CN111920778A - Levetiracetam tablet and preparation method thereof - Google Patents
Levetiracetam tablet and preparation method thereof Download PDFInfo
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- CN111920778A CN111920778A CN202010804912.XA CN202010804912A CN111920778A CN 111920778 A CN111920778 A CN 111920778A CN 202010804912 A CN202010804912 A CN 202010804912A CN 111920778 A CN111920778 A CN 111920778A
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 17
- 239000011248 coating agent Substances 0.000 claims abstract description 65
- 238000000576 coating method Methods 0.000 claims abstract description 65
- 239000000463 material Substances 0.000 claims abstract description 41
- 239000008187 granular material Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000000314 lubricant Substances 0.000 claims abstract description 22
- 238000002156 mixing Methods 0.000 claims abstract description 22
- 238000007873 sieving Methods 0.000 claims abstract description 21
- 239000007788 liquid Substances 0.000 claims abstract description 20
- 239000000853 adhesive Substances 0.000 claims abstract description 19
- 230000001070 adhesive effect Effects 0.000 claims abstract description 19
- 239000007884 disintegrant Substances 0.000 claims abstract description 17
- 239000006185 dispersion Substances 0.000 claims abstract description 15
- 238000005507 spraying Methods 0.000 claims abstract description 6
- 239000002270 dispersing agent Substances 0.000 claims abstract description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 20
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 20
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000011230 binding agent Substances 0.000 claims description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 16
- 239000007921 spray Substances 0.000 claims description 16
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 239000004480 active ingredient Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 229920000609 methyl cellulose Polymers 0.000 claims description 11
- 239000001923 methylcellulose Substances 0.000 claims description 11
- 235000010981 methylcellulose Nutrition 0.000 claims description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 9
- 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 9
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229960002900 methylcellulose Drugs 0.000 claims description 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
- 239000000428 dust Substances 0.000 abstract description 10
- 238000005469 granulation Methods 0.000 abstract description 8
- 230000003179 granulation Effects 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 239000003826 tablet Substances 0.000 description 88
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 24
- 238000004090 dissolution Methods 0.000 description 17
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- 239000002245 particle Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 238000007908 dry granulation Methods 0.000 description 9
- 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 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000005550 wet granulation Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 238000007907 direct compression Methods 0.000 description 5
- 238000007599 discharging Methods 0.000 description 5
- 239000007891 compressed tablet Substances 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000019633 pungent taste Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000873 masking effect Effects 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
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Abstract
The invention discloses levetiracetam tablets and a preparation method thereof. Comprises levetiracetam with the active component accounting for 85 to 92 percent of the total weight of the tablet, adhesive accounting for 1.0 to 5.0 percent of the total weight, disintegrant accounting for 4.0 to 6.0 percent of the total weight, glidant accounting for 1.0 to 5.0 percent of the total weight, lubricant accounting for 0.2 to 0.5 percent of the total weight and coating material accounting for 1.0 to 6.0 percent of the total weight. Preparation: (1) mixing levetiracetam, a disintegrating agent, part of an adhesive and a flow aid to obtain a mixed material; (2) adding the rest of the adhesive into the dispersing agent to form dispersion liquid, adding the dispersion liquid into the mixed material, and then granulating; (3) sieving the prepared granules, grading, sieving, mixing with lubricant, and tabletting; (4) dissolving the coating material into coating liquid, and spraying the coating liquid on the tabletting for coating. The invention adopts a one-step granulation method, has simple process, solves the problem of dust flying and improves the stability of the tablet.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, and in particular relates to levetiracetam tablets and a preparation method thereof.
Background
The chemical name of levetiracetam is (-) - (S) -alpha-ethyl-2-oxo-1-pyrrolidineacetamide, and the structural formula is as follows:
levetiracetamThe triptan is a novel broad-spectrum antiepileptic drug, is used as a first-line drug for newly diagnosing patients with focal seizures, and is the only antiepileptic drug for preventing epileptic attack. The traditional Chinese medicine composition is mainly used for treating partial seizure of adults and children over 4 years old in clinic. The prior production processes disclosed by the levetiracetam tablet comprise a wet granulation process, a dry granulation process and a direct-mixing tabletting process.
