CN109820827A - A kind of injection azacitidine freeze-dried powder and preparation method thereof - Google Patents
A kind of injection azacitidine freeze-dried powder and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of injection azacitidine freeze-dried powder, raw material recipe ratio by weight includes: 2~8 parts of azacitidines, 2~8 portions of mannitol, 100~300 parts of acetonitriles and 684~896 parts of water.It additionally provides the preparation method of injection azacitidine freeze-dried powder: partial syringe water being added in Agitation Tank；Addition parts by weight are 100~300 parts of acetonitriles, are stirred to clarify；It is 2~8 parts of mannitol that parts by weight, which are added, and stirring is cooled to 0~4 DEG C to being completely dissolved；The azacitidine bulk pharmaceutical chemicals that the parts by weight being micronized in advance are 2~8 parts are weighed, after some residual water for injection rinse, Agitation Tank is added, and are vigorously stirred to dissolution, water for injection is added and is settled to 1000 parts；Aseptic filtration, it is filling, after freeze-drying, obtain formulation products.Partial size and the total impurities that product can be effectively controlled are horizontal, and the bioequivalences such as dissolution curve of product index is ground condition with original and worked as, and total impurities level grinds product better than original.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of injection azacitidine freeze-dried powder.
Background technique
Azacitidine is a kind of cytosine nucleoside analogs, is mainly used for treating myelodysplastic syndrome.U.S. FDA
Ratified drug listing in 2004, since the active constituent azacitidine stability of the drug is poor, hydrolysis rapidly in water,
So preparation in the market is powder injection formulation.
The existing U.S. and domestic listing have injection azacitidine freeze-dried powder, and China only has original at present and grinds launch.It should
The difficult point of product development is the product there are two types of administration mode, and one be that redissolve be the laggard row vein infusion of solution, and two be redissolution
To be subcutaneously injected after suspension.Wherein, hypodermic administration mode is due to being related to stability, the safety of drug products for administration
With validity, FDA has issued the bioequivalence Guide to research of the product, it is desirable that particle size (D10, D50, the D90 of product
It is controlled with distribution Span), dissolution, osmotic pressure, pH, viscosity etc. with relevant parameter is administered, and grinds product with original and compare, with
Reach and grinds the comparable bioequivalence of product with original.Meanwhile the principle that imitation medicine is examined according to FDA, imitation medicine in addition to answering first
The satisfaction and it is former grind except the bioequivalence of product, should also meet identical stability and impurity spectrum, that is, imitation medicine long-term and
Accelerated stability Ying Yuyuan grinds condition and works as, and the content reduction during stability is placed should not influence that validity is administered, and stability is put
Impurity growth during setting is not to be exceeded original and grinds product, to prevent security risks caused by higher impurity level and gene poison
Property risk.
Product are ground in the technical data of FDA, EMA and Japan PMDA, entire production process of the Yuan Yanpin in the product according to original
In, low temperature control is carried out including the production line with liquid, filtering, filling, feeding, freeze-drying process, to control the impurity of product
It is horizontal.Meanwhile according to the data, azacitidine has 5 kinds of crystalline state, 3 kinds of pseudocrystalline states, and original is ground product and passed through to dicyandiamide solution and freeze-drying work
The control of skill, the product of output specific crystal formation and partial size.The study found that original, which grinds product, is used only water as solvent formula, output is brilliant
Type I, the mixing crystal form of crystal form II and a small amount of amorphous state, there is specific viscosity, particle size and dissolution rate after redissolution.But root
According to China even the whole world aseptic medicine production equipment Sterilized isolator equipment situation summarize, most producers it is sterile every
Collect folk songs influence to aseptic performance due to being related to low temperature from device and low temperature collect folk songs after the biggish temperature fluctuation range of isolator can
Can be to the influence of HEPA and bulking system filling accuracy, the isolator of most manufacturers is not set using low temperature temperature control in the world
Meter.Therefore, for the production equipment of most manufacturers, filtering, filling, feeding process temperature-controllable be cannot achieve,
And 5 times in the case where the degradation rate of room temperature is about low temperature of the product, therefore in the case where Sterilized isolator non-temperature control, hardly
Possible output and original grind condition when water being used only as freezing solvent system and impurity level with original grinds the comparable product of product.
