CN1699337A - Ambroxol cysteine analogs and their preparation process and use thereof - Google Patents
Ambroxol cysteine analogs and their preparation process and use thereof Download PDFInfo
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Abstract
The invention relates to an ambroxol cysteine analogs and their preparation , the medicinal composition containing the compound, and the use in preparing apophlegmatic medicaments. The method for preparation comprises reacting ambroxol and sulfo-aminolactic acid analogue in solvent, the crystallizing, wherein n=1, 2, A is defined in the specification.
Description
Technical field
The present invention relates to Transbroncho cysteine analogs salt and preparation method thereof, and the pharmaceutical composition that contains this compound of medicine effective dose, and the application that is used to prepare expelling phlegm drugs preparation aspect.
Background technology
Transbroncho (Ambroxol) is the active metabolite of bromhexine, chemistry is called trans-4-[(2-amino-3,5-dibromobenzene methyl) amino] hexalin, it is expelling phlegm drugs commonly used at present, its toxicity is low, determined curative effect, and phlegm-dispelling functions is stronger than bromhexine, its preparation method and pharmacological action are delivered on U.S. Pat 3536713, and this medicine is used for clinical the form with hydrochloride in 1984.Its clinical application is at Respiration 51 Suppl.1, delivers on 37 (1987).At present Ambroxol HCl is widely used in the treatment respiratory system disease in states such as many countries such as the U.S., Britain, Germany, Japan, and clinical effectiveness is good, almost non-toxic side effect.Clinical trial proves: these product can be regulated slurries and mucous secretion, promote the synthetic of lung surface active material, strengthen fibre swing (increasing the removing ability of mucociliary haulage system), and making coughs up phlegm becomes easy.These product also can increase the respiratory tract liquid measure, reduce mucus secretion, can promote the secretion and the segmental bronchus ciliary movement of pulmonary surfactant, make phlegm be easy to expectoration.Ambroxol HCl can improve the lung functions index, the prevention respiratory tract infection.Ambroxol HCl is widely used in acute, the chronic respiratory tract disease with sputum diacrisis and expectoration dysfunction clinically, the for example prophylactic treatment and the assisting therapy of acute/chronic bronchitis, asthmatic bronchitis, bronchiectasis and san bronchial asthma, pulmonary surgery patient's postoperative pulmonary complication, the thick sputum that pulmonary tuberculosis etc. cause, dys-expectoration, and the treatment of premature infant and new-born baby respiratory distress syndrome (IRDS).
Ambroxol hydrochloride oral absorbs rapidly, eliminates transformation period 2～3hr, and its dosage form mainly contains tablet, sustained-release micro-pill capsules, solution, syrup, aqueous injection and other compound preparation, but because Ambroxol HCl water-soluble not ideal are used its preparation and clinical application all is subjected to certain limitation.
The first piece of writing patent of this medicine is by the application of German Boehring Ingelhelm company, and related content is referring to United States Patent (USP) 3,536,713 (1970 years).Up to the present, other salt that yet there are no Transbroncho is used for clinical.Chinese patent CN1454888A discloses rapid-dissoved ambroxol tartrate Salt And Preparation Method, to solve the water-soluble problem of Ambroxol HCl.
The present invention is surprised to find by research, and the new compound behind Transbroncho and acetylcysteine or the Erdosteine salify has very strong phlegm-dispelling functions, and its phlegm-dispelling functions obviously is better than simplification compound phlegm-dispelling functions, has therefore constituted the present invention.The objective of the invention is to prepare the Transbroncho cysteine analogs salt of better efficacy, overcome the deficiency of existing preparation clinical efficacy and therapeutic domain.
Summary of the invention
The object of the present invention is to provide the Transbroncho cysteine analogs, have following structure:
Wherein, n=1,2, A is a cysteine analogs.Described cysteine analogs comprises N-acetyl-L-cysteine, Erdosteine.
