CN1323662C - Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof - Google Patents
Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof Download PDFInfo
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- CN1323662C CN1323662C CNB2005100775504A CN200510077550A CN1323662C CN 1323662 C CN1323662 C CN 1323662C CN B2005100775504 A CNB2005100775504 A CN B2005100775504A CN 200510077550 A CN200510077550 A CN 200510077550A CN 1323662 C CN1323662 C CN 1323662C
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Abstract
The present invention relates to a medicinal composition containing ambroxol and erdosteine or medicinal salts of ambroxol and erdosteine and an application thereof, a medicinal composition containing ambroxol and acetylcysteine or medicinal salts of ambroxol and acetylcysteine and an application thereof, medicinal boxes containing the compositions, and an application of the medical composition to prepare expectorant medicine. The present invention also relates to mixed or synergistic combinations of ambroxol and erdosteine, and ambroxol and acetylcysteine; the synergistic combinations are used for treating sputum ropiness, difficult expectoration, stagnation of sputum in the trachea, etc. caused by diseases such as chronic bronchitis, bronchial asthma, etc. The synergistic combinations can also be used for preventing and treating the complication of difficult expectoration and pneumonitis because of operations.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and application thereof, described pharmaceutical composition contains the two officinal salt of ambroxol and erdosteine or its, described pharmaceutical composition can also contain ambroxol and acetylcysteine or the officinal salt of the two, and such drug regimen is used for preparing control respiratory tract congested and the various inflammation of infection and the application of the medicine of relevant diseases such as eliminating the phlegm, the application of the aspect of particularly eliminating the phlegm.
Background technology
Ambroxol is the active metabolite of bromhexine, and its toxicity is low, determined curative effect, and phlegm-dispelling functions is stronger than bromhexine, and this medicine is used for clinical the form with hydrochlorate in 1984.Ambroxol hydrochloride is widely used in the treatment respiratory system disease in states such as many countries such as the U.S., Britain, German Japan, and clinical effectiveness is good, almost non-toxic side effect.Ambroxol hydrochloride is widely used in acute, the chronic respiratory tract disease with sputum diacrisis and expectoration dysfunction clinically, the for example prophylactic treatment and the auxiliary treatment of acute/chronic bronchitis, asthmatic bronchitis, bronchiectasis and san bronchial asthma, pulmonary surgery patient's postoperative lung symphony complication, the thick sputum that lung structure etc. cause, the treatment of dys-expectoration and premature infant and new-born baby respiratory distress syndrome (IRDS).
Ambroxol hydrochloride oral absorbs rapidly, eliminates half-life 2～3hr, and its dosage form mainly contains tablet, sustained-release micro-pill capsules, solution, syrup, aqueous injection and other compound preparation, but, make its preparation application and clinical practice all be subjected to certain limitation because the water solublity of ambroxol hydrochloride is not ideal.
Erdosteine is a kind of prodrug, the sulfydryl that has non-free sealing in its structure, to local mucin inactive, oral after metabolism produces three and contains the metabolite of free sulfhydryl groups and bring into play pharmacological action, thereby the no obvious gastrointestinal side effect in oral back.Experimental results show that; the erdosteine cylinder metabolism-ure can make mucinous disulfide bonds in the bronchial secretion; and change secretions is formed and rheological property; reduce expectorant viscosity; improve downtrod respiratory function; this product can be removed free radical, effectively protects the anti-Trypsin undergraduate course of α 1-to avoid the oxidation deactivation that cigarette, dirt bring out, and prevents the damage to elastance of lung albumen and neutrophilic granulocyte.This product can also obviously increase IgA/ albumin, lactoferrin/albuminous ratio, weakens local inflammation, increases and improve the osmosis of antibiotic to bronchial mucosa, helps the treatment of the various inflammation of respiratory tract.
The phlegm dissolving expectorant that acetylcysteine is the most frequently used, the clinical suction in order to spraying is main.
We find pleasantly surprisedly, and ambroxol and erdosteine or ambroxol and acetylcysteine compound recipe are united use, and drug effect strengthens, and toxicity reduces.
Summary of the invention
There is wonderful discovery in the present application people, ambroxol and erdosteine, and the drug regimen of ambroxol and acetylcysteine can provide useful especially phlegm-dispelling functions, and does not observe side effect.And this class drug regimen is particularly suitable for treating, and the congested and various inflammation that infect of respiratory tract such as expectorant such as chronic bronchitis, asthma are sticking is difficult for the expectoration patient.
An object of the present invention is to provide two kinds and be used for controlling in advance the new drug regimen of expectorant, described drug regimen comprises that order gives or give simultaneously the ambroxol and the erdosteine of pharmaceutically acceptable amount, the two medicine of ambroxol and acetylcysteine or its can be accepted form, wherein, consumption every day of ambroxol is 1-2000mg, consumption every day of erdosteine is 1-2000mg, and consumption every day of acetylcysteine is 1-2000mg.
