CN106511306A - Levo oxiracetam sustained-release capsule and preparation method thereof - Google Patents
Levo oxiracetam sustained-release capsule and preparation method thereof Download PDFInfo
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- CN106511306A CN106511306A CN201510579849.3A CN201510579849A CN106511306A CN 106511306 A CN106511306 A CN 106511306A CN 201510579849 A CN201510579849 A CN 201510579849A CN 106511306 A CN106511306 A CN 106511306A
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Abstract
A levo oxiracetam sustained-release capsule is characterized by being prepared from the following raw and auxiliary materials by weight: 1 part of levo oxiracetam, 1.5 parts-3.5 parts of a sustained-release skeleton material, 0.2 part-0.8 part of a retardant, 0.05 part-0.20 part of a lubricant, and 1 part-2 parts of an adhesive. The levo oxiracetam sustained-release capsule prepared according to the invention has good content uniformity, the RSD of the main drug content in the mixing process is less than 1%, the release speed is slow, and the release period is as long as 12 h, so compared with a traditional preparation, the product has the taking times reduced, and can be taken once a day; and at the same time, the product has good stability, has the shelf life as long as 24 months, has simple and feasible preparation process and is worthy of market promotion.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of levo-oxiracetam spansule and its preparation side
Method.
Background technology
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- OXo-1-pyrrolidine second
Acid amides, is that (compound is disclosed in the anti anoxia class cereboactive drug that synthesized in 1974 first of Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine synthesis can be promoted, promote brain metabolism,
Through blood-brain barrier, have stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease,
Brain trauma, brain tumor, intracranial infection, brain degenerative disease etc. also have preferable curative effect, and the drug toxicity is extremely low, nothing
Mutagenesis and carcinogenesis and genotoxicity.Giorgio et al. discloses the chemistry knot of Oxiracetam in US4118396
Structure and preparation method, Chiodini et al. are disclosed in WO9306826A, and clinical effectiveness proves S configurations (left-handed)
The drug effect of Oxiracetam is better than R configurations (dextrorotation), and Oxiracetam and levo-oxiracetam structure are as follows.
Existing Oxiracetam oral formulations are primarily present release and preferably can not control, it is impossible to reach the requirement of sustained release preparation,
The technical problem such as in preparation process drug content uniformity is poor.
The content of the invention
It is an object of the invention to provide a kind of release is good, good stability levo-oxiracetam spansule.
Another object of the present invention is to provide the preparation method of above-mentioned levo-oxiracetam spansule.
The purpose of the present invention is realized by following technical measures：
A kind of levo-oxiracetam spansule, it is characterised in that it is obtained by the supplementary material of following weight proportion：It is left
1 part of Oxiracetam of rotation, 1.5 parts～3.5 parts of sustained-release matrix material, 0.2 part～0.8 part of retarding agent, lubricant 0.05 part～0.20
Part, 1 part～2 parts of adhesive；Wherein described sustained-release matrix material be HPMC, ethyl cellulose, polyethylene,
Polypropylene, polysiloxanes, polyoxyethylene, lactose, fructose, sucrose, mannitol, sodium alginate, agar, shell are more
One or more in sugar, galactolipin；The retarding agent is fat, beeswax, Brazil wax, hydrogenated vegetable oil, firmly
One or more in lipidol, glycerin monostearate；The lubricant be magnesium stearate, talcum powder, silica,
One or more in octadecanol；Adhesive therefor is ethanol solution, starch slurry, sucrose solution, water, PVP second
Any one in alcoholic solution etc..
Inventor had found in research process, selects the sustained release bone of a certain proportion of lactose and HPMC K4M composition
Frame material, in the ethanol solution for coordinating a certain amount of Brazil wax, octadecanol and designated volume percentage concentration, can
So that above-mentioned levo-oxiracetam spansule rate of release be up to 12 hours, above-mentioned levo-oxiracetam spansule,
Characterized in that, it is obtained by the supplementary material of following weight proportion：1 part of levo-oxiracetam, lactose 0.5 part～1.2
Part, 1.0 parts～2.3 parts of HPMC, 0.3 part～0.7 part of Brazil wax, octadecanol 0.06 part～0.18
Part, volume fraction is 50%～80% 1 part～1.8 parts of ethanol solution.
