Agomelatine coating preparation and processing technology thereof

Abstract

The 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, distearoyl phosphatidyl ethanolamine, soybean sterol and a mixed solvent, uniformly stirring, removing the solvent under reduced pressure, adding a monopotassium phosphate-dipotassium phosphate buffer solution, shaking, uniformly stirring, homogenizing and emulsifying, filtering, and freeze-drying to obtain agomelatine liposome; s2, uniformly mixing agomelatine powder, agomelatine lipidosome, povidone K30, carboxymethyl starch sodium, starch and lactose according to an equivalent incremental method, adding water, uniformly stirring, sieving, drying, adding silicon dioxide and magnesium stearate, and stamping to obtain agomelatine particles; and S3, coating the agomelatine particles with the coating solution, coating again with the taste-masking coating agent, and cooling to obtain the agomelatine coated preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and discloses an agomelatine coated preparation and its processing technology. Background Art

[0002] Depression is a common mental illness. With the accelerating pace of life, the incidence of depression is increasing continuously and it has now become the fourth largest disease in the world. Agomelatine, with the chemical name N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide, is a new type of antidepressant drug. It is a melatonin 1,2 (MT1, MT2) receptor agonist and also a 5-hydroxytryptamine 2c (5HT2C) receptor antagonist. It is the first melatonin-like antidepressant drug and can directly bind to the 5HT2C receptor on the postsynaptic membrane of the nerve synapse, thus having good curative effects and few side effects.

[0003] However, agomelatine is a water-insoluble compound and is not very satisfactory in terms of dissolution rate, etc., resulting in low bioavailability in the human body and large biological differences within the same individual and among different individuals. Although the agomelatine preparations prepared by the prior art have good dissolution effects after detection, there are problems such as a long time required for complete dissolution and unstable dissolution rate, and the problem of poor taste caused by the strong bitterness of agomelatine itself is not considered, reducing the adaptability of patients. In summary, it is of great significance to study an agomelatine coated preparation with high dissolution rate, reasonable dissolution time, stable dissolution rate and good taste and its processing technology. Summary of the Invention

[0004] The purpose of the present invention is to provide an agomelatine coated preparation and its processing technology to solve the problems raised in the above background art.

[0005] To solve the above technical problems, the present invention provides the following technical solution: A processing technology for an agomelatine coated preparation, including the following steps: S1: Take agomelatine powder, distearoyl phosphatidylethanolamine, stigmasterol, and a mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add a potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45 μm microporous membrane, and freeze-dry at -40°C to obtain agomelatine liposomes; S2: Mix agomelatine powder, agomelatine liposomes, polyvinylpyrrolidone K30, sodium carboxymethyl starch, starch, and lactose evenly according to the equal increment method, add water, stir evenly, sieve and dry, add silicon dioxide and magnesium stearate, and press with a 7 mm punch die to obtain agomelatine granules; S3: Heat the coating pan to 40-45°C, pump the coating liquid into the coating pan with a peristaltic pump, and spray the coating liquid into the coating pan in a mist form with compressed air to coat the agomelatine particles. Stop coating after the weight increases by 1.5-2.0%, cool the particles, and coat again with a taste-masking coating agent. Stop coating after the weight increases by 5-8%, cool the particles, and obtain an agomelatine coating preparation.

[0006] Preferably, the agomelatine liposome comprises the following raw materials, by weight: 2-3 parts of agomelatine powder, 20-25 parts of distearoylphosphatidylethanolamine, 3-5 parts of soybean sterols, 50-80 parts of mixed solvent, and 500-600 parts of potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution; 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 carboxymethyl starch, 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.

[0007] More optimally, the agomelatine powder is 100 mesh and the lactose is 80 mesh.

[0008] 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.

[0009] More optimally, the coating solution includes 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-adhesive agent, 0.1 to 0.2 parts of microcrystalline cellulose, and 0.3 to 0.5 parts of glutaraldehyde.

[0010] 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 10-15h, 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 sterols, stirring at 70-75°C for 10-15h, filtering the solid, washing, and drying to obtain the anti-sticking agent.

