Escomeprazole enteric capsule as well as preparation method and application thereof

Abstract

The invention relates to an escomeprazole enteric capsule as well as a preparation method and application thereof, and belongs to the field of pharmaceutical preparations. The enteric capsule comprises an escomeprazole magnesium enteric pellet, the enteric pellet sequentially comprises a blank pellet core, an upper drug layer, an isolation layer and an enteric layer from inside to outside, the upper drug layer comprises escomeprazole and tris (hydroxymethyl) aminomethane, and the weight ratio of escomeprazole to tris (hydroxymethyl) aminomethane is 1: (0.01-0.03).

Description

Technical Field

[0001] This invention relates to an esomeprazole enteric-coated capsule, its preparation method, and its uses, belonging to the field of pharmaceutical preparations. Background Technology

[0002] With the increasingly fast pace of life, digestive system diseases have become a prevalent and serious threat to people's health. Peptic ulcer is one of the most common digestive system diseases, a chronic condition with an incidence rate of up to 10%, characterized by spontaneous remission and recurrent episodes. Before the 1970s, only weakly alkaline antacids could be used to treat peptic ulcers, but this treatment could not address the underlying cause of excessive gastric acid secretion, resulting in numerous cases requiring surgical removal.

[0003] Currently, drug therapy remains the primary treatment for peptic ulcers, mainly including proton pump inhibitors (PPIs) and H2 receptor antagonists. PPIs include irreversible and reversible PPIs. Irreversible PPIs such as rabeprazole and omeprazole are commonly used in clinical practice.

[0004] As the S-isomer of omeprazole, esomeprazole stands out from thousands of compounds as the first PPI with only a single optical isomer. Its pharmacokinetics are superior to omeprazole, and it can more effectively inhibit acidity.

[0005] Esomeprazole magnesium, developed by AstraZeneca, is the first proton pump inhibitor with a single optical isomer. It was first marketed in Sweden in 2000 as enteric-coated tablets in 20mg and 40mg strengths, and subsequently approved for marketing in several other countries, including Europe and the United States. The original AstraZeneca-marketed oral formulations of esomeprazole magnesium worldwide include enteric-coated capsules, enteric-coated tablets, and enteric-coated dry suspensions, under the brand name "NEXIUM®". These formulations are bioequivalent, and the indications are consistent across all formulations. my country approved AstraZeneca's enteric-coated esomeprazole magnesium tablets in 2002. In recent years, generic versions of enteric-coated esomeprazole magnesium tablets and capsules have also been approved for marketing, but the original enteric-coated capsules are not yet available in my country.

[0006] Esomeprazole magnesium contains a sulfonylbenzimidazole structure, which is easily degraded by acidic compounds, making it unstable in acidic media. Therefore, current research on enteric-coated capsules of esomeprazole magnesium mainly focuses on improving the stability of esomeprazole in acidic environments. For example: Chinese patent CN118649150A discloses a method for preparing esomeprazole magnesium enteric-coated capsules, which uses a dry coating process to directly disperse polymer excipients on microcapsules, thereby improving the stability and dissolution of esomeprazole.

[0007] Chinese patent CN116807990A discloses an esomeprazole magnesium enteric-coated capsule and its preparation method, which improves the acid resistance of esomeprazole by using peptides containing basic amino acids.

[0008] Chinese patent CN105326801A discloses an esomeprazole magnesium enteric-coated capsule and its preparation method. The quality of the enteric coating is improved by controlling the droplet size distribution during the coating process, thereby enhancing the acid resistance of esomeprazole.

[0009] However, although the S-configuration omeprazole (i.e., esomeprazole) is metabolized much slower than the R-configuration omeprazole (which is the main reason why esomeprazole is mainly used in this field), existing esomeprazole reagents still have technical problems such as excessively rapid metabolism and low bioavailability. Summary of the Invention

[0010] A first aspect of the present invention is to provide an enteric-coated capsule of esomeprazole, comprising: an esomeprazole magnesium enteric-coated microsphere contained in the capsule, wherein the enteric-coated microsphere comprises, from the inside out: a blank core, a drug-coated layer, an isolation layer and an enteric layer, wherein the drug-coated layer comprises esomeprazole and tris(hydroxymethyl)aminomethane, and the weight ratio of esomeprazole to tris(hydroxymethyl)aminomethane is 1:0.01-0.03.