A=acetylcysteine A=Erdosteine
N-acetyl-L-cysteine (Acetylcysteine; chemistry is called N-ethanoyl-L-halfcystine) and Erdosteine (Erdosteine; chemistry N-[2-by name (carboxymethyl is dredged base) ethanoyl] homocysteine thiolactone) be two cysteine analogs that are used to eliminate the phlegm of having gone on the market at present; its preparation method and pharmacological action are delivered on U.S. Pat 3184505 and US4411909 respectively; its clinical application is respectively at document N.Engl.J.Med.319; 1557 (1988) and Thorax 43,585 (1988) on deliver.
N-acetylcystein (NAC) is a kind of known compound for a long time, main as mucolysis and expectorant in medical treatment, this product has stronger mucolysis effect, contained sulfydryl can make the two sulphur splitting of chain in the glycoprotein polypeptide chain in the sputum in its molecule, reduce the viscosity of sticking phlegm and make it liquefaction, make phlegm be easy to expectoration.This product is rapid-action, be applicable to that clinically a large amount of sticking phlegm block expiratory dyspnea and the dys-expectoration person who causes, dys-expectoration and tracheotomy patients after for example performing the operation, thick sputum and be difficult for expectoration person, the thick sputum that acute and chronic bronchitis, bronchiectasis, pulmonary tuberculosis, pneumonia, pulmonary emphysema etc. cause and difficult expectoration person, sputum blocks the tracheae person.General apophlegmatisant nonresponder all can be effective.Usually NAC is by topical routes or with the form oral administration of particle or tablet.
Erdosteine is a kind of new bronchitis expectorant, and nineteen ninety-five in succession in the listing of European countries such as Switzerland, Italy, Britain, is used for the treatment of chronic obstructive bronchitis, comprises that the acute infection of chronic bronchitis increases the weight of later in French Initial Public Offering.This product has the activity of well going the phlegm effect and removing free radical, and is inhibited to the free radical that the smoker produces.Erdosteine has good and curative effect and tolerance to clinical studies show this product of chronic obstructive disease of lung patient.Particularly advantageous is that Erdosteine can improve microbiotic (as penbritin) the bronchitis acute infection is treated curative effect, has significantly reduced antibiotic dosage, shortened treatment time.The less generation untoward reaction of Erdosteine, because chemoprotectant sulfydryl in its molecule becomes radical behind hepatic metabolism, performance is removed phlegm and relieving cough and is removed free radical activity, has reduced gastrointestinal side effect.
New compound behind Transbroncho and acetylcysteine or the Erdosteine salify has very strong phlegm-dispelling functions, and its phlegm-dispelling functions obviously is better than simplification compound phlegm-dispelling functions; Because the low toxic side effect of above-claimed cpd, the present invention not only relates to the salt that Transbroncho alkali is become with unit molecule halfcystine acid-like substance, and comprises the salt that Transbroncho alkali is become with bimolecular halfcystine acid-like substance.Here said salt comprises the crystallization with ad hoc structure and physico-chemical property, also comprises unformed pressed powder or lyophilized powder; They can be used for the preparation of various formulations commonly used.
Another object of the present invention is to provide Transbroncho cysteine analogs salt preparation method.Salt-forming reaction takes place with Transbroncho and cysteine analogs in this preparation method in solvent, use to concentrate then, treatment processs such as mixed solvent crystallization, crystal formation conversion, filtration or lyophilize, to obtain the white crystals or the lyophilized powder of Transbroncho cysteine analogs salt.Described mixed solvent is meant water-miscible organic solvent.Water-miscible organic solvent refers to lower alcohols, acetone etc.; More preferably lower alcohols.Lower alcohols refers to methyl alcohol, ethanol, propyl alcohol or Virahol.
Above-mentioned water-soluble solvent comprises lower alcohols, acetone etc., preferred lower alcohols.Lower alcohols comprises methyl alcohol, ethanol, propyl alcohol, Virahol.Mixed solvent is meant the mixture of water-soluble solvent and water-insoluble solvent, and water-insoluble solvent comprises halohydrocarbon solvent and ether solvent, preferred chloroform, methylene dichloride, ether, isopropyl ether etc.
