Agomelatine coating preparation and processing technology thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and discloses an agomelatine coating preparation and a processing technology thereof. The processing technology comprises the following steps: S1: taking agomelatine powder, distearoylphosphatidylethanolamine, soybean sterol, and a mixed solvent, stirring them evenly, and then removing the solvent under reduced pressure, adding a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution, shaking, stirring evenly, homogenizing and emulsifying, filtering, and freeze-drying to obtain agomelatine liposomes; S2: mixing agomelatine powder, agomelatine liposomes, povidone K30, sodium starch glycolate, starch, and lactose evenly in equal amounts, adding water, stirring evenly, sieving, drying, adding silicon dioxide and magnesium stearate, and pressing with a die to obtain agomelatine granules; S3: coating the agomelatine granules with a coating solution, coating them again with a taste-masking coating agent, and cooling to obtain the agomelatine coating preparation.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations and discloses an agomelatine coating preparation and a processing technology thereof. Background Art

[0002] Depression is a common mental illness. With the accelerating pace of life, its incidence continues to rise, and it has now become the fourth most common disease in the world. Agomelatine, chemically known as N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, is a new antidepressant. It is a melatonin 1, 2 (MT1, MT2) receptor agonist and a 5-hydroxytryptamine 2c (5HT2C) receptor antagonist. It is the first melatonin-based antidepressant that directly binds to the 5HT2C receptor on the postsynaptic membrane, resulting in excellent efficacy and minimal side effects.

[0003] However, agomelatine is a poorly water-soluble compound with less than ideal dissolution properties, resulting in low bioavailability in the human body and large biovariability within the same body and between different individuals. Although the agomelatine preparations prepared by the prior art have been tested to have good dissolution effects, they have problems such as a long time required for complete dissolution and an unstable dissolution rate. In addition, the strong bitterness of agomelatine itself, which leads to a poor taste, is not considered, which reduces patient adaptability. In summary, it is of great significance to study an agomelatine coating preparation with high dissolution, reasonable dissolution time, stable dissolution rate, and good taste, and its processing technology. Summary of the Invention

[0004] The object of the present invention is to provide an agomelatine coating preparation and a processing technology thereof, so as to solve the problems raised in the above background technology.

[0005] In order to solve the above technical problems, the present invention provides the following technical solution: A processing process for an agomelatine coating preparation, comprising the following steps: S1: taking agomelatine powder, distearoylphosphatidylethanolamine, soybean sterol, and a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1), stirring them uniformly, and then removing the solvent under reduced pressure, adding a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8, shaking, stirring uniformly, homogenizing and emulsifying, filtering through a 0.45 μm microporous membrane, and freeze-drying at -40°C to obtain agomelatine liposomes;

[0006] S2: Agomelatine powder, agomelatine liposomes, povidone K30, sodium starch glycolate, starch, and lactose were mixed uniformly in equal amounts, water was added, and the mixture was sieved and dried. Silicon dioxide and magnesium stearate were added, and the mixture was pressed using a 7 mm die to obtain agomelatine granules.

[0007] S3: Heat the coating pot to 40-45°C, pump the coating liquid into the coating pot with a peristaltic pump, and spray the coating liquid into the coating pot in a mist form with compressed air to coat the agomelatine particles. Stop coating after the weight gain reaches 1.5-2.0%, cool the particles, and coat again with a taste-masking coating agent. Stop coating after the weight gain reaches 5-8%, cool the particles, and obtain the agomelatine coating preparation.

[0008] More optimally, the agomelatine liposomes comprise the following raw materials, calculated by mass: 2-3 parts of agomelatine powder, 20-25 parts of distearoylphosphatidylethanolamine, 3-5 parts of soybean sterols, 50-80 parts of a mixed solvent, and 500-600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution;

[0009] The agomelatine granules include the following raw materials, calculated by mass: 5-10 parts of agomelatine powder, 15-20 parts of agomelatine liposomes, 3-5 parts of povidone K30, 5-10 parts of sodium starch glycolate, 20-25 parts of starch, 5-8 parts of water, 60-65 parts of lactose, 5-8 parts of silicon dioxide, and 1-2 parts of magnesium stearate.

