CN107510657A - Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof - Google Patents
Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof Download PDFInfo
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Abstract
A kind of good levo-oxiracetam particle of content uniformity is made by following supplementary material：1 part of levo-oxiracetam, 0.5 ~ 1.1 part of L cysteines, 0.7 ~ 1.2 part of mannitol, 0.6 ~ 1.2 part of microcrystalline cellulose, 0.8 ~ 1.3 part of sodium carboxymethylcellulose, 0.9 ~ 1.7 part of lactose, 0.6 ~ 1.3 part of sorbierite, 0.12 ~ 0.17 part of talcum powder, 1.0 ~ 1.5 parts of Macrogol 4000,0.9 ~ 1.6 part of hydroxypropyl methylcellulose, 9 ~ 15 parts of the starch slurry that mass fraction is 6% ~ 8%, 2 ~ 7 parts of the ethanol solution that volume fraction is 30% ~ 50%；According to levo-oxiracetam particulate production impurity incrementss produced by the present invention are smaller, incrementss are only 0.04%, bisque amount is few, uniform particle diameter, good fluidity, not sub- angle are less than 38 °, content uniformity is less than ± 5%, granule content uniformity is good, and the content RSD of multiple spot is less than 2%, and storage stability is good, product is not easy moisture absorption caking, and shelf life is up to 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of good levo-oxiracetam particle of content uniformity and its system
Preparation Method.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, is only used for
Central nervous system, cerebral cortex, hippocampus are mainly distributed on, have activation, protection or the functional rehabilitation for promoting nerve cell, change
The mnemonic learning function of kind disturbance of intelligence patient, and medicine also acts in itself without direct vasoactive without central excitation,
Influence to ability of learning and memory is a kind of lasting facilitation.
The medicine listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Parenteral solution, 5ml: 1g.
It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.Ye Lei etc. is in public affairs
The number of opening is obvious to the promoting wakening gone into a coma caused by alcoholism to mention levo-oxiracetam in the A patents of CN 103735545, and right
Rotation Oxiracetam does not act on substantially, and the awake effect of above-mentioned rush of levo-oxiracetam is 2 times of racemization Oxiracetam；Left-handed Aura west
The smooth promoting wakening to stupor caused by wound, anesthesia is notable.Peak etc. is opened to drape over one's shoulders in Publication No. CN 103599101A patent
Dew levo-oxiracetam has significantly to traumatic brain injury learning and memory in rats cognition dysfunction caused by hydraulic pressure and freely falling body
Improvement result, its drug effect are far above dextrorotation Oxiracetam.And 200mg/kg levo-oxiracetams and 400mg/kg Oxiracetams
Effect is suitable.Pharmacokinetic study results are shown：Levo-oxiracetam and dextrorotation Oxiracetam are in beasle dog body without obvious hand
Property conversion.Beasle dog single intravenous injection gives after left-handed and 2 multiple doses racemization Oxiracetams levo-oxiracetam in blood plasma
The equal no significant difference of main pharmacokinetic parameters.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level,
Levo-oxiracetam is with Oxiracetam to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows,
Levo-oxiracetam is the main active that drug effect is played in Oxiracetam body, and this product, which is used alone, can reduce Clinical practice dosage,
Reduce potential toxicity.
Existing levo-oxiracetam particle be primarily present preparation process impurity increase it is larger, particle bisque is more, and particle diameter is difficult to control,
Mixed process main ingredient is not easy to be well mixed, content lack of homogeneity, and storage process stability is poor, and particle hygroscopicity is strong, easy adhesion
Lump, the technical problems such as shelf life is short.
The content of the invention
It is an object of the invention to provide the levo-oxiracetam particle that a kind of content uniformity is good, stability is good.
Another object of the present invention is to provide the preparation method of above-mentioned levo-oxiracetam particle.
The purpose of the present invention is realized by following technical measures：
A kind of good levo-oxiracetam particle of content uniformity, it is characterised in that it be using levo-oxiracetam as raw material, then
A certain amount of filler, flavouring, adhesive, lubricant, coating material is added to be made；Wherein described filler be starch,
Lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose, sodium carboxymethylcellulose, sorbierite, L-
One or more in cysteine；The flavouring be sweet sucrose, maltose, ethylmaltol, Sucralose, stevia rebaudianum, sorbierite,
One or more in mannitol, glucose, aspartame；Described adhesive is water, ethanol, sucrose, starch slurry, dextrin, carboxylic first
One or more in base cellulose, polyvinylpyrrolidone；The lubricant be talcum powder, magnesium stearate, polyethylene glycol, stearic acid,
One or more in calcium stearate, lauryl sodium sulfate, superfine silica gel powder, magnesia, paraffin；The coating material is polyethylene glycol
4000th, Macrogol 6000, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene acetaldehyde diethyl ester, hydroxypropyl methyl cellulose
One or more in phthalate ester.