The present invention also provides a kind of pharmaceutical composition, contains said structure Transbroncho cysteine analogs salt and medicine auxiliarys such as pharmaceutically acceptable carrier, vehicle or thinner as the treatment effective dose of activeconstituents.
Described pharmaceutical composition be by Transbroncho cysteine analogs salt that method for preparing is obtained with after pharmaceutically acceptable medicine auxiliary mixes, according to the conventional preparation method of preparation to prepare required dosage form.Said composition can be tablet, capsule, pulvis, particle, lozenge, suppository, or the oral or parenteral administrations of liquid preparation form such as oral liquid or aseptic parenteral solution, its route of administration, dosage and administration number of times can suitably be adjusted according to patient age, body weight and disease.
Said composition also can be big or dosage forms such as small-volume injection, freeze-dried powder, aseptic powder packing.
The single agent representation that is used for oral administration can be tablet and capsule, and can contain conventional excipients such as tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth or polyvinylpyrrolidone; Weighting agent, for example lactose, sugar, W-Gum, calcium phosphate, sorbyl alcohol or glycine; Compressing tablet 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.
Solid oral composition can prepare with conventional mixing, filling or pressed disc method.Repeating married operation can be used for promoting agent fully is distributed to the composition that uses a large amount of filling doses.Conventional in such operation yes this area.Tablet can make coating 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 drying products and exists, and water or other suitable carriers reconstitute again before the use.This liquid preparation can contain conventional additives, such as suspension agent, and for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent, for example Yelkin TTS, anhydro sorbitol-oleic acid ester or gum arabic; Anhydrous carrier (can comprise edible oil), for example Prunus amygdalus oil, heating up in a steamer Oleum Cocois or oily ester, described oily ester comprises glyceryl ester, propylene glycol or ethanol; Sanitas, for example methyl p-hydroxybenzoate or propyl ester or Sorbic Acid; If desired, also can add conventional seasonings or tinting material.
For parenteral admin, particularly injection can be dissolved in active ingredient sterile carrier and prepare the unit liquid dosage form.When preparation solution, activeconstituents can be dissolved in water for injection and filtration sterilization, be filled in bottle or the ampoule afterwards and sealing.Advantageously, auxiliary such as local anesthetic, sanitas and buffer reagent 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.Or in said composition, comprise tensio-active agent or wetting agent, be beneficial to the uniform distribution of this compound.
In addition, also can pharmaceutical composition be made sustained-release preparation, as sustained release pellet or controlled release micro pill according to ordinary method.
Another object of the present invention is to provide Transbroncho cysteine analogs salt or the application of its composition in the medicine that preparation is eliminated the phlegm, and the application that is used for useful in preparing drug formulations.
Embodiment
Explain the present invention in more detail below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment 1: the preparation of Transbroncho N-acetylcystein salt
In the 2000ml reaction flask, drop into Transbroncho 37.8g (0.1mol), N-acetylcystein 28.2g (0.1mol) adds ethanol 200ml, stirring and dissolving, be evaporated to dried oily matter, the 1000ml that adds methylene chloride, heating in water bath dissolving, be evaporated to muddiness and separate out the oily precipitation, add ether 400ml, be stirred to precipitate and be converted into white crystals, concentrate then and steam most of solvent, drip ether 200ml again, stirred 2 hours at 40 ℃ then, room temperature was placed 2 hours, filtered, ether is washed, 50 ℃ of vacuum-dryings get white crystals 46.3g, yield 85.6%.Fusing point: 75～78 ℃.(
1HNMR(D
2O)δ：1.18(m，4H)，1.95(m，4H)，2.08(s，3H)，2.72(m，1H)，2.95(d，2H)，3.35(m，1H)，3.95(s，2H)，4.60(m，1H)，7.25(d，1H)，7.50(d，1H))
Embodiment 2: Transbroncho Erdosteine salt
In the 500ml reaction flask, with Transbroncho (37.8g, 0.1mol) and Erdosteine (24.9g, 0.1mol) be dissolved in respectively in the 150ml dehydrated alcohol, filter, the two filtrate is merged, be heated to backflow, put coldly, filter, ethanol is washed, oven dry, get white solid 58g, yield 92.5%, 170～172 ℃ of fusing points.(
1HNMR(D
2O)，1.20(m，4H)，δ：1.20(m，4H)，1.90(m，4H)，2.13(m，1H)，2.40(m，1H)，2.70(m，1H)，3.20(s，2H)，3.25(s，2H)，3.30(m，1H)，3.40(m，2H)，3.90(s，2H)，4.50(m，1H)，7.31(d，1H)，7.54(d，1H))
Embodiment 3: the preparation of the two N-acetylcystein salt lyophilized powders of Transbroncho
In the 250ml reaction flask, drop into Transbroncho 4.00g (10.6mmol), N-acetylcystein 3.454g (21.2mmol) adds deionized water 60ml, and stirring and dissolving is used filtering with microporous membrane, and lyophilize gets lyophilized powder 7.34g, yield 98.5%.
