CN107625749A - It is a kind of（S）Pyrrolidine acetamide spansule of 4 hydroxyl, 2 oxo 1 and preparation method thereof - Google Patents
It is a kind of（S）Pyrrolidine acetamide spansule of 4 hydroxyl, 2 oxo 1 and preparation method thereof Download PDFInfo
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- CN107625749A CN107625749A CN201610550502.0A CN201610550502A CN107625749A CN 107625749 A CN107625749 A CN 107625749A CN 201610550502 A CN201610550502 A CN 201610550502A CN 107625749 A CN107625749 A CN 107625749A
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Abstract
It is a kind of（S）The pyrrolidine acetamide spansule of 4 hydroxyl, 2 oxo 1 is made up of following supplementary material：（S）1 part of 4 hydroxyl, 2 oxo, 1 pyrrolidine acetamide, 1.2 parts ~ 1.9 parts of lactose, 1.1 parts ~ 1.7 parts of HPMC K4M, 0.8 part ~ 1.5 parts of Brazil wax, 0.12 part ~ 0.18 part of octadecanol, magnesium stearate 0.11 ~ 0.19,0.03 ~ 0.09 part of sodium thiosulfate, 2.5 parts ~ 3.5 parts of 50% ~ 70% ethanol solution；The present invention（S）The pyrrolidine acetamide spansule of 4 hydroxyl, 2 oxo 1 has that mobility of particle is good, and particle angle of repose is less than 36 °, and rate of release is slow, deenergized period is up to 12 hours, meanwhile, this product stability is good, relevant material only increases by 0.06% in shelf life, and shelf life is up to 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to the OXo-1-pyrrolidine acetyl of one kind (S) -4- hydroxyls -2
Amine spansule and preparation method thereof.
Background technology
Levo-oxiracetam chemical name is：S- (-) -4- hydroxyl -2- oxo-pyrrolidine-N- acetamides, are white micro-crystals
Sprills, 135~136 DEG C of fusing point, -36 ° of optical activity (C=1.00 in water), the OXo-1-pyrrolidine of (S) -4- hydroxyls -2
The dissolubility of acetamide is substantially better than raceme.Shown in the following schema of chemical structural formula：
The medicine listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Parenteral solution, 1g/
5ml.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.Ye Lei
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is mentioned to alcoholism Deng in the A patents of Publication No. CN 103735545
The promoting wakening of caused stupor is obvious, and dextrorotation Oxiracetam does not act on substantially, the OXo-1-pyrrolidine second of (S) -4- hydroxyls -2
The awake effect of the above-mentioned rush of acid amides is 2 times of racemization Oxiracetam；(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 to wound,
The promoting wakening of stupor is notable caused by anesthesia.Open peak etc. and (S) -4- is disclosed in the A of Publication No. CN 103599101 patent
The oxo-1-pyrrolidine ethanamide of hydroxyl -2 is to traumatic brain injury learning and memory in rats cognitive function caused by hydraulic pressure and freely falling body
Obstacle improves significantly, and its drug effect is far above dextrorotation Oxiracetam.And oxo-the 1- of 200mg/kg (S) -4- hydroxyls -2
Pyrrolidine acetamide is suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：(S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single dose intravenous is noted
Penetrate the master for giving the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 in blood plasma after left-handed and 2 multiple doses racemization Oxiracetams
Want the equal no significant difference of pharmacokinetic parameters.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level,
(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 and Oxiracetam are to animal subject or the toxicity no significant difference of cell.On
State preclinical result of study to show, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is to play drug effect in Oxiracetam body
Main active, be used alone this product can reduce Clinical practice dosage, reduce potential toxicity.
The existing oxo-1-pyrrolidine ethanamide spansule of (S) -4- hydroxyls -2, which is primarily present release, preferably to be controlled
System, it is impossible to reach the requirement of sustained release preparation, mobility of particle is bad, and filling loading amount process content uniformity is larger, influences to use medicament
Amount, the relevant material of storage process increase the technical problem such as larger.
