CN106220517A - A kind of method of the ambroxol compound crystal prepared for preparing ambroxol hydrochloride composition - Google Patents

A kind of method of the ambroxol compound crystal prepared for preparing ambroxol hydrochloride composition Download PDF

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CN106220517A
CN106220517A CN201610598129.6A CN201610598129A CN106220517A CN 106220517 A CN106220517 A CN 106220517A CN 201610598129 A CN201610598129 A CN 201610598129A CN 106220517 A CN106220517 A CN 106220517A
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ambroxol
ambroxol hydrochloride
compound
freeze
crystal
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胡广花
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention discloses a kind of method preparing ambroxol compound, belong to pharmaceutical technology field.Ambroxol compound prepared by the method is crystal compound, use the X ray powder diffraction pattern that Cu K alpha ray measurement obtains as shown in Figure 1, it it is a kind of ambroxol hydrochloride being different from prior art report, find through test, the ambroxol compound of the present invention has preferable dissolubility and higher stability, facilitating the preparation of various preparation, the lyophilized injectable powder component utilizing the present invention to provide ambroxol hydrochloride crystal-form compound to make is simple, good stability.

Description

A kind of ambroxol compound prepared for preparing ambroxol hydrochloride composition is brilliant The method of body
The application is that the application for a patent for invention that applicant Miao Yiwen proposes is (invention entitled: one treats respiratory system disease Sick medicine ambroxol hydrochloride composition, Application No.: 2015102479443, filing date: on May 15th, 2015) division Application.
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of method preparing ambroxol compound crystal.
Background technology
Ambroxol hydrochloride (Ambroxol Hydrochloride) has another name called Ambroxol Hydrochloride, be a kind of respiratory tract lubrication expectorant and Mucolytic, ambroxol hydrochloride, chemical name is trans-4-[(2-amino-3,5-dibromo-benzyl) amino] Hexalin hydrochloric acid Salt, for white to slightly yellow crystalline powder；Ambroxol hydrochloride has mucus and gets rid of facilitation and dissolve the characteristic of secretions, It can promote the eliminating of thick secretions in respiratory tract and reduce the delay of mucus, thus remarkably promotes expectoration, improves and breathes shape Condition.The secretion of pulmonary surfactant, the secretion of air flue liquid and ciliary movement can be promoted.Ambroxol hydrochloride is the most extensively used The thick sputum that causes in various acute and chronic respiratory tract diseases, dys-expectoration etc..
Polymorphic currently, with respect to ambroxol hydrochloride has been disclosed for a lot of patent and document.
Patent ZL201210513123.6 discloses a kind of ambroxol hydrochloride crystal formation and the medicine prepared by this crystal formation Compositions, described ambroxol hydrochloride crystal formation in the X-ray powder diffraction pattern represented with the 2 θ ± 0.2 ° angles of diffraction at 6.9 °, 7.2 °, 12.8 °, 15.6 °, 17.5 °, 20 °, 21 °, 22 °, at 24 °, demonstrate characteristic diffraction peak.
Patent ZL201210231927.7 relates to a kind of unformed ambroxol compound and preparation method thereof, and this nothing is fixed The X-ray powder diffraction pattern of type powder is without obvious characteristic peak.
Patent application 201410071920.2 relates to a kind of ambroxol compound and oral cavity disintegration tablet.The salt of the present invention The X-ray powder diagram that acid ambroxol use Cu-K alpha ray measurement obtains is as shown in Figure 1.Orally disintegrating tablet of ambroxol hydrochloride In containing ambroxol hydrochloride 10～30 weight portion, filler 50～80 weight portion, disintegrating agent 10～15 weight portion, fluidizer 0.3 ～1.6 weight portions, lubricant 0.4～1.6 weight portion, correctives 8～16 weight portion.