[0011] In a further embodiment, the weight ratio of esomeprazole to tris(hydroxymethyl)aminomethane is 1:0.02.

[0012] In one embodiment, the drug-coated layer further comprises L-arginine, and the weight ratio of esomeprazole, tris(hydroxymethyl)aminomethane and L-arginine is 1:0.067-0.02:0.033-0.01.

[0013] In another embodiment, the weight ratio of the tris(hydroxymethyl)aminomethane to L-arginine is 1:0.5-2.

[0014] In another embodiment, the top dressing layer further comprises a binder and talc, wherein the binder is selected from one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene, or polyethylene glycol; and the weight ratio of esomeprazole, binder, and talc is 1:0.1-0.5:0.001-0.01. More specifically, the weight ratio of esomeprazole, binder, and talc is 1:0.16:0.004.

[0015] In another embodiment, the insulating layer excipient is selected from hydroxypropyl cellulose, talc, and / or magnesium stearate. Further, the weight ratio of esomeprazole, hydroxypropyl cellulose, talc, and magnesium stearate is 1:0.2-0.4:0.3-0.5:0.01-0.05, and even more specifically, 1:0.235:0.42:0.03.

[0016] In yet another embodiment, the enteric coating excipient is selected from Eutec L30D. 55. Triethyl citrate, glyceryl mono- and glyceryl di-stearate, and / or polysorbate 80. Further, the esomeprazole, eutectic L30D... 55. The weight ratio of triethyl citrate, glyceryl monostearate and glyceryl distearate and polysorbate 80 is 1:0.5-1.5:0.05-0.2:0.01-0.1:0.01-0.03; more specifically, 1:0.96:0.096:0.048:0.019.

[0017] A second aspect of the present invention is to provide a method for preparing the esomeprazole enteric-coated capsules, comprising: 1) Drug coating: Prepare the drug coating solution: Add the weighed excipients to purified water and stir until completely dissolved. Add the weighed esomeprazole magnesium and tris(hydroxymethyl)aminomethane and continue stirring until completely dissolved. Set aside for later use. Coating: Add the sucrose pellet cores to the coating machine, adjust the pump speed, coat, and dry; Sifting: The dried drug pellets were sieved using 600... The micro-pills are sieved through a sieve of m, and the qualified micro-pills are placed in a clean container for later use. (2) Coating of the isolation layer Preparation of the isolation layer coating solution: Add the weighed excipients to purified water and stir until completely dissolved.

[0018] Coating: Add the drug micro-pellets to the coating machine, adjust the pump speed, coat, and dry; Sieving: The dried isolation microspheres were sieved using 600... The microspheres are sieved through a sieve of m, and the qualified isolation pellets are placed in a clean container for later use. (3) Enteric coating Preparation of enteric coating solution: Add the weighed excipients to purified water for emulsification, add purified water while stirring, cool to below 30°C to form an aqueous dispersion of Euterich L30D-55, then pour the cooled emulsion into the Euterich L30D-55 aqueous dispersion and stir for later use.

[0019] Coating: Add the isolated micro-pellets into the coating machine, adjust the pump speed, coat, and dry; Sieving: The dried enteric-coated microspheres were sieved using 710. The microcapsules are sieved through a sieve of m, and the qualified enteric-coated microcapsules are placed in a clean container for later use. (4) Total mixed capsules General mixing: First, add about half of the enteric-coated microcapsules to the column mixing hopper. Then, add talc powder through a 60-mesh sieve to the column mixing hopper. Finally, add the other half of the enteric-coated microcapsules to the column mixing hopper. Set the mixing speed to 1000 rpm, start the mixing equipment, and mix for 10 minutes. After mixing, discharge the material, pass the microcapsules through a 16-mesh sieve, and then fill the enteric-coated microcapsules into capsule shells to obtain the final product.

[0020] A third aspect of the present invention is to provide the use of the esomeprazole enteric-coated capsules in the preparation of a medicament for treating peptic ulcer disease.

