Escomeprazole magnesium capsule preparation and preparation method thereof

Abstract

The invention provides an escomeprazole magnesium capsule preparation which is composed of a normal-release pellet and a sustained-release pellet, compared with a reference preparation 'NEXIUM', the escomeprazole magnesium capsule preparation has the effect taking speed close to that of the reference preparation and can maintain the effect taking time of 1-2 days, the drug administration frequency can be reduced, and the bioavailability of the escomeprazole magnesium capsule preparation is improved. The selectivity is increased for some patients who cannot take medicine every day, cannot be administrated in time or are inconvenient to take medicine for multiple times every day.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and particularly relates to an esomeprazole magnesium capsule preparation and its preparation method. Background Technology

[0002] Gastroesophageal reflux disease (GERD) is a chronic condition in which stomach contents (including stomach acid, bile, and food) reflux into the esophagus, throat, or mouth, causing discomfort and / or complications. It is one of the most common diseases of the digestive system, with a global prevalence of approximately 10%-20%, and this prevalence is on the rise.

[0003] Esomeprazole magnesium, the S-configuration optical isomer of omeprazole, is a new generation proton pump inhibitor (PPI) widely used in the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD) and peptic ulcers. Due to the presence of the sulfoxide group in its structure, esomeprazole magnesium is extremely unstable in acidic environments and prone to degradation. Therefore, enteric-coated formulations are necessary to protect the drug from gastric acid and ensure its release and absorption in the intestines.

[0004] Currently available esomeprazole magnesium enteric-coated microcapsules or capsules are only immediate-release formulations, requiring 1-2 doses daily. This may present problems for some patients who work long hours and are unable to take the medication on time.

[0005] Furthermore, commercially available products only have two layers outside the drug-loaded layer: an isolation layer and an enteric coating. To ensure product stability and that impurities meet quality requirements during the stability period, the enteric coating and isolation layers have a higher weight gain, resulting in higher costs. Additionally, during the stability period, there is a trend of increasing related substances and decreasing dissolution. After one month of exposure to high temperatures following opening, the increase in related substances in the product is significant. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide an esomeprazole magnesium capsule formulation composed of immediate-release and sustained-release microcapsules. This esomeprazole magnesium capsule formulation not only has a similar onset speed to commercially available formulations but also offers a longer treatment duration. It features a thinner coating, lower cost, and greater stability in terms of related substances and dissolution release at high temperatures and after opening. By adjusting the ratio of immediate-release to sustained-release microcapsules, continuous administration for 1-2 days can be achieved, reducing the frequency of dosing, and the resulting drug meets clinical medication requirements.

[0007] To achieve the purpose of the invention, the present invention adopts the following technical solution: An esomeprazole magnesium capsule formulation comprises two parts: immediate-release microcapsules and sustained-release microcapsules. The immediate-release microcapsules consist of a blank core, a drug-loaded layer, an isolation layer, an enteric coating layer, and a thin film layer. The sustained-release microcapsules consist of a blank core, a drug-loaded layer, an isolation layer, an enteric coating layer, and a sustained-release layer. The blank core in both the immediate-release and sustained-release microcapsules is drug-free and has a particle size of 0.25–0.60 mm. The immediate-release microcapsules account for 33.3% to 66.7% of the total weight, and the sustained-release microcapsules account for 66.7% to 33.3% of the total weight.

[0008] Furthermore, in the ordinary-release microcapsules, the weight of the drug-loaded layer of the blank capsule core is 150% to 250% of the weight of the blank capsule core, the weight of the isolation layer is 120% to 180% of the weight of the blank capsule core, the weight of the enteric coating layer is 50% to 80% of the weight of the blank capsule core, and the weight of the film layer is 5% to 50% of the weight of the blank capsule core.

[0009] Furthermore, in the sustained-release microcapsules, the weight of the drug-loaded layer of the blank capsule core is 150% to 250% of the weight of the blank capsule core, the weight of the isolation layer is 120% to 180% of the weight of the blank capsule core, the weight of the enteric coating layer is 50% to 80% of the weight of the blank capsule core, and the weight of the sustained-release layer is 50% to 100% of the weight of the blank capsule core.

