CN107510682A - It is a kind of（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof - Google Patents
It is a kind of（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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Abstract
It is a kind of（S）The pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1, it is made by the supplementary material of following weight proportion：（S）1 part of 4 hydroxyl, 2 oxo, 1 pyrrolidine acetamide, 1.3 ~ 1.8 parts of mannitol, 0.9 ~ 1.5 part of microcrystalline cellulose, 0.6 ~ 1.2 part of sodium carboxymethylcellulose, 0.5 ~ 1.1 part of lactose, 0.08 ~ 0.15 part of magnesium stearate, 0.5 ~ 1.2 part of Macrogol 4000,0.8 ~ 1.6 part of hydroxypropyl methylcellulose, 0.5 ~ 1.0 part of low-substituted hydroxypropyl cellulose, 0.03 ~ 0.09 part of polyoxyethylene sorbitan monoleate, 0.3 ~ 0.9 part of honey, 2 ~ 8 parts of the ethanol solution that volume fraction is 50% ~ 70%；According to produced by the present invention（S）The pyrrolidine acetamide particle pelletization of 4 hydroxyl, 2 oxo 1 will not adhesion screen cloth, be easy to pelletize, product, which has, leaches that speed is fast, and particle all leached the time not over 30 seconds, 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 the OXo-1-pyrrolidine acetyl of one kind (S) -4- hydroxyls -2
Amine particle and preparation method thereof.
Background technology
Levo-oxiracetam chemical name is：S- (-) -4- hydroxyl -2- oxo-pyrrolidine-N- acetamides, are white micro-crystals
Sprills, 135~136 DEG C of fusing point, -36 ° of optical activity (C=1.00inwater), the OXo-1-pyrrolidine second of (S) -4- hydroxyls -2
The dissolubility of acid amides is substantially better than raceme.Chemical structural formula is shown below：
The medicine listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Parenteral solution, 1g/
5ml.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.Ye Lei
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is mentioned to alcoholism Deng in Publication No. CN 103735545A patents
The promoting wakening of caused stupor is obvious, and dextrorotation Oxiracetam does not act on substantially, the OXo-1-pyrrolidine second of (S) -4- hydroxyls -2
The awake effect of the above-mentioned rush of acid amides is 2 times of racemization Oxiracetam；(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 to wound,
The promoting wakening of stupor is notable caused by anesthesia.Open peak etc. and (S) -4- is disclosed in the A of Publication No. CN 103599101 patent
The oxo-1-pyrrolidine ethanamide of hydroxyl -2 is to traumatic brain injury learning and memory in rats cognitive function caused by hydraulic pressure and freely falling body
Obstacle improves significantly, and its drug effect is far above dextrorotation Oxiracetam.And oxo-the 1- of 200mg/kg (S) -4- hydroxyls -2
Pyrrolidine acetamide is suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：(S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single dose intravenous is noted
Penetrate the master for giving the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 in blood plasma after left-handed and 2 multiple doses racemization Oxiracetams
Want the equal no significant difference of pharmacokinetic parameters.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level,
(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 and Oxiracetam are to animal subject or the toxicity no significant difference of cell.On
State preclinical result of study to show, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is to play drug effect in Oxiracetam body
Main active, be used alone this product can reduce Clinical practice dosage, reduce potential toxicity.
The existing oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 is primarily present the easy adhesion screen cloth of pelletization, system
Grain is difficult, and product storage process stability is poor, and particle hygroscopicity is strong, and connecting block easy to stick, shelf life is short, and it is slow that particle leaches speed
Etc. technical problem.