[0011] More optimally, the polyethylene glycol-modified talc comprises the following raw materials, calculated by mass: 10-15 parts of talc and 3-5 parts of dialdehyde polyethylene glycol; the anti-adhesive agent comprises the following raw materials, calculated by mass: 10-15 parts of polyethylene glycol-modified talc and 1-2 parts of soybean sterol.

[0012] Preferably, the molecular weight of the dialdehyde group polyethylene glycol is 2000-5000.

[0013] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: Agomelatine is a drug that requires rapid release, so its dissolution rate needs to be improved, but the release rate should not be too fast, otherwise it will cause discomfort to patients. The stability of the release rate also needs to be controlled to avoid adverse reactions caused by sudden release. At the same time, Agomelatine is bitter in taste and needs to be taste-masked. Based on the above requirements, the solution adopted in the present invention is as follows: Agomelatine liposomes and Agomelatine powder are mixed in a certain proportion and then coated. The Agomelatine liposomes improve the stability and bioavailability of Agomelatine. Although the final dissolution rate is high, the release rate is relatively slow, which does not meet the requirements of Agomelatine as a rapidly released drug. Therefore, Agomelatine powder is also added. Due to the addition of auxiliary materials such as lactose, starch, and microcrystalline cellulose and the appropriate particle size, the dissolution rate 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 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. Too much addition of Agomelatine liposomes will lead to a decrease in the release rate, and too much addition of Agomelatine powder will cause the release rate to be too fast, which is likely to cause discomfort to patients. The present invention also prepares a coating solution. The anti-sticking agent is modified talc powder, and polyethylene glycol is introduced to play a plasticizing role, improving the toughness and uniformity of the coating film, which is helpful for the stable release rate. The viscosity of 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 the coating film to be uneven, resulting in an uncontrollable release rate. Soybean sterol has good biocompatibility, can increase the stability of the coating film, reduce the oxidation of the drug, and improve the fluidity of the film. An appropriate amount of glutaraldehyde is also introduced as a cross-linking agent in the coating solution to increase the cross-linking degree of the coating film, reduce its deformation, and improve the uniformity and stability of the film. However, the addition amount of the cross-linking agent should not be too much, as too much will cause the drug release rate to slow down. When coating with this coating solution, stop coating after the weight gain reaches 1.5-2.0%, and then coat with the taste-masking coating agent Eudragit E100. Stop coating after the weight gain reaches 5-8%. Since the coating solution is used for coating in advance, the dosage of the taste-masking coating agent is greatly reduced, and finally an Agomelatine coated preparation with a high dissolution rate, a reasonable release rate, and no bitterness is obtained. Specific Embodiments

[0014] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0015] It should be noted that there are no special restrictions on the purchase manufacturers of all raw materials involved in the present invention. Exemplarily, they include: talcum powder (400-mesh pharmaceutical grade, Shaanxi Ruichengkang Medical Technology Co., Ltd.); dialdehyde polyethylene glycol (CHO-PEG-CHO, Chongqing Yusai Medical Technology Co., Ltd., molecular weight 3400, and other molecular weights can be customized); stigmasterol (stigmasterol A, purity HPLC≥98%, Yuanye B28198); polyacrylic acid resin (pharmaceutical excipient polyacrylic acid resin IV, Shaanxi Ruichengkang Medical Technology Co., Ltd.); microcrystalline cellulose (pharmaceutical grade); distearoyl phosphatidylethanolamine (pharmaceutical grade); polyvinylpyrrolidone K30 (BASF Povidone K30S); sodium carboxymethyl starch (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's Eudragit E100); Unless otherwise specified, the following are all in parts by mass or mass ratio; Example 1: S1: Add 12 parts of talcum powder to 100 parts of water, stir evenly, adjust the pH to 3 with hydrochloric acid, add 4 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stir at 75°C for 15 h, filter to obtain the solid, wash, and dry to obtain polyethylene glycol-modified talcum powder; take 15 parts of polyethylene glycol-modified talcum powder and add it to 100 parts of DMSO, stir evenly, adjust the pH to 3 with hydrochloric acid, add 1 part of stigmasterol, stir at 75°C for 15 h, filter to obtain the solid, wash, and dry to obtain an anti-adhesive agent; S2: Take 6 parts of polyacrylic acid resin and 8 parts of absolute ethanol, stir evenly, take 3 parts of anti-adhesive agent, 0.1 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, and mix evenly to obtain a coating solution; S3: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 4 parts of stigmasterol, and 70 parts of a mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of a potassium dihydrogen phosphate-potassium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45-μm microporous membrane, and freeze-dry at -40°C to obtain agomelatine liposomes; S4: Mix 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposome, 3 parts of polyvinylpyrrolidone K30, 6 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of 80-mesh lactose evenly by the equal increment method. Add 5 parts of water, stir evenly, then pass through a 18-mesh sieve, dry at 60 °C, add 5 parts of silicon dioxide and 1 part of magnesium stearate, and press with a 7-mm diameter punch die to obtain agomelatine granules; S5: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, spray the coating solution into the coating pan in a mist form with compressed air, coat the agomelatine granules, stop coating after a 2.0% weight gain, cool, and then coat again with the taste masking coating agent Eudragit E100. Stop coating after a 6% weight gain, cool to obtain the agomelatine coated preparation.

