CN112870176B

CN112870176B - Levetiracetam tablet and preparation method thereof

Info

Publication number: CN112870176B
Application number: CN202110089239.0A
Authority: CN
Inventors: 陶佑波; 高欣; 彭慧; 王宇杰; 王衡新; 宋志林
Original assignee: Tiandi Hengyi Pharmaceutical Co ltd
Current assignee: Tiandi Hengyi Pharmaceutical Co ltd
Priority date: 2021-01-22
Filing date: 2021-01-22
Publication date: 2021-11-02
Anticipated expiration: 2041-01-22
Also published as: CN112870176A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a levetiracetam tablet and a preparation method thereof. The preparation method comprises the following steps: the method comprises the following steps: sieving levetiracetam, hydroxypropyl cellulose, croscarmellose sodium and part of colloidal silicon dioxide together for later use; step two: mixing the granulated materials in the step one, adding magnesium stearate, and uniformly mixing to obtain premixed powder; step three: putting the premixed powder in the step two into a dry granulation method and finishing granules to obtain a granule and powder mixture; step four: mixing the granules and powder mixture granulated in the step three with the rest colloidal silicon dioxide, and tabletting; step five: and (4) coating. The preparation method provided by the invention has the characteristics of simple process flow, strong operability, low production cost and stability.

Description

Levetiracetam tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a levetiracetam tablet and a preparation method thereof.

Background

Levetiracetam is a pyrrolidone derivative, and the chemical structure of levetiracetam is unrelated to the chemical structure of the existing antiepileptic drugs. The anti-epileptic effect of levetiracetam was evaluated in a variety of animal models of epilepsy. Levetiracetam has no inhibitory effect on simple seizures induced by maximal stimulation with electric current or with a variety of convulsants and shows only weak activity in sub-maximal stimulation and threshold tests. Protection was observed against systemic seizures secondary to pilocarpine-and kainic-induced focal seizures, and these two chemical convulsants mimic the characteristics of some human complex partial seizures accompanied by secondary systemic seizures. Levetiracetam has inhibitory effects on both the light-off process and the light-off status of the rat light-off model with complex partial seizures. The predictive value of these animal models for a particular type of epilepsy in the human body is not clear. In vivo and in vitro experiments show that levetiracetam inhibits hippocampal epileptiform burst discharge without affecting normal neuronal excitability, and suggest that levetiracetam may selectively inhibit epileptiform burst discharge hypersynchrony and spread of epileptiform seizures.

The drug was developed by the company UCB Belgium under the trade name of

Are currently registered by the European Medical Evaluation Agency (EMEA) and the U.S. Food and Drug Administration (FDA) and are in clinical use. The levetiracetam has unique action mechanism, long duration of curative effect, less adverse reaction and good safety and tolerance, can be used for the additive treatment, adjuvant treatment or single-drug treatment of various epileptic seizures, and has wide clinical application prospect. The chemical structural formula is as follows:

UCB applies composition patent CN101068534A aiming at the medicine, and the medicine composition containing levetiracetam and the preparation method thereof. In this patent, it is disclosed that a dry granulation process produces tablets: mixing the medicinal composition materials, compacting, pulverizing, and compressing to obtain plain tablet and film coating. The method is simple to operate, and avoids active ingredient degradation caused by contact with wet phase during processing. However, the composition and the formula disclosed in the patent have the problems of slightly low hardness and high friability of the tablets in the actual preparation process. And because the tablet still involves many links such as quality control, packing after the piece, above-mentioned hardness is low, the friability is high and will appear in the tablet production later stage and reach the patient during "bad piece" more in quantity, can't satisfy actual quality control and production standard.

In addition, in the process of practical research, the unknown single impurity content is found to increase rapidly after levetiracetam and polyethylene glycol in the original tablet prescription are mixed and tableted and then are placed under a high-temperature condition for a certain time, so that the stability of the product is reduced.

In order to solve the problems, most enterprises select wet granulation with complicated processing technology or make improvement on the formula during the processing process.

For example, chinese patent CN105434375A discloses a levetiracetam tablet and a preparation method thereof, wherein wet granulation is adopted by selecting auxiliary materials and selecting the content of the auxiliary materials and the main drug, so as to improve the stability of the tablet and improve the dissolution curve parameters, and the starch content is higher than that of lactose, thereby reducing the cost.

