CN115702885A - Brivaracetam tablet and preparation method thereof - Google Patents
Brivaracetam tablet and preparation method thereof Download PDFInfo
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- CN115702885A CN115702885A CN202110899759.8A CN202110899759A CN115702885A CN 115702885 A CN115702885 A CN 115702885A CN 202110899759 A CN202110899759 A CN 202110899759A CN 115702885 A CN115702885 A CN 115702885A
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- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 title claims abstract description 60
- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000002156 mixing Methods 0.000 claims abstract description 36
- 239000000463 material Substances 0.000 claims abstract description 30
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 26
- 229920000881 Modified starch Polymers 0.000 claims abstract description 24
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 20
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 20
- 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 abstract description 17
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 17
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 13
- 229960004977 anhydrous lactose Drugs 0.000 claims abstract description 13
- 229960001375 lactose Drugs 0.000 claims abstract description 13
- 239000008101 lactose Substances 0.000 claims abstract description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 13
- 238000007908 dry granulation Methods 0.000 claims abstract description 6
- 239000008187 granular material Substances 0.000 claims abstract description 6
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 14
- 239000007941 film coated tablet Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 5
- 239000007888 film coating Substances 0.000 claims description 3
- 238000009501 film coating Methods 0.000 claims description 3
- 238000003825 pressing Methods 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 25
- 239000003814 drug Substances 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 11
- 230000009466 transformation Effects 0.000 abstract description 8
- 238000003860 storage Methods 0.000 abstract description 7
- 239000000853 adhesive Substances 0.000 abstract description 4
- 230000001070 adhesive effect Effects 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000004220 aggregation Methods 0.000 abstract 1
- 230000002776 aggregation Effects 0.000 abstract 1
- 238000010008 shearing Methods 0.000 abstract 1
- 230000008569 process Effects 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- 229920000858 Cyclodextrin Polymers 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000001116 FEMA 4028 Substances 0.000 description 5
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 5
- 229960004853 betadex Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000011835 investigation Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000005056 compaction Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 description 1
- 101710084141 Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a brivaracetam tablet and a preparation method thereof, belongs to the technical field of pharmaceutical preparations, and solves the problems of crystal transformation and isomer impurities generation of brivaracetam preparations in the prior art during preparation and storage. The brivaracetam tablet of the present invention comprises: 10-25 parts of brivaracetam, 25-45 parts of lactose, 1-10 parts of pregelatinized starch, 1-6 parts of croscarmellose sodium, 25-45 parts of anhydrous lactose and 0.5-2 parts of magnesium stearate. The preparation method comprises the following steps: premixing brivaracetam, pregelatinized starch, partially cross-linked sodium carboxymethyl cellulose and lactose; dry granulation; mixing the granules with anhydrous lactose, the balance of croscarmellose sodium and magnesium stearate, and tabletting. The brivaracetam tablet adopting the pregelatinized starch as the adhesive has stable crystal form and does not generate crystal transformation; the isomer impurities are stable. The invention adopts a high-shearing mode to mix materials, thereby reducing the risk of uneven mixing caused by the aggregation of the bulk drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a brivaracetam tablet and a preparation method thereof.
Background
Brivaracetam, a modulator of synaptic vesicle glycoprotein 2A (SV 2A), is used in the first line or additive treatment of focal seizures.
The brivaracetam raw material is white or white-like crystalline powder, is very easy to dissolve in water, has low melting point and high viscosity among raw materials, is very easy to agglomerate, and influences the smoothness of the product process and the content uniformity of finished products.
Chinese patent application No. CN201080005399.2 discloses an immediate release pharmaceutical composition comprising brivaracetam as active ingredient, which comprises a cyclodextrin agent, a disintegrant and a diluent. By adding the cyclodextrin agent to the pharmaceutical composition, good compaction characteristics, compaction capacity are produced, and material binding during compaction, particularly rolling, is reduced.
