CN101856335A - Azithromycin composite freeze-dried powder for injection - Google Patents
Azithromycin composite freeze-dried powder for injection Download PDFInfo
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Abstract
The invention relates to azithromycin composite freeze-dried powder for injection. The composite is prepared by dissolving azithromycin, phosphoric acid and disodium hydrogen phosphate into water for injection and freeze-drying the mixture. The molar ratio of azithromycin to phosphoric acid to disodium hydrogen phosphate is 1:2-2.05:0.02-0.1, preferably 1:2.01-2.05:0.05-0.1. The main granularity of the azithromycin composite freeze-dried powder for injection is between 300 and 500nm, preferably between 350 and 450nm. The distribution dispersion of the azithromycin composite freeze-dried powder for injection is between 100 and 150nm, preferably between 110 and 135nm. The azithromycin composite freeze-dried powder of the invention has excellent redissolution property and stability.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of macrolide antibiotics, is a kind of Azithromycin composite freeze-dried powder for injection in particular.
Background technology
Azithromycin is 15 yuan of rings Macrolide, i.e. first kinds of nitrogen lactone.Its mechanism of action is identical with erythromycin, mainly combines with the 50S subunit of bacterial ribosome, and the albumen that inhibition depends on RNA synthesizes.This product is to micrococcus scarlatinae, streptococcus pneumoniae and the good antibacterial action of hemophilus influenza tool, and staphylococcus is also had an antibacterial activity.Azithromycin is slightly poor than erythromycin to the antibacterial action of gram positive coccus such as staphylococcus, Streptococcus, antibacterial action to hemophilus influenza and moraxelle catarrhalis is strong 4～8 times and 2～4 times than erythromycin, also can have a bacteriostasis to minority escherichia coli, Salmonella, Shigella.Azithromycin is to tool good resistance microbial actions such as anaerobe such as Peptostreptococcus, mycoplasma pneumoniae and chlamydia trachomatiss.
Along with to the continually developing of erythromycin derivatives, its series of products have obtained extensive use, make the status of this class medicine obtain brand-new evaluation.At its upstream under the situation that product sulfur cyanogen erythromycin production capacity is constantly expanded, adopt azithromycin, clarithromycin, Roxithromycin, the erythromycin ethylsuccinate production line of semi-synthesis method production to build up one after another like rain the back spring bamboo, the bright spot that has become these series of products to increase, azithromycin is exactly outstanding person wherein.
A new generation's erythromycin medicine can reduce the degraded of former medicine effectively, medicine stability and pharmacokinetics in vivo also is improved, and expanded fungicidal spectrum, reduced incidence rate of adverse reaction simultaneously, through clinical widely, obtained doctor, patient's approval.Azithromycin wherein demonstrates the distinctive feature of antagonism whole body bacterial infection with its advantage, and has occupied the staple market of these series of products.
Azithromycin is to change the peptide process by hindering antibacterial, thereby Profilin matter synthetic reaches bacteriostasis, medicine is stable to acid, can extensively be distributed in each histoorgan of human body, and gram positive bacteria, Gram-negative coccus, bacillus and anaerobe all there is stronger effect, medicine in blood and the tissue in concentration height, long half time, be applicable to the treatment of mixed infection.Azithromycin blood drug level is 2～10 times of erythromycin, and length of penetration is strong in tissue, is 12～50 times of blood drug level, because the corresponding minimizing with number of times of dosage, untoward reaction is lower, is more suitable for using in children with to penicillin medicaments insensitive patient.
In recent years, some areas, the whole world drop to 40% gradually to the sensitivity of common erythromycin, thereby have incured loss through delay the healing of disease, especially in responsive rate aspect gonococcal strain up to 98.04%, plain higher more than 1 times than penicillium communne, therefore also promoted the use of azithromycin.Along with international interchange is strengthened, and the transformation of humane idea, human immune deficiency infection and incidence rate are more, the sickness rate of nongonococcal urethritis also increases thereupon, for this reason, U.S. FDA infection Advisory Board has recommended azithromycin to be used for infection such as the caused respiratory tract of sensitive bacterial, urogenital tract, skin and soft tissue, and this medicine has good active to mycoplasma pneumoniae, sand holes chlamydia and treponema pallidum, because non-complex gonorrhea and chlamydia urethritis, cervicitis cure rate are reached more than 99%.
