CN100496464C - Folic acid freeze-dried injection and preparation thereof - Google Patents
Folic acid freeze-dried injection and preparation thereof Download PDFInfo
- Publication number
- CN100496464C CN100496464C CNB2008100011886A CN200810001188A CN100496464C CN 100496464 C CN100496464 C CN 100496464C CN B2008100011886 A CNB2008100011886 A CN B2008100011886A CN 200810001188 A CN200810001188 A CN 200810001188A CN 100496464 C CN100496464 C CN 100496464C
- Authority
- CN
- China
- Prior art keywords
- folic acid
- freeze
- mannitol
- temperature
- injectable powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention provides a folic acid lyophiled powder injection and a preparation method, comprising folic acid and mannitol. The invention is characterized in that the weight ratio of the folic acid and the mannitol is 1:2.5 to 10. The preparation method has the advantages of simple prescription, little side effect, adopting an advanced freeze drying craft, and plump appearance, good double solubility and fine quality for the prepared product.
Description
Technical field
The present invention relates to a kind of folic acid freeze-dried injection and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Folic acid is a kind of water miscible vitamin B group, stores abundant in green vegetable, fruit and animal livers.Folic acid participates in the metabolic overall process of human body, be to make the indispensable material of erythrocyte, the effect of helpful protein metabolism, folic acid also is the necessary vitamin of synthesized human important substance DNA, in the manufacturing of nucleic acid (DNA, RNA), play the part of important role, be indispensable material in the hyperplasia, can also promote galactopoiesis, prevention anemia.Its shortage also can make the abnormal rate of organs such as eye, lip, palate, gastrointestinal tract, cardiovascular, kidney, skeleton increase except can causing the fetal neural tube deformity.Point out that according to research before conceived beginning takes the folic acid of 400 μ g every day, can reduce by 70% neonate neural tube defect (NTDs) generation probability.Therefore, prepare conceived women, should before pregnancy, just begin to take every day the folic acid of 400 μ g.
Folic acid (Folic Acid for Injection, molecular formula: C
19H
19N
7O
6, molecular weight: 441.40) chemical name: N-[4-[(2-amino-4-oxo-1,4-dihydro-6-pteridine) methylamino] benzoyl]-L-glutamic acid.Its chemical structural formula is as follows:
The folic acid dosage form of prior art mainly contains two kinds, a kind of is tablet, provide a kind of folic acid enriching substance that is used to prevent neural tube defects as application number for the Chinese patent of CN97106707.4, containing small dosage of folic acid and be 0.01-0.4% is that 99.99-99.60% arbitrary proportion is formed 100% composition with containing medicinal carrier, according to conventional method with folic acid with after pharmaceutical carrier mixes, add binding agent, the system soft material, the granulation granulate, tabletting.
Another kind of dosage form is an injection, at present domestic have only Shanghai No.1 Bio-Chemical Pharmacetical Industry Co., Ltd to produce, two kinds of specifications of 1ml:15mg and 2ml:30mg are arranged, and the accurate word of traditional Chinese medicines is H31022473 and H31022474, the sterile water solution that is mixed and made into for folic acid, nicotiamide and vitamin B12.Contain folic acid (C19H19N706) and all should be 90.0%～110.0% of labelled amount with nicotiamide (C6H6N20).
The freeze-dried powder water content is low, and is stable, helps long term store, and particle matter is few, but does not find folic acid freeze-dried injection as yet at present.Tracing it to its cause, is that because its poorly water-soluble, dissolubility only be 1.6mg/L (25 ℃) because the folic acid injectable powder is made difficulty, even adding alkali impels its dissolving, poor, the shortcoming such as become turbid of solubility can appear in the prepared powder pin of lyophilizing.
In view of this, the inventor is through a large amount of experiments, selection and freeze-dry process to its adjuvant improve, finally overcome above difficulty, only add a kind of adjuvant of mannitol, not only prescription is simple, avoided adding the side effect that too much brings because of adjuvant, the patient uses safer, and improves with regard to freeze-drying time, mode etc. on traditional freeze-dry process, makes that the preparation outward appearance that is made into is full, be white loose block or powder, solubility is good, has better stability, and the while is also reduced production cost of products because of the minimizing of supplementary product consumption.
Summary of the invention
The object of the present invention is to provide a kind of folic acid freeze-dried injection.
Another object of the present invention is to provide the preparation method of above-mentioned folic acid freeze-dried injection.