Researches find that the phenomenon of crystal transformation caused by unstable crystal form exists in the preparation process of brivaracetam and the storage process of preparation products; and isomer impurities are easily generated, which is not beneficial to the quality control of products and the clinical use safety.
The applicant has unexpectedly found in previous studies that the cyclodextrin used as a binder, although it improves the problem of material adhesion during compression, causes the modification of the crystalline form of the formulated product during preparation and storage, and also generates isomer impurities during storage, which is not good for product quality control and clinical safety. Therefore, there is a need to develop a new brivaracetam pharmaceutical composition to solve the above problems.
Disclosure of Invention
One of the purposes of the invention is to provide a brivaracetam tablet, which adopts pregelatinized starch as a bonding agent, can improve the problems that the brivaracetam preparation is easy to be bonded into a mass in the preparation process, so that the process smoothness and the content uniformity are influenced, and also solves the problems that the brivaracetam preparation in the prior art is subjected to crystal transformation and isomer impurities are generated in the preparation and storage processes.
The other object of the present invention is to provide a method for producing the brivaracetam tablet.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the brivaracetam tablet provided by the invention comprises the following components in parts by weight in each unit preparation: 10-25 parts of brivaracetam, 25-45 parts of lactose, 1-10 parts of pregelatinized starch, 1-6 parts of croscarmellose sodium, 25-45 parts of anhydrous lactose and 0.5-2 parts of magnesium stearate.
In some embodiments of the invention, the following components are included in each unit formulation in parts by weight: 15-20 parts of brivaracetam, 30-40 parts of lactose, 2-8 parts of pregelatinized starch, 1-5 parts of croscarmellose sodium, 30-40 parts of anhydrous lactose and 0.8-1.5 parts of magnesium stearate.
In some embodiments of the invention, the following components are included in each unit formulation in parts by weight: 18.5 parts of brivaracetam, 35.9 parts of lactose, 5 parts of pregelatinized starch, 3.7 parts of croscarmellose sodium, 35.8 parts of anhydrous lactose and 1.1 parts of magnesium stearate.
The applicant finds that the pregelatinized starch is used as the adhesive, the problems that materials are bonded into a mass in the preparation process of the brivaracetam tablet to influence the process smoothness and the content uniformity can be solved, and meanwhile, the prepared preparation has stable crystal form, does not generate crystal transformation in the preparation and storage processes, and has stable isomer impurities and no remarkable increase.
In some embodiments of the invention, the brivaracetam tablet is a film-coated tablet, preferably, the film-coated tablet is a gastric-soluble film-coated tablet.
In some embodiments of the invention, the brivaracetam tablet comprises brivaracetam in an amount of 25mg, 50mg or 100mg per unit formulation.
The invention provides a preparation method of brivaracetam tablets, which comprises the following steps:
and 4, mixing the granules prepared in the step 3 with anhydrous lactose, the rest of croscarmellose sodium and magnesium stearate, and tabletting.
In some embodiments of the present invention, in the step 2, the pre-mixing is performed by three-dimensional mixing or high shear mixing, preferably high shear mixing.
In some embodiments of the invention, during high shear mixing, the stirring speed is 60-100 rpm, the cutter speed is 600-1000 rpm, and the mixing time is 10-20 min; preferably, the stirring speed is 80rpm, the cutter speed is 800rpm, and the mixing time is 15min.
In some embodiments of the present invention, in the dry granulation in step 3, the rotation speed of the material conveying motor is controlled to be 500rpm, the rotation speed of the pinch roller motor is controlled to be 250rpm, and the oil pressure is controlled to be 65kg/cm 2 。
In some embodiments of the present invention, the ratio of the amount of croscarmellose sodium used in step 2 to step 4 is from 0.5 to 2:0.5 to 2; preferably 1:1.
in some embodiments of the invention, the tabletted plain tablets are optionally film coated to produce film coated tablets.
