Agomelatine pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to an agomelatine pharmaceutical composition as well as a preparation method and application thereof. The agomelatine pharmaceutical composition comprises inner-layer particles, a coating layer and outer-layer auxiliary materials, the inner-layer particles are prepared from the following raw materials: agomelatine, hydroxypropyl methylcellulose, mannitol and colloidal silicon dioxide; the coating layer is obtained by coating a chitosan-sodium carboxymethyl starch suspension on the surfaces of the inner-layer particles; the outer-layer auxiliary material is prepared from the following raw materials: glyceryl behenate, cane sugar, povidone, sodium carboxymethyl starch and magnesium stearate. The agomelatine pharmaceutical composition provided by the invention is stable in dissolution, extremely low in impurity content, controllable in quality and excellent in stability, and can be used for treating depression and related diseases thereof.

Description

Technical Field

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

[0002] Agomelatine is a new type of melatonin receptor agonist and 5-hydroxytryptamine 2C receptor antagonist, which is widely used to treat depression. It improves patients' sleep quality and emotional state by regulating circadian rhythm and neurotransmitter levels, and has a unique mechanism of action and significant clinical efficacy. However, the formulation development of agomelatine faces many technical difficulties, which limits its further promotion and application in the field of pharmaceutical preparations.

[0003] Agomelatine is chemically sensitive and is prone to degradation and impurities under high temperature and high humidity conditions. 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 preparation development.

[0004] The dissolution behavior of agomelatine is difficult to control. In the formulation, the release rate of agomelatine may show a burst release phenomenon, that is, the drug is released quickly in a short period of time, resulting in a rapid increase in blood drug concentration. This phenomenon not only reduces the bioavailability of the drug, but may also cause adverse reactions and affect the patient's treatment compliance. Therefore, how to achieve stable release of agomelatine and avoid burst release 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, solve the problems of burst release and impurity generation

[0006] Based on the above purpose, the present invention provides an agomelatine pharmaceutical composition, comprising an inner layer of microparticles, a coating layer and an outer layer of auxiliary materials.

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

[0008] Furthermore, 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;

[0009] Furthermore, 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, then 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.

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

[0011] Furthermore, 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 povidone, 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 of the 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 coating.

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

[0016] Preferably, the agomelatine pharmaceutical composition is obtained by mixing an outer layer of excipients and an inner layer of microparticles containing a coating layer, followed by hot melt wet granulation and tableting.

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

[0018] Preferably, the main tableting pressure 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] Furthermore, the present invention also provides a method for preparing an agomelatine pharmaceutical composition, comprising the following steps:

[0020] (1) placing agomelatine, hypromellose, mannitol, and colloidal silicon dioxide into a mixer, mixing at a speed of 40-60 rpm for 15-25 min, and then placing the mixture 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 melt-wet granulation with various auxiliary materials. The cross-linked coating layer effectively regulates the dissolution rate of the drug, avoids the sudden release phenomenon, protects the inner layer of the drug during the hot-melt wet granulation process, and significantly reduces the drug degradation and impurity generation problems caused by high temperature. DETAILED DESCRIPTION

[0030] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments.

[0031] Embodiment 1:

[0032] (1) 15 g agomelatine passed through a 60-mesh sieve, 10 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 1 g mannitol passed through a 40-mesh sieve, and 1 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at 40 rpm for 10 min, and then placed in a dry granulator, with the roller pressure set to 5 MPa, the roller gap set to 0.4 mm, the screen mesh set to 15 mesh, and the inner layer of particles;

[0033] (2) 3 g of chitosan passed through a 60-mesh sieve was dissolved in 15 g of an ethanol aqueous solution having a concentration of 60 wt% to obtain a chitosan solution, and 5 g of sodium carboxymethyl starch passed through an 80-mesh sieve was dissolved in 15 g of deionized water to obtain a sodium carboxymethyl starch solution, and the sodium carboxymethyl starch solution was added dropwise to the chitosan solution. After the addition was completed, the mixture was stirred at a speed of 350 rpm for 25 min to obtain a chitosan-sodium carboxymethyl starch suspension, and the inner layer particles were placed in a fluidized bed coater, and the inner layer particles prepared in step (1) were spray-coated with the chitosan-sodium carboxymethyl starch suspension, with the atomization pressure controlled at 0.05 MPa and the ventilation volume at 40 m 3 / h, material temperature 25℃, after coating, turn off the atomization pressure to keep the pellets in fluidized state for 10min, and finally dry at 50℃ to obtain coated particles;