Azithromycin has obtained certainly in the clinical achievement of China, thereby occupies an important position in the medication of whole body infection, has become the leading kind in the macrolide antibiotics at present.Azithromycin is the macrolide antibiotics of Development and Production in recent years, is a kind of broad ectrum antibiotic that obtains after modifying on the erythromycin chemical constitution.These product are gone on the market in this state at first by Yugoslavia Sour Pliva company research and development back at first, and Pfizer Inc. pushes it against the world market after awarding and having allowed global development weigh.Nineteen ninety, this product of JIUYUE went on the market in Britain, obtained the FDA approval end of the year 1991 in U.S.'s listing, and commodity be called Zithromax (Zithromax), these product in October, 2005 patent expire.
But because the azithromycin water solublity is little, can't directly make preparation, thereby usually with the clinical use of oral agents, but the oral agents bioavailability is low, only is 40% effect.Had in the prior art azithromycin has been made water soluble salt, the double salt of a kind of citric acid and azithromycin formation is disclosed as patent application 98124980, patent 03150874.X discloses a kind of preparation method of azithromycin water-soluble phosphate, but the pH value of this salt is on the low side, and solubility and stability still remain to be improved.
For this reason, the Azithromycin composite freeze-dried powder that the invention provides a kind of solubility, has good stability.
Summary of the invention
Primary goal of the invention of the present invention is to provide a kind of Azithromycin composite freeze-dried powder.
First goal of the invention of the present invention is to provide the preparation method of this Azithromycin composite freeze-dried powder.
In order to realize the present invention's purpose, the technical scheme of employing is:
The invention provides a kind of Azithromycin composite freeze-dried powder for injection, lyophilizing formed after described compositions was dissolved in water for injection by azithromycin, phosphoric acid and sodium hydrogen phosphate, wherein, the mol ratio of azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2～2.05: 0.02～0.1, be preferably 1: 2.01～2.05: 0.05～and 0.1.
First preferred version of the present invention is: the main granularity of described azithromycin injection freeze-dried powder is 300～500nm, and the dispersion of distribution is 100～150nm; Preferred main granularity is 350～450nm, and the dispersion of distribution is 110～135nm.
The present invention also provides this described Azithromycin composite freeze-dried powder for injection preparation method:
(1) azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH with sodium hydrogen phosphate, adding water for injection to the concentration of azithromycin is 0.0068g/ml～0.008g/ml;
(2) in the medicinal liquid of step (1) preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, packing false add plug;
(3) lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 0～4 ℃, the medicinal liquid of packing in the step (2) is placed 15～30min in freeze drying box, freeze drying box is cooled to-30～-20 ℃ with the speed of 20～30 ℃/min, was warming up to-12～-8 ℃ then in 1～4 hour, be incubated 1～2 hour; Again freeze drying box is cooled to-35～-25 ℃ with the speed of 20～30 ℃/min, was warming up to-15～-12 ℃ then in 0.5～1 hour; Be cooled to-55～-45 ℃ with 30～40 ℃/min speed then, be incubated freezing 3～5 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15～20Pa, at the uniform velocity slowly freeze drying box was warming up to-15～-10 ℃ then at 10～15 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.2～0.5 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
First optimal technical scheme of preparation method of the present invention is, the condition of the pre-freeze repeatedly of step (3) is: the freeze drying box temperature is reduced to 2 ℃, divide the medicinal liquid that installs to place 20min in freeze drying box, freeze drying box is cooled to-20 ℃ with the speed of 20 ℃/min, be warming up to-10 ℃ then in 2 hours, be incubated 1 hour; Again freeze drying box is cooled to-30 ℃ with the speed of 30 ℃/min, was warming up to-15 ℃ then in 1 hour; Be cooled to-50 ℃ with 40 ℃/min speed then, be incubated freezing 3～4 hours.
