Enteric-coated tablet containing rabeprazole sodium and application of enteric-coated tablet

Abstract

The invention provides an enteric-coated tablet containing rabeprazole sodium and application of the enteric-coated tablet. The enteric-coated tablet containing rabeprazole sodium comprises a tablet core, an isolating layer and an enteric-coated layer. The applicant directly mixes the rabeprazole sodium and the cimetidine to prepare the enteric-coated tablet for treating peptic ulcer, when the concentration ratio of the rabeprazole sodium to the cimetidine is in a proper range, the treatment effect can be obviously improved compared with that of single rabeprazole sodium treatment, and toxic and side effects are not increased. The compound rabeprazole sodium enteric-coated tablet, which is different from the prior art, is prepared by adopting specific auxiliary materials and selecting a proper ratio, and the compound rabeprazole sodium enteric-coated tablet is relatively good in dissolution performance and high in bioavailability, and has a remarkable clinical value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to an enteric-coated tablet containing rabeprazole sodium and its uses. Background Art

[0002] Acid-related diseases are induced or caused by the action of gastric acid. According to different pathophysiological mechanisms, they can be divided into gastroesophageal reflux disease, peptic ulcer, Helicobacter pylori infection, Zollinger-Ellison syndrome, upper gastrointestinal bleeding, and stress-induced gastric mucosal lesions.

[0003] With the in-depth study of acid-related diseases, acid-suppressing drugs have evolved from H2 receptor antagonists to proton pump inhibitors represented by rabeprazole sodium. Since proton pump inhibitors inhibit the last step of gastric acid secretion, they can significantly reduce gastric acid secretion and are currently the main drugs for treating acid-related diseases.

[0004] The main symptoms of gastric ulcer include upper abdominal pain, digestive difficulties, loss of appetite, etc., which seriously affect the quality of life of patients. The factors inducing gastric ulcer are diverse, such as Helicobacter pylori infection, long-term intake of non-steroidal anti-inflammatory drugs, mental and psychological stress, etc. Therefore, improving the above symptoms, ameliorating the ulcer condition, and avoiding recurrence have become the primary tasks in the treatment of gastric ulcer. Although medical treatment methods have been constantly progressing and many treatment regimens have emerged, the treatment effect and drug safety are usually the most concerned topics for patients and medical staff. Most treatment methods are to inhibit gastric acid production and eliminate the cause, but due to the different sensitivities and tolerances of patients to drugs, a single treatment method cannot meet the needs of all patients.

[0005] Rabeprazole sodium is a proton pump inhibitor, which has the effect of selectively inhibiting gastric acid secretion, and has the advantages of rapid and long-lasting acid suppression and strong acid-suppressing ability. Its in vitro anti-HP effect is strong and it is widely used clinically. The main adverse reactions of rabeprazole sodium are mainly digestive tract symptoms, and the most common are clinical symptoms such as nausea, vomiting, and abdominal pain.

[0006] Enteric-coated tablets need to be insoluble in the stomach and gradually shed in the intestine to exert their drug effects. At present, there are already multiple different brands of enteric-coated preparations of rabeprazole sodium for clinical use, but a large amount of ethanol solvent is used in the prescription of enteric-coated tablets of rabeprazole sodium, resulting in a relatively high ethanol residue in the products.

[0007] Therefore, improving the efficacy of rabeprazole sodium, protecting the gastrointestinal tract, and reducing its adverse reactions are urgent problems to be solved at present. Summary of the Invention

[0008] Aiming at the existing adverse reactions of enteric-coated tablets of rabeprazole sodium and the trouble of combined use of multiple drugs, the present application provides an enteric-coated tablet containing rabeprazole sodium, its preparation method, and its application.