[0034] (3) putting 1 g of glyceryl behenate passed through a 60-mesh sieve, 15 g of sucrose passed through a 60-mesh sieve, 2 g of povidone K30 passed through a 60-mesh sieve, 3 g of sodium carboxymethyl starch passed through a 60-mesh sieve, and the coated particles prepared in step (2) into a mixer, mixing at a speed of 40 rpm for 5 min, and then putting them into a hot melt wet granulator, setting 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, passing through a 15-mesh sieve, and then putting them into a mixer together with 1 g of magnesium stearate passed through a 100-mesh sieve, mixing at a speed of 15 rpm for 5 min to obtain composite particles;

[0035] (4) The composite particles prepared in step (3) were added to a tablet press for tableting, and the tablets were punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press was set to 8 kN, the hardness was controlled at 100 N, and the weight of agomelatine in each tablet was controlled to be 15 mg, thereby obtaining an agomelatine pharmaceutical composition.

[0036] Embodiment 2:

[0037] (1) 25 g agomelatine passed through a 60-mesh sieve, 25 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 2 g mannitol passed through a 40-mesh sieve, and 2 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at a speed of 50 rpm for 20 min, and then placed in a dry granulator, with the roller pressure set to 6 MPa, the roller gap set to 0.5 mm, the screen mesh set to 20 mesh, and the inner layer of particles;

[0038] (2) dissolving 5 g of chitosan passed through a 60-mesh sieve in 20 g of an ethanol aqueous solution having a concentration of 70 wt % to obtain a chitosan solution, and then dissolving 10 g of sodium carboxymethyl starch passed through an 80-mesh sieve in 20 g of deionized water to obtain a sodium carboxymethyl starch solution, and adding the sodium carboxymethyl starch solution dropwise to the chitosan solution. After the addition is complete, stirring is performed at a speed of 400 rpm for 30 min to obtain a chitosan-sodium carboxymethyl starch suspension, placing the inner layer particles in a fluidized bed coating machine, and spraying the inner layer particles prepared in step (1) with the chitosan-sodium carboxymethyl starch suspension, with the atomization pressure controlled at 0.1 MPa and the ventilation volume at 50 m 3 / h, material temperature 30℃, after coating, turn off the atomization pressure to keep the pellets in fluidized state for 15min, and finally dry at 55℃ to obtain coated particles;

[0039] (3) putting 2 g of glyceryl behenate passed through a 60-mesh sieve, 20 g of sucrose passed through a 60-mesh sieve, 4 g of povidone K30 passed through a 60-mesh sieve, 5 g of sodium carboxymethyl starch passed through a 60-mesh sieve, and the coated particles prepared in step (2) into a mixer, mixing at a speed of 50 rpm for 10 min, and then putting them into a hot melt wet granulator, setting the temperature to 65° C., the stirring frame speed to 1 r / s, the cutting blade speed to 10 r / s, and the granulation time to 5 min. After the granulation is completed, passing through a 20-mesh sieve, and then putting them into a mixer together with 2 g of magnesium stearate passed through a 100-mesh sieve, mixing at a speed of 20 rpm for 10 min to obtain composite particles;

[0040] (4) The composite particles prepared in step (3) were added to a tablet press for tableting, and the tablets were punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press was set to 10 kN, the hardness was controlled to 120 N, and the weight of agomelatine in each tablet was controlled to 25 mg, thereby obtaining an agomelatine pharmaceutical composition.

