CN107510676A - A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof - Google Patents
A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof Download PDFInfo
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Abstract
It is a kind of（S）The pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 is made by following supplementary material：（S）1 part of 4 hydroxyl, 2 oxo, 1 pyrrolidine acetamide, 0.7 ~ 1.2 part of L cysteines, 0.6 ~ 1.0 part of mannitol, 1.1 ~ 1.6 parts of microcrystalline cellulose, 0.5 ~ 1.2 part of sodium carboxymethylcellulose, 0.8 ~ 1.3 part of lactose, 0.13 ~ 0.18 part of talcum powder, 1.1 ~ 1.7 parts of Macrogol 4000, 0.9 ~ 1.5 part of hydroxypropyl methylcellulose, 0.6 ~ 1.3 part of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.11 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sorbierite, 10 ~ 16 parts of 6% ~ 8% starch slurry, 20% ~ 30% 2 ~ 5 parts of ethanol solution；（S）The pyrrolidine acetamide particulate production impurity of 4 hydroxyl, 2 oxo 1 only increases by 0.03%, and particle bisque amount is few, uniform particle diameter, good fluidity, not sub- angle is less than 38 °, and content uniformity is less than 5%, and it is fast to leach speed, the time is leached less than 30 seconds, content uniformity is good, and the RSD of multiple assays is respectively less than 2%, 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 uniform oxo -1- of (S) -4- hydroxyls -2 of content
Pyrrolidine acetamide particle and preparation method thereof.
Background technology
Oxiracetam listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Injection
Liquid, 1g/5ml.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic
Body.Ye Lei etc. mentions levo-oxiracetam to the rush gone into a coma caused by alcoholism in the A patents of Publication No. CN 103735545
Effect of waking up is obvious, and dextrorotation Oxiracetam does not act on substantially, and the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura west
Smooth 2 times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Peak etc. is opened in Publication No. CN
Levo-oxiracetam is disclosed in 103599101 A patent to the study note of traumatic brain injury rat caused by hydraulic pressure and freely falling body
Recall cognition dysfunction to improve significantly, its drug effect is far above dextrorotation Oxiracetam.And the left-handed Auras of 200mg/kg
It is western smooth suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：Levo-oxiracetam and dextrorotation are difficult to understand
La Xitan is in beasle dog body without obvious chiral inversion.It is difficult to understand that beasle dog single intravenous injection gives left-handed and 2 multiple doses racemizations
The equal no significant difference of the main pharmacokinetic parameters of levo-oxiracetam in blood plasma after La Xitan.The examinations such as safe pharmacology, anxious malicious, long poison
Test result to show, under isodose level, levo-oxiracetam is with Oxiracetam to the toxicity of animal subject or cell without bright
Significant difference is different.Above-mentioned preclinical result of study shows that levo-oxiracetam is the chief active that drug effect is played in Oxiracetam body
Composition, this product, which is used alone, can reduce Clinical practice dosage, reduce potential toxicity.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) the entitled 4- hydroxyls -2- OXo-1-pyrrolidines of chemistry
Acetamide, (compound is disclosed in the anti anoxia class cereboactive drug synthesized first in 1974 for Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promotes brain metabolism, through blood brain
Barrier, there is stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease, brain trauma, brain
Knurl, intracranial infection, brain degenerative disease etc. also have the effect of preferable, and the drug toxicity is extremely low, no mutagenesis and carcinogenic work
With and genotoxicity.Giorgio et al. discloses the chemical constitution and preparation method of Oxiracetam in US4118396,
Chiodini et al. is disclosed in W09306826A, and clinical effectiveness proves that the drug effect of the Oxiracetam of S configurations (left-handed) is better than R structures
Type (dextrorotation), Oxiracetam and levo-oxiracetam structure are as follows.
The existing oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 is primarily present the increase of preparation process impurity substantially,
Particle bisque is more, and particle diameter is difficult to control, and content uniformity is poor, and storage process stability is bad, and particle hygroscopicity is strong, easy to stick
Connecting block, shelf life is short, and particle leaches the technical problems such as speed is slow.
