CN107510677A - A kind of levo-oxiracetam particle in good taste and preparation method thereof - Google Patents
A kind of levo-oxiracetam particle in good taste 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
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. 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
- 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)
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Abstract
A kind of levo-oxiracetam particle in good taste is made by following supplementary material：1 part of levo-oxiracetam, 0.5 ~ 1.0 part of L cysteines, 0.9 ~ 1.6 part of mannitol, 0.7 ~ 1.2 part of microcrystalline cellulose, 0.9 ~ 1.5 part of sodium carboxymethylcellulose, 0.5 ~ 0.9 part of lactose, 0.13 ~ 0.18 part of talcum powder, 0.9 ~ 1.5 part of Macrogol 4000,0.6 ~ 1.2 part of hydroxypropyl methylcellulose, 0.5 ~ 1.1 part of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.10 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sucrose, 0.2 ~ 0.7 part of ethylmaltol, 10 ~ 15 parts of the starch slurry that mass fraction is 6% ~ 8%；Levo-oxiracetam particulate production impurity incrementss of the present invention are few, are only 0.04%, and product bisque amount is few, and grain diameter is homogeneous, good fluidity, not sub- angle is less than 37 °, and content uniformity is less than 5%, and it is fast that particle leaches speed, particle all leached the time not over 30 seconds, it is in good taste, it can be received by most of patient, storage process 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 levo-oxiracetam particle in good taste and preparation method thereof.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, in being only used for
Pivot nervous system, cerebral cortex, hippocampus are mainly distributed on, there is activation, protection or the functional rehabilitation for promoting nerve cell, improved
The mnemonic learning function of disturbance of intelligence patient, and medicine also acts in itself without direct vasoactive without central excitation, it is right
The influence of 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, 1g/5ml.
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 mentions the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 to alcoholism institute stunning in the A patents of CN 103735545
The promoting wakening of fan is obvious, and dextrorotation Oxiracetam does not act on substantially, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2
The awake effect of above-mentioned rush is 2 times of racemization Oxiracetam；(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 is to wound, anesthesia institute
The promoting wakening of stunning fan is notable.Open peak etc. and (S) -4- hydroxyls -2 are disclosed in the A of Publication No. CN 103599101 patent
Oxo-1-pyrrolidine ethanamide has to traumatic brain injury learning and memory in rats cognition dysfunction caused by hydraulic pressure and freely falling body
Obvious improvement result, its drug effect are far above dextrorotation Oxiracetam.And the OXo-1-pyrrolidine of 200mg/kg (S) -4- hydroxyls -2
Acetamide is suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：(S) oxo -1- of -4- hydroxyls -2
Pyrrolidine acetamide and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection is given left-handed
With the main pharmacokinetic ginseng of the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 in blood plasma after the racemization Oxiracetam of 2 multiple doses
The equal no significant difference of number.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level, (S) -4- hydroxyls
- 2 oxo-1-pyrrolidine ethanamides are with Oxiracetam to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical grinds
To study carefully result to show, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is the main active that drug effect is played in Oxiracetam body,
This product, which is used alone, can reduce Clinical practice dosage, reduce potential toxicity.
Existing Oxiracetam particle be primarily present preparation process impurity increase it is larger, particle bisque is more, and particle diameter is difficult to control, storage
Process stability is poor, and particle hygroscopicity is strong, and connecting block easy to stick, shelf life is short, and particle leaches that speed is slow, and mouthfeel is bad is not easy
The technical problem such as receive by many patients.
The content of the invention
It is an object of the invention to provide a kind of size tunable, the levo-oxiracetam particle that stability is good, in good taste.
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 levo-oxiracetam particle in good taste, it be using levo-oxiracetam as raw material, add a certain amount of filler,
Flavouring, adhesive, lubricant, disintegrant, coating material are made；Wherein described filler is starch, lactose, dextrin, sugar
One or more in powder, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose, sodium carboxymethylcellulose, Cys；
The flavouring is sweet sucrose, maltose, ethylmaltol, Sucralose, stevia rebaudianum, sorbierite, mannitol, glucose, A Sipa
One or more in smooth；Described adhesive is water, ethanol, sucrose, starch slurry, dextrin, carboxymethyl cellulose, polyvinylpyrrolidine
One or more in ketone；The lubricant is talcum powder, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, dodecyl sulphur
One or more in sour sodium, superfine silica gel powder, magnesia, paraffin；The disintegrant is low-substituted hydroxypropyl cellulose, polysorbate
80th, the one or more in sodium carboxymethyl starch, dried starch；The coating material be Macrogol 4000, Macrogol 6000,
One or more in hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene acetaldehyde diethyl ester, hydroxypropyl methyl cellulose phthalate.
