CN109481665B - A kind of injection anidulafungin redissolves medicament and preparation method thereof - Google Patents
A kind of injection anidulafungin redissolves medicament and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to technical field of medicine, and in particular to a kind of injection anidulafungin redissolves medicament and preparation method thereof.Injection anidulafungin provided by the invention redissolves medicament, including following component and mass fraction: 45~55 parts of anidulafungin, 45~55 parts of fructose, 220~280 parts of mannitol, 5~7 parts of tartaric acid, 150~200 parts of cosolvent, 2~3.7 parts of pH adjusting agent.The redissolution time that injection anidulafungin provided by the invention redissolves medicament is obviously shortened, and for particulate matter well below limit value, sample is placed in 25 DEG C of acceleration environments lower 6 months, and the redissolution time still conforms to require with effect is redissolved.
Description
Fields
The invention belongs to technical field of medicine, and in particular to a kind of injection anidulafungin redissolves medicament and its preparation
Method.
Background technique
Echinocandin is the inhibitor of fungal cell wall biosynthesis.Its synthesis by destroying 1,3- callose
It plays a role.Anidulafungin (anidulafungin) is the semi-synthetic antifungal of third generation echinocandin class, is echinocandin
The derivative of B is docked by the echinocandin B generated from aspergillus nidulans with the side chain synthesized.
Its molecular structural formula is as follows:
Injection anidulafungin is the Injectable sterile freeze-dried powder of anidulafungin, is developed by Vicuron drugmaker, the U.S.,
In December, 2006 in U.S.'s Initial Public Offering, trade name ERAXIS, anidulafungin does not list at home at present.
Anidulafungin is not soluble in water, is slightly soluble in ethyl alcohol, and the redissolution of anidulafungin is larger problem after freeze-drying, and ERAXIS was once
The use of 20% sterile ethanol solution is to redissolve solvent, rapidly, but ethyl alcohol increases the adverse reaction of patient for dissolution, after change
For the sterile water for injection of same volume, although reducing adverse reaction, dissolution is slack-off, and the redissolution time extends to 5 minutes,
Particulate matter in medical fluid be above standard possibility increase, and redissolve overlong time, equally increase the risk of microbiological contamination, institute
It is needed with developing the injection anidulafungin for being easy to redissolve.Chinese patent application CN12345229A discloses a kind of spine
The prescription of the freeze-dried powder of white rhzomorph, the freeze-dried powder that its echinocandin is mentioned in background of invention was usually redissolved at 1 minute, but was not said
The conditions such as the bright redissolution solvent used.Chinese patent application CN106860856A discloses a kind of prescription of injection anidulafungin
And preparation process, but the data of redissolution are not mentioned.
In conclusion anidulafungin is insoluble in water, it is sterile water for injection that injection anidulafungin, which redissolves solvent, at present,
Redissolve that situation is simultaneously unstable, addition 3ml sterile water for injection dissolves that form anidulafungin dense in the anidulafungin of usual every 10mg
Degree be about 3.33mg/mL solution, dissolve it is slower, can make the particulate matter in medical fluid be above standard possibility increase, and
Time extension is redissolved, the risk of microbiological contamination is equally increased.
Summary of the invention
For the above the deficiencies in the prior art, the purpose of the present invention is to provide a kind of injection anidulafungins to redissolve medicament
And preparation method thereof.Injection anidulafungin provided by the invention redissolves medicament and preparation method thereof, from the redissolution medicament of drug
And lyophilized technique is set about, and by many experiments, is surprised to find that injection anidulafungin prepared by the present invention redissolves answering for medicament
The molten time is obviously shortened, and for particulate matter well below limit value, sample is placed in (sample storage temperature under 25 DEG C of acceleration environments
It is 2~8 DEG C) 6 months, the redissolution time still conforms to require with effect is redissolved.
Technical scheme is as follows:
A kind of injection anidulafungin redissolution medicament, including following component and mass fraction:
45~55 parts of anidulafungin, 45~55 parts of fructose, 220~280 parts of mannitol, 5~7 parts of tartaric acid, cosolvent 150
~200 parts, 2~3.7 parts of pH adjusting agent.