The content of the invention
It is an object of the invention to provide a kind of content is uniform, stability is good, leaches the fireballing oxygen of (S) -4- hydroxyls -2
Generation -1- pyrrolidine acetamide particles.
Another object of the present invention is to provide the preparation of the above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2
Method.
The purpose of the present invention is realized by following technical measures：
A kind of uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, it is with (S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide is raw material, adds a certain amount of filler, flavouring, adhesive, lubricant, disintegrant, bag
Clothing material is made；Wherein described filler be starch, lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose,
One or more in glucose, sodium carboxymethylcellulose, Cys；The flavouring is sucrose, maltose, ethyl wheat
Bud phenol, Sucralose, stevia rebaudianum are sweet, the one or more in sorbierite, mannitol, glucose, aspartame；Described adhesive is
One or more in water, ethanol, sucrose, starch slurry, dextrin, carboxymethyl cellulose, polyvinylpyrrolidone；The lubricant
For talcum powder, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, lauryl sodium sulfate, superfine silica gel powder, magnesia, stone
One or more in wax；The disintegrant is low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sodium carboxymethyl starch, Gan Dian
One or more in powder；The coating material is Macrogol 4000, Macrogol 6000, hydroxypropyl cellulose, hydroxypropyl first
One or more in cellulose, polyethylene acetaldehyde diethyl ester, hydroxypropyl methyl cellulose phthalate.
The rational prescription proportioning of inventor, coordinates specific preparation method, may be such that the above-mentioned oxo -1- pyrroles of (S) -4- hydroxyls -2
Cough up that alkyl acetamide particulate production impurity increase is smaller, and product cut size uniform, controllable, storage process is not easy moisture absorption, is not easy adhesion
Caking, product stability are good, and shelf life length, granule content is uniformly and to leach speed fast；Above-mentioned oxo-the 1- of (S) -4- hydroxyls -2
Pyrrolidine acetamide particle, it is characterised in that it is made by the supplementary material of following weight proportion：(S) oxo of-4- hydroxyls-2-
1 part of 1- pyrrolidine acetamides, 0.7~1.2 part of Cys, 0.6~1.0 part of mannitol, 1.1~1.6 parts of microcrystalline cellulose,
0.5~1.2 part of sodium carboxymethylcellulose, 0.8~1.3 part of lactose, 0.13~0.18 part of talcum powder, Macrogol 4000 1.1~
1.7 parts, 0.9~1.5 part of hydroxypropyl methylcellulose, 0.6~1.3 part of low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate 0.05~
0.11 part, 1~5 part of sorbierite, mass fraction be 6%~8% 10~16 parts of starch slurry, volume fraction be 20%~30% second
2~5 parts of alcoholic solution；The polyoxyethylene sorbitan monoleate of recipe quantity, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is taken to be dissolved in recipe quantity
Ethanol solution in, it is standby；Another Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, the breast for taking recipe quantity
Sugar, low-substituted hydroxypropyl cellulose, sorbierite are placed in Universalpulverizer, crushed 100 mesh sieves, standby；Pre-treatment is good
Mixed accessories powder is placed in wet granulator, adds the previously processed good oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2
The starch slurry of ethanol solution and recipe quantity, start granulator (18 mesh nylon mesh of installation), 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 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；By above-mentioned dry particl
Put into fluid bed, be passed through hot-air, be allowed to suspension fluidization, bed temperature is 40~50 DEG C；The nozzle that coating solution is passed through into fluid bed
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.
