Compound preparation capsule and preparation method thereof

Abstract

The invention discloses a compound medicine preparation capsule and a preparation method thereof, wherein the compound medicine preparation capsule is composed of a vonoprazan or medicinal salt microtablet thereof, an amoxicillin microtablet and a levornidazole or levornidazole phosphate microtablet. The Vonoprazan is a novel potassium ion competitive acid blocker, and the compound preparation capsule is used for treating gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, and helicobacter pylori infection and helicobacter pylori infection gastritis in the stomach after early gastric cancer endoscopic therapy. According to the compound preparation capsule, the cure rate of helicobacter pylori can be increased, the drug resistance can be reduced, and a better treatment choice is provided for clinical patients.

Description

Technical Field

[0001] The invention relates to the field of drugs for treating Helicobacter pylori, and in particular to a compound preparation capsule for treating Helicobacter pylori and a preparation method thereof. Background Art

[0002] Helicobacter pylori is a Gram-negative bacterium that often parasitizes in gastric mucosal tissue. Studies have confirmed that Helicobacter pylori is the main cause of chronic gastritis, peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. In 2017, the World Health Organization's International Agency for Research on Cancer (IARC) included Helicobacter pylori in the list of Class I carcinogens, and related reports show that the risk of gastric cancer in people infected with Helicobacter pylori is 2 to 3 times higher than that of normal people. It can be seen that the harm of Helicobacter pylori infection is huge, and as the public pays more attention to health care, Helicobacter pylori infection will gradually attract more attention.

[0003] The recognized standard therapy for eradicating Helicobacter pylori is triple therapy based on clarithromycin or quadruple therapy based on bismuth. Due to the problem of drug resistance in triple therapy, it has basically been abandoned. Bismuth-based quadruple therapy includes proton pump inhibitors + bismuth + two antibiotics. The latest global preparation is the combined packaged drug Pylera (bismuth + metronidazole + tetracycline hydrochloride capsules) approved in the United States, which contains metronidazole. It also has the risk of drug resistance. The efficacy will decrease over time, and Pylera + proton pump inhibitors need to be taken at the same time. The medical expenses are high and the patient compliance is poor. The use of drugs in the treatment of this disease increases with drug resistance and decreases in efficacy. Patients face the risk of having no medicine to treat. Helicobacter pylori patients urgently need new drugs with low drug resistance and good efficacy for treatment.

[0004] Currently, proton pump inhibitors (PPIs) have been widely prescribed for the first-line treatment of acid-related diseases. However, PPIs do not always provide adequate efficacy, and the inhibitory effect on gastric acid secretion may vary from person to person. This is because CYP-2C19, a protein involved in PPI metabolism, has genetic polymorphisms in its encoding gene in different individuals. However, vonoprazan is not mainly metabolized by CYP2C19, and vonoprazan's inhibitory effect on the proton pump does not require acid activation. The drug enters the stomach at high concentrations and can produce the maximum inhibitory effect at the first dose, and this effect can last for 24 hours.

[0005] Vonoprazan Fumarate (TAK-38) was jointly developed by Takeda Pharmaceutical and Otsuka Pharmaceutical and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on December 26, 2014. The specific structural formula is as follows: Vonoprazan fumarate is a new type of potassium ion (K + ) Competitive acid blockers (P-CABs) can competitively inhibit K in the final step of gastric acid secretion by gastric parietal cells. + With H + -K + -ATPase (proton pump) binding effect, resulting in a strong and lasting inhibition of gastric acid secretion. The drug is suitable for gastric ulcer, duodenal ulcer, reflux esophagitis, erosive esophagitis, gastroesophageal reflux disease, Helicobacter infection and peptic ulcer.

[0006] Currently, vonoprazan fumarate is packaged in combination with amoxicillin capsules and metronidazole tablets ( Pack), vonoprazan fumarate combined with amoxicillin capsules and metronidazole tablets ( Pack 400&800) was jointly developed by Takeda Pharmaceutical and Otsuka Pharmaceutical for the treatment of Helicobacter pylori and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in June 2016.

[0007] Amoxicillin hydrate acts by inhibiting bacterial cell wall synthesis, while vonoprazan does not require acid activation and inhibits H in a reversible and potassium-competitive manner. + , K + -ATPase. Vonoprazan is strongly alkaline and stays in the acid-producing sites of gastric parietal cells for a long time, inhibiting the production of gastric acid. Vonoprazan does not show anti-Helicobacter pylori activity or Helicobacter pylori urease inhibitory activity. Metronidazole is reduced and converted into a nitroso compound (R-NO) through a reaction of the nitroreductase system in Helicobacter pylori. This R-NO shows a bactericidal effect against Helicobacter pylori. In addition, the hydroxyl radicals produced during the reaction will cleave DNA, resulting in an unstable DNA helical structure. The effect of vonoprazan in triple therapy with amoxicillin and metronidazole is believed to be to enhance the antibacterial activity of amoxicillin and metronidazole by increasing gastric pH.

[0008] When the vonoprazan fumarate pharmaceutical composition currently marketed in Japan is used to treat Helicobacter pylori, the three ingredients are taken separately, and patient compliance is poor. It is necessary to provide a new method to solve the above problem.

[0009] In addition, we found in our study that the combination of levonidazole or levonidazole phosphate, vonoprazan fumarate and amoxicillin has a strong inhibitory effect on Helicobacter pylori strains and low drug resistance; the clinical cure rate is high, and the adverse reactions caused by impurities produced by possible interactions between raw materials are reduced. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a compound preparation capsule for treating Helicobacter pylori and a preparation method thereof, which ensures a high Helicobacter pylori eradication rate and low drug resistance, simplifies the medication regimen, improves patient medication compliance, reduces the risk of missed doses; and reduces adverse reactions caused by impurities generated by possible interactions between raw materials.

[0011] The present invention is achieved through the following technical solutions: A compound preparation capsule is composed of vonoprazan or its pharmaceutical salt microtablets, amoxicillin microtablets, levornidazole or its levornidazole phosphate microtablets and a capsule shell; wherein the active ingredients are vonoprazan or its pharmaceutical salt, amoxicillin and levornidazole or its levornidazole phosphate; and the excipients are fillers, disintegrants, binders, stabilizers, glidants and / or lubricants.

