CN107510685A - Uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of content and preparation method thereof - Google Patents
Uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of content and preparation method thereof Download PDFInfo
- Publication number
- CN107510685A CN107510685A CN201610430419.XA CN201610430419A CN107510685A CN 107510685 A CN107510685 A CN 107510685A CN 201610430419 A CN201610430419 A CN 201610430419A CN 107510685 A CN107510685 A CN 107510685A
- Authority
- CN
- China
- Prior art keywords
- particle
- oxo
- recipe quantity
- hydroxyls
- parts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
-
- 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
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of content is uniform（S）The pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1, it is made by following supplementary material：（S）1 part of 4 hydroxyl, 2 oxo, 1 pyrrolidine acetamide, 1.3 ~ 1.9 parts of mannitol, 1.1 ~ 1.6 parts of microcrystalline cellulose, 0.5 ~ 1.0 part of sodium carboxymethylcellulose, 0.8 ~ 1.3 part of lactose, 0.15 ~ 0.21 part of talcum powder, 0.7 ~ 1.3 part of Macrogol 4000, 0.8 ~ 1.5 part of hydroxypropyl methylcellulose, 0.5 ~ 1.2 part of low-substituted hydroxypropyl cellulose, 0.03 ~ 0.09 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sorbierite, 0.15 ~ 0.21 part of honey, 8 ~ 13 parts of 60% ~ 80% ethanol solution, 20% ~ 30% 2 ~ 6 parts of ethanol solution；According to produced by the present invention（S）The pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 is easy to pelletize, and bisque amount is few, uniform particle diameter, good fluidity, not sub- angle is less than 38 °, and content uniformity is less than 5%, and it is fast that particle leaches speed, particle all leached the time less than 30 seconds, content uniformity is good, and the RSD of multiple assays is less than 2%, and stability is good, product is not easy the moisture absorption, and shelf life is up to 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of uniform oxo -1- of (S) -4- hydroxyls -2 of content
Pyrrolidine acetamide particle and preparation method thereof.
Background technology
Oxiracetam listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Injection
Liquid, 1g/5ml.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic
Body.Ye Lei etc. mentions levo-oxiracetam to the rush gone into a coma caused by alcoholism in the A patents of Publication No. CN 103735545
Effect of waking up is obvious, and dextrorotation Oxiracetam does not act on substantially, and the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura west
Smooth 2 times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Peak etc. is opened in Publication No. CN
Levo-oxiracetam is disclosed in 103599101 A patent to the study note of traumatic brain injury rat caused by hydraulic pressure and freely falling body
Recall cognition dysfunction to improve significantly, its drug effect is far above dextrorotation Oxiracetam.And the left-handed Auras of 200mg/kg
It is western smooth suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：Levo-oxiracetam and dextrorotation are difficult to understand
La Xitan is in beasle dog body without obvious chiral inversion.It is difficult to understand that beasle dog single intravenous injection gives left-handed and 2 multiple doses racemizations
The equal no significant difference of the main pharmacokinetic parameters of levo-oxiracetam in blood plasma after La Xitan.The examinations such as safe pharmacology, anxious malicious, long poison
Test result to show, under isodose level, levo-oxiracetam is with Oxiracetam to the toxicity of animal subject or cell without bright
Significant difference is different.Above-mentioned preclinical result of study shows that levo-oxiracetam is the chief active that drug effect is played in Oxiracetam body
Composition, this product, which is used alone, can reduce Clinical practice dosage, reduce potential toxicity.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) the entitled 4- hydroxyls -2- OXo-1-pyrrolidines of chemistry
Acetamide, (compound is disclosed in the anti anoxia class cereboactive drug synthesized first in 1974 for Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promotes brain metabolism, through blood brain
Barrier, there is stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease, brain trauma, brain
Knurl, intracranial infection, brain degenerative disease etc. also have the effect of preferable, and the drug toxicity is extremely low, no mutagenesis and carcinogenic work
With and genotoxicity.Giorgio et al. discloses the chemical constitution and preparation method of Oxiracetam in US4118396,
Chiodini et al. is disclosed in 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 is primarily present the easy adhesion screen cloth of pelletization, system
Grain is difficult, and particle bisque is more, and particle diameter is difficult to control, and content uniformity is poor, and storage process stability is bad, particle hygroscopicity
By force, connecting block easy to stick, shelf life is short, and particle leaches the technical problems such as speed is slow.