Chinese patent CN200680001279.9 (original research UCB medicine ltd) discloses a pharmaceutical composition containing levetiracetam and a preparation method thereof. The pharmaceutical composition comprises levetiracetam as an active ingredient and 2.0 to 9.0% by weight of disintegrant, 0.0 to 3.0% by weight of glidant, 0.5 to 6.0% by weight of binder, and 0.0 to 1.0% by weight of lubricant, relative to the total weight of the pharmaceutical composition. And is prepared by a process which is called dry granulation in pharmaceutics. In addition, the prescription composition and the preparation method of the levetiracetam tablet used by UCB company in the early period are also disclosed. The prescription comprises levetiracetam as an active ingredient and the total weight of the pharmaceutical composition: 17.85% corn starch, 2.31% polyvinylpyrrolidone, 1.23% anhydrous colloidal silicon dioxide, 1.54% talc, 0.15% magnesium stearate, and 3.08% Opadry coating. The preparation method uses a process which is called wet granulation in pharmacy to prepare the medicine.
Chinese patent CN200910206148 (Zhejiang Huahai pharmaceutical industry Co., Ltd.) discloses levetiracetam tablets and a preparation method thereof. The formulation comprises levetiracetam as active ingredient and a binder in an amount of more than 6% by weight relative to the total weight of the tablet. The preparation method is used for preparing the powder by a process which is called powder direct compression in pharmaceutics.
After the levetiracetam pharmaceutical composition prepared by the wet granulation process disclosed by UCB company is packaged by a bubble cap and stored for 6 months under the conditions of 40 ℃ and 75% of relative humidity, the dissolution rate is remarkably reduced within 15 minutes in a dissolution test, and the dissolution kinetics is remarkably deteriorated. The drug contacts high temperature and high humidity conditions in the wet granulation process, so that the instability of the drug is increased, and the wet granulation process is complex and has higher cost. The dry granulation process disclosed by UCB (CN200680001279.9) improves the dissolution stability of the pharmaceutical composition, but the dry granulation process is complex, the dust is serious, and the factors influencing the compactibility and the particle size distribution of the particles are various, so that the product quality is unstable, and the quality control of the commercial mass production is not facilitated.
The levetiracetam tablet prepared by adopting the powder direct compression process disclosed by the Chinese patent CN200910206148 improves the stability of dissolution kinetics, but the powder direct compression process also has the problem of dust flying, and secondly, the levetiracetam raw material medicine has pungent taste, the proportion in the prescription is large, and the compliance of the production process is poor.
The levetiracetam pharmaceutical composition prepared by the dry granulation process has serious dust flying in the preparation process, and the coating is influenced by a plurality of factors influencing the compactibility and the particle size distribution of the granules and further influencing the friability of the tablet core, so that the quality of the product is unstable; the tablet is prepared by adopting a powder direct compression process, the dust is seriously blown in the preparation process, and the prescription of the raw material medicine is large, the pungent taste is strong, the irritation to the respiratory tract of an experimenter is large, and the production compliance is poor.
Therefore, a preparation method needs to be explored, which can improve the dissolution stability of a preparation prepared by a wet granulation process, and can solve the problems of serious dust flying and unstable product quality in dry granulation, serious dust flying in a powder direct-compression process and poor compliance of pungent odor of raw material medicines.
Disclosure of Invention
The invention aims to provide a simple levetiracetam tablet preparation process, the tablet adopts a one-step granulation method to quickly prepare granules with good fluidity and compressibility, dust flying is reduced, the problem of poor compliance of the production process of raw material medicines is solved, and the stability of the tablet is improved.
The invention is realized by the following technical scheme:
a levetiracetam tablet is characterized by comprising levetiracetam with an active ingredient accounting for 85-92% of the total weight of the tablet, a binder accounting for 1.0-5.0% of the total weight of the tablet, a disintegrant accounting for 4.0-6.0% of the total weight of the tablet, a glidant accounting for 1.0-5.0% of the total weight of the tablet, a lubricant accounting for 0.2-0.5% of the total weight of the tablet and a coating material accounting for 1.0-6.0% of the total weight of the tablet.
