Eperisone hydrochloride solid tablet composition and preparation method thereof

Abstract

The invention discloses an eperisone hydrochloride solid tablet composition and a preparation method thereof, the solid tablet composition contains eperisone hydrochloride, a filler, a disintegrating agent, an adhesive, a flow aid, a lubricant and a coating agent, and the preparation method comprises the following steps: preparing an adhesive aqueous solution; carrying out wet granule preparation, fluidized drying and granule finishing on the internally added materials in a fluidized drying granulator by using the adhesive solution, and mixing, tabletting and coating dry granules with a flow aid and a lubricant; the acidic disintegrating agent is introduced, so that the increase of related substances of the finished product under high temperature, high temperature and high humidity can be remarkably reduced; a fluidized bed is adopted for one-step granulation, and the prepared finished product has good dissolution rate and stability equivalent to that of a reference preparation; the eperisone hydrochloride tablet provided by the invention is stable in quality, simple and feasible in production process, high in controllability and easy for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a solid tablet composition of etorizine hydrochloride and its preparation method. Background Technology

[0002] Eperisone hydrochloride is a centrally acting skeletal muscle relaxant with various pharmacological effects. It is commonly used to relieve pain caused by conditions such as frozen shoulder, lumbar disc herniation, and arthritis. It can also alleviate paralysis caused by post-traumatic sequelae and spastic spinal cord paralysis. Studies have shown that this product has calcium channel blocker-like effects and can block sympathetic nerve activity in muscles. It can act on vascular smooth muscle, dilate blood vessels, and increase blood flow; it also has analgesic effects at the spinal cord level. Its chemical name is 1-(4-ethylphenyl)-2-methyl-3-(piperidin-1-yl)-1-propanone hydrochloride, and its molecular formula is C1. 17 H 25 NO·HCl, molecular weight: 295.85, chemical structure formula as follows:

[0003]

[0004] Eperisone hydrochloride is readily soluble in water or methanol, and very slightly soluble in acetone; it is readily soluble in 0.1 mol / L hydrochloric acid solution. According to literature, eperisone hydrochloride belongs to the BCSI class of drugs. Oral solid dosage forms of eperisone hydrochloride are easily degraded under high-temperature conditions to produce compounds of the following formula (II).

[0005]

[0006] To address the issue of the easy degradation of oral solid dosage forms of etorizine hydrochloride under high-temperature conditions, patent WO2013 / 105819A1 proposes adding acidic reagents such as organic acids (alginic acid) and inorganic acids (phosphoric acid, sulfuric acid, hydrochloric acid, boric acid, hydrobromic acid, etc.) to make the pH value of the composition less than 7 when dissolved or dispersed in water, more preferably less than 5. This reduces the generation of etorizine hydrochloride-related substances and improves the stability of the etorizine hydrochloride composition.

[0007] Patent CN117298056 also adds citric acid to the formula to adjust the pH value. When the pH value is in the range of 2.0 to 4.0, after being placed at a high temperature of 60°C for 30 days, the impurity E and total impurities meet the limit requirements.

[0008] Therefore, the present invention provides a stable solid tablet composition of eperisone hydrochloride that does not contain organic acids and a method for preparing the same, in order to solve the problem that the oral solid dosage form of eperisone hydrochloride is easily degraded under high temperature conditions. Summary of the Invention

[0009] The purpose of this invention is to provide an etorizine hydrochloride solid tablet composition and its preparation method, so as to solve the problems mentioned in the background art.

[0010] To achieve the above objectives, the present invention provides the following technical solution: a solid tablet composition of eperisone hydrochloride, comprising the following components in the indicated weight proportions: 50 parts of eperisone hydrochloride, 15-25 parts of filler, 0-5 parts of disintegrant, 0-5 parts of binder, 0-2 parts of flow aid, 0-2 parts of lubricant, and 1-5 parts of coating agent.

[0011] Preferably, the filler is selected from one or more of corn starch, microcrystalline cellulose, pregelatinized starch, lactose, and mannitol.

[0012] Preferably, the adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, corn starch, and pregelatinized starch.

[0013] Preferably, the filler is corn starch and microcrystalline cellulose.

[0014] Preferably, the adhesive is hydroxypropyl cellulose.

[0015] Preferably, the flow aid is selected from one or more of silica, talc, and colloidal silica.

[0016] Preferably, the lubricant is selected from one or more of stearic acid, polyethylene glycol 6000, calcium stearate, magnesium stearate, and sodium stearate fumarate.

[0017] Preferably, the flow aid is silicon dioxide.

[0018] Preferably, the gliding agent is calcium stearate.