[0012] Optionally, the active ingredient accounts for 30-90%, the filler accounts for 10-40%, the disintegrant accounts for 1-10%, and the glidant and / or lubricant accounts for 0.8-2.5%; among the active ingredients, vonoprazan or its pharmaceutically acceptable salt accounts for 1%-3%, amoxicillin accounts for 72%-74%, and levonidazole or its levonidazole phosphate accounts for 23-25%.

[0013] Optionally, the pharmaceutically acceptable salt of vonoprazan is fumarate, succinate, maleate, malate or tartrate.

[0014] Optionally, the filler is one or more of microcrystalline cellulose, lactose, corn starch, pregelatinized starch, mannitol and low-substituted hydroxypropyl cellulose; the disintegrant is one or more of sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; the stabilizer is fumaric acid; and the solvent or binder is one or more of purified water, hydroxypropyl cellulose, hypromellose, povidone or sodium carboxymethyl cellulose.

[0015] Optionally, the glidant is one or more of silicon dioxide and talc; the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, and glyceryl behenate.

[0016] Optionally, the micro-tablets of vonoprazan or its pharmaceutically acceptable salt have a specification of 4 to 10 mg, a tablet weight of 10 to 35 mg, and a diameter of 1.5 to 3 mm.

[0017] Optionally, the specification of amoxicillin microtablets is 15-25 mg, the tablet weight is 20-35 mg, and the diameter is 1.5-3 mm.

[0018] Optionally, the specification of levonidazole microtablets is 12.5-25 mg, the tablet weight is 15-35 mg, and the diameter is 1.5-3 mm.

[0019] Optionally, the specification of levornidazole phosphate microtablets (calculated as levornidazole) is 12.5-25 mg, the tablet weight is 15-35 mg, and the diameter is 1.5-3 mm.

[0020] Optionally, the particle size distribution D50 of vonoprazan or its pharmaceutical salt in the vonoprazan or its pharmaceutical salt microtablets is 10 to 30 μm, and the particle size D50 of levonidazole or levonidazole phosphate in the levonidazole microtablets or levonidazole phosphate microtablets is 10 to 30 μm.

[0021] Optionally, the capsule includes vonoprazan or its pharmaceutical salt microtablets, amoxicillin microtablets, levonidazole microtablets or levonidazole phosphate microtablets and a capsule shell; wherein the number of vonoprazan or its pharmaceutical salt microtablets is 1 to 2, the number of amoxicillin microtablets is 6 to 10, the number of levonidazole or levonidazole phosphate microtablets is 2 to 4 and the capsule shell is No. 1, No. 0 and No. 00.

[0022] In a second aspect, the present application provides the composition of each microtablet in a compound preparation capsule.

[0023] The vonoprazan or its pharmaceutical salt micro-tablets are composed of a tablet core and a gastric soluble coating.

[0024] The tablet core is prepared by wet preparation, drying, granulation, adding lubricant, mixing and pressing of vonoprazan or its pharmaceutical salt, filler, disintegrant, stabilizer and adhesive. In the microtablets of vonoprazan or its pharmaceutical salt, the core composition is as follows: in weight percentage, the filler accounts for 60% to 80%, the disintegrant accounts for 1 to 5%, the binder accounts for 2 to 8%, the lubricant accounts for 0.5% to 2%, the stabilizer accounts for 0.1% to 0.5%, and the balance is vonoprazan or its pharmaceutical salt. The filler is selected from lactose, pregelatinized starch, mannitol, corn starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose or microcrystalline cellulose mannitol co-processed product. The mass ratio of microcrystalline cellulose to mannitol in the filler is 1: (0.5 to 10). The disintegrant is sodium starch glycolate, cross-linked sodium carboxymethyl cellulose or cross-linked povidone. The stabilizer is fumaric acid. The binder is hydroxypropyl cellulose or hydroxypropyl methylcellulose, povidone, sodium carboxymethyl cellulose. The lubricant is magnesium stearate.

[0025] Preferably, the vonoprazan or its pharmaceutical salt microtablets are composed of a vonoprazan or its pharmaceutical salt tablet core and a coating component, wherein the vonoprazan or its pharmaceutical salt tablet core is composed of microcrystalline cellulose mannitol co-processed product (1: (6-8)), cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, fumaric acid, and magnesium stearate; and the gastric soluble coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, a colorant, etc. The percentages of each excipient are as follows: Vonoprazan or its pharmaceutically acceptable salt accounts for 15% to 25%, preferably 19% to 23%.

[0026] The microcrystalline cellulose mannitol co-processed product accounts for 60% to 80%, preferably 65% ​​to 75%.

[0027] The cross-linked sodium carboxymethyl cellulose accounts for 2% to 5%, preferably 2.5% to 3.5%.

[0028] Hydroxypropyl cellulose accounts for 2% to 8%, preferably 4% to 6%.

[0029] Fumaric acid accounts for 0.1% to 0.5%, preferably 0.2% to 0.4%.

[0030] The magnesium stearate accounts for 0.5% to 2%, preferably 0.7% to 1.3%.

[0031] The coating weight of the plain tablets is increased by 2% to 6%, preferably 3% to 4%.

[0032] The prescription composition of the vonoprazan or its pharmaceutically acceptable salt micro-tablets (1000 tablets) is as follows: Tablet core: 5.344 g of vonoprazan or its pharmaceutically acceptable salt (containing 4 g of vonoprazan), 22.0 g of microcrystalline cellulose mannitol co-processed product, 1.5 g of hydroxypropyl cellulose, 0.04 g of fumaric acid, and 0.3 g of magnesium stearate.

[0033] Coating ingredients: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant.

[0034] The amoxicillin microtablets are composed of a tablet core and a gastric soluble coating.

