A pharmaceutical preparation for treating helicobacter pylori infection and a method for preparing the same

Abstract

This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a pharmaceutical formulation for treating Helicobacter pylori infection and its preparation method. The pharmaceutical formulation for treating Helicobacter pylori infection provided by this invention comprises, from top to bottom, a bismuth immediate-release layer, a proton pump inhibitor enteric-coated layer, and an antibiotic sustained-release layer. Specifically, the bismuth immediate-release layer contains 8%–15% disintegrant by weight, ensuring a disintegration time of ≤3 minutes and rapid bismuth protection; the antibiotic sustained-release layer contains 20%–35% sustained-release matrix material by weight, ensuring uniform and long-lasting antibiotic release; the enteric-coated layer ensures that the proton pump inhibitor does not disintegrate or release in gastric juice for 2 hours and releases rapidly in intestinal juice. This invention, through a three-layer physical isolation structure, achieves time- and zone-specific release of the bismuth immediate-release protective film, long-lasting antibiotic antibacterial effect, and proton pump inhibitor targeted intestinal release, effectively avoiding drug incompatibilities, simplifying medication regimens, and improving patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a pharmaceutical preparation for treating Helicobacter pylori infection and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Helicobacter pylori parasitizes the gastric mucosa and can cause gastritis, peptic ulcers, and other diseases. Currently, the optimal first-line treatment for Helicobacter pylori infection is quadruple therapy, consisting of two antibiotics, bismuth, and a proton pump inhibitor (PPI). However, quadruple therapy is complex: PPIs need to be taken before meals to avoid gastric acid degradation and targeted intestinal release; bismuth should be taken before meals to disperse rapidly and form a diffuse protective layer in the acidic environment of the stomach; and antibiotics need to be taken after meals to reduce gastric irritation and maintain effective blood concentrations with long-lasting antibacterial action. Traditional formulations release antibiotics too quickly, and short-term high concentrations can easily cause gastrointestinal irritation, while insufficient concentrations in the later stages lead to antibacterial inactivation and drug resistance. The complex timing and interval requirements result in poor patient compliance, leading to missed doses, incorrect doses, or dosage errors, especially in the elderly and children, which can reduce efficacy or increase side effects.

[0004] Existing multilayer tablet formulations are mostly bilayer structures, which cannot simultaneously meet the requirements of immediate release, sustained release, and enteric coating. Furthermore, they do not precisely limit the proportion of disintegrants and sustained-release matrix, resulting in defects such as slow disintegration of the bismuth immediate-release layer, slow onset of action of bismuth, and burst release or incomplete release of antibiotic sustained-release layer. These deficiencies make them unsuitable for the precise treatment requirements of Helicobacter pylori quadruple therapy.

[0005] In summary, there is currently a lack of integrated quadruple therapy formulations for treating Helicobacter pylori infection. Furthermore, the dosing regimens for treating Helicobacter pylori infection are complex, and traditional dosing methods cannot meet the needs of clinical applications, forcing the pharmaceutical industry to consider new drug production methods. Summary of the Invention

[0006] In view of this, the present invention provides a pharmaceutical formulation for treating Helicobacter pylori infection and its preparation method. The pharmaceutical formulation provided by the present invention comprises a three-layered tablet consisting of a bismuth immediate-release layer, an antibiotic sustained-release layer, and a proton pump inhibitor enteric-coated layer. By controlling the dosage ratio of the bismuth immediate-release layer disintegrant and the antibiotic sustained-release layer sustained-release matrix, the three drugs are isolated, delivered in stages, and released in a targeted manner. This effectively solves the technical problems of existing quadruple therapy, such as cumbersome administration, drug interference, slow onset of action of bismuth, burst release or incomplete release of antibiotics, and gastrointestinal irritation of proton pump inhibitors, and significantly improves the stability and therapeutic effect of the pharmaceutical formulation.

[0007] To achieve the above objectives, the technical solution of the present invention is as follows: The first aspect of the present invention provides a pharmaceutical preparation for treating Helicobacter pylori infection, wherein the pharmaceutical preparation comprises, from top to bottom, a bismuth immediate-release layer, a proton pump inhibitor enteric layer, and an antibiotic sustained-release layer; The mass ratio of the bismuth immediate-release layer, the proton pump inhibitor enteric layer, and the antibiotic sustained-release layer is (15~25):(5~15):(60~80). The bismuth agent quick-release layer comprises the following raw materials in parts by weight: 35-60 parts bismuth agent, 8-15 parts disintegrant, 30-40 parts filler, 2-5 parts binder, and 0.5-2 parts lubricant.

[0008] The antibiotic sustained-release layer comprises the following raw materials in parts by weight: 40-75 parts antibiotic, 20-35 parts sustained-release matrix material, 1-38 parts filler, 2-5 parts adhesive, and 0.5-2 parts lubricant.

[0009] The proton pump inhibitor enteric coating layer comprises a pellet core and an isolation layer and an enteric coating layer sequentially wrapped around the pellet core; the proton pump inhibitor enteric coating layer comprises the following raw materials in parts by weight: 8-15 parts proton pump inhibitor, 30-50 parts filler, 3-6 parts disintegrant, 0.5-2 parts lubricant, 15-25 parts isolation layer, and 6-12 parts enteric coating layer.

