CN113876726B - Brivaracetam tablet and preparation process thereof - Google Patents
Brivaracetam tablet and preparation process thereof Download PDFInfo
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- CN113876726B CN113876726B CN202111284451.9A CN202111284451A CN113876726B CN 113876726 B CN113876726 B CN 113876726B CN 202111284451 A CN202111284451 A CN 202111284451A CN 113876726 B CN113876726 B CN 113876726B
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The invention discloses a brivaracetam tablet and a preparation process thereof, wherein the tablet formula comprises the following components in percentage by mass: 18-19% of brivaracetam; 35-36% of anhydrous lactose; 40-41% of lactose monohydrate; 3.6 to 3.8 percent of carboxyl cellulose salt; 0.5-0.6% of stearate lubricant; 1.1-1.2% of stearic fumarate lubricant. According to the scheme, the auxiliary material components and the proportion of a tablet prescription are improved, the tablet is prepared by a secondary granulation process in a targeted manner, the powder mixing uniformity in the granulation process is good, the fluctuation of the main pressure in the tabletting process is small, the production efficiency is high, the content uniformity deviation of the formed tablet is small, and the dissolution behavior difference of the finished tablet is obviously reduced.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a brivaracetam tablet and a preparation process thereof.
Background
Brivaracetam is mainly used for treating epilepsy. Clinical trials brivaracetam (5, 20, 50 and 150 mg/day) was evaluated for efficacy and safety in adjuvant treatment of adult patients (16-65 years) with the presence or absence of refractory partial seizures.
The particle size distribution of the total mixed material obtained by the conventional prescription and dry granulation process of brivaracetam is dumbbell-shaped and non-Gaussian, larger particles and fine powder account for a larger proportion, and the mixed powder has poor uniformity, so that the particles with the particle size distribution cannot effectively control the uniformity of the filler in the production of small-specification (25 mg specification) tablets, the fluctuation of main pressure in the tabletting process is obvious and exceeds the tolerance range, discontinuous machine halt is caused, normal production cannot be realized, the content uniformity deviation of the tablets is overlarge, and the dissolution behavior difference in finished product batches is large, and the improvement is needed.
Disclosure of Invention
In order to solve at least one technical defect, the invention provides the following technical scheme:
the first aspect of the application document discloses a brivaracetam tablet, which comprises the following components in percentage by mass:
18-19% of brivaracetam;
35-36% of anhydrous lactose;
40-41% of lactose monohydrate;
3.6 to 3.8 percent of carboxyl cellulose salt;
0.5 to 0.6 percent of stearate lubricant;
1.1-1.2% of stearic fumarate lubricant.
In the scheme, the auxiliary material components and the proportion of a tablet prescription are improved, the tablet refers to a bare chip, the mixed powder uniformity in the granulating process is good, the fluctuation of the main pressure in the tabletting process is small, the production efficiency is high, the content uniformity deviation of the formed tablet is small, and the dissolution behavior difference of the finished tablet is obviously reduced.
The preferred prescription ratio is: 18.52% of brivaracetam, 35.74% of anhydrous lactose, 40.37% of lactose monohydrate, 3.7% of carboxyl cellulose salt, 0.56% of stearate lubricant and 1.11% of stearic fumarate lubricant.
Further, the carboxymethyl cellulose salt comprises one or more of carboxymethyl cellulose salt, carboxyethyl cellulose salt and cross-linked carboxymethyl cellulose salt, and preferably, the carboxymethyl cellulose salt is cross-linked sodium carboxymethyl cellulose.
Further, the stearate lubricant comprises one or more of magnesium stearate, sodium stearate and calcium stearate, and preferably magnesium stearate.
Further, the stearyl fumarate lubricant is sodium stearyl fumarate.
In a second aspect of the application, a brivaracetam tablet coating preparation method is disclosed, which comprises the following steps:
firstly, weighing brivaracetam, lactose monohydrate, part of anhydrous lactose and part of carboxyl cellulose salt according to a proportion, uniformly mixing, adding a stearyl fumarate lubricant, mixing again, and performing dry granulation;
secondly, screening the granules prepared in the first step, and performing dry granulation on the screened granules and the powder again;
thirdly, uniformly mixing the particles which are not sieved in the first step, the particles prepared in the second step and the residual anhydrous lactose and carboxyl cellulose salt, adding stearate lubricant, uniformly mixing again and tabletting.
