CN115869277A - Levetiracetam sustained release tablet and preparation method thereof - Google Patents
Levetiracetam sustained release tablet and preparation method thereof Download PDFInfo
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- CN115869277A CN115869277A CN202111137215.4A CN202111137215A CN115869277A CN 115869277 A CN115869277 A CN 115869277A CN 202111137215 A CN202111137215 A CN 202111137215A CN 115869277 A CN115869277 A CN 115869277A
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- levetiracetam
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 78
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract description 78
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 239000008187 granular material Substances 0.000 claims abstract description 28
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 27
- 239000000463 material Substances 0.000 claims abstract description 11
- 238000013268 sustained release Methods 0.000 claims abstract description 9
- 239000012730 sustained-release form Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract 3
- 239000003826 tablet Substances 0.000 claims abstract 2
- 238000001035 drying Methods 0.000 claims description 42
- 238000002156 mixing Methods 0.000 claims description 33
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 27
- 229920002125 Sokalan® Polymers 0.000 claims description 27
- 229960001631 carbomer Drugs 0.000 claims description 27
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 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 description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000011159 matrix material Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002994 raw material Substances 0.000 claims 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims 1
- 229920000178 Acrylic resin Polymers 0.000 claims 1
- 239000004925 Acrylic resin Substances 0.000 claims 1
- 239000001856 Ethyl cellulose Substances 0.000 claims 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims 1
- 229920000881 Modified starch Polymers 0.000 claims 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims 1
- 229920002472 Starch Polymers 0.000 claims 1
- 229960000913 crospovidone Drugs 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 235000019325 ethyl cellulose Nutrition 0.000 claims 1
- 229920001249 ethyl cellulose Polymers 0.000 claims 1
- 230000002496 gastric effect Effects 0.000 claims 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 1
- 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 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 229960002900 methylcellulose Drugs 0.000 claims 1
- -1 polyoxyethylene Polymers 0.000 claims 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 1
- 238000010008 shearing Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 235000010413 sodium alginate Nutrition 0.000 claims 1
- 239000000661 sodium alginate Substances 0.000 claims 1
- 229940005550 sodium alginate Drugs 0.000 claims 1
- 239000002195 soluble material Substances 0.000 claims 1
- 238000005507 spraying Methods 0.000 claims 1
- 239000008107 starch Substances 0.000 claims 1
- 235000019698 starch Nutrition 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 239000000230 xanthan gum Substances 0.000 claims 1
- 235000010493 xanthan gum Nutrition 0.000 claims 1
- 229920001285 xanthan gum Polymers 0.000 claims 1
- 229940082509 xanthan gum Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 3
- 239000000969 carrier Substances 0.000 abstract 1
- 238000013265 extended release Methods 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 34
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 30
- 229940049654 glyceryl behenate Drugs 0.000 description 30
- 239000002245 particle Substances 0.000 description 27
- 238000007873 sieving Methods 0.000 description 26
- 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 description 25
- 229930195725 Mannitol Natural products 0.000 description 25
- 239000000594 mannitol Substances 0.000 description 25
- 235000010355 mannitol Nutrition 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 235000019359 magnesium stearate Nutrition 0.000 description 17
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 16
- 239000007779 soft material Substances 0.000 description 16
- 229910001220 stainless steel Inorganic materials 0.000 description 15
- 239000010935 stainless steel Substances 0.000 description 15
- 238000007580 dry-mixing Methods 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 238000010902 jet-milling Methods 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 230000004584 weight gain Effects 0.000 description 8
- 235000019786 weight gain Nutrition 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229960001855 mannitol Drugs 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 6
- 239000012467 final product Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010061334 Partial seizures Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000003179 convulsant agent Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
An extended release pharmaceutical composition of levetiracetam, a daily dosage regimen and a process for its preparation. The levetiracetam sustained-release granules are prepared by taking insoluble framework materials as framework carriers, then the sustained-release granules are pressed into round tablets under proper pressure, and finally coating is carried out, wherein the weight of the coating is increased by 2-5%. It works by eliminating troughs and grains and peaks of drug concentration in the patient's plasma. The levetiracetam sustained release tablet prepared by the invention has stable process, can well play a sustained release role, is stable in release within 16h, and has no phenomena of burst release and difficult dissolution.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a levetiracetam sustained-release tablet and a preparation method thereof.
