Agomelatine pharmaceutical composition, its preparation method and its application

Abstract

The present invention relates to the field of pharmaceutical technology, and particularly relates to an agomelatine pharmaceutical composition, a preparation method thereof and an application thereof. The agomelatine pharmaceutical composition comprises inner layer microparticles, a coating layer and outer layer excipients; the inner layer microparticles comprise the following raw materials: agomelatine, hypromellose, mannitol and colloidal silicon dioxide; the coating layer is obtained by coating a chitosan-sodium carboxymethyl starch suspension on the surface of the inner layer microparticles; the outer layer excipients comprise the following raw materials: glyceryl behenate, sucrose, polyvinylpyrrolidone, sodium carboxymethyl starch and magnesium stearate. The agomelatine pharmaceutical composition provided by the present invention has stable dissolution, extremely low impurities, controllable quality and excellent stability, and can be used for treating depression and related diseases.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to an agomelatine pharmaceutical composition, a preparation method thereof, and an application thereof. Background Art

[0002] Agomelatine is a novel melatonin receptor agonist and 5-hydroxytryptamine 2C receptor antagonist, which is widely used in the treatment of depression. By regulating the circadian rhythm and neurotransmitter levels, it can improve the sleep quality and mood state of patients, and has a unique mechanism of action and significant clinical efficacy. However, the formulation development of agomelatine faces many technical problems, which limit its further promotion and application in the field of pharmaceutical preparations.

[0003] The chemical properties of agomelatine are relatively sensitive and it is prone to degradation under high temperature and high humidity conditions, generating impurities. The generation of these impurities will not only reduce the content of the active ingredient of the drug, but may also cause potential toxic effects, seriously affecting the safety and effectiveness of the drug. Therefore, how to improve the chemical stability of agomelatine preparations and reduce the generation of impurities is a key issue in formulation development.

[0004] The dissolution behavior of agomelatine is difficult to control. In the preparation, the release rate of agomelatine may show an immediate release phenomenon, that is, the drug is rapidly released in a short time, resulting in a rapid increase in blood drug concentration. This phenomenon will not only reduce the bioavailability of the drug, but may also cause adverse reactions and affect the treatment compliance of patients. Therefore, how to achieve the stable release of agomelatine and avoid the immediate release phenomenon is an important challenge in formulation design. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide an agomelatine pharmaceutical composition, a preparation method thereof, and an application thereof, so as to improve the dissolution stability and chemical stability of the agomelatine pharmaceutical composition and solve the problems of immediate release and impurity generation.

[0006] Based on the above purpose, the present invention provides an agomelatine pharmaceutical composition, which includes inner layer microparticles, a coating layer, and outer layer excipients.

[0007] Further, the weight ratio of the inner layer microparticles, the coating layer, and the outer layer excipients is 27 - 66:8 - 25:22 - 45.

[0008] Further, the inner layer microparticles include the following raw materials by weight parts: 15 - 30 parts of agomelatine, 10 - 30 parts of hydroxypropyl methylcellulose, 1 - 3 parts of mannitol, and 1 - 3 parts of colloidal silicon dioxide;

[0009] Further, the coating layer is obtained by coating a chitosan - sodium carboxymethyl starch suspension on the surface of the inner layer particles; the preparation method of the chitosan - sodium carboxymethyl starch suspension is as follows: Dissolve chitosan in an ethanol aqueous solution with a concentration of 60wt% - 80wt% to obtain a chitosan solution, then dissolve sodium carboxymethyl starch in deionized water to obtain a sodium carboxymethyl starch solution, and then drop the sodium carboxymethyl starch solution into the chitosan solution. After the dropping is completed, stir at a speed of 350 - 450 rpm for 25 - 35 min to obtain a chitosan - sodium carboxymethyl starch suspension.

[0010] Further, the weight ratio of chitosan, ethanol aqueous solution, sodium carboxymethyl starch, and deionized water is 3 - 10:15 - 30:5 - 15:20:15 - 3.

[0011] Further, the outer layer excipients include the following raw materials by weight: 1 - 3 parts of glyceryl behenate, 15 - 25 parts of sucrose, 2 - 6 parts of polyvinylpyrrolidone, 3 - 8 parts of sodium carboxymethyl starch, and 1 - 3 parts of magnesium stearate.