Of course, it is preferred to coat the above prepared bare chips in an opadry coating solution.
Through the secondary granulation technology in this scheme to improve the order of adding of auxiliary material, better promote production efficiency with the performance parameter of finished product.
Furthermore, in the third step, the anhydrous lactose accounts for 5-15% of the mass ratio of the tablet, and the mass ratio of the carboxyl cellulose salt is 1.
Further, the dry-prepared granules were sieved in a second step with pharmacopoeia # 5 sieve.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention improves the formula of the brivaracetam tablet, and uses a plurality of lactose to be matched with carboxyl cellulose salt, stearate lubricant and stearyl fumarate lubricant to form auxiliary materials, so as to better improve the production efficiency and the performance of the finished product.
2. The invention improves the preparation method of the brivaracetam tablet in a targeted way, the secondary granulation process and the auxiliary material adding sequence, thereby further improving the production efficiency and the performance of the finished product.
Drawings
FIG. 1 is a graph comparing particle size distributions of particles of examples 1 and 4;
FIG. 2 is a schematic diagram of the fluctuation of the main pressure tolerance during the lamination process in examples 1 and 4.
Detailed Description
The invention is further described with reference to the following figures and specific examples.
1. Preparation:
the invention is specifically illustrated and described in the following 5 examples, wherein examples 1 and 2 employ a conventional one-step dry granulation process, and examples 3, 4 and 5 employ a secondary granulation process of the present invention.
In the examples, hopper mixer model: canaan HZD; a dry granulator: a canan LG dry granulation device; tabletting equipment: a FETTE tabletting device; the coating adopts an Opadry 15wt% coating solution, and the coating accounts for 3.4% of the tablet by mass; wherein each device employs conventional parameter settings.
The component ratios of the tablets in examples 1 and 2 are shown in table 1, for example:
table 1: the composition ratio of the prescription
The preparation process comprises the following steps:
firstly, weighing brivaracetam and an internally added auxiliary material (except for sodium stearyl fumarate) according to a prescription amount, uniformly mixing in a Canaan HZD hopper mixer, and adding sodium stearyl fumarate for lubrication to obtain a mixed material.
Secondly, granulating the mixed material by using a Canaan LG dry granulation device to obtain a particle size of 0.4mm, adding additional auxiliary materials (except magnesium stearate) for total mixing after granulation, and adding magnesium stearate for lubrication to obtain the total mixed material.
Thirdly, tabletting by using a FETTE tabletting device to obtain the bare chip.
Fourthly, dispersing opadry in purified water to obtain a coating solution, spraying the coating solution on the bare chip in a film coating device to obtain a film coated tablet containing brivaracetam, and sequentially preparing a coated tablet containing 100mg/50mg/25mg brivaracetam.
The components in example 3, example 4 and example 5 are shown in tables 2 and 3:
table 2: the composition ratio of the prescription
Table 3: the composition ratio of the prescription
The preparation process comprises the following steps:
firstly, weighing brivaracetam in a prescription amount, uniformly mixing the brivaracetam and all internally added auxiliary materials (except sodium stearyl fumarate) in a Canaan HZD hopper mixer, adding sodium stearyl fumarate for lubrication, and granulating the obtained mixed material by using a Canaan LG dry granulation device to obtain granules with the particle size of 0.4mm.
Secondly, screening the prepared particles by a pharmacopeia 5# sieve, taking the particles and powder which pass through the pharmacopeia 5# sieve, and performing dry granulation again, wherein the parameter setting is consistent with that of the first step.
And thirdly, mixing the part which is not sieved in the first granulation with the granules in the second granulation, adding additional auxiliary materials (except magnesium stearate) for total mixing, adding magnesium stearate for lubrication to obtain a total mixed material, and tabletting by using FETTE tabletting equipment to obtain the bare chips.