A kind of folic acid freeze-dried injection provided by the invention is characterized in that, is made up of folic acid and mannitol in the described injectable powder, and the weight ratio of folic acid and mannitol is 1:2.5-10, preferred 1:3-7.
Wherein, comprise folic acid 10-40mg in every injectable powder, preferred 15mg or 30mg.
The specification of described injectable powder is 15mg:1ml or 30mg:2ml.
Comprise mannitol 100-200mg in every injectable powder, comprise mannitol 100mg in preferred every injectable powder.
The present invention also provides the preparation method of above-mentioned folic acid freeze-dried injection, comprises
With proper amount of water for injection, folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and make its pH value 6.5-8.5, stir then 20 minutes pH constant after, adding water for injection to mannitol content is 50-100mg/ml, uses the active carbon coarse filtration then, then successively through 1.0um, 0.45um, 0.22um the microporous filter membrane aseptic filtration, sterilizing room is advanced in filter, measures the pH value and the folate content of solution, after qualified, half plug is pressed in fill, puts into the freeze drying box that is cooled to-50 ℃, 35 hours tamponade outlets of frozen drying roll lid.
Wherein, described activated carbon concentration is 0.005mg/ml.
Described frozen drying process is:
(1) freezing period:
It is freezing that medicine is put into freeze drying box, and temperature is-50 ℃, and the time is 100min;
(2) the distillation phase
After medicine freezes, start the vacuum machine and be evacuated to 10Pa and permitted, close fridge, heat up to make to medicine and freeze the product temperature and rise to-20 ℃; Time is 20 hours 20min;
(3) dry period:
Medicine is warming up to 0 ℃ gradually, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h.
Preferred described freezing period,, process was about-20.5 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stopped temperature-fall period, made temperature autobalance in the medicinal liquid, eliminated the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-50 ℃, freezing 100 minutes.
The preferred described distillation phase is suitably mixed gas, and vacuum values is fluctuateed in 10-20Pa, can shorten distillation phase time 2-3h.
Below be detailed introduction of the present invention:
At first from the screening of prescription, because folic acid is almost insoluble in water, dissolubility only is 1.6mg/L (25 ℃); Saturated solution concentration also only is 1% in the boiling water; Therefore to make lyophilized injectable powder, must be dissolved in it in aqueous slkali earlier earlier; Though it is easily molten in the weak solution of sodium hydroxide or sodium carbonate to introduce folic acid in CAS, these two kinds of solution also are the pH regulator agent commonly used of injectable powder; But the inventor finds to use the prepared powder pin of these two kinds of solution very poor, the shortcoming such as become turbid of solubility can occur; And use the dissolved words of sodium bicarbonate solution, can effectively improve this situation.
Simultaneously, in the selection of adjuvant, the inventor follows and can prepare on the basis of stable and controllable for quality, the product that meets clinical needs the few more good more principle of the kind of adjuvant, consumption; This is because supplementary product kind is few more, can simplify batching step greatly when meaning production technology; The side effect that is difficult to expect that simultaneously can avoid various adjuvants to bring.Therefore, a kind of excipient is only used in final decision of the present invention; Having compared glucose, sodium chloride, dextran and mannitol respectively after the appearance as filler, find that the effect of mannitol is better, so the present invention adopts a kind of excipient of mannitol, mannitol mainly plays caffolding agent.
Because it is a kind of that used adjuvant only has, so the ratio of folic acid and mannitol has directly determined character such as the outward appearance, solubility of freeze-dried powder.Through a large amount of experiments, find that having only the weight ratio of folic acid and mannitol is at 1:2.5-10 o'clock, the outward appearance of product is loose block, under process conditions of the present invention, solubility has also reached requirement, but wherein portioned product has the phenomenon of cracking slightly (seeing) from top to bottom, but not stratified; Though quality is qualified, outward appearance is good inadequately, will influence the sale of product, and is therefore further preferred to its ratio, and when the two ratio was 1:3-7, it is optimum that the outward appearance of product, solubility, clarity reach.Little based on human body to the demand of folic acid, therefore preferably include folic acid 10-40mg in every injectable powder, preferred 15mg or 30mg; Specification commonly used is 15mg:1ml or 30mg:2ml; Wherein mannitol content must be more than 100mg in every injectable powder, otherwise product appearance atrophy will take place, subsides; Can be referring to experimental example 1; Based on cost consideration, be preferably 100-200mg, most preferably 100mg.