The patent of invention of publication number CN101632643A provides and a kind of treats myelodysplastic syndrome drug Ah Zhas
Freeze-dried powder of cytidine and preparation method thereof, azacitidine freeze-drying powder injection prescription is by azacitidine, mannitol and dimension
Raw element C composition.The purpose of patent of invention auxiliary material is added to vitamin C is caused for " being not in the case where forming crystal form "
The dissolved corrosion and stability for dissolving out partial size cannot control, and can not prove its validity.
The patent of invention of publication number CN104706650A provides a kind of azacitidine lyophilized preparation that property is stable, living
Property ingredient be therapeutically effective amount azacitidine, also containing organic solvent, freeze-drying proppant and water for injection in solution before being lyophilized,
The organic solvent be selected from ethyl alcohol, isopropanol, methanol or its arbitrarily compare mixed liquor.The patent has used ethyl alcohol, isopropanol, methanol
Or other hydroxyl alcohols as solvent accelerate pharmaceutically active agents dissolution, but the study found that ethyl alcohol, isopropanol, methanol or its
When its hydroxyl alcohols is as solvent, since there are several hydroxyls for the ribose ring of mannitol and azacitidine, with solvent hydroxyl
Interaction can be substantially reduced in the partial size of crystal that the freeze-drying stage is formed, thus its bioequivalence for redissolving suspension without
Method reaches requirement of the FDA to the product bioequivalence.
International monopoly WO2014076616 discloses a kind of azacitidine freeze-dried composition, and raw material includes azacitidine, sweet
Reveal pure and mild acetonitrile, ratio is about 4:4:320.Since azacitidine is almost insoluble in acetonitrile, although a high proportion of acetonitrile can prolong
The degradation rate of slow hydrolysis impurity, but equally obstruction can be generated to bulk pharmaceutical chemicals solution rate is improved, and a high proportion of acetonitrile needs
Longer dissolution time keeps it limited to the inhibiting effect of bulk pharmaceutical chemicals dissolution phase impurity level, makes initial after medical fluid constant volume
Impurity level can't be significantly improved.Also, it is crystal form IV to crystal form VIII that this document, which mentions the patent system for crystal form, is ground with original
Product crystal form I and crystal form II have significant difference, therefore its partial size also may grind product with original and have any different, the difference of crystal form and partial size, lead to
It often will cause the significant difference of dissolution curve, therefore, product can not have by U.S. FDA bioequivalence guidelines
Practicability.
Summary of the invention
To solve problems of the prior art, the present invention provides a kind of injection azacitidine freeze-dried powder and its
Preparation method, partial size and the total impurities that product can be effectively controlled are horizontal, produce the bioequivalences such as dissolution curve index and original
It grinds condition to work as, meets bioequivalence requirement, total impurities level grinds the product of product better than original.
In order to achieve the object of the present invention, the technical solution adopted by the present invention is that:
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Than are as follows: 2~8 parts of azacitidines, 2~8 portions of mannitol and 100~300 parts of acetonitriles.
Preferably, a kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, heavy
Measure part recipe ratio are as follows: 4~6 parts of azacitidines, 4~6 portions of mannitol and 140~240 parts of acetonitriles.
Preferably, ratio of the acetonitrile in material liquid system is 140~240mg/g.
The present invention also provides a kind of methods for preparing injection azacitidine freeze-dried powder, include the following steps:
(1) partial syringe water is added in Agitation Tank；
(2) parts by weight are added is 100~300 parts of acetonitriles, is stirred to clarify；
(3) mannitol that parts by weight are 2~8 parts is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added,
Remaining water for injection additional amount is calculated, 0~4 DEG C is cooled to and is sufficiently stirred；
(4) the azacitidine bulk pharmaceutical chemicals that the parts by weight being micronized in advance are 2~8 parts are weighed, some residual injection is used
After water rinse, Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1000 parts；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
Preferably, the step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
Preferably, the partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1-1.2 μm, and the raw material of micronization can dissolve in
It is significant to shorten the production technology time in liquid dicyandiamide solution, reduce the generation of hydrolysis impurity, and the raw material being micronized pass through it is specific
Charging sequence, different supplementary material when being added temperature and the sequence of cooling step and the difference of solution rate be significantly reduced it is molten
Acetonitrile and bulk pharmaceutical chemicals/mannitol bonding force in liquid, the residual acetonitrile being substantially reduced in finished product is horizontal, and the residual for reducing product is molten
Agent risk.
