CN105997897B - A kind of amikacin sulfate lyophilized formulations and preparation method thereof - Google Patents
A kind of amikacin sulfate lyophilized formulations and preparation method thereof Download PDFInfo
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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Abstract
The present invention relates to a kind of amikacin sulfate lyophilized formulations, the lyophilized formulations use the raw material for including following parts by weight to be prepared：0.1~0.2 part of amikacin sulfate, 0.1~0.2 part of natrium adetate, 10~20 parts of sodium hydrogensulfite, 200~400 parts of mannitol.Invention further provides the preparation method of the amikacin sulfate lyophilized formulations.Formula provided by the invention and preparation method can shorten freeze-drying time, the stability of amikacin sulfate is guaranteed, while reduce energy consumption, improve unit interval production production capacity, reduce production cost.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of amikacin sulfate medicament freeze-drying preparation and preparation method thereof.
Background technology
Amikacin (Kanamycin A Sulfate), chemical name are：O-3- amino -3- deoxidation-α-D- Glucopyranyl-(1 → 6) -
O- [6- amino -6- deoxidation-α-D- Glucopyranyl-(1 → 4)]-N- (4- amino -2- hydroxyl -1- oxygen-butyls) -2- deoxidations-D-
Streptamine sulfuric acid, is the sulfate of the semi-synthetic derivative of that penicillin of card a, white or off-white color crystalline powder, almost without
It is smelly, it is tasteless.This product is readily soluble in water, almost insoluble in ethanol.
Amikacin sulfate belongs to aminoglycoside antibiotics.This product to most enterobacteriaceae lactobacteriaceaes, as escherichia coli,
Klebsiella, Enterobacter, Proteus etc. have good action, to pseudomonas aeruginosa and other pseudomonads, no
Lever Pseudomonas, alcaligenes etc. also have good action；To Neisseria meningitidis, NEISSERIA GONORRHOEAE, haemophilus influenzae, Yale
Gloomy Pseudomonas, campylobacter fetus, tubercle bacillus and some non-tuberculous mycobacterias, which belong to, also has preferable antibacterial action, its antibacterial activity compared with
Gentamicin is lower slightly.The advantages of this product is most prominent is to aminoglycoside inactive enzyme caused by many enteric gram-negative bacillis
Stablize, will not for this class enzymatic inactivation and lose antibacterial activity.This product is invalid to anaerobic bacteria, and mechanism of action is to act on bacterium ribose
The 30S subunits of body, inhibit bacteria synthetic protein.Amikacin is shared and often may be used with semi-synthetic penicillins or cephalosporins
Obtain synergetic antibacterial effect.
Amikacin sulfate is suitable for pseudomonas aeruginosa and other pseudomonads of part, escherichia coli, proteus
The sensitivity gram negative bacilli such as category, Klebsiella, Enterobacter, Serratia, acinetobacter and staphylococcus (methoxy
XiLin sensitive strain) caused by severe infections, such as bacteremia or septicemia, bacterial endocarditis, lower respiratory tract infection, Bones and joints sense
Dye, infection of biliary tract, abdominal cavity infection, complexity urinary tract infections, skin soft-tissue infection etc..Since this product is to most aminoglycosides
Inactive enzyme is stablized, therefore is particularly suitable for treatment gram negative bacilli to kanamycins, gentamicin or tobramycin antibody-resistant bacterium
Caused severe infections.
Amikacin sulfate needs intramuscular injection or intravenous drip in application process.Traditional amikacin sulfate dry preparation
Formula be：Amikacin sulfate 0.2g, sodium hydrogensulfite 20.0g, 2M sulfuric acid 1000.0mL, adds water for injection 10000mL.
