CN108567749A - A kind of levo-oxiracetam oral preparation of suitable children taking and preparation method thereof - Google Patents
A kind of levo-oxiracetam oral preparation of suitable children taking and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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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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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- 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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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention provides a kind of levo-oxiracetam oral preparations of suitable children taking and preparation method thereof, use particular crystalline form levo-oxiracetam（Angle of diffraction 2θIt is 12.500 ± 0.2 °,13.940±0.2°,15.000±0.2°,16.540±0.2°,17.400±0.2°,19.320±0.2°,20.520±0.2°,20.840±0.2°,21.980±0.2°,23.340±0.2°,25.120±0.2°,25.840±0.2°,26.240±0.2°,27.660±0.2°,28.100±0.2°,30.040±0.2°,30.660±0.2°,31.040±0.2°,31.780±0.2°,34.300±0.2°,35.180±0.2°,37.060±0.2°,38.020±0.2°,42.240 ± 0.2 ° have diffraction maximum）For raw material, it is aided with the ratio of adjuvant selected meticulously, through fluidized bed granulation, mobility of particle is good, without there is " arch formation " and " rat hole phenomenon " during compacting oral disnitegration tablet, while crystal phenomenon not occurring in preparation process；The disintegrated tablet hardness of extrusion is moderate, and disintegration time is short, and tablet weight variation is small, is very suitable for the children year patient of dysphagia.Preparation method of the present invention is simple, is suitble to industrialized production.
Description
Technical field
The present invention relates to levo-oxiracetam oral preparations, and in particular to a kind of levo-oxiracetam oral disintegrated preparation and
Preparation method.
Background technology
Oxiracetam was synthesized in 1974 by Italian history Bick Qie Mu companies, a kind of promotion of exploitation listing in 1987
The novel medicine for central nervous system of ability of learning and memory is clinically mainly used for treating senile dementia, multi-infarct dementia agent god
Through function card, brain trauma, cerebral function is not complete caused by the diseases such as encephalitis, memory disorder.Studies have shown that its levo form is (left-handed
Oxiracetam) select body or d-isomer that there is better efficacy and saferry than mixed, it is likely that in later stage replacing as Oxiracetam
For drug.
Although levo-oxiracetam good effect, safe, its pharmaceutical preparation is still in development phase.About left-handed Austria
La Xitan preparation researches focus primarily upon injection (including freeze drying powder injection) and two aspect of oral preparation.Injection, it is directly fast
Speed enters human body, the protection of no human body normal physiological barrier, if therefore dosage is improper or injection is too fast or drug quality presence is asked
Topic, is possible to bring harm to patient, or even cause the consequence that can not be retrieved；In addition injection pain, cannot be by patient oneself
Administration, injection site generate scleroma and intravenous injection existing major issue when to cause vascular inflammation all be clinical application.Cause
And consider in drug safety, preferentially select oral preparation (such as capsule, tablet).Oral preparation (capsule or piece simultaneously
Agent) there is also apparent drawbacks：On the one hand, either capsule or conventional tablet work slow, and bioavilability is low；Separately
On the one hand, it is children or old man to take significant proportion in the patient of levo-oxiracetam, and this kind of patient usually swallows drug
Difficulty takes levo-oxiracetam capsule, conventional tablet is inconvenient.
Oral disnitegration tablet, can under the conditions of anhydrous in oral cavity fater disintegration, enter alimentary canal, internal row with swallowing act
It is consistent with conventional tablet；Compared with ordinary preparation, have it is convenient to take, absorb that fast, bioavilability is high, is pierced to alimentary canal mucous membrane
Swash the advantages that property is small, is very suitable for the patients such as children and takes.Through looking into, Wang Lijiang et al. is disclosed in Chinese patent CN101766595A
A kind of levo-oxiracetam oral disnitegration tablet, with levo-oxiracetam raw material, sodium carboxymethyl starch, cross-linked carboxymethyl cellulose
The auxiliary materials such as sodium are made by adhesive of water；It finds when repeating the patent, since left-handed levo-oxiracetam water solubility is fabulous, inhales
Moist strong, material is easy agglomerating in wet-granulation process, while most of material is sticked in granulation pot wall, causes particle uneven
It is even, increase the difficulty of granulation, it is difficult to it is uniformly mixed and particle that particle diameter distribution is relatively narrow, and particle compressibility is poor,
It is unfavorable for preparation production.Thus, it is very necessary to develop the new preparation technique for preparing levo-oxiracetam oral disnitegration tablet.
Invention content
The purpose of the present invention is to provide a kind of levo-oxiracetam oral disnitegration tablets.
Another object of the present invention is to provide the preparation methods of above-mentioned levo-oxiracetam oral disnitegration tablet.
During preparing levo-oxiracetam oral disnitegration tablet, since levo-oxiracetam prescription dosage is big and hygroscopicity
By force, thus the disintegrated tablet prepared to be susceptible to tablet weight variation larger, it is serious to there is also phenomena such as really up to the mark, excessively soft, loose pieces
" arch formation " or/and " rat hole phenomenon ", off quality so as to cause the oral disnitegration tablet of preparation, curative effect is unstable.Invention
People passes through numerous studies, finally found that, using the levo-oxiracetam of particular crystalline form, is used to prepare oral disnitegration tablet,
Grain good fluidity, tableting processes do not have " arch formation " or/and " rat hole phenomenon ", and the disintegrated tablet hardness of extrusion is moderate, when disintegration
Between it is short, tablet weight variation is small；Crystal phenomenon does not occur for drug ingedient in preparation process simultaneously, meets pharmaceutical formulations requirement.