Ambroxol hydrochloride is insoluble in water, and the preparation to preparation brings the biggest difficulty, and the present invention proposes a kind of new hydrochloric acid Ammonia bromine compounds, has preferable dissolubility and higher stability, facilitates the preparation of various preparation, utilize the present invention to provide The lyophilized injectable powder component that ambroxol hydrochloride crystal-form compound is made is simple, good stability.
Summary of the invention
It is an object of the invention to provide a kind of method preparing ambroxol compound crystal, salt prepared by the method Acid ambroxol compound crystal, uses the X-ray powder diagram that Cu-K alpha ray measurement obtains as shown in Figure 1.
Preparation method of the present invention comprises the following steps:
(1) ambroxol hydrochloride solid is added in the mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile, the body of mixed solvent Amassing 8 times for ambroxol hydrochloride weight, the volume ratio of methanol, 2-methyltetrahydrofuran and acetonitrile is 8:3.5:2.5；
(2) control temperature under conditions of 35-45 DEG C, the solution that step (1) obtains adds the mixed of ethanol and ethyl acetate Bonding solvent, the volume of mixed solvent is 10 times of ambroxol hydrochloride weight, and the volume ratio of ethanol and ethyl acetate is 5:1.5；
(3), after adding the mixed solvent of ethanol and ethyl acetate, it is cooled to-10 DEG C with speed for 3-4.5 DEG C/min, at-10 DEG C Stand 5-7 hour, separate out crystal, filter, filter cake washing with alcohol, after vacuum drying, obtain ambroxol compound.
This ambroxol compound forms a kind of medicine ambroxol hydrochloride group treating respiratory system disease with mannitol Compound；Ambroxol hydrochloride is 1:3.5-10 with the weight ratio of mannitol.
Preferably, above-mentioned ambroxol hydrochloride is 1:5.5-8 with the weight ratio of mannitol.
Preferably, above-mentioned ambroxol hydrochloride is 1:6 with the weight ratio of mannitol.
The preparation method of described compositions comprises the following steps:
Take above-mentioned ambroxol compound, use water for injection stirring and dissolving, add the mannitol of recipe quantity, regulate pH value, so After 20 minutes pH of rear stirring are constant, mend and inject water to 10L, then use activated carbon coarse filtration, successively through 1.0 μm, 0.45 μm, The microporous filter membrane aseptic filtration of 0.22 μm, filters into sterilizing room, measure pH and content qualified after, fill, pressure half plug, put into and lower the temperature To the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid.
Preferably, the above regulation pH is 5.5-6.5.
Preferably, the above frozen drying process is:
Pre-freeze: medicine being put into freeze drying box freezing, temperature is-50 DEG C, and the time is 100min；
Distillation: after medicine freezes, starts vacuum machine and is evacuated to 10Pa, close fridge, and heating up to medicine makes to freeze product temperature Rising to-20 DEG C, the time is 20 hours 20min；
It is dried: medicine is gradually heating to 0 DEG C, insulation vacuum drying 10h, is continuously heating to 25 DEG C of insulation vacuum drying 3h.
Below technical scheme is made further explanation:
The present invention, by the precise controlling to crystallization condition, has prepared a kind of ambroxol hydrochloride unlike the prior art the most brilliant Type, the X-ray powder diagram of this ambroxol hydrochloride crystal is unlike the prior art.Simultaneously because the ins and outs of this crystal formation, Find that through test the new hydrochloric acid ammonia bromine compounds that the present invention proposes has preferable dissolubility and higher stability, convenient The preparation of various preparations, the lyophilized injectable powder component utilizing the present invention to provide the ambroxol hydrochloride crystal-form compound to make is simple, Good stability.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction spectrum of the ambroxol hydrochloride crystal of the embodiment of the present invention 1 preparation.
Detailed description of the invention
Below by specific embodiment, the summary of the invention of the present invention is described in further detail, but the most therefore limits Determine present disclosure.
