Eomeprazole magnesium enteric-coated particles and preparation method thereof

Abstract

The invention particularly relates to an escomeprazole magnesium enteric-coated particle and a preparation method thereof. The esomeprazole magnesium enteric-coated particles are particles prepared from a pellet core material by a fluidized bed coating medicine carrying layer, an isolating layer and an enteric-coated layer in sequence, the drug carrying layer is prepared from a laminated suspension, the isolation layer is prepared from an isolation pill suspension, the enteric-coated layer is prepared from an enteric-coated pill solution, and escomeprazole magnesium is enriched in the drug carrying layer. According to the preparation method, an aqueous dispersion membrane control technology is adopted, and a multi-unit esomeprazole magnesium enteric-coated particle administration form is adopted, so that burst release is not easy to occur, and the safety is high. The escomeprazole magnesium enteric-coated particles which are stable in quality, smaller in particle size, free of sand feeling during oral administration and higher in compliance are obtained by combining air jet pulverization with fluidized bed liquid phase lamination and microencapsulation technologies, and are suitable for being taken by children.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to esomeprazole magnesium enteric-coated microparticles and a preparation method thereof. Background Art

[0002] In modern society, due to the increasing pressure of life and irregular lifestyle, the incidence of acute and chronic gastritis, peptic ulcer, gastroesophageal reflux disease (GERD), functional dyspepsia and other digestive diseases is on the rise. Gastroesophageal reflux disease (GERD) refers to a series of symptoms or complications caused by the reflux of gastric contents into the esophagus or above the esophagus. The incidence of GERD in children is extremely high. According to statistics, the incidence of gastroesophageal reflux in healthy children is 40-65%. At present, GERD has become a chronic disease that seriously affects children's health.

[0003] Esomeprazole (EMZ) is the first single proton pump inhibitor (PPI) developed by AstraZeneca. It is another new type of proton pump inhibitor after omeprazole, lansoprazole and pantoprazole. It mainly acts on H + / K + - ATPase, thereby inhibiting gastric acid secretion. It is mainly used for the treatment of gastroesophageal reflux, Helicobacter pylori (HP)-positive peptic ulcers and gastric acid-related digestive system disorders. Compared with omeprazole and R-isomer, EMZ has a lower metabolic rate in the body, blood drug concentration, bioavailability, and better acid inhibition effect.

[0004] After AstraZeneca produced esomeprazole, it developed esomeprazole magnesium enteric-coated tablets and esomeprazole magnesium enteric-coated capsules. However, traditional capsules and tablets are difficult to swallow for children under 6 years old, the elderly and special medication groups. If the enteric-coated tablets are broken or the enteric-coated capsules are removed for taking, esomeprazole will degrade in the stomach. Therefore, in view of the physiological characteristics of special medication groups such as children and the elderly, AstraZeneca has developed esomeprazole magnesium enteric-coated dry suspension. It overcomes the problems of poor drug stability, inconvenient storage and packaging, and inaccurate dosage of liquid oral preparations commonly used in clinical practice. However, the particle size of the micropellets in the commercially available esomeprazole magnesium enteric-coated dry suspension is above 400 microns, and there is a sense of gravel when taken orally, which is poor compliance for patients.

[0005] Therefore, there is an urgent need to develop an enteric dry suspension of esomeprazole magnesium with a micropellet size of less than 250 μm, less oral grittiness and better compliance. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a novel enteric-coated esomeprazole magnesium microparticles and a preparation method thereof. The characteristics of the present invention are that the enteric-coated esomeprazole magnesium microparticles adopt a membrane-controlled enteric material, and the preparation using the enteric-coated esomeprazole magnesium microparticles has stable drug release. At the same time, the preparation process of the enteric-coated esomeprazole magnesium microparticles is simple, has high reproducibility, and is suitable for industrial production.

[0007] The purpose of the present invention is to provide a novel enteric-coated microgranules of esomeprazole magnesium to solve the problems that ordinary sustained-release tablets and sustained-release microgranules are not suitable for special drug administration groups and have poor compliance.