[0019] A method for preparing an etorizine hydrochloride solid tablet composition includes the following steps:

[0020] S1: Adhesive preparation: Add the prescribed amount of purified water to the mixing tank, turn on the stirrer, slowly add hydroxypropyl cellulose and stir until dissolved to prepare a 3% to 5% adhesive solution for later use;

[0021] S2: Granulation: Add corn starch, etorizine hydrochloride, disintegrant, and microcrystalline cellulose to the fluidized bed, adjust the relevant parameters of the fluidized bed, set the inlet air temperature to 55℃~75℃, and adjust the air volume to 1000m³ / h. 3 / h~2000m 3 / h, begin fluidized mixing; when the material temperature is ≥40℃, add the prepared 5% binder solution to the granulator via top spraying, with a spraying speed of 0.1kg / min~1.0kg / min, atomization pressure of 1.0bar~5.0bar, and control the material temperature at 30℃~40℃; after spraying, dry, and when the material temperature is ≥40℃, take a sample to test the moisture content, control the moisture content to <2.0%, and then discharge;

[0022] S3: Granulation: Place the dry granules prepared in step S2 into a dry granulator for granulation. The screen aperture of the dry granulator is... Rotation speed 300rpm~500rpm;

[0023] S4: Total mixing: Add silica and calcium stearate to the particles prepared in step S3, set the speed of the total mixer to 8-12 rpm, mix for 5 min, and obtain total mixed particles;

[0024] S5: Tableting: Install a circular mold with a diameter of 6mm, and press tablets according to the theoretical tablet weight, controlling the tablet weight difference to ±5.0% and the friability to ≤1%.

[0025] S6: Coating: Select a film coating premix and prepare a 12% (w / w) coating solution with purified water; place the etorizine hydrochloride tablets prepared in step S5 into a suitable high-efficiency coating machine, control the coating pan speed to 2 rpm to 10 rpm, the air inlet temperature to 70℃ to 90℃, and control the weight gain to 2% to 4% to obtain the finished product.

[0026] Compared with the prior art, the beneficial effects of the present invention are:

[0027] This invention introduces an acidic disintegrant, which can significantly reduce the growth of related substances in the finished product under high temperature and high humidity conditions; the one-step fluidized bed granulation method produces a finished product with good dissolution and stability comparable to the reference formulation; the etorizine hydrochloride tablets provided by this invention have stable quality, a simple and feasible production process, strong controllability, and are easy to industrialize. Detailed Implementation

[0028] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1

[0030] The composition of etorizine hydrochloride tablets is as follows:

[0031]

[0032]

[0033] Preparation method: (1) Adhesive preparation: Add the prescribed amount of purified water to the mixing tank, turn on the stirring, slowly add hydroxypropyl cellulose and stir until dissolved to prepare a 5% adhesive solution for later use;

[0034] (2) Granulation: Corn starch, ethperisone hydrochloride, carboxymethyl cellulose, and microcrystalline cellulose are added to a fluidized bed. The relevant parameters of the fluidized bed are adjusted, the inlet air temperature is set to 55℃~75℃, and the air volume is adjusted to 1000m³. 3 / h~2000m 3 / h, begin fluidized mixing. When the material temperature is ≥40℃, add the prepared 5% binder solution to the granulator via top spraying, with a spraying speed of 0.1kg / min~1.0kg / min, atomization pressure of 1.0bar~5.0bar, and control the material temperature at 30℃~40℃. After spraying, dry the material. When the material temperature is ≥40℃, take a sample to test the moisture content, control the moisture content to <2.0%, and then discharge the material.

[0035] (3) Granulation: Place the dry granules prepared in step (2) into a dry granulator (screen mesh size). Granulation (speed 300rpm~500rpm);

[0036] (4) Mixing: Add silica and calcium stearate to the particles prepared in step (3), set the speed of the mixer to 8-12 rpm, mix for 5 min, and obtain mixed particles.

[0037] (5) Tableting: Install a circular mold with a diameter of 6mm, and press the tablets according to the theoretical tablet weight, controlling the tablet weight difference to ±5.0% and the brittleness to ≤1%.

[0038] (6) Coating: Select a film coating premix (gastric-soluble type) and prepare a 12% (W / W) coating solution with purified water; place the etorizine hydrochloride tablets prepared in step (5) into a suitable high-efficiency coating machine, control the coating pan speed to 2 rpm to 10 rpm, the air inlet temperature to 70℃ to 90℃, and control the weight gain to 2% to 4% to obtain the finished product.

[0039] Example 2

[0040] The composition of etorizine hydrochloride tablets is as follows:

[0041]

[0042]

[0043] Preparation method: Same as in Example 1.

[0044] Example 3

[0045] The composition of etorizine hydrochloride tablets is as follows:

[0046]

[0047] Preparation method: Same as in Example 1.

[0048] Comparative Example 1

[0049] The composition of etorizine hydrochloride tablets is as follows:

[0050]

[0051] Preparation method: Same as in Example 1.