[0021] To improve the bioavailability and acid resistance of esomeprazole, this invention, through extensive excipient screening, obtained a tris(hydroxymethyl)aminomethane excipient that significantly improves the bioavailability of esomeprazole and also enhances its acid resistance. Although it slightly reduces the dissolution rate of enteric-coated microspheres, this does not affect the application of the excipient. To further improve the formulation quality of esomeprazole, this invention further screened an excipient combination, namely tris(hydroxymethyl)aminomethane and L-arginine, which improves dissolution while ensuring the bioavailability of esomeprazole.

[0022] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 In vivo pharmacokinetic curve of esomeprazole enteric-coated capsules and enteric-coated microcapsules in rats. Detailed Implementation The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Example 1: Effect of excipients on the metabolism of esomeprazole in hepatic microsomes To improve the bioavailability of esomeprazole, the first-pass effect in the liver must be considered. Therefore, finding suitable excipients that can slow down the metabolism of esomeprazole in the liver should significantly improve its bioavailability. Furthermore, the excipients should be absorbable or partially absorbable in the intestine; otherwise, they cannot slow down the metabolism of esomeprazole in the liver. This invention, combining excipient design software, esomeprazole and excipient compatibility tests, and in vitro Caco2 cell permeability assays, has preliminarily screened the following excipients that meet the above requirements for liver microsome assays: vitamin E polyethylene glycol succinate, chitosan, L-arginine, tris(hydroxymethyl)aminomethane (Tris), and nicotinamide.

[0026] Test method: Preparation of liver microsomes: SD rats, approximately 200g in size, were fasted for 16 hours and then euthanized by decapitation. The livers were quickly removed, and rat liver microsomes were extracted using the calcium salt precipitation method and homogenized. The protein concentration of rat liver microsomes was determined using the Coomassie brilliant blue binding method, and the total CYP450 was determined using the Omura method.

[0027] In vitro metabolic culture: The initial culture system included 50 μL of rat liver microsomal protein suspension (protein concentration 50 mg / L), 20 μL of 1 mg / L esomeprazole magnesium PBS solution, 20 μL of 0.02 mg / mL excipient solution, 20 μL of 50 mmol / L NADPH PBS solution, and finally 0.1 mol / L phosphate culture medium to a final volume of 1 mL. The mixture was vortexed for 30 s, reacted in a 37°C water bath for 20 min, then 2 mL of ice-cold dichloromethane and 20 μL of phenacetin internal standard were added. The mixture was vortexed for 30 s (to precipitate the protein and stop the reaction), centrifuged at 12000 rpm for 5 min, and 1 mL of the organic layer was collected, dried under N2 gas, dissolved in 50 μL of mobile phase, vortexed for 30 s, centrifuged at 12000 rpm for 5 min, and 20 μL of the supernatant was injected for analysis.

[0028] Detection of 5-hydroxyomeprazole (5-OHOMZ) and esomeprazole magnesium (S-OMZ): Detection method: Chromatographic conditions: octadecylsilane-bonded silica gel column (Microspher C18 column, 4.6 mm) as the packing material. 100mm, 5 m); the mobile phase was acetonitrile-0.02 mol / L phosphoric acid aqueous solution (26:74, V / V), and the sample was pre-treated with 0.45 μL of chlorine dioxide before injection. The sample was filtered through a microporous membrane and degassed by ultrasound; the detection wavelength was 302 nm; the column temperature was 30℃; and the injection volume was 20 μL. Phenacetin was used as an internal standard to calculate the contents of 5-hydroxyomeprazole and esomeprazole magnesium, and the ratio of 5-hydroxyomeprazole to esomeprazole magnesium was further calculated to assess the effect of excipients on the hepatic metabolism of esomeprazole magnesium.

[0029] The results are as follows: Existing research has confirmed that the primary metabolic pathway of esomeprazole is via the CYP2C19 enzyme in the liver, which metabolizes esomeprazole to 5-hydroxyomeprazole. Therefore, in in vitro liver microsomal assays, the ratio of 5-hydroxyomeprazole to esomeprazole can be used to assess the relevant effects of excipients on metabolism. A higher ratio indicates that esomeprazole is metabolized by liver microsomes more rapidly.