[0010] Furthermore, in the bismuth immediate-release layer, the disintegrant accounts for 8-15% of the mass percentage of the bismuth immediate-release layer; or, in the antibiotic sustained-release layer, the sustained-release matrix material accounts for 20-35% of the mass percentage of the antibiotic sustained-release layer.

[0011] Further, the bismuth agent is bismuth potassium citrate, colloidal pectin bismuth, or bismuth subcarbonate; or, the antibiotic is one or more of amoxicillin, clarithromycin, and metronidazole; or, the sustained-release matrix material is one or more of hydroxypropyl methylcellulose, ethylcellulose, and polyethylene oxide; or, the proton pump inhibitor is omeprazole, lansoprazole, pantoprazole, or rabeprazole; or, the enteric coating material is one or more of methacrylic acid resin or hydroxypropyl methylcellulose phthalate.

[0012] Furthermore, the material of the isolation layer includes an adhesive and a release agent; even further, the release agent is talc. The adhesive is one of povidone, hydroxypropyl methylcellulose, and an aqueous ethanol solution.

[0013] Further, the disintegrant is one or more of crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose; or, the filler is one or more of microcrystalline cellulose, lactose, starch, and mannitol; or, the binder is one of povidone, hydroxypropyl methylcellulose, and an aqueous ethanol solution; or, the lubricant is one or more of magnesium stearate, talc, and micronized silica gel.

[0014] Furthermore, the hardness of the pharmaceutical preparation is 50-100 N.

[0015] A second aspect of the present invention provides a method for preparing the pharmaceutical preparation described in the first aspect, comprising the following steps: (1) Prepare bismuth preparation immediate release layer particles, antibiotic sustained release layer particles and proton pump inhibitor enteric layer particles respectively; (2) Using a three-layer tablet press, antibiotic sustained-release layer particles, proton pump inhibitor enteric coating layer particles and bismuth immediate-release layer particles are sequentially filled and stacked to form the drug preparation.

[0016] Furthermore, the preparation method of the bismuth agent immediate release layer particles is as follows: weigh the bismuth agent, filler, disintegrant and binder according to the ratio, mix them evenly, add purified water to make a soft material, pass it through a 20-30 mesh sieve to make wet particles, dry it at 40-60℃, granulate it with a 15-30 mesh, add lubricant and mix evenly to obtain the final product; Alternatively, the preparation method of the antibiotic sustained-release layer particles is as follows: weigh the antibiotic, sustained-release skeleton material, filler and binder according to the ratio, mix them evenly, add alcohol solution to make soft material, pass through 18-25 mesh sieve to make wet particles, dry at 45-55℃, granulate with 18-25 mesh, add lubricant and mix evenly to obtain the final product. Alternatively, the preparation method of the proton pump inhibitor enteric coating particles is as follows: weigh the proton pump inhibitor, filler and disintegrant according to the ratio, mix them evenly, add water to make soft material, make 30-40 mesh pellet cores by pelletizing machine, and dry; coat the pellet cores with an isolation layer using an adhesive and an isolation agent, and dry at 30-50°C; then coat them with an enteric coating material, and finally add a lubricant and mix well to obtain the final product.

[0017] Furthermore, in step (2), the pressure of the tablet press is 15~30 kN and the rotation speed of the tablet press is 10~20 r / min.

[0018] A third aspect of the present invention provides the use of the pharmaceutical preparation described in the first aspect in the preparation of a medicament for treating Helicobacter pylori infection.

[0019] The beneficial effects of this invention are: This invention controls the weight percentage of disintegrant in the immediate-release layer of bismuth preparations to 8%–15%, enabling the immediate-release layer to rapidly disintegrate within 3 minutes in gastric juice. This allows for the rapid release of bismuth and the formation of a protective film on the gastric mucosa, achieving rapid onset of action. When the disintegrant percentage is below 8%, disintegration is slow and the onset of action of the bismuth is delayed; when it is above 15%, tablet formability is poor and tablets are prone to cracking. The ratio range described in this invention achieves the optimal balance between disintegration rate and formulation formability.

[0020] This invention uses a sustained-release matrix material comprising 20%–35% of the antibiotic sustained-release layer by weight, enabling uniform and prolonged release of the antibiotic in the stomach. The cumulative release rate reaches 63%–84% after 8 hours and over 90% after 12 hours, maintaining an effective antibacterial blood concentration and avoiding gastrointestinal irritation caused by sudden drug release and drug resistance due to insufficient concentration in the later stages. When the weight percentage of the sustained-release matrix material is less than 20%, the sustained-release matrix network is not dense enough, resulting in excessively rapid drug release; when it is greater than 35%, the matrix is ​​too dense, leading to incomplete drug release.

[0021] This invention forms a three-layer physical isolation structure by independently placing bismuth preparations, antibiotics, and proton pump inhibitors in the immediate-release layer, sustained-release layer, and enteric layer, respectively. This avoids drug efficacy attenuation caused by adsorption and complexation interactions between drugs when taken simultaneously, and significantly reduces side effects such as gastrointestinal irritation. In addition, by integrating the three single-drug formulations into a single-tablet oral solid dosage form, patients can complete the combined treatment of the three core drugs with a single dose, greatly reducing the types and frequency of medications. This avoids the problems of missed or incorrect doses caused by the cumbersome medication administration in traditional quadruple therapy, and significantly improves patient medication adherence.