[0009] The applicant directly mixed rabeprazole sodium and cimetidine to prepare enteric-coated tablets for the treatment of digestive tract ulcers. It was found that when the concentration ratio of rabeprazole sodium to cimetidine was within a suitable range, a significantly improved therapeutic effect compared to the treatment with rabeprazole sodium alone could be obtained without increasing the toxic and side effects. By using specific excipients and selecting appropriate ratios, the present invention prepared a compound rabeprazole sodium enteric-coated tablet different from the prior art, which has good dissolution performance and high bioavailability, and has significant clinical value.

[0010] The present invention aims to provide an enteric-coated tablet containing rabeprazole sodium and its use.

[0011] To achieve the above object, the present invention adopts the following technical solutions:

[0012] In a first aspect of the present invention, there is provided an enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0013] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0014] The tablet core is composed of the following raw materials in parts by mass: 50 - 60 parts of rabeprazole sodium, 10 - 18 parts of cimetidine, 0.3 - 0.7 part of solubilizer, 12 - 15 parts of filler, 13 - 18 parts of disintegrant, 4 - 6 parts of lubricant, 3 - 6 parts of antioxidant, 8 - 12 parts of binder, and 3 - 6 parts of stabilizer.

[0015] Further, the solubilizer is anhydrous citric acid.

[0016] Further, the filler is microcrystalline cellulose.

[0017] Further, the disintegrant is cross-linked carboxymethylcellulose sodium.

[0018] Further, the lubricant is calcium stearate.

[0019] Further, the antioxidant is glycine.

[0020] Further, the binder is polyvinylpyrrolidone K30 and hydroxypropyl cellulose with a mass ratio of 2:3.

[0021] Further, the stabilizer is anhydrous sodium carbonate.

[0022] In an embodiment of the present invention, the tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of solubilizer, 15 parts of filler, 15 parts of disintegrant, 5 parts of lubricant, 5 parts of antioxidant, 10 parts of binder, and 5 parts of stabilizer.

[0023] In a preferred embodiment of the present invention, the tablet core is composed of the following raw materials in parts by mass: rabeprazole sodium 55 parts, cimetidine 15 parts, anhydrous citric acid 0.6 part, microcrystalline cellulose 15 parts, croscarmellose sodium 15 parts, calcium stearate 5 parts, glycine 5 parts, polyvinylpyrrolidone K30 4 parts, hydroxypropyl cellulose 6 parts, anhydrous sodium carbonate 5 parts.

[0024] The separating layer is composed of the following raw materials in parts by mass: hypromellose 2.0 - 2.5 parts, polyvinyl alcohol 0.5 - 1 part.

[0025] Further, the separating layer is composed of the following raw materials in parts by mass: hypromellose 2.5 parts, polyvinyl alcohol 1 part.

[0026] The enteric coating layer is composed of the following raw materials in parts by mass: enteric material 50 - 70 parts, lubricant 5 - 10 parts, anti - sticking agent 4 - 8 parts, plasticizer 10 - 16 parts, light - shielding agent 1.5 - 2.5 parts.

[0027] Further, the enteric material in the enteric coating layer is selected from type A methacrylic acid copolymer.

[0028] Further, the lubricant in the enteric coating layer is selected from magnesium lauryl sulfate.

[0029] Further, the anti - sticking agent in the enteric coating layer is selected from colloidal silicon dioxide.

[0030] Further, the plasticizer in the enteric coating layer is selected from glycerol.

[0031] Further, the light - shielding agent in the enteric coating layer is selected from titanium dioxide.

[0032] In an embodiment of the present invention, the enteric coating layer is composed of the following raw materials in parts by mass: enteric material 60 parts, lubricant 8 parts, anti - sticking agent 6 parts, plasticizer 12 parts, light - shielding agent 2.0 parts.

[0033] In a preferred embodiment of the present invention, the enteric coating layer is composed of the following raw materials in parts by mass: type A methacrylic acid copolymer 60 parts, magnesium lauryl sulfate 8 parts, colloidal silicon dioxide 6 parts, glycerol 12 parts, titanium dioxide 2.0 parts.