Administration simultaneously comprises and gives ambroxol and erdosteine or ambroxol and acetylcysteine, perhaps with the independent preparation administration simultaneously basically of every kind of activating agent.
Should be appreciated that ambroxol and erdosteine, ambroxol and acetylcysteine be respectively with its pharmaceutically acceptable form as the pharmaceutically active agents administration, its pharmaceutically acceptable form comprises pharmaceutically acceptable salt, ester and solvate.
" pharmaceutically acceptable " of the present invention comprises people and veterinary purpose.
For fear of query, the scalar of the ambroxol of the pharmaceutically acceptable form that the present invention provides or erdosteine or acetylcysteine, when comprising the mg amount, this scalar provides about chemical compound itself: for example the ambroxol of 50mg hydrochloride form is meant the amount of the hydrochlorate that contains the 50mg ambroxol; For example the erdosteine of 200mg hydrochloride form is meant the amount of the hydrochlorate of the erdosteine that contains 200mg.
A particular aspects, this drug regimen comprises the ambroxol that gives 1-2000mg every day.Particularly, this drug regimen comprises the ambroxol that gives 1-500mg, 500-1000mg or 1000-2000mg every day.Preferably, this drug regimen comprises the ambroxol that gives 100-1000mg every day.
A particular aspects, this drug regimen comprises the erdosteine that gives 1-2000mg every day.Particularly, this drug regimen comprises the erdosteine that gives 1-500mg, 500-1000mg or 1000-2000mg every day.Preferably, this drug regimen comprises the erdosteine that gives 1-1000mg every day.
A particular aspects, this drug regimen comprises the acetylcysteine that gives 1-2000mg every day.Particularly, this drug regimen comprises the acetylcysteine that gives 1-500mg, 500-1000mg or 1000-2000mg every day.Preferably, this drug regimen comprises the acetylcysteine that gives 1-1000mg every day.
The present invention proves by experiment, ambroxol and erdosteine, available useful especially control respiratory tract hyperemia of the drug regimen of ambroxol and acetylcysteine and inflammation such as the dys-expectoration effects of infecting such as chronic bronchitis, asthma, and show with respect to the synergism that contrasts, described contrast is contemplated to the effect summation of independent active agents.
Phlegm-dispelling functions can utilize conventional method to describe its feature, for example by measuring the increase of expectoration amount.
One preferred aspect, the dosage level of two kinds of activating agents of drug regimen of the present invention will less than reach add merely and the needed dosage of phlegm-dispelling functions.
In the present invention, active medicine is preferably with the form administration of pharmaceutical composition, and is as implied above, and two kinds of compositionss can comprise multiple medicine or only a kind of medicine.Therefore, another object of the present invention provides a kind of pharmaceutical composition, said composition contains the erdosteine of the ambroxol of 1-2000mg and 1-2000mg or contains the ambroxol of 1-2000mg and acetylcysteine or its two pharmaceutically acceptable salt of 1-2000mg, and pharmaceutically acceptable carrier.
In other words, the present invention relates to a kind of various inflammation that respiratory tract is congested and infect that are used to prevent and treat, be used for the expectorant pharmaceutical composition, described pharmaceutical composition comprises that order gives or give simultaneously ambroxol and the erdosteine or the acetylcysteine of pharmaceutically acceptable form, wherein, the content of ambroxol is 1-2000mg, and the content of erdosteine is 1-2000mg, and the content of acetylcysteine is 1-2000mg.
Described ambroxol is alkali or its officinal salt.The dosage form of pharmaceutical composition of the present invention is injection, injectable powder, spray, tablet, slow releasing agent, drop pill, granule, capsule, solution or slow-release micro-pill.
This shows that the present invention also provides the application of a kind of pharmaceutical composition of the present invention in preparation expectorant medicine.
The present composition can by with 1-2000mg ambroxol and 1-2000mg erdosteine or contain the ambroxol of 1-2000mg and the acetylcysteine of 1-2000mg or its two pharmaceutically acceptable salt with after pharmaceutically acceptable carrier mixes, prepared according to the preparation method of routine.
Usually this based composition is suitable for oral administration and drug administration by injection, also is fit to other medication, for example percutaneous dosing.
Said composition can be tablet, capsule, powder, spray, granule, lozenge, suppository, or oral administration solution or liquid preparation forms such as aseptic parenteral solution or suspension.
Said composition can be big or dosage forms such as small-volume injection, freeze-dried powder, aseptic powder packing.
In order to reach the concordance of administration, the present composition is preferably single agent form.
The single agent representation that is used for oral administration can be tablet and capsule, and can contain conventional excipients such as binding agent, for example syrup, arabic gum, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Filler, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Tabletting lubricant, for example magnesium stearate; Disintegrating agent, for example starch, polyvinylpyrrolidone, Explotab or microcrystalline Cellulose; Or pharmaceutically acceptable wetting agent, such as sodium lauryl sulphate.
