CN106619528A - (S)-4-hydroxy-2oxo-1-pyrrolidine acetamide particle with good mouthfeel and preparation method thereof - Google Patents
(S)-4-hydroxy-2oxo-1-pyrrolidine acetamide particle with good mouthfeel and preparation method thereof Download PDFInfo
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Abstract
(S)-4-hydroxy-2oxo-1-pyrrolidine acetamide particle with good mouthfeel is prepared from the following raw materials and auxiliary materials (by weight): (S)-4-hydroxy-2oxo-1-pyrrolidine acetamide, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, magnesium stearate, polyethylene glycol 4000, hydroxypropyl methylcellulose, low-substituted hydroxy propyl cellulose, polysorbate 80, cane sugar, ethyl maltol, and 50-70% (by volume) of an ethanol solution. The prepared (S)-4-hydroxy-2oxo-1-pyrrolidine acetamide particle has advantages of fast dissolution and dispersion speed and good stability during storage process. The product is not easy for moisture absorption or caking. Shelf life of the product reaches up to 36 months. The preparation technology is simple and feasible, and is worthy of market promotion.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of oxo -1- pyrroles of (S) -4- hydroxyls -2 in good taste
Alkyl acetamide particle and preparation method thereof.
Background technology
In 1987 in Italy's listing, the formulation of listing is tablet to Oxiracetam, 800mg；Capsule, 800mg；Note
Penetrate liquid, 1g/5ml.At present domestic only have oxiracetam capsule and parenteral solution listing, and main active used be it is outer
Raceme.Caused by Ye Lei etc. mentions levo-oxiracetam to alcoholism in the A patents of Publication No. CN 103735545
The promoting wakening of stupor is obvious, and dextrorotation Oxiracetam is not acted on substantially, and the awake effect of above-mentioned rush of levo-oxiracetam is
2 times of racemization Oxiracetam；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Zhang Feng etc.
It is traumatic caused by levo-oxiracetam is disclosed in the patent of the A of Publication No. CN 103599101 to hydraulic pressure and freely falling body
Brain injury in rats learning and memory cognition dysfunction improves significantly, and its drug effect is far above dextrorotation Oxiracetam.
And 200mg/kg levo-oxiracetams are suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results show：
Levo-oxiracetam and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection gives
The main pharmacokinetic parameters of levo-oxiracetam nothing is substantially poor in blood plasma after left-handed and 2 multiple doses racemization Oxiracetam
It is different.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level, levo-oxiracetam and Aura
It is western smooth to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows, levo-oxiracetam
It is the main active that drug effect is played in Oxiracetam body, this product is used alone can reduce Clinical practice dosage, reduces latent
Toxicity.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- OXo-1-pyrrolidine second
Acid amides, is that (compound is disclosed in the anti anoxia class cereboactive drug that synthesized first in 1974 of Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine synthesis can be promoted, promotes brain metabolism,
Through blood-brain barrier, have stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease,
Brain trauma, brain tumor, intracranial infection, brain degenerative disease etc. also have preferable curative effect, and the drug toxicity is extremely low, nothing
Mutagenesis and carcinogenesis and genotoxicity.Giorgio et al. discloses the chemistry knot of Oxiracetam in US4118396
Structure and preparation method, Chiodini et al. are disclosed in WO9306826A, and clinical effectiveness proves S configurations (left-handed)
The drug effect of Oxiracetam is better than R configurations (dextrorotation), and Oxiracetam and levo-oxiracetam structure are as follows.
The existing oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 be primarily present storage process stability it is poor, 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 difficult by extensive patients institute
The technical problems such as acceptance.
The content of the invention
It is an object of the invention to provide one kind is in good taste, leach the fireballing OXo-1-pyrrolidine second of (S) -4- hydroxyls -2
Acid amides particle.