[0016] Example 2: S1: Add 10 parts of talcum powder to 100 parts of water, stir evenly, adjust the pH to 3 with hydrochloric acid, add 3 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stir at 75 °C for 15 h, filter to obtain the solid, wash, and dry to obtain polyethylene glycol modified talcum powder; Take 10 parts of polyethylene glycol modified talcum powder and add it to 100 parts of DMSO, stir evenly, adjust the pH to 3 with hydrochloric acid, add 1 part of stigmasterol, stir at 75 °C for 15 h, filter to obtain the solid, wash, and dry to obtain the anti-sticking agent; S2: Take 6 parts of polyacrylic resin and 8 parts of absolute ethanol, stir evenly, take 2 parts of anti-sticking agent, 0.2 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, mix evenly to obtain the coating solution; S3: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 3 parts of stigmasterol, and 70 parts of a mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of potassium dihydrogen phosphate-potassium hydrogen phosphate buffer solution with a pH of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45-μm microporous membrane, and freeze-dry at -40 °C to obtain agomelatine liposome; S4: Mix 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposome, 5 parts of polyvinylpyrrolidone K30, 5 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of 80-mesh lactose evenly by the equal increment method. Add 5 parts of water, stir evenly, then pass through a 18-mesh sieve, dry at 60 °C, add 5 parts of silicon dioxide and 2 parts of magnesium stearate, and press with a 7-mm diameter punch die to obtain agomelatine granules; S5: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, spray the coating solution into the coating pan in a mist form with compressed air, coat the agomelatine granules, stop coating after a 2.0% weight gain, cool, and then coat again with the taste masking coating agent Eudragit E100. Stop coating after a 6% weight gain, cool to obtain the agomelatine coated preparation.

[0017] Example 3: S1: Add 15 parts of talcum powder to 100 parts of water, stir evenly, adjust the pH to 3 with hydrochloric acid, add 5 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stir at 75 °C for 15 h, filter to obtain the solid, wash and dry to obtain polyethylene glycol modified talcum powder; Take 15 parts of polyethylene glycol modified talcum powder and add it to 100 parts of DMSO, stir evenly, adjust the pH to 3 with hydrochloric acid, add 2 parts of stigmasterol, stir at 75 °C for 15 h, filter to obtain the solid, wash and dry to obtain the anti-sticking agent; S2: Take 6 parts of polyacrylic resin and 10 parts of absolute ethanol, stir evenly, take 2 parts of anti-sticking agent, 0.2 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, mix evenly to obtain the coating solution; S3: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 5 parts of stigmasterol, and 70 parts of mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of potassium dihydrogen phosphate-potassium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45 μm microporous membrane, and freeze-dry at -40 °C to obtain agomelatine liposomes; S4: Mix 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 5 parts of polyvinylpyrrolidone K30, 10 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of 80-mesh lactose evenly by the equal increment method, add 5 parts of water, stir evenly and then pass through an 18-mesh sieve, dry at 60 °C, add 5 parts of silicon dioxide and 1 part of magnesium stearate, and press with a 7-mm diameter punch die to obtain agomelatine granules; S5: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, spray the coating solution into the coating pan in a mist with compressed air, coat the agomelatine granules, stop coating after a weight gain of 2.0%, cool, and coat again with the taste-masking coating agent Eudragit E100, stop coating after a weight gain of 6%, cool to obtain the agomelatine coated preparation.