The production procedure of traditional amikacin sulfate lyophilized formulations is：Drug solution preparing-filling partly jump a queue-freezes dry
Dry, tamponade-roll lid-visual inspection-packaging.Specifically include：(1) preparation of liquid：Recipe quantity amikacin sulfate is added into injection
Water dissolves, and obtains solution 1.；Recipe quantity auxiliary material is weighed again to be dissolved in appropriate water for injection, obtains solution 2.；Merge solution 1., solution
2. adding the pin of amount of preparation 0.05% to be stirred at room temperature 15 minutes with charcoal, filtering decarbonization, is adjusted resulting solution pH with 1mol/L sulfuric acid
In to critical field (6.0-7.5), supplement water for injection is settled to recipe quantity, uses 0.22 μm of the degerming membrane filtration in aperture
Afterwards, drug solution preparing is completed；(2) it is freeze-dried：Prepared liquid is by 1ml dress 2ml cillin bottles, 2ml dress 5ml two kinds of rule of cillin bottle
Lattice liquid drug, puts freeze-drying mechanical goods room flaggy, and pre-freeze is when insulation 5 is small within 3 hours to -30 DEG C, opens water vessel and freezes and opens
Close, after insulation, open vacuum pump, when vacuum pump reading is down to below 20 pas, gradually rise flaggy temperature to -10
DEG C, insulation 7 it is small when, be warming up to 0 DEG C continue insulation 4 it is small when, when products temperature and flaggy temperature it is close when, continue raise flaggy temperature
Degree to 32 DEG C and keep the temperature 6 it is small when more than, terminate to freeze when products temperature is again close to flaggy temperature, vacuum fall lid, tamponade,
Packaging, is freezed.
Traditional amikacin sulfate will first be configured to aqueous solution in lyophilized formulations production process, then by being filled to
Freeze-drying, amikacin sulfate are in that non-dry state for time is shorter, and product quality is more stable：Liquid is in freezing dry process
In it is not easily molded, appearance formulation is loose；When freeze-drying time is small more than 25 in freezing dry process at the same time, freeze-drying time is longer,
Amikacin sulfate is in that non-dry state for time is longer, and product quality is more unstable；Freeze-drying time is longer at the same time, and energy consumption is got over
Greatly, production cost is higher.
The content of the invention
A kind of the defects of the purpose of the present invention is overcoming the prior art, there is provided amikacin sulfate lyophilized formulations.
Specifically, the present invention provides a kind of amikacin sulfate lyophilized formulations, the lyophilized formulations, which use, to be included such as
The raw material of lower parts by weight is freeze-dried to be formed：
0.1~0.2 part of amikacin sulfate, 0.1~0.2 part of natrium adetate, 10~20 parts of sodium hydrogensulfite, mannitol
200~400 parts.
Water for injection is further included in the raw material.It is dry that the amount of the water for injection routinely prepares freezing using this area
The dosage addition of water for injection during dry preparation.
As a preferred embodiment of the present invention, per in 10000ml~20000ml raw materials, following component is included：Sulfuric acid Ah
Meter Ka Xing 0.1g~0.2g, natrium adetate 0.1g~0.2g, sodium hydrogensulfite 10g~20g, mannitol 200g~400g, note
Penetrate and use water surplus.
The present invention can promote lyophilized formation by adding mannitol；By add suitable sodium hydrogensulfite and according to
Ground acid disodium is used cooperatively, and can play the role of anti-oxidant and protection.The present invention further to the relative usage of each raw material into
Row is preferred, it can be ensured that the property of products obtained therefrom is stablized.
Invention further provides the preparation method of the amikacin sulfate lyophilized formulations, the described method includes：It is former
Mixing, bottling, freeze-drying and the sealing of material.
Specifically, the freeze-drying includes the following steps：
1) pre-freeze：It will mix, the raw material after bottling is when pre-freeze 1~3 is small below -32 DEG C；
2) primary drying：Vacuum is adjusted to below 15Pa, is rapidly heated to 0 ± 1 DEG C, when insulation 4~5 is small；
3) redrying：Holding vacuum is 12~13Pa, is rapidly heated to 8 ± 1 DEG C, when insulation 1~2 is small；It is quick again
It is warming up to 36 ± 1 DEG C, when insulation 4~5 is small, you can.