[0034] The second aspect of the present invention provides a preparation method of an enteric - coated tablet containing rabeprazole sodium, comprising the following steps:

[0035] (1) Mix the tablet core raw materials such as rabeprazole sodium, cimetidine, anhydrous citric acid, microcrystalline cellulose, croscarmellose sodium, calcium stearate, glycine, polyvinylpyrrolidone K30, hydroxypropyl cellulose, and anhydrous sodium carbonate evenly, put them into a wet granulator, spray an appropriate amount of ethanol for granulation, and press into tablets to obtain the tablet core;

[0036] (2) Mix hydroxypropyl methylcellulose and polyvinyl alcohol to form a coating premix, add water to prepare a coating solution, evenly spray the coating solution on the surface of the tablet core, and perform fluidized bed drying treatment after spraying is completed;

[0037] (3) Add water to magnesium lauryl sulfate, colloidal silicon dioxide, glycerin, and titanium dioxide, stir evenly, add to type A methacrylic acid copolymer, stir, and perform enteric coating on the tablet core wrapped with the isolation layer to obtain the enteric-coated tablet containing rabeprazole sodium of the present invention.

[0038] In the third aspect of the present invention, there is provided the use of the above enteric-coated tablet containing rabeprazole sodium in the preparation of drugs for treating digestive tract ulcers.

[0039] Furthermore, the digestive tract ulcer is gastric ulcer or duodenal ulcer.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The applicant directly mixed rabeprazole sodium and cimetidine to prepare an enteric-coated tablet for the treatment of digestive tract ulcers. It was found that when the concentration ratio of rabeprazole sodium to cimetidine was within a suitable range, a significantly improved therapeutic effect compared with the treatment with rabeprazole sodium alone could be obtained without increasing the toxic and side effects. By using specific excipients and selecting appropriate ratios, the present invention prepared a compound rabeprazole sodium enteric-coated tablet different from the prior art, which has good dissolution performance and high bioavailability, and has significant clinical value.

[0042] The preparation process of the enteric-coated tablet containing rabeprazole sodium of the present invention is simple, suitable for industrial scale production, beneficial to expanding the clinical application of rabeprazole sodium, and has important social value. Description of the Drawings

[0043] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0044] Figure 1 Effect on the total gastric acid value of rats. Different lowercase letters above the bar graph indicate significant differences between different groups (P < 0.05). Specific Embodiments

[0045] The following further elaborates on the content of the present invention through specific embodiments, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following embodiments. The following embodiments are used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Those of ordinary skill in the art who modify or equivalently replace the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention still fall within the protection scope of the present invention.

[0046] Example 1

[0047] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, an isolating layer, and an enteric coating layer.

[0048] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0049] The isolating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0050] The enteric coating layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0051] The weight ratio of the tablet core to the isolating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0052] The preparation method includes the following steps:

[0053] (1) Thoroughly mix the raw materials of the tablet core such as rabeprazole sodium, cimetidine, anhydrous citric acid, microcrystalline cellulose, croscarmellose sodium, calcium stearate, glycine, polyvinylpyrrolidone K30, hydroxypropyl cellulose, and anhydrous sodium carbonate, put them into a wet granulator, spray an appropriate amount of ethanol for granulation, and press into tablets to obtain the tablet core;

[0054] (2) Mix hypromellose and polyvinyl alcohol to form a coating premix, add water to prepare a coating solution, evenly spray the coating solution on the surface of the tablet core, and perform fluidized bed drying treatment after spraying;

[0055] (3) Add water to magnesium lauryl sulfate, colloidal silicon dioxide, glycerol, and titanium dioxide, stir evenly, add them to methacrylic acid copolymer type A, stir, and perform enteric coating on the tablet core wrapped with the isolating layer to obtain the enteric-coated tablet containing rabeprazole sodium of the present invention.

[0056] Example 2

[0057] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0058] The tablet core is composed of the following raw materials in parts by mass: 50 parts of rabeprazole sodium, 18 parts of cimetidine, 0.3 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 18 parts of croscarmellose sodium, 6 parts of calcium stearate, 4 parts of glycine, 3.2 parts of polyvinylpyrrolidone K30, 4.8 parts of hydroxypropyl cellulose, and 3 parts of anhydrous sodium carbonate.