The object of the present invention is achieved like this：
A kind of levo-oxiracetam oral disnitegration tablet, by comprising levo-oxiracetam, filler, disintegrant, adhesive, rectify
Raw material including taste agent and lubricant is made through fluidized bed granulation tabletting；It is characterized in that：Levo-oxiracetam 44~85%,
Filler 0~20%, disintegrant 5~25%, adhesive 1~5%, corrigent 1~5%, lubricant 0~5%, with quality percentage
Than meter；The levo-oxiracetam be crystal form, 2 θ of angle of diffraction be 12.500 ± 0.2 °, 13.940 ± 0.2 °,
15.000±0.2°、16.540±0.2°、17.400±0.2°、19.320±0.2°、20.520±0.2°、20.840±
0.2°、21.980±0.2°、23.340±0.2°、25.120±0.2°、25.840±0.2°、26.240±0.2°、27.660
±0.2°、28.100±0.2°、30.040±0.2°、30.660±0.2°、31.040±0.2°、31.780±0.2°、
34.300 ± 0.2 °, 35.180 ± 0.2 °, 37.060 ± 0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° have diffraction maximum.
Above-mentioned filler is in mannitol, microcrystalline cellulose, medicinal calcium carbonate, lactose, cornstarch, amylum pregelatinisatum
One or more combination.Above-mentioned disintegrant is selected from dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, is crosslinked and gathers
One or more of vinylpyrrolidone, croscarmellose sodium combine.Above-mentioned adhesive be selected from ethyl alcohol, starch slurry,
One in sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone
Kind or several combinations.Above-mentioned corrigent is selected from the mixing of one or more of Sucralose, xylitol, acesulfame potassium, essence.It is above-mentioned
Lubricant is selected from the combination of one or more of superfine silica gel powder, magnesium stearate, talcum powder.
In order to improve the mouthfeel of levo-oxiracetam oral disnitegration tablet, shorten disintegration time limited, above-mentioned levo-oxiracetam mouth
Cavity disintegrating tablet raw material include levo-oxiracetam 55~85%, filler 0~15%, disintegrant 10~20%, adhesive 2~
5%, corrigent 1~3%, lubricant 0~3%；The filler is selected from mannitol, microcrystalline cellulose, medicinal calcium carbonate, can press
Property the combination of one or more of starch；The disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, is crosslinked and gathers
One or more of vinylpyrrolidone combines；Described adhesive is selected from sodium carboxymethylcellulose, methylcellulose, polyethylene
One or more of pyrrolidones combines；The one kind of the corrigent in Sucralose, xylitol, acesulfame potassium, essence
Or several mixing；The lubricant is selected from the combination of one or more of superfine silica gel powder, magnesium stearate, talcum powder.
Inventor is had been surprisingly found that by experiment, and after a certain amount of mannitol is added in prescription, Oxiracetam is brilliant in preparation
The stability of type can obtain a degree of raising.It is fine with low substituted hydroxy-propyl using a certain proportion of sodium carboxymethyl starch simultaneously
Dimension element is used as disintegrant, can accelerate medicine disintegration, accelerates drug-eluting.
Above-mentioned levo-oxiracetam oral disnitegration tablet, above-mentioned filler are mannitol and microcrystalline cellulose according to mass ratio 1：
1~3 mixes；Above-mentioned disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose according to mass ratio 1:2~3 mixing
It forms.
Or
Above-mentioned filler is medicinal calcium carbonate and mannitol according to mass ratio 1：2~5 mix；Above-mentioned disintegrant is carboxylic
Methyl starch sodium is with low-substituted hydroxypropyl cellulose according to mass ratio 1:2~3 mix.
Further preferably, above-mentioned adhesive is polyvinylpyrrolidone or sodium carboxymethylcellulose.
Above-mentioned levo-oxiracetam crystal form is made using following methods:
By the medicinal dimethylacetylamide of levo-oxiracetam chemical raw material, isopropanol or n-Butanol soluble, it is stirred continuously, obtains
To clear solution, ether is added dropwise into clear solution under the conditions of 5~25 DEG C of temperature, until solution starts muddiness, filters, it will
Filtrate stands 24-48h, then centrifuge is used to be centrifuged 5-10 minutes with the rotating speed of 5000-9000rpm, obtains white precipitate, vacuum
Degree >=0.08MPa is dried in vacuo 4~10h, both.
The common method for preparing oral disnitegration tablet mainly has desivac, solid solution method, fluidized bed granulation method, powder straight
Connect pressed disc method etc..In contrast, desivac and solid solution method need particular device, and cost is higher, and complex process；Although
Direct powder compression is at low cost, simple for process, but the oral disnitegration tablet poor quality control prepared, and mouthfeel is poor, has more
Sand type.The present invention selects fluidized bed granulation method, can effectively ensure the quality of oral disnitegration tablet, while cost is relatively
It is low.It is found in research, also the same existing defects of levo-oxiracetam oral disnitegration tablet, work is prepared using fluid-bed marumerization method
Skill control is bad to make material powders be not easy to reach fluidized state, cause plug nozzle and filter bag, while may also result in system
The particle obtained has color spot or grain size bigger than normal, is unevenly distributed, to influence the dissolution and absorption of drug.
The preparation method of above-mentioned levo-oxiracetam oral disnitegration tablet, includes the following steps：
1) dispensing：Levo-oxiracetam, filler, disintegrant, corrigent, lubricant are sieved with 100 mesh sieve respectively, it is spare；
2) fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet mixing,
Wherein inlet air temperature is 24~66 DEG C, is 820~1250m into airspeed3/ hour；Inlet air temperature is increased, using top spray or side spray
Mode spray into binder solution, mixed under conditions of lasting air inlet, be dry, obtaining levo-oxiracetam particle, wherein into
Airspeed is 1080~1520m3/ hour, inlet air temperature are 47~109 DEG C, the penetrating speed of described adhesive solution is 10~
30mL/ minutes.