The step 1) is specially：The condenser temperature of freeze drying box is down to less than -42 DEG C in advance, by mixing, bottling
Raw material afterwards is positioned on the flaggy in freeze drying box, flaggy temperature fast cooling is down to less than -32 DEG C, holding 1~3 is small
When.
In freeze-drying method provided by the invention, it is described be rapidly heated/cool down refer to the interior heating/cooling when 1 is small.
In freezing dry process provided by the invention, flaggy temperature, products temperature, condenser temperature etc. should be checked, with true
Insulation degree is in setting range, so that it is guaranteed that the stabilization of freeze-drying products obtained therefrom comprehensive performance.
The mixing of raw material of the present invention is specially：Appropriate water for injection is taken, leads to CO2To saturation, sulfuric acid A meter Ka is added
Star fully dissolves, and adds sodium sulfite and natrium adetate, dissolve solution 1.；Mannitol is taken to be dissolved in appropriate water for injection
In, obtain solution 2.；Merge solution 1. with solution 2., add needle-use activated carbon, be sufficiently stirred at room temperature, filtering decarbonization, adjust pH value
To 6.0~7.5, the water for injection of surplus, membrane filtration are added, you can.
Preferably, the mixing of the raw material is specially：The water for injection for accounting for raw material cumulative volume 50~70% is taken, leads to CO2Extremely
Saturation, add amikacin sulfate fully dissolve, add sodium sulfite and natrium adetate, dissolve solution 1.；Take sweet dew
Alcohol is dissolved in appropriate water for injection, obtains solution 2.；Merge solution 1. with solution 2., addition account for raw material cumulative volume 0.03~
0.07% needle-use activated carbon, is sufficiently stirred at room temperature, filtering decarbonization, with 1mol/L sulfuric acid tune pH value to 6.0~7.5, adds surplus
The water for injection of surplus, with 0.22 μm of the membrane filtration in aperture, you can.
Bottling of the present invention is preferably uniformly to be sub-packed in mixed raw material in cillin bottle.
Sealing of the present invention is preferably jumped a queue method using hydraulic pressure.
Preparation method provided by the invention can shorten freeze-drying time, by existing process 25 it is small when more than foreshorten to 15~
18 it is small when so that amikacin sulfate departs from non-dry state as early as possible, the stability of amikacin sulfate is further obtained
Ensure.Meanwhile preparation method provided by the invention can reduce energy consumption, unit interval production production capacity is improved, reduces and is produced into
This.
Embodiment
Following embodiments are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1
Lot number is present embodiments provided as 140601, the amikacin sulfate lyophilized formulations of 10000 bottles of yield；It is by as follows
Raw material is prepared：
Amikacin sulfate 100mg；Sodium hydrogensulfite 10g；Natrium adetate 100mg；Mannitol 200g；Water for injection adds
To 10000ml.
The present embodiment additionally provides the preparation method of the amikacin sulfate lyophilized formulations, is specially：
(1) preparation of liquid：The water for injection of amount of preparation cumulative volume about 60% is taken, leads to CO2To 15~30 minutes to saturation
State (pH 4.0), recipe quantity amikacin sulfate is added in water for injection and is dissolved, adds recipe quantity anhydrous sodium sulfite
And natrium adetate, dissolve solution 1.；Weigh recipe quantity mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Merge
Solution 1., solution 2., add the pin of amount of preparation 0.05% to be stirred at room temperature 15 minutes with charcoal, filtering decarbonization, with 1mol/L sulfuric acid by institute
PH value of solution is adjusted to 6.8, supplement water for injection is settled to recipe quantity, complete after the degerming membrane filtration in 0.22 μm of aperture
Into drug solution preparing；
(2) encapsulate：By prepared liquid by 1ml dress 2ml cillin bottle liquid drugs, freeze-drying mechanical goods room plate is put
Layer；
(3) it is freeze-dried：
1) pre-freeze：Condenser temperature is down to -42 DEG C in advance first, it is interior when 1 is small after product inlet that flaggy temperature is down to -32
DEG C, when keeping low-temperature condition 2 small；
2) primary drying：Vacuum pump is opened, keeps below vacuum 14Pa, 1 is warming up to 0 DEG C, when insulation 4 is small when small, into
Row primary drying；
3) redrying：After product primary drying, flaggy is warming up to 8 DEG C (vacuum degree control is in 13Pa) by 1 when small keeps the temperature 1
Hour, then heat up 1 hour to 36 DEG C, when insulation 4 is small；
4) in freeze-drying process, flaggy temperature, products temperature, condenser temperature etc. are checked, after freezing, hydraulic pressure is carried out and adds
Plug.