The content of the invention
It is an object of the invention to provide it is a kind of easily prepare, leach speed is fast, stability the is good oxo of (S)-4- hydroxyls-2-
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：
The oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, it is with the oxo -1- pyrroles of (S) -4- hydroxyls -2
Alkyl acetamide is raw material, adds a certain amount of filler, flavouring, adhesive, lubricant, disintegrant, coating material and is made；
Wherein described filler is starch, lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose, carboxylic first
One or more in base sodium cellulosate；The flavouring be sucrose, maltose, ethylmaltol, Sucralose, stevia rebaudianum it is sweet,
One or more in sorbierite, mannitol, glucose, aspartame；Described adhesive be water, ethanol, sucrose, starch slurry,
One or more in dextrin, carboxymethyl cellulose, polyvinylpyrrolidone, honey；The lubricant is talcum powder, stearic acid
One kind or more in magnesium, polyethylene glycol, stearic acid, calcium stearate, lauryl sodium sulfate, superfine silica gel powder, magnesia, paraffin
Kind；The disintegrant is low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sodium carboxymethyl starch, one kind in dried starch or more
Kind；The coating material is Macrogol 4000, Macrogol 6000, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene second
One or more in aldehyde diethylamine ethyl 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
Alkyl acetamide particle pelletization is coughed up to be easy to pelletize, will not adhesion screen cloth, product is not easy moisture absorption, is not easy adhesion caking, stability
It is good, shelf life length, it is fast to leach speed；The above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, it is characterised in that it
It is to be made according to the following steps by the supplementary material of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, sweet
Reveal 1.3~1.8 parts of alcohol, 0.9~1.5 part of microcrystalline cellulose, 0.6~1.2 part of sodium carboxymethylcellulose, 0.5~1.1 part of lactose,
0.08~0.15 part of magnesium stearate, 0.5~1.2 part of Macrogol 4000,0.8~1.6 part of hydroxypropyl methylcellulose, low substitution hydroxyl
0.5~1.0 part of propyl cellulose, 0.03~0.09 part of polyoxyethylene sorbitan monoleate, 0.3~0.9 part of honey, volume fraction be 50%~
2~8 parts of 70% ethanol solution；The honey of recipe quantity is taken, is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stirring
Uniformly, 100~105 DEG C are heated to, is incubated 20~25 minutes, is taken out, with 80 mesh screens, is taken filtrate, prescription is added after letting cool
The ethanol of amount, stirring and dissolving are standby；Separately take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, mannitol, microcrystalline cellulose,
Sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose are placed in Universalpulverizer, crushed be placed in after 100 mesh sieves it is wet
In method granulator, previously processed good honey ethanol solution and polyoxyethylene sorbitan monoleate are added, starts granulator (24 mesh nylon of installation
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)；Macrogol 4000, the 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, 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 after clock, cooling discharging, produce coated granule.
Further, in order to which further speed up the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 leaches speed,
Improve granule stability, Shelf-life；The above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, it is characterised in that
It is made by the supplementary material of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, mannitol 1.5~
1.7 parts, 1.1~1.3 parts of microcrystalline cellulose, 0.7~1.0 part of sodium carboxymethylcellulose, 0.6~0.9 part of lactose, magnesium stearate
0.11~0.13 part, 0.7~1.1 part of Macrogol 4000,0.9~1.3 part of hydroxypropyl methylcellulose, low substituted hydroxy-propyl fiber
0.7~0.9 part of element, 0.05~0.08 part of polyoxyethylene sorbitan monoleate, 0.5~0.8 part of honey, the second that volume fraction is 50%~70%
4~7 parts of alcoholic solution；The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs, add
Heat is incubated 20~25 minutes to 100~105 DEG C, takes out, with 80 mesh screens, takes filtrate, and the second of recipe quantity is added after letting cool
Alcohol, stirring and dissolving are standby；Separately take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, mannitol, microcrystalline cellulose, carboxymethyl
Sodium cellulosate, lactose, low-substituted hydroxypropyl cellulose are placed in Universalpulverizer, and wet granulation is placed in after crushed 100 mesh sieves
In machine, previously processed good honey ethanol solution and polyoxyethylene sorbitan monoleate are added, starts granulator (24 mesh nylon mesh of installation), starts
Granulation；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)；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that matter is made
The coating solution that fraction is 6%~9% is measured, it is standby；Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension flow
Change, 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.
