Compound preparation for treating helicobacter pylori and preparation method thereof

Abstract

The invention relates to the field related to treatment or prevention of helicobacter pylori infection, in particular to a compound preparation for treating helicobacter pylori, which comprises the following components: Vonoprasone, rifbutin and metronidazole, and in each unit of the preparation, the Vonoprasone content is 20mg, the rifbutin content is 50mg, and the metronidazole content is 400mg. The compound preparation disclosed by the invention has a unique medicine combination mechanism, and the compound preparation innovatively combines the Vonoprasone, the rifobetine and the metronidazole together. Compared with a traditional proton pump inhibitor, the novel potassium ion competitive acid blocker has the advantages that the unique action mechanism of the novel potassium ion competitive acid blocker enables the novel potassium ion competitive acid blocker to have remarkable advantages in the aspect of inhibiting gastric acid secretion, H < + >-K < + >-ATPase in resting and activated states can be inhibited at the same time, the novel potassium ion competitive acid blocker is slightly influenced by CYP2C19 gene polymorphism, the effect is reversible, the novel potassium ion competitive acid blocker takes effect quickly, and acid is inhibited for a long time.

Description

Technical Field

[0001] The present invention relates to the field of treatment or prevention of Helicobacter pylori infection, and in particular to a compound preparation for treating Helicobacter pylori and a preparation method thereof. Background Art

[0002] Helicobacter pylori is a micro-anaerobic, spiral-shaped bacterium with fastidious growth requirements that lives in the human stomach. Most cases of chronic gastritis are caused by Helicobacter pylori. Chronic inflammation, through repeated infection, can lead to gastric mucosal lesions and eventually various digestive system diseases, such as peptic ulcers. Therefore, the eradication of Helicobacter pylori is extremely important and necessary.

[0003] Combination therapy in which two antibiotics and antacids such as proton pump inhibitors are taken as independent dosage forms has been commonly used in Helicobacter pylori eradication therapy. However, it has been shown that commonly used combination therapy is less effective in Helicobacter pylori eradication therapy. If the patient has good compliance, an eradication rate (>85%) can be achieved after 7 to 14 days of treatment. However, the major disadvantage of this combination therapy may be attributed to poor compliance. Patients receiving combination therapy are often given an average of 5 tablets, twice a day. Therefore, using two antibiotics and antacids as independent dosage forms will greatly improve the patient's compliance.

[0004] Traditional acid suppressants are proton pump inhibitors. Exploration of their mechanism of action revealed that they only inhibit the active H+-K+-ATPase. Their action is irreversible, slow to take effect, and short-lived, making them susceptible to nocturnal gastric acid breakthrough due to insufficient gastric acid suppression. Proton pump inhibitors are primarily metabolized in the liver via CYP2C19. The activity of this enzyme exhibits significant genetic polymorphism in the human population, resulting in significant inter-individual variability in the acid-suppressing effects of PPIs. Furthermore, proton pump inhibitors can affect the metabolism of other drugs by influencing the activity of hepatic CYP isoenzymes. Vonoprazan, short for potassium-competitive acid blocker, is a new type of acid suppressant that inhibits both resting and activated H+-K+-ATPase. Its action is reversible, acting unchanged in the body without requiring in vivo conversion, resulting in a rapid onset of action.

[0005] Vonoprazan is primarily metabolized in an inactive form by CYP3A4, with some metabolism occurring via CYP2B6, CYP2C19, CYP2D6, and SULT2A1. This multiple metabolism suggests that vonoprazan's plasma levels and its acid-inhibitory effect are not affected by individual differences in CYP2C19 levels and are therefore less susceptible to CYP2C19 genetic polymorphisms. Compared with traditional proton pump inhibitors, vonoprazan offers greater efficacy and safety in the treatment of Helicobacter pylori-positive peptic ulcers due to its unique mechanism of action. Summary of the Invention

[0006] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a compound preparation for treating Helicobacter pylori and a preparation method thereof.

[0007] Provided herein is a single oral solid dosage form comprising a composition having at least two antibiotics and a potassium ion competitive acid blocker. The single oral solid dosage form according to some aspects of the present invention can be used to treat cancer associated with Helicobacter pylori infection or prevent the recurrence of a condition associated with Helicobacter pylori infection.

[0008] According to some aspects, the pharmaceutical composition comprises: a first dosage composition comprising at least two antibiotics; a second dosage composition comprising a potassium ion competitive acid blocker.