[0010] More optimally, the agomelatine powder is 100 mesh and the lactose is 80 mesh.

[0011] More optimally, the preparation of the coating solution includes the following steps: taking polyacrylic acid resin and anhydrous ethanol, stirring evenly, adding anti-sticking agent, microcrystalline cellulose, and cross-linking agent glutaraldehyde, and mixing evenly to obtain a coating solution.

[0012] More optimally, the coating solution includes the following raw materials, calculated by mass: 6 to 10 parts of polyacrylic acid resin, 6 to 10 parts of anhydrous ethanol, 2 to 3 parts of anti-sticking agent, 0.1 to 0.2 parts of microcrystalline cellulose, and 0.3 to 0.5 parts of glutaraldehyde.

[0013] More optimally, the preparation of the anti-sticking agent includes the following steps: adding talc powder to water, stirring evenly, adjusting the pH to 3-4 with hydrochloric acid, adding dialdehyde polyethylene glycol, stirring at 70-75°C for 10-15 hours, filtering the solid, washing, and drying to obtain polyethylene glycol-modified talc powder; adding polyethylene glycol-modified talc powder to dimethyl sulfoxide (DMSO), stirring evenly, adjusting the pH to 3-4, adding soybean sterol, stirring at 70-75°C for 10-15 hours, filtering the solid, washing, and drying to obtain the anti-sticking agent.

[0014] More optimally, the polyethylene glycol-modified talc powder includes the following raw materials, calculated by mass: 10-15 parts of talc powder and 3-5 parts of dialdehyde polyethylene glycol; the anti-sticking agent includes the following raw materials, calculated by mass: 10-15 parts of polyethylene glycol-modified talc powder and 1-2 parts of soybean sterol.

[0015] More optimally, the molecular weight of the dialdehyde polyethylene glycol is 2000-5000.

[0016] Compared with the prior art, the beneficial effects achieved by the present invention are: agomelatine is a drug that needs to be released quickly, so its solubility needs to be improved, but the release rate should not be too fast, otherwise it will cause discomfort to the patient, and the stability of the release rate also needs to be controlled to avoid adverse reactions caused by sudden release; at the same time, agomelatine tastes bitter and needs to be taste-masked; based on the above requirements, the use scheme of the present invention is: agomelatine liposomes and agomelatine powder are mixed in a certain proportion and then coated; agomelatine liposomes improve the stability and bioavailability of agomelatine, and although the final solubility is high, the release rate is relatively The release rate of agomelatine is slow, which does not meet the requirements of agomelatine as a rapid-release drug. Therefore, agomelatine powder is also added. Due to the addition of auxiliary materials such as lactose, starch, and microcrystalline cellulose, and the moderate size, the solubility is good and the release rate is fast. In summary, the agomelatine coated preparation prepared by mixing agomelatine liposomes and agomelatine powder in a certain proportion and then coating them has a fast initial release rate, a high total dissolution rate, and a stable subsequent release rate. The addition ratio of the two needs to be controlled. Adding too much agomelatine liposomes will lead to a reduced release rate, and adding too much agomelatine powder will lead to an excessively fast release rate, which may easily cause discomfort to patients.

[0017] The present invention also prepares a coating solution, wherein the anti-sticking agent is modified talc, and polyethylene glycol is introduced into the coating solution to play a plasticizing role, thereby improving the toughness and uniformity of the coating film and facilitating a stable release rate. The viscosity of the polyethylene glycol needs to be controlled within a certain range. If the molecular weight is too small, the plasticizing effect is not obvious. If the molecular weight is too large, the viscosity increases, which is not conducive to subsequent coating and may cause uneven coating film, resulting in uncontrollable release rate. Soy sterol has good biocompatibility and can increase the stability of the coating film, reduce drug oxidation, and improve the fluidity of the film. An appropriate amount of glutaraldehyde is also introduced into the coating solution as a cross-linking agent to increase the cross-linking degree of the coating film, reduce its deformation, and improve the uniformity and stability of the film. However, the amount of cross-linking agent added should not be too much, as excessive addition will slow the drug release rate.

