CN107510666A - It is a kind of leach it is fast（S）Oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 and preparation method thereof - Google Patents
It is a kind of leach it is fast（S）Oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 and preparation method thereof Download PDFInfo
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- CN107510666A CN107510666A CN201610428250.4A CN201610428250A CN107510666A CN 107510666 A CN107510666 A CN 107510666A CN 201610428250 A CN201610428250 A CN 201610428250A CN 107510666 A CN107510666 A CN 107510666A
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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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, 0.6 ~ 1.3 part of L cysteines, 1.4 ~ 1.9 parts of mannitol, 0.6 ~ 1.3 part of microcrystalline cellulose, 0.8 ~ 1.5 part of sodium carboxymethylcellulose, 0.5 ~ 1.1 part of lactose, 0.13 ~ 0.19 part of magnesium stearate, 1.2 ~ 1.7 parts of Macrogol 4000, 0.9 ~ 1.5 part of hydroxypropyl methylcellulose, 1.0 ~ 1.5 parts of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.11 part of polyoxyethylene sorbitan monoleate, 0.7 ~ 1.2 part of sorbierite, volume fraction is 50% ~ 70% 12 ~ 18 parts of ethanol solution；It is produced by the present invention（S）The pyrrolidine acetamide particulate production impurity incrementss of 4 hydroxyl, 2 oxo 1 are smaller, are only 0.04%, content uniformity is good, the content RSD of multiple points is less than 2%, it is fast to leach speed, the time is all leached less than 30 seconds, it is good to store process stability, 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 to leach the fast oxo -1- pyrroles of (S) -4- hydroxyls -2
Cough up alkyl acetamide particle and preparation method thereof.
Background technology
It is a kind of new medicine for central nervous system for promoting study, strengthening memory that cereboactive drug, which is also known as cereboactive drug,.
Nootropics requires that selection index system in cerebral cortex, has selection activation, protection and promotes damaged nerve cell functional rehabilitation
Feature.Different from other neurologic agents be a little their above-mentioned effect not by network or olfactory bulb, but directly
Act on cortex.Behavior is neither influenceed, also without calm excitation, therefore such medicine has caused the extensive concern of people and emerging
Interest, it is also growing day by day to the demand of such medicine.
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 WO9306826A, 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 be primarily present preparation process impurity increase it is larger,
Main ingredient is not easy to be well mixed, content lack of homogeneity, and preparation process particle bisque is more, and particle diameter is difficult to control, and stores process stabilization
Property is poor, and particle hygroscopicity is strong, connecting block easy to stick, and shelf life is short, and it is slow that particle leaches speed, etc. technical problem.
The content of the invention
It is an object of the invention to provide one kind to leach soon, the good OXo-1-pyrrolidine second of (S) -4- hydroxyls -2 of stability
Acid amides particle.
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 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 made；Wherein described filler is starch, lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, Portugal
One or more in grape sugar, sodium carboxymethylcellulose, sorbierite, Cys；The flavouring be sucrose, maltose,
Ethylmaltol, Sucralose, stevia rebaudianum are sweet, the one or more in sorbierite, mannitol, glucose, aspartame；It is described viscous
Mixture is the one or more in water, ethanol, sucrose, starch slurry, dextrin, carboxymethyl cellulose, polyvinylpyrrolidone；It is described
Lubricant is talcum powder, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, lauryl sodium sulfate, superfine silica gel powder, oxidation
One or more in magnesium, paraffin；The disintegrant be low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sodium carboxymethyl starch,
One or more in dried starch；The coating material is Macrogol 4000, Macrogol 6000, hydroxypropyl cellulose, hydroxyl
One or more in third methylcellulose, 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 main ingredient is well mixed with auxiliary material, and content uniformity is good, and product stored
Cheng Buyi moisture absorptions, it is good to be not easy adhesion caking, stability, and shelf life length, it is fast that particle leaches speed；It is above-mentioned to leach fast (S) -4- hydroxyls
The oxo-1-pyrrolidine ethanamide particle of base -2, it is characterised in that it is made by the supplementary material of following weight proportion：(S)-4-
1 part of the oxo-1-pyrrolidine ethanamide of hydroxyl -2,0.6~1.3 part of Cys, 1.4~1.9 parts of mannitol, microcrystalline cellulose
0.6~1.3 part, 0.8~1.5 part of sodium carboxymethylcellulose, 0.5~1.1 part of lactose, 0.13~0.19 part of magnesium stearate, poly- second
4,000 1.2~1.7 parts of glycol, 0.9~1.5 part of hydroxypropyl methylcellulose, 1.0~1.5 parts of low-substituted hydroxypropyl cellulose, poly- mountain
80 0.05~0.11 part of pear ester, 0.7~1.2 part of sorbierite, 12~18 parts of the ethanol solution that volume fraction is 50%~70%；
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, the polyoxyethylene sorbitan monoleate of recipe quantity is taken to be dissolved in ethanol solution, it is standby；Separately
Take Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, the low substituted hydroxy-propyl fiber of recipe quantity
Element, sorbierite are placed in Universalpulverizer, are placed in after crushed 100 mesh sieves in wet granulator, and it is previously processed good to add
(S) the oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2, start granulator (24 mesh nylon mesh of installation), start to pelletize；
Wet granular is put into 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, adds water that quality point is made
Number is 6%~9% coating solution, standby；Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed
Temperature is 40~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, setting spouting velocity 50~
60rpm, atomizing pressure are 0.8~1.0bar, continue air intake and dry, and solution stops adding after continuing heating after having sprayed 10~15 minutes
Heat, cooling discharging, produce coated granule.
