Compound formulation capsules and preparation method therefor

Abstract

The present disclosure discloses compound pharmaceutical formulation capsules consisting of vonoprazan or pharmaceutically acceptable salt micro-tablets thereof, amoxicillin micro-tablets, and levornidazole or levornidazole phosphate ester micro-tablets, and a preparation method therefor.

Description

A compound preparation capsule and its preparation method

[0001] Priority information

[0002] This application claims priority and benefit to patent application No. 202411809998.X, filed with the China National Intellectual Property Administration on December 10, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of drugs for treating Helicobacter pylori, specifically to compound preparation capsules for treating Helicobacter pylori and their preparation methods. Background Technology

[0004] Helicobacter pylori (H. pylori) is a Gram-negative bacterium that commonly resides in the gastric mucosa. Studies have confirmed that H. pylori is a major cause of chronic gastritis, peptic ulcers, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. In 2017, the International Agency for Research on Cancer (IARC) of the World Health Organization classified H. pylori as a Group 1 carcinogen, and related reports show that individuals infected with H. pylori have a 2 to 3 times higher risk of developing gastric cancer than the general population. Therefore, the harm caused by H. pylori infection is significant, and with increasing public awareness of health and hygiene, H. pylori infection will gradually receive more attention.

[0005] The generally accepted standard of care for eradicating Helicobacter pylori is either clarithromycin-based triple therapy or bismuth-based quadruple therapy. Triple therapy has been largely abandoned due to resistance issues. Bismuth-based quadruple therapy includes a proton pump inhibitor, bismuth, and two antibiotics. The latest globally approved formulation is Pylera (bismuth + metronidazole + tetracycline hydrochloride capsules), a combination packaged drug approved in the US. This combination includes metronidazole, which also carries the risk of resistance, with efficacy decreasing over time. Furthermore, it requires concurrent administration of Pylera and a proton pump inhibitor, leading to high costs and poor patient adherence. With increasing resistance and decreasing efficacy, patients face the risk of having no effective treatment options. Helicobacter pylori patients urgently need new drugs with low resistance rates and high efficacy for treatment.

[0006] Currently, proton pump inhibitors (PPIs) are widely prescribed as first-line treatment for acid-related diseases. However, PPIs do not always provide sufficient efficacy, and the inhibitory effect on gastric acid secretion can vary from person to person. This is because the gene encoding CYP-2C19, a protein involved in PPI metabolism, exhibits genetic polymorphism across different individuals. Vonoprazan, however, is not primarily metabolized by CYP2C19, and its inhibitory effect on the proton pump does not require acid activation. The drug enters the stomach at high concentrations, producing the maximum inhibitory effect upon first administration, and this effect can last for 24 hours.

[0007] Vonoprazan fumarate (TAK-38), jointly developed by Takeda and Otsuka, was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on December 26, 2014. Its specific structural formula is as follows:

[0008] Vonoprazan fumarate is a novel potassium (K+) competitive acid blocker (P-CAB) that competitively inhibits K+ secretion during the final stage of gastric acid secretion by parietal cells. + With H + -K + It works by binding to ATPase (proton pump), producing a strong and long-lasting inhibitory effect on gastric acid secretion. This drug is suitable for gastric ulcers, duodenal ulcers, reflux esophagitis, erosive esophagitis, gastroesophageal reflux disease, Helicobacter pylori infection, and peptic ulcers.

[0009] Currently, vonoprazan fumarate is packaged in combination with amoxicillin capsules and metronidazole tablets. Pack), combination package of drugs including vonoprazan fumarate with amoxicillin capsules and metronidazole tablets ( Pack 400 & 800, jointly developed by Takeda and Otsuka, is a drug for the treatment of Helicobacter pylori and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in June 2016.

[0010] Amoxicillin hydrate works by inhibiting bacterial cell wall synthesis; vonoprazan does not require acid activation and inhibits H+ in a reversible, potassium-competitive manner. + K + -ATPase. Vonoprazan is strongly alkaline and remains for a long time at the acid-producing sites of gastric parietal cells, inhibiting gastric acid production. Vonoprazan does not show activity against Helicobacter pylori or inhibit Helicobacter pylori urease. Metronidazole is reduced to a nitrosamine (R-NO) by the nitroreductase system in Helicobacter pylori. This R-NO exhibits bactericidal activity against Helicobacter pylori. Furthermore, the hydroxyl radicals generated during the reaction cleave DNA, leading to instability in the DNA helical structure. The role of vonoprazan in triple therapy with amoxicillin and metronidazole is thought to be by increasing gastric pH, thereby enhancing the antibacterial activity of amoxicillin and metronidazole.

[0011] Currently, the vonoprazan fumarate drug combination available in Japan for the treatment of Helicobacter pylori requires all three drugs to be taken separately, resulting in poor patient compliance. It is necessary to provide a new method to solve the above problems.

[0012] In addition, our research found that levonornidazole or levonornidazole phosphate combined with vonoprazan fumarate and amoxicillin has a strong inhibitory effect on Helicobacter pylori strains and low drug resistance; it has a high clinical cure rate and reduces adverse reactions caused by impurities resulting from possible interactions between raw materials. Summary of the Invention

[0013] The technical problem to be solved by this disclosure is to provide a compound preparation capsule for treating Helicobacter pylori and its preparation method, 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 resulting from possible interactions between raw materials.

[0014] This disclosure is achieved through the following technical solution:

[0015] In a first aspect, this disclosure provides a compound preparation. According to embodiments of this disclosure, the compound preparation comprises an active ingredient, said active ingredient including vonoprazan or its pharmaceutical salt, amoxicillin, and levonornidazole or its levonornidazole phosphate.

[0016] Optionally, the medicinal salt of vonoprazan is selected from fumarate, succinate, maleate, malate, or tartrate.

[0017] Optionally, the compound preparation is a compound preparation capsule, which includes vonoprazan or its pharmaceutical salt microplates, amoxicillin microplates, levonidazole or its levonidazole phosphate microplates, and a capsule shell.

[0018] Optionally, the compound preparation is a compound preparation capsule, wherein the capsule is composed of vonoprazan or its pharmaceutical salt microplates, amoxicillin microplates, levonidazole or its levonidazole phosphate microplates, and a capsule shell; wherein the active ingredients are vonoprazan or its pharmaceutical salt, amoxicillin, and levonidazole or its levonidazole phosphate.

[0019] Optionally, the excipients of the compound formulation may be fillers, disintegrants, binders, stabilizers, flow aids and / or lubricants.

[0020] Optionally, this disclosure provides a compound preparation capsule composed of vonoprazan or its pharmaceutical salt microplates, amoxicillin microplates, levonidazole or its levonidazole phosphate microplates, and a capsule shell; wherein the active ingredients are vonoprazan or its pharmaceutical salt, amoxicillin, and levonidazole or its levonidazole phosphate; and the excipients are fillers, disintegrants, binders, stabilizers, flow aids, and / or lubricants.

[0021] Optionally, the filler is one or more of microcrystalline cellulose, microcrystalline cellulose mannitol co-treated product, lactose, mannitol, pregelatinized starch, corn starch, and low-substituted hydroxypropyl cellulose;

[0022] The disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, and croscarmellose.

[0023] The stabilizer is fumaric acid;

[0024] The solvent is purified water;

[0025] The adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, or sodium carboxymethyl cellulose.

[0026] The flow aid is one or more of silica and talc.

[0027] The lubricant is one or more of the following: stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, glyceryl behenate, and sodium stearate fumarate.