[0059] The separating layer is composed of the following raw materials in parts by mass: 2.0 parts of hydroxypropyl methylcellulose and 0.5 part of polyvinyl alcohol.

[0060] The enteric layer is composed of the following raw materials in parts by mass: 50 parts of type A methacrylic acid copolymer, 5 parts of magnesium lauryl sulfate, 4 parts of colloidal silicon dioxide, 10 parts of glycerol, and 1.5 parts of titanium dioxide.

[0061] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0062] The preparation method refers to Example 1.

[0063] Example 3

[0064] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0065] The tablet core is composed of the following raw materials in parts by mass: 60 parts of rabeprazole sodium, 10 parts of cimetidine, 0.7 part of anhydrous citric acid, 12 parts of microcrystalline cellulose, 13 parts of croscarmellose sodium, 4 parts of calcium stearate, 6 parts of glycine, 4.8 parts of polyvinylpyrrolidone K30, 7.2 parts of hydroxypropyl cellulose, and 6 parts of anhydrous sodium carbonate.

[0066] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hydroxypropyl methylcellulose and 0.5 part of polyvinyl alcohol.

[0067] The enteric layer is composed of the following raw materials in parts by mass: 70 parts of type A methacrylic acid copolymer, 10 parts of magnesium lauryl sulfate, 8 parts of colloidal silicon dioxide, 16 parts of glycerol, and 2.5 parts of titanium dioxide.

[0068] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0069] The preparation method refers to Example 1.

[0070] Example 4

[0071] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0072] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0073] The separating layer is composed of the following raw materials in parts by mass: 2.0 parts of hypromellose and 1 part of polyvinyl alcohol.

[0074] The enteric coating layer is composed of the following raw materials in parts by mass: 65 parts of methacrylic acid copolymer type A, 10 parts of magnesium lauryl sulfate, 8 parts of colloidal silica, 10 parts of glycerol, and 2.5 parts of titanium dioxide.

[0075] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0076] The preparation method refers to Example 1.

[0077] Example 5

[0078] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric coating layer.

[0079] The tablet core is composed of the following raw materials in parts by mass: 60 parts of rabeprazole sodium, 10 parts of cimetidine, 0.7 part of anhydrous citric acid, 12 parts of microcrystalline cellulose, 13 parts of croscarmellose sodium, 4 parts of calcium stearate, 6 parts of glycine, 4.8 parts of polyvinylpyrrolidone K30, 7.2 parts of hydroxypropyl cellulose, and 6 parts of anhydrous sodium carbonate.

[0080] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0081] The enteric coating layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silica, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0082] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0083] The preparation method refers to Example 1.

[0084] Example 6

[0085] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric coating layer.

[0086] The tablet core is composed of the following raw materials in parts by mass: 50 parts of rabeprazole sodium, 18 parts of cimetidine, 0.3 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 18 parts of croscarmellose sodium, 6 parts of calcium stearate, 4 parts of glycine, 3.2 parts of povidone K30, 4.8 parts of hydroxypropyl cellulose, and 3 parts of anhydrous sodium carbonate.

[0087] The isolating layer is composed of the following raw materials in parts by mass: 2.0 parts of hydroxypropyl methylcellulose and 1 part of polyvinyl alcohol.

[0088] The enteric coating layer is composed of the following raw materials in parts by mass: 55 parts of type A methacrylic acid copolymer, 10 parts of magnesium lauryl sulfate, 6 parts of colloidal silica, 15 parts of glycerol, and 1.5 parts of titanium dioxide.

[0089] The weight ratio of the tablet core to the isolating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0090] The preparation method refers to Example 1.

[0091] Comparative Example 1

[0092] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, an isolating layer, and an enteric coating layer.