[0012] Preferably, the inner layer particles are obtained by dry granulation.

[0013] Preferably, the roller pressure for dry granulation is 5 - 7 MPa, the roller gap is 0.4 - 0.6 mm, and the mesh number of the sieve is 15 - 25 meshes.

[0014] Preferably, the coating layer is obtained by fluidized bed coating.

[0015] Preferably, the atomization pressure for fluidized bed coating is 0.05 - 0.15 MPa, the ventilation volume is 40 - 60 m 3 / h, and the material temperature is 25 - 35 °C.

[0016] Preferably, the agomelatine pharmaceutical composition is obtained by mixing the outer layer excipients and the inner layer particles containing the coating layer, and then through hot - melt wet granulation and tabletting.

[0017] Preferably, the temperature for hot - melt wet granulation is 60 - 70 °C, the rotation speed of the stirring frame is 0.5 - 2 r / s, the cutting speed of the cutter is 8 - 12 r / s, and the granulation time is 4 - 6 min.

[0018] Preferably, the main pressure for tabletting is 8 - 12 kN, the hardness is controlled at 100 - 140 N, and the weight of agomelatine in each tablet is controlled at 15 - 30 mg.

[0019] Further, the present invention also provides a preparation method of an agomelatine pharmaceutical composition, including the following steps:

[0020] (1) putting agomelatine, hypromellose, mannitol and colloidal silicon dioxide into a mixer, mixing at a speed of 40-60 rpm for 15-25 min, and then putting into a dry granulator for granulation to obtain inner layer particles;

[0021] (2) placing the inner layer particles obtained in step (1) in a fluidized bed coating machine, spray coating the inner layer particles with a chitosan-sodium carboxymethyl starch suspension, and after coating, turning off the atomization pressure to keep the particles in a fluidized state for 10-20 minutes, and finally drying at 50-60° C. to obtain coated particles;

[0022] (3) putting glyceryl behenate, sucrose, povidone and sodium carboxymethyl starch into a mixer together with the coated microparticles prepared in step (2), mixing at a speed of 40-60 rpm for 5-15 min, and then putting them into a hot melt wet granulator for granulation. After granulation, sieve through a 15-25 mesh sieve, and then putting them into a mixer together with magnesium stearate, mixing at a speed of 15-25 rpm for 5-15 min to obtain composite microparticles;

[0023] (4) adding the composite microparticles prepared in step (3) into a tablet press for tableting to obtain an agomelatine pharmaceutical composition.

[0024] Furthermore, the present invention also provides an application of an agomelatine pharmaceutical composition for treating depression and related diseases.

[0025] Preferably, the related diseases include but are not limited to anxiety disorders, sleep disorders, seasonal affective disorder, bipolar disorder, post-traumatic stress disorder and obsessive-compulsive disorder.

[0026] Beneficial effects of the present invention:

[0027] The agomelatine pharmaceutical composition provided by the present invention has a stable dissolution rate, no burst release phenomenon, and a dissolution rate of more than 99.5% after 60 minutes, thereby ensuring the stable release of the drug in the body, improving the bioavailability, and reducing the fluctuation of the blood drug concentration, thereby enhancing the therapeutic effect and reducing the risk of side effects. In addition, the stability of the dissolution behavior contributes to the consistency of the preparation in different batches of production, ensuring the quality controllability of the drug and the safety of clinical use.

[0028] After the agomelatine pharmaceutical composition provided by the present invention is placed under high temperature and high humidity (50±5°C, humidity 75±5%) conditions for 12 months, the total impurity content is not higher than 0.05%, and the maximum single impurity content is not higher than 0.03%, showing excellent chemical stability and very little impurity generation. This not only prolongs the shelf life of the drug, but also improves the quality controllability of the drug, meets the needs of long-term storage and transportation, and provides reliable guarantee for clinical application.

[0029] The present invention forms a coating layer by cross-linking chitosan and sodium carboxymethyl starch, and then performs hot-melt wet granulation with various excipients. The cross-linked coating layer effectively regulates the dissolution rate of the drug, avoids the phenomenon of sudden release, and protects the inner-layer drug during the hot-melt wet granulation process, significantly reducing the problems of drug degradation and impurity generation caused by high temperature. Detailed implementation mode

[0030] To make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the following further details the present invention in conjunction with specific embodiments.