[0028] Optionally, the active ingredient comprises 30-90%, filler 10-40%, disintegrant 1-10%, and flow aid and / or lubricant 0.8-2.5%; among the active ingredients, vonoprazan or its pharmaceutical salt comprises 1%-3%, amoxicillin comprises 72%-74%, and levonidazole or its levonidazole phosphate comprises 23-25%.

[0029] Optional, the medicinal salts of vonoprazan are fumarate, succinate, maleate, malate, or tartrate.

[0030] 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 carboxymethyl starch, croscarmellose sodium, and croscarmellose; the stabilizer is fumaric acid; and the solvent or binder is one or more of purified water, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, or sodium carboxymethyl cellulose.

[0031] Optionally, the flow aid is one or more of silica and talc; the lubricant is one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, and glyceryl behenate.

[0032] Optionally, vonoprazan or its pharmaceutical salt tablets are available in strengths of 4–10 mg, with a tablet weight of 10–35 mg and a diameter of 1.5–3 mm.

[0033] Optionally, amoxicillin tablets are available in 15–25 mg tablet sizes, weighing 20–35 mg tablets and with a diameter of 1.5–3 mm.

[0034] Optionally, the specifications of levonornidazole microtablets are 12.5–25 mg, the tablet weight is 15–35 mg, and the diameter is 1.5–3 mm.

[0035] Optionally, the specifications of levonornidazole phosphate microtablets (calculated as levonornidazole) are 12.5-25 mg, the tablet weight is 15-35 mg, and the diameter is 1.5-3 mm.

[0036] Optionally, the particle size distribution D50 of vonoprazan or its pharmaceutical salt microplates is 10-30 μm, and the particle size D50 of levonornidazole or its pharmaceutical salt in the levonornidazole microplates or levonornidazole phosphate microplates is 10-30 μm.

[0037] Optionally, the capsule comprises vonoprazan or its pharmaceutical salt microplates, amoxicillin microplates, levonornidazole microplates or levonornidazole phosphate microplates, and a capsule shell; wherein the number of vonoprazan or its pharmaceutical salt microplates is 1 to 2 tablets, the number of amoxicillin microplates is 6 to 10 tablets, the number of levonornidazole or levonornidazole phosphate microplates is 2 to 4 tablets, and the capsule shell is a No. 1, No. 0, or No. 00 capsule shell.

[0038] Optionally, the vonoprazan or its pharmaceutical salt microtablets contain 4 mg / tablet or 5 mg / tablet of vonoprazan, and each capsule is filled with 2 tablets; or, the vonoprazan or its pharmaceutical salt microtablets contain 10 mg / tablet of vonoprazan, and each capsule is filled with 1 tablet.

[0039] Optionally, the amoxicillin microtablets contain 15 mg of amoxicillin per tablet, with each capsule filled with 10 tablets; or, they contain 25 mg of amoxicillin per tablet, with each capsule filled with 15 tablets or 6 tablets.

[0040] Optionally, the levonornidazole microtablets contain 12.5 mg / tablet of levonornidazole, with each capsule containing 4 tablets; or, the levonornidazole microtablets contain 25 mg / tablet of levonornidazole, with each capsule containing 2 tablets; or, the levonornidazole phosphate microtablets contain 12.5 mg / tablet of levonornidazole phosphate, calculated as levonornidazole, with each capsule containing 4 tablets; or, the levonornidazole phosphate microtablets contain 25 mg / tablet of levonornidazole phosphate, calculated as levonornidazole, with each capsule containing 2 tablets.

[0041] This application provides the composition of each microplate in a compound preparation capsule.

[0042] The aforementioned vonoprazan or its pharmaceutical salt microtablets consist of a tablet core and a gastrointestinal coating.

[0043] The tablet core is made by wet processing, drying, granulation, adding lubricant, and pressing of vonoprazan or its pharmaceutical salt, along with fillers, disintegrants, stabilizers, and binders. The tablet core of the vonoprazan or its pharmaceutical salt microtablets comprises, by weight percentage, 60%–80% filler, 1%–5% disintegrant, 2%–8% binder, 0.5%–2% lubricant, 0.1%–0.5% stabilizer, and the remainder being vonoprazan or its pharmaceutical salt. The filler is selected from lactose, pregelatinized starch, mannitol, corn starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, or a microcrystalline cellulose-mannitol co-processed product. The mass ratio of microcrystalline cellulose to mannitol in the filler is 1:(0.5–10). Microcrystalline cellulose and mannitol can be provided in the form of a co-processed product. The disintegrant is sodium carboxymethyl starch, croscarmellose sodium, or croscarmellose. The stabilizer is fumaric acid. The binder is hydroxypropyl cellulose or hydroxypropyl methyl cellulose, povidone, or sodium carboxymethyl cellulose. The lubricant is magnesium stearate.

[0044] Preferably, the vonoprazan or its pharmaceutical salt tablets consist of a vonoprazan or its pharmaceutical salt tablet core and a coating component. The vonoprazan or its pharmaceutical salt tablet core is composed of microcrystalline cellulose mannitol co-treated compound (1:(6-8)), croscarmellose sodium, hydroxypropyl cellulose, fumaric acid, and magnesium stearate. The gastrointestinal coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant, etc. The percentages of each excipient are as follows, based on the weight of the tablets:

[0045] The content of vonoprazan or its medicinal salt is 15% to 25%, preferably 19% to 23%.

[0046] The proportion of microcrystalline cellulose and mannitol co-treated product is 60%–80%, preferably 65%–75%.

[0047] The proportion of croscarmellose sodium is 2% to 5%, preferably 2.5% to 3.5%.

[0048] Hydroxypropyl cellulose accounts for 2% to 8%, preferably 4% to 6%.

[0049] The proportion of fumaric acid is 0.1% to 0.5%, preferably 0.2% to 0.4%.

[0050] The magnesium stearate content is 0.5% to 2%, preferably 0.7% to 1.3%.

[0051] The weight gain of uncoated tablets is 2% to 6%, preferably 3% to 4%.

[0052] In some embodiments, the core of the vonoprazan or its pharmaceutical salt microplate comprises the following raw materials in parts by weight: 12% to 16% vonoprazan or its pharmaceutical salt, 73% to 80% filler, 6% to 11% binder, 0.1% to 0.5% stabilizer, and 0.5% to 2% lubricant, based on the weight of the core of the vonoprazan or its pharmaceutical salt microplate; the coating of the vonoprazan or its pharmaceutical salt microplate is 3% to 7%, based on the weight percentage of the vonoprazan or its pharmaceutical salt microplate.

[0053] In some embodiments, the vonoprazan or its pharmaceutical salt microplates comprise the following raw materials in parts by weight:

[0054] The content of vonoprazan or its medicinal salt is 10% to 25%;

[0055] The proportion of microcrystalline cellulose and mannitol co-treated product is 60%–80%;

[0056] Hydroxypropyl cellulose accounts for 2% to 6%;

[0057] Fumaric acid accounts for 0.1% to 0.5%;

[0058] Magnesium stearate accounts for 0.5% to 2%;

[0059] Coating 2%–6%;

[0060] Based on the weight of the vonoprazan or its pharmaceutical salt microplates.

[0061] The formulation of the vonoprazan or its pharmaceutical saline microtablets (1000 tablets) is as follows:

[0062] Tablet core: 5.344g of vonoprazan or its pharmaceutical salt (containing 4g of vonoprazan), 22.0g of microcrystalline cellulose mannitol co-processed product, 1.5g of hydroxypropyl cellulose, 0.04g of fumaric acid, and 0.3g of magnesium stearate.

[0063] Coating ingredients: hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant.

[0064] The amoxicillin microtablets consist of a tablet core and a gastrointestinal coating.