[0041] Embodiment 3:

[0042] (1) 30 g agomelatine passed through a 60-mesh sieve, 30 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 3 g mannitol passed through a 40-mesh sieve, and 3 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at a speed of 50 rpm for 30 min, and then placed in a dry granulator, with the roller pressure set to 7 MPa, the roller gap set to 0.6 mm, the screen mesh set to 25 mesh, and the inner layer of particles;

[0043] (2) dissolving 10 g of chitosan that has passed through a 60-mesh sieve in 30 g of an ethanol aqueous solution having a concentration of 80 wt% to obtain a chitosan solution, and then dissolving 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, and adding the sodium carboxymethyl starch solution dropwise to the chitosan solution. After the addition is complete, stirring is performed at a speed of 450 rpm for 35 min to obtain a chitosan-sodium carboxymethyl starch suspension, placing the inner layer particles in a fluidized bed coater, and spraying the inner layer particles prepared in step (1) with the chitosan-sodium carboxymethyl starch suspension, with the atomization pressure controlled at 0.15 MPa and the ventilation volume at 60 m 3 / h, material temperature 35°C, after coating, turn off the atomization pressure to keep the pellets in fluidized state for 20 min, and finally dry at 60°C to obtain coated particles;

[0044] (3) putting 3 g of glyceryl behenate passed through a 60-mesh sieve, 25 g of sucrose passed through a 60-mesh sieve, 6 g of povidone K30 passed through a 60-mesh sieve, 8 g of sodium carboxymethyl starch passed through a 60-mesh sieve, and the coated particles prepared in step (2) into a mixer, mixing at a speed of 60 rpm for 15 min, and then putting them into a hot melt wet granulator, setting the temperature to 70° C., the stirring frame speed to 2 r / s, the cutting blade speed to 12 r / s, and the granulation time to 6 min. After the granulation is completed, passing through a 25-mesh sieve, and then putting them into a mixer together with 3 g of magnesium stearate passed through a 100-mesh sieve, mixing at a speed of 25 rpm for 15 min to obtain composite particles;

[0045] (4) The composite particles prepared in step (3) were added to a tablet press for tableting, and the tablets were punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press was set to 12 kN, the hardness was controlled to 140 N, and the weight of agomelatine in each tablet was controlled to 30 mg, thereby obtaining an agomelatine pharmaceutical composition.

[0046] Comparative Example 1:

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

[0048] The specific steps are as follows:

[0049] (1) 25 g agomelatine passed through a 60-mesh sieve, 25 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 2 g mannitol passed through a 40-mesh sieve, and 2 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at a speed of 50 rpm for 20 min, and then placed in a dry granulator, with the roller pressure set to 6 MPa, the roller gap set to 0.5 mm, the screen mesh set to 20 mesh, and the inner layer of particles;

[0050] (2) dissolving 5 g of chitosan passed through a 60-mesh sieve in 20 g of an ethanol aqueous solution having a concentration of 70 wt % to obtain a chitosan solution, and then dissolving 10 g of sodium carboxymethyl starch passed through an 80-mesh sieve in 20 g of deionized water to obtain a sodium carboxymethyl starch solution, and adding the sodium carboxymethyl starch solution dropwise to the chitosan solution. After the addition is complete, stirring is performed at a speed of 400 rpm for 30 min to obtain a chitosan-sodium carboxymethyl starch suspension, placing the inner layer particles in a fluidized bed coating machine, and spraying the inner layer particles prepared in step (1) with the chitosan-sodium carboxymethyl starch suspension, with the atomization pressure controlled at 0.1 MPa and the ventilation volume at 50 m 3 / h, material temperature 30℃, after coating, turn off the atomization pressure to keep the pellets in fluidized state for 15min, and finally dry at 55℃ to obtain coated particles;

[0051] (3) The coated microparticles prepared in step (2) are added to a tablet press for tableting, and the films are punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press is set to 10 kN, the hardness is controlled at 120 N, and the weight of agomelatine in each tablet is controlled to be 25 mg, thereby obtaining an agomelatine pharmaceutical composition.