Further, the adhesive is any one or a mixture of several of polyvinylpyrrolidone, methylcellulose, hypromellose and polyethylene glycol 6000. The number 6000 after the polyethylene glycol refers to the average molecular weight of the polyethylene glycol.
Further, the disintegrating agent is any one of sodium carboxymethyl starch, croscarmellose sodium and low-substituted hypromellose. The prepared tablet has good water absorption and expansibility by adding the disintegrating agent, so that the tablet can be rapidly disintegrated in water or gastrointestinal liquid, and functional components can be rapidly dissolved and absorbed to play a role.
Further, the glidant is colloidal silicon dioxide.
Further, the lubricant is magnesium stearate. The flowability and compressibility of the prepared levetiracetam tablet are effectively improved by using the lubricant.
A preparation method of levetiracetam tablets comprises the following steps:
(1) mixing levetiracetam, 50-60% of total amount of a disintegrating agent and an adhesive and a flow aid to obtain a mixed material, wherein the particle size of the levetiracetam is 80-300 mu m;
(2) adding the rest of the adhesive into the dispersing agent to form dispersion liquid, adding the dispersion liquid into the mixed material, and then granulating;
(3) sieving the prepared granules, grading, sieving, mixing with lubricant, and tabletting;
(4) dissolving the coating material into coating liquid, and spraying the coating liquid on the tabletting for coating. The coating material has a taste masking effect and is Opadry (Opadry). The levetiracetam tablet provided by the invention adopts a one-step granulation method to rapidly prepare granules with good flowability and compressibility, so that dust flying is reduced, the problem of poor compliance in the production process of raw material medicines is solved, the dissolution kinetic stability of the tablet is improved, and the commercial production is favorably realized.
Further, in the step (1), 50-60% of levetiracetam, disintegrant and adhesive and glidant are mixed for 2-5 minutes, then the mixture is sieved by a 20-mesh sieve and then mixed for 2-5 minutes to obtain a mixed material.
Further, in the step (2), the residual adhesive is added into water to prepare a dispersion liquid with the mass fraction of 2-5%, the dispersion liquid is added into the mixed material, and then granulation is carried out by adopting a fluidized bed at the temperature of 40-60 ℃.
Further, in the step (3), the prepared granules are sieved by a 20-mesh sieve, and after sieving, the granules are mixed with the lubricant for 1-3 minutes and then tabletted.
Further, dissolving the coating material in water to form a coating solution, placing the tablet in a coating pan, and controlling the rotation speed of the coating pan to be 3-5 r/min; spraying the coating solution onto the surface of the tablet by a spray gun at 50-70 deg.C at a spray speed of 0.7-2 g/min for coating.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention adopts a one-step granulation method, granulation and drying are carried out simultaneously, granules with better fluidity and compressibility can be rapidly prepared, and the production cycle is shortened;
(2) compared with a wet granulation process, the preparation method simplifies the production process, shortens the drying time and improves the quality stability of the tablet;
(3) compared with the dry granulation and powder direct-pressing process, the preparation method disclosed by the invention avoids dust flying, improves the compliance of the raw material medicines in the production process, has high automation degree, and can ensure that the produced product has stable and reliable quality.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 is a flow chart of the preparation of the process of the present invention;
FIG. 2 is a pre-accelerated and post-accelerated dissolution profile of levetiracetam tablets prepared in example 2 of the invention;
fig. 3 is a graph showing the pre-accelerated and post-accelerated dissolution profiles of levetiracetam tablets prepared in comparative example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A levetiracetam tablet comprising, as active ingredient, 87.4% levetiracetam, relative to the total weight of the tablet, hypromellose (binder), 2.1% hypromellose (binder), 5.2% croscarmellose sodium (disintegrant), 2.1% colloidal silicon dioxide (glidant), 0.2% magnesium stearate (lubricant), and 3.0% Opadry (coating material), relative to the total weight of the tablet.