These compositionss are preferably to make unit dose with the amount that relevant daily dose suits.The unit dose of suitable ambroxol comprises the various dosage of 1-2000mg.Can the administration every day 1-6 time, but most preferably administration every day 1 time (drug administration by injection) or 3 times (oral administration).
The suitable dose of erdosteine comprises the various dosage that give 1-2000mg every day, but most preferably administration every day 1 time (drug administration by injection) or 3 times (oral administration).
The suitable dose of acetylcysteine comprises the various dosage that give 1-2000mg every day, but most preferably administration every day 1 time (drug administration by injection) or 3 times (oral administration).
Solid oral composition can prepare with conventional mixing, filling or pressed disc method.Repeating married operation can be used for activating agent fully is distributed to the compositions of using a large amount of filling doses.Conventional in such operation yes this area.Tablet can make coated tablet or plain sheet according to conventional preparation method.
Oral liquid can be the form of example emulsion, syrup or elixir, perhaps can be used as dry products and exists, and water or other suitable carriers reconstitute again before the use.This liquid preparation can contain conventional additives, such as suspending agent, and for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent, for example lecithin, anhydro sorbitol-oleate or arabic gum; Anhydrous carrier (can comprise edible oil), for example almond oil, heating up in a steamer Oleum Cocois or oily ester, described oily ester comprises glyceride, propylene glycol or ethanol; Antiseptic, for example methyl parahydroxybenzoate or propyl ester or sorbic acid; If desired, also can add conventional flavoring agent or coloring agent.
For parenteral, particularly injection can utilize two kinds of active components to prepare the unit liquid dosage form with sterile carrier respectively, and according to used concentration with its suspension or be dissolved in the carrier.When preparation solution, active component can be dissolved in water for injection and filtration sterilization, be filled in bottle or the ampoule afterwards and sealing.Advantageously, adjuvant such as local anesthetic, antiseptic and buffer agent can be dissolved in this carrier.For enhanced stability, recharge in the bottle after can be with said composition freezing, and under vacuum, remove moisture.The parenteral suspension is to prepare and get with identical in fact mode, and just active component is not to be dissolved in the carrier, but is suspended in the carrier, and sterilizes and be not accomplished by filtration.This active component can be by with after oxirane contacts, and resuspending is in sterile carrier and sterilize.Advantageously, in said composition, comprise surfactant or wetting agent to promote this chemical compound uniform distribution.
In addition, also can single active ingredient or pharmaceutical composition in the drug regimen be made sustained-release preparation, as slow-release micro-pill or controlled release micro pill according to conventional method.
According to different medications, compositions can contain 0.1%-99% weight, the active substance of preferred 1-60% weight.
Therefore, the invention still further relates to ambroxol and erdosteine, ambroxol and acetylcysteine add and or cooperative compositions, these cooperative compositions are used for thick sputum, the difficulty of coughing up phlegm and the stagnation of phlegm trachea etc. that diseases such as chronic bronchitis, bronchial asthma cause, also can be used for cough up phlegm after control is performed the operation difficulty and pneumonia complication.
The present invention can also relate to a kind of medicine box, it is characterized in that it contains ambroxol, erdosteine, acetylcysteine, or their pharmaceutically acceptable salt, wherein, the content of ambroxol is 1-2000mg, the content of erdosteine is 1-2000mg, and the content of acetylcysteine is 1-2000mg.The patient uses the interior described medicine of medicine box to reach the purpose of using the present composition in order and/or simultaneously.
Following examples are in order to further elaboration the present invention, and do not play any restriction.
Description of drawings
Fig. 1 is the influence of compound recipe erdosteine ambroxol (etc. quality) to the phenol red secretion test in mouse breathing road.
The specific embodiment
The phenol red excretory influence in 1 pair of mouse breathing road of experimental example
1), test method
With 360 healthy male mices, be divided into 12 groups at random, be respectively negative control group, erdosteine group, compound recipe erdosteine ambroxol (etc. quality) 6 dosage groups, the basic, normal, high dosage group of ambroxol hydrochloride and potassium iodide groups.Every day, the oral test sample was 1 time, and continuous oral 3 days, administration volume are 0.4ml/20g, and negative control group is oral with the volume normal saline.Last administration fasting in preceding 1 day, 0.5 hour lumbar injection 2.5% phenol red solution 500mg/kg after the last administration, 0.4ml/20g.Give excessive anesthetics again after 0.5 hour and put to death animal, separate trachea, insert entry needle, use the 2ml normal saline flushing, flushing liquor adds 1M NaOH 0.1ml colour developing, in 546nm wavelength colorimetric, calculates phenol red content with 722 type spectrophotometers.