[0031] Example 1:

[0032] (1) Put 15 g of agomelatine sieved through 60 mesh, 10 g of hypromellose E5 sieved through 40 mesh, 1 g of mannitol sieved through 40 mesh, and 1 g of colloidal silicon dioxide sieved through 100 mesh into a mixer, mix at a speed of 40 rpm for 10 min, and then put it into a dry granulator. Set the roller pressure to 5 MPa, the roller gap to 0.4 mm, and the screen mesh number to 15 mesh to obtain inner-layer microparticles;

[0033] (2) Dissolve 3 g of chitosan sieved through 60 mesh in 15 g of ethanol aqueous solution with a concentration of 60 wt% to obtain a chitosan solution. Then dissolve 5 g of sodium carboxymethyl starch sieved through 80 mesh in 15 g of deionized water to obtain a sodium carboxymethyl starch solution. Drop the sodium carboxymethyl starch solution into the chitosan solution. After the dropping is completed, stir at a speed of 350 rpm for 25 min to obtain a chitosan-sodium carboxymethyl starch suspension. Place the inner-layer microparticles in a fluidized bed coater, and perform bottom spraying coating on the inner-layer microparticles prepared in step (1) with the chitosan-sodium carboxymethyl starch suspension. Control the atomization pressure at 0.05 MPa, the ventilation volume at 40 m 3 / h, the material temperature at 25 °C. After the coating is completed, close the atomization pressure to keep the pellets in a fluidized state for 10 min, and finally dry at 50 °C to obtain coated microparticles;

[0034] (3) Put 1 g of glyceryl behenate sieved through 60 mesh, 15 g of sucrose sieved through 60 mesh, 2 g of polyvinylpyrrolidone K30 sieved through 60 mesh, 3 g of sodium carboxymethyl starch sieved through 60 mesh, and the coated microparticles prepared in step (2) into a mixer, mix at a speed of 40 rpm for 5 min, and then put it into a hot-melt wet granulator. Set the temperature to 60 °C, the stirring frame speed to 0.5 r / s, the cutter speed to 8 r / s, and the granulation time to 4 min. After the granulation is completed, sieve through 15 mesh, and then put it into a mixer together with 1 g of magnesium stearate sieved through 100 mesh and mix at a speed of 15 rpm for 5 min to obtain composite microparticles;

[0035] (4) Add the composite particles prepared in step (3) into a tableting machine for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tableting machine to 8 kN, control the hardness at 100 N, and control the weight of agomelatine in each tablet to be 15 mg to obtain the agomelatine pharmaceutical composition.

[0036] Example 2:

[0037] (1) Put 25 g of agomelatine sieved through 60 mesh, 25 g of hypromellose E5 sieved through 40 mesh, 2 g of mannitol sieved through 40 mesh, and 2 g of colloidal silicon dioxide sieved through 100 mesh into a mixer, mix at a speed of 50 rpm for 20 min, and then put it into a dry granulator. Set the roller pressure to 6 MPa, the roller gap to 0.5 mm, and the screen mesh number to 20 mesh to obtain the inner layer particles;

[0038] (2) Dissolve 5 g of chitosan sieved through 60 mesh in 20 g of ethanol aqueous solution with a concentration of 70 wt% to obtain a chitosan solution. Then dissolve 10 g of sodium carboxymethyl starch sieved through 80 mesh in 20 g of deionized water to obtain a sodium carboxymethyl starch solution. Drop the sodium carboxymethyl starch solution into the chitosan solution. After dropping, stir at a speed of 400 rpm for 30 min to obtain a chitosan-sodium carboxymethyl starch suspension. Place the inner layer particles in a fluidized bed coater and perform bottom spraying coating on the inner layer particles prepared in step (1) with the chitosan-sodium carboxymethyl starch suspension. Control the atomization pressure at 0.1 MPa, the ventilation volume at 50 m 3 / h, the material temperature at 30 °C. After coating, turn off the atomization pressure to keep the pellets in a fluidized state for 15 min, and finally dry at 55 °C to obtain the coated particles;