[0010] Furthermore, the drug-loaded layer in the immediate-release and sustained-release microcapsules is composed of an adhesive and esomeprazole magnesium; the adhesive is selected from one or more of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0011] Furthermore, the isolation layer in the immediate-release microcapsules and the sustained-release microcapsules is composed of a film-forming material, an anti-sticking agent, and a lubricant; the film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose; the anti-sticking agent is one or more of talc, sodium stearate fumarate, and mono- and di-stearic acid glycerides; the lubricant is magnesium stearate; and the weight ratio of the film-forming material, the anti-sticking agent, and the lubricant is 3~4:3~4:1.

[0012] Further, the enteric coating layer in the immediate-release and sustained-release microcapsules is composed of a film-forming material, a plasticizer, a surfactant, and an anti-sticking agent; the film-forming material is selected from one or more of Eutectic LD30-55, acrylic resin, hydroxypropyl methylcellulose phthalate, and polyacrylic acid resin latex; the plasticizer is selected from one or more of polyethylene glycol, propylene glycol, triethyl citrate, tributyl citrate, and glyceryl triacetate; the surfactant is Tween 80; the anti-sticking agent is one or more of talc and glyceryl mono- and glyceryl di- and glyceryl mono- and glyceryl di-; the weight ratio of the film-forming material (based on solid content), plasticizer, surfactant, and anti-sticking agent is 1:0~20:1~2:0.1~0.2:0.5~1.5.

[0013] Furthermore, the film layer of the immediate-release microcapsules is composed of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose; the sustained-release layer of the sustained-release microcapsules is composed of one or more of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and methyl cellulose.

[0014] As a preferred embodiment, an esomeprazole magnesium capsule formulation comprises two parts: immediate-release microcapsules and sustained-release microcapsules, with the following components and amounts: Formula 1: The microcapsules contain: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 4.46 mg hydroxypropyl methylcellulose; 7.84 mg hydroxypropyl cellulose; 0.38 mg talc; 7.07 mg mono- and di-stearylglycerols; 2.02 mg magnesium stearate; 16.43 mg hydroxypropyl methylcellulose phthalate; 1.99 mg triethyl citrate; and 0.32 mg Tween 80. Sustained-release microcapsules, comprising: blank capsule core 13.65 mg; esomeprazole magnesium 22.7 mg; hydroxypropyl methylcellulose 4.46 mg; methylcellulose 4.46 mg; ethylcellulose 0.77 mg; talc 0.38 mg; glyceryl monostearate and glyceryl distearate 7.07 mg; magnesium stearate 2.02 mg; hydroxypropyl methylcellulose phthalate 16.43 mg; triethyl citrate 1.99 mg; and Tween 80 0.32 mg. Alternatively, Formula Two: The microcapsules consist of: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 9.57 mg hydroxypropyl cellulose; 0.77 mg hydroxyethyl cellulose; 7.07 mg talc; 2.02 mg magnesium stearate; 16.43 mg polyacrylic acid resin latex; 1.99 mg triethyl citrate; and 0.32 mg Tween 80. Sustained-release microcapsules, comprising: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 9.57 mg hydroxypropyl cellulose; 0.77 mg hydroxyethyl cellulose; 7.7 mg ethyl cellulose; 0.38 mg talc; 2.02 mg magnesium stearate; 16.43 mg polyacrylic acid resin latex; 1.99 mg triethyl citrate; and 0.32 mg Tween 80. Alternatively, Formula 3: The microcapsules contain: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 4.46 mg hydroxypropyl methylcellulose; 9.57 mg hydroxypropyl cellulose; 7.07 mg talc; 0.99 mg mono- and di-stearylglycerol; 2.02 mg magnesium stearate; 19.716 mg LD30-55 of Eutrapeptide; 1.99 mg triethyl citrate; and 0.39 mg Tween 80. Sustained-release microcapsules, comprising: blank capsule core 13.65 mg; esomeprazole magnesium 22.7 mg; hydroxypropyl methylcellulose 4.46 mg; hydroxypropyl cellulose 7.84 mg; ethyl cellulose 7.7 mg; talc 7.07 mg; glyceryl monostearate and glyceryl distearate 0.99 mg; magnesium stearate 2.02 mg; eutectic LD30-55 19.716 mg; triethyl citrate 1.99 mg; and Tween 80 0.39 mg. Alternatively, formula four: The microcapsules contain: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 9.57 mg hydroxypropyl methylcellulose; 4.46 mg hydroxyethyl cellulose; 0.38 mg talc; 7.07 mg mono- and di-stearylglycerols; 2.02 mg magnesium stearate; 19.716 mg LD30-55 of Eucerin; 1.99 mg triglyceride; and 0.32 mg Tween 80. The sustained-release microcapsules consist of: a blank capsule core of 13.65 mg; esomeprazole magnesium of 22.7 mg; hydroxypropyl cellulose of 9.57 mg; hydroxyethyl cellulose of 4.46 mg; talc of 0.38 mg; glyceryl monostearate and glyceryl distearate of 7.07 mg; magnesium stearate of 2.02 mg; eutectic LD30-55 of 19.716 mg; glyceryl triacetate of 1.99 mg; and Tween 80 of 0.32 mg.