2), statistical analysis
(x ± s) expression, check with t by the statistical analysis of data with mean ± standard deviation for all data
3), result of the test
Result of the test sees the following form
Result of the test shows, compares with negative control group, and compound recipe erdosteine ambroxol (etc. quality) be though 2mg/kg dosage group oral administration can increase the phenol red secretory volume in mouse breathing road in 3 days, no difference of science of statistics (P＞0.05); 4mg/kg dosage group and normal saline group P value=0.058 relatively, further each group of increase dosage is compared with the feminine gender group and all can be increased the phenol red secretory volume in mouse breathing road (P＜0.01) very significantly, and compound recipe erdosteine ambroxol (etc. quality) 16mg/kg increases excretory effect with the ambroxol hydrochloride of dosage group and strengthens (P＜0.01) significantly, the action intensity of dosage 16 and 32mg/kg is close, when dosage increases to 64mg/kg secretion increase effect is shown downward trend (seeing figure).It is the strongest that the KI group increases the phenol red secretory volume effect in mouse breathing road, it increases each dosage group of effect and ambroxol hydrochloride of the phenol red secretory volume in mouse breathing road and compound recipe erdosteine ambroxol (etc. quality) 2mg/kg, 4mg/kg organizes and compares that all there were significant differences (P＜0.05), but with compound recipe erdosteine ambroxol (etc. quality) 8mg/kg, 16mg/kg, the 32mg/kg difference (P＞0.05) of comparing with 64mg/kg dosage group that there are no significant.
Test specimen is to the phenol red excretory influence in mouse breathing road (x ± s)
| Sample | Number of animals n | Dosage mg/kg | Phenol red amount (μ g/ml) | Increase percentage rate |
| (±SD) | ％ | |||
| Physiological saline KI Erdosteine compound Erdosteine ambroxol (etc. quality) | 30 30 30 30 30 30 30 30 30 30 30 30 | 20ml/kg 5000 40 2 4 8 16 32 64 16 32 64 | 0.72±0.17 1.10±0.25 ** 1.00±0.24 ** 0.80±0.20 0.84±0.21 a 1.00±0.25 ** 1.04±0.24 ##** 1.05±0.20 ** 0.99±0.21 ** 0.89±0.19 ** 0.93±0.27 ** 0.96±0.29 ** | - 52.8 38.5 10.5 14.7 38.6 44.8 45.6 37.6 22.9 29.2 32.5 |
*P＜0.05,
*Compare with the normal saline group P＜0.01;
#P＜0.05,
##The ambroxol hydrochloride group of P＜0.01 and Isodose relatively;
4), conclusion
Referring to Fig. 1, result of the test shows, each administration group all can increase the phenol red secretory volume in mouse breathing road, compare with the feminine gender group, KI, erdosteine, compound recipe erdosteine ambroxol (etc. quality) 8mg/kg, 16mg/kg, 32mg/kg, each dosage group oral administration of 64mg/kg dosage group and ambroxol hydrochloride all can increase the phenol red secretory volume in mouse breathing road by highly significant in 3 days, erdosteine wherein, compound recipe erdosteine ambroxol (etc. quality) 8mg/kg, 16mg/kg, 32mg/kg, the increase secretory action of 64mg/kg dosage group is compared with positive group KI, do not have significant difference statistically, and compound recipe erdosteine ambroxol (etc. quality) to increase excretory effect strong than the ambroxol hydrochloride of Isodose.
2 pairs of excretory influences of rabbit sputum of experimental example
1), experimental technique
With 80 of rabbit, be divided into 8 groups at random, be respectively compound recipe erdosteine ambroxol (mass ratio 2: 1) 1,2,4 and four dosage groups of 8mg/kg and ambroxol hydrochloride 2,4 and three dosage groups of 8mg/kg and negative control group and erdosteine 4mg/kg group.Animal is used the urethane intraperitoneal anesthesia, plugs endotracheal tube, constantly provides preheating (37 ℃) to be connected with the device of constant humidity (80%) breathe air with one.Lower end in the cross tracheal intubation connects a graduated cylinder that fixes, and is used to collect secretions.For preventing to produce condensed water, adopt a device that separates with Cotton Gossypii, all animals all freely breathe and guarantee the breathe air amount that it is required.Through 2 hours stable observation, will test medicine and deliver to stomach through esophagus.Collect 3 hours secretions after the administration immediately continuously, measure secretory volume.Calculate the excretory rate of change of sputum.
2), statistical analysis
(x ± s) expression, check with t by the statistical analysis of data with mean ± standard deviation for all data.
