CN106619529A - Levorotatory oxiracetam granule with good content uniformity and preparation method thereof - Google Patents
Levorotatory oxiracetam granule with good content uniformity and preparation method thereof Download PDFInfo
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- CN106619529A CN106619529A CN201510706591.9A CN201510706591A CN106619529A CN 106619529 A CN106619529 A CN 106619529A CN 201510706591 A CN201510706591 A CN 201510706591A CN 106619529 A CN106619529 A CN 106619529A
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- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title abstract description 12
- 239000008187 granular material Substances 0.000 title abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 65
- 239000000463 material Substances 0.000 claims abstract description 14
- 229920002472 Starch Polymers 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000008107 starch Substances 0.000 claims abstract description 13
- 235000019698 starch Nutrition 0.000 claims abstract description 13
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 12
- 229930195725 Mannitol Natural products 0.000 claims abstract description 12
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 12
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008101 lactose Substances 0.000 claims abstract description 12
- 239000000594 mannitol Substances 0.000 claims abstract description 12
- 235000010355 mannitol Nutrition 0.000 claims abstract description 12
- 239000002002 slurry Substances 0.000 claims abstract description 12
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 12
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000843 powder Substances 0.000 claims abstract description 4
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- 238000001035 drying Methods 0.000 claims description 14
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- 239000012467 final product Substances 0.000 claims description 10
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 claims description 10
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- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 2
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- 239000002775 capsule Substances 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- QVPLPSZGHFSYEQ-UHFFFAOYSA-N 2-amino-2-hydroxybutanoic acid Chemical compound CCC(N)(O)C(O)=O QVPLPSZGHFSYEQ-UHFFFAOYSA-N 0.000 description 1
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- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
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- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Levorotatory oxiracetam granule with good content uniformity is characterized by being prepared from the following raw materials and auxiliary materials (by weight): 1 part of levorotatory oxiracetam, 0.8-1.3 parts of mannitol, 1.0-1.5 parts of microcrystalline cellulose, 0.9-1.5 parts of sodium carboxymethylcellulose, 0.7-1.1 parts of lactose, 0.5-1.0 part of sorbitol, 0.08-0.12 part of talcum powder, 1.2-1.7 parts of polyethylene glycol 4000, 0.6-1.2 parts of hydroxypropyl methylcellulose, 5-10 parts of 6-8 wt% of starch slurry, and 3-8 parts of 30-50% (by volume) of an ethanol solution. The prepared levorotatory oxiracetam granule has the following advantages: powder layer amount is less; granular diameter is uniform; fluidity is good; angle of repose is less than 38 degrees; content uniformity is lower than +/- 5%; content uniformity of the granule is good; content RSD of multiple points is less than 1%; stability of storage process is good; the product is not easy for moisture absorption or caking; shelf life of the product is as long as 36 months; and the preparation technology is simple and feasible and is worthy of market promotion.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of good levo-oxiracetam particle of content uniformity and
Its preparation method.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, only
For central nervous system, cerebral cortex, hippocampus are mainly distributed on, have activation, protection or promote the function of nerve cell
Recover, improve the mnemonic learning function of disturbance of intelligence patient, and medicine itself without direct vasoactive, also without in
Pivot excitation, the impact to ability of learning and memory is a kind of lasting facilitation.
In 1987 in Italy's listing, the formulation of listing is tablet to the medicine, 800mg；Capsule, 800mg；Parenteral solution,
5ml：1g.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.
The rush that Ye Lei etc. goes into a coma caused by mentioning levo-oxiracetam in the A patents of Publication No. CN 103735545 to alcoholism
Effect of waking up is obvious, and dextrorotation Oxiracetam is not acted on substantially, and the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura
Western smooth 2 times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Zhang Feng etc. is in Publication No.