Compared with the prior art, the invention has the following beneficial effects:
on one hand, the pregelatinized starch is used as an adhesive, so that the crystal transformation of the active ingredient distribution risitant in the preparation process or the storage process is avoided, the crystal form is kept stable, and the drug effect of the drug is effectively guaranteed; meanwhile, related substances and isomer impurities of the brivaracetam pharmaceutical composition provided by the invention can be controlled at a very low limit level, and the product quality is ensured.
On the other hand, the brivaracetam pharmaceutical composition provided by the invention reduces the pressure between rollers during granulation, further reduces the wheel sticking phenomenon caused by high viscosity of the raw material medicine and the risk of blocking a screen by the material in the granulating process, can obtain particles with certain hardness and good formability, and ensures that the whole process is smooth and steady and has strong operability.
The brivaracetam pharmaceutical composition provided by the invention has the advantages that the obtained materials are uniformly mixed, the problem of non-uniform content in the prior art is effectively solved, and the product quality is uniform and controllable.
Drawings
FIG. 1 shows XRPD superimposed spectrum of crystal form of crude drug before and after being placed under high temperature, high humidity and illumination conditions for 30 days;
FIG. 2 is a crystal form XRPD superimposed spectrum of beta cyclodextrin mixed with bulk drug and placed under high humidity condition for 28 days;
FIG. 3 shows an XRPD overlay of a 28-day crystal form after mixing pregelatinized starch with a bulk drug under high humidity conditions;
figure 4 is an overlay of the XRPD pattern of tablet C and comparative example 1 after standing for 3 months under extended conditions.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The reference preparations 1 to 3 described in the embodiments of the present invention are respectively:
Example 1
This example discloses a formulation of brivaracetam tablets in mg/tablet as shown in the following table:
table 1 ingredient table of the invention
Example 2
Adopting a tablet core formula of a formula 1 in a table 1 of example 1, preparing brivaracetam tablets with the specification of 100 mg/tablet by adopting three different premixing modes and feeding modes, and investigating different premixing modes and feeding modes by taking a dissolution curve and content uniformity of premixed materials as indexes; the preparation method comprises the following steps:
the 1 st: weighing brivaracetam, lactose, pregelatinized starch, croscarmellose sodium and anhydrous lactose in the formula amount, mixing for 20min by using a three-dimensional mixer, and obtaining a premixed material at a mixing rotating speed of 23 rpm; adding the mixture into a dry granulating machine for granulating, adjusting the rotation speed of a material conveying motor to be 500rpm, the rotation speed of a pinch roller motor to be 250rpm, and the oil pressure to be 65kg/cm 2 Performing dry granulation, and finishing granules by using a sieve with the aperture of 1.0 mm; mixing the obtained material with magnesium stearate for 5min; and tabletting the total mixed material to obtain a tablet core I.
The 2 nd: weighing brivaracetam, lactose, pregelatinized starch and a half amount of croscarmellose sodium in a prescribed amount, mixing for 20min by using a three-dimensional mixer, and obtaining a premixed material at a mixing rotation speed of 23 rpm; adding the mixture into a dry granulating machine for granulating, adjusting the rotation speed of a material conveying motor to be 500rpm, the rotation speed of a pinch roller motor to be 250rpm, and the oil pressure to be 65kg/cm 2 Performing dry granulation, and finishing granules by using a sieve with the aperture of 1.0 mm; mixing the obtained material with anhydrous lactose and rest croscarmellose sodium added with the rest materials for 20min, adding magnesium stearate, and mixing for 5min; and tabletting the total mixed material to obtain a tablet core II.
And (3) type: balanceMixing brivaracetam, lactose, pregelatinized starch and half of croscarmellose sodium according to the formula amount by using a high-shear mixing granulator at a stirring speed of 80rpm and a cutter speed of 800rpm for 15min to obtain a premixed material; adding the mixture into a dry granulating machine for granulating, adjusting the rotation speed of a material conveying motor to be 500rpm, the rotation speed of a pinch roller motor to be 250rpm, and the oil pressure to be 65kg/cm 2 Performing dry granulation, and finishing granules by using a sieve with the aperture of 1.0 mm; mixing the obtained material with anhydrous lactose and rest croscarmellose sodium added, adding magnesium stearate, and mixing for 5min; and tabletting the total mixed material to obtain a tablet core III.