[0030] The test results of the above excipients show that although these five excipients may affect the metabolic enzymes in liver microsomes from a computational chemistry perspective, the experimental results indicate that chitosan not only did not reduce the metabolic rate of esomeprazole, but actually accelerated it. Nicotinamide had no significant effect on the metabolism of esomeprazole. Tris, vitamin E polyethylene glycol succinate, and L-arginine all significantly reduced the metabolism of esomeprazole, with vitamin E polyethylene glycol succinate showing the most significant effect. Therefore, subsequent experiments will mainly investigate the use of Tris, vitamin E polyethylene glycol succinate, and L-arginine as excipients in the preparation of enteric-coated capsules and enteric-coated microspheres.

[0031] Example 2 Preparation of esomeprazole enteric-coated microcapsules Prescription composition: Sugar-coated pellets (0.25-0.45mm) 600g Upper layer of medicine: 1 kg of esomeprazole magnesium, 160 g of hydroxypropyl methylcellulose, 20 g of vitamin E polyethylene glycol succinate, and 4.64 kg of purified water.

[0032] Isolation layer: Hydroxypropyl cellulose 235g, talc 42g, magnesium stearate 30g, purified water 4.7kg.

[0033] Enteric coating: Eutec L30D-55 960g, Triethyl Citrate 96g, Glyceryl Mono- and Di-Stearates 48g, Polysorbate 8019g, Purified Water 1.32kg Preparation method: 1) Drug coating: Prepare the drug coating solution: Add the weighed hydroxypropyl methylcellulose to purified water and stir until completely dissolved. Add the weighed esomeprazole magnesium and vitamin E polyethylene glycol succinate and continue stirring until completely dissolved. Set aside.

[0034] Coating: Add the sucrose pellet cores to the coating machine, adjust the pump speed, and perform coating and drying. The coating machine should be set with the following parameters: preheat for at least 30 minutes, fan frequency: 23.00Hz; inlet air humidity: 8±3g / m³. 3 Air inlet temperature: 80℃; Material temperature: 40℃.

[0035] Sifting: The dried drug pellets were sieved using 600... The micro-pills are sieved through a sieve of m, and the qualified micro-pills are placed in a clean container for later use. (2) Coating of the isolation layer Preparation of the isolation layer coating solution: Add the weighed hydroxypropyl cellulose to purified water and stir until completely dissolved. Add magnesium stearate and talc and continue stirring until evenly dispersed. Set aside for later use.

[0036] Coating: Add the drug-coated microcapsules to the coating machine, adjust the pump speed, and perform coating and drying. The coating machine should be set with the following parameters: preheat for at least 30 minutes; fan frequency: 28.00Hz; inlet air humidity: 8±3g / m³. 3 Air inlet temperature: 80℃; Material temperature: 40℃.

[0037] Sieving: The dried isolation microspheres are sieved through a 600μm sieve. Qualified isolation microspheres are placed in a clean container for later use. (3) Enteric coating Preparation of enteric coating solution: Weigh out polysorbate 80, triethyl citrate and glyceryl mono- and di-stearates and emulsify in purified water. Add purified water while stirring and cool to below 30°C to prepare an aqueous dispersion of Euterich L30D-55. Pour the cooled emulsion into the Euterich L30D-55 aqueous dispersion and stir for later use.

[0038] Coating: Add the isolation microparticles to the coating machine, adjust the pump speed, perform coating, and dry; set the coating machine parameters as follows: preheat for at least 30 minutes, fan frequency: 31.00Hz; inlet air humidity: 8±3g / m³. 3 Air inlet temperature: 45℃; Material temperature: 30℃.

[0039] Sieving: The dried enteric-coated microspheres are sieved through a 710μm sieve. Qualified enteric-coated microspheres are placed in a clean container for later use.