The content of the invention
It is an object of the invention to provide a kind of content is uniform, stability is good, leaches the fireballing oxygen of (S) -4- hydroxyls -2
Generation -1- pyrrolidine acetamide particles.
Another object of the present invention is to provide the preparation of the above-mentioned oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2
Method.
The purpose of the present invention is realized by following technical measures：
A kind of uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, it is with (S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide is raw material, adds a certain amount of filler, flavouring, adhesive, lubricant, disintegrant, bag
Clothing material is made；Wherein described filler be starch, lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose,
One or more in glucose, sodium carboxymethylcellulose；The flavouring is sucrose, maltose, ethylmaltol, trichlorine sugarcane
Sugar, stevia rebaudianum are sweet, the one or more in sorbierite, mannitol, glucose, aspartame；Described adhesive is water, ethanol, sugarcane
One or more in sugar, starch slurry, dextrin, carboxymethyl cellulose, polyvinylpyrrolidone, honey；The lubricant is cunning
In stone flour, magnesium stearate, polyethylene glycol, stearic acid, calcium stearate, lauryl sodium sulfate, superfine silica gel powder, magnesia, paraffin
One or more；The disintegrant is in low-substituted hydroxypropyl cellulose, polyoxyethylene sorbitan monoleate, sodium carboxymethyl starch, dried starch
One or more；The coating material is Macrogol 4000, Macrogol 6000, hydroxypropyl cellulose, hypromellose
One or more in element, 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
Alkyl acetamide particle pelletization is coughed up to be easy to pelletize, will not adhesion screen cloth, uniform particle sizes are controllable, and storage process is not easy moisture absorption, no
Connecting block easy to stick, product stability are good, shelf life length, and granule content is uniformly and to leach speed fast；Above-mentioned (S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide particle, it is characterised in that it is made by the supplementary material of following weight proportion：(S) -4- hydroxyls -
21 part of oxo-1-pyrrolidine ethanamides, 1.3~1.9 parts of mannitol, 1.1~1.6 parts of microcrystalline cellulose, sodium carboxymethylcellulose
0.5~1.0 part, 0.8~1.3 part of lactose, 0.15~0.21 part of talcum powder, 0.7~1.3 part of Macrogol 4000, hydroxypropyl first it is fine
0.8~1.5 part of dimension element, 0.5~1.2 part of low-substituted hydroxypropyl cellulose, 0.03~0.09 part of polyoxyethylene sorbitan monoleate, sorbierite 1~5
8~13 parts of ethanol solution that part, 0.15~0.21 part of honey, volume fraction are 60%~80%, volume fraction be 20%~
30% 2~6 parts of 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 is equal
It is even, 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
Volume fraction is 60%~80% ethanol, and stirring and dissolving is standby；Another oxo -1- the pyrroles of (S) -4- hydroxyls -2 for taking recipe quantity
Alkyl acetamide and polyoxyethylene sorbitan monoleate be dissolved in recipe quantity volume fraction be 20%~30% ethanol solution in, it is standby；Separately take place
Mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, the sorbierite just measured are placed in omnipotent
In pulverizer, 100 mesh sieves are crushed, are placed in wet granulator, add the previously processed good oxo -1- pyrroles of (S) -4- hydroxyls -2
Alkyl acetamide ethanol solution and honey ethanol solution are coughed up, starts granulator (18 mesh nylon mesh of installation), starts to pelletize；By wet
In grain input fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying, and drying time is 50~55 minutes；Take recipe quantity
Macrogol 4000, hydroxypropyl methylcellulose, add water be made quality volume fraction be 8%~10% coating solution, 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 fluidisation
The nozzle atomization of bed 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, cooling discharging after continuing heating after having sprayed 10~15 minutes；Coated granule is placed in crushing and pelletizing
In machine, with 20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, added in the particle after whole grain, with three-dimensional
Movement mixer mixing 10min~20min is produced.