Because the used adjuvant of this product is simple; Must carry out all improvement from the lyophilizing of preparing burden to technology, just can produce qualified products.To this, the inventor has paid all effort, obtains following technology finally:
At first, with proper amount of water for injection, folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and adjust its pH value 6.5-8.5, this is that the related substances of final products (being impurity) content is minimum because in this pH scope, and the result can be referring to experimental example 2.
Folic acid all dissolving and transfer pH after, stir 20 minutes pH constant after; Adding water for injection to mannitol content is 50-100mg/ml, and only in this concentration range, the outward appearance of final products just is the loose block of off-white color.Use the active carbon coarse filtration then, at this, the selection of activated carbon concentration is most important, the effect of activated carbon is to adsorb pyrogen in the supplementary material, impurity etc., improve the purity and the yield rate of product, but consumption is excessive, can drug content be reduced the absorption principal agent, consumption is very few, and impurity content is too high in the final products, and the clarity of final products is defective.The screening experiment of activated carbon is seen experimental example 3, and finally selecting concentration is the activated carbon of 0.005mg/ml.
Behind the active carbon filtration, successively through 1.0um, 0.45um, the microporous filter membrane aseptic filtration of 0.22um, thoroughly to remove the pyrogen in the powder pin, sterilizing room is advanced in filter then, measures the pH value and the folate content of solution, qualified after, half plug is pressed in fill, puts into the freeze drying box that is cooled to-50 ℃, lyophilization.Lyophilization is the freeze-dried powder key of success, has directly influenced the various performances of product; The present invention has done significant improvement to Freeze Drying Technique just, just makes the so simple folic acid freeze-dried injection of adjuvant be able to success.
In brief, freezing dry process of the present invention also is divided into three processes: pre-freeze, distillation and drying are the detailed process process below:
1, pre-freeze is freezing period
It is freezing medicine to be put into the freeze drying box that is cooled to-50 ℃, and the time is 100 minutes;
The purpose of pre-freeze is for fixed product, so that distil under vacuum.If do not freeze reality, then product can emit bottle outlet external during evacuation, causes the spray bottle, does not have certain shape; If temperature is low excessively, then wasted the energy and time, in addition, the pre-freeze process has also determined the quality of the speed and the freeze-drying prods of dry run to a great extent.
Because the eutectic point of this product is-10.5 ℃, the design cryogenic temperature is-50 ℃, and why freeze drying box will be cooled in advance-50 ℃, is in order to strengthen the temperature difference of shelf in medicine and the freeze dryer.In practical operation, the medicine of bottling mainly with freeze dryer in shelf finish exchange heat.Shelf temperature is low, and the temperature difference of shelf is big in medicine and the freeze dryer, and rate of temperature fall is fast more, and the degree of supercooling of solution and degree of supersaturation are bigger, and critical crystalline granularity is then little, and nucleation rate is fast more, can form the less thin ice crystal of the more size of granule easily.After these thin ice crystal distillations, the pore-size that forms in the material is less, though dry rate afterwards is low, it is good to do the back solubility.Otherwise, not cooling in advance, rate of temperature fall is slow, forms oarse-grained ice crystal, and the aqueous vapor discharge channel size that ice crystal distillation back forms is bigger, though help improving dry rate, it is poor to do the back solubility.
In the selection of time, because the pre-freeze temperature is lower, so the pre-freeze time is shorter, is 100min, and the screening of cooling time can be referring to experimental example 4 tables 4-1.
The freeze drying box resulting product solubility of lowering the temperature in advance is good, and product appearance is also qualified substantially, but the slightly atrophy of product of minority bottle is arranged, and this is because the present invention is a freeze drying process that adopts bottle to freeze, and is heated and can not accomplishes fully evenly.In when cooling, the medicinal liquid in the bottle up and down two parts can to produce thermograde poor, in the propulsive from bottom to top process in ice interface, upwards migration of solute causes the solute of upper epidermis often more in the solution, density is higher, and bottom density is less down, short texture.Though because the design cryogenic temperature is lower, shortened crystallization time to a great extent, shortened the solute migration time equally, improved the atrophy situation that causes owing to density variation greatly, but in order to reach better effect, the present invention preferably adopts three-step approach pre-freeze, being about to medicinal liquid is cooled to eutectic point earlier from room temperature and is about-20.5 ℃, stop temperature-fall period, make temperature autobalance in the medicinal liquid, eliminate the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-50 ℃, freezing 100 minutes, can reduce like this in the bottle medicinal liquid up and down two parts can to produce thermograde poor, and it is supercool to make that easily medicinal liquid forms, when energy accumulation is enough, whole crystallizations of moment, prepared product solubility is splendid, and outward appearance is full, color even, hole densification, and is better than the outward appearance that adopts direct pre-freeze method product, clarity and stability.Can be referring to experimental example 4 tables 4-2
2, distillation
After medicine freezes, start the vacuum machine and be evacuated to 10Pa and permitted, close fridge, heat up to make to medicine and freeze the product temperature and rise to-20 ℃; Insulation then, the time is total up to 20 hours 20min.