The rational prescription proportioning of inventor, coordinates specific preparation method, may be such that above-mentioned levo-oxiracetam particulate production impurity increases
Add smaller, uniform particle sizes are controllable, and storage process is not easy moisture absorption, and it is good to be not easy adhesion caking, product stability, shelf life length,
Grain leaches that speed is fast and particle mouthfeel is good, is easily easily accepted by the patient；Above-mentioned levo-oxiracetam particle, it is characterised in that it
It is to be made by the supplementary material of following weight proportion：1 part of levo-oxiracetam, 0.5~1.0 part of Cys, mannitol 0.9~1.6
Part, 0.7~1.2 part of microcrystalline cellulose, 0.9~1.5 part of sodium carboxymethylcellulose, 0.5~0.9 part of lactose, talcum powder 0.13~0.18
Part, 0.9~1.5 part of Macrogol 4000,0.6~1.2 part of hydroxypropyl methylcellulose, 0.5~1.1 part of low-substituted hydroxypropyl cellulose,
0.05~0.10 part of polyoxyethylene sorbitan monoleate, 1~5 part of sucrose, 0.2~0.7 part of ethylmaltol, the starch that mass fraction is 6%~8%
10~15 parts of slurry；Take levo-oxiracetam, Cys, mannitol, microcrystalline cellulose, the carboxymethyl cellulose of recipe quantity
Sodium, lactose, low-substituted hydroxypropyl cellulose, sucrose, ethylmaltol are placed in Universalpulverizer, crushed 100 mesh sieves,
It is placed in wet granulator, adds polyoxyethylene sorbitan monoleate, the starch slurry that mass fraction is 6%~8%, start granulator (installation 18
Mesh nylon mesh), start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying, dries
Time is 50~55 minutes；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that quality volume fraction is made to be
8%~10% coating solution, it is standby；Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature
For 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, mist
Change 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, added
Enter in the particle after whole grain, produced with three-dimensional motion mixer mixing 10min~20min.
Further, in order to further speed up the speed that leaches of levo-oxiracetam particle, improve mouthfeel, improve stability, prolong
Long shelf life, a kind of levo-oxiracetam particle in good taste, it is characterised in that it is by the supplementary material system of following weight proportion
：1 part of levo-oxiracetam, 0.6~0.9 part of Cys, 1.1~1.3 parts of mannitol, 0.9~1.1 part of microcrystalline cellulose,
1.1~1.4 parts of sodium carboxymethylcellulose, 0.6~0.8 part of lactose, 0.14~0.17 part of talcum powder, 1.1~1.3 parts of Macrogol 4000,
0.8~1.1 part of hydroxypropyl methylcellulose, 0.7~1.0 part of low-substituted hydroxypropyl cellulose, 0.06~0.09 part of polyoxyethylene sorbitan monoleate, sucrose
2~4 parts, 0.3~0.6 part of ethylmaltol, mass fraction be 6%~8% 11~14 parts of starch slurry；Take left-handed Austria of recipe quantity
La Xitan, Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose,
Sucrose, ethylmaltol are placed in Universalpulverizer, be crushed 100 mesh sieves, are placed in wet granulator, add polysorbate
80th, mass fraction is 6%~8% starch slurry, starts granulator (18 mesh nylon mesh of installation), starts to pelletize；Wet granular is thrown
In fluidized bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying, and drying time is 50~55 minutes；Take the poly- of recipe quantity
Ethylene glycol 4000, hydroxypropyl methylcellulose, add water that the coating solution that quality volume fraction is 8%~10% is made, it is standby；Will be above-mentioned dry
In particle input fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature is 40~50 DEG C；Coating solution is passed through into fluid bed
Nozzle atomization is continuously added to fluid bed, sets 50~60rpm of spouting velocity, and atomizing pressure is 0.8~1.0bar, continues air intake and dries,
Solution stops heating, cooling discharging after continuing heating after having sprayed 10~15 minutes；Coated granule is placed in crushing and pelletizing machine, used
20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion
Conjunction machine mixing 10min~20min is produced.
