CN103284961B - Preparing method of cobamamide freeze-drying formulation for injection - Google Patents

Abstract

The invention relates to a cobamamide freeze-drying formulation for injection and a preparing method thereof. According to a specific amount, the amount ratio of adenosylcobalamin, mannitol and water for injection is 0.52 g: 25 g: 500 ml. The preparing method comprises: operating in a dark environment, weighing mannitol according to a prescribed amount, adding the water for injection in an amount of about 90%, then stirring to achieve complete dissolution, adding cobamamide, and stirring to achieve complete dissolution; adding the water for injection to the full amount, stirring evenly, adding activated carbon in a preparation amount of 0.02% (W/V), and fully stirring; performing coarsely filtered decarburization of the obtained solution, then performing refined filtration with a 0.22 [mu]m microporous filtering membrane, determining the content, and calculating a package amount; sub-packaging; and performing freeze drying to obtain the final product. The method is simple in operation, has no need of any additional stabilizers and inert gas for protection, and has high product stability.

Description

A kind of preparation method of cobamamide lyophilized preparation for injection

technical field:

The present invention relates to the preparation method of pharmaceutical preparation, specifically a kind of cobamamide lyophilized preparation for injection with and preparation method thereof.

background technology:

Cobamamide, claims again Cobamamide, and chemistry 5,6-dimethylbenzimidazole base-5-deoxyadenosine base cobalt amine by name, is one of active coenzyme form of vitamin B12.The cobamamide initial stage is mainly used in treating pernicious anemia, also share with folic acid, is used for the treatment of anemia that various megaloblastic anemias, antifolic cause etc., and it is also for nervous system disease.Its range of application is constantly expanded in recent ten years, now is also usually used in treating the diseases such as radiculitis, polyneuritis, peripheral neuritis, ophthalmoplegia.Its application in fields such as hepatopathy, cancer, chronic atrophic gastritis, reproductive system diseases has also had new progress.Cobamamide dosage form comprises cobamamide tablet and injection cobamamide lyophilized injectable powder.Due to cobamamide crude drug poor chemical stability, especially to photaesthesia, thereby, in the time of preparation injection cobamamide lyophilized injectable powder, conventionally to add the agent of the plurality of stable such as antibacterial, chelating agent, and prepare in lucifuge environment at present.But because operator can not carry out work under the environment of complete lucifuge, and the bad control of lucifuge condition, so sometimes also need to pass into inert gas shielding and add stabilizing agent.Even if but in the situation that adding stabilizing agent, the stability of product is still not ideal enough.Moreover stabilizing agent can be brought potential hazard to health.Therefore, clinical needing badly obtains one and prepares simply, containing stabilizing agent, and the more stable cobamamide lyophilized injectable powder of product quality.

summary of the invention:

Object of the present invention is exactly that a kind of new method of preparing cobamamide lyophilized preparation for injection will be provided, to for the clinical one that provides is containing stabilizing agent, and the more stable cobamamide lyophilized injectable powder of product quality.Applicant of the present invention gropes by a large amount of reagent screening and great many of experiments, has finally determined proportioning and the preparation method of the cobamamide lyophilized formulations with optimum stability.

The object of the present invention is achieved like this:

The preparation method of cobamamide lyophilized preparation for injection provided by the present invention, comprises the following steps:

1, drug component

Cobamamide, mannitol, water for injection, its amount ratio is: 0.52g:25g:500ml.By every batch of 1000 calculating, its consumption part is such as following table:

prescription composition

Specification	0.5mg	1.0mg	1.5mg
				Cobamamide *	0.52g	1.04g	1.56g
Mannitol	25g	50g	75g
				Water for injection	500ml	1000ml	1500ml
Subpackage volume	0.5ml	1.0ml	1.5ml

*: cobamamide consumption is the theoretical value of calculating by dry product, at middle conversion moisture and the content of needing that feeds intake.