The distillation phase can be removed the moisture about 90%.
The choice relation of sublimation temperature is to the speed of distillation, why select-20 ℃, rather than it is higher more near-18 ℃ of eutectic point,-15 ℃, be because when distillation, the upper materials drying that will take the lead in, if it is too fast that its temperature rises, might reach the temperature of caving in (or being referred to as the disintegrate temperature), porous skeleton rigidity reduces, and coming off appears in the granule in the drying layer, can seal the micro channel of drying nest, stop the carrying out of distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, influence the content of goods residual moisture, cause solubility, stability and clarity is variation simultaneously.
In addition, temperature retention time is unsuitable long, this is because the small crystals that medicinal liquid quick freezing of the present invention produces has very high surface energy, when heating recrystallize might take place; mutually combining between the little ice crystal forms big ice crystal; make its surface to volume ratio reach minimum, and big ice crystal makes the dried frozen aquatic products outward appearance bad, solubility is poor.
Therefore, excessive temperature or after distillation for a long time or insulation all has adverse effect to the present invention, through a large amount of experiment screenings, can be elevated temperature and be-20 ℃ referring to experimental example 5, and temperature retention time is 20 hours 20min.
Pressure during the distillation is 10Pa, rather than lower, though this is because the low distillation that helps ice in the product of pressure, because pressure is unfavorable to conducting heat when too low, product is difficult for the acquisition heat, and rate of sublimation reduces on the contrary.But when pressure was too high, the rate of sublimation of ice slowed down in the product, and minimizing falls in the product caloric receptivity.So the temperature of product self rises, when being higher than temperature of eutectic point, product will melt, and cause the lyophilizing failure.Therefore, pressure is set at 10Pa, not only has been beneficial to the transmission of heat but also has been beneficial to the carrying out of distillation.
In addition, can also suitably mix gas, vacuum values is fluctuateed in 10-20Pa at sublimation stage, can shorten distillation phase time 2-3h, this is because it no longer is leading by conduction of heat that this way makes thermaltransmission mode, has also strengthened the mode of thermal convection current, has accelerated the speed that moisture is resolved.
3, drying
In case the ice distillation finishes in the product, can enter drying stage.Do not freeze ice though in this stage product, do not exist, also have the moisture content about 10% in the product, reach qualified remaining water content in order to make product, must be further dry to product.
Exsiccant process is for to be warming up to 0 ℃ gradually with medicine, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h.
More than 3 the step lyophilization total times be 35h.
Folic acid powder pin of the present invention, prescription is simple, few side effects, and has taked advanced freeze drying process, and the product appearance that makes is full, and solubility is good, and is best in quality.
Description of drawings
Fig. 1: process chart of the present invention
The specific embodiment
Embodiment 1
Folic acid 15g, mannitol 100g, with proper amount of water for injection, folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and make its pH value 6.5, stir then 20 minutes pH constant after, add water for injection to 2000ml, be 0.005mg/ml active carbon coarse filtration with concentration then, then successively through 1.0um, 0.45um, the microporous filter membrane aseptic filtration of 0.22um, sterilizing room is advanced in filter, measures the pH value and the folate content of solution, qualified after, half plug is pressed in fill, puts into the freeze drying box that is cooled to-50 ℃, pre-freeze, the time is 100min
After medicine freezes, start the vacuum machine and be evacuated to 10Pa and permitted, close fridge, heat up to make to medicine and freeze the product temperature and rise to-25 ℃; Time is 20 hours 20min, then medicine is warming up to 0 ℃ gradually, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h, and the tamponade outlet rolls lid.