Further, in order that the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 drug content evenly,
Leach speed faster；The above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, it is characterised in that it is by following heavy
The supplementary material of amount proportioning is made：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, 0.8~1.1 part of Cys, sweet
Reveal 1.6~1.8 parts of alcohol, 0.8~1.1 part of microcrystalline cellulose, 1.1~1.3 parts of sodium carboxymethylcellulose, 0.8~1.0 part of lactose,
0.15~0.18 part of magnesium stearate, 1.3~1.6 parts of Macrogol 4000,1.1~1.3 parts of hydroxypropyl methylcellulose, low substitution hydroxyl
1.2~1.4 parts of propyl cellulose, 0.07~0.10 part of polyoxyethylene sorbitan monoleate, 0.8~1.1 part of sorbierite, volume fraction 50%
13~16 parts of~70% ethanol solution；The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, polyoxyethylene sorbitan monoleate is taken to be dissolved in second
It is standby in alcoholic solution；Separately take Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl
Base cellulose, sorbierite are placed in Universalpulverizer, are placed in after crushed 100 mesh sieves in wet granulator, are added previously processed
The good oxo-1-pyrrolidine ethanamide ethanol solution of (S) -4- hydroxyls -2, start granulator (24 mesh nylon mesh of installation), start to make
Grain；Wet granular is put into air dry oven, setting temperature 50 C~60 DEG C drying time is 120min~150min so that
Grain water content≤3% (weight/mass percentage composition)；The Macrogol 4000 and hydroxypropyl methylcellulose of recipe quantity are taken, adds water that quality is made
Fraction is 6%~9% coating solution, standby；Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization,
Bed temperature is 40~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, setting spouting velocity 50~
60rpm, atomizing pressure are 0.8~1.0bar, continue air intake and dry, and solution stops adding after continuing heating after having sprayed 10~15 minutes
Heat, cooling discharging, produce coated granule.
A kind of preparation method for leaching the fast oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, 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 and polyoxyethylene sorbitan monoleate of recipe quantity
It is dissolved in the adhesive of recipe quantity, it is standby；Separately take filler, flavouring, disintegrant to be placed in Universalpulverizer, crushed
100 mesh sieves, it is standby；
2. granulation：Take gained auxiliary material mixed-powder after pre-treatment, be placed in wet granulator, add processed good (S)-
The oxo-1-pyrrolidine ethanamide solution of 4- hydroxyls -2, start granulator (24 mesh nylon mesh of installation), start to pelletize；
3. dry：By wet granular put into air dry oven in, settings temperature 50 C~60 DEG C drying time for 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, adds water that the bag that quality volume fraction is 6%~9% is made
Clothing 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 24 mesh nylon mesh sieving whole grain, controls environment
Below 25 DEG C of temperature, 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 (S) -4- hydroxyls -2 produced by the present invention compared with
It is small, be only 0.04%, content uniformity is good, and the content RSD of multiple points is less than 2%, and it is fast to leach speed, all leaches the time and is less than
30 seconds, storage process stability was good, and product is not easy moisture absorption caking, and 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 oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 leached, 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 | 1.6 part |
| Microcrystalline cellulose | 0.8 part |
| Sodium carboxymethylcellulose | 1.1 part |
| Lactose | 0.8 part |
| Magnesium stearate | 0.15 part |
| Macrogol 4000 | 1.3 part |
| Hydroxypropyl methylcellulose | 1.1 part |
| Low-substituted hydroxypropyl cellulose | 1.2 part |
| Polyoxyethylene sorbitan monoleate | 0.07 part |
| Sorbierite | 0.8 part |
| The ethanol solution of volume fraction 50% | 13 parts |
It is made 1000 bags
Preparation process：
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 ethanol；Separately take Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low substitution carboxylic
Methylcellulose, sorbierite are placed in Universalpulverizer, crushed 100 mesh sieves, standby；
2. granulation：Gained mixed accessories powder after pre-treatment is taken, is placed in wet granulator, it is previously processed good to add
(S) the oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2, start granulator (24 mesh nylon mesh of installation), start to pelletize；
3. dry：By wet granular put into air dry oven in, settings temperature 50 C~60 DEG C drying time for 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, adds water that mass fraction is made
It is standby for 6%~9% 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 24 mesh nylon mesh sieving whole grain, controls environment
Below 25 DEG C of temperature, relative humidity is below 50%；
It is 6. total mixed：Magnesium stearate was crushed into 100 mesh sieves, adds in the particle after whole grain, is mixed with three-dimensional motion mixer
Close 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：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 two：Leach timing
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) | 27 seconds | 23 seconds | 21 seconds | 28 seconds | 25 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 23 seconds | 26 seconds | 24 seconds | 23 seconds | 26 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 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 0.04%, hence it is evident that
Better than control sample.