Table 1：140601 complete testing results of lot number (0 month)
Embodiment 2
Lot number is present embodiments provided as 140603, the amikacin sulfate lyophilized formulations of 10000 bottles of yield；It is by as follows
Raw material is prepared：
Amikacin sulfate 120mg；Sodium hydrogensulfite 12g；Natrium adetate 120mg；Mannitol 250g；Water for injection adds
To 10000ml.
The present embodiment additionally provides the preparation method of the amikacin sulfate lyophilized formulations, is specially：
(1) preparation of liquid：The water for injection of amount of preparation cumulative volume about 60% is taken, leads to CO2To 15~30 minutes to saturation
State (pH 4.0), recipe quantity amikacin sulfate is added in water for injection and is dissolved, adds recipe quantity anhydrous sodium sulfite
And natrium adetate, dissolve solution 1.；Weigh recipe quantity mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Merge
Solution 1., solution 2., add the pin of amount of preparation 0.05% to be stirred at room temperature 15 minutes with charcoal, filtering decarbonization, with 1mol/L sulfuric acid by institute
PH value of solution is adjusted to 6.8, supplement water for injection is settled to recipe quantity, complete after the degerming membrane filtration in 0.22 μm of aperture
Into drug solution preparing；
(2) encapsulate：By prepared liquid by 1ml dress 2ml cillin bottle liquid drugs, freeze-drying mechanical goods room plate is put
Layer, drying to be frozen；
(3) it is freeze-dried：
1) pre-freeze：Condenser temperature is down to -42 DEG C in advance first, it is interior when 1 is small after product inlet flaggy temperature is down to -
Less than 32 DEG C, when keeping low-temperature condition 2 small；
2) primary drying：Vacuum pump is opened, keeps below vacuum 15Pa, 1 is warming up to 0 DEG C, when insulation 4 is small when small, into
Row primary drying；
3) redrying：After product primary drying, flaggy is warming up to 8 DEG C (vacuum degree control is in 13Pa) by 1 when small keeps the temperature 1
Hour, then heat up 1 hour to 36 DEG C, when insulation 4 is small；
4) in freeze-drying process, flaggy temperature, products temperature, condenser temperature etc. are checked, after freezing, hydraulic pressure is carried out and adds
Plug.
Table 2：140603 complete testing results of lot number (0 month)
Embodiment 3
Lot number is present embodiments provided as 140605, the amikacin sulfate lyophilized formulations of 10000 bottles of yield；It is by as follows
Raw material is prepared：
Amikacin sulfate 150mg；Sodium hydrogensulfite 15g；Natrium adetate 150mg；Mannitol 300g；Water for injection adds
To 20000ml.