3), result of the test
Result of the test sees the following form
Result of the test shows, compare with negative control group, compound recipe erdosteine ambroxol (mass ratio 2: 1) 1,2,4 and four dosage groups of 8mg/kg and erdosteine 4mg/kg oral administration all can obviously increase rabbit respiratory tract sputum secretory volume, compound recipe erdosteine ambroxol (mass ratio 2: 1) 1mg/kg compares P＜0.05 with the feminine gender group, other each dosage group is compared the P value all＜0.01 with the feminine gender group, and the short sputum secretory action and the dosage of compound recipe erdosteine ambroxol (mass ratio 2: 1) are tangible positive correlation.Ambroxol hydrochloride also can obviously promote the secretion of rabbit respiratory tract sputum in dose dependent ground, but a little less than the compound recipe erdosteine ambroxol (mass ratio 2: 1) of effect than Isodose.
4), conclusion
Result of the test shows, compare with negative control group, the equal obviously dose dependent ground of compound recipe erdosteine ambroxol (mass ratio 2: 1) and ambroxol hydrochloride oral administration increases the secretion of rabbit respiratory tract sputum, and the secretory action of compound recipe erdosteine ambroxol (mass ratio 2: 1) increase sputum is strong than the ambroxol hydrochloride of Isodose.Erdosteine 4mg/kg oral administration also can obviously increase the secretion of rabbit respiratory tract sputum.
Test specimen is to the influence of rabbit expectorant sputum secretory volume (x ± s)
| Group | Dosage (mg/kg) | Secretory volume (g) | Rate of change (%) |
| Negative control compound Erdosteine ambroxol (mass ratio 2: 1) ambroxol hydrochloride Erdosteine | NS 1ml/kg 1 2 4 8 2 4 8 4 | 0.0452±0.0118 0.0608±0.0139 *0.0889±0.0276 ** 0.0941±0.0285 **0.1013±0.0218 **0.0624±0.0176 *0.0688±0.0135 **0.0844±0.0245 **0.0736±0.0216 ** | 34.5 96.6 108.1 124.0 38.0 52.0 86.5 62.8 |
3 pairs of Canis familiaris L. isolated tracheals of experimental example effect on ciliary movement
1), test method
About grass Canis familiaris L. 10kg, the male and female dual-purpose, the anesthesia back is separated trachea rapidly, puts logical O
2Tyrode's solution in, preserve standby.During experiment, clip trachea 0.5～1cm is long.The center is cut off, and vertically is divided into two, gets monolithic and tiltedly is put on the moistening Cotton Gossypii of 37 ℃ of tyrode's solutions (the larynx end up).(0.2mm) places the trachea lower end with hair, observe with low power microscope, and the record hair operation required time of 2mm, to observe 3 times, every observation 1 time is put into 37 ℃ of tyrode's solution rinsings with the trachea sheet.Put into the nutritional solution 5min that contains medicinal liquid then, observe 3 times with method.Calculate the administration front and back hair difference of running time, and compare with the feminine gender group.
2), statistical procedures
All data represent that with x ± S the statistical analysis of data is checked with t
3), result of the test
Following table result shows, compare with negative control group, compound recipe erdosteine ambroxol (etc. quality) is 0.5-1mg/ml and ambroxol hydrochloride in concentration in concentration is that 0.125-1mg/ml can shorten hair and moves the required time of 2mm, but because of individual variation is big, the compound recipe erdosteine ambroxol when only high concentration (1mg/ml) ambroxol hydrochloride is with 0.5mg/ml, concentration (etc. quality) is compared with matched group has significant difference (P＜0.05) statistically; 1.0mg/ml comparing with matched group, the compound recipe erdosteine ambroxol during concentration (etc. quality) has significant differences statistically (P＜0.01).
4), conclusion
Result of the test shows compound recipe erdosteine ambroxol (etc. quality) 0.5mg/ml and the ambroxol hydrochloride 1.0mg/ml Canis familiaris L. tracheal cilia motion of all obviously accelerating to exsomatize, the Canis familiaris L. tracheal cilia motion of very obviously accelerating to exsomatize during compound recipe erdosteine ambroxol (etc. quality) 1.0mg/ml concentration.And compound recipe erdosteine ambroxol (etc. quality) 0.5mg/ml and ambroxol hydrochloride 1.0mg/ml accelerate the to exsomatize effect of Canis familiaris L. tracheal cilia motion is suitable.
