO, Japan; SARTORIUS GMBH GOTTINGEN precision balance (precision: 0.00001), Germany; Double superclean bench, SW-CT-ZF type, Chinese Suzhou; Centrifugal precipitation mechanism, LXT-II type, Chinese Shanghai; Vacuum freeze drier, MRK, Japan; Binocular microscope, OLYMPUSBHF.
Reagent: IMDM cell culture fluid, HyClone company, the U.S.; Newborn calf serum, Dalian biochemical reagents factory.
Animal and raising condition: hybridization far away is Kunming kind white mice, and closed colony originates from Switzerland, 1989 by Chinese Academy of Sciences's introduction, male and female dual-purpose, body weight 13-15g, the animal quality certification number: 960101017,1000 of number of animals, the aseptic observation ward of closed isolation raises.Provide by the Jilin Prov. Inst. of Chinese Medicine and Chinese Medical Science animal feeding room.
Strain: influenza virus A 1 type Mus lung adapted strain (H1N1) is provided by Changchun Biological Products Institute.
Cell: Madin-Darby canine kidney(cell line) (MDCK) (MDCK) is provided by Shanghai Chinese Academy of Sciences cell bank.
Test key step and result
1. experiment grouping: mice male and female dual-purpose, random packet, every cage is with 10 raisings of sex.Experiment is divided into 5 groups, the normal control group; The virus control group; Western medicine positive drug (moroxydine hydrochloride sheet) matched group, 13.3mg/kg; Arbidol HCl group and arbidol HCl compound medicine experimental group.Establish 3 dosetest groups in the experimental group again, arbidol HCl compound recipe high dose group (352mg/kg); Dosage group (117.2mg/kg) in the arbidol HCl compound recipe; Arbidol HCl compound recipe low dose group (70.4mg/kg).
2. virus virulence is measured: got 20 mices in preceding 7 days in test, collunarium infects influenza A1 type Mus lung adapted strain virus, and dilution factor is respectively 10
-1, 10
-2, 10
-3With 10
-4Viral liquid 0.03ml, begin to add up dead % next day, calculate LD50.The measurement result of LD50 is 100TCID50/0.03ml.
3. the mice influenza virus is caused the inhibitory action of pneumonia: began gastric infusion in preceding 1 day in infecting, every Mus 0.1ml, for three days on end, normal control group and virus control group gavage the normal saline of equal volume continuously.After the perfusion the 3rd day, each experimental group (except the normal control group) was through the shallow degree anesthesia of ether collunarium influenza virus A 1 type Mus lung adapted strain 15LD50/0.05ml down.Infect the back experimental group and continue to irritate stomach by above-mentioned dosage every day and take medicine, 10 of picked at random are cutd open mice extremely and are got lung and weigh after 96 hours, calculate the meansigma methods of each experimental group lung ponderal index, respectively with the virus control group relatively, calculate pneumonopathy and become suppression ratio.The results are shown in Table 1.3 dosage groups of arbidol HCl compound recipe all have significant therapeutic effect.The arbidol HCl group has similar effect too, compares with positive drug moroxydine matched group, and its effect is significantly improved, and compares with the virus control group, and difference is utmost point significant level.
4. the influence that body inner virus granule is bred: with influenza A1 type Mus lung adapted strain virus stock solution used 50 μ l collunarium infecting mouses, the drug study group begins gastric infusion 0.1ml the previous day in viral infection, infecting the back experimental group continues to take medicine by same dosage filling stomach every day, cut open mice extremely after 8 days, get lung homogenate and make suspension, centrifugal and freezing vacuum concentrated supernatant, behind the trace bacteria filter bacteriological filtration, the inoculation mdck cell, observe CPE every day, after treating that virus control group cell pathological changes occurs more than 90%, collect and respectively organize cell, multigelation three times is measured the virus titer (TCID50) in each experimental group lung suspension on mdck cell, compare with the virus control group, reduce by 1 with TCID50 and be judged to more than the logarithm value effectively
[1], determine that medicine in animal body to the influence of virion propagation, the results are shown in Table 2, each experimental group and virus control group compare, and the TCID50 value all reduces by 1 above logarithm value, and difference is utmost point significant level.
