CN107510674A - 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, it is made by following supplementary material：1 part of levo-oxiracetam, 0.8 ~ 1.6 part of mannitol, 0.5 ~ 1.2 part of microcrystalline cellulose, 0.9 ~ 1.6 part of sodium carboxymethylcellulose, 0.5 ~ 1.1 part of lactose, 0.13 ~ 0.18 part of talcum powder, 0.8 ~ 1.5 part of Macrogol 4000,0.5 ~ 1.2 part of hydroxypropyl methylcellulose, 0.9 ~ 1.7 part of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.09 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sucrose, 0.2 ~ 0.7 part of ethylmaltol, 0.15 ~ 0.22 part of honey, 50% ~ 70% 12 ~ 18 parts of ethanol；According to levo-oxiracetam particle pelletization produced by the present invention will not adhesion screen cloth, be easy to pelletize, product bisque amount is few, and grain diameter is homogeneous, good fluidity, not sub- angle is less than 38 °, and content uniformity is less than 5%, and it is fast that particle leaches speed, all the time is leached not over 30 seconds, this product is in good taste, can be received by most of patient, and 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 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
In central nervous system, cerebral cortex, hippocampus are mainly distributed on, has activation, protection or the functional rehabilitation for promoting nerve cell, changes
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, 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
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is mentioned to alcoholism Deng in the A patents of Publication No. CN 103735545
The promoting wakening of caused stupor is obvious, and dextrorotation Oxiracetam does not act on substantially, the OXo-1-pyrrolidine second of (S) -4- hydroxyls -2
The awake effect of the above-mentioned rush of acid amides is 2 times of racemization Oxiracetam；(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 to wound,
The promoting wakening of stupor is notable caused by anesthesia.Open peak etc. and (S) -4- is disclosed in the A of Publication No. CN 103599101 patent
The oxo-1-pyrrolidine ethanamide of hydroxyl -2 is to traumatic brain injury learning and memory in rats cognitive function caused by hydraulic pressure and freely falling body
Obstacle improves significantly, and its drug effect is far above dextrorotation Oxiracetam.And oxo-the 1- of 200mg/kg (S) -4- hydroxyls -2
Pyrrolidine acetamide is suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：(S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single dose intravenous is noted
Penetrate the master for giving the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 in blood plasma after left-handed and 2 multiple doses racemization Oxiracetams
Want the equal no significant difference of pharmacokinetic parameters.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level,
(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 and Oxiracetam are to animal subject or the toxicity no significant difference of cell.On
State preclinical result of study to show, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is to play drug effect in Oxiracetam body
Main active, be used alone this product can reduce Clinical practice dosage, reduce potential toxicity.
Existing Oxiracetam particle is primarily present the easy adhesion screen cloth of pelletization, granulation difficulty, and particle bisque is more, particle diameter
Whard to control, storage process stability is poor, and particle hygroscopicity is strong, and connecting block easy to stick, shelf life is short, and it is slow that particle leaches speed,
Mouthfeel is bad to be not easy the technical problem such as to 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 is using levo-oxiracetam as raw material, is added a certain amount of
Filler, flavouring, adhesive, lubricant, disintegrant, coating material are made；Wherein described filler is starch, lactose, paste
One or more in essence, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose, sodium carboxymethylcellulose；Institute
State flavouring for sucrose, maltose, ethylmaltol, Sucralose, stevia rebaudianum be sweet, sorbierite, mannitol, glucose, A Sipa
One or more in smooth；Described adhesive is water, ethanol, sucrose, starch slurry, dextrin, carboxymethyl cellulose, polyvinyl pyrrole
One or more in alkanone, honey；The lubricant be talcum powder, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate,
One or more in lauryl sodium sulfate, superfine silica gel powder, magnesia, paraffin；The disintegrant is that low substituted hydroxy-propyl is fine
Tie up the one or more in element, polyoxyethylene sorbitan monoleate, sodium carboxymethyl starch, dried starch；The coating material be Macrogol 4000,
Macrogol 6000, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene acetaldehyde diethyl ester, hydroxypropyl methyl cellulose
One or more in phthalate ester.