[0035] The tablet core is made of amoxicillin and fillers, disintegrants, glidants and lubricants through total mixing and compression. In the amoxicillin microtablets, the tablet core composition is: by weight percentage, the filler accounts for 10% to 30%, the disintegrant accounts for 1% to 5%, the glidant accounts for 0.5% to 2.5%, the lubricant accounts for 0.5% to 2%, and the balance is amoxicillin. The filler is selected from lactose and microcrystalline cellulose, the disintegrant is sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone, the glidant is silicon dioxide, and the lubricant is magnesium stearate; the gastric soluble coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant, etc.

[0036] Preferably, the amoxicillin microtablets are composed of an amoxicillin tablet core and a coating component, wherein the amoxicillin tablet core is composed of microcrystalline cellulose, cross-linked polyvinylpyrrolidone, silicon dioxide, and magnesium stearate; and the gastric soluble coating is composed of hypromellose, polyethylene glycol 6000, titanium dioxide, a colorant, etc. The percentages of each auxiliary material are as follows: Amoxicillin accounts for 67% to 85%, preferably 72% to 80%.

[0037] The microcrystalline cellulose accounts for 10% to 30%, preferably 15% to 21%.

[0038] The cross-linked polyvinylpyrrolidone accounts for 1% to 5%, preferably 2.0% to 3.0%.

[0039] The silicon dioxide accounts for 0.5% to 2.5%, preferably 1.5% to 2.2%.

[0040] The magnesium stearate accounts for 0.5% to 2%, preferably 0.7% to 1.3%.

[0041] The coating weight of the plain tablets is increased by 2% to 6%, preferably 3% to 4%.

[0042] The prescription composition of the amoxicillin microtablets (1000 tablets) is as follows: Tablet core: amoxicillin 25g, microcrystalline cellulose 6g, crospovidone 0.6g, silicon dioxide 0.3g, magnesium stearate 0.3g.

[0043] Coating ingredients: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant.

[0044] The levornidazole or levornidazole phosphate microtablets are composed of a tablet core and a gastric soluble coating.

[0045] The tablet core is made of levornidazole or levornidazole phosphate and fillers, disintegrants and binders through wet preparation, drying, granulation, adding lubricants and mixing, and then pressing. The tablet core composition is: in weight percentage, the filler accounts for 10% to 30%, the disintegrant accounts for 1% to 5%, the binder accounts for 1.0% to 4.0%, and the lubricant accounts for 0.5% to 1.5%. The filler is selected from lactose, mannitol, microcrystalline cellulose, and corn starch. The disintegrant is sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone. The binder is hydroxypropyl cellulose or hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, the glidant is silicon dioxide, and the lubricant is magnesium stearate; the gastro-soluble coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant, etc.

[0046] Preferably, the levornidazole or levornidazole phosphate microtablets are composed of levornidazole or levornidazole phosphate tablet core and coating ingredients, the levornidazole tablet core is composed of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, hypromellose, and magnesium stearate; the levornidazole phosphate tablet core is composed of mannitol, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, silicon dioxide, and magnesium stearate; the gastric soluble coating is composed of hypromellose, polyethylene glycol 6000, titanium dioxide, colorant, etc. The percentages of each auxiliary material are as follows: The levornidazole or levornidazole phosphate accounts for 20% to 90%, preferably 40% to 85%.

[0047] The microcrystalline cellulose accounts for 10% to 30%, preferably 13% to 18%.

[0048] The cross-linked sodium carboxymethyl cellulose accounts for 1% to 5%, preferably 2.0% to 3.0%.

[0049] The hydroxypropyl cellulose accounts for 1.0% to 4.0%, preferably 1.5% to 2.5%.

[0050] The magnesium stearate accounts for 0.5% to 1.5%, preferably 0.7% to 1.3%.

[0051] The coating weight of the plain tablets is increased by 2% to 6%, preferably 3% to 4%.

[0052] The prescription composition of the levornidazole or levornidazole phosphate micro-tablets (1000 tablets) is as follows: Levoornidazole tablet core: 25g of levonidazole, 5g of microcrystalline cellulose, 1g of cross-linked carboxymethylcellulose sodium, 0.6g of hypromellose, and 0.3g of magnesium stearate; Levoornidazole phosphate tablet core: 17.05g of levoornidazole phosphate, 5g of microcrystalline cellulose, 0.6g of cross-linked sodium carboxymethyl cellulose, 0.6g of silicon dioxide, and 0.3g of magnesium stearate.

[0053] Coating ingredients: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant.

[0054] In a third aspect, the present application provides a method for preparing a compound preparation capsule, comprising the following steps: The method for preparing the vonoprazan or its pharmaceutically acceptable salt micro-tablets comprises the following specific steps: (1) Granulation: dissolving fumaric acid and hydroxypropyl cellulose in purified water and stirring to prepare a binder solution; adding vonoprazan or a pharmaceutically acceptable salt thereof, microcrystalline cellulose mannitol co-processed product, and cross-linked sodium carboxymethyl cellulose into a fluidized bed granulator, spraying the binder solution into the fluidized bed granulator, and granulating; (2) Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Total mixing: adding the dry granules, cross-linked sodium carboxymethyl cellulose and magnesium stearate into a three-dimensional mixer and mixing evenly; (5) Tablet compression: The tablet diameter is 3 mm, the tablet weight is about 32 mg, and the hardness ranges from 4 to 6 kgf; (6) coating: adding hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant to purified water to prepare a solution with a solid content of 8% to 20% for coating, and the coating weight gain is 2% to 6wt%; The preparation method of the amoxicillin microtablets comprises the following specific steps: (1) Total mixing: adding amoxicillin granules, cross-linked sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate into a three-dimensional mixer and mixing evenly; (2) Tablet compression: Tablet diameter: 3 mm, tablet weight about 35 mg, hardness range 4-6 kgf; (3) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to prepare a solution with a solid content of 8% to 20% for coating, and the coating weight gain is 2 to 6 wt.%.