Levo-oxiracetam is disclosed in the patent of the A of CN 103599101 to traumatic brain injury rat caused by hydraulic pressure and freely falling body
Learning and memory cognition dysfunction improves significantly, and its drug effect is far above dextrorotation Oxiracetam.And 200mg/kg
Levo-oxiracetam is suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results show：Left-handed Aura
Western smooth and dextrorotation Oxiracetam is in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection gives left-handed and 2
After the racemization Oxiracetam of multiple dose in blood plasma levo-oxiracetam the equal no significant difference of main pharmacokinetic parameters.Safe medicine
The result of the tests such as reason, anxious malicious, long poison show that under isodose level, levo-oxiracetam is with Oxiracetam to tested
Animal or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows that levo-oxiracetam is Oxiracetam
The main active of drug effect is played in vivo, this product is used alone can reduce Clinical practice dosage, reduce potential poison secondary anti-
Should.
Existing levo-oxiracetam particle is primarily present mixed process main ingredient and is difficult to be well mixed, content lack of homogeneity, prepares
Process particle bisque is more, and particle diameter is wayward, and storage process stability is poor, and particle hygroscopicity is strong, connecting block easy to stick,
The technical problem such as shelf life is short.
The content of the invention
It is an object of the invention to provide a kind of content uniformity is good, good stability levo-oxiracetam particle.
Another object of the present invention is to provide the preparation method of above-mentioned levo-oxiracetam particle.
The purpose of the present invention is realized by following technical measures：
A kind of good levo-oxiracetam particle of content uniformity, it is characterised in that it be with levo-oxiracetam as raw material,
Add a certain amount of filler, flavouring, adhesive, lubricant, coating material to be obtained；Wherein described filler is
Starch, lactose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline cellulose, glucose, sodium carboxymethylcellulose,
One or more in sorbierite；The flavouring is that sucrose, maltose, ethylmaltol, Sucralose, stevia rebaudianum be sweet, mountain
One or more in pears alcohol, mannitol, glucose, aspartame；Described adhesive be water, ethanol, sucrose, starch slurry,
One or more in dextrin, carboxymethylcellulose calcium, polyvinylpyrrolidone；The lubricant be talcum powder, magnesium stearate,
One or more in polyethylene glycol, stearic acid, calcium stearate, lauryl sodium sulfate, superfine silica gel powder, magnesia, paraffin；
The coating material is Macrogol 4000, Macrogol 6000, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, polyethylene acetaldehyde
One or more in diethylamine ethyl ester, hydroxypropyl methyl cellulose phthalate.
Inventor has found that rational prescription proportion relation coordinates again specific supplementary material processing mode in research process, can make
Obtain above-mentioned levo-oxiracetam particle and be difficult moisture absorption, be difficult adhesion caking, grain diameter uniformly, content uniformity is little, product
Good stability, shelf life is long, and main ingredient is easier to mix, and content uniformity is good；The good left-handed Aura west of above-mentioned content uniformity
Smooth particle, it is characterised in that it is obtained by the supplementary material of following weight proportion：1 part of levo-oxiracetam, mannitol
0.8～1.3 part, 1.0～1.5 parts of microcrystalline cellulose, 0.9～1.5 part of sodium carboxymethylcellulose, 0.7～1.1 part of lactose, sorb
0.5～1.0 part of alcohol, 0.08～0.12 part of talcum powder, 1.2～1.7 parts of Macrogol 4000, Hydroxypropyl methylcellulose 0.6～1.2
Part, 5～10 parts of the starch slurry that mass fraction is 6%～8%, 3～8 parts of the ethanol solution that volume fraction is 30%～50%；
The levo-oxiracetam of recipe quantity is taken, the ethanol solution dissolving of recipe quantity is added, it is standby；Separately take mannitol, microcrystalline cellulose
Element, sodium carboxymethylcellulose, lactose, sorbierite are placed in Universalpulverizer, to be crushed and be placed in wet method system after 100 mesh sieves
In grain machine, the above-mentioned levo-oxiracetam ethanol solution handled well and starch slurry that mass fraction is 6%～8% are added, opened
Dynamic granulator (installing 18 mesh nylon mesh), starts granulation；Wet granular is put in fluid bed, hotbed temperature setting 50
DEG C～70 DEG C, starting drying, drying time is 50～55 minutes；Take Macrogol 4000, the hypromellose of recipe quantity
Element, add water the coating solution for making that quality volume fraction is 8%～10%, standby；Above-mentioned dry particl is put in fluid bed,
Hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50 DEG C；Coating solution is continuously added by the nozzle atomization of fluid bed
Fluidized bed, sets 50～60rpm of spouting velocity, and atomizing pressure is 0.8～1.0bar, continues air intake and is dried, and solution has sprayed
Continue afterwards to stop heating, cooling discharging after heating 10～15 minutes；Coated granule is placed in crushing and pelletizing machine, 20 are used
Mesh sieve whole grain；The talcum powder of recipe quantity was crushed into 100 mesh sieves, in adding the particle after whole grain, three-dimensional motion was used
Mixer mixing 10min～20min is obtained final product.