Further, speed is leached faster for the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, particle contains
Evenly, stability is more preferable, and the term of validity is longer, the oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, its feature for amount
It is, it is made by the supplementary material of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, the Guangs of L- half
0.8~1.1 part of propylhomoserin, 0.7~0.9 part of mannitol, 1.2~1.5 parts of microcrystalline cellulose, sodium carboxymethylcellulose 0.7~1.0
Part, 0.9~1.2 part of lactose, 0.15~0.17 part of talcum powder, 1.2~1.5 parts of Macrogol 4000, hydroxypropyl methylcellulose 1.0~
1.3 parts, 0.8~1.1 part of low-substituted hydroxypropyl cellulose, 0.07~0.10 part of polyoxyethylene sorbitan monoleate, 2~4 parts of sorbierite, quality point
Count 11~15 parts of the starch slurry for 6%~8%, volume fraction is 3~5 parts of 20%~30% ethanol solution；Take the poly- of recipe quantity
Sorb ester 80, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 are dissolved in the ethanol solution of recipe quantity, standby；Separately take place
The Cys just measured, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, mountain
Pears alcohol is placed in Universalpulverizer, crushed 100 mesh sieves, standby；The good mixed accessories powder of pre-treatment is placed in wet granulation
In machine, the starch of the previously processed good oxo-1-pyrrolidine ethanamide ethanol solution of (S) -4- hydroxyls -2 and recipe quantity is added
Slurry, start granulator (18 mesh nylon mesh of installation), start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 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
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,
Suspension fluidization is allowed to, bed temperature is 40~50 DEG C；Coating solution is continuously added to fluid bed, setting spray by the nozzle atomization of fluid bed
50~60rpm of speed is starched, atomizing pressure is 0.8~1.0bar, continues air intake and dries, solution continues 10~15 points of heating after having sprayed
Stop heating, cooling discharging after clock；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；By recipe quantity
Talcum powder crushed 100 mesh sieves, adds in the particle after whole grain, is produced with three-dimensional motion mixer mixing 10min~20min.
A kind of preparation method of the uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, its feature exist
In it is obtained as follows：
1. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, the polyoxyethylene sorbitan monoleate of recipe quantity molten
Solution is standby in the ethanol solution of recipe quantity；Separately the filler, flavouring, disintegrant of recipe quantity is taken to be placed in Universalpulverizer,
100 mesh sieves are crushed, it is standby；
2. granulation：Gained mixed-powder is placed in wet granulator after taking pre-treatment, adds previously processed good (S) -4-
The adhesive of the oxo-1-pyrrolidine ethanamide of hydroxyl -2 ethanol solution and recipe quantity, 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；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%；
4. 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；
5. 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 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,
Below relative humidity 50%, produce.
The present invention has following beneficial effect：
The oxo-1-pyrrolidine ethanamide particulate production impurity incrementss of the present invention (S) -4- hydroxyls -2 are smaller, are only
0.03%, particle bisque amount is few, uniform particle diameter, good fluidity, and not sub- angle is less than 38 °, and content uniformity is less than 5%, and particle leaches
Speed is fast, all leaches the time less than 30 seconds, content uniformity is good, and the RSD of multiple assays is respectively less than 2%, stores
Journey stability is good, and product is not easy moisture absorption caking, and shelf life is up to 24 months, and preparation technology simple possible, worth market pushes away
Extensively.