[0093] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of povidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0094] The isolating layer is composed of the following raw materials in parts by mass: 2.5 parts of hydroxypropyl methylcellulose and 1 part of polyvinyl alcohol.

[0095] The enteric coating layer is composed of the following raw materials in parts by mass: 60 parts of type A methacrylic acid copolymer, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silica, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0096] The weight ratio of the tablet core to the isolating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0097] The preparation method refers to Example 1.

[0098] Compared with Example 1, the difference in this comparative example is that it does not contain cimetidine.

[0099] Comparative Example 2

[0100] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, an isolating layer, and an enteric coating layer.

[0101] The tablet core is composed of the following raw materials in parts by mass: 45 parts of rabeprazole sodium, 20 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0102] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0103] The enteric coating layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0104] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0105] The preparation method refers to Example 1.

[0106] Compared with Example 1, the difference in this comparative example lies in the different ratio of rabeprazole sodium to cimetidine.

[0107] Comparative Example 3

[0108] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric coating layer.

[0109] The tablet core is composed of the following raw materials in parts by mass: 65 parts of rabeprazole sodium, 8 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0110] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0111] The enteric coating layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0112] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric coating layer is 10:1.8.

[0113] The preparation method refers to Example 1.

[0114] Compared with Example 1, the difference in this comparative example lies in the different ratio of rabeprazole sodium to cimetidine.

[0115] Comparative Example 4

[0116] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0117] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0118] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0119] The enteric layer is composed of the following raw materials in parts by mass: 60 parts of type A methacrylic acid copolymer, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0120] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0121] The preparation method refers to Example 1.

[0122] Compared with Example 1, the difference in this comparative example is that cimetidine is replaced with famotidine.

[0123] Comparative Example 5

[0124] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0125] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0126] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0127] The enteric layer is composed of the following raw materials in parts by mass: 60 parts of type A methacrylic acid copolymer, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0128] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0129] The preparation method refers to Example 1.

[0130] Compared with Example 1, the difference in this comparative example is that the raw materials constituting the tablet core do not contain polyvinylpyrrolidone K30 and microcrystalline cellulose.

[0131] Comparative Example 6

[0132] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0133] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, and 5 parts of anhydrous sodium carbonate.

[0134] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0135] The enteric layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0136] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0137] The preparation method refers to Example 1.

[0138] Compared with Example 1, the difference in this comparative example is that the raw materials of the tablet core do not contain anhydrous citric acid and hydroxypropyl cellulose.

[0139] Comparative Example 7

[0140] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, a separating layer, and an enteric layer.

[0141] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0142] The separating layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose.

[0143] The enteric layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of colloidal silicon dioxide, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0144] The weight ratio of the tablet core to the separating layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0145] The preparation method refers to Example 1.

[0146] Compared with Example 1, the difference in this comparative example is that the raw materials constituting the isolation layer do not contain polyvinyl alcohol.

[0147] Comparative Example 8

[0148] An enteric-coated tablet containing rabeprazole sodium, comprising a tablet core, an isolation layer, and an enteric layer.

[0149] The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 part of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of croscarmellose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of polyvinylpyrrolidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate.

[0150] The isolation layer is composed of the following raw materials in parts by mass: 2.5 parts of hypromellose and 1 part of polyvinyl alcohol.

[0151] The enteric layer is composed of the following raw materials in parts by mass: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of talc powder, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

[0152] The weight ratio of the tablet core to the isolation layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.8.

[0153] The preparation method refers to Example 1.

[0154] Compared with Example 1, the difference in this comparative example is that the anti-adhesive agent in the raw materials constituting the enteric layer is talc powder.

[0155] Dissolution test

[0156] Refer to the method for determination of dissolution and release in Method 1 of the second method in General Principles 0931, Volume IV of the Chinese Pharmacopoeia 2020 edition.

[0157] Using the samples of Example 1, Comparative Example 5, Comparative Example 6, Comparative Example 7, and Comparative Example 8 as the test enteric-coated tablets, using 700 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 100 revolutions / min, at 120 min, the test enteric-coated tablets shall not show discoloration, cracks, or disintegration.