Further, speed is leached faster for the oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2, particle contains
Evenly, stability is more preferable, and the term of validity is longer, the oxo-1-pyrrolidine ethanamide particle of one kind (S) -4- hydroxyls -2, its feature for amount
It is, it is made by the supplementary material of following weight proportion：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, mannitol
1.5~1.7 parts, 1.3~1.5 parts of microcrystalline cellulose, 0.6~0.9 part of sodium carboxymethylcellulose, 0.9~1.1 part of lactose, talcum
0.17~0.20 part of powder, 0.8~1.2 part of Macrogol 4000,0.9~1.3 part of hydroxypropyl methylcellulose, low substituted hydroxy-propyl fiber
0.7~1.1 part of element, 0.05~0.08 part of polyoxyethylene sorbitan monoleate, 2~4 parts of sorbierite, 0.17~0.20 part of honey, volume fraction are
60%~80% 9~12 parts of ethanol solution, volume fraction are 3~5 parts of 20%~30% ethanol solution；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, is heated to 100~105 DEG C, insulation 20~25
Minute, take out, with 80 mesh screens, take filtrate, the ethanol that recipe quantity volume fraction is 60%~80%, stirring are added after letting cool
Dissolving, it is standby；Separately the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of recipe quantity and polyoxyethylene sorbitan monoleate is taken to be dissolved in recipe quantity
Volume fraction be 20%~30% ethanol solution in, it is standby；Another mannitol, microcrystalline cellulose, the carboxymethyl fibre for taking recipe quantity
Tie up plain sodium, lactose, low-substituted hydroxypropyl cellulose, sorbierite to be placed in Universalpulverizer, crushed 100 mesh sieves, be placed in wet method
In granulator, previously processed good the oxo-1-pyrrolidine ethanamide ethanol solution of (S) -4- hydroxyls -2 and honey ethanol are added
Solution, start granulator (18 mesh nylon mesh of installation), start to pelletize；Wet granular is put into fluid bed, hotbed temperature setting 50
DEG C~70 DEG C, start drying, drying time is 50~55 minutes；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, is added
The coating solution that quality volume fraction is 8%~10% is made in water, standby；Above-mentioned dry particl is put into fluid bed, is passed through hot sky
Gas, is allowed to suspension fluidization, and bed temperature is 40~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, if
Determine 50~60rpm of spouting velocity, atomizing pressure is 0.8~1.0bar, continue air intake dry, solution continue after having sprayed heating 10~
Stop heating, cooling discharging after 15 minutes；Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；By prescription
The talcum powder of amount crushed 100 mesh sieves, adds in the particle after whole grain, is with three-dimensional motion mixer mixing 10min~20min
.
A kind of preparation method of the uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, its feature exist
In it is obtained as follows：
1. 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 that side's amount volume fraction is 60%~80%, stirring and dissolving are standby；
2. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 and polyoxyethylene sorbitan monoleate of recipe quantity
Be dissolved in recipe quantity volume fraction be 20%~30% ethanol solution in, it is standby；The another filler for taking recipe quantity, flavouring,
Disintegrant is placed in Universalpulverizer, crushed 100 mesh sieves, standby；
3. granulation：Gained mixed-powder is placed in wet granulator after taking pre-treatment, adds previously processed good (S) -4-
The oxo-1-pyrrolidine ethanamide of hydroxyl -2 ethanol solution and adhesive, start granulator (18 mesh nylon mesh of installation), start to make
Grain；
4. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying；Observe at any time
Particle boiling situation, air blast situation, prevent the particle-bonded ceramic the bottom of a pan, cause particle coking or gelatinization, and drying time is 50~55 points
Clock, ensure pellet moisture≤3%；
5. coating：
(1) preparation of coating solution：The coating material of recipe quantity is taken, adds water that the coating that mass fraction is 8%~10% is made
Liquid, it is standby；
(2) coating process：Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature 40
~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50~60rpm of spouting velocity, atomization
Pressure is 0.8~1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10~15 minutes, cools down out
Material, produces coated granule；
6. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, controls environment temperature
Less than 25 DEG C, relative humidity is below 50%；
It is 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 the present invention (S) -4- hydroxyls -2 will not adhesion screen cloth, be easy to make
Grain, bisque amount is few, uniform particle diameter, good fluidity, and not sub- angle is less than 38 °, and content uniformity is less than 5%, and it is fast that particle leaches speed,