[0065] The tablet core is formed by mixing and pressing amoxicillin with fillers, disintegrants, flow aids, and lubricants. The amoxicillin tablet core composition, by weight percentage, is as follows: filler 10%–30%, disintegrant 1%–5%, flow aid 0.5%–2.5%, lubricant 0.5%–2%, with the balance being amoxicillin. The filler is selected from lactose and microcrystalline cellulose; the disintegrant is sodium carboxymethyl starch, croscarmellose sodium, or croscarmellose; the flow aid is silica; and the lubricant is magnesium stearate. The gastric-soluble coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, and colorants.

[0066] Preferably, the amoxicillin microtablets consist of an amoxicillin tablet core and a coating component. The amoxicillin tablet core is composed of microcrystalline cellulose, crospovidone, silica, and magnesium stearate. The gastrointestinal coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, and colorants. The percentages of each excipient are as follows, based on the weight of the microtablets:

[0067] Amoxicillin should comprise 67%–85% of the total content, with an optimal proportion of 72%–80%.

[0068] The proportion of microcrystalline cellulose is 10% to 30%, preferably 15% to 21%.

[0069] The cross-linked polyvinylpyrrolidone content is 1% to 5%, preferably 2.0% to 3.0%.

[0070] The silica content is 0.5% to 2.5%, preferably 1.5% to 2.2%.

[0071] The magnesium stearate content is 0.5% to 2%, preferably 0.7% to 1.3%.

[0072] The weight gain of uncoated tablets is 2% to 6%, preferably 3% to 4%.

[0073] In some embodiments, the amoxicillin microplate core comprises the following raw materials in parts by weight: 75%–80% amoxicillin, 10%–30% filler, 0.5%–3% lubricant, 0.5%–2.5% flow aid, and 0%–5% disintegrant, based on the weight of the amoxicillin microplate core; the coating of the amoxicillin microplate is 2%–8%, based on the weight percentage of the amoxicillin microplate.

[0074] In some embodiments, the amoxicillin microplates comprise the following parts by weight of raw materials:

[0075] Amoxicillin accounts for 67% to 85% of the total.

[0076] Microcrystalline cellulose accounts for 10% to 30%;

[0077] Cross-linked polyvinylpyrrolidone accounts for 1% to 5%;

[0078] Magnesium stearate accounts for 0.5% to 2%;

[0079] Coating 2%–6%;

[0080] Based on the weight of the amoxicillin microplates.

[0081] The amoxicillin microtablets (1000 tablets) have the following formulation:

[0082] Tablet core: Amoxicillin 25g, microcrystalline cellulose 6g, crospovidone 0.6g, silicon dioxide 0.3g, magnesium stearate 0.3g.

[0083] Coating ingredients: hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant.

[0084] The aforementioned levonornidazole or levonornidazole phosphate microtablets consist of a tablet core and a gastrointestinal coating.

[0085] The tablet core is formed by wet processing, drying, granulation, and compression with the addition of lubricant, using levonitrile or levonitrile phosphate, fillers, disintegrants, and binders. The tablet core composition is as follows (by weight percentage): filler 10%–30%, disintegrant 1%–5%, binder 1.0%–4.0%, and lubricant 0.5%–1.5%. The filler is selected from lactose, mannitol, microcrystalline cellulose, and corn starch; the disintegrant is sodium carboxymethyl starch, croscarmellose sodium, or croscarmellose; the binder is hydroxypropyl cellulose or hydroxypropyl methyl cellulose, povidone, or sodium carboxymethyl cellulose; the flow aid is silica; and the lubricant is magnesium stearate. The gastrointestinal coating consists of hydroxypropyl methyl cellulose, polyethylene glycol 6000, titanium dioxide, and colorants.

[0086] Preferably, the levonornidazole or levonornidazole phosphate microplates consist of a levonornidazole or levonornidazole phosphate tablet core and a coating component. The levonornidazole tablet core is composed of microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate; the levonornidazole phosphate tablet core is composed of mannitol, microcrystalline cellulose, croscarmellose sodium, silica, and magnesium stearate; the gastrointestinal coating is composed of hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, and colorants. The percentages of each excipient are as follows, based on the weight of the microplates:

[0087] The proportion of levonornidazole or levonornidazole phosphate is 20% to 90%, preferably 40% to 85%.

[0088] The proportion of microcrystalline cellulose is 10% to 30%, preferably 13% to 18%.

[0089] The proportion of croscarmellose sodium is 1% to 5%, preferably 2.0% to 3.0%.

[0090] The proportion of hydroxypropyl cellulose is 1.0% to 4.0%, preferably 1.5% to 2.5%.

[0091] The magnesium stearate content is 0.5% to 1.5%, preferably 0.7% to 1.3%.

[0092] The weight gain of uncoated tablets is 2% to 6%, preferably 3% to 4%.

[0093] In some embodiments, the core of the levonornidazole or levonornidazole phosphate microplate comprises the following raw materials in parts by weight: 44%–83% levonornidazole or levonornidazole phosphate, 10%–50% filler, 0%–4% binder; 0.2%–4% lubricant, 0%–4% flow aid; 1%–5% disintegrant, based on the weight of the core of the levonornidazole or levonornidazole phosphate microplate; and the coating of the levonornidazole or levonornidazole phosphate microplate is 1%–7%, based on the weight percentage of the levonornidazole or levonornidazole phosphate microplate.

[0094] In some embodiments, the levonornidazole or levonornidazole phosphate microplates comprise the following raw materials in parts by weight:

[0095] Levonidazole or levonidazole phosphate account for 5% to 90%;

[0096] Microcrystalline cellulose accounts for 5% to 80%;

[0097] Cross-linked sodium carboxymethyl cellulose accounts for 1% to 5%;

[0098] Hydroxypropyl cellulose accounts for 1.0% to 4.0%;

[0099] Magnesium stearate accounts for 0.5% to 1.5%;

[0100] Uncoated tablets gain 2%–6% weight.

[0101] The weight is based on the levonornidazole or levonornidazole phosphate microplates.

[0102] The formulation of the levonornidazole or levonornidazole phosphate microtablets (1000 tablets) is as follows:

[0103] Levonidazole tablet core: 25g levonidazole, 5g microcrystalline cellulose, 1g croscarmellose sodium cellulose, 0.6g hydroxypropyl methylcellulose, 0.3g magnesium stearate;

[0104] Levofloxacin phosphate tablet core: 17.05g levofloxacin phosphate, 5g microcrystalline cellulose, 0.6g croscarmellose sodium, 0.6g silica, 0.3g magnesium stearate.

[0105] Coating ingredients: hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, colorant.

[0106] Secondly, this application provides a method for preparing a compound preparation capsule.

[0107] In some embodiments, the method for preparing the vonoprazan or its pharmaceutical salt microplates includes the following steps:

[0108] (1) Granulation: Dissolve fumaric acid and hydroxypropyl cellulose in purified water and stir to prepare a binder solution; add vonoprazan or its pharmaceutical salt and microcrystalline cellulose mannitol co-treated product to a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate;

[0109] (2) Drying: Dry the granules in a fluidized bed granulator, heat them, cool them, and discharge them;

[0110] (3) Granulation: The dry granules are granulated using a granulator;

[0111] (4) Mixing: Add the dry granules and magnesium stearate to a three-dimensional mixer and mix evenly;

[0112] (5) Tableting;

[0113] (6) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to make a solution for coating.