The beneficial effects of the present invention are:
1, only original grinds launch at present in China, and production technology of the invention can produce every bioequivalence of product
Property index includes that viscosity, partial size, microscopic morphology, dissolution curve etc. are all ground condition with original and worked as, and the residual solvent acetonitrile in product is low
In ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) daily intaking amount limit 410ppm, total impurities level is ground better than original
Product.
2, azacitidine can be degraded to single order hydrolysate formyl amidino groups ribosyl urea in aqueous solution, further be degraded to two
Rank hydrolysate amidino groups ribosyl urea and its isomers slow down single order hydrolysate and second order the purpose of the present invention is preventing to degrade
The generation rate of hydrolysate.Organic solvent acetonitrile is added in formula and screens suitable 140~240mg/g of solvent ratios to subtract
Low in hydrolysis rate.
3, active pharmaceutical ingredient is micronized to 1-1.2 μm of partial size in advance to accelerate rate of dissolution.If not passing through acceleration
The mode of rate of dissolution, entire art production process, hydrolysis impurity caused by dissolution of raw material total time is more than 2.5%, is exceeded
The acceptable standard that finished product is let pass, makes to produce almost impossible progress.And by this technique, hydrolysis can be kept within a few hours
Impurity content is less than 2.5%.Meanwhile temperature and cooling walk when being added by control partial size, feeding sequence and different supplementary materials
Rapid sequence is to reduce the bonding force of acetonitrile in bulk pharmaceutical chemicals and dicyandiamide solution, to reduce acetonitrile residual solvent level, by ICH
The residual of (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) II class solvent acetonitrile is reduced to well below daily intaking amount safety
Below the mark level avoids the genotoxicity risk of residual solvent.And it is walked using low temperature with liquid, adjusting process in production process
Rapid sequence is to shorten the process time.
4, optimization of the present invention to production technology uses acetonitrile as the solvent for accelerating dissolution, both avoids using other
Some organic solvents, the product crystal form and partial size and reference preparation difference of output are larger, are not able to satisfy bioequivalence requirement, again
The formation speed for having significantly slowed azacitidine hydrolysis impurity makes it to produce the drug that impurity level grinds product better than original, subtract
The genotoxicity hidden danger of related impurities in impurity spectrum is lacked.
5, use 0~4 DEG C of low temperature with liquid, adjusting process sequence of steps to shorten the process time in production process, usually
Drug solution preparing process be solubilizer plus auxiliary material, plus raw material, rinse raw material feeding-distribution device, constant volume of weighing after dissolution of raw material, this
Technique adds raw material, rinse and constant volume using solubilizer plus auxiliary material, pre-weighed constant volume, and constant volume step is set in auxiliary material and is added
Afterwards, it directly weighs constant volume weight of solvent and uses the weight solvent rinse, the synchronous dissolution drug of rinse significantly shortens raw material
The process time of dissolution and constant volume improves liquid medicine stability, to improve the quality of the pharmaceutical preparations.
Detailed description of the invention
Fig. 1 is the dissolution curve comparison diagram that original grinds ginseng product preparation and present invention self-control sample.
Fig. 2 is the XRD testing result of present invention self-control sample.
Specific embodiment
In order to it is clearer, explain purpose of the present invention technical solution in detail, below by related embodiment to this hair
It is bright to be described further.Following embodiment is only to illustrate implementation method of the invention, does not limit protection of the invention
Range.
Embodiment 1
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Are as follows: 2g azacitidine, 2g mannitol, 100g acetonitrile and 896g water.