Grain all leaches the time less than 30 seconds, and content uniformity is good, and the RSD of multiple assays is respectively less than 2%, and storage process is steady
Qualitative good, 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 uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, 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 that side's amount volume fraction is 60%~80%, stirring and dissolving are standby；
2. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 and polyoxyethylene sorbitan monoleate of recipe quantity
Be dissolved in recipe quantity volume fraction be 20%~30% ethanol solution in, it is standby；Another mannitol, the microcrystalline cellulose for taking recipe quantity
Element, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose, sorbierite are placed in Universalpulverizer, crushed 100 mesh
Sieve, it is standby；
3. granulation：Gained mixed-powder is placed in wet granulator after taking pre-treatment, adds previously processed good (S) -4-
The oxo-1-pyrrolidine ethanamide of hydroxyl -2 ethanol solution and adhesive, start granulator (18 mesh nylon mesh of installation), start to make
Grain；
4. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C~70 DEG C, starts drying；Observe at any time
Particle boiling situation, air blast situation, prevent the particle-bonded ceramic the bottom of a pan, cause particle coking or gelatinization, and drying time is 50~55 points
Clock, ensure pellet moisture≤3%；
5. coating：
(1) preparation of coating solution：Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that mass fraction is made
It is standby for 8%~10% coating solution；
(2) coating process：Above-mentioned dry particl is put into fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature 40
~50 DEG C；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50~60rpm of spouting velocity, atomization
Pressure is 0.8~1.0bar, continues air intake and dries, and solution stops heating after continuing heating after having sprayed 10~15 minutes, cools down out
Material, produces coated granule；
6. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, controls environment temperature
Less than 25 DEG C, relative humidity is below 50%；
It is 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：Particle stops sub- angle measure
1. test material：Sample after the completion of always being mixed in the preparation process of embodiment 1
2. test method：After the completion of embodiment 1 is always mixed, respectively in the upper, middle and lower of three-dimensional motion mixer, left and right each point
Separately sampled measure angle of repose, judges its mobility；
3. result of the test：
4. conclusion (of pressure testing)：It can be seen that by upper table result of the test, five times measurement angle of repose is respectively less than 37 °, shows particle flow
Property is good.
Experiment two：Content uniformity
1. test material：Sample after the completion of always being mixed in the preparation process of embodiment 1
2. test method：After the completion of embodiment 1 is always mixed, respectively in the upper, middle and lower of three-dimensional motion mixer, left and right each point
Separately sampled 5g, content detection is carried out according to content assaying method, the content RSD of each sample point is calculated, evaluates whether to be well mixed；
3. result of the test：
4. conclusion (of pressure testing)：It can be seen that by upper table result of the test, this product content uniformity is good, and RSD is less than 1%
Experiment three：Content uniformity
1. test material：10 bags of particulate samples made from Example 1, shine《Chinese Pharmacopoeia》Two annex of version in 2010
Content uniformity inspection under granula item.
2. determination method：The weight of 10 bags of test sample, respectively weighed every bag of content is taken, every bag of weight is with indicating loading amount phase
Compare.
3. result of the test：Content uniformity inspection result see the table below：
4. conclusion (of pressure testing)：This product content uniformity is respectively less than ± 5% it can be seen from upper table result of the test, shows that loading amount is poor
Different stabilization, content uniformity are small.
Experiment four：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 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 five：Dissolution test
1. test material：The oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 made from embodiment 1；
2. test method：10 bags of -2 oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls, puts made from Example 1
In 100m1 beakers, the purified water that 50m1 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 | 24 seconds | 28 seconds | 23 seconds | 22 seconds |
| Test number | 6# | 7# | 8# | 9# | 10# |
| Leach the time (min) | 27 seconds | 25 seconds | 24 seconds | 26 seconds | 25 seconds |
4. conclusion (of pressure testing)：It can be seen that by upper table result of the test, repeatedly measure particle and leach the time less than 30 seconds, it was demonstrated that press
It is fast that particle produced by the present invention leaches speed.
