A compound pharmaceutical composition and its application in preventing Helicobacter pylori infection

Abstract

The present invention relates to a compound pharmaceutical composition and its application in preventing Helicobacter pylori infection, and more specifically, to the compound pharmaceutical composition, pharmaceutical preparation, preparation method and use. The composition comprises at least two selected from the following components: (I) vonoprazan or a pharmaceutically acceptable salt thereof; (II) amoxicillin or a pharmaceutically acceptable salt thereof; (III) clarithromycin; and (IV) a bismuth agent. The composition prepared by compounding different anti-infective active ingredients can not only effectively solve the problems of patient compliance and medication convenience, such as reducing the dosage of tablets and avoiding patients from taking the wrong tablets, missing a dose, or taking more than one dose, but also unexpectedly improve the stability and safety of the preparation, and is particularly conducive to reducing the content of harmful impurities.

Description

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on December 26, 2023, with patent application number 202311809477.X, entitled “A Compound Pharmaceutical Composition and Its Use in Treating Helicobacter pylori Infection.” The entire text of that application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compositions, and in particular relates to a compound pharmaceutical composition and its application in resisting Helicobacter pylori infection. Background Art

[0003] Helicobacter pylori infection is an infectious disease with a global infection rate of up to 50%. It is closely associated with the development of dyspepsia, gastritis, peptic ulcers, and gastric cancer. Eradication of Helicobacter pylori can effectively control the progression of these diseases and reduce their incidence.

[0004] However, at the same time, during the use of antibiotics to treat Helicobacter pylori infection, the rate of antibiotic resistance has gradually increased, resulting in a continuous decrease in the success rate of eradicating Helicobacter pylori infection. In addition, due to differences in disease patterns and accessibility to therapeutic drugs between regions, it is usually difficult for known marketed drugs to achieve consistent and satisfactory therapeutic effects. Currently, there are many types of drugs for the clinical treatment of Helicobacter pylori infection, and patients are required to take different drugs 2 to 4 times a day, with large dosages and at least two weeks of continuous medication, resulting in poor compliance. Therefore, there is an urgent need to develop new drugs for the treatment of Helicobacter pylori infection that can solve problems such as drug resistance, improve patient compliance, convenience of medication, safety and stability. Summary of the Invention

[0005] In order to solve the problems existing in the prior art, in a first aspect, the present invention provides a compound pharmaceutical composition, which comprises at least two selected from the following ingredients:

[0006] (I) vonoprazan or a pharmaceutically acceptable salt thereof;

[0007] (II) amoxicillin or a pharmaceutically acceptable salt thereof;

[0008] (III) clarithromycin;

[0009] (IV) Bismuth agents.

[0010] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following two components:

[0011] (I) vonoprazan or a pharmaceutically acceptable salt thereof; and

[0012] (II) Amoxicillin or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following two components:

[0014] (I) vonoprazan or a pharmaceutically acceptable salt thereof; and

[0015] (III) Clarithromycin.

[0016] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following two components:

[0017] (I) vonoprazan or a pharmaceutically acceptable salt thereof; and

[0018] (IV) Bismuth agents.

[0019] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following three components:

[0020] (I) vonoprazan or a pharmaceutically acceptable salt thereof;

[0021] (II) amoxicillin or a pharmaceutically acceptable salt thereof; and

[0022] (IV) Bismuth agents.

[0023] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following three components:

[0024] (I) vonoprazan or a pharmaceutically acceptable salt thereof;

[0025] (III) clarithromycin; and

[0026] (IV) Bismuth agents.

[0027] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following three components:

[0028] (I) vonoprazan or a pharmaceutically acceptable salt thereof;

[0029] (II) amoxicillin or a pharmaceutically acceptable salt thereof; and

[0030] (III) Clarithromycin.

[0031] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following four ingredients:

[0032] (I) vonoprazan or a pharmaceutically acceptable salt thereof;

[0033] (II) amoxicillin or a pharmaceutically acceptable salt thereof;

[0034] (III) clarithromycin; and

[0035] (IV) Bismuth agents.

[0036] According to an embodiment of the present invention, the bismuth agent is selected from one or more of colloidal bismuth pectin, potassium bismuth citrate, bismuth subcarbonate, bismuth aluminate, and bismuth subsalicylate. In one embodiment of the present invention, the bismuth agent is selected from colloidal bismuth pectin.

[0037] According to one embodiment of the present invention, the pharmaceutically acceptable salt of vonolac comprises one or more of fumarate, acetate, hydrochloride, malate, maleate, sulfate or citrate.

[0038] According to an embodiment of the present invention, the amoxicillin is amoxicillin anhydrate or amoxicillin hydrate. In one embodiment of the present invention, the pharmaceutically acceptable salt of amoxicillin includes a sodium salt.

[0039] According to an embodiment of the present invention, in the compound pharmaceutical composition, when comprising component (I) vonoprazan or a pharmaceutically acceptable salt thereof, the component (I) is 10-40 parts by weight, preferably 10-30 parts by weight, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 parts by weight.

[0040] According to an embodiment of the present invention, in the compound pharmaceutical composition, when component (II) amoxicillin or a pharmaceutically acceptable salt thereof is included, the component (II) is 500-2000 parts, preferably 500-1500 parts, more preferably 700-1200 parts, for example, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 parts, calculated as anhydrous amoxicillin.