Inventor has found that rational prescription proportion relation coordinates specific supplementary material processing mode again in research process, may be such that
State that levo-oxiracetam particulate production impurity increase is smaller, and grain diameter is uniform, and content uniformity is small, and product stability is good,
Moisture absorption is not easy, is not easy adhesion caking, shelf life length, main ingredient is easier to mix, and content uniformity is good；Above-mentioned content uniformity is good
Levo-oxiracetam particle, it is characterised in that it is made by the supplementary material of following weight proportion：1 part of levo-oxiracetam,
0.5~1.1 part of Cys, 0.7~1.2 part of mannitol, 0.6~1.2 part of microcrystalline cellulose, sodium carboxymethylcellulose 0.8~1.3
Part, 0.9~1.7 part of lactose, 0.6~1.3 part of sorbierite, 0.12~0.17 part of talcum powder, 1.0~1.5 parts of Macrogol 4000, hydroxyl
The ethanol that 9~15 parts of starch slurry that third 0.9~1.6 part of methylcellulose, mass fraction are 6%~8%, volume fraction are 30%~50%
2~7 parts of solution；The levo-oxiracetam of recipe quantity is taken, adds the ethanol solution dissolving of recipe quantity, it is standby；Separately take the Guang ammonia of L- half
Acid, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite are placed in Universalpulverizer, crushed 100
It is placed in after mesh sieve in wet granulator, it is 6%~8% to add above-mentioned the levo-oxiracetam ethanol solution handled well and mass fraction
Starch slurry, start granulator (18 mesh nylon mesh of installation), start to pelletize；Wet granular is put into fluid bed, hotbed temperature is set
It is fixed 50 DEG C~70 DEG C, start drying, drying time is 50~55 minutes；Take Macrogol 4000, the hypromellose of recipe quantity
Element, add water that the coating solution that quality volume fraction is 8%~10% is made, it is standby；Above-mentioned dry particl is put into fluid bed, is passed through
Hot-air, is allowed to suspension fluidization, and bed temperature is 40~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed,
50~60rpm of spouting velocity is set, atomizing pressure is 0.8~1.0bar, continues air intake and dries, solution continues heating 10~15 after having sprayed
Stop heating, cooling discharging after minute；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；By recipe quantity
Talcum powder crushed 100 mesh sieves, add in the particle after whole grain, produced with three-dimensional motion mixer mixing 10min~20min.
Further, in order that obtaining above-mentioned levo-oxiracetam granule content evenly, stability is more preferable, and shelf life is longer, and one
Kind levo-oxiracetam particle, it is characterised in that it is made by the supplementary material of following weight proportion：1 part of levo-oxiracetam,
0.7~1.0 part of Cys, 0.8~1.1 part of mannitol, 0.9~1.1 part of microcrystalline cellulose, sodium carboxymethylcellulose 0.9~1.2
Part, 1.2~1.5 parts of lactose, 0.8~1.1 part of sorbierite, 0.13~0.16 part of talcum powder, 1.1~1.3 parts of Macrogol 4000, hydroxyl
The ethanol that 10~13 parts of starch slurry that third 1.0~1.2 parts of methylcellulose, mass fraction are 6%~8%, volume fraction are 30%~50%
3~6 parts of solution；The levo-oxiracetam of recipe quantity is taken, adds the ethanol solution dissolving of recipe quantity, it is standby；Separately take the Guang ammonia of L- half
Acid, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite are placed in Universalpulverizer, crushed 100
It is placed in after mesh sieve in wet granulator, it is 6%~8% to add above-mentioned the levo-oxiracetam ethanol solution handled well and mass fraction
Starch slurry, start granulator (18 mesh nylon mesh of installation), start to pelletize；Wet granular is put into fluid bed, hotbed temperature is set
It is fixed 50 DEG C~70 DEG C, start drying, drying time is 50~55 minutes；Take Macrogol 4000, the hypromellose of recipe quantity
Element, add water that the coating solution that quality volume fraction is 8%~10% is made, it is standby；Above-mentioned dry particl is put into fluid bed, is passed through
Hot-air, is allowed to suspension fluidization, and bed temperature is 40~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed,
50~60rpm of spouting velocity is set, atomizing pressure is 0.8~1.0bar, continues air intake and dries, solution continues heating 10~15 after having sprayed
Stop heating, cooling discharging after minute；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；By recipe quantity
Talcum powder crushed 100 mesh sieves, add in the particle after whole grain, produced with three-dimensional motion mixer mixing 10min~20min.