Conclusion (of pressure testing): result of the test shows that the arbidol HCl compound preparation has stronger inhibitory action to influenza A1 type virus, and its effect obviously is better than positive control medicine moroxydine.Prompting: the influenza that the arbidol HCl compound recipe causes influenza virus has certain therapeutical effect.Above-mentioned experimental result shows that arbidol HCl compound recipe popularity flu has certain therapeutical effect, simultaneously to having certain recovery and protective effect by the damage of the histiocyte due to the viral infection.The antivirus action of arbidol HCl compound recipe can provide the pharmacodynamics foundation for this Drug therapy influenza.
Conclusion: in sum, arbidol HCl and compound preparation can reach treatment flu, grippal main pharmacodynamics effect.Hydrochloric acid Yang Biduoer compound preparation is compared with clinical practice medicine ribavirin injection with positive control medicine guanidine hydrochloride, has tangible raising on antivirus action.
Embodiment 3
Take by weighing Abiduoer 10kg, acetaminophen 25kg raw material and adjuvant Icing Sugar 1.9kg, starch 3.6kg, paste producing starch 1.4kg, magnesium stearate 0.5kg for preparing 100,000 tablets of medicines.Other project should meet 2000 editions tablet projects of Pharmacopoeia of People's Republic of China relevant requirements.
Embodiment 4
Take by weighing Abiduoer 20kg, acetaminophen 55kg raw material and adjuvant Icing Sugar 1.9kg, starch 4.0kg, paste producing starch 1.9kg, 50% ethanol is an amount of, granulates granulate, oven dry, dress 1# capsule, every 0.2g.Other project should meet 2000 editions capsule projects of Pharmacopoeia of People's Republic of China relevant requirements.
Claims (5)
1, a kind of compound recipe Abiduoer broad-spectrum antiviral cold medicine is characterized in that it mainly being to be made by following parts by weight crude drug:
50～500 parts of Abiduoers, 150～400 parts of acetaminophen.
2, medicine according to claim 1, wherein the consumption of each crude drug is:
100 parts of Abiduoers, 250～350 parts of acetaminophen.
3, medicine according to claim 1 and 2, wherein crude drug also has:
1～2 part of chlorphenamine.
4, medicine according to claim 1 and 2, wherein crude drug also has:
1～5 part.
5, be any peroral dosage form of pharmaceutics according to the described medicine of claim 1-4.
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| CNA2003101159163A CN1546019A (en) | 2003-12-12 | 2003-12-12 | Compound abiduoer preparation with wide spectrum in resisting influenza viral |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100428935C (en) * | 2006-06-26 | 2008-10-29 | 四川百利药业有限责任公司 | Abiduoer granular formulation |
| CN102260205A (en) * | 2011-09-01 | 2011-11-30 | 湖北丽益医药科技有限公司 | Method for synthesizing Arbidol mesylate |
| CN102423488A (en) * | 2011-11-23 | 2012-04-25 | 石家庄中硕药业集团有限公司 | Medicine composition used for treating herpes zoster |
-
2003
- 2003-12-12 CN CNA2003101159163A patent/CN1546019A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100428935C (en) * | 2006-06-26 | 2008-10-29 | 四川百利药业有限责任公司 | Abiduoer granular formulation |
| CN102260205A (en) * | 2011-09-01 | 2011-11-30 | 湖北丽益医药科技有限公司 | Method for synthesizing Arbidol mesylate |
| CN102423488A (en) * | 2011-11-23 | 2012-04-25 | 石家庄中硕药业集团有限公司 | Medicine composition used for treating herpes zoster |
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