Compound recipe erdosteine ambroxol (etc. quality) to the Canis familiaris L. effect on ciliary movement (x ± s, n=12)
| Group | Drug level (mg/ml) | n | The administration time that moves forward and backward changes (s) |
| Matched group compound recipe erdosteine ambroxol (waiting mole) | - 0.125 0.25 0.5 1.0 0.5 | 12 12 12 12 12 12 | 3.17±5.59 -3.33±9.86 -2.08±7.03 -4.33±9.53 *-5.25±7.01 **-2.33±8.00 |
| Ambroxol hydrochloride ambroxol hydrochloride matched group relatively | 0.5 1.0 | 12 12 | -2.33±8.00 -4.50±7.83 * |
The antitussive effect of 4 pairs of ammonia inducing mouse coughs of experimental example
1), experimental technique
Given in 3 days in advance by the reagent thing.After 4 hours, each is organized medicine and irritates stomach by 0.2ml/10g volume per os in formal experiment mice fasting on the same day, the oral tragakanta 0.2ml/10g of blank group, and administration begins test after 1 hour.Experiment mice is put into inverted 500ml beaker, put into ammonia 2ml in the aerosol apparatus, nozzle stretches into 1cm in the beaker, atomisation pressure 50KPa, air mass flow 400ml/s, spraying 8s.Open greatly with the mice mouth, abdominal part acutely is punctured into cough, record spraying beginning is extremely coughed the time first as the number of times of coughing in cough latent period and the spraying back 5min, calculate the x ± s that respectively organizes incubation period and cough number of times, with the t method of inspection between group, each group mean is compared with the blank group.
2), experimental result
Experimental result sees the following form
Compound recipe erdosteine ambroxol (etc. quality) antitussive pharmacodynamic study (n=12, x ± s)
| Group | Dosage mg/kg | Cough latent period (s) | The cough number of times (inferior/5min) |
| The blank ambroxol hydrochloride | - 8 16 32 8 16 32 | 42.7±19.4 59.1±21.4 60.9±18.5 * 74.3±32.1 ** 60.8±30.4 74.3±32.4 ** 83.4±22.8 *** | 39.6±14.5 28.9±13.4 23.2±9.8 ** 20.7±8.2 ** 28.8±17.1 22.2±10.7 ** 18.7±11.5 *** |
● P＜0.05,
*P＜0.01,
* *P＜0.001 with the blank group relatively
The cough latent period that compound recipe erdosteine ambroxol (etc. quality) 8～32mg/kg can make ammonia bring out prolongs, and the cough number of times in the 5min is reduced, and all with the dosage positive correlation.Compound recipe erdosteine ambroxol (etc. quality) 16mg/kg, it is 74.3 ± 32.4s that ammonia draws the incubation period of coughing, with the blank group significant differences (P＜0.01) is arranged relatively, and the 32mg/kg group is 83.4 ± 22.8s incubation period, with the blank group significant differences (P＜0.001) is arranged relatively.Compound recipe erdosteine ambroxol (etc. quality) draws the preclinical prolongation effect coughed all greater than the ambroxol hydrochloride of Isodose to ammonia, and ambroxol hydrochloride high dose 32mg/kg is suitable to dosage 16mg/kg in the prolongation effect of cough latent period and the compound recipe erdosteine ambroxol (etc. quality).Reach identical prolongation effect compound erdosteine ambroxol (etc. quality) and only need half dosage of ambroxol hydrochloride.
The mouse cough number of times that compound recipe erdosteine ambroxol (etc. quality) 8～32mg/kg can make ammonia bring out reduces, and the degree and the dosage positive correlation that reduce.Compound recipe erdosteine ambroxol (etc. quality) 16mg/kg, the cough number of times that ammonia causes is 22.2 ± 10.7 times, with 39.6 ± 14.5 times of blank group significant differences (P＜0.01) is arranged relatively, compound recipe erdosteine ambroxol (etc. quality) 32mg/kg, the cough number of times that ammonia causes is 18.7 ± 11.5 times, with the blank group utmost point significant differences (P＜0.001) is arranged relatively.Compound recipe erdosteine ambroxol (etc. quality) 32mg/kg is better than the Isodose ambroxol hydrochloride to the minimizing effect of cough number of times.
3), conclusion
The mouse cough highly significant incubation period prolongation that compound recipe erdosteine ambroxol (etc. quality) 16～32mg/kg can make ammonia cause makes the minimizing of cough number of times highly significant.Compound recipe erdosteine ambroxol (etc. quality) draws the prolongation effect of coughing cough latent period to ammonia and is better than ambroxol hydrochloride.Compound recipe erdosteine ambroxol (etc. quality) 32mg/kg also is better than the ambroxol hydrochloride of Isodose to the minimizing effect of cough number of times.Compound recipe erdosteine ambroxol (etc. quality) has tangible antitussive effect, and antitussive effect is better than ambroxol hydrochloride.
Experimental example 5 compound recipe erdosteine ambroxol mice oral administration acute toxicity testings
1) given the test agent 1
Title: compound recipe erdosteine ambroxol
Source: Lianyun Harbour gloomy Pharmaceutical of person of outstanding talent limited company
Character: white powder crystallization
Solvent: 0.5% tragakanta
Preparation: after compound recipe erdosteine ambroxol (etc. quality) accurately taken by weighing, add the suspension that 0.5% tragakanta is diluted to 200mg/ml, and then press 1: 0.75 dilution proportion with 0.5% tragakanta
2) given the test agent 2
Title: ambroxol hydrochloride
Source: Lianyun Harbour gloomy Pharmaceutical of person of outstanding talent limited company
Character: white powder crystallization
Solvent: 0.5% tragakanta
Prepare: after ambroxol hydrochloride is accurately taken by weighing, add the suspension that 0.5% tragakanta is diluted to 200mg/ml, and then press 1: 0.75 dilution proportion with 0.5% tragakanta
3) laboratory animal and raising
Strain: Kunming mouse
Sex: male and female half and half
Body weight: 18-20g
The source: Shanghai Institute of Pharmaceutical Industry's Animal House provides
The quality certification number: SYXK (Shanghai) 2004-0015
Raise: animal feeding in positive pressure purification ventilation Animal House, 25 ± 2 ℃ of temperature, ad lib and drinking-water.