[0039] (3) Put 2 g of glyceryl behenate sieved through 60 mesh, 20 g of sucrose sieved through 60 mesh, 4 g of polyvinylpyrrolidone K30 sieved through 60 mesh, 5 g of sodium carboxymethyl starch sieved through 60 mesh and the coated particles prepared in step (2) into a mixer, mix at a speed of 50 rpm for 10 min, and then put it into a hot melt wet granulator. Set the temperature to 65 °C, the stirring frame speed to 1 r / s, the cutter speed to 10 r / s, and the granulation time to 5 min. After granulation, sieve through 20 mesh, and then put it into a mixer together with 2 g of magnesium stearate sieved through 100 mesh and mix at a speed of 20 rpm for 10 min to obtain the composite particles;

[0040] (4) Add the composite particles prepared in step (3) into a tableting machine for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tableting machine to 10 kN, control the hardness at 120 N, and control the weight of agomelatine in each tablet to be 25 mg to obtain the agomelatine pharmaceutical composition.

[0041] Example 3:

[0042] (1) Put 30 g of agomelatine that has passed through a 60-mesh sieve, 30 g of hypromellose E5 that has passed through a 40-mesh sieve, 3 g of mannitol that has passed through a 40-mesh sieve, and 3 g of colloidal silicon dioxide that has passed through a 100-mesh sieve into a mixer, mix at a speed of 50 rpm for 30 min, then put it into a dry granulator, set the roller pressure to 7 MPa, the roller gap to 0.6 mm, the sieve mesh number to 25 meshes, and the inner layer of microparticles;

[0043] (2) Dissolve 10 g of chitosan that has passed through a 60-mesh sieve in 30 g of an ethanol aqueous solution with a concentration of 80 wt% to obtain a chitosan solution. Then dissolve 20 g of sodium carboxymethyl starch that has passed through an 80-mesh sieve in 30 g of deionized water to obtain a sodium carboxymethyl starch solution. Drop the sodium carboxymethyl starch solution into the chitosan solution. After dropping, stir at a speed of 450 rpm for 35 min to obtain a chitosan-sodium carboxymethyl starch suspension. Place the inner layer of microparticles in a fluidized bed coater, and use the chitosan-sodium carboxymethyl starch suspension to perform bottom spraying coating on the inner layer of microparticles prepared in step (1). Control the atomization pressure at 0.15 MPa, the ventilation volume at 60 m 3 / h, the material temperature at 35 °C. After coating, turn off the atomization pressure to keep the pellets in a fluidized state for 20 min, and finally dry at 60 °C to obtain coated microparticles;

[0044] (3) Put 3 g of glyceryl behenate that has passed through a 60-mesh sieve, 25 g of sucrose that has passed through a 60-mesh sieve, 6 g of polyvinylpyrrolidone K30 that has passed through a 60-mesh sieve, 8 g of sodium carboxymethyl starch that has passed through a 60-mesh sieve, and the coated microparticles prepared in step (2) into a mixer, mix at a speed of 60 rpm for 15 min, then put it into a hot melt wet granulator, set the temperature at 70 °C, the stirring frame speed at 2 r / s, the cutter speed at 12 r / s, the granulation time at 6 min. After granulation, pass through a 25-mesh sieve, and then put it into a mixer together with 3 g of magnesium stearate that has passed through a 100-mesh sieve and mix at a speed of 25 rpm for 15 min to obtain composite microparticles;

[0045] (4) Add the composite microparticles prepared in step (3) to a tableting machine for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tableting machine at 12 kN, control the hardness at 140 N, and control the weight of agomelatine in each tablet at 30 mg to obtain an agomelatine pharmaceutical composition.

[0046] Comparative Example 1:

[0047] The difference between Comparative Example 1 and Example 2 is that the coated microparticles are directly tableted, and the weight of agomelatine in each tablet is controlled at 25 mg;

[0048] The specific steps are as follows:

[0049] (1) Put 25 g of agomelatine that has passed through a 60-mesh sieve, 25 g of hypromellose E5 that has passed through a 40-mesh sieve, 2 g of mannitol that has passed through a 40-mesh sieve, and 2 g of colloidal silicon dioxide that has passed through a 100-mesh sieve into a mixer, mix at a speed of 50 rpm for 20 min, then put it into a dry granulator, set the roller pressure to 6 MPa, the roller gap to 0.5 mm, and the sieve mesh number to 20 mesh, inner layer particles;