[0055] The preparation method of the levornidazole micro-tablets comprises the following specific steps: (1) Granulation: Hydroxypropyl methylcellulose is dissolved in purified water and stirred to prepare a binder solution. Levo-ornidazole, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose are added to a fluidized bed granulator, and the binder solution is sprayed into the fluidized bed granulator to granulate; (2) Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Total mixing: adding the granular magnesium stearate into a three-dimensional mixer and mixing evenly; (5) Tablet compression: The tablet diameter is 3 mm, the tablet weight is about 35 mg, and the hardness ranges from 4 to 6 kgf; (6) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to prepare a solution with a solid content of 8% to 20% for coating, and the coating weight gain is 2 to 6 wt%.

[0056] The preparation method of the levonidazole phosphate micro-tablets comprises the following specific steps: (1) Granulation: Add levonidazole phosphate, mannitol, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose into a fluidized bed granulator, and spray purified water into the fluidized bed granulator to granulate; (2) Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Total mixing: adding the granules, silicon dioxide and magnesium stearate into a three-dimensional mixer and mixing evenly; (5) Tablet compression: The tablet diameter is 3 mm, the tablet weight is about 35 mg, and the hardness ranges from 4 to 6 kgf; (6) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to prepare a solution with a solid content of 8% to 20% for coating, and the coating weight gain is 2 to 6 wt%.

[0057] Compared with the prior art, the present invention has the following beneficial effects: 1. The compound preparation capsule of the present invention overcomes the problem of antibiotic resistance, improves the eradication rate of Helicobacter pylori, and provides a new option for clinical patients to cure diseases caused by Helicobacter pylori. Moreover, patients only need to take one drug, which improves the compliance of patients with drug administration.

[0058] 2. In the compound preparation capsule of the present invention, each main component is compressed and coated separately, thereby blocking the adverse reactions caused by impurities generated by possible interactions between the main components and ensuring the safety of clinical medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 Dissolution curves of vonoprazan fumarate microtablets in different dissolution media Figure 2 Dissolution curves of amoxicillin microtablets in different dissolution media Figure 3 Dissolution curves of levornidazole microtablets in different dissolution media Figure 4 Dissolution curves of levo-ornidazole phosphate microtablets in different dissolution media DETAILED DESCRIPTION

[0060] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0061] Example 1 The compound preparation capsule of the present invention comprises vonoprazan fumarate microtablets, amoxicillin microtablets and levornidazole microtablets, and the raw material composition thereof is calculated by weight, as shown in Table 1.

[0062] Table 1 Composition and proportion of each component Preparation process: The preparation of vonoprazan fumarate micro-tablets comprises the following steps: Granulation: dissolve fumaric acid and hydroxypropyl cellulose in purified water, add vonoprazan fumarate, microcrystalline cellulose mannitol co-processed product, and cross-linked sodium carboxymethyl cellulose into a wet granulator, with a stirring paddle speed of 300 rpm and a cutting blade of 500 rpm, and mix for 5 minutes; with a stirring paddle speed of 200 rpm and a cutting blade of 500 rpm, spray the hydroxypropyl cellulose aqueous solution through atomization, and add it in about 8 minutes; with a stirring paddle speed of 250 rpm and a cutting blade of 1200 rpm, granulate for 2 minutes; discharge, use a granulator screen of 3×3 mm, a rotation speed of 400 rpm, and wet granulate.

[0063] Drying: Add wet granules into the fluidized bed, feed air at 60℃ and 30Hz, dry. When the material temperature reaches 40℃, take samples to measure the moisture content. When the moisture content is lower than 2.0%, stop heating and cool the material for discharge.

[0064] Granulation: Granulation machine screen diameter 1mm, rotation speed 400rpm, granulation.

[0065] Total mixing: Add the granules and magnesium stearate into a three-dimensional mixer at a mixing speed of 30 Hz for 10 min.

[0066] Tablet compression: 3.0mm shallow concave punch, tablet weight 32mg, hardness range 4~6kgf.

[0067] Coating: Hydroxypropyl methylcellulose (E5), polyethylene glycol (PEG6000), titanium dioxide and colorant are added to purified water to prepare a solution with a concentration of 10wt%; the inlet air temperature is 45-60°C, the tablet bed temperature is 38-45°C, and the coating weight gain is 3-4%.

[0068] The preparation of amoxicillin microtablets comprises the following steps: Total mixing: Add aspirin, microcrystalline cellulose, crospovidone, silicon dioxide and magnesium stearate into a three-dimensional mixer at a mixing speed of 30 Hz for 20 minutes. Stop the machine and add magnesium stearate into the three-dimensional mixer at a mixing speed of 30 Hz for 10 minutes.

[0069] Tablet compression: 3.0mm shallow concave punch, tablet weight 32mg, hardness range 4~6kgf.

[0070] Coating: Hydroxypropyl methylcellulose (E5), polyethylene glycol (PEG6000), titanium dioxide and colorant are added to purified water to prepare a solution with a concentration of 10wt%; the inlet air temperature is 45-60°C, the tablet bed temperature is 38-45°C, and the coating weight gain is 3-4%.

[0071] The preparation of levornidazole micro-tablets comprises the following steps: Granulation: dissolve hydroxypropyl cellulose in purified water, add levornidazole, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose into a wet granulator, set the stirring paddle speed at 300 rpm and the cutting blade at 500 rpm, and mix for 5 min; set the stirring paddle speed at 200 rpm and the cutting blade at 500 rpm, and spray the hydroxypropyl methyl cellulose solution into the granulator through atomization, and add it in about 8 min; set the stirring paddle speed at 250 rpm and the cutting blade at 1200 rpm, and granulate for 2 min; discharge, use a granulator screen of 3×3 mm, rotate at 400 rpm, and wet granulate.

[0072] Drying: Add wet granules into the fluidized bed, feed air at 60℃ and 30Hz, dry. When the material temperature reaches 40℃, take samples to measure the moisture content. When the moisture content is lower than 2.0%, stop heating and cool the material for discharge.

[0073] Granulation: Granulation machine screen diameter 1mm, rotation speed 400rpm, granulation.

[0074] Total mixing: Add the granules and magnesium stearate into a three-dimensional mixer at a mixing speed of 30 Hz for 5 min.