[0009] In some embodiments, the first dose and second dose compositions may be in the form of microtablets.

[0010] In some embodiments, the pharmaceutical composition is an oral solid dosage form. For example, the pharmaceutical composition can be in the form of a capsule, caplet, granule, powder, tablet or sachet.

[0011] In some embodiments, the first dosage composition may include metronidazole and ansamycins, derivatives thereof, or pharmaceutically acceptable salts and solvates thereof. Ansamycins may include rifampicin, rifabutin, derivatives thereof, pharmaceutically acceptable salts and solvates thereof, or combinations thereof.

[0012] In some embodiments, in the second dosage composition, the potassium ion competitive acid blocker is one of the following: vonoprazan fumarate, vonoprazan fumarate, ticoprazan, pharmaceutically acceptable salts and solvates thereof, or a combination thereof.

[0013] In some embodiments, the pharmaceutical composition may comprise rifabutin, vonoprazan, and metronidazole.

[0014] In some embodiments, the first and second dosage compositions may further comprise a diluent, a disintegrant, a binder, a surfactant, a lubricant, or a combination thereof.

[0015] According to some aspects of the present invention, the pharmaceutical composition comprises a first dosage composition and a second dosage composition, wherein the first dosage composition comprises 50 mg of rifabutin and 400 mg of metronidazole, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, and the second dosage composition comprises 20 mg of vonoprazan, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0016] The present invention exhibits advantages such as full effect in the first dose, long-lasting acid suppression, good consistency and low incidence of adverse reactions induced by interactions.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention has a unique drug combination mechanism. This compound preparation innovatively combines vonoprazan, rifabutin and metronidazole. As a new potassium ion competitive acid blocker, vonoprazan has a unique mechanism of action compared to traditional proton pump inhibitors, which gives it a significant advantage in inhibiting gastric acid secretion. It can simultaneously inhibit resting and activated H + -K+-ATPase, and is less affected by CYP2C19 gene polymorphism, has a reversible effect, rapid onset and long-lasting acid suppression. Rifabutin and metronidazole, as antibiotics, work synergistically with vonoprazan, targeting different survival mechanisms of Helicobacter pylori, attacking multiple targets, and greatly improving the eradication effect of Helicobacter pylori. For example, vonoprazan competitively inhibits the reaction of potassium ions with H + -K + The binding of rifabutin to the ATPase rapidly reduces gastric acid secretion, changing the acidic environment in which H. pylori survives and making it more susceptible to antibiotics. Rifabutin inhibits bacterial RNA synthesis, while metronidazole interferes with bacterial DNA metabolism. Together with vonoprazan, these two drugs inhibit and kill H. pylori from different angles, effectively overcoming H. pylori's resistance to antibiotics and improving the success rate of treatment.

[0019] The optimized dosage form design of this invention utilizes a single oral solid dosage form, such as a capsule or caplet, to overcome the inconvenience of multiple separate dosage forms in traditional combination therapies. This design not only reduces the number and quantity of daily medications required, improving patient compliance, but also, through a rational formulation process, ensures drug release and absorption in the gastrointestinal tract, enabling the drug to more effectively reach its site of action and exert its therapeutic effect.

[0020] Taking capsules as an example, the capsule shell protects the drug from gastric acid, allowing for more stable release in the intestine. Furthermore, the size and shape of the capsule make it easier for patients to swallow, reducing medication discomfort. Caplets combine the advantages of both capsules and tablets. The outer shell provides a controlled-release effect, allowing the drug to be slowly released within the body, maintaining stable blood concentrations, improving efficacy, and reducing adverse reactions.

[0021] The present invention balances a high eradication rate with safety, demonstrating exceptional performance in increasing Helicobacter pylori eradication rates, achieving an intended-to-treat eradication rate of 90% or higher, significantly outperforming traditional treatment options. Furthermore, the rational proportioning of the various ingredients and the optimization of drug interactions reduce the incidence of adverse reactions. Vonoprazan's safety profile and its synergistic effects with other ingredients reduce adverse reactions caused by excessive or insufficient gastric acid suppression and drug interactions, such as nocturnal gastric acid breakthrough and interference with drug metabolism, providing patients with a safer and more effective treatment option.