[0008] An enteric-coated granule of esomeprazole magnesium, characterized in that the enteric-coated granule of esomeprazole magnesium is a granule prepared by sequentially fluidizing a core material to coat a drug-carrying layer, an isolation layer, and an enteric layer; the drug-carrying layer is prepared from a layered suspension, the isolation layer is prepared from an isolation pellet suspension, and the enteric layer is prepared from an enteric pellet solution, wherein the esomeprazole magnesium is enriched in the drug-carrying layer; The layered suspension comprises 1-50 parts of esomeprazole magnesium, 1-20 parts of a binder, 1-5 parts of an anti-adherent agent, and 50-500 parts of water by weight; the isolation pellet suspension comprises 1-20 parts of isolation pellet material, 0.4-1 parts of an anti-adherent agent, and 100-1000 parts of water by weight; the enteric-coated pellets comprise 1-20 parts of an enteric material, 1-10 parts of an anti-adherent agent, 0.05-20 parts of a plasticizer, and 100-1000 parts of water by weight, and may also contain pharmaceutically acceptable anti-adherent agents, colorants, and fragrances.

[0009] The capsule core material is selected from sucrose, microcrystalline cellulose 301, microcrystalline cellulose 302, CP102, TP102 and TP203. The esomeprazole content of the enteric-coated microparticles is 1%-30% of the prescribed amount.

[0010] The layered suspension comprises 1-50 parts of esomeprazole magnesium, 1-20 parts of a binder, 1-5 parts of an anti-adherent, and 50-500 parts of water by weight. Wherein, the hydrophilic carrier material is one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and cross-linked polyvinylpyrrolidone; the anti-sticking agent is one or more of talc, magnesium stearate, and micro-powder silica gel; and the charge stabilizer is sodium dodecyl sulfate.

[0011] The hydrophilic carrier material can wet and disperse the hydrophobic drugs, prevent aggregation, and improve bioavailability.

[0012] The anti-adhesive agent is a pharmaceutical excipient that reduces the self-adhesiveness of the rubber or adhesive, reduces surface adhesion, and has the effect of producing a slightly rough surface.

[0013] The isolation pellet suspension comprises 1-20 parts of isolation pellet material, 0.4-1 part of anti-adhesive agent and 100-1000 parts of water by weight.

[0014] Wherein, the isolation layer material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and ethyl cellulose.

[0015] The isolation layer coating material functions to isolate substances and prevent moisture or other substances from entering.

[0016] The enteric-coated pellets include 1-20 parts of enteric material, 1-10 parts of anti-adhesive agent, 0.05-20 parts of plasticizer, and 100-1000 parts of water by weight, and may also contain pharmaceutically acceptable anti-adhesive agent, colorant, and aromatic agent.

[0017] Wherein, the enteric material is one or more of acrylic resin, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and polyvinyl phthalate.

[0018] The plasticizer is one or more of triethyl citrate, diethyl phthalate and tributyl citrate.

[0019] The particle size of the esomeprazole magnesium enteric-coated microparticles of the present invention is 1 μm-1000 μm.

[0020] The method for preparing the esomeprazole magnesium enteric-coated microparticles of the present invention comprises the following steps: (1) Preparation of layered suspension: Add the binder into water, heat and dissolve it, add esomeprazole magnesium and other excipients into the binder solution, disperse them evenly, transfer them into a grinder, micronize the drug, and obtain a layered suspension; Alternatively, esomeprazole magnesium is crushed, and the crushed drug and other excipients are added to the binder solution, and after being evenly dispersed, a layered suspension is obtained; (2) Preparation of esomeprazole magnesium drug-loaded microparticles: The pellet core material is loaded into the fluidized bed for fluidization, and the layered suspension is sprayed onto the surface of the pellet core material and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1300rpm, atomization pressure 0.15-0.25mpa, material temperature 30-38℃; (3) Preparation of isolated particles: The isolation layer coating material and other excipients are mixed to prepare an isolation layer coating solution, which is sprayed onto the surface of the esomeprazole magnesium drug-loaded microparticles and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1500rpm, atomization pressure 0.15-0.25mpa, and material temperature 30-38°C; (4) Preparation of enteric-coated microparticles: The enteric coating material is mixed with other auxiliary materials to prepare an enteric coating liquid, which is sprayed onto the surface of the esomeprazole magnesium isolation particles and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1300-1800rpm, atomization pressure 0.15-0.25mpa, and material temperature 23-28°C.

