CN110314141A - A kind of dextrorotation oxiracetam freeze drying powder injection and preparation method thereof - Google Patents
A kind of dextrorotation oxiracetam freeze drying powder injection and preparation method thereof Download PDFInfo
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- CN110314141A CN110314141A CN201810956414.XA CN201810956414A CN110314141A CN 110314141 A CN110314141 A CN 110314141A CN 201810956414 A CN201810956414 A CN 201810956414A CN 110314141 A CN110314141 A CN 110314141A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides a kind of dextrorotation oxiracetam freeze drying powder injection, pass through special ratios dextrorotation oxiracetam compound, the auxiliary material combination of isopropanol or n-butanol and lactose or mannitol, combining specific lyophilized technique, not only effectively slow down the hydrolysis of dextrorotation oxiracetam, drug and auxiliary material is also set to form crystalline state substance, avoid the formation of class glass state material, to manufacture unobstructed distillation duct, greatly speed up rate of sublimation, it is obviously shortened freeze-drying time, obtain the product appearance of white chunks object, standing when being redissolved using diluent can be completely dissolved, it is short to redissolve the time, product stability is high.Preparation method of the present invention is simple, is suitble to industrialized production.
Description
Technical field
The present invention relates to dextrorotation oxiracetam compositions, and in particular to a kind of dextrorotation oxiracetam freeze drying powder injection and its system
Preparation Method.
Background technique
Dextrorotation oxiracetam (CAS No.:68252-28-8) is the dextrorotation of oxiracetam (CAS No.:62613-82-5)
Body, research shows that (106166150 A of CN), dextrorotation oxiracetam can promote turn of cerebral cortex and hippocampus position acetylcholine
Fortune increases to the affinity of Choline uptake and the activity of brain phosphate A1, the tool in terms of epilepsy, especially epileptic episodes
There is good activity, there is the possibility for being developed further into antiepileptic.It is well known that for epileptic treatment clinically
The method for mostly using dropleting medicine-feeding, drug effect is rapider, acts on more reliable；Though injection products are dropleting medicine-feeding, it is with liquid
Form exists, and dextrorotation oxiracetam intramolecular contains amido bond, and hydrolyzable can accelerate at carboxylic acid and ammonia or amine, acid, alkali, heat
It is hydrolyzed, therefore liquid forms obviously do not have advantage compared with lyophilized solid dosage form, and freeze drying powder injection has
Effect ingredient is not degradable, and stability is good, is more convenient for storing and transport.During studying dextrorotation oxiracetam freeze drying powder injection,
Inventor's discovery when dextrorotation oxiracetam is degraded in water in solving the problems, such as production process, medical fluid is in freezing dry process
Not easily molded, appearance dosage form is loose, and freeze-drying time is longer in freezing dry process, and product quality is more unstable；It is lyophilized simultaneously
Time is longer, and energy consumption is bigger, and production cost is higher.
Summary of the invention
According to the first aspect of the invention, the purpose of the present invention is to provide a kind of dextrorotation oxiracetam freeze drying powder injection,
Powder-injection formula is simple, appearance is good, stablizes, and freeze-drying time is short.Unless otherwise specified, percentage of the present invention is attached most importance to
Percentage is measured, the number is parts by weight.
The object of the present invention is achieved like this:
Dextrorotation oxiracetam freeze drying powder injection of the present invention, including 50-400g dextrorotation oxiracetam compound, 50-120mL are different
Propyl alcohol or n-butanol, 80-150g lactose or mannitol, qs pH adjuster, water for injection add to after 1000mL is configured to solution
It is lyophilized.
The present inventor by long-term a large amount of development test, have been surprisingly found that using special ratios lactose and mannitol simultaneously
As excipient, in conjunction with the isopropanol or n-butanol in a certain amount of organic solvent, i.e., according to 100-300g dextrorotation oxiracetam
Close supplementary material proportion (pH adjusting agent and the note of object, 80-120mL isopropanol or n-butanol, 30-50g lactose, 50-100g mannitol
Penetrate with except water) when, two kinds of auxiliary materials are outer in addition to there is the effect of skeleton excipient, moreover it is possible to and promote dextrorotation oxiracetam to crystallize, growing the grain, it can be with
Effectively achieve drilling effect；The present invention also uses special lyophilized technique simultaneously, that is, passes through multiple alternating temperature pre-freeze forming technique,
Under several different temperatures, slowly temperature is carried out with given pace respectively and is become, main ingredient dextrorotation oxiracetam and the auxiliary material in medical fluid are made
It is formed together crystal, and is grown into and becomes larger, is finally freezed together, more loose duct is generated between crystal.The freeze-drying
Preparation and its technique make drug and auxiliary material form crystalline state substance, i.e. crystal form compound, avoid the formation of class glass state material, from
And unobstructed distillation duct has been manufactured, greatly speed up rate of sublimation, hence it is evident that shorten freeze-drying time.