[0022] More importantly, this invention utilizes a three-layer physically isolated, stacked structure to allow bismuth to be rapidly released in the stomach and form a protective mucosal layer, while antibiotics are released slowly and continuously to maintain a long-lasting antibacterial concentration. The proton pump inhibitor is protected by an enteric layer to prevent degradation in gastric acid, and is released after reaching the intestines to inhibit gastric acid secretion. The three drugs are released sequentially at different times and sites of action according to their respective therapeutic needs, matching the dosing rhythm required for Helicobacter pylori eradication therapy. This solves the problems of traditional single-drug combination therapy, where the release rates of each drug cannot be individually controlled, they interfere with each other, and their effects are not synergistic. Detailed Implementation

[0023] Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the invention. Specific conditions not specified in the embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Components whose manufacturers are not specified are all commercially available conventional products.

[0024] In this invention, the terms "from top to bottom" or "from bottom to top" refer to the layered arrangement based on the formulation core, with the bottom layer being the antibiotic sustained-release layer, the middle layer being the proton pump inhibitor enteric-coated layer, and the top layer being the bismuth immediate-release layer. The middle proton pump inhibitor enteric-coated layer is buffered and protected by the outer particles during tableting, preventing the enteric coating from rupturing under compression pressure. Simultaneously, after the drug formulation enters the stomach, the top bismuth immediate-release layer first contacts the gastric juice and rapidly disintegrates to release the drug; the lower antibiotic sustained-release layer hydrates and gels to provide sustained release; and the middle enteric-coated core remains intact in the acidic environment of the stomach and releases the drug after entering the intestines, thus achieving a time-phased drug release mechanism of "immediate release-sustained release-enteric coating".

[0025] In this invention, the term "disintegrant" refers to a pharmaceutical excipient that enables the immediate-release layer to rapidly absorb water, swell, and break down into fine particles in gastric juice. This invention has screened and strictly limited its dosage through extensive experiments to 8%–15% of the total weight of the immediate-release layer. When the disintegrant dosage is below 8%, the immediate-release layer cannot completely disintegrate within 3 minutes, resulting in delayed onset of action of the bismuth preparation and prolonged exposure of the gastric mucosa to irritation. When the disintegrant dosage is above 15%, tablet formability significantly decreases, and the tablets are prone to moisture absorption and cracking during storage. The range described in this invention achieves an optimal balance between disintegration rate and formulation stability, ensuring rapid release of the bismuth preparation in the stomach and the formation of a protective film.

[0026] In this invention, the term "sustained-release matrix material" refers to a polymeric material capable of forming a three-dimensional gel network structure, thereby delaying drug release. This invention strictly limits its usage to 20%–35% of the total weight of the sustained-release layer. Below 20%, the matrix network is not dense enough, resulting in excessively rapid antibiotic release, with a release rate exceeding 50% within 2 hours. This not only causes gastrointestinal irritation but also adsorbs onto the bismuth released from the immediate-release layer, hindering absorption and weakening the antibacterial effect. Above 35%, the matrix is ​​too dense, leading to incomplete drug release, with a cumulative release rate of less than 75% after 12 hours, resulting in insufficient antibacterial concentration in the later stages and easily inducing drug resistance. The range described in this invention enables a cumulative antibiotic release rate of 60%–85% after 8 hours and over 90% after 12 hours, achieving uniform, long-lasting, and complete release characteristics.

[0027] In this invention, the term "core" refers to a spherical drug-containing core containing the active ingredient of a proton pump inhibitor, with a particle size controlled between 30 and 40 mesh. This particle size range balances the efficiency of fluidized bed coating and the integrity of the enteric coating. If the particle size is too small, the specific surface area will be too large, resulting in uneven coating and easy adhesion; if the particle size is too large, it will be easily broken during tableting. After the core is made, it undergoes a release coating and an enteric coating in sequence: the release coating physically isolates the core from the acidic enteric material, preventing the proton pump inhibitor from directly contacting and degrading with the acidic material during the coating process; the enteric coating ensures that the core remains intact in gastric juice and releases the drug rapidly in the intestine.

[0028] In this invention, the term "isolation layer" refers to the intermediate protective layer surrounding the pellet core, comprising an adhesive and an isolating agent, preferably talc. This layer is applied to the pellet core surface using fluidized bed bottom spray coating technology, forming a dense powder coating layer. Its core function is to prevent residual free acid or acidic groups in the enteric coating layer from penetrating into the pellet core, thus avoiding degradation of the proton pump inhibitor due to the migration of trace acidic substances during long-term storage, thereby significantly improving the long-term stability of the formulation. In this invention, the term "enteric coating layer" refers to an acid-resistant polymer coating film surrounding the isolation layer, made from methacrylic acid resin or hydroxypropyl methylcellulose phthalate. This coating film remains intact in gastric juice with pH < 5.0, showing no disintegration or leakage for 2 hours, ensuring that the proton pump inhibitor is not destroyed by gastric acid; it dissolves rapidly in the intestinal environment with pH ≥ 5.5, achieving a release rate of no less than 80% within 30 minutes, thus achieving targeted intestinal drug release.