[0021] After the three kinds of particles are fluidized coated and dried, they are sieved. The esomeprazole magnesium drug-loaded microparticles are sieved through a 100-120 mesh sieve; the isolation microparticles are sieved through a 80-100 mesh sieve; and the enteric-coated microparticles are sieved through a 70-80 mesh sieve.

[0022] Beneficial effects of the present invention: At present, the main dosage forms of esomeprazole magnesium on the market abroad are enteric-coated tablets, enteric-coated capsules and enteric-coated dry suspensions. Enteric-coated tablets and enteric-coated capsules are already on the market in China, but the corresponding dry suspension dosage forms have not yet been launched in China. In addition, the particle size of the enteric-coated dry suspension of esomeprazole magnesium suitable for children is above 400 microns, which feels gritty when taken orally and has poor compliance. Therefore, the call for preparing an enteric-coated dry suspension with a pellet size of less than 250 microns, a weaker oral gritty feeling, and stronger compliance than the already marketed preparations is becoming increasingly strong.

[0023] The present invention relies on water dispersion membrane control technology and adopts a multi-unit esomeprazole magnesium enteric-coated microparticles administration form, which is not prone to sudden release and has high safety. The esomeprazole magnesium enteric-coated microparticles with stable quality, smaller particle size, no sandy feeling when taken orally, and higher compliance are obtained by air flow pulverization combined with fluidized bed liquid phase stratification and microencapsulation technology, which are suitable for children's medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The esomeprazole magnesium enteric-coated microgranules prepared in Example 3-5 and the esomeprazole magnesium enteric-coated micropellets marketed in Japan

[0025] Comparison of dissolution profile of (reference preparation) in water.

[0026] Figure 2 Scanning electron micrograph of esomeprazole magnesium enteric-coated microparticles; a) Uncoated microparticles.

[0027] Figure 3 a) SEM image of enteric-coated esomeprazole magnesium microparticles; b) microparticles coated with isolation coating. Figure 4 A) is a scanning electron micrograph of esomeprazole magnesium enteric-coated microparticles; c) enteric-coated microparticles. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described below through specific embodiments. Example

[0029] The invention discloses an esomeprazole magnesium drug-loaded particle, comprising a capsule core material and a drug-loaded layer prepared by a layered suspension, wherein the capsule core material is sucrose, and in the preparation process of the drug-loaded layer, ultrafine talcum powder is used as an anti-adhesive agent, and hydroxypropyl methylcellulose is used as an adhesive, and esomeprazole is mainly enriched in the drug-loaded layer.

[0030] The formulation of the esomeprazole magnesium drug-loaded microparticles of this embodiment is shown in Table 1; Table 1 Example 1 Prescription of esomeprazole magnesium drug-loaded microparticles

[0031] The method for preparing the esomeprazole magnesium drug-loaded microparticles described in this embodiment comprises the following steps: 1. Preparation of layered suspension: Heat the prescribed amount of water to 80°C, weigh the prescribed amount of hydroxypropyl methylcellulose and add it to the heated water, stirring until it is completely dissolved, cool to room temperature, and set aside; Add the prescribed amount of esomeprazole magnesium and ultrafine talc to the hydroxypropyl methylcellulose aqueous solution that has been cooled to room temperature, and mix for 10 minutes to obtain a coarse layered suspension; 2. Preparation of Esomeprazole Magnesium Drug-Loaded Microparticles: Add the prescribed amount of sucrose pellets into the fluidizing chamber of the fluidized bed, adjust the air volume to 1100-1300rpm, the atomization pressure to 0.15-0.25mpa, and the material temperature to 30-38°C, then turn on the fan. When the material temperature reaches 35°C, start spraying until the stratified liquid is completely coated. Finish coating and continue drying. Pass the dried particles through a 100-120 mesh sieve to obtain esomeprazole magnesium drug-loaded microparticles, which are stored for later use.