The preparation method of the oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, it is characterised in that it is by such as
Made from lower step：
1. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs
Mix uniformly, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool at addition
The ethanol just measured, stirring and dissolving, is produced；
2. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, filler, flavoring of recipe quantity
Agent, disintegrant are placed in Universalpulverizer, crushed 100 mesh sieves, standby；
3. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive and polysorbate
80, start granulator (24 mesh nylon mesh of installation), start to pelletize；
4. 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)；
5. coating：
(1) configuration of coating solution：The coating material of recipe quantity is taken, adds water that the coating that mass fraction is 6%~9% is made
Liquid, it is standby；
(2) coating process：Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature 40
~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50~60rpm of spouting velocity, atomization
Pressure is 0.8~1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10~15 minutes, cools down out
Material, produces coated granule；
6. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 24 mesh nylon mesh sieving whole grain, controls environment
Below 25 DEG C of temperature, relative humidity is below 50%；
It is 7. total mixed：Lubricant be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer
10min~20min；
Wrapped in 8.：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature,
Below relative humidity 50%, produce.
The present invention has following beneficial effect：
The oxo-1-pyrrolidine ethanamide particle pelletization of (S) -4- hydroxyls -2 produced by the present invention will not adhesion screen cloth,
It is easy to pelletize, product, which has, leaches that speed is fast, and particle all leached the time not over 30 seconds, and storage process stability is good, production
Product are 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
The oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, is made according to the following steps：
| Composition | Dosage |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Mannitol | 1.5 part |
| Microcrystalline cellulose | 1.1 part |
| Sodium carboxymethylcellulose | 0.7 part |
| Lactose | 0.6 part |
| Magnesium stearate | 0.11 part |
| Macrogol 4000 | 0.7 part |
| Hydroxypropyl methylcellulose | 0.9 part |
| Low-substituted hydroxypropyl cellulose | 0.7 part |
| Polyoxyethylene sorbitan monoleate | 0.05 part |
| Honey | 0.5 part |
| The ethanol of volume fraction 50% | 4 parts |
It is made 1000 bags
Preparation process：
1. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs
Mix uniformly, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool at addition
The ethanol just measured, stirring and dissolving, is produced；
2. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, filler, flavoring of recipe quantity
Agent, disintegrant are placed in Universalpulverizer, crushed 100 mesh sieves, standby；
3. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive and polysorbate
80, start granulator (24 mesh nylon mesh of installation), start to pelletize；
4. 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)；
5. 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；
6. 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 7. total mixed：Lubricant be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer
10min~20min；
Wrapped in 8.：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature,
Below relative humidity 50%, produce.
In pelletization, observation understands that the pelletization of embodiment 1 does not find the situation of adhesion screen cloth, and product is easy to make
Grain.
Experiment one：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) | 21 seconds | 28 seconds | 23 seconds | 22 seconds | 25 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 24 seconds | 27 seconds | 20 seconds | 21 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 two：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.
Embodiment 2
The oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, is made according to the following steps：
| Composition | Dosage |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Mannitol | 1.7 part |
| Microcrystalline cellulose | 1.3 part |
| Sodium carboxymethylcellulose | 1.0 part |
| Lactose | 0.9 part |
| Magnesium stearate | 0.13 part |
| Macrogol 4000 | 1.1 part |
| Hydroxypropyl methylcellulose | 1.3 part |
| Low-substituted hydroxypropyl cellulose | 0.9 part |
| Polyoxyethylene sorbitan monoleate | 0.08 part |
| Honey | 0.8 part |
| The ethanol solution of volume fraction 70% | 7 parts |
It is made 1000 bags
Preparation process：It is made according to the preparation technology of embodiment 1.Observation product pelletization does not find showing for adhesion screen cloth
As product is easy to pelletize.Tested by the test method of embodiment 1, leaching timing, to show that this product leaches speed fast, more
Individual sample leaches the time and is respectively less than 30 seconds, and stability test result shows to accelerate June sample quality stable, long-term 24 months quality
It is stable, therefore this product term of validity at least 24 months.