[0114] For example, the preparation method of the vonoprazan or its pharmaceutical salt microplates includes the following specific steps:

[0115] (1) Granulation: Dissolve fumaric acid and hydroxypropyl cellulose in purified water and stir to prepare a binder solution; add vonoprazan or its pharmaceutical salt and microcrystalline cellulose mannitol co-treated product to a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate;

[0116] (2) Drying: Dry the granules in a fluidized bed granulator. Stop heating when the moisture content is below 3% and cool the granules before discharging.

[0117] (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm;

[0118] (4) Mixing: Add the dry granules and magnesium stearate to a three-dimensional mixer and mix evenly;

[0119] (5) Tableting: The tablet diameter is 3mm, the tablet weight is about 32mg, and the hardness range is 4-6kgf;

[0120] (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. The coating weight gain is 2% to 6 wt%.

[0121] In some embodiments, the preparation method of the amoxicillin microplates includes the following specific steps:

[0122] (1) Total mixing: Add amoxicillin, crospovidone, silica and magnesium stearate to a three-dimensional mixer and mix well;

[0123] (2) Tableting;

[0124] (3) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000 and colorant are added to purified water to make a solution for coating.

[0125] For example, the preparation method of the amoxicillin microplates includes the following specific steps:

[0126] (1) Total mixing: Add amoxicillin, crospovidone, silica and magnesium stearate to a three-dimensional mixer and mix well;

[0127] (2) Tableting: Tablet diameter: 3mm, tablet weight: approximately 35mg, hardness range: 4-6kgf;

[0128] (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. The coating weight gain is 2 to 6 wt%.

[0129] In some embodiments, the preparation method of the levonornidazole phosphate or levonornidazole microplates includes the following steps:

[0130] (1) Granulation: Dissolve hydroxypropyl methylcellulose in purified water and stir to prepare a binder solution; add levonidazole or levonidazole phosphate and croscarmellose sodium to a fluidized bed granulator, and spray purified water or binder solution into the fluidized bed granulator to granulate;

[0131] (2) Drying: Drying the granules in a fluidized bed granulator;

[0132] (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm;

[0133] (4) Mixing: Add the granules and magnesium stearate to a three-dimensional mixer and mix evenly;

[0134] (5) Tableting;

[0135] (6) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to make a solution for coating.

[0136] For example, the preparation method of the levonornidazole microplates includes the following specific steps:

[0137] (1) Granulation: Hydroxypropyl methylcellulose was dissolved in purified water and stirred to prepare a binder solution. Levonidazole, microcrystalline cellulose, and croscarmellose sodium were added to a fluidized bed granulator, and the binder solution was sprayed into the fluidized bed granulator for granulation.

[0138] (2) Drying: Dry the granules in a fluidized bed granulator. Stop heating when the moisture content is below 3% and cool the granules before discharging.

[0139] (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm;

[0140] (4) Mixing: Add the granular magnesium stearate to a three-dimensional mixer and mix evenly;

[0141] (5) Tableting: The tablet diameter is 3mm, the tablet weight is about 35mg, and the hardness range is 4-6kgf;

[0142] (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. The coating weight gain is 2 to 6 wt%.

[0143] The specific steps for preparing the levonornidazole phosphate microplates are as follows:

[0144] (1) Granulation: Add levofloxacin phosphate, mannitol, microcrystalline cellulose and croscarmellose sodium cellulose to a fluidized bed granulator, spray purified water into the fluidized bed granulator and granulate;

[0145] (2) Drying: Dry the granules in a fluidized bed granulator. Stop heating when the moisture content is below 3% and cool the granules before discharging.

[0146] (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm;

[0147] (4) Mixing: Add the granules, silica and magnesium stearate to a three-dimensional mixer and mix evenly;

[0148] (5) Tableting: The tablet diameter is 3mm, the tablet weight is about 35mg, and the hardness range is 4-6kgf;

[0149] (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. The coating weight gain is 2 to 6 wt%.

[0150] Thirdly, this disclosure provides the use of the aforementioned compound preparation in the preparation of anti-Helicobacter pylori drugs.

[0151] In some embodiments, the compound preparation is used to treat diseases caused by Helicobacter pylori.

[0152] In some embodiments, the compound preparation is used to treat gastric ulcers, duodenal ulcers, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicobacter pylori infection in the stomach after endoscopic treatment of early gastric cancer, and Helicobacter pylori-infected gastritis.

[0153] Fourthly, this disclosure provides a method for treating Helicobacter pylori or diseases caused by Helicobacter pylori, comprising: administering the aforementioned compound preparation. Specifically, the compound preparation may be administered orally or by injection.

[0154] Fifthly, this disclosure proposes a method for treating gastric ulcers, duodenal ulcers, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicobacter pylori infection in the stomach after endoscopic treatment of early gastric cancer, and Helicobacter pylori-infected gastritis, comprising: applying the aforementioned compound preparation.

[0155] Compared with the prior art, this disclosure has the following beneficial effects:

[0156] 1. The compound preparation capsules described in this disclosure overcome the problem of antibiotic resistance, improve the eradication rate of Helicobacter pylori, provide a new option for clinical patients to eradicate diseases caused by Helicobacter pylori, and patients only need to take one drug, which improves patient compliance.

[0157] 2. The compound capsule preparations described in this disclosure are prepared by compressing and coating each major component separately, which blocks the adverse reactions caused by impurities resulting from possible interactions between the major components, thus ensuring the safety of clinical medication. Attached Figure Description

[0158] Figure 1. Dissolution curves of vonoprazan fumarate microplates in different dissolution media;

[0159] Figure 2 Dissolution curves of amoxicillin microplates in different dissolution media;

[0160] Figure 3. Dissolution curves of levonornidazole microplates in different dissolution media;

[0161] Figure 4. Dissolution curves of levonornidazole phosphate microplates in different dissolution media. Detailed Implementation

[0162] The embodiments of this disclosure will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this disclosure. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0163] Example 1

[0164] The compound preparation capsule disclosed herein includes vonoprazan fumarate microtablets, amoxicillin microtablets, and levonornidazole microtablets, the composition of which, by weight, is shown in Table 1.

[0165] Table 1. Composition and proportion of each component

[0166] Preparation process:

[0167] The preparation of vonoprazan fumarate microplates includes the following steps:

[0168] Granulation: Fumaric acid and hydroxypropyl cellulose are dissolved in purified water and then added to a wet granulator along with vonoprazan fumarate and mannitol microcrystalline cellulose. The mixing speed is 300 rpm and the cutter speed is 500 rpm for 5 minutes. The atomized aqueous solution of fumaric acid and hydroxypropyl cellulose is then sprayed in at a speed of 200 rpm and a cutter speed of 500 rpm, and the addition is completed in about 8 minutes. The mixing speed is 250 rpm and the cutter speed is 1200 rpm for 2 minutes. The granulation is then carried out by wet granulation with a 3×3 mm sieve and a rotation speed of 400 rpm.

[0169] Drying: Add wet granules to a fluidized bed, introduce air at 60℃ and 30Hz, and dry. When the material temperature reaches 40℃, take a sample to determine the moisture content. Stop heating when the moisture content is below 2.0%, and cool and discharge the material.

[0170] Granulation: Granulator screen diameter 1mm, rotation speed 400rpm, granulation.

[0171] Total mixing: Add the granules and magnesium stearate to a three-dimensional mixer, mix at 30 Hz for 10 min.

[0172] Tableting: 3.0mm shallow concave punch, tablet weight 32mg, hardness range 4~6kgf.

[0173] Coating: Hydroxypropyl methylcellulose (E5), polyethylene glycol (PEG6000), titanium dioxide, and colorant are added to purified water to prepare a 10wt% solution; the inlet air temperature is 45-60℃, the tablet bed temperature is 38-45℃, and the coating weight gain is 3-4%.