Embodiment 4: the preparation of the two Erdosteine salt lyophilized powders of Transbroncho
In the 2000ml reaction flask, drop into Transbroncho 4.00g (10.6mmol), Erdosteine 5.28g (21.2mmol) adds deionized water 1200ml, and stirring and dissolving is used filtering with microporous membrane, and lyophilize gets lyophilized powder 9.29g, yield 100.1%.
Embodiment 5: the preparation of Transbroncho acetylcysteine powder injection
Transbroncho acetylcysteine 50g
N.F,USP MANNITOL 70g
Transbroncho cysteine salt 30g adds an amount of water for injection dissolving, and N.F,USP MANNITOL 70g adds an amount of water for injection dissolving, and two solution are mixed, add injection and be diluted with water to 2000ml, with the filtering with microporous membrane of 0.22um, under the aseptic condition, be loaded in the cillin bottle respectively, sabot, send in the freeze drying box, after the lyophilize, outlet, roll lid, get final product.
Embodiment 6: the preparation of Transbroncho acetylcysteine powder injection
Transbroncho acetylcysteine 50g
Sodium-chlor 9g
Water for injection 2000ml
Take by weighing the sodium-chlor of recipe quantity, add the water for injection of cumulative volume amount about 85%, stirring and dissolving, add the Transbroncho cysteine salt, stir and make it dissolving, survey pH (regulating with hydrochloric acid soln or sodium hydroxide solution in case of necessity) 4.5～5.5, add the injection water to total amount, after stirring evenly, with 0.22 μ m filtering with microporous membrane, inflated with nitrogen, embedding, 100 ℃ of flowing steam sterilizations 30 minutes, lamp inspection, packing.
Embodiment 7: the preparation of Transbroncho Erdosteine tablet
Transbroncho Erdosteine 52.4g
Starch 50g
Microcrystalline Cellulose 30g
Secondary calcium phosphate 20g
8% polyvinylpyrrolidone is an amount of
Magnesium Stearate 0.9g
Transbroncho Erdosteine, starch, Microcrystalline Cellulose, secondary calcium phosphate are mixed, add the 8% polyvinylpyrrolidone aqueous solution and make softwood, granulate with 20 order nylon mesh, 55-60 ℃ of drying adds Magnesium Stearate, through the whole grain of 20 eye mesh screens, mixing is used the tabletting machine compressing tablet.
Embodiment 8: the preparation of Transbroncho acetylcysteine granule
Transbroncho acetylcysteine 50g
N.F,USP MANNITOL 80g
Icing Sugar 20g
Essence is an amount of
The Transbroncho cysteine salt is water-soluble, add soluble starch 80g, Icing Sugar 20g, it is an amount of to add essence again, and mixing is granulated with 30 mesh sieves, and is dry below 60 ℃, packing.