Background
Levetiracetam (Levetiracetam) is an antiepileptic drug and is mainly used for the additive treatment of partial seizures of epilepsy patients of adults and children over 4 years old. The anti-epileptic effect of levetiracetam was evaluated in a variety of animal models of epilepsy. Levetiracetam has no inhibitory effect on simple seizures induced by maximal stimulation with electric current or with a variety of convulsants and shows only weak activity in sub-maximal stimulation and threshold tests. The product is suitable for children patients, and can be made into sustained release dosage form by improving dosage form, so that the medicine can be slowly and uniformly released at a certain speed after entering human body to maintain steady blood concentration.
Carbomer has the main functions of thickening and increasing adhesiveness, has a specific cross-linking structure and good viscosity and hydrophilic gel property, is neutralized in water and then expands to form a uniformly dispersed skeleton system, and insoluble components can be wrapped in the gaps of the skeleton. Carbomer has been used as a matrix material of sustained release agents because it has good adhesion and hydrophilic gel properties, which makes it have good sustained and controlled release effects.
Disclosure of Invention
The invention aims to solve the problems in the prior art, and provides a levetiracetam sustained-release tablet, which is prepared by using a composite sustained-release material with a unique proportion to slowly release levetiracetam, so that the blood concentration fluctuation is small, the administration frequency is low, levetiracetam can be uniformly released within 24 hours, and only 1 time of administration is needed every day.
In order to realize the purpose, the invention provides a levetiracetam sustained-release tablet which is composed of the following components in parts by weight: 50% of levetiracetam, 28% -31% of mannitol, 2-5% of croscarmellose sodium, 0.5-1% of sodium dodecyl sulfate, 14-17% of carbomer, 2% -5% of glyceryl behenate and 1-2% of magnesium stearate. Preferably, the composition consists of the following components in parts by weight: 50 parts of levetiracetam, 28 parts of mannitol, 2 parts of croscarmellose sodium, 14 parts of carbomer, 4 parts of glyceryl behenate, 1 part of magnesium stearate and 1 part of sodium dodecyl sulfate.
The invention also provides a preparation process of the levetiracetam sustained release tablet, which is characterized by comprising the following steps of:
(1) Crushing and sieving: performing jet milling on levetiracetam to obtain particles with the particle size of less than 10 mu m, and sieving with a 200-mesh sieve after mannitol is milled;
(2) Mixing: weighing levetiracetam, mannitol, croscarmellose sodium and carbomer according to the formula of claim 1, dry-mixing, and mixing to obtain a dry-mixed mixture;
(3) And (3) granulating: adding melted glyceryl behenate into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material to prepare wet granules;
(4) And (3) drying: putting the wet granules obtained in the step (3) into a drying oven for drying at the drying temperature of 50-60 ℃ for 3-5 hours;
(5) Straightening: sieving the dried particles obtained in the step (4) through a stainless steel sieve to complete the particles;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the granules totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: coating the gastric-soluble film coating premixed powder to prepare a coating solution, and controlling the weight gain rate to be 2-4% to obtain a finished product.
The invention has the beneficial effects that: the invention creatively selects carbomer and glyceryl behenate as composite sustained-release materials, so that the levetiracetam drug is released smoothly, the levetiracetam can be released uniformly within 16 hours, the blood concentration fluctuation is small, and the compound sustained-release tablet is only required to be taken for 1 time every day; when the mass ratio of carbomer to glyceryl behenate is 6, the balance point of the synergistic effect of carbomer and glyceryl behenate can be reached, so that the medicine with the specified concentration at the early-stage release position of the levetiracetam medicine can be ensured, the administration effect can be quickly reached, the medicine can be ensured not to be released too fast, and the side effect of a patient can be generated.