Chinese patent CN201210358301.2 discloses a levetiracetam film coated tablet and a preparation method thereof, the invention adopts wet granulation, starch slurry is used as a bonding agent, croscarmellose sodium is used as a disintegrating agent, the disintegrating principle is that the tablet is wetted by virtue of capillary action, the disintegrating agent plays a disintegrating role after undergoing a gelling process in the process, the levetiracetam particles prepared by the method have very high hardness, and the final tablet is very slow in disintegration and dissolution. In the actual production process, the wet granulation process has more steps compared with the dry granulation process, the process parameters are relatively complicated, the dissolution effect of the product is poor and unstable, and the control of the product quality and the commercial production are not facilitated.

Direct compression methods are also a matter of choice. For example, chinese patent CN200910236406 discloses a pharmaceutical composition containing levetiracetam tablet and a preparation method thereof, the invention directly adopts direct tabletting or a powder direct filling method to prepare the capsule, the method is easy to cause flying dust and easy to crack the tablet, when the levetiracetam specification is increased to 500 mg/tablet or 1000 mg/tablet, the auxiliary materials which can be added are obviously reduced, thereby causing the flowability of the drug to be poor, the tablet weight difference to be increased, the moldability to be poor, even the direct tabletting of the powder can not be realized, the method needs to be equipped with special equipment, and the production cost is increased.

Therefore, a preparation method of levetiracetam tablets, which has the advantages of simple process flow, low production cost, good product stability, good formability and good dissolution effect and is suitable for commercial production, is needed.

Disclosure of Invention

In order to solve the problems in the prior art, the invention aims to provide a preparation method of levetiracetam tablets, which can well solve the problems of poor stability, tabletting forming, dissolution effect and the like of levetiracetam in the preparation development process, and is simple in process flow, low in production cost and suitable for commercial production.

In order to achieve the above object, the present invention provides the following technical solutions:

a method for preparing levetiracetam tablets, comprising the steps of:

the method comprises the following steps: sieving levetiracetam, hydroxypropyl cellulose, croscarmellose sodium and part of colloidal silicon dioxide in formula ratio together for later use as granulating material;

step two: mixing the granulated material obtained in the step one for several minutes, adding magnesium stearate, and mixing to uniformly mix the raw materials and the auxiliary materials to obtain premixed powder;

step three: putting the premixed powder in the step two into a dry-process granulator, granulating and finishing granules to obtain a granule and powder mixture;

step four: mixing the granules and powder mixture granulated in the step three with the rest colloidal silicon dioxide, and tabletting;

step five: and coating the plain tablets to obtain the levetiracetam tablets.

Further, the particle size D50 of the levetiracetam is 139-231 μm. For comparison, the applicant examined the performance of tablets when levetiracetam of different particle sizes was used as an active ingredient, but as a result, found that when the particle size D50 was in the range of about 120-235 μm, a molded tablet could be obtained and exhibited superior dissolution performance; when the particle size D50 is 139-231 μm, the dissolution performance of the tablet is better consistent with that of the original preparation. When the particle size D50 is beyond the particle size range, the prepared particles have poor compressibility and cannot be tabletted and molded; or the dissolution is faster, and the dissolution performance of the tablet has larger difference with the original research.

Further, the material conveying speed set by the dry method granulator in the third step is 10-30rpm, and/or the rotating speed of a pressure wheel is 5-15rpm, and/or the hydraulic pressure is 4-6 Mpa; and/or the ribbon whole grain sieve is 20 meshes.

Furthermore, the ratio of the material conveying speed to the pressing wheel rotating speed set by the dry granulation machine in the third step is 1-3: 1.

Further, the mass ratio of the colloidal silica to the levetiracetam added in the first step is 1: 100.

the mass ratio of the colloidal silicon dioxide to the levetiracetam added in the fourth step is 1: 93.

further, the model of the hydroxypropyl cellulose in the first step is EXF. The inventor inspects the influence of different types of hydroxypropyl cellulose on the tablet in the research process, and finds that the dissolution performance, the tablet stability and the forming performance of the tablet prepared by selecting the hydroxypropyl cellulose EXF are best.

Further, the levetiracetam tablet is prepared from the following components in parts by weight: 750 parts of levetiracetam, 18 parts of hydroxypropyl cellulose, 21.75 parts of croscarmellose sodium, 7.5 parts of colloidal silicon dioxide and 0.94 part of magnesium stearate.