[0041] According to an embodiment of the present invention, in the compound pharmaceutical composition, when component (III) clarithromycin is included, the amount of clarithromycin is 100-2000 parts by weight, preferably 200-800 parts, more preferably 400-600 parts, for example, 100, 200, 300, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 parts.

[0042] According to an embodiment of the present invention, in the compound pharmaceutical composition, when component (IV) bismuth is included, the bismuth content is 100-300 parts by weight, preferably 200-250 parts, for example, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 parts.

[0043] According to one embodiment of the present invention, when the composite composition comprises four components, namely, component (I), component (II), component (III) and component (IV), the weight ratio of component (I), component (II), component (III) and component (IV) is 1: (5-120): (1-120): (1-50), preferably 1: (25-75): (10-40): (5-15), preferably 1 :(35-60):(20-30):(10-12.5), for example 1:50:25:11, 1:50:25:5, 1:50:25:20, 1:10:25:11, 1:100:25:11, 1:50:5:11, 1:50:100:11, 1:50:25:12.5, 1:50:25:15, 1:25:25:11, 1:35:25:11.

[0044] According to one embodiment of the present invention, the compound composition comprises the following three components in parts by weight:

[0045] (I) 10-40 parts of vonoprazan or a pharmaceutically acceptable salt thereof (calculated as vonoprazan);

[0046] (II) 800-1300 parts of amoxicillin or a pharmaceutically acceptable salt thereof (calculated as anhydrous amoxicillin) and

[0047] (III) 400-600 parts of clarithromycin.

[0048] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following three components:

[0049] (I) 10-40 parts of vonoprazan or a pharmaceutically acceptable salt thereof (calculated as vonoprazan);

[0050] (II) 800-1300 parts of amoxicillin or a pharmaceutically acceptable salt thereof (calculated as anhydrous amoxicillin); and

[0051] (IV) 200-250 parts of bismuth agent (calculated by bismuth content).

[0052] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following three components:

[0053] (I) 10-40 parts of vonoprazan or a pharmaceutically acceptable salt thereof (calculated as vonoprazan);

[0054] (III) 400-600 parts of clarithromycin; and

[0055] (IV) 200-250 parts of bismuth agent (calculated by bismuth content).

[0056] In one embodiment of the present invention, the compound pharmaceutical composition comprises the following four ingredients:

[0057] (I) 10-40 parts of vonoprazan or a pharmaceutically acceptable salt thereof (calculated as vonoprazan);

[0058] (II) 800-1300 parts of amoxicillin or a pharmaceutically acceptable salt thereof (calculated as anhydrous amoxicillin);

[0059] (III) 400-600 parts of clarithromycin; and

[0060] (IV) 200-250 parts of bismuth agent (calculated by bismuth content).

[0061] According to an embodiment of the present invention, the compound pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0062] According to an embodiment of the present invention, the compound pharmaceutical composition is a solid preparation, preferably, the solid preparation is a tablet.

[0063] In one embodiment of the present invention, in the compound pharmaceutical composition, the weight ratio of the total amount of active ingredients (such as at least two of ingredients I, II, III, and IV) to the total amount of pharmaceutically acceptable excipients is 10:1 to 1:10, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.8:1, 1.5:1, 1.7:1, 1.6:1, 1.3:1, 1.2:1, 1.15:1, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10.

[0064] In one embodiment of the present invention, in the compound pharmaceutical composition, the weight ratio of the total amount of active ingredients to the total amount of the pharmaceutically acceptable excipients is 5:1 to 1:1.

[0065] According to an embodiment of the present invention, the pharmaceutically acceptable excipients include one or more of (A) a filler, (B) a binder, (C) a disintegrant, (D) a glidant, and (E) a lubricant.

[0066] According to an embodiment of the present invention, the filler is selected from one or more of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose lactose co-processed product, microcrystalline cellulose mannitol co-processed product, mannitol and starch derivatives; the starch derivative is preferably one or more of starch and pregelatinized starch.

[0067] In one embodiment of the present invention, the filler is preferably one or more of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose lactose co-processed product, microcrystalline cellulose mannitol co-processed product and mannitol.

[0068] According to an embodiment of the present invention, the mass ratio of the total amount of the filler to the total amount of the active pharmaceutical ingredient is 1:20 to 1:1, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20. Preferably, the mass ratio of the total amount of the filler to the total amount of the active pharmaceutical ingredient is 1:3 to 1:1.1.

[0069] In certain embodiments of the present invention, the mass ratio of the total amount of filler to the total amount of active pharmaceutical ingredient is 1:8 to 1:1, for example, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0070] According to an embodiment of the present invention, when the filler is selected from two or more ingredients, the mass ratio of each filler to the total amount of the active ingredient is 1:20 to 1:1, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20.

[0071] In certain embodiments of the present invention, when the filler is selected from two or more ingredients, the mass ratio of each filler to the total amount of the active pharmaceutical ingredient is 1:8 to 1:1, for example, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8.

[0072] In one embodiment of the present invention, the binder is selected from one or more of starch derivatives, cellulose derivatives, gelatin, polyvidone (PVP), polyethylene glycol, sodium alginate, and polyvinyl alcohol (PVA); the starch derivative is preferably one or more of starch and pregelatinized starch; the cellulose derivative is preferably one or more of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), and ethyl cellulose (EC); the polyethylene glycol is preferably one or more of PEG4000 and PEG6000.

[0073] In one embodiment of the present invention, the binder is preferably one or more of polyvidone (PVP), hydroxypropyl cellulose (HPC) and sodium carboxymethyl cellulose (CMC-Na); more preferably hydroxypropyl cellulose (HPC).