[0032] Example 2 The invention discloses an esomeprazole magnesium isolation particle, comprising a capsule core material, a drug-carrying layer and an isolation layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer, and the drug-carrying particles are wrapped by a hydroxypropyl cellulose aqueous solution through a fluidized bed air suspension method to obtain the esomeprazole magnesium isolation particle.

[0033] The prescription of the isolated particles of esomeprazole magnesium in this example is shown in Table 2.

[0034] Table 2 Example 2 Esomeprazole magnesium isolated microparticles formulation

[0035] The method for preparing the isolated esomeprazole magnesium microparticles of this embodiment comprises the following steps: 1. Preparation of isolation layer coating solution: Heat the prescribed amount of water to 80°C, weigh the prescribed amount of hydroxypropyl cellulose and add it to the heated water, stirring while adding until it is completely dissolved, cool to room temperature and set aside; add other excipients and continue stirring until uniform to prepare an isolation layer coating solution and spray it onto the surface of the esomeprazole magnesium drug-loaded particles; 2. Preparation of Esomeprazole Magnesium Isolated Microparticles: The above-mentioned esomeprazole magnesium drug-loaded microparticles are added into the fluidizing chamber of the fluidized bed, and the fan, atomization pressure, and material temperature are adjusted (air intake volume 1100-1500rpm, atomization pressure 0.15-0.25mpa, material temperature 30-38°C), and the fan is turned on. When the material temperature reaches 33°C, the spray is turned on until the weight gain reaches more than 25% to end the coating, and the drying is continued. The dried particles are passed through an 80-100 mesh sieve to obtain esomeprazole magnesium isolation microparticles, which are stored for later use.

[0036] Example 3 The invention discloses an enteric-coated microparticle of esomeprazole magnesium, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the isolation microparticles are wrapped with the enteric material through a fluidized bed air suspension method to obtain the enteric-coated microparticle of esomeprazole magnesium.

[0037] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Table 3.

[0038] Table 3 Example 3 Formulation of Esomeprazole Magnesium Enteric-Coated Microparticles

[0039] The preparation method of esomeprazole magnesium enteric-coated microgranules in this embodiment comprises the following steps: 1. Preparation of enteric coating solution: Heat the prescribed amount of water to 80°C, weigh other excipients and add them into the heated water, stirring while adding until all are dissolved; high-speed shear at 3000r for 10 minutes, cool to room temperature, add the prescribed amount of Eudragit aqueous dispersion, and stir magnetically for 45 minutes.

[0040] 2. Preparation of Esomeprazole Magnesium Enteric-coated Microparticles: Add the prescribed amount of esomeprazole magnesium isolated particles into the fluidizing chamber of the fluidized bed, adjust the fan, atomization pressure, and material temperature (air intake volume 1300-1800rpm, atomization pressure 0.15-0.25mpa, material temperature 23-28°C), turn on the fan, and when the material temperature reaches 24°C, start spraying until the weight gain reaches more than 40% to end the coating, continue drying, and pass the dried particles through an 80-mesh sieve to obtain esomeprazole magnesium enteric-coated particles, which are stored for later use.

[0041] Example 4 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0042] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Table 4-6.

[0043] Table 4 Example 4 Prescription of esomeprazole magnesium drug-loaded microparticles

[0044] Table 5 Example 4 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0045] Table 6 Example 4 Prescription of Esomeprazole Magnesium Enteric-Coated Microgranules

[0046] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the amount of enteric layer coating material Eudragit aqueous dispersion added is reduced by 50g, so the weight gain will be reduced, the enteric effect will be different, and the release of enteric microparticles will be accelerated.

[0047] Example 5 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0048] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 7-9.