Embodiment 1: the preparation of ambroxol hydrochloride crystal
(1) ambroxol hydrochloride solid is added in the mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile, the body of mixed solvent Amassing 8 times for ambroxol hydrochloride weight, the volume ratio of methanol, 2-methyltetrahydrofuran and acetonitrile is 8:3.5:2.5；
(2) control temperature under conditions of 35-45 DEG C, the solution that step (1) obtains adds the mixed of ethanol and ethyl acetate Bonding solvent, the volume of mixed solvent is 10 times of ambroxol hydrochloride weight, and the volume ratio of ethanol and ethyl acetate is 5:1.5；
(3), after adding the mixed solvent of ethanol and ethyl acetate, it is cooled to-10 DEG C with speed for 3-4.5 DEG C/min, at-10 DEG C Stand 5-7 hour, separate out crystal, filter, filter cake washing with alcohol, after vacuum drying, obtain ambroxol compound.
The ambroxol hydrochloride crystal prepared uses X-ray powder diagram such as Fig. 1 that Cu-K alpha ray measurement obtains Shown in, its purity of high-performance liquid chromatogram determination is 99.99%.
Embodiment 2: the preparation of ambroxol hydrochloride freeze-dried powder injection agent, step is as follows:
Take the ambroxol hydrochloride crystal 30g of the embodiment of the present invention 1 preparation, use water for injection stirring and dissolving, add the manna of 105g Alcohol, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then thick with activated carbon Filter, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, Fill, pressure half plug, put into and be cooled in the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid.
Lyophilization is divided into pre-freeze, distils and be dried:
Pre-freeze: medicine being put into freeze drying box freezing, temperature is-50 DEG C, and the time is 100min;
Distillation: after medicine freezes, starts vacuum machine and is evacuated to 10Pa, close fridge, and heating up to medicine makes to freeze product temperature Rising to-20 DEG C, the time is 20 hours 20min；
It is dried: medicine is gradually heating to 0 DEG C, insulation vacuum drying 10h, is continuously heating to 25 DEG C of insulation vacuum drying 3h.
Embodiment 3: the preparation of ambroxol hydrochloride freeze-dried powder injection agent, step is as follows:
Take the ambroxol hydrochloride crystal 30g of the embodiment of the present invention 1 preparation, use water for injection stirring and dissolving, add the manna of 165g Alcohol, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then thick with activated carbon Filter, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, Fill, pressure half plug, put into and be cooled in the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid.
Lyophilization is divided into pre-freeze, distils and be dried:
Pre-freeze: medicine being put into freeze drying box freezing, temperature is-50 DEG C, and the time is 100min;
Distillation: after medicine freezes, starts vacuum machine and is evacuated to 10Pa, close fridge, and heating up to medicine makes to freeze product temperature Rising to-20 DEG C, the time is 20 hours 20min；
It is dried: medicine is gradually heating to 0 DEG C, insulation vacuum drying 10h, is continuously heating to 25 DEG C of insulation vacuum drying 3h.
Embodiment 4: the preparation of ambroxol hydrochloride freeze-dried powder injection agent, step is as follows:
Take the ambroxol hydrochloride crystal 30g of the embodiment of the present invention 1 preparation, use water for injection stirring and dissolving, add the manna of 180g Alcohol, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then thick with activated carbon Filter, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, Fill, pressure half plug, put into and be cooled in the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid.
Lyophilization is divided into pre-freeze, distils and be dried:
Pre-freeze: medicine being put into freeze drying box freezing, temperature is-50 DEG C, and the time is 100min;
Distillation: after medicine freezes, starts vacuum machine and is evacuated to 10Pa, close fridge, and heating up to medicine makes to freeze product temperature Rising to-20 DEG C, the time is 20 hours 20min；
It is dried: medicine is gradually heating to 0 DEG C, insulation vacuum drying 10h, is continuously heating to 25 DEG C of insulation vacuum drying 3h.
Embodiment 5: the preparation of ambroxol hydrochloride freeze-dried powder injection agent, step is as follows:
Take the ambroxol hydrochloride crystal 30g of the embodiment of the present invention 1 preparation, use water for injection stirring and dissolving, add the manna of 240g Alcohol, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then thick with activated carbon Filter, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, Fill, pressure half plug, put into and be cooled in the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid.