The content of the invention
It is an object of the invention to provide the OXo-1-pyrrolidine of (S) -4- hydroxyls -2 that a kind of release is good, stability is good
Acetamide spansule.
Another object of the present invention is to provide the above-mentioned oxo-1-pyrrolidine ethanamide spansule of (S) -4- hydroxyls -2
Preparation method.
The purpose of the present invention is realized by following technical measures：
The oxo-1-pyrrolidine ethanamide spansule of one kind (S) -4- hydroxyls -2, it is characterised in that it is with (S) -4- hydroxyls
The oxo-1-pyrrolidine ethanamide of base -2 is raw material, adds a certain amount of sustained-release matrix material, retarding agent, lubricant, adhesive
It is made with stabilizer；Wherein described sustained-release matrix material is HPMC, ethyl cellulose, polyethylene, polypropylene, poly-
One kind in siloxanes, polyoxyethylene, lactose, fructose, sucrose, mannitol, sodium alginate, agar, chitin, galactolipin or
It is several；The retarding agent is one in fat, beeswax, Brazil wax, hydrogenated vegetable oil, stearyl alcohol, glycerin monostearate
Kind is several；The lubricant is the one or more in magnesium stearate, talcum powder, silica, octadecanol；Bonding used
Agent is ethanol solution, starch slurry, sucrose solution, water, any of PVP ethanol solution；The stabilizer is vitamin C,
Methionine, the one or more in sodium thiosulfate, citric acid, tartaric acid, cysteine, glutathione.
Inventor is in research process discovery, specific supplementary material species and specific proportion relation, then coordinates specific
Granulation whole grain blend step, may be such that the above-mentioned oxo-1-pyrrolidine ethanamide spansule release time of (S) -4- hydroxyls -2
Up to 12 hours, mobility of particle was more preferable, and filling process content uniformity is more stable, and the relevant material increment of storage process is also smaller,
The above-mentioned oxo-1-pyrrolidine ethanamide spansule of (S) -4- hydroxyls -2, it is characterised in that it is by the original of following weight proportion
Auxiliary material is made：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, 1.2 parts~1.9 parts of lactose, HPMC
1.1 parts~1.7 parts of K4M, 0.8 part~1.5 parts of Brazil wax, 0.12 part~0.18 part of octadecanol, magnesium stearate 0.11~
0.19,0.03~0.09 part of sodium thiosulfate, volume fraction is 50%~70% 2.5 parts~3.5 parts of ethanol solution；Take prescription
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, lactose, HPMC K4M, Brazil wax, the thio sulphur of amount
Sour sodium puts co-grinding in mixing mill and (is all sieved by No. 5 into fine powder and can must not be less than total amount by the amounts of No. 6 sieves
95%), sieve；Ethanol solution is added, 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, magnesium stearate were crushed
100 mesh sieves, add in the particle after whole grain, with three-dimensional motion mixer mixing 10min~20min.
Further, in order that obtaining the oxo-1-pyrrolidine ethanamide spansule mobility of particle of (S) -4- hydroxyls -2 more
Good, filling process content uniformity is more stable, the above-mentioned oxo-1-pyrrolidine ethanamide spansule of (S) -4- hydroxyls -2, its feature
It is：(S) 1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, 1.5 parts~1.8 parts of lactose, HPMC K4M
1.3 parts~1.5 parts, 0.9 part~1.2 parts of Brazil wax, 0.15 part~0.17 part of octadecanol, magnesium stearate 0.13~
0.16,0.05~0.08 part of sodium thiosulfate, volume fraction is 50%~70% 2.8 parts~3.2 parts of ethanol solution；Take prescription
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, lactose, HPMC K4M, Brazil wax, the thio sulphur of amount
Sour sodium puts co-grinding in mixing mill and (is all sieved by No. 5 into fine powder and can must not be less than total amount by the amounts of No. 6 sieves
95%), sieve；Ethanol solution is added, 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, magnesium stearate were crushed
100 mesh sieves, add in the particle after whole grain, with three-dimensional motion mixer mixing 10min~20min.