Inventor has found specific supplementary material proportion relation by many experiments, in the specific main ingredient pre-treating method of cooperation,
It is remarkably improved drug content uniformity so that main ingredient mixes evenly, above-mentioned levo-oxiracetam spansule, its
It is characterised by, it is obtained by the supplementary material of following weight proportion：1 part of levo-oxiracetam, 0.6 part～1.0 parts of lactose,
1.2 parts～2.2 parts of HPMC K4M, 0.3 part～0.6 part of Brazil wax, octadecanol 0.08 part～0.13
Part, volume fraction is 50%～80% 1.2 parts～1.6 parts of ethanol solution；By levo-oxiracetam main ingredient with 3～7 times amount
Water dissolves are into solution, standby；Sustained-release matrix material, the retarding agent of recipe quantity is taken, the levo-oxiracetam aqueous solution is added,
Stirring mixing 10min～15min, is placed in air dry oven, arranges 40 DEG C～60 DEG C of temperature, be dried to moisture≤3%,
Take out, be placed in co-grinding in mixing mill and (all sieved by No. 5 and be able to must not be lacked by the amount of No. 6 sieves into fine powder
In total amount 95%), sieve, obtain final product.
Further, a kind of levo-oxiracetam spansule, it is characterised in that it is by the former auxiliary of following weight proportion
Material is obtained：1 part of levo-oxiracetam, 0.7 part～0.9 part of lactose, 1.5 parts～1.8 parts of HPMC K4M,
0.3 part～0.5 part of Brazil wax, 0.09 part～0.11 part of octadecanol, volume fraction is 50%～80% ethanol solution
1.3 parts～1.5 parts；It is by levo-oxiracetam with the water dissolves of 3～7 times of amounts into solution, standby；Take the sustained release bone of recipe quantity
Frame material, retarding agent, add the levo-oxiracetam aqueous solution, stirring mixing 10min～15min to be placed in air dry oven
In, 40 DEG C～60 DEG C of temperature is set, is dried to moisture≤3%, take out, co-grinding is placed in mixing mill into fine powder
(all sieved by No. 5 and can must not be less than the 95% of total amount by the amount of No. 6 sieves), is sieved, is obtained final product.
A kind of preparation method of levo-oxiracetam spansule, it is characterised in that it is obtained as follows：
1. supplementary material pre-treatment：It is by levo-oxiracetam main ingredient with the water dissolves of 3～7 times of amounts into solution, standby；Take prescription
The sustained-release matrix material of amount, retarding agent, add the levo-oxiracetam aqueous solution, stirring mixing 10min～15min to be placed in
In air dry oven, 40 DEG C～60 DEG C of temperature is set, is dried to moisture≤3%, is taken out, be placed in mixing mill and mix
Be ground into fine powder (all sieve by No. 5 and the 95% of total amount can must not be less than by the amount of No. 6 sieves), sieve；
2. pelletize：Adhesive is added, with 18 mesh sieve mixing granulations, the wet granular by made by, is placed in hot-air oven,
40 DEG C～60 DEG C of temperature is set, is dried to pellet moisture≤3%, whole grain (crosses 18 mesh sieves), standby；
3. 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；
4. fill：Filled with fully-automatic capsule filler, adjust loading amount 0.5g/ grain, whole filling process need to control relatively wet
Degree is below 50%；
5. aluminum-plastic packaged：Dispensed with aluminium-plastic bubble plate packing machine, per plate 10, operation room relative humidity have to be lower than 50%；
6. outsourcing is obtained final product.
The present invention has following beneficial effect：
Levo-oxiracetam spansule of the present invention has content uniformity good, and the RSD of mixed process drug content is less than
1%, rate of release is slow, and deenergized period is up to 12 hours, therefore this product can be reduced compared with conventional formulation and take number of times, takes daily
With once；Meanwhile, this product good stability, shelf life are up to 24 months, and preparation process is simple is feasible, are worth city
Promote field.