Further, in order that above-mentioned levo-oxiracetam granule content evenly, more preferably, shelf life is longer for stability,
A kind of levo-oxiracetam particle, it is characterised in that it is obtained by the supplementary material of following weight proportion：Left-handed Aura west
Smooth 1 part, 0.9～1.2 part of mannitol, 1.3～1.5 parts of microcrystalline cellulose, 1.0～1.3 parts of sodium carboxymethylcellulose, lactose
0.7～0.9 part, 0.7～0.9 part of sorbierite, 0.09～0.11 part of talcum powder, 1.3～1.5 parts of Macrogol 4000, hydroxypropyl first
0.8～1.0 part of cellulose, 6～9 parts of starch slurry, the ethanol that volume fraction is 30%～50% that mass fraction is 6%～8%
3～5 parts of solution；The levo-oxiracetam of recipe quantity is taken, the ethanol solution dissolving of recipe quantity is added, it is standby；Separately take sweet dew
Alcohol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite are placed in Universalpulverizer, crush 100 mesh sieves
After be placed in wet granulator, add the above-mentioned levo-oxiracetam ethanol solution handled well and mass fraction to be 6%～8%
Starch slurry, start granulator (install 18 mesh nylon mesh), start granulation；Wet granular is put in 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 the coating solution for making that quality volume fraction is 8%～10%, standby；By above-mentioned dry particl input
In fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature is 40～50 DEG C；The nozzle that coating solution is passed through into fluid bed
Atomization is continuously added to fluid bed, sets 50～60rpm of spouting velocity, and atomizing pressure is 0.8～1.0bar, continues air intake and is dried,
Solution stops heating, cooling discharging after continuing to heat 10～15 minutes after having sprayed；Coated granule is placed in crushing and pelletizing machine,
With 20 mesh sieve whole grains；The talcum powder of recipe quantity was crushed into 100 mesh sieves, in adding the particle after whole grain, three was used
Dimension movement mixer mixing 10min～20min is obtained final product.
The preparation method of the good levo-oxiracetam particle of a kind of content uniformity, it is characterised in that it is as follows
It is obtained：
1. supplementary material pre-treatment：The levo-oxiracetam for taking recipe quantity adds the ethanol solution dissolving of recipe quantity, obtains left-handed Austria
La Xitan ethanol solutions, it is standby；Take the filler of recipe quantity, flavouring to be placed in Universalpulverizer, crush 100 mesh
Sieve, it is standby；
2. pelletize：Gained mixed accessories powder and levo-oxiracetam ethanol solution after pre-treatment are taken, wet granulator is placed in
In, adhesive is added, start granulator (installing 18 mesh nylon mesh), start granulation；
3. it is dried：Wet granular is put in 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
Minute, it is ensured that pellet moisture≤3%；
4. coating：
(1) configuration of coating solution：The coating material of recipe quantity is taken, add water the solution for making that quality volume fraction is 8%～10%,
It is standby；
(2) coating process：Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50
℃；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity, atomization is set
Pressure is 0.8～1.0bar, continues air intake and is dried, and solution stops heating, cooling after continuing to heat 10～15 minutes after having sprayed
Discharging, obtains final product coated granule；
5. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, environment temperature is controlled
Less than 25 DEG C, relative humidity is below 50%；
6. total mixed：Lubricant was crushed into 100 mesh sieves, in adding the particle after whole grain, was mixed with three-dimensional motion mixer
10min～20min；
7. bag in：Packed with particles packing machine, set packing specification as 1g/ bags, below 25 DEG C of environment temperature of control,
Below relative humidity 50%, obtain final product.