[0022] In clinical studies, compared with traditional treatment regimens, patients treated with this combination preparation achieved significantly higher Helicobacter pylori eradication rates and significantly lower rates of adverse reactions. For example, while traditional treatment regimens may cause adverse reactions of varying degrees in approximately 15%-20% of patients, the incidence of adverse reactions in the treatment group with this combination preparation was controlled within 5%-10%. Most adverse reactions were mild gastrointestinal discomfort, such as nausea, vomiting, and diarrhea, and generally resolved on their own without special treatment.

[0023] The pharmaceutical composition may include one or more pharmaceutically acceptable excipients, adjuvants, diluents or carriers generally known in the art. As used herein, "tablet excipients" refer to conventional excipients used when making tablets or microtablets from granules or by direct compression technology.

[0024] Solid forms for oral administration may contain pharmaceutically acceptable binders, sweeteners, disintegrants, diluents, flavorings, coatings, preservatives, lubricants, and / or time delay agents, or any combination thereof. Suitable binders include, but are not limited to, gum acacia, gelatin, corn starch, tragacanth gum, sodium alginate, various forms of cellulose, and various forms of pyrrolidine or polyethylene glycol. Suitable sweeteners include, but are not limited to, sucrose, lactose, glucose, aspartame, or saccharin, or a combination thereof. Suitable disintegrants include, but are not limited to, various forms of starch, various forms of cellulose, and various forms of pyrrolidine. Suitable diluents include, but are not limited to, lactose, sorbitol, mannitol, dextrose, kaolin, various forms of cellulose, various forms of starch, calcium carbonate, calcium silicate, or dicalcium phosphate, or a combination thereof. Suitable surfactants include, but are not limited to, sodium lauryl sulfate, poloxamer, polyethylene glycol, or polysorbate, or a combination thereof. Suitable flavorings include, but are not limited to, peppermint oil, wintergreen oil, cherry, orange, or raspberry flavorings. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac or gluten or combinations thereof. Suitable preservatives include, but are not limited to, sodium benzoate, vitamin E, α-tocopherol, ascorbic acid, methylparaben, propylparaben or sodium bisulfite or combinations thereof. Suitable lubricants include, but are not limited to, magnesium stearate, stearic acid, sodium octadecyl fumarate, sodium oleate, sodium chloride or talc or combinations thereof.

[0025] Regarding manufacturing methods, certain aspects of the present invention relate to a method for formulating a composition for treating conditions associated with Helicobacter pylori infection. In some embodiments, the method may include the steps of preparing an immediate-release first-dose composition comprising at least two antibiotics, preparing a delayed-release second-dose composition comprising at least one proton pump inhibitor, preparing a carrier, and introducing the first and second dose compositions.

[0026] The pharmaceutical compositions of the present invention can be prepared by means known in the art for preparing pharmaceutical compositions, including blending, milling, homogenizing, suspending, dissolving, emulsifying, dispersing, extruding, spheronizing, compressing, drying, coating, granulating (including wet and dry granulation) and, where appropriate, mixing the active drug with one or more excipients, diluents, carriers and adjuvants.

[0027] In some embodiments, the first and / or second dosage compositions can be compressed into dosage forms having small dimensions (i.e., microtablets, pills, granules, etc.). In some embodiments, the dosage forms are compressed into microtablets of approximately 2 mm. Each dosage form can be further coated with a protective coating.

[0028] In some embodiments, the vonoprazan dosage composition can be coated with an outer coating and an enteric coating. In some embodiments, the outer coating layer can be an enteric coating layer, and after the enteric coating, an additional clear coating can be applied. This additional coating is intended to protect the antibiotic, such as rifabutin, from interacting with the vonoprazan enteric coating layer.

[0029] In some embodiments, the rifabutin / metronidazole dosage composition can be coated with a clear solution.

[0030] In some embodiments, the vonoprazan dosage composition and the rifabutin / metronidazole dosage composition can be filled into 00 gauge hard gelatin capsules.

[0031] The active ingredients of the present invention are preferably formulated in a single oral dosage form containing all active pharmaceutical ingredients. The compositions of the present invention can be formulated in solid or liquid form. It should be noted that solid formulations are preferred due to their improved stability and better patient compliance compared to liquid formulations.

[0032] The pharmaceutical compositions of the present invention can be formulated in a single solid dosage form, such as a capsule, tablet, lozenge, pill, or troche. Generally, a first and second dosage composition are prepared and introduced into a carrier member. In some embodiments, the carrier member can comprise a capsule. The carrier member can be prepared from an aqueous solution of a gelling agent, such as an animal protein including gelatin, a plant polysaccharide, or a derivative thereof such as carrageenan, or modified forms of starch and cellulose. DETAILED DESCRIPTION

[0033] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0034] A compound preparation for treating Helicobacter pylori, comprising the following ingredients: vonoprazan, rifabutin and metronidazole, wherein each preparation unit contains 20 mg of vonoprazan, 50 mg of rifabutin and 400 mg of metronidazole.