2, solution preparation

Under lucifuge environment, operate, take mannitol by recipe quantity, add the water for injection of recipe quantity approximately 90%, stirring makes entirely molten, adds cobamamide, and stirring makes entirely molten; Add to the full amount of water for injection, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir.Solution, after the de-charcoal of coarse filtration, then is used 0.22um microporous filter membrane fine straining; Regulate pH value 5.5-7.0.

3, assay, pH value, visible foreign matters, calculating loading amount

4, aseptic filtration, fill

Filter and draw aseptic filtration liquid with 0.22um, after the diverter that filtrate enters filling machine through pipeline, to fill syringe needle, get medicinal liquid 20 times.By aseptic filtration liquid debugging loading amount;

Carry out subpackage according to assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg(theoretical volume should be respectively 0.5ml, 1.0ml, 1.5ml) embedding is to the brown cillin bottle of 2ml.

5, lyophilization

(1) pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to-40 DEG C of left and right, maintain 5 hours;

(2) sublimation drying: open vacuum pump, sublimation drying;

A. the first stage: it is 5 DEG C/h that flaggy heating rate is set, is warming up to-20 DEG C, maintains this temperature to solid ice and completely rises and eliminate;

B. second stage: it is 5 DEG C/h that flaggy heating rate is set, and sample temperature is risen to 25 DEG C, maintains 25 DEG C and reaches requirement to sample moisture, checks drying baker vacuum, to without obviously becoming.

6, in case, compress plug, put into pure air and make to reach normal pressure, take out product

The chemical stabilizer such as bacteriostatic agent, chelating agent, opacifier not in the inventive method, but by ratio and the rational technology controlling and process of best cobamamide and mannitol and water, the adjuvant amount that this product is used is less, and less on the impact of principal agent is that stability is better; Preparation is simultaneously simple, does not need to pass into inert gas shielding in whole process.The main component of lyophilizing liquid is that mannitol is easy to lyophilizing, when lyophilization, adopt the method for gradient sublimation drying, guarantee can distil and unlikelyly make too fast distillation and make proppant distortion, can be good at controlling the moisture in final products, has therefore further improved again the stability of product.

detailed description of the invention:

The first step: solution preparation

Take mannitol 50g by recipe quantity, add the water for injection of the about 900ml of recipe quantity, stirring makes entirely molten, adds cobamamide 1.02g, and stirring makes entirely molten; Inject water to 1000ml, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir.Solution, after the de-charcoal of coarse filtration, then is used 0.22um microporous filter membrane fine straining, regulates pH value 5.5-7.0.

Second step: assay, pH value, visible foreign matters, calculating loading amount

Lucifuge operation.Get cobamamide reference substance 25mg, accurately weighed, put in 100ml measuring bottle, be dissolved in water and be diluted to scale, precision measures 2ml, puts in 10ml measuring bottle, is diluted with water to scale, shakes up, in contrast product solution; Get 10 of this product, be dissolved in water and move in 250ml measuring bottle, water gradation washing container, washing liquid is incorporated in measuring bottle, and is diluted to scale, shakes up, as need testing solution.Get respectively the each 10 μ l of reference substance solution and need testing solution, injection liquid chromatography, records chromatogram, by external standard method with calculated by peak area content.

The 3rd step: aseptic filtration, fill

Filter and draw aseptic filtration liquid with 0.22um, after the diverter that filtrate enters filling machine through pipeline, to fill syringe needle, get medicinal liquid 20 times.By aseptic filtration liquid debugging loading amount;

Carry out subpackage according to assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg(theoretical volume should be respectively 0.5ml, 1.0ml, 1.5ml) embedding is to the brown cillin bottle of 2ml.

The 4th step: lyophilization

(1) pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to-40 DEG C of left and right, maintain 5 hours;

(2) sublimation drying: open vacuum pump, sublimation drying;

A. the first stage: it is 5 DEG C/h that flaggy heating rate is set, is warming up to-20 DEG C, maintains this temperature to solid ice and completely rises and eliminate;

B. second stage: it is 5 DEG C/h that flaggy heating rate is set, and sample temperature is risen to 25 DEG C, maintains 25 DEG C and reaches requirement to sample moisture, checks drying baker vacuum, to without significant change.