The present invention has following beneficial effect：
Levo-oxiracetam particle bisque amount of the present invention is few, and grain diameter is homogeneous, good fluidity, and not sub- angle is less than 38 °,
Content uniformity is less than ± 5%, and granule content uniformity is good, and content RSD of multiple points is less than 1%, and storage process stability is good,
Product is difficult moisture absorption caking, and shelf life is up to 36 months, and preparation process is simple is feasible, is worth marketing.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are served only for
The present invention is further described, it is impossible to be interpreted as limiting the scope of the invention, without departing substantially from spirit of the invention
In the case of essence, the modification made to the inventive method, step or condition or replacement belong to the scope of the present invention.
Embodiment 1
A kind of good levo-oxiracetam particle of content uniformity, is obtained according to the following steps：
Preparation process：
1. supplementary material pre-treatment：The levo-oxiracetam for taking recipe quantity is dissolved in the ethanol solution of recipe quantity to obtain left-handed Aura
Western smooth ethanol solution, it is standby；Separately take mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite to be placed in
In Universalpulverizer, 100 mesh sieves were crushed, it is standby；
2. pelletize：The mixed-powder and levo-oxiracetam ethanol solution of pre-treatment gained auxiliary material are placed in wet granulator,
Starch slurry is added, starts granulator (installing 18 mesh nylon mesh), start granulation；
3. it is dried：Wet granular is put in 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
Minute, it is ensured that pellet moisture≤3%；
4. coating：
(1) configuration of coating solution：Macrogol 4000, the Hydroxypropyl methylcellulose of recipe quantity are taken, is added water and is made quality volume integral
Number is 8%～10% solution, standby；
(2) coating process：Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50
℃；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity, atomization is set
Pressure is 0.8～1.0bar, continues air intake and is dried, and solution stops heating, cooling after continuing to heat 10～15 minutes after having sprayed
Discharging, obtains final product coated granule；
5. whole grain, sub-sieve：Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, environment temperature is controlled
Less than 25 DEG C, relative humidity is below 50%；
6. total mixed：Talcum powder was crushed into 100 mesh sieves, in adding the particle after whole grain, was mixed with three-dimensional motion mixer
10min～20min；
7. bag in：Packed with particles packing machine, set packing specification as 1g/ bags, below 25 DEG C of environment temperature of control,
Below relative humidity 50%, obtain final product.
Test one：Particle is stopped sub- angle and is determined
1. test material：Sample after the completion of always mixing in the preparation process of embodiment 1
2. test method：After the completion of embodiment 1 is always mixed, respectively in upper, middle and lower of three-dimensional motion mixer, left and right
The separately sampled measure angle of repose of each point, judges its mobility；
3. result of the test：
4. conclusion (of pressure testing)：Can be seen that by upper table result of the test, five times measurement angle of repose is respectively less than 38 °, shows particle flow
Property is good.
Test two：Content uniformity
1. test material：Sample after the completion of always mixing in the preparation process of embodiment 1
2. test method：After the completion of embodiment 1 is always mixed, respectively in upper, middle and lower of three-dimensional motion mixer, left and right
The separately sampled 5g of each point, according to content assaying method content detection is carried out, and calculates content RSD of each sample point,
Evaluate whether to be well mixed；
3. result of the test：
4. conclusion (of pressure testing)：Can be seen that by upper table result of the test, this product content uniformity is good, RSD is less than 1%
Test three：Content uniformity
1. test material：10 bags of particulate samples obtained in Example 1, shine《Chinese Pharmacopoeia》Version two is attached within 2010
Content uniformity inspection under record granule item.
2. determination method：Take 10 bags of test sample, the weight of the weighed every bag of content of difference, per bag of weight and sign loading amount
Compare.