Embodiment 2
A kind of uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, is made according to the following steps：
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, not sub- angle experiment measurement result shows this product particle stream
Dynamic property is good, and not sub- angle is less than 36 °, and content uniformity test result shows that this product content uniformity is good, its total mixed rear each point particle
Content RSD be less than 1%, content uniformity experiment shows that this product content uniformity is less than 4%, and this product loading amount is stable, controllable, leaches examination
Test result and show repeatedly to determine this product and leach the time and be respectively less than 30 seconds, therefore this product can leach rapidly, stability test result shows
Accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 3
A kind of uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of content, is made according to the following steps：
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, not sub- angle experiment measurement result shows this product particle stream
Dynamic property is good, and not sub- angle is less than 38 °, and content uniformity test result shows that this product content uniformity is good, its total mixed rear each point particle
Content RSD be less than 2%, content uniformity experiment shows that this product content uniformity is less than 5%, and this product loading amount is stable, controllable, leaches examination
Test result and show repeatedly to determine this product and leach the time and be respectively less than 30 seconds, therefore this product can leach rapidly, stability test result shows
Accelerate June sample quality stable, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Embodiment 4-6：The uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of content, by following heavy
The supplementary material of amount is prepared, and preparation method is the same as embodiment 1：
Preparation process：It is made according to the preparation technology of embodiment 1.The observation product pelletization of embodiment 4,5,6 is not found
The phenomenon of adhesion screen cloth, product are easy to pelletize.Tested by the test method of embodiment 1, not sub- angle experiment measurement result table
The bright product particle good fluidity of embodiment 4,5,6, not sub- angle are respectively lower than 36 °, 37 °, 36 °, content uniformity test result table
The bright product content uniformity of embodiment 4,5,6 is good, and the content RSD of its total mixed rear each point particle is respectively smaller than 1%, 2%, 2%, dress
Amount difference test shows that the product content uniformity of embodiment 4,5,6 is respectively less than 5%, and this product loading amount is stable, controllable, dissolution test result
Show repeatedly to determine the product of embodiment 4,5,6 and leach the time and be respectively less than 30 seconds, therefore this product can leach rapidly, embodiment 4,5,6 is produced
Product stability test result shows that acceleration sample quality in June is stable, long-term 24 months steady qualities, therefore this product term of validity at least 24
Individual month.
Claims (3)
1. a kind of content is uniform（S）The oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, it is characterised in that it is by following
The supplementary material and preparation method of weight proportion are made：（S）- 1 part of -2 oxo-1-pyrrolidine ethanamide of 4- hydroxyls, mannitol 1.3 ~
1.9 parts, 1.1 ~ 1.6 parts of microcrystalline cellulose, 0.5 ~ 1.0 part of sodium carboxymethylcellulose, 0.8 ~ 1.3 part of lactose, talcum powder 0.15 ~
0.21 part, 0.7 ~ 1.3 part of Macrogol 4000,0.8 ~ 1.5 part of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose 0.5 ~ 1.2
Part, the ethanol that 0.03 ~ 0.09 part of polyoxyethylene sorbitan monoleate, 1 ~ 5 part of sorbierite, 0.15 ~ 0.21 part of honey, volume fraction are 60% ~ 80%
8 ~ 13 parts of solution, volume fraction are 2 ~ 6 parts of 20% ~ 30% ethanol solution；The honey of recipe quantity is taken, is placed in iron pan, adds honey 2
The purified water of times parts by weight, stirs, and is heated to 100 ~ 105 DEG C, is incubated 20 ~ 25 minutes, takes out, with 80 mesh screens, takes
Filtrate, adds the ethanol that recipe quantity volume fraction is 60% ~ 80% after letting cool, stirring and dissolving is standby；Separately take recipe quantity（S）-4-
The volume fraction that the oxo-1-pyrrolidine ethanamide of hydroxyl -2 and polyoxyethylene sorbitan monoleate are dissolved in recipe quantity is 20% ~ 30% ethanol solution
In, it is standby；The another mannitol for taking recipe quantity, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, low-substituted hydroxypropyl cellulose,
Sorbierite is placed in Universalpulverizer, be crushed 100 mesh sieves, is placed in wet granulator, and it is previously processed good to add（S）-4-
The oxo-1-pyrrolidine ethanamide of hydroxyl -2 ethanol solution and honey ethanol solution, start granulator（18 mesh nylon mesh are installed）,
Start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, and drying time is 50 ~ 55
Minute；Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity are taken, adds water that the coating that quality volume fraction is 8% ~ 10% is made
Liquid, 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
Liquid 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, cooling discharging after continuing heating after having sprayed 10 ~ 15 minutes；By coated granule
It is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, after adding whole grain
In particle, produced with three-dimensional motion mixer mixing 10min ~ 20min.