[0052] Comparative Example 2:

[0053] The difference between Comparative Example 2 and Example 2 is that the inner layer microparticles and glyceryl behenate, sucrose, povidone K30 and 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) 25 g agomelatine passed through a 60-mesh sieve, 25 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 2 g mannitol passed through a 40-mesh sieve, and 2 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at a speed of 50 rpm for 20 min, and then placed in a dry granulator, with the roller pressure set to 6 MPa, the roller gap set to 0.5 mm, the screen mesh set to 20 mesh, and the inner layer of particles;

[0056] (2) putting 2 g of glyceryl behenate passed through a 60-mesh sieve, 20 g of sucrose passed through a 60-mesh sieve, 4 g of povidone K30 passed through a 60-mesh sieve, 5 g of sodium carboxymethyl starch passed through a 60-mesh sieve, and the inner layer particles prepared in step (2) into a mixer, mixing at a speed of 50 rpm for 10 min, and then putting them into a hot melt wet granulator, setting the temperature to 65° C., the stirring frame speed to 1 r / s, the cutting blade speed to 10 r / s, and the granulation time to 5 min. After the granulation is completed, passing through a 20-mesh sieve, and then putting them into a mixer together with 2 g of magnesium stearate passed through a 100-mesh sieve, mixing at a speed of 20 rpm for 10 min to obtain composite particles;

[0057] (3) The composite particles prepared in step (2) are added to a tablet press for tableting, and the tablets are punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press is set to 10 kN, the hardness is controlled to 120 N, and the weight of agomelatine in each tablet is controlled to be 25 mg, thereby obtaining an 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 to be 25 mg;

[0060] The specific steps are as follows:

[0061] (1) 25 g agomelatine passed through a 60-mesh sieve, 25 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 2 g mannitol passed through a 40-mesh sieve, and 2 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at a speed of 50 rpm for 20 min, and then placed in a dry granulator, with the roller pressure set to 6 MPa, the roller gap set to 0.5 mm, the screen mesh set to 20 mesh, and the inner layer of particles;

[0062] (2) 5 g of chitosan passed through a 60-mesh sieve was dissolved in 20 g of an ethanol aqueous solution having a concentration of 70 wt % to obtain a chitosan solution. The inner layer particles were placed in a fluidized bed coater and the inner layer particles prepared in step (1) were spray-coated with the chitosan solution. The atomization pressure was controlled at 0.1 MPa and the ventilation volume was 50 m 3 / h, material temperature 30℃, after coating, turn off the atomization pressure to keep the pellets in fluidized state for 15min, and finally dry at 55℃ to obtain coated particles;

[0063] (3) putting 2 g of glyceryl behenate passed through a 60-mesh sieve, 20 g of sucrose passed through a 60-mesh sieve, 4 g of povidone K30 passed through a 60-mesh sieve, 5 g of sodium carboxymethyl starch passed through a 60-mesh sieve, and the coated particles prepared in step (2) into a mixer, mixing at a speed of 50 rpm for 10 min, and then putting them into a hot melt wet granulator, setting the temperature to 65° C., the stirring frame speed to 1 r / s, the cutting blade speed to 10 r / s, and the granulation time to 5 min. After the granulation is completed, passing through a 20-mesh sieve, and then putting them into a mixer together with 2 g of magnesium stearate passed through a 100-mesh sieve, mixing at a speed of 20 rpm for 10 min to obtain composite particles;

[0064] (4) The composite particles prepared in step (3) were added to a tablet press for tableting, and the tablets were punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press was set to 10 kN, the hardness was controlled to 120 N, and the weight of agomelatine in each tablet was controlled to 25 mg, thereby obtaining an 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 to be 25 mg;

[0067] (1) 25 g agomelatine passed through a 60-mesh sieve, 25 g hydroxypropyl methylcellulose E5 passed through a 40-mesh sieve, 2 g mannitol passed through a 40-mesh sieve, and 2 g colloidal silicon dioxide passed through a 100-mesh sieve were placed in a mixer, mixed at a speed of 50 rpm for 20 min, and then placed in a dry granulator, with the roller pressure set to 6 MPa, the roller gap set to 0.5 mm, the screen mesh set to 20 mesh, and the inner layer of particles;

[0068] (2) Dissolve 10 g of sodium carboxymethyl starch passed through an 80-mesh sieve in 20 g of deionized water to obtain a sodium carboxymethyl starch solution. Place the inner layer particles in a fluidized bed coater and spray coat the inner layer particles prepared in step (1) with the sodium carboxymethyl starch solution. The atomization pressure is controlled at 0.1 MPa and the ventilation volume is 50 m 3 / h, material temperature 30℃, after coating, turn off the atomization pressure to keep the pellets in fluidized state for 15min, and finally dry at 55℃ to obtain coated particles;

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

[0070] (4) The composite particles prepared in step (3) were added to a tablet press for tableting, and the tablets were punched into oval tablets with a diameter of 7 mm. The main pressure of the tablet press was set to 10 kN, the hardness was controlled to 120 N, and the weight of agomelatine in each tablet was controlled to 25 mg, thereby obtaining an agomelatine pharmaceutical composition.

