CN107510662A - A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste and preparation method thereof - Google Patents
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
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- 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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- 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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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 ~ 1.0 part of L cysteines, 0.8 ~ 1.3 part of mannitol, 0.6 ~ 1.2 part of microcrystalline cellulose, 0.7 ~ 1.4 part of sodium carboxymethylcellulose, 0.9 ~ 1.5 part of lactose, 0.15 ~ 0.23 part of magnesium stearate, 1.3 ~ 1.8 parts of Macrogol 4000, 0.7 ~ 1.6 part of hydroxypropyl methylcellulose, 0.9 ~ 1.6 part of low-substituted hydroxypropyl cellulose, 0.15 ~ 0.19 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sucrose, 0.3 ~ 0.7 part of ethylmaltol, 1.1 ~ 1.7 parts of honey, 9 ~ 15 parts of 50% ~ 70% ethanol solution；It is produced by the present invention（S）The pyrrolidine acetamide particulate production impurity of 4 hydroxyl, 2 oxo 1 only increases by 0.04%, pelletization will not adhesion screen cloth, be easy to pelletize, it is fast that product leaches speed, the time is all leached less than 30 seconds, storage stability is good, and product is not easy moisture absorption caking, and shelf life is up to 24 months, it is in good taste, it can be received by most of patient.
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
Cough up alkyl acetamide particle and preparation method thereof.
Background technology
Oxiracetam listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Injection
Liquid, 1g/5ml.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic
Body.Ye Lei etc. mentions levo-oxiracetam to the rush gone into a coma caused by alcoholism in Publication No. CN 103735545A patents
Effect of waking up is obvious, and dextrorotation Oxiracetam does not act on substantially, and the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura west
Smooth 2 times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Peak etc. is opened in Publication No. CN
Levo-oxiracetam is disclosed in 103599101A patent to the study note of traumatic brain injury rat caused by hydraulic pressure and freely falling body
Recall cognition dysfunction to improve significantly, its drug effect is far above dextrorotation Oxiracetam.And the left-handed Auras of 200mg/kg
It is western smooth suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：Levo-oxiracetam and dextrorotation are difficult to understand
La Xitan is in beasle dog body without obvious chiral inversion.It is difficult to understand that beasle dog single intravenous injection gives left-handed and 2 multiple doses racemizations
The equal no significant difference of the main pharmacokinetic parameters of levo-oxiracetam in blood plasma after La Xitan.The examinations such as safe pharmacology, anxious malicious, long poison
Test result to show, under isodose level, levo-oxiracetam is with Oxiracetam to the toxicity of animal subject or cell without bright
Significant difference is different.Above-mentioned preclinical result of study shows that levo-oxiracetam is the chief active that drug effect is played in Oxiracetam body
Composition, this product, which is used alone, can reduce Clinical practice dosage, reduce potential toxicity.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) the entitled 4- hydroxyls -2- OXo-1-pyrrolidines of chemistry
Acetamide, (compound is disclosed in the anti anoxia class cereboactive drug synthesized first in 1974 for Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promotes brain metabolism, through blood brain
Barrier, there is stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease, brain trauma, brain
Knurl, intracranial infection, brain degenerative disease etc. also have the effect of preferable, and the drug toxicity is extremely low, no mutagenesis and carcinogenic work
With and genotoxicity.Giorgio et al. discloses the chemical constitution and preparation method of Oxiracetam in US4118396,
Chiodini et al. is disclosed in 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 in preparation process impurity increase compared with
Greatly, the easy adhesion screen cloth of pelletization, granulation are difficult, and storage process stability is poor, and particle hygroscopicity is strong, connecting block easy to stick, goods
The frame phase is short, and particle leaches that speed is slow and mouthfeel is bad, is not easy the technical problem such as to receive by many patients.