Above-mentioned dextrorotation oxiracetam freeze drying powder injection, freeze-dried powder is the crystal form compound that drug and auxiliary material are formed, described
Crystal form compound is radiated using Cu Ka, powder diffraction measure (XRPD) 2 θ of angle of reflection be 17.12 ± 0.2 °, 18.88 ±
0.2 °, 19.24 ± 0.2 °, 21.18 ± 0.2 °, 24.88 ± 0.2 ° has diffraction maximum, further 2 θ of angle of diffraction be 18.88 ±
Relative peak intensities at 0.2 ° are 100%；The relative peak intensities for being 21.18 ± 0.2 ° and 24.88 ± 0.2 ° in 2 θ of angle of diffraction
Greater than 80% less than 100%；2 θ of angle of diffraction is 17.12 ± 0.2 °, 19.24 ± 0.2 ° of relative peak intensities are not less than
60%.
According to the second aspect of the invention, the purpose of the present invention is to provide above-mentioned dextrorotation oxiracetam freeze drying powder injections
Preparation method.The preparation method of dextrorotation oxiracetam freeze drying powder injection of the present invention, preparation and step of freeze drying including freezing liquid,
It is characterized in that, the preparation of the freezing liquid are as follows: dextrorotation oxiracetam compound is dispersed in isopropanol or n-butanol, is added
Enter the lactose or mannitol solution dissolved by water for injection, adjusts pH value of solution to 4.5-6.2 with pH adjusting agent after mixing, live
Property carbon decoloring, filtering with microporous membrane obtain filtrate i.e. freezing liquid.The pH adjusting agent be citric acid/sodium citrate, hydrochloric acid/
The combination of one or more of sodium hydroxide, sodium dihydrogen phosphate.
Dextrorotation oxiracetam compound described in above-mentioned dextrorotation oxiracetam freeze drying powder injection is by commercially available dextrorotation oxiracetam
Feed purification is made, the purification step are as follows: dextrorotation oxiracetam is added with the concentration of 5mg/mL-45mg/mL in normal propyl alcohol,
It is stirred continuously, 35 DEG C~65 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution sealing is placed on -17 DEG C
Crystallisation by cooling in~-19 DEG C of low temperature environment filters to isolate crystallization, 30-80 DEG C, relative humidity be 0-20% under the conditions of it is dry
Dry 3-5h, both.The freeze drying process are as follows: pre-freeze and thermal balance: starting compressor, being located in 0.5h~1h will freezing
Temperature is down to -5 DEG C~-12 DEG C in drying equipment, and maintains 0.5~1.5h；Freeze and system balancing: after heat release, being located at
Temperature in freeze drying equipment is down to -30 DEG C hereinafter, after -30 DEG C of temperature arrival in 0.5~1h, will be freezed in 0.5~1h
Temperature is down to -45 DEG C or less in drying equipment；Then control freeze drying equipment in pressure to 10Pa or less and maintain 1.0~
2.0h；Distillation early period: temperature is set in freeze drying equipment as -3~-5 DEG C and vacuum maintains 10Pa hereinafter, keeping the temperature 4~6h；It rises
The magnificent later period: adjustment vacuum degree is 50 ± 30Pa and temperature in freeze drying equipment is maintained to continue 6~9h of heat preservation at -4 DEG C；Parsing:
After distillation, if temperature is 30 DEG C~45 DEG C in freeze drying equipment, 3~5h is maintained, and adjusting vacuum degree is 35 ± 20Pa；
After temperature reaches 35 DEG C and at least two product temperature probes more than 25 DEG C in freeze drying equipment, freeze drying equipment is controlled
Interior pressure recovery 10Pa or less and after keeping 1h, total head plug, outlet is after detection is qualified up to the freeze drying powder injection.