4) experimental technique
Animal is evenly divided into groups by body weight, each 10 animal of every dosage group male and female, all at 949～4000mg/kg, dosage was in ratio setting in 1: 75 through the dosage range of selected female, the male mice of prerun.Fasting is 4 hours before the zoopery.The administration group is pressed the heavy every 0.2ml/10g volume of animal body and is irritated the appetite clothes, matched group gives 0.5% tragakanta solution of Isodose, observe reaction of animals after the administration continuously, and animal dead number in record 1h, 2h, 4h, 1d, 2d, 3d to the 14d equal time, dead animal is carried out each main organs situation of anatomic observation, and surviving animals was dissected at the 7th day.Each dosage treated animal death toll is calculated other LD of male and female two individual characteies with bliss method in the Ministry of Public Health new drug statistical procedure
50(95% fiducial limit) value.
5) experimental result
Behind the mice oral administered compound erdosteine ambroxol (etc. quality), promptly occur after 5 minutes prostrate, turn round body, startle, twitch until death, individual animal also occurs spinning and the death of tetanic property, no convulsions phenomenon takes place.Except that 3000 and each 1 animal of 1688mg/kg group between 4～24 hours the death, all the other animal deads are all after administration in 1 hour.Each dosage group existence animals administer recovered normal activity after 1 day.Existence and dead animal show no obvious abnormalities through each main organs of anatomic observation.The LD that calculates with the Bliss method
50(95% fiducial limit) is female to be 2254.88 (1897.32～2725.56) mg/kg, and male is 2195.44 (1837.46～2664.75), two kinds of sex LD of male and female
50Be worth no significant difference (p＞0.05).
Behind the ambroxol hydrochloride oral, reaction symptom of animal and death condition and compound recipe erdosteine ambroxol (etc. quality) are similar, the LD that calculates with the Bliss method
50(95% fiducial limit) is female to be 1512.22 (1310.70～1738.07) mg/kg, and male is 1547.29 (1329.17～1793.42) mg/kg.Two kinds of sex LD of male and female
50Be worth no significant difference (p＞0.05)
Embodiment 1:
Ambroxol 30mg
Erdosteine 150mg
Microcrystalline Cellulose 27.5mg
Lactose fruit monohydrate is an amount of
Magnesium stearate 0.5mg
Every 208mg
After pressing above-mentioned raw materials, adjuvant mix homogeneously, according to conventional wet granulation, drying, tabletting.
Embodiment 2:
Ambroxol 30mg
Acetylcysteine 30mg
NaCl 0.9g
Water for injection is an amount of
Every 100ml
Get sodium chloride, use the water for injection stirring and dissolving, add ambroxol, acetylcysteine then respectively, continue to stir to make fully and dissolve, add water for injection, filter to clear and bright to total amount, embedding, sterilization, promptly.
Embodiment 3:
The slow-release micro-pill preparation
Slow-released part prescription (ball 1)
Ball core prescription
Ambroxol 30g
Erdosteine 150g
Microcrystalline Cellulose 15g
Hypromellose 5g
Pure water 200ml
Make 1000
The coating prescription
25% ethyl cellulose aqueous dispersions 184g
Pure water 123g
Make 1000
Respectively microcrystalline Cellulose, ambroxol, erdosteine were pulverized 100 mesh sieves in advance, took by weighing by ball 1 prescription, mix homogeneously, the hydroxypropyl methylcellulose aqueous solution is done binding agent, and the system micropill in 50～60 ℃ of dryings, selects 20～30 purpose pillers with it, and is standby.
With the micropill for preparing and choose, put in the fluid bed, adopt end spray mode, by hot-air suspension fluidisation, inlet temperature is 55 ℃, when the material bed tempertaure is controlled at 30 ℃, regulates peristaltic pump and make its speed provide coating solution, atomizing pressure 2bar by per minute 5g serosity, begin fluidizing piller is whitewashed continuously, after whitewashing finishes, reduce air quantity, make micropill for a moment dry in 40 ℃ under slight boiling condition.Taking-up was placed in 40 ℃ of baking ovens dry 24 hours, and it is about 18% to increase weight, and measures content, promptly.