Embodiment 9: the preparation of Transbroncho Erdosteine capsule
Transbroncho Erdosteine 52.4g
Microcrystalline Cellulose 40g
Lactose 60g
Water is an amount of
Magnesium Stearate 1g
Micropowder silica gel 1g
The Transbroncho Erdosteine, Microcrystalline Cellulose, lactose sieves respectively, and mixes, and adds water and makes softwood in right amount, crosses 20 mesh sieves and granulates, and wet granular is dry under 55-60 ℃, and dried particle is crossed the whole grain of 20 mesh sieves, with Magnesium Stearate, micropowder silica gel mixing, the can capsule.
Embodiment 10: the preparation of Transbroncho acetylcysteine oral liquid
Transbroncho acetylcysteine 50g
Propylene glycol 5g
Glycerine 1g
Sodium alginate 2g
Sucrose 10g
Sodium Benzoate 0.1
Citric acid 1.5g
Essence is an amount of
Pure water 100g
Behind Transbroncho acetyl-cysteine salt and auxiliary material adding pure water, stirring and dissolving, packing, promptly.
Embodiment 11: the preparation of Transbroncho acetylcysteine sustained release pellet
Transbroncho acetylcysteine 50g
Microcrystalline Cellulose 15g
Lactose 15g
Hypromellose 5g
Ethyl cellulose aqueous dispersions 184g
Pure water 200g
Respectively Microcrystalline Cellulose, lactose, Transbroncho acetylcysteine were pulverized 80 mesh sieves in advance, and mixed, the HPMC aqueous solution is made tackiness 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 fluidized-bed, adopt the spray packet mode, by warm air suspension fluidisation, inlet temperature is 55 ℃, when the material bed tempertaure is controlled at 30 ℃, regulate the speed feed flow of peristaltic pump, atomizing pressure 2bar, begin the 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, promptly got the coated slow release piller.
Experimental example 1: the pharmacological experiments of Transbroncho acetyl-cysteine salt and Transbroncho Erdosteine salt.
1), test method
160 male mices are divided into 15 groups at random, be respectively negative control group, the basic, normal, high dosage group of Ambroxol HCl, the basic, normal, high dosage group of acetylcysteine, the basic, normal, high dosage group of Erdosteine, the basic, normal, high dosage group of Transbroncho acetyl-cysteine salt, the basic, normal, high dosage group of Transbroncho Erdosteine salt, every day, the oral test sample was 1 time, continuous oral 3 days, the administration volume is 0.4ml, and negative control group is oral with volume physiological saline.Last administration fasting in preceding 1 day, 0.5 hour abdominal injection 5% phenol red solution 500mg/kg after the last administration, 0.2ml/ are only.Give excessive narcotic again after 0.5 hour and put to death animal, separate tracheae, insert entry needle, use the 2ml normal saline flushing, washing fluid adds 1M NaOH 0.1ml colour developing, in 546nm wavelength colorimetric, calculates phenol red content with 722 type spectrophotometers.
2), test-results
Test-results sees Table 1.
| Sample | Dosage (μ mol/kg) | Phenol red amount (μ g/ml) (± SD) | Increase percentage (%) |
| Physiological saline | ??20ml/kg | ??0.70±0.25 | ??- |
| Ambroxol HCl | ??39.7 ??79.4 ??158.7 | ??0.87±0.20 ??0.91±0.26 | ??34.3 ??24.3 ??30.0 |
| ??0.94±0.34 | |||
| Acetylcysteine | ??39.7 ??79.4 ??158.7 | ??0.86±0.18 ??0.90±0.25 ??0.95±0.31 | ??22.8 ??27.1 ??35.7 |
| Erdosteine | ??39.7 ??79.4 ??158.7 | ??0.93±0.34 ??0.96±0.36 ??0.98±0.35 | ??32.9 ??37.1 ??40.0 |
| The Transbroncho acetyl-cysteine salt | ??39.7 ??79.4 ??158.7 | ??0.98±0.31 ??1.04±0.28 ??1.08±0.33 | ??40.0 ??48.6 ??54.3 |
| Transbroncho Erdosteine salt | ??39.7 ??79.4 ??158.7 | ??1.14±0.29 ??1.18±0.33 ??1.20±0.20 | ??62.8 ??68.6 ??71.4 |
Test-results shows, compare with negative control group, Ambroxol HCl, acetylcysteine and Erdosteine oral administration three days, all can increase the phenol red secretory volume in mouse breathing road, and Transbroncho acetyl-cysteine salt and Transbroncho Erdosteine salt all can increase the phenol red secretory volume in mouse breathing road very significantly, compare with single medicine to have significant difference.
