CN110314139A - The good dextrorotation oxiracetam lyophilized preparation and preparation method thereof of solubility - Google Patents
The good dextrorotation oxiracetam lyophilized preparation and preparation method thereof of solubility Download PDFInfo
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Abstract
The present invention provides a kind of dextrorotation oxiracetam lyophilized preparation, including 100-400g dextrorotation oxiracetam compound, 40-80mL normal propyl alcohol or the tert-butyl alcohol, 50-100g mannitol or dextran, water for injection are added to after 1000mL is configured to solution and is lyophilized.The present invention combines specific lyophilized technique using specific ratio of adjuvant, and lyophilized preparation Drug structure homogeneity obtained is good, and full appearance not atrophy, color are uniform, and dried frozen aquatic products moisture is few, solubility is splendid, dissolved particles and visible foreign matters item are good invariably.Preparation method of the present invention is simple, is suitble to industrialized production.
Description
Technical field
The present invention relates to dextrorotation oxiracetam pharmaceutical compositions, and in particular to a kind of dextrorotation hydroxyl oxygen pyrrole vinegar that solubility is good
Amine lyophilized preparation and preparation method thereof.
Background technique
Epilepsy is the syndrome of acute brain malfunction, is as caused by the extremely synchronized electric discharge of cerebral neuron.It is insane
Epilepsy is extremely serious on the influence of the nervous function of patient, even catastrophic for the infant of growth and development early stage.Go out in people
It is the gold period of human nervous system's development in 3 years after life, in this period, nervous system will be gradually formed normally
Neural network is to be done step-by-step for example: the functions such as movement, speech, memory, comprehension, and due to the recurrent exerbation of epilepsy, cause
The nervous system of infant can not establish normal connection, neuromotor function developmental lag then occur, seriously affect infant
Prognosis, and following life.And for adult, influence of the epilepsy to nervous function be also that should not be overlooked, due to repeatedly
Epileptic attack, causes patient decrease of memory, cognitive ability decline occur, and phrenoblabia etc., patient can not work normally, give birth to
Living, study, causes mental burden very serious to patient.Therefore, insane no matter for patient, or for household
Epilepsy has become a kind of serious economic and burden on society.Past existing antiepileptic (AEDs) such as phenytoinum naticum carbamazepine,
Clonazepam, ethymal, valproic acid and barbiturate are widely used, but there are a series of side effects for these drugs.
There are five million peoples with epilepsy in the world, and having in annual every 100,000 people just there are 16 to 51 newly to send out epilepsy cases.Moreover, having
Studies have shown that there is the nearly patient of 20-30% to being currently available that healing potion has resistance.The community study of South of France is estimated
Meter, up to 22.5% epileptic have drug resistant epilepsy.Drug resistant epilepsy patient's premature death, injured, Psychosocial function
Energy obstacle and the risk of quality of life decline increase.The study found that dextrorotation oxiracetam (No. CAS is 68252-28-8) exists
There is special biological activity in anti-epileptic field, and its toxicity is low, and drug safe range is big, is expected to become existing high toxicity
The substitute of anti-epileptic class drug.It is well known that for the method that the treatment of epileptic clinically mostly uses dropleting medicine-feeding, medicine
Effect is rapider, acts on more reliable；Though injection products are dropleting medicine-feeding, it exists in liquid form, and dextrorotation hydroxyl oxygen pyrrole vinegar
Contain amido bond in amine molecule, hydrolyzable can accelerate its hydrolysis, therefore liquid preparation shape at carboxylic acid and ammonia or amine, acid, alkali, heat
Formula does not obviously have advantage compared with lyophilized solid dosage form, and lyophilized preparation is more convenient for storing and be transported.Inventor exists
It studies dextrorotation oxiracetam lyophilized preparation and finds that the lyophilized preparation product shaping often occurred is bad, table in the process
Face collapses, and redissolving time length etc. influences the situation of dextrorotation oxiracetam lyophilized preparation quality.
Summary of the invention
In order to solve the problems in the prior art, the purpose of the present invention is to provide a kind of freeze-dryings of dextrorotation oxiracetam to make
Agent, said preparation are seen with loose white chunks beyond the region of objective existence, and formability is good, and it is short to redissolve the time.Unless otherwise specified, of the present invention hundred
Ratio is divided to be weight percentage, the number is parts by weight.