3. result of the test：Content uniformity inspection result see the table below：
4. conclusion (of pressure testing)：This product content uniformity can be seen that by upper table result of the test and be respectively less than ± 5%, it was demonstrated that content uniformity is steady
Fixed, content uniformity is little.
Test four：A kind of levo-oxiracetam granule stability experiment of the present invention
Experiment material：
Levo-oxiracetam particle：It is obtained for embodiment 1.
Acceleration study method：By levo-oxiracetam particle obtained in embodiment 1 by listing packaging, in putting Acceleration study case,
Certain hour is sampled, and investigation project is tested.
Acceleration study temperature：40±2℃
Acceleration study humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：Proterties, moisture, granularity, melting, relevant material, content, microbial limit
Accelerated test stability is recorded：
Acceleration study result shows：Accelerate June sample suitable with 0 month sample items Testing index quality, show that this product adds
Speed experiment June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：By levo-oxiracetam particle obtained in embodiment 1 by listing packaging, put and keep sample for a long time in case,
Certain hour is sampled, and investigation project is tested.
Long-term experiment temperature：25±2℃
Long-term experiment humidity：RH60% ± 10%
The investigation time：0th, 3,6,9,12,18,24,36 months
Inspection target：Proterties, moisture, granularity, melting, relevant material, content, microbial limit
Long term test stability is recorded：
Long term test shows：36 months proterties of this product long term test, moisture, granularity, melting, relevant material, contain
Amount, microbial limit without significant changes, meet every relevant regulations of production quality standard draft.This product is long-term
36 months steady qualities of test, therefore this product term of validity is minimum 36 months, long term test is still during continuing to investigate.
Embodiment 2
A kind of good levo-oxiracetam particle of content uniformity, is obtained according to the following steps：
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, particle is carried out respectively and is stopped
Test measurement result in sub- angle measure, content uniformity, content uniformity inspection and sample stability test, not sub- angle
Show that this product mobility of particle is good, not sub- angle is less than 37 °, and content uniformity test result shows that this product content uniformity is good,
Content RSD of its total mixed rear each point particle is less than 1%, and content uniformity test shows this product content uniformity less than ± 5%,
This product loading amount is stablized, controllable, and stability test result shows to accelerate June sample quality to stablize, long-term 36 months quality
It is stable, therefore this product term of validity at least 36 months.
Embodiment 3
A kind of good levo-oxiracetam particle of content uniformity, is obtained according to the following steps：
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, particle is carried out respectively and is stopped
Test measurement result in sub- angle measure, content uniformity, content uniformity inspection and sample stability test, not sub- angle
Show that this product mobility of particle is good, not sub- angle is less than 38 °, and content uniformity test result shows that this product content uniformity is good,
Content RSD of its total mixed rear each point particle is less than 1%, and content uniformity test shows this product content uniformity less than ± 5%,
This product loading amount is stablized, controllable, and stability test result shows to accelerate June sample quality to stablize, long-term 36 months quality
It is stable, therefore this product term of validity at least 36 months.
Embodiment 4-6：The good levo-oxiracetam particle of a kind of content uniformity, by the supplementary material preparation of following weight
, preparation method is with embodiment 1：
| Embodiment | 4 | 5 | 6 |
| Levo-oxiracetam | 1 part | 1 part | 1 part |
| Mannitol | 0.9 part | 1.0 part | 1.1 part |
| Microcrystalline cellulose | 1.5 part | 1.4 part | 1.3 part |
| Sodium carboxymethylcellulose | 1.3 part | 1.2 part | 1.1 part |
| Lactose | 0.7 part | 0.8 part | 0.9 part |
| Sorbierite | 0.7 part | 0.8 part | 0.9 part |
| Talcum powder | 0.09 part | 0.10 part | 0.11 part |
| Macrogol 4000 | 1.5 part | 1.4 part | 1.3 part |
| Hydroxypropyl methylcellulose | 0.8 part | 0.9 part | 1.0 part |
| Mass fraction is 7% starch slurry | 9 parts | 8 parts | 7 parts |
| Volume fraction is 30% ethanol | 3 parts | 4 parts | 5 parts |
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, embodiment 4,5,6
Particle is carried out respectively and stops the test of sub- angle measure, content uniformity, content uniformity inspection and sample stability, implement
Example 4,5,6 is stopped sub- angle test measurement result and shows that this product mobility of particle is good, and not sub- angle is less than 37 °, embodiment 4,
5th, 6 content uniformity test results show that this product content uniformity is good, and content RSD of its total mixed rear each point particle is less than
1%, the test of the content uniformity of embodiment 4,5,6 shows this product content uniformity less than ± 5%, and this product loading amount is stablized, controllable,
The stability test result of embodiment 4,5,6 shows to accelerate June sample quality to stablize, long-term 36 months steady qualities,
Therefore this product term of validity at least 36 months.
