A preparation method of esomeprazole magnesium enteric-coated capsules

Abstract

The invention discloses a preparation method of esomeprazole magnesium enteric-coated capsules, belonging to the technical field of medical preparations. The preparation method comprises the following steps: preparing drug layer base pills, preparing disintegration layer base pills, preparing isolation layer base pills, preparing enteric-coated layer base pills, and filling capsules; the preparation of disintegration layer base pills comprises the following steps: preparing disintegration layer coating powder, coating the disintegration layer, and screening the disintegration layer; in the preparation of disintegration layer coating powder, cetyl alcohol ester wax is crushed to obtain cetyl alcohol ester wax powder, and the cetyl alcohol ester wax powder is uniformly mixed with cross-linked sodium carboxymethyl cellulose to obtain disintegration layer coating powder; the invention can greatly shorten the coating time, effectively reduce the loss of raw and auxiliary materials in the coating process, improve production efficiency and product yield, and improve the bioavailability of drugs.

Description

Technical Field

[0001] The invention relates to the technical field of medical preparations, and in particular to a method for preparing esomeprazole magnesium enteric-coated capsules. Background Art

[0002] Proton pump inhibitors (PPIs) are a class of inactive prodrugs that can specifically act on gastric mucosal cells and reduce H + / K + -ATPase activity, thereby inhibiting acid production caused by various factors. It has a very obvious inhibitory effect on basal, nocturnal gastric acid and gastric acid secretion stimulated by pentagastrin, and is the most powerful type of gastric acid secretion inhibitor discovered so far.

[0003] Esomeprazole magnesium is a proton pump inhibitor antiulcer drug that can be used to treat duodenal ulcers, gastric ulcers and esophagitis, as well as refractory ulcers. It is also effective in treating Zollinger-Ellison syndrome.

[0004] The preparation method of esomeprazole magnesium enteric-coated capsules is mainly a fluidized bed bottom spray coating process. The prepared esomeprazole magnesium enteric-coated capsules are divided into three layers: drug layer, isolation layer, and enteric layer. The original research drug of esomeprazole magnesium enteric-coated capsules adopts a fluidized bed coating process, using the initial sucrose pellet core as a carrier, and the drug layer, isolation layer, and enteric layer are coated to obtain esomeprazole magnesium enteric-coated micropellets, which are then filled into capsules to obtain esomeprazole magnesium enteric-coated capsules of different specifications.

[0005] Chinese patent CN112472712A discloses a pharmaceutical composition, which directly uses esomeprazole magnesium API mixed with alkaline sodium bicarbonate for capsule filling, and uses alkaline sodium bicarbonate to neutralize gastric acid, so that the API begins to be released in the stomach, eliminating the tedious coating step.

[0006] Chinese patent CN105147621A discloses an esomeprazole magnesium enteric-coated microcapsule, capsule and preparation method thereof. The isolation layer uses behenic acid glyceryl as a film-forming material and is directly sprayed to form a film using a hot melt process, which can effectively isolate esomeprazole magnesium from water without affecting the release of the drug, thereby greatly improving the stability of the drug.

[0007] Chinese patent CN105106168A discloses an esomeprazole magnesium enteric capsule and a preparation method thereof, which adopts a conventional fluidized bed coating process, but adds an alkalizing agent and an antioxidant to the drug layer and the isolation layer formulation, and adds an isolation II protective layer, so that the stability of the API is significantly improved.

[0008] Chinese patent CN104940170A discloses an esomeprazole magnesium enteric-coated capsule and a preparation method thereof, which adopts a conventional fluidized bed coating process, wherein the microcapsules are divided into two parts: sustained-release microcapsules and quick-release microcapsules. The two types of microcapsules are filled into capsules according to a certain ratio to obtain esomeprazole magnesium enteric-coated capsules, which can reduce the number of medications for patients, reduce the irritation of the drug to the gastrointestinal tract, and provide a stable blood drug concentration without peak and valley phenomena.

[0009] Chinese patent CN116807990A discloses esomeprazole magnesium enteric-coated capsules and a preparation method thereof, which adopt a conventional fluidized bed coating process, wherein protective agents L-histidine, L-lysine and / or peptides containing basic amino acids are added to the drug layer coating liquid to prevent the API from deterioration and make it more stable.