[0018] Comparative Example 1 (changing the addition amounts of agomelatine liposomes and agomelatine granules, and the other method steps are the same as in Example 1): S1: Add 12 parts of talcum powder to 100 parts of water, stir evenly, adjust the pH to 3 with hydrochloric acid, add 4 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stir at 75 °C for 15 h, filter to obtain the solid, wash and dry to obtain polyethylene glycol modified talcum powder; Take 15 parts of polyethylene glycol modified talcum powder and add it to 100 parts of DMSO, stir evenly, adjust the pH to 3 with hydrochloric acid, add 1 part of stigmasterol, stir at 75 °C for 15 h, filter to obtain the solid, wash and dry to obtain the anti-sticking agent; S2: Take 6 parts of polyacrylic resin and 8 parts of absolute ethanol, stir evenly, take 3 parts of anti-sticking agent, 0.1 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, mix evenly to obtain the coating solution; S3: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 4 parts of stigmasterol, and 70 parts of a mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45 μm microporous membrane, and freeze-dry at -40 °C to obtain agomelatine liposomes; S4: Mix 4 parts of 100-mesh agomelatine powder, 22 parts of agomelatine liposomes, agomelatine powder, 3 parts of polyvinylpyrrolidone K30, 6 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of 80-mesh lactose evenly according to the equal increment method, add 5 parts of water, stir evenly, pass through an 18-mesh sieve, dry at 60 °C, add 5 parts of silica and 1 part of magnesium stearate, and press with a 7-mm diameter punch die to obtain agomelatine granules; S5: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, spray the coating solution into the coating pan in a mist with compressed air, coat the agomelatine granules, stop coating after a 2.0% weight gain, cool, and coat again with the taste-masking coating agent Eudragit E100, stop coating after a 6% weight gain, and cool to obtain the agomelatine coated preparation.

[0019] Comparative Example 2 (changing the addition amounts of agomelatine liposomes and agomelatine granules, and the other method steps are the same as in Example 1): S1: Add 12 parts of talcum powder to 100 parts of water, stir evenly, adjust the pH to 3 with hydrochloric acid, add 4 parts of dialdehyde polyethylene glycol with a molecular weight of 3400, stir at 75 °C for 15 h, filter to obtain the solid, wash, and dry to obtain polyethylene glycol-modified talcum powder; Take 15 parts of polyethylene glycol-modified talcum powder and add it to 100 parts of DMSO, stir evenly, adjust the pH to 3 with hydrochloric acid, add 1 part of stigmasterol, stir at 75 °C for 15 h, filter to obtain the solid, wash, and dry to obtain the anti-adhesive agent; S2: Take 6 parts of polyacrylic resin and 8 parts of absolute ethanol, stir evenly, take 3 parts of anti-adhesive agent, 0.1 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, and mix evenly to obtain the coating solution; S3: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 4 parts of stigmasterol, and 70 parts of a mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45 μm microporous membrane, and freeze-dry at -40 °C to obtain agomelatine liposomes; S4: Mix 13 parts of agomelatine powder of 100 mesh, 13 parts of agomelatine liposome, 3 parts of polyvinylpyrrolidone K30, 6 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of lactose of 80 mesh evenly by the equal increment method. Add 5 parts of water, stir evenly, then pass through a 18-mesh sieve, dry at 60 °C, add 5 parts of silicon dioxide and 1 part of magnesium stearate, and press with a punch die of 7 mm in diameter to obtain agomelatine granules; S5: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, and spray the coating solution into the coating pan in a mist form with compressed air to coat the agomelatine granules. Stop coating after a 2.0% weight gain, cool, and then coat again with the taste masking coating agent Eudragit E100. Stop coating after a 6% weight gain, cool, to obtain the agomelatine coated preparation.