[0015] This invention also relates to a method for preparing the above-mentioned esomeprazole magnesium capsule formulation, which adopts the following technical solution: A method for preparing the esomeprazole magnesium capsule formulation includes the following steps: Step 1: Preparing immediate-release microcapsules, including: A. Preparation of drug-loaded microspheres: The drug-loaded microspheres are prepared by coating the blank pellet core with the drug-loaded layer composition using fluidized bed bottom spraying technology. B. Preparation of isolation microspheres: The drug-loaded microspheres are coated with an isolation layer composition using fluidized bed bottom spraying technology to obtain isolation microspheres; C. Preparation of enteric-coated microspheres: The isolated microspheres are coated with an enteric coating composition using fluidized bed bottom spraying technology to obtain enteric-coated microspheres; D. Preparation of constant-release microcapsules: The enteric-coated microcapsules were coated with a thin film material and sieved using fluidized bed bottom spraying technology to obtain constant-release microcapsules; Step 2: Preparation of sustained-release microspheres, including: E. Preparation of drug-loaded microspheres: The drug-loaded microspheres are prepared by coating the blank pellet core with the drug-loaded layer composition using fluidized bed bottom spraying technology. F. Preparation of isolation microspheres: The drug-loaded microspheres are coated with an isolation layer composition using fluidized bed bottom spraying technology to obtain isolation layer drug-loaded microspheres; G. Preparation of enteric-coated microspheres: The isolated microspheres are coated with an enteric coating composition using fluidized bed bottom spraying technology to obtain enteric-coated microspheres; H. Preparation of sustained-release microcapsules: The enteric-coated microcapsules were coated with a sustained-release material and sieved using fluidized bed bottom spraying technology to obtain sustained-release microcapsules; Step 3: Mix the immediate-release microspheres and sustained-release microspheres obtained in Step 1 and Step 2, with the immediate-release microspheres accounting for 25% to 75% of the total weight and the sustained-release microspheres accounting for 75% to 25% of the total weight. Step 4: Fill the mixed microspheres obtained in Step 3 into capsules.

[0016] Furthermore, the fluidized bed material temperature in A and E is 35~38℃, and the atomization pressure is 1.8~2.0 bar.

[0017] Furthermore, the fluidized bed material temperature in B and F is 35~38℃, and the atomization pressure is 1.8~2.0 bar.

[0018] Furthermore, the fluidized bed material temperature in C and G is 30~32℃, and the atomization pressure is 2.0~2.5 bar.

[0019] Furthermore, the fluidized bed material temperature in D is 30~32℃; the atomization pressure is 1.8~2.0 bar; and the screen mesh size is 30~60 mesh.

[0020] Furthermore, the fluidized bed material temperature in H is 35~40℃; the atomization pressure is 1.8~2.0 bar; and the screen mesh size is 30~60 mesh.

[0021] Further, in step three, a mixer is used for mixing, with a mixing time of 15-30 minutes and a mixing speed of 10-15 rpm.

[0022] This invention also provides an esomeprazole magnesium capsule formulation prepared based on the above-mentioned microparticles, with a specification of 20mg or 40mg per capsule calculated based on esomeprazole. The only differences between the different specifications are the fill weight and the size of the empty capsule. The beneficial effects of this invention are reflected in: 1. Through research on the formulation ratio and dosage, this invention has obtained a formulation with lower coating weight gain and less dosage, reducing the amount of expensive imported excipients such as Eucerin LD30-55 and lowering the cost of this product.