[0158] Add 300 mL of 0.6 mol / L tris(hydroxymethyl)aminomethane solution at 37°C to the operating container, adjust the pH value to 8.0 with 2 mol / L sodium hydroxide solution. At 5, 10, 15, 20, 25, 30, and 35 min respectively, take out the solution, filter it through a filter membrane with a pore size of 0.45 μm, accurately transfer 3 mL of the subsequent filtrate, place it in a test tube, immediately accurately add 1 mL of 0.5 mol / L sodium hydroxide solution, mix well, and use it as the test solution. Determine the content of rabeprazole sodium by high performance liquid chromatography and calculate the dissolution at different time points.

[0159] The results are shown in Table 1.

[0160] Table 1 Dissolution of each sample at different time points

[0161] Group 5 min 10 min 15 min 20 min 25 min 30 min 35 min Example 1 9.6％ 17.5％ 57.1％ 79.5％ 98.9％ 99.6％ 99.9％ Comparative Example 5 11.1％ 25.7％ 30.5％ 54.3％ 67.5％ 78.3％ 89.5％ Comparative Example 6 6.3％ 20.4％ 28.7％ 49.1％ 55.8％ 61.9％ 73.4％ Comparative Example 7 10.3％ 19.7％ 26.1％ 38.2％ 53.7％ 60.3％ 71.5％ Comparative Example 8 12.6％ 20.6％ 32.9％ 41.6％ 55.9％ 67.8％ 83.4％

[0162] It can be seen from the dissolution results in Table 1 that changing the raw materials of the tablet core, the isolating layer, and the enteric-coated layer will all affect the dissolution of the drug. The dissolution performance of the product in Example 1 is better.

[0163] Study on the effect of enteric-coated tablets containing rabeprazole sodium of the present invention on gastric ulcer

[0164] 1. Animal grouping and drug administration

[0165] Fifty-four SPF-grade SD rats, half male and half female, with a body weight of 180 - 200 g. Randomly select 6 rats as the blank control group, and the remaining rats are divided into 8 groups according to the random number method, with 6 rats in each group, namely the model control group, Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, Comparative Example 2 group, Comparative Example 3 group, and Comparative Example 4 group.

[0166] All rats in each group were fasted for 24 h before the experiment. Except for the blank control group, rats in each group started gastric gavage administration 7 days before the modeling operation. The Example 1 group was given the rabeprazole sodium enteric-coated tablets of Example 1 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium), the Example 2 group was given the rabeprazole sodium enteric-coated tablets of Example 2 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium), the Example 3 group was given the rabeprazole sodium enteric-coated tablets of Example 3 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium), the Comparative Example 1 group was given the rabeprazole sodium enteric-coated tablets of Comparative Example 1 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium), the Comparative Example 2 group was given the rabeprazole sodium enteric-coated tablets of Comparative Example 2 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium), the Comparative Example 3 group was given the rabeprazole sodium enteric-coated tablets of Comparative Example 3 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium), and the Comparative Example 4 group was given the rabeprazole sodium enteric-coated tablets of Comparative Example 4 at 1.5 mg / kg (calculated according to the content of rabeprazole sodium). Each group was administered once a day for 7 days. The blank control group and the ulcer model group were gavaged with the same volume of normal saline.

[0167] 1 h after the last administration, under anesthesia, open the abdominal cavity of the rats, expose the stomach, thread a suture under the pylorus and ligate the pylorus; rats in the blank control group were not ligated, and other operations were the same as those in the ulcer model group. After ligation, each group of rats was injected with the medicinal solution once through the duodenum. The normal control group and the ulcer model group were injected with the same volume of normal saline, then suture the abdominal wall incision and disinfect routinely. Put it back into the breeding cage and fast and withhold water.