The 5th step: compress plug in case, put into pure air and make to reach normal pressure, take out product.

The 6th step: entirely examine by standard.

The 7th step: after qualified, label, mounted box, vanning, warehouse-in.

Finally it should be noted that, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement technical scheme of the present invention, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.

Claims (2)

1. a cobamamide lyophilized preparation for injection, is characterized in that: cobamamide, mannitol, water for injection, and its amount ratio is: 0.52g:25g:500ml; And adopt with the following method and prepare:

(1) solution preparation;

Under lucifuge environment, operate, take mannitol by recipe quantity, add the water for injection of recipe quantity approximately 90%, stirring makes entirely molten, adds cobamamide, and stirring makes entirely molten; Add to the full amount of water for injection, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir, solution, after the de-charcoal of coarse filtration, then is used 0.22um microporous filter membrane fine straining; Regulate pH value 5.5-7.0;

(2) assay, pH value, visible foreign matters, calculating loading amount;

(3) aseptic filtration, fill;

Filter and draw aseptic filtration liquid with 0.22um, after the diverter that filtrate enters filling machine through pipeline, to fill syringe needle, get medicinal liquid 20 times, by aseptic filtration liquid debugging loading amount;

Carry out subpackage according to assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg, embedding is to the brown cillin bottle of 2ml;

(4) lyophilization;

1. pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to-40 DEG C of left and right, maintain 5 hours;

2. sublimation drying: open vacuum pump, sublimation drying;

A. the first stage: it is 5 DEG C/h that flaggy heating rate is set, is warming up to-20 DEG C, maintains this temperature to solid ice and completely rises and eliminate;

B. second stage: it is 5 DEG C/h that flaggy heating rate is set, and sample temperature is risen to 25 DEG C, maintains 25 DEG C and reaches requirement to sample moisture, checks drying baker vacuum, to without significant change;

(5) in case, compress plug, put into pure air and make to reach normal pressure, take out product.

2. prepare a method for cobamamide lyophilized preparation for injection, its feature is as follows:

(1) drug component: cobamamide, mannitol, water for injection, its amount ratio is: 0.52g:25g:500ml;

(2) solution preparation;

Under lucifuge environment, operate, take mannitol by recipe quantity, add the water for injection of recipe quantity approximately 90%, stirring makes entirely molten, adds cobamamide, and stirring makes entirely molten; Add to the full amount of water for injection, stir, add the active carbon of amount of preparation 0.2 ‰ (W/V), fully stir, solution, after the de-charcoal of coarse filtration, then is used 0.22um microporous filter membrane fine straining; Regulate pH value 5.5-7.0;

(3) assay, pH value, visible foreign matters, calculating loading amount;

(4) aseptic filtration, fill;

Filter and draw aseptic filtration liquid with 0.22um, after the diverter that filtrate enters filling machine through pipeline, to fill syringe needle, get medicinal liquid 20 times, by aseptic filtration liquid debugging loading amount;

Carry out subpackage according to assay value, every content of dispersion is respectively: 0.5mg; 1.0mg; 1.5mg, embedding is to the brown cillin bottle of 2ml;

(5) lyophilization;

1. pre-freeze: open cryodesiccation chamber's refrigeration machine, put into sample, sample temperature is down to-40 DEG C of left and right, maintain 5 hours;

2. sublimation drying: open vacuum pump, sublimation drying;

A. the first stage: it is 5 DEG C/h that flaggy heating rate is set, is warming up to-20 DEG C, maintains this temperature to solid ice and completely rises and eliminate;

B. second stage: it is 5 DEG C/h that flaggy heating rate is set, and sample temperature is risen to 25 DEG C, maintains 25 DEG C and reaches requirement to sample moisture, checks drying baker vacuum, to without significant change;

(6) in case, compress plug, put into pure air and make to reach normal pressure, take out product.