Embodiment 3
The oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, is made according to the following steps：
| Composition | Dosage |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 1 part |
| Mannitol | 1.6 part |
| Microcrystalline cellulose | 1.2 part |
| Sodium carboxymethylcellulose | 0.9 part |
| Lactose | 0.7 part |
| Magnesium stearate | 0.12 part |
| Macrogol 4000 | 0.9 part |
| Hydroxypropyl methylcellulose | 1.1 part |
| Low-substituted hydroxypropyl cellulose | 0.8 part |
| Polyoxyethylene sorbitan monoleate | 0.07 part |
| Honey | 0.7 part |
| The ethanol solution of volume fraction 70% | 6 parts |
It is made 1000 bags
Preparation process：It is made according to the preparation technology of embodiment 1.Observation product pelletization does not find showing for adhesion screen cloth
As product is easy to pelletize.Tested by the test method of embodiment 1, leaching timing, to show that this product leaches speed fast, more
Individual sample leaches the time and is respectively less than 30 seconds, and stability test result shows to accelerate June sample quality stable, long-term 24 months quality
It is stable, therefore this product term of validity at least 24 months.
Embodiment 4-6：The oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, by the supplementary material of following weight
It is prepared, preparation method is the same as embodiment 1：
Preparation process：It is made according to the preparation technology of embodiment 1.The observation product pelletization of embodiment 4,5,6 is not found
The phenomenon of adhesion screen cloth, the product of embodiment 4,5,6 are easy to pelletize.Finished product obtained by embodiment 4,5,6 presses the examination of embodiment 1
Proved recipe method is tested, and the sample obtained by embodiment 4,5,6 leaches timing fast, the multiple samples that show that this product leaches speed
Leaching the time is respectively less than 30 seconds, and the sample stability result of the test obtained by embodiment 4,5,6 shows to accelerate June sample quality steady
It is fixed, long-term 24 months steady qualities, therefore the sample term of validity obtained by embodiment 4,5,6 at least 24 months.
Claims (3)
- It is 1. a kind of（S）The oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, it is characterised in that it is by following weight proportion Supplementary material is made according to the following steps：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, 1.3 ~ 1.8 parts of mannitol, crystallite It is 0.9 ~ 1.5 part of cellulose, 0.6 ~ 1.2 part of sodium carboxymethylcellulose, 0.5 ~ 1.1 part of lactose, 0.08 ~ 0.15 part of magnesium stearate, poly- 4,000 0.5 ~ 1.2 parts of ethylene glycol, 0.8 ~ 1.6 part of hydroxypropyl methylcellulose, 0.5 ~ 1.0 part of low-substituted hydroxypropyl cellulose, poly- sorb 80 0.03 ~ 0.09 part of ester, 0.3 ~ 0.9 part of honey, 2 ~ 8 parts of the ethanol solution that volume fraction is 50% ~ 70%；Take the honeybee of recipe quantity Honey, it is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stir, be heated to 100 ~ 105 DEG C, is incubated 20 ~ 25 points Clock, take out, with 80 mesh screens, take filtrate, the ethanol of recipe quantity is added after letting cool, stirring and dissolving is standby；Separately take（S）- 4- hydroxyls The oxo-1-pyrrolidine ethanamide of base -2, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low substituted hydroxy-propyl are fine Dimension element is placed in Universalpulverizer, is placed in after crushed 100 mesh sieves in wet granulator, adds previously processed good honey ethanol Solution and polyoxyethylene sorbitan monoleate, start granulator（24 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into air dry oven In, setting temperature 50 C ~ 60 DEG C drying time is 120min ~ 150min so that particle water content≤3%（Weight/mass percentage composition）； Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that the coating solution that mass fraction is 6% ~ 9% is made, it is standby；Will be upper State in dry particl input fluid bed, be passed through hot-air, be allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Coating solution is passed through into fluid bed Nozzle atomization be continuously added to fluid bed, set 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, is persistently entered air-dried Dry, solution stops heating after continuing heating after having sprayed 10 ~ 15 minutes, cooling discharging, produces 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 of following weight proportion is made：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, 