The object of the present invention is achieved like this:
Dextrorotation oxiracetam lyophilized preparation of the present invention, including 100-400g dextrorotation oxiracetam compound, 40-80mL
Normal propyl alcohol or the tert-butyl alcohol, 50-100g mannitol or/and dextran, water for injection are added to after 1000mL is configured to solution and are freezed
Drying forms.
Dextrorotation oxiracetam compound is dispersed in normal propyl alcohol or uncle by above-mentioned dextrorotation oxiracetam lyophilized preparation
In butanol, the mannitol or/and dextran solution dissolved by water for injection is added, is adjusted after mixing with pH adjusting agent molten
Liquid pH to 4.2-6.5, active carbon decoloring, filtering with microporous membrane are freeze-dried after obtaining filtrate.
In the present invention, the pH adjusting agent is selected from hydrochloric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, acetate, boric acid, boron
Sand, citric acid, citrate, citric acid hydrogen salt, citric acid dihydric salt, monohydrate potassium, Monopotassium citrate, carbonate, carbonic acid
Hydrogen salt, sodium hydroxide, potassium hydroxide, phosphate, dihydric phosphate, hydrophosphate, tartaric acid, biatrate, amino acid and
One or more of its salt.
In order to improve the purity of lyophilized preparation, dextrorotation hydroxyl oxygen pyrrole used in dextrorotation oxiracetam lyophilized preparation of the present invention
Vinegar amine compounds are made by commercially available dextrorotation oxiracetam feed purification, the purification step are as follows: with hexamethylene by dextrorotation hydroxyl oxygen
Pyrrole vinegar amine raw material is sealed with concentration 20mg/mL-40mg/mL dissolution, is 20-32 DEG C with 200-350r/min's in temperature
Speed stirs 20-25h, and filtrate is stood volatilization crystallization, collects crystal by filtering, dry, obtains dextrorotation hydroxyl oxygen pyrrole vinegar after purification
Amine compounds；It is 40-75 DEG C that the drying, which is in temperature, relative humidity dry 3-7h under conditions of being 15-30%.
Freeze drying process is generally divided into pre-freeze processing and lyophilization.Pre-freeze is exactly that the preparation of liquid is frozen into ice crystal
The solid of kenel, the shape for making it keep it when freezing after lyophilization under vacuum conditions.If preparation does not have deep colling,
It preparation can boil vial of emerging under vacuum conditions, the condition of preparation will be destroyed.When solution is quick-frozen, crystal grain is kept
Visible size under the microscope, obtains freezing that crystal grain is thinner, and tiny crystal grain will not make biological products crystal grain grow up and make
At mechanical injuries.But since crystal grain is tiny, the gap left after ice crystal distillation is narrow, and the resistance of water sublimed is big, dry
Speed is slow, and the production cycle extends, and the product after drying is particularly easy to moisture absorption, brings difficulty to preservation, this is quick-frozen lacks
Point.Opposite slow the crystallization naked eyes of formation are as it can be seen that crystal grain is larger, and after ice crystal distillation, the gap left is also big when freezing, water when distillation
Split pole easily overflows, and dry speed ratio is very fast, shortens lyophilization cycle, improves production efficiency.But slow freeze is easy to cause
Occurring " supercooling " phenomenon in freezing process, " supercooling " phenomenon can cause to generate concentration by dried product, and cause homogeneity poor, and shadow
Ring the appearance of freeze-drying prods.
Preferably, lyophilized technique of the present invention is as follows: pre-freeze are as follows: before product inlet, shelf is first cooled to 5~15 DEG C, then
Canned product is put into freeze drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature up to -
35 DEG C ± 5 DEG C, continue heat preservation 4~6 hours；Lyophilization are as follows: after vacuum degree is down to 10pa or less, by shelf temperature in 4~6 hours
Degree is slowly increased to -5 ± 1 DEG C, keeps the temperature after product ice crystal completely disappears, continues heat preservation 3~5 hours；Desorbing and drying are as follows: and then with
It is warming up to 30 DEG C ± 5 DEG C for 10~12 DEG C per hour, after products temperature up to after 30 DEG C, then keeps the temperature 2~4 hours.