Specifically, the preparation method of dextrorotation oxiracetam freeze drying powder injection of the present invention will include that 100-300g dextrorotation is difficult to understand
Draw amide compound, 80-120mL isopropanol or n-butanol, 30-50g lactose, 50-100g mannitol, qs pH adjuster, note
It penetrates to be added to after 1000mL is configured to solution with water and be lyophilized, preparation process is as follows:
(1) dextrorotation Austria the purifying of dextrorotation oxiracetam raw material: is added with the concentration of 5mg/mL-45mg/mL in normal propyl alcohol
Amide is drawn, is stirred continuously, 35 DEG C~65 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution is sealed and is placed
The crystallisation by cooling in -17 DEG C~-19 DEG C of low temperature environment filters to isolate crystallization, in 30-80 DEG C, relative humidity 0-20%
Under the conditions of dry 3-5h, obtain dextrorotation oxiracetam compound after purification；
(2) preparation of solution: dextrorotation oxiracetam compound is dispersed in isopropanol or n-butanol, is added by infusing
The lactose or mannitol solution dissolved with water is penetrated, pH value of solution is adjusted to 4.5-6.2 with pH adjusting agent after mixing, needle is added and uses
Active carbon, is stirred at room temperature 15-30min, filtering decarbonization, and 0.22 μm of filtering with microporous membrane of filtrate obtains refined filtration liquid；
(3) lyophilized technique: pre-freeze and thermal balance: starting compressor, being located in 0.5h~1h will be warm in freeze drying equipment
Degree is down to -5 DEG C~-12 DEG C, and maintains 0.5~1.5h；Freeze and system balancing: after heat release, being located in 0.5~1h will be cold
Freeze drying equipment in temperature be down to -30 DEG C hereinafter, temperature reach -30 DEG C after, by temperature in freeze drying equipment in 0.5~1h
It is down to -45 DEG C or less；Then the pressure in freeze drying equipment is controlled to 10Pa or less and maintains 1.0~2.0h；It distils early period:
If temperature is -3~-5 DEG C in freeze drying equipment and vacuum maintains 10Pa hereinafter, 4~6h of heat preservation；Distil the later period: adjustment is true
Reciprocal of duty cycle is 50 ± 30Pa and temperature in freeze drying equipment is maintained to continue 6~9h of heat preservation at -4 DEG C；Parsing: after distillation, if
Temperature is 30 DEG C~45 DEG C in freeze drying equipment, maintains 3~5h, and adjusting vacuum degree is 35 ± 20Pa；When freeze-drying is set
After standby interior temperature reaches 35 DEG C and at least two product temperature probes more than 25 DEG C, the pressure recovery in freeze drying equipment is controlled
10Pa or less and after keeping 1h, total head plug, outlet is after detection is qualified up to the freeze drying powder injection.
The utility model has the advantages that
The present invention provides a kind of dextrorotation oxiracetam freeze drying powder injection of high solubility, passes through special ratios dextrorotation Aura acyl
The auxiliary material combination of amine compounds, isopropanol or n-butanol and lactose or mannitol is cooperating specific lyophilized technique, is not only having
Effect slows down the hydrolysis of dextrorotation oxiracetam, so that drug and auxiliary material is formed crystalline state substance, avoids the shape of class glass state material
At greatly speeding up rate of sublimation to manufacture unobstructed distillation duct, hence it is evident that shorten freeze-drying time, obtain white chunks
The product appearance of object, standing when being redissolved using diluent can be completely dissolved, and the redissolution time is short, and product stability is high.The present invention
Freeze drying powder injection has crystalline solid form existence form, radiates its powder diffraction measurement (XRPD) in 2 θ of angle of reflection using Cu Ka and is
17.12 ± 0.2 °, 18.88 ± 0.2 °, 19.24 ± 0.2 °, 21.18 ± 0.2 °, 24.88 ± 0.2 ° have diffraction maximum, further exist
2 θ of angle of diffraction is that the relative peak intensities at 18.88 ± 0.2 ° are 100%；It is 21.18 ± 0.2 ° and 24.88 in 2 θ of angle of diffraction
± 0.2 ° of relative peak intensities are greater than 80% less than 100%；In the phase that 2 θ of angle of diffraction is 17.12 ± 0.2 °, 19.24 ± 0.2 °
60% is not less than to peak intensity.Preparation process of the present invention is simple, facilitate it is feasible, it is reproducible, it is easy to realize that industrialization is big raw
Produce, freeze-drying time is short, and rejection rate is low, and lamp inspection inspection rejects difficulty is low, save manpower, the shorter production cycle, lower rejection rate and
Lower human cost, is greatly lowered production cost, can produce considerable economic and social benefit.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to aforementioned present invention content.Unless otherwise specified, institute of the present invention
Stating number is parts by weight, and the percentage is mass percent.The raw materials used in the present invention and reagent are commercial product.