Another object of the present invention is to provide the preparation side 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 oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, it is with the oxygen of (S) -4- hydroxyls -2
Generation -1- pyrrolidine acetamides are raw material, add a certain amount of filler, flavouring, adhesive, lubricant, disintegrant,
Coating material is obtained；Wherein described filler is starch, lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, crystallite
One or more in cellulose, glucose, sodium carboxymethylcellulose；The flavouring is sucrose, maltose, ethyl malt
Phenol, Sucralose, stevia rebaudianum are sweet, one or more in sorbierite, mannitol, glucose, aspartame；Described adhesive
For one or more in water, ethanol, sucrose, starch slurry, dextrin, carboxymethylcellulose calcium, polyvinylpyrrolidone；It is described
Lubricant be talcum powder, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, lauryl sodium sulfate, superfine silica gel powder,
One or more in magnesia, paraffin；The disintegrant is low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, carboxymethyl shallow lake
One or more in powder sodium, dried starch；The coating material is Macrogol 4000, Macrogol 6000, hydroxypropyl fibre
One or more in dimension element, Hydroxypropyl methylcellulose, AEA, hydroxypropyl methyl cellulose phthalate.
The rational prescription proportioning of inventor, coordinates specific preparation method, can cause the above-mentioned OXo-1-pyrrolidine of (S) -4- hydroxyls -2
Acetamide particle is difficult moisture absorption, is difficult that adhesion caking, product stability are good, and shelf life is long, and it is fast that particle leaches speed, produces
Product are in good taste；The above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, it is characterised in that it is
It is obtained by the supplementary material of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, mannitol 0.6～1.0
Part, 0.5～1.3 part of microcrystalline cellulose, 0.7～1.2 part of sodium carboxymethylcellulose, 0.8～1.2 part of lactose, magnesium stearate
0.07～0.13 part, 0.8～1.3 part of Macrogol 4000,0.7～1.2 part of Hydroxypropyl methylcellulose, low substituted hydroxy-propyl fiber
0.5～1.2 part of element, 0.11～0.15 part of polyoxyethylene sorbitan monoleate, 2～6 parts of sucrose, 0.5～0.9 part of ethylmaltol, volume integral
Number is 50%～70% 5～12 parts of ethanol solution；Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, mannitol,
Microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sucrose, second
Base maltol is placed in Universalpulverizer, was crushed and is placed in after 100 mesh sieves in wet granulator, adds ethanol solution, is opened
Dynamic granulator (installing 24 mesh nylon mesh), starts granulation；Wet granular is put in air dry oven, temperature 50 is set
DEG C～60 DEG C of drying times are 120min～150min so that particle water content≤3% (weight/mass percentage composition)；Take recipe quantity
Macrogol 4000 and Hydroxypropyl methylcellulose, add water the coating solution for making that mass fraction is 6%～9%, standby；Will be upper
In stating 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
The nozzle atomization of fluid bed is continuously added to fluid bed, sets 50～60rpm of spouting velocity, and atomizing pressure is 0.8～1.0bar,
Continue air intake to be dried, solution stops heating after continuing to heat 10～15 minutes after having sprayed, and cooling discharging obtains final product coated granule.
Further, in order that (S) -4- hydroxyls -2 oxo-1-pyrrolidine ethanamide particles leaches speed faster, goods
The frame phase is longer, and mouthfeel is more preferable；The above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, it is characterised in that it
It is to be obtained by the supplementary material of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, mannitol 0.7～0.9
Part, 0.6～1.0 part of microcrystalline cellulose, 0.8～1.1 part of sodium carboxymethylcellulose, 0.9～1.2 part of lactose, magnesium stearate
0.08～0.11 part, 0.9～1.2 part of Macrogol 4000,0.8～1.1 part of Hydroxypropyl methylcellulose, low substituted hydroxy-propyl fiber
0.6～1.0 part of element, 0.11～0.13 part of polyoxyethylene sorbitan monoleate, 3～6 parts of sucrose, 0.6～0.8 part of ethylmaltol, volume integral
Number is 50%～70% 7～10 parts of ethanol solution；Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, mannitol,
Microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sucrose, second
Base maltol is placed in Universalpulverizer, was crushed and is placed in after 100 mesh sieves in wet granulator, adds ethanol solution, is opened
Dynamic granulator (installing 24 mesh nylon mesh), starts granulation；Wet granular is put in air dry oven, temperature 50 is set
DEG C～60 DEG C of drying times are 120min～150min so that particle water content≤3% (weight/mass percentage composition)；Take recipe quantity
Macrogol 4000 and Hydroxypropyl methylcellulose, add water the coating solution for making that mass fraction is 6%～9%, standby；Will be upper
In stating 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
The nozzle atomization of fluid bed is continuously added to fluid bed, sets 50～60rpm of spouting velocity, and atomizing pressure is 0.8～1.0bar,
Continue air intake to be dried, solution stops heating after continuing to heat 10～15 minutes after having sprayed, and cooling discharging obtains final product coated granule.