The present inventor has been surprisingly found that the mannitol and dextran using special ratios by long-term a large amount of development test
It is used as excipient simultaneously, in conjunction with the normal propyl alcohol or the tert-butyl alcohol in a certain amount of organic solvent, i.e., according to 100-300g dextrorotation hydroxyl oxygen pyrrole
Vinegar amine compounds, 40-80mL normal propyl alcohol or the tert-butyl alcohol, 20-40g mannitol, 30-60g dextran supplementary material match (pH tune
Except section agent and water for injection) when, two kinds of auxiliary materials are other than having the effect of skeleton excipient, moreover it is possible to dextrorotation oxiracetam is promoted to crystallize,
Growing the grain can effectively achieve drilling effect；Simultaneously the present invention also use special lyophilized technique, i.e., in combination with first cool down after
Heat up the program to heat up again, when being first cooled to -40 ± 2 DEG C in freezing dry process, stops cooling, keeps the temperature 4~6 hours, delays
Slowly it is warming up to -5 ± 1 DEG C, keeps the temperature 3~5 hours, then is warming up to 30 ± 5 DEG C of freeze drying process, not only effectively slows down dextrorotation
Oxiracetam hydrolysis, dextrorotation oxiracetam solution surface first crystallizes also in freeze-drying process, avoids the accumulation of surface solute,
Chimney-like is presented in vertical direction in the ice crystal of freeze samples simultaneously, does not have Freeze concentration layer in drug substance surface, Drug structure is uniform
Property good, therefore resistance to mass tranfer very little when dry, steam flows smoothly in freeze-drying process, obtains the product of white chunks object
Appearance, standing when being redissolved using diluent can be completely dissolved.
Above-mentioned dextrorotation oxiracetam lyophilized preparation, 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 16.68 °, 17.52 °, 19.44 °,
There is diffraction maximum at 21.01 °, 22.17 °, 23.45 °, 25.34 °, 26.06 °, 30.96 °, error range is ± 0.2 °.
The present invention also provides the preparation methods of above-mentioned dextrorotation oxiracetam lyophilized preparation, using following preparation process:
(1) purifying of dextrorotation oxiracetam raw material: with hexamethylene by dextrorotation oxiracetam raw material with concentration 25mg/
ML-35mg/mL dissolution, seals, and is that the 25-30 DEG C of speed with 200-350r/min stirs 22-25h in temperature, filters, will
Filtrate stands volatilization crystallization, collects crystal, is 55-75 DEG C in temperature, relative humidity dry 3-5h under conditions of being 15-30%,
Obtain dextrorotation oxiracetam compound after purification；
(2) dextrorotation oxiracetam compound after purification the preparation of solution: is dispersed in normal propyl alcohol or the tert-butyl alcohol
In, the freeze drying protectant dissolved by water for injection is added, adjusts pH value of solution to 5.2- with qs pH adjuster after mixing
6.0, needle-use activated carbon is added, 15-30min, filtering decarbonization is stirred at room temperature, 0.22 μm of filtering with microporous membrane of filtrate obtains refined filtration
Liquid；
(3) lyophilized technique: pre-freeze are as follows: before product inlet, shelf is first cooled to 5~15 DEG C, then by canned product
It is put into freeze drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature reaches -35 DEG C ± 5 DEG C, continues
Heat preservation 4~6 hours；Lyophilization are as follows: after vacuum degree is down to 10pa or less, shelf temperature is slowly increased to -5 in 4~6 hours ±
It 1 DEG C, keeps the temperature after product ice crystal completely disappears, continues heat preservation 3~5 hours；Desorbing and drying are as follows: and then with 10~12 DEG C per hour
30 DEG C ± 5 DEG C are warming up to, after products temperature up to after 30 DEG C, then keeps the temperature 2~4 hours.