[0018] When coating with the coating liquid, coating is stopped after the weight gain is 1.5-2.0%, and then coating is performed with the taste-masking coating agent Eudragit E100, and coating is stopped after the weight gain is 5-8%. Since the coating liquid is used in advance for coating, the amount of the taste-masking coating agent is greatly reduced, and finally an agomelatine coating preparation with high solubility, reasonable release rate and no bitterness is obtained. DETAILED DESCRIPTION

[0019] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0020] It should be noted that there are no special restrictions on the purchase manufacturers of all raw materials involved in the present invention, and illustratively include: talc (400 mesh pharmaceutical grade, Shaanxi Ruichengkang Pharmaceutical Technology Co., Ltd.); bisaldehyde polyethylene glycol (CHO-PEG-CHO, Chongqing Yusi Pharmaceutical Technology Co., Ltd., molecular weight 3400, other molecular weights can be customized); soybean sterols (soybean sterol A, purity HPLC ≥98%, Yuanye B28198); polyacrylic acid resin (pharmaceutical excipient polyacrylic acid resin IV, Shaanxi Ruichengkang Pharmaceutical Technology Co., Ltd.); microcrystalline cellulose (pharmaceutical grade); distearoylphosphatidylethanolamine (pharmaceutical grade); povidone K30 (BASF Povidone K30S); sodium starch glycolate (pharmaceutical grade); starch (pharmaceutical grade corn starch); lactose (80 mesh pharmaceutical anhydrous lactose); silicon dioxide (pharmaceutical grade, Muchenglin 0056236); magnesium stearate (pharmaceutical grade); taste masking coating agent (Evonik Eudragit E100);

[0021] Unless otherwise specified, the following are parts by mass and mass ratios;

[0022] Example 1: S1: 12 parts of talc were added to 100 parts of water, stirred evenly, adjusted to pH 3 with hydrochloric acid, added 4 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stirred at 75°C for 15 hours, filtered to obtain a solid, washed, and dried to obtain polyethylene glycol-modified talc; 15 parts of polyethylene glycol-modified talc were added to 100 parts of DMSO, stirred evenly, adjusted to pH 3 with hydrochloric acid, added 1 part of soybean sterol, stirred at 75°C for 15 hours, filtered to obtain a solid, washed, and dried to obtain an anti-sticking agent;

[0023] S2: Take 6 parts of polyacrylic acid resin and 8 parts of anhydrous ethanol, stir evenly, take 3 parts of anti-sticking agent, 0.1 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde, mix evenly to obtain a coating solution;

[0024] S3: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 4 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to emulsify. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0025] S4: 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 3 parts of povidone K30, 6 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed uniformly in equal amounts, 5 parts of water were added, the mixture was stirred uniformly, and then passed through an 18-mesh sieve, dried at 60°C, 5 parts of silicon dioxide and 1 part of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules;

[0026] S5: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0027] Example 2: S1: 10 parts of talc were added to 100 parts of water, stirred evenly, adjusted to pH 3 with hydrochloric acid, 3 parts of dialdehyde polyethylene glycol with a molecular weight of 3400 were added, stirred at 75°C for 15 hours, the solid was filtered, washed, and dried to obtain polyethylene glycol-modified talc; 10 parts of polyethylene glycol-modified talc were added to 100 parts of DMSO, stirred evenly, adjusted to pH 3 with hydrochloric acid, 1 part of soybean sterol was added, stirred at 75°C for 15 hours, the solid was filtered, washed, and dried to obtain an anti-sticking agent;

[0028] S2: Take 6 parts of polyacrylic acid resin and 8 parts of anhydrous ethanol, stir evenly, take 2 parts of anti-sticking agent, 0.2 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde, mix evenly to obtain a coating solution;

[0029] S3: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 3 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to form an emulsified mixture. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0030] S4: 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 5 parts of povidone K30, 5 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed uniformly in equal amounts, 5 parts of water were added, the mixture was stirred uniformly, passed through an 18-mesh sieve, and dried at 60°C. 5 parts of silicon dioxide and 2 parts of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules.