3) tabletting：Levo-oxiracetam particle prepared by fluid bed, mixes, then tabletting system with lubricant, corrigent
.
Inventor also found that before fluidized bed granulation is hydrojet, dry material is vulnerable to electrostatic and is adhered to fluidisation
In bed wall and on filter bag, these materials sticked cannot participate in pelletizing, and the uniformity of particle and yield is caused to receive influence, if viscous
When wall is serious, or even it will appear the phenomenon that collapsing pot and can not be carried out so as to cause follow-up granulation work.
Above-mentioned steps (2) fluidized bed granulation is that fluidised bed granulator is added in levo-oxiracetam, filler, disintegrant
In, air inlet mixing, wherein inlet air temperature are 35~62 DEG C, are 970~1230m into airspeed3/ hour；Inlet air temperature is increased, is adopted
Binder solution is sprayed into the mode of top spray or side spray, is mixed under conditions of lasting air inlet, is dry, obtaining levo-oxiracetam
Particle, wherein into airspeed be 1240~1450m3/ hour, inlet air temperature are 65~95 DEG C, the penetrating of described adhesive solution
Speed is 10~30mL/ minutes.A concentration of quality volumn concentration of described adhesive solution is calculated as 5%-20% with g/mL
Polyvinylpyrrolidone or carboxymethylcellulose sodium solution.
The preparation method of above-mentioned levo-oxiracetam oral disnitegration tablet, includes the following steps：
1) dispensing：By levo-oxiracetam 55~85%, filler 0~15%, disintegrant 10~20%, adhesive 2~
5%, corrigent 1~3%, lubricant 1~3% sieves with 100 mesh sieve respectively, spare；The filler is mannitol and microcrystalline cellulose
Element is according to mass ratio 1：1~3 mixes；The disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose according to matter
Measure ratio 1:2~3 mix；Described adhesive is polyvinylpyrrolidone or sodium carboxymethylcellulose.
2) fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet mixing,
Wherein inlet air temperature is 38~58 DEG C, is 1000~1210m into airspeed3/ hour；Inlet air temperature is increased, using top spray or side
The mode of spray sprays into binder solution, is mixed under conditions of lasting air inlet, is dry, obtaining levo-oxiracetam particle, wherein
It is 1250~1400m into airspeed3/ hour, inlet air temperature are 68~90 DEG C, the penetrating speed of described adhesive solution is 10~
30mL/ minutes；A concentration of quality volumn concentration of described adhesive solution is calculated as the polyethylene pyrrole of 6%-18% with g/mL
Pyrrolidone or carboxymethylcellulose sodium solution.
3) tabletting：Levo-oxiracetam particle prepared by fluid bed, is put into after mixing with lubricant and corrigent
It is tabletted in rotary tablet machine, turntable 18~30r/min of rotating speed, stuffing pressure be 30~40N, depth of fill be 10~
18mm。
The preparation method of above-mentioned levo-oxiracetam oral disnitegration tablet, includes the following steps：
1) dispensing：By levo-oxiracetam 55~85%, filler 0~15%, disintegrant 10~20%, adhesive 2~
5%, corrigent 1~3%, lubricant 1~3% sieves with 100 mesh sieve respectively, spare；The filler is medicinal calcium carbonate and sweet dew
Alcohol is according to mass ratio 1：2~5 mix；The disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose according to matter
Measure ratio 1:2~3 mix；Described adhesive is polyvinylpyrrolidone or sodium carboxymethylcellulose.
2) fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet mixing,
Wherein inlet air temperature is 38~58 DEG C, is 1020~1200m into airspeed3/ hour；Inlet air temperature is increased, using top spray or side
The mode of spray sprays into binder solution, is mixed under conditions of lasting air inlet, is dry, obtaining levo-oxiracetam particle, wherein
It is 1250~1420m into airspeed3/ hour, inlet air temperature are 68~92 DEG C, the penetrating speed of described adhesive solution is 10~
30mL/ minutes；A concentration of quality volumn concentration of described adhesive solution is calculated as the polyethylene pyrrole of 7%-18% with g/mL
Pyrrolidone or carboxymethylcellulose sodium solution.
