CN105997905A - Method for preparing ambroxol hydrochloride freeze-dried powder injection for treating respiratory system diseases - Google Patents
Method for preparing ambroxol hydrochloride freeze-dried powder injection for treating respiratory system diseases Download PDFInfo
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- CN105997905A CN105997905A CN201610599302.4A CN201610599302A CN105997905A CN 105997905 A CN105997905 A CN 105997905A CN 201610599302 A CN201610599302 A CN 201610599302A CN 105997905 A CN105997905 A CN 105997905A
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- 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
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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
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- 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
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- 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
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- 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
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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
- A61K9/0012—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
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- 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
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- 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 method for preparing ambroxol hydrochloride freeze-dried powder injection for treating respiratory system diseases, and belongs to the technical field of medicine. The freeze-dried powder injection prepared by the method contains simple components, and has high stability.
Description
The application is the divisional application of the application for a patent for invention (invention entitled: a kind of medicine ambroxol hydrochloride composition treating respiratory system disease, Application No.: 2015102479443, filing date: on May 15th, 2015) that applicant Miao Yiwen proposes.
Technical field
The invention belongs to pharmaceutical technology field, a kind of method relating to ambroxol hydrochloride freeze-dried powder injection agent preparing treatment respiratory system disease.
Background technology
Ambroxol hydrochloride (Ambroxol Hydrochloride) has another name called Ambroxol Hydrochloride, it is a kind of respiratory tract lubrication expectorant and mucolytic, ambroxol hydrochloride, chemical name is trans-4-[(2-amino-3,5-dibromo-benzyl) amino] cyclohexanol HCI, for white to slightly yellow crystalline powder;Ambroxol hydrochloride has mucus and gets rid of facilitation and dissolve the characteristic of secretions, and it can promote the eliminating of thick secretions in respiratory tract and reduce the delay of mucus, thus remarkably promotes expectoration, improves breath state.The secretion of pulmonary surfactant, the secretion of air flue liquid and ciliary movement can be promoted.Ambroxol hydrochloride is widely used in thick sputum, dys-expectoration that various acute and chronic respiratory tract disease causes etc. clinically.
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 pharmaceutical composition prepared by this crystal formation, 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 the X-ray powder diffraction pattern of this unformed powder is without obvious characteristic peak.
Patent application 201410071920.2 relates to a kind of ambroxol compound and oral cavity disintegration tablet.The X-ray powder diagram that the ambroxol hydrochloride use Cu-K alpha ray measurement of the present invention obtains is as shown in Figure 1.Containing ambroxol hydrochloride 10~30 weight portion, filler 50~80 weight portion, disintegrating agent 10~15 weight portion, fluidizer 0.3~1.6 weight portion, lubricant 0.4~1.6 weight portion, correctives 8~16 weight portion in Orally disintegrating tablet of ambroxol hydrochloride.
Ambroxol hydrochloride is insoluble in water, preparation to preparation brings the biggest difficulty, the present invention proposes a kind of new hydrochloric acid ammonia bromine compounds, there is 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.
Summary of the invention
A kind of method that it is an object of the invention to provide ambroxol hydrochloride freeze-dried powder injection agent preparing treatment respiratory system disease.
A kind of method preparing ambroxol compound crystal of offer, ambroxol compound crystal prepared by the method are provided, use 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) being added by ambroxol hydrochloride solid in the mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile, the volume of mixed solvent is 8 times of ambroxol hydrochloride weight, and the volume ratio of methanol, 2-methyltetrahydrofuran and acetonitrile is 8:3.5:2.5;
(2) control temperature is under conditions of 35-45 DEG C, adds ethanol and the mixed solvent of ethyl acetate in the solution that step (1) obtains, and 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, stands 5-7 hour at-10 DEG C, 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 composition treating respiratory system disease with mannitol;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, regulation pH value, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 be cooled in 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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 novel crystal forms unlike the prior art, and 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 through test, the new hydrochloric acid ammonia bromine compounds that the present invention proposes, there is 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.
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 present disclosure.