The rational prescription proportioning of inventor, coordinates specific preparation method, may be such that above-mentioned levo-oxiracetam particle granulation
Process is easy to pelletize, will not adhesion screen cloth, uniform particle sizes are controllable, and storage process is not easy moisture absorption, and it is stable to be not easy adhesion caking, product
Property good, shelf life length, it is fast and in good taste that particle leaches speed, is easily easily accepted by the patient；Above-mentioned levo-oxiracetam particle, its
It is characterised by, it is made by the supplementary material of following weight proportion：1 part of levo-oxiracetam, 0.8~1.6 part of mannitol, crystallite
0.5~1.2 part of cellulose, 0.9~1.6 part of sodium carboxymethylcellulose, 0.5~1.1 part of lactose, 0.13~0.18 part of talcum powder,
It is 0.8~1.5 part of Macrogol 4000,0.5~1.2 part of hydroxypropyl methylcellulose, 0.9~1.7 part of low-substituted hydroxypropyl cellulose, poly-
80 0.05~0.09 part of sorb ester, 1~5 part of sucrose, 0.2~0.7 part of ethylmaltol, 0.15~0.22 part of honey, volume integral
Number is 50%~70% 12~18 parts of ethanol；The honey of recipe quantity is taken, is placed in iron pan, adds the pure of 2 times of parts by weight of honey
Change water, stir, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool
The ethanol of recipe quantity is added, stirring and dissolving is standby；Another levo-oxiracetam, mannitol, microcrystalline cellulose, the carboxylic for taking recipe quantity
Sodium carboxymethylcellulose pyce, lactose, low-substituted hydroxypropyl cellulose, sucrose, ethylmaltol are placed in Universalpulverizer, crushed
100 mesh sieves, are placed in wet granulator, add the polyoxyethylene sorbitan monoleate of previously processed good honey ethanol solution and recipe quantity, open
Dynamic granulator (18 mesh nylon mesh of installation), starts to pelletize；Wet granular is put into fluid bed, hotbed temperature setting 50 DEG C~70
DEG C, start drying, drying time is 50~55 minutes；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water to be made
Quality volume fraction is 8%~10% coating solution, standby；Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to
Suspension fluidization, bed temperature are 40~50 DEG C；Coating solution is continuously added to fluid bed, setting whitewashing speed by the nozzle atomization of fluid bed
50~60rpm is spent, atomizing pressure is 0.8~1.0bar, continues air intake and dries, solution continues heating 10~15 minutes after having sprayed after
Stop heating, cooling discharging；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；By the talcum of recipe quantity
Powder crushed 100 mesh sieves, adds in the particle after whole grain, is produced with three-dimensional motion mixer mixing 10min~20min.
In order to further speed up the speed that leaches of levo-oxiracetam particle, improve mouthfeel, improve stability, extend shelf
Phase, a kind of levo-oxiracetam particle in good taste, it is characterised in that it is made by the supplementary material of following weight proportion：It is left
Revolve 1 part of Oxiracetam, 0.9~1.3 part of mannitol, 0.7~1.0 part of microcrystalline cellulose, 1.1~1.5 parts of sodium carboxymethylcellulose,
0.7~1.0 part of lactose, 0.15~0.17 part of talcum powder, 1.1~1.3 parts of Macrogol 4000, hydroxypropyl methylcellulose 0.8~
1.0 parts, 1.2~1.5 parts of low-substituted hydroxypropyl cellulose, 0.06~0.08 part of polyoxyethylene sorbitan monoleate, 2~4 parts of sucrose, ethyl wheat
0.3~0.6 part of bud phenol, 0.17~0.20 part of honey, 13~17 parts of the ethanol that volume fraction is 50%~70%；Take recipe quantity
Honey, it is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stir, be heated to 100~105 DEG C, insulation 20~
25 minutes, take out, with 80 mesh screens, take filtrate, the ethanol of recipe quantity is added after letting cool, stirring and dissolving is standby；Separately take prescription
Levo-oxiracetam, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, the sugarcane of amount
Sugar, ethylmaltol are placed in Universalpulverizer, be crushed 100 mesh sieves, are placed in wet granulator, and it is previously processed good to add
The polyoxyethylene sorbitan monoleate of honey ethanol solution and recipe quantity, start granulator (18 mesh nylon mesh of installation), start to pelletize；By wet granular
Put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying, and drying time is 50~55 minutes；Take recipe quantity
Macrogol 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
In dry particl 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 be continuously added to fluid bed, set 50~60rpm of spouting velocity, atomizing pressure be 0.8~1.0bar, persistently air intake
Dry, solution stops heating, cooling discharging after continuing heating after having sprayed 10~15 minutes；Coated granule is placed in crushing and pelletizing machine
In, with 20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, added in the particle after whole grain, with three maintenance and operations
Dynamic mixer 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
's：
1. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs
Mix uniformly, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool at addition
The ethanol just measured, stirring and dissolving are standby；
2. supplementary material pre-treatment：Levo-oxiracetam, filler, flavouring, the disintegrant of recipe quantity is taken to be placed in omnipotent powder
In broken machine, 100 mesh sieves are crushed, it is standby；
3. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive, starts granulator
(18 mesh nylon mesh of installation), start to pelletize；
4. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying；Observe at any time
Particle boiling situation, air blast situation, prevent the particle-bonded ceramic the bottom of a pan, cause particle coking or gelatinization, and drying time is 50~55 points
Clock, ensure pellet moisture≤3%；
5. coating：
(1) preparation of coating solution：The coating material of recipe quantity is taken, adds water that the coating that mass fraction is 8%~10% is made
Liquid, it is standby；
(2) coating process：Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature 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, atomization
Pressure is 0.8~1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10~15 minutes, cools down out
Material, produces coated granule；
6. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, controls environment temperature
Less than 25 DEG C, relative humidity is below 50%；
It is 7. 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 8.：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature,
Below relative humidity 50%, produce.