3) tabletting：Levo-oxiracetam particle prepared by fluid bed, is put into after mixing with lubricant and corrigent
It is tabletted in rotary tablet machine, turntable 20~30r/min of rotating speed, stuffing pressure be 30~40N, depth of fill be 10~
20mm。
Advantageous effect：
The present invention provides a kind of levo-oxiracetam oral disnitegration tablets, use particular crystalline form levo-oxiracetam
(2 θ of angle of diffraction be 12.500 ± 0.2 °, 13.940 ± 0.2 °, 15.000 ± 0.2 °, 16.540 ± 0.2 °, 17.400 ±
0.2°、19.320±0.2°、20.520±0.2°、20.840±0.2°、21.980±0.2°、23.340±0.2°、25.120
±0.2°、25.840±0.2°、26.240±0.2°、27.660±0.2°、28.100±0.2°、30.040±0.2°、
30.660±0.2°、31.040±0.2°、31.780±0.2°、34.300±0.2°、35.180±0.2°、37.060±
0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° has diffraction maximum) it is active constituent, it is aided with the ratio of adjuvant selected meticulously, through stream
Change bed granulation, mobility of particle is good, without there is " arch formation " and " rat hole phenomenon " during compacting oral disnitegration tablet, simultaneously
Crystal phenomenon does not occur in preparation process；The disintegrated tablet hardness of extrusion is moderate, and disintegration time is short, and tablet weight variation is small, can be anhydrous
Under conditions of (or only a small amount of water presence) fater disintegration in oral cavity, enter alimentary canal with swallowing act, internal behavior with it is common
Tablet is consistent, is very suitable for the child patient of dysphagia.Levo-oxiracetam oral disnitegration tablet of the present invention is in 25 DEG C ± 2 of temperature
DEG C, carry out long-term stable experiment under the conditions of relative humidity 60% ± 10%, respectively in March, June, September, December, 18 months, 36
Six time points of the moon are detected respectively, and sample property, content, related substance meet regulation；Stability study sample is good in taste,
Long shelf-life.It is filler that the present invention, which is used containing a certain amount of mannitol, be aided with the sodium carboxymethyl starches of special ratios with it is low
Replace hydroxypropyl cellulose as disintegrant, the stability of the levo-oxiracetam oral disnitegration tablet Oxiracetam crystal form of preparation
Good, medicine disintegration is rapid, and dissolution is fast, while without sand type.The present invention prepares levo-oxiracetam mouth by fluidized bed granulation method
Cavity disintegrating tablet, by the control of the series of parameters such as inlet air temperature, intake velocity, in effective solution fluid bed granulation
Material powders are not easy to reach fluidized state, and plug nozzle and filter bag and particle obtained is caused to have color spot or grain size bigger than normal,
The technical issues of being unevenly distributed, the fluid bed granulate fine uniform of preparation, angle of repose is between 30-35 degree, good fluidity,
Tableting processes tablet without fragmentation, softening or it is viscous it is puckery rush phenomenon, oral disnitegration tablet hardness obtained is very suitable for giving birth in 35-45N
Production, transport, packaging, storage；Disintegration time limited 30-40S, good in taste, no sand type, it is more than 85% that 20min, which adds up dissolution rate,.Together
When, by further state modulator, solves dry material and be vulnerable to electrostatic and be adhered in fluidisation bed wall and on filter bag
And the problem of influencing the uniformity and yield of particle, it ensure that being smoothed out for fluidized bed granulation.Preparation method of the present invention is simple,
It is suitble to industrialized production.
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.The raw materials used in the present invention and reagent are equal
For commercial product.Levo-oxiracetam medicinal chemicals of the present invention is provided by Chongqing East pool Pharmaceuticals Ltd, and purity 99% is non-
Single crystal form.Unless otherwise specified, number of the present invention is parts by weight, and the percentage is mass percent.
(1), the preparation of levo-oxiracetam crystal form
Embodiment 1 (raw material levo-oxiracetam crystal form of the present invention)
Levo-oxiracetam 1g (Chongqing East pool Pharmaceuticals Ltd provides, purity 99%) is dissolved with isopropanol 8mL, constantly
Stirring, obtains clear solution, ether is added dropwise into clear solution for 15 DEG C or so in temperature, conventional until solution starts muddiness
Filtering, 36h is stood by filtrate, then centrifuge is used to be centrifuged 10 minutes with the rotating speed of 8000rpm, is obtained white precipitate, vacuum degree
>=0.08MPa is dried in vacuo 8h, both.
The powder of the crystal type product obtained is measured using Bruker D8Advance diffractometers, determination condition is as follows：Cu
K α, 40kV, 40mV are light source, 0.12 ° of step-length, 10 °/min of sweep speed, 5~45 ° of scanning range, room temperature, X-ray powder
In diffraction pattern, the crystal type levo-oxiracetam 2 θ of angle of diffraction be 12.500 ± 0.2 °, 13.940 ± 0.2 °, 15.000
±0.2°、16.540±0.2°、17.400±0.2°、19.320±0.2°、20.520±0.2°、20.840±0.2°、
21.980±0.2°、23.340±0.2°、25.120±0.2°、25.840±0.2°、26.240±0.2°、27.660±
0.2°、28.100±0.2°、30.040±0.2°、30.660±0.2°、31.040±0.2°、31.780±0.2°、34.300
± 0.2 °, 35.180 ± 0.2 °, 37.060 ± 0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° has diffraction maximum.
With reference to the preparation method of embodiment 1, isopropanol is replaced with dimethylacetylamide or n-butanol, by levo-oxiracetam
Medicinal chemicals dissolves, and is stirred continuously, obtains clear solution, and ether is added dropwise into clear solution under the conditions of 5~25 DEG C of temperature,
Until solution starts muddiness, filtrate is stood 24-48h by filtering, then centrifuge is used to be centrifuged with the rotating speed of 5000-9000rpm
5-10 minutes, white precipitate is obtained, vacuum degree >=0.08MPa is dried in vacuo 4~10h, above-described embodiment 1 can be prepared
Crystal type levo-oxiracetam.
Comparative example 1
Levo-oxiracetam crude product (Chongqing East pool Pharmaceuticals Ltd provides, purity 99%) 100g is taken, 220mL first is added
Alcohol dissolves, and is concentrated to dryness, obtains levo-oxiracetam compound.It is measured and is obtained using Bruker D8Advance diffractometers
Crystal type levo-oxiracetam powder, determination condition is as follows：Cu K α, 40kV, 40mV are light source, 0.12 ° of step-length, scanning
10 °/min of speed, 5~45 ° of scanning range, room temperature, in x-ray diffractogram of powder, the crystal type levo-oxiracetam exists
2 θ of angle of diffraction is 10.46,12.48,13.92,15.00,16.51,17.36,18.67,19.27,20.16,20.56,
There is feature suction at 20.83,21.23,21.95,23.34,24.22,25.07,25.93,26.28,30.04,30.73,31.09 °
Receive peak.