[0010] However, the above patents mostly use fluidized bed bottom spray coating technology, which is divided into a drug layer, an isolation layer or a multi-layer isolation layer, and an enteric layer. Since each coating layer uses a large amount of solid content and requires a large amount of purified water to dissolve and disperse, it takes a relatively long time to consume the coating solution. As the coating time increases, material loss will also increase, and the production efficiency and product yield are low. In addition, the thickness of each coating layer varies with different technologies. Since esomeprazole magnesium is mainly absorbed in the small intestine, the adult small intestine is about 5-7 meters long and is divided into three parts from top to bottom: the duodenum, jejunum, and ileum, and the duodenum is the main absorption site. Ordinary enteric-coated microcapsules may cause the drug to pass through the duodenum quickly without being fully released due to individual absorption speed and intestinal peristalsis differences, affecting the drug utilization rate and thus making the drug efficacy unclear. Combined with the individual absorption speed and intestinal peristalsis differences of the medication, it is very likely that the drug will be quickly discharged from the small intestine without being fully released, affecting the drug efficacy. Summary of the invention

[0011] In view of the deficiencies in the prior art, the present invention provides a method for preparing esomeprazole magnesium enteric-coated capsules, which can significantly shorten the coating time, effectively reduce the loss of raw and auxiliary materials during the coating process, improve production efficiency and product yield, and improve the bioavailability of the drug.

[0012] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0013] A method for preparing esomeprazole magnesium enteric-coated capsules, comprising the following steps: preparing drug layer base pellets, preparing disintegration layer base pellets, preparing isolation layer base pellets, preparing enteric-coated layer base pellets, and filling capsules;

[0014] The preparation of the drug layer base pellets comprises the following steps: preparing a drug layer plasticizer, preparing a drug layer coating powder, coating the drug layer, and screening the drug layer;

[0015] The drug layer plasticizer is prepared by uniformly mixing purified water, polyethylene glycol 400 and glyceryl monostearate to obtain a drug layer plasticizer solution;

[0016] In the plasticizer for preparing the drug layer, the mass ratio of purified water to polyethylene glycol 400 is 9.5-10:0.9;

[0017] The mass fraction of polyethylene glycol 400 in all solid raw materials in the contents of esomeprazole magnesium enteric-coated capsules is 0.3-0.35%;

[0018] The mass fraction of glyceryl monostearate in all solid raw materials in the contents of esomeprazole magnesium enteric-coated capsules is 0.5-0.6%;

[0019] The drug layer coating powder is prepared by uniformly mixing esomeprazole magnesium, ethyl cellulose and talcum powder to obtain the drug layer coating powder;

[0020] In the prepared drug layer coating powder, the mass fraction of the esomeprazole magnesium in the content of the esomeprazole magnesium enteric-coated capsule is 17-17.5%;

[0021] The mass fraction of the ethyl cellulose in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 2.5-2.7%;

[0022] The mass fraction of the talc powder in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 3-3.5%;

[0023] The drug layer coating is performed by setting the fluidized bed inlet temperature to 120-125°C, preheating the fluidized bed to an outlet temperature of 100-105°C, placing the sucrose pellet core into the fluidized bed material chamber, placing the drug coating powder into the feeder, raising the fluidized bed inlet temperature to 140-145°C, and setting the air volume to 1500-1600m 3 / h for coating, spray the drug layer plasticizer solution onto the surface of the pellets through a side spray device, and at the same time, sprinkle the drug layer coating powder onto the surface of the pellets with a feeder, keep the material temperature unchanged during the coating process, and finally dry to obtain drug layer pellets;

[0024] During the drug layer coating, the air volume of the preheated fluidized bed is 1000-1100m 3 / h;

[0025] The spray gun atomization pressure in the coating is 3.0-3.5 bar, the peristaltic pump speed is 40-50 rpm, and the feeder stirring speed is 15-20 rpm;

[0026] The particle size of the sucrose pellet core is 50-60 mesh;

[0027] The mass fraction of the sucrose pellet core in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 7.5-8%;

[0028] The drug layer is screened to collect drug layer pellets with mesh sizes between 35 and 60 to obtain drug layer base pellets;

[0029] The preparation of the disintegrating layer base pellets comprises the following steps: preparing disintegrating layer coating powder, coating the disintegrating layer, and screening the disintegrating layer;

[0030] The disintegrating layer coating powder is prepared by crushing the cetyl alcohol ester wax to obtain the cetyl alcohol ester wax powder, and uniformly mixing the cetyl alcohol ester wax powder with cross-linked sodium carboxymethyl cellulose to obtain the disintegrating layer coating powder;

[0031] In the disintegrating layer coating powder, the mass fraction of the cetyl alcohol ester wax in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 1.5-1.6%;

[0032] The mass fraction of the cross-linked carboxymethyl cellulose sodium in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 7.5-8%;

[0033] The disintegration layer coating is performed by setting the fluidized bed air inlet temperature to 60-65°C to preheat the fluidized bed to an air outlet temperature of 40-45°C, placing the drug layer base pills into the fluidized bed material chamber, placing the disintegration layer coating powder into the feeder, raising the fluidized bed air inlet temperature to 70-75°C, and setting the air inlet volume to 1500-1600m 3 / h for coating. While the pellets are fluidized, the coating powder is sprinkled on the surface of the pellets by the feeder. The material temperature is kept constant during the coating process. Finally, the pellets are dried to obtain disintegration layer pellets.