The preparation method of the good levo-oxiracetam particle of a kind of content uniformity, it is characterised in that it is obtained as follows
's：
1. supplementary material pre-treatment：Take the levo-oxiracetam of recipe quantity to add the ethanol solution dissolving of recipe quantity, obtain left-handed Aura west
Smooth ethanol solution, it is standby；Take the filler of recipe quantity, flavouring to be placed in Universalpulverizer, crushed 100 mesh sieves, it is standby；
2. granulation：Gained mixed accessories powder and levo-oxiracetam ethanol solution after pre-treatment are taken, is placed in wet granulator, adds
Enter adhesive, start granulator (18 mesh nylon mesh of installation), start to pelletize；
3. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying；Particle boiling is observed at any time
Situation, air blast situation are risen, prevents the particle-bonded ceramic the bottom of a pan, causes particle coking or gelatinization, drying time is 50~55 minutes, is protected
Demonstrate,prove pellet moisture≤3%；
4. coating：
(1) configuration of coating solution：The coating material of recipe quantity is taken, adds water that the solution that quality volume fraction is 8%~10% is made, it is standby
With；
(2) coating process：Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40~50
℃；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50~60rpm of spouting velocity, atomizing pressure is
0.8~1.0bar, continue air intake and dry, solution stops heating after continuing heating after having sprayed 10~15 minutes, cooling discharging, produces bag
Clothing particle；
5. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, 25 DEG C of control environment temperature with
Under, relative humidity is below 50%；
It is 6. total mixed：Lubricant be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer
10min~20min；
Wrapped in 7.：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature, relatively
Below humidity 50%, produce.
The present invention has following beneficial effect：
Levo-oxiracetam particulate production impurity incrementss of the present invention are smaller, incrementss are only 0.04%, and particle bisque amount is few,
Uniform particle diameter, good fluidity, not sub- angle are less than 38 °, and content uniformity is less than ± 5%, and granule content uniformity is good, multiple points
Content RSD is less than 2%, and storage process stability is good, and product is not easy moisture absorption caking, and shelf life is up to 24 months, is prepared
Technique simple possible, it is worth marketing.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be following examples be served only for this
Invention is further described, it is impossible to limiting the scope of the invention is interpreted as, without departing substantially from spirit of the invention and essence
In the case of, the modifications or substitutions made to the inventive method, step or condition belong to the scope of the present invention.
Embodiment 1
A kind of good levo-oxiracetam particle of content uniformity, is made according to the following steps：
Preparation process：
1. supplementary material pre-treatment：Take the levo-oxiracetam of recipe quantity to be dissolved in the ethanol solution of recipe quantity and obtain levo-oxiracetam
Ethanol solution, it is standby；Separately take Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite
It is placed in Universalpulverizer, crushed 100 mesh sieves, it is standby；
2. granulation：The mixed-powder of auxiliary material obtained by pre-treatment and levo-oxiracetam ethanol solution are placed in wet granulator, added
Starch slurry, start granulator (18 mesh nylon mesh of installation), start to pelletize；
3. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying；Particle boiling is observed at any time
Situation, air blast situation are risen, prevents the particle-bonded ceramic the bottom of a pan, causes particle coking or gelatinization, drying time is 50~55 minutes, is protected
Demonstrate,prove pellet moisture≤3%；
4. coating：
(1) configuration of coating solution：Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that quality volume fraction is made to be
8%~10% solution, it is standby；
(2) coating process：Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40~50
℃；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50~60rpm of spouting velocity, atomizing pressure is
0.8~1.0bar, continue air intake and dry, solution stops heating after continuing heating after having sprayed 10~15 minutes, cooling discharging, produces bag
Clothing particle；
5. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, 25 DEG C of control environment temperature with
Under, relative humidity is below 50%；
It is 6. total mixed：Talcum powder be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer
10min~20min；
Wrapped in 7.：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature, relatively
Below humidity 50%, produce.