[ detailed description ] embodiments
Example 1:
a levetiracetam sustained release tablet is composed of the following components in parts by weight: 20 parts of levetiracetam, 40 parts of mannitol, 0.5 part of sodium dodecyl sulfate, 5 parts of carbomer, 2 parts of glyceryl behenate and 0.5 part of magnesium stearate.
The preparation process of the levetiracetam sustained release tablet comprises the following steps:
(1) Crushing and sieving: the levetiracetam is subjected to jet milling, the particle size of the levetiracetam is smaller than 10 mu m, and the levetiracetam is sieved by a 200-mesh sieve after being milled by mannitol;
(2) Mixing: weighing levetiracetam, mannitol, sodium dodecyl sulfate and carbomer according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry mixed mixture;
(3) Granulating: melting glyceryl behenate at 75 ℃, adding the melted glyceryl behenate into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet particles obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 50 ℃, and the drying time is 3 hours;
(5) Straightening: sieving the dried particles in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the particles totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: coating with coating liquid prepared from Opadry, and controlling the weight gain rate at 2% -4% to obtain the final product.
Example 2:
a levetiracetam sustained release tablet is composed of the following components in parts by weight: 50 parts of levetiracetam, 28 parts of mannitol, 2 parts of sodium dodecyl sulfate, 16 parts of carbomer, 2 parts of glyceryl behenate and 2 parts of magnesium stearate.
The preparation process of the levetiracetam sustained-release tablet comprises the following steps:
(1) Crushing and sieving: the levetiracetam is subjected to jet milling, the particle size of the levetiracetam is smaller than 10 mu m, and the levetiracetam is sieved by a 200-mesh sieve after being milled by mannitol;
(2) Mixing: weighing levetiracetam, mannitol, sodium dodecyl sulfate and carbomer according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry mixed mixture;
(3) And (3) granulating: melting glyceryl behenate at 75 ℃, adding the melted glyceryl behenate into the dry-mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet particles obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 60 ℃, and the drying time is 5 hours;
(5) Straightening: sieving the particles dried in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the granules totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: coating with coating liquid prepared from Opadry, and controlling the weight gain rate at 2% -4% to obtain the final product.
Example 3:
a levetiracetam sustained release tablet is composed of the following components in parts by weight: 50 parts of levetiracetam, 34 parts of mannitol, 1 part of sodium dodecyl sulfate, 10 parts of carbomer, 4 parts of glyceryl behenate and 1 part of magnesium stearate.
The preparation process of the levetiracetam sustained-release tablet comprises the following steps:
(1) Crushing and sieving: the levetiracetam is subjected to jet milling, the particle size of the levetiracetam is smaller than 10 mu m, and the levetiracetam is sieved by a 200-mesh sieve after being milled by mannitol;
(2) Mixing: weighing levetiracetam, mannitol, sodium dodecyl sulfate and carbomer according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry mixed mixture;
(3) And (3) granulating: melting glyceryl behenate at 75 ℃, adding the melted glyceryl behenate into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet particles obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 55 ℃, and the drying time is 3.5 hours;
(5) Straightening: sieving the dried particles in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the granules totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: coating with coating liquid prepared from Opadry, and controlling the weight gain rate at 2% -4% to obtain the final product.
Example 4:
a levetiracetam sustained release tablet is composed of the following components in parts by weight: 50 parts of levetiracetam, 34 parts of mannitol, 1 part of sodium dodecyl sulfate, 8 parts of carbomer, 6 parts of glyceryl behenate and 1 part of magnesium stearate.