[0074] In one embodiment of the present invention, the mass ratio of the binder to the total amount of the active pharmaceutical ingredient is 0 to 1:5.

[0075] In one embodiment of the present invention, the mass ratio of the binder to the total amount of the active pharmaceutical ingredient is 1:200 to 1:5, for example, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200; preferably, the mass ratio of the binder to the total amount of the active pharmaceutical ingredient is 1:150 to 1:6.

[0076] In certain embodiments of the present invention, the mass ratio of the binder to the total amount of the active pharmaceutical ingredient is 0 to 1:15, for example, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200.

[0077] According to an embodiment of the present invention, the disintegrant is selected from one or more of starch derivatives, cellulose derivatives, cross-linked polyvinylpyrrolidone (PVPP), alginic acid, and sodium alginate; the starch derivative is preferably one or more of starch and sodium carboxymethyl starch (CMS-Na); the cellulose derivative is preferably one or more of low-substituted hydroxypropyl cellulose (L-HPC), cross-linked sodium carboxymethyl cellulose (CCNa), and carboxymethyl cellulose calcium.

[0078] In one embodiment of the present invention, the disintegrant is preferably one or more of low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl starch (CMS-Na) and cross-linked polyvinylpyrrolidone (PVPP).

[0079] In one embodiment of the present invention, the mass ratio of the disintegrant to the total amount of the active pharmaceutical ingredient is 1:200 to 1:2, for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:200; preferably, the mass ratio of the disintegrant to the total amount of the active ingredient is 1:150 to 1:3.

[0080] In certain embodiments of the present invention, the mass ratio of the disintegrant to the total amount of the active pharmaceutical ingredient is 1:65 to 1:9, for example, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, or 1:65.

[0081] In one embodiment of the present invention, the glidant is selected from one or more of silicon dioxide, talc, and colloidal silicon dioxide.

[0082] In one embodiment of the present invention, the mass ratio of the glidant to the total amount of the active pharmaceutical ingredient is 0 to 1:10.

[0083] In one embodiment of the present invention, the mass ratio of the glidant to the total amount of the active pharmaceutical ingredient is 1:1000 to 1:10, for example, the mass ratio of the glidant to the total amount of the active pharmaceutical ingredient is 1:750 to 1:10, for example, the mass ratio of the glidant to the total amount of the active pharmaceutical ingredient is 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:10 0, 1:150, 1:155, 1:165, 1:170, 1:175, 1:180, 1:185, 1:190, 1:195, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:650, 1:700, 1:750, 1:800, 1:850, 1:900, 1:950, 1:1000.

[0084] In certain embodiments of the present invention, the mass ratio of the glidant to the total amount of the active pharmaceutical ingredient is 0 to 1:165, for example, 1:165, 1:170, 1:180, 1:190, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:650, 1:700, 1:750, 1:800, 1:850, 1:900, 1:950, or 1:1000.

[0085] In one embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, and wheat starch; the polyethylene glycol is preferably one or more of PEG4000 and PEG6000.

[0086] In one embodiment of the present invention, the mass ratio of the lubricant to the total amount of the active pharmaceutical ingredient is 1:1000 to 1:10, for example, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:30, 1:35, 1:40, 1:45, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, 1:180, 1:190, 1:100, 1:111 :110, 1:120, 1:130, 1:140, 1:150, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:650, 1:700, 1:750, 1:800, 1:850, 1:900, 1:950, 1:1000; preferably, the mass ratio of the lubricant to the total amount of the active ingredient of the medicine is 1:750 to 1:20.

[0087] In certain embodiments of the present invention, the mass ratio of the lubricant to the total amount of the active pharmaceutical ingredient is 1:120 to 1:35, for example, 1:35, 1:40, 1:45, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:110, or 1:120.

[0088] In one embodiment of the present invention, in the compound pharmaceutical composition, when component (A) filler is included, the weight portion of component (A) is 150-5000 parts, preferably 230-2700 parts, and in certain embodiments, preferably 230-1500 parts, for example, 150, 200, 220, 230, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000 copies.

[0089] In parts by weight, when the binder component (B) is included, the weight of the component (B) is 0-300 parts, preferably 30-400 parts, and in certain embodiments, preferably 0-120 parts, for example, 0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 6, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400 copies.

[0090] In parts by weight, when the disintegrant (C) is included, the weight of the component (C) is 10-400 parts, preferably 30-200 parts, and in certain embodiments, preferably 40-115 parts, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 6, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400 copies.

[0091] 38,39,40,50 parts by weight.

[0092] In parts by weight, when the lubricant component (E) is included, the weight of the component (E) is 2-150 parts, preferably 10-60 parts, in some embodiments, preferably 10-35 parts, for example 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 8, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150 copies.

[0093] In a second aspect, the present invention further provides a method for preparing the compound pharmaceutical composition described in the first aspect, wherein the compound composition can be prepared by direct tableting or dry granulation tableting.

[0094] According to an embodiment of the present invention, the method for preparing the compound pharmaceutical composition comprises the following steps:

[0095] (1) All raw materials and auxiliary materials are mixed and sieved, bagged or mixed evenly with a mixer;

[0096] (2) Filling capsules or pressing tablets, and packaging to obtain the finished product.