[0031] S5: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0032] Example 3: S1: 15 parts of talc were added to 100 parts of water, stirred evenly, adjusted to pH 3 with hydrochloric acid, added 5 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stirred at 75°C for 15 hours, filtered to obtain the solid, washed, and dried to obtain polyethylene glycol-modified talc; 15 parts of polyethylene glycol-modified talc were added to 100 parts of DMSO, stirred evenly, adjusted to pH 3 with hydrochloric acid, added 2 parts of soybean sterols, stirred at 75°C for 15 hours, filtered to obtain the solid, washed, and dried to obtain an anti-sticking agent;

[0033] S2: Take 6 parts of polyacrylic acid resin and 10 parts of anhydrous ethanol, stir evenly, take 2 parts of anti-sticking agent, 0.2 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde, mix evenly to obtain a coating solution;

[0034] S3: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 5 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to form an emulsified mixture. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0035] S4: 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 5 parts of povidone K30, 10 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed uniformly in equal amounts, 5 parts of water were added, the mixture was stirred uniformly, and the mixture was passed through an 18-mesh sieve and dried at 60°C. 5 parts of silicon dioxide and 1 part of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules.

[0036] S5: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0037] Comparative Example 1 (the amount of agomelatine liposomes and agomelatine particles added was changed, and the remaining method steps were consistent with Example 1): S1: 12 parts of talc were added to 100 parts of water, and the mixture was stirred evenly. The pH was adjusted to 3 with hydrochloric acid, and 4 parts of dialdehyde polyethylene glycol with a molecular weight of 3400 were added. The mixture was stirred at 75° C. for 15 hours. The solid was filtered, washed, and dried to obtain polyethylene glycol-modified talc. 15 parts of polyethylene glycol-modified talc were added to 100 parts of DMSO, and the mixture was stirred evenly. The pH was adjusted to 3 with hydrochloric acid, and 1 part of soybean sterol was added. The mixture was stirred at 75° C. for 15 hours. The solid was filtered, washed, and dried to obtain an anti-adhesive agent.

[0038] S2: Take 6 parts of polyacrylic acid resin and 8 parts of anhydrous ethanol, stir evenly, take 3 parts of anti-sticking agent, 0.1 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde, mix evenly to obtain a coating solution;

[0039] S3: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 4 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to emulsify. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0040] S4: 4 parts of 100-mesh agomelatine powder, 22 parts of agomelatine liposomes, 3 parts of povidone K30, 6 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed in equal amounts, 5 parts of water were added, the mixture was stirred evenly, and the mixture was passed through an 18-mesh sieve and dried at 60°C. 5 parts of silicon dioxide and 1 part of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules.

[0041] S5: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0042] Comparative Example 2 (the amount of agomelatine liposomes and agomelatine particles added was changed, and the remaining method steps were the same as Example 1): S1: 12 parts of talc were added to 100 parts of water, and the mixture was stirred evenly. The pH was adjusted to 3 with hydrochloric acid, and 4 parts of dialdehyde polyethylene glycol with a molecular weight of 3400 were added. The mixture was stirred at 75° C. for 15 hours. The solid was filtered, washed, and dried to obtain polyethylene glycol-modified talc. 15 parts of polyethylene glycol-modified talc were added to 100 parts of DMSO, and the mixture was stirred evenly. The pH was adjusted to 3 with hydrochloric acid, and 1 part of soybean sterol was added. The mixture was stirred at 75° C. for 15 hours. The solid was filtered, washed, and dried to obtain an anti-adhesive agent.

[0043] S2: Take 6 parts of polyacrylic acid resin and 8 parts of anhydrous ethanol, stir evenly, take 3 parts of anti-sticking agent, 0.1 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde, mix evenly to obtain a coating solution;

[0044] S3: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 4 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to emulsify. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0045] S4: 13 parts of 100-mesh agomelatine powder, 13 parts of agomelatine liposomes, 3 parts of povidone K30, 6 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed in equal amounts, 5 parts of water were added, the mixture was stirred evenly, and then passed through an 18-mesh sieve, dried at 60°C, 5 parts of silicon dioxide and 1 part of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules.