Experiment one：Particle stops sub- angle measure
1. test material：Sample after the completion of always being mixed in the preparation process of embodiment 1
2. test method：After the completion of embodiment 1 is always mixed, respectively in the upper, middle and lower of three-dimensional motion mixer, left and right each point
Separately sampled measure angle of repose, judges its mobility；
3. result of the test：
4. conclusion (of pressure testing)：It can be seen that by upper table result of the test, five times measurement angle of repose is respectively less than 38 °, shows that mobility of particle is good.
Experiment two：Content uniformity
1. test material：Sample after the completion of always being mixed in the preparation process of embodiment 1
2. test method：After the completion of embodiment 1 is always mixed, respectively in the upper, middle and lower of three-dimensional motion mixer, left and right each point
Separately sampled 5g, content detection is carried out according to content assaying method, the content RSD of each sample point is calculated, evaluates whether to mix
Close uniform；
3. result of the test：
4. conclusion (of pressure testing)：It can be seen that by upper table result of the test, this product content uniformity is good, and RSD is less than 2%
Experiment three：Content uniformity
1. test material：10 bags of particulate samples made from Example 1, shine《Chinese Pharmacopoeia》Two annex of version in 2010
Content uniformity inspection under granula item.
2. determination method：The weight of 10 bags of test sample, respectively weighed every bag of content is taken, every bag of weight is compared with sign loading amount.
3. result of the test：Content uniformity inspection result see the table below：
4. conclusion (of pressure testing)：This product content uniformity is respectively less than ± 5% it can be seen from upper table result of the test, it was demonstrated that and content uniformity is stable,
Content uniformity is small.
Experiment four：A kind of levo-oxiracetam particle prescription of the present invention is on the increased influence of preparation process impurity
1. experiment material：
Levo-oxiracetam particulate samples：Prepared by embodiment 1.
Levo-oxiracetam particle control sample：To lack the sample obtained by Cys on the basis of the prescription of embodiment 1,
Its preparation technology is the same as embodiment 1.
2. experimental method：In the preparation process of embodiment 1, levo-oxiracetam bulk drug and levo-oxiracetam particle are determined respectively
The relevant material of finished product, observation levo-oxiracetam particle impurity in preparation process increase situation.Meanwhile take and lack the Guangs of L- half
The prescription of the embodiment 1 of propylhomoserin is prepared by the preparation method of embodiment 1 as control prescription, equally determines left-handed Aura respectively
The relevant material of western smooth particulate material medicine and levo-oxiracetam finished granule, observation levo-oxiracetam particle is in preparation process
Impurity increases situation.
3. experimental result see the table below：
4. experiment conclusion：The prescription of embodiment 1, coordinate specific preparation method, relevant material increase is only 0.04%, hence it is evident that excellent
In control sample.
Experiment five：A kind of levo-oxiracetam granule stability experiment of the present invention
Experiment material：
Levo-oxiracetam particle：It is made for embodiment 1.
Acceleration study method：Levo-oxiracetam particle made from embodiment 1 is packed by listing, put in Acceleration study case, one
Fix time sampling, investigation project is tested.
Acceleration study temperature：40±2℃
Acceleration study humidity：RH75% ± 5%
Investigate the time：0th, 1,2,3, June
Inspection target：Character, moisture, granularity, melting, relevant material, content, microbial limit
Accelerated test stability records：
Acceleration study result shows：Acceleration sample in June is suitable with 0 month sample items Testing index quality, and it is real to show that this product accelerates
Test June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：Levo-oxiracetam particle made from embodiment 1 is packed by listing, put in the long-term case that keeps sample, one
Fix time sampling, investigation project is tested.
Long-term experiment temperature：25±2℃
Long-term experiment humidity：RH60% ± 10%
Investigate the time：0th, 3,6,9,12,18,24 months
Inspection target：Character, moisture, granularity, melting, relevant material, content, microbial limit
Long term test stability records：
Long term test shows：It is 24 months characters of this product long term test, moisture, granularity, melting, relevant material, content, micro-
Biological limit meets every relevant regulations of production quality standard draft without significant changes.This product long term test 24 months
Steady quality, therefore minimum 24 months of this product term of validity, long term test is still during investigation is continued.