[0071] Performance Testing:

[0072] Dissolution test: Take the tablets prepared in the embodiment and the comparative example, and perform the dissolution test method (Appendix XC Method 2 of Part II of the Chinese Pharmacopoeia 2010 Edition), with 900 mL of 0.1 mol / L hydrochloric acid as the dissolution medium, and the rotation speed is 50 rpm. After 5 min, 15 min, 35 min, 45 min, and 60 min, take the solution for filtration, take the subsequent filtrate, and measure the absorbance at a wavelength of 276 nm according to the UV-visible spectrophotometry (Appendix IVA of Part II of the Chinese Pharmacopoeia 2010 Edition); separately, accurately weigh 25 mg of agomelatine reference substance, place it in a 10 mL volumetric flask, add ethanol to dissolve and dilute to the scale, shake well, accurately measure 1 mL and place it in a 100 mL volumetric flask, add 0.1 mol / L hydrochloric acid to dilute to the scale, 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: The tablets prepared in the examples and comparative examples were placed at a temperature of 50±5°C and a humidity of 75±5% for 0 and 12 months, and the maximum single impurity and total impurity contents were detected. 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, no burst release phenomenon, and the dissolution rate after 60 minutes can reach more than 99.5%, which helps to ensure the stable release of the drug in the body, improve bioavailability, reduce blood drug concentration fluctuations, 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 conducive to the consistency of the preparation in different batches of production, ensuring the quality controllability of the drug and the safety of clinical use.

[0077] From the data of the stability test of Examples 1-3 in Table 1, it can be seen that the agomelatine pharmaceutical composition prepared by the present invention has an extremely low impurity content, and after being placed for 12 months under the conditions of temperature 50±5°C and humidity 75±5%, the total impurity content is not higher than 0.05%, and the maximum single impurity content is not lower than 0.03%, which shows that the pharmaceutical composition of the present invention has excellent stability, can maintain the stability of chemical properties for a long time under harsh environments such as high temperature and high humidity, and generates very few impurities, thereby 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 needs of long-term storage and transportation, and provides reliable guarantee for clinical application.

[0078] From the data of Example 2 and Comparative Example 1 in Table 1, it can be seen that the tablets obtained by directly using a layer of coated particles for tableting have a faster dissolution rate in the early stage, and after being placed under the conditions of temperature 50±5°C and humidity 75±5% for 12 months, the total impurity content reached 0.15%. The maximum single impurity content reached 0.11%, and the stability was poor. This is mainly because a layer of coating is difficult to effectively isolate the drug from the external environment (such as moisture, oxygen, etc.), resulting in degradation reactions of the drug during storage, thereby generating more impurities. In addition, the protective effect of a layer of coating is limited, and it is impossible to fully inhibit the migration and chemical reactions of the active ingredients in the tablets, especially under high temperature and high humidity conditions, the degradation rate of the drug is accelerated, resulting in a significant increase in the impurity content. This fluctuation in 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 potential risk of adverse reactions.

[0079] It can be seen from the data of Example 2 and Comparative Example 2 in Table 1 that the coating formed by cross-linking chitosan and sodium carboxymethyl starch can effectively regulate the dissolution rate of the drug and prevent sudden release of the drug. At the same time, it effectively protects the inner layer of the drug and avoids the problem of drug degradation and increased impurity content caused by excessively high temperatures during the hot-melt wet granulation process.

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

[0081] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative 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 may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

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 3-10:15-30:5-15:20:15-30; 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.

10. Use of the agomelatine pharmaceutical composition according to any one of claims 1 to 8, characterized in that: Used to treat depression and related disorders.

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