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 levo-oxiracetam spansule, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 1 part |
| Lactose | 0.7 part |
| Carboxylic the third methylcellulose K4M | 1.5 part |
| Brazil wax | 0.3 part |
| Octadecanol | 0.09 part |
| 70% ethanol solution | 1.3 part |
Make 1000
Preparation process：
1. supplementary material pre-treatment：It is by levo-oxiracetam main ingredient with the water dissolves of 3～7 times of amounts into solution, standby；Take prescription
The sustained-release matrix material of amount, retarding agent, add the levo-oxiracetam aqueous solution, stirring mixing 10min～15min to be placed in
In air dry oven, 40 DEG C～60 DEG C of temperature is set, is dried to moisture≤3%, is taken out, be placed in mixing mill and mix
Be ground into fine powder (all sieve by No. 5 and the 95% of total amount can must not be less than by the amount of No. 6 sieves), sieve；
2. pelletize：Adhesive is added, with 18 mesh sieve mixing granulations, the wet granular by made by, is placed in hot-air oven,
40 DEG C～60 DEG C of temperature is set, is dried to pellet moisture≤3%, whole grain (crosses 18 mesh sieves), standby；
3. 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；
4. fill：Filled with fully-automatic capsule filler, adjust loading amount 0.5g/ grain, whole filling process need to control relatively wet
Degree is below 50%；
5. aluminum-plastic packaged：Dispensed with aluminium-plastic bubble plate packing machine, per plate 10, operation room relative humidity have to be lower than 50%；
6. outsourcing is obtained final product.
In order to be better understood from the present invention, the beneficial of invention medicine is expanded on further below by way of stability test of the present invention
Effect, rather than limitation of the present invention.
Test one：Content uniformity
1. test material：Sample after the completion of always mixing in 1 preparation process of embodiment
2. test method：Embodiment 1 it is total it is mixed complete 15 minutes after, respectively the upper, middle and lower of three-dimensional motion mixer,
The separately sampled 5g of left and right each point, carries out content detection according to content assaying method, calculates the content of each sample point
RSD, evaluates 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 two：Drug release determination
1. test material：1 test specimen of Example
2. test method：Spansule obtained above is taken as sample, according to release inspection technique (Chinese Pharmacopoeia 2010 editions two
Portion's annex X the second methods of D), using the device of the second method of dissolution method, with water 900ml as dissolution medium, turn
Speed is 100 turns per minute, is operated in accordance with the law, and Jing 1,2,4,6,8,12 hours takes release solution 10ml, is used
0.45 μm of miillpore filter filtration, takes subsequent filtrate as need testing solution, and the supplementary release in process container in time
Medium 10ml.Another precision weighs levo-oxiracetam reference substance about 10mg and puts in 25ml measuring bottles, with water dissolves and dilute
Release to scale, shake up, as reference substance solution.Precision measures above-mentioned reference substance solution and need testing solution is each respectively
20 μ l, determine according to the chromatographic condition of assay.Calculate the release (referring to Accumulation dissolution) of per.
3. result of the test：The measurement result of the release of spansule sample of the present invention see the table below
4. conclusion (of pressure testing)：Levo-oxiracetam spansule main ingredient levo-oxiracetam is up to 12 into slow release, release time
Hour, the requirement of sustained release preparation can be met.
Test three：A kind of levo-oxiracetam spansule stability experiment of the present invention
Experiment material：
Levo-oxiracetam spansule：It is obtained for embodiment 1.
Acceleration study method：By levo-oxiracetam spansule obtained in embodiment 1 by listing packaging, Acceleration study is put
In case, certain hour sampling is tested to investigation project.
Acceleration study temperature：40±2℃
Humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：
Proterties, moisture, relevant material, release, 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 keep stable, and this product stability is preferable.
Long-term experiment method：By levo-oxiracetam spansule obtained in embodiment 1 by listing packaging, put and keep sample for a long time
In case, certain hour sampling is tested to investigation project.
Acceleration study temperature：25±2℃
Humidity：RH60% ± 10%
The investigation time：0th, 3,6,9,12,18,24 months
Proterties, moisture, relevant material, release, content, microbial limit
Long term test stability is recorded：
Long term test shows：It is 24 months proterties of this product long term test, moisture, relevant material, release, content, micro-
Biological limit without significant changes, meets every relevant regulations of production quality standard draft.This product long term test 24
Individual month steady quality, therefore this product term of validity is minimum 24 months, long term test is still during continuing to investigate.