Comparative example 2
Levo-oxiracetam crude product (Chongqing East pool Pharmaceuticals Ltd provides, purity 99%) 100g is taken, 280mL second is added
(volume ratio is ethyl alcohol to the mixed solvent of alcohol and water：Water=10: 1) dissolving, and is subsequently cooled to 12 DEG C, and stirring and crystallizing filters, finally
It is dried in vacuo at 45~55 DEG C, obtains levo-oxiracetam powder.It is measured and is obtained using Bruker D8Advance diffractometers
Crystal type levo-oxiracetam powder, determination condition is as follows：Cu K α, 40kV, 40mV are light source, 0.12 ° of step-length, scanning
10 °/min of speed, 5~45 ° of scanning range, room temperature, in x-ray diffractogram of powder, the crystal type levo-oxiracetam exists
2 θ of angle of diffraction is that 2 θ are 12.43,13.90,14.99,16.52,17.38,19.28,20.54,20.82,21.97,23.31,
There is characteristic absorption peak at 25.12,25.87,26.24,28.08,30.03,30.66.
(1), the preparation of levo-oxiracetam oral disnitegration tablet of the present invention
Embodiment 2
With crystal form levo-oxiracetam (2 θ be 12.500 ± 0.2 °, 13.940 ± 0.2 °, 15.000 ± 0.2 °,
16.540±0.2°、17.400±0.2°、19.320±0.2°、20.520±0.2°、20.840±0.2°、21.980±
0.2°、23.340±0.2°、25.120±0.2°、25.840±0.2°、26.240±0.2°、27.660±0.2°、28.100
±0.2°、30.040±0.2°、30.660±0.2°、31.040±0.2°、31.780±0.2°、34.300±0.2°、
35.180 ± 0.2 °, 37.060 ± 0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° have diffraction maximum) it is active constituent, addition is filled out
The auxiliary materials such as agent, disintegrant, adhesive, corrigent and lubricant are filled, by fluidized bed granulation, tabletting prepares left-handed Aura west
Smooth oral disnitegration tablet.
Prescription：Levo-oxiracetam 60g, mannitol 6g, microcrystalline cellulose 12g, sodium carboxymethyl starch 5g, low-substituted hydroxypropyl
Base cellulose 11g, polyvinylpyrrolidone 3g, xylitol 2g, magnesium stearate 1g.Preparation method：
(1) dispensing：Levo-oxiracetam, mannitol, microcrystalline cellulose, sodium carboxymethyl starch, low substituted hydroxy-propyl is fine
Dimension element, polyvinylpyrrolidone, xylitol, magnesium stearate sieve with 100 mesh sieve respectively, spare；
(2) fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet is mixed
It closes, wherein inlet air temperature is 52 DEG C, is 1120m into airspeed3/ hour；Inlet air temperature is increased, is sprayed by the way of top spray viscous
Mixture solution mixes under conditions of lasting air inlet, is dry, levo-oxiracetam particle being obtained, wherein being into airspeed
1350m3/ hour, inlet air temperature are 86 DEG C, and a concentration of quality volumn concentration of binder solution is calculated as 10% with g/mL
The penetrating speed of polyvinylpyrrolidonesolution solution, binder solution is 25mL/ minutes；
(3) tabletting：Levo-oxiracetam particle prepared by fluid bed, is put into after mixing with lubricant and corrigent
It is tabletted in rotary tablet machine, turntable rotating speed 20r/min, stuffing pressure 34N, depth of fill 15mm.
With the levo-oxiracetam of the comparative example 1-2 crystal forms prepared and the levo-oxiracetam of embodiment 1
Raw material (Chongqing East pool Pharmaceuticals Ltd provide, purity 99% do not crystallize) is active constituent, with reference to the method for embodiment 2, with
Mannitol, microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, xylitol, tristearin
The auxiliary materials such as sour magnesium prepare levo-oxiracetam oral disnitegration tablet through fluidized bed granulation tabletting.
The levo-oxiracetam for investigating embodiment 2, comparative example 1,2 levo-oxiracetam crystal forms and embodiment 1 is former
Expect (not crystallizing) be active constituent, the tabletting situation and stability of crystal form of the levo-oxiracetam oral disnitegration tablet of preparation, specifically
As a result it see the table below 1.
1 different crystal forms of table prepare the tabletting situation of levo-oxiracetam oral disnitegration tablet and stability of crystal form is investigated
Found out by upper table 1, the levo-oxiracetam of crystal form prepared by comparative example 1 is active constituent, through fluidisation
Mobility of particle after bed granulation is good, and tablet weight variation is small, and hardness is moderate, and tablet weight variation is small, in good taste, while the disintegrated tablet prepared
Crystal form and corresponding crystal form levo-oxiracetam raw material are inconsistent, and there are crystal transfers in preparation process；Comparative example 2 is made
The levo-oxiracetam of standby crystal form is active constituent, and the mobility of particle after fluidized bed granulation is general, tablet weight variation
Greatly, part tablet disintegration times are longer, grittiness sense, while the disintegration platelet-shaped prepared and the left-handed Aura west of corresponding crystal form
Smooth raw material is inconsistent, and there are crystal transfers in preparation process；The use of the left raw material (not crystallizing) difficult to understand of embodiment 1 is active constituent, warp
Mobility of particle after fluidized bed granulation is poor, there is bridge formation and rat hole phenomenon, and tablet weight variation is big, part tablet disintegration times compared with
It is long.Crystal form levo-oxiracetam that as apparent from the above results, the present invention uses (2 θ are 12.500 ± 0.2 °,
13.940±0.2°、15.000±0.2°、16.540±0.2°、17.400±0.2°、19.320±0.2°、20.520±
0.2°、20.840±0.2°、21.980±0.2°、23.340±0.2°、25.120±0.2°、25.840±0.2°、26.240
±0.2°、27.660±0.2°、28.100±0.2°、30.040±0.2°、30.660±0.2°、31.040±0.2°、
31.780±0.2°、34.300±0.2°、35.180±0.2°、37.060±0.2°、38.020±0.2°、42.240±0.2°
Have diffraction maximum), oral disnitegration tablet is prepared through fluidized bed granulation tabletting, mobility of particle is good, and tableting processes are without " arch formation "
The disintegrated tablet hardness of " rat hole phenomenon ", extrusion is moderate, and disintegration time is short, and tablet weight variation is small；Do not occur in preparation process simultaneously
Crystal phenomenon meets pharmaceutical formulations requirement.