Second optimal technical scheme of preparation method of the present invention is: the sublimation condition among step (3) b at the uniform velocity slowly was warming up to freeze drying box-12 ℃ for being evacuated to 18Pa at 12 hours.
The 3rd optimal technical scheme of preparation method of the present invention is: the exsiccant condition among step (3) c is at the uniform velocity to be warming up to 20 ℃ with freeze drying box with 0.25 ℃/min.
The 4th optimal technical scheme of preparation method of the present invention is: the pH described in the step (1) is 6～7.
The 5th optimal technical scheme of preparation method of the present invention is: the described medical activated carbon consumption of step (2) is 0.1% of a liquor capacity.
Below technical scheme of the present invention is further described in detail:
The invention provides a kind of Azithromycin composite freeze-dried powder for injection, lyophilizing formed after the said composition freeze-dried powder was dissolved in water for injection by azithromycin, phosphoric acid and sodium hydrogen phosphate, the mol ratio of described azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2～2.05: 0.02～0.1, be preferably 1: 2.01～2.05: 0.05～and 0.1.
Through scanning electron microscope, add up to such an extent that the main granularity of lyophilized azithromycin powder pin of the present invention is 300～500nm azithromycin injection freeze-dried powder of the present invention, the dispersion of distribution is 100～150nm; Preferred main granularity is 350～450nm, and the dispersion of distribution is 110～135nm.The particle diameter of Azithromycin composite freeze-dried powder of the present invention reduces, and row is still good but it flows, and is 26 °～29 ° through measuring its angle of repose.
Wherein, azithromycin and phosphatase reaction have generated azithromycin phosphate and have been prepared from, wherein, the mol ratio of azithromycin and phosphoric acid is 1: 2～2.1, preferred 1: 2.01～2.05, in course of reaction, need phosphoric acid capacity or the excessive azithromycin complete reaction that just can guarantee to form the azithromycin phosphate of solubility, and the pH value of azithromycin phosphate itself is about 5, unreacted phosphoric acid has further reduced the phosphatic pH value of azithromycin, stimulates thereby produce when intravenous injection is used; Therefore, the present invention has added sodium hydrogen phosphate pH value has been controlled in freeze-dried powder, and pH is controlled between 6～7, has adapted to the needs of clinical vein injection more.Simultaneously, sodium hydrogen phosphate also is a kind of safe pharmaceutic adjuvant.Simultaneously, the azithromycin phosphate freeze-dried powder of sodium hydrogen phosphate has been added in the discovery that the inventor is also pleasantly surprised, has good stable more.
Usually the solution of azithromycin phosphate being made 0.125～0.33g/ml in the prior art carries out lyophilizing, and the inventor finds by a large amount of experiments, azithromycin phosphate is made the solution of 0.0068g/ml～0.008g/ml, carry out lyophilization then, can reduce the particle diameter of product significantly, make main particle size reduction, the dispersion of distribution narrows down.Thereby phosphatic solubility of azithromycin and stability are further enhanced, are suitable for needs more with clinical practice.