[0035] As a technical optimization solution of the present invention, the preparation is in the form of capsules, caplets, granules, powders, tablets or sachets.

[0036] As a technical optimization solution of the present invention, the pharmaceutical composition includes: a first dose composition of rifabutin and metronidazole, a second dose composition of vonoprazan, and an outer layer of the first dose and second dose compositions.

[0037] As a technical optimization solution of the present invention, the first-dose and second-dose compositions are in the form of micro-tablets, and the first-dose composition further comprises a diluent, a disintegrant, a binder, a surfactant, a lubricant or a combination thereof.

[0038] As a technical optimization solution of the present invention, the second dose composition further comprises a diluent, a disintegrant, a binder, a surfactant, a lubricant or a combination thereof.

[0039] A method for preparing a compound preparation for treating Helicobacter pylori comprises the steps of preparing each component according to corresponding proportions and dosage form requirements.

[0040] A method for preparing a compound preparation for treating Helicobacter pylori is used in preparing drugs for treating Helicobacter pylori infection and drugs for recurrence of related diseases, comprising the step of administering any compound preparation to a patient.

[0041] A method for preparing a compound preparation for treating Helicobacter pylori, wherein the dosage is 3 times a day, 4 capsules each time, each capsule containing 20 mg of vonoprazan, 50 mg of rifabutin, and 400 mg of metronidazole, and the treatment period is 14 days.

[0042] A drug combination for treating Helicobacter pylori infection comprises any one of the above compound preparations and a pharmaceutically acceptable carrier.

[0043] A package for the compound preparation for treating Helicobacter pylori, comprising any one of the compound preparations and packaging materials for explaining the method of use and precautions of the compound preparation.

[0044] In some embodiments, the pharmaceutical compositions of the present invention can be used as follows:

[0045] Dosage regimen 4 capsules 3 times a day (once every 8 hours) Unit dose 20mg vonoprazan 50mg rifabutin 400mg metronidazole Total daily dose 60mg vonoprazan 150mg rifabutin 1200mg metronidazole Treatment days 14

[0046] To prepare a pharmaceutical composition for oral delivery, 20 mg of vonoprazan, 50 mg of rifabutin, 400 mg of metronidazole, and starch are mixed. The mixture is incorporated into an oral unit dosage form suitable for oral administration, such as a hard gelatin capsule. The pharmaceutical composition can also be in the form of capsules, caplets, granules, powders, tablets, or sachets.

[0047] The following human pharmacodynamics experiments will illustrate the therapeutic effect of the pharmaceutical composition of the present invention on the treatment of Helicobacter pylori infection.

[0048] Effectiveness evaluation

[0049] 13C urea breath test

[0050] A 13C urea breath test was used to verify H. pylori status before administration of the test product and to determine whether H. pylori eradication had been successful. Participants were required to abstain from solid food for at least 1 hour before the visit. They must have taken any antibiotics before screening and for four consecutive weeks since the end of treatment, or not taken proton pump inhibitors or bismuth preparations within 2 weeks prior to the post-treatment assessment, or H2 receptor antagonists the night before the 13C urea breath test.

[0051] This study was designed to recruit 90 patients, including 30 patients who received placebo, 30 patients who received a combination of the three traditional drugs as a control group, and 30 patients who received the compound capsule group.

[0052] Statistical analysis

[0053] The primary efficacy endpoint in this study was H. pylori eradication documented by 13C UBT test results at the test-of-cure visit among subjects randomized to active treatment. Test-of-cure was assessed at the visit in subjects randomized to active treatment.

[0054] Subjects with negative test results were considered to have had successful treatment.

[0055] A total of 90 patients were enrolled in this study. All enrolled patients were H. pylori positive and tested positive for stool antigen prior to enrollment. Study medication was administered for 14 days, and post-treatment H. pylori status was assessed by UBT at least 4 weeks after treatment completion. Eradication was considered successful if the UBT test result was negative. All patients were planned to be treated for 14 days with placebo, conventional triple therapy, or the investigational agent (vonoprazan (60 mg daily), rifabutin (150 mg daily), and metronidazole (1200 mg daily)). Medication tolerance, compliance, and clinical laboratory test results were recorded by the investigator during and after treatment.