[0034] In the disintegrating layer coating, the preheated air volume is 1000-1100m 3 / h;

[0035] The stirring speed of the feeder in the coating is 15-20 rpm;

[0036] The disintegrating layer is sieved to collect disintegrating layer pellets with mesh sizes of 35-58 to obtain disintegrating layer base pellets;

[0037] The preparation of the isolation layer base pellets comprises the following steps: preparing an isolation layer plasticizer, preparing an isolation layer coating powder, coating the isolation layer, and screening the isolation layer;

[0038] The isolation layer plasticizer is prepared by uniformly mixing purified water, polyethylene glycol 400, and glyceryl monostearate to obtain an isolation layer plasticizer solution;

[0039] In the preparation of the isolation layer plasticizer, the mass ratio of purified water to polyethylene glycol 400 is 9.5-10:0.9;

[0040] The mass fraction of the polyethylene glycol 400 in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 0.45-0.5%;

[0041] The mass fraction of the glyceryl monostearate in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 0.75-0.8%;

[0042] The isolation layer coating powder is prepared by uniformly mixing hydroxypropyl cellulose and talcum powder to obtain the isolation layer coating powder;

[0043] In the prepared isolation layer coating powder, the mass fraction of hydroxypropyl cellulose in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 3.4-3.6%;

[0044] The mass fraction of the talc powder in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 12.5-13%;

[0045] The isolation layer coating is performed by starting the fluidized bed, setting the air inlet temperature to 120-125°C to preheat the fluidized bed, preheating the air outlet temperature to 100-105°C, placing the disintegration layer base pellets into the fluidized bed material chamber, placing the isolation layer coating powder into the feeder, raising the air inlet temperature to 150-155°C, and setting the air inlet volume to 2000-2100m 3 / h for coating, spray the isolation layer plasticizer solution onto the surface of the pellets through a side spray device, and at the same time, sprinkle the isolation layer coating powder onto the surface of the pellets with a feeder, keep the material temperature unchanged during the coating process, and finally dry to obtain isolation layer pellets;

[0046] In the isolation layer coating, the air volume during preheating is 1500-1600m 3 / h;

[0047] The spray gun atomization pressure in the coating is 3.0-3.5 bar, the peristaltic pump speed is 40-50 rpm, and the feeder stirring speed is 15-20 rpm;

[0048] The isolation layer is screened to collect isolation layer pellets with a mesh size of 35-50 to obtain isolation layer base pellets;

[0049] The preparation of the enteric layer base pills comprises the following steps: preparing an enteric layer coating solution, coating the enteric layer, and screening the enteric layer;

[0050] The enteric coating liquid is prepared by mixing the first portion of purified water, glyceryl monostearate, and triethyl citrate to obtain liquid A; stirring the second portion of purified water, adding Eudragit L30D-55 and talcum powder to mix to obtain liquid B; and mixing liquid A and liquid B to obtain an enteric coating liquid;

[0051] In the preparation of the enteric layer coating solution, the mass ratio of the first portion of purified water to the second portion of purified water is 1:2;

[0052] The mass ratio of the total mass of the first portion of purified water and the second portion of purified water to glyceryl monostearate is 120-125:1.4;

[0053] The mass fraction of the glyceryl monostearate in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 0.5-0.6%;

[0054] The mass fraction of triethyl citrate in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 1-1.2%;

[0055] The mass fraction of the Eudragit L30D-55 in all solid raw materials in the contents of the esomeprazole magnesium enteric-coated capsules is 35-37%;

[0056] The mass fraction of the talc powder in all solid raw materials in the esomeprazole magnesium enteric-coated capsules is 4.4-4.6%;

[0057] The enteric layer coating is performed by starting the fluidized bed, setting the air inlet temperature to 50-55°C for preheating, preheating to an air outlet temperature of 40-45°C, placing the isolation layer base pellets into the fluidized bed material chamber, setting the air inlet temperature to 40-45°C for coating, spraying the enteric layer coating liquid, and then drying to obtain enteric layer micropellets;

[0058] In the enteric layer coating, the air inlet volume of the preheated fluidized bed is 1500-1600m 3 / h;

[0059] The air volume in the coating is 2000-2100m 3 / h, spray gun atomization pressure 3.5-4.0bar, peristaltic pump speed 50-55rpm;

[0060] The enteric layer is screened to collect enteric layer pellets with mesh sizes between 30 and 50 to obtain enteric layer base pellets;

[0061] The capsule filling comprises filling the enteric-coated base pellets into capsules to obtain the esomeprazole magnesium enteric-coated capsules.