Embodiment 1
The purifying of dextrorotation oxiracetam: dextrorotation oxiracetam is added in normal propyl alcohol with the concentration of 25mg/mL-35mg/mL
Enter dextrorotation oxiracetam, be stirred continuously, 45 DEG C~50 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution is close
Envelope is placed on crystallisation by cooling in -17 DEG C~-19 DEG C of low temperature environment, filters to isolate crystallization, is in 62-72 DEG C, relative humidity
Dry 3-5h, collects crystallization under the conditions of 15-20%.
With the dextrorotation oxiracetam of the present invention of the dextrorotation oxiracetam compound preparation embodiment 2-4 of embodiment 1 after purification
Freeze drying powder injection.
Embodiment 2
Prescription: by 150g dextrorotation oxiracetam compound, 82mL n-butanol, 30g lactose, 80g mannitol, appropriate pH is adjusted
Agent (0.1M citric acid/sodium citrate), water for injection.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in n-butanol, and addition is dissolved by water for injection
Lactose and mannitol, adjust pH value of solution to 5.8 with qs pH adjuster (0.1M citric acid/sodium citrate) after mixing,
Needle-use activated carbon is added, 25-30min, filtering decarbonization is stirred at room temperature, 0.22 μm of filtering with microporous membrane of filtrate obtains refined filtration liquid；
Lyophilized technique: pre-freeze and thermal balance: starting compressor, be located in 0.8h temperature in freeze drying equipment is down to-
10 DEG C, and maintain 0.7h；Freeze and system balancing: after heat release, be located in 0.8h temperature in freeze drying equipment is down to-
30 DEG C hereinafter, be down to -45 DEG C or less for temperature in freeze drying equipment in 0.7h after -30 DEG C of temperature arrival；Then it controls cold
The pressure frozen in drying equipment to 10Pa or less and maintains 1.5h；Distillation early period: setting in freeze drying equipment temperature as -4 DEG C and
Vacuum maintains 10Pa hereinafter, heat preservation 5h；Distil the later period: adjustment vacuum degree is 60Pa and maintains temperature in freeze drying equipment
At -4 DEG C, continue to keep the temperature 7h；Parsing: after distillation, if temperature is 40 DEG C in freeze drying equipment, 4h is maintained, and adjust true
Reciprocal of duty cycle is 45Pa；After temperature reaches 35 DEG C and at least two product temperature probes more than 25 DEG C in freeze drying equipment, control
Pressure recovery 10Pa or less in freeze drying equipment and after keeping 1h, total head plug, outlet is after detection is qualified up to the jelly
Dry powder injection.
Embodiment 3
Prescription: by 100g dextrorotation oxiracetam compound, 95mL n-butanol, 40g lactose, 50g mannitol, appropriate pH is adjusted
Agent (0.1M sodium dihydrogen phosphate), water for injection.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in n-butanol, and addition is dissolved by water for injection
Lactose and mannitol, adjust pH value of solution to 5.2 with qs pH adjuster (0.1M sodium dihydrogen phosphate) after mixing, needle be added
With active carbon, 15-20min, filtering decarbonization is stirred at room temperature, 0.22 μm of filtering with microporous membrane of filtrate obtains refined filtration liquid；
Lyophilized technique: pre-freeze and thermal balance: starting compressor is located in 0.5h temperature in freeze drying equipment being down to -5
DEG C, and maintain 0.5h；Freeze and system balancing: after heat release, being located in 0.5h and temperature in freeze drying equipment is down to -30
DEG C hereinafter, temperature reach -30 DEG C after, temperature in freeze drying equipment is down to -45 DEG C or less in 0.5h；Then control freezing
Pressure in drying equipment to 10Pa or less and maintains 2.0h；It distils early period: it is as -3 DEG C and true to set temperature in freeze drying equipment
Sky maintains 10Pa hereinafter, heat preservation 6h；Distil the later period: adjustment vacuum degree is 50 ± 30Pa and maintains temperature in freeze drying equipment
At -4 DEG C, continue to keep the temperature 6h；Parsing: after distillation, if temperature is 30 DEG C in freeze drying equipment, 5h is maintained, and adjust true
Reciprocal of duty cycle is 35 ± 20Pa；After temperature reaches 35 DEG C and at least two product temperature probes more than 25 DEG C in freeze drying equipment,
After controlling the pressure recovery 10Pa or less in freeze drying equipment and keeping 1h, total head plug, outlet is after detection is qualified up to described
Freeze drying powder injection.