[0029] Pharmaceutical excipients refer to all additives in a formulation other than the active ingredient, including fillers, binders, lubricants, etc. In this invention, the filler is selected from one or more combinations of microcrystalline cellulose, lactose, starch, and mannitol. Microcrystalline cellulose has both filling and binding functions, while lactose improves powder flowability; the combination of the two significantly improves tableting properties. The binder is selected from povidone, hydroxypropyl methylcellulose, or an aqueous ethanol solution. Its function is to agglomerate the powder into particles with a certain particle size and flowability during granulation. The lubricant is selected from magnesium stearate, talc, or micronized silica gel. It is added before tableting to reduce friction between particles and between particles and the mold wall, ensuring smooth tableting. Simultaneously, micronized silica gel has both flow-aiding and anti-sticking properties, preventing enteric-coated pellets from sticking together before tableting.

[0030] The present invention will be further described in detail below with reference to specific embodiments.

[0031] Example 1 1. A pharmaceutical preparation for treating Helicobacter pylori infection, comprising an antibiotic sustained-release layer, a proton pump inhibitor enteric-coated layer, and a bismuth immediate-release layer, with the following composition of each layer: (1) Bismuth agent immediate release layer, by weight, includes the following components: 50 parts of potassium bismuth citrate, 12 parts of cross-linked polyvinyl chloride, 34 parts of microcrystalline cellulose, 3 parts of polyvinyl chloride, and 1 part of magnesium stearate.

[0032] (2) Antibiotic sustained-release layer, by weight, contains the following components: 47 parts amoxicillin, 23 parts clarithromycin, 25 parts hydroxypropyl methylcellulose K15M (HPMC K15M), 3 parts hydroxypropyl methylcellulose K100 (HPMC K100), and 2 parts magnesium stearate.

[0033] (3) The proton pump inhibitor enteric coating contains the following components by weight: 10 parts omeprazole, 34 parts mannitol, 15 parts microcrystalline cellulose, 2 parts disodium hydrogen phosphate, 5 parts crospovidone, 8 parts hydroxypropyl methylcellulose (E5), 15 parts talc, 10 parts Eutectic L30D-55, and 1 part micronized silica gel.

[0034] 2. Preparation method (1) Preparation of bismuth agent quick-release layer particles: weigh bismuth potassium citrate, cross-linked polyvinyl ketone, microcrystalline cellulose and polyvinyl ketone according to the proportion, mix evenly, make soft material with purified water, sieve wet particles through 24 mesh, dry at 55℃, granulate through 24 mesh, add magnesium stearate and mix well for later use.

[0035] (2) Preparation of antibiotic sustained-release layer particles: Amoxicillin, HPMC K15M, clarithromycin and HPMC K100 are mixed in proportion, 40% ethanol solution is added to make soft material, granulated by 20 mesh sieve, dried at low temperature of 50℃, granulated by 20 mesh, and magnesium stearate is added and mixed well for later use.

[0036] (3) Preparation of proton pump inhibitor enteric coating particles: Omeprazole, mannitol, microcrystalline cellulose, disodium hydrogen phosphate, hydroxypropyl methylcellulose, and cross-linked polyvinylpyrrolidone were mixed evenly according to the above weight parts, and water was added to form soft material. The pellets were made into 30-40 mesh pellets by a fully automatic pelleting machine and dried at 60°C. Then, hydroxypropyl methylcellulose was used as a binder and talc was used as an isolation coating. The pellets were coated by fluidized bed bottom spray coating and dried at 40°C. Utec L30D-55 was used as the enteric coating material. The proton pump inhibitor pellets with the isolation layer were coated by fluidized bed bottom spray coating. Finally, micronized silica gel was added and mixed evenly.

[0037] (4) Three-layer tableting: A three-layer tableting machine is used with a pressure of 20 kN and a rotation speed of 15 r / min. The antibiotic sustained-release layer (73 parts), proton pump inhibitor enteric layer (7 parts), and bismuth agent immediate-release layer particles (20 parts) are sequentially filled and stacked. After polishing and sieving, the finished product is obtained.

[0038] Example 2 1. A bismuth immediate-release, antibiotic sustained-release, and proton pump inhibitor enteric-coated three-layer tablet, comprising a bismuth immediate-release layer, an antibiotic sustained-release layer, and a proton pump inhibitor enteric-coated layer, with the following composition of each layer: (1) Bismuth agent quick-release layer, by weight, contains the following components: 60 parts colloidal pectin bismuth, 10 parts cross-linked polyvinylpyrrolidone, 26 parts microcrystalline cellulose, 3 parts polyvinylpyrrolidone, and 1 part magnesium stearate.

[0039] (2) Antibiotic sustained-release layer, by weight, contains the following components: 47 parts amoxicillin, 10 parts metronidazole, 25 parts hydroxypropyl methylcellulose K15M, 3 parts hydroxypropyl methylcellulose K100, 13 parts microcrystalline cellulose, and 2 parts magnesium stearate.