The preparation process of the levetiracetam sustained-release tablet comprises the following steps:
(1) Crushing and sieving: performing jet milling on levetiracetam to obtain particles with the particle size of less than 10 mu m, and sieving with a 200-mesh sieve after mannitol is milled;
(2) Mixing: weighing levetiracetam, mannitol, sodium dodecyl sulfate and carbomer according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry mixed mixture;
(3) And (3) granulating: melting glyceryl behenate at 75 ℃, adding the melted glyceryl behenate into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet particles obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 55 ℃, and the drying time is 3.5 hours;
(5) Straightening: sieving the dried particles in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the particles totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: the opadry is prepared into coating liquid for coating, the weight gain rate is controlled to be 2-4 percent, and the finished product is prepared.
Example 5:
a levetiracetam sustained release tablet comprises the following components in parts by weight: 50 parts of levetiracetam, 34 parts of mannitol, 1 part of sodium dodecyl sulfate, 12 parts of carbomer, 2 parts of glyceryl behenate and 1 part of magnesium stearate.
The preparation process of the levetiracetam sustained-release tablet comprises the following steps:
(1) Crushing and sieving: the levetiracetam is subjected to jet milling, the particle size of the levetiracetam is smaller than 10 mu m, and the levetiracetam is sieved by a 200-mesh sieve after being milled by mannitol;
(2) Mixing: weighing levetiracetam, mannitol, sodium dodecyl sulfate and carbomer according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry mixed mixture;
(3) And (3) granulating: melting glyceryl behenate at 75 ℃, adding the melted glyceryl behenate into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet granules obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 55 ℃, and the drying time is 3.5 hours;
(5) Straightening: sieving the dried particles in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the particles totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: coating with coating liquid prepared from Opadry, and controlling the weight gain rate at 2% -4% to obtain the final product.
Comparative example 1:
a levetiracetam sustained release tablet is composed of the following components in parts by weight: 50 parts of levetiracetam, 34 parts of mannitol, 1 part of sodium dodecyl sulfate, 4 parts of glyceryl behenate and 1 part of magnesium stearate.
The preparation process of the levetiracetam sustained release tablet comprises the following steps:
(1) Crushing and sieving: the levetiracetam is subjected to jet milling, the particle size of the levetiracetam is smaller than 10 mu m, and the levetiracetam is sieved by a 200-mesh sieve after being milled by mannitol;
(2) Mixing: weighing levetiracetam, mannitol and sodium dodecyl sulfate according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry-mixed mixture;
(3) And (3) granulating: melting glyceryl behenate at 75 ℃, adding the melted glyceryl behenate into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet granules obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 55 ℃, and the drying time is 3.5 hours;
(5) Straightening: sieving the dried particles in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the granules totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: the opadry is prepared into coating liquid for coating, the weight gain rate is controlled to be 2-4 percent, and the finished product is prepared.
Comparative example 2:
a levetiracetam sustained release tablet is composed of the following components in parts by weight: 50 parts of levetiracetam, 34 parts of mannitol, 1 part of sodium dodecyl sulfate, 10 parts of carbomer and 1 part of magnesium stearate.
The preparation process of the levetiracetam sustained release tablet comprises the following steps:
(1) Crushing and sieving: the levetiracetam is subjected to jet milling, the particle size of the levetiracetam is smaller than 10 mu m, and the levetiracetam is sieved by a 200-mesh sieve after being milled by mannitol;
(2) Mixing: weighing levetiracetam, mannitol, sodium dodecyl sulfate and carbomer according to the formula, carrying out dry mixing, and uniformly mixing to obtain a dry mixed mixture;
(3) And (3) granulating: adding 85% ethanol into the dry mixed mixture obtained in the step (2) to prepare a soft material, and sieving the soft material with a 20-mesh stainless steel sieve to prepare wet granules;
(4) And (3) drying: putting the wet particles obtained in the step (3) into a drying oven for drying, wherein the drying temperature is 55 ℃, and the drying time is 3.5 hours;
(5) Straightening: sieving the dried particles in the step (4) through a stainless steel sieve of 20 meshes for finishing;
(6) Total mixing: adding magnesium stearate into the granules after finishing the granulation in the step (5), and uniformly mixing to obtain a total mixed mixture;
(7) Tabletting: tabletting the granules totally mixed in the step (6) by using a shallow concave punch;
(8) Coating: coating with coating liquid prepared from Opadry, and controlling the weight gain rate at 2% -4% to obtain the final product.