[0050] (2) Dissolve 5 g of chitosan that has passed through a 60-mesh sieve in 20 g of an ethanol aqueous solution with a concentration of 70 wt% to obtain a chitosan solution. Then dissolve 10 g of sodium carboxymethyl starch that has passed through an 80-mesh sieve in 20 g of deionized water to obtain a sodium carboxymethyl starch solution. Drop the sodium carboxymethyl starch solution into the chitosan solution. After dropping, stir at a speed of 400 rpm for 30 min to obtain a chitosan-sodium carboxymethyl starch suspension. Place the inner layer particles in a fluidized bed coater, and perform bottom spraying coating on the inner layer particles prepared in step (1) with the chitosan-sodium carboxymethyl starch suspension. Control the atomization pressure at 0.1 MPa, the ventilation volume at 50 m 3 / h, the material temperature at 30 °C. After coating, turn off the atomization pressure to keep the pellets in a fluidized state for 15 min, and finally dry at 55 °C to obtain coated particles;

[0051] (3) Add the coated particles prepared in step (2) to a tableting machine for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tableting machine to 10 kN, control the hardness at 120 N, and control the weight of agomelatine in each tablet to be 25 mg to obtain an agomelatine pharmaceutical composition.

[0052] Comparative Example 2:

[0053] The difference between Comparative Example 2 and Example 2 is that the inner layer particles and glyceryl behenate, sucrose, polyvinylpyrrolidone K30 and those passing through a 60-mesh sieve are directly subjected to hot-melt wet granulation, and the weight of agomelatine in each tablet is controlled to be 25 mg;

[0054] The specific steps are as follows:

[0055] (1) Put 25 g of agomelatine that has passed through a 60-mesh sieve, 25 g of hypromellose E5 that has passed through a 40-mesh sieve, 2 g of mannitol that has passed through a 40-mesh sieve, and 2 g of colloidal silicon dioxide that has passed through a 100-mesh sieve into a mixer, mix at a speed of 50 rpm for 20 min, then put it into a dry granulator, set the roller pressure to 6 MPa, the roller gap to 0.5 mm, and the sieve mesh number to 20 mesh, inner layer particles;

[0056] (2) Put 2 g of glyceryl behenate that has passed through a 60-mesh sieve, 20 g of sucrose that has passed through a 60-mesh sieve, 4 g of polyvinylpyrrolidone K30 that has passed through a 60-mesh sieve, 5 g of sodium carboxymethyl starch that has passed through a 60-mesh sieve, and the inner layer microparticles prepared in step (2) into a mixer, mix at a speed of 50 rpm for 10 min, then put them into a hot-melt wet granulator, set the temperature at 65 °C, the stirring frame speed at 1 r / s, the cutter speed at 10 r / s, the granulation time at 5 min. After granulation, pass through a 20-mesh sieve, and then put them into a mixer together with 2 g of magnesium stearate that has passed through a 100-mesh sieve and mix at a speed of 20 rpm for 10 min to obtain composite microparticles;

[0057] (3) Add the composite microparticles prepared in step (2) to a tablet press for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tablet press at 10 kN, control the hardness at 120 N, and control the weight of agomelatine in each tablet at 25 mg to obtain the agomelatine pharmaceutical composition.

[0058] Comparative Example 3:

[0059] The difference between Comparative Example 3 and Example 2 is that chitosan solution is directly used for coating, and the weight of agomelatine in each tablet is controlled at 25 mg;

[0060] The specific steps are as follows:

[0061] (1) Put 25 g of agomelatine that has passed through a 60-mesh sieve, 25 g of hypromellose E5 that has passed through a 40-mesh sieve, 2 g of mannitol that has passed through a 100-mesh sieve, and 2 g of colloidal silicon dioxide that has passed through a 100-mesh sieve into a mixer, mix at a speed of 50 rpm for 20 min, then put them into a dry granulator, set the roller pressure at 6 MPa, the roller gap at 0.5 mm, and the sieve mesh number at 20 mesh to obtain inner layer microparticles;

[0062] (2) Dissolve 5 g of chitosan that has passed through a 60-mesh sieve in 20 g of an ethanol aqueous solution with a concentration of 70 wt% to obtain a chitosan solution. Place the inner layer microparticles in a fluidized bed coater and perform bottom spraying coating on the inner layer microparticles prepared in step (1) with the chitosan solution. Control the atomization pressure at 0.1 MPa, the ventilation volume at 50 m 3 / h, the material temperature at 30 °C. After coating, close the atomization pressure to keep the pellets in a fluidized state for 15 min, and finally dry them at 55 °C to obtain coated microparticles;