Embodiment 4
Prescription: by 300g dextrorotation oxiracetam compound, 120mL isopropanol, 50g lactose, 100g mannitol, appropriate pH tune
It saves agent (0.1M hydrochloric acid/sodium hydroxide), water for injection.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in isopropanol, and addition is dissolved by water for injection
Lactose and mannitol, after mixing with qs pH adjuster (0.1M hydrochloric acid/sodium hydroxide) adjust pH value of solution to 6.2, add
Enter needle-use activated carbon, 20-25min, filtering decarbonization is stirred at room temperature, 0.22 μm of filtering with microporous membrane of filtrate obtains refined filtration liquid；
Lyophilized technique: pre-freeze and thermal balance: starting compressor is located in 1h temperature in freeze drying equipment being down to -12
DEG C, and maintain 1.5h；Freeze and system balancing: after heat release, being located in 1h and temperature in freeze drying equipment is down to -30 DEG C
Hereinafter, temperature in freeze drying equipment is down to -45 DEG C or less in 1h after temperature reaches -30 DEG C；Then control freeze-drying
Pressure in equipment to 10Pa or less and maintains 1.0h；Distillation early period: setting in freeze drying equipment temperature is -5 DEG C and vacuum dimension
It holds in 10Pa hereinafter, keeping the temperature 4h；Distil the later period: adjustment vacuum degree is temperature in 50 ± 30Pa and maintenance freeze drying equipment -4
DEG C, continue to keep the temperature 9h；Parsing: after distillation, if temperature is 45 DEG C in freeze drying equipment, 3h is maintained, and adjust vacuum degree
For 35 ± 20Pa；After temperature reaches 35 DEG C and at least two product temperature probes more than 25 DEG C in freeze drying equipment, control
Pressure recovery 10Pa or less in freeze drying equipment and after keeping 1h, total head plug, outlet is after detection is qualified up to the jelly
Dry powder injection.
The dextrorotation oxiracetam freeze drying powder injection HPLC purity of 2-4 of embodiment of the present invention preparation: 99.90% or more, it is organic
Within dissolvent residual 0.01% (GC), chimney-like is presented in vertical direction in the ice crystal of freeze samples, is not freezed in drug substance surface
Enriched layer, Drug structure homogeneity is good, obtains the product appearance of white chunks object, and standing when being redissolved using diluent can be complete
Fully dissolved redissolves the time less than 1min, and clarity of solution, particulate matter, visible foreign matters, dissolvent residual meet version in 2015
Regulation of the Chinese Pharmacopoeia about freeze drying powder injection.To 2-4 of the embodiment of the present invention preparation dextrorotation oxiracetam freeze drying powder injection into
Row powder diffraction measures (XRPD): test equipment condition: room temperature test is carried out using Bruker D2PHASER powder diffractometer,
Test condition are as follows: with Cu KaFor light source, voltage 30kV, electric current 10mA test 0.014 ° of step-length, scanning speed
0.1s/step, 5-40 ° of scanning range (2 θ).Through detecting, 2 θ of angle of diffraction be 17.12 ± 0.2 °, 18.88 ± 0.2 °,
19.24 ± 0.2 °, 21.18 ± 0.2 °, 24.88 ± 0.2 ° have diffraction maximum, wherein being at 18.88 ± 0.2 ° in 2 θ of angle of diffraction
Relative peak intensities are 100%；In 2 θ of angle of diffraction be 21.18 ± 0.2 ° and 24.88 ± 0.2 ° of relative peak intensities are small greater than 80%
In 100%；2 θ of angle of diffraction is 17.12 ± 0.2 °, 19.24 ± 0.2 ° of relative peak intensities are not less than 60%.