[0049] Table 7 Example 5 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0050] Table 8 Example 5 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0051] Table 9 Example 5 Prescription of Esomeprazole Magnesium Enteric-Coated Microgranules

[0052] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the amount of plasticizer added to the enteric layer coating solution is increased by 8g, which will have different effects on the dissolution results of the prepared preparation. The specific effects are described in Example 16.

[0053] Example 6 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0054] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 10-12.

[0055] Table 10 Prescription of Example 6 Esomeprazole Magnesium Drug-Loaded Microparticles

[0056] Table 11 Example 6 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0057] Table 12 Example 6 Formulation of Esomeprazole Magnesium Enteric-Coated Microgranules

[0058] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 1, the binder of the drug-carrying layer is changed from the original hydroxypropyl methylcellulose to sodium carboxymethyl cellulose. Although both have a binder effect, due to certain differences in properties, they will have different effects on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0059] Example 7 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0060] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 13-15.

[0061] Table 13 Example 7 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0062] Table 14 Example 7 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0063] Table 15 Example 7 Formulation of Esomeprazole Magnesium Enteric-Coated Microgranules

[0064] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 1, the drug-carrying layer binder is changed from the original hydroxypropyl methylcellulose to polyvinyl pyrrolidone. Although both have a binder effect, due to certain differences in properties, they will have different effects on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0065] Example 8 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0066] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 16-18.

[0067] Table 16 Example 8 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0068] Table 17 Example 8 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0069] Table 18 Example 8 Prescription of Esomeprazole Magnesium Enteric-Coated Microgranules

[0070] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 1, the drug-carrying layer binder is changed from the original hydroxypropyl methylcellulose to cross-linked polyvinylpyrrolidone. Although both have the function of binders, due to certain differences in properties, they will have different effects on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0071] Example 9 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0072] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 19-21.

[0073] Table 19 Example 9 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0074] Table 20 Example 9 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0075] Table 21 Example 9 Formulation of Esomeprazole Magnesium Enteric-Coated Granules

[0076] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Examples 1, 2, and 3, the types of anti-adhesive agents in the drug-carrying layer, the isolation layer, and the enteric layer are changed, and micro-powdered silica gel replaces ultrafine talc. The effects and functions are similar, but due to certain differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0077] Example 10 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0078] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 22-24.

[0079] Table 22 Example 10 Formulation of Esomeprazole Magnesium Drug-Loaded Microparticles

[0080] Table 23 Example 10 Prescription of Esomeprazole Magnesium Isolated Pellets

[0081] Table 24 Example 10 Formulation of Esomeprazole Magnesium Enteric-Coated Microgranules

[0082] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Examples 1, 2, and 3, the types of anti-adhesive agents in the drug-carrying layer, the isolation layer, and the enteric layer are changed, and magnesium stearate replaces ultrafine talc. The effects and functions are similar, but due to certain differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0083] Embodiment 11 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0084] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 25-27.

[0085] Table 25 Example 11 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0086] Table 26 Example 11 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0087] Table 27 Example 11 Formulation of Esomeprazole Magnesium Enteric-Coated Microgranules

[0088] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the type of isolation layer coating material is changed, and hydroxypropyl methylcellulose replaces hydroxypropyl cellulose. The effects and functions are similar, but due to certain differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0089] Example 12 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0090] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 28-30.

[0091] Table 28 Example 12 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0092] Table 29 Example 12 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0093] Table 30 Example 12 Prescription of Esomeprazole Magnesium Enteric-Coated Microgranules

[0094] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the type of isolation layer coating material is changed, and ethyl cellulose replaces hydroxypropyl cellulose. The effects and functions are similar, but due to certain differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0095] Embodiment 13 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0096] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 31-33.

[0097] Table 31 Example 13 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0098] Table 32 Example 13 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0099] Table 33 Example 13 Prescription of Esomeprazole Magnesium Enteric-Coated Microgranules

[0100] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the type of plasticizer in the enteric layer coating material is changed, and diethyl phthalate replaces triethyl citrate. The effects and functions are similar, but due to certain differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are described in Example 16.

[0101] Embodiment 14 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0102] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 34-36.