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 uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, is made according to the following steps：
| Composition | Dosage |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Cys | 0.8 part |
| Mannitol | 0.7 part |
| Microcrystalline cellulose | 1.2 part |
| Sodium carboxymethylcellulose | 0.7 part |
| Lactose | 0.9 part |
| Talcum powder | 0.15 part |
| Macrogol 4000 | 1.2 part |
| Hydroxypropyl methylcellulose | 1.0 part |
| Low-substituted hydroxypropyl cellulose | 0.8 part |
| Polyoxyethylene sorbitan monoleate | 0.07 part |
| Sorbierite | 2 parts |
| Mass fraction is 6% starch slurry | 11 parts |
| Volume fraction is 20% ethanol solution | 3 parts |
It is made 1000 bags
Preparation process：
1. supplementary material pre-treatment：Take polyoxyethylene sorbitan monoleate, (S) -4- -2 oxo-1-pyrrolidine ethanamides of hydroxyl of recipe quantity molten
Solution is standby in the ethanol solution of recipe quantity；Separately take recipe quantity, Cys, mannitol, microcrystalline cellulose, carboxymethyl
Sodium cellulosate, lactose, low-substituted hydroxypropyl cellulose, sorbierite are placed in Universalpulverizer, crushed 100 mesh sieves, standby；
2. granulation：Take mixed-powder obtained by pre-treatment to be placed in wet granulator, add previously processed good (S) -4- hydroxyls
The starch slurry of the oxo-1-pyrrolidine ethanamide of base -2 ethanol solution and recipe quantity, start granulator (18 mesh nylon mesh of installation), open
Begin to pelletize；
3. 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%；
4. 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；
5. 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 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,
Below relative 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 particle flow
Property 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 be well mixed；
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：Present invention one kind (S) -4- -2 oxo-1-pyrrolidine ethanamide particle prescriptions of hydroxyl are miscellaneous to preparation process
The increased influence of matter
1. experiment material：
(S) the oxo-1-pyrrolidine ethanamide particulate samples of -4- hydroxyls -2：Prepared by embodiment 1.
(S) the oxo-1-pyrrolidine ethanamide particle control sample of -4- hydroxyls -2：To be lacked on the basis of the prescription of embodiment 1
Sample obtained by few Cys, its preparation technology is the same as embodiment 1.
2. experimental method：In the preparation process of embodiment 1, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is determined respectively
The relevant material of bulk drug and the oxo-1-pyrrolidine ethanamide finished granule of (S) -4- hydroxyls -2, the oxygen of observation (S) -4- hydroxyls -2
Generation -1- pyrrolidine acetamide particles impurity in preparation process increases situation.Meanwhile take the embodiment 1 for lacking Cys
Prescription as control prescription, prepared by the preparation method of embodiment 1, equally determine the oxo -1- pyrroles of (S) -4- hydroxyls -2 respectively
The relevant material of alkyl acetamide particulate material medicine and the oxo-1-pyrrolidine ethanamide finished granule of (S) -4- hydroxyls -2 is coughed up, is observed
(S) the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 impurity in preparation process 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 0.03%, hence it is evident that
Better than control sample.
Experiment four：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 ± 5% it can be seen from upper table result of the test, shows that loading amount is poor
Different stabilization, content uniformity are small.
Experiment five：The oxo-1-pyrrolidine ethanamide granule stability of present invention one kind (S) -4- hydroxyls -2 is tested
Experiment material：
(S) the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2：It is made for embodiment 1.
Acceleration study method：By the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 made from embodiment 1 by listing
Packaging, puts in Acceleration study case, 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
Record：
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：By the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 made from embodiment 1 by listing
Packaging, put in the long-term case that keeps sample, 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 six：Dissolution test
1. test material：The oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 made from embodiment 1；
2. test method：10 bags of -2 oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls, puts made from Example 1
In 100ml beakers, the purified water that 50ml temperature is 25 DEG C is added, static, 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) | 26 seconds | 23 seconds | 28 seconds | 22 seconds | 25 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 28 seconds | 26 seconds | 24 seconds | 25 seconds | 27 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.
Embodiment 2
A kind of uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, is made according to the following steps：
| Composition | Dosage |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Cys | 1.1 part |
| Mannitol | 0.9 part |
| Microcrystalline cellulose | 1.5 part |
| Sodium carboxymethylcellulose | 1.0 part |
| Lactose | 1.2 part |
| Talcum powder | 0.17 part |
| Macrogol 4000 | 1.5 part |
| Hydroxypropyl methylcellulose | 1.3 part |
| Low-substituted hydroxypropyl cellulose | 1.1 part |
| Polyoxyethylene sorbitan monoleate | 0.10 part |
| Sorbierite | 4 parts |
| Mass fraction is 8% starch slurry | 15 parts |
| Volume fraction is 30% ethanol solution | 5 parts |
It is made 1000 bags
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, not sub- angle examination
Test measurement result and show that this product mobility of particle is good, not sub- angle is less than 36 °, and content uniformity test result shows that this product content is equal
Even property is good, and the content RSD of its total mixed rear each point particle is less than 1%, and product prescription is increased on preparation process impurity to influence experiment
As a result 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, and controllable, dissolution test result shows that repeatedly determining this product leaches
Time is respectively less than 30 seconds, therefore this product can leach rapidly, and stability test result shows to accelerate sample quality stabilization in June, long-term by 24
Individual month steady quality, therefore this product term of validity at least 24 months.