Experiment four：The present invention is a kind of to leach the fast oxo-1-pyrrolidine ethanamide granule stability of (S) -4- hydroxyls -2 reality
Test
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 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：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.
Embodiment 2
It is a kind of to leach the fast oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, it 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 | 1.8 part |
| Microcrystalline cellulose | 1.1 part |
| Sodium carboxymethylcellulose | 1.3 part |
| Lactose | 1.0 part |
| Magnesium stearate | 0.18 part |
| Macrogol 4000 | 1.6 part |
| Hydroxypropyl methylcellulose | 1.3 part |
| Low-substituted hydroxypropyl cellulose | 1.4 part |
| Polyoxyethylene sorbitan monoleate | 0.10 part |
| Sorbierite | 1.1 part |
| The ethanol solution of volume fraction 70% | 16 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, content is uniform
Property result of the test show that this product content uniformity is good, content RSD of each point particle is less than 1% after it is total mixed, leaches timing
It is fast to show that this product leaches speed, multiple samples leach the time and are respectively less than 30 seconds, and product prescription is to the increased shadow of preparation process impurity
Ring result of the test and show that this product preparation process impurity incrementss are smaller, relevant material only increases by 0.02% in preparation process, stabilization
Property result of the test show to accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 3
It is a kind of to leach the fast oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, it 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 | 1.7 part |
| Microcrystalline cellulose | 1.0 part |
| Sodium carboxymethylcellulose | 1.2 part |
| Lactose | 0.9 part |
| Magnesium stearate | 0.16 part |
| Macrogol 4000 | 1.4 part |
| Hydroxypropyl methylcellulose | 1.2 part |
| Low-substituted hydroxypropyl cellulose | 1.3 part |
| Polyoxyethylene sorbitan monoleate | 0.09 part |
| Sorbierite | 0.9 part |
| The ethanol solution of volume fraction 60% | 15 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, content is uniform
Property result of the test show that this product content uniformity is good, content RSD of each point particle is less than 2% after it is total mixed, leaches timing
It is fast to show that this product leaches speed, multiple samples leach the time and are respectively less than 30 seconds, and product prescription is to the increased shadow of preparation process impurity
Ring result of the test and show that this product preparation process impurity incrementss are smaller, relevant material only increases by 0.04% in preparation process, stabilization
Property result of the test show to accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 4-6：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 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 sample size uniformity test results show that this product content uniformity is good, and the content RSD of its total mixed rear each point particle is respectively less than
2%, embodiment 4,5,6 leaches timing, and to show that this product leaches speed fast, and multiple samples leach the time and are respectively less than 30 seconds, implement
The product prescription of example 4,5,6 it is increased on preparation process impurity influence result of the test show this product preparation process impurity incrementss compared with
Small, relevant material only increases by 0.02%, 0.04%, 0.03% respectively in preparation process, the experiment of the sample stability of embodiment 4,5,6
As a result show to accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Claims (3)
1. it is a kind of leach it is fast（S）The oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, it is characterised in that it is by following heavy
The supplementary material and preparation method for measuring proportioning are made：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, Cys 0.6
~ 1.3 parts, 1.4 ~ 1.9 parts of mannitol, 0.6 ~ 1.3 part of microcrystalline cellulose, 0.8 ~ 1.5 part of sodium carboxymethylcellulose, lactose 0.5 ~
1.1 parts, 0.13 ~ 0.19 part of magnesium stearate, 1.2 ~ 1.7 parts of Macrogol 4000,0.9 ~ 1.5 part of hydroxypropyl methylcellulose, low substitution
1.0 ~ 1.5 parts of hydroxypropyl cellulose, 0.05 ~ 0.11 part of polyoxyethylene sorbitan monoleate, 0.7 ~ 1.2 part of sorbierite, volume fraction be 50% ~
12 ~ 18 parts of 70% ethanol solution；Take recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, polyoxyethylene sorbitan monoleate dissolving
It is standby in ethanol solution；Another Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, the breast for taking recipe quantity