[0097] In one embodiment of the present invention, the method for preparing the compound pharmaceutical composition comprises the following steps:

[0098] (1) Sieve the raw and auxiliary materials separately;

[0099] (2) mixing vonoprazan or a pharmaceutically acceptable salt thereof with a disintegrant, and then adding a filler and mixing;

[0100] (3) adding clarithromycin, amoxicillin or pharmaceutically acceptable salts thereof to the mixed powder and mixing well;

[0101] (4) using a dry granulation process to compress the mixed powder into granules or not using a dry granulation process;

[0102] (5) Add lubricant and mix well;

[0103] (6) The obtained material is capsule-filled or tablet-pressed, and packaged to obtain the finished product.

[0104] In one embodiment of the present invention, step (2) is to mix vonoprazan or a pharmaceutically acceptable salt thereof with a disintegrant and a binder, and then add a filler and mix.

[0105] In one embodiment of the present invention, step (3) is to add clarithromycin, amoxicillin or pharmaceutically acceptable salts thereof and a glidant to the mixed powder and mix them evenly.

[0106] In one embodiment of the present invention, the method for preparing the compound pharmaceutical composition comprises the following steps:

[0107] (1) Sieve the raw and auxiliary materials separately;

[0108] (2) mixing vonoprazan or a pharmaceutically acceptable salt thereof with a disintegrant, and then adding a filler and mixing;

[0109] (3) adding bismuth, clarithromycin, amoxicillin or pharmaceutically acceptable salts thereof to the mixed powder and mixing thoroughly;

[0110] (4) using a dry granulation process to compress the mixed powder into granules or not using a dry granulation process;

[0111] (5) Add lubricant and mix well;

[0112] (6) The obtained material is capsule-filled or tablet-pressed, and packaged to obtain the finished product.

[0113] In one embodiment of the present invention, step (2) is to mix vonoprazan or a pharmaceutically acceptable salt thereof with a disintegrant and a binder, and then add a filler and mix.

[0114] In one embodiment of the present invention, step (3) is to add clarithromycin, amoxicillin or pharmaceutically acceptable salts thereof and a glidant to the mixed powder and mix them evenly.

[0115] In a third aspect, the present invention also provides use of the compound pharmaceutical composition in preparing drugs for resisting Helicobacter pylori infection.

[0116] In some embodiments, the present invention provides use of the compound pharmaceutical composition in preparing a medicament for treating dyspepsia, gastritis, peptic ulcer and gastric cancer.

[0117] Terms and abbreviations

[0118] The abbreviations used in this invention have the following definitions:

[0119] PVP is povidone, PVPP is cross-linked polyvidone, PEG is polyethylene glycol, PVA is polyvinyl alcohol, HPC is hydroxypropyl cellulose, L-HPC is low-substituted hydroxypropyl cellulose, CMC-Na is sodium carboxymethyl cellulose, HPMC is hydroxypropyl methylcellulose, CCNa is cross-linked sodium carboxymethyl cellulose, and CMS-Na is sodium starch glycolate.

[0120] Unless otherwise specified, percentages in the examples are by mass.

[0121] Unless otherwise indicated, all numbers used in this specification and claims to indicate content, concentration, ratio, weight, percentage, technical effect, etc. should be understood as being modified by the term "about" or "approximately" in any case. "About" represents a range of ±10%, preferably a range of ±5%, of the value it modifies.

[0122] Beneficial effects

[0123] Currently, a wide variety of drugs are available for the clinical treatment of Helicobacter pylori infection, and patients are required to take different drugs two to four times daily, requiring large dosages and requiring at least two weeks of continuous medication, resulting in poor compliance. The present invention has discovered that a composition prepared by combining different anti-infective active ingredients can not only effectively address issues of patient compliance and medication convenience, such as reducing the number of tablets required and preventing patients from taking the wrong, missed, or overdose tablets, but also unexpectedly improves the stability and safety of the formulation, and is particularly beneficial in reducing the content of harmful impurities. DETAILED DESCRIPTION

[0124] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0125] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0126] The structural formula of the impurities involved in the embodiments of the present invention is as follows:

[0127] The structural formula of vonoprazan N-nitroso compound is: (Molecular formula: C 17 H 15 FN4O3S; molecular weight: 374.39).

[0128] The structural formula of vonoprazan degradation impurity 20 is: (Molecular formula: C 21 H 20 FN3O6S; molecular weight: 461.46).

[0129] The structural formula of vonoprazan impurity 25 is: (Molecular formula: C 12 H 13 FN2; molecular weight: 204.25).

[0130] The structural formula of vonoprazan impurity 34 is: (Molecular formula: C 17 H 16 FN3O3S; molecular weight: 361.39).

[0131] Amoxicillin impurities D1 and D2 are diastereomers with the structural formula: (Molecular formula:

[0132] C 16 H 21 N3O6S; molecular weight: 383.43).

[0133] The structural formula of amoxicillin impurity C is: (Molecular formula: C 16 H 19 N3O5S; molecular weight: 365.40).

[0134] The structural formula of amoxicillin impurity J is: (Molecular formula: C 32 H 38 N6O 10 S2; molecular weight: 730.82).

[0135] The structural formula of clarithromycin impurity 17 is: (Molecular formula: C 38 H 69 NO 14 ; molecular weight: 763.96).

[0136] The structural formula of clarithromycin impurity A is: (Molecular formula: C 38 H 69 NO 14 ; molecular weight: 763.96).

[0137] The structural formula of clarithromycin impurity F is: (Molecular formula: C 39 H 71 NO 13 ; molecular weight: 761.99).