Further, the injection anidulafungin redissolves medicament, including following component and mass fraction:
50 parts of anidulafungin, 50 parts of fructose, 250 parts of mannitol, 5.6 parts of tartaric acid, 175 parts of cosolvent, pH adjusting agent 2.6
Part.
Further, the cosolvent is by polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 8~11:4 in mass ratio
Composition.
Further, the cosolvent is by polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 10:4 group in mass ratio
At.
Further, the pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 5~10 times and dissolved,
Adjusting pH with pH adjusting agent is 4.0~5.5, and temperature remains 10~15 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material
Liquid A；
S2, water for injection of the quality in step S1 20~40% will be added in mixed raw material liquid A made from step S1,
Temperature remains 10~15 DEG C, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: it is filling in cillin bottle by the degerming membrane filtration degerming of mixed raw material liquid C made from step S3, often
Bottle 5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, baffle temperature is reduced to -10~-5
DEG C, 10~30min is kept, baffle temperature is down to -50~-45 DEG C in 20~30min, keeps 1~3h, baffle temperature liter
Temperature keeps 1~2h to -35~-30 DEG C, then temperature is down to -55~-50 DEG C, keeps 2~3h, obtains pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 10~20Pa, partition
Temperature is warming up to -25~-20 DEG C with the heating rate of 3~6 DEG C/h, keeps 5~10h, obtains xeraphium；
3) xeraphium that step 2) is dried to obtain for the first time is carried out second of drying: baffle temperature is warming up to 20 DEG C, does
Dry 5~10h, tamponade, gland to get.
Further, the cellulose microporosity filter membrane that degerming filter membrane is 0.22 μm in the step S4.
The redissolution time of lyophilized preparation, there is no uniform requirements at present, and redissolving rapid freeze-drying sample can be complete in 30 seconds
At some products redissolved the time up to 30 minutes.Overlong time is redissolved, the underproof possibility increasing of medical fluid is redissolved in addition to increasing
Add, also increase the time of patient medication, while also increasing the risk that product is polluted by bacterium, is very unfavorable to patient.
Injection anidulafungin prepared by the present invention redissolves medicament and is redissolved with sterile water for injection, at room temperature in 2 minutes
It can redissolve completely, compared with external commercialized product ERAXIS is up to 5 minutes redissolution time, the required redissolution time obviously subtracts
Few, particulate matter is well below limit value.And the present invention be placed under 25 DEG C of acceleration environments (sample storage temperature be 2~8
DEG C) place 6 months, redissolve the time, particulate matter inspection still conforms to require.
Compared with prior art, beneficial effects of the present invention are as follows:
(1) injection anidulafungin provided by the invention redissolves medicament, and cosolvent uses polyoxyethylene sorbitan monoleate and polyoxyethylene
Rilanit special 60, the two effect mutually collaboration, is not only greatly promoted the dissolution that anidulafungin redissolves medicament, also improves
The stability of medicament can place for a long time under storage condition, and quality is still stable.
(2) preparation method of injection anidulafungin redissolution medicament provided by the invention is dry using multistep freeze, not only
Help is provided to the redissolution of medicament, meanwhile, also improve the stability of medicament storage.
(3) injection anidulafungin provided by the invention redissolves medicament each component and mutually matches, and has reached excellent redissolution
Effect redissolves it in 2min completely, and the required redissolution time significantly reduces, and particulate matter is well below limit value.And
And injection anidulafungin provided by the invention redissolves the stability that medicament improves medicament, places sample storage 6 months, it is multiple
Molten time, particulate matter inspection still conform to require.