[0023] 2. The outermost layer of the immediate-release microspheres of the present invention is coated with a thin film layer, and the outermost layer of the sustained-release microspheres is coated with a sustained-release material. Since these materials and most of the auxiliary additives are high-molecular materials with excellent physicochemical properties, the coating not only provides moisture protection, light protection, odor masking, and wear resistance, but also makes it less prone to mold growth, resulting in better stability of the product.

[0024] 3. This invention designs different release modules: immediate-release microcapsules release the drug immediately in the intestine after administration, rapidly reaching therapeutic concentrations; sustained-release microcapsules continuously release the drug, maintaining therapeutic efficacy. By adjusting the ratio of immediate-release to sustained-release microcapsules, capsule formulations that can be administered continuously for 1-2 days can be obtained.

[0025] Compared with traditional esomeprazole magnesium preparations, it has the following advantages: (1) Controllable rate: Combining rapid onset of action with long-term maintenance to meet treatment needs; (2) Synergistic effect: Multiple mechanisms combined to break through the bottleneck of single drug efficacy; (3) Long-lasting and convenient: Extends the release period, reduces the number of times to administer the medication, and improves patient compliance. Attached Figure Description

[0026] Figure 1 This is a comparison chart of the acid resistance (pH 5.5) of the self-developed reagent Example 5 and the reference reagent. Detailed Implementation

[0027] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.

[0028] Example A method for preparing an enteric-coated formulation of esomeprazole magnesium includes the following steps: Step 1: Preparation of immediate-release microcapsules, including: Preparation of drug-loaded microcapsules: 1. Add the prescribed amount of adhesive to purified water and stir until dissolved; 2. Add the prescribed amount of esomeprazole magnesium to the solution from the previous step and stir until evenly dispersed; 3. Place the blank pellet core in a fluidized bed and use a top spray method to control the material temperature at 35~38℃ and the atomization pressure at 1.8~2.0 bar to uniformly spray the drug-loaded solution onto the blank pellet core; the spraying process is continuously stirred. 4. After spraying, the drug-loaded microspheres are dried until the moisture content is ≤1.5%; The adhesive is selected from one or more of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0029] B. Preparation of isolation microspheres: 1. Add the prescribed amount of film-forming material to purified water and stir until dissolved; 2. Add the prescribed amount of anti-sticking agent and lubricant to the solution from the previous step and stir until evenly dispersed; 3. The drug-loaded microcapsules are placed in a fluidized bed and sprayed from the top. The material temperature is controlled at 35~38℃ and the atomization pressure is 1.8~2.0 bar. The isolation layer solution is sprayed evenly onto the microcapsules. The spraying process is continuously stirred. 4. After spraying, dry the isolation pellets until the moisture content is ≤1.5%; The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose; the anti-sticking agent is one or more of talc, sodium stearate fumarate, and mono- and di-stearic acid glycerides; and the lubricant is magnesium stearate.

[0030] C. Preparation of enteric-coated microcapsules: 1. Dissolve the prescribed amount of plasticizer, anti-sticking agent and surfactant in an 80°C water bath, homogenize at 10,000 rpm for 10 min, then add talc and continue homogenizing for another 10 min. 2. Place the sample from the previous step at room temperature and stir to cool until the temperature does not exceed 30℃; 3. Add the sample from the previous step to the prescribed amount of film-forming material and stir until homogeneous; 4. The microcapsules are placed in a fluidized bed and sprayed from the top. The material temperature is controlled at 30~32℃ and the atomization pressure is 2.0~2.5 bar. The enteric coating solution is sprayed evenly onto the microcapsules. The spraying process is continuously stirred. 5. After spraying, the enteric-coated microspheres are dried until the moisture content is ≤1.5%; The film-forming material is selected from one or more of the following: Eute LD30-55, acrylic resin, hydroxypropyl methylcellulose phthalate, and polyacrylic resin latex; the plasticizer is selected from one or more of the following: polyethylene glycol, propylene glycol, triethyl citrate, tributyl citrate, and triethyl glycerol; the surfactant is Tween 80; and the anti-sticking agent is one or more of the following: talc and glyceryl mono- and di-stearates.