Fourthly, dispersing the opadry in purified water to obtain a coating solution, spraying the coating solution on the naked tablets in a film coating device to obtain film coated tablets containing the brivaracetam, and sequentially preparing brivaracetam coated tablets containing 100mg/50mg/25mg of brivaracetam.
2. Detection of
1) The intermediate product has the powder properties shown in table 4:
table 4: angle of repose, particle size distribution
And aiming at the particle size distribution comparison graphs prepared in the examples 1 and 4, as shown in figure 1, the problem that the particle size distribution of the total mixed material is not concentrated can be seen by the primary granulating process, and when the addition proportion of the anhydrous lactose is 5 percent ～ Within 15 percent, the secondary granulation process can obtain intermediate granules with better fluidity and more concentrated particle size distribution, which accord with Gaussian distribution and are beneficial to the smooth implementation of the subsequent tabletting process.
The particle size distribution and angle of repose detection method is as follows:
the particle size distribution detection method comprises the following steps: selecting screens with various apertures, weighing the screens, and taking test samples 25 according to the tested bulk density ～ 100 g The top (aperture) of the largest drug sieve is placed in alignment (the bottom of the sieve is provided with or contains a container). Setting vibration mode and vibration frequency, after vibrating for 5 minutes, taking the medicine screening and receiving container, weighing, and calculating the weight difference (%) of particles and powder on the screening and receiving container of the medicine before and after screening. Using an instrument: gardeman SS2000 vibratory screening apparatus.
Angle of repose detection method: the vibration reduction table device is placed in a positioning hole in the center of the instrument, and then the material receiving disc and the repose angle sample table are placed on the vibration reduction table device. Prepare the sample, open the baffle, slowly feed in raw material with the spoon at the charge door, the material is through the screen cloth, the discharge gate is spilt on the sample platform, forms the cone. And when the sample falls on the sample table and is in a symmetrical cone shape, stopping feeding, placing the angle meter at the left side of the sample tray, enabling the angle meter to be close to the material pile and be flush with the inclined plane of the conical material pile, and measuring the angle of repose. The angle of repose should be determined from three different positions when measuring the angle of repose, and then an average value is taken, which is the angle of repose (θ r) for this sample. Using an instrument: sotax PF1 powder flowability tester.
2) Intermediate product mixing homogeneity
The difference of the particle size distribution directly influences the mixing uniformity of the total mixed material, and the particle size distribution is 25m g The mix uniformity of the product of the 25mg specification was examined as shown in Table 5 for evaluation since the product of the specification was limited by the amount of sample taken during this step to maximize the risk of mix uniformityThe difference before and after process improvement was estimated.
Table 5: uniformity of mixing
Note: the percentage content in the table;
and (4) conclusion: the fluidity is good, and the materials with concentrated particle size distribution have better mixing uniformity; is more beneficial to the smooth proceeding of the subsequent tabletting process and better content uniformity of the final product.
Content determination method
Adopting high performance liquid chromatography, and the test conditions are as follows: mobile phase: 0.1% phosphoric acid solution: acetonitrile =80:20 (V/V); and (3) chromatographic column: octadecylsilane chemically bonded silica C18 chromatographic column; column temperature: 25 ℃; flow rate: 1.0mL/min; detection wavelength: 205nm; sample introduction amount: 10 mu L of the solution; operating time: 20min; calculating according to the peak area by an external standard method to obtain the product.
3) Tolerance fluctuation of tabletting and content uniformity of final product (CU)
The tablet weight of 25mg standard product is the smallest, so the influence of material flowability and particle size distribution is the largest in the tabletting process, and therefore, in the tabletting process, the particle size is compared with 50m g And 100m g Product specification, with greater risk of content uniformity; and meanwhile, the main pressure tolerance fluctuation in the tabletting process has a greater risk, so that the tabletting inspection of 25mg specification products is carried out, as shown in tables 6 and 7, so as to evaluate the influence before and after the process improvement.
Table 6: tolerance fluctuation
Table 7: content uniformity of 25mg tablet
And is plotted as the tolerance fluctuation values of example 1 and example 4, as shown in fig. 2.