The preparation method of the levetiracetam tablet comprises the following steps:
(1) mixing 500mg of levetiracetam (levetiracetam with the particle size of 200 mu m), 30mg of croscarmellose sodium (disintegrant), 6mg of hydroxypropyl methylcellulose (hydroxypropyl methylcellulose is used as an adhesive, and the levetiracetam tablet contains 12mg of hydroxypropyl methylcellulose in total, one part of the hydroxypropyl methylcellulose is mixed with other components, and the other part of the hydroxypropyl methylcellulose is used for standby) and 12mg of colloidal silicon dioxide (glidant) for 2 minutes, then sieving by a 20-mesh sieve, and then mixing for 3 minutes to obtain a mixed material;
(2) adding the rest 6mg of hydroxypropyl methylcellulose (adhesive) into water to prepare a hydroxypropyl methylcellulose solution (dispersion liquid) with the mass fraction of 2%, adding the hydroxypropyl methylcellulose solution into the mixed material, then granulating at 50 ℃ by adopting a fluidized bed in one step, drying until the water content of the granules is 1%, and stopping discharging;
(3) sieving the prepared granule with 20 mesh sieve, grading, sieving, mixing the granule with 1.5mg magnesium stearate (lubricant) for 2 min, and tabletting;
(4) dissolving 16.6mg of Opadry (coating material) in water to form a coating solution, and then placing the tablet in a coating pan, wherein the rotating speed of the coating pan is controlled to be 3 revolutions per minute; spraying the coating solution on the surface of the tablet by a spray gun at a spray speed of 1 g/min at 60 ℃ to coat,
the above preparation process is shown in FIG. 1.
Example 2
A levetiracetam tablet comprising, as active ingredient, 87.4% levetiracetam, relative to the total weight of the tablet, 2.6% polyethylene glycol 6000 (binder), relative to the total weight of the tablet, 4.9% croscarmellose sodium (disintegrant), relative to the total weight of the tablet, 1.9% colloidal silicon dioxide (glidant), 0.3% magnesium stearate (lubricant), relative to the total weight of the tablet, and 2.9% Opadry (coating material), relative to the total weight of the tablet.
The preparation method of the levetiracetam tablet comprises the following steps:
(1) mixing 500mg of levetiracetam (levetiracetam with the particle size of 150 mu m is selected), 28mg of croscarmellose sodium (disintegrant), 9mg of polyethylene glycol 6000 (polyethylene glycol 6000 is used as an adhesive, wherein the levetiracetam tablet contains 15mg of polyethylene glycol 6000, one part of the polyethylene glycol 6000 is mixed with other components, and the other part of the polyethylene glycol 6000 is used for standby) and 11mg of colloidal silicon dioxide (glidant) for 5 minutes, then sieving by a 20-mesh sieve, and then mixing for 5 minutes to obtain a mixed material;
(2) adding the rest 5mg of polyethylene glycol 6000 (adhesive) into water to prepare polyethylene glycol 6000 solution (dispersion liquid) with the mass fraction of 3%, adding the polyethylene glycol 6000 solution into the mixed material, then adopting a fluidized bed to carry out one-step granulation at 40 ℃, drying the granules until the moisture content is 2%, and stopping discharging;
(3) sieving the prepared granule with 20 mesh sieve, grading, sieving, mixing the granule with 1.5mg magnesium stearate (lubricant) for 3 min, and tabletting;
(4) 16.6mg of Opadry (coating material) was dissolved in water to form a coating solution, and the tablets were then placed in a coating pan, and the coating solution was sprayed onto the tablet surface at 50 ℃ by a spray gun at a spray rate of 2 g/min, while controlling the rotation speed of the coating pan at 5 rpm.
Example 3
A levetiracetam tablet comprises levetiracetam with an active ingredient of 85.3 percent of the total weight of the tablet, a binder (the binder is a mixture of polyethylene glycol 6000 and polyvinylpyrrolidone with the mass ratio of 1: 1), sodium carboxymethyl starch (a disintegrating agent) with the total weight of the tablet of 4.8 percent, colloidal silicon dioxide (a glidant) with the total weight of the tablet of 2.8 percent, magnesium stearate (a lubricant) with the total weight of the tablet of 0.4 percent and Opadry (a coating material) with the total weight of the tablet of 2.9 percent.