A kind of preparation method of the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, it is characterised in that
It is obtained as follows：
1. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, filler, the flavoring of recipe quantity
Agent, disintegrant are placed in Universalpulverizer, crush 100 mesh sieves, standby；
2. pelletize：Gained mixed-powder after pre-treatment is taken, in being placed in wet granulator, adhesive is added, starts granulator
(installing 24 mesh nylon mesh), starts granulation；
3. it is dried：It is by temperature 50 C～60 DEG C drying time in wet granular input air dry oven, is arranged
120min～150min so that particle water content≤3% (weight/mass percentage composition)；
4. coating：
(1) configuration of coating solution：The coating material of recipe quantity is taken, add water the coating solution for making that quality volume fraction is 6%～9%,
It is standby；
(2) coating process：Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50
℃；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity, atomization is set
Pressure is 0.8～1.0bar, continues air intake and is dried, and solution stops heating, cooling after continuing to heat 10～15 minutes after having sprayed
Discharging, obtains final product coated granule；
5. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, is sieved whole grain with 24 mesh nylon mesh, control environment
Below 25 DEG C of temperature, relative humidity is below 50%；
6. total mixed：Lubricant was crushed into 100 mesh sieves, in adding the particle after whole grain, was mixed with three-dimensional motion mixer
10min～20min；
7. bag in：Packed with particles packing machine, set packing specification as 1g/ bags, below 25 DEG C of environment temperature of control,
Below relative humidity 50%, obtain final product.
The present invention has following beneficial effect：
The oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 obtained in the present invention has fast, the particle whole that leaches speed
The time is leached less than 30 seconds, storage process stability is good, product is difficult moisture absorption caking, shelf life is up to 36 months,
Products taste is good, can be received by most of patient, and preparation process is simple is feasible, is worth marketing.
Specific 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 served only for
The present invention is further described, it is impossible to be interpreted as limiting the scope of the invention, without departing substantially from spirit of the invention
In the case of essence, the modification made to the inventive method, step or condition or replacement belong to the scope of the present invention.
Embodiment 1
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, is obtained according to the following steps：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Mannitol | 0.7 part |
| Microcrystalline cellulose | 0.6 part |
| Sodium carboxymethylcellulose | 0.8 part |
| Lactose | 0.9 part |
| Magnesium stearate | 0.08 part |
| Macrogol 4000 | 0.9 part |
| Hydroxypropyl methylcellulose | 0.8 part |
| Low-substituted hydroxypropyl cellulose | 0.6 part |
| Polyoxyethylene sorbitan monoleate | 0.11 part |
| Sucrose | 3 parts |
| Ethylmaltol | 0.6 part |
| The ethanol solution of volume fraction 50% | 7 parts |
Make 1000 bags
Preparation process：
1. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, mannitol, the crystallite of recipe quantity
Cellulose, sodium carboxymethylcellulose, lactose, low substituted carboxymethyl cellulose, polyoxyethylene sorbitan monoleate, sucrose, ethyl malt
Phenol is placed in Universalpulverizer, crushes 100 mesh sieves, standby；
2. pelletize：Gained mixed-powder after pre-treatment is taken, in being placed in wet granulator, the ethanol solution of recipe quantity is added,
Start granulator (installing 24 mesh nylon mesh), start granulation；
3. it is dried：It is by temperature 50 C～60 DEG C drying time in wet granular input air dry oven, is arranged
120min～150min so that particle water content≤3% (weight/mass percentage composition)；
4. coating：
(1) configuration of coating solution：Macrogol 4000, the Hydroxypropyl methylcellulose of recipe quantity are taken, is added water and is made mass fraction and be
6%～9% coating solution, it is standby；
(2) coating process：Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50
℃；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity, atomization is set
Pressure is 0.8～1.0bar, continues air intake and is dried, and solution stops heating, cooling after continuing to heat 10～15 minutes after having sprayed
Discharging, obtains final product coated granule；
5. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, is sieved whole grain with 24 mesh nylon mesh, control environment
Below 25 DEG C of temperature, relative humidity is below 50%；
6. total mixed：Magnesium stearate was crushed into 100 mesh sieves, it is mixed with three-dimensional motion mixer in adding the particle after whole grain
Close 10min～20min；
7. bag in：Packed with particles packing machine, set packing specification as 1g/ bags, below 25 DEG C of environment temperature of control,
Below relative humidity 50%, obtain final product.