[0138] The structural formula of clarithromycin impurity G is: (Molecular formula: C 39 H 72 N2O 13 ; molecular weight: 777.01).

[0139] The structural formula of clarithromycin impurity K is: (Molecular formula: C 30 H 51 NO8; molecular weight: 553.74).

[0140] The detection method of the related substances involved in the present invention is as follows:

[0141] (1) Detection methods for vonoprazan-related substances

[0142] Solvent: mobile phase A-water (1:1).

[0143] Test solution: Place one tablet of the preparation sample into a 10 ml centrifuge tube, accurately add an appropriate amount of the aforementioned solvent, manually shake for 3 minutes, centrifuge at 10,000 rpm for 5 minutes, take the supernatant, and filter to obtain the solution (containing approximately 1 mg / ml of vonoprazan).

[0144] Chromatographic conditions: Octadecylsilane bonded silica gel as the filler (Agilent Eclipse XDB-C18, 4.6 mm × 250 mm, 5 μm or equivalent column); 0.05 mol / L potassium dihydrogen phosphate solution as the mobile phase A (dissolve approximately 6.8 g of potassium dihydrogen phosphate in water and dilute to 1000 ml, adjust the pH to 6.8 with 10% potassium hydroxide solution); methanol as the mobile phase B; linear gradient elution according to the table below; flow rate, 1.0 ml / min; column temperature, 30°C; detection wavelength, 254 nm; injection volume, 10 μl.

[0145]

[0146]

[0147] (2) Detection methods for amoxicillin-related substances

[0148] Solvent: water-methanol-acetonitrile (6:5:4).

[0149] Test solution: Take one tablet of the preparation sample and put it into a 100ml volumetric flask, add appropriate amount of the above-mentioned solvent, shake manually for 3 minutes, dilute to the scale with solvent, shake well, centrifuge at 10,000 rpm for 5 minutes, take the supernatant, filter, and obtain (containing approximately 2 mg / ml of amoxicillin).

[0150] Chromatographic conditions: Octadecylsilane bonded silica gel as the filler (Agela Venusil ASB C18, 4.6 mm × 250 mm, 5 μm or equivalent column); 0.1% difluoroacetic acid aqueous solution as mobile phase A, acetonitrile as mobile phase B, linear gradient elution as shown in the table below; flow rate, 1.0 ml / min; column temperature, 30°C; detection wavelength, 230 nm; injection volume, 10 μl.

[0151]

[0152] (3) Detection methods for clarithromycin-related substances

[0153] Solvent: water-methanol-acetonitrile (6:5:4).

[0154] Reference solution: Take an appropriate amount of clarithromycin reference substance, add the aforementioned solvent to dissolve by ultrasonication and quantitatively dilute to prepare solutions containing approximately 1.2 μg, 2.4 μg, and 4.8 μg per ml, which are used as reference substance (1), reference substance (2), and reference substance (3), respectively.

[0155] Test solution: Place one tablet of the preparation sample into a 50 ml volumetric flask, add an appropriate amount of the aforementioned solvent, shake manually for 3 minutes, dilute to the scale with the solvent, shake well, centrifuge at 10,000 rpm for 5 minutes, take the supernatant, and filter to obtain (containing approximately 2 mg / ml of clarithromycin).

[0156] Chromatographic conditions: Octadecylsilane bonded silica gel was used as the filler (Agela Venusil ASB C18, 4.6 mm × 250 mm, 5 μm or equivalent performance column); 0.1% difluoroacetic acid aqueous solution was used as mobile phase A, acetonitrile-methanol (7:3) was used as mobile phase B, and methanol was used as mobile phase C, with linear gradient elution as shown in the table below; the flow rate was 1.0 ml / min; the column temperature was 30°C; the detection wavelength was 230 nm; the injection volume was 50 μl; and the measurement was performed using an evaporative light scattering detector (high-temperature splitless mode: drift tube temperature was 115°C, and the carrier gas flow rate was 3.2 L / min).

[0157]

[0158] Example 1 Single prescription preparation and its stability test

[0159] Weigh the raw materials and excipients according to Table 1-1, mix them through a 60-mesh sieve, and place them in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the tablets, divide them into three tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 50 tablets.

[0160] Table 1-1 Composition of single prescription preparations

[0161]

[0162]

[0163] Experimental investigation on the factors affecting high temperature (60°C): The compressed plain tablets were divided into sealed vials and placed in a 60°C oven. The genotoxic impurity N-nitroso compound and vonoprazan degradation impurity 20 were investigated in vonoprazan fumarate tablets; the changes of amoxicillin impurity D1, amoxicillin impurity D2, amoxicillin impurity J (3 days, 6 days) and related substances (1 month) were investigated in amoxicillin tablets.

[0164] Table 1-2 Stability of single prescription preparation composition

[0165]

[0166] The results showed that N-nitroso compounds in vonoprazan fumarate tablets increased significantly under high temperature conditions, exceeding 50 ppm after six days at 60°C. However, there was no significant increase in vonoprazan degradation impurities, 20. Amoxicillin tablets showed no significant changes in impurities after one month at 60°C.

[0167] Example 2 Two-combination compound preparation and its stability test

[0168] Weigh the raw materials and excipients according to Table 2-1, mix them, pass them through a 60-mesh sieve, and place them in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the tablets, divide them into three or four tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 50 tablets.