Claims (9)
1. a kind of dextrorotation oxiracetam freeze drying powder injection, including 50-400g dextrorotation oxiracetam compound, 50-120mL isopropanol
Or n-butanol, 80-150g lactose or mannitol, qs pH adjuster, water for injection are added to after 1000mL is configured to solution and are lyophilized
It forms.
2. dextrorotation oxiracetam freeze drying powder injection as described in claim 1, it is characterised in that: including 100-300g dextrorotation Aura acyl
Amine compounds, 80-120mL isopropanol or n-butanol, 30-50g lactose, 50-100g mannitol, qs pH adjuster, injection
Water is added to after 1000mL is configured to solution and is lyophilized.
3. dextrorotation oxiracetam freeze drying powder injection as claimed in claim 2, it is characterised in that: the freeze-dried powder be drug with it is auxiliary
Expect that the crystal form compound formed, the crystal form compound are radiated using Cu Ka, powder diffraction measures (XRPD) in angle of reflection 2θ is
17.12 ± 0.2 °, 18.88 ± 0.2 °, 19.24 ± 0.2 °, 21.18 ± 0.2 °, 24.88 ± 0.2 ° have diffraction maximum.
4. dextrorotation oxiracetam freeze drying powder injection as claimed in claim 3, it is characterised in that: the crystal form compound is in angle of diffraction
2θ isRelative peak intensities at 18.88 ± 0.2 ° are 100%；In angle of diffraction 2θ is21.18 ± 0.2 ° and 24.88 ± 0.2 °
Relative peak intensities are greater than 80% less than 100%；In angle of diffraction 2θ is17.12 ± 0.2 °, 19.24 ± 0.2 ° of relative peak intensities
Not less than 60%.
5. the preparation method of dextrorotation oxiracetam freeze drying powder injection, matching including freezing liquid as described in claim any one of 1-4
System and step of freeze drying, it is characterised in that: the freezing liquid is formulated as dextrorotation oxiracetam compound being dispersed in isopropyl
In alcohol or n-butanol, the lactose or mannitol solution dissolved by water for injection is added, is adjusted after mixing with pH adjusting agent molten
Liquid pH to 4.5-6.2, active carbon decoloring, filtering with microporous membrane obtain filtrate i.e. freezing liquid.
6. method as claimed in claim 5, it is characterised in that: the pH adjusting agent be citric acid/sodium citrate, hydrochloric acid/
The combination of one or more of sodium hydroxide, sodium dihydrogen phosphate.
7. such as method described in claim 5 or 6, it is characterised in that: the dextrorotation oxiracetam compound is by commercially available dextrorotation
Oxiracetam feed purification is made, the purification step are as follows: dextrorotation is added with the concentration of 5mg/mL-45mg/mL in normal propyl alcohol
Oxiracetam is stirred continuously, and 35 DEG C ~ 65 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution is sealed and is placed
The crystallisation by cooling in -17 DEG C ~ -19 DEG C of low temperature environment filters to isolate crystallization, is 0-20% item in 30-80 DEG C, relative humidity
Dry 3-5h under part, both.
8. such as method described in claim 5 or 6, it is characterised in that: the lyophilized technique is as follows: pre-freeze and thermal balance: starting
Compressor is located in 0. 5h~1h temperature in freeze drying equipment being down to -5 DEG C~-12 DEG C, and maintains 0.5~1.5h；
Freeze and system balancing: after heat release, being located in 0.5~1h and temperature in freeze drying equipment is down to -30 DEG C hereinafter, temperature
After degree reaches -30 DEG C, temperature in freeze drying equipment is down to -45 DEG C or less in 0.5~1h；Then control freeze-drying
Pressure in equipment to 10Pa or less and maintains 1.0~2.0h；Distillation early period: temperature is set in freeze drying equipment as -3~-5
DEG C and vacuum maintain 10Pa hereinafter, heat preservation 4~6h；Distil the later period: adjustment vacuum degree is 50 ± 30Pa and maintains freezing dry
Temperature continues 6~9h of heat preservation at -4 DEG C in dry equipment；Parsing: after distillation, if temperature is 30 DEG C in freeze drying equipment
~45 DEG C, 3~5h is maintained, and adjusting vacuum degree is 35 ± 20Pa；When temperature reaches 35 DEG C and at least two in freeze drying equipment
After branch product temperature probe is more than 25 DEG C, after controlling the pressure recovery 10Pa or less in freeze drying equipment and keeping 1h, entirely
Tamponade, outlet is after detection is qualified up to the freeze drying powder injection.