(4) injection anidulafungin provided by the invention redissolves medicament each component and mutually matches, and redissolves rapid, it is only necessary to use
Water for injection redissolves, and it is not necessary that ethyl alcohol hydrotropy is added, reduces the adverse reaction of patient, increases the safety of medicament.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
Embodiment 1, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
45 parts of anidulafungin, 45 parts of fructose, 220 parts of mannitol, 5 parts of tartaric acid, 150 parts of cosolvent, 2 parts of pH adjusting agent.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 8:4 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 5 times and dissolved, pH is used
It is 4.0 that regulator, which adjusts pH, and temperature remains 10 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material liquid A；
S2, water for injection of the quality in step S1 20%, temperature will be added in mixed raw material liquid A made from step S1
10 DEG C are remained, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: 0.22 μm of cellulose microporosity filter membrane filtration sterilization of mixed raw material liquid C made from step S3 fills
Loaded in cillin bottle, every bottle of 5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -5 DEG C, is kept
Baffle temperature is down to -45 DEG C in 20min by 10min, keeps 1h, and baffle temperature is warming up to -30 DEG C, keeps 1h, then temperature
Degree is down to -50 DEG C, keeps 2h, obtains pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 10Pa, baffle temperature
- 20 DEG C are warming up to the heating rate of 3 DEG C/h, 5h is kept, obtains xeraphium；
3) xeraphium that step 2) is dried to obtain for the first time is carried out second of drying: baffle temperature is warming up to 20 DEG C, does
Dry 5h, tamponade, gland to get.
Embodiment 2, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
55 parts of anidulafungin, 55 parts of fructose, 280 parts of mannitol, 7 parts of tartaric acid, 200 parts of cosolvent, pH adjusting agent 3.7
Part.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 11:4 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 10 times and dissolved, is used
It is 5.5 that pH adjusting agent, which adjusts pH, and temperature remains 15 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material liquid A；
S2, water for injection of the quality in step S1 40%, temperature will be added in mixed raw material liquid A made from step S1
15 DEG C are remained, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: 0.22 μm of cellulose microporosity filter membrane filtration sterilization of mixed raw material liquid C made from step S3 fills
Loaded in cillin bottle, every bottle of 5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -10 DEG C, is protected
30min to be held, baffle temperature is down to -50 DEG C in 30min, keeps 3h, baffle temperature is warming up to -35 DEG C, keep 2h, then
Temperature is down to -55 DEG C, keeps 3h, obtains pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 20Pa, baffle temperature
- 25 DEG C are warming up to the heating rate of 6 DEG C/h, 10h is kept, obtains xeraphium；
3) xeraphium that step 2) is dried to obtain for the first time is carried out second of drying: baffle temperature is warming up to 20 DEG C, does
Dry 10h, tamponade, gland to get.
Embodiment 3, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
50 parts of anidulafungin, 50 parts of fructose, 250 parts of mannitol, 5.6 parts of tartaric acid, 175 parts of cosolvent, pH adjusting agent 2.6
Part.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 10:4 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 7 times and dissolved, pH is used
It is 4.5 that regulator, which adjusts pH, and temperature remains 12 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material liquid A；
S2, water for injection of the quality in step S1 30%, temperature will be added in mixed raw material liquid A made from step S1
12 DEG C are remained, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: 0.22 μm of cellulose microporosity filter membrane filtration sterilization of mixed raw material liquid C made from step S3 fills
Loaded in cillin bottle, every bottle of 5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -8 DEG C, is kept
Baffle temperature is down to -42 DEG C in 25min by 20min, keeps 2h, and baffle temperature is warming up to -32 DEG C, keeps 1h, then temperature
Degree is down to -52 DEG C, keeps 2h, obtains pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 15Pa, baffle temperature
- 25 DEG C are warming up to the heating rate of 5 DEG C/h, 8h is kept, obtains xeraphium；
3) xeraphium that step 2) is dried to obtain for the first time is carried out second of drying: baffle temperature is warming up to 20 DEG C, does
Dry 8h, tamponade, gland to get.