Further, the levetiracetam tablet is prepared from the following components in parts by weight: 750 parts of levetiracetam as an active ingredient, 7.5 parts of hydroxypropyl cellulose, 21.75 parts of croscarmellose sodium, 15.56 parts of colloidal silicon dioxide and 0.94 part of magnesium stearate.

Compared with the prior art, the preparation method of the levetiracetam tablet provided by the invention has the following beneficial effects:

(1) the preparation method of the levetiracetam tablet provided by the invention has the advantages of simple process flow, strong operability and low production cost, and although the preparation method of the invention has a large proportion of active ingredients and a small proportion of other auxiliary materials, a more complex method with equivalent incremental increase is not required for mixing operation, so that a better mixing effect can be achieved. Thereby saving the working hours of the process operation and improving the production efficiency.

(2) The particle size range D (V,0.5) of the levetiracetam is 139-231 mu m, the weight ratio of the levetiracetam is up to 93%, the good formability can still be shown, and the brittleness of the prepared plain tablets is low; but also can avoid the problem of stability reduction caused by high temperature conditions of levetiracetam and polyethylene glycol 6000 in the original prescription.

(3) According to the preparation method, other compressible auxiliary materials are not required to be added, the adding mode of the colloidal silicon dioxide is divided into adding (internal adding) before granulation and adding (external adding) during total mixing, and the inventor researches show that the adding mode of the colloidal silicon dioxide internal adding and the external adding can obviously improve the compressibility of levetiracetam tablet particles and powder mixtures, the hardness of plain tablets is obviously improved, the disintegration time is prolonged, and then the dissolution of the tablets is similar to that of the original ground tablets, so that a better dissolution degree is achieved.

(4) In the research process of the invention, it is found that various process parameters such as pressure, auxiliary material speed, pressing wheel rotating speed and the like in the granulation process also have important influence on the compressibility, intermediate, dissolution and other properties of the granules in the granulation process.

Drawings

FIG. 1 is a graph comparing in vitro dissolution profiles of tablets prepared according to formulas 1-9 with a reference formulation in a medium at pH 4.5.

Detailed Description

The present invention will be further explained with reference to specific embodiments in order to make the technical means, the original characteristics, the achieved objects and the effects of the present invention easy to understand, but the following embodiments are only preferred embodiments of the present invention, and not all embodiments are possible. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.

In the following examples, unless otherwise specified, all the procedures and equipment used were conventional procedures and equipment used was conventional equipment.

Example 1

A method of making levetiracetam tablets, comprising the steps of:

(1) weighing and preparing materials: weighing and preparing materials according to the formula proportion in the following table; TABLE 1

(2) Preparation method

TABLE 2

Example 2

The levetiracetam tablets prepared according to different formulations in example 1 were taken, the friability was determined and the composition was examined

The shape property; the experimental results are as follows: according to the measurement result, the hydroxypropyl cellulose with the model of EXF is selected to prepare the tablet, the friability of the tablet is small, and the formability is good.

TABLE 3

	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Friability (%)	0.50 (with unfilled corner)	0.52 (with unfilled corner)	0.45 (with slight unfilled corner)	0.33 (no-powder-falling unfilled corner)
Hardness (kg)	12-14	12-15	14-17	14-17

Note: in the hardness and friability testing process in this example, 10 tablets of the formulation of the same batch were taken for each test, and the hardness data in table 3 is the hardness distribution range of the 10 tablets.

Example 3

TABLE 4

Preparation method

TABLE 5

From the above examples, it can be seen that the mode of adding colloidal silicon dioxide has a great influence on the formation of tablets, and when colloidal silicon dioxide is added in both internal and external modes, the compressibility of the material is significantly improved, the hardness of the tablet is significantly increased, and the friability is significantly reduced.

Example 4

The levetiracetam tablets prepared by different formulas in example 1 are placed at 60 ℃ for 10 days, high-temperature experiments are carried out, relevant substances of the product are examined, and the experimental results are shown in the following table 6:

from the stability test results of table 6, it can be seen that: the stability of the tablet provided by the formula 4 of the invention under high temperature conditions is obviously superior to that of the original tablet. The results of the measurement in example 2 and example 4 are combined to show that when the hydroxypropyl cellulose with the model of EXF is selected as the binder in the formula, the friability of the tablet can be improved, the problem of the formability of the tablet can be solved, the problems of related substances of the product can be improved, and the stability of the product can be improved.