[0169] Table 2-1 Composition of two-drug compound preparation

[0170]

[0171]

[0172] The samples in Table 2-1 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0173] Table 2-2 Stability of the two-combination compound preparation

[0174]

[0175] The results showed that when vonoprazan fumarate was prepared as a dual-combination preparation, the growth of N-nitroso compounds was significantly reduced compared to the single-combination preparation at 60°C. However, after one month at 60°C, the vonoprazan degradation impurity 20 in the dual-combination preparation increased significantly compared to the single-combination preparation, with the lowest growth observed in the dual-combination preparation of vonoprazan fumarate and amoxicillin. There was no significant difference in the growth of amoxicillin impurities when the dual-combination preparation was prepared as amoxicillin compared to the single-combination preparation after one month at 60°C.

[0176] Example 3 Triple compound preparation and its stability test

[0177] (1) Weigh the raw materials and excipients according to Table 3-1, sieve through a 60-mesh screen after mixing, and place in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the large weight of the tablets, divide them into four tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 50 tablets.

[0178] Table 3-1 Composition of triple compound preparation

[0179]

[0180]

[0181] The samples in Table 3-1 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0182] Table 3-2 Stability of triple combination preparation

[0183]

[0184] The results showed that after vonoprazan fumarate was prepared into a triple preparation, the growth of N-nitroso compounds was further reduced under high temperature conditions of 60°C.

[0185] (2) Weigh the raw materials and excipients according to Table 3-3, sieve through a 60-mesh sieve after mixing, and place in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the large weight of the tablets, divide them into three to five tablets for tableting. The die size is 16 mm × 7 mm. The batch size of the prescription is 40 to 100 tablets.

[0186] Table 3-3 Composition of triple compound preparation

[0187]

[0188] The samples in Table 3-3 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0189] Table 3-4 Stability of triple compound preparation composition

[0190]

[0191] The results showed that after the active ingredients of different drugs were prepared into triple preparations, the growth of N-nitroso compounds, amoxicillin impurity J and other largest single impurities of amoxicillin further increased under high temperature conditions of 60°C.

[0192] Example 4 Investigation of the dosage of excipients for the triple compound preparation

[0193] Weigh the raw and excipient materials according to Table 4-1-1 or 4-1-2, mix them, pass them through a 60-mesh sieve, place them in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the large weight of the prescribed tablets, divide them into two, three, or four tablets for tableting. The die size is 10mm × 20mm. The prescription batch size is 50 to 80 tablets.

[0194] Table 4-1-1 Composition of triple compound preparation

[0195]

[0196] Table 4-1-2 Composition of triple compound preparation

[0197]

[0198] Table 4-2 Stability of triple compound preparation composition

[0199]

[0200]

[0201] Example 5 Quadruple Compound Preparation and Its Stability

[0202] Weigh the raw and excipient materials according to Table 5-1-1 or 5-1-2, mix them, pass them through a 60-mesh sieve, and place them in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the prescribed tablets, divide them into four or five tablets for tableting. The die size is 10mm × 20mm. The prescribed batch size is 50 tablets.

[0203] Table 5-1-1 Quadruple compound preparations

[0204] a indicates that this prescription does not use direct compression like other prescriptions, but uses a wet granulation process: the raw material, filler and disintegrant are mixed, and a pre-prepared aqueous solution of hydroxypropyl cellulose is added to granulate. After the granulation is completed, dry granules are obtained by wet granulation, drying and dry granulation. A flow aid and a lubricant are then added for total mixing to obtain the total mixed granules. A single punch tablet press is used for tableting. Due to the large weight of the prescription tablets, they are divided into four or five tablets for tableting, and the die size is 10 mm × 20 mm.

[0205] Table 5-1-2 Quadruple compound preparations

[0206]

[0207]

[0208] b. Specifications of active ingredients and excipients are the same as those in 5-1-1.

[0209] The samples in Table 5-1-1 and 5-1-2 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0210] Table 5-2-1 Stability of the Quadruple Compound Preparation Composition

[0211]

[0212] The samples in Table 5-1-2 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0213] Table 5-2-2 Stability of the quadruple compound preparation composition

[0214]

[0215]

[0216] The results showed that the growth rate of N-nitroso compounds in the quadruple compound preparation was relatively slower at 60°C.

[0217] Example 6 Quadruple compound preparation containing different antibiotics and its stability test

[0218] Weigh the raw materials and excipients according to Table 6-1, pass through a 60-mesh sieve after mixing, and place in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the tablets, divide them into four or five tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 40 tablets.

[0219] Table 6-1 Quadruple compound preparations

[0220]

[0221] The samples in Table 6-1 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0222] Table 6-2 Quadruple compound preparations

[0223]

[0224]

[0225] The results showed that when other antibiotics were used instead of clarithromycin to prepare quadruple compound preparations, the N-nitroso compounds of the quadruple preparations except tetracycline increased rapidly under high temperature conditions of 60°C for 6 days, and the amoxicillin impurity produced by the quadruple compound preparations prepared with tetracycline would increase significantly.

[0226] Example 7 Investigation of the dosage of excipients for the quadruple compound preparation

[0227] Weigh the raw materials and excipients according to Table 7-1, pass through a 60-mesh sieve after mixing, and place in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the tablets, divide them into four or five tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 30 to 40 tablets.

[0228] Table 7-1 Investigation on the dosage of excipients for quadruple compound preparations

[0229]

[0230] The samples in Table 7-1 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0231] Table 7-2 Investigation on the stability of excipient dosage in quadruple preparation

[0232]

[0233]

[0234] Example 8 Investigation of excipients and stability test of quadruple compound preparation

[0235] Weigh the raw materials and excipients according to Table 8-1, pass through a 60-mesh sieve after mixing, and place in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the tablets, divide them into four or five tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 40 tablets.