It is 2. as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, it is characterised in that it be by
The supplementary material and preparation method of following weight proportion are made：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, mannitol
1.5 ~ 1.7 parts, 1.3 ~ 1.5 parts of microcrystalline cellulose, 0.6 ~ 0.9 part of sodium carboxymethylcellulose, 0.9 ~ 1.1 part of lactose, talcum powder
0.17 ~ 0.20 part, 0.8 ~ 1.2 part of Macrogol 4000,0.9 ~ 1.3 part of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose
0.7 ~ 1.1 part, 0.05 ~ 0.08 part of polyoxyethylene sorbitan monoleate, 2 ~ 4 parts of sorbierite, 0.17 ~ 0.20 part of honey, volume fraction be 60% ~
80% 9 ~ 12 parts of ethanol solution, volume fraction are 3 ~ 5 parts of 20% ~ 30% ethanol 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, is stirred, is heated to 100 ~ 105 DEG C, is incubated 20 ~ 25 minutes, is taken out, with 80 mesh
Filter is sieved through, takes filtrate, the ethanol that recipe quantity volume fraction is 60% ~ 80% is added after letting cool, stirring and dissolving is standby；Separately take prescription
Amount（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 and polyoxyethylene sorbitan monoleate be dissolved in the volume fraction of recipe quantity for 20% ~
It is standby in 30% ethanol solution；Another mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, the low substitution hydroxyl for taking recipe quantity
Propyl cellulose, sorbierite are placed in Universalpulverizer, be crushed 100 mesh sieves, are placed in wet granulator, are added previously processed
Alright（S）The oxo-1-pyrrolidine ethanamide ethanol solution of -4- hydroxyls -2 and honey ethanol solution, start granulator（Installation 18
Mesh nylon mesh）, start to pelletize；Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying, when drying
Between be 50 ~ 55 minutes；Take Macrogol 4000, the hydroxypropyl methylcellulose of recipe quantity, add water be made quality volume fraction for 8% ~
10% coating solution, it is standby；Above-mentioned dry particl is put into fluid bed, is passed through hot-air, is allowed to suspension fluidization, bed temperature is 40 ~ 50
℃；Coating solution is continuously added to fluid bed by the nozzle atomization of fluid bed, sets 50 ~ 60rpm of spouting velocity, atomizing pressure is
0.8 ~ 1.0bar, continue air intake and dry, solution stops heating, cooling discharging after continuing heating after having sprayed 10 ~ 15 minutes；Will coating
Particle is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains；The talcum powder of recipe quantity be crushed into 100 mesh sieves, add whole grain
In particle afterwards, produced with three-dimensional motion mixer mixing 10min ~ 20min.