(1) The dissolution profiles of cores I, II, III were determined (paddle method, 900ml of pH6.4 phosphate buffer, 50 rpm) and the results are shown in the following table:
the preparation method of the pH6.4 phosphate buffer solution comprises the following steps: 250ml of 0.2mol/L potassium dihydrogen phosphate solution is mixed with 58.0ml of 0.2mol/L sodium hydroxide solution, diluted to 1000ml by water and shaken up to obtain the potassium dihydrogen phosphate.
TABLE 2 dissolution Curve results for tablet cores I-III
The results show that the tablet cores I, II and III can be quickly dissolved in the dissolution medium, and the in-vitro dissolution requirements of the product are met.
(2) Content uniformity (%) of the premixed material of the brivaracetam tablet prepared by three different premixing modes and feeding modes is detected, and the obtained results are as follows:
table 3 table of content uniformity test results
Experimental data show that the traditional three-dimensional mixing mode is adopted for mixing materials, the feeding mode of the materials is improved, namely, the feeding mode is divided into an internal feeding mode and an external feeding mode, and the mixing uniformity of the materials can be improved to a certain extent; on the basis of the feeding mode, a three-dimensional mixing mode is replaced by a high-shear mixing mode, and the mixing uniformity of the materials is further improved.
Example 3
Three groups of formulas in example 1 were used to prepare Blisteritan film-coated tablets with tablet core specifications of 25mg, 50mg and 100mg, respectively, wherein the preparation method of the plain tablet was as in example 2, and the obtained plain tablet was used
Coating with the film coating premix to obtain the brivaracetam film-coated tablet, wherein the three standard brivaracetam film-coated tablets are respectively marked as tablet A, tablet B and tablet C. Dissolution profiles (paddle method, ph6.4 phosphate buffer, 50 rpm) of the prepared brivaracetam film-coated tablets of three specifications were determined and compared with the reference formulation, and the results were as follows:
TABLE 4 dissolution Curve results for tablets A-C
The dissolution curve results show that: the three-specification coated tablets prepared by the invention can be quickly dissolved in the aqueous buffer solution, the dissolution behaviors of the three specifications are consistent with those of a reference preparation sold in the market, and the product quality is equal.
Comparative example 1
Compared with the tablet C in the example 3, the pregelatinized starch is replaced by beta-cyclodextrin, the rest materials and the preparation method are the same, and the brivaracetam film-coated tablet prepared by the comparative example is marked as the tablet of the comparative example 1.
Test example 1 Effect of Binders on Crystal form of bulk drugs
Beta-cyclodextrin and pregelatinized starch are used as adhesives and are respectively mixed with the raw material brivaracetam, the change conditions of the crystal forms of the materials before and after mixing are investigated, the investigation conditions and the results are shown in the following table, and the XRPD superposition patterns of the crystal forms are shown in the attached figures 1 to 3:
TABLE 5 influence of the Binder on the Crystal form of the crude drugs
And (4) analyzing results: the data show that after the beta cyclodextrin and the brivaracetam bulk drug are mixed, the beta cyclodextrin and the brivaracetam bulk drug interact with each other under a high-humidity condition, so that the phenomenon of drug crystal form transformation of the bulk drug is caused; the pregelatinized starch is amorphous, has stable crystal form under high humidity, and does not react with the raw material medicines. Therefore, the pregelatinized starch is more beneficial to ensuring the stability of the crystal form of the product.
Test example 2
The stability of the crystal forms of the tablet C of the invention and the tablet of the comparative example 1 was examined, and the results are shown in the following table, wherein the XRPD overlay patterns of the crystal forms of the samples before and after being placed for 3 months under long-term conditions are shown in the attached figure 4:
TABLE 6 table of crystal form stability investigation test results
The result shows that the brivaracetam film-coated tablet adopting the pregelatinized starch does not generate crystal form transformation and has better crystal form stability.