Claims (3)
1. the good levo-oxiracetam particle of a kind of content uniformity, it is characterised in that it is by the original of following weight proportion
Auxiliary material and following steps are obtained：1 part or so of levo-oxiracetam, 0.8～1.3 part or so of mannitol, microcrystalline cellulose 1.0～1.5
Part or so, 0.9～1.5 part or so of sodium carboxymethylcellulose, 0.7～1.1 part or so of lactose, 0.5～1.0 part or so of sorbierite,
0.08～0.12 part or so of talcum powder, 1.2～1.7 parts or so of Macrogol 4000,0.6～1.2 part or so of Hydroxypropyl methylcellulose,
Mass fraction is 6%～8% 5～10 parts or so of starch slurry, 3～8 parts of left sides of ethanol solution that volume fraction is 30%～50%
It is right；The levo-oxiracetam of recipe quantity is taken, the ethanol solution dissolving of recipe quantity is added, it is standby；Separately take mannitol, crystallite
Cellulose, sodium carboxymethylcellulose, lactose, sorbierite are placed in Universalpulverizer, crushed be placed in after 100 mesh sieves it is wet
In method granulator, the above-mentioned levo-oxiracetam ethanol solution handled well and starch slurry that mass fraction is 6%～8% are added,
Start granulator (installing 18 mesh nylon mesh), start granulation；Wet granular is put in fluid bed, hotbed temperature setting 50
DEG C～70 DEG C, starting drying, drying time is 50～55 minutes；Take Macrogol 4000, the hypromellose of recipe quantity
Element, add water the coating solution for making that quality volume fraction is 8%～10%, standby；Above-mentioned dry particl is put in fluid bed,
Hot-air is passed through, suspension fluidization is allowed to, bed temperature is 40～50 DEG C；Coating solution is continuously added by the nozzle atomization of fluid bed
Fluidized bed, sets 50～60rpm of spouting velocity, and atomizing pressure is 0.8～1.0bar, continues air intake and is dried, and solution has sprayed
Continue afterwards to stop heating, cooling discharging after heating 10～15 minutes；Coated granule is placed in crushing and pelletizing machine, 20 are used
Mesh sieve whole grain；The talcum powder of recipe quantity was crushed into 100 mesh sieves, in adding the particle after whole grain, three-dimensional motion was used
Mixer mixing 10min～20min is obtained final product.