[0062] Compared with the prior art, the present invention has the following beneficial effects:

[0063] (1) The preparation method of the esomeprazole magnesium enteric-coated capsules of the present invention adopts a dry coating process, directly spreads the polymer excipients on the micropills, raises the material temperature to its glassy state to directly form a film, and adopts a side spray process to improve the air inlet angle and liquid spray angle of the fluidized bed, thereby avoiding the solid powder from being drawn out of the filter bag during the coating process, reducing material loss and improving product yield. A disintegration layer is added between the drug layer and the isolation layer, so that the drug disintegrates and is absorbed more rapidly after entering the small intestine, thereby improving bioavailability; a large amount of water or other solvents are not required to prepare the coating solution, and only a small amount of water needs to be added to simply mix the raw and excipients used and spread them on the micropills to directly form a film, which greatly saves production time and improves production efficiency; fewer types of excipients are used, which effectively reduces the generation of drug impurities and improves the stability and safety of the drug; the drug is released and absorbed more rapidly, has a higher bioavailability, and is applicable to a wider population;

[0064] (2) The preparation method of the esomeprazole magnesium enteric-coated capsules of the present invention can shorten the coating time. The coating time of the drug layer is 5.4-5.6 hours, the coating time of the disintegrating layer is 1.7-1.8 hours, the coating time of the isolation layer is 7.7-7.8 hours, and the coating time of the enteric layer is 4.7-4.8 hours.

[0065] (3) The preparation method of the esomeprazole magnesium enteric-coated capsules of the present invention can improve the yield in the preparation of the esomeprazole magnesium enteric-coated capsules, increase the yield of the drug layer to 98.9-99.3%, increase the yield of the disintegration layer to 97.1-97.9%, increase the yield of the isolation layer to 99.3-99.5%, and increase the yield of the enteric layer to 98.7-99.0%;

[0066] (4) The preparation method of the esomeprazole magnesium enteric-coated capsules of the present invention can improve the solubility of the esomeprazole magnesium enteric-coated capsules. The solubility of the prepared esomeprazole magnesium enteric-coated capsules is 67-69% at 10 min, 89-90% at 20 min, 89-93% at 30 min, 95-96% at 40 min, 94-98% at 50 min, and 91-97% at 60 min.

[0067] (5) The preparation method of the esomeprazole magnesium enteric-coated capsules of the present invention can improve the stability of the esomeprazole magnesium enteric-coated capsules. The esomeprazole magnesium enteric-coated capsules prepared by the present invention are subjected to an accelerated test under an environment of 40°C±2°C and 75%RH±5%RH. After 6 months of acceleration, the esomeprazole magnesium content is 99.6-102.7%, the solubility is 93-95%, the acid resistance is 3.7-5.6%, the single impurity content is 0.05-0.06%, and the total impurity content is 0.4-0.6%. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 This is a schematic diagram of the dosage form of the esomeprazole magnesium enteric-coated capsules of Example 1;

[0069] Figure 2 The dissolution curves of Examples 1-2, Comparative Example 1 and the reference preparation Nexium in a pH 6.8 dissolution medium. DETAILED DESCRIPTION

[0070] In order to have a clearer understanding of the technical features, purposes and effects of the present invention, the specific implementation methods of the present invention are now described.

[0071] Example 1

[0072] An enteric-coated capsule of esomeprazole magnesium, the dosage form diagram is shown in Figure 1 As shown;

[0073] An esomeprazole magnesium enteric-coated capsule, the raw materials and dosages used are as follows:

[0074]

[0075] The particle size of the sucrose pellet core is 60 meshes.

[0076] According to the raw materials and dosages in the above table, a method for preparing esomeprazole magnesium enteric-coated capsules is specifically as follows:

[0077] 1. Preparation of drug-layered pellets

[0078] (1) Preparation of plasticizer

[0079] Weigh the prescribed amount of purified water and stir it with a stirrer, add the prescribed amount of polyethylene glycol 400 and glyceryl monostearate, continue stirring until dissolved, and set aside to obtain a plasticizer solution.

[0080] (2) Preparation of drug layer coating powder

[0081] Weigh the prescribed amount of esomeprazole magnesium, ethyl cellulose and talc into a hopper mixer, set the mixing speed to 10 rpm, and mix for 5 minutes to obtain a drug layer coating powder.