[0075] Tablet compression: 3.0mm shallow concave punch, tablet weight 32mg, hardness range 4~6kgf.

[0076] Coating: Hydroxypropyl methylcellulose (E5), polyethylene glycol (PEG6000), titanium dioxide and colorant are added to purified water to prepare a solution with a concentration of 10wt%; the inlet air temperature is 45-60°C, the tablet bed temperature is 38-45°C, and the coating weight gain is 3-4%.

[0077] Made into compound capsules: Take 1 vonoprazan fumarate microtablet, 6 amoxicillin microtablets and 2 levornidazole microtablets mentioned above respectively, fill them into 1# hollow capsules to prepare vonoprazan fumarate / amoxicillin / levornidazole capsules (4mg / 150mg / 50mg).

[0078] Example 2 The compound preparation capsule of the present invention comprises vonoprazan fumarate microtablets, amoxicillin microtablets and levonidazole phosphate microtablets, and the raw material composition thereof is calculated by weight, as shown in Table 2.

[0079] Table 2 Composition and proportion of each component The preparation process is the same as in Example 1 Made into compound capsules: Take 1 vonoprazan fumarate microtablet, 6 amoxicillin microtablets and 4 levonidazole phosphate microtablets mentioned above respectively, fill them into 1# hollow capsules to prepare vonoprazan fumarate / amoxicillin / levonidazole phosphate capsules (4mg / 150mg / 50mg).

[0080] Embodiments 3 to 6 The compound preparation capsule of the present invention comprises vonoprazan fumarate microtablets, amoxicillin microtablets and levornidazole microtablets, and the raw material composition thereof is calculated by weight, as shown in Table 3.

[0081] Table 3 Composition and proportion of each component The preparation process is the same as in Example 1 Embodiments 7 to 10 The compound preparation capsule of the present invention comprises vonoprazan fumarate microtablets, amoxicillin microtablets and levonidazole phosphate microtablets, and the raw material composition thereof is calculated in parts by weight, as shown in Table 4.

[0082] Table 4 Composition and proportion of each component The preparation process is the same as in Example 1 Example 11 Evaluation of dissolution curve of vonoprazan fumarate / amoxicillin / levonidazole or levonidazole phosphate capsules After oral administration of solid preparations, the absorption of drugs depends on the dissolution or release of drugs from the preparations, the dissolution of drugs under physiological conditions, and the penetration of drugs in the gastrointestinal tract. Since the dissolution and dissolution of drugs have an important influence on absorption, the dissolution behavior of drugs in vitro may predict their in vivo behavior, and the dissolution behavior of drugs in vitro can reflect the quality of preparations to a certain extent. In this study, the dissolution curve of self-made preparations was studied in 4 basic media simulating body fluids in the human digestive tract.

[0083] In Example 1, the dissolution curve of vonoprazan fumarate microtablets was measured and evaluated. The dissolution method was as follows: According to the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia (General Rules 0931 of Part IV), the second method (paddle method) device was used, with pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water as dissolution media, respectively, with a volume of 900 mL and a speed of 50 r / min, and the operation was carried out in accordance with the law. 5 mL was sampled at 5, 10, 15, 30, and 45 min, filtered with a 0.45 μm filter membrane, and the filtrate was used as the test solution, and the dissolution medium of the same temperature and volume was added at the same time.

[0084] Preparation of dissolution medium: pH 1.2 hydrochloric acid solution: measure 7.65mL of hydrochloric acid, dilute to 1000mL with water, shake well.

[0085] pH 4.5 acetate buffer: Take 2.99 g of sodium acetate and 14.0 mL of 2 mol / L acetic acid solution [take 120.0 g (114 mL) of glacial acetic acid and dilute it to 1000 mL with water to obtain], add water to dissolve and dilute to 1000 mL, shake well, and obtain.

[0086] pH 6.8 phosphate buffer: 0.2 mol·L -1 Mix 250 mL of potassium dihydrogen phosphate solution (take 27.22 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000 mL) and 112.0 mL of 0.2 mol / L sodium hydroxide solution (take 8.00 g of sodium hydroxide, dissolve it in water and dilute it to 1000 mL), then add water to dilute it to 1000 mL, shake well, and you have the product.

[0087] Water: Degassed purified water.

[0088] Chromatographic conditions: HPLC, C18 (4.6 mm × 25 cm, particle size 5 μm), detection wavelength 230 nm, column temperature 25 ° C, flow rate 1 ml / min, injection volume 50 μl. Mobile phase: 0.05 M sodium phosphate buffer (pH 6.8) / acetonitrile / methanol (17:7:6).

[0089] Test solution: Take an appropriate amount of the dissolution solution, filter it, accurately measure an appropriate amount of the filtrate, and quantitatively dilute it with water to make a solution containing approximately 0.1 mg of vonoprazan per 1 ml.

[0090] Reference solution: Take an appropriate amount of reference substance, weigh accurately, dissolve in water and quantitatively dilute to make a solution containing approximately 0.1 mg per 1 ml.

[0091] Determination method: Take the test solution and the control solution, determine them according to the high performance liquid chromatography method (General Rules 0512 of the 2020 Edition of the Chinese Pharmacopoeia), and calculate the dissolution amount of each tablet.

[0092] The cumulative dissolution test results of different dissolution media are shown in Table 5: Table 5 Cumulative dissolution test results of vonoprazan fumarate microtablets in different dissolution media According to the pharmacokinetic parameters of vonoprazan fumarate, vonoprazan fumarate tablets are released in the stomach and absorbed in the small intestine, and the bioavailability is low. Therefore, the dissolution medium is determined to be pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water to simulate the in vivo environment. The dissolution rate of the four dissolution curves at 15 minutes is greater than 85%.