2. the good levo-oxiracetam particle of a kind of content uniformity as claimed in claim 1, it is characterised in that it is
It is obtained by the supplementary material and following steps of following weight proportion：1 part or so of levo-oxiracetam, 0.9～1.2 part of mannitol
Left and right, 1.3～1.5 parts or so of microcrystalline cellulose, 1.0～1.3 parts or so of sodium carboxymethylcellulose, 0.7～0.9 part of lactose,
0.7～0.9 part or so of sorbierite, 0.09～0.11 part or so of talcum powder, 1.3～1.5 parts or so of Macrogol 4000, hydroxypropyl
0.8～1.0 part or so of methylcellulose, 6～9 parts or so of the starch slurry that mass fraction is 6%～8%, volume fraction are 30%～50%
3～5 parts or so of ethanol solution；The levo-oxiracetam of recipe quantity is taken, the ethanol solution dissolving of recipe quantity is added, it is standby；
Separately take mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, lactose, sorbierite to be placed in Universalpulverizer, crushed
It is placed in after 100 mesh sieves in wet granulator, the above-mentioned levo-oxiracetam ethanol solution handled well of addition and mass fraction are
6%～8% starch slurry, starts granulator (installing 18 mesh nylon mesh), starts granulation；Wet granular is put in 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 the coating solution for making that quality volume fraction is 8%～10%, standby；By above-mentioned dry particl input
In fluid bed, hot-air is passed through, is allowed to suspension fluidization, bed temperature is 40～50 DEG C；The nozzle that coating solution is passed through into fluid bed
Atomization is continuously added to fluid bed, sets 50～60rpm of spouting velocity, and atomizing pressure is 0.8～1.0bar, continues air intake and is dried,
Solution stops heating, cooling discharging after continuing to heat 10～15 minutes after having sprayed；Coated granule is placed in crushing and pelletizing machine,
With 20 mesh sieve whole grains；The talcum powder of recipe quantity was crushed into 100 mesh sieves, in adding the particle after whole grain, three was used
Dimension movement mixer mixing 10min～20min is obtained final product.
3. the preparation method of the good levo-oxiracetam particle of a kind of content uniformity as claimed in claim 1 or 2, its
It is characterised by, it is obtained as follows：
A. supplementary material pre-treatment：The levo-oxiracetam for taking recipe quantity adds the ethanol solution dissolving of recipe quantity, obtains left-handed Austria
La Xitan ethanol solutions, it is standby；Take the filler of recipe quantity, flavouring to be placed in Universalpulverizer, crush 100 mesh
Sieve, it is standby；
B. pelletize：Gained mixed accessories powder and levo-oxiracetam ethanol solution after pre-treatment are taken, wet granulator is placed in
In, adhesive is added, start granulator (installing 18 mesh nylon mesh), start granulation；
C. it is dried：Wet granular is put in 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
Minute, it is ensured that pellet moisture≤3%；
D. coating：
The configuration of D (1) coating solution：Take the coating material of recipe quantity, add water make quality volume fraction be 8%～10% it is molten
Liquid, it is standby；
D (2) coating process：Above-mentioned dry particl is put in fluid bed, hot-air is passed through, suspension fluidization is allowed to, bed temperature is
40～50 DEG C；Coating solution is continuously added to into fluid bed by the nozzle atomization of fluid bed, 50～60rpm of spouting velocity is set,
Atomizing pressure is 0.8～1.0bar, continues air intake and is dried, and solution stops heating after continuing to heat 10～15 minutes after having sprayed,
Cooling discharging, obtains final product coated granule；
E. whole grain, sub-sieve:Coated granule is placed in crushing and pelletizing machine, with 20 mesh sieve whole grains, environment temperature is controlled
Less than 25 DEG C, relative humidity is below 50%；
F. always mix：Lubricant was crushed into 100 mesh sieves, in adding the particle after whole grain, was mixed with three-dimensional motion mixer
10min～20min；
G. interior bag：Packed with particles packing machine, set packing specification as 1g/ bags, below 25 DEG C of environment temperature of control,
Below relative humidity 50%, obtain final product.
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| CN201510706591.9A CN106619529A (en) | 2015-10-27 | 2015-10-27 | Levorotatory oxiracetam granule with good content uniformity and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510706591.9A CN106619529A (en) | 2015-10-27 | 2015-10-27 | Levorotatory oxiracetam granule with good content uniformity and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
| 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 |
| CN103599101A (en) * | 2013-11-08 | 2014-02-26 | 南京优科生物医药研究有限公司 | Application of levo-oxiracetam in preparation of medicine for treating memory and intelligence disturbance |
-
2015
- 2015-10-27 CN CN201510706591.9A patent/CN106619529A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
| 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 |
| CN103599101A (en) * | 2013-11-08 | 2014-02-26 | 南京优科生物医药研究有限公司 | Application of levo-oxiracetam in preparation of medicine for treating memory and intelligence disturbance |
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