A kind of preparation method of levo-oxiracetam particle in good taste, it is characterised in that it is obtained as follows：
1. supplementary material pre-treatment：Levo-oxiracetam, filler, flavouring, the disintegrant of recipe quantity is taken to be placed in Universalpulverizer
In, 100 mesh sieves are crushed, it is standby；
2. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds the polyoxyethylene sorbitan monoleate of recipe quantity and viscous
Mixture, 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) preparation of coating solution：The coating material of recipe quantity is taken, adds water that the coating solution that mass fraction is 8%~10% is made, 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：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, are only 0.04%, and product bisque amount is few, particle
Uniform particle diameter, good fluidity, not sub- angle are less than 37 °, and content uniformity is less than 5%, and particle leaches that speed is fast, and particle all leaches
Time is in good taste not over 30 seconds, can be received by most of patient, and storage process stability is good, and product is not easy moisture absorption knot
Block, shelf life are up to 24 months, preparation technology simple possible, are 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 levo-oxiracetam particle in good taste, is made according to the following steps：
Preparation process：
1. supplementary material pre-treatment：Take the levo-oxiracetam of recipe quantity, Cys, mannitol, microcrystalline cellulose, carboxylic first
Base sodium cellulosate, lactose, low-substituted hydroxypropyl cellulose, sucrose, ethylmaltol are placed in Universalpulverizer, crushed 100
Mesh sieve, it is standby；
2. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, starch slurry and polyoxyethylene sorbitan monoleate is added, opens
Dynamic granulator (18 mesh nylon mesh of installation), starts 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) preparation of coating solution：Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that mass fraction is made to be
8%~10% coating 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 37 °, shows that mobility of particle is good.
Experiment two：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 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, coordinates specific preparation method, and relevant material increase is only 0.03%, hence it is evident that better than pair
Product in the same old way.
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 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.
Experiment five：Dissolution test
1. test material：Levo-oxiracetam particle made from embodiment 1；
2. test method：10 bags of levo-oxiracetam particle made from Example 1, are placed in 100ml beakers, add 50ml
Temperature is 25 DEG C of purified water, static, and observation all leaches the required time；
3. result of the test see the table below：
| Test number | 1# | 2# | 3# | 4# | 5# |
| Leach the time (min) | 25 seconds | 24 seconds | 28 seconds | 22 seconds | 27 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 26 seconds | 28 seconds | 23 seconds | 26 seconds | 28 seconds |
4. conclusion (of pressure testing)：It can be seen that by upper table result of the test, repeatedly measure particle and leach the time less than 30 seconds, it was demonstrated that by this hair
It is fast that bright obtained particle leaches speed.
Experiment six：Taste, mouthfeel market survey
1. a kind of levo-oxiracetam particle in good taste of the present invention is by specific supplementary material compatibility, it is made by repeatedly seasoning,
With excellent taste, taste is fragrant and sweet, the advantages of being received by many patients.
2. method：The people of crowd 1000 of random selection more than 10 years old, taste trial test is carried out, will now taste result statistics such as following table：
Levo-oxiracetam particle taste application form
| It is very good | Preferably | Typically | Difference |
| 581 | 125 | 129 | 165 |
3. it can be seen from taste tastes market survey, this product is easy to be received by many patients, according to incompletely statistics, feels taste
It is extraordinary to account for the 58.1% of whole crowd, feel taste it is relatively good account for 12.5%, think that taste in general accounts for 12.9%, feel
Distasteful accounts for 16.5%.Therefore this product has the characteristics of in good taste, easily to be received by many patients colony.
Embodiment 2
A kind of levo-oxiracetam particle in good taste, 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 product prescription is increased on preparation process impurity to influence examination
Test result and show that this product preparation process impurity incrementss are smaller, relevant material only increases by 0.02% in preparation process, content uniformity examination
Test and show that this product content uniformity is less than 4%, this product loading amount is stable, controllable, when dissolution test result shows that repeatedly determining this product leaches
Between be respectively less than 30 seconds, therefore this product can leach rapidly, and mouthfeel investigation shows that this product taste is easily received by most of patient, stability
Result of the test shows to accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 3
A kind of levo-oxiracetam particle in good taste, 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 product prescription is increased on preparation process impurity to influence examination
Test result and show that this product preparation process impurity incrementss are smaller, relevant material only increases by 0.03% in preparation process, content uniformity examination
Test and show that this product content uniformity is less than 5%, this product loading amount is stable, controllable, when dissolution test result shows that repeatedly determining this product leaches