The present embodiment additionally provides the preparation method of the amikacin sulfate lyophilized formulations, is specially：
(1) preparation of liquid：The water for injection of amount of preparation cumulative volume about 60% is taken, leads to CO2To 15~30 minutes to saturation
State (pH 4.0), recipe quantity amikacin sulfate is added in water for injection and is dissolved, adds recipe quantity anhydrous sodium sulfite
And natrium adetate, dissolve solution 1.；Weigh recipe quantity mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Merge
Solution 1., solution 2., add the pin of amount of preparation 0.05% to be stirred at room temperature 15 minutes with charcoal, filtering decarbonization, with 1mol/L sulfuric acid by institute
PH value of solution is adjusted to 6.8, supplement water for injection is settled to recipe quantity, complete after the degerming membrane filtration in 0.22 μm of aperture
Into drug solution preparing；
(2) encapsulate：Prepared liquid fills 5ml cillin bottle liquid drugs by 2ml, puts freeze-drying mechanical goods room flaggy,
Drying to be frozen；
(3) it is freeze-dried：
1) pre-freeze：Condenser temperature is down to -43 DEG C in advance first, it is interior that flaggy temperature is quick when 1 is small after product inlet
Less than -33 DEG C are down to, when keeping low-temperature condition 2 small；
2) primary drying：Vacuum pump is opened, keeps vacuum 13Pa, 1 is warming up to 0 DEG C, when insulation 4 is small when small, carry out one
Secondary drying；
3) redrying：After product primary drying, flaggy is warming up to 8 DEG C (vacuum degree control is in 12Pa) by 1 when small keeps the temperature 1
Hour, then heat up 1 hour to 36 DEG C, when insulation 5 is small；
4) in freeze-drying process, flaggy temperature, products temperature, condenser temperature etc. are checked, after freezing, hydraulic pressure is carried out and adds
Plug.
Table 3：140605 complete testing results of lot number (0 month)
Embodiment 4
Lot number is present embodiments provided as 140607, the amikacin sulfate lyophilized formulations of 10000 bottles of yield；It is by as follows
Raw material is prepared：
Amikacin sulfate 180mg；Sodium hydrogensulfite 18g；Natrium adetate 180mg；Mannitol 350g；Water for injection adds
To 20000ml.
The present embodiment additionally provides the preparation method of the amikacin sulfate lyophilized formulations, is specially：
(1) preparation of liquid：The water for injection of amount of preparation cumulative volume about 60% is taken, leads to CO2To 15~30 minutes to saturation
State (pH 4.0), recipe quantity amikacin sulfate is added in water for injection and is dissolved, adds recipe quantity anhydrous sodium sulfite
And natrium adetate, dissolve solution 1.；Weigh recipe quantity mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Merge
Solution 1., solution 2., add the pin of amount of preparation 0.05% to be stirred at room temperature 15 minutes with charcoal, filtering decarbonization, with 1mol/L sulfuric acid by institute
PH value of solution is adjusted in critical field (internal control 6.0-7.5), supplement water for injection is settled to recipe quantity, uses 0.22 μm of aperture
Degerming membrane filtration after, complete drug solution preparing；
(2) encapsulate：Prepared liquid fills 5ml cillin bottle liquid drugs by 2ml, puts freeze-drying mechanical goods room flaggy,
Drying to be frozen；
(3) it is freeze-dried：
1) pre-freeze：Condenser temperature is first down to -43 DEG C in advance, be quickly down to flaggy temperature when 1 is small after product inlet -
33 DEG C, when keeping low-temperature condition 2 small；
2) primary drying：Vacuum pump is opened, keeps below vacuum 12Pa, 1 is warming up to 0 DEG C, when insulation 4 is small when small, into
Row primary drying；
3) redrying：After product primary drying, flaggy is warming up to 8 DEG C (vacuum degree control is in 12Pa) by 1 when small keeps the temperature 2
Hour, then heat up 1 hour to 36 DEG C, when insulation 5 is small；
4) in freeze-drying process, flaggy temperature, products temperature, condenser temperature etc. are checked, after freezing, hydraulic pressure is carried out and adds
Plug.
Table 4：140607 complete testing results of lot number (0 month)
Embodiment 5
Lot number is present embodiments provided as 140609, the amikacin sulfate lyophilized formulations of 10000 bottles of yield；It is by as follows
Raw material is prepared：
Amikacin sulfate 200mg；Sodium hydrogensulfite 20g；Natrium adetate 200mg；Mannitol 400g；Water for injection adds
To 20000ml.