Embodiment 3
A kind of uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, is made according to the following steps：
| Composition | Dosage |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Cys | 1.0 part |
| Mannitol | 0.8 part |
| Microcrystalline cellulose | 1.3 part |
| Sodium carboxymethylcellulose | 0.9 part |
| Lactose | 1.1 part |
| Talcum powder | 0.16 part |
| Macrogol 4000 | 1.3 part |
| Hydroxypropyl methylcellulose | 1.2 part |
| Low-substituted hydroxypropyl cellulose | 1.0 part |
| Polyoxyethylene sorbitan monoleate | 0.08 part |
| Sorbierite | 3 parts |
| Mass fraction is 7% starch slurry | 13 parts |
| Volume fraction is 25% ethanol solution | 4 parts |
It is made 1000 bags
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, not sub- angle examination
Test measurement result and show that this product mobility of particle is good, not sub- angle is less than 38 °, and content uniformity test result shows that this product content is equal
Even property is good, and the content RSD of its total mixed rear each point particle is less than 2%, and product prescription is increased on preparation process impurity to influence experiment
As a result 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, and controllable, dissolution test result shows that repeatedly determining this product leaches
Time is respectively less than 30 seconds, therefore this product can leach rapidly, and stability test result shows to accelerate sample quality stabilization in June, long-term by 24
Individual month steady quality, therefore this product term of validity at least 24 months.
Embodiment 4-6：The uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of content, by following heavy
The supplementary material of amount is prepared, and preparation method is the same as embodiment 1：
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, embodiment 4,
5th, 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 34 °, 35 °, 37 °, implements
The sample size uniformity test result of example 4,5,6 shows that this product content uniformity is good, RSD points of the content of its total mixed rear each point particle
Not little Yu 1%, 2%, 2%, the product prescription of embodiment 4,5,6 it is increased on preparation process impurity influence result of the test show this product
Preparation process impurity incrementss are smaller, and relevant material only increases by 0.02%, 0.03%, 0.03% respectively in preparation process, implements
The experiment of the product content uniformity of example 4,5,6 shows that this product content uniformity is respectively less than 5%, and this product loading amount is stable, controllable, embodiment 4,
5th, 6 sample dissolution test results, which show repeatedly to determine this product and leach the time, is respectively less than 30 seconds, therefore this product can leach rapidly, embodiment
4th, 5,6 stability test results show that this product accelerates sample quality stabilization in June, long-term 24 months steady qualities, therefore this product is effective
At least 24 months phase.