The preparation method of the oxo-1-pyrrolidine ethanamide spansule of one kind (S) -4- hydroxyls -2, it is characterised in that it is
It is obtained as follows：
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：
The oxo-1-pyrrolidine ethanamide spansule of the present invention (S) -4- hydroxyls -2 has mobility of particle good, and particle is stopped
Angle till is less than 36 °, and rate of release is slow, and deenergized period is up to 12 hours, therefore this product can reduce compared with conventional formulation and take number, daily
Take once；Meanwhile this product stability is good, relevant material only increases by 0.06% in shelf life, 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
The oxo-1-pyrrolidine ethanamide spansule of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：
1. supplementary material pre-treatment：Take the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, lactose, hydroxypropyl first of recipe quantity
Base cellulose K4M, Brazil wax, sodium thiosulfate put in mixing mill co-grinding into fine powder (all by No. 5 sieves and
Can by No. 6 sieve amounts must not be less than total amount 95%), sieving；
2. granulation：Ethanol solution is added, with 18 mesh sieve mixing granulations, manufactured wet granular is placed in hot-air oven, if
40~60 DEG C of temperature is put, is dried to pellet moisture≤3%, whole grain (crosses 24 mesh sieves), standby；
It is 3. total mixed：Octadecanol, magnesium stearate were crushed into 100 mesh sieves, adds in the particle after whole grain, uses three-dimensional motion
Mixer 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：Particle flow performance determines
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, distinguish respectively in the upper, middle and lower of three-dimensional motion mixer, each point
Angle of repose is measured by sampling, 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, measure angle of repose three times and be respectively less than 36 °, show particle flow
Property is good.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 (S) -4- hydroxyls
The oxo-1-pyrrolidine ethanamide of base -2 reference substance about 10mg is put in 25ml measuring bottles, is dissolved with water and is diluted to scale, shaken up, and is made
For reference substance solution.Precision measures above-mentioned reference substance solution and each 20 μ l of need testing solution respectively, according to the chromatostrip of assay
Part determines.Calculate the release (referring to Accumulation dissolution) of every.
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)：(S) oxygen of -2 oxo-1-pyrrolidine ethanamide spansule main ingredient (S) -4- hydroxyls of -4- hydroxyls -2
Generation -1- pyrrolidine acetamides discharge into slow, and release time is up to 12 hours, can meet the requirement of sustained release preparation.
Experiment three：The oxo-1-pyrrolidine ethanamide spansule stability experiment of present invention one kind (S) -4- hydroxyls -2
Experiment material：
(S) the oxo-1-pyrrolidine ethanamide spansule of -4- hydroxyls -2：It is made for embodiment 1.
Acceleration study method：The oxo-1-pyrrolidine ethanamide spansule of (S) -4- hydroxyls -2 made from embodiment 1 is pressed
Listing packaging, puts in Acceleration study 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：The oxo-1-pyrrolidine ethanamide spansule of (S) -4- hydroxyls -2 made from embodiment 1 is pressed
Listing packaging, put in the long-term case that keeps sample, 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, long-term 24 months impurity increments only 0.06%, therefore minimum 24 months of this product term of validity, and long term test still is continuing to investigate
Cheng Zhong.
Embodiment 2
The oxo-1-pyrrolidine ethanamide spansule of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, angle of repose knot
Fruit shows this product good fluidity, and angle of repose is less than 35 °, and drug release determination result of the test shows the oxo -1- pyrroles of (S) -4- hydroxyls -2
Cough up alkyl acetamide spansule to be up to 12 hours in slowly release, release time, the requirement of sustained release preparation, stability can be met
Result of the test shows that acceleration sample quality in June is stable, accelerates relevant material in June only to increase by 0.05%, long-term 24 months quality are steady
Fixed, long-term 24 months relevant materials only increase by 0.06%, therefore this product term of validity at least 24 months.