The present embodiment additionally provides the preparation method of the amikacin sulfate lyophilized formulations, is specially：
(1) preparation of liquid：The water for injection of amount of preparation cumulative volume about 60% is taken, leads to CO2To 15~30 minutes to saturation
State (pH is between 4.0), recipe quantity amikacin sulfate is added in water for injection and is dissolved, adds the anhydrous sulfurous of recipe quantity
Sour sodium and natrium adetate, dissolve solution 1.；Weigh recipe quantity mannitol to be dissolved in appropriate water for injection, obtain solution 2.；
Merge solution 1., solution 2., add the pin of amount of preparation 0.05% to be stirred at room temperature 15 minutes with charcoal, filtering decarbonization, with 1mol/L sulfuric acid
Resulting solution pH is adjusted to 6.8, supplement water for injection is settled to recipe quantity, uses 0.22 μm of the degerming membrane filtration in aperture
Afterwards, drug solution preparing is completed；
(2) encapsulate：Prepared liquid puts freeze-drying mechanical goods by 2ml dress 5ml two kinds of specification liquid drugs of cillin bottle
Room flaggy, drying to be frozen；
(3) it is freeze-dried：
1) pre-freeze：Condenser temperature is down to less than -43 DEG C in advance first, it is interior by flaggy temperature when 1 is small after product inlet
It is quick to be down to less than -33 DEG C, when keeping low-temperature condition 2 small；
2) primary drying：Vacuum pump is opened, keeps below vacuum 12Pa, 1 is warming up to 0 DEG C, when insulation 5 is small when small, into
Row primary drying；
3) redrying：After product primary drying, flaggy is warming up to 8 DEG C (vacuum degree control is in 12Pa) by 1 when small keeps the temperature 2
Hour, then heat up 1 hour to 36 DEG C, when insulation 5 is small；
4) in freeze-drying process, flaggy temperature, products temperature, condenser temperature etc. are checked, after freezing, hydraulic pressure is carried out and adds
Plug.
Table 5：140609 complete testing results of lot number (0 month)
Experimental example：Accelerated stability test
Taking lot number 130712 (formula and preparation process are with embodiment 1), lot number 130714, (formula and preparation process are same to be implemented
Example 3) and three batches of lot number 130716 (formula and preparation process with embodiment 5) product, respectively at the 0th month and the 6th
The moon (passing through six months Accelerated stability tests) carries out full item detection.
Wherein, the product full item testing result of the 0th month that lot number is 130712 is shown in Table 6, and the full item testing result in June is shown in
Table 7；The product full item testing result of the 0th month that lot number is 130714 is shown in Table 8, and the full item testing result in June is shown in Table 9；Lot number
10 are shown in Table for the 130716 product full item testing result of the 0th month, the full item testing result in June is shown in Table 11.
Table 6：130712 complete testing results of lot number (the 0th month)
Table 7：130712 complete testing results of lot number (June)
Table 8：130714 complete testing results of lot number (the 0th month)
Table 9：130714 complete testing results of lot number (June)
Table 10：130716 complete testing results of lot number (the 0th month)
Table 11：130716 complete testing results of lot number (June)
Three above batch products character, acid-base value, loss on drying, total impurities, content five after 6 months accelerated tests
The index of a investigation project collects as shown in table 12；As shown in Table 12, each product meets amikacin sulfate without significant change
Regulation in the lyophilized formulations drug standards, using the amikacin sulfate lyophilized formulations stability of technique productions provided by the invention
Preferably, good appearance.
Table 12：Six months Accelerated stability test results
Detection keeps sample sample after six months Accelerated stability tests, and indices meet the national drug standards, the 6th month
The changes of contents of last sample is respectively 1.68%, 1.78%, 1.75%, average out to (1.74 ± 0.05) %, RSD=2.87, into
One step demonstrates the reliability of manufacturing condition.
Comparative example 1
Compared with claim 1, it is differed only in, and the natrium adetate is replaced with mosatil.