Claims (3)
1. a kind of content is uniform（S）The oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, it is characterised in that it is by following
The supplementary material of weight proportion is made according to the following steps：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, Cys
0.7 ~ 1.2 part, 0.6 ~ 1.0 part of mannitol, 1.1 ~ 1.6 parts of microcrystalline cellulose, 0.5 ~ 1.2 part of sodium carboxymethylcellulose, lactose 0.8
~ 1.3 parts, 0.13 ~ 0.18 part of talcum powder, 1.1 ~ 1.7 parts of Macrogol 4000,0.9 ~ 1.5 part of hydroxypropyl methylcellulose, low substitution
0.6 ~ 1.3 part of hydroxypropyl cellulose, 0.05 ~ 0.11 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sorbierite, the shallow lake that mass fraction is 6% ~ 8%
10 ~ 16 parts of slurry, volume fraction are 2 ~ 5 parts of 20% ~ 30% ethanol solution；Take recipe quantity polyoxyethylene sorbitan monoleate,（S）- 4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide is dissolved in the ethanol solution of recipe quantity, standby；Another Cys, the sweet dew for taking recipe quantity
Alcohol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sorbierite are placed in Universalpulverizer,
100 mesh sieves are crushed, it is standby；The good mixed accessories powder of pre-treatment is placed in wet granulator, it is previously processed good to add
（S）The starch slurry of the oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2 and recipe quantity, start granulator（18 mesh are installed
Nylon mesh）, start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, drying time
For 50 ~ 55 minutes or so；Take Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity, add water be made quality volume fraction for 8% ~
10% coating solution, 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 or so；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomization pressure
Power 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；Will
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
In particle after whole grain, produced with three-dimensional motion mixer mixing 10min ~ 20min.
It is 2. as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, it is characterised in that it be by
The supplementary material of following weight proportion is made according to the following steps：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, the Guangs of L- half
0.8 ~ 1.1 part of propylhomoserin, 0.7 ~ 0.9 part of mannitol, 1.2 ~ 1.5 parts of microcrystalline cellulose, 0.7 ~ 1.0 part of sodium carboxymethylcellulose, breast
It is 0.9 ~ 1.2 part of sugar, 0.15 ~ 0.17 part of talcum powder, 1.2 ~ 1.5 parts of Macrogol 4000,1.0 ~ 1.3 parts of hydroxypropyl methylcellulose, low
It is 6% ~ 8% to substitute 0.8 ~ 1.1 part of hydroxypropyl cellulose, 0.07 ~ 0.10 part of polyoxyethylene sorbitan monoleate, 2 ~ 4 parts of sorbierite, mass fraction
11 ~ 15 parts of starch slurry, volume fraction be 3 ~ 5 parts of 20% ~ 30% ethanol solution；Take recipe quantity polyoxyethylene sorbitan monoleate,（S）- 4- hydroxyls
The oxo-1-pyrrolidine ethanamide of base -2 is dissolved in the ethanol solution of recipe quantity, standby；The another Cys for taking recipe quantity,
Mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sorbierite are placed in Universalpulverizer
In, 100 mesh sieves are crushed, it is standby；The good mixed accessories powder of pre-treatment is placed in wet granulator, it is previously processed good to add
's（S）The starch slurry of the oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2 and recipe quantity, 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, when drying
Between be 50 ~ 55 minutes；Take Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity, add water be made quality volume fraction for 8% ~
10% coating solution, 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
℃；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, cooling discharging after continuing heating after having sprayed 10 ~ 15 minutes；Will coating
Particle 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 whole grain
In particle afterwards, produced with three-dimensional motion mixer mixing 10min ~ 20min.
It is 3. as claimed in claim 1 or 2（S）The preparation method of the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, its feature
It is, it is obtained as follows：
A. supplementary material pre-treatment：Take recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, polyoxyethylene sorbitan monoleate are dissolved in
It is standby in the ethanol solution of recipe quantity；Separately take the filler, flavouring, disintegrant of recipe quantity to be placed in Universalpulverizer, crush
100 mesh sieves are crossed, it is standby；
B. pelletize：Gained mixed-powder is placed in wet granulator after taking pre-treatment, and it is previously processed good to add（S）- 4- hydroxyls-
The adhesive of 2 oxo-1-pyrrolidine ethanamide ethanol solutions and recipe quantity, start granulator（18 mesh nylon mesh are installed）, start
Granulation；
C. 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%；
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
℃；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；
E. 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%；
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, relatively
Below humidity 50%, produce.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610427249.XA CN107510676A (en) | 2016-06-15 | 2016-06-15 | A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof |
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|---|---|---|---|
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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 CN201610427249.XA patent/CN107510676A/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 |
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