Embodiment 2
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Are as follows: 8mg azacitidine, 8mg mannitol, 300mg acetonitrile and 684mg water.
Embodiment 3
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Are as follows: 4g azacitidine, 4g mannitol, 140g acetonitrile and 852g water.
Embodiment 4
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Are as follows: 6g azacitidine, 6g mannitol, 240g acetonitrile and 748g water.
Embodiment 5
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Are as follows: 5mg azacitidine, 5mg mannitol and 160mg acetonitrile and 830mg water.
Embodiment 6
A kind of injection azacitidine freeze-dried powder, raw material include azacitidine, mannitol and acetonitrile, parts by weight formula
Are as follows: 5mg azacitidine, 5mg mannitol, 180mg acetonitrile and 890mg water.
Embodiment 7
The preparation method of 1 injection azacitidine freeze-dried powder of embodiment, comprising the following steps:
(1) water for injection of part formulation amount is added in Agitation Tank；
(2) acetonitrile of formula ratio is added, stirs to clarify；
(3) mannitol of formula ratio is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining
Water for injection additional amount, and it is cooled to 0 DEG C；
(4) the azacitidine bulk pharmaceutical chemicals for weighing the formula ratio being micronized in advance, after some residual water for injection rinse,
Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1kg；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
Embodiment 8
The preparation method of 2 injection azacitidine freeze-dried powder of embodiment, comprising the following steps:
(1) water for injection of part formulation amount is added in Agitation Tank；
(2) acetonitrile of formula ratio is added, stirs to clarify；
(3) mannitol of formula ratio is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining
Water for injection additional amount, and it is cooled to 4 DEG C；
(4) the azacitidine bulk pharmaceutical chemicals for weighing the formula ratio being micronized in advance, after some residual water for injection rinse,
Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1g；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1 μm.
Embodiment 9
The preparation method of 3 injection azacitidine freeze-dried powder of embodiment, comprising the following steps:
(1) water for injection of part formulation amount is added in Agitation Tank；
(2) acetonitrile of formula ratio is added, stirs to clarify；
(3) mannitol of formula ratio is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining
Water for injection additional amount, and it is cooled to 4 DEG C；
(4) the azacitidine bulk pharmaceutical chemicals for weighing the formula ratio being micronized in advance, after some residual water for injection rinse,
Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1kg；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1 μm.
Embodiment 10
The preparation method of 4 injection azacitidine freeze-dried powder of embodiment, step are same as Example 9.
Embodiment 11
The preparation method of 5 injection azacitidine freeze-dried powder of embodiment, comprising the following steps:
(1) water for injection of 80% formula ratio is added in Agitation Tank；
(2) acetonitrile of formula ratio is added, stirs to clarify；
(3) mannitol of formula ratio is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining
Water for injection additional amount, and it is cooled to 1 DEG C；
(4) the azacitidine bulk pharmaceutical chemicals for weighing the formula ratio being micronized in advance, after some residual water for injection rinse,
Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1g；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1.2 μm.
Embodiment 12
The preparation method of 6 injection azacitidine freeze-dried powder of embodiment, comprising the following steps:
(1) water for injection of 80% formula ratio is added in Agitation Tank；
(2) acetonitrile of formula ratio is added, stirs to clarify；
(3) mannitol of formula ratio is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining
Water for injection additional amount, and it is cooled to 2 DEG C；
(4) the azacitidine bulk pharmaceutical chemicals for weighing the formula ratio being micronized in advance, after some residual water for injection rinse,
Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1g；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1.1 μm.
Embodiment 13
A kind of preparation method of injection azacitidine freeze-dried powder, comprising the following steps:
(1) 680mg water for injection is added in Agitation Tank；
(2) 142mg acetonitrile is added, stirs to clarify；
(3) 4mg mannitol is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining injection
Water additional amount, and it is cooled to 2 DEG C；
(4) the 4mg azacitidine bulk pharmaceutical chemicals being micronized in advance are weighed, after 100mg water for injection rinse, is added and matches liquid
Tank, and be vigorously stirred to dissolution, water for injection is added and is settled to 1g；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1.1 μm.