The content of the invention
It is an object of the invention to provide it is a kind of it is in good taste, leach the fireballing OXo-1-pyrrolidine of (S) -4- hydroxyls -2
Acetamide 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, Cys；The flavouring is sucrose, maltose, ethyl malt
Phenol, Sucralose, stevia rebaudianum are sweet, the one or more in sorbierite, mannitol, glucose, aspartame；Described adhesive is
One or more in water, ethanol, sucrose, starch slurry, dextrin, carboxymethyl cellulose, polyvinylpyrrolidone, honey；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 incrementss are smaller, and pelletization is easy to pelletize, will not adhesion screen cloth, product is not easy to inhale
Wet, it is good to be not easy adhesion caking, stability, shelf life length, and it is fast that particle leaches speed, in good taste；Above-mentioned (S) -4- hydroxyls in good taste
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 -2,0.6~1.0 part of Cys, 0.8~1.3 part of mannitol, microcrystalline cellulose
0.6~1.2 part, 0.7~1.4 part of sodium carboxymethylcellulose, 0.9~1.5 part of lactose, 0.15~0.23 part of magnesium stearate, poly- second
4,000 1.3~1.8 parts of glycol, 0.7~1.6 part of hydroxypropyl methylcellulose, 0.9~1.6 part of low-substituted hydroxypropyl cellulose, poly- mountain
80 0.15~0.19 part of pear ester, 1~5 part of sucrose, 0.3~0.7 part of ethylmaltol, 1.1~1.7 parts of honey, volume fraction are
9~15 parts of 50%~70% ethanol solution；The honey of recipe quantity is taken, is placed in iron pan, adds the purifying of 2 times of parts by weight of honey
Water, stir, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, take filtrate, add after letting cool
Enter the ethanol of recipe quantity, stirring and dissolving is standby；Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, Cys, sweet
Dew alcohol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sucrose, ethylmaltol are placed in ten thousand
In energy pulverizer, it is placed in after crushed 100 mesh sieves in wet granulator, adds previously ready honey ethanol solution and poly- mountain
Pear ester 80, start granulator (24 mesh nylon mesh of installation), start to pelletize；Wet granular is put into air dry oven, temperature is set
50 DEG C~60 DEG C 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 be made mass fraction be 6%~9% coating solution, it is standby；Will be above-mentioned dry
In particle input fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature is 40~50 DEG C；Coating solution is passed through into fluid bed
Nozzle atomization is continuously added to fluid bed, sets 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.
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 is under
The supplementary material of row weight proportion is made：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, Cys 0.7~0.9
Part, 0.9~1.2 part of mannitol, 0.8~1.1 part of microcrystalline cellulose, 0.9~1.2 part of sodium carboxymethylcellulose, lactose 1.1~
1.3 parts, it is 0.17~0.20 part of magnesium stearate, 1.5~1.7 parts of Macrogol 4000,0.9~1.2 part of hydroxypropyl methylcellulose, low
1.1~1.3 parts of hydroxypropyl cellulose of substitution, 0.16~0.18 part of polyoxyethylene sorbitan monoleate, 2~4 parts of sucrose, ethylmaltol 0.4~
0.6 part, 1.3~1.5 parts of honey, volume fraction be 50%~70% 11~14 parts of ethanol solution；The honey of recipe quantity is taken, is put
In iron pan, the purified water of 2 times of parts by weight of honey is added, is stirred, be heated to 100~105 DEG C, be incubated 20~25 minutes,
Take out, with 80 mesh screens, take filtrate, the ethanol of recipe quantity is added after letting cool, stirring and dissolving is standby；Take (S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide, Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low substitution hydroxyl
Propyl cellulose, sucrose, ethylmaltol are placed in Universalpulverizer, are placed in wet granulator, are added after crushed 100 mesh sieves
Enter previous ready honey ethanol solution and polyoxyethylene sorbitan monoleate, start granulator (24 mesh nylon mesh of installation), start to pelletize；Will
In wet granular input air dry oven, setting temperature 50 C~60 DEG C drying time is 120min~150min so that particle contains
Water≤3% (weight/mass percentage composition)；The Macrogol 4000 and hydroxypropyl methylcellulose of recipe quantity are taken, adds water that mass fraction is made
It is standby for 6%~9% coating solution；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,
Atomizing pressure is 0.8~1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10~15 minutes, cold
But discharge, produce 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. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs
Mix uniformly, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool at addition
The ethanol just measured, stirring and dissolving are standby；
2. supplementary material pre-treatment：Take 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 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；
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 particulate production impurity incrementss of (S) -4- hydroxyls -2 produced by the present invention compared with
It is small, only increase by 0.04%, pelletization will not adhesion screen cloth, be easy to pelletize, product leaches that speed is fast, and particle all leaches the time
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, and products taste is good, energy
Received by most of patient, preparation technology simple possible, be 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 in good taste, is made according to the following steps：
Preparation process：
1. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, the purified water of 2 times of parts by weight of honey is added, stirs
Mix uniformly, be heated to 100~105 DEG C, be incubated 20~25 minutes, take out, with 80 mesh screens, filtrate is taken, after letting cool at addition
The ethanol just measured, stirring and dissolving are standby；
2. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of recipe quantity, Cys,
Mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sucrose, ethylmaltol are placed in
In Universalpulverizer, 100 mesh sieves are crushed, it is standby；
3. granulation：Gained mixed-powder after pre-treatment is taken, is placed in wet granulator, adds adhesive 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 Macrogol 4000 and hydroxypropyl methylcellulose of recipe quantity are taken, adds water that quality volume is made
Fraction is 6%~9% coating solution, 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.