Test one：Leach timing
1. test material：The oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 obtained in embodiment 1；
2. test method：10 bags of -2 oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls obtained in Example 1,
In being placed in 100ml beakers, the purified water that 50ml temperature is 25 DEG C is added, it is static, needed for observation is all leached
The time wanted；
3. result of the test see the table below：
| Test number | 1# | 2# | 3# | 4# | 5# |
| Leach the time (min) | 27 seconds | 22 seconds | 25 seconds | 24 seconds | 23 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 26 seconds | 25 seconds | 26 seconds | 23 seconds | 25 seconds |
4. conclusion (of pressure testing)：Can be seen that by upper table result of the test, repeatedly measurement particle leaches the time less than 30 seconds, it was demonstrated that press
It is fast that obtained particle of the invention leaches speed.
Test two：A kind of oxo-1-pyrrolidine ethanamide granule stability of (S) -4- hydroxyls -2 experiment in good taste of the present invention
Experiment material：
(S) the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2：It is obtained for embodiment 1.
Acceleration study method：By the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 obtained in embodiment 1 by listing
Packaging, in putting Acceleration study case, certain hour sampling is tested to investigation project.
Acceleration study temperature：40±2℃
Acceleration study humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：Proterties, moisture, granularity, melting, relevant material, content, microbial limit
Accelerated test stability is recorded：
Acceleration study result shows：Accelerate June sample suitable with 0 month sample items Testing index quality, show that this product adds
Speed experiment June, 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 obtained in embodiment 1 by listing
Packaging, puts and keep sample for a long time in case, certain hour sampling, and investigation project is tested.
Long-term experiment temperature：25±2℃
Long-term experiment humidity：RH60% ± 10%
The investigation time：0th, 3,6,9,12,18,24,36 months
Inspection target：Proterties, moisture, granularity, melting, relevant material, content, microbial limit
Long term test stability is recorded：
Long term test shows：36 months proterties of this product long term test, moisture, granularity, melting, relevant material, contain
Amount, microbial limit without significant changes, meet every relevant regulations of production quality standard draft.This product is long-term
36 months steady qualities of test, therefore this product term of validity is minimum 36 months, long term test is still during continuing to investigate.
Test three：Taste, mouthfeel market survey
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste of the present invention is matched somebody with somebody through specific supplementary material
5, make through multiple seasoning, with excellent taste, taste is fragrant and sweet, can be received by extensive patients.
Method：The random selection people of crowd 1000 of more than 10 years old, carries out taste trial test, will now taste result statistics as follows
Table：
(S) the oxo-1-pyrrolidine ethanamide particle taste application form of -4- hydroxyls -2
| It is very good | Preferably | Typically | Difference |
| 539 | 167 | 238 | 56 |
It can be seen from taste tastes market survey, this product is easy to be received by extensive patients, according to incompletely statistics, feels taste
Road is extraordinary to account for the 53.9% of whole crowd, thinks that taste is reasonable and accounts for 16.7%, feel taste it is general account for 23.8%,
Think that distasteful accounts for 5.6%.Therefore this product have it is in good taste, the characteristics of easily acceptance by extensive patients colony.