And (4) conclusion: the material prepared by the improved secondary granulation process has smaller main pressure tolerance fluctuation in the tabletting process and better content uniformity, and is remarkably superior to the material prepared by the primary granulation process in two indexes, thereby showing that the material prepared by the secondary granulation process has better process feasibility.
4) In vitro Release behavior of the end product
Of the three gauge products of the invention, 100m g The product with the specification has the largest tablet weight, more granules need to be filled in the tabletting process, and the distribution of the filled granules has direct influence on the in-vitro release behavior, so that the in-batch difference of the in-vitro release behavior is more easily influenced by the tablet weight and has higher risk, and the in-vitro release behavior of the final product is researched by adopting the product with the specification of 100mg to evaluate the difference of different granulating processes.
Table 8: comparison of dissolution curves of Blisteritant tablets (100 mg)
Dissolution test method
The test conditions are as follows: medium: acetate solution at pH 4.5; volume of medium: 900m; a paddle method; rotating speed: 50rpm; temperature: 37 plus or minus 0.5 ℃; sampling time: 5min, 10min, 15min, 20min, 30min
The detection method comprises the following steps: HPLC method
The specific test operation is as follows: taking 6 test samples, respectively putting the test samples into 6 dissolution cups, setting a method to start an instrument, sampling until the specified sampling time, filtering by using a 0.45 mu m PTFE filter membrane, taking the subsequent filtrate for measurement, and calculating the accumulated dissolution amount of each sample at each time point.
And (4) conclusion: after the secondary granulation process is adopted to improve the particle size distribution of the material, the dissolution rate RSD values at the time points of 5 minutes and 10 minutes are obviously reduced, and the intra-batch difference is effectively controlled; and simultaneously still meets the requirement of quick release of the brivaracetam tablet.
The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above-mentioned embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (7)
1. The brivaracetam tablet is characterized by comprising the following components in percentage by mass:
18-19% of brivaracetam;
35-36% of anhydrous lactose;
40-41% of lactose monohydrate;
3.6 to 3.8 percent of carboxyl cellulose salt;
0.5 to 0.6 percent of stearate lubricant;
1.1-1.2% of a stearyl fumarate lubricant;
the preparation process of the brivaracetam tablet comprises the following steps:
firstly, weighing brivaracetam, lactose monohydrate, part of anhydrous lactose and part of carboxyl cellulose salt according to a proportion, uniformly mixing, adding a stearyl fumarate lubricant, mixing again, and performing dry granulation;
secondly, screening the granules prepared in the first step, and performing dry granulation on the screened granules and the powder again;
thirdly, uniformly mixing the particles which are not sieved in the first step, the particles prepared in the second step and the residual anhydrous lactose and carboxyl cellulose salt, adding a stearate lubricant, uniformly mixing again and tabletting;
in the third step, the anhydrous lactose accounts for 5-15% of the mass ratio of the tablet, and the mass ratio of the carboxyl cellulose salt in the first step and the third step is 1.
2. The brivaracetam tablet according to claim 1, wherein: 18.52% of brivaracetam, 35.74% of anhydrous lactose, 40.37% of lactose monohydrate, 3.7% of carboxyl cellulose salt, 0.56% of stearate lubricant and 1.12% of stearic fumarate lubricant.
3. The brivaracetam tablet according to claim 1, wherein: the carboxyl cellulose salt comprises one or more of carboxymethyl cellulose salt, carboxyethyl cellulose salt and cross-linked carboxymethyl cellulose salt.
4. The brivaracetam tablet according to claim 3, wherein: the carboxymethyl cellulose salt is croscarmellose sodium.
5. The brivaracetam tablet according to claim 1, wherein: the stearate lubricant comprises one or more of magnesium stearate, sodium stearate and calcium stearate.
6. The brivaracetam tablet according to claim 1, wherein: the stearyl fumarate lubricant is sodium stearyl fumarate.
7. The brivaracetam tablet according to claim 1, wherein: in the second step the dry prepared granules were sieved with a pharmacopeia 5# sieve.
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