Embodiment 2
Folic acid 30g, mannitol 100g, with proper amount of water for injection, folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and make its pH value 8.5, stir then 20 minutes pH constant after, add water for injection to 2000ml, be 0.005mg/ml active carbon coarse filtration with concentration then, then successively through 1.0um, 0.45um, the microporous filter membrane aseptic filtration of 0.22um, sterilizing room is advanced in filter, measures the pH value and the folate content of solution, qualified after, half plug is pressed in fill, puts into the freeze drying box that is cooled to-50 ℃, pre-freeze, the time is 100min
After medicine freezes, start the vacuum machine and be evacuated to 10Pa and permitted, close fridge, heat up to make to medicine and freeze the product temperature and rise to-25 ℃; Time is 20 hours 20min, then medicine is warming up to 0 ℃ gradually, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h, and the tamponade outlet rolls lid.
Embodiment 3
Folic acid 40g, mannitol 200g, with proper amount of water for injection, folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and make its pH value 7.0, stir then 20 minutes pH constant after, add water for injection to 2000ml, be 0.005mg/ml active carbon coarse filtration with concentration then, then; Then successively through 1.0um, 0.45um, the microporous filter membrane aseptic filtration of 0.22um, sterilizing room is advanced in filter, measures the pH value and the folate content of solution, qualified after, half plug is pressed in fill, puts into the freeze drying box that is cooled to-50 ℃, pre-freeze, the time is 100min,
After medicine freezes, start the vacuum machine and be evacuated to 10Pa and permitted, close fridge, heat up to make to medicine and freeze the product temperature and rise to-25 ℃; Time is 20 hours 20min, then medicine is warming up to 0 ℃ gradually, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h, and the tamponade outlet rolls lid.
Embodiment 4
Folic acid 10g, mannitol 100g, with proper amount of water for injection, folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and make its pH value 75, stir then 20 minutes pH constant after, add water for injection to 2000ml, be 0.005mg/ml active carbon coarse filtration with concentration then, then; Then successively through 1.0um, 0.45um, the microporous filter membrane aseptic filtration of 0.22um, sterilizing room is advanced in filter, measures the pH value and the folate content of solution, qualified after, half plug is pressed in fill, puts into the freeze drying box that is cooled to-50 ℃, pre-freeze, the time is 100min,
After medicine freezes, start the vacuum machine and be evacuated to 10Pa and permitted, close fridge, heat up to make to medicine and freeze the product temperature and rise to-25 ℃; Time is 20 hours 20min, then medicine is warming up to 0 ℃ gradually, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h, and the tamponade outlet rolls lid.
Embodiment 5
Other process is with embodiment 1.
Freezing period,, process was about-20 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stopped temperature-fall period, made temperature autobalance in the medicinal liquid, eliminated the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-50 ℃, freezing 100 minutes.
Distillation phase process fluctuates vacuum values for suitably mixing gas in 10-20Pa, can shorten 2h drying time.
Embodiment 6
Other process is with embodiment 2.
Freezing period,, process was about-20 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stopped temperature-fall period, made temperature autobalance in the medicinal liquid, eliminated the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-50 ℃, freezing 100 minutes.
Distillation phase process fluctuates vacuum values for suitably mixing gas in 10-20Pa, can shorten 3h drying time.
Experimental example 1
Freeze-dry process such as embodiment 1, by situation after the lyophilizing as seen, when mannitol amount in the sample reaches more than the 100g, the products obtained therefrom good water solubility, appearance character is that off-white color is loose block, outward appearance is full, surfacing.Therefore consider that from convenience and the production cost produced it is optimum selection that the mannitol amount adds 100g.
Table 1-1 specification: 15mg prescription adjuvant is selected tables of data
Table 1-2 specification: 30mg prescription adjuvant is selected tables of data
Experimental example 2
This experimental example is the screening experiment example of pH in the freeze-dried powder preparation process, other component technological parameter is all with embodiment 1, in preparation process, folic acid is dissolved with an amount of 4% sodium bicarbonate solution, and regulate pH and divide and be clipped to 6.0,6.5,7,8.5,9, the assay method of pH is seen two ones of Chinese Pharmacopoeia versions in 2000.
The test of table 2 pH value scope
As seen, pH its related substances 6.5-8.5 time is minimum.