[0040] (3) The proton pump inhibitor enteric coating contains the following components by weight: 10 parts rabeprazole, 34 parts mannitol, 15 parts microcrystalline cellulose, 2 parts disodium hydrogen phosphate, 5 parts crospovidone, 8 parts hydroxypropyl methylcellulose (E5), 15 parts talc, 10 parts Eudragit L30D-55, and 1 part micronized silica gel.

[0041] 2. Preparation method (1) Preparation of bismuth agent quick-release layer particles: Weigh colloidal pectin bismuth, cross-linked polyvinyl ketone, microcrystalline cellulose and polyvinyl ketone according to the proportion, mix evenly, make soft material with purified water, sieve wet particles through 24 mesh, dry at 55℃, granulate through 24 mesh, add magnesium stearate and mix well for later use.

[0042] (2) Preparation of antibiotic sustained-release layer particles: Amoxicillin, HPMC K15M, metronidazole and hydroxypropyl methylcellulose K100 are mixed in proportion, 40% ethanol solution is added to make soft material, granulated by 20 mesh sieve, dried at 50℃, granulated by 20 mesh, and magnesium stearate is added and mixed well for later use.

[0043] (3) Preparation of proton pump inhibitor enteric coating particles: Rabeprazole, mannitol, microcrystalline cellulose, disodium hydrogen phosphate, hydroxypropyl methylcellulose, and cross-linked polyvinylpyrrolidone were mixed evenly according to the above weight parts, and water was added to form soft material. The pellets were made into 30-40 mesh pellets by a fully automatic pelleting machine and dried at 60°C. Then, hydroxypropyl methylcellulose was used as a binder and talc was used as an isolation coating. The pellets were isolated and coated using a centrifugal coating granulator and dried at 40°C. Utec L30D-55 was used as the enteric coating material. The proton pump inhibitor pellets with the isolation layer were enteredic coated using a centrifugal coating granulator. Finally, micronized silica gel was added and mixed evenly.

[0044] (4) Three-layer tableting: A three-layer tableting machine is used with a pressure of 20 kN and a rotation speed of 15 r / min. The antibiotic sustained-release layer (73 parts), proton pump inhibitor enteric layer (7 parts), and bismuth agent immediate-release layer particles (20 parts) are sequentially filled and stacked. After polishing and sieving, the finished product is obtained.

[0045] Example 3 1. A bismuth immediate-release, antibiotic sustained-release, and proton pump inhibitor enteric-coated three-layer tablet, comprising a bismuth immediate-release layer, an antibiotic sustained-release layer, and a proton pump inhibitor enteric-coated layer, with the following composition of each layer: (1) The bismuth agent immediate release layer, by weight, contains the following components: 35 parts of bismuth subcarbonate, 14 parts of cross-linked sodium carboxymethyl cellulose, 50 parts of microcrystalline cellulose, and 1 part of silicon dioxide.

[0046] (2) Antibiotic sustained-release layer, by weight, contains the following components: 47 parts amoxicillin, 10 parts metronidazole, 32 parts hydroxypropyl methylcellulose (HPMC K4M), 7 parts microcrystalline cellulose, 3 parts povidone (K30), and 1 part magnesium stearate.

[0047] (3) The proton pump inhibitor enteric coating contains the following components by weight: 20 parts pantoprazole, 24 parts mannitol, 15 parts microcrystalline cellulose, 2 parts disodium hydrogen phosphate, 5 parts crospovidone, 8 parts hydroxypropyl methylcellulose (E5), 15 parts talc, 10 parts Eutectic L30D-55, and 1 part micronized silica gel.

[0048] 2. Preparation method (1) Preparation of bismuth agent quick-release layer particles: weigh bismuth subcarbonate, cross-linked sodium carboxymethyl cellulose and microcrystalline cellulose according to the proportion, mix them evenly, make soft material with purified water, sieve wet particles through 24 mesh, dry at 55℃, granulate through 24 mesh, add silica and mix well for later use.

[0049] (2) Preparation of antibiotic sustained-release layer particles: Amoxicillin, HPMC K4M, microcrystalline cellulose and metronidazole are mixed in proportion, and a povidone (K30) aqueous solution is added to make a soft material. The material is granulated through a 20-mesh sieve, dried at 50°C, granulated through a 20-mesh sieve, and then mixed with magnesium stearate for later use.

[0050] (3) Preparation of proton pump inhibitor enteric coating particles: Pantoprazole, mannitol, microcrystalline cellulose, disodium hydrogen phosphate, hydroxypropyl methylcellulose, and cross-linked polyvinylpyrrolidone were mixed evenly according to the above weight ratios. Water was added to form soft material and pellets were made into 30-40 mesh pellets using a fully automatic pelletizing machine and dried at 60°C. Then, hydroxypropyl methylcellulose was used as a binder and talc was used as an isolation coating. The pellets were isolated and coated using a centrifugal coating granulator and dried at 40°C. Utec L30D-55 was used as the enteric coating material and the proton pump inhibitor pellets with the isolation layer were enteredic coated using a centrifugal coating granulator. Finally, micronized silica gel was added and mixed evenly.

[0051] (4) Three-layer tableting: A three-layer tableting machine is used with a pressure of 20 kN and a rotation speed of 15 r / min. The antibiotic sustained-release layer (73 parts), proton pump inhibitor enteric layer (7 parts), and bismuth agent immediate-release layer particles (20 parts) are sequentially filled and stacked. After polishing and sieving, the finished product is obtained.