[0031] D. Preparation of ordinary-release microcapsules: 1. Add the prescribed amount of film material to purified water and stir until dissolved; 2. The enteric-coated microcapsules are placed in a fluidized bed and sprayed from the top. The material temperature is controlled at 30~32℃ and the atomization pressure is 1.8~2.0 bar. The film layer solution is sprayed evenly onto the microcapsules. The spraying process is continuously stirred. 3. After spraying, the microcapsules are dried until the moisture content is ≤1.5%; 4. Screen the microcapsules using a sieve with a mesh size of 30-60 mesh; The film layer is composed of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose.

[0032] Step 2: Preparation of sustained-release microspheres, including: E. Preparation of drug-loaded microcapsules: 1. Add the prescribed amount of adhesive to purified water and stir until dissolved; 2. Add the prescribed amount of esomeprazole magnesium to the solution from the previous step and stir until evenly dispersed; 3. Place the blank pellet core in a fluidized bed and use a top spray method to control the material temperature at 35~38℃ and the atomization pressure at 1.8~2.0 bar to uniformly spray the drug-loaded solution onto the blank pellet core; the spraying process is continuously stirred. 4. After spraying, the drug-loaded microspheres are dried until the moisture content is ≤1.5%; The adhesive is selected from one or more of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

[0033] Preparation of isolation microspheres: Add the prescribed amount of film-forming material to purified water and stir until dissolved; 2. Add the prescribed amount of anti-sticking agent and lubricant to the solution from the previous step and stir until evenly dispersed; 3. The drug-loaded microcapsules are placed in a fluidized bed and sprayed from the top. The material temperature is controlled at 35~38℃ and the atomization pressure is 1.8~2.0 bar. The isolation layer solution is sprayed evenly onto the microcapsules. The spraying process is continuously stirred. After spraying, the isolation microspheres are dried until the moisture content is ≤1.5%; The film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose; the anti-sticking agent is one or more of talc, sodium stearate fumarate, and mono- and di-stearic acid glycerides; and the lubricant is magnesium stearate.

[0034] Preparation of enteric-coated microcapsules: 1. Dissolve the prescribed amount of plasticizer, anti-sticking agent and surfactant in an 80°C water bath, homogenize at 10,000 rpm for 10 min, then add talc and continue homogenizing for another 10 min. 2. Place the sample from the previous step at room temperature and stir to cool until the temperature does not exceed 30℃; 3. Add the sample from the previous step to the prescribed amount of film-forming material and stir until homogeneous; 4. The microcapsules are placed in a fluidized bed and sprayed from the top. The material temperature is controlled at 30~32℃ and the atomization pressure is 2.0~2.5 bar. The enteric coating solution is sprayed evenly onto the microcapsules. The spraying process is continuously stirred. 5. After spraying, the enteric-coated microspheres are dried until the moisture content is ≤1.5%; The film-forming material is selected from one or more of the following: Eute LD30-55, acrylic resin, hydroxypropyl methylcellulose phthalate, and polyacrylic resin latex; the plasticizer is selected from one or more of the following: polyethylene glycol, propylene glycol, triethyl citrate, tributyl citrate, and triethyl glycerol; the surfactant is Tween 80; and the anti-sticking agent is one or more of the following: talc and glyceryl mono- and di-stearates.

[0035] Preparation of sustained-release microcapsules: 1. Add the prescribed amount of sustained-release material to ethanol and stir until dissolved; 2. The enteric-coated microcapsules are placed in a fluidized bed and sprayed from the top. The material temperature is controlled at 35~40℃ and the atomization pressure is 1.8~2.0 bar. The slow-release solution is sprayed evenly onto the microcapsules. The spraying process is continuously stirred. 3. After spraying, the slow-release microspheres are dried until the moisture content is ≤1.5%.

[0036] 4. Screen the sustained-release microspheres using a sieve with a mesh size of 30-60 mesh; The sustained-release material is selected from one or more of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methyl cellulose.