In crystalline form levo-oxiracetam (2 θ be 12.500 ± 0.2 °, 13.940 ± 0.2 °, 15.000 ± 0.2 °,
16.540±0.2°、17.400±0.2°、19.320±0.2°、20.520±0.2°、20.840±0.2°、21.980±
0.2°、23.340±0.2°、25.120±0.2°、25.840±0.2°、26.240±0.2°、27.660±0.2°、28.100
±0.2°、30.040±0.2°、30.660±0.2°、31.040±0.2°、31.780±0.2°、34.300±0.2°、
35.180 ± 0.2 °, 37.060 ± 0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° has diffraction maximum) it is active constituents of medicine, ginseng
Filler, disintegrant, adhesive, corrigent and lubricant is added according to the prescription of the following table 2 according to the preparation method of embodiment 2
Equal auxiliary materials, by fluidized bed granulation, tabletting prepares the levo-oxiracetam oral disnitegration tablet of embodiment 3-9.
The levo-oxiracetam oral disnitegration tablet preparation prescription of 2 embodiment 3-9 of table
Embodiment 10
Prescription：Levo-oxiracetam 60g, mannitol 10g, medicinal calcium carbonate 5g, sodium carboxymethyl starch 6g,
Low-substituted hydroxypropyl cellulose 12g, polyvinylpyrrolidone 4g, Sucralose 2g, magnesium stearate 1g.Preparation side
Method：
(1) dispensing：Levo-oxiracetam, mannitol, medicinal calcium carbonate, sodium carboxymethyl starch, low substituted hydroxy-propyl is fine
Dimension element, polyvinylpyrrolidone, Sucralose, magnesium stearate sieve with 100 mesh sieve respectively, spare；
(2) fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet is mixed
It closes, wherein inlet air temperature is 50 DEG C (being denoted as initial inlet air temperature), is 1100m into airspeed3/ hour (is denoted as initially into wind speed
Rate)；Inlet air temperature is increased, binder solution is sprayed by the way of top spray, is mixed under conditions of lasting air inlet, is dry, obtained
To levo-oxiracetam particle, wherein into airspeed be 1320m3/ hour (is denoted as inlet air temperature again), and inlet air temperature is 90 DEG C
(being denoted as inlet air temperature again), a concentration of quality volumn concentration of binder solution are calculated as 15% polyethylene pyrrole with g/mL
The penetrating speed of pyrrolidone solution, binder solution is 20mL/ minutes；
(3) tabletting：Levo-oxiracetam particle prepared by fluid bed, is put into after mixing with lubricant and corrigent
It is tabletted in rotary tablet machine, turntable rotating speed 23r/min, stuffing pressure 32N, depth of fill 14mm.
In crystalline form levo-oxiracetam (2 θ be 12.500 ± 0.2 °, 13.940 ± 0.2 °, 15.000 ± 0.2 °,
16.540±0.2°、17.400±0.2°、19.320±0.2°、20.520±0.2°、20.840±0.2°、21.980±
0.2°、23.340±0.2°、25.120±0.2°、25.840±0.2°、26.240±0.2°、27.660±0.2°、28.100
±0.2°、30.040±0.2°、30.660±0.2°、31.040±0.2°、31.780±0.2°、34.300±0.2°、
35.180 ± 0.2 °, 37.060 ± 0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° have diffraction maximum) it is active constituents of medicine, ginseng
Filler, disintegrant, adhesive, corrigent and lubrication is added according to the preparation process of the following table 3 according to the method for embodiment 10
The auxiliary materials such as agent, by fluidized bed granulation, tabletting prepares the levo-oxiracetam oral disnitegration tablet of embodiment 11-16.
3 embodiment 11-16 levo-oxiracetam oral disnitegration tablet preparation technology parameters of table
(3) quality evaluation of levo-oxiracetam oral disnitegration tablet of the present invention
Embodiment 17
Experiment 1：At graininess and compressibility inspection
So that material to be measured is freely fallen from the fixed funnel of sustained height, accumulation body formed on the disk that radius is r,
Until material is overflowed from disk border, the height h of accumulation body is measured, replication 3 times is averaged, and is labeled as hIt is average, i.e. hIt is average
=(h1+h2+h3)/3 calculates arctan (hIt is average/ r), if arctan (hIt is average/ r) 35 ° of ＜, and 25 ° of ＞, that is, think that particle is equal
It is even, it is conducive to industrialized production.It is suppressed with the tablet press machine of same model, by hardness control within the scope of 35-50N.Emphasis
It checks hardness, and has seen whether the abnormal conditions such as fragmentation, softening or viscous puckery punching.
Experiment 2：Disintegration time limited checks
It takes 2mL water (37 DEG C) to be placed in 5mL test tubes, sample prepared by above-described embodiment is added, start timing, until all collapsing
It is shattered into independent fine particle, stops timing, records disintegration time, test tube needs to stand in disintegrating procedue, takes 6 progress every time
Detection, takes its average value.