[0174] The preparation of amoxicillin microplates includes the following steps:

[0175] Final mixing: Add aspirin, microcrystalline cellulose, crospovidone, and silica to a three-dimensional mixer and mix at 30 Hz for 20 min. Stop the mixer and add magnesium stearate to the three-dimensional mixer. Mix at 30 Hz for another 10 min.

[0176] Tableting: 3.0mm shallow concave punch, tablet weight 32mg, hardness range 4~6kgf.

[0177] Coating: Hydroxypropyl methylcellulose (E5), polyethylene glycol (PEG6000), and colorant are added to purified water to prepare a 10wt% solution; the inlet air temperature is 45-60℃, the tablet bed temperature is 38-45℃, and the coating weight gain is 3-4%.

[0178] The preparation of levonornidazole microplates includes the following steps:

[0179] Granulation: Dissolve hydroxypropyl methylcellulose in purified water. Add levonornidazole, microcrystalline cellulose, and croscarmellose sodium to a wet granulator. Mix for 5 minutes with a stirring paddle speed of 300 rpm and a cutter speed of 500 rpm. Then, spray the hydroxypropyl methylcellulose solution into the wet granulator at a stirring paddle speed of 200 rpm and a cutter speed of 500 rpm, completing the addition in about 8 minutes. Finally, granulate for 2 minutes with a stirring paddle speed of 250 rpm and a cutter speed of 1200 rpm. Discharge the granulator and wet granulate it at a 3×3 mm screen speed of 400 rpm.

[0180] Drying: Add wet granules to a fluidized bed, introduce air at 60℃ and 30Hz, and dry. When the material temperature reaches 40℃, take a sample to determine the moisture content. Stop heating when the moisture content is below 2.0%, and cool and discharge the material.

[0181] Granulation: Granulator screen diameter 1mm, rotation speed 400rpm, granulation.

[0182] Total mixing: Add the granules and magnesium stearate to a three-dimensional mixer, mix at 30 Hz for 5 min.

[0183] Tableting: 3.0mm shallow concave punch, tablet weight 32mg, hardness range 4~6kgf.

[0184] Coating: Hydroxypropyl methylcellulose (E5), polyethylene glycol (PEG6000), and colorant are added to purified water to prepare a 10wt% solution; the inlet air temperature is 45-60℃, the tablet bed temperature is 38-45℃, and the coating weight gain is 3-4%.

[0185] Formulated into compound capsules:

[0186] Take 1 tablet of vonoprazan fumarate microparticles, 6 tablets of amoxicillin microparticles and 2 tablets of levonidazole microparticles, respectively, and fill them into empty capsules No. 1 to prepare vonoprazan fumarate / amoxicillin / levonidazole capsules (4mg / 150mg / 50mg).

[0187] Example 2

[0188] The compound preparation capsule disclosed herein includes vonoprazan fumarate microtablets, amoxicillin microtablets, and levonornidazole phosphate microtablets, the raw material composition of which is shown in Table 2 by weight.

[0189] Table 2 Composition and proportion of each component

[0190] The preparation process is the same as in Example 1, except that the granulation steps for the levonornidazole microplates are as follows:

[0191] Hydroxypropyl cellulose was dissolved in purified water. Levofloxacin phosphate, mannitol, microcrystalline cellulose, croscarmellose sodium cellulose, and silica were added to a wet granulator. The mixing speed was 300 rpm and the cutter speed was 500 rpm for 5 minutes. The hydroxypropyl methyl cellulose solution was then atomized and sprayed into the granulator at a speed of 200 rpm and a cutter speed of 500 rpm, which took about 8 minutes to complete. The granulation process was then carried out at a speed of 250 rpm and a cutter speed of 1200 rpm for 2 minutes. The granulated material was then discharged through a granulator with a 3×3 mm screen and a rotation speed of 400 rpm for wet granulation.

[0192] Formulated into compound capsules:

[0193] Take 1 tablet of vonoprazan fumarate micro-tablets, 6 tablets of amoxicillin micro-tablets, and 4 tablets of levonornidazole phosphate micro-tablets, respectively, and fill them into #1 empty capsules to prepare vonoprazan fumarate / amoxicillin / levonornidazole phosphate capsules (4mg / 150mg / 50mg).

[0194] Examples 3-6

[0195] The compound preparation capsule described in this disclosure includes vonoprazan fumarate microtablets, amoxicillin microtablets, and levonornidazole microtablets, the raw material composition of which is shown in Table 3 by weight.

[0196] Table 3 Composition and proportion of each component

[0197] The preparation process is the same as in Example 1.

[0198] Examples 7-10

[0199] The compound preparation capsule described in this disclosure includes vonoprazan fumarate microtablets, amoxicillin microtablets, and levonornidazole phosphate microtablets, the raw material composition of which is shown in Table 4 by weight.

[0200] Table 4 Composition and proportion of each component

[0201] The preparation process is the same as in Example 1.

[0202] Example 11: Evaluation of dissolution curve determination of vonoprazan fumarate / amoxicillin / levonidazole or levonidazole phosphate capsules

[0203] After oral administration of solid dosage forms, drug absorption depends on the dissolution or release of the drug from the formulation, its solubility under physiological conditions, and its penetration into the gastrointestinal tract. Since drug dissolution and solubility significantly influence absorption, in vitro dissolution behavior can potentially predict its in vivo behavior, and in vitro dissolution behavior can reflect the quality of the formulation to some extent. This study investigated the dissolution profiles of a self-developed formulation in four basic media simulating human digestive tract fluids.

[0204] Evaluation of dissolution curve determination of vonoprazan fumarate microplates in Example 1

[0205] Dissolution method: Following the method for determination of dissolution and release in the 2025 edition of the Chinese Pharmacopoeia (Part IV, General Chapter 0931), the second method (paddle method) was used. Dissolution media included pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and water, with a volume of 900 mL and a rotation speed of 50 rpm. Samples (5 mL) were taken sequentially at 5, 10, 15, 30, and 45 min, filtered through a 0.45 μm filter membrane, and the filtrate was used as the test solution. Simultaneously, dissolution media of the same volume and temperature were added.

[0206] Preparation of dissolution medium:

[0207] pH 1.2 hydrochloric acid solution: Measure 7.65 mL of hydrochloric acid, dilute with water to 1000 mL, and shake well.

[0208] 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 with water to 1000 mL to obtain], dissolve in water and dilute to 1000 mL, shake well to obtain the buffer.

[0209] pH 6.8 phosphate buffer: Take 250 mL of 0.2 mol·L⁻¹ potassium dihydrogen phosphate solution (take 27.22 g of potassium dihydrogen phosphate, dissolve in water and dilute to 1000 mL) and add 0.2 mol / L... -1Mix 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 dilute it with water to 1000 mL and shake well to obtain the solution.

[0210] Water: Degassed and purified water.

[0211] Chromatographic conditions: HPLC, C18 (4.6 mm × 25 cm, particle size 5 μm), detection wavelength 230 nm, column temperature 25 ℃, 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).

[0212] Test solution: Take an appropriate amount of the dissolution solution, filter it, accurately measure an appropriate amount of the filtrate, and dilute it quantitatively with water to prepare a solution containing approximately 0.1 mg of vonoprazan per ml.

[0213] Control solution: Take an appropriate amount of the control standard, accurately weigh it, dissolve it in water and dilute it quantitatively to prepare a solution containing about 0.1 mg per 1 ml.

[0214] Assay: Take the test solution and the control solution, and determine the dissolution amount per tablet according to the high performance liquid chromatography method (General Chapter 0512 of Chinese Pharmacopoeia 2025).