Experimental example 3
This experimental example is the screening experiment of activated carbon concentration.Other component technological parameter selects for use the injection active carbon of variable concentrations to adsorb respectively all with embodiment 2, serves as to investigate index with folate content, clarity, the consumption of screening active carbon.Two clarity inspection techniques of Chinese Pharmacopoeia version in 2000 are adopted in the inspection of clarity, the results are shown in Table 3:
Table 3 activated carbon dosage screening test
By drawing in the table, the active carbon of 0.005g/ml can make the clarity of lyophilizing liquid qualified, and is less to principal agent absorption, and pollutes minimumly, is that the active carbon of 0.005 (g/ml) adsorbs so select concentration for use.
Experimental example 4
This experimental example is the screening experiment of pre-freeze time and pre-freeze mode.
Other parameter is with embodiment 1
Table 4-1
Table 4-2
Experimental example 5
This experimental example is the screening experiment of sublimation temperature and time.
Other parameter is with embodiment 2
Experimental example 6:
This experimental example is the stability test of product of the present invention.
At 40 ℃ ± 2 ℃, placed 12 months by relative humidity 75% ± 5% through temperature for the folic acid freeze-dried powder of embodiment 1-6, and accelerated test shows that significant change does not all take place for its character, basicity, clarity, related substance and content; The folic acid freeze-dried powder is through 25 ℃ ± 2 ℃, and relative humidity 60% ± 10% is placed test in 18 months and investigated, and the result shows that significant change does not all take place for its character, basicity, clarity, related substance and content, and folic acid freeze-dried powder stable in properties is described.
Claims (11)
1, a kind of folic acid freeze-dried injection, it is characterized in that, form by folic acid and mannitol in the described injectable powder, the weight ratio of folic acid and mannitol is 1:2.5-10, and with proper amount of water for injection, folic acid and mannitol mixed when described folic acid injectable powder prepared, be stirred to pasty state, slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and adjust its pH 6.5～8.5.
2, folic acid freeze-dried injection according to claim 1 is characterized in that, the weight ratio of folic acid and mannitol is 1:3-7.
3, folic acid freeze-dried injection according to claim 1 is characterized in that, comprises folic acid 10-40mg in every injectable powder.
4, folic acid freeze-dried injection according to claim 3 is characterized in that, comprises folic acid 15mg or 30mg in every injectable powder.
5, folic acid freeze-dried injection according to claim 4 is characterized in that, the specification of described injectable powder is 15mg:1ml or 30mg:2ml.
6, folic acid freeze-dried injection according to claim 1 is characterized in that, comprises mannitol 100-200mg in every injectable powder.
7, folic acid freeze-dried injection according to claim 6 is characterized in that, comprises mannitol 100mg in every injectable powder.
8, the preparation method of any described folic acid freeze-dried injection of claim 1-7 is characterized in that, comprises proper amount of water for injection, and folic acid and mannitol mix, and are stirred to pasty state; Slowly add 4% sodium bicarbonate solution, make its whole dissolvings, and make its pH value 6.5-8.5, stir then 20 minutes pH constant after, adding water for injection to mannitol content is 50-100mg/ml, uses the active carbon coarse filtration then, then successively through 1.0um, 0.45um, the microporous filter membrane aseptic filtration of 0.22um, sterilizing room is advanced in filter, measure the pH value and the folate content of solution, after qualified, half plug is pressed in fill, put into the freeze drying box that is cooled to-50 ℃, 35 hours tamponade outlets of frozen drying roll lid, and described frozen drying process is:
(1) freezing period:
It is freezing that medicine is put into freeze drying box, and temperature is-50 ℃, and the time is 100min;
(2) the distillation phase
After medicine freezes, start the vacuum machine and be evacuated to 10Pa, close fridge, heat up to make to medicine and freeze the product temperature and rise to-20 ℃; Time is 20 hours 20min;
(3) dry period:
Medicine is warming up to 0 ℃ gradually, and insulation vacuum drying 10h continues to be warming up to 25 ℃ of insulation vacuum drying 3h.
9, preparation method according to claim 8 is characterized in that, described activated carbon concentration is 0.005mg/ml.
10, preparation method according to claim 8 is characterized in that, described freezing period process be about-20 ℃ for medicinal liquid is cooled to eutectic point earlier from room temperature, stop temperature-fall period, make temperature autobalance in the medicinal liquid, eliminate the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-50 ℃, freezing 100 minutes.