The method provided according to experimental example, is detected, this contrast in June (passing through six months Accelerated stability tests)
Occur obvious caking in example products obtained therefrom and clarity does not meet standard regulation.
Comparative example 2
Compared with claim 1, it is differed only in, and the mannitol is replaced with sorbierite.
The method provided according to experimental example, is detected, this contrast in June (passing through six months Accelerated stability tests)
Occur part atrophy in example products obtained therefrom and clarity does not meet standard regulation.
Comparative example 3
Compared with claim 1, it is differed only in, and the composition of the raw material is：Amikacin sulfate 200mg, according to ground
Acid disodium 0.5g, sodium hydrogensulfite 15g, mannitol 500g, water for injection add to 10000ml.
The method provided according to experimental example, is detected, this contrast in June (passing through six months Accelerated stability tests)
Occur part atrophy in example products obtained therefrom and clarity does not meet standard regulation.
Comparative example 4
Compared with Example 1, differ only in, the freeze-drying is specially：Freeze-drying mechanical goods room flaggy is put, in advance
Freeze 3 hours to -30 DEG C insulation 5 it is small when, after insulation, unlatching vacuum pump, when vacuum pump reading is down to below 20Pa, gradually
Flaggy temperature is raised to -10 DEG C, when insulation 7 is small, then be warming up to 0 DEG C continue insulation 4 it is small when, when products temperature and flaggy temperature connect
When near, continue raise flaggy temperature to 32 DEG C and keep the temperature 6 it is small when more than, terminate when products temperature is again close to flaggy temperature
It is lyophilized.
The method provided according to experimental example, is detected, this contrast in June (passing through six months Accelerated stability tests)
Occur impurity in example products obtained therefrom and do not meet standard regulation more than quality standard and clarity.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Scope.
Claims (10)
1. a kind of amikacin sulfate lyophilized formulations, it is characterised in that per in 10000ml~20000ml raw materials, include such as the following group
Point：Amikacin sulfate 0.1g~0.2g, natrium adetate 0.1g~0.2g, sodium hydrogensulfite 10g~20g, mannitol 200g
~400g, water for injection surplus；
The lyophilized formulations are prepared by the method included the following steps：The mixing of raw material, bottling, freeze-drying and close
Envelope；The freeze-drying is specially：
1) pre-freeze：It will mix, the raw material after bottling is when pre-freeze 1~3 is small below -32 DEG C；
2) primary drying：Vacuum is adjusted to below 15Pa, is rapidly heated to 0 ± 1 DEG C, when insulation 4~5 is small；
3) redrying：Holding vacuum is 12~13Pa, is rapidly heated to 8 ± 1 DEG C, when insulation 1~2 is small；It is rapidly heated again
To 36 ± 1 DEG C, when insulation 4~5 is small, you can.
2. the preparation method of amikacin sulfate lyophilized formulations described in claim 1, it is characterised in that the mixing including raw material,
Bottling, freeze-drying and sealing：
The freeze-drying is specially：
1) pre-freeze：It will mix, the raw material after bottling is when pre-freeze 1~3 is small below -32 DEG C；
2) primary drying：Vacuum is adjusted to below 15Pa, is rapidly heated to 0 ± 1 DEG C, when insulation 4~5 is small；
3) redrying：Holding vacuum is 12~13Pa, is rapidly heated to 8 ± 1 DEG C, when insulation 1~2 is small；It is rapidly heated again
To 36 ± 1 DEG C, when insulation 4~5 is small, you can.
3. according to the method described in claim 2, it is characterized in that, the step 1) is specially：By the condensation of freeze drying box
Device temperature is down to less than -42 DEG C in advance, will mix, bottling after raw material be positioned on the flaggy in freeze drying box, by flaggy temperature
Degree fast cooling is down to less than -32 DEG C, when holding 1~3 is small.
4. according to the method in claim 2 or 3, it is characterised in that it is described be rapidly heated/cool down refer to the interior liter when 1 is small
Temperature/cooling.