The present invention has following beneficial effect：
Levo-oxiracetam particle pelletization of the present invention will not adhesion screen cloth, be easy to pelletize, product bisque amount is few, particle
Uniform particle diameter, good fluidity, not sub- angle are less than 38 °, and content uniformity is less than 5%, and it is fast that particle leaches speed, all leaches the time not
Can be more than 30 seconds, this product is in good taste, can be received by most of patient, and storage process stability is good, and product is not easy moisture absorption caking,
Shelf life is up to 24 months, preparation technology simple possible, is worth marketing.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are only used
It is further described in the present invention, it is impossible to limiting the scope of the invention is interpreted as, without departing substantially from spirit of the invention
In the case of essence, 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. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs
Mix uniformly, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool at addition
The ethanol just measured, stirring and dissolving are standby；
2. supplementary material pre-treatment：Take levo-oxiracetam, 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, standby
With；
3. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive and polysorbate
80, start granulator (18 mesh nylon mesh of installation), start to pelletize；
4. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying；Observe at any time
Particle boiling situation, air blast situation, prevent the particle-bonded ceramic the bottom of a pan, cause particle coking or gelatinization, and drying time is 50~55 points
Clock, ensure pellet moisture≤3%；
5. coating：
(1) preparation of coating solution：Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that mass fraction is made
It is standby for 8%~10% coating solution；
(2) coating process：Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature 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, atomization
Pressure is 0.8~1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10~15 minutes, cools down out
Material, produces coated granule；
6. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, controls environment temperature
Less than 25 DEG C, relative humidity is below 50%；
It is 7. total mixed：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；
Wrapped in 8.：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature,
Below relative humidity 50%, produce.
In pelletization, observation understands that the pelletization of embodiment 1 does not find the situation of adhesion screen cloth, and product is easy to make
Grain.
In order to be better understood from the present invention, having for invention medicine is expanded on further below by way of stability test of the present invention
Beneficial effect, rather than limitation of the present invention.
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 particle flow
Property is good.
Experiment two：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 with indicating loading amount phase
Compare.
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 ± 4% it can be seen from upper table result of the test, it was demonstrated that loading amount is poor
Different stabilization, content uniformity are small.
Experiment three：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, puts Acceleration study case
In, certain 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, shows that this product adds
Speed is tested June, and quality keeps stable, and this product stability is preferable.
Long-term experiment method：Levo-oxiracetam particle made from embodiment 1 is packed by listing, puts the long-term case that keeps sample
In, certain 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
Month steady quality, therefore minimum 24 months of this product term of validity, long term test is still during investigation is continued.
Experiment four：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) | 23 seconds | 25 seconds | 28 seconds | 21 seconds | 23 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 27 seconds | 22 seconds | 26 seconds | 25 seconds | 22 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 press
It is fast that particle produced by the present invention leaches speed.