In cryodesiccated process, because the present invention makes the solution of 0.0068g/ml～0.008g/ml with azithromycin phosphate, carry out lyophilization after the bottling again, the volume of solution is big, bottle takes place easily freeze the uneven phenomenon of being heated; Because the sample initial temperature is high more, the thermograde of sample liquid top and the bottom is big more, and ice-crystal growth speed is slow more.Solution is if lower the temperature at a slow speed, and it is thicker then to form ice crystal, and the propulsive from bottom to top speed in ice interface is slow, solute migration time abundance in the solution, and solution surface frozen crust solute gathers also just many.Thereby causing the solute of upper epidermis often more, density is higher, and bottom density is less down, short texture.Simultaneously, the sample that under different pre-freeze temperature, freezes, dry after-poppet pore size has notable difference.The pre-freeze temperature is lower, and the brace aperture diameter is littler.This lamination embodies the most obviously on the goods of skeleton difference, perhaps bottom atrophy, perhaps in phantom, perhaps top boss, perhaps top one deck duricrust that comes off.Therefore, it is undesirable that the present invention adopts conventional method lyophilizing effect in lyophilizing.For this reason, the inventor takes pre-freeze method repeatedly by a large amount of discovering repeatedly in the pre-freeze process, promptly lower the temperature-heat up-lower the temperature-heat up-the pre-freeze process of cooling at last again, and control temperature, time, the speed of each step, thereby overcome the uneven difficult problem of being heated.
Azithromycin composite freeze-dried powder of the present invention, through experiment confirm, the more existing azithromycin salt of its solubility and stability all has remarkable redissolution to improve.
The specific embodiment of the present invention only is used for further explaining and explanation the present invention, content of the present invention is not construed as limiting.
The specific embodiment
The preparation of embodiment 1 Azithromycin composite freeze-dried powder for injection
1. azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulating pH with sodium hydrogen phosphate is 6.5, and adding water for injection to the concentration of azithromycin is 0.0075g/ml; Wherein, the mol ratio of azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2.05: 0.05～0.1;
2. in the medicinal liquid of step 1 preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, every of packing 20ml, false add plug; The medical activated carbon consumption is 0.1% of a liquor capacity;
3. lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 4 ℃, the medicinal liquid of packing in the step (2) is placed 30min in freeze drying box, freeze drying box is cooled to-30 ℃ with the speed of 30 ℃/min, be warming up to-8 ℃ then in 4 hours, be incubated 1 hour; Again freeze drying box is cooled to-35 ℃ with the speed of 20 ℃/min, was warming up to-15 ℃ then in 0.5 hour; Be cooled to-55 ℃ with 30～40 ℃/min speed then, be incubated freezing 3 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15Pa, at the uniform velocity slowly freeze drying box was warming up to-15 ℃ then at 10 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.2～0.5 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
Through sem observation, detection, adding up its main granularity is 350～480nm with the Azithromycin composite lyophilized powder that obtains, and the dispersion of distribution is 100～150nm.Measuring its angle of repose simultaneously is 28 °.
The preparation of embodiment 2 Azithromycin composite freeze-dried powder for injection
1. azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH6 with sodium hydrogen phosphate, adding water for injection to the concentration of azithromycin is 0.007g/ml; Wherein, the mol ratio of azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2.05: 0.05～0.1;
2. in the medicinal liquid of step 1 preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, every of packing 20ml, false add plug; The medical activated carbon consumption is 0.1% of a liquor capacity.
3. lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 0 ℃, the medicinal liquid of packing in the step (2) is placed 30min in freeze drying box, the speed of freeze drying box with 20 ℃/min is cooled to--20 ℃, be warming up to-8 ℃ then in 2 hours, be incubated 1 hour; Again freeze drying box is cooled to-25 ℃ with the speed of 30 ℃/min, was warming up to-12 ℃ then in 0.5 hour; Be cooled to-45 ℃ with 40 ℃/min speed then, be incubated freezing 4 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 18Pa, at the uniform velocity slowly freeze drying box was warming up to-15～-10 ℃ then at 12 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.25 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
Through sem observation, detection, adding up its main granularity is 300～450nm with the Azithromycin composite lyophilized powder that obtains, and the dispersion of distribution is 110～150nm.Measuring its angle of repose simultaneously is 27 °.