[0236] Table 8-1 Investigation of excipient models for quadruple compound preparations

[0237]

[0238] Table 8-2 Investigation of excipient models for quadruple compound preparations

[0239]

[0240] The samples in Table 8-1 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0241] Table 8-3-1 Investigation on the stability of excipients in the composition of quadruple compound preparation

[0242]

[0243]

[0244] The samples in Table 8-2 were tested for high temperature (60°C) influencing factors. The results are shown in the following table:

[0245] Table 8-3-2 Investigation on the stability of excipients in the composition of quadruple compound preparation

[0246]

[0247] Example 9: Inspection of Specification Range and Stability Experiment of Quadruple Compound Preparation

[0248] Weigh the raw materials and auxiliary materials according to Table 9-1-1 or 9-1-2, pass through a 60-mesh sieve after mixing, put them into a PE bag and mix for 5 minutes. After mixing, use a single punch tablet press to compress the tablets. Due to the large weight of the prescription tablets, divide them into four, five or six tablets for tableting. The die size is

[0249] 10mm×20mm. The prescription batch size is 40 tablets.

[0250] Table 9-1-1 Prescription table for the specification range of quadruple compound preparations

[0251]

[0252]

[0253] Table 9-1-2 Prescription table for the specification range of quadruple compound preparations

[0254]

[0255] Note*: The ratio of the four components = bismuth content: vonoprazan: amoxicillin anhydrate: clarithromycin.

[0256] The samples in Table 9-1-1 were tested for the influence factors of high temperature (60°C) and high humidity (92.5% RH). The results are shown in the following table:

[0257] Table 9-2-1 Stability study of the specification range of quadruple compound preparation

[0258]

[0259]

[0260] The samples in Table 9-1-2 were tested for the influence factors of high temperature (60℃) and high humidity (92.5%RH). The results are shown in the following table:

[0261] Table 9-2-2 Stability study of the specification range of quadruple compound preparation

[0262]

[0263] Referring to the prescriptions of Examples 7-9, the bismuth agent was removed from the prescriptions, and the amounts of the excipients were reduced accordingly according to the proportion of bismuth agent in the active ingredients of the drug. The stability of the prepared triple compound preparation was tested using the same stability method as in Examples 7-9. The results showed that the N-nitroso compounds and amoxicillin impurities in the triple compound preparation after deleting the bismuth agent also met the quality control requirements.

[0264] Example 10 Accelerated stability test

[0265] Weigh the raw materials and excipients according to Table 10-1, pass through a 60-mesh sieve after mixing, place in a PE bag and mix for 5 minutes. After mixing, use a single-punch tablet press to compress the tablets. Due to the heavy weight of the tablets, divide them into four tablets for tableting. The die size is 10 mm × 20 mm. The batch size is 30 to 40 tablets.

[0266] Table 10-1 Prescription of quadruple compound preparation

[0267]

[0268]

[0269] The samples in Table 10-1 were tested for stability under accelerated conditions (40°C / 75% RH). The results are as follows:

[0270] Table 10-2 Accelerated stability test results of quadruple compound preparation

[0271]

[0272] The results showed that after six months of storage under accelerated test conditions (40°C / 75% RH), vonoprazan showed only a slight increase in impurity 20; clarithromycin impurities remained essentially unchanged; and amoxicillin impurities showed a slight increase. Overall, the quadruple compound preparation of the present invention exhibited good stability under accelerated test conditions (40°C / 75% RH).

[0273] The above describes exemplary embodiments of the present invention. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound pharmaceutical composition, characterized in that: The compound pharmaceutical composition comprises the following three components: (I) vonoprazan or a pharmaceutically acceptable salt thereof; (II) amoxicillin or a pharmaceutically acceptable salt thereof; and (III) clarithromycin; Wherein, in parts by weight, the amount of component (I) is 10-40 parts based on vonolac; the amount of component (II) is 500-2000 parts based on anhydrous amoxicillin; and the amount of clarithromycin is 100-2000 parts; Or the compound pharmaceutical composition comprises the following four ingredients: (I) vonoprazan or a pharmaceutically acceptable salt thereof; (II) amoxicillin or a pharmaceutically acceptable salt thereof; (III) clarithromycin; and (IV) bismuth; Wherein, in parts by weight, the component (I) is 10-40 parts based on the content of vonola; the component (II) is 500-2000 parts based on the content of anhydrous amoxicillin; the component (IV) is 100-2000 parts based on the content of bismuth; The bismuth agent is selected from colloidal bismuth pectin; The three-component or four-component composition comprises a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from one or more of (A) a filler, (B) a binder, (C) a disintegrant, (D) a glidant, and (E) a lubricant; and the ratio of the total amount of the active pharmaceutical ingredient to the total amount of the excipient is 5:1 to 1:1; The filler (A) is selected from one or more of lactose, microcrystalline cellulose, silicified microcrystalline cellulose, microcrystalline cellulose lactose co-processed product, microcrystalline cellulose mannitol co-processed product, and mannitol; The (B) binder is selected from one or more of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), and ethyl cellulose (EC); The (C) disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose (L-HPC), cross-linked carboxymethyl cellulose sodium (CCNa), sodium carboxymethyl starch (CMS-Na) and cross-linked polyvinylpyrrolidone (PVPP); The (D) glidant is selected from one or more of silicon dioxide, talc, and colloidal silicon dioxide; The (E) lubricant is selected from one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate.