Embodiment 1 :The preparation of ambroxol hydrochloride crystal
(1) being added by ambroxol hydrochloride solid in the mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile, the volume of mixed solvent is 8 times of ambroxol hydrochloride weight, and the volume ratio of methanol, 2-methyltetrahydrofuran and acetonitrile is 8:3.5:2.5;
(2) control temperature is under conditions of 35-45 DEG C, adds ethanol and the mixed solvent of ethyl acetate in the solution that step (1) obtains, and 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, stands 5-7 hour at-10 DEG C, separate out crystal, filter, filter cake washing with alcohol, after vacuum drying, obtain ambroxol compound.
The X-ray powder diagram that the ambroxol hydrochloride crystal use Cu-K alpha ray measurement prepared obtains is as it is shown in figure 1, 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 mannitol of 105g, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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 mannitol of 165g, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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 mannitol of 180g, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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 mannitol of 240g, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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 mannitol of 300g, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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, use fixed funnel method, the suitable height that funnel is placed on graph paper, ambroxol compound is made freely to flow down from bell mouth, until the cone top formed contacts with bell mouth, measure 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, to put in sealing clean container, place 10 days at a temperature of 40 ± 2 DEG C, 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.
2. high humility test
The lyophilized injectable powder that Example 4 prepares, simulation listing packaging, put in sealing clean container, place 10 days under conditions of 25 ± 2 DEG C of relative humiditys 90% ± 5%, in sampling in the 5th day and the 10th day, detecting 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 to place 10 days under conditions of 4500lx, sampled in the 5th day and the 10th day, detects by stability high spot reviews project, and 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, under high temperature, high humidity, high light conditions, all keeps stable performance.The ambroxol hydrochloride freeze-dried powder injection agent preparing other embodiments of the invention carries out influence factor's experiment, has obtained identical experimental result.
Claims (1)
1. the method for the ambroxol hydrochloride freeze-dried powder injection agent preparing treatment respiratory system disease, it is characterised in that: described ambroxol hydrochloride freeze-dried powder injection agent is made up of ambroxol hydrochloride, mannitol;Described ambroxol hydrochloride is crystal, uses the X-ray powder diagram that Cu-K alpha ray measurement obtains as shown in Figure 1;Preparation method comprises the following steps:
(1) preparation of described ambroxol hydrochloride crystal
(1) being added by ambroxol hydrochloride solid in the mixed solvent of methanol, 2-methyltetrahydrofuran and acetonitrile, the volume of mixed solvent is 8 times of ambroxol hydrochloride weight, and the volume ratio of methanol, 2-methyltetrahydrofuran and acetonitrile is 8:3.5:2.5;
(2) control temperature is under conditions of 35-45 DEG C, adds ethanol and the mixed solvent of ethyl acetate in the solution that step (1) obtains, and 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, stands 5-7 hour at-10 DEG C, separate out crystal, filter, filter cake washing with alcohol, after vacuum drying, obtain ambroxol hydrochloride crystal;
(2) preparation of described ambroxol hydrochloride freeze-dried powder injection agent, step is as follows:
Take the ambroxol hydrochloride crystal 30g of above-mentioned preparation, use water for injection stirring and dissolving, add the mannitol of 165g, regulation pH value is 5.5-6.5, after then 20 minutes pH of stirring are constant, mend and injects water to 10L, then activated carbon coarse filtration is used, 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 be cooled in the freeze drying box of-50 DEG C, 35 hours tamponade outlets of frozen drying, roll lid, to obtain final product;
Described 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, makes to freeze product temperature to medicine intensification and rises to-20 DEG C, and 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.
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CN201510247944.3A CN104860832B (en) | 2015-05-15 | 2015-05-15 | A kind of medicine ambroxol hydrochloride composition treating respiratory system disease |
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CN201610598129.6A Withdrawn CN106220517A (en) | 2015-05-15 | 2015-05-15 | A kind of method of the ambroxol compound crystal prepared for preparing ambroxol hydrochloride composition |
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 |
CN201610598861.3A Withdrawn CN106265615A (en) | 2015-05-15 | 2015-05-15 | A kind of ambroxol compound crystal of the pharmaceutical composition for preparing treatment respiratory system disease |
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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 |
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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 |
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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 |
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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CN106176629A (en) | 2016-12-07 |
CN106265615A (en) | 2017-01-04 |
CN104860832B (en) | 2016-08-24 |
CN106220517A (en) | 2016-12-14 |
CN105997902A (en) | 2016-10-12 |
CN105997903A (en) | 2016-10-12 |
CN105997904A (en) | 2016-10-12 |
CN104860832A (en) | 2015-08-26 |
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