Embodiment 3
The oxo-1-pyrrolidine ethanamide spansule of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：It is made according to the preparation technology of embodiment 1.Tested by the test method of embodiment 1, angle of repose knot
Fruit shows this product good fluidity, and angle of repose is less than 36 °, and drug release determination result of the test shows the oxo -1- pyrroles of (S) -4- hydroxyls -2
Cough up alkyl acetamide spansule to be up to 12 hours in slowly release, release time, the requirement of sustained release preparation, stability examination can be met
Testing result shows to accelerate June sample quality stable, accelerates relevant material in June only to increase by 0.05%, long-term 24 months steady qualities,
Long-term 24 months relevant materials only increase by 0.05%, therefore this product term of validity at least 24 months.
Embodiment 4-6：The oxo-1-pyrrolidine ethanamide spansule of one kind (S) -4- hydroxyls -2, by the original of following weight
Auxiliary material is prepared, and preparation method is the same as embodiment 1：
Tested by the test method of embodiment 1, the angle of repose result of the test of embodiment 4,5,6 shows this product mobility
Good, angle of repose is respectively smaller than 36 °, 37 °, 35 °, and the drug release determination result of the test of embodiment 4,5,6 shows the oxygen of (S) -4- hydroxyls -2
It is up to 12 hours in slowly release, release time for -1- pyrrolidine acetamides spansule, wanting for sustained release preparation can be met
Ask, the stability test result of embodiment 4,5,6 shows to accelerate June sample quality stable, accelerates the relevant material increment in June to be respectively
0.05%th, 0.05%, 0.06%, long-term 24 months steady qualities, long-term 24 months relevant materials are respectively 0.06%, 0.06%,
0.06%, therefore this product term of validity at least 24 months.
Claims (3)
- It is 1. a kind of（S）The oxo-1-pyrrolidine ethanamide spansule of -4- hydroxyls -2, it is characterised in that it is matched somebody with somebody by following weight The supplementary material of ratio is made：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, 1.2 parts ~ 1.9 parts of lactose, hydroxypropyl are fine Tie up plain 1.1 parts ~ 1.7 parts of K4M, 0.8 part ~ 1.5 parts of Brazil wax, 0.12 part ~ 0.18 part of octadecanol, magnesium stearate 0.11 ~ 0.19,0.03 ~ 0.09 part of sodium thiosulfate, volume fraction is 50% ~ 70% 2.5 parts ~ 3.5 parts of ethanol solution；Take recipe quantity （S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, lactose, HPMC K4M, Brazil wax, 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；Ethanol solution is added, 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（Cross 24 mesh sieves）, it is standby；Octadecanol, magnesium stearate were crushed 100 Mesh sieve, add in the particle after whole grain, with three-dimensional motion mixer mixing 10min ~ 20min.
- It is 2. as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide spansule of -4- hydroxyls -2, it is characterised in that it It is to be made by the supplementary material of following weight proportion：（S）1 part of -2 oxo-1-pyrrolidine ethanamide of -4- hydroxyls, lactose 1.5 parts ~ 1.8 Part, 1.3 parts ~ 1.5 parts of HPMC K4M, 0.9 part ~ 1.2 parts of Brazil wax, 0.15 part ~ 0.17 part of octadecanol, Magnesium stearate 0.13 ~ 0.16,0.05 ~ 0.08 part of sodium thiosulfate, volume fraction are 50% ~ 70% ethanol solution 2.8 parts ~ 3.2 Part；Take recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, lactose, HPMC K4M, babassu Wax, sodium thiosulfate put in mixing mill co-grinding into fine powder（All by No. 5 sieve and can by No. 6 sieve amounts must not Less than the 95% of total amount）, sieving；Ethanol solution 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, magnesium stearate 100 mesh sieves are crushed, are added in the particle after whole grain, 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 spansule of -4- hydroxyls -2, Characterized in that, it is obtained as follows：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.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| 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 |
-
2016
- 2016-07-13 CN CN201610550502.0A patent/CN107625749A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| 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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