The preparation of embodiment 3 Azithromycin composite freeze-dried powder for injection
1. azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH6.5 with sodium hydrogen phosphate, adding water for injection to the concentration of azithromycin is 0.0068g/ml; Wherein, the mol ratio of azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2.04: 0.05～0.1;
2. in the medicinal liquid of step 1 preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, every of packing 20ml, false add plug; The medical activated carbon consumption is 0.1% of a liquor capacity;
3. lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 2 ℃, the medicinal liquid of packing in the step 2 is placed 20min in freeze drying box, freeze drying box is cooled to-25 ℃ with the speed of 25 ℃/min, be warming up to-10 ℃ then in 3 hours, be incubated 1.5 hours;
Again freeze drying box is cooled to-25 ℃ with the speed of 25 ℃/min, was warming up to-15 ℃ then in 45 minutes; Be cooled to-50 ℃ with 40 ℃/min speed then, be incubated freezing 4.5 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 19Pa, at the uniform velocity slowly freeze drying box was warming up to-14 ℃ then at 14 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.4 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
Through sem observation, detection, adding up its main granularity is 350～450nm with the Azithromycin composite lyophilized powder that obtains, and the dispersion of distribution is 110～140nm.Measuring its angle of repose simultaneously is 27 °.
The preparation of embodiment 4 Azithromycin composite freeze-dried powder for injection
1. azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH6.8 with sodium hydrogen phosphate, adding water for injection to the concentration of azithromycin is 0.008g/ml; Wherein, the mol ratio of azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2.03: 0.05～0.1;
2. in the medicinal liquid of step 1 preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, every of packing 20ml, false add plug; The medical activated carbon consumption is 0.1% of a liquor capacity.
3. lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 2 ℃, the medicinal liquid of packing in the step (2) is placed 20min in freeze drying box, freeze drying box is cooled to-25 ℃ with the speed of 25 ℃/min, be warming up to-12 ℃ then in 3 hours, be incubated 1.5 hours; Again freeze drying box is cooled to-35 ℃ with the speed of 28 ℃/min, was warming up to-15 ℃ then in 1 hour; Be cooled to-55 ℃ with 35 ℃/min speed then, be incubated freezing 3.5 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 16Pa, at the uniform velocity slowly freeze drying box was warming up to-13 ℃ then at 12 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.45 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
Through sem observation, detection, adding up its main granularity is 350～450nm with the Azithromycin composite lyophilized powder that obtains, and the dispersion of distribution is 110～150nm.Measuring its angle of repose simultaneously is 28 °.
The preparation of embodiment 5 Azithromycin composite freeze-dried powder for injection
1. azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH6.8 with sodium hydrogen phosphate, adding water for injection to the concentration of azithromycin is 0.0068g/ml; Wherein, the mol ratio of azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2.02: 0.08～0.1;
2. in the medicinal liquid of step 1 preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, every of packing 20ml, false add plug; The medical activated carbon consumption is 0.1% of a liquor capacity.
3. lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 3 ℃, the medicinal liquid of packing in the step 2 is placed 25min in freeze drying box, freeze drying box is cooled to-30 ℃ with the speed of 28 ℃/min, be warming up to-12 ℃ then in 3 hours, be incubated 1 hour; Again freeze drying box is cooled to-35 ℃ with the speed of 30 ℃/min, was warming up to-15 ℃ then in 35 minutes; Be cooled to-50 ℃ with 40 ℃/min speed then, be incubated freezing 3 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 18Pa, at the uniform velocity slowly freeze drying box was warming up to-14 ℃ then at 12 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.35 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
Through sem observation, detection, adding up its main granularity is 350～450nm with the Azithromycin composite lyophilized powder that obtains, and the dispersion of distribution is 110～135nm.Measuring its angle of repose simultaneously is 27 °.
Experimental example 1 solubility
The product of embodiment 1～5 is got in this experiment, 2000 bottles of each embodiment preparation of product, each embodiment product are got 200 bottles at random and are divided into 4 groups, 50 bottles every group, leave standstill 6～24 months (the placement condition is 25 ℃ ± 2 ℃, and relative humidity is 75% ± 5%) according to the time shown in the table 1.