Embodiment 2
A kind of good levo-oxiracetam particle of content uniformity, is made according to the following steps：
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, not sub- angle experiment
Measurement result shows that this product mobility of particle is good, and not sub- angle is less than 36 °, and content uniformity test result shows that this product content is uniform
Property it is good, content RSD of each point particle is less than 1% after it is total mixed, and content uniformity experiment shows that this product content uniformity is less than ± 4%,
This product loading amount is stable, controllable, and the product prescription result of the test that influences increased on preparation process impurity shows this product preparation process impurity
Incrementss are smaller, and relevant material only increases by 0.02% in preparation process, and stability test result shows that acceleration sample quality in June is steady
It is fixed, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 3
A kind of good levo-oxiracetam particle of content uniformity, is made according to the following steps：
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, not sub- angle experiment
Measurement result shows that this product mobility of particle is good, and not sub- angle is less than 37 °, and content uniformity test result shows that this product content is uniform
Property it is good, content RSD of each point particle is less than 2% after it is total mixed, and content uniformity experiment shows that this product content uniformity is less than ± 5%,
This product loading amount is stable, controllable, and the product prescription result of the test that influences increased on preparation process impurity shows this product preparation process impurity
Incrementss are smaller, and relevant material only increases by 0.03% in preparation process, and stability test result shows that acceleration sample quality in June is steady
It is fixed, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 4-6：A kind of good levo-oxiracetam particle of content uniformity, is prepared by the supplementary material of following weight, system
Preparation Method is the same as embodiment 1：
| Embodiment | 4 | 5 | 6 |
| Levo-oxiracetam | 1 part | 1 part | 1 part |
| Cys | 0.8 part | 0.9 part | 0.7 part |
| Mannitol | 1.1 part | 1.0 part | 0.9 part |
| Microcrystalline cellulose | 1.0 part | 1.1 part | 0.9 part |
| Sodium carboxymethylcellulose | 1.0 part | 1.1 part | 1.1 part |
| Lactose | 1.3 part | 1.4 part | 1.4 part |
| Sorbierite | 0.9 part | 1.0 part | 0.9 part |
| Talcum powder | 0.14 part | 0.15 part | 0.16 part |
| Macrogol 4000 | 1.2 part | 1.1 part | 1.3 part |
| Hydroxypropyl methylcellulose | 1.0 part | 1.1 part | 1.2 part |
| Mass fraction is 7% starch slurry | 1.1 part | 1.2 part | 1.2 part |
| Volume fraction is 30% ethanol | 5 parts | 4 parts | 5 parts |
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, embodiment 4,5,
6 samples stop sub- angle experiment measurement result and show that this product mobility of particle is good, and not sub- angle is respectively lower than 36 °, 37 °, 36 °, in fact
Apply the sample size uniformity test result of example 4,5,6 and show that this product content uniformity is good, the content RSD of its total mixed rear each point particle
2% is below, the experiment of the sample content uniformity of embodiment 4,5,6 shows that this product content uniformity is respectively less than ± 5%, and this product loading amount is steady
Fixed, controllable, the sample prescription of embodiment 4,5,6 result of the test that influences increased on preparation process impurity shows this product preparation process
Impurity incrementss are smaller, and relevant material only increases by 0.03%, 0.02%, 0.04% respectively in preparation process, embodiment 4,5,6
Sample stability result of the test shows to accelerate sample quality stabilization in June, long-term 24 months steady qualities, therefore this product term of validity is at least
24 months.
Claims (3)
1. the good levo-oxiracetam particle of a kind of content uniformity, it is characterised in that it is made according to the following steps by the supplementary material of following weight proportion：1 part of levo-oxiracetam, 0.5 ~ 1.1 part of Cys, 0.7 ~ 1.2 part of mannitol, 0.6 ~ 1.2 part of microcrystalline cellulose, 0.8 ~ 1.3 part of sodium carboxymethylcellulose, 0.9 ~ 1.7 part of lactose, 0.6 ~ 1.3 part of sorbierite, 0.12 ~ 0.17 part of talcum powder, 1.0 ~ 1.5 parts of Macrogol 4000,0.9 ~ 1.6 part of hydroxypropyl methylcellulose, 9 ~ 15 parts of the starch slurry that mass fraction is 6% ~ 8%, 2 ~ 7 parts of the ethanol solution that volume fraction is 30% ~ 50%；The levo-oxiracetam of recipe quantity is taken, adds the ethanol solution dissolving of recipe quantity, it is standby；Separately Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite etc. is taken to be placed in Universalpulverizer; it is placed in after crushed 100 mesh sieves in wet granulator; the starch slurry that above-mentioned the levo-oxiracetam ethanol solution handled well and mass fraction are about 6% ~ 8% is added, starts granulator（18 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, and drying time is 50 ~ 55 minutes；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that the coating solution that quality volume fraction is 8% ~ 10% is made, it is standby；Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, continues air intake and dries, and solution stops heating, cooling discharging after continuing heating after having sprayed 10 ~ 15 minutes；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, add in the particle after whole grain, produced with three-dimensional motion mixer mixing 10min ~ 20min.