The utility model has the advantages that
The present invention provides a kind of dextrorotation oxiracetam lyophilized preparation, fully considers that dextrorotation oxiracetam is unstable in water
Fixed feature, auxiliary material solution are made of the aqueous solution of the organic solvent containing certain proportion, are heated up again in combination with first cooling down to heat up afterwards
Program, when being first cooled to -40 ± 2 DEG C in freezing dry process, stop cooling, keep the temperature 4~6 hours, be to slowly warm up to -5
± 1 DEG C, 3~5 hours are kept the temperature, then is warming up to 30 ± 5 DEG C of freeze drying process, not only effectively slows down dextrorotation oxiracetam
Hydrolysis, also makes the product after freezing keep full appearance not atrophy, color uniform during heating, the finished product after drying
Dried frozen aquatic products moisture is few, solubility is good, and dissolved particles and visible foreign matters item inspection result are good invariably, lyophilized preparation purity obtained
Height, organic solvent residual reach within 0.01% level.Dextrorotation oxiracetam solution surface is first tied in freeze-drying process of the present invention
Crystalline substance avoids the accumulation of surface solute, while chimney-like is presented in vertical direction in the ice crystal of freeze samples, does not freeze in drug substance surface
Enriched layer is tied, Drug structure homogeneity is good, therefore resistance to mass tranfer very little when dry, and steam circulation is suitable in freeze-drying process
Freely, the product appearance for obtaining white chunks object, standing when being redissolved using diluent can be completely dissolved.Lyophilized preparation tool of the present invention
Have crystalline solid form existence form, using Cu Ka radiate its powder diffraction measurement (XRPD) 2 θ of angle of reflection be 16.68 °,
There is diffraction maximum at 17.52 °, 19.44 °, 21.01 °, 22.17 °, 23.45 °, 25.34 °, 26.06 °, 30.96 °, impurity content is low,
Better stability of preparation.Preparation method of the present invention is simple, is suitble to industrialized production.
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.
The purifying of 1 dextrorotation oxiracetam of embodiment:
By unformed dextrorotation oxiracetam with 25mg/mL-35mg/mL hexamethylene stirring and dissolving, seal, in temperature
Degree stirs 24-25h for the 25-30 DEG C of speed with 250-300r/min, and filtrate is stood volatilization crystallization, collects crystal by filtering,
Temperature is 65-70 DEG C, and relative humidity dry 4-5h under conditions of being 20-25% collects crystallization.
It is used to prepare 2-4's of the embodiment of the present invention referring to the dextrorotation oxiracetam compound of 1 method of embodiment after purification
Dextrorotation oxiracetam lyophilized preparation.
Embodiment 2
Prescription: by 158g dextrorotation oxiracetam compound, the 68mL tert-butyl alcohol, 25g mannitol, 55g dextran, in right amount
PH adjusting agent (0.1M hydrochloric acid/sodium hydroxide), water for injection is added to after 1000mL is configured to solution and is lyophilized.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in the tert-butyl alcohol, is added water-soluble by injection
The mannitol and dextran of solution, after mixing with qs pH adjuster (0.1M hydrochloric acid/sodium hydroxide) adjust pH value of solution to
5.5, 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 are as follows: before product inlet, shelf is first cooled to 10 DEG C, is then put into canned product cold
Freeze in drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature reaches -35 DEG C ± 2 DEG C, continues heat preservation 5
Hour；Lyophilization are as follows: after vacuum degree is down to 10pa or less, shelf temperature is slowly increased to -5 ± 1 DEG C in 5 hours, heat preservation to
After product ice crystal completely disappears, continue heat preservation 4 hours；Desorbing and drying are as follows: and then 30 DEG C ± 2 DEG C are warming up to 12 DEG C per hour,
After products temperature up to after 30 DEG C, then keeps the temperature 3 hours and dextrorotation oxiracetam lyophilized preparation of the present invention is made.