Embodiment 14
A kind of preparation method of injection azacitidine freeze-dried powder, comprising the following steps:
(1) 600mg water for injection is added in Agitation Tank；
(2) 238mg acetonitrile is added, stirs to clarify；
(3) 6mg mannitol is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining injection
Water additional amount, and it is cooled to 2 DEG C；
(4) the 6mg azacitidine bulk pharmaceutical chemicals being micronized in advance are weighed, after 100mg water for injection rinse, is added and matches liquid
Tank, and be vigorously stirred to dissolution, water for injection is added and is settled to 1g；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1.1 μm.
Embodiment 15
A kind of preparation method of injection azacitidine freeze-dried powder, comprising the following steps:
(1) 700g water for injection is added in Agitation Tank；
(2) 124g acetonitrile is added, stirs to clarify；
(3) 3g mannitol is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates remaining injection
Water additional amount, and it is cooled to 2 DEG C；
(4) the 3g azacitidine bulk pharmaceutical chemicals being micronized in advance are weighed, after 120g water for injection rinse, is added and matches liquid
Tank, and be vigorously stirred to dissolution, water for injection is added and is settled to 1kg；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
The step (5) carries out aseptic filtration to medical fluid by two concatenated sterilizing filters.
The partial size D50 of the azacitidine bulk pharmaceutical chemicals is 1.0 μm.
Embodiment 16
Agitation Tank tare weight is weighed, about 80L water for injection is added in Agitation Tank, 16.0kg acetonitrile is added and stirs to clarify, adds
Enter 500g mannitol to stir to dissolution, weigh and auxiliary material total weight has been added, calculates remaining water for injection additional amount.Use temperature control system
After system is cooled to 0-4 DEG C and is sufficiently stirred, it is added and is micronized azacitidine bulk pharmaceutical chemicals 500g in advance, be vigorously stirred complete to bulk pharmaceutical chemicals
Fully dissolved.Remaining water for injection is added, medical fluid is settled to crowd volume 100kg.By two concatenated sterilizing filters to medical fluid
Aseptic filtration is carried out, filter pressure is no more than 0.2MPa.No. 2 filters of medicine liquid washing and bulking system are used before filling beginning,
Filling 20.0mL medical fluid after freeze-drying, obtains formulation products into 30mL neutrality borosilicate clear vial.
The present invention uses acetonitrile to need to consider as dicyandiamide solution at 3 points:
1) acetonitrile is ICH II class solvent, has potential genetoxic, therefore ICH is limited to its day maximum intake
410ppm can generate the residue problem of acetonitrile in product.
2) azacitidine is almost insoluble in acetonitrile, can delay the degradation rate of hydrolysis impurity, but equally can be former to improving
Expect that medicine solution rate generates obstruction.Therefore it may require that longer dissolution time after acetonitrile being added, limit it and bulk pharmaceutical chemicals are dissolved
The inhibiting effect of stage impurity level significantly improve initial impurity level after medical fluid constant volume cannot.Meanwhile with raw material
The extension of medicine dissolution time, residual solvent ethane nitrile content can also significantly improve, the study found that this may be due to acetonitrile/water
Caused by bonding force intensity/quantity with the formed hydrogen bond of supplementary material.Therefore, in order to delay the degradation rate of hydrolysis impurity, again
The dissolution of azacitidine is not influenced, and the acetonitrile residual solvent of finished product is controlled in ICH limit hereinafter, the reasonable preparation of selection
Method is extremely important to the qualified product of production.
3) acetonitrile, due to solvation, can inhibit azacitidine to form crystal form I and crystal form II in high proportion,
And tend to be formed crystal form IV to crystal form VIII, it is therefore desirable to control suitable acetonitrile ratio and special lyophilized technique to guarantee
Crystal form needed for it forms azacitidine drug.
The present invention solves the problems, such as the 1st, 2 by the way that the partial size D50 for controlling azacitidine bulk pharmaceutical chemicals is 1-1.2 μm.Pass through
Adjustment acetonitrile ratio is 140~240mg/g come crystal form needed for ensuring to be formed azacitidine drug.