In pelletization, observation understands that the pelletization of embodiment 1 does not find the situation of adhesion screen cloth, and product is easy to make
Grain.
In order to be better understood from the present invention, having for invention medicine is expanded on further below by way of stability test of the present invention
Beneficial effect, rather than limitation of the present invention.
Experiment one：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) | 26 seconds | 23 seconds | 27 seconds | 22 seconds | 25 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 24 seconds | 27 seconds | 28 seconds | 25 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：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
Cough up the relevant material of alkyl acetamide bulk drug and the oxo-1-pyrrolidine ethanamide finished granule of (S) -4- hydroxyls -2, observation (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 three：A kind of oxo-1-pyrrolidine ethanamide granule stability of (S) -4- hydroxyls -2 in good taste of the present invention is real
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.
Experiment four：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 by specific supplementary material
Compatibility, it is made by repeatedly seasoning, there is excellent taste, taste is fragrant and sweet, can be received by many patients.
Method：The people of crowd 1000 of random selection more than 10 years old, taste trial test is carried out, it is as follows will now to taste result statistics
Table：
(S) the oxo-1-pyrrolidine ethanamide particle taste application form of -4- hydroxyls -2
| It is very good | Preferably | Typically | Difference |
| 537 | 161 | 159 | 143 |
It can be seen from taste tastes market survey, this product is easy to be received by many patients, according to incompletely statistics, feels taste
Road is extraordinary to account for the 53.7% of whole crowd, feel taste it is relatively good account for 16.1%, think that taste in general accounts for 15.9%,
Think that distasteful accounts for 14.3%.Therefore this product has the characteristics of in good taste, easily to be received by many patients colony.
Embodiment 2
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, is made according to the following steps：
Preparation process：It is made according to the preparation technology of embodiment 1.Observation product pelletization does not find showing for adhesion screen cloth
As product is easy to pelletize.Tested by the test method of embodiment 1, leaching timing, to show that this product leaches speed fast, more
Individual sample leaches the time and is respectively less than 30 seconds, and the product prescription result of the test that influences increased on preparation process impurity shows prepared by this product
Process Impurity incrementss are smaller, and relevant material only increases by 0.02% in preparation process；Stability test result shows to accelerate 6 lunar samples
Quality is stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months, and taste investigation shows that this product is delicious,
Easily received by most of patient.
Embodiment 3
A kind of oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 in good taste, is made according to the following steps：
Preparation process：It is made according to the preparation technology of embodiment 1.Observation product pelletization does not find showing for adhesion screen cloth
As product is easy to pelletize.Tested by the test method of embodiment 1, leaching timing, to show that this product leaches speed fast, more
Individual sample leaches the time and is respectively less than 30 seconds, and the product prescription result of the test that influences increased on preparation process impurity shows prepared by this product
Process Impurity incrementss are smaller, and relevant material only increases by 0.03% in preparation process；Stability test result shows to accelerate 6 lunar samples
Quality is stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months, and taste investigation shows that this product is delicious,
Easily received by most of patient.
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.The observation product pelletization of embodiment 4,5,6 does not find to glue
The even phenomenon of screen cloth, therefore product is easy to pelletize.Tested by the test method of embodiment 1, when the product of embodiment 4,5,6 leaches
Between measure to show that this product leaches speed fast, multiple samples leach the time and are respectively less than 30 seconds, and the product prescription of embodiment 4,5,6 is to preparing
The increased result of the test that influences of Process Impurity shows that this product preparation process impurity incrementss are smaller, relevant material in preparation process
Only increase by 0.03%, 0.03%, 0.02% respectively；The product stability result of the test of embodiment 4,5,6 shows to accelerate 6 lunar sample qualities
Amount is stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months, and the investigation of the product taste of embodiment 4,5,6 shows
This product is delicious, is easily received by most of patient.