[0052] Experimental Example 1: The dissolution curves of etorizine hydrochloride tablets prepared according to the examples were measured in aqueous medium for the samples prepared in Examples 1, 2, 3 and Comparative Example 1.

[0053] Dissolution curve determination method:

[0054] Leaching medium: water

[0055] Dissolution medium volume: 900ml

[0056] Dissolution method: Paddle method

[0057] Rotational speed: 50 r / min

[0058] Temperature: 37℃

[0059] Sampling points (min): 10, 15, 30

[0060] Detection method: UV method

[0061] Dissolution curve determination results:

[0062]

[0063] The above results indicate that the etorizine hydrochloride tablets prepared in the embodiments of the present invention all exhibit good and similar dissolution curves. Therefore, the formulation and preparation method of the etorizine hydrochloride tablets implemented in this invention are reasonable and reliable.

[0064] Experimental Example 2: Stability Study: The relevant substances of Examples 1, 2, 3 and Comparative Example 1 were measured after being placed at a high temperature of 60°C for 10 days and 30 days.

[0065] The results are as follows:

[0066]

[0067]

[0068] The above experimental results show that the disintegrant used in Example 1 is carboxymethyl cellulose, the disintegrant used in Example 2 is sodium carboxymethyl starch (type B), the disintegrant used in Example 3 is sodium carboxymethyl starch (type A), and the comparative example uses low-substituted hydroxypropyl cellulose. The acidic disintegrants in Examples 1 and 2 are beneficial to the stability of the self-made preparation. The disintegrants in Example 3 and Comparative Example 1 are near neutral or alkaline, which are not conducive to the stability of the self-made preparation.

[0069] The etorizine hydrochloride tablets prepared by the present invention using an acidic disintegrant maintained good stability under high temperature (60°C) test conditions.

[0070] Although embodiments of the invention have been shown and described in detail above, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A composition of etorizine hydrochloride solid tablets, characterized in that: It comprises the following components in the indicated weight proportions: 50 parts of etorizine hydrochloride, 15-25 parts of filler, 0-5 parts of disintegrant, 0-5 parts of binder, 0-2 parts of flow aid, 0-2 parts of lubricant, and 1-5 parts of coating agent.

2. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The filler is selected from one or more of corn starch, microcrystalline cellulose, pregelatinized starch, lactose, and mannitol.

3. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, corn starch, and pregelatinized starch.

4. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The filler is corn starch and microcrystalline cellulose.

5. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The adhesive is hydroxypropyl cellulose.

6. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The flow aid is selected from one or more of silica, talc, and colloidal silica.

7. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The lubricant is selected from one or more of stearic acid, polyethylene glycol 6000, calcium stearate, magnesium stearate, and sodium stearate fumarate.

8. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The flow aid is silicon dioxide.

9. The etorizine hydrochloride solid tablet composition according to claim 1, characterized in that: The gliding agent is calcium stearate.

10. The method for preparing the etorizine hydrochloride solid tablet composition according to any one of claims 1-9, characterized in that, It includes the following steps: S1: Adhesive preparation: Add the prescribed amount of purified water to the mixing tank, turn on the stirrer, slowly add hydroxypropyl cellulose and stir until dissolved to prepare a 3% to 5% adhesive solution for later use; S2: Granulation: Add corn starch, etorizine hydrochloride, disintegrant, and microcrystalline cellulose to the fluidized bed, adjust the relevant parameters of the fluidized bed, set the inlet air temperature to 55℃~75℃, and adjust the air volume to 1000m³ / h. 3 / h~2000m 3 / h, begin fluidized mixing; when the material temperature is ≥40℃, add the prepared 5% binder solution to the granulator via top spraying, with a spraying speed of 0.1kg / min~1.0kg / min, atomization pressure of 1.0bar~5.0bar, and control the material temperature at 30℃~40℃; after spraying, dry, and when the material temperature is ≥40℃, take a sample to test the moisture content, control the moisture content to <2.0%, and then discharge; S3: Granulation: Place the dry granules prepared in step S2 into a dry granulator for granulation. The dry granulator has a screen aperture of φ1.0mm and a rotation speed of 300rpm~500rpm. S4: Total mixing: Add silica and calcium stearate to the particles prepared in step S3, set the speed of the total mixer to 8-12 rpm, mix for 5 min, and obtain total mixed particles; S5: Tableting: Install a circular mold with a diameter of 6mm, and press tablets according to the theoretical tablet weight, controlling the tablet weight difference to ±5.0% and the friability to ≤1%. S6: Coating: Select a film coating premix and prepare a 12% (w / w) coating solution with purified water; place the etorizine hydrochloride tablets prepared in step S5 into a suitable high-efficiency coating machine, control the coating pan speed to 2 rpm to 10 rpm, the air inlet temperature to 70℃ to 90℃, and control the weight gain to 2% to 4% to obtain the finished product.

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