The results of the sample release measurements for each example are shown in table 1:
TABLE 1
Comparing the example 3, the comparative example 1 and the comparative example 2, the dissolution curves of the comparative example 1 and the comparative example 2 are large in fluctuation, and when the carbomer and the glyceryl behenate are added, the dissolution curves are smooth, so that the effect of uniform slow release is achieved.
Comparing the experimental results of examples 3-5, in example 4, when the mass ratio of carbomer to glyceryl behenate is low, the early-stage release of the drug is too slow, and a rapid therapeutic effect may not be achieved; in example 5, when the mass ratio of carbomer to glyceryl behenate is high, the early-stage release of the drug is fast, and the patient is prone to side effects of drug administration; through experimental screening, in example 3, when the mass ratio of carbomer to glyceryl behenate is 5, the carbomer and glyceryl behenate are most suitable, so that the therapeutic effect of drug delivery can be achieved, the carbomer and glyceryl behenate can be slowly and uniformly released at the early stage, and the side effect of drug delivery is not easy to generate.
The above embodiments are illustrative of the present invention, and are not intended to limit the present invention, and any simple modifications of the present invention are within the scope of the present invention.
Claims (7)
1. The levetiracetam sustained-release tablet is characterized by being prepared from the following raw materials in percentage by weight:
50% of levetiracetam, 2-5% of disintegrating agent, 16-25% of framework type slow release material, 1-2% of glidant and 28-31% of filler.
2. The levetiracetam sustained-release tablet of claim 1, which is characterized by being prepared from the following raw materials in percentage by weight:
50% of levetiracetam, 2% of disintegrating agent, 18% of framework type slow release material, 2% of glidant and 28% of filler.
3. The levetiracetam sustained release tablet of claim 1 or 2, wherein the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, pregelatinized starch, or sodium carboxymethyl starch.
4. The levetiracetam sustained-release tablet according to claim 1 or 2, characterized in that the matrix-type sustained-release material is selected from a hydrophilic gel matrix, a bioerodible matrix or an insoluble matrix; the hydrophilic gel skeleton is one or more of hydroxypropyl methylcellulose, carbomer, sodium alginate, methylcellulose, polyoxyethylene and xanthan gum, the bioerodible skeleton is a waxy material, a gastric soluble or enteric soluble material, and the insoluble skeleton is ethyl cellulose or permeable acrylic resin.
5. A method for preparing the levetiracetam sustained release tablet of any one of claims 1 to 4, characterized by comprising the following steps:
(1) Premixing levetiracetam, a disintegrating agent, a filling agent and a part of skeleton type slow-release materials to obtain a premix;
(2) Dissolving the rest of the skeleton type slow-release material with water to prepare a solution, spraying the solution into the premix, and granulating;
(3) Granulating, wet-finishing, and drying to obtain dry granules;
(4) Dry finishing the dry granules, and adding a flow aid and a filling agent for total mixing;
(5) Tabletting the totally mixed materials;
(6) And coating the tabletted tablets to obtain the levetiracetam sustained release tablets.
6. The production method according to claim 5, wherein in the step (1), the stirring speed at the time of the premixing is 330rpm, and the shearing speed is 1500rpm.
7. The production method according to claim 5, wherein in the step (3), the drying conditions are: the air inlet temperature of the fluidized bed is 50 ℃, the material temperature is 30-35 ℃, and the drying is carried out until the moisture is less than 2%.
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