[0215] The cumulative dissolution test results for different dissolution media are shown in Table 5 and Figure 1:

[0216] Table 5. Results of cumulative dissolution of vonoprazan fumarate microplates in different dissolution media

[0217] Based on the pharmacokinetic parameters of vonoprazan fumarate, vonoprazan fumarate tablets are released in the stomach and absorbed in the small intestine, resulting in low bioavailability. Therefore, to simulate the in vivo environment, the dissolution media were determined to be pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and water. All four dissolution curves showed a dissolution rate greater than 85% at 15 minutes.

[0218] Evaluation of Amoxicillin Microplate Dissolution Curve in Example 1

[0219] Dissolution method: Following the method for determination of dissolution and release in the 2025 edition of the Chinese Pharmacopoeia (Part IV, General Chapter 0931), the second method (paddle method) was used. Dissolution media included pH 1.2 hydrochloric acid solution, pH 4.0 acetate buffer, pH 6.8 phosphate buffer, and water, with a volume of 900 mL and a rotation speed of 50 rpm. Samples of 5 mL were taken sequentially at 5, 10, 15, 30, 45, 60, and 90 min, filtered through a 0.45 μm filter membrane, and the filtrate was used as the test solution. Simultaneously, dissolution media of the same volume and temperature were added.

[0220] Preparation of dissolution medium:

[0221] pH 1.2 hydrochloric acid solution: Measure 7.65 mL of hydrochloric acid, dilute with water to 1000 mL, and shake well.

[0222] 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 with water to 1000 mL to obtain], dissolve in water and dilute to 1000 mL, shake well, and you have the solution.

[0223] pH 6.8 phosphate buffer: Take 250 mL of 0.2 mol / L potassium dihydrogen phosphate solution (take 27.22 g of potassium dihydrogen phosphate, dissolve in water and dilute to 1000 mL) and add 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 dilute it with water to 1000 mL and shake well to obtain the solution.

[0224] Test solution: Take an appropriate amount of the dissolution, filter, accurately measure an appropriate amount of the filtrate, and dilute quantitatively with water to prepare a solution containing approximately amoxicillin per ml (according to C). 16 H 19 A solution containing 0.13 mg of N3O5S.

[0225] Control solution: Take 10 tablets of this product, grind them into a fine powder, accurately weigh an appropriate amount (approximately equivalent to the average tablet weight), add water to dissolve and quantitatively dilute to prepare a solution containing approximately 0.13 mg per 1 ml, filter, and collect the filtrate.

[0226] Assay: Take the test solution and the control solution, and measure the absorbance at a wavelength of 272 nm using ultraviolet-visible spectrophotometry (General Chapter 0401 of Chinese Pharmacopoeia 2025). Calculate the dissolution amount of each tablet.

[0227] Table 6 and Figure 2 show the cumulative dissolution test results for different dissolution media:

[0228] Table 6. Results of Cumulative Dissolution of Amoxicillin Microtablets in Different Dissolution Media

[0229] Conclusion: The dissolution rate of amoxicillin in four different solvents was greater than 80% within 30 minutes, which meets the limit specified in the pharmacopoeia.

[0230] Evaluation of the dissolution curve of levonornidazole microplates in Example 1

[0231] Dissolution method: Following the method for determination of dissolution and release in the 2025 edition of the Chinese Pharmacopoeia (Part IV, General Chapter 0931), the second method (paddle method) was used. Dissolution media included pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and water, with a volume of 1000 mL and a rotation speed of 50 rpm. Samples were taken at 5, 10, 15, 30, 45, 60, 90, and 120 min (from pH 1.0 hydrochloric acid solution to 90 min), filtered through a 0.45 μm filter membrane, and the filtrate was used as the test solution. Simultaneously, dissolution media of the same volume and temperature were added.

[0232] Preparation of dissolution medium:

[0233] pH 1.0 hydrochloric acid solution: Measure 9 mL of hydrochloric acid, dilute with water to 1000 mL, and shake well.

[0234] 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 with water to 1000 mL to obtain], dissolve in water and dilute to 1000 mL, shake well to obtain the buffer.

[0235] pH 6.8 phosphate buffer: Take 0.2 mol·L⁻¹ -1 Potassium dihydrogen phosphate solution (take 27.22 g of potassium dihydrogen phosphate, dissolve in water and dilute to 1000 mL) 250 mL and 0.2 mol·L⁻¹ -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 dilute it with water to 1000 mL and shake well to obtain the solution.

[0236] Water: Degassed and purified water.

[0237] 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 The column temperature was 30℃; the injection volume was 10μL.

[0238] 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 prepare a solution containing approximately 0.5 mg of levonornidazole per 1 ml.

[0239] Reference solution: Weigh an appropriate amount of levonornidazole reference standard accurately, dissolve it in dissolution medium and dilute quantitatively to prepare a solution containing approximately 0.5 mg per ml.

[0240] Assay: Take the test solution and the reference solution, inject them into the high performance liquid chromatograph, and calculate the dissolution amount of each tablet.

[0241] The cumulative dissolution test results for different dissolution media are shown in Table 7 and Figure 3:

[0242] Table 7. Results of Cumulative Dissolution of Levonidazole in Different Dissolution Media

[0243] Conclusion: The dissolution rate of levonornidazole in four different solvents was greater than 80% within 30 minutes. The solubility was affected by the pH value of the solution, indicating that it is a pH-dependent drug.

[0244] Evaluation of the dissolution curve of levonornidazole phosphate microplates in Example 2

[0245] The dissolution method and dissolution medium preparation are the same as those for levonornidazole tablets.

[0246] Chromatographic conditions: C18 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: 30 ℃; injection volume: 20 μl.

[0247] 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 prepare a solution containing approximately 0.7 mg of levonornidazole phosphate per 1 ml.

[0248] Reference solution: Weigh an appropriate amount of levonornidazole phosphate reference standard accurately, dissolve it in dissolution medium and dilute quantitatively to prepare a solution containing approximately 0.7 mg per ml.

[0249] Assay: Take the test solution and the reference solution, inject them into the high performance liquid chromatograph, and calculate the dissolution amount of each tablet.

[0250] The cumulative dissolution test results for different dissolution media are shown in Table 8 and Figure 4:

[0251] Table 8. Results of Cumulative Dissolution of Levonidazole Phosphate in Different Dissolution Media

[0252] Conclusion: The solubility of levonornidazole phosphate in four different solvents was greater than 85% within 15 minutes, indicating that it is a highly soluble drug. The solubility was not affected by the pH of the solution.

[0253] Example 12: Antibacterial activity against Helicobacter pylori (in vitro)

[0254] (1) Single drug sensitivity test

[0255] 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 the Pharmacodynamic Test of Antibacterial Drugs" and the CLSI M100-S17 document. The resistance of H. pylori to antibacterial drugs was judged by the criteria of levornidazole MIC ≥ 2 μg / ml, clarithromycin MIC ≥ 2 μg / ml, amoxicillin MIC ≥ 8 μg / ml, and metronidazole MIC ≥ 8 μg / ml, and was characterized by the resistance rate.

[0256] As shown in Table 9, the 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 resistance rate of H. pylori to clarithromycin was the highest, and the resistance rate to levornidazole was the lowest.

[0257] Table 9 In vitro antibacterial effects of different drugs on H. pylori

[0258] (2) Sensitivity test of combined drugs

[0259] On the basis of screening out the antibacterial drugs sensitive to Helicobacter pylori H. pylori, the "checkerboard method" was used to conduct the drug sensitivity test of vonoprazan fumarate combined with 2 antibacterial drugs respectively, and 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. The results are shown in Table 10.