[0093] Example 1 Amoxicillin microtablet dissolution curve determination evaluation dissolution method: According to the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia (General Rules 0931 of Part 4), the second method (paddle method) device is used, with pH 1.2 hydrochloric acid solution, pH 4.0 acetate buffer, pH 6.8 phosphate buffer and water as dissolution media, respectively, with a volume of 900 mL and a speed of 50 r / min, and operated in accordance with the law. 5 mL was sampled at 5, 10, 15, 30, 45, 60, and 90 min, filtered with a 0.45 μm filter membrane, and the filtrate was used as the test solution, and the dissolution medium of the same temperature and volume was added at the same time.

[0094] Preparation of dissolution medium: pH 1.2 hydrochloric acid solution: measure 7.65mL of hydrochloric acid, dilute to 1000mL with water, shake well.

[0095] pH 4.0 acetate buffer: Take 1.22 g of sodium acetate and 20.5 mL of 2 mol / L acetic acid solution [take 120.0 g (114 mL) of glacial acetic acid and dilute it to 1000 mL with water to obtain], add water to dissolve and dilute to 1000 mL, shake well, and obtain.

[0096] pH 6.8 phosphate buffer: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution (dissolve 27.22 g of potassium dihydrogen phosphate in water and dilute to 1000 mL) and 0.2 mol·L -1 Mix 112.0 mL of sodium hydroxide solution (take 8.00 g of sodium hydroxide, dissolve it in water and dilute it to 1000 mL), then add water to dilute it to 1000 mL, shake well, and you have it.

[0097] Test solution: Take an appropriate amount of the dissolution solution, filter it, accurately measure an appropriate amount of the filtrate, and dilute it with water to make a volume of about 1 ml of amoxicillin (according to C 16 H 19 N3O5S) 0.13 mg solution.

[0098] Control solution: Take 10 tablets of this product, grind them into powder, accurately weigh an appropriate amount (approximately equivalent to the average tablet weight), dissolve them in water according to the labeled amount and quantitatively dilute them to make a solution containing approximately 0.13 mg per 1 ml, filter and take the filtrate.

[0099] Determination method: Take the test solution and the control solution, and measure the absorbance at a wavelength of 272nm according to the UV-visible spectrophotometry (General Rules 0401 of the 2020 Edition of the Chinese Pharmacopoeia), and calculate the dissolution amount of each tablet.

[0100] Cumulative dissolution test results of different dissolution media Table 6: Table 6 Cumulative dissolution test results of amoxicillin microtablets in different dissolution media Conclusion: The dissolution rates of amoxicillin in the four different solvents within 30 minutes were all greater than 80%, which was in line with the limits specified in the pharmacopoeia.

[0101] The dissolution curve of left ornidazole microtablets in Example 1 was measured and evaluated for dissolution method: according to the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia (General Rule 0931 of Part 4), the second method (paddle method) device was used, with pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water as dissolution media, respectively, with a volume of 1000 mL and a rotation speed of 50 r / min, and operated in accordance with the law. 5 mL was sampled at 5, 10, 15, 30, 45, 60, 90, and 120 min (pH 1.0 hydrochloric acid solution to 90 min), filtered with a 0.45 μm filter membrane, and the filtrate was used as the test solution, and the dissolution medium of the same temperature and volume was added at the same time.

[0102] Preparation of dissolution medium: pH 1.0 hydrochloric acid solution: measure 9 mL of hydrochloric acid, dilute to 1000 mL with water, shake well, and you have it.

[0103] pH 4.5 acetate buffer: Take 2.99 g of sodium acetate and 14.0 mL of 2 mol / L acetic acid solution [take 120.0 g (114 mL) of glacial acetic acid and dilute it to 1000 mL with water to obtain], add water to dissolve and dilute to 1000 mL, shake well, and obtain.

[0104] pH 6.8 phosphate buffer: 0.2 mol·L -1 Potassium dihydrogen phosphate solution (27.22 g potassium dihydrogen phosphate, dissolved in water and diluted to 1000 mL) 250 mL and 0.2 mol·L -1 Mix 112.0 mL of sodium hydroxide solution (take 8.00 g of sodium hydroxide, dissolve it in water and dilute it to 1000 mL), then add water to dilute it to 1000 mL, shake well, and you have it.

[0105] Water: Degassed purified water.

[0106] Chromatographic conditions: C18 column (4.6 mm × 150 mm, 5 μm); mobile phase: methanol-water (30:70); UV detector, detection wavelength: 318 nm; flow rate: 1.0 mL min -1 ; Column temperature was 30°C; Injection volume was 10 μL.

[0107] Test solution: Take an appropriate amount of the dissolution solution, filter it, accurately measure an appropriate amount of the filtrate, and quantitatively dilute it with the dissolution medium to make a solution containing approximately 0.5 mg of levonidazole per 1 ml.

[0108] Reference solution: Take an appropriate amount of levornidazole reference substance, weigh accurately, add dissolution medium to dissolve and quantitatively dilute to make a solution containing approximately 0.5 mg per 1 ml.

[0109] Determination method: Take the test solution and the reference solution, inject them into the high performance liquid chromatograph, and calculate the dissolution amount of each tablet.

[0110] The cumulative dissolution test results of different dissolution media are shown in Table 7: Table 7 Cumulative dissolution test results of left ornidazole in different dissolution media Conclusion: The solubility of levornidazole in four different solvents within 30 minutes was greater than 80%. The solubility was affected by the pH value of the solution, and it was a pH-dependent drug.

[0111] Evaluation of the dissolution curve of levonidazole phosphate microtablets in Example 2 The dissolution method and dissolution medium preparation are the same as those of levonidazole microtablets.

[0112] Chromatographic conditions: C18 chromatographic column (4.6 mm × 150 mm, 5 μm); mobile phase: 0.05 mol / L potassium dihydrogen phosphate solution (pH 3.0)-methanol (80:20); UV detector, detection wavelength: 312 nm; flow rate: 1.0 mL min -1 ; Column temperature was 30°C; Injection volume was 20 μl.

[0113] Test solution: Take an appropriate amount of the dissolution solution, filter it, accurately measure an appropriate amount of the filtrate, and quantitatively dilute it with the dissolution medium to make a solution containing approximately 0.7 mg of levonidazole phosphate per 1 ml.