2. levo-oxiracetam particle as claimed in claim 1, it is characterised in that it is made according to the following steps by the supplementary material of following weight proportion：1 part of levo-oxiracetam, 0.7 ~ 1.0 part of Cys, 0.8 ~ 1.1 part of mannitol, 0.9 ~ 1.1 part of microcrystalline cellulose, 0.9 ~ 1.2 part of sodium carboxymethylcellulose, 1.2 ~ 1.5 parts of lactose, 0.8 ~ 1.1 part of sorbierite, 0.13 ~ 0.16 part of talcum powder, 1.1 ~ 1.3 parts of Macrogol 4000,1.0 ~ 1.2 parts of hydroxypropyl methylcellulose, 10 ~ 13 parts of the starch slurry that mass fraction is 6% ~ 8%, 3 ~ 6 parts of the ethanol solution that volume fraction is 30% ~ 50%；The levo-oxiracetam of recipe quantity is taken, adds the ethanol solution dissolving of recipe quantity, it is standby；Separately Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite is taken to be placed in Universalpulverizer; it is placed in after crushed 100 mesh sieves in wet granulator; the starch slurry that above-mentioned the levo-oxiracetam ethanol solution handled well and mass fraction are 6% ~ 8% is added, starts granulator（18 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, and drying time is 50 ~ 55 minutes；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that the coating solution that quality volume fraction is 8% ~ 10% is made, it is standby；Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, continues air intake and dries, and solution stops heating, cooling discharging after continuing heating after having sprayed 10 ~ 15 minutes；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, add in the particle after whole grain, produced with three-dimensional motion mixer mixing 10min ~ 20min.
3. the preparation method of levo-oxiracetam particle as claimed in claim 1 or 2, it is characterised in that it is obtained as follows：
A. supplementary material pre-treatment：Take the levo-oxiracetam of recipe quantity to add the ethanol solution dissolving of recipe quantity, obtain levo-oxiracetam ethanol solution, it is standby；Take the filler of recipe quantity, flavouring to be placed in Universalpulverizer, crushed 100 mesh sieves, it is standby；
B. pelletize：Gained mixed accessories powder and levo-oxiracetam ethanol solution after pre-treatment are taken, is placed in wet granulator, adds adhesive, starts granulator（18 mesh nylon mesh are installed）, start to pelletize；
C. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying；Particle boiling situation, air blast situation are observed at any time, prevents the particle-bonded ceramic the bottom of a pan, causes particle coking or gelatinization, and drying time is 50 ~ 55 minutes, ensures pellet moisture≤3%；
D. it is coated：
The configuration of D (1) coating solutions：The coating material of recipe quantity is taken, adds water that the solution that quality volume fraction is 8% ~ 10% is made, it is standby；
D (2) coating process：Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10 ~ 15 minutes, cooling discharging, produces coated granule；
E. whole grain, sub-sieve:Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, controlled below 25 DEG C of environment temperature, relative humidity is below 50%；
F. it is total mixed：Lubricant be crushed into 100 mesh sieves, added in the particle after whole grain, with three-dimensional motion mixer mixing 10min ~ 20min；
G. interior bag：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature, relative humidity produces below 50%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113331294A (en) * | 2021-06-03 | 2021-09-03 | 唐传生物科技（厦门）有限公司 | Preparation method of healthy sugar with low glycemic index |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579386A (en) * | 2012-03-19 | 2012-07-18 | 北京德众万全药物技术开发有限公司 | Stable oxiracetam preparation |
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2016
- 2016-06-15 CN CN201610421817.5A patent/CN107510657A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579386A (en) * | 2012-03-19 | 2012-07-18 | 北京德众万全药物技术开发有限公司 | Stable oxiracetam preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113331294A (en) * | 2021-06-03 | 2021-09-03 | 唐传生物科技（厦门）有限公司 | Preparation method of healthy sugar with low glycemic index |
| CN113331294B (en) * | 2021-06-03 | 2024-02-09 | 谷创芯生物科技(厦门)有限公司 | Preparation method of low glycemic index healthy sugar |
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