It is 3. as claimed in claim 1 or 2（S）The preparation method of the oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2, 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
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
Volume fraction is 60% ~ 80% ethanol, and stirring and dissolving is standby；
B. supplementary material pre-treatment：Take recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 and polyoxyethylene sorbitan monoleate dissolving
In recipe quantity volume fraction be 20% ~ 30% ethanol solution in, it is standby；Separately the filler, flavouring, disintegrant of recipe quantity is taken to put
In Universalpulverizer, 100 mesh sieves are crushed, it is standby；
C. pelletize：Gained mixed-powder is placed in wet granulator after taking pre-treatment, and it is previously processed good to add（S）- 4- hydroxyls-
2 oxo-1-pyrrolidine ethanamide ethanol solutions and adhesive, start granulator（18 mesh nylon mesh are installed）, start to pelletize；
D. dry：Wet granular is put into fluid bed, hotbed temperature sets 50 DEG C ~ 70 DEG C, starts drying；Particle boiling is observed at any time
Situation, air blast situation are risen, prevents the particle-bonded ceramic the bottom of a pan, causes particle coking or gelatinization, drying time is 50 ~ 55 minutes, is ensured
Pellet moisture≤3%；
E. it is coated：
The preparation of E (1) coating solutions：The coating material of recipe quantity is taken, adds water that the coating solution that mass fraction is 8% ~ 10% is made, it is standby；
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 20 mesh sieve whole grains, controls 25 DEG C of environment temperature
Hereinafter, 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610430419.XA CN107510685B (en) | 2016-06-15 | 2016-06-15 | (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles with uniform content and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610430419.XA CN107510685B (en) | 2016-06-15 | 2016-06-15 | (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles with uniform content and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107510685A true CN107510685A (en) | 2017-12-26 |
| CN107510685B CN107510685B (en) | 2020-07-21 |
Family
ID=60720316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610430419.XA Active CN107510685B (en) | 2016-06-15 | 2016-06-15 | (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide particles with uniform content and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107510685B (en) |
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 |
| 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 |
| WO2014087367A2 (en) * | 2012-12-09 | 2014-06-12 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and its associated complications |
-
2016
- 2016-06-15 CN CN201610430419.XA patent/CN107510685B/en active Active
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 |
| 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 |
| WO2014087367A2 (en) * | 2012-12-09 | 2014-06-12 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and its associated complications |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107510685B (en) | 2020-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107510685A (en) | Uniform oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of content and preparation method thereof | |
| CN107510679A (en) | A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN107510664A (en) | A kind of levo-oxiracetam particle and preparation method thereof | |
| CN107510657A (en) | Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof | |
| CN106943376B (en) | A kind of levo-oxiracetam particle and preparation method thereof | |
| CN107510665A (en) | Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof | |
| CN107510676A (en) | A kind of content is uniform（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN101991859A (en) | Beta-cyclodextrin inclusion compound of huperzine A, and preparation method and preparation thereof | |
| CN106943377A (en) | A kind of levo-oxiracetam particle and preparation method thereof | |
| CN106606485A (en) | Good taste levo S-oxiracetam particle and preparation method thereof | |
| CN106619526A (en) | Good-stability (S)-4-hydroxy-2 oxo-1-pyrrolidine acetamide granule and preparation method thereof | |
| CN107510684A (en) | Good levo-oxiracetam particle of a kind of content uniformity and preparation method thereof | |
| CN107510667A (en) | A kind of stability is good（S）Oxo-1-pyrrolidine ethanamide particle of -4- hydroxyls -2 and preparation method thereof | |
| CN107510678A (en) | One kind leaches fireballing levo-oxiracetam particle and preparation method thereof | |
| CN107510683A (en) | One kind leaches fireballing levo-oxiracetam particle and preparation method thereof | |
| CN107510673A (en) | One kind leaches fireballing levo-oxiracetam particle and preparation method thereof | |
| CN106619525A (en) | (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide particles having uniform content, and preparation method thereof | |
| CN107510674A (en) | A kind of levo-oxiracetam particle in good taste and preparation method thereof | |
| CN107510656A (en) | Good oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of stability and preparation method thereof | |
| CN107510681A (en) | It is a kind of（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN107510680A (en) | It is a kind of in good taste（S）Pyrrolidine acetamide particle of 4 hydroxyl, 2 oxo 1 and preparation method thereof | |
| CN107510663A (en) | A kind of levo-oxiracetam particle in good taste and preparation method thereof | |
| CN106606484A (en) | L-oxiracetam particles with high dissolution and dispersion speed and preparation method thereof | |
| CN107510672A (en) | Good oxo-1-pyrrolidine ethanamide particle of (S) -4- hydroxyls -2 of a kind of stability and preparation method thereof | |
| CN106619529A (en) | Levorotatory oxiracetam granule with good content uniformity and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220714 Address after: 430000 No. 88, shendun fifth road, East Lake Development Zone, Wuhan, Hubei Province Patentee after: Wuhan Hengxinyuan Pharmaceutical Co.,Ltd. Address before: No. 9, Yubei District industry road, Chongqing, Chongqing Patentee before: CHONGQING RUNZE PHARMACEUTICAL Co.,Ltd. |