Lyophilization is divided into pre-freeze, distils and be dried:
Pre-freeze: medicine being put into freeze drying box freezing, temperature is-50 DEG C, and the time is 100min;
Distillation: after medicine freezes, starts vacuum machine and is evacuated to 10Pa, close fridge, and heating up to medicine makes to freeze product temperature Rising to-20 DEG C, the time is 20 hours 20min；
It is dried: medicine is gradually heating to 0 DEG C, insulation vacuum drying 10h, is continuously heating to 25 DEG C of insulation vacuum drying 3h.
Embodiment 6: the preparation of ambroxol hydrochloride freeze-dried powder injection agent, step is as follows:
Take the ambroxol hydrochloride crystal 30g of the embodiment of the present invention 1 preparation, use water for injection stirring and dissolving, add the manna of 300g Alcohol, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then thick with activated carbon Filter, successively through 1.0 μm, 0.45 μm, the microporous filter membrane aseptic filtration of 0.22 μm, filter into sterilizing room, measure pH and content qualified after, Fill, pressure half plug, put into and be cooled in the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid.
Lyophilization is divided into pre-freeze, distils and be dried:
Pre-freeze: medicine being put into freeze drying box freezing, temperature is-50 DEG C, and the time is 100min;
Distillation: after medicine freezes, starts vacuum machine and is evacuated to 10Pa, close fridge, and heating up to medicine makes to freeze product temperature Rising to-20 DEG C, the time is 20 hours 20min；
It is dried: medicine is gradually heating to 0 DEG C, insulation vacuum drying 10h, is continuously heating to 25 DEG C of insulation vacuum drying 3h.
Experimental example 1: mobility is tested
The mobility of the ambroxol compound of the embodiment of the present invention 1 is detected by this experimental example, uses fixed funnel method, The suitable height being placed on graph paper by funnel, makes ambroxol compound freely flow down from bell mouth, until the circle formed Cone top contacts with bell mouth, measures hypotenuse and the horizontal angle (θ angle of repose) of ambroxol compound accumulation horizon. Experimental result is as shown in table 1.
Table 1: mobility experimental result
From the interpretation of table 1, the mobility of the ambroxol compound that the embodiment of the present invention 1 prepares is fine.
Experimental example 2: dissolubility contrast test
The dissolubility of following ambroxol hydrochloride is detected,
Comparative example 1: commercially available ambroxol hydrochloride (Wuhan English and pharmaceutical Co. Ltd)；
Comparative example 2: prepare according to the embodiment 1 of patent ZL201210513123.6；
Comparative example 3: prepare according to the embodiment 1 of patent ZL201210231927.7；
Comparative example 4: prepare according to the embodiment 1 of patent application 201410071920.2；
1. measure the quality of ambroxol hydrochloride in 100g water saturation solution under the conditions of 20 DEG C；Experimental result is as shown in table 2.
Table 2 dissolubility comparative test result
As can be seen from Table 2, the water solublity of ambroxol hydrochloride of the present invention is greatly improved, and brings conveniently to preparation preparation.
Experimental example 3: influence factor tests
1. hot test
The lyophilized injectable powder that Example 4 prepares, simulation listing packaging, put in sealing clean container, in 40 ± 2 DEG C of temperature Lower placement 10 days, in sampling in the 5th day and the 10th day, is detected by stability high spot reviews project, result of the test and 0 day ratio Relatively.
2. high humility test
The lyophilized injectable powder that Example 4 prepares, simulation listing packaging, put in sealing clean container, at 25 ± 2 DEG C relatively Place 10 days under conditions of humidity 90% ± 5%, in sampling in the 5th day and the 10th day, detect by stability high spot reviews project, Result of the test compared with 0 day.