[0052] Example 4 Compared with Example 1, the difference is that the bismuth agent immediate release layer, by weight, contains the following components: 50 parts of potassium bismuth citrate, 8 parts of cross-linked polyvinyl chloride, 38 parts of microcrystalline cellulose, 3 parts of polyvinyl chloride, and 1 part of magnesium stearate.

[0053] Example 5 Compared with Example 1, the difference is that the bismuth agent immediate release layer, by weight, contains the following components: 50 parts of potassium bismuth citrate, 15 parts of cross-linked polyvinyl chloride, 31 parts of microcrystalline cellulose, 3 parts of polyvinyl chloride, and 1 part of magnesium stearate.

[0054] Example 6 Compared with Example 1, the difference is that the antibiotic sustained-release layer, by weight, contains the following components: 47 parts amoxicillin, 23 parts clarithromycin, 20 parts hydroxypropyl methylcellulose K15M, 8 parts hydroxypropyl methylcellulose K100, and 2 parts magnesium stearate.

[0055] Example 7 Compared with Example 1, the difference is that the antibiotic sustained-release layer, by weight, contains the following components: 41 parts amoxicillin, 20 parts clarithromycin, 35 parts hydroxypropyl methylcellulose K15M, 3 parts hydroxypropyl methylcellulose K100, and 1 part magnesium stearate.

[0056] Comparative Example 1 Compared with Example 1, the difference is that the bismuth agent immediate release layer, by weight, contains the following components: 50 parts of potassium bismuth citrate, 6 parts of cross-linked polyvinyl chloride, 40 parts of microcrystalline cellulose, 3 parts of polyvinyl chloride, and 1 part of magnesium stearate.

[0057] The remaining components, their proportions, and preparation methods are the same as in Example 1.

[0058] Comparative Example 2 Compared with Example 1, the difference is that the bismuth agent immediate release layer, by weight, contains the following components: 50 parts of potassium bismuth citrate, 18 parts of cross-linked polyvinyl chloride, 28 parts of microcrystalline cellulose, 3 parts of polyvinyl chloride, and 1 part of magnesium stearate.

[0059] The remaining components, their proportions, and preparation methods are the same as in Example 1.

[0060] Comparative Example 3 Compared with Example 1, the difference is that the antibiotic sustained-release layer, by weight, contains the following components: 47 parts amoxicillin, 23 parts clarithromycin, 18 parts hydroxypropyl methylcellulose (K15M), 10 parts hydroxypropyl methylcellulose (K100), and 2 parts magnesium stearate.

[0061] The remaining components, their proportions, and preparation methods are the same as in Example 1.

[0062] Comparative Example 4 Compared with Example 1, the difference is that the antibiotic sustained-release layer, by weight, contains the following components: 40 parts amoxicillin, 18 parts clarithromycin, 38 parts hydroxypropyl methylcellulose (K15M), 3 parts hydroxypropyl methylcellulose (K100), and 1 part magnesium stearate.

[0063] The remaining components, their proportions, and preparation methods are the same as in Example 1.

[0064] Performance testing: Performance tests were conducted on the finished products of each embodiment and comparative example. The compound multilayer tablets (upper bismuth immediate-release layer, middle proton pump inhibitor enteric layer and lower antibiotic sustained-release layer) were tested according to the disintegration time test method 0921 and the dissolution and release rate test method 0931 of the Chinese Pharmacopoeia 2025 edition.

[0065] I. Test method for disintegration time of bismuth preparations' immediate release layer (General rule 0921 Disintegration time method) Purpose of the test: To detect only the rapid disintegration of the outer bismuth immediate-release layer without damaging the sustained-release layer or enteric layer, and to determine the mucosal protective effect of rapid dissolution in the stomach.

[0066] Instruments: Lift-type disintegrator, basket with 6 glass tubes, purified water medium at 37℃±1℃, sieve 2.0 mm.

[0067] Test sample: 6 intact multilayer sheets, without cracks, delamination or damage.

[0068] The operation steps are as follows: 1. Preheat the water bath to 37℃±1℃, and adjust the height of the basket: the lowest point of the screen should be 25 mm from the bottom of the beaker, and the highest point of the screen should be 15 mm below the liquid surface; do not add baffles.

[0069] 2. Place one complete multi-layer sheet into each tube, and start the lifting mechanism while timing is running.

[0070] 3. The endpoint criterion is to visually observe the tablet's outer layer (bismuth layer) to ensure it completely detaches and crumbles through the sieve; and to ensure the internal sustained-release antibiotic core remains intact, firm, and without cracking or disintegration.

[0071] 4. Record the time it takes for each outer layer to completely collapse.

[0072] 5. Time Limit Standards Bismuth preparation rapid release layer: ≤3 min; Results determination: If the outer layer (bismuth layer) of all 6 tablets falls off and breaks through the sieve within 3 minutes, and the other layers remain intact, the result is qualified; if 1 tablet exceeds the time limit, 6 tablets are retested, and all of them pass the retest; if ≥2 tablets exceed the time limit, the result is unqualified.