[0020] Comparative Example 3 (changing the preparation method of the coating solution, and the other method steps are the same as those in Example 1): S1: Take 6 parts of polyacrylic resin and 8 parts of absolute ethanol, stir evenly, take 3 parts of talc powder, 0.1 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, and mix evenly to obtain the coating solution; S2: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 4 parts of stigmasterol, and 70 parts of mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of potassium dihydrogen phosphate-potassium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45 μm microporous membrane, and freeze-dry at -40 °C to obtain agomelatine liposome; S3: Mix 8 parts of agomelatine powder of 100 mesh, 18 parts of agomelatine liposome, 3 parts of polyvinylpyrrolidone K30, 6 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of lactose of 80 mesh evenly by the equal increment method. Add 5 parts of water, stir evenly, then pass through a 18-mesh sieve, dry at 60 °C, add 5 parts of silicon dioxide and 1 part of magnesium stearate, and press with a punch die of 7 mm in diameter to obtain agomelatine granules; S4: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, and spray the coating solution into the coating pan in a mist form with compressed air to coat the agomelatine granules. Stop coating after a 2.0% weight gain, cool, and then coat again with the taste masking coating agent Eudragit E100. Stop coating after a 6% weight gain, cool, to obtain the agomelatine coated preparation.

[0021] Comparative Example 4 (changing the molecular weight of dialdehyde polyethylene glycol, and the remaining method steps are the same as those in Example 1): S1: Add 12 parts of talcum powder to 100 parts of water, stir evenly, adjust the pH to 3 with hydrochloric acid, add 4 parts of dialdehyde polyethylene glycol with a molecular weight of 10,000, stir at 75 °C for 15 h, filter to obtain the solid, wash, and dry to obtain polyethylene glycol-modified talcum powder; Take 15 parts of polyethylene glycol-modified talcum powder and add it to 100 parts of DMSO, stir evenly, adjust the pH to 3 with hydrochloric acid, add 1 part of stigmasterol, stir at 75 °C for 15 h, filter to obtain the solid, wash, and dry to obtain the anti-sticking agent; S2: Take 6 parts of polyacrylic resin and 8 parts of absolute ethanol, stir evenly, take 3 parts of anti-sticking agent, 0.1 part of microcrystalline cellulose, and 0.3 part of glutaraldehyde, mix evenly to obtain the coating solution; S3: Take 3 parts of agomelatine powder, 20 parts of distearoyl phosphatidylethanolamine, 4 parts of stigmasterol, and 70 parts of mixed solvent (tert-butanol and methanol with a volume ratio of 1:1), stir evenly, remove the solvent under reduced pressure, add 600 parts of potassium dihydrogen phosphate-potassium hydrogen phosphate buffer solution with a pH value of 5.8, shake, stir evenly, homogenize and emulsify, filter through a 0.45 μm microporous membrane, and freeze-dry at -40 °C to obtain agomelatine liposomes; S4: Mix 8 parts of 100-mesh agomelatine powder, 18 parts of agomelatine liposomes, 3 parts of polyvinylpyrrolidone K30, 6 parts of sodium carboxymethyl starch, 20 parts of starch, and 60 parts of 80-mesh lactose evenly by the equal increment method, add 5 parts of water, stir evenly, pass through an 18-mesh sieve, dry at 60 °C, add 5 parts of silicon dioxide and 1 part of magnesium stearate, and press with a 7-mm diameter punching die to obtain agomelatine granules; S5: Heat the coating pan to 45 °C, pump the coating solution into it with a peristaltic pump, spray the coating solution into the coating pan in a mist form with compressed air, coat the agomelatine granules, stop coating after a weight gain of 2.0%, cool, and coat again with the taste-masking coating agent Eudragit E100, stop coating after a weight gain of 6%, cool to obtain the agomelatine coated preparation.