Experiment 3：Mouthfeel inspection
Healthy volunteer 6 is chosen, sample prepared by above-described embodiment is placed on lingual surface and starts timing, until in the oral cavity
Whole disintegration start-stops stop timing, record disintegration time, and experience slice, thin piece and be placed in certainly in mouth to the feeling in oral cavity after complete disintegration,
Such as sweet tea/hardship, whether there is or not grittiness etc..
Experiment 4：Dissolved corrosion inspection
In view of the unpub levo-oxiracetam elution test method in Chinese food Drug Administration official website, it is contemplated that
Physics, chemistry and the biological property of levo-oxiracetam, thus it is speculated that absorbed in enteron aisle, while molten in the saturation of detection bulk pharmaceutical chemicals
Xie Du is relatively low, and in about pH5.6-5.8, saturation solubility is maximum, has pH dependences, and bulk pharmaceutical chemicals are weak acidic drug, therefore
It is screening medium to determine+1% tween of pH6.8 acetate buffers (surface), and condition is as follows：
Testing liquid：+ 1% tween of pH6.8 acetate buffers
Paddle rotating speed：50rpm
Experimental liquid volume：900mL.
The evaluation result of above-described embodiment such as the following table 4.
Fluid bed granulate fine uniform prepared by embodiment 2-14, angle of repose is between 30-35 degree, good fluidity, pressure
Piece process without arch formation or rat hole phenomenon, tablet without fragmentation, softening or it is viscous it is puckery rush phenomenon, tablet weight variation is small, oral cavity obtained
Disintegrated tablet hardness is very suitable for production, transport, packaging, storage in 35-40N；Disintegration time limited 25-35S, good in taste, no gravel
Sense, it is more than 85% that 20min, which adds up dissolution rate,；In production process, drug crystal forms do not change, meet pharmacy requirement.It adopts
With the composite filler containing mannitol combine compound disintegrant prepare disintegrated tablet (embodiment 2-6), more single filler or/and
Disintegrated tablet (embodiment 7-9) disintegration time limited prepared by disintegrant is slightly shorter, and it is more that 20min adds up dissolution rate (%).Using stream
Change during bed prepares oral disnitegration tablet and find, different technique can cause prodigious difference.As inlet air temperature with into wind speed
Degree control is bad, and particulate brittleness can be caused big, and bulk density and mobility are small, and dry interior wet outside partial particulate, color is relatively deep (as implemented
Example 13)；The concentration of adhesive and addition speed control are bad, and grain diameter can be caused big, and brittleness is small, and hardness is big, material caking,
Plug nozzle causes actual binder dosage insufficient, and fine powder is more, or even has the danger (such as embodiment 14) for the bed that collapses.
Levo-oxiracetam oral disnitegration tablet prepared by above-described embodiment 2-14, in 25 DEG C ± 2 DEG C of temperature, relative humidity
Long-term stable experiment is carried out under the conditions of 60% ± 10%, respectively at March, June, September, December, 18 months, 36 months six time points
It detects respectively, sample property, content, related substance meet regulation；Sample was detected at 36 months simultaneously, containing sweet in prescription
The levo-oxiracetam oral disnitegration tablet (such as embodiment 2-6) for revealing alcohol, relative to the levo-oxiracetam mouth without containing mannitol
The related content of material of cavity disintegrating tablet (such as embodiment 7-9) is lower；Stability study sample is good in taste, shows sample at 36 months
Effect phase internal stability is good.
Claims (9)
1. a kind of levo-oxiracetam oral disnitegration tablet, by including levo-oxiracetam, filler, disintegrant, adhesive, flavoring
Raw material including agent and lubricant is made through fluidized bed granulation tabletting；It is characterized in that：Levo-oxiracetam 44~85%, is filled out
Fill agent 0~20%, disintegrant 5~25%, adhesive 1~5%, corrigent 1~5%, lubricant 0~5%, by percentage to the quality；Institute
It is crystal form to state levo-oxiracetam, in angle of diffraction 2θFor 12.500 ± 0.2 °, 13.940 ± 0.2 °, 15.000 ±
0.2°、 16.540±0.2°、 17.400±0.2°、19.320±0.2°、 20.520±0.2°、 20.840±0.2°、
21.980±0.2°、 23.340±0.2°、 25.120±0.2°、 25.840±0.2°、 26.240±0.2°、 27.660
±0.2°、 28.100±0.2°、 30.040±0.2°、 30.660±0.2°、 31.040±0.2°、 31.780±0.2°、
34.300 ± 0.2 °, 35.180 ± 0.2 °, 37.060 ± 0.2 °, 38.020 ± 0.2 °, 42.240 ± 0.2 ° have diffraction maximum.
2. levo-oxiracetam oral disnitegration tablet as described in claim 1, it is characterised in that：The filler is selected from sweet dew
One or more of alcohol, microcrystalline cellulose, medicinal calcium carbonate, lactose, cornstarch, amylum pregelatinisatum combine；The disintegration
It is fine that agent is selected from dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, cross-linked carboxymethyl
The combination of one or more of the plain sodium of dimension；Described adhesive is selected from ethyl alcohol, starch slurry, sodium carboxymethylcellulose, hydroxy propyl cellulose
One or more of element, methylcellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone combine；The corrigent choosing
It is mixed from one or more of Sucralose, xylitol, acesulfame potassium, essence；The lubricant is selected from superfine silica gel powder, stearic acid
One or more of magnesium, talcum powder combine.
3. levo-oxiracetam oral disnitegration tablet as described in claim 1, it is characterised in that：The levo-oxiracetam oral cavity
It includes levo-oxiracetam 55~85%, filler 0~15%, disintegrant 10~20%, adhesive 2~5%, flavoring to be disintegrated tablet raw material
Agent 1~3%, lubricant 0~3%；The filler is in mannitol, microcrystalline cellulose, medicinal calcium carbonate, amylum pregelatinisatum
One or more combination；The disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrrolidines
One or more of ketone combines；Described adhesive is in sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone
One or more combination；The corrigent is selected from the mixing of one or more of Sucralose, xylitol, acesulfame potassium, essence；
The lubricant is selected from the combination of one or more of superfine silica gel powder, magnesium stearate, talcum powder.