[0037] Step 3: Mix the immediate-release microspheres and sustained-release microspheres obtained in Step 1 and Step 2 using a mixer, with the immediate-release microspheres accounting for 25% to 75% of the total weight and the sustained-release microspheres accounting for 75% to 25% of the total weight. The mixing time is 20 minutes and the mixing speed is 15 rpm.

[0038] Step 4: Fill the prepared mixed microspheres into capsules, with a filling specification of 40mg (3# empty capsules) or 20mg (4# empty capsules).

[0039] Following the steps of the above embodiments and using different adjuvants, the esomeprazole magnesium capsule formulations of Examples 1 to 7 were prepared as shown in the table below: Evaluation method Experimental Example 1: In vitro dissolution curve determination: Methods: Dissolution conditions: After soaking in 0.1N hydrochloric acid for 2 hours, the samples were transferred to pH 6.0 phosphate buffer at 100 rpm. Dissolution curves were investigated for samples from Examples 1 to 7 according to the procedure.

[0040] Table 1. Cumulative dissolution rate (%) in pH 5.5 dissolution medium The reference formulation information is as follows: Chinese name: Esomeprazole Magnesium Enteric-Coated Capsules; English name: Esomeprazole Magnesium Enteric-Coated Capsules; Brand: NEXIUM.

[0041] As shown in Table 1, the dissolution curves of the esomeprazole magnesium capsules prepared in Examples 1-3 and Example 5 are consistent with the reference formulation, and the preparation process is simple and easy to achieve large-scale commercial production. Among them, the product prepared in Example 5 is the best and can meet the requirement of once-daily dosing.

[0042] Three batches of samples were prepared according to the formulation and preparation method of Example 5, and then the in vitro dissolution curves were detected according to the above dissolution method. The results are shown in Table 2.

[0043] Table 2. Cumulative dissolution rate (%) of esomeprazole magnesium capsule formulations from multiple batches of example samples in dissolution medium at pH 6.0. As shown in Table 2, the esomeprazole magnesium capsule formulation prepared by this invention has stable process and good reproducibility.

[0044] To investigate the stability of the esomeprazole magnesium capsule formulation prepared in the embodiments of the present invention, the reference formulation and the esomeprazole magnesium capsule formulation prepared in Example 5 were subjected to influencing factors and accelerated testing, and the test results are shown in Table 5.

[0045] Table 3. Detection results of related substances and their contents under influencing factors. As shown in Table 3, compared with the reference formulation, the esomeprazole magnesium capsule formulation prepared in Example 5 of this invention is more stable in terms of related substances under influencing factors and accelerated conditions, and the product quality is better than that of the reference formulation.

[0046] Figure 1 This is a comparison chart of the acid resistance (pH 5.5) of the self-developed formulation in Example 5 and the reference formulation. Esomeprazole magnesium changes color when it comes into contact with acid. The color change rate and proportion of the microcapsules also confirm that the self-developed formulation has an onset speed close to that of the reference formulation and can maintain an onset time of 1 to 2 days, which can reduce the number of times the drug can be administered.

Claims

1. An esomeprazole magnesium capsule formulation, characterized in that, It consists of two parts: immediate-release microcapsules and sustained-release microcapsules. The immediate-release microcapsules consist of a blank core, a drug-loaded layer, an isolation layer, an enteric coating layer, and a thin film layer. The sustained-release microcapsules consist of a blank core, a drug-loaded layer, an isolation layer, an enteric coating layer, and a sustained-release layer. The blank cores in both the immediate-release and sustained-release microcapsules are drug-free and have a particle size of 0.25~0.60mm. The immediate-release microcapsules account for 33.3% to 66.7% of the total weight, and the sustained-release microcapsules account for 66.7% to 33.3% of the total weight.

2. The esomeprazole magnesium capsule formulation according to claim 1, characterized in that, The weight of the drug-loaded layer of the blank pellet core in the conventionally released microcapsules is 150% to 250% of the weight of the blank pellet core, the weight of the isolation layer is 120% to 180% of the weight of the blank pellet core, the weight of the enteric coating layer is 50% to 80% of the weight of the blank pellet core, and the weight of the film layer is 5% to 50% of the weight of the blank pellet core.