[0063] (3) Put 2 g of glyceryl behenate that has passed through a 60-mesh sieve, 20 g of sucrose that has passed through a 60-mesh sieve, 4 g of polyvinylpyrrolidone K30 that has passed through a 60-mesh sieve, 5 g of sodium carboxymethyl starch that has passed through a 60-mesh sieve, and the coated microparticles prepared in step (2) into a mixer, mix at a speed of 50 rpm for 10 min, then put them into a hot-melt wet granulator, set the temperature at 65 °C, the stirring frame speed at 1 r / s, the cutter speed at 10 r / s, the granulation time at 5 min. After granulation, pass through a 20-mesh sieve, and then put them into a mixer together with 2 g of magnesium stearate that has passed through a 100-mesh sieve and mix at a speed of 20 rpm for 10 min to obtain composite microparticles;

[0064] (4) Add the composite microparticles prepared in step (3) to a tableting machine for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tableting machine at 10 kN, control the hardness at 120 N, and control the weight of agomelatine in each tablet at 25 mg to obtain the agomelatine pharmaceutical composition.

[0065] Comparative Example 4:

[0066] The difference between Comparative Example 4 and Example 2 is that sodium carboxymethyl starch solution is directly used for coating, and the weight of agomelatine in each tablet is controlled at 25 mg;

[0067] (1) Put 25 g of agomelatine that has passed through a 60-mesh sieve, 25 g of hypromellose E5 that has passed through a 40-mesh sieve, 2 g of mannitol that has passed through a 100-mesh sieve, and 2 g of colloidal silicon dioxide that has passed through a 100-mesh sieve into a mixer, mix at a speed of 50 rpm for 20 min, then put them into a dry granulator, set the roller pressure at 6 MPa, the roller gap at 0.5 mm, and the sieve mesh number at 20 meshes to obtain inner-layer microparticles;

[0068] (2) Dissolve 10 g of sodium carboxymethyl starch that has passed through an 80-mesh sieve in 20 g of deionized water to obtain a sodium carboxymethyl starch solution. Place the inner-layer microparticles in a fluidized bed coater and perform bottom spraying coating on the inner-layer microparticles prepared in step (1) with the sodium carboxymethyl starch solution. Control the atomization pressure at 0.1 MPa, the ventilation volume at 50 m 3 / h, the material temperature at 30 °C. After coating, turn off the atomization pressure to keep the pellets in a fluidized state for 15 min, and finally dry them at 55 °C to obtain coated microparticles;

[0069] (3) Put 2 g of glyceryl behenate that has passed through a 60-mesh sieve, 20 g of sucrose that has passed through a 60-mesh sieve, 4 g of povidone K30 that has passed through a 60-mesh sieve, 5 g of sodium carboxymethyl starch that has passed through a 60-mesh sieve, and the coated microparticles prepared in step (2) into a mixer, mix at a speed of 50 rpm for 10 min, then put them into a hot-melt wet granulator, set the temperature at 65 °C, the stirring frame speed at 1 r / s, the cutter speed at 10 r / s, the granulation time at 5 min. After granulation, pass through a 20-mesh sieve, and then put them into a mixer together with 2 g of magnesium stearate that has passed through a 100-mesh sieve and mix at a speed of 20 rpm for 10 min to obtain composite microparticles;

[0070] (4) Add the composite microparticles prepared in step (3) to a tableting machine for tableting. The punching die is an oval tablet with a diameter of 7 mm. Set the main pressure of the tableting machine at 10 kN, control the hardness at 120 N, and control the weight of agomelatine in each tablet at 25 mg to obtain the agomelatine pharmaceutical composition.

[0071] Performance test:

[0072] Dissolution test: Take the tablets prepared in the examples and comparative examples, according to the dissolution test method (Second Method in Appendix XC of Part II of Chinese Pharmacopoeia 2010 Edition), use 900 mL of 0.1 mol / L hydrochloric acid as the dissolution medium, rotate at a speed of 50 rpm, operate according to the law. At 5 min, 15 min, 35 min, 45 min, and 60 min, filter the solution, take the subsequent filtrate, and according to the ultraviolet-visible spectrophotometry (Appendix IVA of Part II of Chinese Pharmacopoeia 2010 Edition), measure the absorbance at a wavelength of 276 nm; Separately, accurately weigh 25 mg of agomelatine reference substance, place it in a 10-mL volumetric flask, dissolve it with ethanol and dilute to the mark, shake well, accurately measure 1 mL and place it in a 100-mL volumetric flask, add 0.1 mol / L hydrochloric acid and dilute to the mark, shake well, and measure in the same way to calculate the dissolution amount of each tablet. The results are shown in Table 1.