[0168] 2. Index detection

[0169] After 6 hours, the rats in each group were sacrificed, the cardia was ligated, the stomach was removed, cut along the greater curvature of the stomach and unfolded, and the gastric mucus and blood clots were gently wiped off with a small cotton ball to observe the degree and morphology of gastric mucosal injury.

[0170] Calculation of ulcer index: The ulcer index was evaluated according to the Guth standard to assess the degree of gastric mucosal injury; the ulcer index was calculated based on the length (mm) of mucosal ulcers or erosions: punctate erosion was 1 point, erosion < 1 mm was 2 points, erosion between 1 - 2 mm was 3 points, erosion 2 - 4 mm was 4 points, erosion > 4 mm was 5 points; if the erosion width > 1 mm, the score was multiplied by 2; the sum of the scores was the total injury score. The sum of the gastric ulcer indices of all animals in each group divided by the number of animals was the average ulcer index of that group.

[0171] Determination of total gastric juice acidity value: When taking the stomach, all the gastric juice was drawn out and placed in a centrifuge tube for centrifugation at 3000 r / min for 20 min. A part of the supernatant was taken and titrated with 0.1 mol / L NaOH solution to measure the total acidity of the gastric juice.

[0172] 3. Statistical methods

[0173] Graphpad Prism 9.0 software was used for data processing. Measurement data were expressed as mean ± standard deviation For comparison among multiple groups, one-way analysis of variance was used, and pairwise comparison between groups was performed using SNK-q. A P < 0.05 was considered statistically significant.

[0174] 4. Experimental results

[0175] 4.1 Effects on the ulcer index of rats

[0176] Compared with the blank control group, the ulcer index of the rats in the model control group was significantly increased.

[0177] Compared with the model control group, the ulcer index of the rats in each group of the examples was significantly decreased, and there were significant differences in reducing the ulcer index of rats between each group of the examples and the comparative example groups 1 - 4. The results are shown in Table 2.

[0178] Table 2 Effects on the ulcer index of rats

[0179]

[0180] Note: Different lowercase letters in the same column indicate significant differences between different groups (P < 0.05).

[0181] 4.2 Effects on the total gastric juice acidity value of rats

[0182] Compared with the blank control group, the total gastric juice acidity value of the rats in the model control group was significantly increased.

[0183] Compared with the model control group, the total gastric acid value of rats in each group of the examples was significantly decreased. Compared with the groups of Comparative Examples 1-4, there were significant differences in reducing the total gastric acid value of rats in each group of the examples. The results are shown in Figure 1 .

[0184] The enteric-coated tablets containing rabeprazole sodium of the present invention have a significant effect on treating gastric ulcers. The therapeutic effects of the groups of Example 1, Example 2, and Example 3 are significantly better than those of the comparative example groups (containing cimetidine or the content not within the technical solution of the present invention), and there are significant differences. The inventor believes that there may be a synergistic effect between cimetidine and rabeprazole sodium, and the combination of the two improves the anti-ulcer effect of rabeprazole sodium, providing a treatment approach for treating ulcerative diseases such as gastric ulcers.

[0185] The above embodiments do not impose any formal limitations on the present invention. For those skilled in the art, any modifications, substitutions, etc. made within the scope of the technical solution of the present invention based on the technical essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. An enteric-coated tablet containing rabeprazole sodium, characterized in that: The enteric-coated tablet containing rabeprazole sodium comprises a tablet core, a separation layer and an enteric-coated layer; The tablet core is composed of the following raw materials in parts by mass: 50-60 parts of rabeprazole sodium, 10-18 parts of cimetidine, 0.3-0.7 parts of cosolvent, 12-15 parts of filler, 13-18 parts of disintegrant, 4-6 parts of lubricant, 3-6 parts of antioxidant, 8-12 parts of binder, and 3-6 parts of stabilizer; The isolation layer is composed of the following raw materials in parts by weight: 2.0-2.5 parts of hydroxypropyl methylcellulose and 0.5-1 part of polyvinyl alcohol; The enteric layer is composed of the following raw materials in parts by weight: 50-70 parts of enteric material, 5-10 parts of lubricant, 4-8 parts of anti-adherent agent, 10-16 parts of plasticizer, and 1.5-2.5 parts of sunscreen; The weight ratio of the tablet core to the isolation layer is 10:0.05, and the weight ratio of the tablet core to the enteric layer is 10:1.