Between be respectively less than 30 seconds, therefore this product can leach rapidly, and mouthfeel investigation shows that this product taste is easily received by most of patient, stability
Result of the test shows to accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 4-6：One kind leaches fireballing levo-oxiracetam particle, is prepared by the supplementary material of following weight, prepares
Method is the same as embodiment 1：
| Embodiment | 4 | 5 | 6 |
| Levo-oxiracetam | 1 part | 1 part | 1 part |
| Cys | 0.8 part | 0.7 part | 0.8 part |
| Mannitol | 1.3 part | 1.2 part | 1.1 part |
| Microcrystalline cellulose | 0.9 part | 1.0 part | 1.1 part |
| Sodium carboxymethylcellulose | 1.2 part | 1.3 part | 1.2 part |
| Lactose | 0.7 part | 0.6 part | 0.8 part |
| Talcum powder | 0.14 part | 0.15 part | 0.16 part |
| Macrogol 4000 | 1.3 part | 1.2 part | 1.1 part |
| Hydroxypropyl methylcellulose | 0.8 part | 0.9 part | 1.0 part |
| Low-substituted hydroxypropyl cellulose | 1.0 part | 0.8 part | 0.9 part |
| Polyoxyethylene sorbitan monoleate | 0.07 part | 0.08 part | 0.09 part |
| Sucrose | 3 parts | 2 parts | 4 parts |
| Ethylmaltol | 0.5 part | 0.4 part | 0.6 part |
| Mass fraction is 7% starch slurry | 11 parts | 14 parts | 12 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 °, 35 °, 37 °, in fact
Apply the product prescription of example 4,5,6 it is increased on preparation process impurity influence result of the test show this product preparation process impurity incrementss compared with
Small, relevant material only increases by 0.03%, 0.04%, 0.03% respectively in preparation process, the sample content uniformity of embodiment 4,5,6
Experiment shows that this product content uniformity is respectively less than 5%, and this product loading amount is stable, controllable, the sample dissolution test result of embodiment 4,5,6
Show repeatedly to determine this product and leach the time and be respectively less than 30 seconds, therefore this product can leach rapidly, the investigation of the products taste of embodiment 4,5,6
Show that this product taste is easily received by most of patient, the product stability result of the test of embodiment 4,5,6 shows to accelerate 6 lunar samples
Quality is stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Claims (3)
1. a kind of levo-oxiracetam particle in good taste, 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 ~ 1.0 part of Cys, 0.9 ~ 1.6 part of mannitol, 0.7 ~ 1.2 part of microcrystalline cellulose, 0.9 ~ 1.5 part of sodium carboxymethylcellulose, 0.5 ~ 0.9 part of lactose, 0.13 ~ 0.18 part of talcum powder, 0.9 ~ 1.5 part of Macrogol 4000,0.6 ~ 1.2 part of hydroxypropyl methylcellulose, 0.5 ~ 1.1 part of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.10 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sucrose, 0.2 ~ 0.7 part of ethylmaltol, 10 ~ 15 parts of the starch slurry that mass fraction is 6% ~ 8%；Levo-oxiracetam, Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sucrose, the ethylmaltol of recipe quantity is taken to be placed in Universalpulverizer; it crushed 100 mesh sieves; it is placed in wet granulator; add polyoxyethylene sorbitan monoleate, the starch slurry that mass fraction is 6% ~ 8%, start 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, 0.6 ~ 0.9 part of Cys, 1.1 ~ 1.3 parts of mannitol, 0.9 ~ 1.1 part of microcrystalline cellulose, 1.1 ~ 1.4 parts of sodium carboxymethylcellulose, 0.6 ~ 0.8 part of lactose, 0.14 ~ 0.17 part of talcum powder, 1.1 ~ 1.3 parts of Macrogol 4000,0.8 ~ 1.1 part of hydroxypropyl methylcellulose, 0.7 ~ 1.0 part of low-substituted hydroxypropyl cellulose, 0.06 ~ 0.09 part of polyoxyethylene sorbitan monoleate, 2 ~ 4 parts of sucrose, 0.3 ~ 0.6 part of ethylmaltol, 11 ~ 14 parts of the starch slurry that mass fraction is 6% ~ 8%；Levo-oxiracetam, Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sucrose, the ethylmaltol of recipe quantity is taken to be placed in Universalpulverizer; it crushed 100 mesh sieves; it is placed in wet granulator; add polyoxyethylene sorbitan monoleate, the starch slurry that mass fraction is 6% ~ 8%, start 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 levo-oxiracetam, filler, flavouring, the disintegrant of recipe quantity to be placed in Universalpulverizer, crushed 100 mesh sieves, it is standby；
B. pelletize：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive and polyoxyethylene sorbitan monoleate, 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 preparation of D (1) coating solutions：The coating material of recipe quantity is taken, adds water that the coating solution that mass 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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| Application Number | Priority Date | Filing Date | Title |
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| CN201610427272.9A CN107510677A (en) | 2016-06-15 | 2016-06-15 | A kind of levo-oxiracetam particle in good taste and preparation method thereof |
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| CN201610427272.9A CN107510677A (en) | 2016-06-15 | 2016-06-15 | A kind of levo-oxiracetam particle in good taste and preparation method thereof |
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Citations (2)
| 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 |
| CN104739796A (en) * | 2013-12-27 | 2015-07-01 | 重庆东泽医药科技发展有限公司 | An oxiracetam tablet and a preparing method thereof |
-
2016
- 2016-06-15 CN CN201610427272.9A patent/CN107510677A/en not_active Withdrawn
Patent Citations (2)
| 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 |
| CN104739796A (en) * | 2013-12-27 | 2015-07-01 | 重庆东泽医药科技发展有限公司 | An oxiracetam tablet and a preparing method thereof |
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