Embodiment 4, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
48 parts of anidulafungin, 47 parts of fructose, 240 parts of mannitol, 6 parts of tartaric acid, 160 parts of cosolvent, pH adjusting agent 2.8
Part.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 9:4 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 6 times and dissolved, pH is used
It is 5.0 that regulator, which adjusts pH, and temperature remains 10 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material liquid A；
S2, water for injection of the quality in step S1 25%, temperature will be added in mixed raw material liquid A made from step S1
10 DEG C are remained, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: 0.22 μm of cellulose microporosity filter membrane filtration sterilization of mixed raw material liquid C made from step S3 fills
Loaded in cillin bottle, every bottle of 5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -10 DEG C, is protected
30min to be held, baffle temperature is down to -50 DEG C in 30min, keeps 3h, baffle temperature is warming up to -35 DEG C, keep 2h, then
Temperature is down to -55 DEG C, keeps h, obtains pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 20Pa, baffle temperature
- 25 DEG C are warming up to the heating rate of 6 DEG C/h, 10h is kept, obtains xeraphium；
3) xeraphium that step 2) is dried to obtain for the first time is carried out second of drying: baffle temperature is warming up to 20 DEG C, does
Dry 10h, tamponade, gland to get.
Embodiment 5, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
50 parts of anidulafungin, 50 parts of fructose, 260 parts of mannitol, 6.5 parts of tartaric acid, 180 parts of cosolvent, pH adjusting agent 2.7
Part, 4450 parts of water for injection.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 11:4 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 8 times and dissolved, pH is used
It is 5.0 that regulator, which adjusts pH, and temperature remains 14 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material liquid A；
S2, water for injection of the quality in step S1 35%, temperature will be added in mixed raw material liquid A made from step S1
14 DEG C are remained, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: 0.22 μm of cellulose microporosity filter membrane filtration sterilization of mixed raw material liquid C made from step S3 fills
Loaded in cillin bottle, every bottle of 5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -8 DEG C, is kept
Baffle temperature is down to -50 DEG C in 25min by 25min, keeps 3h, and baffle temperature is warming up to -35 DEG C, keeps 2h, then temperature
Degree is down to -55 DEG C, keeps 3h, obtains pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 20Pa, baffle temperature
- 25 DEG C are warming up to the heating rate of 6 DEG C/h, 10h is kept, obtains xeraphium；
3) xeraphium that step 2) is dried to obtain for the first time is carried out second of drying: baffle temperature is warming up to 20 DEG C, does
Dry 10h, tamponade, gland to get.
Comparative example 1, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
50 parts of anidulafungin, 50 parts of fructose, 250 parts of mannitol, 5.6 parts of tartaric acid, 175 parts of cosolvent, pH adjusting agent 2.6
Part.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 1:1 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The preparation process that the injection anidulafungin redissolves medicament is same as Example 3.
Comparative example 1 is substantially the same manner as Example 3, and difference is, the cosolvent polyoxyethylene sorbitan monoleate and polyoxyethylene of comparative example 1
The ratio of rilanit special 60 becomes 1:1.
Comparative example 2, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
50 parts of anidulafungin, 50 parts of fructose, 250 parts of mannitol, 5.6 parts of tartaric acid, 175 parts of polyoxyethylene sorbitan monoleate, pH are adjusted
2.6 parts of agent.
The pH adjusting agent is sodium hydroxide.
The preparation process that the injection anidulafungin redissolves medicament is same as Example 3.
Comparative example 2 is substantially the same manner as Example 3, and difference is, the cosolvent of comparative example 2 is one-component polysorbate
80。
Comparative example 3, a kind of injection anidulafungin redissolve medicament
The injection anidulafungin redissolves medicament, is made of following component and mass fraction:
50 parts of anidulafungin, 50 parts of fructose, 250 parts of mannitol, 5.6 parts of tartaric acid, 175 parts of cosolvent, pH adjusting agent 2.6
Part.
The cosolvent is made of polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60 10:4 in mass ratio.
The pH adjusting agent is sodium hydroxide.