Dextrorotation oxiracetam lyophilized preparation prepared by the embodiment of the present invention 2 has outside the product of white loose block
It sees, the tert-butyl alcohol remains 0.01% (GC), redissolves the time less than 1min, clarity of solution, particulate matter, visible foreign matters, solvent
Residual meets regulation of the version Chinese Pharmacopoeia in 2015 about freeze drying powder injection.To dextrorotation oxiracetam lyophilized preparation of the present invention
It carries out powder diffraction measurement (XRPD): test equipment condition: carrying out room temperature survey using Bruker D2 PHASER powder diffractometer
Examination, 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, invention dextrorotation oxiracetam lyophilized preparation crystal
Compound 2 θ of angle of diffraction be 16.68 °, 17.52 °, 19.44 °, 21.01 °, 22.17 °, 23.45 °, 25.34 °, 26.06 °,
There is diffraction maximum at 30.96 °.
Embodiment 3
Prescription: by 300g dextrorotation oxiracetam compound, the 40mL tert-butyl alcohol, 20g mannitol, 30g dextran, in right amount
PH adjusting agent (0.1M sodium dihydrogen phosphate), water for injection are added to after 1000mL is configured to solution and are lyophilized.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in the tert-butyl alcohol, is added water-soluble by injection
The mannitol and dextran of solution adjust pH value of solution to 5.2 with qs pH adjuster (0.1M sodium dihydrogen phosphate) after mixing,
Needle-use activated carbon is added, 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 are as follows: before product inlet, shelf is first cooled to 5 DEG C, and canned product is then put into freezing
In drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature reaches -35 DEG C ± 5 DEG C, and it is small to continue heat preservation 4
When；Lyophilization are as follows: after vacuum degree is down to 10pa or less, shelf temperature is slowly increased to -5 ± 1 DEG C in 4 hours, is kept the temperature wait make
After product ice crystal completely disappears, continue heat preservation 3 hours；Desorbing and drying are as follows: and then 30 DEG C ± 5 DEG C are warming up to 10 DEG C per hour, to
Products temperature is up to after 30 DEG C, then keeps the temperature 2 hours and dextrorotation oxiracetam lyophilized preparation of the present invention is made.
Embodiment 4
Prescription: by 100g dextrorotation oxiracetam compound, 80mL normal propyl alcohol, 40g mannitol, 60g dextran, in right amount
PH adjusting agent (0.1M hydrochloric acid/sodium hydroxide), water for injection is added to after 1000mL is configured to solution and is lyophilized.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in normal propyl alcohol, is added water-soluble by injection
The mannitol and dextran of solution, after mixing with qs pH adjuster (0.1M hydrochloric acid/sodium hydroxide) adjust pH value of solution to
6.0, needle-use activated carbon is added, 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 are as follows: before product inlet, shelf is first cooled to 15 DEG C, is then put into canned product cold
Freeze in drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature reaches -35 DEG C ± 5 DEG C, continues heat preservation 6
Hour；Lyophilization are as follows: after vacuum degree is down to 10pa or less, shelf temperature is slowly increased to -5 ± 1 DEG C in 6 hours, heat preservation to
After product ice crystal completely disappears, continue heat preservation 5 hours；Desorbing and drying are as follows: and then 30 DEG C ± 5 DEG C are warming up to 12 DEG C per hour,
After products temperature up to after 30 DEG C, then keeps the temperature 4 hours and dextrorotation oxiracetam lyophilized preparation of the present invention is made.
Embodiment 5
Prescription: by 220g dextrorotation oxiracetam compound, 75mL normal propyl alcohol, 35g mannitol, 45g dextran, in right amount
PH adjusting agent (0.1M sodium dihydrogen phosphate), water for injection are added to after 1000mL is configured to solution and are lyophilized.
The preparation of solution: dextrorotation oxiracetam compound is dispersed in normal propyl alcohol, is added water-soluble by injection
The mannitol and dextran of solution adjust pH value of solution to 6.5 with qs pH adjuster (0.1M sodium dihydrogen phosphate) after mixing,
Needle-use activated carbon is added, 20-22min, 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 are as follows: before product inlet, shelf is first cooled to 12 DEG C, is then put into canned product cold
Freeze in drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature reaches -35 DEG C ± 5 DEG C, continues heat preservation 5
Hour；Lyophilization are as follows: after vacuum degree is down to 10pa or less, shelf temperature is slowly increased to -5 ± 1 DEG C in 5 hours, heat preservation to
After product ice crystal completely disappears, continue heat preservation 6 hours；Desorbing and drying are as follows: and then 30 DEG C ± 5 DEG C are warming up to 10 DEG C per hour,
After products temperature up to after 30 DEG C, then keeps the temperature 4 hours and dextrorotation oxiracetam lyophilized preparation of the present invention is made.