[0056] Clinical application case analysis

[0057] Case 1

[0058] Patient Information: A 44-year-old male patient, surnamed Zhang, presented with recurrent stomach pain and bloating for over a year, which worsened over a month. Gastroscopy revealed a gastric ulcer, and pathological examination was positive for Helicobacter pylori. The patient had no history of drug allergies, normal liver and kidney function, and no other major underlying medical conditions.

[0059] - Treatment regimen: The compound preparation of the present invention is used for treatment, at a dosage of 4 capsules (each capsule containing 20 mg of vonoprazan, 50 mg of rifabutin, and 400 mg of metronidazole) three times a day for 14 consecutive days.

[0060] Treatment Efficacy: During treatment, the patient's stomach pain and bloating symptoms gradually subsided. Four weeks after the end of treatment, a 13C urea breath test confirmed successful eradication of Helicobacter pylori. A gastroscopy revealed significant healing of the gastric ulcer and a significant reduction in gastric mucosal inflammation. The patient experienced no significant adverse reactions during treatment, with only mild nausea initially present, which resolved spontaneously after 2-3 days.

[0061] Case 2

[0062] Patient Information: A 34-year-old female patient, surnamed Zhang, was diagnosed with Helicobacter pylori infection during a physical examination. She had no obvious gastrointestinal symptoms, but her family had a history of gastric cancer. She had no history of allergies, normal liver and kidney function, and was generally in good health with no unhealthy lifestyle habits.

[0063] Treatment: This combination preparation is administered three times daily, four capsules each time, for a total of 14 days. Doctors also recommend that patients maintain a healthy diet during treatment and avoid sharing eating utensils to prevent the spread of Helicobacter pylori.

[0064] Treatment Effectiveness: Following treatment, the Helicobacter pylori test result was negative, indicating successful eradication. The patient maintained good compliance throughout treatment and experienced no discomfort. This treatment not only eliminated the patient's potential infection risk but also reduced the risk of further gastric disease from H. pylori infection. This is particularly important for preventing gastric cancer, given her family history of the disease.

[0065] Case 3

[0066] Patient Information: A 61-year-old male patient, surnamed Liu, had suffered from chronic gastritis for many years. His symptoms had recently worsened, accompanied by loss of appetite and weight loss. Examination revealed a positive result for Helicobacter pylori, along with mild liver function abnormalities (alanine aminotransferase and aspartate aminotransferase levels were slightly above the upper limit of the normal range).

[0067] Treatment: Given the patient's abnormal liver function, the physician should use this combination preparation with caution while closely monitoring liver function. The dosage should be adjusted to 3 capsules 3 times daily, with concurrent administration of liver-protective medications. Liver function should be reviewed regularly during treatment.

[0068] - Therapeutic Efficacy: After 14 days of treatment, the patient's chronic gastritis symptoms significantly improved, his appetite increased, and his weight gradually recovered. A follow-up examination for Helicobacter pylori was negative, indicating successful eradication. His liver function did not deteriorate further during treatment and gradually returned to normal after completion. This demonstrates that this compound preparation can be used safely and effectively in special populations (with mild liver function abnormalities) under close monitoring, and also highlights the importance of comprehensive treatment (combined with liver-protective medications).

[0069] Results Statistics

[0070] Group Number of people Negative Positive Eradication rate Placebo 30 2 28 7％ control group 30 25 5 83％ Compound group 30 29 1 97％

[0071] Comparison with existing technology

[0072] Comparison of eradication rates

[0073] Compared with traditional Helicobacter pylori eradication regimens (such as a proton pump inhibitor plus two antibiotics), this combination has demonstrated higher eradication rates in clinical studies and real-world applications. While traditional regimens typically have eradication rates of around 70%-85%, this combination is expected to achieve an intention-to-treat eradication rate of 90% or higher. For example, in the aforementioned case, patients treated with this combination achieved significant eradication of Helicobacter pylori, maintaining a high success rate across diverse disease states and individual patient differences.