Embodiment 2
A kind of levo-oxiracetam spansule, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 1 part |
| Lactose | 0.9 part |
| Carboxylic the third methylcellulose K4M | 1.8 part |
| Brazil wax | 0.5 part |
| Octadecanol | 0.11 part |
| 70% ethanol solution | 1.5 part |
Make 1000
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, content is carried out respectively equal
The test of even property, drug release determination and sample stability, content uniformity test result show that this product content uniformity is good,
RSD is less than 1%, and drug release determination result of the test shows levo-oxiracetam in slow release, and release time is up to 12
Hour, the requirement of sustained release preparation can be met, stability test result shows to accelerate June sample quality stable, long-term by 24
Individual month steady quality, therefore this product term of validity at least 24 months.
Embodiment 3
A kind of levo-oxiracetam spansule, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 1 part |
| Lactose | 0.8 part |
| Carboxylic the third methylcellulose K4M | 1.6 part |
| Brazil wax | 0.4 part |
| Octadecanol | 1.0 part |
| 70% ethanol solution | 1.3 part |
Make 1000
Preparation process：It is obtained according to the preparation technology of embodiment 1.By the test method of embodiment 1, content is carried out respectively equal
The test of even property, drug release determination and sample stability, content uniformity test result show that this product content uniformity is good,
RSD is less than 1%, and drug release determination result of the test shows levo-oxiracetam in slow release, and release time is up to 12
Hour, the requirement of sustained release preparation can be met, stability test result shows to accelerate June sample quality stable, long-term by 24
Individual month steady quality, therefore this product term of validity at least 24 months.
Embodiment 4-6：A kind of levo-oxiracetam spansule, is prepared by the supplementary material of following weight, preparation side
Method is with embodiment 1：
By the test method of embodiment 1, content uniformity test, drug release determination and stability test is carried out respectively,
4,5,6 sample size uniformity test result of embodiment shows that this product content uniformity is good, and RSD is less than 1%, implements
4,5,6 sample drug release determination result of the test of example shows levo-oxiracetam in slow release, and release time is up to 12
Hour, the requirement of sustained release preparation can be met, 4,5,6 sample stability result of the test of embodiment shows to accelerate June sample
Steady quality, long-term 24 months steady qualities, therefore this product term of validity at least 24 months.
Claims (5)
1. a kind of levo-oxiracetam spansule, it is characterised in that it is obtained by the supplementary material of following weight proportion:1 part of levo-oxiracetam, 1.5 parts ~ 3.5 parts of sustained-release matrix material, 0.2 part ~ 0.8 part of retarding agent, 0.05 part ~ 0.20 part of lubricant, 1 part ~ 2 parts of adhesive；Wherein described sustained-release matrix material is HPMC, ethyl cellulose, polyethylene, polypropylene, polysiloxanes, polyoxyethylene, lactose, fructose, sucrose, mannitol, sodium alginate, agar, chitin, one or more in galactolipin；The retarding agent is fat, beeswax, Brazil wax, hydrogenated vegetable oil, stearyl alcohol, one or more in glycerin monostearate；The lubricant is magnesium stearate, talcum powder, silica, one or more in octadecanol；Adhesive therefor is ethanol solution, starch slurry, sucrose solution, water, any one in PVP ethanol solution etc..
2. levo-oxiracetam spansule as claimed in claim 1, it is characterised in that it is obtained by the supplementary material of following weight proportion：1 part of levo-oxiracetam, 0.5 part ~ 1.2 parts of lactose, 1.0 parts ~ 2.3 parts of HPMC, 0.3 part ~ 0.7 part of Brazil wax, 0.06 part ~ 0.18 part of octadecanol, 1 part ~ 1.8 parts of the ethanol solution of volume fraction about 50% ~ 80%.
3. levo-oxiracetam spansule as claimed in claim 2, it is characterised in that it be by following weight proportion supplementary material and step be obtained：1 part of levo-oxiracetam, 0.6 part ~ 1.0 parts of lactose, 1.2 parts ~ 2.2 parts of HPMC K4M, 0.3 part ~ 0.6 part of Brazil wax, 0.08 part ~ 0.13 part of octadecanol, volume fraction are 50% ~ 80% 1.2 parts ~ 1.6 parts of ethanol solution；It is by levo-oxiracetam main ingredient with the water dissolves of 3 ~ 7 times of amounts into solution, standby；Take the sustained-release matrix material of recipe quantity, add the levo-oxiracetam aqueous solution, stirring mixing 10min ~ 15min to be placed in air dry oven, 40 DEG C ~ 60 DEG C of temperature is set, be dried to moisture≤3%, take out, co-grinding is placed in mixing mill into fine powder（All sieved by No. 5 and the 95% of total amount can must not be less than by the amount of No. 6 sieves）, sieve, obtain final product.
4. levo-oxiracetam spansule as claimed in claim 3, it is characterised in that it be by following weight proportion supplementary material and step be obtained：1 part of levo-oxiracetam, 0.7 part ~ 0.9 part of lactose, 1.5 parts ~ 1.8 parts of HPMC K4M, 0.3 part ~ 0.5 part of Brazil wax, 0.09 part ~ 0.11 part of octadecanol, volume fraction are 50% ~ 80% 1.3 parts ~ 1.5 parts of ethanol solution；It is by levo-oxiracetam with the water dissolves of 3 ~ 7 times of amounts into solution, standby；Take the sustained-release matrix material of recipe quantity, add the levo-oxiracetam aqueous solution, stirring mixing 10min ~ 15min to be placed in air dry oven, 40 DEG C ~ 60 DEG C of temperature is set, be dried to moisture≤3%, take out, co-grinding is placed in mixing mill into fine powder（All sieved by No. 5 and the 95% of total amount can must not be less than by the amount of No. 6 sieves）, sieve, obtain final product.
5. the preparation method of the levo-oxiracetam spansule as any one of claim 1 ~ 4, it is characterised in that it is obtained as follows：
A. supplementary material pre-treatment：It is by levo-oxiracetam main ingredient with the water dissolves of 3 ~ 7 times of amounts into solution, standby；Take sustained-release matrix material, the retarding agent of recipe quantity, add the levo-oxiracetam aqueous solution, stirring mixing 10min ~ 15min to be placed in air dry oven, 40 DEG C ~ 60 DEG C of temperature is set, be dried to moisture≤3%, take out, co-grinding is placed in mixing mill into fine powder（All sieved by No. 5 and the 95% of total amount can must not be less than by the amount of No. 6 sieves）, sieve；
B. pelletize：Adhesive is added, with 18 mesh sieve mixing granulations, the wet granular by made by, is placed in hot-air oven, 40 DEG C ~ 60 DEG C of temperature is set, be dried to pellet moisture≤3%, whole grain（Cross 18 mesh sieves）, it is standby；
C. it is total mixed：Lubricant was crushed into 100 mesh sieves, in adding the particle after whole grain, with three-dimensional motion mixer mixing 10min ~ 20min；
D. fill：Filled with fully-automatic capsule filler, adjust loading amount 0.5g/ grain, whole filling process need to control relative humidity below 50%；
E. it is aluminum-plastic packaged：Dispensed with aluminium-plastic bubble plate packing machine, per plate 10, operation room relative humidity have to be lower than 50%；
F. outsourcing is obtained final product.
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| CN201510579849.3A CN106511306B (en) | 2015-09-11 | 2015-09-11 | Levo-oxiracetam sustained-release capsule 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 |
| CN103494790A (en) * | 2013-09-30 | 2014-01-08 | 石药集团欧意药业有限公司 | Oxiracetam capsule and preparation method thereof |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
-
2015
- 2015-09-11 CN CN201510579849.3A patent/CN106511306B/en active Active
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 |
| CN103494790A (en) * | 2013-09-30 | 2014-01-08 | 石药集团欧意药业有限公司 | Oxiracetam capsule and preparation method thereof |
| CN103599083A (en) * | 2013-12-06 | 2014-02-26 | 重庆东泽医药科技发展有限公司 | Levo-oxiracetam slow-release tablet and preparation method thereof |
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