Dextrorotation oxiracetam is molten in the dextrorotation oxiracetam lyophilized preparation freeze-drying process of 3-5 of embodiment of the present invention preparation
Liquid surface first crystallizes, and the accumulation of surface solute is avoided, while chimney-like is presented in vertical direction in the ice crystal of freeze samples, in drug
Surface does not have Freeze concentration layer, and Drug structure homogeneity is good, therefore resistance to mass tranfer very little when dry, water in freeze-drying process
Vapour flows smoothly, and the uniform loose white chunks object freeze-dried powder of full appearance not atrophy, color is obtained, when redissolving using diluent
Standing, which can be completely dissolved, (redissolves the time less than 60s), organic solvent residual reaches within 0.01% level (GC), powder diffraction
The diffraction maximum error model again of dextrorotation oxiracetam crystalline compounds prepared by the diffraction maximum and embodiment 2 for measuring crystalline compounds
In enclosing (± 0.2 °)；The indexs such as clarity of solution, particulate matter, visible foreign matters, dissolvent residual meet version China in 2015
Regulation of the pharmacopeia about freeze drying powder injection.
Embodiment 6
By the dextrorotation oxiracetam lyophilized preparation of embodiment 2-5 at 40 ± 2 DEG C of temperature, the item of relative humidity 75 ± 5%
It is placed 6 months under part, respectively at 0th month, the 1st month, the 2nd month, the 3rd month and 6th month sample detection, it was stood article
Indexs, the testing results such as redissolution time, character, clarity, moisture, pH value, related substance and content under part are shown in Table 1.
The dextrorotation oxiracetam lyophilized preparation performance measurement of 1 embodiment 2-5 of table
As seen from Table 1, dextrorotation oxiracetam lyophilized preparation of the present invention is at 40 ± 2 DEG C of temperature, relative humidity 75 ± 5%
Under conditions of place 6 months, redissolve the indexs such as time, character, clarity, moisture, pH value, related substance and content and meet
Regulation of the version Chinese Pharmacopoeia in 2015 about freeze drying powder injection.
Claims (8)
1. a kind of dextrorotation oxiracetam lyophilized preparation, including 100-400g dextrorotation oxiracetam compound, 40-80mL positive third
Alcohol or the tert-butyl alcohol, 50-100g mannitol or/and dextran, water for injection are added to after 1000mL is configured to solution and are freeze-dried
It forms.
2. lyophilized preparation as described in claim 1, it is characterised in that: dextrorotation oxiracetam compound to be dispersed in just
In propyl alcohol or the tert-butyl alcohol, the mannitol or/and dextran solution dissolved by water for injection is added, is adjusted after mixing with pH
Agent adjusting pH value of solution to 4.2-6.5, active carbon decoloring, filtering with microporous membrane is freeze-dried after obtaining filtrate.
3. lyophilized preparation as claimed in claim 2, it is characterised in that: the pH adjusting agent is selected from hydrochloric acid, phosphoric acid, hydrogen bromine
Acid, formic acid, acetic acid, acetate, boric acid, borax, citric acid, citrate, citric acid hydrogen salt, citric acid dihydric salt, a hydration
Citric acid, Monopotassium citrate, carbonate, bicarbonate, sodium hydroxide, potassium hydroxide, phosphate, dihydric phosphate, hydrophosphate,
One or more of tartaric acid, biatrate, amino acid and its salt.
4. lyophilized preparation as described in any one of claims 1-3, it is characterised in that: the dextrorotation oxiracetam compound by
Commercially available dextrorotation oxiracetam feed purification be made, the purification step are as follows: with hexamethylene by dextrorotation oxiracetam raw material with
Concentration 20mg/mL-40mg/mL dissolution, seals, and is that the 20-32 DEG C of speed with 200-350r/min stirs 20- in temperature
Filtrate is stood volatilization crystallization, collects crystal by 25h, filtering, dry, obtains dextrorotation oxiracetam compound after purification；Institute
State dry to be 40-75 DEG C in temperature, relative humidity dry 3-7h under conditions of being 15-30%.