[0103] Table 34 Example 14 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0104] Table 35 Example 14 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0105] Table 36 Example 14 Prescription of Esomeprazole Magnesium Enteric-Coated Granules

[0106] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the type of plasticizer in the enteric layer coating material is changed, tributyl citrate replaces triethyl citrate, and its effect and function are similar, but because of certain differences in properties, it will have different effects on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0107] Embodiment 15 The invention discloses enteric-coated esomeprazole magnesium microparticles, comprising a capsule core material, a drug-carrying layer, an isolation layer and an enteric-coated layer, wherein the esomeprazole magnesium is mainly enriched in the drug-carrying layer; the drug-carrying microparticles are coated with a suspension of a drug and an adhesive by a fluidized bed air suspension method to obtain the enteric-coated esomeprazole magnesium microparticles.

[0108] The formulation of the esomeprazole magnesium enteric-coated microgranules of this example is shown in Tables 37-39.

[0109] Table 37 Example 15 Prescription of Esomeprazole Magnesium Drug-Loaded Microparticles

[0110] Table 38 Example 15 Prescription of Esomeprazole Magnesium Isolated Microparticles

[0111] Table 39 Example 15 Prescription of Esomeprazole Magnesium Enteric-Coated Microgranules

[0112] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the type of plasticizer in the enteric layer coating material is changed, dibutyl sebacate replaces triethyl citrate, and its effect and function are similar, but because of certain differences in properties, it will have different effects on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0113] Example 16 The dissolution curves of the esomeprazole magnesium enteric-coated microgranules prepared in Example 3-5 and the esomeprazole magnesium enteric-coated micropellets (reference preparation) marketed in Japan in water are shown in FIG1 . It can be seen from the figure that the in vitro release of the esomeprazole magnesium enteric-coated microgranules prepared by the present invention is consistent with that of the product marketed in Japan, and the scanning electron micrograph of the esomeprazole magnesium enteric-coated microgranules is shown in FIG3 . In addition, by adjusting the formulation of the coating solution, the dissolution results are different to a certain extent, which confirms the role of various changes in the excipients.

[0114] Example 3-15 Determination of in vitro cumulative release of prepared esomeprazole magnesium enteric-coated microgranules and esomeprazole magnesium enteric-coated micropellets (reference preparation) marketed in Japan: The determination method is as follows: Take the esomeprazole magnesium enteric-coated microparticles prepared in Example 3-15, first dissolve them in 300ml of 0.1mol / L hydrochloric acid solution at 100r / min for 2 hours, then add 700ml of 0.086mol / L disodium hydrogen phosphate solution, keep the speed unchanged, and take 6mL of the solution after 5, 10, 15, 20, 30, and 60min, respectively, pass through a 0.45μm filter membrane, and measure the absorbance.

[0115] The f2 similarity factor method was used for comparison. The release results are shown in Table 40.

[0116] Table 40 Release results

[0117] The results showed that the in vitro release of the esomeprazole magnesium enteric-coated microparticles prepared in Example 3 was similar to that of the reference preparation. f 2 is greater than 70, the similarity is good.

[0118] In summary, the present invention prepares enteric-coated esomeprazole magnesium microparticles by drug micronization and microencapsulation, using Eudragit aqueous dispersion as enteric coating material. Since the drug is administered in the form of a multi-unit preparation, the breakage of a single microparticle does not have a significant impact on the whole, the particle size is less than 200 microns, there is no sandy feeling when taken orally, and the patient compliance is strong; the production process of the present invention is simple, and the safe and environmentally friendly Eudragit aqueous dispersion is used for coating, while also reducing its toxic and side effects.

[0119] The preferred embodiments and principles of the present invention are described in detail above. For those skilled in the art, according to the ideas provided by the present invention, there may be changes in the specific implementation methods, and these changes should also be regarded as the protection scope of the present invention.