[0082] (3) Drug coating

[0083] Set the fluidized bed inlet air temperature to 120°C and the air volume to 1000m 3 / h, preheat the fluidized bed to an outlet air temperature of 100°C, put the blank pill cores of the prescribed amount into the fluidized bed material chamber, put the drug coating powder into the feeder, increase the fluidized bed inlet air temperature to 140°C, and set the air inlet volume to 1500m 3 / h, spray gun atomization pressure 3.0bar, peristaltic pump speed 40rpm, feeder stirring speed 15rpm, the plasticizer solution is atomized and sprayed onto the surface of the micropellets through the side spray device, and the feeder sprinkles the drug layer coating powder onto the surface of the micropellets. During the coating process, the material temperature is maintained at 133°C to allow the coating film to fuse better, and finally dried to obtain drug layer micropellets.

[0084] (4) Screening

[0085] The drug-layered pellets are placed into a sieving machine, and the drug-layered pellets with mesh sizes between 35 and 60 are collected to obtain drug-layered base pellets.

[0086] 2. Preparation of disintegrating layer base pellets

[0087] (1) Preparation of disintegrating layer coating powder

[0088] The prescribed amount of cetyl alcohol ester wax was weighed and pulverized with a mechanical pulverizer. The pulverization was performed for 5 seconds and then stopped for 1 minute as one pulverization cycle. After two cycles, cetyl alcohol ester wax powder was obtained. The cetyl alcohol ester wax powder and the prescribed amount of cross-linked sodium carboxymethyl cellulose were added to a hopper mixer. The mixing speed was set to 7 rpm and mixed for 5 minutes to obtain a disintegrating layer coating powder.

[0089] (2) Disintegration layer coating

[0090] First, set the fluidized bed air inlet temperature to 60°C and air volume to 1000m 3 / h to preheat the fluidized bed to an outlet air temperature of 40°C, put the drug layer base pills into the fluidized bed material chamber, put the disintegration layer coating powder into the feeder, increase the fluidized bed inlet air temperature to 70°C, and set the air inlet volume to 1500m 3 / h, the stirring speed of the feeder is 15rpm. While the pellets are fluidized, the coating powder is sprinkled on the surface of the pellets by the feeder. The material temperature is maintained at 45°C during the coating process to allow the coating film to fuse better. Finally, the pellets are dried to obtain disintegration layer pellets.

[0091] (3) Screening

[0092] The disintegrating layer pellets are put into a sieving machine, and the disintegrating layer pellets between 35-58 meshes are collected to obtain the disintegrating layer base pellets.

[0093] 3. Preparation of isolation layer base pellets

[0094] (1) Preparation of plasticizer

[0095] Weigh the prescribed amount of purified water and stir it, add the prescribed amount of polyethylene glycol 400 and glyceryl monostearate, continue stirring until dissolved, and obtain a plasticizer solution.

[0096] (2) Preparation of isolation layer coating powder

[0097] Weigh the prescribed amount of hydroxypropyl cellulose and talc into a hopper mixer, set the mixing speed to 10 rpm, and mix for 5 minutes to obtain an isolation layer coating powder.

[0098] (3) Isolation layer coating

[0099] Turn on the fluidized bed and set the air inlet temperature to 120°C and the air volume to 1500m 3 / h to preheat the fluidized bed to an outlet air temperature of 100°C, put the disintegration layer base pellets into the fluidized bed material chamber, put the isolation layer coating powder into the feeder, increase the inlet air temperature to 150°C, and set the inlet air volume to 2000m 3 / h, spray gun atomization pressure 3.0bar, peristaltic pump speed 40rpm, feeder stirring speed 15rpm, the plasticizer solution is atomized and sprayed onto the surface of the micropellets through the side spray device, and the feeder sprinkles the isolation layer coating powder onto the surface of the micropellets. The material temperature is maintained at 135°C during the coating process to allow the coating film to fuse better, and finally dried to obtain isolation layer micropellets.

[0100] (4) Screening

[0101] The isolation layer pellets are put into a sieving machine, and pellets between 35 and 50 meshes are collected to obtain isolation layer base pellets.

[0102] 4. Preparation of Enteric Layer Base Pellets

[0103] (1) Preparation of enteric coating solution

[0104] Weigh one-third of the prescribed amount of purified water and stir, add the prescribed amount of glyceryl monostearate and triethyl citrate and stir until dissolved or dispersed evenly to obtain liquid A, weigh two-thirds of the prescribed amount of purified water and stir, add the prescribed amount of Eudragit L30D-55 and talcum powder and stir and disperse evenly to obtain liquid B, add liquid A to liquid B and stir to mix evenly to obtain an enteric layer coating solution.