[0260] Table 10 FIC analysis of different antibacterial drug combinations against Hp

[0261] The synergistic inhibitory effect of vonoprazan combined with amoxicillin and clarithromycin (0.33) and the synergistic inhibitory effect of vonoprazan combined with amoxicillin and levornidazole or levornidazole phosphate (0.27) were the strongest. Vonoprazan combined with metronidazole and amoxicillin and vonoprazan combined with metronidazole and levornidazole had a synergistic inhibitory effect. Vonoprazan combined with clarithromycin and levornidazole or levornidazole phosphate had an additive antibacterial effect, while the inhibitory effect of vonoprazan combined with clarithromycin and metronidazole had no association. Therefore, vonoprazan combined with amoxicillin and levornidazole or levornidazole phosphate was selected to prepare a compound preparation.

[0262] (3) Antibacterial experiment of compound capsules against Helicobacter pylori

[0263] The Helicobacter pylori strain (ATCC26695) was inoculated into a culture medium (Columbian blood agar containing 7% defibrinated sheep blood) and cultured.

[0264] The cultured Helicobacter pylori strain (ATCC26695) was prepared into a 3.0×10⁻⁶ ppm solution. 8 A bacterial suspension of CFU / mL was prepared to form Helicobacter pylori liquid culture medium containing different concentrations of capsules (capsules of Examples 1-10) of 48, 24, 12, 6.4, 3, 1.5, and 0.75 μmol / mL. The medium was incubated at 37°C for 72 h and the minimum inhibitory concentration (MIC) of the composition and capsules was read. The MIC of the capsules in all 10 examples was 6.4 μg / mL.

[0265] This indicates that the capsule formulation disclosed herein has a strong inhibitory effect on Helicobacter pylori.

[0266] (4) Antibacterial experiment of compound capsules on mice infected with Helicobacter pylori

[0267] One hundred and forty male C57BL / 6 mice were randomly divided into a blank control group, a positive control group (sample 1 (prepared according to Example 4 of Publication No. CN110354125A), sample 2 (prepared according to Example 1 of Authorization No. CN117398360B), and sample 3 (…). The drugs were packaged in a combination pack, and the test sample group was also included. The mice were administered the drugs for 7 days, one tablet of each prescription twice daily. All mice were sacrificed after administration, and their stomach tissues were removed for RUT and WS staining. Mice with negative RUT and WS staining results were considered successfully eradicated from Helicobacter pylori. The eradication rates for each group were calculated, and the results are shown in Table 11.

[0268] Table 11 shows the antibacterial experiment results of each group against Helicobacter pylori-infected mice (n=10).

[0269] The above results indicate that after 7 days of treatment, the eradication rate of the compound capsules provided in this disclosure is better than that of the positive control group and the blank group, reaching 100%. Therefore, it can be concluded that the compound capsules provided in this disclosure have a very good eradication rate against Helicobacter pylori, and their efficacy is better than that of previously disclosed technical solutions.

[0270] Although this disclosure has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, such modifications or improvements made without departing from the spirit of this disclosure are all within the scope of protection claimed by this disclosure.

Claims

1. A compound preparation, characterized in that, The compound preparation includes active ingredients, which include vonoprazan or its pharmaceutical salt, amoxicillin, and levonornidazole or its levonornidazole phosphate.

2. The compound preparation according to claim 1, characterized in that, The medicinal salts of the vonoprazan are selected from fumarate, succinate, maleate, malate, or tartrate.

3. The compound preparation according to claim 1, characterized in that, The compound preparation is a compound preparation capsule, which includes vonoprazan or its pharmaceutical salt microplates, amoxicillin microplates, levonidazole or its levonidazole phosphate microplates, and a capsule shell.

4. The compound preparation according to claim 1, characterized in that, The compound preparation is a compound capsule, which consists of vonoprazan or its pharmaceutical salt microplates, amoxicillin microplates, levonornidazole or its levonornidazole phosphate microplates, and a capsule shell; wherein the active ingredients are vonoprazan or its pharmaceutical salt, amoxicillin, and levonornidazole or its levonornidazole phosphate.

5. The compound preparation according to claim 1, characterized in that, The excipients of the compound preparation are fillers, disintegrants, binders, stabilizers, flow aids and / or lubricants.

6. The compound preparation according to claim 5, characterized in that, The filler is one or more of the following: microcrystalline cellulose, microcrystalline cellulose mannitol co-treated product, lactose, mannitol, pregelatinized starch, corn starch, and low-substituted hydroxypropyl cellulose; The disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, and croscarmellose. The stabilizer is fumaric acid; The solvent is purified water; The adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, or sodium carboxymethyl cellulose. The flow aid is one or more of silica and talc. The lubricant is one or more of the following: stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, glyceryl behenate, and sodium stearate fumarate.

7. The compound preparation according to any one of claims 1-6, characterized in that, The vonoprazan or its pharmaceutical salt microplates comprise the following raw materials in parts by weight: 18%–23% vonoprazan or its pharmaceutical salt, 66%–73% microcrystalline cellulose mannitol co-processed product, 2%–4% croscarmellose sodium, 0.2%–0.4% stabilizer, 3%–6% binder, and 0.5%–1.5% lubricant; The amoxicillin microplates comprise the following raw materials in parts by weight: 65%–85% amoxicillin, 12%–25% microcrystalline cellulose, 1%–5% crospovidone or crospovidone sodium carboxymethyl cellulose, 1%–3% flow aid, and 0.5%–1.5% lubricant. The levonornidazole or levonornidazole phosphate microplates comprise the following raw materials in parts by weight: 70%–90% levonornidazole or levonornidazole phosphate, 10%–20% lactose or mannitol or pregelatinized starch and microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 1%–5% croscarmellose sodium, 1.0%–4.0% binder, 0%–2% flow aid, and 0.5%–1.5% lubricant; The particle size distribution D50 of the vonoprazan or its pharmaceutical salt microcapsules is 10-30 μm, and the particle size distribution D50 of the levonornidazole phosphate or levonornidazole microcapsules is 10-30 μm.

8. The compound preparation according to any one of claims 1-6, characterized in that, The tablet core of the vonoprazan or its pharmaceutical salt microtablets comprises the following raw materials in parts by weight: 12%–16% vonoprazan or its pharmaceutical salt, 73%–80% filler, 6%–11% binder, 0.1%–0.5% stabilizer, and 0.5%–2% lubricant, based on the weight of the tablet core of the vonoprazan or its pharmaceutical salt microtablets; the coating of the vonoprazan or its pharmaceutical salt microtablets is 3%–7%, based on the weight percentage of the vonoprazan or its pharmaceutical salt microtablets; The amoxicillin microplate core comprises the following raw materials in parts by weight: 75%–80% amoxicillin, 10%–30% filler, 0.5%–3% lubricant, 0.5%–2.5% flow aid, and 0%–5% disintegrant, based on the weight of the amoxicillin microplate core; the coating of the amoxicillin microplate is 2%–8%, based on the weight percentage of the amoxicillin microplate. The core of the levonornidazole or levonornidazole phosphate microplate comprises the following raw materials in parts by weight: 44%–83% levonornidazole or levonornidazole phosphate, 10%–50% filler, 0%–4% binder, 0.2%–4% lubricant, 0%–4% flow aid, and 1%–5% disintegrant, based on the weight of the core of the levonornidazole or levonornidazole phosphate microplate; the coating of the levonornidazole or levonornidazole phosphate microplate is 1%–7%, based on the weight percentage of the levonornidazole or levonornidazole phosphate microplate.