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 7 times and dissolved, pH is used
It is 4.5 that regulator, which adjusts pH, and temperature remains 12 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material liquid A；
S2, water for injection of the quality in step S1 30%, temperature will be added in mixed raw material liquid A made from step S1
12 DEG C are remained, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering obtains
Mixed raw material liquid C；
S4, degerming: 0.22 μm of cellulose microporosity filter membrane filtration sterilization of mixed raw material liquid C made from step S3 fills
Loaded in cillin bottle, every bottle of 5mL；
S5, freeze-drying: it is -8 DEG C of pre-cooling 2h that the canned cillin bottle of step S4, which is placed in temperature on drying box shelf, so
It is afterwards -52 DEG C in temperature, under the conditions of vacuum degree is 15Pa, dry 8h, tamponade, gland to obtain the final product.
Comparative example 4 is substantially the same manner as Example 3, and difference is, the method dry using directly freezed of comparative example 4.
Test example one redissolves time test
1, test material: the injection anidulafungin of embodiment 1-5 and comparative example 1-3 preparation redissolves medicament.
2, test method:
The injection anidulafungin of Example 1-5 and comparative example 1-3 preparation redissolves medicament respectively, and aseptic injection is added and uses
Water (anidulafungin of every 10mg redissolves medicament and uses 3ml sterile water for injection), takes same amount of pure anidulafungin drug powder,
It repeats above-mentioned dissolution and operates and be denoted as control, visual observations 2min, the dissolution degree of each group, the clarity for redissolving liquid.Test knot
Fruit is as shown in table 1.
Then, that 25 DEG C of above-mentioned sample placements are carried out above-mentioned visual observations test result in 6 months is as shown in table 2.
Particulate determination: taking the solution after redissolving, by (the particulate matter inspection of " Chinese Pharmacopoeia " the 4th general rule 0903
Look into method) the first method inspection, the population of every bottle of partial size >=10 μm must not cross 6000, and the population of every bottle of partial size >=25 μm must not
Cross 600.
Table 1 redissolves 2min and redissolves test data
As shown in Table 1, compared with the control, the sample of 1-5 of the embodiment of the present invention, which redissolves, stablizes, and can redissolve within 2 minutes completely,
Particulate matter inspection meets the requirements, and wherein 3 effect of embodiment is good, is highly preferred embodiment of the present invention；With comparative example 1-3 phase
Than the effect of the embodiment of the present invention 3 is more excellent.
25 DEG C of 2 sample of table placements, 6 months redissolution test datas
As can be seen from Table 2, compared with the control, the sample of 1-5 of the embodiment of the present invention is placed 6 months in 25 DEG C of acceleration, multiple
Molten time, particulate matter inspection still conform to require, wherein and 3 effect of embodiment is good, is highly preferred embodiment of the present invention, with
Comparative example 1-3 is compared, and redissolution time of embodiment 3, particulate matter inspection result are more preferably, it is anticipated that the present invention is in storage rings
It is placed for a long time under border, quality is still stable.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (5)
1. a kind of injection anidulafungin redissolves medicament, which is characterized in that including following component and mass fraction:
45~55 parts of anidulafungin, 45~55 parts of fructose, 220~280 parts of mannitol, 5~7 parts of tartaric acid, cosolvent 150
~200 parts, 2~3.7 parts of pH regulator；The cosolvent is pressed by polyoxyethylene sorbitan monoleate and polyoxyethylene hydrogenated castor oil 60
8~11:4 of mass ratio composition；The pH regulator is sodium hydroxide；
The injection anidulafungin redissolves the preparation process of medicament, comprises the following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 5~10 times and dissolved, is used
It is 4.0~5.5 that pH regulator, which adjusts pH, and temperature remains 10~15 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material
Liquid A；
S2, water for injection of the quality in step S1 20~40%, temperature will be added in mixed raw material liquid A made from step S1
Degree remains 10~15 DEG C, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering is mixed
Close material liquid C；
S4, degerming: it is filling in cillin bottle by the degerming membrane filtration degerming of mixed raw material liquid C made from step S3, every bottle
5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -10~-5 DEG C,
10~30min is kept, baffle temperature is down to -50~-45 DEG C in 20~30min, keeps 1~3h, baffle temperature
- 35~-30 DEG C are warming up to, 1~2h is kept, then temperature is down to -55~-50 DEG C, keeps 2~3h, obtain pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 10~20Pa, partition
Temperature is warming up to -25~-20 DEG C with the heating rate of 3~6 DEG C/h, keeps 5~10h, obtains xeraphium；
3) by xeraphium that step 2) is dried to obtain for the first time carry out second it is dry: baffle temperature is warming up to 20 DEG C, dry 5~
10h, tamponade, gland to get.