1.5 ~ 1.7 parts of mannitol, 1.1 ~ 1.3 parts of microcrystalline cellulose, 0.7 ~ 1.0 part of sodium carboxymethylcellulose, 0.6 ~ 0.9 part of lactose, magnesium stearate 0.11 ~ 0.13 Part, 0.7 ~ 1.1 part of Macrogol 4000,0.9 ~ 1.3 part of hydroxypropyl methylcellulose, 0.7 ~ 0.9 part of low-substituted hydroxypropyl cellulose, 0.05 ~ 0.08 part of polyoxyethylene sorbitan monoleate, 0.5 ~ 0.8 part of honey, 4 ~ 7 parts of the ethanol solution that volume fraction is 50% ~ 70%；Take prescription The honey of amount, is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stirs, and is heated to 100 ~ 105 DEG C, insulation 20 ~ 25 minutes, take out, with 80 mesh screens, take filtrate, the ethanol of recipe quantity is added after letting cool, stirring and dissolving is standby；Separately take （S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low substitution Hydroxypropyl cellulose is placed in Universalpulverizer, is placed in after crushed 100 mesh sieves in wet granulator, and it is previously processed good to add Honey ethanol solution and polyoxyethylene sorbitan monoleate, start granulator（24 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into air blast In drying box, setting temperature 50 C ~ 60 DEG C drying time is 120min ~ 150min so that particle water content≤3%（Quality percentage Content）；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that the coating solution that mass fraction is 6% ~ 9% is made, it is standby With；Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Coating solution is led to The nozzle atomization for crossing fluid bed is continuously added to fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, is held Continuous air intake is dried, and solution stops heating after continuing heating after having sprayed 10 ~ 15 minutes, cooling discharging, produces coated granule.
- 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, it is special Sign is that it is obtained as follows：A. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stirring is equal It is even, 100 ~ 105 DEG C are heated to, is incubated 20 ~ 25 minutes, takes out, with 80 mesh screens, takes filtrate, recipe quantity is added after letting cool Ethanol, stirring and dissolving, produce；B. supplementary material pre-treatment：Take recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, filler, flavouring, collapse Solution agent is placed in Universalpulverizer, crushed 100 mesh sieves, standby；C. pelletize：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adhesive and polyoxyethylene sorbitan monoleate is added, opens Dynamic granulator（24 mesh nylon mesh are installed）, start to pelletize；D. 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）；E. it is coated：E1. the configuration of coating solution：The coating material of recipe quantity is taken, adds water that the coating solution that mass fraction is 6% ~ 9% is made, it is standby；E2. coating process：Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 ℃；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, continue air intake and dry, solution stops heating after continuing heating after having sprayed 10 ~ 15 minutes, cooling discharging, produces bag Clothing particle；F. whole grain, sub-sieve:Coated granule is placed in crushing and pelletizing machine, with 24 mesh nylon mesh sieving whole grain, controls environment temperature Less than 25 DEG C, relative humidity is below 50%；G. it is total mixed：Lubricant be crushed into 100 mesh sieves, added in the particle after whole grain, with three-dimensional motion mixer mixing 10min ~20min；H. interior bag：Packed with particles packing machine, set packing specification as 1g/ bags, controlled below 25 DEG C of environment temperature, relatively Below humidity 50%, produce.
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| 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 |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
| CN103735545A (en) * | 2011-11-23 | 2014-04-23 | 重庆润泽医药有限公司 | Applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma |
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2016
- 2016-06-15 CN CN201610428366.8A patent/CN107510682A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766595A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Solid preparation with levo-oxiracetam as active component |
| CN103735545A (en) * | 2011-11-23 | 2014-04-23 | 重庆润泽医药有限公司 | Applications of levorotary oxiracetam and oxiracetam in preparing drugs for preventing or treating coma |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
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