Experiment five：Taste, mouthfeel market survey
1. a kind of levo-oxiracetam particle in good taste of the present invention is by specific supplementary material compatibility, by repeatedly seasoning
And be made, there is 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, it is as follows will now to taste result statistics
Table：
Levo-oxiracetam particle taste application form
| It is very good | Preferably | Typically | Difference |
| 568 | 132 | 217 | 83 |
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 is extraordinary to account for the 56.8% of whole crowd, feel taste it is relatively good account for 13.2%, think that taste in general accounts for
21.7%, think that distasteful accounts for 8.3%.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.Observation product pelletization does not find showing for adhesion screen cloth
As product is easy to pelletize.Tested by the test method of embodiment 1, not sub- angle experiment measurement result shows this product particle stream
Dynamic property is good, and not sub- angle is less than 37 °, and content uniformity experiment shows that this product content uniformity is less than 5%, and this product loading amount is stable, controllable, molten
Scattered result of the test, which shows repeatedly to determine this product and leaches the time, to be respectively less than 30 seconds, therefore this product can leach rapidly, and mouthfeel investigation shows this
Taste road is easily received by most of patient, and stability test result shows to accelerate sample quality stabilization in June, long-term 24 lunar geology
Amount is stable, 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.Observation product pelletization does not find showing for adhesion screen cloth
As product is easy to pelletize.Tested by the test method of embodiment 1, not sub- angle experiment measurement result shows this product particle stream
Dynamic property is good, and not sub- angle is less than 36 °, and content uniformity experiment shows that this product content uniformity is less than 4%, and this product loading amount is stable, controllable, molten
Scattered result of the test, which shows repeatedly to determine this product and leaches the time, to be respectively less than 30 seconds, therefore this product can leach rapidly, and mouthfeel investigation shows this
Taste road is easily received by most of patient, and stability test result shows to accelerate sample quality stabilization in June, long-term 24 lunar geology
Amount is stable, therefore this product term of validity at least 24 months.
Embodiment 4-6：One kind leaches fireballing levo-oxiracetam particle, by the supplementary material preparation of following weight
, preparation method is the same as embodiment 1：
| Embodiment | 4 | 5 | 6 |
| Levo-oxiracetam | 1 part | 1 part | 1 part |
| Mannitol | 1.2 part | 1.1 part | 1.0 part |
| Microcrystalline cellulose | 0.8 part | 0.9 part | 0.8 part |
| Sodium carboxymethylcellulose | 1.2 part | 1.3 part | 1.4 part |
| Lactose | 0.9 part | 0.8 part | 0.9 part |
| Talcum powder | 0.17 part | 0.16 part | 0.15 part |
| Macrogol 4000 | 1.1 part | 1.2 part | 1.3 part |
| Hydroxypropyl methylcellulose | 0.9 part | 0.9 part | 0.9 part |
| Low-substituted hydroxypropyl cellulose | 1.4 part | 1.3 part | 1.4 part |
| Polyoxyethylene sorbitan monoleate | 0.06 part | 0.07 part | 0.08 part |
| Sucrose | 4 parts | 2 parts | 3 parts |
| Ethylmaltol | 0.5 part | 0.4 part | 0.5 part |
| Honey | 0.18 part | 0.19 part | 0.20 part |
| Volume fraction is 60% ethanol | 16 parts | 14 parts | 16 parts |
Preparation process：It is made according to the preparation technology of embodiment 1.The observation product pelletization of embodiment 4,5,6 is not found
The phenomenon of adhesion screen cloth, product are easy to pelletize.Tested by the test method of embodiment 1, the product of embodiment 4,5,6 stops sub- angle
Experiment measurement result shows that this product mobility of particle is good, and not sub- angle is respectively lower than 36 °, 38 °, 35 °, the product of embodiment 4,5,6 dress
Amount difference test shows that this product content uniformity is respectively less than 4%, and loading amount is stable, controllable, and dissolution test result shows that repeatedly measure is real
Apply the product of example 4,5,6 and leach the time and be respectively less than 30 seconds, therefore this product can leach rapidly, mouthfeel investigation shows the product of embodiment 4,5,6
Taste is easily received by most of patient, and the product stability result of the test of embodiment 4,5,6 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.
Claims (3)
- A kind of 1. levo-oxiracetam particle in good taste, it is characterised in that it be by following weight proportion supplementary material by with Lower step is made：1 part of levo-oxiracetam, 0.8 ~ 1.6 part of mannitol, 0.5 ~ 1.2 part of microcrystalline cellulose, sodium carboxymethylcellulose 0.9 ~ 1.6 part, 0.5 ~ 1.1 part of lactose, 0.13 ~ 0.18 part of talcum powder, 0.8 ~ 1.5 part of Macrogol 4000, hydroxypropyl methylcellulose 0.5 ~ 1.2 part, 0.9 ~ 1.7 part of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.09 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sucrose, ethyl wheat 0.2 ~ 0.7 part of bud phenol, 0.15 ~ 0.22 part of honey, 12 ~ 18 parts of the ethanol that volume fraction is 50% ~ 70%；The honey of recipe quantity is taken, It is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stir, be heated to 100 ~ 105 DEG C, is incubated 20 ~ 25 minutes, Take out, with 80 mesh screens, take filtrate, the ethanol of recipe quantity is added after letting cool, stirring and dissolving is standby；The another left side for taking recipe quantity Revolve Oxiracetam, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sucrose, ethyl Maltol is placed in Universalpulverizer, be crushed 100 mesh sieves, is placed in wet granulator, adds previously processed good honey second The polyoxyethylene sorbitan monoleate of alcoholic solution and recipe quantity, start granulator（18 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into and flowed Change in bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, and drying time is 50 ~ 55 minutes；Take the polyethylene glycol of recipe quantity 4000th, hydroxypropyl methylcellulose, 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 In fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Coating solution is connected by the nozzle atomization of fluid bed It is continuous to add fluid bed, 50 ~ 60rpm of spouting velocity is set, atomizing pressure is 0.8 ~ 1.0bar, continues air intake and dries, solution has sprayed After continue heating 10 ~ 15 minutes after stop heating, cooling discharging；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve mistakes Sieve whole grain；The talcum powder of recipe quantity be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer 10min ~ 20min is produced.