[0105] (2) Enteric coating

[0106] Turn on the fluidized bed and set the air inlet temperature to 50°C and the air inlet volume to 1500m 3 / h for preheating, preheat to the outlet air temperature of 40℃, put the isolation layer base pellets into the fluidized bed material chamber, set the inlet air temperature to 40℃ and the inlet air volume to 2000m 3 / h, spray gun atomization pressure of 3.5 bar, peristaltic pump speed of 50 rpm, use enteric layer coating liquid for spraying, and dry after the enteric layer coating liquid is sprayed to obtain enteric layer micropellets.

[0107] (3) Screening

[0108] The enteric-coated pellets were placed in a sieving machine, and pellets with mesh sizes between 30 and 50 were collected to obtain enteric-coated base pellets.

[0109] 5. Filling capsules

[0110] According to the content of the micropellets, the center filling amount was calculated, and the filling speed was set to 40,000 capsules / hour. The enteric-coated base pellets were filled into capsules to obtain esomeprazole magnesium enteric-coated capsules.

[0111] Example 2

[0112] An esomeprazole magnesium enteric-coated capsule, the raw materials and dosages used are as follows:

[0113]

[0114] The particle size of the sucrose pellet core is 60 meshes.

[0115] This example adopts the same preparation method of esomeprazole magnesium enteric-coated capsules as that of Example 1.

[0116] Comparative Example 1

[0117] An esomeprazole magnesium enteric-coated capsule, the raw materials and dosages used are as follows:

[0118]

[0119] The particle size of the sucrose pellet core is 60 meshes.

[0120] According to the raw materials and dosages in the above table, a method for preparing esomeprazole magnesium enteric-coated capsules is specifically as follows:

[0121] 1. Preparation of drug-layered pellets

[0122] (1) Preparation of drug layer coating solution

[0123] Weigh the prescribed amount of purified water and stir it, add the prescribed amount of polyethylene glycol 400 and glyceryl monostearate and stir to dissolve, then add hypromellose and stir to dissolve, finally add esomeprazole magnesium and talc, stir and disperse evenly to obtain a drug layer coating solution.

[0124] (2) Drug coating

[0125] Turn on the fluidized bed and set the air inlet temperature to 50°C and the air inlet volume to 1000m 3 / h to preheat the fluidized bed to an outlet air temperature of 35°C, put the prescribed amount of sucrose pellets into the fluidized bed material chamber, connect the infusion tube to the fluidized bed, set the fluidized bed inlet air temperature to 60°C, and set the air inlet volume to 1500m 3 / h, spray gun atomization pressure 3.0bar, peristaltic pump speed 50rpm, use the drug layer coating liquid to start spraying, maintain the material temperature at 40℃ during the spraying process, dry after coating to obtain drug layer micropellets.

[0126] (3) Screening

[0127] The drug-layered pellets are placed in a sieving machine, and pellets between 35 and 60 meshes are collected to obtain drug-layered base pellets.

[0128] 2. Preparation of isolation layer base pellets

[0129] (1) Preparation of isolation layer coating solution

[0130] Weigh the prescribed amount of purified water and stir it, add the prescribed amount of polyethylene glycol 400 and glyceryl monostearate and stir to dissolve, then add hydroxypropyl cellulose and talc and stir thoroughly to obtain an isolation layer coating solution.

[0131] (2) Isolation layer coating

[0132] Turn on the fluidized bed and set the air inlet temperature to 60°C and the air volume to 1000m 3 / h to preheat the fluidized bed to an outlet air temperature of 40°C, put the drug layer base pellets into the fluidized bed material chamber, connect the infusion tube to the fluidized bed, set the fluidized bed inlet air temperature to 65°C, and set the air inlet volume to 2000m 3 / h, spray gun atomization pressure 3.0bar, peristaltic pump speed 60rpm, use isolation layer coating liquid for spraying, maintain the material temperature at 42℃ during spraying, dry after coating to obtain isolation layer micropellets.

[0133] (3) Screening

[0134] The isolation layer pellets are placed in a sieving machine, and pellets between 35 and 50 meshes are collected to obtain isolation layer base pellets.

[0135] 3. Preparation of Enteric Layer Base Pellets

[0136] (1) Preparation of enteric coating solution

[0137] Weigh one third of the prescribed amount of purified water and stir, add the prescribed amount of glyceryl monostearate and triethyl citrate and stir until dissolved to obtain liquid A, weigh two thirds of the prescribed amount of purified water and stir, add the prescribed amount of L30D-55 and stir and disperse evenly to obtain liquid B, add liquid A to liquid B and stir and mix evenly to obtain an enteric layer coating solution.