The preparation method of the levetiracetam tablet comprises the following steps:
(1) 500mg of levetiracetam (levetiracetam with the particle size of 250 mu m is selected), 28mg of sodium carboxymethyl starch (disintegrant), 11.25mg of a mixture of polyethylene glycol 6000 and polyvinylpyrrolidone (the mass ratio of the polyethylene glycol 6000 to the polyvinylpyrrolidone is 1: 1; the mixture of the polyethylene glycol 6000 and the polyvinylpyrrolidone is used as a binder), 22.5mg of the mixture of the polyethylene glycol 6000 and the polyvinylpyrrolidone is contained in the levetiracetam tablet, one part of the mixture is mixed with other components, the other part of the mixture is used for standby), and 16.5mg of colloidal silicon dioxide (glidant) are mixed for 3 minutes, then the mixture is sieved by a 20-mesh sieve and then mixed for 2 minutes to obtain a mixed material;
(2) adding the rest 11.25mg of the mixture (adhesive) of the polyethylene glycol 6000 and the polyvinylpyrrolidone into water to prepare a mixed solution (dispersion liquid) of the polyethylene glycol 6000 and the polyvinylpyrrolidone with the mass fraction of 5%, adding the mixed solution of the polyethylene glycol 6000 and the polyvinylpyrrolidone into the mixed material, then adopting a fluidized bed to granulate at 60 ℃, drying the granules until the moisture content is 1%, and stopping discharging;
(3) sieving the prepared granule with 20 mesh sieve, grading, sieving, mixing the granule with 2.25mg magnesium stearate (lubricant) for 1 min, and tabletting;
(4) dissolving 16.6mg of Opadry (coating material) in water to form a coating solution, and then placing the tablet in a coating pan, wherein the rotating speed of the coating pan is controlled to be 4 revolutions per minute; the coating solution was sprayed onto the surface of the compressed tablets at 70 ℃ by means of a spray gun at a spray rate of 0.7 g/min.
Example 4
A levetiracetam tablet comprising, as active ingredient, 87.7% levetiracetam, based on the total weight of the tablet, 1.3% methylcellulose (binder), based on the total weight of the tablet, 4.9% low-substituted hypromellose (disintegrant), based on the total weight of the tablet, 2.9% colloidal silicon dioxide (glidant), 0.3% magnesium stearate (lubricant), based on the total weight of the tablet, and 2.9% Opadry (coating material), based on the total weight of the tablet.
The preparation method of the levetiracetam tablet comprises the following steps:
(1) mixing 500mg of levetiracetam (levetiracetam with the particle size of 80 mu m is selected), 28mg of low-substituted hydroxypropyl methylcellulose (disintegrant), 3.75mg of methylcellulose (methylcellulose is used as an adhesive, the levetiracetam tablet contains 7.5mg of methylcellulose in total, one part of methylcellulose is mixed with other components, and the other part of methylcellulose is used for standby) and 16.5mg of colloidal silicon dioxide (glidant) for 2 minutes, then sieving by a 20-mesh sieve, and then mixing for 3 minutes to obtain a mixed material;
(2) adding the rest 3.75mg of methylcellulose (adhesive) into water to prepare a methylcellulose solution (dispersion liquid) with the mass fraction of 4%, adding the methylcellulose solution into the mixed material, then granulating at 55 ℃ by adopting a fluidized bed in one step, drying until the moisture of the granules is 1%, and stopping discharging;
(3) sieving the prepared granule with 20 mesh sieve, grading, sieving, mixing the granule with 1.5mg magnesium stearate (lubricant) for 3 min, and tabletting;
(4) dissolving 16.6mg of Opadry (coating material) in water to form a coating solution, then placing the tablet in a coating pan, and controlling the rotation speed of the coating pan to be 5 r/min; the coating solution was sprayed onto the surface of the compressed tablets at 60 ℃ by means of a spray gun at a spray rate of 1.5 g/min.