[0073] II. Method for detecting the release rate of antibiotic sustained-release layers (General Rule 0931 Release Rate of Sustained-Release Preparations - Method I / Paddle Method) Testing prerequisites: The outer bismuth immediate-release layer is removed manually or dissolved in a water bath beforehand. The complete antibiotic sustained-release core without the bismuth layer is used as the test sample to eliminate interference from the dissolution of the outer bismuth layer.

[0074] Instruments: Dissolution tester, paddle method (50 rpm), 1000 mL dissolution vessel, temperature 37℃±0.5℃; equipped with UV / LC content determination system.

[0075] Medium: pH 4.5 acetate buffer.

[0076] The standard operating procedure is as follows: 1. Remove the bismuth immediate-release layer: Place the whole tablet in pure water at 37℃ and let it stand for 15 minutes. The outer bismuth layer will be completely removed. Take out the sustained-release core, wash it gently with pure water, blot it dry with filter paper, and take 6 sustained-release cores.

[0077] 2. Add 900 mL of acetate buffer (pH 4.5) to the dissolution vessel, preheat at 37°C, add the slow-release core, paddle speed 50 rpm, and start timing.

[0078] 3. Sampling time points (general sampling points for sustained-release antibiotics: 2 h, 4 h, 8 h, 12 h): Take 5 mL of the dissolution solution at 2 h, 4 h, 8 h, and 12 h respectively (add 5 mL of the same temperature and medium), filter, and determine the amount of antibiotic released by HPLC; 4. Calculate the cumulative release percentage at each time point.

[0079] 5. Sustained-release limit (cumulative release) - 2h: 10% ~ 30%; - 4h: 30% ~ 55%; - 8h: 60% ~ 85%; - 12h: ≥90%.

[0080] III. The enteric coating of proton pump inhibitors (PPIs) was determined using a two-step acid-base assay (0931 dissolution and release assay). PPIs (omeprazole, rabeprazole, pantoprazole) are easily degraded in acid. The enteric coating layer is required to remain stable in acid for 2 hours without breaking. When transferred to intestinal fluid at pH 6.8, they rapidly disintegrate and release.

[0081] Quantitative determination of enteric coating release (mandatory method for R&D and stability studies, paddle method) Phase 1: Release in acid (pH 1.2 hydrochloric acid) 1. Dissolution medium: 900 mL 0.1 mol / L hydrochloric acid, 37℃, paddle speed 50 rpm; add 6 portions of the separated PPI enteric coating unit.

[0082] 2.2 h. Take a precise 5 mL sample, filter it, and then determine the PPI content by HPLC.

[0083] 3. Qualification standard: Drug release in acid for 2 hours ≤10% (proving that enteric coating blocks gastric acid and protects PPI from degradation).

[0084] 4. Discard all acidic media and rinse the enteric-coated granules with water.

[0085] Phase 2: Intestinal fluid release test (pH 6.8 phosphate buffer) 1. Replace with 900 mL of pH 6.8 phosphate buffer and continue the experiment at the same temperature and rotation speed.

[0086] 2. Sampling time points: 0.5 h and 1 h after transfer to intestinal fluid.

[0087] 3. Limit standards: ≥75% release of intestinal fluid in 0.5 h, ≥90% release in 1 h.

[0088] The performance test results are shown in Table 1.

[0089] Table 1 Performance Test Results

[0090] As shown in Table 1, the three-layer structure of the finished products in Examples 1-7 of this invention is stable and does not delaminate or crack. The disintegration time of the bismuth immediate-release layer is 54 seconds to 172 seconds, all ≤3 min, meeting the requirements for rapid disintegration and dispersion. The release rate of the antibiotic sustained-release layer is 14% to 29% at 2 h, 32% to 54% at 4 h, 63% to 84% at 8 h, and ≥90% at 12 h, with stable drug release and no burst release. The proton pump inhibitor enteric layer remains intact and has no release in artificial gastric fluid at 2 h (2 h release ≤10%), and rapidly releases the drug into the intestine (0.5 h release ≥75%, 1 h release ≥90%), fully meeting the needs of clinical treatment.

[0091] Comparative Examples 1-4 were excluded because the proportion of core excipients exceeded the scope of protection of this invention. In Comparative Examples 1 and 2, the weight ratio of disintegrant in the immediate-release layer of bismuth preparations was not within the range of 8% to 15%. Comparative Example 1 showed slow drug release (exceeding 3 minutes), resulting in delayed onset of action of the bismuth preparation. The tablets in Comparative Example 2 showed appearance defects. In Comparative Examples 3 and 4, the weight ratio of sustained-release matrix material in the sustained-release layer of antibiotics was not within the range of 20% to 35%. The release rate of Comparative Example 3 exceeded 50% in 2 hours, indicating excessively rapid release. This could easily cause stomach irritation of the antibiotics, and the drug efficacy would be reduced due to interactions such as adsorption and complexation with the bismuth preparation. The release rate of Comparative Example 4 did not reach 75% in 12 hours, indicating incomplete drug release. This demonstrates that the weight ratio of disintegrant in the immediate-release layer of bismuth preparations as defined in this invention is 8% to 15%, ensuring that the disintegration time of the immediate-release layer is ≤3 minutes, allowing the bismuth preparation to quickly protect the film. The weight ratio of sustained-release matrix material in the sustained-release layer of antibiotics is 20% to 35%, enabling the antibiotics to release drugs at a uniform rate and for a long time.