[0138] (2) Enteric coating

[0139] Turn on the fluidized bed and set the air volume to 1500m 3 / h, preheat the air at an inlet temperature of 50℃, preheat to an outlet temperature of 35℃, put the isolation layer base pellets into the fluidized bed material chamber, set the inlet temperature to 45℃, and the air volume to 2000m 3 / h, spray gun atomization pressure of 3.5bar, peristaltic pump speed of 50rpm for spraying, keep the material temperature at 32℃ for coating, and dry after coating to obtain enteric-coated pellets.

[0140] (3) Screening

[0141] The enteric-coated pellets were placed in a sieving machine, and pellets with mesh sizes between 30 and 50 were collected to obtain enteric-coated base pellets.

[0142] 4. Capsule filling

[0143] According to the content of the micropellets, the center filling amount was calculated, and the filling speed was set to 40,000 capsules / hour. The enteric-coated base pellets were filled into capsules to obtain esomeprazole magnesium enteric-coated capsules.

[0144] Test Example 1

[0145] Statistics were performed on the coating in the preparation of esomeprazole magnesium enteric-coated capsules in Examples 1-2 and Comparative Example 1, and the statistical results are as follows:

[0146]

[0147] It can be seen from the above table that the coating time used in Example 1-2 through the dry side spray coating process is much shorter than that of Comparative Example 1.

[0148] Test Example 2

[0149] The yields of the preparation of esomeprazole magnesium enteric-coated capsules in Examples 1-2 and Comparative Example 1 were statistically analyzed, and the statistical results are as follows:

[0150]

[0151] It can be seen from the above table that the yield of each coating layer obtained by the dry side spray coating process in Examples 1-2 is higher than that in Comparative Example 1.

[0152] Test Example 3

[0153] The dissolution of the esomeprazole magnesium enteric-coated capsules prepared in Examples 1-2 and Comparative Example 1 was statistically analyzed, and the statistical results are as follows:

[0154]

[0155] The dissolution curves of Examples 1-2, Comparative Example 1 and the reference preparation Nexium in a pH 6.8 dissolution medium are shown in Figure 2 .

[0156] It can be seen from the dissolution rate and dissolution curve that, compared with the reference preparation Nexium, the products prepared in Examples 1-2 and Comparative Example 1 are less destroyed in gastric juice, and Examples 1-2 having a disintegration layer can be released more rapidly, that is, the effect is faster after the patient takes the medicine and the bioavailability is higher; this shows that the products prepared in Examples 1-2 of the present invention are more effective than commercially available products and can control gastric acid secretion for a long time.

[0157] Test Example 4

[0158] The stability of the esomeprazole magnesium enteric-coated capsules prepared in Examples 1-2 and Comparative Example 1 was tested, and the test results are as follows:

[0159] Accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH) were set to test the esomeprazole magnesium content, dissolution, acid resistance, and related substance content of Examples 1-2, Comparative Example 1, and the reference preparation Nexin at 0 month, 3 months, and 6 months, respectively. The results are as follows:

[0160]

[0161] As can be seen from the above table, after accelerated storage for 6 months, the esomeprazole magnesium content, solubility, acid resistance and related substance content of the products prepared in Examples 1-2 and Comparative Example 1 were not significantly different from those of the reference preparation, and the stability was good.

[0162] Unless otherwise specified, all percentages used in the present invention are by mass.