Example 5
A levetiracetam tablet comprising, as active ingredient, 87.3% of levetiracetam, relative to the total weight of the tablet, 3.9% of polyvinylpyrrolidone (binder), relative to the total weight of the tablet, 4.2% of croscarmellose sodium (disintegrant), relative to the total weight of the tablet, 2.9% of colloidal silicon dioxide (glidant), 0.3% of magnesium stearate (lubricant), relative to the total weight of the tablet, and 1.4% of Opadry (coating material), relative to the total weight of the tablet.
The preparation method of the levetiracetam tablet comprises the following steps:
(1) mixing 500mg of levetiracetam (levetiracetam with the particle size of 300 mu m is selected), 24mg of croscarmellose sodium (disintegrating agent), 11.25mg of polyvinylpyrrolidone (polyvinylpyrrolidone is used as a binder, the levetiracetam tablet contains 22.5mg of polyvinylpyrrolidone in total, one part of polyvinylpyrrolidone is mixed with other components, the other part of polyvinylpyrrolidone is used for standby) and 16.5mg of colloidal silicon dioxide (glidant) for 3 minutes, then sieving by a 20-mesh sieve, and then mixing for 5 minutes to obtain a mixed material;
(2) adding the rest 11.25mg of polyvinylpyrrolidone (adhesive) into water to prepare a polyvinylpyrrolidone solution (dispersion liquid) with the mass fraction of 2%, adding the polyvinylpyrrolidone solution into the mixed material, then granulating at 50 ℃ by adopting a fluidized bed in one step, drying the granules until the moisture content is 1%, and stopping discharging;
(3) sieving the prepared granule with 20 mesh sieve, grading, sieving, mixing the granule with 1.5mg magnesium stearate (lubricant) for 3 min, and tabletting;
(4) dissolving 8.3mg of Opadry (coating material) in water to form a coating solution, then placing the tablet in a coating pan, and controlling the rotation speed of the coating pan to be 3 r/min; the coating solution was sprayed onto the surface of the compressed tablets at 60 ℃ by means of a spray gun at a spray rate of 1.5 g/min.
Comparative example 1
(1) Mixing 500mg of levetiracetam (levetiracetam with the particle size of 150 mu m), 28mg of croscarmellose sodium (disintegrant), 15mg of polyethylene glycol 6000 (adhesive) and 11mg of colloidal silicon dioxide (glidant) for 5 minutes to obtain a mixed material;
(2) adding 1.5mg of magnesium stearate to the above-obtained mixture and mixing for 2 minutes to obtain a mixture;
(3) tabletting the mixture obtained in the step (2), crushing the mixture after tabletting, and compressing the crushed mixture to obtain levetiracetam tablets;
(4) dissolving 16.6mg of Opadry (coating material) in water to form a coating solution, then placing the levetiracetam tablet in a coating pan, and controlling the rotation speed of the coating pan to be 5 revolutions per minute; the coating solution was sprayed onto the levetiracetam tablet surface at 50 ℃ with a spray gun at a spray rate of 2 g/min.
Comparative example 1 a levetiracetam tablet is prepared by adopting a dry granulation technology, and the contents of all components of comparative example 1 and example 2 are kept consistent except for the preparation method.
Test example 1
The dissolution kinetics of the levetiracetam tablets prepared in example 2 were compared to the dissolution kinetics of the levetiracetam tablets prepared in comparative example 1 by a dry granulation technique. The levetiracetam tablets prepared in example 2 were packaged with aluminum-plastic blisters and placed with the levetiracetam tablets prepared in comparative example 1 for accelerated storage (i.e., storage in blisters at 40 ℃ and 75% relative humidity (40 ℃, 75% RH) for 6 months). The dissolution kinetics test was performed according to the second dissolution method (paddle method) of "Chinese pharmacopoeia" 2015 edition, with a medium volume of 900ml, a rotation speed of 50rpm, a temperature of 37 ℃, a sampling point of 5min, 10min, 15min, 30min, 45min, and comparing with the dissolution data before acceleration, and the results are shown in Table 1.