8.

2. The enteric-coated tablet containing rabeprazole sodium according to claim 1, characterized in that: The cosolvent in the tablet core material is anhydrous citric acid; the filler is microcrystalline cellulose; the disintegrant is cross-linked sodium carboxymethyl cellulose; the lubricant is calcium stearate; the antioxidant is glycine; the binder is composed of povidone K30 and hydroxypropyl cellulose; and the stabilizer is anhydrous sodium carbonate.

3. The enteric-coated tablet containing rabeprazole sodium according to claim 2, characterized in that: The adhesive is povidone K30 and hydroxypropyl cellulose in a mass ratio of 2:

3.

4. The enteric-coated tablet containing rabeprazole sodium according to claim 1, characterized in that: The isolation layer is composed of the following raw materials in parts by mass: 2.5 parts of hydroxypropyl methylcellulose and 1 part of polyvinyl alcohol.

5. The enteric-coated tablet containing rabeprazole sodium according to claim 1, characterized in that: The enteric material in the enteric layer is selected from methacrylic acid copolymer type A; the lubricant is selected from magnesium lauryl sulfate; the anti-adhesive agent is selected from micro powder silica gel; the plasticizer is selected from glycerin; and the sunscreen is selected from titanium dioxide.

6. The enteric-coated tablet containing rabeprazole sodium according to claim 1, characterized in that: The tablet core is composed of the following raw materials in parts by mass: 55 parts of rabeprazole sodium, 15 parts of cimetidine, 0.6 parts of anhydrous citric acid, 15 parts of microcrystalline cellulose, 15 parts of cross-linked carboxymethyl cellulose sodium, 5 parts of calcium stearate, 5 parts of glycine, 4 parts of povidone K30, 6 parts of hydroxypropyl cellulose, and 5 parts of anhydrous sodium carbonate; The isolation layer is composed of the following raw materials in parts by mass: 2.5 parts of hydroxypropyl methylcellulose and 1 part of polyvinyl alcohol; The enteric layer is composed of the following raw materials in parts by weight: 60 parts of methacrylic acid copolymer type A, 8 parts of magnesium lauryl sulfate, 6 parts of micro powder silica gel, 12 parts of glycerol, and 2.0 parts of titanium dioxide.

7. A method for preparing enteric-coated tablets containing rabeprazole sodium, comprising the following steps: (1) fully mixing the raw materials for the tablet core, including rabeprazole sodium, cimetidine, anhydrous citric acid, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, calcium stearate, glycine, povidone K30, hydroxypropyl cellulose, anhydrous sodium carbonate, etc., putting the mixture into a wet granulator, spraying an appropriate amount of ethanol for granulation, and pressing the mixture into tablets to obtain the tablet core; (2) mixing hydroxypropyl methylcellulose and polyvinyl alcohol into a coating premix, adding water to prepare a coating solution, spraying the coating solution evenly on the surface of the tablet core, and performing fluidized bed drying after spraying; (3) adding water to the magnesium lauryl sulfate, silica gel powder, glycerin and titanium dioxide, stirring evenly, adding to the methacrylic acid copolymer type A, stirring, and coating the core tablets coated with the isolation layer with an enteric layer to obtain the enteric-coated tablets containing rabeprazole sodium of the present invention.

8. Use of the enteric-coated tablets containing rabeprazole sodium according to claim 1 in the preparation of a drug for peptic ulcer.

9. The use according to claim 8, characterized in that The digestive tract ulcer is a gastric ulcer or a duodenal ulcer.

10. The use according to claim 9, characterized in that The digestive tract ulcer is a gastric ulcer.

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