Table 1: redissolution speed experiment flow:
Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5
0 month 50 bottles 50 bottles 50 bottles 50 bottles 50 bottles
6 months 50 bottles 50 bottles 50 bottles 50 bottles 50 bottles
12 months 50 bottles 50 bottles 50 bottles 50 bottles 50 bottles
24 months 50 bottles 50 bottles 50 bottles 50 bottles 50 bottles
Every set product is measured the average speed that redissolves under identical condition (every bottle adds 20ml water for injection, same model agitator is provided with identical frequency of vibration 60 times/min), experimental result sees Table 2.
Table 2, the experimental result of redissolving:
Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5
0 month (second) 1.10 1.12 1.14 1.12 1.08
6 months (second) 1.24 1.38 1.22 1.32 1.26
12 months (second) 1.98 2.02 1.78 2.10 2.14
24 months (second) 3.06 2.88 3.10 2.96 3.04
As shown in Table 2, the Azithromycin composite freeze-dried powder agent of the present invention's preparation, its redissolution is respond well, even after long-term the placement, its redissolution is still good.
Experimental example 2 solubility comparative tests
This experimental example has compared the redissolution performance of Azithromycin composite freeze-dried powder agent of the present invention.
Matched group 1: adopt the preparation method among the patent ZL03150874.X embodiment 1 to prepare azithromycin phosphate, be distributed into 0.15g/ bottle in azithromycin, prepare 2000 bottles altogether, get 200 bottles at random and be divided into 4 groups, every group 50 bottles, leave standstill 6,12,24 months (the placement condition is 25 ℃ ± 2 ℃, and relative humidity is 75% ± 5%) respectively.Adopt the identical condition determination of experimental example, the experimental result that records redissolution is as shown in table 3:
Table 3: solubility comparative test result
Embodiment 1 matched group 1
0 month (second) 1.10 5.02
6 months (second) 1.24 7.14
12 months (second) 1.98 9.38
24 months (second) 3.06 9.86
By above experimental result as can be known, adopt the solubility of the Azithromycin composite freeze-dried powder that preparation method of the present invention makes significantly better than adopting prior art.
Experimental example 3 stability tests
Matched group 2: the stability of more not adding the Azithromycin composite freeze-dried powder of sodium hydrogen phosphate
Azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, adding water for injection to the concentration of azithromycin is 0.0075g/ml; Wherein, azithromycin, phosphoric acid molar ratios are 1: 2.05; Measuring its pH value is 5.5; The back adopts the preparation method identical with embodiment 1 to be prepared into freeze-dried powder.Prepare 4000 bottles, get 350 bottles at random and carry out stability test.
1. hot test
Get the lyophilized azithromycin powder pin of embodiment 1, matched group 2 gained, simulation listing packing is put in the sealing clean container, under 40 ℃ of temperature, placed 10 days, in the 5th day and sampling in the 10th day, detect result of the test and comparison in 0 day by stable high spot reviews project.
2. high humility test
Get the lyophilized azithromycin powder pin of embodiment 1, matched group 2 gained, simulation listing packing is put in the constant humidity hermetic container, under the condition of 25 ℃ of relative humiditys 90% ± 5%, placed 10 days, in the 5th day and sampling in the 10th day, detect result of the test and comparison in 0 day by stable high spot reviews project.
3. strong illumination test
Get the lyophilized azithromycin powder pin of embodiment 1, matched group 2 gained, simulation listing packing is put in the sealing clean container, placing illumination is to place 10 days under the condition of 4500lx, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stable high spot reviews project.
Influence factor's result of the test sees the following form 4:
Table 4: influence factor's result of the test
The result shows: this product was placed 10 days down at high temperature (40 ℃) under the condition of simulation listing packing, and removing related substance slightly increases, and outside content slightly reduced, other every indexs did not have significant change.Every index has no significant change under illumination and super-humid conditions.And adopting identical preparation method but the amount and the content that do not add related substance in the matched group 2 of sodium hydrogen phosphate all increases to some extent, the stability that sodium hydrogen phosphate can increase product is added in the present embodiment explanation.