[0092] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A pharmaceutical preparation for treating Helicobacter pylori infection, characterized in that, The pharmaceutical preparation consists of, from top to bottom, a bismuth immediate-release layer, a proton pump inhibitor enteric layer, and an antibiotic sustained-release layer. The mass ratio of the bismuth immediate-release layer, the proton pump inhibitor enteric layer, and the antibiotic sustained-release layer is (15~25):(5~15):(60~80). The bismuth agent immediate-release layer comprises the following raw materials in parts by weight: 35-60 parts bismuth agent, 8-15 parts disintegrant, 30-40 parts filler, 2-5 parts binder, and 0.5-2 parts lubricant. The antibiotic sustained-release layer comprises the following raw materials in parts by weight: 40-75 parts antibiotic, 20-35 parts sustained-release matrix material, 1-38 parts filler, 2-5 parts adhesive, and 0.5-2 parts lubricant. The proton pump inhibitor enteric coating layer comprises a pellet core and an isolation layer and an enteric coating layer sequentially wrapped around the pellet core; the proton pump inhibitor enteric coating layer comprises the following raw materials in parts by weight: 8-15 parts proton pump inhibitor, 30-50 parts filler, 3-6 parts disintegrant, 0.5-2 parts lubricant, 15-25 parts isolation layer, and 6-12 parts enteric coating layer.

2. The pharmaceutical preparation according to claim 1, characterized in that, In the bismuth preparation rapid release layer, the disintegrant accounts for 8-15% of the mass percentage of the bismuth preparation rapid release layer; Alternatively, in the antibiotic sustained-release layer, the sustained-release skeleton material accounts for 20-35% of the mass percentage of the antibiotic sustained-release layer.

3. The pharmaceutical preparation according to claim 1, characterized in that, The bismuth agent is potassium bismuth citrate, colloidal pectin bismuth, or bismuth subcarbonate. Alternatively, the antibiotic may be one or a combination of amoxicillin, clarithromycin, and metronidazole; Alternatively, the sustained-release matrix material may be one or more of hydroxypropyl methylcellulose, ethylcellulose, and polyethylene oxide; Alternatively, the proton pump inhibitor may be omeprazole, lansoprazole, pantoprazole, or rabeprazole; Alternatively, the enteric coating layer may be made of one or more of methacrylic acid resin or hydroxypropyl methylcellulose phthalate.

4. The pharmaceutical preparation according to claim 1, characterized in that, The materials of the isolation layer include adhesives and isolation agents; Preferably, the separating agent is talc; Preferably, the adhesive is one of polyvinylpyrrolidone, hydroxypropyl methylcellulose, and an aqueous ethanol solution.

5. The pharmaceutical preparation according to claim 1, characterized in that, The disintegrant is one or a combination of crospovidone, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose. Alternatively, the filler may be one or more of microcrystalline cellulose, lactose, starch, and mannitol; Alternatively, the adhesive may be one of polyvinylpyrrolidone, hydroxypropyl methylcellulose, or an aqueous ethanol solution; Alternatively, the lubricant may be one or more of magnesium stearate, talc, and micronized silica gel.

6. The pharmaceutical preparation according to claim 1, characterized in that, The hardness of the pharmaceutical preparation is 50-100 N.

7. A method for preparing a pharmaceutical preparation according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Prepare bismuth preparation immediate release layer particles, antibiotic sustained release layer particles and proton pump inhibitor enteric layer particles respectively; (2) Using a three-layer tablet press, antibiotic sustained-release layer particles, proton pump inhibitor enteric coating layer particles and bismuth immediate-release layer particles are sequentially filled and stacked to form the drug preparation.

8. The preparation method according to claim 7, characterized in that, The preparation method of the bismuth agent quick-release layer particles is as follows: weigh the bismuth agent, filler, disintegrant and binder according to the ratio, mix them evenly, add purified water to make soft material, pass through a 20-30 mesh sieve to make wet particles, dry at 40-60℃, granulate with 15-30 mesh, add lubricant and mix evenly to obtain the final product. Alternatively, the preparation method of the antibiotic sustained-release layer particles is as follows: weigh the antibiotic, sustained-release skeleton material, filler and binder according to the ratio, mix them evenly, add alcohol solution to make soft material, pass through 18-25 mesh sieve to make wet particles, dry at 45-55℃, granulate with 18-25 mesh, add lubricant and mix evenly to obtain the final product. Alternatively, the preparation method of the proton pump inhibitor enteric coating particles is as follows: weigh the proton pump inhibitor, filler and disintegrant according to the ratio, mix them evenly, add water to make soft material, make 30-40 mesh pellet cores by pelletizing machine, and dry; coat the pellet cores with an isolation layer using an adhesive and an isolation agent, and dry at 30-50°C; then coat them with an enteric coating material, and finally add a lubricant and mix well to obtain the final product.

9. The preparation method according to claim 7, characterized in that, In step (2), the pressure of the tablet press is 15~30kN and the speed of the tablet press is 10~20 r / min.

10. The pharmaceutical preparation according to any one of claims 1 to 6 is used in the preparation of a medicament for treating Helicobacter pylori infection.

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