Claims

1. An esomeprazole magnesium enteric-coated pellet, characterized in that: The esomeprazole magnesium enteric-coated micropellets are particles prepared by sequentially fluidizing the core material with a drug-carrying layer, an isolation layer, and an enteric layer; the drug-carrying layer is prepared from a layered suspension, the isolation layer is prepared from an isolation pellet suspension, and the enteric layer is prepared from an enteric pellet solution, wherein the esomeprazole magnesium is enriched in the drug-carrying layer; The layered suspension comprises 1-50 parts of esomeprazole magnesium, 1-20 parts of a binder, 1-5 parts of an anti-adherent agent, and 50-500 parts of water by weight; the isolation pellet suspension comprises 1-20 parts of isolation pellet material, 0.4-1 parts of an anti-adherent agent, and 100-1000 parts of water by weight; the enteric-coated pellets comprise 1-20 parts of an enteric material, 1-10 parts of an anti-adherent agent, 0.05-20 parts of a plasticizer, and 100-1000 parts of water by weight, and may also contain pharmaceutically acceptable anti-adherent agents, colorants, and fragrances.

2. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The weight proportion of each layer of the esomeprazole magnesium enteric-coated microcapsules is as follows: the enteric layer accounts for 20%-50% of the esomeprazole magnesium enteric-coated microcapsules, the isolation layer accounts for 10%-20% of the esomeprazole magnesium enteric-coated microcapsules, the drug-loaded layer accounts for 1%-10% of the esomeprazole magnesium enteric-coated microcapsules, and the pill core material accounts for 40%-60% of the esomeprazole magnesium enteric-coated microcapsules, totaling 100%.

3. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The pellet core material is selected from sucrose, microcrystalline cellulose 301, microcrystalline cellulose 302, CP102, TP102 and TP203.

4. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The esomeprazole content of the enteric-coated micropellets is 1%-30% of the prescribed amount.

5. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The hydrophilic carrier material is one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and cross-linked polyvinylpyrrolidone; the anti-adhesive agent is one or more of talc, magnesium stearate, and micro-powder silica gel; and the charge stabilizer is sodium lauryl sulfate.

6. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The plasticizer is one or more of triethyl citrate, diethyl phthalate, tributyl citrate and dibutyl sebacate.

7. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The enteric material is one or more of acrylic resin, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and polyvinyl phthalate.

8. The esomeprazole magnesium enteric-coated pellets according to claim 1, characterized in that: The isolation layer material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and polyethylene film coating materials.

9. A method for preparing the esomeprazole magnesium enteric-coated micropellets according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) Preparation of layered suspension: Add the binder into water, heat and dissolve it, add esomeprazole magnesium and other excipients into the binder solution, disperse them evenly, transfer them into a grinder, micronize the drug, and obtain a layered suspension; Alternatively, esomeprazole magnesium is crushed, and the crushed drug and other excipients are added to the binder solution, and after being evenly dispersed, a layered suspension is obtained; (2) Preparation of Esomeprazole Magnesium Drug-Loaded Granules: The pellet core material is loaded into the fluidized bed for fluidization, and the layered suspension is sprayed onto the surface of the pellet core material and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1300rpm, atomization pressure 0.15-0.25mpa, material temperature 30-38℃; (3) Preparation of isolated pellets: The isolation layer coating material and other excipients are mixed to prepare an isolation layer coating solution, which is sprayed onto the surface of the esomeprazole magnesium drug-loaded particles and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1500rpm, atomization pressure 0.15-0.25mpa, and material temperature 30-38°C; (4) Preparation of enteric-coated pellets: The enteric coating material is mixed with other auxiliary materials to prepare an enteric coating liquid, which is sprayed onto the surface of the esomeprazole magnesium enteric-coated micropellets and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1300-1800rpm, atomization pressure 0.15-0.25mpa, and material temperature 23-28°C.

10. The method for preparing esomeprazole magnesium enteric-coated pellets according to claim 9, characterized in that: After the three kinds of particles are fluidized coated and dried, they are sieved. The esomeprazole magnesium drug-loaded microparticles are sieved through a 100-120 mesh sieve; the isolation micropellets are sieved through an 80-100 mesh sieve; and the enteric-coated micropellets are sieved through a 70-80 mesh sieve.

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