11, preparation method according to claim 8 is characterized in that, the described distillation phase is suitably mixed gas, and vacuum values is fluctuateed in 10-20Pa, can shorten distillation phase time 2-3h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2008100011886A CN100496464C (en) | 2007-08-14 | 2008-01-18 | Folic acid freeze-dried injection and preparation thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710016392.0 | 2007-08-14 | ||
| CN200710016392 | 2007-08-14 | ||
| CNB2008100011886A CN100496464C (en) | 2007-08-14 | 2008-01-18 | Folic acid freeze-dried injection and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101244042A CN101244042A (en) | 2008-08-20 |
| CN100496464C true CN100496464C (en) | 2009-06-10 |
Family
ID=39944866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2008100011886A Active CN100496464C (en) | 2007-08-14 | 2008-01-18 | Folic acid freeze-dried injection and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100496464C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105997902A (en) * | 2015-05-15 | 2016-10-12 | 苗怡文 | Ambroxol hydrochloride composition serving as medicine for treating respiratory system diseases |
| CN108567746B (en) * | 2018-07-20 | 2020-12-18 | 扬子江药业集团上海海尼药业有限公司 | Preparation method of bivalirudin for injection suitable for large-scale industrial production |
| CN113274361B (en) * | 2021-06-08 | 2022-05-06 | 吉林津升制药有限公司 | Nicotinamide freeze-dried powder injection and preparation method thereof |
-
2008
- 2008-01-18 CN CNB2008100011886A patent/CN100496464C/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101244042A (en) | 2008-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100484525C (en) | Pantoprazole sodium freeze-dried powder injection and preparing method thereof | |
| CN100506217C (en) | Ambroxol hydrochloride freeze-dried powder injection and preparing method thereof | |
| US5039540A (en) | Freeze dry composition and method for oral administration of drugs, biologicals, nutrients and foodstuffs | |
| CN102106833B (en) | Pemetrexed disodium freeze-dried powder injection and preparation method thereof | |
| CN100560062C (en) | A kind of clindamycin phosphate freeze-dried powder needle and preparation method thereof | |
| JP6906307B2 (en) | Chinese herbal medicine compositions, their formulations and uses | |
| CN101627996B (en) | Rabeprazole sodium composition and preparation method thereof | |
| CN102327238B (en) | Levocarnitine composition for injection and preparation method of levocarnitine composition | |
| EP0271622A1 (en) | Process for freeze drying cyclophosphamide | |
| CN103159769B (en) | Doxofylline compound and medicine composition thereof | |
| CN100563633C (en) | Hydrochloric acid diltiazem freeze-dried powder injection for injections and preparation method thereof | |
| CN100496464C (en) | Folic acid freeze-dried injection and preparation thereof | |
| JP2020526588A (en) | Injectable formulation of Prusatilla saponin B4 | |
| CN108938654A (en) | A kind of injection preparation of anemoside B4 | |
| CN108785262A (en) | A kind of preparation method of levo-carnitine for injection | |
| CN101229133A (en) | Omeprazole sodium freeze-dried powder injection and preparing method thereof | |
| CN102091046B (en) | Fludarabine phosphate freeze-dried powder injection and preparation method thereof | |
| CN101947208A (en) | Fludarabine phosphate composition for injection and preparation method thereof | |
| CN106389353A (en) | Compound ammonium glycyrrhetate S for injection, and preparation method therefor | |
| CN100528141C (en) | Freeze dried ligustrazine hydrochloride preparation for injection and its preparation process | |
| CN101647781B (en) | Preparation method of ligustrazine phosphate powder injection | |
| CN102058548B (en) | Ambroxol hydrochloride composition for injection and preparation method thereof | |
| CN100593404C (en) | Ketorolac tromethamine freezing-dried power injection and preparation method thereof | |
| CN103417474B (en) | Calcium dibutyacyladenosine cyclophosphate-containing composition for injection | |
| CN102166198A (en) | Stable naloxone hydrochloride freeze-dry preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: SHANDONG LUOXIN PHARMACY GROUP CO., LTD. Free format text: FORMER NAME: SHANDONG LUOXIN PHARMACY STOCK CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Seven of 276017 Shandong province Linyi city Luozhuang District Patentee after: Shandong Luo Xin Pharmaceutical Group Plc Address before: Seven of 276017 Shandong province Linyi city Luozhuang District Patentee before: SHANDONG LUOXIN PHARMACY STOCK Co., LTD. |