[0163] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is 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 can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing esomeprazole magnesium enteric-coated capsules, characterized in that: The raw materials and dosages used are as follows: the unit dosage of the sucrose core in the core is 20.0 mg; the dosage of esomeprazole magnesium in the drug layer is 44.5 mg, the dosage of ethyl cellulose is 6.7 mg, the dosage of polyethylene glycol 400 is 0.9 mg, the dosage of glyceryl monostearate is 1.5 mg, the dosage of talc is 8.5 mg, and the dosage of purified water is 9.6 mg; the dosage of hexadecyl ester wax in the disintegrating layer is 4.0 mg, and the dosage of cross-linked carboxymethyl cellulose sodium is 20.0 mg; The amount of hydroxypropyl cellulose in the isolation layer is 9.0 mg, the amount of polyethylene glycol 400 is 1.2 mg, the amount of glyceryl monostearate is 2.0 mg, the amount of talc is 33.0 mg, and the amount of purified water is 12.8 mg; the amount of Eudragit L30D-55 in the enteric layer is 93.6 mg, the amount of glyceryl monostearate is 1.4 mg, the amount of triethyl citrate is 2.8 mg, the amount of talc is 11.7 mg, and the amount of purified water is 121.5 mg; The preparation method comprises the following steps: preparing drug layer base pills, preparing disintegration layer base pills, preparing isolation layer base pills, preparing enteric layer base pills, and filling capsules; The preparation of the drug layer base pellets comprises the following steps: preparing a drug layer plasticizer, preparing a drug layer coating powder, coating the drug layer, and screening the drug layer; The drug layer coating powder is prepared by uniformly mixing esomeprazole magnesium, ethyl cellulose and talcum powder to obtain the drug layer coating powder; The drug layer coating is performed by setting the fluidized bed inlet temperature to 120-125°C, preheating the fluidized bed to an outlet temperature of 100-105°C, placing the sucrose pellet core into the fluidized bed material chamber, placing the drug coating powder into the feeder, raising the fluidized bed inlet temperature to 140-145°C, and setting the air volume to 1500-1600m 3 / h for coating, spray the drug layer plasticizer solution onto the surface of the pellets through a side spray device, and at the same time, sprinkle the drug layer coating powder onto the surface of the pellets with a feeder, keep the material temperature unchanged during the coating process, and finally dry to obtain drug layer pellets; The preparation of the disintegrating layer base pellets comprises the following steps: preparing disintegrating layer coating powder, coating the disintegrating layer, and screening the disintegrating layer; The disintegrating layer coating powder is prepared by crushing the cetyl alcohol ester wax to obtain the cetyl alcohol ester wax powder, and uniformly mixing the cetyl alcohol ester wax powder with cross-linked sodium carboxymethyl cellulose to obtain the disintegrating layer coating powder; The disintegration layer coating is performed by setting the fluidized bed air inlet temperature to 60-65°C to preheat the fluidized bed to an air outlet temperature of 40-45°C, placing the drug layer base pills into the fluidized bed material chamber, placing the disintegration layer coating powder into the feeder, raising the fluidized bed air inlet temperature to 70-75°C, and setting the air inlet volume to 1500-1600m 3 / h for coating. While the pellets are fluidized, the coating powder is sprinkled on the surface of the pellets by the feeder. The material temperature is kept constant during the coating process. Finally, the pellets are dried to obtain disintegration layer pellets. The preparation of the isolation layer base pellets comprises the following steps: preparing an isolation layer plasticizer, preparing an isolation layer coating powder, coating the isolation layer, and screening the isolation layer; The isolation layer coating powder is prepared by uniformly mixing hydroxypropyl cellulose and talcum powder to obtain the isolation layer coating powder; The isolation layer coating is performed by starting the fluidized bed, setting the air inlet temperature to 120-125°C to preheat the fluidized bed, preheating the air outlet temperature to 100-105°C, placing the disintegration layer base pellets into the fluidized bed material chamber, placing the isolation layer coating powder into the feeder, raising the air inlet temperature to 150-155°C, and setting the air inlet volume to 2000-2100m 3 / h for coating, spray the isolation layer plasticizer solution onto the surface of the pellets through a side spray device, and at the same time, sprinkle the isolation layer coating powder onto the surface of the pellets with a feeder, keep the material temperature unchanged during the coating process, and finally dry to obtain isolation layer pellets; The preparation of the enteric layer base pills comprises the following steps: preparing an enteric layer coating solution, coating the enteric layer, and screening the enteric layer; The enteric coating liquid is prepared by mixing the first portion of purified water, glyceryl monostearate, and triethyl citrate to obtain liquid A; stirring the second portion of purified water, adding Eudragit L30D-55 and talcum powder to mix to obtain liquid B; and mixing liquid A and liquid B to obtain an enteric coating liquid; For the enteric layer coating, the fluidized bed is turned on, the air inlet temperature is set to 50-55°C for preheating, and the air outlet temperature is preheated to 40-45°C, and the isolation layer base pellets are put into the fluidized bed material chamber, and the air inlet temperature is set to 40-45°C for coating, and the enteric layer coating liquid is used for spraying, and then drying is performed to obtain enteric layer micropellets.

2. The method for preparing esomeprazole magnesium enteric-coated capsules according to claim 1, characterized in that: During the drug layer coating, the air volume of the preheated fluidized bed is 1000-1100m 3 / h; The spray gun atomization pressure in the coating is 3.0-3.5 bar, the peristaltic pump speed is 40-50 rpm, and the feeder stirring speed is 15-20 rpm; The particle size of the sucrose sphere core is 50-60 meshes.

3. The method for preparing esomeprazole magnesium enteric-coated capsules according to claim 1, characterized in that: In the disintegrating layer coating, the preheated air volume is 1000-1100m 3 / h; The stirring speed of the feeder in the coating process is 15-20 rpm.

4. The method for preparing esomeprazole magnesium enteric-coated capsules according to claim 1, characterized in that: In the isolation layer coating, the air volume during preheating is 1500-1600m 3 / h; During the coating, the spray gun atomization pressure is 3.0-3.5 bar, the peristaltic pump speed is 40-50 rpm, and the feeder stirring speed is 15-20 rpm.

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