Claims (10)
1. Transbroncho cysteine analogs salt is characterized in that having following structural:
Wherein, n=1,2; A is a cysteine analogs.
2. compound according to claim 1 is characterized in that A is acetylcysteine or is Erdosteine.
3. method for preparing the described compound of claim 1, the step that this method comprises is:
The salt-forming reaction in water or water-soluble solvent or mixed solvent of Transbroncho and cysteine analogs;
Use to concentrate, mixed solvent crystallization, crystal formation conversion, filtration or cryodesiccated treatment process, to obtain the white crystals of Transbroncho Gelucystine analogue.
4. method according to claim 3, wherein said mixed solvent comprises water-soluble solvent and water-insoluble, described water-soluble solvent is selected from lower alcohol, acetone or its mixture; Described water-insoluble solvent is selected from halohydrocarbon solvent or ether solvent or its mixture.
5. preparation method according to claim 4, wherein lower alcohol comprises methyl alcohol, ethanol, propyl alcohol, Virahol; Ethers refers to ether, isopropyl ether.
6. preparation method according to claim 4, wherein lower alcohol is an ethanol, ethers is an ether.
7. pharmaceutical composition that is used to eliminate the phlegm, it contains compound shown in medicine effective dose as claimed in claim 1 as activeconstituents and pharmaceutically acceptable carrier.
8. pharmaceutical composition according to claim 7, its dosage form comprise tablet, capsule, pulvis, particle, lozenge, suppository, oral liquid, big or small-volume injection, freeze-dried powder, aseptic powder packing or its sustained-release preparation.
9. pharmaceutical composition according to claim 8, described sustained-release preparation comprises controlled release micro pill or sustained release pellet.
10. as the application of each described compound of claim 1-3 in the preparation expelling phlegm drugs.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100423638A CN1303065C (en) | 2004-05-20 | 2004-05-20 | Ambroxol cysteine analogs and their preparation process and use thereof |
| PCT/CN2005/000685 WO2005113492A1 (en) | 2004-05-20 | 2005-05-18 | Cysteine analogues salts of ambroxol, preparation methods and uses thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100423638A CN1303065C (en) | 2004-05-20 | 2004-05-20 | Ambroxol cysteine analogs and their preparation process and use thereof |
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| CN1699337A true CN1699337A (en) | 2005-11-23 |
| CN1303065C CN1303065C (en) | 2007-03-07 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144956A1 (en) * | 2007-05-28 | 2008-12-04 | Tianjin Institute Of Pharmaceutical Research | New ambroxol compounds, their preparation processes and uses |
| CN101544572A (en) * | 2008-03-26 | 2009-09-30 | 连云港恒邦医药科技有限公司 | Ambroxol derivative and method for preparing same |
| CN105055321A (en) * | 2015-09-01 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal ambroxol hydrochloride composition dry suspension for treating coughs |
| CN106146456A (en) * | 2015-04-30 | 2016-11-23 | 苗怡文 | A kind of method of the erdosteine compound preparing treatment respiratory inflammation |
| CN112745251A (en) * | 2019-10-31 | 2021-05-04 | 华创合成制药股份有限公司 | Compound for eliminating phlegm and preparation method and application thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176629A (en) * | 2015-05-15 | 2016-12-07 | 苗怡文 | A kind of method of the ambroxol hydrochloride freeze-dried powder injection agent preparing treatment respiratory system disease |