4. levo-oxiracetam oral disnitegration tablet as described in claim 1, it is characterised in that：The levo-oxiracetam oral cavity
Disintegrated tablet, above-mentioned filler are mannitol and microcrystalline cellulose according to mass ratio 1：1~3 mixes；Above-mentioned disintegrant is carboxylic
Methyl starch sodium is with low-substituted hydroxypropyl cellulose according to mass ratio 1:2~3 mix.
5. levo-oxiracetam oral disnitegration tablet as described in claim 1, it is characterised in that：Described adhesive is polyethylene pyrrole
Pyrrolidone or sodium carboxymethylcellulose.
6. levo-oxiracetam oral disnitegration tablet as described in claim 1, it is characterised in that：The levo-oxiracetam crystal form
It is made using following methods:
It by the medicinal dimethylacetylamide of levo-oxiracetam chemical raw material, isopropanol or n-Butanol soluble, is stirred continuously, obtains clear
Ether is added dropwise into clear solution under the conditions of 5~25 DEG C of temperature for clear solution, until solution starts muddiness, filtering, by filtrate
24-48h is stood, then centrifuge is used to be centrifuged 5-10 minutes with the rotating speed of 5000-9000rpm, obtains white precipitate, vacuum degree >=
0.08MPa is dried in vacuo 4~10h, both.
7. the preparation method of levo-oxiracetam oral disnitegration tablet as claimed in any one of claims 1 to 6, which is characterized in that packet
Include following steps：
1）Dispensing：Levo-oxiracetam, filler, disintegrant, corrigent, lubricant are sieved with 100 mesh sieve respectively, it is spare；
2）Fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet mixing, wherein
Inlet air temperature is 24~66 DEG C, is 820~1250m into airspeed3/ hour；Inlet air temperature is increased, using the side of top spray or side spray
Formula sprays into binder solution, is mixed under conditions of lasting air inlet, is dry, levo-oxiracetam particle being obtained, wherein into wind speed
Rate is 1080~1520m3/ hour, inlet air temperature are 47~109 DEG C, and the penetrating speed of described adhesive solution is 10~30mL/
Minute；
3）Tabletting：Levo-oxiracetam particle prepared by fluid bed, mixes with lubricant, corrigent, and then tabletting is made.
8. the preparation method of levo-oxiracetam oral disnitegration tablet as claimed in claim 7, which is characterized in that including following step
Suddenly：The step（2）Fluidized bed granulation is that levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet
Mixing, wherein inlet air temperature are 35~62 DEG C, are 970~1230m into airspeed3/ hour；Inlet air temperature is increased, using top spray
Or the mode of side spray sprays into binder solution, is mixed under conditions of lasting air inlet, dry, obtains levo-oxiracetam particle,
It is wherein 1240~1450m into airspeed3/ hour, inlet air temperature are 65~95 DEG C, and the penetrating speed of described adhesive solution is
10~30mL/ minutes；Described adhesive is the polyvinylpyrrolidone or carboxymethylcellulose sodium solution of 5%-20%, with mass body
Product percentage composition g/mL meters.
9. the preparation method of levo-oxiracetam oral disnitegration tablet as claimed in claim 7, which is characterized in that including following step
Suddenly：
1）Dispensing：By levo-oxiracetam 55~85%, filler 0~15%, disintegrant 10~20%, adhesive 2~5%, flavoring
Agent 1~3%, lubricant 1~3% sieves with 100 mesh sieve respectively, spare；The filler is mannitol and microcrystalline cellulose according to quality
Than 1：1~3 mixes；The disintegrant is sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose according to mass ratio 1:2~3
It mixes；Described adhesive is polyvinylpyrrolidone or sodium carboxymethylcellulose；
2）Fluidized bed granulation：Levo-oxiracetam, filler, disintegrant are added in fluidised bed granulator, air inlet mixing, wherein
Inlet air temperature is 38~58 DEG C, is 1000~1210m into airspeed3/ hour；Inlet air temperature is increased, using top spray or side spray
Mode sprays into binder solution, is mixed under conditions of lasting air inlet, is dry, levo-oxiracetam particle being obtained, wherein entering the wind
Rate is 1250~1400m3/ hour, inlet air temperature are 68~90 DEG C, the penetrating speed of described adhesive solution is 10~
30mL/ minutes；Described adhesive is the polyvinylpyrrolidone or carboxymethylcellulose sodium solution of 6%-18%, with quality volume hundred
Divide content g/mL meters；
3）Tabletting：Levo-oxiracetam particle prepared by fluid bed, rotation is put into lubricant and corrigent after mixing
Tabletted in formula tablet press machine, turntable 18~30r/min of rotating speed, stuffing pressure is 30~40N, and depth of fill is 10~18mm.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766595A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Solid preparation with levo-oxiracetam as active component |
| CN102249975A (en) * | 2010-05-21 | 2011-11-23 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof |
| WO2014087367A2 (en) * | 2012-12-09 | 2014-06-12 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and its associated complications |
-
2017
- 2017-03-14 CN CN201710150612.2A patent/CN108567749A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766595A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Solid preparation with levo-oxiracetam as active component |
| CN102249975A (en) * | 2010-05-21 | 2011-11-23 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof |
| WO2014087367A2 (en) * | 2012-12-09 | 2014-06-12 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and its associated complications |
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Application publication date: 20180925 |
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