2. the injection anidulafungin as described in claim 1 redissolves medicament, which is characterized in that including following component and quality
Number:
50 parts of anidulafungin, 50 parts of fructose, 250 parts of mannitol, 5.6 parts of tartaric acid, 175 parts of cosolvent, pH adjusting agent
2.6 part.
3. the injection anidulafungin as described in claim 1 redissolves medicament, which is characterized in that the cosolvent is by poly- sorb
Ester 80 and polyoxyethylene hydrogenated castor oil 60 10:4 in mass ratio composition.
4. the preparation process that a kind of injection anidulafungin as described in claim 1 redissolves medicament, which is characterized in that include
Following steps:
S1, match liquid: tartaric acid, fructose, mannitol, cosolvent being added in the water for injection that quality is 5~10 times and dissolved, is used
It is 4.0~5.5 that pH regulator, which adjusts pH, and temperature remains 10~15 DEG C, and anidulafungin, which is added, to be made to dissolve, and obtains mixed raw material
Liquid A；
S2, water for injection of the quality in step S1 20~40%, temperature will be added in mixed raw material liquid A made from step S1
Degree remains 10~15 DEG C, is uniformly mixed, obtains mixed raw material liquid B；
S3, it removes endotoxin: active carbon being added into the mixed raw material liquid B that step S2 is obtained and stirs 30min, filtering is mixed
Close material liquid C；
S4, degerming: it is filling in cillin bottle by the degerming membrane filtration degerming of mixed raw material liquid C made from step S3, every bottle
5mL；
S5, freeze-drying:
1) pre-freeze: the canned cillin bottle of step S4 is placed on drying box shelf, and baffle temperature is reduced to -10~-5 DEG C,
10~30min is kept, baffle temperature is down to -50~-45 DEG C in 20~30min, keeps 1~3h, baffle temperature
- 35~-30 DEG C are warming up to, 1~2h is kept, then temperature is down to -55~-50 DEG C, keeps 2~3h, obtain pre- agar；
2) the pre- agar for obtaining step 1) pre-freeze carries out dry for the first time: drying box vacuum degree is 10~20Pa, baffle temperature
- 25~-20 DEG C are warming up to the heating rate of 3~6 DEG C/h, 5~10h is kept, obtains xeraphium；
3) by xeraphium that step 2) is dried to obtain for the first time carry out second it is dry: baffle temperature is warming up to 20 DEG C, dry 5~
10h, tamponade, gland to get.
5. the preparation process that the injection anidulafungin as described in claim 4 redissolves medicament, which is characterized in that the step
The cellulose microporosity filter membrane that degerming filter membrane is 0.22 μm in S4.
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| AU776782C (en) * | 1999-03-03 | 2005-04-07 | Eli Lilly And Company | Echinocandin pharmaceutical formulations containing micelle-forming surfactants |
| US6991800B2 (en) * | 2002-06-13 | 2006-01-31 | Vicuron Pharmaceuticals Inc. | Antifungal parenteral products |
| CN102488888B (en) * | 2011-01-31 | 2014-07-30 | 上海天伟生物制药有限公司 | Medicinal composition containing echinocandin antifungal agent and preparation method and application thereof |
| CN105641678A (en) * | 2014-12-03 | 2016-06-08 | 博瑞生物医药（苏州）股份有限公司 | Anidulafungin parenteral preparation and preparation method thereof |
| PL3058958T3 (en) * | 2015-02-23 | 2019-02-28 | Selectchemie Ag | Anidulafungin composition |
| CN106860856B (en) * | 2015-12-14 | 2019-05-31 | 山东新时代药业有限公司 | A kind of freeze-dried powder and preparation method containing anidulafungin |
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