| CN104788327B (en) * | 2015-05-15 | 2016-08-24 | 烟台市蓝洋之草医药生物科技有限公司 | A kind of ambroxol compound treating respiratory system disease and preparation method thereof |
| CN104922079A (en) * | 2015-05-26 | 2015-09-23 | 苗怡文 | Apophlegmatic medicinal ambroxol hydrochloride freeze-dried powder injection composition |
| CN104971057A (en) * | 2015-08-05 | 2015-10-14 | 青岛蓝盛洋医药生物科技有限责任公司 | Ambroxol hydrochloride composition capsule medicine for treating respiratory system diseases |
| CN105012245A (en) * | 2015-08-10 | 2015-11-04 | 青岛蓝盛洋医药生物科技有限责任公司 | Phlegm-dispersing drug ambroxol hydrochloride composition granules and preparing method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1216837B (en) * | 1987-01-07 | 1990-03-14 | Erregierre Ind Chim | SALTS OF N- (TRANS-P-IDROSSI-CICLOESIL) - (2 AMINO-3,5-DIBROMO) BENZYLAMINE EQUIPPED WITH MUCOLYTIC ACTIVITY. |
| ZA963590B (en) * | 1995-05-10 | 1996-11-19 | Adcock Ingram Ltd | Pharmaceutical composition |
| JPH08337532A (en) * | 1995-06-14 | 1996-12-24 | Takeda Chem Ind Ltd | Medicinal composition |
-
2004
- 2004-05-20 CN CNB2004100423638A patent/CN1303065C/en not_active Expired - Fee Related
-
2005
- 2005-05-18 WO PCT/CN2005/000685 patent/WO2005113492A1/en active Application Filing
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144956A1 (en) * | 2007-05-28 | 2008-12-04 | Tianjin Institute Of Pharmaceutical Research | New ambroxol compounds, their preparation processes and uses |
| CN101544572A (en) * | 2008-03-26 | 2009-09-30 | 连云港恒邦医药科技有限公司 | Ambroxol derivative and method for preparing same |
| CN101544572B (en) * | 2008-03-26 | 2013-03-20 | 连云港恒邦医药科技有限公司 | Ambroxol derivative and method for preparing same |
| CN106146456A (en) * | 2015-04-30 | 2016-11-23 | 苗怡文 | A kind of method of the erdosteine compound preparing treatment respiratory inflammation |
| CN106187992A (en) * | 2015-04-30 | 2016-12-07 | 苗怡文 | A kind of method of the erdosteine compound preparing treatment respiratory inflammation |
| CN106220604A (en) * | 2015-04-30 | 2016-12-14 | 苗怡文 | A kind of method of the erdosteine compound preparing treatment respiratory inflammation |
| CN106220605A (en) * | 2015-04-30 | 2016-12-14 | 苗怡文 | A kind of method of the erdosteine compound preparing treatment respiratory inflammation |
| CN105055321A (en) * | 2015-09-01 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal ambroxol hydrochloride composition dry suspension for treating coughs |
| CN112745251A (en) * | 2019-10-31 | 2021-05-04 | 华创合成制药股份有限公司 | Compound for eliminating phlegm and preparation method and application thereof |
| WO2021082501A1 (en) * | 2019-10-31 | 2021-05-06 | 华创合成制药股份有限公司 | Expectorant compound and preparation method and use thereof |
| CN112745251B (en) * | 2019-10-31 | 2023-10-27 | 华创合成制药股份有限公司 | Compound for treating phlegm and preparation method and application thereof |
| US11993561B2 (en) | 2019-10-31 | 2024-05-28 | HC Synthetic Pharmaceutical Co., Ltd. | Expectorant compound, preparation method thereof and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1303065C (en) | 2007-03-07 |
| WO2005113492A1 (en) | 2005-12-01 |
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Address after: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: 222006, building nine, block B, long river building, Cangwu Road, Lianyungang, Jiangsu, China Patentee before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |
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