[0114] Reference substance solution: Take an appropriate amount of levonidazole phosphate reference substance, weigh accurately, add dissolution medium to dissolve and quantitatively dilute to make a solution containing approximately 0.7 mg per 1 ml.

[0115] Determination method: Take the test solution and the reference solution, inject them into the high performance liquid chromatograph, and calculate the dissolution amount of each tablet.

[0116] The cumulative dissolution test results of different dissolution media are shown in Table 8: Table 8 Cumulative dissolution test results of levonidazole phosphate in different dissolution media Conclusion: The dissolution rates of levornidazole phosphate in four different solvents within 15 minutes were all greater than 85%, indicating that it is a highly soluble drug, and its solubility is not affected by the pH value of the solution.

[0117] Example 12 Antibacterial activity against Helicobacter pylori (in vitro) (1) Single drug sensitivity test The agar dilution method was used to determine the in vitro sensitivity of H. pylori to amoxicillin, clarithromycin, metronidazole, and levornidazole. The test method followed the CLSI M7-A7 document. The minimum inhibitory concentration (MIC) of H. pylori against antibacterial drugs was referred to the "Judgment Criteria for Antibacterial Drug Efficacy Tests" and the CLSI M100-S17 document. The resistance of H. pylori to antibacterial drugs was judged based on the criteria that the MIC of levornidazole ≥ 2 μg / ml, the MIC of clarithromycin ≥ 2 μg / ml, the MIC of amoxicillin ≥ 8 μg / ml, and the MIC of metronidazole ≥ 8 μg / ml.

[0118] (2) Sensitivity test of combined drugs On the basis of screening out the antibacterial drugs sensitive to H. pylori, the "checkerboard method" was used to conduct the drug sensitivity test of vonoprazan fumarate combined with 2 antibacterial drugs respectively. The antibacterial effect of vonoprazan fumarate combined with 2 antibacterial drugs was evaluated by calculating the fractional inhibitory concentration (FIC). Judgment criteria: FIC ≤ 0.5 indicates that vonoprazan fumarate combined with 2 antibacterial drugs has a synergistic effect; 0.5 < FIC ≤ 1 indicates that vonoprazan fumarate combined with 2 antibacterial drugs has an additive effect; 1 < FIC ≤ 2 indicates that vonoprazan fumarate combined with 2 antibacterial drugs has no associated effect.

[0119] (3) Analysis of in vitro antibacterial effects of different drugs on H. pylori The drug resistance rates of 90 strains of H. pylori to different drugs from high to low were clarithromycin 52.2%, metronidazole 22.2%, amoxicillin 8.9%, and levornidazole 3.3%. The drug resistance rate of H. pylori to clarithromycin was the highest, and the drug resistance rate to levornidazole was the lowest. The results are shown in Table 9.

[0120] Table 9 In vitro antibacterial effects of different drugs on H. pylori Trial Drugs Sensitive / strain Drug resistance / strain Drug resistance rate / % Clarithromycin 43 47 52.2 Metronidazole 70 20 22.2 Amoxicillin 82 8 8.9 Levoornidazole 87 3 3.3 (4) Analysis of in vitro antibacterial effects of triple antibacterial drug therapy on Hp Table 10 FIC analysis of different combined antibacterial drugs on Hp The synergistic inhibitory effect of vonoprazan fumarate combined with amoxicillin and clarithromycin, vonoprazan fumarate combined with amoxicillin and levornidazole or levornidazole phosphate is the strongest. Vonoprazan fumarate combined with metronidazole and amoxicillin, vonoprazan fumarate combined with metronidazole and levornidazole has a synergistic inhibitory effect. Vonoprazan fumarate combined with clarithromycin and levornidazole or levornidazole phosphate has an additive antibacterial effect, while the inhibitory effect of vonoprazan fumarate combined with clarithromycin and metronidazole has no association.

[0121] Experimental Example 1 Antibacterial Experiment of Compound Capsules against Helicobacter pylori Helicobacter pylori strain (ATCC26695) was inoculated into a culture medium (Columbia blood agar containing 7% defibrinated sheep blood) and cultured.

[0122] The cultured Helicobacter pylori strain (ATCC26695) was collected and prepared into 3.0×10 8 cfu / mL of bacterial suspension was prepared with Helicobacter pylori liquid culture medium containing capsules of different concentrations (capsules of Examples 1-10), and the culture was placed in a 37°C incubator. After culturing for 72 hours, the minimum inhibitory concentration (MIC) of the capsules was read, which was 6.4 μg / mL.

[0123] This indicates that the capsule of the present invention has a strong inhibitory effect on Helicobacter pylori.

[0124] Experimental Example 2 Antibacterial Experiment of Compound Capsules on Mice Infected with Helicobacter pylori 140 male C57BL / 6 mice were randomly divided into a blank control group, a positive control group (comparative sample 1 (prepared according to the sample of Example 4 of Publication No. CN110354125A), a comparative sample 2 (prepared according to the sample of Example 1 of Authorization Announcement No. CN117398360B), a comparative sample 3 ( Pack combination packaged drugs)), test group. The drugs were administered for 7 days in total; the mice were killed after administration, and the stomach tissues were taken out for RUT experiment and WS staining. If the RUT and WS staining results were negative, it was judged that Helicobacter pylori was successfully eradicated. The eradication rate of each group was calculated, and the results are shown in Table 11.

[0125] Table 11 shows the antibacterial test results of each group on mice infected with Helicobacter pylori (n=10) The above results show that after 7 days of treatment, the eradication rate of the compound capsule provided by the present invention is better than that of the positive control group and the blank group, and the eradication rate can reach 100%. It can be concluded that the compound capsule provided by the present invention has a good eradication rate for Helicobacter pylori and has better efficacy than the publicly disclosed technical solutions.

[0126] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A compound preparation capsule, characterized in that: The capsule is composed of vonoprazan or its pharmaceutical salt microtablets, amoxicillin microtablets, levornidazole or its levornidazole phosphate microtablets and a capsule shell; the active ingredients are vonoprazan or its pharmaceutical salt, amoxicillin and levornidazole or its levornidazole phosphate; the auxiliary materials are fillers, disintegrants, binders, stabilizers, glidants and / or lubricants.