3. The esomeprazole magnesium capsule formulation according to claim 1, characterized in that, The weight of the drug-loaded layer of the blank pellet in the sustained-release microcapsule is 150% to 250% of the weight of the blank pellet, the weight of the isolation layer is 120% to 180% of the weight of the blank pellet, the weight of the enteric coating layer is 50% to 80% of the weight of the blank pellet, and the weight of the sustained-release layer is 50% to 100% of the weight of the blank pellet.

4. The esomeprazole magnesium capsule formulation according to claim 1, characterized in that, The drug-loaded layer in the immediate-release and sustained-release microcapsules is composed of a binder and esomeprazole magnesium; the binder is selected from one or more of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

5. The esomeprazole magnesium capsule formulation according to claim 1, characterized in that, The isolation layer in the immediate-release and sustained-release microcapsules is composed of a film-forming material, an anti-sticking agent, and a lubricant; the film-forming material is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose; the anti-sticking agent is one or more of talc, sodium stearate fumarate, and mono- and di-stearic acid glycerides; the lubricant is magnesium stearate; the weight ratio of the film-forming material, anti-sticking agent, and lubricant is 3~4:3~4:

1.

6. The enteric-coated formulation of esomeprazole magnesium according to claim 1, characterized in that, The enteric coating layer of the immediate-release and sustained-release microcapsules is composed of a film-forming material, a plasticizer, a surfactant, and an anti-sticking agent. The film-forming material is selected from one or more of Eutectic LD30-55, acrylic resin, hydroxypropyl methylcellulose phthalate, and polyacrylic acid resin latex. The plasticizer is selected from one or more of polyethylene glycol, propylene glycol, triethyl citrate, tributyl citrate, and triethyl glycerol. The surfactant is Tween 80. The anti-sticking agent is one or more of talc and glyceryl mono- and glyceryl di- ...

7. The enteric-coated formulation of esomeprazole magnesium according to claim 1, characterized in that, The film layer of the immediate-release microcapsules is composed of one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose; the sustained-release layer of the sustained-release microcapsules is composed of one or more of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and methyl cellulose.

8. An esomeprazole magnesium capsule formulation, characterized in that, It consists of two parts: immediate-release microcapsules and sustained-release microcapsules. The components and their quantities are as follows: Formula 1: The microcapsules contain: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 4.46 mg hydroxypropyl methylcellulose; 7.84 mg hydroxypropyl cellulose; 0.38 mg talc; 7.07 mg mono- and di-stearylglycerols; 2.02 mg magnesium stearate; 16.43 mg hydroxypropyl methylcellulose phthalate; 1.99 mg triethyl citrate; and 0.32 mg Tween 80. Sustained-release microcapsules, comprising: blank capsule core 13.65 mg; esomeprazole magnesium 22.7 mg; hydroxypropyl methylcellulose 4.46 mg; methylcellulose 4.46 mg; ethylcellulose 0.77 mg; talc 0.38 mg; glyceryl monostearate and glyceryl distearate 7.07 mg; magnesium stearate 2.02 mg; hydroxypropyl methylcellulose phthalate 16.43 mg; triethyl citrate 1.99 mg; Tween 80 0.32 mg; Alternatively, Formula Two: The microcapsules consist of: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 9.57 mg hydroxypropyl cellulose; 0.77 mg hydroxyethyl cellulose; 7.07 mg talc; 2.02 mg magnesium stearate; 16.43 mg polyacrylic acid resin latex; 1.99 mg triethyl citrate; and 0.32 mg Tween 80. Sustained-release microcapsules, comprising: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 9.57 mg hydroxypropyl cellulose; 0.77 mg hydroxyethyl cellulose; 7.7 mg ethyl cellulose; 0.38 mg talc; 2.02 mg magnesium stearate; 16.43 mg polyacrylic acid resin latex; 1.99 mg triethyl citrate; and 0.32 mg Tween 80. Alternatively, Formula 3: The microcapsules contain: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 4.46 mg hydroxypropyl methylcellulose; 9.57 mg hydroxypropyl cellulose; 7.07 mg talc; 0.99 mg mono- and di-stearylglycerol; 2.02 mg magnesium stearate; 19.716 mg LD30-55 of Eutrapeptide; 1.99 mg triethyl citrate; and 0.39 mg Tween 80. Sustained-release microcapsules, comprising: blank capsule core 13.65 mg; esomeprazole magnesium 22.7 mg; hydroxypropyl methylcellulose 4.46 mg; hydroxypropyl cellulose 7.84 mg; ethyl cellulose 7.7 mg; talc 7.07 mg; glyceryl monostearate and glyceryl distearate 0.99 mg; magnesium stearate 2.02 mg; eutectic LD30-55 19.716 mg; triethyl citrate 1.99 mg; Tween 80 0.39 mg; Alternatively, formula four: The microcapsules contain: 13.65 mg blank capsule core; 22.7 mg esomeprazole magnesium; 9.57 mg hydroxypropyl methylcellulose; 4.46 mg hydroxyethyl cellulose; 0.38 mg talc; 7.07 mg mono- and di-stearylglycerols; 2.02 mg magnesium stearate; 19.716 mg LD30-55 of Eucerin; 1.99 mg triglyceride; and 0.32 mg Tween 80. The sustained-release microcapsules consist of: a blank capsule core of 13.65 mg; esomeprazole magnesium of 22.7 mg; hydroxypropyl cellulose of 9.57 mg; hydroxyethyl cellulose of 4.46 mg; talc of 0.38 mg; glyceryl monostearate and glyceryl distearate of 7.07 mg; magnesium stearate of 2.02 mg; eutectic LD30-55 of 19.716 mg; glyceryl triacetate of 1.99 mg; and Tween 80 of 0.32 mg.