9. The compound preparation according to any one of claims 1-6, characterized in that, The vonoprazan or its pharmaceutical salt microplates comprise the following raw materials in parts by weight: The content of vonoprazan or its medicinal salt is 10% to 25%; The proportion of microcrystalline cellulose and mannitol co-treated product is 60%–80%; Hydroxypropyl cellulose accounts for 2% to 6%; Fumaric acid accounts for 0.1% to 0.5%; Magnesium stearate accounts for 0.5% to 2%; Coating 2%–6%; Based on the weight of the vonoprazan or its pharmaceutical salt microplates.

10. The compound preparation according to any one of claims 1-6, characterized in that, The amoxicillin microplates comprise the following raw materials in parts by weight: Amoxicillin accounts for 67% to 85% of the total. Microcrystalline cellulose accounts for 10% to 30%; Cross-linked polyvinylpyrrolidone accounts for 1% to 5%; Magnesium stearate accounts for 0.5% to 2%; Coating 2%–6%; Based on the weight of the amoxicillin microplates.

11. The compound preparation according to any one of claims 1-6, characterized in that, The levonornidazole or levonornidazole phosphate microplates comprise the following raw materials in parts by weight: Levonidazole or levonidazole phosphate account for 5% to 90%; Microcrystalline cellulose accounts for 5% to 80%; Cross-linked sodium carboxymethyl cellulose accounts for 1% to 5%; Hydroxypropyl cellulose accounts for 1.0% to 4.0%; Magnesium stearate accounts for 0.5% to 1.5%; Uncoated tablets gain 2%–6% weight. The weight is based on the levonornidazole or levonornidazole phosphate microplates.

12. The compound preparation according to claim 3 or 4, characterized in that, The preparation method of the vonoprazan or its pharmaceutical salt microplates includes the following steps: (1) Granulation: Dissolve fumaric acid and hydroxypropyl cellulose in purified water and stir to prepare a binder solution; add vonoprazan or its pharmaceutical salt and microcrystalline cellulose mannitol co-treated product to a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate; (2) Drying: Drying the granules in a fluidized bed granulator; (3) Granulation: The dry granules are granulated using a granulator; (4) Mixing: Add the dry granules and magnesium stearate to a three-dimensional mixer and mix evenly; (5) Tableting; (6) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to make a solution for coating.

13. The compound preparation according to claim 3 or 4, characterized in that, The preparation method of the vonoprazan or its pharmaceutical salt microplates includes the following steps: (1) Granulation: Dissolve fumaric acid and hydroxypropyl cellulose in purified water and stir to prepare a binder solution; add vonoprazan or its pharmaceutical salt and microcrystalline cellulose mannitol co-treated product to a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate; (2) Drying: Dry the granules in a fluidized bed granulator. Stop heating when the moisture content is below 3% and cool the granules before discharging. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Mixing: Add the dry granules and magnesium stearate to a three-dimensional mixer and mix evenly; (5) Tableting: The tablet diameter is 1.5-3 mm, the tablet weight is about 32 mg, and the hardness range is 4-6 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. The coating weight gain is 2% to 6%.

14. The compound preparation according to claim 3 or 4, characterized in that, The preparation method of the amoxicillin microplates includes the following steps: (1) Total mixing: Add amoxicillin, crospovidone, silica and magnesium stearate to a three-dimensional mixer and mix well; (2) Tableting; (3) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to make a solution for coating.

15. The compound preparation according to claim 3 or 4, characterized in that, The preparation method of the amoxicillin microplates includes the following steps: (1) Total mixing: Add amoxicillin, crospovidone, silica and magnesium stearate to a three-dimensional mixer and mix well; (2) Tableting: Tablet diameter: 3mm, tablet weight: approximately 30mg, hardness range: 4-6kgf; (3) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to make a solution with a solid content of 8% to 20% for coating. The coating weight gain is 2% to 6%.

16. The compound preparation according to claim 3 or 4, characterized in that, The preparation method of the levonornidazole phosphate or levonornidazole microplates includes the following steps: (1) Granulation: Dissolve hydroxypropyl methylcellulose in purified water and stir to prepare a binder solution; add levonidazole or levonidazole phosphate, microcrystalline cellulose crosslinked sodium carboxymethyl cellulose into a fluidized bed granulator, and spray purified water or binder solution into the fluidized bed granulator to granulate; (2) Drying: Drying the granules in a fluidized bed granulator; (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Mixing: Add the granules and magnesium stearate to a three-dimensional mixer and mix evenly; (5) Tableting; (6) Coating: Hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide and colorant are added to purified water to make a solution for coating.

17. The compound preparation according to claim 3 or 4, characterized in that, The preparation method of the levonornidazole phosphate or levonornidazole microplates includes the following steps: (1) Granulation: Dissolve hydroxypropyl methylcellulose in purified water and stir to prepare a binder solution; add levonidazole or levonidazole 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 spray purified water or binder solution into the fluidized bed granulator to granulate; (2) Drying: Dry the granules in a fluidized bed granulator. Stop heating when the moisture content is below 3% and cool the granules before discharging. (3) Granulation: The dry granules are granulated by a granulator with a screen diameter of 1.0 mm; (4) Total mixing: Add the granules, cross-linked sodium carboxymethyl cellulose, and magnesium stearate to a three-dimensional mixer and mix evenly; (5) Tableting: The tablet diameter is 1.5-3 mm, the tablet weight is about 30 mg, and the hardness range is 4-6 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. The coating weight gain is 2% to 6%.

18. The compound preparation according to claim 3 or 4, characterized in that, The vonoprazan or its pharmaceutical salt microtablets contain 4 mg / tablet or 5 mg / tablet of vonoprazan, and each capsule is filled with 2 tablets; Alternatively, the vonoprazan or its pharmaceutical salt microtablets contain 10 mg of vonoprazan per tablet, with each capsule filled with one tablet.

19. The compound preparation according to claim 3 or 4, characterized in that, The amoxicillin microtablets contain 15mg of amoxicillin per tablet, and each capsule is filled with 10 tablets; Alternatively, it contains amoxicillin at 25mg / tablet, with each capsule filled with 15 tablets or each capsule filled with 6 tablets.

20. The compound preparation according to claim 3 or 4, characterized in that, The levonornidazole microtablets contain 12.5 mg of levonornidazole per tablet, and each capsule is filled with 4 tablets; Alternatively, the levonornidazole microtablets contain 25mg of levonornidazole per tablet, with each capsule filled with 2 tablets; Alternatively, the levonornidazole phosphate microtablets contain 12.5 mg / tablet of levonornidazole phosphate, and each capsule is filled with 4 tablets based on levonornidazole. Alternatively, the levonornidazole phosphate microtablets contain 25 mg of levonornidazole phosphate per tablet, and each capsule is filled with 2 tablets based on levonornidazole.

21. The use of the compound preparation according to any one of claims 1-20 in the preparation of an anti-Helicobacter pylori drug.

22. The application according to claim 21, characterized in that, The compound preparation is used to treat diseases caused by Helicobacter pylori.

23. The application according to claim 21, characterized in that, The compound preparation is used to treat gastric ulcers, duodenal ulcers, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicobacter pylori infection in the stomach after endoscopic treatment of early gastric cancer, and Helicobacter pylori-infected gastritis.

24. A method for treating Helicobacter pylori or diseases caused by Helicobacter pylori, characterized in that, include: Apply the compound preparation according to any one of claims 1-20.

25. A method for treating gastric ulcers, duodenal ulcers, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicobacter pylori infection in the stomach after endoscopic treatment of early gastric cancer, and Helicobacter pylori-infected gastritis, characterized in that, include: Apply the compound preparation according to any one of claims 1-20.

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