2. The compound preparation capsule according to claim 1, characterized in that: The pharmaceutically acceptable salt of vonoprazan is selected from fumarate, succinate, maleate, malate or tartrate.

3. The compound preparation capsule according to claim 1, characterized in that: The vonoprazan or pharmaceutical salt thereof microtablets include the following raw materials in parts by weight: 18% to 23% of vonoprazan or pharmaceutical salt thereof, 66% to 73% of microcrystalline cellulose mannitol co-processed product, 2% to 4% of cross-linked sodium carboxymethyl cellulose, 0.2% to 0.4% of stabilizer, 3% to 6% of binder, and 0.5% to 1.5% of lubricant; The amoxicillin microtablets include the following raw materials in parts by weight: 65% to 85% amoxicillin, 12% to 25% microcrystalline cellulose, 1% to 5% cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose, 1% to 3% glidant, and 0.5% to 1.5% lubricant; The levornidazole or levornidazole phosphate microtablets include the following raw materials in parts by weight: levornidazole or levornidazole phosphate 70% to 90%, lactose or mannitol or pregelatinized starch and microcrystalline cellulose or low-substituted hydroxypropyl cellulose 10% to 20%, cross-linked sodium carboxymethyl cellulose 1% to 5%, a binder accounting for 1.0% to 4.0%, a glidant accounting for 0 to 2%, and a lubricant accounting for 0.5% to 1.5%; The particle size distribution D50 of the vonoprazan or pharmaceutical salt thereof microtablets is 10 to 30 μm, and the particle size distribution D50 of the levornidazole phosphate or levornidazole microtablets is 10 to 30 μm.

4. The compound preparation capsule according to claim 1, characterized in that: The preparation method comprises the preparation of vonoprazan or its pharmaceutical salt microtablets, amoxicillin microtablets and levornidazole phosphate or levornidazole microtablets, and comprises the following steps: The method for preparing the vonoprazan or its pharmaceutically acceptable salt micro-tablets comprises the following specific steps: (1) Granulation: dissolving fumaric acid and hydroxypropyl cellulose in purified water and stirring to prepare a binder solution; adding vonoprazan or its pharmaceutically acceptable salt, microcrystalline cellulose mannitol co-processed product, and cross-linked sodium carboxymethyl cellulose into a fluidized bed granulator, spraying the binder solution into the fluidized bed granulator, and granulating; (2) Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Total mixing: Add the dry granules, cross-linked sodium carboxymethyl cellulose and magnesium stearate into a three-dimensional mixer and mix well; (5) Tablet compression: The tablet diameter is 1.5-3 mm, the tablet weight is about 32 mg, and the hardness ranges from 4 to 6 kgf; (6) Coating: Add hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant into purified water to prepare a solution with a solid content of 8% to 20% for coating, and the coating weight gain is 2% to 6%; The preparation method of the amoxicillin microtablets comprises the following specific steps: (1) Total mixing: Add amoxicillin granules, cross-linked sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate into a three-dimensional mixer and mix well; (2) Tablet compression: Tablet diameter: 3 mm, tablet weight about 30 mg, hardness range 4-6 kgf; (3) Coating: Add hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant into purified water to prepare a solution with a solid content of 8% to 20% for coating, and the coating weight gain is 2 to 6%; The preparation method of the levornidazole or levornidazole phosphate micro-tablets comprises the following specific steps: (1) Granulation: Dissolve hydroxypropyl methylcellulose in purified water and stir to prepare a binder solution; Adding levornidazole or levornidazole phosphate, lactose or mannitol, pregelatinized starch and microcrystalline cellulose or low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose into a fluidized bed granulator, and spraying purified water or a binder solution into the fluidized bed granulator to granulate; (2) Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Total mixing: Add the granules, sodium carboxymethyl cellulose and magnesium stearate into a three-dimensional mixer and mix them evenly; (5) Tablet compression: The tablet diameter is 1.5-3 mm, the tablet weight is about 30 mg, and the hardness ranges from 4 to 6 kgf; (6) Coating: Add hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant into purified water to prepare a solution with a solid content of 8% to 20% for coating. The coating weight gain is 2 to 6%.

5. The compound preparation capsule according to claim 1, characterized in that: The above-obtained vonoprazan or pharmaceutical salt microtablets contain 4 mg or 5 mg of vonoprazan per tablet, and each capsule is filled with 2 tablets; the above-obtained vonoprazan or pharmaceutical salt microtablets contain 10 mg of vonoprazan per tablet, and each capsule is filled with 1 tablet; the above-obtained amoxicillin microtablets contain 15 mg of amoxicillin per tablet, and each capsule is filled with 10 tablets; the above-obtained amoxicillin microtablets contain 25 mg of amoxicillin per tablet, and each capsule is filled with 15 tablets or 6 tablets; the above-obtained levonidazole microtablets contain 12.5 mg of levonidazole per tablet, and each capsule is filled with 4 tablets; the above-obtained levonidazole microtablets contain 12.5 mg of levonidazole phosphate (calculated as levonidazole) per tablet, and each capsule is filled with 4 tablets; the above-obtained levonidazole phosphate microtablets contain 25 mg of levonidazole phosphate (calculated as levonidazole) per tablet, and each capsule is filled with 2 tablets, to obtain compound preparation capsules.

6. The compound preparation capsule according to claim 1, characterized in that: The filler is one or more of microcrystalline cellulose, lactose, mannitol, pregelatinized starch, corn starch, and low-substituted hydroxypropyl cellulose; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; the stabilizer is fumaric acid; the solvent is purified water; the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, or sodium carboxymethyl cellulose; the glidant is one or more of silicon dioxide and talc; and the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, glyceryl behenate, and sodium stearyl fumarate.

7. The compound preparation capsule according to claim 1, characterized in that: The compound preparation capsule is used in preparing anti-Helicobacter pylori drugs.

Images