[0073] Stability test: Take the tablets prepared in the examples and comparative examples, place them under the conditions of temperature 50 ± 5 °C and humidity 75 ± 5% for 0 month and 12 months, and detect the maximum single impurity and total impurity contents. The results are shown in Table 1.

[0074]

[0075] Data analysis:

[0076] From the dissolution data of Examples 1 - 3 in Table 1, it can be seen that the agomelatine pharmaceutical composition prepared by the present invention has a stable dissolution rate, without burst release phenomenon. Moreover, the dissolution rate after 60 minutes can reach more than 99.5%, which helps to ensure the stable release of the drug in vivo, improve the bioavailability, reduce the fluctuation of blood drug concentration, thereby enhancing the therapeutic effect of the drug and reducing the risk of side effects. In addition, the stability of the dissolution behavior is also beneficial to the consistency of the preparation in different batch productions, ensuring the quality controllability of the drug and the safety of clinical use.

[0077] From the stability test data of Examples 1 - 3 in Table 1, it can be seen that the agomelatine pharmaceutical composition prepared by the present invention has extremely low impurity content. Moreover, after being placed at a temperature of 50 ± 5°C and a humidity of 75 ± 5% for 12 months, the total impurity content is not higher than 0.05%, and the maximum single impurity content is not lower than 0.03%. This shows that the pharmaceutical composition of the present invention has excellent stability, can maintain the chemical stability for a long time under harsh environments such as high temperature and high humidity, with extremely few impurities generated, thus ensuring the safety and effectiveness of the drug. This stability not only extends the shelf life of the drug, but also improves the quality controllability of the drug, meets the requirements of long-term storage and transportation, and provides a reliable guarantee for clinical applications.

[0078] From the data of Example 2 and Comparative Example 1 in Table 1, it can be seen that the tablets obtained by directly compressing one-layer coated microparticles have a relatively fast dissolution rate in the early stage. Moreover, after being placed at a temperature of 50 ± 5°C and a humidity of 75 ± 5% for 12 months, the total impurity content reaches 0.15%, and the maximum single impurity content reaches 0.11%, with poor stability. This is mainly because the one-layer coating is difficult to effectively isolate the drug from the external environment (such as moisture, oxygen, etc.), resulting in the degradation reaction of the drug during storage, thus generating more impurities. In addition, the protective effect of the one-layer coating is limited and cannot fully inhibit the migration and chemical reaction of the active ingredients in the tablets. Especially under high temperature and high humidity conditions, the degradation rate of the drug accelerates, leading to a significant increase in the impurity content. The fluctuation of the dissolution rate and the generation of impurities not only affect the stability of the drug, but also may reduce the efficacy of the drug and increase the risk of potential adverse reactions.

[0079] From the data of Example 2 and Comparative Example 2 in Table 1, it can be seen that the coating formed by crosslinking chitosan and sodium carboxymethyl starch can effectively regulate the dissolution rate of the drug, prevent burst release of the drug. At the same time, it effectively protects the inner layer of the drug, avoiding the problem of drug degradation and increased impurity content caused by excessive temperature during the hot melt wet granulation process.

[0080] From the data of Example 2 and Comparative Examples 3-4 in Table 1, it can be seen that the coating layers formed by chitosan and sodium carboxymethyl starch alone are difficult to solve the problem of sudden drug release, and it is difficult to achieve stable drug dissolution. Most importantly, it will lead to a decrease in drug stability. This is mainly because the coating layers formed by chitosan and sodium carboxymethyl starch alone will melt during hot-melt wet granulation, making it difficult to effectively protect the inner-layer drug. Moreover, chitosan and sodium carboxymethyl starch alone cannot form a cross-linked structure, thus making it difficult to effectively protect the inner-layer drug and control the drug dissolution rate.