[0040] (4) Total Mix Weigh 0.75% of the weight of the enteric-coated microcapsules, put them into a pharmaceutical low-density polyethylene bag, and tie it with a cable tie. General mixing: First, add about half of the enteric-coated microcapsules to the column mixing hopper. Then, add talc powder through a 60-mesh sieve to the column mixing hopper. Finally, add the other half of the enteric-coated microcapsules to the column mixing hopper. Set the mixing speed to 10.00 rpm, start the mixing equipment, and mix for 10 minutes. After mixing, discharge the material, pass the microcapsules through a 16-mesh sieve, and pack the sieved microcapsules into double-layer pharmaceutical low-density polyethylene bags and tie them securely for later use.

[0041] Example 3: Preparation of enteric-coated microcapsules for esomeprazole enteric-coated capsules The method is the same as in Example 2, except that vitamin E polyethylene glycol succinate is replaced with an equal weight of L-arginine.

[0042] Example 4: Preparation of enteric-coated microcapsules for esomeprazole enteric-coated capsules The method is the same as in Example 2, except that vitamin E polyethylene glycol succinate is replaced with an equal weight of Tris.

[0043] Example 5: Investigation of acid resistance and dissolution rate of esomeprazole enteric-coated capsules and enteric-coated microcapsules Acid resistance test method: The test method (General Rule 0931, Method 1) published in the acid resistance test section of the Chinese Pharmacopoeia 2025 Edition, Part II, "Omeprazole Enteric-coated Capsules", was adopted. The dissolution medium was NaCl HCl solution (1 g NaCl, 3.5 ml hydrochloric acid, and water to 500 ml). The rotation speed was 100 rpm. After 120 minutes, the basket was removed, and the enteric-coated microspheres in the basket were washed with water until neutral. Then, the content of esomeprazole magnesium in the microspheres was determined (HPLC method, see the Chinese Pharmacopoeia 2020 Edition, Part II, "Omeprazole Enteric-coated Capsules" for details). The degradation rate in acid was calculated (degradation rate = (labeled amount - microsphere content) / labeled amount).

[0044] Dissolution testing: The first basket method (0931) of Part IV, General Chapter, Chinese Pharmacopoeia 2025 Edition was used. The dissolution medium was 100 rpm. For the first two hours, 300 ml of pH 1.2 hydrochloric acid solution was used as the dissolution medium. After two hours, 700 ml of pH 6.8 phosphate buffer was used as the dissolution medium. The content of esomeprazole magnesium in the dissolution medium was determined using the above method, and the dissolution rate was calculated.

[0045] The enteric-coated microspheres prepared in Examples 2-4 were tested for acid resistance and dissolution rate, and the specific results are as follows: 1) Acid resistance of the enteric-coated microspheres prepared in Examples 2-4 The comparative preparation method is the same as in Example 2, except that vitamin E polyethylene glycol succinate is not added. 2) Dissolution rate of enteric-coated microspheres prepared in Examples 2-4 The results above show that in terms of acid resistance, the group using vitamin E polyethylene glycol succinate as an excipient in Example 2 was worse. This may be related to the slightly acidic nature of vitamin E polyethylene glycol succinate itself. Therefore, from the perspective of acid resistance and stability, although vitamin E polyethylene glycol succinate can improve the bioavailability of esomeprazole, based on the current formulation design, it is more suitable as an excipient and needs to be incorporated into the formulation design in the future from a more comprehensive excipient configuration perspective. Groups 3 and 4 showed excellent acid resistance, but the dissolution rate of group 4 was slightly worse, although this did not affect the application of the enteric-coated microcapsules of Example 4 from a formulation perspective. Considering the excellent potential of Tris as an excipient in slowing the dissolution of esomeprazole in liver microsomes, in order to further improve the dissolution rate of the enteric-coated microcapsules of group 4, this invention further explored the acid resistance and dissolution rate of enteric-coated microcapsules prepared by combining Tris with L-arginine.

[0046] Example 6: Investigation of acid resistance and dissolution rate of esomeprazole enteric-coated capsules and enteric-coated microcapsules Preparation of enteric-coated microcapsules: The method is the same as in Example 2, except that the amount of vitamin E polyethylene glycol succinate is replaced with the following excipient combination: Group 1: L-arginine 6.7g, Tris 13.3g; Group 2: L-arginine 10g, Tris 10g; Group 3: L-arginine 13.3g, Tris 6.7g; The methods for testing acid resistance and dissolution rate are the same as in Example 5. The results are as follows: 1) Acid resistance results: 2) Dissolution results The results above show that the combination of L-arginine and Tris significantly improved the dissolution rate of enteric-coated microspheres, while the acid resistance did not decrease significantly.