[0074] Comparison of compliance

[0075] Traditional combination therapies typically require patients to take multiple medications in different dosage forms simultaneously. For example, proton pump inhibitors may be available as tablets or capsules, and antibiotics may come in different sizes and dosage forms. This increases the patient's medication burden and can easily lead to decreased compliance. The compound preparation of the present invention, however, uses a single oral solid dosage form, such as a capsule. Patients only need to take one medication at the prescribed dosage and time, greatly simplifying the medication process and improving patient compliance. Clinical observations have shown that patients are more accepting of this compound preparation and are more likely to persist and complete the entire course of treatment.

[0076] Security comparison

[0077] Traditional proton pump inhibitors are affected by CYP2C19 gene polymorphisms, which may lead to large individual differences in acid suppression effects. Long-term use may also increase the risk of certain adverse reactions, such as fractures and hypomagnesemia. Furthermore, drug interactions in traditional combination therapies may affect the metabolism of other drugs, triggering potential adverse reactions. The vonoprazan in this compound preparation is less affected by CYP2C19 gene polymorphisms, and its combination with rifabutin and metronidazole, at reasonable doses, reduces the incidence of adverse reactions by optimizing drug interactions. For example, in clinical application cases, most patients did not experience significant adverse reactions, and the few mild adverse reactions were within the tolerable range and did not affect the treatment process.

[0078] Comparison of acid suppression effects

[0079] Conventional proton pump inhibitors only inhibit the activated state of H + -K + -ATPase, the action is irreversible, slow in onset, short in duration, and prone to nocturnal gastric acid breakthrough. Vonoprazan, as the acid-suppressing component in this compound preparation, can simultaneously inhibit the resting and activated H + -K+ Vonoprazan inhibits ATPase, acting reversibly, rapidly and sustainably, effectively maintaining a stable gastric pH and creating a more favorable environment for antibiotics to take effect, thereby improving overall therapeutic efficacy. In the treatment of patients with gastric ulcers, this compound preparation can more quickly relieve symptoms such as stomach pain and promote ulcer healing, which is closely related to the excellent acid-suppressing effect of vonoprazan.

[0080] The preferred embodiments of the present invention disclosed above are intended only to help illustrate the present invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the present invention to the specific embodiments described. Obviously, many modifications and variations are possible based on the content of this specification. These embodiments are selected and described in detail in this specification to better explain the principles and practical applications of the present invention, thereby enabling those skilled in the art to better understand and utilize the present invention. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A compound preparation for treating Helicobacter pylori, characterized in that: The invention comprises the following ingredients: vonoprazan, rifabutin and metronidazole, wherein each preparation unit contains 20 mg of vonoprazan, 50 mg of rifabutin and 400 mg of metronidazole.

2. A compound preparation for treating Helicobacter pylori according to claim 1, characterized in that: The preparation is in the form of capsules, caplets, granules, powders, tablets or sachets.

3. A compound preparation for treating Helicobacter pylori according to claim 2, characterized in that: The pharmaceutical composition includes: a first dosage composition of rifabutin and metronidazole, a second dosage composition of vonoprazan, and an outer layer of the first dosage and second dosage compositions.

4. A compound preparation for treating Helicobacter pylori according to claim 3, characterized in that: The first dose and the second dose compositions are in the form of microtablets, and the first dose composition further comprises a diluent, a disintegrant, a binder, a surfactant, a lubricant, or a combination thereof.

5. The compound preparation for treating Helicobacter pylori according to claim 3, characterized in that: The second dosage composition further comprises a diluent, a disintegrant, a binder, a surfactant, a lubricant, or a combination thereof.

6. The method for preparing a compound preparation for treating Helicobacter pylori according to claim 5, characterized in that: The method includes the steps of preparing the components according to corresponding proportions and dosage form requirements.

7. The method for preparing a compound preparation for treating Helicobacter pylori according to claim 6, characterized in that: The application of the compound preparation in the preparation of drugs for treating Helicobacter pylori infection and drugs for recurrence of related diseases comprises the step of administering any one of the compound preparations to the patient.

8. The method for preparing a compound preparation for treating Helicobacter pylori according to claim 7, characterized in that: The dosage is 3 times a day, 4 capsules each time, each capsule contains 20 mg of vonoprazan, 50 mg of rifabutin, and 400 mg of metronidazole, and the treatment days are 14 days.

9. A drug combination for treating Helicobacter pylori infection, characterized in that: Contains any one of the above compound preparations and a pharmaceutically acceptable carrier.

10. A packaging of the compound preparation for treating Helicobacter pylori, characterized in that: A combination preparation comprising any one of the above-mentioned combination preparations and packaging materials for explaining the method of use and precautions of the combination preparation.