[0046] S5: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0047] Comparative Example 3 (the preparation method of the coating solution was changed, and the remaining steps were the same as those in Example 1): S1: 6 parts of polyacrylic acid resin and 8 parts of anhydrous ethanol were mixed uniformly, and 3 parts of talc, 0.1 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde were mixed uniformly to obtain a coating solution;

[0048] S2: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 4 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to emulsify. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0049] S3: 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 3 parts of povidone K30, 6 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed in equal amounts, 5 parts of water were added, the mixture was stirred evenly, and then passed through an 18-mesh sieve, dried at 60°C, 5 parts of silicon dioxide and 1 part of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules.

[0050] S4: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0051] Comparative Example 4 (Changing the molecular weight of the dialdehyde polyethylene glycol, the remaining method steps are the same as those in Example 1): S1: 12 parts of talc were added to 100 parts of water, stirred evenly, adjusted to pH 3 with hydrochloric acid, 4 parts of dialdehyde polyethylene glycol with a molecular weight of 10,000 were added, and stirred at 75° C. for 15 hours. The solid was filtered, washed, and dried to obtain polyethylene glycol-modified talc; 15 parts of polyethylene glycol-modified talc were added to 100 parts of DMSO, stirred evenly, adjusted to pH 3 with hydrochloric acid, 1 part of soybean sterol was added, stirred at 75° C. for 15 hours, the solid was filtered, washed, and dried to obtain an anti-sticking agent;

[0052] S2: Take 6 parts of polyacrylic acid resin and 8 parts of anhydrous ethanol, stir evenly, take 3 parts of anti-sticking agent, 0.1 parts of microcrystalline cellulose, and 0.3 parts of glutaraldehyde, mix evenly to obtain a coating solution;

[0053] S3: 3 parts of agomelatine powder, 20 parts of distearoylphosphatidylethanolamine, 4 parts of soybean sterols, and 70 parts of a mixed solvent (tert-butyl alcohol and methanol in a volume ratio of 1:1) were mixed and uniformly stirred. The solvent was removed under reduced pressure, and 600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution with a pH value of 5.8 was added. The mixture was shaken, stirred, and homogenized to emulsify. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried at -40°C to obtain agomelatine liposomes.

[0054] S4: 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 3 parts of povidone K30, 6 parts of sodium starch glycolate, 20 parts of starch, and 60 parts of 80-mesh lactose were mixed uniformly in equal amounts, 5 parts of water were added, the mixture was stirred uniformly, and then passed through an 18-mesh sieve, dried at 60°C, 5 parts of silicon dioxide and 1 part of magnesium stearate were added, and the mixture was pressed using a die with a diameter of 7 mm to obtain agomelatine granules;

[0055] S5: The coating pan was heated to 45° C., the coating liquid was pumped into the coating pan using a peristaltic pump, and the coating liquid was sprayed into the coating pan in a mist form using compressed air to coat the agomelatine particles. The coating process was stopped after the weight gain reached 2.0%, and the particles were cooled. The particles were coated again with a taste-masking coating agent, Eudragit E100. The coating process was stopped after the weight gain reached 6%, and the particles were cooled to obtain an agomelatine coating preparation.

[0056] Performance test: The agomelatine coating preparations prepared in Examples 1 to 3 and Comparative Examples 1 to 4 were taken; (1) the dissolution rates at 5, 15, 30, and 45 min were measured according to the second method of Appendix XC of Part II of the Chinese Pharmacopoeia 2005 edition; (2) the mouthfeel was tested; see Table 1 for details;

[0057] Table 1:

[0058]

[0059] Conclusion: In Comparative Example 1, the amount of agomelatine liposomes added was increased, but the release rate was slow, which did not meet the demand for agomelatine as a drug that requires rapid release; in Comparative Example 2, the amount of agomelatine liposomes added was reduced, but the release rate was too fast, which easily caused discomfort; in Comparative Example 3, the preparation method of the coating solution was changed, that is, talc was directly used as an anti-adherent agent without modification, resulting in uneven coating film, unstable release rate and bitter taste; in Comparative Example 4, the molecular weight of dialdehyde polyethylene glycol was increased, but the viscosity increased, resulting in decreased uniformity of the coating film, and the same problems of unstable release rate and bitter taste; in summary, the agomelatine coating preparation prepared by the present invention has a reasonable release rate, no bitter taste, and will not cause discomfort when taken.