Test example 3
The impurity levels of tablet C and the comparative example 1 tablet were examined and compared to the reference formulation and the results are shown in the following table:
table 7 table of isomer impurity level investigation results
TABLE 8 investigation results of the relevant substance levels
Wherein the impurities are shown in the following table:
TABLE 9 list of impurities
The results show that: the brivaracetam film-coated tablets of the present invention using pregelatinized starch have lower levels of isomers and related substances and show no significant increase in stability.
The brivaracetam tablet and the preparation method thereof disclosed and provided by the invention can be realized by appropriately changing links such as raw materials, process parameters and the like by referring to the contents in the text. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and products described herein may be made and equivalents employed to practice the techniques of the present invention without departing from the spirit and scope of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (10)
1. The brivaracetam tablet is characterized in that each unit of preparation comprises the following components in parts by weight: 10-25 parts of brivaracetam, 25-45 parts of lactose, 1-10 parts of pregelatinized starch, 1-6 parts of croscarmellose sodium, 25-45 parts of anhydrous lactose and 0.5-2 parts of magnesium stearate.
2. The brivaracetam tablet according to claim 1, wherein the brivaracetam tablet comprises the following components in parts by weight per unit preparation: 15-20 parts of brivaracetam, 30-40 parts of lactose, 2-8 parts of pregelatinized starch, 1-5 parts of croscarmellose sodium, 30-40 parts of anhydrous lactose and 0.8-1.5 parts of magnesium stearate.
3. The brivaracetam tablet according to claim 2, wherein the following components are contained in each unit of preparation in parts by weight: 18.5 parts of brivaracetam, 35.9 parts of lactose, 5 parts of pregelatinized starch, 3.7 parts of croscarmellose sodium, 35.8 parts of anhydrous lactose and 1.1 parts of magnesium stearate.
4. A brivaracetam tablet according to claim 1 or 2, wherein the brivaracetam tablet is a film-coated tablet, preferably the film-coating is a gastric-soluble film-coating.
5. A brivaracetam tablet according to any one of claims 1 to 3, wherein brivaracetam is contained in an amount of 25mg, 50mg or 100mg per unit preparation.
6. The method for preparing a brivaracetam tablet according to any one of claims 1 to 5, comprising the following steps:
step 1, preparing each component material according to the prescription amount,
step 2, premixing brivaracetam, pregelatinized starch, partially cross-linked sodium carboxymethyl cellulose and lactose;
step 3, dry granulating the mixture prepared in the step 2;
and 4, mixing the granules prepared in the step 3 with anhydrous lactose, the rest amount of croscarmellose sodium and magnesium stearate, and tabletting.
7. The method according to claim 6, wherein the pre-mixing in step 2 is performed by three-dimensional mixing or high shear mixing, preferably high shear mixing.
8. The preparation method according to claim 7, wherein the stirring speed is 60 to 100rpm, the cutter speed is 600 to 1000rpm, and the mixing time is 10 to 20min during the high shear mixing; preferably, the stirring speed is 80rpm, the cutter speed is 800rpm, and the mixing time is 15min.
9. The method according to claim 6, wherein the ratio of the amount of croscarmellose sodium used in step 2 to step 4 is 0.5 to 2:0.5 to 2; preferably 1:1.
10. the method according to claim 6, wherein in the dry granulation in step 3, the rotation speed of the feeding motor is controlled to be 500rpm, the rotation speed of the pressing wheel motor is controlled to be 250rpm, and the oil pressure is controlled to be 65kg/cm 2 。
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| CN202110899759.8A CN115702885A (en) | 2021-08-06 | 2021-08-06 | Brivaracetam tablet and preparation method thereof |
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| CN202110899759.8A CN115702885A (en) | 2021-08-06 | 2021-08-06 | Brivaracetam tablet and preparation method thereof |
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