Experimental example 4: stability test-accelerated tests
Get Azithromycin composite freeze-dried powder, the simulation listing packing of embodiment 1, matched group 2 gained, put in the sealing clean container, under 40 ℃ of temperature, placed 6 months, at duration of test once respectively at 1,2,3,6 sampling at the end of month, each stable high spot reviews project is tested, the results are shown in Table 5.
Table 5: accelerated test result:
By the accelerated test result as can be known, this product was investigated through accelerated test in 6 months, and related substance slightly increases, and content slightly reduces, but all is better than the product of matched group 2.
This has also carried out identical test to the aseptic freeze-dried powder pin of the prepared Azithromycin composite of other embodiment of the present invention, and the result of its acquisition is similar.
Experimental example 5: long term test
Get embodiment 1, the aseptic freeze-dried powder needle mould plan of matched group 2 gained Azithromycin composites listing packing, put in the sealing clean container, under 6 ℃ ± 2 ℃ conditions of temperature, placed 36 months, at duration of test once, each inspection item is tested respectively at the 3rd, 6,9,12,18,24,36 sampling at the end of month.Result of the test sees the following form 6:
Table 6: azithromycin injection composition sterile freeze-dried powder long term test is investigated the result
By long-term test results as can be known, this product was investigated through long term test in 24 months, and significant change does not all take place every index, all in prescribed limit.Simultaneously aseptic, pyrogen of long term test 24 months and bacterial endotoxin inspection are all up to specification.
This has also carried out identical test to the aseptic freeze-dried powder pin of the prepared Azithromycin composite of other embodiment of the present invention, and the result of its acquisition is similar.
Claims (8)
1. Azithromycin composite freeze-dried powder for injection, it is characterized in that, lyophilizing formed after described compositions was dissolved in water for injection by azithromycin, phosphoric acid and sodium hydrogen phosphate, the mol ratio of described azithromycin, phosphoric acid, sodium hydrogen phosphate is 1: 2～2.05: 0.02～0.1, be preferably 1: 2.01～2.05: 0.05～and 0.1.
2. Azithromycin composite freeze-dried powder for injection according to claim 1 is characterized in that, the main granularity of described Azithromycin composite freeze-dried powder for injection is 300～500nm, and the dispersion of distribution is 100～150nm; Preferred main granularity is 350～450nm, and the dispersion of distribution is 110～135nm.
3. Azithromycin composite freeze-dried powder for injection according to claim 1 is characterized in that, described Azithromycin composite freeze-dried powder for injection preparation method is:
(1) azithromycin and phosphoric acid are added in the dosing cylinder, add water for injection and be stirred to whole dissolvings, regulate pH with sodium hydrogen phosphate, adding water for injection to the concentration of azithromycin is 0.0068g/ml～0.008g/ml;
(2) in the medicinal liquid of step (1) preparation, add medical activated carbon, stirring at room 15 minutes, filtering decarbonization, filtrate is surveyed pH value, content, packing false add plug;
(3) lyophilizing:
A, pre-freeze repeatedly: the freeze drying box temperature is reduced to 0～4 ℃, the medicinal liquid of packing in the step (2) is placed 15～30min in freeze drying box, freeze drying box is cooled to-30～-20 ℃ with the speed of 20～30 ℃/min, was warming up to-12～-8 ℃ then in 1～4 hour, be incubated 1～2 hour; Again freeze drying box is cooled to-35～-25 ℃ with the speed of 20～30 ℃/min, was warming up to-15～-12 ℃ then in 0.5～1 hour; Be cooled to-55～-45 ℃ with 30～40 ℃/min speed then, be incubated freezing 3～5 hours;
B, distillation: the medicinal liquid evacuation that pre-freeze is good, to 15～20Pa, at the uniform velocity slowly freeze drying box was warming up to-15～-10 ℃ then at 10～15 hours, be incubated 5 ℃;
C, drying: freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.2～0.5 ℃/min, and heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
4. Azithromycin composite freeze-dried powder for injection according to claim 3, it is characterized in that, the condition of the pre-freeze repeatedly of step (3) is: the freeze drying box temperature is reduced to 2 ℃, divide the medicinal liquid that installs to place 20min in freeze drying box, freeze drying box is cooled to-20 ℃ with the speed of 20 ℃/min, be warming up to-10 ℃ then in 2 hours, be incubated 1 hour; Again freeze drying box is cooled to-30 ℃ with the speed of 30 ℃/min, was warming up to-15 ℃ then in 1 hour; Be cooled to-50 ℃ with 40 ℃/min speed then, be incubated freezing 3～4 hours.