[0022] Performance test: Take the agomelatine coated preparations prepared in Examples 1 to 3 and Comparative Examples 1 to 4; (1) Determine the dissolution degrees at 5, 15, 30, and 45 min respectively with reference to the second method in Appendix XC of the second part of the Chinese Pharmacopoeia 2005 edition; (2) Test the taste; see Table 1 for details; Table 1:

[0023] Conclusion: In Comparative Example 1, increasing the addition amount of agomelatine liposome resulted in a slower release rate, which did not meet the requirement of agomelatine as a drug requiring rapid release; in Comparative Example 2, reducing the addition amount of agomelatine liposome led to an overly fast release rate, which was likely to cause discomfort; in Comparative Example 3, changing the preparation method of the coating solution, that is, directly using talc powder without modification as an anti-sticking agent, there was a problem of uneven coating film, unstable release rate and bitterness; in Comparative Example 4, increasing the molecular weight of dialdehyde polyethylene glycol led to a decrease in the uniformity of the coating film due to the increased viscosity, and there was also a problem of unstable release rate and bitterness. In summary, the agomelatine coating preparation prepared by the present invention has a reasonable release rate, no bitterness, and will not cause discomfort when taken.

[0024] Finally, it should be noted that the above are only the 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 foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A processing technology of agomelatine coating preparation, characterized in that: The following steps are involved: S1: taking agomelatine powder, distearoylphosphatidylethanolamine, soybean sterol and a mixed solvent, stirring them evenly, removing the solvent under reduced pressure, adding potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer solution, shaking, stirring evenly, homogenizing and emulsifying, filtering through a 0.45 μm microporous membrane, and freeze-drying to obtain agomelatine liposomes; S2: Agomelatine powder, agomelatine liposomes, povidone K30, sodium starch glycolate, starch and lactose are mixed uniformly according to the equal amount increasing method, water is added, the mixture is sieved and dried after being stirred uniformly, silicon dioxide and magnesium stearate are added, and the mixture is pressed by punching and die to obtain agomelatine granules; S3: coating the agomelatine particles with the coating liquid, stopping the coating after the weight increases by 1.5-2.0%, cooling, coating again with the taste-masking coating agent, stopping the coating after the weight increases by 5-8%, cooling, and obtaining the agomelatine coating preparation.

2. The processing technology of the agomelatine coating preparation according to claim 1, characterized in that: The agomelatine liposome comprises the following raw materials, calculated by weight: 2-3 parts of agomelatine powder, 20-25 parts of distearoylphosphatidylethanolamine, 3-5 parts of soybean sterol, 50-80 parts of mixed solvent, and 500-600 parts of 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 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 carboxymethyl starch, 20-25 parts of starch, 60-65 parts of lactose, 5-8 parts of silicon dioxide, and 1-2 parts of magnesium stearate.

4. The processing technology of the agomelatine coating preparation according to claim 1, characterized in that: 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.

5. The processing technology of the agomelatine coating preparation according to claim 4, 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-adhesive agent, 0.1 to 0.2 parts of microcrystalline cellulose, and 0.3 to 0.5 parts of cross-linking agent.

6. The processing technology of the agomelatine coating preparation according to claim 4, characterized in that: The preparation of the anti-sticking agent comprises the following steps: adding talc powder into water, stirring evenly, adjusting the pH value to 3-4, adding dialdehyde polyethylene glycol, stirring at 70-75° C. for 10-15 hours, filtering out solids, washing, and drying to obtain polyethylene glycol-modified talc powder; adding polyethylene glycol-modified talc powder into DMSO, stirring evenly, adjusting the pH value to 3-4, adding soybean sterol, stirring at 70-75° C. for 10-15 hours, filtering out solids, washing, and drying to obtain the anti-sticking agent.

7. The processing technology of the agomelatine coating preparation according to claim 6, characterized in that: The polyethylene glycol-modified talc comprises the following raw materials, calculated by weight: 10-15 parts of talc 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 and 1-2 parts of soybean sterol.

8. The processing technology of the agomelatine coating preparation according to claim 6, characterized in that: The molecular weight of the dialdehyde polyethylene glycol is 2000-5000.

9. The agomelatine coating preparation prepared according to the processing technology of the agomelatine coating preparation according to any one of claims 1 to 8.

Images