[0060] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or substitute equivalents for some of the technical features. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A processing technology for an agomelatine coating preparation, characterized in that: The following steps are involved: S1: Agomelatine powder, distearoylphosphatidylethanolamine, soybean sterols, and a mixed solvent were mixed and stirred, and the solvent was removed under reduced pressure. Potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution was added, shaken, stirred, and emulsified. The mixture was filtered through a 0.45 μm microporous membrane and freeze-dried to obtain agomelatine liposomes. S2: Agomelatine powder, agomelatine liposomes, povidone K30, sodium starch glycolate, starch, and lactose were mixed uniformly in equal amounts, water was added, and the mixture was stirred uniformly, sieved, and dried. Silicon dioxide and magnesium stearate were added, and the mixture was pressed into a die to obtain agomelatine granules. S3: coating the agomelatine granules with the coating liquid until the weight increases by 1.5-2.0%, stopping the coating, cooling, and coating again with the taste-masking coating agent until the weight increases by 5-8%, stopping the coating, cooling, and obtaining the agomelatine coating preparation; The agomelatine granules include the following raw materials, calculated by mass: 5-10 parts of agomelatine powder, 15-20 parts of agomelatine liposomes, 3-5 parts of povidone K30, 5-10 parts of sodium starch glycolate, 20-25 parts of starch, 60-65 parts of lactose, 5-8 parts of silicon dioxide, and 1-2 parts of magnesium stearate; The preparation of the coating solution comprises the following steps: Take polyacrylic acid resin and anhydrous ethanol, stir evenly, add anti-sticking agent, microcrystalline cellulose and cross-linking agent, mix evenly to obtain coating solution; The preparation of the anti-sticking agent comprises the following steps: adding talc powder to water, stirring evenly, adjusting the pH to 3-4, adding dialdehyde polyethylene glycol, stirring at 70-75° C. for 10-15 hours, filtering out the solid, washing, and drying to obtain polyethylene glycol-modified talc powder; adding polyethylene glycol-modified talc powder to DMSO, stirring evenly, adjusting the pH to 3-4, adding soybean sterol, stirring at 70-75° C. for 10-15 hours, filtering out the solid, washing, and drying to obtain the anti-sticking agent; The polyethylene glycol-modified talc powder comprises the following raw materials, calculated by weight: 10-15 parts of talc powder and 3-5 parts of dialdehyde polyethylene glycol; the anti-adhesive agent comprises the following raw materials, calculated by weight: 10-15 parts of polyethylene glycol-modified talc powder and 1-2 parts of soybean sterol; The molecular weight of the dialdehyde polyethylene glycol is 2000-5000.

2. The processing technology of the agomelatine coating preparation according to claim 1, characterized in that: The agomelatine liposomes include the following raw materials, calculated by mass: 2-3 parts of agomelatine powder, 20-25 parts of distearoylphosphatidylethanolamine, 3-5 parts of soybean sterols, 50-80 parts of a mixed solvent, and 500-600 parts of a potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution.

3. The processing technology of the agomelatine coating preparation according to claim 1, characterized in that: The coating solution comprises the following raw materials, calculated by weight: 6 to 10 parts of polyacrylic acid resin, 6 to 10 parts of anhydrous ethanol, 2 to 3 parts of anti-sticking agent, 0.1 to 0.2 parts of microcrystalline cellulose, and 0.3 to 0.5 parts of a cross-linking agent.

4. The agomelatine coating preparation prepared according to the processing technology of the agomelatine coating preparation according to any one of claims 1 to 3.

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