[0047] Example 7 Pharmacokinetic Study of Esomeprazole Enteric-coated Microcapsules Thirty SD rats were randomly divided into 5 groups. Before the experiment, the rats were fasted but allowed free access to water. Each rat was administered esomeprazole enteric-coated microcapsules via gavage at a dose of 5 mg / kg. Subsequently, at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h, approximately 0.5 ml of blood was collected from the retro-orbital venous plexus and placed in heparinized centrifuge tubes. After centrifugation at 11000 rpm for 10 minutes, the supernatant was collected and stored at -20℃ for analysis.

[0048] Group 1: Preparation method is the same as in Example 3; Group 2: Preparation method is the same as in Example 4; Group 3: The preparation method is the same as Group 1 in Example 6; Group 4: The preparation method is the same as in Example 3; the only difference is that L-arginine is not added. Group 5: The preparation method is the same as in Example 3; the only difference is that L-arginine is replaced with an equal weight of magnesium oxide. Detection method: Chromatographic conditions: octadecylsilane-bonded silica gel as the packing material (Microspher C18 column, 4.6 mm). 100mm, The mobile phase was acetonitrile-0.02 mol / L phosphoric acid aqueous solution (26:74, V / V). The sample was pre-treated with 0.45 mL of chlorine dioxide before injection. Microporous membrane filtration followed by ultrasonic degassing; detection wavelength: 302 nm; column temperature: 30 °C; injection volume: 20 μL. l.

[0049] Plasma sample processing: Remove 100 plasma samples l, add 100 1 acetonitrile, vortex for 1 min, centrifuge at 12000 r / min for 10 min, and take the supernatant for analysis.

[0050] A standard curve was established using esomeprazole as a standard, and the blood drug concentration of each sample was calculated. The linearity, sensitivity, precision, accuracy, recovery rate, and stability of the detection method all met the detection requirements.

[0051] The results are as follows: See the drug-time curve. Figure 1 The pharmacokinetic parameters are shown in the table below: Combination Figure 1 As shown in the table above, there were no significant differences in peak time and peak plasma concentration among the five groups of enteric-coated microcapsules. However, during metabolism, the enteric-coated microcapsules containing Tris (group 2) and Tris and L-arginine (group 3) exhibited significantly slower metabolic rates compared to group 1 (group with added L-arginine), group 4 (group without added L-arginine), and group 5 (group with added alkali protectant), resulting in significantly improved bioavailability (P<0.01, t-test). There was no statistically significant difference in bioavailability between groups 2 and 3. Group 1 also showed some improvement in bioavailability compared to groups 4 and 5, but this difference was not statistically significant.

[0052] Example 8: Preparation of Esomeprazole Enteric-coated Capsules The enteric-coated microcapsules prepared in Example 4 were used for capsule filling. No. 4 gelatin empty capsules were used and filled according to the relevant specifications (20mg: 2000-2600 capsules / minute). After filling, the capsules were sealed and weighed.

[0053] Example 9: Preparation of Esomeprazole Enteric-coated Capsules The enteric-coated microspheres prepared in Group 1 of Example 6 were encapsulated using the same method as in Example 8. Example 10 Preparation of Esomeprazole Enteric-coated Capsules The method is the same as in Example 8, except that the amount of Tris in the enteric-coated microcapsules is 30 mg.

[0054] Example 11 Preparation of esomeprazole enteric-coated capsules The method is the same as in Example 8, except that the amount of Tris in the enteric-coated microcapsules is 10 mg.

[0055] Example 12 Preparation of esomeprazole enteric-coated capsules The method is the same as in Example 9, except that the amount of Tris in the enteric-coated microcapsules is 20 mg and the amount of L-arginine is 10 mg.