Embodiment 2
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, is obtained according to the following steps：
Make 1000 bags
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, when being leached respectively
Between determine, sample stability test and mouthfeel market survey, leaching timing, to show that this product leaches speed fast, multiple
Sample leaches the time and is respectively less than 30 seconds, and stability test result shows to accelerate June sample quality to stablize, long-term 36 months
Steady quality, therefore this product term of validity at least 36 months, taste investigation shows that this product is delicious, easily by most of patient institute
Receive.
Embodiment 3
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, is obtained according to the following steps：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Mannitol | 0.8 part |
| Microcrystalline cellulose | 0.9 part |
| Sodium carboxymethylcellulose | 1.0 part |
| Lactose | 1.1 part |
| Magnesium stearate | 0.09 part |
| Macrogol 4000 | 1.1 part |
| Hydroxypropyl methylcellulose | 0.9 part |
| Low-substituted hydroxypropyl cellulose | 0.8 part |
| Polyoxyethylene sorbitan monoleate | 0.12 part |
| Sucrose | 5 parts |
| Ethylmaltol | 0.7 part |
| The ethanol solution of volume fraction 60% | 8 parts |
Make 1000 bags
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, when being leached respectively
Between determine, sample stability test and mouthfeel market survey, leaching timing, to show that this product leaches speed fast, multiple
Sample leaches the time and is respectively less than 30 seconds, and stability test result shows to accelerate June sample quality to stablize, long-term 36 months
Steady quality, therefore this product term of validity at least 36 months, taste investigation shows that this product is delicious, easily by most of patient institute
Receive.
Embodiment 4-6：A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, by following weight
Supplementary material be prepared, preparation method is with embodiment 1：
Preparation process：It is obtained according to the preparation technology of embodiment 1.Embodiment 4,5,6 is pressed into the test method of embodiment 1,
Carry out leaching timing, sample stability test and mouthfeel market survey respectively, obtained by embodiment 4,5,6
Sample leaches timing, and to show that this product leaches speed fast, and multiple samples leach the time and are respectively less than 30 seconds, embodiment 4,5,
Sample stability result of the test obtained by 6 shows to accelerate June sample quality to stablize, long-term 36 months steady qualities, therefore
The sample term of validity obtained by embodiment 4,5,6 at least 36 months, the taste of embodiment 4,5,6 investigation shows this product
It is delicious, easily received by most of patient.
Claims (3)
1. a kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, it is characterised in that it is by under
The supplementary material and following steps of row weight proportion is obtained：(S) about 1 part of the oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, sweet
About 0.6～1.0 part of alcohol of dew, about 0.5～1.3 part of microcrystalline cellulose, about 0.7～1.2 part of sodium carboxymethylcellulose, lactose about 0.8～1.2
Part, about 0.07～0.13 part of magnesium stearate, about 0.8～1.3 part of Macrogol 4000, Hydroxypropyl methylcellulose about 0.7～1.2
Part, about 0.5～1.2 part of low-substituted hydroxypropyl cellulose, about 0.11～0.15 part of polyoxyethylene sorbitan monoleate, about 2～6 parts of sucrose,
About 0.5～0.9 part of ethylmaltol, about 5～12 parts of the ethanol solution that volume fraction is 50%～70%；Take (S) -4- hydroxyls
- 2 oxo-1-pyrrolidine ethanamides, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low substituted hydroxy-propyl
Cellulose, polyoxyethylene sorbitan monoleate, sucrose, ethylmaltol are placed in Universalpulverizer, are crushed and are placed in after 100 mesh sieves
In wet granulator, ethanol solution is added, start granulator (installing 24 mesh nylon mesh), start granulation；By wet granular
In input air dry oven, setting temperature 50 C～60 DEG C drying time is 120min～150min so that particle water content
≤ 3% (weight/mass percentage composition)；The Macrogol 4000 and Hydroxypropyl methylcellulose of recipe quantity are taken, is added water and is made quality point
Number is 6%～9% coating solution, standby；Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension flow is allowed to
Change, bed temperature is 40～50 DEG C；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, spouting velocity is set
50～60rpm, atomizing pressure is 0.8～1.0bar, continues air intake and is dried, after solution continues to heat 10～15 minutes after having sprayed
Stop heating, cooling discharging obtains final product coated granule.