9. a kind of preparation method of dextrorotation oxiracetam freeze drying powder injection, will include 100-300g dextrorotation oxiracetam compound,
80-120mL isopropanol or n-butanol, 30-50g lactose, 50-100g mannitol, qs pH adjuster, water for injection add to
1000mL is lyophilized after being configured to solution, and preparation process is as follows:
(1) dextrorotation Aura acyl the purifying of dextrorotation oxiracetam raw material: is added with the concentration of 5mg/mL-45mg/mL in normal propyl alcohol
Amine is stirred continuously, and 35 DEG C ~ 65 DEG C heating for dissolving, filtering forms supersaturated solution；Supersaturated solution sealing is placed on -17 DEG C
Crystallisation by cooling in ~ -19 DEG C of low temperature environment filters to isolate crystallization, 30-80 DEG C, relative humidity be 0-20% under the conditions of it is dry
3-5h obtains dextrorotation oxiracetam compound after purification；
(2) preparation of solution: dextrorotation oxiracetam compound is dispersed in isopropanol or n-butanol, is added by injection
The lactose or mannitol solution of water dissolution adjust pH value of solution to 4.5-6.2 with pH adjusting agent after mixing, needle activity are added
Charcoal, is stirred at room temperature 15-30min, filtering decarbonization, and 0.22 μm of filtering with microporous membrane of filtrate obtains refined filtration liquid；
(3) lyophilized technique: pre-freeze and thermal balance: starting compressor is located at temperature in freeze drying equipment in 0. 5h~1h
- 5 DEG C~-12 DEG C are down to, and maintains 0.5~1.5h；Freeze and system balancing: after heat release, being located in 0.5~1h will be cold
Freeze after temperature in drying equipment is down to -30 DEG C hereinafter, temperature reaches -30 DEG C, it will be warm in freeze drying equipment in 0.5~1h
Degree is down to -45 DEG C or less；Then the pressure in freeze drying equipment is controlled to 10Pa or less and maintains 1.0~2.0h；Before distillation
Phase: setting in freeze drying equipment temperature as -3~-5 DEG C and vacuum maintains 10Pa hereinafter, 4~6h of heat preservation；It distils the later period: adjusting
Whole vacuum degree is 50 ± 30Pa and temperature in freeze drying equipment is maintained to continue 6~9h of heat preservation at -4 DEG C；Parsing: distillation knot
Shu Hou maintains 3~5h if temperature is 30 DEG C~45 DEG C in freeze drying equipment, and adjusting vacuum degree is 35 ± 20Pa；When cold
After temperature reaches 35 DEG C and at least two product temperatures probes more than 25 DEG C in jelly drying equipment, control in freeze drying equipment
Pressure recovery 10Pa or less and after keeping 1h, total head plug, outlet is after detection is qualified up to the freeze drying powder injection.
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| CN201810269998 | 2018-03-29 | ||
| CN2018102699983 | 2018-03-29 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766596A (en) * | 2009-01-04 | 2010-07-07 | 北京润德康医药技术有限公司 | Solid preparation with dextro-oxiracetam as active component |
| CN102512466A (en) * | 2011-12-27 | 2012-06-27 | 广西梧州制药（集团）股份有限公司 | Panax notoginseng saponins freeze-dried powder injection and preparation method thereof |
| CN102603607A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (R)-oxiracetam |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
-
2018
- 2018-08-21 CN CN201810956414.XA patent/CN110314141A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766596A (en) * | 2009-01-04 | 2010-07-07 | 北京润德康医药技术有限公司 | Solid preparation with dextro-oxiracetam as active component |
| CN102603607A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (R)-oxiracetam |
| CN102512466A (en) * | 2011-12-27 | 2012-06-27 | 广西梧州制药（集团）股份有限公司 | Panax notoginseng saponins freeze-dried powder injection and preparation method thereof |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
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Application publication date: 20191011 |