- 2. levo-oxiracetam particle as claimed in claim 1, it is characterised in that it is by the supplementary material of following weight proportion It is made according to the following steps：1 part of levo-oxiracetam, 0.9 ~ 1.3 part of mannitol, 0.7 ~ 1.0 part of microcrystalline cellulose, carboxymethyl cellulose Plain 1.1 ~ 1.5 parts of sodium, 0.7 ~ 1.0 part of lactose, 0.15 ~ 0.17 part of talcum powder, 1.1 ~ 1.3 parts of Macrogol 4000, hydroxypropyl first are fine 0.8 ~ 1.0 part of dimension element, 1.2 ~ 1.5 parts of low-substituted hydroxypropyl cellulose, 0.06 ~ 0.08 part of polyoxyethylene sorbitan monoleate, 2 ~ 4 parts of sucrose, second 0.3 ~ 0.6 part of base maltol, 0.17 ~ 0.20 part of honey, 13 ~ 17 parts of the ethanol that volume fraction is 50% ~ 70%；Take the honeybee of recipe quantity Honey, it is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stir, be heated to 100 ~ 105 DEG C, is incubated 20 ~ 25 points Clock, take out, with 80 mesh screens, take filtrate, the ethanol of recipe quantity is added after letting cool, stirring and dissolving is standby；Separately take recipe quantity Levo-oxiracetam, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sucrose, second Base maltol is placed in Universalpulverizer, be crushed 100 mesh sieves, is placed in wet granulator, adds previously processed good honey The polyoxyethylene sorbitan monoleate of ethanol solution and recipe quantity, start granulator（18 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into In fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, and drying time is 50 ~ 55 minutes；Take the poly- second two of recipe quantity Alcohol 4000, hydroxypropyl methylcellulose, add water that the coating solution that quality volume fraction is 8% ~ 10% is made, it is standby；Above-mentioned dry particl is thrown In fluidized bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；The nozzle atomization that coating solution is passed through into fluid bed Fluid bed is continuously added to, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, continues air intake and dries, solution spray Stop heating, cooling discharging after continuing heating after complete 10 ~ 15 minutes；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieves Sieving whole grain；The talcum powder of recipe quantity be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer 10min ~ 20min is closed to produce.
- 3. the preparation method of levo-oxiracetam particle as claimed in claim 1 or 2, it is characterised in that it is by following step It is rapid obtained：A. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stirring Uniformly, 100 ~ 105 DEG C are heated to, is incubated 20 ~ 25 minutes, is taken out, with 80 mesh screens, is taken filtrate, recipe quantity is added after letting cool Ethanol, stirring and dissolving is standby；B. 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；C. pelletize：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive, starts granulator（Installation 18 mesh nylon mesh）, start to pelletize；D. 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 ensured Pellet moisture≤3%；E. it is coated：The preparation of E (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；E (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；F. whole grain, sub-sieve:Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, controls 25 DEG C of environment temperature Hereinafter, relative humidity is below 50%；G. 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；H. interior bag：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature, relatively Below humidity 50%, produce.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610423231.2A CN107510674A (en) | 2016-06-15 | 2016-06-15 | A kind of levo-oxiracetam particle in good taste and preparation method thereof |
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|---|---|---|---|
| CN201610423231.2A CN107510674A (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 (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 |
| CN103599101A (en) * | 2013-11-08 | 2014-02-26 | 南京优科生物医药研究有限公司 | Application of levo-oxiracetam in preparation of medicine for treating memory and intelligence disturbance |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
-
2016
- 2016-06-15 CN CN201610423231.2A patent/CN107510674A/en not_active Withdrawn
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 |
| CN103599101A (en) * | 2013-11-08 | 2014-02-26 | 南京优科生物医药研究有限公司 | Application of levo-oxiracetam in preparation of medicine for treating memory and intelligence disturbance |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
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Application publication date: 20171226 |