9. A method for preparing an esomeprazole magnesium capsule formulation as described in any one of claims 1-8, characterized in that, Includes the following steps: Step 1: Preparation of immediate-release microcapsules, including: Preparation of drug-loaded microcapsules: The drug-loaded layer composition is coated onto the blank pellet core using fluidized bed bottom spraying technology to obtain drug-loaded microcapsules; B. Preparation of isolation microspheres: The drug-loaded microspheres are coated with an isolation layer composition using fluidized bed bottom spraying technology to obtain isolation microspheres; C. Preparation of enteric-coated microspheres: The isolated microspheres are coated with an enteric coating composition using fluidized bed bottom spraying technology to obtain enteric-coated microspheres; D. Preparation of constant-release microcapsules: The enteric-coated microcapsules were coated with a thin film material and sieved using fluidized bed bottom spraying technology to obtain constant-release microcapsules; Step 2: Preparation of sustained-release microspheres, including: E. Preparation of drug-loaded microspheres: The drug-loaded microspheres are prepared by coating the blank pellet core with the drug-loaded layer composition using fluidized bed bottom spraying technology. F. Preparation of isolation microspheres: The drug-loaded microspheres are coated with an isolation layer composition using fluidized bed bottom spraying technology to obtain isolation layer drug-loaded microspheres; G. Preparation of enteric-coated microspheres: The isolated microspheres are coated with an enteric coating composition using fluidized bed bottom spraying technology to obtain enteric-coated microspheres; H. Preparation of sustained-release microcapsules: The enteric-coated microcapsules were coated with a sustained-release material and sieved using fluidized bed bottom spraying technology to obtain sustained-release microcapsules; Step 3: Mix the immediate-release microspheres and sustained-release microspheres obtained in Step 1 and Step 2, with the immediate-release microspheres accounting for 25% to 75% of the total weight and the sustained-release microspheres accounting for 75% to 25% of the total weight. Step 4: Fill the mixed microspheres obtained in Step 3 into capsules.

10. The method for preparing the esomeprazole magnesium capsule formulation according to claim 9, characterized in that, The fluidized bed material temperature in A and E is 35~38℃, and the atomization pressure is 1.8~2.0 bar; the fluidized bed material temperature in B and F is 35~38℃, and the atomization pressure is 1.8~2.0 bar; the fluidized bed material temperature in C and G is 30~32℃, and the atomization pressure is 2.0~2.5 bar; the fluidized bed material temperature in D is 30~32℃, the atomization pressure is 1.8~2.0 bar, and the sieve mesh size is 30~60 mesh; the fluidized bed material temperature in H is 35~40℃, the atomization pressure is 1.8~2.0 bar, and the sieve mesh size is 30~60 mesh; in step three, a mixer is used for mixing, the mixing time is 15~30 min, and the mixing speed is 10~15 rpm.

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