[0056] Example 13 Preparation of esomeprazole enteric-coated capsules The method is the same as in Example 9, except that the amount of Tris in the enteric-coated microcapsules is 6.7 mg and the amount of L-arginine is 3.3 mg.

Claims

1. An enteric-coated capsule of esomeprazole, comprising: The capsule contains esomeprazole magnesium enteric-coated microspheres, which, from the inside out, consist of: a blank core, a drug-coated layer, an isolation layer, and an enteric layer. The drug-coated layer contains esomeprazole and tris(hydroxymethyl)aminomethane, and the weight ratio of esomeprazole to tris(hydroxymethyl)aminomethane is 1:0.01-0.

03.

2. The enteric-coated capsule of esomeprazole according to claim 1, characterized in that, The weight ratio of esomeprazole to tris(hydroxymethyl)aminomethane is 1:0.

02.

3. The enteric-coated capsule of esomeprazole according to claim 1, characterized in that, The drug-coated layer also contains L-arginine, and the weight ratio of esomeprazole, tris(hydroxymethyl)aminomethane and L-arginine is 1:0.067-0.02:0.033-0.

01.

4. The enteric-coated capsule of esomeprazole according to claim 3, characterized in that, The weight ratio of the tris(hydroxymethyl)aminomethane to L-arginine is 1:0.5-2.

5. The enteric-coated capsule of esomeprazole according to claim 1, characterized in that, The drug-coated layer also includes an adhesive and talc, wherein the adhesive is selected from one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyoxyethylene, or polyethylene glycol.

6. The enteric-coated capsule of esomeprazole according to claim 1, characterized in that, The insulating layer material is selected from hydroxypropyl cellulose, talc and / or magnesium stearate.

7. The enteric-coated capsule of esomeprazole according to claim 1, characterized in that, The enteric coating excipient is selected from Eutec L30D.

55. Triethyl citrate, glyceryl mono- and di-stearates and / or polysorbate 80.

8. A method for preparing the esomeprazole enteric-coated capsules according to any one of claims 1-7, characterized in that, It includes: 1) Drug coating: Prepare the drug coating solution: Add the weighed excipients to purified water and stir until completely dissolved. Add the weighed esomeprazole magnesium and tris(hydroxymethyl)aminomethane and continue stirring until completely dissolved. Set aside for later use. Coating: Add the sucrose pellet cores to the coating machine, adjust the pump speed, coat, and dry; Sieving: The dried drug pellets were sieved using 600... The micro-pills are sieved through a sieve of m, and the qualified micro-pills are placed in a clean container for later use. (2) Coating of the isolation layer Preparation of the isolation layer coating solution: Add the weighed excipients to purified water and stir until completely dissolved; set aside. Coating: Add the drug micro-pellets to the coating machine, adjust the pump speed, coat, and dry; Sieving: The dried isolation microspheres were sieved using 600... The microspheres are sieved through a sieve of m, and the qualified isolation pellets are placed in a clean container for later use. (3) Enteric coating Preparation of enteric coating solution: Add the weighed excipients to purified water for emulsification, add purified water while stirring, cool to below 30°C to make a water dispersion of Euterich L30D-55, then pour the cooled emulsion into the Euterich L30D-55 water dispersion and stir for later use; Coating: Add the isolated micro-pellets into the coating machine, adjust the pump speed, coat, and dry; Sieving: The dried enteric-coated microspheres were sieved using 710. The microcapsules are sieved through a sieve of m, and the qualified enteric-coated microcapsules are placed in a clean container for later use. (4) Total mixed capsules General mixing: First, add about half of the enteric-coated microcapsules to the column mixing hopper. Then, add talc powder through a 60-mesh sieve to the column mixing hopper. Finally, add the other half of the enteric-coated microcapsules to the column mixing hopper. Set the mixing speed to 1000 rpm, start the mixing equipment, and mix for 10 minutes. After mixing, discharge the material, pass the microcapsules through a 16-mesh sieve, and then fill the enteric-coated microcapsules into capsule shells to obtain the final product.

9. The use of the esomeprazole enteric-coated capsules according to any one of claims 1-7 in the preparation of a medicament for treating peptic ulcer disease.

Images