Example 5

A process for the preparation of levetiracetam tablets, comprising the steps of;

(1) weighing and preparing materials: weighing and preparing materials according to the formula proportion in the following table 7; TABLE 7

(2) A preparation method;

weighing levetiracetam, hydroxypropyl cellulose (EXF), croscarmellose sodium and colloidal silicon dioxide (internal addition) according to the prescription amount, using a fixed lifting material transferring granulator to pass through a sieve with the aperture of phi 1.0mm for later use; mixing the sieved raw materials and auxiliary materials for 15min, adding magnesium stearate in a prescription amount, and mixing for 5min for later use; and (3) putting the mixed raw and auxiliary materials into a dry granulating machine for granulation, setting the conveying speed of the dry granulating machine to be 30rpm, the rotating speed of a pressing wheel to be 15rpm, the hydraulic pressure to be 4Mpa, and the mesh number of a whole-grain screen to be 20 meshes. And then mixing the granulated granule and powder mixture with colloidal silicon dioxide (added) for 10min, tabletting and coating to obtain the levetiracetam tablet.

Example 6

The dissolution curves of the products of different prescriptions in example 5 were determined according to the second method of determination of dissolution and release of 0931 in the general rules of the four divisions of the "chinese pharmacopoeia", 2020 edition, wherein the dissolution medium: pH4.5 acetate buffer 500ml, rotation speed: 50rpm, the results are given in Table 8 below:

the dissolution rate of the solid preparation is related to the release of the drug in vivo, and when the dissolution of the active ingredient from the solid preparation is too slow, the drug may not reach an effective concentration in the blood and thus a desired therapeutic effect may not be achieved. Conversely, when the active ingredient is dissolved out of the solid preparation too quickly, the concentration of the drug in the blood will increase rapidly with a consequent increase in the risk of side effects. Levetiracetam is a high-solubility medicine, but the weight percentage of levetiracetam in the product prepared by the invention is up to 93%, and the difference of particle sizes can influence the dissolution of levetiracetam from tablets, when the particle size D (V,0.5) selected by the levetiracetam in the invention is 139-231 mu m, on one hand, the composition can be prepared into proper particles, which is beneficial to tabletting and forming, and on the other hand, the dissolution speed of the product is similar to that of the original grinding.

As shown in fig. 1, the dissolution profile for each formulation. As can also be seen, recipes 4, 8, and 9 are better than recipes 1-3 in terms of their level of compliance with the original study.

Example 7

This example examines the effect of the feed delivery speeds and the pinch roller speed on the performance of tablets of formula 8 during the preparation process.

The rotating speed of the pinch roller is set to be 5r/min, the hydraulic pressure is set to be 8Mpa, the ratios of the single variable design conveying rotating speeds to the rotating speed of the pinch roller are respectively 5r/min, 10r/min and 15r/min and 1:1, 2:1 and 3:1, and the influences of different conveying rotating speeds on the compressibility of granules and the dissolution of tablets are examined (6 tablets are taken in each batch of experiments, and the average value is taken).

TABLE 9 developing and setting table for material-conveying speed and pinch roller speed parameters

TABLE 10 development results of material conveying speed and pinch roller speed parameters

As can be seen from the data in Table 9, when the hydraulic pressure is 8Mpa, the ratio of the conveying rotating speed to the pressing wheel rotating speed is in the range of 1:1 to 3:1, the compressibility and the friability of the granules are not obviously affected, the dissolution behavior of the tablets is consistent with that of the original grinding, the 30-min cumulative dissolution is more than 85%, the similarity factor f2 is more than 50, and the tablets prepared by the parameters 1-3 are similar to the reference reagent. When the ratio of the conveying rotating speed to the pressing wheel rotating speed is increased again (more than 3:1), materials are seriously extruded due to too fast conveying, the materials exceed the load of equipment, the performance of the equipment is lost, and granulation cannot be carried out; when the ratio of the material conveying rotating speed to the pressing wheel rotating speed is reduced again (less than 1:1), particles cannot be prepared due to too slow material conveying.

Example 8

This example examined the effect of hydraulic pressure on tablet properties during the manufacturing process for the tablet of formula 8.