Sugar, low-substituted hydroxypropyl cellulose, sorbierite are placed in Universalpulverizer, are placed in after crushed 100 mesh sieves in wet granulator,
It is previously processed good to add（S）The oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2, start granulator（24 mesh Buddhist nuns are installed
Dragon sieve）, start to pelletize；By wet granular put into air dry oven in, settings temperature 50 C ~ 60 DEG C drying time for 120min ~
150min so that particle water content≤3%（Weight/mass percentage composition）；The Macrogol 4000 and hydroxypropyl methylcellulose of recipe quantity are taken,
Add water that the coating solution that mass fraction is 6% ~ 9% is made, it is 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 stops after continuing heating after having sprayed 10 ~ 15 minutes
Only heat, cooling discharging, produce coated granule.
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 and preparation method of following weight proportion are made：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, the Guangs of L- half
0.8 ~ 1.1 part of propylhomoserin, 1.6 ~ 1.8 parts of mannitol, 0.8 ~ 1.1 part of microcrystalline cellulose, 1.1 ~ 1.3 parts of sodium carboxymethylcellulose, breast
Sugar 0.8 ~ 1.0 part, 0.15 ~ 0.18 part of magnesium stearate, 1.3 ~ 1.6 parts of Macrogol 4000,1.1 ~ 1.3 parts of hydroxypropyl methylcellulose,
1.2 ~ 1.4 parts of low-substituted hydroxypropyl cellulose, 0.07 ~ 0.10 part of polyoxyethylene sorbitan monoleate, 0.8 ~ 1.1 part of sorbierite, volume fraction are
13 ~ 16 parts of 50% ~ 70% ethanol solution；Take（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, polyoxyethylene sorbitan monoleate are dissolved in second
It is standby in alcoholic solution；Separately take Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl
Base cellulose, sorbierite are placed in Universalpulverizer, are placed in after crushed 100 mesh sieves in wet granulator, are added previously processed
Alright（S）The oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2, start granulator（24 mesh nylon mesh are installed）, start to make
Grain；Wet granular is put into 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, adds water that quality point is made
Number is 6% ~ 9% coating solution, standby；Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature
For 40 ~ 50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, mist
Change pressure is 0.8 ~ 1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10 ~ 15 minutes, cools down out
Material, produces coated granule.
3. it is as claimed in claim 1 or 2 it is a kind of leach it is fast（S）The system of the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2
Preparation Method, it is characterised in that it is obtained as follows：
A. supplementary material pre-treatment：Take recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 and polyoxyethylene sorbitan monoleate dissolving
It is standby in the adhesive of recipe quantity；Separately take filler, flavouring, disintegrant to be placed in Universalpulverizer, crushed 100 mesh
Sieve, it is standby；
B. pelletize：Gained auxiliary material mixed-powder after pre-treatment is taken, is placed in wet granulator, it is processed good to add（S）- 4- hydroxyls
The oxo-1-pyrrolidine ethanamide solution of base -2, start granulator（24 mesh nylon mesh are installed）, start to pelletize；
C. dry：Wet granular is put into 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）；
D. it is coated：
The configuration of D (1) coating solutions：The coating material of recipe quantity is taken, adds water that the coating solution that quality volume fraction is 6% ~ 9% is made, it is standby
With；
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 24 mesh nylon mesh sieving whole grain, controls environment temperature
Less than 25 DEG C, 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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|---|---|---|---|
| CN201610428250.4A CN107510666A (en) | 2016-06-15 | 2016-06-15 | It is a kind of leach it is fast（S）Oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610428250.4A CN107510666A (en) | 2016-06-15 | 2016-06-15 | It is a kind of leach it is fast（S）Oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN107510666A true CN107510666A (en) | 2017-12-26 |
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Citations (2)
| 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 |
| 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 |
-
2016
- 2016-06-15 CN CN201610428250.4A patent/CN107510666A/en not_active Withdrawn
Patent Citations (2)
| 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 |
| 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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Application publication date: 20171226 |