5. Azithromycin composite freeze-dried powder for injection according to claim 3 is characterized in that, the condition of step (3) distillation at the uniform velocity slowly was warming up to freeze drying box-12 ℃ for being evacuated to 18Pa at 12 hours.
6. Azithromycin composite freeze-dried powder for injection according to claim 3 is characterized in that, step (3) c is dry for freeze drying box at the uniform velocity is warming up to 20 ℃ with 0.25 ℃/min.
7. Azithromycin composite freeze-dried powder for injection according to claim 3 is characterized in that, the pH described in the step (1) is 6～7.
8. Azithromycin composite freeze-dried powder for injection according to claim 3 is characterized in that, the described medical activated carbon consumption of step (2) is 0.1% of a liquor capacity.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102552918A (en) * | 2012-02-02 | 2012-07-11 | 山东齐都药业有限公司 | Stabilizer of lyophilized powder injection for azithromycin injection |
| CN104043103A (en) * | 2013-03-12 | 2014-09-17 | 江苏奥赛康药业股份有限公司 | Polymyxin E methanesulfinic acid sodium salt freeze-dried preparation and preparation method thereof |
| CN108721209A (en) * | 2017-04-20 | 2018-11-02 | 广东东阳光药业有限公司 | A kind of azithromycin injection for animals |
| CN110859812A (en) * | 2019-12-06 | 2020-03-06 | 北京悦康科创医药科技股份有限公司 | Freeze drying method and application thereof |
| CN114796116A (en) * | 2022-05-17 | 2022-07-29 | 中山大学附属第六医院 | Azithromycin inhalant and preparation method thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125871A (en) * | 2007-09-03 | 2008-02-20 | 浙江尖峰药业有限公司 | Sulfuric acid azithromycin, application thereof, freeze dried of the sulfuric acid azithromycin and preparation method for the freeze dried |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101125871A (en) * | 2007-09-03 | 2008-02-20 | 浙江尖峰药业有限公司 | Sulfuric acid azithromycin, application thereof, freeze dried of the sulfuric acid azithromycin and preparation method for the freeze dried |
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| CN102552918A (en) * | 2012-02-02 | 2012-07-11 | 山东齐都药业有限公司 | Stabilizer of lyophilized powder injection for azithromycin injection |
| CN104043103A (en) * | 2013-03-12 | 2014-09-17 | 江苏奥赛康药业股份有限公司 | Polymyxin E methanesulfinic acid sodium salt freeze-dried preparation and preparation method thereof |
| CN104043103B (en) * | 2013-03-12 | 2015-08-05 | 江苏奥赛康药业股份有限公司 | A kind of polymyxin E methanesulfonic sodium lyophilized formulations and preparation method thereof |
| CN108721209A (en) * | 2017-04-20 | 2018-11-02 | 广东东阳光药业有限公司 | A kind of azithromycin injection for animals |
| CN110859812A (en) * | 2019-12-06 | 2020-03-06 | 北京悦康科创医药科技股份有限公司 | Freeze drying method and application thereof |
| CN114796116A (en) * | 2022-05-17 | 2022-07-29 | 中山大学附属第六医院 | Azithromycin inhalant and preparation method thereof |
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| CN101856335B (en) | 2011-05-18 |
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