Claims (3)
- It is 1. a kind of in good taste（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 ~ 1.0 parts, 0.8 ~ 1.3 part of mannitol, 0.6 ~ 1.2 part of microcrystalline cellulose, 0.7 ~ 1.4 part of sodium carboxymethylcellulose, lactose 0.9 ~ 1.5 parts, 0.15 ~ 0.23 part of magnesium stearate, 1.3 ~ 1.8 parts of Macrogol 4000,0.7 ~ 1.6 part of hydroxypropyl methylcellulose, low substitution 0.9 ~ 1.6 part of hydroxypropyl cellulose, 0.15 ~ 0.19 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sucrose, 0.3 ~ 0.7 part of ethylmaltol, honeybee 1.1 ~ 1.7 parts of honey, 9 ~ 15 parts of the ethanol solution that volume fraction is 50% ~ 70%；The honey of recipe quantity is taken, is placed in iron pan, is added The purified water of 2 times of parts by weight of honey, stirs, and is heated to 100 ~ 105 DEG C, is incubated 20 ~ 25 minutes, takes out, with 80 mesh sieve mistakes Filter, takes filtrate, and the ethanol of recipe quantity is added after letting cool, and stirring and dissolving is standby；Take（S）The OXo-1-pyrrolidine second of -4- hydroxyls -2 Acid amides, Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sugarcane Sugar, ethylmaltol are placed in Universalpulverizer, are placed in after crushed 100 mesh sieves in wet granulator, and addition is previously ready to Honey ethanol solution and polyoxyethylene sorbitan monoleate, start granulator（24 mesh nylon mesh are installed）, start to pelletize；Wet granular is put into and roused In wind drying box, setting temperature 50 C ~ 60 DEG C drying time is 120min ~ 150min so that particle water content≤3%（Quality hundred Divide content）；The Macrogol 4000 and hydroxypropyl methylcellulose of recipe quantity are taken, adds 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, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；By coating solution Fluid bed is continuously added to by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, Continue air intake to 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 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 0.7 ~ 0.9 part of propylhomoserin, 0.9 ~ 1.2 part of mannitol, 0.8 ~ 1.1 part of microcrystalline cellulose, 0.9 ~ 1.2 part of sodium carboxymethylcellulose, breast Sugar 1.1 ~ 1.3 parts, 0.17 ~ 0.20 part of magnesium stearate, 1.5 ~ 1.7 parts of Macrogol 4000,0.9 ~ 1.2 part of hydroxypropyl methylcellulose, 1.1 ~ 1.3 parts of low-substituted hydroxypropyl cellulose, 0.16 ~ 0.18 part of polyoxyethylene sorbitan monoleate, 2 ~ 4 parts of sucrose, ethylmaltol 0.4 ~ 0.6 part, 1.3 ~ 1.5 parts of honey, volume fraction be 50% ~ 70% 11 ~ 14 parts of ethanol solution；The honey of recipe quantity is taken, is placed in iron In pot, the purified water of 2 times of parts by weight of honey is added, is stirred, be heated to 100 ~ 105 DEG C, be incubated 20 ~ 25 minutes, taken out, used 80 mesh screens, take filtrate, and the ethanol of recipe quantity is added after letting cool, and stirring and dissolving is standby；Take（S）Oxo-the 1- of -4- hydroxyls -2 Pyrrolidine acetamide, Cys, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low substituted hydroxy-propyl are fine Dimension element, sucrose, ethylmaltol are placed in Universalpulverizer, are placed in after crushed 100 mesh sieves in wet granulator, are added previous Ready honey ethanol solution and polyoxyethylene sorbitan monoleate, start granulator（24 mesh nylon mesh are installed）, start to pelletize；By wet granular 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, it is 6% ~ 9% to add water that mass fraction is made Coating solution, it is standby；Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 DEG C；Will Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, and 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, produce coating Grain.
- 3. as described in claim or 2（S）The preparation method of the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, its feature It is, it is obtained as follows：A. the preparation of adhesive：The honey of recipe quantity is taken, is placed in iron pan, adds the purified water of 2 times of parts by weight of honey, stirring Uniformly, 100 ~ 105 DEG C are heated to, is incubated 20 ~ 25 minutes, is taken out, with 80 mesh screens, is taken filtrate, recipe quantity is added after letting cool Ethanol, stirring and dissolving is standby；B. supplementary material pre-treatment：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：The configuration of E (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；E (2) coating process：Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50 ℃；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is 0.8 ~ 1.0bar, continue air intake and dry, solution stops heating after continuing heating after having sprayed 10 ~ 15 minutes, cooling discharging, produces bag Clothing particle；F. whole grain, sub-sieve:Coated granule is placed in crushing and pelletizing machine, with 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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| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |