CN107625753A - A kind of levo-oxiracetam spansule of high income and preparation method thereof - Google Patents

Abstract

A kind of levo-oxiracetam spansule of high income is made up of following supplementary material：1 part of levo-oxiracetam, 1.2 parts ~ 1.9 parts of lactose, 0.8 part ~ 1.5 parts of HPMC K4M, 0.6 part ~ 1.1 parts of Brazil wax, 0.26 part ~ 0.38 part of octadecanol, 0.2 ~ 0.8 part of calcium monohydrogen phosphate, 0.5 ~ 1.1 part of superfine silica gel powder, 0.12 ~ 0.19 part of sodium thiosulfate, mass fraction are 5% ~ 10% 2.8 parts ~ 3.9 parts of PVP K30 ethanol solution；Bisque is few after the present invention has particle whole grain, product yield is up to more than 92.7%, rate of release is slow, deenergized period up to 12 hours, simultaneously, this product stability is good, storage process capsule will not be sticked together, and impurity increment is only 0.06%, and shelf life is up to 24 months, preparation technology simple possible, it is worth marketing.

Description

A kind of levo-oxiracetam spansule of high income and preparation method thereof

Technical field

The invention mainly relates to pharmaceutical technology field, and in particular to a kind of levo-oxiracetam spansule of high income and Its preparation method.

Background technology

It is a kind of new medicine for central nervous system for promoting study, strengthening memory that cereboactive drug, which is also known as cereboactive drug,. Nootropics requires that selection index system in cerebral cortex, has selection activation, protection and promotes damaged nerve cell functional rehabilitation Feature.Different from other neurologic agents be a little their above-mentioned effect not by network or olfactory bulb, but directly Act on cortex.Behavior is neither influenceed, also without calm excitation, therefore such medicine has caused the extensive concern of people and emerging Interest, it is also growing day by day to the demand of such medicine.

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.

Existing levo-oxiracetam spansule is primarily present release and can not preferably controlled, it is impossible to reaches sustained release preparation It is required that particle bisque is more after whole grain, product yield is low, storage process capsule connecting block easy to stick, the skills such as impurity increment is larger Art problem.

The content of the invention

It is an object of the invention to provide a kind of release is good, levo-oxiracetam spansule of high income.

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 of high income, it is characterised in that it be using levo-oxiracetam as raw material, A certain amount of sustained-release matrix material, retarding agent, lubricant, adhesive and stabilizer is added to be made；Wherein described sustained-release matrix Material is HPMC, ethyl cellulose, polyethylene, polypropylene, polysiloxanes, polyoxyethylene, lactose, fructose, sugarcane One or more in sugar, mannitol, sodium alginate, agar, chitin, galactolipin；The retarding agent be fat, beeswax, In Brazil wax, hydrogenated vegetable oil, stearyl alcohol, glycerin monostearate, superfine silica gel powder, calcium monohydrogen phosphate, microcrystalline cellulose It is one or more of；The lubricant is the one or more in magnesium stearate, talcum powder, silica, octadecanol；It is used viscous Mixture is ethanol solution, starch slurry, sucrose solution, water, any of PVP K30 ethanol solution；The stabilizer is dimension Raw plain C, methionine, the one or more in sodium thiosulfate, citric acid, tartaric acid, cysteine, glutathione.

Inventor has found that specific supplementary material species coordinates specific supplementary material consumption proportion relation in research process, Coordinate specific preparation method again, may be such that above-mentioned levo-oxiracetam spansule release time be up to 12 hours, whole grain it Particle bisque is few afterwards, and product yield is high, storage process capsule will not adhesion caking, relevant material increment is also smaller, above-mentioned left-handed Oxiracetam spansule, it is characterised in that it is made up of the supplementary material of following weight proportion：1 part of levo-oxiracetam, breast 1.2 parts~1.9 parts, 0.8 part~1.5 parts of HPMC K4M of sugar, 0.6 part~1.1 parts of Brazil wax, octadecanol 0.26 part~0.38 part, 0.2~0.8 part of calcium monohydrogen phosphate, 0.5~1.1 part of superfine silica gel powder, 0.12~0.19 part of sodium thiosulfate, Mass fraction is 5%~10% 2.8 parts~3.9 parts of PVP K30 ethanol solution；Take levo-oxiracetam, the breast of recipe quantity Sugar, HPMC K4M, Brazil wax, calcium monohydrogen phosphate, superfine silica gel powder, sodium thiosulfate are put in mixing mill and mixed Conjunction is ground into fine powder (all sieved by No. 5 and can must not be less than the 95% of total amount by the amounts of No. 6 sieves), sieving；Add poly- dimension Ketone K30 ethanol solution adhesives, with 18 mesh sieve mixing granulations, manufactured wet granular is placed in hot-air oven, sets temperature 40 ~60 DEG C, dry to pellet moisture≤3%, whole grain (crosses 24 mesh sieves), standby；Octadecanol lubricant be crushed into 100 mesh sieves, Add in the particle after whole grain, with three-dimensional motion mixer mixing 10min~20min.

Further, in order that particle bisque is less after obtaining levo-oxiracetam spansule whole grain, product yield is higher, Above-mentioned levo-oxiracetam spansule, it is characterised in that it is made by the supplementary material of following weight proportion：Left-handed Aura west Smooth 1 part, 1.3 parts~1.6 parts of lactose, 1.1 parts~1.3 parts of HPMC K4M, 0.8 part~1.0 parts of Brazil wax, 0.28 part~0.31 part of octadecanol, 0.5~0.7 part of calcium monohydrogen phosphate, 0.8~1.0 part of superfine silica gel powder, sodium thiosulfate 0.15~ 0.18 part, mass fraction is 6%~8% 3.1 parts~3.5 parts of PVP K30 ethanol solution；Take the left-handed Aura west of recipe quantity Smooth, lactose, HPMC K4M, Brazil wax, calcium monohydrogen phosphate, superfine silica gel powder, sodium thiosulfate put mixing mill Middle co-grinding (is all sieved by No. 5 into fine powder and can must not be less than the 95% of total amount by the amounts of No. 6 sieves), sieving；Add PVP K30 ethanol solution adhesive, with 18 mesh sieve mixing granulations, manufactured wet granular is placed in hot-air oven, temperature is set 40~60 DEG C of degree, dry to pellet moisture≤3%, whole grain (crosses 24 mesh sieves), standby；Octadecanol lubricant crushed 100 Mesh sieve, add in the particle after whole grain, with three-dimensional motion mixer mixing 10min~20min.

The preparation method of the levo-oxiracetam spansule of a kind of high income, it is characterised in that it is as follows It is obtained：

1. supplementary material pre-treatment：Main ingredient, sustained-release matrix material, retarding agent and the stabilizer of recipe quantity is taken to put co-grinding Co-grinding (is all sieved by No. 5 into fine powder and can must not be less than the 95% of total amount by the amounts of No. 6 sieves) in machine, sieving；

2. granulation：Adhesive is added, with 18 mesh sieve mixing granulations, manufactured wet granular is placed in hot-air oven, is set 40~60 DEG C of temperature, dry to pellet moisture≤3%, whole grain (crosses 24 mesh sieves), standby；

It is 3. total mixed：Lubricant be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion mixer 10min~20min；

4. filling：Filled with fully-automatic capsule filler, adjust loading amount 0.5g/ grains, whole filling process need to control relatively Humidity is below 50%；

It is 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 produces.

The present invention has following beneficial effect：

Bisque is few after levo-oxiracetam spansule of the present invention has particle whole grain, product yield be up to 92.7% with On, rate of release is slow, and deenergized period was up to 12 hours, therefore this product can reduce compared with conventional formulation and take number, take once a day ；Meanwhile this product stability is good, storage process capsule will not stick together, and impurity increment is only 0.05%, and shelf life is up to 24 months, preparation technology simple possible, it 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 levo-oxiracetam spansule of high income, is made according to the following steps：

Composition	Dosage
		Levo-oxiracetam	1 part
Lactose	1.3 part
		HPMC K4M	1.1 part
Brazil wax	0.8 part
		Octadecanol	0.28 part
Calcium monohydrogen phosphate	0.5 part
		Superfine silica gel powder	0.8 part
Sodium thiosulfate	0.15 part
		6% PVP K30 ethanol solution	3.1 part

It is made 1000

Preparation process：

1. supplementary material pre-treatment：Take the levo-oxiracetam of recipe quantity, lactose, HPMC K4M, babassu Wax, calcium monohydrogen phosphate, superfine silica gel powder, sodium thiosulfate put in mixing mill co-grinding into fine powder (all by No. 5 sieves and energy By No. 6 sieve amounts must not be less than total amount 95%), sieving；

2. granulation：PVP K30 ethanol solution adhesive is added, with 18 mesh sieve mixing granulations, manufactured wet granular is put In hot-air oven, 40~60 DEG C of temperature is set, dried to pellet moisture≤3%, whole grain (crosses 24 mesh sieves), standby；

It is 3. total mixed：Octadecanol lubricant be crushed into 100 mesh sieves, add in the particle after whole grain, mixed with three-dimensional motion Conjunction machine mixing 10min~20min；

4. filling：Filled with fully-automatic capsule filler, adjust loading amount 0.5g/ grains, whole filling process need to control relatively Humidity is below 50%；

It is 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 produces.

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：Yield calculates

1. test material：Gained finished product in the preparation process of embodiment 1

2. test method：With quality obtained by the quality of inventory and finished product, product yield is calculated；

3. result of the test：It see the table below

Name of product	Inventory	Packaging material weight	Finished weight	Yield
					Embodiment 1	498.7g	32.7g	492.7g	92.7%

4. conclusion (of pressure testing)：It can be seen that product yield is up to 92.7% by upper table result of the test.

Experiment two：Drug release determination

1. test material：The test specimen of Example 1

2. test method：Spansule obtained above is taken as sample, according to release inspection technique (Chinese Pharmacopoeia 2010 editions Two the second methods of annex X D), using the device of the method for dissolution method second, using water 900ml as dissolution medium, rotating speed is every 100 turns of minute, operate in accordance with the law, through 1,2,4,6,8,12 hour, take release solution 10ml, filtered with 0.45 μm of miillpore filter, Subsequent filtrate is taken as need testing solution, and supplements dissolution medium 10ml in process container in time.Another precision weighs left-handed Aura Western smooth reference substance about 10mg is put in 25ml measuring bottles, is dissolved with water and is diluted to scale, shaken up, as reference substance solution.Essence respectively It is close to measure above-mentioned reference substance solution and each 20 μ l of need testing solution, determined according to the chromatographic condition of assay.Calculate every Release (refers to Accumulation dissolution).

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 discharges into slow, release time length Up to 12 hours, the requirement of sustained release preparation can be met.

Experiment three：A kind of levo-oxiracetam spansule stability experiment of the present invention

Experiment material：

Levo-oxiracetam spansule：It is made for embodiment 1.

Acceleration study method：Levo-oxiracetam spansule made from embodiment 1 is packed by listing, puts Acceleration study In case, certain time sampling, investigation project is tested.

Acceleration study temperature：40±2℃

Humidity：RH75% ± 5%

Investigate the time：0th, 1,2,3, June

Inspection target：

Character, moisture, relevant material, release, 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：Levo-oxiracetam spansule made from embodiment 1 is packed by listing, puts and keeps sample for a long time In case, certain time sampling, investigation project is tested.

Acceleration study temperature：25±2℃

Humidity：RH60% ± 10%

Investigate the time：0th, 3,6,9,12,18 months

Character, moisture, relevant material, release, content, microbial limit

Long term test stability records：

Long term test shows：24 months characters of this product long term test, moisture, relevant material, release, content, microorganism Limit meets every relevant regulations of production quality standard draft without significant changes.24 lunar geology of this product long term test Amount is stable, and impurity increment is only 0.05%, therefore minimum 24 months of this product term of validity, and long term test is still during investigation is continued.

Embodiment 2

A kind of levo-oxiracetam spansule, is made according to the following steps：

Composition	Dosage
		Levo-oxiracetam	1 part
Lactose	1.6 part
		HPMC K4M	1.3 part
Brazil wax	1.0 part
		Octadecanol	0.31 part
Calcium monohydrogen phosphate	0.7 part
		Superfine silica gel powder	1.0 part
Sodium thiosulfate	0.18 part
		8% PVP K30 ethanol solution	3.5 part

It is made 1000

Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, divide yield meter Calculate result and show that product yield is up to 94.6%, drug release determination result of the test shows levo-oxiracetam spansule in slow Release, release time are up to 12 hours, can meet the requirement of sustained release preparation, and stability test result shows to accelerate 6 lunar sample qualities Amount is stable, does not find capsule adhesion phenomenon, impurity increment is only 0.06%, long-term 24 months steady qualities, does not find that capsule glues Even phenomenon, impurity increment is only 0.06%, therefore this product term of validity at least 24 months.

Embodiment 3

A kind of levo-oxiracetam spansule, is made according to the following steps：

Composition	Dosage
		Levo-oxiracetam	1 part
Lactose	1.5 part
		HPMC K4M	1.2 part
Brazil wax	0.9 part
		Octadecanol	0.30 part
Calcium monohydrogen phosphate	0.6 part
		Superfine silica gel powder	0.9 part
Sodium thiosulfate	0.17 part
		7% PVP K30 ethanol solution	3.3 part

It is made 1000

Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, divide yield meter Calculate result and show that product yield is up to 93.7%, drug release determination result of the test shows levo-oxiracetam spansule in slow Release, release time are up to 12 hours, can meet the requirement of sustained release preparation, and stability test result shows to accelerate 6 lunar sample qualities Amount is stable, does not find capsule adhesion phenomenon, impurity increment is only 0.05%, long-term 24 months steady qualities, does not find that capsule glues Even phenomenon, impurity increment is only 0.06%, therefore this product term of validity at least 24 months.

Embodiment 4-6：A kind of levo-oxiracetam spansule, is prepared, preparation side by the supplementary material of following weight Method is the same as embodiment 1：

It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, the yield point of embodiment 4,5,6 Not Wei 95.1%, 94.6%, 93.7%, the drug release determination result of the test of embodiment 4,5,6 show levo-oxiracetam be sustained glue Capsule can meet the requirement of sustained release preparation, the stability of embodiment 4,5,6 in slowly release, release time up to 12 hours Result of the test shows that acceleration sample quality in June is stable, and sample does not occur capsule adhesion phenomenon, and impurity increment is only respectively 0.04%th, 0.04%, 0.05%, long-term 24 months steady qualities, sample does not occur capsule adhesion phenomenon, impurity increment difference Only 0.05%, 0.04%, 0.06%, therefore this product term of validity at least 24 months.

Claims (3)

1. the levo-oxiracetam spansule of a kind of high income, it is characterised in that it is by the supplementary material of following weight proportion Composition：1 part of levo-oxiracetam, 1.2 parts ~ 1.9 parts of lactose, 0.8 part ~ 1.5 parts of HPMC K4M, Brazil wax 0.6 part ~ 1.1 parts, 0.26 part ~ 0.38 part of octadecanol, 0.2 ~ 0.8 part of calcium monohydrogen phosphate, 0.5 ~ 1.1 part of superfine silica gel powder, thio sulphur Sour 0.12 ~ 0.19 part of sodium, mass fraction are 5% ~ 10% 2.8 parts ~ 3.9 parts of PVP K30 ethanol solution；Take the left-handed of recipe quantity Oxiracetam, lactose, HPMC K4M, Brazil wax, calcium monohydrogen phosphate, superfine silica gel powder, sodium thiosulfate are put mixed Co-grinding is closed in pulverizer into fine powder（All sieved by No. 5 and can must not be less than the 95% of total amount by the amounts of No. 6 sieves）, mistake Sieve；PVP K30 ethanol solution adhesive is added, with 18 mesh sieve mixing granulations, by manufactured wet granular, is placed in hot-air oven In, 40 ~ 60 DEG C of temperature is set, dried to pellet moisture≤3%, whole grain（Cross 24 mesh sieves）, it is standby；By octadecanol lubricant powder The broken mesh sieve of mistake 100, add in the particle after whole grain, with three-dimensional motion mixer mixing 10min ~ 20min.

2. levo-oxiracetam spansule as claimed in claim 1, it is characterised in that it is by the original of following weight proportion Auxiliary material is made：1 part of levo-oxiracetam, 1.3 parts ~ 1.6 parts of lactose, 1.1 parts ~ 1.3 parts of HPMC K4M, cohune 0.8 part ~ 1.0 parts of palmitic acid wax, 0.28 part ~ 0.31 part of octadecanol, 0.5 ~ 0.7 part of calcium monohydrogen phosphate, 0.8 ~ 1.0 part of superfine silica gel powder, sulphur 0.15 ~ 0.18 part of sodium thiosulfate, mass fraction are 6% ~ 8% 3.1 parts ~ 3.5 parts of PVP K30 ethanol solution；Take recipe quantity Levo-oxiracetam, lactose, HPMC K4M, Brazil wax, calcium monohydrogen phosphate, superfine silica gel powder, sodium thiosulfate Co-grinding is put in mixing mill into fine powder（All sieved by No. 5 and can must not be less than total amount by the amounts of No. 6 sieves 95%）, sieving；PVP K30 ethanol solution adhesive is added, with 18 mesh sieve mixing granulations, by manufactured wet granular, is placed in heat In wind baking oven, 40 ~ 60 DEG C of temperature is set, dried to pellet moisture≤3%, whole grain（Cross 24 mesh sieves）, it is standby；Octadecanol is moistened Lubrication prescription crushed 100 mesh sieves, add in the particle after whole grain, with three-dimensional motion mixer mixing 10min ~ 20min.

3. the preparation method of levo-oxiracetam spansule as claimed in claim 1 or 2, it is characterised in that it is by such as Made from lower step：

A. supplementary material pre-treatment：Main ingredient, sustained-release matrix material, retarding agent and the stabilizer of recipe quantity is taken to put in mixing mill Co-grinding is into fine powder（All sieved by No. 5 and can must not be less than the 95% of total amount by the amounts of No. 6 sieves）, sieving；

B. pelletize：Adhesive is added, with 18 mesh sieve mixing granulations, manufactured wet granular is placed in hot-air oven, temperature is set 40 ~ 60 DEG C, dry to pellet moisture≤3%, whole grain（Cross 24 mesh sieves）, it is standby；

C. 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；

D. fill：Filled with fully-automatic capsule filler, adjust loading amount 0.5g/ grains, 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 produces.