It is found in research, since it is smaller when the particle size of azacitidine bulk pharmaceutical chemicals is greater than 1.2 μm in dissolution
Specific surface area, make dissolve interface dissolution time extend；And when azacitidine bulk pharmaceutical chemicals particle size less than 1 μm, due to
The effect of its surface tension and surface charge, easily agglomerates during feeding intake, and needs longer dissolution time, and partial size instead
The too small liquid dispensing container wall that is easily adsorbed in during feeding intake causes content loss.Therefore bulk pharmaceutical chemicals are micronized by applicant, and are controlled
Making specific particle size is 1-1.2 μm, significantly shortens liquid preparation time (dissolution time is no more than 15 minutes), therefore significant
The initial impurity for improving medical fluid is horizontal (impurity is no more than 0.1% when 0 after constant volume), grinds the impurity level of product lower than original
Product.
Experiment discovery, the sequence and bulk pharmaceutical chemicals of temperature and cooling step when different charging sequence, different supplementary materials are added
Partial size has a significant impact the bonding force of residual solvent.The present invention has carried out following experiment, to confirm different key combinations
Whether SOLUTION PROPERTIES can be had an impact, applicant generates the sample of different Hydrogenbond modes by different charging sequences
Product replace acetonitrile using poly- acetonitrile, and macromolecular is easier to unfold and crimp in the solution, so as to generate shadow to solution properties
It rings, is easy to observe the property of medical fluid by different Testing index, result of study is as follows:
As seen from the above table, there are about 1% difference for medical fluid density prepared by different charging sequence, the possible reason is
Poly- acetonitrile is formed by the bonding force of hydrogen bond with mannitol, bulk pharmaceutical chemicals after being added and is bonded quantity difference, makes the molecule of poly- acetonitrile
In the state of diastole or curling difference, so that solution density different from.In addition, the rheology viscosity to the two batches medical fluid carries out
Detection, similarly finds its rheology viscosity different from.Therefore, above-mentioned the experiment proves that identical substance and material concentration,
Key combination and quantity will affect solution properties, to influence product attribute.
Further experiment discovery, identical acetonitrile ratio, its dissolution time of the bulk pharmaceutical chemicals of different-grain diameter size is variant,
Equally there were significant differences for residual solvent, is as follows:
As seen from the above table, residual solvent ethane nitrile content does not reduce with partial size and is reduced, but with the shortening of dissolution time
And it reduces.It may be since the course of dissolution that substance reaches equilbrium solubility is bonding force such as hydrogen bond, ion inside substance
The bonding forces such as key, Van der Waals force dissociate or depolymerization, while reaching the process of balance with external solvent system intermolecular linkage resultant force.Ah
The solubility of bundle cytidine in water is bigger, and almost insoluble in acetonitrile, faster solution rate makes the key between azacitidine/water
Quantity and intensity are easier to reach balance, thus the emulative generation for inhibiting azacitidine/acetonitrile bond number amount and intensity, from
And residual solvent is had an impact, residual solvent is far below ICH standard, obtains total impurities level more preferably product.
Therefore, the present invention has carried out comprehensive research to preparation steps and technological parameter, to optimize technique in process
Step, the creative Optimal Control realized to residual solvent.
Table 1, present invention self-control sample and the former partial size contrast table for grinding product
Table 2, present invention self-control sample and original grind product Comprehensive Correlation.
The Detection of Stability of product under table 3, acceleration environment
By table 1- table 3 as it can be seen that the present invention is by the optimization to production technology, the every bioequivalence for producing product refers to
Mark all grinds condition with original including viscosity, partial size, microscopic morphology, dissolution curve (Fig. 1) etc. and works as.XRD testing result (Fig. 2) is also shown
The crystal form of this product grinds that product are consistent with original, therefore this product meets bioequivalence requirement of the FDA to the product, practicability compared with
It is good.Also, the total impurities level of this product grinds product also superior to original, not only conforms to the fundamental requirement of national drug Conformance Assessment,
The shelf life of product may be extended to 5 years from 4 years by lower total impurities controlled level, to improve the economy of product storage
Property and validity.