2. the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 as claimed in claim 1, it is characterised in that it
It is to be obtained by the supplementary material and following steps of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls,
0.7～0.9 part of mannitol, 0.6～1.0 part of microcrystalline cellulose, 0.8～1.1 part of sodium carboxymethylcellulose, 0.9～1.2 part of lactose,
0.08～0.11 part of magnesium stearate, 0.9～1.2 part of Macrogol 4000,0.8～1.1 part of Hydroxypropyl methylcellulose, low replacement hydroxyl
0.6～1.0 part of propyl cellulose, 0.11～0.13 part of polyoxyethylene sorbitan monoleate, 3～6 parts of sucrose, 0.6～0.8 part of ethylmaltol,
Volume fraction is 50%～70% 7～10 parts of ethanol solution；Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, sweet
Dew alcohol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sugarcane
Sugar, ethylmaltol are placed in Universalpulverizer, are crushed and are placed in after 100 mesh sieves in wet granulator, add ethanol molten
Liquid, starts granulator (installing 24 mesh nylon mesh), starts granulation；Wet granular is put in air dry oven, temperature is set
50 DEG C～60 DEG C drying times of degree are 120min～150min so that particle water content≤3% (weight/mass percentage composition)；Take
The Macrogol 4000 and Hydroxypropyl methylcellulose of recipe quantity, add water the coating solution for making that mass fraction is 6%～9%, standby；
Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50 DEG C；By coating solution
Fluid bed is continuously added to by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity is set, atomizing pressure is
0.8～1.0bar, continues air intake and is dried, and solution has sprayed and stopped heating after rear continuation is heated 10～15 minutes, cooling discharging,
Obtain final product coated granule.
3. a kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste as claimed in claim 1 or 2
Preparation method, it is characterised in that it is obtained as follows：
A. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, filler, the flavoring of recipe quantity
Agent, disintegrant are placed in Universalpulverizer, crush 100 mesh sieves, standby；
B. pelletize：Gained mixed-powder after pre-treatment is taken, in being placed in wet granulator, adhesive is added, starts granulator
(installing 24 mesh nylon mesh), starts granulation；
C. it is dried：It is by temperature 50 C～60 DEG C drying time in wet granular input air dry oven, is arranged
120min～150min so that particle water content≤3% (weight/mass percentage composition)；
D. coating：
The configuration of D (1) coating solution：The coating material of recipe quantity is taken, add water the coating for making that quality volume fraction is 6%～9%
Liquid, it is standby；
D (2) coating process：Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is
40～50 DEG C；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity is set,
Atomizing pressure is 0.8～1.0bar, continues air intake and is dried, and solution stops heating after continuing to heat 10～15 minutes after having sprayed,
Cooling discharging, obtains final product coated granule；
E. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, is sieved whole grain with 24 mesh nylon mesh, control environment
Below 25 DEG C of temperature, relative humidity is below 50%；
F. always mix：Lubricant was crushed into 100 mesh sieves, in adding the particle after whole grain, was mixed with three-dimensional motion mixer
10min～20min；
G. interior bag：Packed with particles packing machine, set packing specification as 1g/ bags, below 25 DEG C of environment temperature of control,
Below relative humidity 50%, obtain final product.
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| CN201510705315.0A CN106619528A (en) | 2015-10-27 | 2015-10-27 | (S)-4-hydroxy-2oxo-1-pyrrolidine acetamide particle with good mouthfeel and preparation method thereof |
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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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2015
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| 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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