The configuration of medicine box
Medicine box a kind of use clinically or that family uses, wherein dispose the tablet of two kinds or three kinds medicines, it is ambroxol, its content is 1-2000mg and erdosteine, its content is 1-2000mg, perhaps ambroxol, its content is 1-2000mg and acetylcysteine, its content is 1-2000mg.
Those skilled in the art adopt known method can finish the configuration of the present composition in conjunction with the content of above-mentioned disclosure.
Claims (7)
1. one kind is used to prevent and treat various inflammation and the expectorant pharmaceutical composition that respiratory tract is congested and infect, described pharmaceutical composition comprises the ambroxol of pharmaceutically acceptable form and is selected from the another kind of medicine of erdosteine or acetylcysteine, wherein, the content of ambroxol is 1-2000mg, the content of erdosteine is 1-2000mg, and the content of acetylcysteine is 1-2000mg.
2. pharmaceutical composition according to claim 1, described ambroxol are alkali or its officinal salt.
3. pharmaceutical composition according to claim 1, wherein ambroxol, erdosteine or acetylcysteine adopt separately independently medicine type respectively.
4. pharmaceutical composition according to claim 1 and 2, the dosage form of its pharmaceutical composition are injection, spray, tablet, slow releasing agent, drop pill, granule or capsule.
5. the application of pharmaceutical composition according to claim 1 and 2 in preparation expectorant medicine.
6. a medicine box is characterized in that containing ambroxol and erdosteine or their pharmaceutically acceptable salt, and wherein, the content of ambroxol is 1-2000mg, and the content of erdosteine is 1-2000mg.
7. a medicine box is characterized in that containing ambroxol and acetylcysteine or their pharmaceutically acceptable salt, and wherein, the content of ambroxol is 1-2000mg, and the content of acetylcysteine is 1-2000mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100775504A CN1323662C (en) | 2004-06-18 | 2005-06-17 | Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200410048798 | 2004-06-18 | ||
| CN200410048798.3 | 2004-06-18 | ||
| CNB2005100775504A CN1323662C (en) | 2004-06-18 | 2005-06-17 | Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1720911A CN1720911A (en) | 2006-01-18 |
| CN1323662C true CN1323662C (en) | 2007-07-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005100775504A Expired - Fee Related CN1323662C (en) | 2004-06-18 | 2005-06-17 | Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101214227B (en) * | 2007-12-29 | 2013-06-19 | 沈阳药科大学 | Ambroxol hydrochloride dry powder inhalant and preparation thereof |
| CN101606931B (en) * | 2009-08-06 | 2011-06-15 | 山东罗欣药业股份有限公司 | Erdosteine composition and preparation method thereof |
| CN105055348A (en) * | 2015-07-30 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal erdosteine composition tablet for treating respiratory tract inflammation and preparation method of tablet |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2083749A (en) * | 1980-09-17 | 1982-03-31 | Thomae Gmbh Dr K | Drug combination comprising ambroxol and an antibiotic for the treatment of infectious diseases of the respiratory tract |
| DE3530761A1 (en) * | 1985-08-28 | 1987-03-05 | Klinge Co Chem Pharm Fab | Pharmaceutical combination having synergistic action |
| CN1130354A (en) * | 1993-09-07 | 1996-09-04 | 普罗克特和廿保尔公司 | Compositions containing amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of decongestant an expectorant, an antihistamine and an antitussive |
| JP2002363072A (en) * | 2001-04-03 | 2002-12-18 | Taisho Pharmaceut Co Ltd | Antitussive composition |
| CN1422162A (en) * | 2000-03-30 | 2003-06-04 | 先灵公司 | Composition and method for treating allergic and inflammatory conditions with cough containing a non-sedating histamine and an expectorant |
-
2005
- 2005-06-17 CN CNB2005100775504A patent/CN1323662C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2083749A (en) * | 1980-09-17 | 1982-03-31 | Thomae Gmbh Dr K | Drug combination comprising ambroxol and an antibiotic for the treatment of infectious diseases of the respiratory tract |
| DE3530761A1 (en) * | 1985-08-28 | 1987-03-05 | Klinge Co Chem Pharm Fab | Pharmaceutical combination having synergistic action |
| CN1130354A (en) * | 1993-09-07 | 1996-09-04 | 普罗克特和廿保尔公司 | Compositions containing amino acid salt of propionic acid non-steroidal anti-inflammatory agent and at least one of decongestant an expectorant, an antihistamine and an antitussive |
| CN1422162A (en) * | 2000-03-30 | 2003-06-04 | 先灵公司 | Composition and method for treating allergic and inflammatory conditions with cough containing a non-sedating histamine and an expectorant |
| JP2002363072A (en) * | 2001-04-03 | 2002-12-18 | Taisho Pharmaceut Co Ltd | Antitussive composition |
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| Publication number | Publication date |
|---|---|
| CN1720911A (en) | 2006-01-18 |
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