According to the development results of the material conveying rotating speed and the pinch roller rotating speed, the material conveying rotating speed is preferably selected: the ratio of the rotating speed of the pinch roller is 2:1, namely the material conveying rotating speed is 10r/min, the rotating speed of the pinch roller is 5r/min, and when the single variable design hydraulic pressure values are 2Mpa, 4Mpa, 6Mpa, 8Mpa and 10Mpa, the influences of different hydraulic pressures on the flowability and compressibility of granules and the dissolution of tablets are examined, the parameter development design is shown in a table 10, and the parameter development result is shown in a table 11. TABLE 10 hydraulic pressure parameter development setting table

TABLE 11 development results of hydraulic pressure parameters

The result shows that the formability of the belt-shaped object, the compressibility of granules and the friability of plain tablets are not obviously affected by the hydraulic pressure within the range of 4-10Mpa under the condition that the ratio of the material conveying rotating speed to the pressing wheel rotating speed is preferably 2:1, namely the material conveying rotating speed is 10r/min and 5r/min, the dissolution behavior of the tablets is consistent with that of the original grinding, the 30-min cumulative dissolution is more than 85%, and the similarity factor f2 is more than 50. When the hydraulic pressure is respectively 2Mpa, the dissolution is not satisfactory, and when the hydraulic pressure is respectively 10Mpa, the pressure is higher, and the loss of the performance of equipment and the compressibility of materials is larger. Therefore, it is preferably 4 to 6 MPa.

Example 9

This example examines the same ratio of the feeding speed and the pressing wheel speed in the preparation process of the tablet of formula 8

According to the development results of the material conveying rotating speed, the pinch roller rotating speed ratio and the hydraulic pressure, the material conveying rotating speed is preferably selected: when the pinch roller rotating speed ratio is 2:1 and the designed hydraulic pressure values are 4Mpa and 6Mpa respectively, the material conveying rotating speed and the pinch roller rotating speed are increased in the same ratio, the influence of the material conveying rotating speed and the pinch roller rotating speed on the flowability and the compressibility of particles and the dissolution of tablets is examined, the parameter development design is shown in a table 12, and the parameter development result is shown in a table 13.

TABLE 12 developing and setting table for increasing parameters of material-conveying rotating speed and pinch roller rotating speed in same ratio

Watch 13

TABLE 14

The result shows that under the condition that the ratio of the material conveying rotating speed to the pinch roller rotating speed is preferably 2:1, namely the material conveying rotating speed is 10r/min and 5r/min, when the hydraulic pressure is 4-6Mpa, the material conveying rotating speed and the pinch roller rotating speed are increased by 1-3 times in the same ratio (2:1), namely the material conveying rotating speed is 10-30r/min and 5-15r/min, the formability of a belt-shaped object, the fine powder rate, the fluidity and the compressibility of particles and the friability of plain tablets are not obviously influenced, the dissolution behavior of the tablets is consistent with that of the original grinding, the 30min cumulative dissolution is more than 85%, and the similarity factor f2 is more than 50.

Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of levetiracetam tablets is characterized by comprising the following steps:

step five: coating the plain tablets to obtain levetiracetam tablets;

the model of the hydroxypropyl cellulose in the step one is EXF; the particle size D50 of the levetiracetam is 139-231 mu m;

the levetiracetam tablet is prepared from the following components in parts by weight: the active ingredients are 750 parts of levetiracetam, 18 parts of hydroxypropyl cellulose, 21.75 parts of croscarmellose sodium, 15.56 parts of colloidal silicon dioxide and 0.94 part of magnesium stearate; or the levetiracetam tablet is prepared from the following components in parts by weight: the active ingredients comprise 750 parts of levetiracetam, 7.5 parts of hydroxypropyl cellulose, 32.25 parts of croscarmellose sodium, 15.56 parts of colloidal silicon dioxide and 0.94 part of magnesium stearate.

2. The preparation method according to claim 1, wherein the dry granulator in the third step is set to have a feeding speed of 10-30rpm and/or a pressure wheel rotation speed of 5-15 rpm.

3. The method of claim 1, wherein the hydraulic pressure is 4 to 6 Mpa.

4. The method as claimed in claim 1, wherein the dry granulator in the third step has a ratio of the feeding speed to the rotation speed of the pressing wheel of 1-3: 1.

5. The method of claim 1, wherein the granulating comprises passing the dry granulated ribbon through a 20-mesh sieve.

6. A levetiracetam tablet made by the process of manufacture of any of claims 1-5.