3. strong illumination test
The lyophilized injectable powder that Example 4 prepares, simulation listing packaging, put in sealing clean container, being placed in illumination is Place 10 days under conditions of 4500lx, in sampling in the 5th day and the 10th day, detect by stability high spot reviews project, result Compared with 0 day.Result see table:
Table 3 influence factor's result of the test
Result shows: ambroxol hydrochloride freeze-dried powder injection agent of the present invention, and its stability is good, at high temperature, high humidity, high light conditions Under, all keep stable performance.The ambroxol hydrochloride freeze-dried powder injection agent that other embodiments of the invention are prepared carry out affecting because of Element experiment, has obtained identical experimental result.

Claims (1)

1. the method for the ambroxol compound crystal prepared for preparing ambroxol hydrochloride composition, it is characterised in that Comprise the following steps:
(1) ambroxol hydrochloride solid is added in the mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile, the body of mixed solvent Amassing 8 times for ambroxol hydrochloride weight, the volume ratio of methanol, 2-methyltetrahydrofuran and acetonitrile is 8:3.5:2.5；
(2) control temperature under conditions of 35-45 DEG C, the solution that step (1) obtains adds the mixed of ethanol and ethyl acetate Bonding solvent, the volume of mixed solvent is 10 times of ambroxol hydrochloride weight, and the volume ratio of ethanol and ethyl acetate is 5:1.5；
(3), after adding the mixed solvent of ethanol and ethyl acetate, it is cooled to-10 DEG C with speed for 3-4.5 DEG C/min, at-10 DEG C Stand 5-7 hour, separate out crystal, filter, filter cake washing with alcohol, after vacuum drying, obtain ambroxol compound crystal；
Described ambroxol hydrochloride composition is made up of ambroxol hydrochloride, mannitol；Described ambroxol compound crystal makes The X-ray powder diagram obtained with Cu-K alpha ray measurement is as shown in Figure 1.
CN201610598129.6A 2015-05-15 2015-05-15 A kind of method of the ambroxol compound crystal prepared for preparing ambroxol hydrochloride composition Withdrawn CN106220517A (en)

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CN201610599134.9A Withdrawn CN105997904A (en) 2015-05-15 2015-05-15 Method for preparing medicinal ambroxol hydrochloride composition for treating respiratory system diseases
CN201610598961.6A Withdrawn CN105997903A (en) 2015-05-15 2015-05-15 Ambroxol hydrochloride composition serving as medicine for treating respiratory system diseases
CN201610599487.9A Withdrawn CN106176629A (en) 2015-05-15 2015-05-15 A kind of method of the ambroxol hydrochloride freeze-dried powder injection agent preparing treatment respiratory system disease
CN201610598760.6A Withdrawn CN105997902A (en) 2015-05-15 2015-05-15 Ambroxol hydrochloride composition serving as medicine for treating respiratory system diseases
CN201610599302.4A Withdrawn CN105997905A (en) 2015-05-15 2015-05-15 Method for preparing ambroxol hydrochloride freeze-dried powder injection for treating respiratory system diseases
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CN104997739A (en) * 2015-08-31 2015-10-28 青岛蓝盛洋医药生物科技有限责任公司 Medicine lansoprazole composition freeze-dried powder injection for treating digestive system diseases
CN105078883A (en) * 2015-09-10 2015-11-25 青岛蓝盛洋医药生物科技有限责任公司 Ambroxol hydrochloride pharmaceutical composition aqueous injection for treating diseases of respiratory system
CN105078896A (en) * 2015-09-22 2015-11-25 青岛华之草医药科技有限公司 Ambroxol hydrochloride pharmaceutical composition dry suspension for treating cough
CN108324693A (en) * 2018-04-29 2018-07-27 广东伊茗药业有限公司 A kind of double auxiliary material Ambroxol Hydrochloride for Injection freeze drying powder injections
CN112546007A (en) * 2020-12-31 2021-03-26 浙江诺得药业有限公司 Oral solid tablet containing montelukast sodium and preparation method thereof

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