5. lyophilized preparation according to any one of claims 1-4, it is characterised in that: the lyophilized technique is as follows: pre-freeze are as follows: system
Before product inlet, shelf is first cooled to 5~15 DEG C, and then canned product is put into freeze drying box, with more than 60 minutes
Shelf temperature is down to -40 ± 2 DEG C, products temperature reaches -35 DEG C ± 5 DEG C, continues heat preservation 4~6 hours；Lyophilization are as follows: vacuum
After degree is down to 10pa or less, shelf temperature is slowly increased to -5 ± 1 DEG C in 4~6 hours, heat preservation is completely disappeared to product ice crystal
Afterwards, continue heat preservation 3~5 hours；Desorbing and drying are as follows: and then 30 DEG C ± 5 DEG C are warming up to 10~12 DEG C per hour, to products temperature
Up to after 30 DEG C, then keep the temperature 2~4 hours.
6. lyophilized preparation as described in any one in claim 1-5, it is characterised in that: including 100-300g dextrorotation oxiracetam
Compound, 40-80mL normal propyl alcohol or the tert-butyl alcohol, 20-40g mannitol, 30-60g dextran, water for injection add to 1000mL and match
It is freeze-dried after solution is made.
7. lyophilized preparation as claimed in any one of claims 1 to 6, it is characterised in that: the dextrorotation oxiracetam freeze-dried powder
For the crystal form compound that drug and auxiliary material are formed, the crystal form compound is radiated using Cu Ka, and powder diffraction measures (XRPD) anti-
Firing angle 2θ isHave at 16.68 °, 17.52 °, 19.44 °, 21.01 °, 22.17 °, 23.45 °, 25.34 °, 26.06 °, 30.96 ° and spreads out
Penetrate peak.
8. the preparation method of dextrorotation oxiracetam lyophilized preparation as described in claim any one of 1-7, using following preparation work
Skill:
(1) purifying of dextrorotation oxiracetam raw material: with hexamethylene by dextrorotation oxiracetam raw material with concentration 25mg/mL-
35mg/mL dissolution, seals, and is that the 25-30 DEG C of speed with 200-350r/min stirs 22-25h in temperature, filtering will filter
Liquid stands volatilization crystallization, collects crystal, is 55-75 DEG C in temperature, and relative humidity dry 3-5h under conditions of being 15-30% is obtained
Dextrorotation oxiracetam compound after purification；
(2) preparation of solution: dextrorotation oxiracetam compound after purification is dispersed in normal propyl alcohol or the tert-butyl alcohol, is added
Enter the freeze drying protectant dissolved by water for injection, adjusts pH value of solution to 5.2-6.0 with qs pH adjuster after mixing, be added
Needle-use activated 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 are as follows: before product inlet, shelf is first cooled to 5~15 DEG C, is then put into canned product
In freeze drying box, shelf temperature is down to -40 ± 2 DEG C with more than 60 minutes, products temperature reaches -35 DEG C ± 5 DEG C, after continuation of insurance
Temperature 4~6 hours；Lyophilization are as follows: after vacuum degree is down to 10pa or less, shelf temperature is slowly increased to -5 ± 1 in 4~6 hours
DEG C, it keeps the temperature after product ice crystal completely disappears, continues heat preservation 3~5 hours；Desorbing and drying are as follows: and then with 10~12 DEG C per hour
30 DEG C ± 5 DEG C are warming up to, after products temperature up to after 30 DEG C, then keeps the temperature 2~4 hours.
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| CN2018102700976 | 2018-03-29 | ||
| CN201810270097 | 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 |
| CN102512380A (en) * | 2011-12-20 | 2012-06-27 | 海南锦瑞制药股份有限公司 | Freeze-dried powder injection with omeprazole sodium as active component 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
- 2018-06-14 CN CN201810612502.8A patent/CN110314139A/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 |
| CN102512380A (en) * | 2011-12-20 | 2012-06-27 | 海南锦瑞制药股份有限公司 | Freeze-dried powder injection with omeprazole sodium as active component 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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