TABLE 1
As can be seen from the dissolution results of table 1, the levetiracetam tablets prepared by the one-step granulation method employed in the present invention have better dissolution kinetic stability than the product prepared in comparative example 1. In the table,% represents the percentage ratio of the amount of the active ingredient eluted relative to the amount represented. To more intuitively compare the stability of the levetiracetam tablets prepared in example 2 with the stability of the levetiracetam tablets prepared in comparative example 1; the test results in Table 1 are plotted as the dissolution profile of levetiracetam tablets (prepared in example 2) shown in FIG. 2 and the dissolution profile of levetiracetam tablets (prepared in comparative example 1) shown in FIG. 3, respectively, and it can be seen that the levetiracetam tablets prepared by the method of the present invention have better dissolution kinetic stability.
The above-mentioned preferred embodiments of the present invention are provided for illustration only and not for the purpose of limiting the invention. Obvious variations or modifications of the present invention are within the scope of the present invention.
Claims (10)
1. A levetiracetam tablet is characterized by comprising levetiracetam with an active ingredient accounting for 85-92% of the total weight of the tablet, a binder accounting for 1.0-5.0% of the total weight of the tablet, a disintegrant accounting for 4.0-6.0% of the total weight of the tablet, a glidant accounting for 1.0-5.0% of the total weight of the tablet, a lubricant accounting for 0.2-0.5% of the total weight of the tablet and a coating material accounting for 1.0-6.0% of the total weight of the tablet.
2. The levetiracetam tablet of claim 1, wherein the binder is any one or a mixture of polyvinyl pyrrolidone, methylcellulose, hypromellose and polyethylene glycol 6000.
3. The levetiracetam tablet according to claim 1, wherein the disintegrant is any one of sodium carboxymethyl starch, croscarmellose sodium and low-substituted hypromellose.
4. Levetiracetam tablet according to claim 1, wherein the glidant is colloidal silicon dioxide.
5. Levetiracetam tablet according to claim 1, characterized in that the lubricant is magnesium stearate.
6. A process for the preparation of levetiracetam tablets according to any of claims 1 to 5, characterized in that it comprises the following steps:
(1) mixing levetiracetam, 50-60% of total amount of disintegrant and adhesive with glidant to obtain a mixed material;
(2) adding the rest of the adhesive into the dispersing agent to form dispersion liquid, adding the dispersion liquid into the mixed material, and then granulating;
(3) sieving the prepared granules, mixing with lubricant after sieving, and tabletting;
(4) dissolving the coating material into coating liquid, and spraying the coating liquid on the tabletting for coating.
7. The preparation method of levetiracetam tablets according to claim 6, wherein in the step (1), 50-60% of levetiracetam, disintegrant and binder and glidant are mixed for 2-5 minutes, then the mixture is sieved by a 20-mesh sieve and then mixed for 2-5 minutes to obtain a mixed material.
8. The method for preparing levetiracetam tablets according to claim 6, wherein the step (2) comprises adding the rest of the binder into water to prepare a dispersion with the mass fraction of 2-5%, adding the dispersion into the mixed materials, and granulating at 40-60 ℃ by using a fluidized bed.
9. The method for preparing levetiracetam tablets according to claim 6, wherein the granules prepared in step (3) are sieved by a 20-mesh sieve, and the granules are mixed with the lubricant for 1-3 minutes and then tabletted.
10. The process for preparing levetiracetam tablet according to claim 6, wherein the coating material is dissolved in water to form a coating solution in step (4), the tablet is placed in a coating pan, and the rotation speed of the coating pan is controlled to be 3-5 r/min; spraying the coating solution onto the surface of the tablet by a spray gun at 50-70 deg.C at a spray speed of 0.7-2 g/min for coating.
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| CN112870176A (en) * | 2021-01-22 | 2021-06-01 | 天地恒一制药股份有限公司 | Levetiracetam tablet and preparation method thereof |
| CN112933060A (en) * | 2021-04-02 | 2021-06-11 | 江西亿友药业有限公司 | Piracetam tablet and preparation method thereof |
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