Lyophilized technique of the invention is as follows:
A, feeding: the freeze dryer that feeding to plate layer temperature is -5~0 DEG C；
B, it freezes: being cooled to -10~-5 DEG C in freeze drying chamber 10min, 3~5h of product pre-freeze；
- 50~-40 DEG C are cooled in 1h, 5~7h of product pre-freeze；
- 12~-8 DEG C are warming up in 2~6h, 3~5h of product pre-freeze；
- 50~-40 DEG C are cooled in 1~5h, 3~5h of product pre-freeze；
- 14~-10 DEG C are warming up in 2~6h, 3~5h of product pre-freeze；
- 50~-40 DEG C are cooled in 1~5h, 3~5h of product pre-freeze；
C, lyophilization: -50~-40 DEG C, 50 μ bar, 15~18h is kept；
It is warming up to -35~-20 DEG C, 50 μ bar in 1h, keeps 5~7h；
It is warming up to -9~-2 DEG C, 50 μ bar in 6h, keeps 5~7h；
D, desorbing and drying: being warming up to 20~30 DEG C, 50 μ bar in 6h, keeps 3h；
It is warming up to 30~40 DEG C, 50 μ bar in 1h, keeps 1h.
In lyophilized technique by the way of Gradient annealing, to pre-freeze velocity and time, pre-freezing temperature and time, annealing temperature
It is optimized with time, gradient steps, gradient temperature, it is consistent to further ensure that output crystal form and bioequivalence with original grind product；
Meanwhile the annealing process after optimization further decreases the residual solvent level in product, reaches the indices of product very
Or product standard is ground better than original.
A specific embodiment of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.
Claims (6)
1. a kind of injection azacitidine freeze-dried powder, which is characterized in that raw material includes azacitidine, mannitol and acetonitrile,
Parts by weight recipe ratio are as follows: 2~8 parts of azacitidines, 2~8 portions of mannitol, 100~300 parts of acetonitriles and 684~896 parts of water.
2. injection azacitidine freeze-dried powder according to claim 1, which is characterized in that raw material includes azacitidine, sweet
Reveal pure and mild acetonitrile, parts by weight recipe ratio are as follows: 4~6 parts of azacitidines, 4~6 portions of mannitol, 140~240 parts of acetonitriles and 748~
852 parts of water.
3. injection azacitidine freeze-dried powder according to claim 1, which is characterized in that acetonitrile is in material liquid system
Ratio is 140~240mg/g.
4. the preparation method of injection azacitidine freeze-dried powder according to claim 1, which is characterized in that including following step
It is rapid:
(1) partial syringe water is added in Agitation Tank；
(2) parts by weight are added is 100~300 parts of acetonitriles, is stirred to clarify；
(3) mannitol that parts by weight are 2~8 parts is added, stirs to being completely dissolved, weighs total weight after Agitation Tank is added, calculates
Remaining water for injection additional amount is cooled to 0~4 DEG C and is sufficiently stirred；
(4) the azacitidine bulk pharmaceutical chemicals that the parts by weight being micronized in advance are 2~8 parts are weighed, are moistened using some residual water for injection
After washing, Agitation Tank is added, and is vigorously stirred to dissolution, water for injection is added and is settled to 1000 parts；
(5) aseptic filtration, it is filling, after freeze-drying, obtain formulation products.
5. the preparation method of injection azacitidine freeze-dried powder according to claim 4, which is characterized in that the step
(5) aseptic filtration is carried out to medical fluid by two concatenated sterilizing filters.
6. a kind of preparation method of injection azacitidine freeze-dried powder according to claim 4, which is characterized in that described
The partial size D50 of azacitidine bulk pharmaceutical chemicals is 1-1.2 μm.
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| WO2013117969A1 (en) * | 2012-02-06 | 2013-08-15 | Fresenius Kabi Oncology Ltd. | Process for preparing stable pharmaceutical compositions of compounds susceptible to hydrolysis |
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