5. according to the method in claim 2 or 3, it is characterised in that the mixing of the raw material is specially：
Appropriate water for injection is taken, leads to CO2To saturation, add amikacin sulfate and fully dissolve, add sodium sulfite and edetic acid(EDTA)
Disodium, dissolve solution 1.；Take mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Merge solution 1. with solution 2., add
Enter needle-use activated carbon, be sufficiently stirred at room temperature, filtering decarbonization, adjusts pH value to add the water for injection of surplus to 6.0~7.5, filter
Membrane filtration, you can.
6. according to the method described in claim 4, it is characterized in that, the mixing of the raw material is specially：
Appropriate water for injection is taken, leads to CO2To saturation, add amikacin sulfate and fully dissolve, add sodium sulfite and edetic acid(EDTA)
Disodium, dissolve solution 1.；Take mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Merge solution 1. with solution 2., add
Enter needle-use activated carbon, be sufficiently stirred at room temperature, filtering decarbonization, adjusts pH value to add the water for injection of surplus to 6.0~7.5, filter
Membrane filtration, you can.
7. according to the method described in claim 5, it is characterized in that, the mixing of the raw material is specially：
The water for injection for accounting for raw material cumulative volume 50~70% is taken, leads to CO2To saturation, add amikacin sulfate and fully dissolve, then add
Enter sodium sulfite and natrium adetate, dissolve solution 1.；Take mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Close
And solution 1. with solution 2., addition accounts for 0.03~0.07% needle-use activated carbon of raw material cumulative volume, is sufficiently stirred at room temperature, and filtering is de-
Charcoal, with 1mol/L sulfuric acid tune pH value to 6.0~7.5, adds the water for injection of surplus, with 0.22 μm of the membrane filtration in aperture,
.
8. according to the method described in claim 6, it is characterized in that, the mixing of the raw material is specially：
The water for injection for accounting for raw material cumulative volume 50~70% is taken, leads to CO2To saturation, add amikacin sulfate and fully dissolve, then add
Enter sodium sulfite and natrium adetate, dissolve solution 1.；Take mannitol to be dissolved in appropriate water for injection, obtain solution 2.；Close
And solution 1. with solution 2., addition accounts for 0.03~0.07% needle-use activated carbon of raw material cumulative volume, is sufficiently stirred at room temperature, and filtering is de-
Charcoal, with 1mol/L sulfuric acid tune pH value to 6.0~7.5, adds the water for injection of surplus, with 0.22 μm of the membrane filtration in aperture,
.
9. according to the method described in claim 2, it is characterized in that, the bottling is specially：Mixed raw material is uniformly divided
Loaded in cillin bottle.
10. according to the method described in claim 2, it is characterized in that, the sealing is jumped a queue method using hydraulic pressure.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040204372A1 (en) * | 2003-04-14 | 2004-10-14 | Wyeth Holdings Corporation | Compositions containing pipercillin and tazobactam sodium useful for injection |
| CN101703484A (en) * | 2009-12-04 | 2010-05-12 | 蚌埠丰原涂山制药有限公司 | Preparation method of hexadecadrol sodium phosphate freeze-dried powder injection |
| CN105213300A (en) * | 2011-12-27 | 2016-01-06 | 四川科伦药物研究院有限公司 | A kind of amikacin sulfate injection and preparation method thereof |
-
2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040204372A1 (en) * | 2003-04-14 | 2004-10-14 | Wyeth Holdings Corporation | Compositions containing pipercillin and tazobactam sodium useful for injection |
| CN101703484A (en) * | 2009-12-04 | 2010-05-12 | 蚌埠丰原涂山制药有限公司 | Preparation method of hexadecadrol sodium phosphate freeze-dried powder injection |
| CN105213300A (en) * | 2011-12-27 | 2016-01-06 | 四川科伦药物研究院有限公司 | A kind of amikacin sulfate injection and preparation method thereof |
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