[0081] Those of ordinary skill in the art should understand that the discussion of any above embodiment is only exemplary and is not intended to imply that the scope of the present invention is limited to these examples; under the concept of the present invention, the technical features in the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations in different aspects of the present invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. An agomelatine pharmaceutical composition, characterized in that: It comprises inner layer particles, a coating layer and an outer layer of auxiliary materials; the weight ratio of the inner layer particles, the coating layer and the outer layer of auxiliary materials is 27-66:8-25:22-45; The inner layer microparticles include the following raw materials by weight: 15-30 parts of agomelatine, 10-30 parts of hypromellose, 1-3 parts of mannitol and 1-3 parts of colloidal silicon dioxide; The coating layer is obtained by coating the surface of the inner layer particles with a chitosan-sodium carboxymethyl starch suspension; The preparation method of the chitosan-sodium carboxymethyl starch suspension is as follows: dissolving chitosan in an ethanol aqueous solution with a concentration of 60wt%-80wt% to obtain a chitosan solution, dissolving sodium carboxymethyl starch in deionized water to obtain a sodium carboxymethyl starch solution, and then dripping the sodium carboxymethyl starch solution into the chitosan solution, and after the dripping is completed, stirring at a speed of 350-450rpm for 25-35min to obtain a chitosan-sodium carboxymethyl starch suspension; The weight ratio of chitosan, ethanol aqueous solution, sodium carboxymethyl starch and deionized water is 3-10:15-30:5-15:15-30; The outer layer auxiliary materials include the following raw materials by weight: 1-3 parts of glyceryl behenate, 15-25 parts of sucrose, 2-6 parts of polyvidone, 3-8 parts of sodium carboxymethyl starch and 1-3 parts of magnesium stearate.

2. The agomelatine pharmaceutical composition according to claim 1, characterized in that: The inner layer particles are obtained by dry granulation.

3. The agomelatine pharmaceutical composition according to claim 2, characterized in that: The roller pressure of the dry granulation is 5-7 MPa, the roller gap is 0.4-0.6 mm, and the mesh number of the screen is 15-25 meshes.

4. The agomelatine pharmaceutical composition according to claim 1, characterized in that: The coating layer is obtained by fluidized coating.

5. The agomelatine pharmaceutical composition according to claim 4, characterized in that: The atomization pressure of the fluidized coating is 0.05-0.15MPa, and the ventilation volume is 40-60m 3 / h, the material temperature is 25-35℃.

6. The agomelatine pharmaceutical composition according to claim 1, characterized in that: The agomelatine pharmaceutical composition is obtained by mixing an outer layer of auxiliary materials and inner layer particles containing a coating layer, and then granulating and tableting by hot melt wet method.

7. The agomelatine pharmaceutical composition according to claim 6, characterized in that: The hot melt wet granulation temperature is 60-70° C., the stirring frame speed is 0.5-2 r / s, the cutter speed is 8-12 r / s, and the granulation time is 4-6 min.

8. The agomelatine pharmaceutical composition according to claim 6, characterized in that: The main pressure of the tableting is 8-12 kN, the hardness is controlled at 100-140 N, and the weight of agomelatine in each tablet is controlled at 15-30 mg.

9. A method for preparing the agomelatine pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) Place agomelatine, hypromellose, mannitol and colloidal silicon dioxide into a mixer, mix at a speed of 40-60 rpm for 15-25 min, and then place into a dry granulator for granulation to obtain inner layer particles; (2) placing the inner layer particles obtained in step (1) in a fluidized bed coating machine, spray coating the inner layer particles with a chitosan-sodium carboxymethyl starch suspension, and after coating, turning off the atomization pressure to allow the particles to continue to be fluidized for 10-20 minutes, and finally drying at 50-60° C. to obtain coated particles; (3) putting glyceryl behenate, sucrose, povidone and sodium carboxymethyl starch together with the coated microparticles prepared in step (2) into a mixer, mixing at a speed of 40-60 rpm for 5-15 minutes, and then putting them into a hot melt wet granulator for granulation. After granulation, the mixture is sieved with a 15-25 mesh sieve, and then put into a mixer together with magnesium stearate for mixing at a speed of 15-25 rpm for 5-15 minutes to obtain composite microparticles; (4) Adding the composite microparticles prepared in step (3) into a tablet press for tableting to obtain an agomelatine pharmaceutical composition.

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