2. The compound pharmaceutical composition according to claim 1, characterized in that The pharmaceutically acceptable salt of vonola is selected from fumarate; The amoxicillin is amoxicillin anhydrate or amoxicillin hydrate.

3. The compound pharmaceutical composition according to claim 1, wherein: The mass ratio of the filler to the total amount of the active pharmaceutical ingredient is 1:20 to 1:1; The mass ratio of the binder to the total amount of the active pharmaceutical ingredient is 0 to 1:5; The mass ratio of the disintegrant to the total amount of the active pharmaceutical ingredient is 1:200 to 1:2; The mass ratio of the glidant to the total amount of the active pharmaceutical ingredient is 0 to 1:10; The mass ratio of the lubricant to the total amount of the active pharmaceutical ingredient is 1:1000 to 1:

10.

4. The compound pharmaceutical composition according to claim 1 or 2, characterized in that: In the compound pharmaceutical composition, when component (I) vonoprazan or a pharmaceutically acceptable salt thereof is included, the amount of component (I) calculated as vonoprazan is 10-30 parts by weight; when component (II) amoxicillin or a pharmaceutically acceptable salt thereof is included, the amount of component (II) calculated as anhydrous amoxicillin is 500-1500 parts by weight; when component (III) clarithromycin is included, the amount of clarithromycin is 200-800 parts by weight; and when component (IV) bismuth is included, the amount of bismuth is 200-250 parts by weight.

5. The compound pharmaceutical composition according to claim 4, characterized in that: In the compound pharmaceutical composition, when component (II) amoxicillin or a pharmaceutically acceptable salt thereof is included, the amount of component (II) calculated as anhydrous amoxicillin is 700-1200 parts by weight; when component (III) clarithromycin is included, the amount of clarithromycin is 400-600 parts by weight.

6. The compound pharmaceutical composition according to claim 1 or 2, characterized in that: When the compound pharmaceutical composition comprises four components, namely component (I), component (II), component (III) and component (IV), the weight ratio of component (I), component (II), component (III) and component (IV) is 1:(5-120):(1-120):(1-50).

7. The compound pharmaceutical composition according to claim 1 or 2, characterized in that: The weight ratio of the component (I), the component (II), the component (III) and the component (IV) is 1:(25-75):(10-40):(5-15).

8. The compound pharmaceutical composition according to claim 1 or 2, characterized in that: The weight ratio of the component (I), the component (II), the component (III) and the component (IV) is 1:(35-60):(20-30):(10-12.5).

9. The compound pharmaceutical composition according to claim 1 or 2, characterized in that The compound pharmaceutical composition comprises the following three components in parts by weight: (I) 10-40 parts of vonoprazan or a pharmaceutically acceptable salt thereof; (II) 800-1300 parts of amoxicillin or a pharmaceutically acceptable salt thereof and (III) 400-600 parts of clarithromycin; Wherein, the component (I) is calculated as vonola; the component (II) is calculated as amoxicillin anhydrate; Or the compound pharmaceutical composition comprises the following four ingredients: (I) 10-40 parts of vonoprazan or a pharmaceutically acceptable salt thereof; (II) 800-1300 parts of amoxicillin or a pharmaceutically acceptable salt thereof; (III) 400-600 parts of clarithromycin; and (IV) 200-250 parts of bismuth; Wherein, the component (I) is calculated based on the content of vonola; the component (II) is calculated based on the content of anhydrous amoxicillin; and the component (IV) is calculated based on the content of bismuth.

10. A method for preparing the compound pharmaceutical composition according to any one of claims 1 to 9, comprising the following steps: (1) All raw materials and auxiliary materials are mixed and sieved, bagged or mixed evenly with a mixer; (2) Filling capsules or pressing tablets, and packaging to obtain the finished product.

11. The method for preparing the compound pharmaceutical composition according to claim 10, comprising the following steps: (1) Sieve the raw and auxiliary materials separately; (2) mixing vonoprazan or a pharmaceutically acceptable salt thereof with a disintegrant, and then adding a filler and mixing; (3) adding clarithromycin, amoxicillin or pharmaceutically acceptable salts thereof to the mixed powder and mixing well; (4) using a dry granulation process to compress the mixed powder into granules or not using a dry granulation process; (5) Add lubricant and mix well; (6) The obtained material is capsule-filled or tablet-pressed, and packaged to obtain the finished product.

12. The method for preparing the compound pharmaceutical composition according to claim 11, characterized in that: Step (2) is to mix vonoprazan or a pharmaceutically acceptable salt thereof with a disintegrant and a binder, and then add a filler and mix; Step (3) is to add clarithromycin, amoxicillin or a pharmaceutically acceptable salt thereof and a glidant to the mixed powder and mix them evenly.

13. The method for preparing the compound pharmaceutical composition according to claim 11, characterized in that: When the compound pharmaceutical composition contains bismuth, step (3) is to add bismuth, clarithromycin, amoxicillin or pharmaceutically acceptable salts thereof and a glidant to the mixed powder and mix them evenly.

14. Use of the compound pharmaceutical composition according to any one of claims 1 to 9 in the preparation of drugs for resisting Helicobacter pylori infection.

15. Use of the compound pharmaceutical composition according to any one of claims 1 to 9 in the preparation of medicaments for treating dyspepsia, gastritis, peptic ulcer and gastric cancer.

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